CN116332871A - 一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物及其应用 - Google Patents
一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物及其应用 Download PDFInfo
- Publication number
- CN116332871A CN116332871A CN202310134987.5A CN202310134987A CN116332871A CN 116332871 A CN116332871 A CN 116332871A CN 202310134987 A CN202310134987 A CN 202310134987A CN 116332871 A CN116332871 A CN 116332871A
- Authority
- CN
- China
- Prior art keywords
- compound
- hydrogen
- mmol
- ethyl acetate
- stirred
- 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
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 title claims abstract description 25
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title claims abstract description 19
- 230000017074 necrotic cell death Effects 0.000 title abstract description 35
- 230000002401 inhibitory effect Effects 0.000 title description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 49
- 239000003814 drug Substances 0.000 claims abstract description 22
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 16
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 206010069351 acute lung injury Diseases 0.000 claims abstract description 7
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 137
- 229910052739 hydrogen Inorganic materials 0.000 claims description 44
- 239000001257 hydrogen Substances 0.000 claims description 44
- -1 cyclohexyl-substituted benzothiazole Chemical class 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 claims description 21
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 claims description 21
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical group 0.000 claims description 12
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- 230000006907 apoptotic process Effects 0.000 claims description 5
- 229940043355 kinase inhibitor Drugs 0.000 claims description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 claims description 5
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 3
- 229940088872 Apoptosis inhibitor Drugs 0.000 claims 1
- 239000000158 apoptosis inhibitor Substances 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- 239000003112 inhibitor Substances 0.000 abstract description 10
- 208000015181 infectious disease Diseases 0.000 abstract description 4
- 230000003412 degenerative effect Effects 0.000 abstract description 3
- 230000002458 infectious effect Effects 0.000 abstract description 3
- 230000000302 ischemic effect Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 218
- 239000000243 solution Substances 0.000 description 83
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 48
- 238000006243 chemical reaction Methods 0.000 description 47
- 230000002829 reductive effect Effects 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 39
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 38
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- 239000007787 solid Substances 0.000 description 38
- 239000012043 crude product Substances 0.000 description 36
- 239000003208 petroleum Substances 0.000 description 36
- 239000003480 eluent Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 238000010898 silica gel chromatography Methods 0.000 description 32
- 238000012544 monitoring process Methods 0.000 description 30
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 29
- 241000699670 Mus sp. Species 0.000 description 24
- 125000005605 benzo group Chemical group 0.000 description 24
- 210000004072 lung Anatomy 0.000 description 24
- 229910052757 nitrogen Inorganic materials 0.000 description 24
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 24
- 241000699666 Mus <mouse, genus> Species 0.000 description 17
- 230000000694 effects Effects 0.000 description 16
- 230000000052 comparative effect Effects 0.000 description 14
- 108090001005 Interleukin-6 Proteins 0.000 description 13
- PNZXMIKHJXIPEK-UHFFFAOYSA-N cyclohexanecarboxamide Chemical compound NC(=O)C1CCCCC1 PNZXMIKHJXIPEK-UHFFFAOYSA-N 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000012530 fluid Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 229940125898 compound 5 Drugs 0.000 description 8
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 7
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 7
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 229940126214 compound 3 Drugs 0.000 description 7
- 238000010586 diagram Methods 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 101001089266 Homo sapiens Receptor-interacting serine/threonine-protein kinase 3 Proteins 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 102100033729 Receptor-interacting serine/threonine-protein kinase 3 Human genes 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 5
- 238000003782 apoptosis assay Methods 0.000 description 5
- 229910052801 chlorine Inorganic materials 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 239000011737 fluorine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000010791 quenching Methods 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 208000004852 Lung Injury Diseases 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 206010069363 Traumatic lung injury Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 230000030833 cell death Effects 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000004054 inflammatory process Effects 0.000 description 4
- 231100000515 lung injury Toxicity 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000005522 programmed cell death Effects 0.000 description 4
- 230000001681 protective effect Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 3
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 3
- 238000008157 ELISA kit Methods 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102000001253 Protein Kinase Human genes 0.000 description 3
- MIFGOLAMNLSLGH-QOKNQOGYSA-N Z-Val-Ala-Asp(OMe)-CH2F Chemical compound COC(=O)C[C@@H](C(=O)CF)NC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)OCC1=CC=CC=C1 MIFGOLAMNLSLGH-QOKNQOGYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000011324 bead Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 3
- 229940116357 potassium thiocyanate Drugs 0.000 description 3
- 108060006633 protein kinase Proteins 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- JSGHMGKJNZTKGF-UHFFFAOYSA-N 3-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1CCCC(C(O)=O)C1 JSGHMGKJNZTKGF-UHFFFAOYSA-N 0.000 description 2
- KXMRDHPZQHAXML-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclohexane-1-carboxylic acid Chemical compound CC(C)(C)OC(=O)NC1CCC(C(O)=O)CC1 KXMRDHPZQHAXML-UHFFFAOYSA-N 0.000 description 2
- TXUWMXQFNYDOEZ-UHFFFAOYSA-N 5-(1H-indol-3-ylmethyl)-3-methyl-2-sulfanylidene-4-imidazolidinone Chemical compound O=C1N(C)C(=S)NC1CC1=CNC2=CC=CC=C12 TXUWMXQFNYDOEZ-UHFFFAOYSA-N 0.000 description 2
- 101100034357 Arabidopsis thaliana RIPK gene Proteins 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 208000031636 Body Temperature Changes Diseases 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 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 2
- 101001011663 Homo sapiens Mixed lineage kinase domain-like protein Proteins 0.000 description 2
- 102100030177 Mixed lineage kinase domain-like protein Human genes 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 229920001213 Polysorbate 20 Polymers 0.000 description 2
- 206010037423 Pulmonary oedema Diseases 0.000 description 2
- 238000011529 RT qPCR Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 2
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 239000002158 endotoxin Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000003304 gavage Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 208000005333 pulmonary edema Diseases 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000037816 tissue injury Diseases 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 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
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-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
- 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
- BLXXCCIBGGBDHI-UHFFFAOYSA-N 2-[3-(trifluoromethyl)phenyl]acetic acid Chemical compound OC(=O)CC1=CC=CC(C(F)(F)F)=C1 BLXXCCIBGGBDHI-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
- HQRSIMQXCAWAJB-UHFFFAOYSA-N 3,3,3-trifluoro-2-phenylpropanoic acid Chemical compound OC(=O)C(C(F)(F)F)C1=CC=CC=C1 HQRSIMQXCAWAJB-UHFFFAOYSA-N 0.000 description 1
- GYJREHMTTLYKRJ-UHFFFAOYSA-N 3-(2-fluorophenyl)-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C=1C=CC=CC=1COC(=O)NC(C(=O)O)CC1=CC=CC=C1F GYJREHMTTLYKRJ-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
- VJCSFNNTQGRAKH-UHFFFAOYSA-N 3-amino-4-fluorophenol Chemical compound NC1=CC(O)=CC=C1F VJCSFNNTQGRAKH-UHFFFAOYSA-N 0.000 description 1
- XYHHQIWETDSNOP-UHFFFAOYSA-N 4-bromobutanamide Chemical compound NC(=O)CCCBr XYHHQIWETDSNOP-UHFFFAOYSA-N 0.000 description 1
- ATQAGKAMBISZQM-HNNXBMFYSA-N 5-benzyl-N-[(3S)-7,9-difluoro-2-oxo-1,3,4,5-tetrahydro-1-benzazepin-3-yl]-1H-1,2,4-triazole-3-carboxamide Chemical compound FC1=CC2=C(NC(=O)[C@H](CC2)NC(=O)C2=NN=C(CC3=CC=CC=C3)N2)C(F)=C1 ATQAGKAMBISZQM-HNNXBMFYSA-N 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 108091007065 BIRCs Proteins 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 description 1
- 102000055031 Inhibitor of Apoptosis Proteins Human genes 0.000 description 1
- 108090000193 Interleukin-1 beta Proteins 0.000 description 1
- 102000003777 Interleukin-1 beta Human genes 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- 101001033286 Mus musculus Interleukin-1 beta Proteins 0.000 description 1
- 101001076414 Mus musculus Interleukin-6 Proteins 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
- 206010030113 Oedema Diseases 0.000 description 1
- 101150071716 PCSK1 gene Proteins 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000235648 Pichia Species 0.000 description 1
- 101710092490 Protein kinase 3 Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 206010037368 Pulmonary congestion Diseases 0.000 description 1
- 206010063837 Reperfusion injury Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 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 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 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
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 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
- 239000012148 binding buffer Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125773 compound 10 Drugs 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
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- XUZICJHIIJCKQQ-ZDUSSCGKSA-N eclitasertib Chemical compound C(C1=CC=CC=C1)C=1NC(=NN=1)C(=O)N[C@@H]1C(N(C2=C(OC1)C=CC=N2)C)=O XUZICJHIIJCKQQ-ZDUSSCGKSA-N 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000703 high-speed centrifugation Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 208000012947 ischemia reperfusion injury Diseases 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 230000021597 necroptosis Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 229940075439 smac mimetic Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical compound NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (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)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Oncology (AREA)
- Rheumatology (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明属于医药技术领域,具体地说,涉及一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物及其应用。
背景技术
细胞死亡是在细胞中观察到生理或病理现象,依形态学特征分为程序性和非程序性细胞死亡。程序性细胞死亡(programmed cell death,PCD)是多细胞生物体中,某些细胞在个体发育过程中受到基因严格调控的细胞死亡,是细胞主动、有序性的死亡方式,在发育的过程中通过程序性细胞死亡清除一些不再需要的结构,调控细胞数目来形成正常组织器官、维持机体稳态,还可以通过清除异常及有潜在危险的细胞发挥保护作用。非程序性细胞死亡又可称为坏死,是细胞受生物、物理或化学等因素刺激,发生以酶溶性变化为特点的因细胞感染或损伤而发生的细胞被动死亡。随着对细胞死亡机制的研究发现,存在着一种具有严格的“程序性调控”特征,使其有序发生的细胞坏死,即程序性细胞坏死(necroptosis)。
程序性细胞坏死是脊椎动物特有的,源于对病原体的二重防御,以确保机体能在应激条件下清除受损细胞维持自身组织平衡。许多研究表明,具有程序性细胞坏死特征的细胞死亡在人类病理中普遍存在,包括感染性疾病、缺血再灌注损伤、神经退行性疾病和肿瘤等一系列急性慢性疾病中,并受受体相互作用蛋白激酶1(receptor-interactingprotein kinase 1,RIPK1)及其下游介质受体相互作用蛋白激酶3(receptor-interactingprotein kinase 3,RIPK3)和混合系激酶区域样蛋白(mixed-lineage kinase domain-like protein,MLKL)的激酶活性控制。
因此,通过干预上述蛋白激酶靶点来进行临床疾病治疗是一种可行的策略。首创型RIPK1抑制剂Necrostatin-1(Nec-1)及其类似物在临床前研究中,已经对多种退行性疾病、炎症、癌症等疾病展示出明确的疗效。GSK3145095单独和与其他抗癌药组合进行了I/II期临床试验;DNL747已进入I期临床试验用于治疗阿尔兹海默症以及肌萎缩侧索硬化;DNL758是一种不透过大脑屏障的RIPK1抑制剂,目前用于治疗风湿性关节炎和牛皮癣等自身免疫疾病并对其进行临床前评估。然而,现有的程序性坏死抑制剂均存在着不同程度的缺陷,如活体抑制活性仍不够理想、药代性质不佳、口服生物利用度低等,还有一些无法透过血脑屏障进入中枢神经系统,或是因不能有效抑制鼠源RIPK1而难以实施临床前动物试验,这些缺点均限制了其进一步的研究与临床应用。
因此,鉴定并发现有效的程序性细胞坏死抑制剂,对于治疗与程序性细胞坏死相关的疾病具有十分重要的意义。
发明内容
本发明的目的是提供一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物。
本发明第二个目的是提供一种所述环己基取代苯并噻唑类衍生物或其药用盐在制备RIPK1激酶抑制剂中的应用。
本发明的第三个目的是提供一种所述环己基取代苯并噻唑类衍生物在制备预防或治疗程序性细胞坏死的药物或在制备程序性细胞坏死抑制剂中的应用。
为了实现上述目的,本发明采用的技术方案如下:
本发明的第一方面提供了一种环己基取代苯并噻唑类衍生物或其药用盐,结构如通式I所示:
R7选自氢、C1~C10烷基;
R11选自氢、卤素(氟、氯、溴、碘);
R12选自氢、卤素(氟、氯、溴、碘);
R13选自氢、卤素(氟、氯、溴、碘);
R14选自氢、卤素(氟、氯、溴、碘);
R15选自氢、卤素(氟、氯、溴、碘);
R16选自氢、C1~C10烷基;
R1、R2、R3、R4、R5不能同时为氢。
较优选的,所述环己基取代苯并噻唑类衍生物中,
R8选自甲基、乙基、异丙基、叔丁基、
R9选自甲基、乙基、异丙基、叔丁基、正丙基、正丁基、异丁基、
R10选自甲基、乙基、异丙基、叔丁基、正丙基、正丁基、异丁基、
R1、R2、R3、R4、R5不能同时为氢。
最优选的,所述环己基取代苯并噻唑类衍生物选自以下化合物的一种:
本发明的第二方面提供了一种所述环己基取代苯并噻唑类衍生物或其药用盐在制备RIPK1激酶抑制剂中的应用。
本发明的第三方面提供了一种所述环己基取代苯并噻唑类衍生物在制备预防或治疗程序性细胞坏死的药物或在制备程序性细胞坏死抑制剂中的应用。
本发明的第四方面提供了一种所述环己基取代苯并噻唑类衍生物或其药用盐在制备治疗程序性细胞坏死相关疾病的药物中的应用,或在制备治疗由RIPK1激酶紊乱、过度激活或过度相互作用引起的疾病的药物中的应用。
本发明的第五方面提供了一种所述环己基取代苯并噻唑类衍生物或其药用盐在制备治疗炎症型急性肺损伤的药物或在制备抗炎的药物中的应用。
由于采用上述技术方案,本发明具有以下优点和有益效果:
本发明的全新型结构的环己基取代苯并噻唑类衍生物可以用于预防或治疗程序性细胞坏死所引起的炎症性、感染性、缺血性或退行性相关疾病,可以作为预防或治疗程序性细胞坏死的药物或作为程序性细胞坏死抑制剂使用。
本发明提供了该类新型环己基取代苯并噻唑类衍生物或其药用盐可以作为程序性细胞坏死相关激酶抑制剂,还可以作为程序性细胞坏死抑制剂,有效地抑制细胞坏死,达到纳摩尔级,其中活性最好的化合物I-7的抗细胞坏死活性达到22.4纳摩尔,特别的是化合物I-7在体内也表现出了良好的活性,可以很好的保护小鼠全身炎症反应综合症(SIRS)模型和小鼠急性肺损伤模型;可以用于制备程序性细胞坏死相关疾病的防治药物,或制备由程序性细胞坏死相关激酶紊乱、过度激活或过度相互作用引起的炎症性、感染性、缺血性或退行性相关疾病或组织损伤的药物。本发明合成简单,合成成本低。
附图说明
图1是小鼠SIRS模型各组小鼠体温变化、生存率和各组小鼠血清中IL-1β和IL-6的结果示意图。
图2是小鼠ALI模型各组肺中参数测定结果示意图。
图3是小鼠ALI模型各组肺泡灌洗液中炎症因子IL-6、TNFα水平和小鼠ALI模型各组肺组织IL-6、TNFα水平的结果示意图。
图4是小鼠ALI模型各组WesternBlot结果示意图。
具体实施方式
为了更清楚地说明本发明,下面结合优选实施例对本发明做进一步的说明。本领域技术人员应当理解,下面所具体描述的内容是说明性的而非限制性的,不应以此限制本发明的保护范围。
下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。所有原料未注明合成方法的均购自探索平台、毕得、Sigma-Aldrich等厂家,均为分析纯。
以下化合物的制备从原料到最终产物,没有涉及手心中心的反应,因此最终产物的构型与原料3-(BOC-氨基)环己甲酸和4-(BOC-氨基)环己甲酸的构型保持一致。
实施例1
叔丁基(3-((5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)氨甲酰基)环己基)氨基甲酸酯即化合物I-1的制备:
步骤a:2-氟-5-(2-氟-4-硝基苯氧基)苯胺化合物2的制备
将化合物1(10.0g,63mmol)、3-氨基-4-氟苯酚(8.0g,63mmol)和碳酸钾(21.7g,157mmol)加到二甲基亚砜(20mL)中,85℃加热搅拌2小时,TLC监测反应完全后加水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-25%乙酸乙酯的石油醚溶液),得15.3g白色固体化合物2,收率91.0%。
步骤b:化合物3的制备
将化合物2(15.3g,57.48mmol)、三氟甲基苯乙酸(17.6g,86.22mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(43.7g,114.96mmol)溶于吡啶(15ml)溶液中,氮气保护条件85℃加热搅拌12小时,TLC监测反应完全后待反应冷却至室温,加水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-10%乙酸乙酯的石油醚溶液),得13.17g白色固体化合物3,收率50.7%。
步骤c:化合物4的制备
将化合物3(15.3g,33.8mmol)溶于乙醇(12mL)中,将氯化铵(7.2g,135.2mmol)溶于水(3ml)然后滴加于含化合物3的乙醇溶液中,分批加入铁粉(7.6g,135.2mmol),80℃加热搅拌7小时,TLC监测反应完全后待反应冷却至室温,硅藻土过滤反应液,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,在减压下浓缩,得13.8g白色固体化合物4,收率96.8%。
步骤d:化合物5的制备
将硫氰酸钾(12.7g,130.8mmol)溶于醋酸(10ml)中室温搅拌10min,加入化合物4(13.8g,32.7mmol)和溴素(2.5ml,49mmol),室温搅拌10小时,TLC监测反应完全后加水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-20%乙酸乙酯的石油醚溶液),得13.7g黄色固体化合物5,收率87.6%。
步骤e:化合物I-1的制备
将化合物5(0.20g,0.42mmol)、3-(BOC-氨基)环己甲酸(0.20g,0.84mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.32g,0.84mmol)加到吡啶(2ml)中,氮气保护条件85℃加热搅拌12小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.16g白色固体化合物Ⅰ-1,收率53.3%。1HNMR(500MHz,DMSO-d6)δ12.30(s,1H),10.12(s,1H),7.86(d,J=8.1Hz,1H),7.73(d,J=11.3Hz,1H),7.65(d,J=3.5Hz,2H),7.58(t,J=5.8Hz,2H),7.57–7.49(m,1H),7.25(t,J=10.5,9.0Hz,1H),6.75(m,1H),6.63(d,J=6.3Hz,1H),3.83(s,2H),3.67(s,1H),2.85(s,1H),1.6(m,3H),1.56(s,2H),1.49(s,3H),1.37(s,8H),1.24–1.12(m,1H).MS:[M+H]+m/zcalcdforC34H33F5N4O5S:704.2,found:705.6.
实施例2
叔丁基(4-((5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)氨甲酰基)环己基)氨基甲酸酯即化合物I-2的制备:
将化合物5(5g,10.5mmol)、4-(BOC-氨基)环己甲酸(5g,21mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(8g,21mmol)加到吡啶(20ml)中,氮气保护条件85℃加热搅拌12小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得4.2g白色固体化合物Ⅰ-2,收率53.3%。1HNMR(500MHz,DMSO-d6)δ12.36(s,1H),10.11(s,1H),7.85(d,J=8.1,1.8Hz,1H),7.73(d,J=11.3Hz,1H),7.69–7.63(m,2H),7.60–7.56(m,2H),7.55–7.49(m,1H),7.25(m,1H),6.75(m,2H),3.83(s,2H),3.27–3.08(m,1H),2.43(m,1H),1.85(m,4H),1.51–1.40(m,2H),1.36(d,J=2.8Hz,9H),1.22–1.11(m,2H).MS:[M+H]+m/zcalcdforC34H33F5N4O5S:704.2,found:705.6.
实施例3
3-(环丙烷甲酰胺)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰胺基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-3的制备:
步骤f:化合物7的制备
在室温条件下,将化合物I-1(0.15g,0.21mmol)溶于二氯甲烷(2ml),缓慢滴加三氟乙酸(0.6ml),反应液在室温下搅拌30分钟,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,在减压下浓缩得到0.1g白色固体化合物7,收率76.9%。
步骤g:化合物I-3的制备
将化合物7(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)上搅拌10分钟,缓慢滴加环丙基甲酰氯(0.03ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.044g白色固体化合物Ⅰ-3,收率38.6%。1HNMR(600MHz,DMSO-d6)δ12.76(s,1H),10.12(s,1H),7.93(s,1H),7.85(s,1H),7.72(s,1H),7.66(s,2H),7.59(d,J=9.5Hz,2H),7.57–7.51(m,1H),7.27(s,1H),6.78(s,1H),3.99(s,1H),3.84(s,2H),2.89(s,1H),1.74(s,3H),1.63(s,3H),1.55(s,3H),1.49(s,1H),0.65(s,2H),0.62(s,1H).MS:[M+H]+m/zcalcdforC33H29F5N4O4S:672.7,found:673.7.
实施例4
3-(环丙烷甲酰胺)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰胺基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-4的制备:
步骤h:化合物9的制备
在室温条件下,将化合物I-2(4.0g,5.68mmol)溶于二氯甲烷(8ml),缓慢滴加三氟乙酸(2.4ml),反应液在室温下搅拌30分钟,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,在减压下浓缩得到2.8g白色固体化合物9,收率82.4%。
步骤i:化合物I-4的制备
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)上搅拌10分钟,缓慢滴加化合物8(0.03ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.045g白色固体化合物Ⅰ-4,收率39.5%。1HNMR(600MHz,DMSO-d6)δ12.39(s,1H),10.11(s,1H),8.02(d,J=7.4Hz,1H),7.86(d,J=8.1Hz,1H),7.74(d,J=11.3Hz,1H),7.69–7.67(m,1H),7.59(d,J=7.8Hz,2H),7.56–7.54(t,J=15.8Hz,1H),7.41–7.36(m,2H),6.78–6.75(m,1H),3.85(s,2H),2.65–2.61(m,1H),1.91–1.86(m,3H),1.68–1.65(m,5H),1.56–1.52(m,2H),0.65–0.63(m,2H),0.61–0.58(m,2H).MS:[M+H]+m/zcalcdforC33H29F5N4O4S:672.7,found:673.7.
实施例5
N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)-4-羟基环己烷-1-甲酰胺即化合物I-5的制备:
将化合物5(0.10g,0.21mmol)、4-羟基环己烷羧酸(0.061g,0.42mmol)和2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.16g,0.42mmol)加到吡啶(2ml)中,氮气保护条件85℃加热搅拌12小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.11g白色固体化合物Ⅰ-5,收率84.6%。1HNMR(500MHz,DMSO-d6)δ12.34(s,1H),10.10(s,1H),7.85(d,J=8.1Hz,1H),7.73(d,J=11.4Hz,1H),7.70–7.63(m,2H),7.58(m,2H),7.56–7.49(m,1H),7.25(m,1H),6.75(m,1H),4.36(d,J=3.2Hz,1H),3.84(s,2H),3.77(s,1H),2.59–2.51(m,1H),1.93–1.75(m,2H),1.72–1.61(m,2H),1.61–1.50(m,2H),1.45(t,J=12.8Hz,2H).MS:[M+H]+m/zcalcdforC29H24F5N3O4S:605.1,found606.3.
实施例6
N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)-4-异丁胺二环己烷-1-甲酰胺即化合物I-6的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)上搅拌10分钟,缓慢滴加化合物10(0.035mg,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.063g白色固体化合物Ⅰ-6,收率54.8%。1HNMR(600MHz,DMSO-d6)δ12.37(s,1H),10.11(s,1H),7.86(d,J=8.2Hz,1H),7.8(d,J=11.4Hz,1H),7.68–7.68(m,3H),7.60–7.58(m,2H),7.55–7.52(t,J=15.4Hz,1H),7.28–7.25(m,1H),6.78–6.75(m,1H),3.85(s,2H),3.79–3.76(s,1H),2.64–2.61(m,1H),2.45–2.41(m,1H),1.91–1.83(m,3H),1.66–1.63(m,3H),1.54–1.49(m,2H),0.98–0.96(m,6H).MS:[M+H]+m/zcalcdforC33H31F5N4O4S:674.2,found675.4.
实施例7
4-(乙基磺胺基)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰胺基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-5的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物11(0.042mg,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.074g白色固体化合物Ⅰ-7,收率62.7%。1HNMR(600MHz,DMSO-d6)δ12.39(s,1H),10.11(s,1H),7.86(d,J=8.2Hz,1H),7.74(d,J=11.5Hz,1H),7.68–7.66(m,2H),7.60–7.58(m,2H),7.55–7.53(t,J=15.2Hz,1H),7.28–7.25(m,2H),6.78–6.75(m,1H),3.85(s,2H),3.82–3.79(m,2H),2.74–2.70(m,2H),2.00–1.95(m,2H),1.77–1.72(m,2H),1.69–1.59(m,4H),1.29–1.22(m,3H).MS:[M+H]+m/zcalcdforC31H29F5N4O5S2:696.1,found697.4.
实施例8
苄基(4-((5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰胺基)苯氧基)苯并[d]噻唑-2-基)氨甲酰)环己基)氨基甲酸酯即化合物I-8的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物12(0.047ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.076g白色固体化合物Ⅰ-8,收率60.3%。1HNMR(600MHz,DMSO-d6)δ12.33(s,1H),10.11(s,1H),7.86(d,J=8.1Hz,1H),7.73(d,J=11.4Hz,1H),7.68–7.66(m,2H),7.60–7.58(m,2H),7.55–7.52(t,J=15.6Hz,1H),7.36(d,J=4.6Hz,4H),7.31–7.24(m,3H),6.77–6.75(m,1H),5.01(s,2H),3.85(s,2H),3.62–3.57(m,1H),2.63–2.59(m,1H),1.90–1.85(m,2H),1.72–1.67(m,2H),1.64–1.60(m,2H),1.58–1.53(m,2H).MS:[M+H]+m/zcalcdfor C37H31F5N4O5S:738.7,found739.9.
实施例9
4-(3-氯丙烷酰胺)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰胺基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-9的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物13(0.042ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.077g白色固体化合物Ⅰ-9,收率65.3%。1HNMR(500MHz,DMSO-d6)δ12.37(s,1H),10.11(s,1H),7.96(d,J=7.3Hz,1H),7.84(d,J=8.1Hz,1H),7.72(d,J=11.3Hz,1H),7.65–7.63(m,2H),7.58–7.56(m,2H),7.53–7.50(t,J=14.8Hz,1H),7.26–7.22(m,1H),6.76–6.73(m,1H),3.82(s,2H),3.77–3.74(t,J=12.6Hz,2H),2.59–2.56(t,J=12.6Hz,2H),1.90–1.79(m,3H),1.65–1.63(m,4H),1.55–1.49(m,3H).MS:[M+H]+m/zcalcdforC32H28F5N4O4S:695.1,found696.4.
实施例10
4-氟-N-(4-((5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)氨甲酰基)环己基)苯甲酰胺即化合物I-10的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物14(0.039ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.086g白色固体化合物Ⅰ-10,收率65.2%。1HNMR(600MHz,DMSO-d6)δ12.40(s,1H),10.12(s,1H),8.25(d,J=7.2Hz,1H),7.96–7.91(m,2H),7.86(d,J=8.1Hz,1H),7.75(d,J=11.3Hz,1H),7.70(dd,J=6.4,3.1Hz,1H),7.67(d,J=2.3Hz,1H),7.61–7.57(m,2H),7.53(t,J=7.7Hz,1H),7.28–7.22(m,2H),6.77(m,1H),4.04–3.95(m,1H),3.86(s,2H),2.73(m,1H),2.07–1.99(m,2H),1.81(m,2H),1.68(m,4H),1.16(t,J=7.1Hz,1H).MS:[M+H]+m/zcalcdforC36H28F6N4O4S:726.2,found727.3.
实施例11
N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)-4-丙酰胺环己烷-1-甲酰胺即化合物I-11的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物15(0.030ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.063g白色固体化合物Ⅰ-11,收率56.2%。1HNMR(500MHz,DMSO-d6)δ12.37(s,1H),10.11(s,1H),7.85(d,J=8.0Hz,1H),7.72(m,2H),7.69–7.63(m,2H),7.61–7.56(m,2H),7.56–7.50(m,1H),7.26(m,1H),6.75(m,1H),3.83(s,2H),3.79(d,J=6.6Hz,1H),2.65–2.57(m,1H),1.97(s,2H),1.67–1.59(m,4H),1.51(m,2H),1.15(t,J=7.1Hz,2H),0.96(t,J=7.6Hz,3H).MS:[M+H]+m/zcalcdforC32H29F5N4O4S:660.2,found661.5.
实施例12
4-(3-溴丙烷酰胺)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰胺基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-12的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物16(0.042ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.087g白色固体化合物Ⅰ-12,收率69.0%。1HNMR(600MHz,DMSO-d6)δ12.39(s,1H),10.13(s,1H),7.97(d,J=7.4Hz,1H),7.85(d,J=7.9Hz,1H),7.74(d,J=11.3Hz,1H),7.66–7.64(m,2H),7.60–7.57(m,2H),7.55–7.52(t,J=15.52Hz,1H),6.77–6.75(m,1H),3.84(s,2H),3.78–3.76(t,J=12.9Hz,2H),3.2(d,J=7.5Hz,1H),2.96(d,J=7.3Hz,1H),2.61–2.58(m,2H),1.67–1.64(m,4H),0.86–0.81(m,4H).MS:[M+H]+m/zcalcdforC32H28BrF5N4O4S:739.6,found740.7.
实施例13
4-(4-溴代丁酰胺)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰胺基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-13的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物17(0.038ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.067g白色固体化合物Ⅰ-13,收率54.9%。1HNMR(600MHz,DMSO-d6)δ12.36(s,1H),10.09(s,1H),7.65(s,1H),7.62(s,2H),7.59–7.57(m,3H),7.56–7.51(m,1H),7.28(d,J=11.8Hz,1H),7.23–7.19(t,J=19.3Hz,1H),6.70–6.67(m,1H),3.83(s,2H),3.65–3.60(m,3H),2.15–2.12(m,3H),2.01–1.96(m,2H),1.92–1.86(m,4H),0.91–0.90(m,4H)..MS:[M+H]+m/zcalcdforC33H30BrF5N4O4S:753.6,found754.7.
实施例14
N-(4-((5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)氨甲酰基)环己基)噻吩-2-甲酰胺即化合物I-14的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物18(0.035ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.088g白色固体化合物Ⅰ-14,收率72.1%。1HNMR(500MHz,DMSO-d6)δ12.40(s,1H),10.11(s,1H),8.21(d,J=7.4Hz,1H),7.87–7.82(m,2H),7.74(d,J=11.3Hz,1H),7.70(m,1H),7.69–7.64(m,2H),7.58(t,J=6.1Hz,2H),7.55–7.49(m,1H),7.26(m,1H),7.10(dd,J=5.0,3.7Hz,1H),6.76(m,1H),3.91(m,1H),3.83(s,2H),2.72(d,J=4.8Hz,1H),2.00(m,2H),1.76(m,2H),1.65(m,4H).MS:[M+H]+m/zcalcdforC34H27F5N4O4S2:714.1,found715.3.
实施例15
4-(环戊烷羰基氨基)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-15的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物19(0.040ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.063g白色固体化合物Ⅰ-15,收率52.9%。1HNMR(500MHz,DMSO-d6)δ12.36(s,1H),10.10(s,1H),7.85(d,J=8.2Hz,1H),7.73(d,J=11.4Hz,1H),7.67–7.64(m,3H),7.59–7.57(m,2H),7.54–7.51(t,J=15.1Hz,2H),6.76–6.73(m,1H),3.83(s,2H),3.77(s,1H),2.62–2.56(m,2H),1.87–1.81(m,2H),1.70–1.66(m,2H),1.63–1.54(m,8H),1.53–1.45(m,4H).MS:[M+H]+m/zcalcdforC35H33F5N4O4S:700.2,found701.4.
实施例16
4-丁酰胺-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-16的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物20(0.034ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.073g白色固体化合物Ⅰ-16,收率63.5%。1HNMR(600MHz,DMSO-d6)δ12.36(s,1H),10.11(s,1H),1HNMR(600MHz,DMSO-d6)δ12.37(s,1H),10.12(s,1H),7.85(d,J=8.1Hz,1H),7.73(m,2H),7.69–7.65(m,3H),7.60–7.56(m,2H),7.56–7.51(m,1H),7.26(m,1H),6.76(m,1H),3.85(s,3H),3.82(m,1H),2.62(m,1H),2.06(t,J=7.3Hz,2H),1.86(m,3H),1.64(m,4H),1.49(m,4H).MS:[M+H]+m/zcalcdforC33H31F5N4O4S:674.2,found675.4.
实施例17
4-戊酰胺-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-17的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物21(0.040ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.074g白色固体化合物Ⅰ-17,收率60.7%。1HNMR(500MHz,DMSO-d6)δ12.37(s,1H),10.11(s,1H),7.85(d,J=8.1Hz,1H),7.73(m,2H),7.70–7.63(m,2H),7.58(t,J=6.4Hz,2H),7.56–7.50(m,1H),7.26(m,2H),6.75(m,1H),3.83(s,2H),3.79(s,1H),2.61(d,J=9.8Hz,1H),2.07(t,J=7.4Hz,2H),1.83(m,2H),1.62(d,J=11.5Hz,4H),1.55–1.47(m,2H),1.47–1.39(m,2H),1.28–1.18(m,2H),0.84(t,J=7.3Hz,3H).MS:[M+H]+m/zcalcdforC34H33F5N4O4S:688.2,found689.5.
实施例18
N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)-4-(3-甲基丁酰胺)环己烷-1-甲酰胺即化合物I-18的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物22(0.040ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.066g白色固体化合物Ⅰ-18,收率56.4%。1HNMR(600MHz,DMSO-d6)δ12.37(s,1H),10.11(s,1H),7.85(m,1H),7.74(m,2H),7.69–7.64(m,2H),7.59(d,J=7.8Hz,2H),7.56–7.51(m,1H),7.26(m,1H),6.76(m,1H),3.84(s,2H),3.81(d,J=7.8Hz,1H),2.62(m,1H),1.97(d,J=3.8Hz,3H),1.85(m,2H),1.53(m,2H),1.28(d,J=1.1Hz,2H),1.24(d,J=1.1Hz,2H),0.86(d,J=1.2Hz,3H),0.85(d,J=1.1Hz,3H).MS:[M+H]+m/zcalcdforC34H33F5N4O4S:688.7,found689.7.
实施例19
N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)-4-(2-甲氧基乙酰氨基)环己烷-1-甲酰胺即化合物I-19的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物23(0.030ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.079g白色固体化合物Ⅰ-19,收率67.5%。1HNMR(500MHz,DMSO-d6)δ12.38(s,1H),10.11(s,1H),7.86(d,J=8.1Hz,1H),7.74(d,J=11.3Hz,1H),7.69–7.63(m,2H),7.60–7.56(m,2H),7.53(m,2H),7.25(m,1H),6.75(m,1H),3.84(s,3H),3.78(s,2H),3.28(d,J=1.8Hz,3H),2.64(m,1H),1.86(m,2H),1.72–1.61(m,3H),1.60–1.48(m,2H),1.39–1.18(m,1H).MS:[M+H]+m/zcalcdforC32H29F5N4O5S:676.7,found677.6.
实施例20
4-(2-乙氧基乙酰氨基)-N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)环己烷-1-甲酰胺即化合物I-20的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物24(0.030ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.074g白色固体化合物Ⅰ-20,收率64.3%。1HNMR(500MHz,DMSO-d6)δ12.38(s,1H),10.11(s,1H),7.84(d,J=8.1Hz,1H),7.72(d,J=11.4Hz,1H),7.69–7.63(m,2H),7.58(d,J=7.8Hz,2H),7.55–7.48(m,2H),7.25(dd,J=10.5,9.0Hz,1H),6.75(m,1H),3.83(s,2H),3.78(s,2H),3.65–3.55(m,2H),3.47(d,J=7.0Hz,2H),1.96–1.85(m,2H),1.85–1.74(m,2H),1.48(m,2H),1.34(m,2H),1.13(t,J=7.0Hz,3H).MS:[M+H]+m/zcalcdforC33H31F5N4O5S:690.7,found691.7.
实施例21
2-((4-((5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)氨甲酰基)环己基)氨基)-2-氧乙基乙酸酯即化合物I-21的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物25(0.036ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.077g白色固体化合物Ⅰ-21,收率64.2%。1HNMR(500MHz,DMSO-d6)δ12.39(s,1H),10.11(s,1H),7.96(d,J=7.4Hz,1H),7.85(d,J=8.1Hz,1H),7.74(d,J=11.3Hz,1H),7.66(d,J=8.0Hz,2H),7.61–7.56(m,2H),7.56–7.49(m,1H),7.25(dd,J=10.5,9.0Hz,1H),6.75(m,1H),4.44(s,2H),3.84(s,2H),3.81(d,J=6.3Hz,1H),2.63(m,1H),2.05(s,3H),1.84(m,2H),1.65(m,4H),1.58–1.48(m,2H).MS:[M+H]+m/zcalcdforC33H29F5N4O6S:704.2,found705.3.
实施例22
N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)-4-(丙基磺酰胺)环己烷-1-甲酰胺即化合物I-22的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物26(0.044ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.089g白色固体化合物Ⅰ-22,收率73.6%。1HNMR(500MHz,DMSO-d6)δ12.37(s,1H),10.11(s,1H),7.85(d,J=8.1Hz,1H),7.74(d,J=11.3Hz,1H),7.68–7.63(m,2H),7.58(t,J=6.6Hz,2H),7.55–7.50(m,1H),7.25(dd,J=10.6,9.0Hz,1H),7.04(d,J=7.8Hz,1H),6.75(m,1H),3.83(s,2H),3.10–3.02(m,1H),2.98–2.92(m,2H),2.46–2.39(m,1H),1.90(m,4H),1.71–1.61(m,2H),1.52–1.42(m,2H),1.24(s,2H),0.96(t,J=7.4Hz,3H).MS:[M+H]+m/zcalcdforC32H31F5N4O5S2:710.2,found711.3.
实施例23
N-(5-氟-6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)-4-(苯基磺酰胺基)环己烷-1-甲酰胺即化合物I-23的制备:
将化合物9(0.1g,0.17mmol)溶于超干吡啶(2ml)中,在氮气保护下,于冰浴(0℃)搅拌10分钟,缓慢滴加化合物27(0.042ml,0.33mmol),0℃搅拌1小时后室温搅拌5小时,TLC监测反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥,过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.098g白色固体化合物Ⅰ-23,收率77.2%。1HNMR(500MHz,DMSO-d6)δ12.32(s,1H),10.11(s,1H),7.86–7.78(m,3H),7.71(t,J=9.4Hz,2H),7.64(t,J=3.3Hz,2H),7.59(m,5H),7.52(t,J=7.6Hz,1H),7.25(t,J=9.8Hz,1H),6.74(m,1H),3.83(s,2H),2.95(m,1H),2.36(m,1H),1.79(d,J=12.7Hz,2H),1.72–1.55(m,2H),1.35(m,2H),1.16(m,2H).MS:[M+H]+m/zcalcdforC35H29F5N4O5S2:744.1,found745.2.
对比例1
SZM-594的制备
(S)-3-苄基-N-(5-甲基-4-氧代-2,3,4,5-四氢苯并[b][1,4]恶唑啉-3-基)-1H-1,2,4-三唑-5-甲酰胺的制备即化合物SZM-594的制备:
合成路线如下:
步骤a:化合物3的制备
将化合物1(1.500g,13.7mmol)、化合物2(1.460mL,13.7mmol)和碳酸钾(5.699g,41.2mmol)加到20mL二甲基亚砜中,85℃加热搅拌2小时,TLC监测反应完全后加水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥、过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-10%乙酸乙酯的石油醚溶液),得2.972g白色固体化合物3,收率93.9%。
步骤b:化合物4的制备
将化合物3(2.892g,12.56mmol)和三氟乙酸酐(3.540mL,25.12mmol)溶于20mL四氢呋喃溶液中,室温搅拌过夜。TLC监测,反应完全后减压浓缩,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥、过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-10%乙酸乙酯的石油醚溶液),得4.006g白色固体化合物4,收率97.63%。
步骤c:化合物5的制备
将化合物4(4.000g,12.26mmol)溶于20mL乙醇中,将氯化铵溶于5mL水中,然后将氯化铵水溶液加入化合物4的乙醇溶液中,加热至80℃后将铁粉(2.746g,49.04mmol)分批加入,继续搅拌5小时。TLC监测,反应完全后减压浓缩,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥、过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得2.372g白色固体化合物5,收率55.12%。
步骤d:化合物6的制备:
在室温条件下,将硫氰酸钾(2.490g,25.65mmol)溶于20mL乙酸中,室温搅拌10分钟,再将化合物5(1.900g,6.41mmol)和溴素(431.0μL,9.62mmol)加入到硫氰酸钾的乙酸溶液中,反应液在室温下继续搅拌3小时,TLC监测,反应完全后用水淬灭,饱和碳酸氢钠溶液调至中性,乙酸乙酯萃取,并用饱和氯化钠溶液洗涤3次,无水硫酸钠干燥、过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得2.080g白色固体化合物6,收率91.28%。
步骤e:化合物7的制备:
在室温条件下,将化合物6(1.555g,4.40mmol)溶于20mL超干吡啶中,氮气保护下0℃搅拌10分钟,再将环丙基甲酰氯(799.0μL,8.80mmol)滴加到化合物6的吡啶溶液中,反应液在0℃下继续搅拌1小时后室温搅拌过夜,TLC监测,反应完全后用水淬灭,乙酸乙酯萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥、过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得1.267g白色固体化合物7,收率68.31%。
步骤f:化合物8的制备:
在室温条件下,将化合物7(0.688g,1.63mmol)溶于10mL乙醇中,在0℃下将硼氢化钠(1.235g,32.65mmol)分批加入,反应体系在0℃下继续搅拌1小时后室温搅拌1小时,TLC监测,反应完全后用减压浓缩,乙酸乙酯稀萃取,饱和氯化钠溶液洗涤3次,无水硫酸钠干燥、过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-30%乙酸乙酯的石油醚溶液),得0.460g白色固体化合物8,收率86.61%。
步骤g:目标化合物SZM-594的制备:
在室温条件下,将化合物8(0.200g,0.58mmol)溶于5mL超干吡啶中,再加入间三氟甲基苯乙酸(0.237g,1.16mmol)反应体系在85℃氮气保护下搅拌过夜,TLC监测,反应完全后用水淬灭,乙酸乙酯萃取,并用饱和氯化钠溶液洗涤,无水硫酸钠干燥、过滤,减压下浓缩得到粗产物,粗产物通过硅胶柱色谱纯化(洗脱剂:含0-50%乙酸乙酯的石油醚溶液),得0.166g白色固体化合物SZM-594,收率54.25%。1HNMR(600MHz,DMSO-d6)δ12.61(s,1H),10.11(s,1H),7.72-7.67(m,3H),7.63(d,J=2.4Hz,1H),7.61-7.59(m,2H),7.56-7.53(m,1H),7.29-7.26(m,1H),7.10(dd,J=2.8Hz,8.4Hz,1H),6.81-6.78(m,1H),3.86(s,2H),2.01-1.97(m,1H),0.96-0.93(m,4H).HRMS(ESI,positive)m/zcalcdforC26H19F4N3O3S[M+H]+530.1156;found530.1169.
对比例2
N-(6-(4-氟-3-(2-(3-(三氟甲基)苯基)乙酰氨基)苯氧基)苯并[d]噻唑-2-基)环己烷甲酰胺即化合物对比例2的制备:
合成路线如下:
步骤a-d按照对比例1化合物SZM-594的步骤a-d制备。
步骤e:化合物7的制备:
将化合物6溶解于吡啶(10ml)中,在氮气氛围下缓慢加入环己甲酰氯(0.155g,1.06mmol),室温搅拌过夜,将反应液直接蒸干,用乙酸乙酯萃取,饱和氯化钠洗涤,无水硫酸钠干燥,硅胶柱色谱纯化残余物(洗脱剂:石油醚/乙酸乙酯=3:1-2:1),得到白色固体0.248g,收率为75%。
步骤f:化合物8的制备:
将3-氟甲基苯乙酸(0.101g,0.41mmol)和化合物7(0.030g,0.08mmol)溶解于吡啶(10ml)中,在室温下向该溶液中加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(0.26g,0.68mmol),将混合物在80℃加热搅拌3小时,将反应混合物减压浓缩,用乙酸乙酯萃取,饱和氯化钠洗涤,无水硫酸钠干燥,滤过不溶物,减压干燥,用硅胶色谱柱纯化(洗脱剂:石油醚/乙酸乙酯=1:1),用乙酸乙酯和石油醚重结晶,得到白色固体0.100g,收率56%。1HNMR(600MHz,DMSO-d6)δ12.23(s,1H),10.11(s,1H),7.71-7.69(m,2H),7.67(s,1H),7.62(d,J=2.4Hz,1H),7.60-7.59(m,2H),7.55-7.53(m,1H),7.28(t,J=10.2Hz,1H),7.09(dd,J=2.4Hz,1H),6.80-6.78(m,1H),3.86(s,2H),2.55-2.53(m,1H),1.27-1.44(m,10H).HRMS(ESI,positive)m/zcalcdforC29H25F4N3O3S[M+H]+572.1602;found572.1633.
实施例24
本发明实施例1~23及对比例1制备的化合物SZM-594和对比例2的化合物的体外抗程序性细胞坏死活性测试。
通过Z-VAD-FMK(20mM)和Smac模拟物(10μM)预处理30分钟后,加入hTNF-α(20ng/mL)诱导肿瘤细胞(HT-29,人结肠癌细胞)的坏死。将本发明实施例1~23及对比例1的SZM-594和对比例2的化合物分别与上述组合的细胞一起孵育10小时。使用CellTiter-Glo发光细胞活力测定试剂盒(Promega)测试细胞活性。用SpectraMax M5酶标仪(MolecularDevices,California)记录化学发光值,计算EC50值,结果见表1。
实施例25
RIPK1、RIPK3激酶实验
采用KINOMEscanTM的RIPK1和RIPK3激酶检测方法,测试了本发明实施例1~23合成化合物、对比例1制备的化合物SZM-594和对比例2的化合物对RIPK1和RIPK3的激酶活性。
使用qPCR检测DNA所标记RIPK1和RIPK3激酶-标记T7噬菌体菌株裂解物。将激酶、配体亲和珠和测试化合物在结合缓冲液(20%SeaBlock,0.17×PBS,0.05%Tween20,6mMDTT)中结合反应。将化合物3倍稀释的方法,设置10个点,室温下振荡孵育1h,并用洗涤缓冲液(1×PBS,0.05%Tween20)洗涤亲和珠,然后将亲和珠在洗脱缓冲液(1×PBS,0.05%吐温20,0.5μM非生物素化的亲和配体)中重悬,并在室温下振荡孵育30min。通过qPCR测量洗脱液中的激酶浓度,计算Kd值,计算公式如下(HillSlope设置为-1),结果见表1:
表1.化合物的抗程序性细胞坏死活性
从表1可以看出,本发明大部分化合物对于hTNF-α诱导的程序性细胞坏死具有良好的抑制活性,活性优于对比例1的化合物SZM-594和对比例2的活性,达到了纳摩尔级,其中化合物I-7的细胞活性明显优于阳性。针对激酶RIPK1和RIPK3,化合物的RIPK1活性均达到了纳摩尔级(RIPK1Kd<100nM),且均优于对比例1制备的化合物SZM-594和对比例2制备的化合物,RIPK3活性均>10000nM,提高了对RIPK1的选择性。
实施例26
化合物I-7小鼠SIRS模型实验
C57BL/6小鼠,6-8周,雄性,适应性喂养一周后随机分为五组,每组10-11只,分别为空白组、模型组、化合物I-75mg/kg组、10mg/kg组和20mg/kg组,禁食过夜。将不同浓度化合物I-7(5mg/ml、10mg/ml和20mg/ml)悬浮在含有10%DMSO的无内毒素PBS中,提前一小时通过灌胃给予小鼠,空白组和模型组给予同等剂量的10%DMSO和无内毒素PBS。30min后腹腔注射Z-VAD-FMK(180μg),15min后静脉注射稀释于无内毒素PBS中的mTNF-α(60mg/kg)200mL,mTNF-α处理1h后,腹腔注射另一剂量的Z-VAD-FMK(70μg)。在不同时间点,使用电子温度计监测小鼠体温并记录小鼠存活率。为了测量血清中mTNF-α诱导的IL-6和IL-1β水平,在注射mTNF-α后3h将小鼠处死,并使用小鼠IL-6和IL-1βELISA试剂盒(MultiSciences,Lianke)收集血清以分析IL-6和IL-1β,结果见图1,图1是小鼠SIRS模型各组小鼠体温变化、生存率和各组小鼠血清中IL-1β和IL-6的结果示意图,图1中A是小鼠SIRS模型各组体温变化示意图,B是小鼠SIRS模型各组生存率统计示意图,C是小鼠SIRS模型各组血清中炎症因子IL-1β水平示意图,D是小鼠SIRS模型各组血清中炎症因子IL-6水平示意图。
从图1可以看出,化合物I-7可以明显的抑制SIRS模型小鼠的体温下降,提高模型小鼠生存率,降低模型小鼠血清中的炎症因子IL-1β和IL-6的增加,且随剂量的增加保护效果增加,且在20mg/kg的剂量时达到了全保护。
以上结果说明,化合物I-7在较低剂量时可以抑制小鼠全身炎症免疫反应,降低炎症因子水平,对炎症具有保护效果,可以作为临床抗炎药及相关疾病药物,并为后续抗炎药物研发提供了先导化合物。
实施例27
化合物I-7小鼠ALI模型实验
C57BL/6小鼠,6-8周,雄性,适应性喂养一周后随机分为五组,每组11-12只,分别为假手术组(control组)、模型组(NNK组)、化合物I-725mg/kg组、50mg/kg组和100mg/kg组。将不同浓度化合物I-7(25mg/ml、50mg/ml和100mg/ml)悬浮在含有10%DMSO的0.5%CMC-Na中提前1h通过灌胃预给药,假手术组和模型组给予同等剂量的10%DMSO和0.5%CMC-Na。1h后开始造模,每只小鼠气道滴注50μL,浓度为1.5mg/50μL的4-甲基亚硝胺基-1-3-吡啶基-1-丁酮(NNK),6h后取材。
在NNK和化合物I-7暴露6h后,将小鼠脱颈椎处死,将小鼠腹部朝上固定于手术台上,小心打开颈部手术处,并用缝合线将小鼠气管上部和左肺组织结扎;用1mL注射器吸取预先准备的0.9%的生理盐水0.5-0.6mL,针头斜面朝上小角度进针后,轻推注射器,按摩胸部5s,吸出灌洗液至预冷的1.5mL离心管中,此过程重复三次并收集于同一离心管;收集后,低温高速离心5000rpm,3min,移液枪吸取上清至一新的预冷1.5mL离心管,-80℃保存用于后续炎症因子检测(ELISA试剂盒:Thermo Fisher Scientific,88-7324、Thermo FisherScientific,88-7013和Thermo Fisher Scientific,88-7064)。收集完肺泡灌洗液后将肺组织取下,并用PBS漂洗干净,左肺用滤纸吸干水分,记录其湿重和干重,计算肺湿重和干重比(W/D)。一部分肺组织采用4%多聚甲醛溶液固定,并进行切片和HE染色,另一部分肺组织进行匀浆提取用于测量组织中炎症因子TNFα和IL-6水平(ELISA试剂盒:Thermo FisherScientific,88-7324、Thermo Fisher Scientific,88-7013和Thermo FisherScientific,88-7064),以及肺组织蛋白的WB,结果见图2、图3和图4。
图2是小鼠ALI模型各组肺中参数测定结果示意图。图2中A是小鼠ALI模型各组肺大体示意图,从图中可看出,给与化合物I-7,可以有效的改善NNK模型对肺部的损伤,且随着给药剂量的增加改善肺组织的充血、水肿。B是小鼠ALI模型各组肺HE染色示意图,NNK组明显可见血管壁增厚,血管内淤血和炎性细胞浸润,随着给药以上症状均有缓解。C是小鼠ALI模型各组肺干/湿重比示意图,图中可见,给药组和空白组肺部干湿/重比近乎无差异,证明化合物I-7可以有效的缓解肺部水肿。D是小鼠ALI模型各组肺组织损伤评分示意图,化合物I-7可以很好降低小鼠NNK模型的肺部损伤,且成浓度依赖型。E是小鼠ALI模型各组肺泡灌洗液BCA蛋白定量示意图,随着给药剂量增加,肺泡灌洗液内总蛋白含量下降,表明肺内炎症下降,蛋白浸出降低。
图3是小鼠ALI模型各组肺泡灌洗液中炎症因子IL-6、TNFα水平和小鼠ALI模型各组肺组织IL-6、TNFα水平的结果示意图。图3中A是小鼠ALI模型各组肺泡灌洗液中炎症因子IL-6水平示意图,B是小鼠ALI模型各组肺组织IL-6水平示意图,C是小鼠ALI模型各组肺泡灌洗液中炎症因子TNFα水平示意图,D是小鼠ALI模型各组肺组织TNFα水平示意图。以上结果可以说明,随着化合物I-7的剂量增加,可以有效的减少肺部损伤,降低肺部组织和肺泡灌洗液中炎症因子水平,达到保护作用。
图4是小鼠ALI模型各组WesternBlot结果示意图。通过图4可以表明,化合物I-7可以在50mg/kg和100mg/kg时有效的抑制了RIPK1的磷酸化,通过抑制RIPK1的磷酸化,来抑制下游RIPK3和MLKL的磷酸化,从而抑制程序性细胞坏死通路的激活。
综上所述,化合物I-7为一种有效的程序性细胞坏死抑制剂,其作用靶点RIPK1,通过抑制RIPK1来达到抑制程序性细胞坏死通路的激活,达到保护作用。此外,在由气管滴注NNK的炎症型急性肺损伤模型中,化合物I-7可以很好的减轻模型的肺部损伤,减少肺水肿、肺充血、肺部炎性细胞浸润,降低肺内炎症因子水平,降低肺内炎症水平。为炎症型急性肺损伤的药物治疗奠定了基础。
因此,本发明的全新结构环己基取代苯并噻唑类衍生物可以作为程序性细胞坏死抑制剂,有效地抑制程序性细胞坏死,抑制小鼠SIRS的发展,保护小鼠ALI模型,可以作为一种新型抗炎药物,达到抗炎,抗炎症型急性肺损伤的作用,可以作为临床抗炎及相关疾病的药物;另外,该系列作用靶点RIPK1激酶,也可以作为RIPK1激酶抑制剂用于制备程序性细胞坏死相关疾病的防治药物。
以上所述仅是本发明的较佳实施例而已,并非对本发明作任何形式上的限制,虽然本发明已以较佳实施例揭露如上,然而并非用以限定本发明,任何熟悉本专利的技术人员在不脱离本发明技术方案范围内,当可利用上述提示的技术内容作出些许更动或修饰为等同变化的等效实施例,但凡是未脱离本发明技术方案的内容,依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与修饰,均仍属于本发明方案的范围内。
Claims (7)
1.一种环己基取代苯并噻唑类衍生物或其药用盐,其特征在于,结构如通式I所示:
R7选自氢、C1~C10烷基;
R11选自氢、卤素;
R12选自氢、卤素;
R13选自氢、卤素;
R14选自氢、卤素;
R15选自氢、卤素;
R16选自氢、C1~C10烷基;
R1、R2、R3、R4、R5不能同时为氢。
4.一种权利要求1至3任一项所述的环己基取代苯并噻唑类衍生物或其药用盐在制备RIPK1激酶抑制剂中的应用。
5.一种权利要求1至3任一项所述的环己基取代苯并噻唑类衍生物在制备预防或治疗程序性细胞坏死的药物或在制备程序性细胞坏死抑制剂中的应用。
6.一种权利要求1至3任一项所述的环己基取代苯并噻唑类衍生物或其药用盐在制备治疗程序性细胞坏死相关疾病的药物中的应用,或在制备治疗由RIPK1激酶紊乱、过度激活或过度相互作用引起的疾病的药物中的应用。
7.一种权利要求1至3任一项所述的环己基取代苯并噻唑类衍生物或其药用盐在制备治疗炎症型急性肺损伤的药物或在制备抗炎的药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310134987.5A CN116332871A (zh) | 2023-02-20 | 2023-02-20 | 一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物及其应用 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202310134987.5A CN116332871A (zh) | 2023-02-20 | 2023-02-20 | 一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物及其应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN116332871A true CN116332871A (zh) | 2023-06-27 |
Family
ID=86886700
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202310134987.5A Pending CN116332871A (zh) | 2023-02-20 | 2023-02-20 | 一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物及其应用 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN116332871A (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109053630A (zh) * | 2018-08-22 | 2018-12-21 | 中国人民解放军第二军医大学 | 一种苯并噻唑类衍生物及其用途 |
CN112094248A (zh) * | 2020-09-17 | 2020-12-18 | 中国人民解放军海军军医大学 | 一种取代苯并噻唑类化合物及其用途 |
-
2023
- 2023-02-20 CN CN202310134987.5A patent/CN116332871A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109053630A (zh) * | 2018-08-22 | 2018-12-21 | 中国人民解放军第二军医大学 | 一种苯并噻唑类衍生物及其用途 |
CN112094248A (zh) * | 2020-09-17 | 2020-12-18 | 中国人民解放军海军军医大学 | 一种取代苯并噻唑类化合物及其用途 |
Non-Patent Citations (1)
Title |
---|
LIJUAN XU等: ""Structure-based optimizations of a necroptosis inhibitor(SZM594) as novel protective agents of acute lung injury"", 《CHINESE CHEMICAL LETTERS》, vol. 33, 24 September 2021 (2021-09-24), pages 2545 - 2549 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE69634416T2 (de) | Chinolin-derivate | |
DE69232060T2 (de) | Stickstoff enthaltende bicyclische Verbindungen, Verfahren zu ihrer Herstellung, ihre Verwendung als Arzneimittel und diese enthaltende Zusammensetzungen | |
DE60319711T2 (de) | Acylamino-substituierte heteroaromatische verbindungen und ihre verwendung als arzneimittel | |
JP4405602B2 (ja) | ヒストン脱アセチル化酵素阻害剤 | |
US20040229889A1 (en) | HDAC inhibitor | |
DE69533408T2 (de) | Chinolinderivate als Tachykinin NK3 Rezeptor Antagonisten | |
DE69426422T2 (de) | Pyridazino-chinolin verbindungen | |
JP4980917B2 (ja) | 非ペプチドブラジキニンアンタゴニストおよびそれによる医薬組成物 | |
JP2016511237A (ja) | 選択的hdac3阻害剤 | |
CA2729275A1 (en) | 5- and 6-membered heterocyclic compounds | |
WO2018157842A1 (zh) | 2-(取代苯氨基)苯甲酸类fto抑制剂治疗白血病的用途 | |
EA028814B1 (ru) | АМИДЗАМЕЩЕННЫЕ ГЕТЕРОЦИКЛИЧЕСКИЕ СОЕДИНЕНИЯ, ПРИМЕНИМЫЕ В КАЧЕСТВЕ МОДУЛЯТОРОВ ОТВЕТОВ, ОПОСРЕДУЕМЫХ IL-12, IL-23 И/ИЛИ IFNα | |
TW201736372A (zh) | Pde1抑制劑 | |
JP2011526294A (ja) | ホスホジエステラーゼ10阻害剤としての二置換フェニル化合物 | |
EP2487175A1 (en) | Pharmaceutical product containing aromatic heterocyclic compound | |
CN107163044B (zh) | 一类具有蛋白酶修饰活性的萘乙二酮化合物及其衍生物 | |
CN111655693A (zh) | 抑制瞬时型感受器电位a1离子通道 | |
CA3022102A1 (en) | Benzoylglycine derivatives and methods of making and using same | |
JP2005507381A (ja) | 心臓障害および代謝障害の治療のための主要環置換甲状腺受容体アンタゴニスト | |
CN111440146B (zh) | 一种具有par4拮抗活性的苯并三嗪类化合物及其应用 | |
WO2018059533A1 (zh) | p38αMAPK激酶抑制剂及其制备方法和应用 | |
CN116332871A (zh) | 一种抑制程序性细胞坏死的环己基取代苯并噻唑类衍生物及其应用 | |
JPH0339073B2 (zh) | ||
EP0562796A1 (en) | Phenoxyacetic acid compounds and medical preparations containing them | |
CN105814018B (zh) | 新型脲类化合物、制备方法及其用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |