CN116768855A - 芳香氨基酸类化合物及其制备方法、药物组合物和应用 - Google Patents
芳香氨基酸类化合物及其制备方法、药物组合物和应用 Download PDFInfo
- Publication number
- CN116768855A CN116768855A CN202210230885.9A CN202210230885A CN116768855A CN 116768855 A CN116768855 A CN 116768855A CN 202210230885 A CN202210230885 A CN 202210230885A CN 116768855 A CN116768855 A CN 116768855A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- ring
- amino acid
- aromatic amino
- 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.)
- Pending
Links
- -1 Aromatic amino acid compound Chemical class 0.000 title claims abstract description 81
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 239000003814 drug Substances 0.000 claims abstract description 16
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 13
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 5
- 229940079593 drug Drugs 0.000 claims description 10
- 238000006467 substitution reaction Methods 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 4
- 238000005917 acylation reaction Methods 0.000 claims description 4
- 125000004429 atom Chemical group 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000004770 neurodegeneration Effects 0.000 claims description 4
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
- 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 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- 238000006722 reduction reaction Methods 0.000 claims description 3
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 229940123923 Butyrylcholinesterase inhibitor Drugs 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 229960004106 citric acid Drugs 0.000 claims description 2
- 235000015165 citric acid Nutrition 0.000 claims description 2
- 229940125904 compound 1 Drugs 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229960002598 fumaric acid Drugs 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 229960000448 lactic acid Drugs 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098895 maleic acid Drugs 0.000 claims description 2
- 239000001630 malic acid Substances 0.000 claims description 2
- 235000011090 malic acid Nutrition 0.000 claims description 2
- 229940099690 malic acid Drugs 0.000 claims description 2
- 229960002510 mandelic acid Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 229960003424 phenylacetic acid Drugs 0.000 claims description 2
- 239000003279 phenylacetic acid Substances 0.000 claims description 2
- 229960004838 phosphoric acid Drugs 0.000 claims description 2
- 230000004224 protection Effects 0.000 claims description 2
- 229940107700 pyruvic acid Drugs 0.000 claims description 2
- 229960004889 salicylic acid Drugs 0.000 claims description 2
- 229940032330 sulfuric acid Drugs 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229960001367 tartaric acid Drugs 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 102100032404 Cholinesterase Human genes 0.000 abstract description 10
- 230000008499 blood brain barrier function Effects 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 8
- 210000001218 blood-brain barrier Anatomy 0.000 abstract description 6
- 230000035699 permeability Effects 0.000 abstract description 6
- 230000003920 cognitive function Effects 0.000 abstract description 5
- 230000004112 neuroprotection Effects 0.000 abstract description 5
- 231100000252 nontoxic Toxicity 0.000 abstract description 3
- 230000003000 nontoxic effect Effects 0.000 abstract description 3
- 101710083761 Cholinesterase Proteins 0.000 abstract description 2
- 230000006993 memory improvement Effects 0.000 abstract description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 53
- 230000015572 biosynthetic process Effects 0.000 description 33
- 238000003786 synthesis reaction Methods 0.000 description 33
- 239000000243 solution Substances 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 102100033639 Acetylcholinesterase Human genes 0.000 description 15
- 108010022752 Acetylcholinesterase Proteins 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 12
- 210000004027 cell Anatomy 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 239000002904 solvent Substances 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- AWBGQVBMGBZGLS-UHFFFAOYSA-N butyrylthiocholine Chemical compound CCCC(=O)SCC[N+](C)(C)C AWBGQVBMGBZGLS-UHFFFAOYSA-N 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- GFFIJCYHQYHUHB-UHFFFAOYSA-N 2-acetylsulfanylethyl(trimethyl)azanium Chemical compound CC(=O)SCC[N+](C)(C)C GFFIJCYHQYHUHB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 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 6
- 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 5
- 108010053652 Butyrylcholinesterase Proteins 0.000 description 5
- 229940022698 acetylcholinesterase Drugs 0.000 description 5
- 125000000814 indol-3-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([H])=C([*])C2=C1[H] 0.000 description 5
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 4
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 4
- 240000000731 Fagus sylvatica Species 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- GPKIELSFWJGBHA-UHFFFAOYSA-N 2-(3,4-dihydro-1h-isoquinolin-2-yl)acetonitrile Chemical compound C1=CC=C2CN(CC#N)CCC2=C1 GPKIELSFWJGBHA-UHFFFAOYSA-N 0.000 description 3
- 229940124596 AChE inhibitor Drugs 0.000 description 3
- 108090000322 Cholinesterases Proteins 0.000 description 3
- 108010047290 Multifunctional Enzymes Proteins 0.000 description 3
- 102000006833 Multifunctional Enzymes Human genes 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 3
- 230000033228 biological regulation Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 210000003169 central nervous system Anatomy 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 229960003530 donepezil Drugs 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- JTEJMGHPAYJBTA-UHFFFAOYSA-N 2-(3,4-dihydro-1h-isoquinolin-2-yl)ethanamine Chemical compound C1=CC=C2CN(CCN)CCC2=C1 JTEJMGHPAYJBTA-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000005779 cell damage Effects 0.000 description 2
- 208000037887 cell injury Diseases 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 229940048961 cholinesterase Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 2
- 229960001685 tacrine Drugs 0.000 description 2
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-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
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- LSDGFGPIFBOTJI-UHFFFAOYSA-N 2-(aziridin-1-yl)ethanamine Chemical compound NCCN1CC1 LSDGFGPIFBOTJI-UHFFFAOYSA-N 0.000 description 1
- UNNGUFMVYQJGTD-UHFFFAOYSA-N 2-Ethylbutanal Chemical compound CCC(CC)C=O UNNGUFMVYQJGTD-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- KIUMMUBSPKGMOY-UHFFFAOYSA-L 5-[(3-carboxylato-4-nitrophenyl)disulfanyl]-2-nitrobenzoate 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-L 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229930182827 D-tryptophan Natural products 0.000 description 1
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 1
- 241001417101 Gymnotidae Species 0.000 description 1
- 231100000002 MTT assay Toxicity 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
- 238000012347 Morris Water Maze Methods 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- NFVNYBJCJGKVQK-ZDUSSCGKSA-N N-[(Tert-butoxy)carbonyl]-L-tryptophan Chemical compound C1=CC=C2C(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CNC2=C1 NFVNYBJCJGKVQK-ZDUSSCGKSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 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 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 239000000823 artificial membrane Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 239000012490 blank solution Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000739 chaotic effect Effects 0.000 description 1
- ZPEIMTDSQAKGNT-UHFFFAOYSA-N chlorpromazine Chemical compound C1=C(Cl)C=C2N(CCCN(C)C)C3=CC=CC=C3SC2=C1 ZPEIMTDSQAKGNT-UHFFFAOYSA-N 0.000 description 1
- 229960001076 chlorpromazine Drugs 0.000 description 1
- 230000007278 cognition impairment Effects 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940125808 covalent inhibitor Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000013505 freshwater Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 231100000863 loss of memory Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000006386 memory function Effects 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 229940094933 n-dodecane Drugs 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 230000000324 neuroprotective effect Effects 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 229960002702 piroxicam Drugs 0.000 description 1
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000013037 reversible inhibitor Substances 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/12—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
- C07D295/125—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- 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
- C07D401/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (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)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类芳香氨基酸类化合物及其制备方法、药物组合物和应用。该化合物结构如式I，其包含其异构体、药学上可接受的盐或它们的混合物。该芳香氨基酸类化合物及其药物组合物可有效地选择性抑制丁酰胆碱酯酶，最优达到纳摩尔浓度水平；同时具有优异的血脑屏障渗透性，此外还几乎无毒。其制备的药物通过神经保护作用、改善记忆和认知功能等多种功效，可有效治疗阿尔兹海默症。
Description
技术领域
本发明涉及一类芳香氨基酸类化合物及其制备方法、药物组合物和应用，尤其涉及一种可制备为丁酰胆碱酯酶选择性抑制剂药物的香氨基酸类化合物及其制备方法、药物组合物和应用。
背景技术
阿尔茨海默症(Alzheimer's disease，AD)是一种进行性发展的致死性神经退行性疾病。临床表现为记忆和认知功能的退行性丧失，日常生活能力的减退并伴有各种神经精神症状。因此，寻找对AD治疗有效的药物及治疗策略已成为整个世界医药领域内亟待解决的关键性难题。
AD发病因素极为复杂，尽管目前科学家们对AD确切病因尚未定论，但前期大量研究表明，AD主要是由于遗传基因、衰老和外界环境因素共同的作用后所诱发的，已经提出了几种假设，包括胆碱能功能障碍，淀粉样蛋白β肽(Aβ)斑块，神经原纤维缠结和氧化应激。
乙酰胆碱酯酶(ACh)是一种胆碱能传递介质，广泛分布于外周和中枢神经系统。在神经元水平，胆碱能神经传递主要有两种胆碱酯酶调节：乙酰胆碱酯酶和丁酰胆碱酯酶。在健康成年人中，AChE对胆碱活性起主要调节作用，BuChE起辅助调节作用。但是BChE的辅助调节功能随着AD病程的发展发生变化，晚期AD患者BuChE/AChE显著上升。BChE代替AChE起水解胆碱的作用。目前，AChE抑制剂广泛应用于恢复ACh水平，但是患者服用AChE抑制剂可能会产生恶心等副作用和呕吐，这些伴随不良的结果主要是由于抑制外周AChE。
当前高选择性的丁酰胆碱酯酶结构类型较少，目前仅有一款处于临床研究中。该化合物为bisnorcymserine，是一种氨基甲酸酯类结构，为BChE共价抑制剂，目前尚未有可逆的BChE抑制剂进入临床。
发明内容
发明目的：针对现有AChE抑制剂药物在AD晚期疗效不佳、不良反应明显等不足以及现有BChE抑制剂药物骨架类型单一、选择性不佳等不足，本发明旨在提供一类可选择性抑制丁酰胆碱酯酶活性的芳香氨基酸类化合物及其制备方法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的芳香氨基酸类化合物具有式I的结构，其包含其异构体、药学上可接受的盐或它们的混合物：
其中：
n＝0～4；
A环选自6～10元芳环或6～10元芳杂环；
B环选自6～10元杂环或6～10元芳环，所述环系被一个或多个氢、C1～C3烷基或C1～C3烷氨基取代；
R1选自一个或多个氢、C1～C6烷基或5～6元芳杂环；R1NH基团所连接的手性原子构型为R、S或消旋体。
本发明的化合物设计了一类天然氨基酸骨架的可逆抑制剂。选择性BChE抑制剂可以规避现有胆碱能毒性，抑制丁酰胆碱酯酶相比选择性乙酰胆碱酯酶的作用将更有效，尤其是针对中晚期AD。
优选，上述结构中：
A环选自6元或10元芳环或者9～10元含氮芳杂环；
B环选自6～10元含氮杂环或苯环，所述环系被一个或多个氢、C1～C3烷基或C1～C3烷氨基取代；
R1选自一个或多个氢、C1～C6烷基或者5～6元含氮或氧的芳杂环；R1NH基团所连接的手性原子构型为R、S或消旋体。
进一步优选，上述结构中：
A环选自：
B环选自：
R1选自：
具体地，上述芳香氨基酸类化合物选自以下任一化合物：
上述芳香氨基酸类化合物的药学上可接受的盐为所述化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
作为本发明涉及的第二方面，上述芳香氨基酸类化合物的制备方法为：
(1)当B环选自时，
化合物1经取代、还原、酰化、脱保护、取代反应得到化合物I；
(2)当B环选自时，
化合物6经取代、保护、酰化、脱保护反应得到化合物I；
其中，n、A环、R1、R2的定义如前所述；
将相应的酸与以上方法制备的化合物I成盐，即得上述芳香氨基酸类化合物的药学上可接受的盐。
作为本发明涉及的第三方面，本发明的药物组合物包含上述芳香氨基酸类化合物以及药学上可接受的载体。
上述芳香氨基酸类化合物可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面，上述芳香氨基酸类化合物及其药物组合物可制备为丁酰胆碱酯酶抑制剂药物，用于治疗神经退行性疾病，具体治疗阿尔茨海默症。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该芳香氨基酸类化合物及其药物组合物可有效地选择性抑制丁酰胆碱酯酶，IC50值最优小于50nM，同时具有优异的血脑屏障渗透性，可有效送达至病灶，此外还几乎无毒；
(2)该芳香氨基酸类化合物及其药物组合物具有良好的神经保护作用，并且显著改善记忆和认知功能，具有多种机制的抗阿尔兹海默症的活性；
(3)化合物制备方法简便、易操作。
附图说明
图1为化合物对人神经母细胞瘤SH-SY5Y细胞的细胞毒性；
图2为化合物18(R)和22(R)对Aβ1-42诱导的对人神经母细胞瘤SH-SY5Y细胞的细胞毒性的神经保护效力；
图3为水迷宫实验中ICR小鼠14天内的每日体重；
图4为水迷宫实验中化合物对ICR Aβ1-42肽诱导小鼠的AD样认知缺陷的影响结果；
图5为水迷宫实验中小鼠的平均轨迹。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
通过核磁共振(NMR)确定化合物的结构。仪器为Bruker AVANCE-300核磁共振仪，测定溶剂是CDCl3，内标为TMS，化学位移是10-6ppm。
实施例1：化合物10的合成
步骤1：2-(3,4-二氢异喹啉-2(1H)-基)乙腈的合成(2a)
1,2,3,4-四氢异喹啉(10mmol)溶于40mL四氢呋喃中，加入碳酸钾(13mmol)以及溴乙腈(12mmol)，室温搅拌3小时，反应完毕后，过滤，滤液真空浓缩，柱层析得(石油醚：乙酸乙酯＝5：1)白色固体，收率87.5％。
1H NMR(500MHz,CDCl3)δ7.21–7.18(m,1H),7.18–7.14(m,2H),7.09–7.05(m,1H),3.82(s,1H),3.74(s,1H),2.99(t,J＝5.9Hz,1H),2.90(t,J＝5.9Hz,1H).
步骤2：2-(3,4-二氢异喹啉-2(1H)-基)乙烷-1-胺的合成
冰浴下，氢化铝锂(20mmol)分散于20mL四氢呋喃溶液中，氩气保护，2-(3,4-二氢异喹啉-2(1H)-基)乙腈缓慢加入其中，室温搅拌2～3小时。稀氢氧化钠淬灭反应，过滤，滤液真空浓缩得粗品黄色油状物，收率91.2％。
步骤3：叔丁基(1-((2-(3,4-二氢异喹啉-2(1H)-基)乙基)氨基)-3-(1H-吲哚-3-基)-1-氧丙烷-2-基)氨基甲酸酯的合成
(R)N-叔丁氧羰基色氨酸(5mmol)溶于20mL N,N’-二甲基甲酰胺，冰浴下加入N,N’-二异丙基乙胺(12mmol)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(6mmol)，2-(3,4-二氢异喹啉-2(1H)-基)乙烷-1-胺(6mmol)，室温搅拌4～5小时。加水20mL淬灭，乙酸乙酯(30mL×3)萃取，合并有机相，分别用水，饱和食盐水洗涤，无水硫酸钠干燥。真空除去溶剂，柱层析(二氯甲烷：甲醇＝100：1)得淡黄色固体，收率67.5％。
步骤4：2-氨基-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)丙胺的合成
叔丁基(1-((2-(3,4-二氢异喹啉-2(1H)-基)乙基)氨基)-3-(1H-吲哚-3-基)-1-氧丙烷-2-基)氨基甲酸酯(3mmol)溶于5mL三氟乙酸，室温下搅拌过夜。真空除去溶剂，得粗品。柱层析(二氯甲烷：甲醇＝50：1)得无色油状物，收率81.2％。
(R)2-氨基-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)丙胺
1H NMR(300MHz,CDCl3)δ8.08(s,1H),7.58(d,J＝7.5Hz,1H),7.34–7.28(m,1H),7.24(d,J＝8.0Hz,1H),7.19(s,2H),7.12(dd,J＝7.1,0.9Hz,1H),6.94(dd,J＝6.8,2.5Hz,2H),3.61(dd,J＝8.0,4.7Hz,1H),3.52(d,J＝7.4Hz,2H),3.36(dd,J＝11.7,5.0Hz,3H),3.24(dd,J＝14.5,4.6Hz,1H),2.89(dd,J＝14.4,8.2Hz,1H),2.75(t,J＝5.6Hz,3H),2.59(t,J＝5.8Hz,3H),2.49(t,J＝6.2Hz,2H).
13C NMR(126MHz,CDCl3)δ175.03,136.35,134.58,134.36,128.68,127.54,126.57,126.23,125.69,123.11,122.14,119.52,118.98,111.69,111.19,56.55,55.75,55.73,50.61,36.18,31.02,29.00.
ESI:m/z[M+H]+,calcd.for C22H26N4O:363.2107；found:363.2180
HPLC:0～20min(A:B＝80:20),tR＝4.778min,Purity:97.708％.
(S)(R)2-氨基-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)丙胺
1H NMR(300MHz,CDCl3)δ8.35(s,1H),7.65(d,J＝7.7Hz,2H),7.32(d,J＝8.0Hz,1H),7.16(dd,J＝14.9,6.1Hz,2H),7.09(dd,J＝8.8,5.6Hz,4H),7.01(d,J＝1.6Hz,2H),6.98(s,1H),3.59(s,2H),3.50(dd,J＝13.6,5.9Hz,1H),3.41(dd,J＝12.8,6.6Hz,1H),3.32(dt,J＝6.9,4.2Hz,2H),2.95–2.89(m,1H),2.84(t,J＝6.4Hz,2H),2.68(t,J＝5.5Hz,2H),2.58(t,J＝6.1Hz,2H).
13C NMR(75MHz,CDCl3)δ175.26,136.47,134.48,134.31,128.73,127.53,126.64,126.32,125.77,125.59,123.41,122.03,119.40,118.93,111.29,56.57,55.76,50.63,36.24,31.08,30.41,28.95.
ESI:m/z[M+H]+,calcd.for C22H26N4O:363.2107；found:363.2180
HPLC:0～20min(A:B＝80:20),tR＝4.837min,Purity:99.245％.
实施例2：化合物11的合成
参考实施例1。
(R)-2-氨基-3-(1H-吲哚-3-基)-N-(2-(1-甲基-3,4-二氢异喹啉-2(1H)-基)乙基)-丙酰胺的合成
1H NMR(300MHz,CDCl3)δ8.08(s,1H),7.58(d,J＝7.5Hz,1H),7.34–7.28(m,1H),7.24(d,J＝8.0Hz,1H),7.19(s,2H),7.12(dd,J1＝7.1,J2＝0.9Hz,1H),6.94(dd,J1＝6.8,J2＝2.5Hz,2H),3.61(dd,J1＝8.0,J2＝4.7Hz,1H),3.52(d,J＝7.4Hz,2H),3.36(dd,J1＝11.7,J2＝5.0Hz,3H),3.24(dd,J1＝14.5,J2＝4.6Hz,1H),2.89(dd,J1＝14.4,J2＝8.2Hz,1H),2.75(t,J＝5.6Hz,3H),2.59(t,J＝5.8Hz,3H),2.49(t,J＝6.2Hz,2H).
13C NMR(126MHz,CDCl3)δ174.96,140.06,136.38,134.12,128.87,127.57,127.34,125.95,125.72,123.10,122.15,119.52,119.00,111.74,111.19,56.65,55.74,52.44,43.48,36.65,31.06,27.41,19.45.
ESI:m/z[M+H]+,calcd.for C22H26N4O:363.2107；found:363.2180
HPLC:0～20min(A:B＝80:20),tR＝5.687min,Purity:95.359％.
实施例3：化合物12的合成
步骤1-4参考实施例1。
步骤5：(R)-2-((环丙基甲基)氨基)氨基-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)丙酰胺的合成
(R)2-氨基-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)丙胺(0.5mmol)溶于干燥的二氯甲烷，加入环丙基甲醛(0.6mmol)，室温下搅拌1小时，加入三乙酰氧基硼氢化钠(0.75mmol),继续室温搅拌2小时。水10mL淬灭，二氯甲烷反淬，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。真空除去溶剂，柱层析(二氯甲烷：甲醇＝100：1)得无色油状物，收率69.5％。
1H NMR(300MHz,CDCl3)δ8.42(s,1H),7.92(d,J＝7.8Hz,1H),7.81(s,1H),7.59(d,J＝8.0Hz,1H),7.52(s,1H),7.37(dd,J＝11.6,5.6Hz,2H),7.28(d,J＝5.9Hz,1H),3.85(d,J＝3.9Hz,1H),3.76(dd,J＝13.3,6.2Hz,1H),3.68(dd,J＝10.6,6.5Hz,1H),3.56(dd,J＝14.5,4.5Hz,1H),3.20(dd,J＝14.4,8.8Hz,1H),3.10(t,J＝5.6Hz,1H),2.95(t,J＝5.7Hz,1H),2.89–2.78(m,1H),2.60(dd,J＝12.0,6.7Hz,1H),2.47(dd,J＝12.0,7.0Hz,1H),0.98–0.84(m,1H),0.55–0.40(m,1H),0.21–0.12(m,1H),0.06(dt,J＝7.6,4.1Hz,1H).
13C NMR(126MHz,CDCl3)δ174.60,136.36,134.62,134.35,128.63,127.50,126.52,126.16,125.64,122.82,122.16,119.51,118.98,111.83,111.13,63.09,56.59,55.69,53.75,50.69,36.06,29.40,29.08,11.15,3.28,2.94.
ESI:m/z[M+H]+,calcd.for C26H33N4O:417.2576；found:417.2646.
HPLC:0～20min(A:B＝80:20),tR＝5.427min,Purity:96.930％.
实施例4：化合物13的合成
步骤1-5参考实施例3。
(R)-2-(丁基氨基)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.13(s,1H),7.71(d,J＝7.8Hz,1H),7.62(t,J＝4.9Hz,1H),7.38(d,J＝8.0Hz,1H),7.25(d,J＝7.0Hz,1H),7.22–7.19(m,1H),7.18(dd,J＝3.1,1.9Hz,2H),7.16(s,1H),7.06(d,J＝5.1Hz,2H),3.64(d,J＝3.1Hz,2H),3.55(dd,J＝13.8,6.0Hz,1H),3.48(d,J＝6.2Hz,3H),3.34(dd,J＝14.4,4.3Hz,1H),2.96(dd,J＝14.4,8.8Hz,1H),2.89(t,J＝5.7Hz,2H),2.78–2.68(m,3H),2.68–2.57(m,3H),1.28–1.20(m,3H),1.11(dq,J＝13.7,7.0Hz,3H),0.72(t,J＝7.2Hz,4H).
13C NMR(126MHz,CDCl3)δ174.63,136.36,134.65,134.37,128.64,127.54,126.51,126.15,125.64,122.80,122.17,119.53,118.98,111.88,111.13,63.48,56.65,55.69,50.71,48.64,36.02,32.23,30.34,29.32,20.17,13.80.
ESI:m/z[M+H]+,calcd.for C26H35N4O:419.2733；found:
HPLC:0～20min(A:B＝80:20),tR＝5.842min,Purity:98.365％.
实施例5：化合物14的合成
参考实施例3。
(R)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)-2-(丙氨基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.13(s,1H),7.71(d,J＝7.8Hz,1H),7.61(s,1H),7.37(d,J＝8.0Hz,1H),7.31(s,1H),7.16(d,J＝5.7Hz,5H),7.05(d,J＝11.5Hz,3H),3.66(t,J＝9.6Hz,3H),3.55(dd,J＝13.3,6.1Hz,1H),3.48–3.40(m,2H),3.34(dd,J＝14.5,4.0Hz,1H),2.97(dd,J＝14.3,8.9Hz,1H),2.87(d,J＝5.4Hz,2H),2.74(d,J＝5.1Hz,2H),2.62(d,J＝4.2Hz,2H),2.42(t,J＝7.0Hz,2H),1.30(s,3H),0.69(t,J＝7.3Hz,3H).
13C NMR(126MHz,CDCl3)δ174.67,136.35,134.66,134.38,128.63,127.54,126.51,126.15,125.63,122.81,122.16,119.53,118.97,111.86,111.13,63.43,56.64,55.67,50.74,36.05,29.70,29.32,29.13,23.18,11.40.
ESI:m/z[M+H]+,calcd.for C25H33N4O:405.2576；found:
HPLC:0～20min(A:B＝80:20),tR＝3.800min,Purity:98.592％.
实施例6：化合物15的合成
参考实施例3
(R)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)-2-(异丁基氨基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.11(s,1H),7.71(d,J＝7.8Hz,1H),7.66(t,J＝4.0Hz,1H),7.37(d,J＝8.0Hz,1H),7.26–7.20(m,1H),7.18(d,J＝4.1Hz,1H),7.16(d,J＝1.8Hz,1H),7.15(s,1H),7.09–7.02(m,2H),3.79(t,J＝6.6Hz,1H),3.63(d,J＝3.9Hz,2H),3.52(ddd,J＝13.9,12.6,5.6Hz,2H),3.41(d,J＝4.3Hz,1H),2.96(dd,J＝13.9,8.4Hz,1H),2.88(t,J＝5.7Hz,2H),2.73(t,J＝5.4Hz,2H),2.63(t,J＝6.1Hz,2H),2.30–2.18(m,2H),1.93–1.87(m,1H),0.69(d,J＝1.9Hz,3H),0.67(d,J＝1.9Hz,3H).
13C NMR(126MHz,CDCl3)δ174.67,136.36,134.60,134.35,128.62,127.54,126.51,126.14,125.62,122.78,122.16,119.52,118.97,111.86,111.13,63.51,56.85,56.61,55.63,50.74,36.03,29.28,29.08,28.42,20.31,20.18.
ESI:m/z[M+H]+,calcd.for C26H35N4O:419.2733；found:
HPLC:0～20min(A:B＝80:20),tR＝4.525min,Purity:95.332％.
实施例7：化合物16的合成
参考实施例3
(R)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-2-((呋喃-2-基甲基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.08(s,1H),7.66(d,J＝7.7Hz,1H),7.57(s,1H),7.37(d,J＝8.1Hz,1H),7.31(s,1H),7.21–7.17(m,2H),7.15(s,3H),7.08(s,1H),7.00(s,1H),6.17(s,1H),5.97(s,1H),3.70(d,J＝14.5Hz,1H),3.65(s,2H),3.58–3.50(m,2H),3.48(d,J＝6.2Hz,2H),3.35–3.26(m,1H),3.01(dd,J＝14.4,8.8Hz,1H),2.86(d,J＝5.2Hz,2H),2.73(t,J＝5.6Hz,2H),2.62(t,J＝5.8Hz,2H).
13C NMR(126MHz,CDCl3)δ174.05,153.00,141.72,136.35,134.64,134.41,128.67,127.47,126.56,126.18,125.66,122.89,122.16,119.54,118.97,111.38,111.10,110.01,107.07,62.07,56.60,55.74,50.62,44.98,36.13,29.20,29.08.
ESI:m/z[M+H]+,calcd.for C27H31N4O:443.2369；found:
HPLC:0～20min(A:B＝80:20),tR＝12.742min,Purity:95.898％.
实施例8：化合物17的合成
参考实施例3。
(R)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)-2-((吡啶-4-基-乙基)氨基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.24(s,1H),8.13(dd,J＝4.5,1.4Hz,2H),7.63(d,J＝7.5Hz,2H),7.34(d,J＝8.1Hz,1H),7.21(d,J＝7.1Hz,1H),7.16(dd,J＝6.5,2.0Hz,2H),7.13(d,J＝4.5Hz,1H),7.09(d,J＝6.8Hz,2H),7.01(s,1H),3.75(t,J＝6.5Hz,2H),3.67(d,J＝14.3Hz,1H),3.58(s,2H),3.48(dd,J＝12.4,5.5Hz,2H),3.43(t,J＝3.8Hz,1H),2.97(dd,J＝14.4,9.0Hz,1H),2.77(d,J＝4.8Hz,2H),2.69–2.62(m,2H),2.58(t,J＝5.9Hz,2H).
13C NMR(126MHz,CDCl3)δ173.76,149.49,148.40,136.41,134.47,134.25,128.73,127.36,126.52,126.37,125.80,123.00,122.68,122.34,119.68,118.83,111.29,111.28,62.80,56.38,55.81,51.31,50.46,35.83,29.31,29.18.
ESI:m/z[M+H]+,calcd.for C28H32N5O:454.2529；found:454.2605
HPLC:0～20min(A:B＝80:20),tR＝5.803min,Purity:99.149％.
(S)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-3-(1H-吲哚-3-基)-2-((吡啶-4-基-乙基)氨基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.51(s,1H),7.87(d,J＝6.4Hz,2H),7.60(d,J＝7.9Hz,2H),7.41(d,J＝8.1Hz,1H),7.29–7.21(m,3H),7.17–7.12(m,2H),7.04(dd,J＝13.1,5.0Hz,5H),3.84–3.76(m,2H),3.66–3.57(m,4H),3.48–3.42(m,2H),3.40(t,J＝4.7Hz,1H),3.04–2.93(m,1H),2.79(t,J＝5.4Hz,2H),2.75–2.70(m,1H),2.66(d,J＝5.7Hz,2H).
ESI:m/z[M+H]+,calcd.for C28H32N5O:454.2529；found:454.2608
HPLC:0～20min(A:B＝80:20),tR＝5.913min,Purity:99.927％.
实施例9：化合物18的合成
参考实施例3。
(R)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.10(s,1H),7.72(t,J＝7.2Hz,2H),7.39(d,J＝8.0Hz,1H),7.32(s,1H),7.25(t,J＝7.5Hz,1H),7.18(dd,J＝4.7,3.2Hz,3H),7.07(dd,J＝12.1,3.8Hz,3H),3.69(d,J＝15.3Hz,2H),3.56(dd,J＝14.0,6.0Hz,1H),3.47(dd,J＝12.8,6.6Hz,1H),3.43–3.34(m,3H),3.03–2.95(m,1H),2.91(t,J＝6.6Hz,3H),2.75(t,J＝5.5Hz,2H),2.65(t,J＝6.1Hz,2H),2.35(d,J＝8.3Hz,3H),1.18–1.07(m,6H),0.70–0.59(m,7H).
13C NMR(126MHz,CDCl3)δ174.79,136.46,134.66,134.39,128.63,127.53,126.53,126.14,125.64,122.85,122.11,119.45,118.92,111.74,111.21,63.84,56.70,55.72,51.79,50.73,41.00,36.06,29.35,29.16,23.65,10.75.
ESI:m/z[M+H]+,calcd.for C28H39N4O:447.3046；found:447.3122
HPLC:0～20min(A:B＝80:20),tR＝6.318min,Purity:96.020％.
(S)-N-(2-(3,4-二氢异喹啉-2(1H)-基)乙基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.13(s,1H),7.73–7.62(m,2H),7.35(d,J＝8.0Hz,1H),7.26(s,1H),7.19(dd,J＝11.0,4.1Hz,1H),7.15–7.05(m,5H),6.97(d,J＝2.7Hz,3H),3.57(s,2H),3.42(tt,J＝11.3,5.7Hz,1H),3.35–3.31(m,1H),3.31–3.25(m,2H),2.92–2.87(m,2H),2.84(d,J＝10.2Hz,1H),2.67(dd,J＝9.1,3.7Hz,2H),2.51(td,J＝7.1,2.1Hz,2H),2.27(s,2H),1.80–1.70(m,3H),1.14–1.00(m,7H),0.69–0.58(m,8H).
13C NMR(75MHz,CDCl3)δ174.95,136.51,134.61,134.37,128.66,127.51,126.56,126.19,125.68,122.98,122.07,119.41,118.89,111.54,111.30,63.86,56.68,55.72,51.78,50.75,40.96,36.08,30.38,29.14,23.84,10.77.
ESI:m/z[M+H]+,calcd.for C28H39N4O:447.3046；found:447.3119
HPLC:0～20min(A:B＝80:20),tR＝6.388min,Purity:96.659％.
实施例10：化合物19的合成
参考实施例3。
(R)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)-N-(2-(1-甲基-3,4-二氢异喹啉-2(1H)-基)乙基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.03(d,J＝7.1Hz,1H),7.68(s,1H),7.66–7.57(m,1H),7.34(d,J＝8.0Hz,1H),7.19(t,J＝7.5Hz,1H),7.14–7.07(m,4H),7.04(d,J＝3.0Hz,1H),7.03(d,J＝3.2Hz,1H),3.77(p,J＝6.7Hz,1H),3.40(dd,J＝11.5,5.6Hz,2H),3.34(t,J＝3.5Hz,1H),3.30(dd,J＝7.4,4.2Hz,1H),3.07–2.96(m,1H),2.95–2.87(m,1H),2.86–2.76(m,1H),2.71–2.60(m,5H),2.35–2.26(m,3H),1.28(dd,J＝6.7,2.3Hz,4H),1.13–1.00(m,6H),0.60(tt,J＝14.2,7.2Hz,7H).
13C NMR(75MHz,CDCl3)δ174.70,140.06,136.43,134.09,128.83,127.55,127.37,125.89,125.68,122.80,122.16,119.49,118.95,111.82,111.18,63.82,56.61,52.45,51.77,43.29,40.96,36.40,30.35,27.37,23.81,19.53,10.68.
ESI:m/z[M+H]+,calcd.for C29H41N4O:461.3202；found:461.3278
HPLC:0～20min(A:B＝80:20),tR＝7.800min,Purity:97.311％.
实施例11：化合物20的合成
参考实施例3。
(R)-N-(3-(3,4-二氢异喹啉-2(1H)-基)丙基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.13(s,1H),7.73–7.62(m,2H),7.35(d,J＝8.0Hz,1H),7.26(s,1H),7.19(dd,J＝11.0,4.1Hz,1H),7.15–7.05(m,5H),6.97(d,J＝2.7Hz,3H),3.57(s,2H),3.42(tt,J＝11.3,5.7Hz,1H),3.35–3.31(m,1H),3.31–3.25(m,2H),2.92–2.87(m,2H),2.84(d,J＝10.2Hz,1H),2.67(dd,J＝9.1,3.7Hz,2H),2.51(td,J＝7.1,2.1Hz,2H),2.27(s,2H),1.80–1.70(m,3H),1.14–1.00(m,7H),0.69–0.58(m,8H).13C NMR(75MHz,CDCl3)δ174.77,136.47,134.64,134.31,128.64,127.51,126.57,126.17,125.66,122.87,122.14,119.50,118.91,111.71,111.24,63.83,56.43,51.56,50.99,40.71,37.90,30.36,29.35,29.08,26.73,23.78,10.71.
ESI:m/z[M+H]+,calcd.for C29H41N4O:461.3202；found:461.3284
HPLC:0～20min(A:B＝80:20),tR＝6.512min,Purity:95.712％.
实施例12：化合物21的合成
参考实施例3。
(R)-N-(4-(3,4-二氢异喹啉-2(1H)-基)丁基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.42(s,1H),7.77–7.69(m,1H),7.47(d,J＝4.5Hz,1H),7.41–7.32(m,3H),7.28–7.15(m,6H),7.06(dd,J＝12.1,3.8Hz,3H),3.66(d,J＝3.7Hz,3H),3.41–3.29(m,5H),3.03–2.90(m,4H),2.83–2.73(m,3H),2.56(d,J＝4.2Hz,3H),2.36(dd,J＝15.3,3.8Hz,3H),1.49(d,J＝4.9Hz,3H),1.32(d,J＝4.5Hz,3H),1.18(s,6H),0.73(dd,J＝13.3,5.8Hz,8H).
13C NMR(75MHz,CDCl3)δ174.81,136.59,134.66,134.26,128.71,127.53,126.65,126.24,125.70,125.57,123.08,122.03,119.37,118.77,111.36,63.85,57.88,56.14,51.62,50.93,40.86,38.85,30.38,29.75,29.35,29.05,27.67,24.47,23.90,23.69.
13C NMR(75MHz,CDCl3)δ174.81,136.59,134.66,134.26,128.71,127.53,126.65,126.24,125.70,125.57,123.08,122.03,119.37,118.77,111.36,63.85,57.88,56.14,50.93,40.86,38.85,30.38,29.75,29.05,27.67,24.47,23.90,10.80.
ESI:m/z[M+H]+,calcd.for C30H43N4O:475.3315；found:475.3440
HPLC:0～20min(A:B＝80:20),tR＝6.867min,Purity:98.125％.
实施例13：化合物22的合成
参考实施例3。
(R)-N-(4-(3,4-二氢异喹啉-2(1H)-基)丁基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.53(s,1H),7.72(d,J＝7.8Hz,1H),7.36(d,J＝9.0Hz,3H),7.23(t,J＝7.4Hz,1H),7.15(s,6H),7.08(s,3H),3.67(s,3H),3.39(d,J＝5.9Hz,1H),3.35(d,J＝4.2Hz,3H),3.32(s,2H),2.97(d,J＝7.2Hz,3H),2.95–2.90(m,2H),2.78(t,J＝5.0Hz,3H),2.54(t,J＝6.3Hz,3H),2.38(s,2H),1.48(d,J＝2.5Hz,8H),1.43(dd,J＝6.0,2.4Hz,3H),1.16(s,8H),0.79–0.66(m,9H).
13C NMR(75MHz,CDCl3)δ174.70,136.66,134.71,134.27,128.67,127.49,126.62,126.15,125.63,123.18,121.82,119.16,118.68,111.43,111.10,63.85,58.34,56.20,51.00,46.32,40.88,38.83,34.25,30.35,29.04,26.51,24.98,23.67,10.73.
ESI:m/z[M+H]+,calcd.for C31H45N4O:489.3515；found:489.3593
HPLC:0～20min(A:B＝80:20),tR＝7.609min,Purity:97.554％.
实施例14：化合物23的合成
步骤1：(2-乙基丁基)-D-色氨酸的合成
D-色氨酸(10mmol)溶于50mL无水乙醇，加入氢氧化钠(10.5mmol)以及2-乙基丁醛(1.5mmol),室温下搅拌2小时，加入硼氢化钠(15mmol)，继续搅拌2～3小时。真空除去大部分溶剂，调节PH＝5，析出大量白色固体，抽滤，滤饼烘干即得，收率96.1％。
1H NMR(300MHz,DMSO)δ10.92(s,1H),7.58(d,J＝7.8Hz,1H),7.36(d,J＝7.9Hz,1H),7.08(t,J＝7.4Hz,1H),6.99(t,J＝7.4Hz,1H),3.50–3.44(m,1H),3.26(dd,J＝14.9,5.2Hz,1H),3.05(dd,J＝14.9,7.8Hz,1H),2.59(dd,J＝12.0,6.9Hz,1H),2.50–2.43(m,1H),1.45–1.32(m,1H),1.32–1.15(m,4H),0.73(t,J＝7.2Hz,6H).
(2-乙基丁基)-L-色氨酸的合成同上步骤，收率92.5％。
步骤2：N-(叔丁氧羰基)-N’-(2-乙基丁基)-D-色氨酸的合成
2-(乙基丁基)-D-色氨酸(8mmol)溶于四氢呋喃：水＝1：1，加入三乙胺(20mmol)，缓慢滴加二碳酸二叔丁酯(20mmol)，室温搅拌过夜。调节PH＝5，乙酸乙酯萃取三次，真空除去溶剂，柱层析(二氯甲烷：甲醇＝100：1)得无色泡状物，收率81.5％。
1H NMR(300MHz,DMSO)δ10.90(s,1H),7.57(d,J＝7.8Hz,1H),7.37(d,J＝7.9Hz,1H),7.07(t,J＝7.4Hz,1H),6.98(t,J＝7.4Hz,1H),3.52–3.44(m,1H),3.20(dd,J＝14.9,5.2Hz,1H),3.06(dd,J＝14.9,7.8Hz,1H),2.58(dd,J＝12.0,6.9Hz,1H),2.50–2.43(m,1H),1.49(s,9H)，1.45–1.32(m,1H),1.32–1.18(m,4H),0.72(t,J＝7.2Hz,6H).
N-(叔丁氧羰基)-N’-(2-乙基丁基)-L-色氨酸的合成同上。
步骤3：叔丁基(R)-(1-((2-(氮杂环-1-基)乙基)氨基)-3-(6,7-二氢-1H-吲哚-3-基)-1-氧丙烷-2-基)(2-乙基丁基)氨基甲酸酯的合成
N-(叔丁氧羰基)-N’-(2-乙基丁基)-D-色氨酸(5mmol)溶于干燥的二氯甲烷，加入碳二亚胺盐酸盐(7.5mmol),1-羟基苯并三唑(7.5mmol),N,N-二异丙基乙胺(15mmol)，在冰浴下搅拌半小时，加入2-(氮杂环丙烷-1-基)乙烷-1-胺(6mmol)，室温下搅拌过夜。反应液分别使用水，饱和食盐水洗涤，无水硫酸钠干燥。真空除去溶剂，柱层析(二氯甲烷：甲醇＝80：1)得无色泡状物，收率70.5％。
1H NMR(300MHz,CDCl3)δ8.07(s,1H),7.66(s,1H),7.37(d,J＝7.8Hz,1H),7.20(t,J＝7.1Hz,2H),7.13(t,J＝7.4Hz,1H),7.04(s,1H),3.47(s,1H),3.33(s,3H),3.06(s,1H),2.63(s,8H),1.60(s,11H),1.48(s,12H),1.19(s,2H),1.13–1.02(m,2H),0.77(t,J＝7.0Hz,4H),0.67(s,3H).
叔丁基(S)-(1-((2-(氮杂环-1-基)乙基)氨基)-3-(6,7-二氢-1H-吲哚-3-基)-1-氧丙烷-2-基)(2-乙基丁基)氨基甲酸酯的合成同上。
步骤4：(R)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺的合成
叔丁基(R)-(1-((2-(氮杂环-1-基)乙基)氨基)-3-(6,7-二氢-1H-吲哚-3-基)-1-氧丙烷-2-基)(2-乙基丁基)氨基甲酸酯(0.5mmol)溶于乙酸乙酯的盐酸溶液(4N)，室温搅拌3～4小时。调节PH>9，乙酸乙酯萃取2次，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥。真空除去溶剂，柱层析(二氯甲烷：甲醇＝60：1)得无色油状物，收率70.8％。
1H NMR(300MHz,CDCl3)δ8.24(s,1H),7.69(d,J＝7.5Hz,1H),7.36(d,J＝8.0Hz,1H),7.22–7.16(m,1H),7.15–7.08(m,1H),7.06(d,J＝2.0Hz,1H),3.39–3.35(m,1H),3.34–3.30(m,2H),3.30–3.20(m,1H),2.91(dd,J＝15.1,10.1Hz,1H),2.55(dd,J＝12.3,5.9Hz,6H),2.42–2.26(m,2H),1.57(s,8H),1.20–1.06(m,5H),0.67(q,J＝7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C25H42N4O:415.3359；found:415.3371.
(S)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺的合成同上。
1H NMR(300MHz,CDCl3)δ8.22(s,1H),7.71(d,J＝7.5Hz,2H),7.38(d,J＝8.0Hz,1H),7.22(t,J＝7.0Hz,1H),7.15(dd,J＝10.9,4.0Hz,1H),7.08(d,J＝2.0Hz,1H),3.38(d,J＝1.5Hz,1H),3.34(d,J＝6.7Hz,2H),3.32–3.23(m,1H),2.93(dd,J＝15.1,10.1Hz,1H),2.57(dd,J＝12.3,6.0Hz,6H),2.36(q,J＝10.9Hz,2H),1.59(s,8H),1.22–1.09(m,5H),0.69(q,J＝7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C25H42N4O:415.3359；found:415.3371.
实施例15：化合物24的合成
参考实施例14。
(R)2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)-N-(2-(哌啶-1-基)乙基)丙胺
1H NMR(300MHz,CDCl3)δ8.30(d,J＝22.6Hz,1H),7.75(d,J＝7.8Hz,1H),7.69(s,1H),7.42(d,J＝8.0Hz,1H),7.25(t,J＝7.0Hz,1H),7.17(t,J＝7.0Hz,1H),7.12(d,J＝1.9Hz,1H),3.52–3.42(m,1H),3.42–3.37(m,2H),3.31(dd,J＝12.7,6.4Hz,1H),2.95(dt,J＝17.5,8.7Hz,1H),2.42(dd,J＝12.3,5.9Hz,8H),1.63–1.55(m,4H),1.48(d,J＝5.0Hz,2H),1.26–1.14(m,5H),0.73(dt,J＝10.8,7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C24H38N4O:399.3046；found:399.3055.
(S)2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)-N-(2-(哌啶-1-基)乙基)丙胺
1H NMR(300MHz,CDCl3)δ8.32(d,J＝22.6Hz,1H),7.75(d,J＝7.8Hz,1H),7.67(s,1H),7.40(d,J＝8.0Hz,1H),7.24(m,1H),7.18(m,1H),7.11(d,J＝1.7Hz,1H),3.40–3.32(m,1H),3.41–3.36(m,2H),3.30(dd,J＝12.1,6.5Hz,1H),2.98(dt,J＝15.1,8.7Hz,1H),2.46(dd,J＝12.5,5.7Hz,8H),1.61–1.55(m,4H),1.50(d,J＝5.0Hz,2H),1.25–1.14(m,5H),0.71(dt,J＝10.8,7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C24H38N4O:399.3046；found:398.3057.
实施例16：化合物25的合成
参考实施例14。
(R)N-(2-((二乙氨基)甲基)苄基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.09(s,1H),7.93(s,1H),7.63(d,J＝7.7Hz,1H),7.34(d,J＝6.9Hz,1H),7.31(d,J＝8.2Hz,1H),7.23(s,2H),7.16(t,J＝7.6Hz,1H),7.08(t,J＝7.4Hz,1H),6.91(s,1H),4.50(ddd,J＝35.3,14.2,6.0Hz,2H),3.60(d,J＝13.1Hz,1H),3.46(d,J＝13.0Hz,1H),3.33–3.21(m,2H),2.90(dd,J＝11.1,5.4Hz,1H),2.37(s,4H),2.34–2.21(m,2H),1.12–1.03(m,5H),0.95(t,J＝6.3Hz,6H),0.62(q,J＝6.8Hz,6H).
ESI:m/z[M+H]+,calcd.for C29H42N4O:463.3359；found:463.3363.
(S)N-(2-((二乙氨基)甲基)苄基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.08(s,1H),7.90(s,1H),7.62(d,J＝7.7Hz,1H),7.33(d,J＝6.9Hz,1H),7.30(d,J＝8.3Hz,1H),7.21(s,2H),7.15(t,J＝7.1Hz,1H),7.06(t,J＝7.0Hz,1H),6.91(s,1H),4.50(m,2H),3.62(d,J＝13.7Hz,1H),3.44(d,J＝13.0Hz,1H),3.30–3.20(m,2H),2.91(dd,J＝11.9,5.7Hz,1H),2.35(s,4H),2.35–2.21(m,2H),1.10–1.01(m,5H),0.93(t,J＝6.3Hz,6H),0.64(q,J＝6.5Hz,6H).
ESI:m/z[M+H]+,calcd.for C29H42N4O:463.3359；found:463.3365.
实施例17：化合物26的合成
参考实施例14。
(R)N-(2-((二乙氨基)甲基)苯乙基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.01(s,1H),7.85(s,1H),7.58(s,1H),7.40(s,1H),7.33(d,J＝8.2Hz,1H),7.20(s,2H),7.14(s,1H),7.08(m,1H),6.98(s,1H),3.60(d,J＝13.1Hz,1H),3.50(m,2H),3.46(d,J＝12.0Hz,1H),3.29–3.21(m,2H),2.80(dd,J＝11.1,5.4Hz,1H),2.37(m,2H),2.30(s,4H),2.25–2.20(m,2H),1.11–1.03(m,5H),0.99(t,J＝6.3Hz,6H),0.69(q,J＝6.8Hz,6H).
ESI:m/z[M+H]+,calcd.for C30H44N4O:477.3514；found:477.3524.
(S)N-(2-((二乙氨基)甲基)苯乙基)-2-((2-乙基丁基)氨基)-3-(1H-吲哚-3-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.00(s,1H),7.84(s,1H),7.59(s,1H),7.41(s,1H),7.32(d,J＝8.2Hz,1H),7.22(s,2H),7.13(s,1H),7.07(m,1H),6.96(s,1H),3.62(d,J＝13.1Hz,1H),3.52(m,2H),3.45(d,J＝12.1Hz,1H),3.29–3.20(m,2H),2.82(dd,J＝11.5,5.4Hz,1H),2.36(m,2H),2.31(s,4H),2.26–2.20(m,2H),1.12–1.03(m,5H),0.99(t,J＝6.3Hz,6H),0.68(q,J＝6.7Hz,6H).
ESI:m/z[M+H]+,calcd.for C30H44N4O:477.3514；found:477.3525.
实施例18：化合物27的合成
参考实施例14。
(R)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-(萘-2-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.01(s,1H),7.99-7.96(m,2H),7.84(d,J＝8.0Hz,1H),7.50–7.41(m,4H),3.71(m,1H),3.39–3.35(m,1H),3.34–3.30(m,2H),2.95(dd,J＝14.1,10.1Hz,1H),2.55(dd,J＝12.3,5.9Hz,6H),2.42–2.26(m,2H),1.57(s,8H),1.20–1.06(m,5H),0.67(q,J＝7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C27H41N3O:424.3250；found:424.3261.
(S)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-(萘-2-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.00(s,1H),7.96-7.93(m,2H),7.82(d,J＝8.3Hz,1H),7.51–7.43(m,4H),3.72(m,1H),3.38–3.35(m,1H),3.34–3.31(m,2H),2.93(dd,J＝14.1,10.1Hz,1H),2.57(dd,J＝12.5,5.9Hz,6H),2.40–2.28(m,2H),1.56(s,8H),1.21–1.06(m,5H),0.69(q,J＝7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C27H41N3O:424.3250；found:424.3260.
实施例19：化合物28的合成
参考实施例14。
(R)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-(喹啉-6-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.81(d,J＝8.3Hz,1H),8.01(s,1H),7.96-7.93(m,2H),7.82(d,J＝8.0Hz,1H),7.51(m,2H),3.72(m,1H),3.38–3.35(m,1H),3.34–3.31(m,2H),2.99(m,1H),2.57(dd,J＝12.5,5.9Hz,6H),2.40–2.28(m,2H),1.56(s,8H),1.21–1.06(m,5H),0.69(q,J＝7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C27H41N4O:425.3202；found:425.3209.
(S)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-(喹啉-6-基)丙酰胺
1H NMR(300MHz,CDCl3)δ8.82(d,J＝8.2Hz,1H),8.00(s,1H),7.97-7.93(m,2H),7.83(d,J＝8.0Hz,1H),7.50(m,2H),3.73(m,1H),3.39–3.35(m,1H),3.35–3.31(m,2H),2.97(m,1H),2.56(dd,J＝12.1,5.8Hz,6H),2.40–2.30(m,2H),1.58(s,8H),1.21–1.07(m,5H),0.68(q,J＝7.2Hz,6H).
ESI:m/z[M+H]+,calcd.for C27H41N4O:425.3202；found:425.3208.
实施例20：化合物29的合成
参考实施例14。
(R)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-苯丙酰胺
1H NMR(300MHz,CDCl3)δ8.05(s,1H),7.19-7.14(m,5H),3.76(m,1H),3.42–3.33(m,1H),3.30–3.21(m,2H),2.97(m,1H),2.50(dd,J＝12.4,5.9Hz,6H),2.45–2.31(m,2H),1.57(s,8H),1.21–1.06(m,5H),0.69(q,J＝7.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C23H39N3O:373.3093；found:373.3099.
(S)N-(2-(氮杂环丙烷-1-基)乙基)-2-(2-乙基丁基)氨基)-3-苯丙酰胺
1H NMR(300MHz,CDCl3)δ8.04(s,1H),7.18-7.14(m,5H),3.75(m,1H),3.41–3.32(m,1H),3.31–3.22(m,2H),2.98(m,1H),2.51(dd,J＝12.4,5.5Hz,6H),2.44–2.30(m,2H),1.56(s,8H),1.21–1.06(m,5H),0.71(q,J＝6.1Hz,6H).
ESI:m/z[M+H]+,calcd.for C23H39N3O:373.3093；found:373.3099.
实施例21：化合物的胆碱酯酶抑制活性
药品与试剂：实施例6-18制得的化合物、AChE(E.C.3.1.1.7，Type VI-S，选自电鳗)、BuChE(E.C.3.1.1.8，选自马血清)、5,5’-二硫双(2-硝基苯甲酸)(DTNB)、乙酰硫代胆碱(ATC)碘化物以及丁酰硫代胆碱(BTC)碘化物均购于西格玛公司；他克林由本实验室合成(纯度＞95％)。
仪器：THERMO Varioskan Flash全波长多功能酶标仪。
实验方法：
(1)配制缓冲液：13.6g磷酸二氢钾溶于1L水中，以氢氧化钾调节pH＝8±0.1。溶液于4℃保存，备用。
(2)配制0.01M DTNB溶液：将0.396g DTNB及0.15g碳酸氢钠溶于100mL水中制得0.01M DTNB溶液，于-20℃保存，备用。
(3)配制0.075M ATC、BTC溶液：将0.217g ATC溶于10mL水中制得0.075M ATC及BTC溶液，于-20℃保存，备用；将0.237g BTC溶于10mL水中制得0.075M BTC溶液，于-20℃保存，备用。
(4)配制AChE、BuChE溶液：将5000单位的AChE溶于1mL 1％的凝胶溶液中，然后用水稀释至100mL制得浓度为5单位/mL的AChE溶液，于-20℃保存，备用；将5000单位的BuChE溶于1mL 1％的凝胶溶液中，然后用水稀释至100mL制得浓度为5单位/mL的BuChE溶液，于-30℃保存，备用。
(5)配制受试物溶液：将受试化合物溶于乙醇中以制得浓度为10-3M的溶液(乙醇不影响测试结果)，然后用水稀释分别制得浓度为10-4、10-5、10-6、10-7、10-8、10-9M的溶液。
实验开始前，所用溶液均加温至室温，并将AChE，BuChE溶液用水稀释一倍制成浓度为2.5单位/mL的酶溶液。用空白缓冲液(3mL)测得背景紫外吸收。先将100μL受试化合物溶液、100μL DTNB溶液、100μL酶溶液加至3mL缓冲液中，加入20μL ATC或BTC溶液触发反应后立即计时并同时快速混匀测试溶液，2min后于412nM波长下测量紫外吸收度。空白对照组用等容积的水代替受试物溶液测得。所有测试均平行操作三次。以空白对照组的紫外吸收值作为100％，记录受试化合物在各个浓度下的吸光度(OD值)，所得结果用GraphPadPrismTM(GraphPad Software,San Diego,CA,USA)软件以非线性衰退分析模式(non-linear regression analysis model)计算得相应的IC50值，如表1所示。
表1化合物的胆碱酯酶抑制活性
aμM or inhibitory rate at 100μM or IC50(μM).
结果分析：测试化合物及其光学异构体对BuChE具有抑制活性(eqBChE:0.04μM～5.4μM；hBChE:IC50 0.033μM～20.0μM)，而且这些化合物没有AChE抑制活性(IC50＞8μM)，说明它们是选择性很好的BuChE抑制剂。
实施例22：化合物的体外血脑屏障渗透试验
药品与试剂：96孔UV板(#3635，Corning)，Multiscreen Permeability FilterPlate(0.4μm，#MPC4NTR10，Millipore)，脑磷脂(#141101P，Avanti)。
仪器：Varioskan Flash多功能酶标仪(ThermoFisher公司)。
实验方法：
(1)化合物溶液的配置：用DMSO将待测化合物配制成5mg/mL的母液，使用PBS：无水乙醇＝7:3的溶液稀释为100μg/mL的化合物储备液。将孕酮、维拉帕米、氯丙嗪、吡罗昔康、氢化可的松及β-雌二醇标准品作为阳性化合物，重复操作配得阳性药储备液。使用同样方法配置不加化合物的空白组。
(2)脑磷脂溶液的配置：用正十二烷将脑磷脂配制成20mg/mL的溶液。
在受体板中加入200μL空白组溶液，在供体板底部中小心加入4μL的脑磷脂溶液，使其均匀覆盖在供体板底，随后迅速在供体板中加入200μL的给药组溶液，把供体板放于受体板上，使人工膜与缓冲溶液接触，每个化合物测试三个复孔，于室温下静置18小时。取下供体板，分别吸取供体板与受体板中的溶液50μL至96孔UV板，于235nm、245nm、255nm、265nm以及275nm波长下读吸光度数值。分别计算5个波长下6个阳性化合物的Pe值，并与文献报道标准数值进行对比，选取拟合程度最佳的波长作为最终标准，选取该波长的给药组数据进行计算，并评价化合物的透膜性。Pe值的计算公式如下：
其中，CD和CA分别为供体板和受体板吸光度，Ceq为平衡浓度，A指0.337cm2的滤膜面积，VD和VA分别为供体板和受体板内反应液体积0.2mL，t指反应时间64800s。结果如表2所示。
表2化合物的体外血脑屏障渗透性
aRanges of permeability of PAMPA-BBB assays(Pe×10-6cm/s).
Compounds of high BBB permeation(CNS+)Pe>5.94
Compounds of uncertain BBB permeation(CNS+/-)5.94>Pe>3.07
Compounds of low BBB permeation(CNS-)Pe<3.07
bValues are expressed as the mean±SD of three independentexperiments.
结果分析：测试化合物及其光学异构体的Pe值均达到高血脑屏障渗透水平，说明它们能够有效到达病灶，发挥药效。
实施例23：化合物的MTT实验
药品与试剂：3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)(购自阿拉丁)。
仪器：THERMO Varioskan Flash全波长多功能酶标仪。
实验方法：将靶细胞(5×103，体积为0.1mL)置于96孔平底培养板中，使细胞在37℃下粘附于板的底部过夜。用各种浓度的化合物处理细胞24小时。孔中加入MTT试剂，将板在37℃下孵育4小时。在孔中加入0.1mL裂解缓冲液破坏细胞。孵化后将它们在37℃再保持24小时，使用酶标仪在570nm测量显色反应。所有组平行3次进行。实验结果如图1所示。
结果分析：所有化合物在10、20和40μM的浓度下均显示出安全性。化合物18(R)和18(S)的细胞毒作用无显著差异。当剂量达到80μM时，大多数化合物显示出轻微的细胞毒性。这些结果表明我们获得的所有这些抑制剂几乎都是无毒的，具有开发为药物的前景。
实施例24：化合物对Aβ1-42诱导的SH-SY5Y细胞损伤的神经保护作用
药品与试剂：3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑溴化物(MTT)(购自阿拉丁)。
仪器：THERMO Varioskan Flash全波长多功能酶标仪。
实验方法：将靶细胞(5×103，体积为0.1mL)置于96孔平底培养板中，使细胞在37℃下粘附于板的底部过夜。用各种浓度的化合物处理细胞24小时。孔中加入MTT试剂，将板在37℃下孵育4小时。在孔中加入0.1ml裂解缓冲液破坏细胞。孵化后将它们在37℃再保持24小时，使用酶标仪在570nm测量显色反应。
结果分析：鉴于化合物18(R)和22(R)显示出最优的BChE抑制活性并且有效抑制Aβ1-42自介导的聚集；进一步使用MTT法对Aβ1-42诱导的SH-SY5Y细胞损伤的神经保护作用。如图2所示，当SH-SY5Y细胞暴露于15μM Aβ1-42时，与未处理组相比，细胞活力急剧下降至45.7％(####，P<0.0001)。当用18(R)和22(R)处理时，增加了细胞活力。在相同条件下，分别为20μM化合物18(R)和22(R)，细胞活力分别增加至73.4％(p＜0.001)和63.0％(p＜0.01)。因此，结果表明化合物18(R)和22(R)对Aβ1-42诱导的SH-SY5Y细胞损伤表现出良好的神经保护作用。
实施例25：水迷宫实验
药品与试剂：化合物18、Aβ自碧云天公司(上海)，他克林(纯度＞95％)。
仪器：Panlab SMART 3.0行为学视频分析仪。
动物：成年雄性ICR小鼠(8-10周，体重18-22克)购自扬州大学医学中心。
实验方法：将40只小鼠随机分成5个亚组(每组8只小鼠)：(i)为空白对照组，(ii)假手术组，(iii)脑内注射Aβ为模型组，(iv)多奈哌齐加Aβ作为阳性对照和(v)化合物18(10mg/kg)加Aβ作为试验组。
圆形水池(直径120厘米，高60厘米)中固定一个逃生平台(直径10厘米)，并填充40厘米深的淡水(保持在25℃)构成水迷宫。置于一个明亮的房间里。在学习和记忆训练5天后，在第6天进行探针试验。为了评估认知功能，每只小鼠在可见平台(用小旗标记，5cm高)上单独训练2天，第3天到第5天在隐藏平台(放置在水面下1cm)的水迷宫训练。所有小鼠每天进行2次训练试验，每次试验持续90秒。记录每只小鼠找到平台的时间(成功逃脱)。如果鼠标在90秒内未能到达平台，则终止测试并用手小心地将鼠标放置到平台。无论是成功与否，每只鼠标都将在平台上保持30秒。在最后一天(第6天)，从池中取出平台，对小鼠进行试验，允许每只小鼠90秒以搜索平台。记录小鼠到达失踪平台位置的时间和轨迹。实验结果如图3-图5所示。
结果分析：如图3所示在进行第一天的Aβ脑内微量注射后，尽管模型组在第三天表现出了体重下降的趋势，但是随后体重增长趋于平稳，表明手术并未对小鼠造成明显的身体机能损伤。给药组18(R)与对照组相比，体重增长相当甚至略高，表明给药的安全性。如图4所示，对照组和假手术组在目标逃逸潜伏期(ELT)上没有显着差异，这表明手术不会影响小鼠的被动回避障碍。Morris水迷宫测试的结果表明，与假手术动物组相比，模型组ELT显著延长(图4，P＜0.0001，####)，表明其学习和记忆受损，造模是成功的。18(R)和多奈哌齐的处理组表现出ELT的显著降低(图4，分别为P＜0.0001和P＜0.01)。结果还表明，与测试剂量的多奈哌齐相比，18(R)对小鼠记忆和认知功能的改善效果更优，这可能归因于具有多功能的抗AD活性。图5为各组小鼠的代表性轨迹图，模型组小鼠的轨迹相对于空白组明显更长更混乱。
Claims (10)
1.一种芳香氨基酸类化合物，其特征在于，具有式I的结构，所述化合物包含其异构体、药学上可接受的盐或它们的混合物：
其中：
n＝0～4；
A环选自6～10元芳环或6～10元芳杂环；
B环选自6～10元杂环或6～10元芳环，所述环系被一个或多个氢、C1～C3烷基或C1～C3烷氨基取代；
R1选自一个或多个氢、C1～C6烷基或5～6元芳杂环；R1NH基团所连接的手性原子构型为R、S或消旋体。
2.根据权利要求1所述的芳香氨基酸类化合物，其特征在于，所述结构中：
A环选自6元或10元芳环或者9～10元含氮芳杂环；
B环选自6～10元含氮杂环或苯环，所述环系被一个或多个氢、C1～C3烷基或C1～C3烷氨基取代；
R1选自一个或多个氢、C1～C6烷基或者5～6元含氮或氧的芳杂环；R1NH基团所连接的手性原子构型为R、S或消旋体。
3.根据权利要求1或2所述的芳香氨基酸类化合物，其特征在于，所述结构中：
A环选自：
B环选自：
R1选自：
4.根据权利要求1或2所述的芳香氨基酸类化合物，其特征在于，所述化合物选自以下任一化合物：
5.根据权利要求1或2所述的芳香氨基酸类化合物，其特征在于，所述药学上可接受的盐为所述化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸。
6.一种权利要求1～5任一所述的芳香氨基酸类化合物的制备方法，其特征在于，所述制备方法为：
(1)B环选自时，
化合物1经取代、还原、酰化、脱保护、取代反应得到化合物I；
(2)当B环选自时，
化合物6经取代、保护、酰化、脱保护反应得到化合物I；
其中，n、A环、R1、R2的定义如权利要求1～4任一所述；
将相应的酸与以上方法制备的化合物I成盐，即得所述芳香氨基酸类化合物的药学上可接受的盐。
7.一种药物组合物，其特征在于，所述药物组合物包含权利要求1～5任一所述的芳香氨基酸类化合物以及药学上可接受的载体。
8.一种权利要求1～5任一所述的芳香氨基酸类化合物或者权利要求7所述的药物组合物在制备丁酰胆碱酯酶抑制剂药物中的应用。
9.根据权利要8所述的应用，其特征在于，所述药物用于治疗神经退行性疾病。
10.根据权利要9所述的应用，其特征在于，所述神经退行性疾病为阿尔茨海默症。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210230885.9A CN116768855A (zh) | 2022-03-09 | 2022-03-09 | 芳香氨基酸类化合物及其制备方法、药物组合物和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210230885.9A CN116768855A (zh) | 2022-03-09 | 2022-03-09 | 芳香氨基酸类化合物及其制备方法、药物组合物和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116768855A true CN116768855A (zh) | 2023-09-19 |
Family
ID=87986542
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210230885.9A Pending CN116768855A (zh) | 2022-03-09 | 2022-03-09 | 芳香氨基酸类化合物及其制备方法、药物组合物和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116768855A (zh) |
-
2022
- 2022-03-09 CN CN202210230885.9A patent/CN116768855A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6936796B2 (ja) | ヒストンデアセチラーゼのヘテロハロ阻害剤 | |
| Lan et al. | Design, synthesis and evaluation of novel tacrine-(β-carboline) hybrids as multifunctional agents for the treatment of Alzheimer’s disease | |
| RU2351596C2 (ru) | Производные n-[гетероарил(пиперидин-2-ил)метил]бензамида и их применение в терапии | |
| RU2722179C2 (ru) | Лечение состояний, ассоциированных с гиперинсулинемией | |
| CA2729275A1 (en) | 5- and 6-membered heterocyclic compounds | |
| JP2000516252A (ja) | １，４―複素環式メタロプロテアーゼ阻害剤 | |
| SG191097A1 (en) | 5,6-DIHYDRO-IMIDAZO[1,2-a]PYRAZIN-8-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE) | |
| US10781202B2 (en) | Azetidinyloxyphenylpyrrolidine compounds | |
| Lu et al. | Investigation of multi-target-directed ligands (MTDLs) with butyrylcholinesterase (BuChE) and indoleamine 2, 3-dioxygenase 1 (IDO1) inhibition: The design, synthesis of miconazole analogues targeting Alzheimer’s disease | |
| US11420950B2 (en) | Heterocyclicalkyl derivative compounds as selective histone deacetylase inhibitors and pharmaceutical compositions comprising the same | |
| JP6521995B2 (ja) | 選択的マトリックスメタロプロテイナーゼ阻害剤 | |
| US20150166448A1 (en) | Substituted Tropolone Derivatives and Methods of Use | |
| CN114181207B (zh) | β-咔波啉类化合物及其制备方法和抗阿尔兹海默病的应用 | |
| KR20000057488A (ko) | 헤테로고리형 티오에스테르의 ｎ-링크된 요소 및 카르바메이트 | |
| CN110627767B (zh) | 选择性丁酰胆碱酯酶抑制剂或其可药用的盐、其制备方法及用途 | |
| US7999000B2 (en) | N-(2-amino-phenyl)-acrylamides | |
| EP2733144B1 (en) | Novel compound having parp inhibitory activity | |
| JP2003514893A (ja) | 複素環式ケトンおよびチオエステル化合物、およびそれらの使用 | |
| EP2727916A1 (en) | Neuroprotective multi-target directed drugs | |
| CN116768855A (zh) | 芳香氨基酸类化合物及其制备方法、药物组合物和应用 | |
| US7910739B2 (en) | Acetylcholinesterase dual inhibitors | |
| WO2001077078A1 (en) | Novel pyridones and their use as modulators of serine hydrolase enzymes | |
| CN112920178A (zh) | 具有苯并咪唑结构的化合物及其制备方法与用途 | |
| US20230041334A1 (en) | Methods and compositions for smoking cessation | |
| EP3268357A1 (en) | Enantiomers of 8-hydroxy quinoline derivatives and the synthesis thereof |
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 |