CN108912040B - 一种水杨酰胺-o-氨基甲酸酯化合物及其制备方法和用途 - Google Patents
一种水杨酰胺-o-氨基甲酸酯化合物及其制备方法和用途 Download PDFInfo
- Publication number
- CN108912040B CN108912040B CN201810672540.2A CN201810672540A CN108912040B CN 108912040 B CN108912040 B CN 108912040B CN 201810672540 A CN201810672540 A CN 201810672540A CN 108912040 B CN108912040 B CN 108912040B
- Authority
- CN
- China
- Prior art keywords
- acid
- salicylamide
- carbamate compound
- compound
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000000126 substance Substances 0.000 claims abstract description 8
- -1 N-methyl-N-ethylamino Chemical group 0.000 claims description 31
- 239000003814 drug Substances 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 11
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000000194 fatty acid Substances 0.000 claims description 6
- 230000000626 neurodegenerative effect Effects 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- 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 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 4
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 4
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 4
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 238000006482 condensation reaction Methods 0.000 claims description 4
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 4
- 150000002191 fatty alcohols Chemical class 0.000 claims description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229960004889 salicylic acid Drugs 0.000 claims description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 125000004193 piperazinyl group Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 30
- 230000000694 effects Effects 0.000 abstract description 17
- 230000005779 cell damage Effects 0.000 abstract description 11
- 208000037887 cell injury Diseases 0.000 abstract description 11
- 230000001681 protective effect Effects 0.000 abstract description 10
- 229940022698 acetylcholinesterase Drugs 0.000 abstract description 9
- 230000005764 inhibitory process Effects 0.000 abstract description 9
- 102100033639 Acetylcholinesterase Human genes 0.000 abstract description 8
- 108010022752 Acetylcholinesterase Proteins 0.000 abstract description 8
- 229910021645 metal ion Inorganic materials 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 108010053652 Butyrylcholinesterase Proteins 0.000 abstract description 6
- 102100032404 Cholinesterase Human genes 0.000 abstract description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract description 6
- 230000003078 antioxidant effect Effects 0.000 abstract description 5
- 238000010668 complexation reaction Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 230000001684 chronic effect Effects 0.000 description 16
- 208000010877 cognitive disease Diseases 0.000 description 16
- 229940079593 drug Drugs 0.000 description 16
- 201000004810 Vascular dementia Diseases 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 8
- 208000028698 Cognitive impairment Diseases 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 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 6
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 6
- 206010012289 Dementia Diseases 0.000 description 5
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 5
- 208000027418 Wounds and injury Diseases 0.000 description 5
- 210000004556 brain Anatomy 0.000 description 5
- 208000026106 cerebrovascular disease Diseases 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- 208000014674 injury Diseases 0.000 description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 230000008506 pathogenesis Effects 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 4
- 229960004373 acetylcholine Drugs 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000001713 cholinergic effect Effects 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 150000003254 radicals Chemical class 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 206010039966 Senile dementia Diseases 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- 239000000544 cholinesterase inhibitor Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 230000006951 hyperphosphorylation Effects 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 102000013498 tau Proteins Human genes 0.000 description 3
- 108010026424 tau Proteins Proteins 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 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
- 208000037259 Amyloid Plaque Diseases 0.000 description 2
- 201000006474 Brain Ischemia Diseases 0.000 description 2
- 206010008120 Cerebral ischaemia Diseases 0.000 description 2
- 102100023460 Choline O-acetyltransferase Human genes 0.000 description 2
- 108010058699 Choline O-acetyltransferase Proteins 0.000 description 2
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000032683 aging Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- 206010008118 cerebral infarction Diseases 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 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 2
- 230000003340 mental effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 230000003961 neuronal insult Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 239000003642 reactive oxygen metabolite Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 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
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ABGXADJDTPFFSZ-UHFFFAOYSA-N 4-benzylpiperidine Chemical class C=1C=CC=CC=1CC1CCNCC1 ABGXADJDTPFFSZ-UHFFFAOYSA-N 0.000 description 1
- 206010065040 AIDS dementia complex Diseases 0.000 description 1
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 1
- 102000003914 Cholinesterases Human genes 0.000 description 1
- 108090000322 Cholinesterases Proteins 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 102000018899 Glutamate Receptors Human genes 0.000 description 1
- 108010027915 Glutamate Receptors Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229940127523 NMDA Receptor Antagonists Drugs 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000003941 amyloidogenesis Effects 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000002555 anti-neurodegenerative effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000008344 brain blood flow Effects 0.000 description 1
- 230000003925 brain function Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 229940048961 cholinesterase Drugs 0.000 description 1
- 208000035850 clinical syndrome Diseases 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 1
- 230000002008 hemorrhagic effect Effects 0.000 description 1
- 230000000971 hippocampal effect Effects 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229910052603 melanterite Inorganic materials 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- 150000004692 metal hydroxides Chemical group 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 210000002241 neurite Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000003962 neuroinflammatory response Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 230000009223 neuronal apoptosis Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000003950 pathogenic mechanism Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 238000005728 strengthening Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000003554 tetrahydropyrrolyl group Chemical group 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/16—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with acylated ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Neurosurgery (AREA)
- Ophthalmology & Optometry (AREA)
- Psychology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明属于有机合成技术领域,具体涉及一种水杨酰胺‑O‑氨基甲酸酯化合物及其制备方法和用途,其化学结构通式如(I)所示。本发明化合物对乙酰胆碱酯酶和丁酰胆碱酯酶均具有显著抑制作用,对金属离子有强络合作用,具有强抗氧化活性,对Aβ1‑42诱导的SH‑SY5Y细胞损伤有显著的保护作用,对过氧化氢诱导的PC12细胞损伤有显著的保护作用。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种水杨酰胺-O-氨基甲酸酯化合物及其制备方法和用途。
背景技术
阿尔茨海默症(Alzheimer’s disease,AD)是老年人中发病率和致死率最高的疾病之一。阿尔茨海默症国际协会(Alzheimer’s disease International,ADI)发布的《2015全球阿尔茨海默症报告》指出,2015年全球已有超过4600万人患上痴呆症,据预测,到2050年,全球将有1.315亿人口受到痴呆的困扰,其中中国痴呆症患者的发病率已达到6.61%。随着人均生存年龄的延长,本病已发展为社会和医疗保健系统的主要负担,并且为社会、患者及家属带来了沉重的精神和经济压力。因而,研究开发新型老年痴呆治疗药物意义重大。从市场需求来看,阿尔茨海默症国际协会预测,到2050年老年痴呆症治疗药物的全球销售额将达6000亿美元;在我国,随着老年痴呆症发病率的迅速上升,这类药物的市场也快速膨胀。
AD是一种慢性的、以进行性记忆和认知功能损害为特征的多病因、多环节参与的复杂神经退行性疾病,其主要病理学特征为β-淀粉样肽(β-amyloid peptide,Aβ)大量沉积形成的老年斑(Senile plaque,SP)、tau蛋白过度磷酸化形成的神经纤维缠结(Neurofibrillary tangle,NFT),并伴随神经元的凋亡和神经突触的退化等。近年来,许多研究者致力于从分子和细胞水平来揭示AD的发病机理,提出了多种假说,如:胆碱能神经元损伤、淀粉样蛋白的沉积、tau蛋白过度磷酸化、炎症、自由基氧化、金属离子失调等,因此,针对这些发病机制来发展的新型治疗途径和手段,将有希望缓解和改善AD患者的病情。目前临床上有效治疗AD的药物主要有两类:(1)基于神经递质乙酰胆碱不足导致认知功能失调的胆碱能假说,采用乙酰胆碱酯酶抑制剂来提高病人脑内乙酰胆碱水平,如:Tacrine、Donepezil、Ravastigmine、Galantamine;(2)采用N-甲基-D-天冬氨酸(NMDA)受体抑制剂减少谷氨酸盐对神经细胞的损伤,如:Memantine Hydrochloride。但长期临床使用表明,这些药物可短期内缓解AD的症状,但不能从根本上有效阻止或逆转病程,而且还会导致经典的胆碱能毒性,如引起幻觉、意识混沌、头晕、恶心、肝脏毒性、食欲不振以及大便频繁等。因此,临床上迫切需要研发具有新型作用机制的AD治疗药物。
AD病因复杂,至今尚未完全阐明其发病机制,但研究表明,患者脑内乙酰胆碱水平降低、β-淀粉样蛋白的过度生成与沉积、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,研究人员采用传统的“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NMDA受体拮抗剂等,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AD致病机理的不断阐明,发现AD的发生和发展具有多机制、多因素作用的特点,不同机制之间有相互关联相互影响,构成了AD发生和发展过程复杂的网络调控系统。基于上述结果,研究人员提出了“多靶点导向药物(Multitarget-directedLigands,MTDLs)”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,此类药也称为“Multifunctional”或“Multipotential”药物。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,研究开发具有新型化学结构、新型作用机制,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不仅符合社会老龄化进程的迫切需求,而且具有良好的市场前景。在前期报道中,发现了灯盏乙素苷元氨基甲酸酯类衍生物(CN10337956A、CN102603698A)、二苯乙烯或乙烷氨基甲酸酯类化合物(CN102816090A)、异黄酮氨基甲酸酯类化合物(CN102827131A),阿魏酸氨基甲酸酯类化合物(CN105837497A、CA105601540A、CN105646289A)这些化合物虽具有较好的乙酰胆碱酯酶抑制活性和抗氧化活性,且对Aβ聚集有一点的抑制作用,同时对丁酰胆碱酯酶的抑制活性非常差,导致这些化合物在动物模型中对AD的治疗疗效欠佳。研究表明,随着AD的发展,AChE水平逐渐降低,而BuChE活性度增加到了正常水平的165%,在敲除AChE基因小鼠体内,选择性AChE抑制剂并没有影响ACh水平,而选择性BuChE抑制剂则使ACh水平增加了5倍,进一步动物实验表明,选择性BuChE抑制剂能够避免典型的胆碱能毒性,且正常情况下BuChE的缺失几乎没有健康方面的副作用。因此,设计并发现同时具有乙酰胆碱酯酶、丁酰胆碱酯酶、金属离子络合作用、抗氧化和神经保护作用的多靶点抗AD治疗药物是目前重要的一个研究方法。
血管性痴呆(Vascular Dementia,VD)是由缺血性脑血管病、出血性脑血管疾病、急性和慢性缺氧性脑血管疾病等各种类型的脑血管疾病所致的智能及认知功能障碍的临床综合征,其主要临床表现包括:认知能力、记忆力和社会生活能力的减退以及情感、性格的改变,是一种慢性进行性疾病。在中国、日本等亚洲国家血管性痴呆是老年期痴呆的第一位原因;随着世界人口向老龄化的不断推进,脑血管病日益增多,血管性痴呆发病率有逐渐上升的趋势,严重影响老年人的工作和生活质量,并给社会和家庭带来沉重的经济和精神负担。因此,VD已成为当今老年医学与精神医学领域中一个重要的研究热点。血管性痴呆由于发病机制复杂,尚无能够阻断疾病发展的药物,目前临床治疗以改善脑部血液循环和脑代谢,加强脑部营养为主。
近年来,国内外研究表明,在VD患者表现认知功能损伤的同时也经常伴有胆碱能系统的异常。VD患者海马区ChAT阳性神经元及纤维密度降低,脑内不同部位的ChAT活性下降,在VD患者脑脊液中的ACh浓度明显低于正常水平,并且其浓度降低的程度与痴呆的严重程度呈正相关;而脑缺血可以导致脑内乙酰胆碱酯酶活性上升;同时也发现乙酰胆碱酯酶抑制剂如:HuperzineA和Revastigmine可以保护缺血造成的神经元损伤,且可以促进脑缺血后神经损伤和脑功能的恢复,这表明乙酰胆碱酯酶抑制剂也可用于血管性痴呆的治疗。
发明内容
为克服上述缺陷,本发明的第一目的在于公开一种水杨酰胺-O-氨基甲酸酯化合物。
本发明的第二目的的还在于公开一种水杨酰胺-O-氨基甲酸酯化合物的制备方法。
本发明的第三目的的还在于公开一种水杨酰胺-O-氨基甲酸酯化合物在药学上可接受的盐,所述的盐由上述的水杨酰胺-O-氨基甲酸酯化合物与酸通过成盐方法制备而成,所述的酸为盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、草酸、苯甲酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或者对甲苯磺酸。
本发明的第四目的还在于公开一种水杨酰胺-O-氨基甲酸酯化合物或其药学上可接受的盐在治疗和/或预防神经退行性相关疾病药物中的用途,所述神经退行性相关疾病为:血管性痴呆、阿尔茨海默氏病、帕金森症、亨廷顿症、HIV相关痴呆症、多发性硬化症、进行性脊髓侧索硬化症、神经性疼痛或者青光眼。
为实现上述目的,本发明采用如下技术方案:
一种水杨酰胺-O-氨基甲酸酯化合物,其化学结构通式如(I)所示:
其中,X为H、O或者S;
Y为C或者N;
Z为-H、-F、-Cl、-Br、-I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、硝基和氰基取代基中任意一种、两种、三种或者四种基团;
R1NR2表示N-甲基-N-乙基胺基、二甲胺基、二乙胺基、二异丙氨基、二丁胺基、二烯丙氨基、吗啉基、哌啶基、4-苄基哌啶基、4-取代苄基哌啶基、4-苯基哌啶基、4-取代苯基哌啶基、苄基哌嗪基、取代苄基哌嗪基、四氢吡咯基或者4-位被C1~C12烷基取代的哌嗪基。
优选地,所述的取代苄基表示F、Cl、Br、I、C1-4烷基、C1-4烷氧基、三氟甲基、三氟甲氧基、硝基和氰基中任意一种、两种、三种或者四种基团在苯环上取代的取代苄基。
一种水杨酰胺-O-氨基甲酸酯化合物的制备方法,包括以下步骤:
a.以羟基苯甲酸(1)和4-取代苄基哌啶(2)为起始原料,在溶剂和缩合剂条件下缩合反应得到2-羟基苯甲酰胺-4-苄基哌啶中间体(3);
b.2-羟基苯甲酰胺-4-苄基哌啶中间体(3)在溶剂和碱性条件下,与酰氯(4)发生酰化反应,得到产物水杨酰胺-O-氨基甲酸酯化合物(I)。
其化学反应通式为:
式中:X、Y、Z、R1NR2的定义与水杨酰胺-O-氨基甲酸酯化合物的化学结构通式(I)相同。
优选地,所述的步骤a中溶剂为C3-8脂肪酮、N,N-二甲基甲酰胺、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、C1-6脂肪酸与C1-6脂肪醇所形成酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、二甲苯、氯苯、邻二氯苯、乙腈、二甲基亚砜和吡啶中一种或几种。
优选地,所述的步骤a中缩合剂为DCC、DMAP、EDCI、HOBT和卡特缩合剂中一种或几种。
优选地,所述的步骤a中缩合剂为EDCI和HOBT,两者摩尔用量比为1:1。
优选地,所述的步骤a中缩合剂为DCC和DMAP,两者摩尔用量比为1:1。
优选地,所述的步骤a中羟基苯甲酸(1)、取代4-苄基哌啶(2)和缩合剂摩尔用量比为:1:1~25:1~50。
优选地,所述的步骤a缩合反应温度为0℃~130℃,反应时间为6~48h。
优选地,所述的步骤b中碱为金属氢氧化物、碱土金属氢氧化物、碱金属、碱土金属碳酸盐、碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种;
优选地,所述的步骤b中溶剂为C3-8脂肪酮、N,N-二甲基甲酰胺、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、C1-6脂肪酸与C1-6脂肪醇所形成的酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、二甲苯、氯苯、邻二氯苯、乙腈、二甲基亚砜和吡啶中一种或几种。
优选地,所述的步骤b中2-羟基苯甲酰胺-4-苄基哌啶中间体(3)、酰氯(4)和碱摩尔用量比为:1:1~25:1~50。
优选地,所述的步骤b中酰化反应温度为25℃~130℃,反应时间为6~48h。
一种水杨酰胺-O-氨基甲酸酯化合物在药学上可接受的盐,所述的盐由上述的水杨酰胺-O-氨基甲酸酯化合物与酸通过成盐方法制备而成,所述的酸为盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、草酸、苯甲酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或者对甲苯磺酸。
一种水杨酰胺-O-氨基甲酸酯类化合物或其药学上可接受的盐在制备治疗和/或预防神经退行性相关疾病药物中的用途,所述的药物由上述的水杨酰胺-O-氨基甲酸酯化合物或其药学上可接受的盐与药学上可接受的载体或者赋形剂制备而成,所述的水杨酰胺-O-氨基甲酸酯类化合物或其药学上可接受的盐的重量百分含量为2%~99.5%。
本发明的积极有益效果:
1.本发明化合物对乙酰胆碱酯酶和丁酰胆碱酯酶均具有显著抑制作用;本发明化合物对金属离子有强络合作用;本发明化合物抗氧化活性为Trolox的1.0-2.0倍,说明该类化合物具有强抗氧化活性;本发明化合物对Aβ1-42诱导的SH-SY5Y细胞损伤有显著的保护作用;本发明化合物对过氧化氢诱导的PC12细胞损伤有显著的保护作用。因此,本发明化合物对AD和VD疾病治疗和/或预防方面具有重要的意义。
附图说明
图1为本发明水杨酰胺-O-氨基甲酸酯类化合物对Aβ1-42诱导的SH-SY5Y细胞损伤的保护作用测定结果图;
图2为本发明水杨酰胺-O-氨基甲酸酯类化合物对H2O2诱导的PC12细胞损伤的保护作用测定结果图。
具体实施方式
下面结合一些具体实施方式,对本发明进一步说明。
一种水杨酰胺-O-氨基甲酸酯化合物,其化学结构通式如(I)所示:
其中,实施例1-52中,X、Y、Z、R1NR2的具体化学结构见表1;
表1本发明实施例1-52水杨酰胺-O-氨基甲酸酯化合物
上述实施例1的水杨酰胺-O-氨基甲酸酯化合物(I)的制备方法,包括以下步骤:
a.在反应瓶中加入10mmol羟基苯甲酸(1)、10mmol4-取代苄基哌啶(2)、15mmolEDCI、15mmolHOBT和50mLTHF,25℃搅拌12h后,减压蒸干溶剂,加入去离子水,用二氯甲烷进行萃取,有机层用饱和氯化钠洗涤,减压蒸干溶剂,残余物经柱层析纯化(石油醚:丙酮=100:1v/v),得相应的羟基苯甲酰胺中间体(3);
b.将10mmol羟基苯甲酰胺中间体(3)、10mmol相应的氨基甲酰氯(4)、11mmol无水碳酸钾和50ml乙腈,搅拌均匀后,升温至65℃回流搅拌反应12h,反应结束后,减压蒸干溶剂,加入去离子水,用二氯甲烷萃取,有机层用饱和氯化钠洗涤,经无水硫酸钠干燥过滤,减压蒸干溶剂,残余物经柱层析纯化(二氯甲烷:丙酮=100:1v/v),得相应的水杨酰胺-O-氨基甲酸酯化合物(I),收率为85.1%,其化学结构均经1H-NMR、13C-NMR和ESI-MS确证,经HPLC测定纯度为98.2%。
上述实施例2-10的水杨酰胺-O-氨基甲酸酯化合物(I)的制备方法与实施例1基本相同,相同之处不重述,不同之处见表2和3。
上述实施例11-52的水杨酰胺-O-氨基甲酸酯化合物(I)的制备方法与实施例1相同。
表2本发明实施例1-10化合物制备方法步骤a参数
表3本发明实施例1-10化合物制备方法步骤b参数
一种水杨酰胺-O-氨基甲酸酯化合物在药学上可接受的盐,所述的盐由实施例1-52的水杨酰胺-O-氨基甲酸酯化合物与酸通过成盐方法制备而成,所述的酸为盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、草酸、苯甲酸、水杨酸、马来酸、富马酸、琥珀酸、酒石酸、柠檬酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或者对甲苯磺酸。
一种水杨酰胺-O-氨基甲酸酯类化合物或其药学上可接受的盐在制备治疗和/或预防神经退行性相关疾病药物中的用途,所述的药物由实施例1-52的水杨酰胺-O-氨基甲酸酯化合物或其药学上可接受的盐与药学上可接受的载体或者赋形剂制备而成,所述的水杨酰胺-O-氨基甲酸酯类化合物或其药学上可接受的盐的重量百分含量为2%~99.5%。
活性试验
(1)水杨酰胺-O-氨基甲酸酯类化合物(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1.0mmol/L碘化硫代乙酰胆碱或硫代丁酰胆碱(均购自Sigma公司)30μL,pH8.0的PBS缓冲液40μL,待测化合物(或阳性对照物)溶液20μL(DMSO含量小于1%)和10μL电鳗乙酰胆碱酯酶(EeAChE)或马血清丁酰胆碱酯酶(eqBuChE),加毕混匀后,37℃孵育15min,向各孔中加入质量分数为0.2%的5,5'-二硫代-双(2-硝基)苯甲酸(DTNB,购自Sigma公司)溶液30μL显色,用酶标仪测定412nm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化合物对乙酰胆碱酯酶和丁酰胆碱酯酶均具有显著抑制作用,其具体IC50见表4,而阳性对照药物——Rivastigmine对乙酰胆碱酯酶和丁酰胆碱酯酶抑制的IC50为5.6μM和1.4μM。
(2)水杨酰胺-O-氨基甲酸酯类化合物(I)与金属离子络合作用的测定
用甲醇溶解CuCl2·2H2O、ZnCl2、FeSO4·7H2O、AlCl3及待测化合物,配成75μmol/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分钟,在多功能酶标仪上记录200-600nm范围内的紫外吸收曲线,并以100μL待测化合物溶液和100μL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化合物(I)对金属离子有强络合作用。
(3)水杨酰胺-O-氨基甲酸酯类化合物(I)的抗氧化活性(ORAC-FL方法)
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1-8μmol/L的溶液,荧光素(flrorescein)用pH7.4的PBS缓冲液配成250nmol/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40mmol/L的溶液。向96孔板中加入50-10μmol/L的化合物溶液和荧光素溶液,混匀,37℃孵育15min,加入AAPH溶液,使每孔总体积为200μL,混匀,立即置于Varioskan Flash Multimode Reader仪中,在485nm激发波长和535nm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/concentration of sample)],每个化合物每次测定3个复孔,每组实验独立重复三次,检测结果见表4。
测定结果表明,本发明实施例中所公开化合物的抗氧化活性为Trolox的1.0-2.0倍,说明该类化合物具有强抗氧化活性。
(4)本发明制备的水杨酰胺-O-氨基甲酸酯类化合物对Aβ1-42诱导的SH-SY5Y细胞损伤的保护作用筛选
SH-SY5Y细胞用含10%胎牛血清、100U·mL-1青霉素、100mg·L-1链霉素的DMEM完全培养基在37℃,5%CO2的恒温培养箱内培养。2d进行一次传代,取对数生长期细胞进行试验。Aβ1-42溶于缓冲液中,4℃孵育48h老化。SH-SY5Y以1×105个/mL密度接种于96孔培养板上,37℃孵育12h后,在给药组与损伤组中分别加入25μΜAβ1-42损伤剂,空白对照组细胞培养液换为无血清DMEM培养液,模型组和待测化合物组(或阳性对照组)用含5μmol·L-1的无血清DMEM培养液后,继续孵育48h后,各组加入5mg/mLMTT溶液,37℃孵育4h,弃培养基,每孔加入150μLDMSO,充分溶解混匀。在490nm的波长下测定各组的OD值,测试结果重复3次,用Duncan’s test方法统计,各组数值表示为均数±S.E.M.,以对照组为100%,给药组及损伤组值以对照组的百分比表示,其中
实施例1-4化合物检测结果见图1。
测定结果表明,本发明实施例中所公开化合物在10-5mol/L和10-6mol/L浓度下对Aβ1-42诱导的SH-SY5Y细胞损伤均有显著的保护作用。
(5)本发明制备的水杨酰胺-O-氨基甲酸酯类化合物(I)对H2O2诱导的PC12细胞损伤的保护作用筛选
PC12细胞用含10%小牛血清的DMEM培养液,以1×105个/mL密度接种于96孔培养板上,接种体积为100mL/孔,随后放入含5%CO2的37℃恒温培养箱内培养。培养24小时后,给药组中加相应浓度的化合物(终浓度为10-5mol/L,10-6mol/L)10mL/孔,预孵育2小时(对照组与损伤组分别加10μL/孔PBS,使其体积保持相等)。PC12细胞孵育2小时后,在给药组与损伤组中分别加入100μΜH2O2损伤剂10μL/孔(对照组加10μL/孔PBS),30分钟后,将各组的培养液均换成无小牛血清的RPMI1640培养液继续放入恒温培养箱内培养24小时,培养液体积认为100μL/孔。继续培养24小时后,各组加入5mg/mLMTT100μL/孔,进行活细胞染色。待3小时后,各组中加入100%DMSO终止液100μL/孔,充分溶解混匀。在490nm的波长下测定各组的OD值,测试结果重复3次,用Duncan’s test方法统计,各组数值表示为均数±S.E.M.,以对照组为100%,给药组及损伤组值以对照组的百分比表示,其中实施例1化合物1检测结果见图2。
测定结果表明,本发明实施例中所公开化合物在10-5mol/L和10-6mol/L浓度下对过氧化氢诱导的PC12细胞损伤均有显著的保护作用。
表4本发明实施例1-52生物活性检测结果
Claims (9)
2.一种权利要求1所述的水杨酰胺-O-氨基甲酸酯化合物的制备方法,其特征在于,包括以下步骤:
a.以羟基苯甲酸和4-取代苄基哌啶为起始原料,在溶剂和缩合剂条件下缩合反应得到2-羟基苯甲酰胺-4-苄基哌啶中间体;
b.2-羟基苯甲酰胺-4-苄基哌啶中间体在溶剂和碱性条件下,与酰氯发生酰化反应,得到产物水杨酰胺-O-氨基甲酸酯化合物(I)。
3.根据权利要求2所述的水杨酰胺-O-氨基甲酸酯化合物的制备方法,其特征在于,所述的步骤a中溶剂为C3-8脂肪酮、N,N-二甲基甲酰胺、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、C1-6脂肪酸与C1-6脂肪醇所形成酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、二甲苯、氯苯、邻二氯苯、乙腈、二甲基亚砜和吡啶中一种或几种;
所述的步骤a中缩合剂为DCC、DMAP、EDCI、HOBT和卡特缩合剂中一种或几种。
4.根据权利要求2所述的水杨酰胺-O-氨基甲酸酯化合物的制备方法,其特征在于,所述的步骤a中羟基苯甲酸、4-取代苄基哌啶和缩合剂摩尔用量比为:1:1~25:1~50。
5.根据权利要求2所述的水杨酰胺-O-氨基甲酸酯化合物的制备方法,其特征在于,所述的步骤a缩合反应温度为0℃~130℃,反应时间为6~48h。
6.根据权利要求2所述的水杨酰胺-O-氨基甲酸酯化合物的制备方法,其特征在于,所述的步骤b中碱为碱金属氢氧化物、碱土金属氢氧化物、碱金属、碱土金属碳酸盐、碱土金属碳酸氢盐、C1-6脂肪酸碱金属盐、哌啶、四氢吡咯、三乙胺、三丁胺、三辛胺、吡啶、N-甲基吗啉、N-甲基哌啶、三乙烯二胺和四丁基氢氧化铵中一种或几种;
所述的步骤b中溶剂为C3-8脂肪酮、N,N-二甲基甲酰胺、乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、乙二醇二甲醚、C1-6脂肪酸与C1-6脂肪醇所形成的酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯、甲苯、二甲苯、氯苯、邻二氯苯、乙腈、二甲基亚砜和吡啶中一种或几种。
7.根据权利要求2所述的水杨酰胺-O-氨基甲酸酯化合物的制备方法,其特征在于,所述的步骤b中2-羟基苯甲酰胺-4-苄基哌啶中间体、酰氯和碱摩尔用量比为:1:1~25:1~50;
所述的步骤b中酰化反应温度为25℃~130℃,反应时间为6~48h。
8.一种权利要求1所述的水杨酰胺-O-氨基甲酸酯化合物在药学上可接受的盐,其特征在于,所述的盐由所述的水杨酰胺-O-氨基甲酸酯化合物与酸通过成盐方法制备而成,所述的酸为盐酸、氢溴酸、硝酸、硫酸、磷酸、C1-6脂肪羧酸、苯甲酸、水杨酸、C1-6烷基磺酸、樟脑磺酸、苯磺酸或者对甲苯磺酸。
9.一种权利要求1所述的水杨酰胺-O-氨基甲酸酯类化合物或其药学上可接受的盐在制备治疗和/或预防神经退行性相关疾病药物中的用途。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810672540.2A CN108912040B (zh) | 2018-06-26 | 2018-06-26 | 一种水杨酰胺-o-氨基甲酸酯化合物及其制备方法和用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810672540.2A CN108912040B (zh) | 2018-06-26 | 2018-06-26 | 一种水杨酰胺-o-氨基甲酸酯化合物及其制备方法和用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108912040A CN108912040A (zh) | 2018-11-30 |
CN108912040B true CN108912040B (zh) | 2020-07-31 |
Family
ID=64422711
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810672540.2A Expired - Fee Related CN108912040B (zh) | 2018-06-26 | 2018-06-26 | 一种水杨酰胺-o-氨基甲酸酯化合物及其制备方法和用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108912040B (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109761883B (zh) * | 2019-01-28 | 2020-11-03 | 南阳师范学院 | 一种4-氨基甲酸酯-肉桂酰胺-4-苄基哌啶类化合物及其制备方法和用途 |
CN109851527A (zh) * | 2019-03-13 | 2019-06-07 | 南阳师范学院 | 一种多靶点氨基甲酸酯类化合物及其制备方法和用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3119826A (en) * | 1961-04-12 | 1964-01-28 | Snc Science Union Et Compagnie | Piperazine derivatives |
EP0353753A1 (en) * | 1988-08-03 | 1990-02-07 | Takeda Chemical Industries, Ltd. | Amide compounds, their production and use |
WO2001064676A2 (en) * | 2000-02-28 | 2001-09-07 | Scios, Inc. | INHIBITORS OF p38-α KINASE |
CN105837497A (zh) * | 2016-04-01 | 2016-08-10 | 南阳师范学院 | 4-氨基甲酸酯-3-甲氧基肉桂酸环胺烷基酰胺类化合物、制备方法及其用途 |
-
2018
- 2018-06-26 CN CN201810672540.2A patent/CN108912040B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3119826A (en) * | 1961-04-12 | 1964-01-28 | Snc Science Union Et Compagnie | Piperazine derivatives |
EP0353753A1 (en) * | 1988-08-03 | 1990-02-07 | Takeda Chemical Industries, Ltd. | Amide compounds, their production and use |
WO2001064676A2 (en) * | 2000-02-28 | 2001-09-07 | Scios, Inc. | INHIBITORS OF p38-α KINASE |
CN105837497A (zh) * | 2016-04-01 | 2016-08-10 | 南阳师范学院 | 4-氨基甲酸酯-3-甲氧基肉桂酸环胺烷基酰胺类化合物、制备方法及其用途 |
Non-Patent Citations (1)
Title |
---|
N-4"-叔丁氧羰基哌嗪-2-羟基苯甲酰胺的制备及合成方法研究;叶梦瑶等;《山东化工》;20171231;第46卷;16-17 * |
Also Published As
Publication number | Publication date |
---|---|
CN108912040A (zh) | 2018-11-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105481706B (zh) | 一类2‑羟基查尔酮类化合物、其制备方法和用途 | |
CN107698492B (zh) | 一类2-羟基查尔酮胺类化合物及其用途 | |
CN103113340B (zh) | 一类金雀异黄酮烷基胺类化合物、其制备方法和用途 | |
CN103087024B (zh) | 一类黄酮烷基胺类化合物、其制备方法和用途 | |
CN108912040B (zh) | 一种水杨酰胺-o-氨基甲酸酯化合物及其制备方法和用途 | |
CN109824637B (zh) | 一种茚酮查尔酮氨基甲酸酯类化合物及其制备方法和用途 | |
CN111170884B (zh) | 一类水杨酰胺类化合物、其制备方法和用途 | |
CN108586335B (zh) | 2-羟基苯甲酰胺-1,2,3,4-四氢异喹啉-o-氨基甲酸酯化合物及其制备方法 | |
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 | |
CN108218744A (zh) | 一种咖啡多巴酰胺氨基甲酸酯类化合物、其制备方法及应用 | |
JPWO2019009355A1 (ja) | 脂質過酸化誘発性疾患の治療薬およびそのスクリーニング方法 | |
CN109734614B (zh) | 3-羟基查尔酮曼尼希碱类化合物、其制备方法和用途 | |
CN108586411A (zh) | 一种柚皮素氨基甲酸酯类化合物、其制备方法及应用 | |
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 | |
CN109678795B (zh) | 4-氨基甲酸酯-阿魏酰胺-1,2,3,4-四氢异喹啉类化合物及其制备方法和用途 | |
CN109761883B (zh) | 一种4-氨基甲酸酯-肉桂酰胺-4-苄基哌啶类化合物及其制备方法和用途 | |
CN108299367B (zh) | 一种芹菜苷元氨基甲酸酯类化合物、其制备方法及应用 | |
CN110240549B (zh) | 一种胺烷氧基查尔酮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 | |
CN113387867B (zh) | 一种氨基甲酸酯类邻氨基苯甲酸色胺衍生物及其制备与应用 | |
CN114805263B (zh) | 3-(羟基苄基)苯酞类化合物、其制备方法和用途 | |
CN109665969B (zh) | 3-甲氧基-4-羟基查尔酮双曼尼希碱类化合物、其制备方法和用途 | |
CN110272349B (zh) | 一种2’-羟基-3苯基苯丙酮化合物及其制备方法和用途 | |
CN108727350B (zh) | 一类哌啶烷基苯酞类化合物、其制备方法和用途 | |
CN110003033B (zh) | 氟比洛芬查尔酮曼尼希碱类化合物、其制备方法和用途 |
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 | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20200731 |