CN110407770A - 3-取代-1,5-苯并氮杂*类化合物及其药物用途 - Google Patents
3-取代-1,5-苯并氮杂*类化合物及其药物用途 Download PDFInfo
- Publication number
- CN110407770A CN110407770A CN201810391788.1A CN201810391788A CN110407770A CN 110407770 A CN110407770 A CN 110407770A CN 201810391788 A CN201810391788 A CN 201810391788A CN 110407770 A CN110407770 A CN 110407770A
- Authority
- CN
- China
- Prior art keywords
- cancer
- compound
- preparation
- formula
- benzo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 51
- 238000006467 substitution reaction Methods 0.000 title abstract 2
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 14
- 230000002159 abnormal effect Effects 0.000 claims abstract description 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 10
- 230000001575 pathological effect Effects 0.000 claims abstract description 9
- 208000001145 Metabolic Syndrome Diseases 0.000 claims abstract description 7
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims abstract description 5
- 201000011510 cancer Diseases 0.000 claims abstract description 5
- 230000002265 prevention Effects 0.000 claims abstract 2
- 238000002360 preparation method Methods 0.000 claims description 72
- 102000001267 GSK3 Human genes 0.000 claims description 33
- 108060006662 GSK3 Proteins 0.000 claims description 33
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 claims description 33
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical class N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
- 125000003884 phenylalkyl group Chemical group 0.000 claims description 8
- 208000024827 Alzheimer disease Diseases 0.000 claims description 7
- 208000012902 Nervous system disease Diseases 0.000 claims description 6
- 208000025966 Neurological disease Diseases 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 150000007942 carboxylates Chemical class 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052757 nitrogen Chemical group 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 201000002212 progressive supranuclear palsy Diseases 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 239000011593 sulfur Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 206010061218 Inflammation Diseases 0.000 claims description 3
- 230000004054 inflammatory process Effects 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010006187 Breast cancer Diseases 0.000 claims description 2
- 208000026310 Breast neoplasm Diseases 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 2
- 201000001342 Fallopian tube cancer Diseases 0.000 claims description 2
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 2
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 2
- 208000032612 Glial tumor Diseases 0.000 claims description 2
- 206010018338 Glioma Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 208000003445 Mouth Neoplasms Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 206010068871 Myotonic dystrophy Diseases 0.000 claims description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 claims description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 claims description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 208000018737 Parkinson disease Diseases 0.000 claims description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 2
- 206010060862 Prostate cancer Diseases 0.000 claims description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 2
- 208000029560 autism spectrum disease Diseases 0.000 claims description 2
- 201000010881 cervical cancer Diseases 0.000 claims description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 2
- 201000004101 esophageal cancer Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 201000008968 osteosarcoma Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000007170 pathology Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 23
- 239000003814 drug Substances 0.000 abstract description 11
- 108091000080 Phosphotransferase Proteins 0.000 abstract description 5
- 102000020233 phosphotransferase Human genes 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 229920002527 Glycogen Polymers 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 229940096919 glycogen Drugs 0.000 abstract description 3
- 230000001537 neural effect Effects 0.000 abstract description 3
- 238000005516 engineering process Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 54
- -1 3-substituted benzazepines Chemical class 0.000 description 45
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 31
- 238000005160 1H NMR spectroscopy Methods 0.000 description 27
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 20
- 239000005711 Benzoic acid Substances 0.000 description 18
- 235000010233 benzoic acid Nutrition 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 13
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 11
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 230000009471 action Effects 0.000 description 9
- 230000002860 competitive effect Effects 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 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 6
- OZDCZHDOIBUGAJ-UHFFFAOYSA-N 4-(trifluoromethyl)benzenesulfonyl chloride Chemical compound FC(F)(F)C1=CC=C(S(Cl)(=O)=O)C=C1 OZDCZHDOIBUGAJ-UHFFFAOYSA-N 0.000 description 6
- ILUJQPXNXACGAN-UHFFFAOYSA-N O-methylsalicylic acid Chemical group COC1=CC=CC=C1C(O)=O ILUJQPXNXACGAN-UHFFFAOYSA-N 0.000 description 6
- 229940125797 compound 12 Drugs 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical group N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- ATVFTGTXIUDKIZ-YFKPBYRVSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-sulfanylpropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CS)C(O)=O ATVFTGTXIUDKIZ-YFKPBYRVSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 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 5
- 229940126086 compound 21 Drugs 0.000 description 5
- 238000007865 diluting Methods 0.000 description 5
- DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- OXOWWPXTTOCKKU-UHFFFAOYSA-N 2-propoxybenzoic acid Chemical compound CCCOC1=CC=CC=C1C(O)=O OXOWWPXTTOCKKU-UHFFFAOYSA-N 0.000 description 4
- 229940126639 Compound 33 Drugs 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- APEJMQOBVMLION-UHFFFAOYSA-N cinnamamide Chemical compound NC(=O)C=CC1=CC=CC=C1 APEJMQOBVMLION-UHFFFAOYSA-N 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 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 4
- BXPNIFICXLSCDW-JTQLQIEISA-N (2s)-3-(2-aminophenoxy)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)COC1=CC=CC=C1N BXPNIFICXLSCDW-JTQLQIEISA-N 0.000 description 3
- FHOAKXBXYSJBGX-YFKPBYRVSA-N (2s)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](CO)C(O)=O FHOAKXBXYSJBGX-YFKPBYRVSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 230000004155 insulin signaling pathway Effects 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 102000013498 tau Proteins Human genes 0.000 description 3
- 108010026424 tau Proteins Proteins 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- PMDFZPHGVXNDOE-VIFPVBQESA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(2-nitrophenoxy)propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)COC1=CC=CC=C1[N+]([O-])=O PMDFZPHGVXNDOE-VIFPVBQESA-N 0.000 description 2
- HXBMIQJOSHZCFX-UHFFFAOYSA-N 1-(bromomethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CBr HXBMIQJOSHZCFX-UHFFFAOYSA-N 0.000 description 2
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical group OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 108010001483 Glycogen Synthase Proteins 0.000 description 2
- 239000004201 L-cysteine Substances 0.000 description 2
- 235000013878 L-cysteine Nutrition 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- JDSJDASOXWCHPN-UHFFFAOYSA-N TDZD-8 Chemical compound O=C1N(C)SC(=O)N1CC1=CC=CC=C1 JDSJDASOXWCHPN-UHFFFAOYSA-N 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940127573 compound 38 Drugs 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 101150090422 gsk-3 gene Proteins 0.000 description 2
- 230000006951 hyperphosphorylation Effects 0.000 description 2
- 238000013507 mapping Methods 0.000 description 2
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 229960003424 phenylacetic acid Drugs 0.000 description 2
- 239000003279 phenylacetic acid Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 2
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- XDZMPRGFOOFSBL-UHFFFAOYSA-N 2-ethoxybenzoic acid Chemical compound CCOC1=CC=CC=C1C(O)=O XDZMPRGFOOFSBL-UHFFFAOYSA-N 0.000 description 1
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 4-chlorobenzenesulfonyl chloride Chemical compound ClC1=CC=C(S(Cl)(=O)=O)C=C1 ZLYBFBAHAQEEQQ-UHFFFAOYSA-N 0.000 description 1
- ZEYHEAKUIGZSGI-UHFFFAOYSA-N 4-methoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C=C1 ZEYHEAKUIGZSGI-UHFFFAOYSA-N 0.000 description 1
- REIDAMBAPLIATC-UHFFFAOYSA-M 4-methoxycarbonylbenzoate Chemical compound COC(=O)C1=CC=C(C([O-])=O)C=C1 REIDAMBAPLIATC-UHFFFAOYSA-M 0.000 description 1
- REIDAMBAPLIATC-UHFFFAOYSA-N 4-methoxycarbonylbenzoic acid Chemical compound COC(=O)C1=CC=C(C(O)=O)C=C1 REIDAMBAPLIATC-UHFFFAOYSA-N 0.000 description 1
- ALBQXDHCMLLQMB-UHFFFAOYSA-N 4-phenylbenzenesulfonyl chloride Chemical compound C1=CC(S(=O)(=O)Cl)=CC=C1C1=CC=CC=C1 ALBQXDHCMLLQMB-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 208000017194 Affective disease Diseases 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- XUJNEKJLAYXESH-UWTATZPHSA-N D-Cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 description 1
- 229930195710 D‐cysteine Natural products 0.000 description 1
- 102100030013 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 1
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 1
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 1
- 101001077604 Homo sapiens Insulin receptor substrate 1 Proteins 0.000 description 1
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
- 101000911513 Homo sapiens Uncharacterized protein FAM215A Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102100036721 Insulin receptor Human genes 0.000 description 1
- 102100025087 Insulin receptor substrate 1 Human genes 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 102100023132 Transcription factor Jun Human genes 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- 102100026728 Uncharacterized protein FAM215A Human genes 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 235000019270 ammonium chloride Nutrition 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
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 210000003050 axon Anatomy 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000002457 bidirectional effect Effects 0.000 description 1
- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical compound C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical class O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 230000016273 neuron death Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- OAHKWDDSKCRNFE-UHFFFAOYSA-N phenylmethanesulfonyl chloride Chemical compound ClS(=O)(=O)CC1=CC=CC=C1 OAHKWDDSKCRNFE-UHFFFAOYSA-N 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- DSNYFFJTZPIKFZ-UHFFFAOYSA-N propoxybenzene Chemical group CCCOC1=CC=CC=C1 DSNYFFJTZPIKFZ-UHFFFAOYSA-N 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical group O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229960001153 serine Drugs 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- WOZVHXUHUFLZGK-UHFFFAOYSA-N terephthalic acid dimethyl ester Natural products COC(=O)C1=CC=C(C(=O)OC)C=C1 WOZVHXUHUFLZGK-UHFFFAOYSA-N 0.000 description 1
- VNNLHYZDXIBHKZ-UHFFFAOYSA-N thiophene-2-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CS1 VNNLHYZDXIBHKZ-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000717 tumor promoter 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域，涉及式Ⅰ结构通式的3‑取代‑1,5‑苯并氮杂酮类化合物及其在医药上的应用。该类3‑取代‑1,5‑苯并氮杂类化合物能选择性地抑制糖原合成激酶‑3β(GSK 3β)的活性，可用于制备预防和/或治疗具有GSK 3β异常病理特征的疾病的药物，所述疾病包括癌症、神经类疾病、代谢综合症等。
Description
技术领域
本发明属于医药技术领域，涉及一类新的式Ⅰ结构的3-取代-1,5-苯并氮杂酮类化合物及其在医药上的应用。该类3-取代苯并氮杂类化合物能选择性地抑制糖原合成激酶-3β(GSK 3β)的活性，可用于制备预防和/或治疗具有GSK 3β异常病理特征的疾病的药物，所述疾病包括癌症、神经类疾病、代谢综合症等。
背景技术
现有技术公开了糖原合成激酶-3β(Glycogen synthase kinase-3β，GSK-3β)是一种多功能的丝氨酸/苏氨酸蛋白激酶，能够磷酸化糖原合成酶并使其失活。研究表明，GSK-3β能够磷酸化多种底物蛋白，参与体内多个重要信号传导通路，包括胰岛素信号通路、Wnt信号通路和NF-κB信号通路等，在调控细胞的分化、代谢、凋亡以及基因表达等方面都起着重要作用，与II型糖尿病、阿尔茨海默病、肿瘤、中风、双向情感障碍和炎症等疾病的发生发展密切相关；因此，GSK3β是一个重要的药物新靶标。
研究表明，在胰岛素信号通路中，胰岛素通过抑制GSK 3的活性从而促进糖原合成酶的去磷酸化和糖原的合成，因此作用于GSK 3的小分子抑制剂可以模拟胰岛素作用，促进葡萄糖向糖原的转化，并且可以克服因胰岛素信号通路受阻引起的胰岛素耐受。另有研究发现，II型糖尿病患者的GSK 3的蛋白表达和活性高于正常水平，且活性异常的GSK 3引起胰岛素受体IRS1磷酸化和活性抑制，导致胰岛素信号通路异常(Eldar-Finkelman H,etal.,Diabetes 48(1999)1662-1666.Nikoulina SE,et al.,Diabetes 49(2000)263-271.Eldar-Finkelman H,et al.,Proc Natl Acad Sci U.S.A.94(1997)9660-9664)，因此，GSK 3β已成为潜在的糖尿病治疗靶标。
研究显示GSK 3β在阿尔兹海默病的发生发展进程中起关键的调控作用，其抑制剂也可应用于治疗阿尔兹海默病。尽管自阿尔兹海默病的发现已过去一个世纪，但其具体成因尚不明确；目前最为流行的病因假说为，不溶性β-淀粉样肽(Aβ)的聚集形成的老年斑块干扰了神经元突触间的联系，导致神经元死亡；AD的另一典型病理特征为Tau蛋白过度磷酸化后形成的神经元纤维缠结(NFT)；GSK 3β几乎存在于所有组织中，在脑组织中尤为丰富，GSK 3β能够磷酸化tau蛋白，很可能在Aβ引起的神经元损伤和NFT形成中扮演重要角色(YanMH,et al.,J.Alzheimers Dis.9(2006)309-317)；在PI3K/Akt信号通路中，Aβ抑制PI3K/Akt的活性，导致GSK 3β被激活，活性异常的GSK 3β继而引起tau蛋白的过度磷酸化，最终导致神经元受损和神经纤维结的形成，与此同时GSK3β的激活导致驱动蛋白磷酸化而失活，轴突转运蛋白能力受阻，导致神经元细胞损伤。
研究显示GSK 3β在细胞周期、细胞凋亡、细胞增殖和胚胎发育等过程中扮演重要角色，GSK 3β通过磷酸化信号转录因子如c-Myc、c-Jun、p53，参与NF-κB信号通路，并影响凋亡相关蛋白Bcl-2和Bax以及周期相关蛋白cyclinD1等表达，影响细胞的生存和增殖，这种情况下GSK 3发挥肿瘤促进剂的作用(Beurel E,et al.,Prog.Neurobiol.79(2006)173-189,McCubrey JA,et al.,Adv.Biol.Regul.54(2014)176-196)。研究发现，GSK 3在一些实体瘤，如结肠癌，肝癌，卵巢癌和胰腺癌中过度表达，抑制GSK 3的活性将会减缓这几类肿瘤的发展进程(Sharkoori A,et al.,Biochem Biophys Res Commun.334(2005)1365-1373,Wang Z,et al.,Nature 455(2008)1205-1210,Ougolkov AV,et al.,Cancer Res.65(2005)2076-2081,Cao Q,et al.,Cell Res.16(2006)671-677)。
目前报道的大多数GSK 3β抑制剂为ATP竞争性抑制剂，由于ATP结合区域在500多种激酶中高度保守，因此作用于该活性区域所带来的选择性及特异性问题不容忽视。相较于ATP竞争型抑制剂，非ATP竞争型抑制剂不仅具有较好的激酶选择性，而且在细胞水平和动物水平的测试中也显示出很好的活性。目前处于临床IIb期用于治疗阿尔兹海默病和进行性核上性麻痹症(PSP)的NP12就属于非ATP竞争型抑制剂，也表明非ATP竞争作用模式的优势。
此外，GSK 3β参与调控多条信号转导通路，正常水平的GSK 3β对于维持机体的生理活动至关重要。研究发现引起机体生物功能失调的GSK 3β水平只是正常水平的2-3倍，而过度抑制其活性很可能会导致严重的毒副作用。
基于现有技术的基础，本申请的发明人拟提供具有更精细更温和的调节作用的GSK 3β抑制剂，具体涉及一类新结构的3-取代-1,5-苯并氮杂酮类化合物及其在医药上的应用。
发明内容
本发明的目的之一在于提供新的GSK 3β抑制剂，具体涉及新的3-取代-1,5-苯并氮杂酮类化合物，其结构通式如式Ⅰ所示：
其中，X选自氧、硫或氮原子；R1选自C1-5的烷基、C2-5的烯基、五元芳香杂环基、苯基、取代苯基、苯基烷基、苯基烯基；R2选自丙烯酰基、硝基苄基；A选自羰基或磺酰基。
优选地，所述取代苯基的取代基取自卤素基、苯基、C1-5的烷氧基、三氟甲基、C1-3的羧酸酯基；所述的五元芳香杂环基取自噻吩基、呋喃基、吡咯基；所述的苯基烷基的烷基为C1-4的烷基；所述的苯基烯基的烯基为C2-4的烯基。
优选地，所述的卤素基包括氟、氯或溴。
本发明所示的式Ⅰ结构的3-取代-1,5-苯并氮杂酮类化合物，包括其手性异构体化合物，结构如式Ⅰa所示：
其中，X选自氧、硫或氮原子；R1选自C1-5的烷基、C2-5的烯基、五元芳香杂环基、苯基、取代苯基、苯基烷基、苯基烯基；R2选自丙烯酰基、硝基苄基；A选自羰基或磺酰基。
优选地，所述取代苯基的取代基取自卤素基、苯基、C1-5的烷氧基、三氟甲基、C1-3的羧酸酯基；所述的五元芳香杂环基取自噻吩基、呋喃基、吡咯基；所述的苯基烷基的烷基为C1-4的烷基；所述的苯基烯基的烯基为C2-4的烯基。
优选地，所述的卤素基包括氟、氯或溴。
优选地，当R2为丙烯酰基时，R1为氟代苯基，A为羰基。
本发明所示的式Ⅰ结构的3-取代-1,5-苯并氮杂酮类化合物，包含式Ⅰb所示的手性化合物：
其中，X选自氧、硫或氮原子；R1选自C1-5的烷基、C2-5的烯基、五元芳香杂环基、苯基、取代苯基、苯基烷基、苯基烯基；R2选自丙烯酰基、硝基苄基；A选自羰基或磺酰基。
优选地，所述取代苯基的取代基取自卤素基、苯基、C1-5的烷氧基、三氟甲基、C1-3的羧酸酯基；所述的五元芳香杂环基取自噻吩基、呋喃基、吡咯基；所述的苯基烷基的烷基为C1-4的烷基；所述的苯基烯基的烯基为C2-4的烯基。
优选地，所述的卤素基包括氟、氯或溴。
优选地，R1选自甲氧基苯基、丙氧基苯基、苄基，R2选自硝基苄基，A为羰基。
本发明所述的式Ⅰ结构的3-取代-1,5-苯并氮杂酮类化合物经酶动力学测试表明对GSK-3β的作用模式为非ATP竞争。
本发明的另一目的是提供式Ⅰ所示的化合物在制备预防或治疗具有GSK 3β异常病理特征的疾病的药物中的用途。
本发明所述的式Ⅰ结构的化合物可用于制备预防或治疗具有GSK 3β异常病理特征的疾病的药物。
优选地，所述具有GSK 3β异常病理特征的疾病包括癌症、神经类疾病、炎症、代谢综合症。
优选地，所述癌症包含肝细胞肝癌、胆管癌、鼻咽癌、乳腺癌、宫颈癌、非小细胞肺癌、小细胞肺癌、胃癌、食道癌、结直肠癌、胰腺癌、黑色素瘤、口腔癌、肾癌、膀胱癌、前列腺癌、骨肉瘤、卵巢癌、输卵管癌症、胃肠间质瘤、神经胶质瘤、头颈部癌症、白血病、淋巴瘤、多发性骨髓瘤、骨髓增生异常综合症。
优选地，所述神经类疾病包括阿尔茨海默病、帕金森病、双向情感障碍、强直性肌营养不良、进行性核上麻痹、自闭症谱系障碍等。
优选地，所述代谢综合症包括糖尿病。
本发明提供了一类新结构的3-取代-1,5-苯并氮杂酮类化合物及其在医药上的应用。该类3-取代苯并氮杂类化合物能选择性地抑制糖原合成激酶-3β(GSK 3β)的活性，可用于制备预防和/或治疗具有GSK 3β异常病理特征的疾病的药物，所述疾病包括癌症、神经类疾病、代谢综合症等。
附图说明
图1是本发明所述的式I结构化合物12对GSK-3β活性测试的动力学数据双倒数图，其中，GS-2浓度不变时，10μM和20μM浓度的化合物12的直线与对照组直线相交于X轴，表明化合物12为非ATP竞争型抑制剂(A)，ATP浓度不变时，10μM和20μM浓度的化合物12的直线与对照组直线相交于X和Y轴以外，表化合物明12为非底物竞争型抑制剂(B)。
本发明所述的3-取代-1,5-苯并氮杂酮类化合物的制备参见以下实施例。
具体实施方式
实施例1：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯甲酰胺(7)，其结构式如下所示：
第一步：制备N-Boc-L-半胱氨酸(1)
向反应瓶中加入L-半胱氨酸(6.0g,50mmol)、NaOH(1.2g,50mmol)、二氧六环(30mL)和水(50mL)，冰浴下加入(Boc)2O(17.0g,70mmol)，继续室温搅拌过夜。减压浓缩除去二氧六环，水层用乙酸乙酯萃取除去未反应的Boc酸酐。水层用1mol/L的盐酸调pH至1-2，乙酸乙酯萃取两次，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得无色糖浆状物2.15g(1)，收率97％。直接用于下步反应；
第二步：制备(S)-2-((叔丁氧羰基)氨基)-3-(2-硝基苯基)硫)丙酸(2)
向反应瓶中加入N-Boc-L-半胱氨酸(1)(12.5g,56mmol)、乙醇(80mL)、NaHCO3(14.2g,169mmol)、水(40mL)，滴加乙醇(20mL)稀释的邻氟硝基苯(7.9g,61mmol)，滴加完毕回流4h。减压浓缩除去乙醇，剩余物用水稀释，乙醚洗涤两次除去脂溶性杂质。水层用1NHCl调pH至4，乙酸乙酯萃取两次，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得淡黄色油状固体14.7g(2)，收率76％。直接用于下步反应；
第三步：制备(S)-3-(2-氨基苯基)硫)-2-((叔丁氧羰基)氨基)丙酸(3)
向反应瓶中加入2(14.7g,43mmol)、锌粉(27.9g,430mmol)、氯化铵固体(4.6g,86mmol)、MeOH(300mL)，回流5h。冷至室温，硅藻土过滤，滤液减压浓缩除去甲醇。剩余物用二氯甲烷稀释，经硅藻土过滤，滤液经水洗、饱和食盐水洗、无水硫酸钠干燥，减压浓缩得类白色固体12.0g(3)，收率89％；
第四步：制备叔丁基-(R)-(4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)氨基甲酸酯(4)
向反应瓶中加入3(2.0g,6mmol)、HATU(2.4g,6mmol)、DIPEA(1.1mL,7mmol)DCM(30mL)，室温搅拌4h。二氯甲烷稀释，依次用水洗、饱和食盐水洗，无水硫酸钠干燥。减压浓缩得粗品，经硅胶柱层析(PE:EA＝80:20)得类白色固体1.3g(4)，收率72％；
第五步：制备叔丁基-(R)-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)氨基甲酸酯(5)
向反应瓶中加入4(3.3g,11mmol)、2-硝基溴苄(2.6g,12mmol)、K2CO3(3.0g,22mmol)、DMF(50mL)，室温搅拌4h。乙酸乙酯稀释，依次用水洗、饱和食盐水洗，无水硫酸钠干燥。减压浓缩得粗品，经硅胶柱层析(PE:EA＝80:20)得淡黄色固体3.3g(5)，收率68％；
第六步：制备(R)-3-氨基-5-(2-硝基苄基)-2,3-二氢-苯并[b][1,4]硫氮杂-4(5H)-酮(6)
向反应瓶中加入5(3.3g,7mmol)、TFA(5mL)、DCM(20mL)，室温搅拌2h。减压浓缩除去溶剂，剩余物经正己烷萃取洗去脂溶性杂质。水层用饱和碳酸钠水溶液调pH至8，二氯甲烷萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得淡黄色固体2.5g(6)，收率98％；
第七步：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯甲酰胺(7)
向反应瓶中加入6(0.13g,0.4mmol)、苯甲酸(0.05g,0.4mmol)、HATU(0.15g,0.4mmol)、DIPEA(0.22mL,1.2mmol)、DCM(30mL)，室温搅拌5h。二氯甲烷稀释，依次用1NHCl、饱和碳酸氢钠、饱和食盐水洗，无水硫酸钠干燥。减压浓缩得粗品，经硅胶柱层析(PE:EA＝75:25)得白色固体0.1g(7)，收率59％。
实施例2：制备甲基-(R)-4-((5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)氨基甲酰)苯甲酸酯(8)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用对苯二甲酸单甲酯代替苯甲酸，得白色固体，收率70％。1H NMR(400MHz,DMSO-d6)δ9.25-9.17(m,1H),8.07-8.00(m,3H),8.00-7.94(m,2H),7.79(d,J＝8.2Hz,1H),7.68(d,J＝7.8Hz,2H),7.51(dd,J＝13.7,8.0Hz,3H),7.33(d,J＝9.1Hz,1H),5.45(d,J＝17.3Hz,1H),5.31(d,J＝17.3Hz,1H),4.67(d,J＝9.7Hz,1H),3.86(s,3H),3.62(t,J＝9.3Hz,1H)。
实施例3：制备(R)-4-甲氧基-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯甲酰胺(9)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用对甲氧基苯甲酸代替苯甲酸，得白色固体，收率50％。1H NMR(400MHz,DMSO-d6)δ8.78(d,J＝7.6Hz,1H),7.98-7.91(m,1H),7.85-7.70(m,3H),7.60(d,J＝8.1Hz,2H),7.47-7.35(m,3H),7.22(dt,J＝9.1,4.7Hz,1H),6.97-6.86(m,2H),5.39(d,J＝17.3Hz,1H),5.23(d,J＝17.2Hz,1H),4.68-4.55(m,1H),3.71(s,3H),3.58-3.47(m,1H),3.30(d,J＝11.4Hz,1H)。
实施例4：制备(R)-4-氟-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯甲酰胺(10)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用对氟苯甲酸代替苯甲酸，得白色固体，收率43％。ESI-MS m/z:452.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 9.06(d,J＝7.6Hz,1H),8.04(d,J＝8.0Hz,1H),7.94(dd,J＝8.4,5.6Hz,2H),7.78(d,J＝7.6Hz,1H),7.70(t,J＝7.6Hz,2H),7.54-7.47(m,3H),7.34-7.30(m,3H),5.45(d,J＝17.2Hz,1H),5.31(d,J＝17.2Hz,1H),4.70-4.63(m,1H),3.61(dd,J＝11.6,7.2Hz,1H),3.13(t,J＝11.6Hz,1H)。
实施例5：制备(R)-2-乙氧基-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯甲酰胺(11)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用2-乙氧基苯甲酸代替苯甲酸，得白色固体，收率35％。1H NMR(400MHz,DMSO-d6)δ8.96(d,J＝7.0Hz,1H),8.00(d,J＝8.1Hz,1H),7.85(d,J＝7.8Hz,1H),7.80(d,J＝7.9Hz,1H),7.67(q,J＝8.4,7.7Hz,2H),7.47(dd,J＝18.4,8.6Hz,5H),7.31(d,J＝7.4Hz,1H),7.12(d,J＝8.3Hz,1H),7.05-6.95(m,1H),5.50(d,J＝17.2Hz,1H),5.40(d,J＝17.2Hz,1H),4.82-4.71(m,1H),4.16(p,J＝6.9Hz,2H),3.74(dd,J＝11.6,6.8Hz,1H),3.15(t,J＝11.6Hz,1H),1.46(t,J＝7.0Hz,3H)。
实施例6：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-2-丙氧苯甲酰胺(12)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用2-丙氧基苯甲酸代替苯甲酸，得白色固体，收率54％。ESI-MS m/z:492.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.88(d,J＝7.2Hz,1H),8.00(d,J＝8.1Hz,1H),7.82(d,J＝7.8Hz,1H),7.76(d,J＝7.9Hz,1H),7.65(dt,J＝19.6,9.8Hz,2H),7.53-7.41(m,4H),7.30(dt,J＝8.7,4.2Hz,1H),7.12(d,J＝8.4Hz,1H),7.00(t,J＝7.6Hz,1H),5.50-5.34(m,2H),4.75(dt,J＝13.1,7.0Hz,1H),4.06(t,J＝6.6Hz,2H),3.72(dd,J＝11.2,6.7Hz,1H),3.10(t,J＝11.6Hz,1H),1.80-1.90(m,2H),0.97(t,J＝7.3Hz,3H)。
实施例7：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)肉桂酰胺(13)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用肉桂酸代替苯甲酸，得白色固体，收率48％。ESI-MS m/z:460.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.77(d,J＝8.0Hz,1H),8.03(d,J＝8.4Hz,1H),7.74(d,J＝8.0Hz,1H),7.69(t,J＝6.8Hz,2H),7.56-7.47(m,5H),7.41-7.38(m,4H),7.32(t,J＝7.2Hz,1H),6.72(d,J＝16Hz,1H),5.42(d,J＝17.2Hz,1H),5.36(d,J＝17.2Hz,1H),4.66-4.59(m,1H),3.59(dd,J＝11.2,6.8Hz,1H),3.13(t,J＝11.2Hz,1H)。
实施例8：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-2-苯乙酰胺(14)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用苯乙酸代替苯甲酸，得白色固体，收率59％。ESI-MS m/z:448.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.81(d,J＝7.6Hz,1H),8.02(d,J＝8.4Hz,1H),7.70(d,J＝7.6Hz,1H),7.66-7.60(m,2H),7.53-7.42(m,3H),7.30-7.19(m,6H),5.36(s,2H),4.50-4.44(m,1H),3.52(dd,J＝11.6,6.8Hz,1H),3.44(s,2H),3.10(t,J＝11.6Hz,1H)。
实施例9：制备(R)-2-甲氧基-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯甲酰胺(15)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用2-甲氧基苯甲酸代替苯甲酸，得白色固体，收率71％。ESI-MS m/z:464.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.82(d,J＝7.2Hz,1H),8.00(d,J＝8.2Hz,1H),7.80(t,J＝8.9Hz,2H),7.67(d,J＝7.9Hz,2H),7.58-7.40(m,4H),7.36-7.24(m,1H),7.14(d,J＝8.4Hz,1H),7.01(t,J＝7.7Hz,1H),5.48(d,J＝17.2Hz,1H),5.38(d,J＝17.1Hz,1H),4.71(dt,J＝13.5,7.1Hz,1H),3.73-3.61(m,1H),3.24(t,J＝11.6Hz,1H)。
实施例10：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-3-苯丙酰胺(16)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用苯丙酸代替苯甲酸，得淡黄色固体，收率86％。ESI-MS m/z:462.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm8.52(d,J＝7.8Hz,1H),8.00(d,J＝8.1Hz,1H),7.70(d,J＝7.9Hz,1H),7.63(d,J＝7.4Hz,2H),7.52-7.40(m,3H),7.27(t,J＝7.6Hz,1H),7.20(t,J＝7.5Hz,2H),7.14(d,J＝7.7Hz,3H),5.39(d,J＝17.2Hz,1H),5.31(d,J＝17.1Hz,1H),4.53-4.43(m,1H),3.45(dd,J＝11.3,6.9Hz,1H),3.02(t,J＝11.8Hz,1H),2.73(t,J＝7.9Hz,2H),2.39(t,J＝7.8Hz,2H)。
实施例11：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-丙烯酰胺(17)，其结构式如下所示：
向反应瓶中加入6(150mg,0.45mmol)，DIPEA(238μL,1.36mmol)，DCM(20mL)，冰浴下加入丙烯酰氯(275μL,2.27mmol)，室温搅拌48h。二氯甲烷稀释，饱和食盐水洗涤两次，无水硫酸钠干燥，减压浓缩得粗品。粗品经硅胶柱层析(PE:EA＝60:40)得类白色固体130mg，收率74％。ESI-MS m/z:384.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.75(d,J＝7.7Hz,1H),7.99(d,J＝8.2Hz,1H),7.71(d,J＝8.0Hz,1H),7.64(d,J＝7.1Hz,2H),7.54-7.38(m,3H),7.29(d,J＝7.7Hz,1H),6.27(dd,J＝17.1,10.3Hz,1H),6.06(d,J＝17.1Hz,1H),5.60(d,J＝10.2Hz,1H),5.34(t,J＝12.9Hz,2H),4.62-4.47(m,1H),3.54(dd,J＝11.3,7.2Hz,1H),3.08(t,J＝11.8Hz,1H)。
实施例12：制备(R,E)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)丁-2-烯胺(18)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用2-丁烯酸代替苯甲酸，得白色固体，收率40％。ESI-MS m/z:398.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm8.52(d,J＝7.8Hz,1H),8.00(d,J＝8.2Hz,1H),7.72(d,J＝7.9Hz,1H),7.64(t,J＝7.2Hz,2H),7.40-7.50(m,3H),7.32-7.23(m,1H),6.55-6.65(m,1H),5.95(dd,J＝15.3,2.3Hz,1H),5.40(d,J＝17.3Hz,1H),5.30(d,J＝17.1Hz,1H),4.50-4.60(m,1H),3.51(dd,J＝11.3,6.9Hz,1H),3.08(t,J＝11.7Hz,1H),1.77-1.71(m,3H)。
实施例13：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-乙酰胺(19)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用乙酸代替苯甲酸，得类白色固体，收率89％。ESI-MS m/z:372.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.50(d,J＝7.7Hz,1H),8.00(d,J＝8.1Hz,1H),7.74-7.58(m,3H),7.52-7.38(m,3H),7.26(t,J＝7.5Hz,1H),5.39(d,J＝17.2Hz,1H),5.28(d,J＝17.1Hz,1H),4.50-4.41(m,1H),3.48(dd,J＝11.3,6.9Hz,1H),3.03(t,J＝11.7Hz,1H),1.79(s,3H)。
实施例14：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-丙酰胺(20)，其结构式如下所示：
制备方法同实施例1中化合物7的制备，用丙酸代替苯甲酸，得类白色固体，收率89％。ESI-MS m/z:386.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm8.46-8.35(m,1H),7.99(d,J＝8.0Hz,1H),7.74-7.58(m,3H),7.54-7.38(m,3H),7.27(s,1H),5.42-5.26(m,2H),4.51-4.42(m,1H),3.47(dd,J＝10.8,5.4Hz,1H),3.05(t,J＝12.1Hz,1H),2.14-2.00(m,2H),0.96-0.87(m,3H)。
实施例15：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-4-(三氟甲基)苯磺酰胺(21)，其结构式如下所示：
向反应瓶中加入6(150mg,0.45mmol)，4-三氟甲基苯磺酰氯(70mg,0.5mmol)，吡啶(15mL)，室温搅拌9h。反应完毕后加入乙酸乙酯，加压浓缩除去吡啶。残余物加入乙酸乙酯稀释，依次用水洗，饱和食盐水洗涤，无水硫酸钠干燥。减压浓缩得粗品，粗品经硅胶柱层析(PE:EA＝65:35)得白色固体120mg，收率49％。ESI-MS m/z:538.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.95(d,J＝9.2Hz,1H),8.06(d,J＝8.4Hz,2H),7.94(d,J＝8.0Hz,1H),7.83(d,J＝8.4Hz,2H),7.65(t,J＝6.8Hz,2H),7.56(t,J＝6.8Hz,2H),7.49-7.43(m,2H),7.32(t,J＝7.6Hz,1H),5.06(d,J＝17.2Hz,1H),4.94(d,J＝17.2Hz,1H),4.03-3.98(m,1H),3.52(dd,J＝11.6,7.2Hz,1H),3.06(t,J＝11.6Hz,1H)。
实施例16：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-甲基磺酰胺(22)，其结构式如下所示：
制备方法上述化合物21，用甲磺酰氯代替4-三氟甲基苯磺酰氯，得白色固体，收率49％。ESI-MS m/z:408.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm7.98(dd,J＝19.1,8.6Hz,2H),7.65(d,J＝8.7Hz,3H),7.48(d,J＝10.8Hz,3H),7.30(d,J＝7.4Hz,1H),5.45-5.27(m,2H),4.06(dd,J＝15.7,7.4Hz,1H),3.59(t,J＝9.2Hz,1H),3.03(t,J＝11.8Hz,1H),2.81(s,3H)。
实施例17：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-噻吩-2-磺酰胺(23)，其结构式如下所示：
制备方法同上述化合物21，用2-噻吩磺酰氯代替4-三氟甲基苯磺酰氯，得白色固体，收率46％。ESI-MS m/z:476.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.82(d,J＝7.6Hz,1H),8.00-7.95(m,2H),7.65(d,J＝7.6Hz,1H),7.60(d,J＝7.6Hz,1H),7.56-7.54(m,2H),7.51-7.45(m,2H),7.40(d,J＝3.6Hz,1H),7.32(t,J＝7.2Hz,1H),7.23(t,J＝3.6Hz,1H),5.14(s,2H),3.98-3.92(m,1H),3.44(dd,J＝11.2,7.2Hz,1H),3.13(t,J＝11.6Hz,1H)。
实施例18：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-1-苯甲基磺酰胺(24)，其结构式如下所示：
制备方法同上述化合物21，用苄基磺酰氯代替4-三氟甲基苯磺酰氯，得白色固体，收率46％。ESI-MS m/z:484.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.00(d,J＝8.1Hz,1H),7.93(d,J＝8.8Hz,1H),7.71-7.60(m,2H),7.56(d,J＝7.7Hz,1H),7.51-7.40(m,2H),7.32(d,J＝8.0Hz,1H),7.26(dd,J＝10.1,6.7Hz,6H),5.35(d,J＝17.2Hz,1H),5.25(d,J＝17.2Hz,1H),4.24(q,J＝13.6Hz,2H),3.65-3.57(m,1H),3.36(d,J＝6.9Hz,1H),2.97(t,J＝11.6Hz,1H)。
实施例19：制备(R)-4-氯-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯磺酰胺(25)，其结构式如下所示：
制备方法同上述化合物21，用对氯苯磺酰氯代替4-三氟甲基苯磺酰氯，得白色固体，收率31％。ESI-MS m/z:504.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.72(d,J＝8.1Hz,1H),7.94(d,J＝8.2Hz,1H),7.71(d,J＝8.6Hz,2H),7.66-7.49(m,6H),7.47-7.41(m,2H),7.30(t,J＝7.5Hz,1H),5.08(d,J＝17.1Hz,1H),4.98(d,J＝17.1Hz,1H),3.93(q,J＝9.1,8.6Hz,1H),3.46(dd,J＝11.4,6.9Hz,1H),3.02(t,J＝11.7Hz,1H)。
实施例20：制备(R)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-[1,1'-联苯]-4-磺酰胺(26)，其结构式如下所示：
制备方法同上述化合物21，用对联苯磺酰氯代替4-三氟甲基苯磺酰氯，得白色固体，收率32％。ESI-MS m/z:546.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.62(d,J＝9.1Hz,1H),7.91(dd,J＝13.6,8.2Hz,3H),7.83-7.76(m,2H),7.70-7.58(m,4H),7.57-7.48(m,5H),7.47-7.35(m,2H),7.34-7.25(m,1H),5.08(d,J＝17.1Hz,1H),5.00(d,J＝17.0Hz,1H),3.98(q,J＝9.8Hz,1H),3.46(dd,J＝11.4,6.9Hz,1H),3.06(t,J＝11.7Hz,1H)。
实施例21：制备(S)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)-苯甲酰胺(33)，其结构式如下所示：
第一步：制备N-Boc-L-丝氨酸(27)
向反应瓶中加入L-丝氨酸(5.3g,50mmol)，TEA(6.9mL,50mmol)，二氧六环(30mL)和水(50mL)，冰浴下加入(Boc)2O(13.1g,60mmol)，继续室温搅拌过夜。减压浓缩除去二氧六环，水层用乙酸乙酯萃取除去未反应的Boc酸酐。水层用1mol/L的盐酸调pH至1-2，乙酸乙酯萃取两次，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得无色糖浆状物9.5g，收率92％。直接用于下步反应；
第二步：制备(S)-2-((叔丁氧羰基)氨基)-3-(2-硝基苯氧基)丙酸(28)
向反应瓶中加入NaH(0.8g,2mmol)，DMF(15mL)，冰浴下依次滴加27(2.0g,1mmol)的DMF溶液(10mL)，邻氟硝基苯(1.4g,1mmol)，滴加完毕后室温搅拌过夜。饱和氯化铵溶液淬灭反应，乙酸乙酯萃取两次，合并有机相并用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得粗品。粗品经硅胶柱层析(PE:EA＝50:50)得淡褐色油状固体2.3g，收率70％。直接用于下步反应；
第三步：制备(S)-3-(2-氨基苯氧基)-2-((叔丁氧羰基)氨基)丙酸(29)
向反应瓶中加入28(9.5g,29mmol)，Pd/C(1.3g,10％)，MeOH(200mL)，氢气常压反应5h。活性炭吸附过滤，滤液减压浓缩得玫红色固体8.4g，收率98％。直接用于下步反应；
第四步：制备(S)-叔丁基-(4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)氨基甲酸酯(30)
向反应瓶中加入29(8.6g,29mmol)，HATU(10.9g,29mmol)，DIPEA(5.6mL,32mmol)，DCM(200mL)，室温搅拌过夜。二氯甲烷稀释，依次用水洗、饱和食盐水洗，无水硫酸钠干燥。减压浓缩得粗品，经正己烷:乙酸乙酯(5:1)超声洗涤得褐色固体6.7g，收率83％。直接用于下步反应；
第五步：制备(S)-叔丁基-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)-氨基甲酸酯(31)
向反应瓶中加入30(2.6g,9mmol)，2-硝基溴苄(2.4g,11mmol)，K2CO3(2.6g,18mmol)，CH3CN(100mL)，回流过夜。乙酸乙酯稀释，依次用水洗、饱和食盐水洗，无水硫酸钠干燥。减压浓缩得粗品，经硅胶柱层析(PE:EA＝80:20)得淡黄色固体2.2g，收率57％；
第六步；制备(S)-3-氨基-5-(2-硝基苄基)-2,3-二氢-苯并[b][1,4]氧氮杂-4(5H)-酮(32)
向反应瓶中加入31(2.2g,5mmol)，TFA(4mL)，DCM(15mL)，室温搅拌2h。减压浓缩除去溶剂，剩余物经正己烷萃取洗去脂溶性杂质。水层用饱和碳酸钠水溶液调pH至8，二氯甲烷萃取，有机层用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得粗品，经正己烷超声洗涤得淡黄色固体1.3g，收率80％；
第七步：制备(S)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)-苯甲酰胺(33)
向反应瓶中加入32(100mg,0.3mmol)，苯甲酸(40mg,0.3mmol)，HATU(130mg,0.3mmol)，DIPEA(170μL,0.9mmol)，DCM(10mL)，室温搅拌3h。二氯甲烷稀释，依次用1mol/L的盐酸水溶液，饱和碳酸氢钠，饱和食盐水洗，无水硫酸钠干燥。减压浓缩得粗品，经硅胶柱层析(PE:EA＝75:25)得白色固体90mg，收率67％。ESI-MS m/z:418.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.78(d,J＝8.3Hz,1H),8.04(d,J＝8.2Hz,1H),7.85(d,J＝7.6Hz,2H),7.68(t,J＝7.7Hz,1H),7.56-7.45(m,6H),7.27(s,3H),5.53(d,J＝17.6Hz,1H),5.32(d,J＝17.6Hz,1H),5.06(q,J＝9.2Hz,1H),4.71(t,J＝10.9Hz,1H),4.50(t,J＝8.9Hz,1H)。
实施例22制备甲基-(S)-4-((5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)氨基甲酰)苯甲酸酯(34)，其结构式如下所示：
制备方法同上述化合物33，对苯二甲酸单甲酯代替苯甲酸，得类白色固体，收率95％。ESI-MS m/z:476.1[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 9.01(d,J＝8.0Hz,1H),8.06(d,J＝8.0Hz,3H),7.98(d,J＝8.2Hz,2H),7.69(t,J＝7.5Hz,1H),7.51(t,J＝6.8Hz,3H),7.28(s,3H),5.53(d,J＝17.6Hz,1H),5.34(d,J＝17.5Hz,1H),5.15-4.98(m,1H),4.72(t,J＝10.8Hz,1H),4.53(t,J＝8.9Hz,1H),3.88(s,3H)。
实施例23：制备(S)-2-乙氧-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)苯甲酰胺(35)，其结构式如下所示：
制备方法同上述化合物33，对氟苯甲酸代替苯甲酸，得类白色固体，收率55％。ESI-MS m/z:462.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.93(d,J＝6.7Hz,1H),8.06(d,J＝8.2Hz,1H),7.89(d,J＝7.8Hz,1H),7.66(q,J＝9.5,8.6Hz,1H),7.57(d,J＝7.9Hz,1H),7.50(d,J＝8.4Hz,3H),7.27(dd,J＝17.3,6.4Hz,3H),7.14(d,J＝8.4Hz,1H),7.03(t,J＝7.6Hz,1H),5.62(d,J＝17.7Hz,1H),5.38(d,J＝17.7Hz,1H),5.19-5.05(m,1H),4.71(t,J＝8.8Hz,1H),4.45(t,J＝10.6Hz,1H),4.25-4.11(m,2H),1.47(t,J＝7.0Hz,3H)。
实施例24：制备(S)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)-2-丙氧基苯甲酰胺(36)，其结构式如下所示：
制备方法同上述化合物33，2-丙氧基苯甲酸代替苯甲酸，得淡黄色固体，收率75％。ESI-MS m/z:476.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.78(d,J＝7.1Hz,1H),8.04(d,J＝8.2Hz,1H),7.82(d,J＝7.5Hz,1H),7.66(t,J＝7.8Hz,1H),7.55(d,J＝7.9Hz,1H),7.49(d,J＝7.5Hz,3H),7.32-7.19(m,3H),7.15(d,J＝8.4Hz,1H),7.02(t,J＝7.6Hz,1H),5.59(d,J＝17.6Hz,1H),5.33(d,J＝17.6Hz,1H),5.07(dt,J＝12.0,7.4Hz,1H),4.64(t,J＝8.8Hz,1H),4.51(t,J＝10.5Hz,1H),3.91(s,3H)。
实施例25：制备(S)-2-甲氧基-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]氧氮杂-3-基)苯甲酰胺(37)，其结构式如下所示：
制备方法同上述化合物33，2-甲氧基苯甲酸代替苯甲酸，得淡黄色固体，收率95％。ESI-MS m/z:448.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.84(d,J＝6.7Hz,1H),8.03(d,J＝8.2Hz,1H),7.86(d,J＝7.8Hz,1H),7.63(d,J＝7.8Hz,1H),7.53(d,J＝7.6Hz,1H),7.46(d,J＝7.7Hz,3H),7.24(d,J＝20.2Hz,3H),7.12(d,J＝8.3Hz,1H),7.01(d,J＝7.8Hz,1H),5.57(d,J＝17.7Hz,1H),5.35(d,J＝17.7Hz,1H),5.11(q,J＝8.5Hz,1H),4.68(t,J＝8.9Hz,1H),4.39(t,J＝10.8Hz,1H),4.05(d,J＝7.1Hz,2H),1.87(p,J＝7.2Hz,2H),0.97(d,J＝7.5Hz,3H)。
实施例26：制备(S)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-2-丙氧基苯甲酰胺(38)，其结构式如下所示：
制备方法同上述化合物12，D-半胱氨酸代替L-半胱氨酸，得类白色固体，收率70％。ESI-MS m/z:492.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.89(d,J＝6.4Hz,1H),8.03(d,J＝7.6Hz,1H),7.83(d,J＝7.2Hz,1H),7.77(d,J＝7.2Hz,1H),7.72-7.67(m,2H),7.52-7.47(m,4H),7.35-7.32(m,1H),7.16(d,J＝8.0Hz,1H),7.05-7.01(m,1H),5.47(d,J＝17.2Hz,1H),5.40(d,J＝17.2Hz,1H),4.78-4.74(m,1H),4.10-4.08(m,2H),3.75-3.71(m,1H),3.10(t,J＝12.0Hz,1H),1.87-1.86(m,2H),0.98(t,J＝6.4Hz,3H)。
实施例27：制备(S)-2-甲氧基-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)苯甲酰胺(39)，其结构式如下所示：
制备方法同上述化合物38，2-甲氧基苯甲酸代替2-丙氧基苯甲酸得淡黄色固体，收率75％。ESI-MS m/z:464.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.83(d,J＝7.2Hz,1H),8.02(d,J＝8.4Hz,2H),7.83-7.78(m,2H),7.69(d,J＝7.6Hz,2H),7.52(m,4H),7.35-7.31(m,1H),7.17(d,J＝8.8Hz,1H),7.04(t,J＝7.6Hz,1H),5.49(d,J＝17.2Hz,1H),5.38(d,J＝17.2Hz,1H),4.74-4.68(m,1H),3.92(s,3H),3.68(dd,J＝11.2,7.2Hz,1H),3.25(t,J＝11.2Hz,1H)。
实施28：制备(S)-N-(5-(2-硝基苄基)-4-氧-2,3,4,5-四氢-苯并[b][1,4]硫氮杂-3-基)-2-苯乙酰胺(40)，其结构式如下所示：
制备方法同上述化合物38，苯乙酸代替2-丙氧基苯甲酸得白色固体，收率74％。ESI-MS m/z:448.2[M+H]+，1H NMR(400MHz,DMSO-d6)δppm 8.81(d,J＝7.2Hz,1H),8.02(d,J＝8.0Hz,1H),7.71-7.60(m,3H),7.53-7.42(m,3H),7.30-7.19(m,6H),5.37(s,2H),4.51-4.44(m,1H),3.52(dd,J＝11.2,6.8Hz,1H),3.44(s,3H),3.10(t,J＝11.2Hz,1H)。
实施例29：本发明所述的化合物对GSK-3β的体外酶抑制活性测试
采用化学发光法进行测试，荧光信号强度与剩余ATP的量成正比，通过检测体系内剩余ATP的量进而推算出GSK-3β磷酸化底物GS-2时消耗的ATP量，从而反映酶的活性水平。计算不同浓度下化合物的抑制率，通过GraphPad软件拟合出半数抑制浓度(IC50值)；
所用的主要试剂：
GSK-3β(Millipore,Lot#:14-306)；GS-2(吉尔生化上海有限公司)；ATP·2Na(Sigma-Aldrich)；Kinase-Glo Luminescent Kinase Assay(Promega corporation)；TDZD-8(MedChem Express Technologies,Lot#:HY-11012).
实验方法：
在96孔板上，将4μL含不同浓度化合物的DMSO溶液用14μL缓冲液稀释，依次加入2μL(10-20ng)的GSK-3β，20μL的GS-2(12.5μM)和ATP(4μM)的缓冲液，于30℃下孵育30分钟，孵育完毕后加入40μL Kinase-Glo试剂，于30℃下孵育10分钟，化学发光仪计数，GraphPad软件计算半数抑制浓度(IC50值)；
结果显示，本发明的3-取代-1,5-苯并氮杂酮类化合物对GSK 3β具有微摩尔浓度级的抑制作用。表1为部分化合物的结构及活性数据。
表1.部分实施例制备的化合物对GSK 3β酶的抑制活性(IC50)
实施例30：动力学测试确定本发明化合物对GSK-3β的作用模式
测试一定浓度下化合物在一系列不同ATP浓度时的GSK-3β活性，计算出反应速率。通过反应速率的倒数(1/v)对ATP浓度的倒数(1/[ATP])作图得到Lineweaver-Burk。直线的相交点反映出化合物的作用类型。若化合物的直线空白对照组的直线相交于Y轴，则表明化合物与ATP存在竞争关系，如果相交于X轴，则表明化合物与ATP不存在竞争关系；
测试一定浓度下化合物在一系列不同GS-2浓度时的GSK-3β活性，计算出反应速率。通过反应速率的倒数(1/v)对GS-2浓度的倒数(1/[GS-2])作图得到Lineweaver-Burk。直线的相交点反映出化合物的作用类型。若化合物的直线空白对照组的直线相交于Y轴，则表明化合物与GS-2存在竞争关系，如果相交于X轴，则表明化合物与GS-2不存在竞争关系；
测试与ATP作用模式时，保持GS-2浓度为6.25μM，ATP的终浓度为8.0μM，4.0μM，2.0μM，1.0μM，0.5μM。运用上述体外激酶活性测试方法测试不同ATP浓度下酶的活性；计算反应速率并对ATP浓度进行双倒数作图；测试与GS-2作用模式时，保持ATP浓度为2μM不变，GS-2的终浓度为12.5μM，6.25μM，3.13μM，1.56μM，0.78μM；运用上述体外激酶活性测试方法测试不同GS-2浓度下酶的活性。计算反应速率并对GS-2浓度进行双倒数作图；根据双倒数图判断化合物的作用模式。
综上所述，本发明提供的具有通式I结构的化合物对于GSK 3β激酶活性具有明显的抑制作用，能用于制备治疗或预防具有GSK 3β异常病理特征的疾病的药物组合物。
尽管本发明的内容已经通过上述优选实施例作了详细介绍，但应当认识到上述的描述不应被认为是对本发明的限制。在本领域技术人员阅读了上述内容后，对于本发明的多种修改和替代都将是显而易见的。因此，本发明的保护范围应由所附的权利要求来限定。
Claims (9)
1.式Ⅰ结构的3-取代-1,5-苯并氮杂类化合物，
其中，
X选自氧、硫或氮原子；
R1选自C1-5的烷基、C2-5的烯基、五元芳香杂环基、苯基、取代苯基、苯基烷基、苯基烯基；
R2选自丙烯酰基、硝基苄基；
A选自羰基或磺酰基。
2.按权利要求1所述的式Ⅰ结构的3-取代-1,5-苯并氮杂类化合物，其特征在于，所述的取代苯基的取代基选自卤素基、苯基、三氟甲基、C1-5的烷氧基、C1-3的羧酸酯基；所述的五元芳香杂环基选自噻吩基、呋喃基、吡咯基；所述的苯基烷基的烷基为C1-4的烷基；所述的苯基烯基的烯基为C2-4的烯基。
3.按权利要求2所述的式Ⅰ结构的3-取代-1,5-苯并氮杂类化合物，其特征在于，所述的卤素基为氟、氯或溴。
4.根据权利要求1-3所述的式Ⅰ结构的3-取代-1,5-苯并氮杂类化合物在用于制备预防和/或治疗具有GSK 3β异常病理特征的疾病的药物组合物中的用途。
5.如权利要求4所述的用途，其特征在于，所述的药物组合物含有治疗有效量的根据权利要求中任意一项所述的化合物或其互变异构体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用盐，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
6.如权利要求4所述的用途，其特征在于，所述具有GSK 3β异常病理特征的疾病为癌症、神经类疾病、炎症或代谢综合症。
7.如权利要求6所述的用途，其特征在于，所述癌症为肝细胞肝癌、胆管癌、鼻咽癌、乳腺癌、宫颈癌、非小细胞肺癌、小细胞肺癌、胃癌、食道癌、结直肠癌、胰腺癌、黑色素瘤、口腔癌、肾癌、膀胱癌、前列腺癌、骨肉瘤、卵巢癌、输卵管癌症、胃肠间质瘤、神经胶质瘤、头颈部癌症、白血病、淋巴瘤、多发性骨髓瘤或骨髓增生异常综合症。
8.如权利要求6所述的用途，其特征在于，所述神经类疾病为阿尔茨海默病、帕金森病、双向情感障碍、强直性肌营养不良、进行性核上麻痹或自闭症谱系障碍。
9.如权利要求6所述的用途，其特征在于，所述代谢综合症为糖尿病。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810391788.1A CN110407770B (zh) | 2018-04-27 | 2018-04-27 | 3-取代-1,5-苯并氮杂䓬类化合物及其药物用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810391788.1A CN110407770B (zh) | 2018-04-27 | 2018-04-27 | 3-取代-1,5-苯并氮杂䓬类化合物及其药物用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110407770A true CN110407770A (zh) | 2019-11-05 |
| CN110407770B CN110407770B (zh) | 2022-12-30 |
Family
ID=68346645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810391788.1A Active CN110407770B (zh) | 2018-04-27 | 2018-04-27 | 3-取代-1,5-苯并氮杂䓬类化合物及其药物用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110407770B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022257288A1 (zh) * | 2021-06-08 | 2022-12-15 | 海南锦瑞制药有限公司 | 盐酸地尔硫卓的合成方法及应用 |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735211A (zh) * | 2008-11-04 | 2010-06-16 | 复旦大学 | 2,3-二氢[1,5]苯并噻氮杂䓬类化合物或其盐在制备GSK-3β抑制剂中的用途 |
| CN103214431A (zh) * | 2012-01-21 | 2013-07-24 | 复旦大学 | 2,3-二氢苯并氮杂*类化合物或其盐及其药物用途 |
| CN105121432A (zh) * | 2013-02-15 | 2015-12-02 | 葛兰素史密斯克莱知识产权发展有限公司 | 作为激酶抑制剂的杂环酰胺 |
| WO2017201449A1 (en) * | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Protac antibody conjugates and methods of use |
-
2018
- 2018-04-27 CN CN201810391788.1A patent/CN110407770B/zh active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101735211A (zh) * | 2008-11-04 | 2010-06-16 | 复旦大学 | 2,3-二氢[1,5]苯并噻氮杂䓬类化合物或其盐在制备GSK-3β抑制剂中的用途 |
| CN103214431A (zh) * | 2012-01-21 | 2013-07-24 | 复旦大学 | 2,3-二氢苯并氮杂*类化合物或其盐及其药物用途 |
| CN105121432A (zh) * | 2013-02-15 | 2015-12-02 | 葛兰素史密斯克莱知识产权发展有限公司 | 作为激酶抑制剂的杂环酰胺 |
| WO2017201449A1 (en) * | 2016-05-20 | 2017-11-23 | Genentech, Inc. | Protac antibody conjugates and methods of use |
Non-Patent Citations (1)
| Title |
|---|
| PHILIP A. HARRIS等: ""DNA-Encoded Library Screening Identifies Benzo[b][1,4]oxazepin-4-ones as Highly Potent and Monoselective Receptor Interacting Protein 1 Kinase Inhibitors"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022257288A1 (zh) * | 2021-06-08 | 2022-12-15 | 海南锦瑞制药有限公司 | 盐酸地尔硫卓的合成方法及应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110407770B (zh) | 2022-12-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2716642B1 (en) | Imidazopyridine compound | |
| EP1845978B1 (fr) | Pyrazolo pyridines substituees, compositions les contenant, procede de fabrication et utilisation | |
| EP2539335B1 (en) | Process for the preparation of isoxazoline derivatives | |
| EP3725787B1 (en) | Piperidine derivatives as hdac1/2 inhibitors | |
| JP2020524158A (ja) | Ｓｓａｏ阻害剤 | |
| CN108864057B (zh) | 含有4-氨基吡唑结构的jak与hdac双靶点抑制剂及其制备方法和应用 | |
| WO2016208576A1 (ja) | （６Ｓ，９ａＳ）－Ｎ－ベンジル－６－［（４－ヒドロキシフェニル）メチル］－４，７－ジオキソ－８－（｛６－［３－（ピペラジン－１－イル）アゼチジン－１－イル］ピリジン－２－イル｝メチル）－２－（プロプ－２－エン－１－イル）－オクタヒドロ－１Ｈ－ピラジノ［２，１－ｃ］［１，２，４］トリアジン－１－カルボキサミド化合物の結晶 | |
| JP2009242437A (ja) | スルホンアミド誘導体 | |
| EA024295B1 (ru) | N-[4-(1H-ПИРАЗОЛО[3,4-b]ПИРАЗИН-6-ИЛ)ФЕНИЛ]СУЛЬФОНАМИДЫ И ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ЛЕКАРСТВЕННЫХ СРЕДСТВ | |
| CN115304583B (zh) | 靶向抑制clk2的5-吡啶-1h-吲唑类化合物及其应用 | |
| Ansari et al. | Exploration of Pd-catalysed four-component tandem reaction for one-pot assembly of pyrazolo [1, 5-c] quinazolines as potential EGFR inhibitors | |
| US20040132786A1 (en) | Differential tumor cytotoxicity compounds and compositions | |
| CN110407770B (zh) | 3-取代-1,5-苯并氮杂䓬类化合物及其药物用途 | |
| CN108774218A (zh) | 1,3,4-恶二唑结构的嘧啶类抗肿瘤化合物及其制备方法和应用 | |
| CN107973783B (zh) | 作为erk抑制剂的苯胺嘧啶衍生物 | |
| CN110950869B (zh) | 一种作用于QC和GSK-3β的多靶向抑制剂的制备方法及其应用 | |
| US20170240535A1 (en) | Hdac1/2 inhibitors for the treatment of neurodegenerative and/or cognitive disorders | |
| JP2013508323A (ja) | 合成大環状アミドｈｄａｃ６阻害剤化合物およびそれらの治療剤としての用途 | |
| KR20090053813A (ko) | 응고 인자 ＩＸａ 억제제로 사용되는 타르트레이트 유도체 | |
| CN114349735B (zh) | 一类O-GlcNAc转移酶抑制剂及其制备方法和应用 | |
| US9365575B2 (en) | Kinase inhibitors | |
| CN108358850A (zh) | PARP-1和Tankyrase1/2多靶点抑制剂、其制法及用途 | |
| CN111072586B (zh) | 一种n－羟基－3－取代－5－甲酰胺化合物及其制备方法和用途 | |
| CN110903292B (zh) | 一种作用于QC和GSK-3β的多靶向抑制剂 | |
| EP3241823B1 (en) | Pyrrole amide compound, preparation method therefor, and use 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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |