CN110218183B - 一种选择性丁酰胆碱酯酶抑制剂及其用途 - Google Patents
一种选择性丁酰胆碱酯酶抑制剂及其用途 Download PDFInfo
- Publication number
- CN110218183B CN110218183B CN201910565545.XA CN201910565545A CN110218183B CN 110218183 B CN110218183 B CN 110218183B CN 201910565545 A CN201910565545 A CN 201910565545A CN 110218183 B CN110218183 B CN 110218183B
- Authority
- CN
- China
- Prior art keywords
- compound
- bche
- formula
- dmso
- nmr
- 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
- 102100032404 Cholinesterase Human genes 0.000 title description 33
- 101710083761 Cholinesterase Proteins 0.000 title description 2
- 229940122601 Esterase inhibitor Drugs 0.000 title description 2
- 239000002329 esterase inhibitor Substances 0.000 title description 2
- 108010053652 Butyrylcholinesterase Proteins 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 9
- 239000003112 inhibitor Substances 0.000 claims abstract description 9
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 4
- 102000021944 Butyrylcholinesterase Human genes 0.000 claims abstract 4
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 229940123923 Butyrylcholinesterase inhibitor Drugs 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 abstract description 56
- 230000000694 effects Effects 0.000 abstract description 15
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 60
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 26
- 102100033639 Acetylcholinesterase Human genes 0.000 description 17
- 108010022752 Acetylcholinesterase Proteins 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 229940022698 acetylcholinesterase Drugs 0.000 description 15
- -1 (3, 4-dihydroisoquinoline-2 (1H) -yl) methyl Chemical group 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 208000024827 Alzheimer disease Diseases 0.000 description 11
- 230000002401 inhibitory effect Effects 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 5
- 229960004373 acetylcholine Drugs 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229940124596 AChE inhibitor Drugs 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 3
- 239000000651 prodrug Substances 0.000 description 3
- 229940002612 prodrug Drugs 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 229960001685 tacrine Drugs 0.000 description 3
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- CQQSQBRPAJSTFB-UHFFFAOYSA-N 4-(bromomethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(CBr)C=C1 CQQSQBRPAJSTFB-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 108090000322 Cholinesterases Proteins 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- 150000003936 benzamides Chemical class 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 229940048961 cholinesterase Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 239000003085 diluting agent Substances 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
- 239000003937 drug carrier Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- YKFPBPSFRYIFFO-UHFFFAOYSA-N 1-chloro-n-(4-pyrrolidin-3-ylphenyl)isoquinoline-3-carboxamide;hydrochloride Chemical compound Cl.C=1C2=CC=CC=C2C(Cl)=NC=1C(=O)NC(C=C1)=CC=C1C1CCNC1 YKFPBPSFRYIFFO-UHFFFAOYSA-N 0.000 description 1
- IAZZNTYMXXEHHT-UHFFFAOYSA-N 2-(1h-pyrrol-2-yl)ethanamine Chemical compound NCCC1=CC=CN1 IAZZNTYMXXEHHT-UHFFFAOYSA-N 0.000 description 1
- AOPBDRUWRLBSDB-UHFFFAOYSA-N 2-bromoaniline Chemical compound NC1=CC=CC=C1Br AOPBDRUWRLBSDB-UHFFFAOYSA-N 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
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- QUIXHCBPIZZIJC-UHFFFAOYSA-N 4-methoxy-n-(4-pyrrolidin-3-ylphenyl)quinoline-2-carboxamide;hydrochloride Chemical compound Cl.N=1C2=CC=CC=C2C(OC)=CC=1C(=O)NC(C=C1)=CC=C1C1CCNC1 QUIXHCBPIZZIJC-UHFFFAOYSA-N 0.000 description 1
- GDWZFPBVRFUYNN-UHFFFAOYSA-N 6-methoxy-n-(4-pyrrolidin-3-ylphenyl)quinoline-2-carboxamide;hydrochloride Chemical compound Cl.C1=CC2=CC(OC)=CC=C2N=C1C(=O)NC(C=C1)=CC=C1C1CCNC1 GDWZFPBVRFUYNN-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 241000700159 Rattus Species 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
- 206010047700 Vomiting Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 201000011529 cardiovascular cancer Diseases 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000006949 cholinergic function Effects 0.000 description 1
- 230000003930 cognitive ability Effects 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229960003980 galantamine Drugs 0.000 description 1
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- CURJNMSGPBXOGK-UHFFFAOYSA-N n',n'-di(propan-2-yl)ethane-1,2-diamine Chemical compound CC(C)N(C(C)C)CCN CURJNMSGPBXOGK-UHFFFAOYSA-N 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- RRUHETMHOJVYMD-UHFFFAOYSA-N n-(4-pyrrolidin-3-ylphenyl)isoquinoline-1-carboxamide;hydrochloride Chemical compound Cl.N=1C=CC2=CC=CC=C2C=1C(=O)NC(C=C1)=CC=C1C1CCNC1 RRUHETMHOJVYMD-UHFFFAOYSA-N 0.000 description 1
- PSLXFKCEQAMGQZ-UHFFFAOYSA-N n-(4-pyrrolidin-3-ylphenyl)quinoline-2-carboxamide;hydrochloride Chemical compound Cl.C=1C=C2C=CC=CC2=NC=1C(=O)NC(C=C1)=CC=C1C1CCNC1 PSLXFKCEQAMGQZ-UHFFFAOYSA-N 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000001734 parasympathetic effect Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960004136 rivastigmine Drugs 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000012748 slip agent Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- 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
- A61P25/28—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
-
- 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
- C07D217/04—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 hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- 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)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种选择性丁酰胆碱酯酶(BChE)抑制剂,4‑((3,4‑二氢异喹啉‑2(1H)‑基)甲基)苯甲酰胺衍生物,及其在制备预防和/或治疗BChE相关的疾病的药物中的应用,本发明的化合物,能够选择性抑制BChE活性,可用于制备预防和/或治疗AD等相关神经退行性疾病的药物。
Description
技术领域
本发明涉及一种丁酰胆碱酯酶抑制剂及其应用,4-((3,4-二氢异喹啉-2(1H)-基)甲基)苯甲酰胺衍生物作为新型选择性丁酰胆碱酯酶抑制剂的应用。
背景技术
阿尔茨海默症(Alzheimer’s Disease,AD)是最常见的神经退行性疾病,约占所有痴呆病患者的60-80%。据统计,全球约有五千万AD患者,预期到2050年患病人数将达到1.3亿。目前,AD已成为第三大死因,仅次于心血管疾病和癌症。
基于胆碱能功能障碍假说,增加脑内乙酰胆碱(ACh)水平进而改善胆碱能神经传递仍是AD治疗中最有效的治疗方法。脑内ACh主要可被两类胆碱酯酶水解,即乙酰胆碱酯酶(AChE)和丁酰胆碱酯酶(BChE)。在健康成年人的大脑中,AChE占乙酰胆碱活性的80%,几乎是BChE的1013倍。因此,AChE抑制剂是被研究的最多且临床上最为普遍认同的一线治疗AD药物,如他克林、多奈哌齐、雷司替明和加兰他敏。然而,这些AChE抑制剂治疗效果均不佳,他克林因肝毒性退出市场、其他几种药物只能在病情发展的特定阶段有限的缓解或稳定病情且伴有恶心、呕吐、腹泻等副作用。
近年来,越来越多的实验证据表明,BChE终止胆碱能神经传递的功能在高度AD患者的大脑中发生了明显的改变,其活性不断增强。敲除AChE的小鼠仍能存活,其BChE的含量仍处于正常水平,表明BChE在一定程度上可以补偿AChE的功能;静默BChE突变则会导致认知功能下降。因此,抑制BChE活性有望有助于改善胆碱能功能。已有报道证实选择性BChE抑制剂可显著提高老年大鼠ACh水平,改善认知能力,且无传统AChE抑制剂所具有的副交感神经副作用。综上所述,研发选择性BChE抑制剂可能是一种很有前途的AD临床治疗策略。
发明内容
本发明人经过对所在实验室化合物库进行活性筛选及结构优化,得到了一类结构相对简单、具有选择性BChE抑制活性的通式I所示的新化合物,由此可能对AD具有治疗作用,从而在制备抗AD药物领域具有潜在的用途。
本发明的第一方面,提供式了一种如通式I所示的化合物,或其药学上可接受的盐、水合物、溶剂化物或前药。
该类化合物的结构如通式I所示:
其中,R1为氢,溴或甲氧基;R2为氢或溴;R3为2-(二乙氨基)乙氨基,2-(二异丙氨基)乙氨基,3-(二甲氧基)丙氨基,2-(吡咯基)乙氨基,吡咯基,2-氟苯氨基,4-氟苯甲氨基,2-溴苯氨基。
上述通式I所示的4-((3,4-二氢异喹啉-2(1H)-基)甲基)苯甲酰胺衍生物的制备方法,它包括以下步骤:
a)将式1化合物与4-溴甲基苯甲酸反应得到式2化合物,其中,催化剂为三乙胺、二异丙基乙胺、二异丙胺、四丁基溴化铵、四丁基氟化铵;反应溶剂为N,N-二甲基甲酰胺、丙酮、二甲基亚砜、1,4-二氧六环、四氢呋喃、甲醇、乙醇、吡啶及水中至少一种;该反应温度为0℃~140℃;反应时间为1~12小时;
b)将式2化合物与对于胺类化合物反应在缩合剂催化作用下得到目标通式I化合物;所用的缩合剂为N,N'-二环己基碳二亚胺、N,N'-二异丙基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、偶氮二甲酸二乙酯、偶氮二甲酸二异丙酯、1-羟基-7-偶氮苯并三氮唑、1-羟基苯并三氮唑、O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯中的一种或两种以上的组合;所用溶剂为甲醇、乙醇、丙醇、异丙醇、乙腈、1,4-二氧六环、二氯乙烷、N,N-二甲基甲酰胺、N,N-二异丙基乙胺、水中的一种或两种以上的组合;反应温度为0℃~130℃;反应时间为6~12小时;所用胺类化合物为2-(二乙氨基)乙胺、2-(二异丙氨基)乙胺、3-(二甲氧基)丙胺、2-(吡咯基)乙胺、2-(1-乙基吡咯基-2-基)乙胺、吡咯、2-氟苯胺,4-氟苯甲胺,2-溴苯胺。
其中,R1为氢,溴或甲氧基;R2为氢或溴;R3为2-(二乙氨基)乙氨基,2-(二异丙氨基)乙氨基,3-(二甲氧基)丙氨基,2-(吡咯基)乙氨基,吡咯基,2-氟苯氨基,4-氟苯甲氨基,2-溴苯氨基。
本发明的第二方面,一种药物组合物,所述药物组合物包含第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药;和药学上可接受的载体。
本发明的第三方面,提供了第一方面所述的式I所示的化合物或其药学上可接受的盐、水合物、溶剂化物或前药用途,用于:
(i)制备BChE抑制剂;
(ii)制备预防和/或治疗BChE相关的疾病的药物。
药学上可接受的载体必须可与配方的其他成分兼容,且不会对其接受者有害,一般为适当载剂、稀释剂及赋形剂是为本领域技术人员所公知且包括诸如碳水化合物、蜡、水溶性及/或泡胀性聚合物、亲水性或疏水性材料、明胶、油、溶剂、水及类似物。所使用的特定载剂、稀释剂或赋形剂将取决于给予本发明化合物的方式及目的。溶剂通常是基于本领域技术人员所认为安全给予哺乳动物的溶剂(GRAS)而选择。通常,安全溶剂为无毒水性溶剂(诸如水)及其他可溶于水或与水可混溶的无毒溶剂。适当水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400或PEG300)等及其混合物。还可包括一或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、不透明剂、助滑剂、加工助剂、着色剂、甜味剂、香料、调味剂及其他提供药物(即本发明化合物或其医学组合物)精美外观或有助于制造药物产品(即用于制备药剂)的已知添加剂。
有益效果
本发明的化合物,能够选择性抑制BChE,可用于制备预防和/或治疗AD等相关神经退行性疾病的药物。
具体实施方式
下面对本发明的实施例作详细说明,本实施例在以本发明技术方案为前提下进行实施,给出了详细的实施方式和具体的操作过程,但本发明的保护范围不限于下述的实施例。
本发明人经过对所在实验室化合物库进行活性筛选及结构优化,发现了一种选择性BChE抑制剂,其能够有效抑制BChE活性,但对AChE无抑制活性或较弱。在此基础上,完成了本发明。
实施实施方式
下面结合具体实施例对本发明做进一步的详细说明。这些实施例仅用于说明本发明而不用于限制本发明的范围。
实施例1式2化合物的制备
将4-溴甲基苯甲酸(200mg,0.93mmol,1当量)溶解到8ml四氢呋喃中,加入式1所示的四氢异喹啉类化合物(1.86mmol,2当量),加热回流8小时,浓缩反应液。将得到的残余物加入到20mL氢氧化钠溶液中,二氯甲烷萃取(3×20mL),之后水相用10%稀盐酸酸化至pH值~1后,得到式2固体化合物。
表1式2化合物具体结构式、所用原料
式2-1化合物,黄色固体,产率90%。1H NMR(600MHz,DMSO-d6)δ11.54(brs,1H,COOH),8.02(d,J=8.2Hz,2H),7.82(d,J=8.2Hz,2H),7.28-7.15(m,4H),4.53(d,J=8.5Hz,2H),4.29(d,J=18.0Hz,2H),3.63(s,2H),3.03(s,2H).13C NMR(150MHz,DMSO-d6)δ166.9,134.5,131.8,131.7,131.5,129.7,128.6,128.3,127.7,126.7,126.6,57.8,51.5,48.6,39.5,24.9.ESI-MS m/z 268.1[M+H]+。
式2-2化合物,黄色固体,产率93%。1H NMR(600MHz,DMSO-d6)δ11.54(brs,1H,COOH),8.02(d,J=7.9Hz,2H),7.83-7.77(m,2H),7.49(s,1H),7.42(d,J=8.3Hz,1H),7.16(d,J=8.3Hz,1H),4.52(d,J=18.9Hz,2H),4.26(s,2H),3.33-3.20(m,3H),3.06(s,1H).13CNMR(150MHz,DMSO-d6)δ166.9,134.3,131.8,131.6,131.1,129.7,129.5,128.9,127.8,120.6,57.7,51.0,48.1,39.5,24.6.ESI-MS m/z 346.0[M+H]+。
式2-3化合物,白色固体,产率87.5%。1H NMR(600MHz,DMSO-d6)δ11.66(brs,1H,COOH),8.02(d,J=8.1Hz,2H),7.81(d,J=8.1Hz,2H),7.50-7.42(m,2H),7.20(d,J=8.2Hz,1H),4.58-4.44(m,2H),4.28(s,2H),3.63(d,J=10.7Hz,2H),3.34-3.17(m,2H).13CNMR(150MHz,DMSO-d6)δ166.9,134.3,131.7,131.6,131.0,130.7,130.4,129.6,129.3,119.3,57.7,50.8,48.3,39.5,24.4.ESI-MS m/z 346.0[M+H]+。
式2-4化合物,白色固体,产率87.7%。1H NMR(600MHz,DMSO-d6)δ7.83(d,J=8.0Hz,2H),7.24(d,J=8.0Hz,2H),6.91-6.87(m,2H),6.61(d,J=2.3Hz,1H),3.69(d,J=2.2Hz,5H),3.61(s,2H),2.87(t,J=5.8Hz,2H),2.78(t,J=5.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ170.0,157.4,139.4,135.3,129.0,127.5,127.3,127.0,126.9,113.5,111.8,61.9,55.0,54.9,50.2,39.5,29.0.ESI-MS m/z 298.1[M+H]+.
实施例2通式I化合物的制备
式2化合物(0.374mmol,1当量)溶解于5mL N,N-二甲基甲酰胺中,加入O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(156.4mg,0.411mmol,1.1当量)、相应的胺基化合物(0.374mmol,1当量)和N,N-二异丙基乙胺(193.3mg,1.496mmol,4当量)。反应液室温搅拌过夜,加入10mL水,乙酸乙酯萃取(3×10mL)。合并有机相,无水硫酸镁干燥,过滤,浓缩得到残余物,经硅胶色谱分离纯化得到相应的通式I化合物。化合物编号、具体结构式以及原料如下表2所示。
表2通式I化合物具体结构式、所用原料
式I-1化合物,淡黄色油体,产率62.5%。1H NMR(600MHz,DMSO-d6)δ8.34(t,J=5.8Hz,1H),7.80(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),7.13-7.06(m,3H),6.99(d,J=7.3Hz,1H),3.69(s,2H),3.53(s,2H),3.32-3.29(m,2H),2.81(t,J=5.8Hz,2H),2.67(t,J=5.8Hz,2H),2.57-2.50(m,6H),0.97(t,J=7.1Hz,6H).13C NMR(150MHz,DMSO-d6)δ165.9,141.7,134.7,134.1,133.4,128.5,127.1,126.3,126.0,125.5,61.4,55.4,51.5,50.3,46.8,39.5,37.5,28.7,11.9.ESI-MS m/z 366.2[M+H]+.HR-ESIMS:[M+H]+calcd forC23H32N3O+366.2545,found 366.2549.
式I-2化合物,淡黄色油体,产率54.7%。1H NMR(600MHz,DMSO-d6)δ8.34(t,J=5.8Hz,1H),7.81(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),7.12-7.06(m,3H),6.99(d,J=7.3Hz,1H),3.69(s,2H),3.53(s,2H),3.21-3.17(m,2H),3.00-2.94(m,2H),2.81(t,J=5.8Hz,2H),2.67(t,J=5.8Hz,2H),2.53-2.50(m,2H),0.98(d,J=6.6Hz,12H).13C NMR(150MHz,DMSO-d6)δ165.8,141.6,134.7,134.0,133.4,128.5,127.1,126.3,126.0,125.5,61.4,55.4,50.3,48.5,44.2,41.0,39.5,28.7,20.7.ESI-MS m/z 394.2[M+H]+.HR-ESIMS:[M+H]+calcd for C25H36N3O+394.2858,found394.2853.
式I-3化合物,淡黄色油体,产率64.3%。1H NMR(600MHz,DMSO-d6)δ8.52((t,J=5.8Hz,1H),7.84(d,J=8.2Hz,2H),7.45(d,J=8.2Hz,2H),7.13-7.05(m,3H),6.99(d,J=7.3Hz,1H),4.52(t,J=5.5Hz,1H),3.69(s,2H),3.53(s,2H),3.38-3.32(m,6H),2.81(t,J=5.8Hz,2H),2.69-2.65(m,2H).13C NMR(150MHz,DMSO-d6)δ166.2,141.9,134.7,134.1,133.0,128.5,128.5,127.3,126.4,126.0,125.5,101.9,61.4,55.4,53.2,53.2,50.3,41.1,39.5,28.7.ESI-MS m/z 355.1[M+H]+.HR-ESIMS:[M+H]+calcd for C21H27N2O3 +355.2022,found 355.2026.
式I-4化合物,淡黄色油体,产率74.5%。1H NMR(600MHz,DMSO-d6)δ8.34(t,J=5.7Hz,1H),7.80(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),7.13-7.05(m,3H),6.99(d,J=7.3Hz,1H),3.69(s,2H),3.53(s,2H),3.43-3.38(m,1H),3.08-3.00(m,2H),2.87-2.82(m,1H),2.81(t,J=5.8Hz,2H),2.67(t,J=5.8Hz,2H),2.57(m,1H),2.27(m,1H),2.15-2.08(m,1H),1.77(m,1H),1.67-1.55(m,3H),1.04(t,J=7.2Hz,3H).13C NMR(150MHz,DMSO-d6)δ166.1,141.7,134.7,134.1,133.4,128.5,127.2,126.3,126.0,125.5,62.7,61.4,55.4,53.3,50.3,48.2,43.2,39.5,28.7,28.6,22.4,13.9.ESI-MS m/z 378.2[M+H]+.HR-ESIMS:[M+H]+calcd for C24H32N3O+378.2545,found 378.2563.
式I-5化合物,淡黄色油体,产率74.0%。1H NMR(600MHz,DMSO-d6)δ7.48(d,J=8.1Hz,2H),7.41(d,J=8.1Hz,2H),7.09(m,3H),6.99(d,J=7.3Hz,1H),3.67(s,2H),3.54(s,2H),3.48-3.39(m,4H),2.81(t,J=5.8Hz,2H),2.68(t,J=5.8Hz,2H),1.88-1.83(m,2H),1.82-1.77(m,2H).13C NMR(150MHz,DMSO-d6)δ168.2,140.2,135.9,134.7,134.1,128.5,128.4,127.1,126.4,126.0,125.5,61.5,55.4,50.3,49.0,45.9,39.5,28.7,26.0,23.9.ESI-MS m/z 321.1[M+H]+.HR-ESIMS:[M+H]+calcd for C21H25N2O+321.1967,found321.1997.
Yellow oil(yield 74%).
式I-6化合物,淡黄色油体,产率64.0%。1H NMR(600MHz,DMSO-d6)δ7.48(d,J=8.1Hz,2H),7.40(d,J=8.1Hz,2H),7.32(d,J=2.1Hz,1H),7.26(dd,J=8.2,2.1Hz,1H),6.99(d,J=8.2Hz,1H),3.68(s,2H),3.50(s,2H),3.45(t,J=6.7Hz,2H),3.38(t,J=6.7Hz,2H),2.82(t,J=5.8Hz,2H),2.66(t,J=5.8Hz,2H),1.88-1.83(m,2H),1.82-1.77(m.2H).13C NMR(150MHz,DMSO-d6)δ168.1,140.0,137.1,135.9,134.2,131.0,128.6,128.4,128.3,127.1,118.8,61.2,54.8,49.7,49.0,45.9,39.5,28.4,26.0,23.9.ESI-MSm/z 399.0[M+H]+.HR-ESIMS:[M+H]+calcd for C21H24BrN2O+399.1072,found 399.1056.
式I-7化合物,淡黄色油体,产率65.0%。1H NMR(600MHz,DMSO-d6)δ7.48(d,J=7.8Hz,2H),7.40(d,J=7.8Hz,2H),7.29(d,J=8.2Hz,1H),7.25(s,1H),7.07(d,J=8.2Hz,1H),3.67(s,2H),3.55(s,2H),3.46(t,J=6.7Hz,2H),3.39(t,J=6.7Hz,2H),2.77(t,J=5.7Hz,2H),2.67(t,J=5.7Hz,2H),1.89-1.83(m,2H),1.82-1.77(m,2H).13C NMR(150MHz,DMSO-d6)δ168.1,140.0,137.5,135.9,133.6,130.7,129.0,128.8,128.3,127.1,118.3,61.1,54.8,49.8,48.9,45.9,39.5,28.1,26.0,23.9.ESI-MS m/z 399.0[M+H]+.HR-ESIMS:[M+H]+calcd for C21H24BrN2O+399.1072,found 399.1062.
式I-8化合物,油体,产率71.0%。1H NMR(600MHz,DMSO-d6)δ7.48(d,J=8.0Hz,2H),7.40(d,J=8.0Hz,2H),6.91(d,J=9.2Hz,1H),6.67(d,J=6.6Hz,2H),3.69(s,3H),3.66(s,2H),3.48-3.44(m,4H),3.39(t,J=6.5Hz,2H),2.79(t,J=5.8Hz,2H),2.65(t,J=5.8Hz,2H),1.88-1.83(m,2H),1.82-1.77(m,2H).13C NMR(150MHz,DMSO-d6)δ168.1,157.5,140.2,135.9,135.2,128.3,127.3,127.1,126.8,113.0,111.9,61.5,54.9,50.2,48.9,45.9,39.5,29.0,26.0,23.9.ESI-MS m/z 351.1[M+H]+.HR-ESIMS:[M+H]+calcd forC22H27N2O2 +351.2073,found351.2079.
式I-9化合物,淡黄色油体,产率37.0%。1H NMR(600MHz,DMSO-d6)δ10.09(brs,1H,NH),7.96(d,J=8.2Hz,2H),7.61-7.57(m,1H),7.52(d,J=8.2Hz,2H),7.32-7.25(m,2H),7.24-7.2(m,1H),7.15-7.06(m,3H),7.01(d,J=7.3Hz,1H),3.74(s,2H),3.56(s,2H),2.83(t,J=5.8Hz,2H),2.70(t,J=5.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ165.3,156.7,155.0,142.7,134.7,134.1,132.7,128.6,128.5,127.9,127.2,126.4,126.0,125.5,124.3,124.3,115.9,115.8,61.4,55.4,50.3,39.5,28.7.ESI-MS m/z 361.0[M+H]+.HR-ESIMS:[M+H]+calcd for C23H22FN2O+361.1716,found 361.1757.
式I-10化合物,淡黄色油体,产率61.2%。1H NMR(600MHz,DMSO-d6)δ9.03(t,J=6.0Hz,1H),7.87(d,J=8.3Hz,2H),7.46(d,J=8.3Hz,2H),7.40-7.31(m,2H),7.17-7.13(m,2H),7.12-7.05(m,3H),6.99(d,J=7.3Hz,1H),4.46(d,J=6.0Hz,2H),3.69(s,2H),3.54(s,2H),2.81(t,J=5.8Hz,2H),2.67(t,J=5.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ166.1,161.9,160.3,142.0,135.9,135.9,134.7,134.0,133.0,129.2,129.2,128.5,128.5,127.3,126.3,126.0,125.5,115.0,114.9,61.4,55.4,50.3,41.9,39.5,28.7.ESI-MS m/z 375.1[M+H]+.HR-ESIMS:[M+H]+calcd for C24H24FN2O+375.1873,found 375.1890.
式I-11化合物,淡黄色油体,产率51.0%。1H NMR(600MHz,DMSO-d6)δ8.69(dd,J=4.4,1.4Hz,1H),8.48(dd,J=8.4,1.4Hz,1H),7.93(d,J=8.2Hz,2H),7.50(d,J=8.2Hz,2H),7.46(dd,J=8.4,4.4Hz,1H),7.14-7.07(m,3H),7.01(d,J=7.3Hz,1H),3.79(s,2H),3.61(s,2H),2.84(t,J=5.8Hz,2H),2.75(t,J=5.8Hz,2H).13C NMR(150MHz,DMSO-d6)δ167.21,150.59,139.59,134.60,134.10,133.79,129.74,129.39,128.92,128.61,128.46,126.38,126.16,125.58,120.44,61.10,55.14,50.19,39.5,28.35.ESI-MS m/z 421.0[M+H]+.HR-ESIMS:[M+H]+calcd for C23H22BrN2O+421.0916,found 421.0910.
实施例3化合物对BChE、AChE酶的抑制活性
丁酰胆碱酯酶(BChE)、乙酰胆碱酯酶(AChE)、作为底物的碘化硫代丁酰胆碱(BUC)和碘化硫代乙酰胆碱(ATC)、作为显色剂的5,5-二硫双(2-硝基苯甲酸)(DTNB)均购自Sigma。AChE抑制活性测定参考Ellan等报道的方法进行。96孔板每孔加入40μL的磷酸缓冲液(pH=8.0),然后将0.39、0.78、1.56、3.125、6.25、12.5、25、50和100μM的10μL待测化合物溶液或空白对照加入到对应的空中,随后加入10μL的BChE或AChE,置于37℃摇床孵育5min。加入20μL的DTNB溶液,再置于37℃摇床孵育5min,随后加入10μL的底物BUC或ATC置于37℃摇床孵育3min后,酶标仪测定412nm处的吸光度,计算待测化合物对BChE或AChE的抑制率。根据抑制曲线求得化合物的IC50值(抑制酶活力50%时的抑制剂浓度),实验结果如表3所示。
表3.化合物对BChE和AChE酶抑制活性
实验结果表明,上述通式I所示化合物对BChE具有较好的选择抑制活性。其中,化合物I-11具有最强的BChE抑制活性,IC50值为0.83±0.08μM,其对BChE的选择性优于对照药物他克林。
实施例4
将下列化合物A1-A5按照实施例3的试验步骤测试对丁酰胆碱酯酶(BChE)、乙酰胆碱酯酶(AChE)的抑制作用。
化合物A1:(RS)-喹啉-2-甲酸(4-吡咯烷-3-基-苯基)-酰胺盐酸盐
化合物A2:(RS)-异喹啉-1-甲酸(4-吡咯烷-3-基-苯基)-酰胺盐酸盐
化合物A3:(RS)-4-甲氧基-喹啉-2-甲酸(4-吡咯烷-3-基-苯基)-酰胺盐酸盐
化合物A4:(RS)-6-甲氧基-喹啉-2-甲酸(4-吡咯烷-3-基-苯基)-酰胺盐酸盐
化合物A5:(RS)-1-氯-异喹啉-3-甲酸(4-吡咯烷-3-基-苯基)-酰胺盐酸盐
经过试验可以得知,化合物A1-A5对于丁酰胆碱酯酶(BChE)、乙酰胆碱酯酶(AChE)均没有抑制作用,因此化合物A1-A5的作用的靶点与本申请是不同的。即使类似的结构,取代基或者官能团类似,但是位置不同,结构的不同,化合物性质也就不同,会直接影响对酶不同的抑制作用,也就是作用的靶点是不同的。即使微小的取代基变化,对于作用靶点或者酶的抑制作用也是很大的差别。
以上以具体的实施例来举例说明本发明化合物的制备步骤、鉴定过程和胆碱酯酶抑制活性筛选,但本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (3)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910565545.XA CN110218183B (zh) | 2019-06-27 | 2019-06-27 | 一种选择性丁酰胆碱酯酶抑制剂及其用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910565545.XA CN110218183B (zh) | 2019-06-27 | 2019-06-27 | 一种选择性丁酰胆碱酯酶抑制剂及其用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110218183A CN110218183A (zh) | 2019-09-10 |
CN110218183B true CN110218183B (zh) | 2022-02-08 |
Family
ID=67815055
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910565545.XA Expired - Fee Related CN110218183B (zh) | 2019-06-27 | 2019-06-27 | 一种选择性丁酰胆碱酯酶抑制剂及其用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110218183B (zh) |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105753795A (zh) * | 2016-04-29 | 2016-07-13 | 济南大学 | 一种具有1,2,3-三氮唑结构片段的生物碱化合物及其用途 |
CN106883225A (zh) * | 2017-02-17 | 2017-06-23 | 济南大学 | 一种具有1,2,4‑恶二唑‑结构片段的香豆素衍生物及其应用 |
CN107129517A (zh) * | 2017-05-19 | 2017-09-05 | 济南大学 | 一种具有α,β‑不饱和酮结构片段的孕烯醇酮衍生物及其用途 |
CN108689982A (zh) * | 2018-06-21 | 2018-10-23 | 济南大学 | 一种具有α,β-不饱和酮结构片段的香豆素衍生物及其制备方法和用途 |
CN109535072A (zh) * | 2018-12-10 | 2019-03-29 | 济南大学 | 一种乙酰胆碱酯酶抑制剂及其应用 |
CN109705136A (zh) * | 2018-12-10 | 2019-05-03 | 济南大学 | 乙酰胆碱酯酶抑制剂及其应用 |
-
2019
- 2019-06-27 CN CN201910565545.XA patent/CN110218183B/zh not_active Expired - Fee Related
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105753795A (zh) * | 2016-04-29 | 2016-07-13 | 济南大学 | 一种具有1,2,3-三氮唑结构片段的生物碱化合物及其用途 |
CN106883225A (zh) * | 2017-02-17 | 2017-06-23 | 济南大学 | 一种具有1,2,4‑恶二唑‑结构片段的香豆素衍生物及其应用 |
CN107129517A (zh) * | 2017-05-19 | 2017-09-05 | 济南大学 | 一种具有α,β‑不饱和酮结构片段的孕烯醇酮衍生物及其用途 |
CN108689982A (zh) * | 2018-06-21 | 2018-10-23 | 济南大学 | 一种具有α,β-不饱和酮结构片段的香豆素衍生物及其制备方法和用途 |
CN109535072A (zh) * | 2018-12-10 | 2019-03-29 | 济南大学 | 一种乙酰胆碱酯酶抑制剂及其应用 |
CN109705136A (zh) * | 2018-12-10 | 2019-05-03 | 济南大学 | 乙酰胆碱酯酶抑制剂及其应用 |
Non-Patent Citations (8)
Title |
---|
Discovery of new acetylcholinesterase and butyrylcholinesterase inhibitors through structurebased virtual screening;Yao Chen,等;《RSC Adv.》;20171231;第7卷;第3429-3438页 * |
New therapeutic approaches and novel alternatives for organophosphate toxicity;Francine S. Katz,等;《Toxicology Letters》;20180331;第291卷;第1-10页 * |
RN: 1311001-07-6;STN-REGISTRY;《RN: 1311001-07-6》;20110630 * |
RN: 426226-87-1;STN-REGISTRY;《RN: 426226-87-1》;20020606 * |
RN:333358-06-8;STN-REGISTRY;《RN:333358-06-8》;20010427 * |
RN:352559-27-4;STN-REGISTRY;《RN:352559-27-4》;20010824 * |
RN:357310-66-8;STN-REGISTRY;《RN:357310-66-8》;20010918 * |
治疗阿尔茨海默症的多靶点药物分子的设计、合成及构效关系研究;李家诚;《济南大学硕士学位论文》;20181231;全文 * |
Also Published As
Publication number | Publication date |
---|---|
CN110218183A (zh) | 2019-09-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108602771B (zh) | 化合物的酸加成盐 | |
CN112543755A (zh) | 一类细胞坏死抑制剂及其制备方法和用途 | |
US6479488B1 (en) | Tetrahydroquinoline derivatives as EAA antagonists | |
JPH02502462A (ja) | 化合物 | |
EP2838538B1 (en) | Cyclopropanecarboxylate esters of purine analogues | |
KR20080015388A (ko) | 효소 억제제 | |
KR20080016604A (ko) | 6-알킬아미노퀴놀린 유도체의 합성 방법 | |
WO1996036596A1 (en) | 3,4-disubstituted-phenylsulphonamides and their therapeutic use | |
EP2722042B1 (en) | Indanone derivatives, pharmaceutically acceptable salts or optical isomers thereof, preparation method for same, and pharmaceutical compositions containing same as active ingredient for preventing or treating viral diseases | |
US11780841B2 (en) | 3,6-methano-1H-pyrrolo[3,2-b]pyridine and 3,6-methano-1H-pyrrolo[3,2-c]pyridine compounds and medicaments using same | |
RU2266280C2 (ru) | Замещенные производные n-бензилиндол-3-ил-глиоксиловой кислоты, обладающие противоопухолевым действием (варианты), их кислотно-аддитивные соли (варианты), фармацевтический препарат, фармацевтическая форма | |
WO2011054171A1 (zh) | 酪氨酸衍生物类组蛋白去乙酰化酶抑制剂及其应用 | |
US5977136A (en) | Tetrahydroquinolines as NMDA antagonists | |
CN110218183B (zh) | 一种选择性丁酰胆碱酯酶抑制剂及其用途 | |
KR101983979B1 (ko) | Kcnq2/3 조절제로서의 치환된 2-옥소- 및 2-티옥소-디하이드로퀴놀린-3-카복스아미드 | |
CN111848454B (zh) | 一种组蛋白去乙酰化酶6抑制剂及其制备方法和应用 | |
CN115175913A (zh) | 取代的双三环化合物及其药物组合物和用途 | |
CN102617487A (zh) | 多取代嘧啶酮类化合物及其制备方法和应用 | |
IE63654B1 (en) | Process for the preparation of quinolonecarboxylic acids | |
WO2021009034A1 (en) | 3-[2(r)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1h-pyrimidine-2,4(1h,3h)-dione hydrochloride salt (i) in solid form, process for preparing same, and use thereof in the synthesis of elagolix | |
US20050245578A1 (en) | Polymorphs of pantoprazole sodium salt and process for the preparation thereof | |
RU2400479C2 (ru) | Кристаллические модификации | |
CN109438347B (zh) | 一种氰基喹啉类ido1抑制剂、其制备方法及应用 | |
WO2011158250A1 (en) | Process for preparation of 2, 3-diaryl-5-substituted pyridines and their intermediates | |
EP0405342A1 (en) | (1,2,3,4-Tetrahydro-9-acridinimino)cyclohexane carboxylic acid and related compounds, a process for their preparation and their use as medicaments |
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: 20220208 |