CN111978318A - 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 - Google Patents
咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 Download PDFInfo
- Publication number
- CN111978318A CN111978318A CN201910430268.1A CN201910430268A CN111978318A CN 111978318 A CN111978318 A CN 111978318A CN 201910430268 A CN201910430268 A CN 201910430268A CN 111978318 A CN111978318 A CN 111978318A
- Authority
- CN
- China
- Prior art keywords
- substituted
- unsubstituted
- compound
- pharmaceutically acceptable
- alkyl
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 102100026299 MAP kinase-interacting serine/threonine-protein kinase 1 Human genes 0.000 title abstract description 11
- 101710139011 MAP kinase-interacting serine/threonine-protein kinase 1 Proteins 0.000 title abstract description 11
- 102100033610 MAP kinase-interacting serine/threonine-protein kinase 2 Human genes 0.000 title abstract description 9
- 101710138999 MAP kinase-interacting serine/threonine-protein kinase 2 Proteins 0.000 title abstract description 9
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 8
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 8
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 84
- 102100027587 Copper-transporting ATPase 1 Human genes 0.000 claims abstract description 31
- 101000936277 Homo sapiens Copper-transporting ATPase 1 Proteins 0.000 claims abstract description 31
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 14
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- -1 hydroxy, amino, carboxyl Chemical group 0.000 claims description 42
- 229910052760 oxygen Inorganic materials 0.000 claims description 25
- 229910052717 sulfur Inorganic materials 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 21
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 14
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 229940002612 prodrug Drugs 0.000 claims description 12
- 239000000651 prodrug Substances 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 9
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- 150000004677 hydrates Chemical class 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 230000006806 disease prevention Effects 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 31
- CKJNUZNMWOVDFN-UHFFFAOYSA-N methanone Chemical compound O=[CH-] CKJNUZNMWOVDFN-UHFFFAOYSA-N 0.000 description 29
- 238000006243 chemical reaction Methods 0.000 description 19
- 239000000243 solution Substances 0.000 description 15
- 125000002757 morpholinyl group Chemical group 0.000 description 13
- 101001082110 Acanthamoeba polyphaga mimivirus Eukaryotic translation initiation factor 4E homolog Proteins 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 101001082109 Danio rerio Eukaryotic translation initiation factor 4E-1B Proteins 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 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
- 108091000080 Phosphotransferase Proteins 0.000 description 9
- 102000020233 phosphotransferase Human genes 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 150000002576 ketones Chemical class 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 108020004999 messenger RNA Proteins 0.000 description 6
- 230000001105 regulatory effect Effects 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- 102000008096 B7-H1 Antigen Human genes 0.000 description 4
- 108010074708 B7-H1 Antigen Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 102000043136 MAP kinase family Human genes 0.000 description 4
- 108091054455 MAP kinase family Proteins 0.000 description 4
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 102000001253 Protein Kinase Human genes 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 108060006633 protein kinase Proteins 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000003827 upregulation Effects 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- FWRFPHJSGLYXTD-UHFFFAOYSA-N 4-[6-[4-(morpholine-4-carbonyl)phenyl]imidazo[1,2-a]pyridin-3-yl]benzonitrile Chemical compound C=1C=C(C2=CN3C(C=4C=CC(=CC=4)C#N)=CN=C3C=C2)C=CC=1C(=O)N1CCOCC1 FWRFPHJSGLYXTD-UHFFFAOYSA-N 0.000 description 3
- HKTBYUWLRDZAJK-UHFFFAOYSA-N 6-[(6-aminopyrimidin-4-yl)amino]-8-methylspiro[2H-imidazo[1,5-a]pyridine-3,1'-cyclohexane]-1,5-dione Chemical compound NC1=CC(=NC=N1)NC1=CC(=C2N(C1=O)C1(NC2=O)CCCCC1)C HKTBYUWLRDZAJK-UHFFFAOYSA-N 0.000 description 3
- FXPMFQUOGYGTAM-UHFFFAOYSA-N 6-bromoimidazo[1,2-a]pyridine Chemical compound C1=C(Br)C=CC2=NC=CN21 FXPMFQUOGYGTAM-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 208000017604 Hodgkin disease Diseases 0.000 description 3
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 3
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 3
- 206010025323 Lymphomas Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 206010035226 Plasma cell myeloma Diseases 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 238000012421 spiking Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000011550 stock solution Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 229940121341 tomivosertib Drugs 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- ODAXNYMENLFYMY-UHFFFAOYSA-N (2-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=CC=C1B(O)O ODAXNYMENLFYMY-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- LILXDMFJXYAKMK-UHFFFAOYSA-N 2-bromo-1,1-diethoxyethane Chemical compound CCOC(CBr)OCC LILXDMFJXYAKMK-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 208000003950 B-cell lymphoma Diseases 0.000 description 2
- 208000011691 Burkitt lymphomas Diseases 0.000 description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108060002636 Eukaryotic Initiation Factor-4E Proteins 0.000 description 2
- 102000005233 Eukaryotic Initiation Factor-4E Human genes 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000010419 agar Nutrition 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940124599 anti-inflammatory drug Drugs 0.000 description 2
- 229940041181 antineoplastic drug Drugs 0.000 description 2
- YNCYPMUJDDXIRH-UHFFFAOYSA-N benzo[b]thiophene-2-boronic acid Chemical compound C1=CC=C2SC(B(O)O)=CC2=C1 YNCYPMUJDDXIRH-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 2
- QONGECDDDTYBGS-UHFFFAOYSA-N dimorpholin-4-ylmethanone Chemical compound C1COCCN1C(=O)N1CCOCC1 QONGECDDDTYBGS-UHFFFAOYSA-N 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 229940014259 gelatin Drugs 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 210000001853 liver microsome Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920005862 polyol Polymers 0.000 description 2
- 150000003077 polyols Chemical class 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- KPZYAGQLBFUTMA-UHFFFAOYSA-K tripotassium;phosphate;trihydrate Chemical compound O.O.O.[K+].[K+].[K+].[O-]P([O-])([O-])=O KPZYAGQLBFUTMA-UHFFFAOYSA-K 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- PQCXFUXRTRESBD-UHFFFAOYSA-N (4-methoxycarbonylphenyl)boronic acid Chemical compound COC(=O)C1=CC=C(B(O)O)C=C1 PQCXFUXRTRESBD-UHFFFAOYSA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- RTBFRGCFXZNCOE-UHFFFAOYSA-N 1-methylsulfonylpiperidin-4-one Chemical compound CS(=O)(=O)N1CCC(=O)CC1 RTBFRGCFXZNCOE-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- JQTMGOLZSBTZMS-UHFFFAOYSA-N 4-methylpiperazine-1-carbaldehyde Chemical compound CN1CCN(C=O)CC1 JQTMGOLZSBTZMS-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N 5-bromopyridin-2-amine Chemical compound NC1=CC=C(Br)C=N1 WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- VJOWMORERYNYON-UHFFFAOYSA-N 5-ethenyl-2-methylpyridine Chemical compound CC1=CC=C(C=C)C=N1 VJOWMORERYNYON-UHFFFAOYSA-N 0.000 description 1
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 description 1
- BKLJUYPLUWUEOQ-UHFFFAOYSA-N 6-bromopyridin-2-amine Chemical compound NC1=CC=CC(Br)=N1 BKLJUYPLUWUEOQ-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- 238000003727 ADP Glo Kinase Assay Methods 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 101100244083 Arabidopsis thaliana PKL gene Proteins 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- YFZZLCIVFQDSBJ-UHFFFAOYSA-N CC(C)C1=CC=CC2=C1OC(B(O)O)=C2 Chemical compound CC(C)C1=CC=CC2=C1OC(B(O)O)=C2 YFZZLCIVFQDSBJ-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 101100232687 Drosophila melanogaster eIF4A gene Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 102100030011 Endoribonuclease Human genes 0.000 description 1
- 101710199605 Endoribonuclease Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 101710091919 Eukaryotic translation initiation factor 4G Proteins 0.000 description 1
- 208000009849 Female Genital Neoplasms Diseases 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
- 239000007821 HATU Substances 0.000 description 1
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 1
- 101710083479 Hepatitis A virus cellular receptor 2 homolog Proteins 0.000 description 1
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 1
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 1
- 102000017578 LAG3 Human genes 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010052178 Lymphocytic lymphoma Diseases 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010027458 Metastases to lung Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000033755 Neutrophilic Chronic Leukemia Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 108010044843 Peptide Initiation Factors Proteins 0.000 description 1
- 102000005877 Peptide Initiation Factors Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 206010065857 Primary Effusion Lymphoma Diseases 0.000 description 1
- 102100040678 Programmed cell death protein 1 Human genes 0.000 description 1
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108090000944 RNA Helicases Proteins 0.000 description 1
- 102000004409 RNA Helicases Human genes 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 101710113029 Serine/threonine-protein kinase Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 230000024932 T cell mediated immunity Effects 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 229940126547 T-cell immunoglobulin mucin-3 Drugs 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N anhydrous glutaric acid Natural products OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 238000003782 apoptosis assay Methods 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004888 barrier function 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
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 201000010903 chronic neutrophilic leukemia Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 150000005232 imidazopyridines Chemical class 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 208000026876 intravascular large B-cell lymphoma Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 210000003071 memory t lymphocyte Anatomy 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 208000025426 neoplasm of thorax Diseases 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 102000027450 oncoproteins Human genes 0.000 description 1
- 108091008819 oncoproteins Proteins 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000005561 phenanthryl group Chemical group 0.000 description 1
- 125000006678 phenoxycarbonyl group Chemical group 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000005522 programmed cell death Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 210000003289 regulatory T cell Anatomy 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000011257 shell material Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 201000003957 thoracic cancer Diseases 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- UAEJRRZPRZCUBE-UHFFFAOYSA-N trimethoxyalumane Chemical compound [Al+3].[O-]C.[O-]C.[O-]C UAEJRRZPRZCUBE-UHFFFAOYSA-N 0.000 description 1
- GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000013414 tumor xenograft model Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000012447 xenograft mouse model Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种咪唑并吡啶类MNK1/MNK2激酶抑制剂及其制备方法和应用，具体地，本发明提供了一种式(I)所示的化合物：或其立体异构体、互变异构体或药学上可接受的盐。本发明的化合物可以用于制备治疗MNK活性或表达量相关的疾病或病症的药物组合物。
Description
技术领域
本发明属于医药技术领域，具体而言，本发明提供了一类新的咪唑并吡啶类化合物或其立体异构体、几何异构体、互变异构体及其药学上可接受的盐、水合物、前药或溶剂合物，及其作为MNK1和MNK2激酶抑制剂的用途。
背景技术
蛋白激酶(protein kinases)在多种细胞功能中发挥着重要的作用，其异常活化与多种疾病相关。丝裂原活化蛋白激酶(mitogen-activated protein kinases，MAPKs)能够接收多种细胞信号(包括生长因子、环境刺激和细胞因子)并被激活，从而调控细胞的增殖、分化、存活、细胞周期控制以及程序性细胞死亡。在接收这些刺激信号后，MAPKs能够激活下游的靶蛋白，即MAPK激活蛋白激酶家族(MAPK-activated protein kinases family，MAPKAPK)，该激酶家族其中包括丝裂原活化蛋白激酶作用激酶(MAPK-interactingkinases，MNKs)。MNK激酶属于丝氨酸/苏氨酸蛋白激酶，能够特异性的将真核起始因子eIF4E(eukaryotic initiation factor4E)的Ser209磷酸化，从而间接的调控mRNA翻译。
真核起始因子eIF4E作为一种重要的转录因子，能够加强编码调控细胞周期蛋白与致癌蛋白mRNA的转录从而引起肿瘤相关蛋白表达的上调。eIF4E与骨架蛋白eIF4G和RNA解旋酶eIF4A组成了真核起始因子复合体eIF4F。由于eIF4E负责该复合体与mRNA的5’末端帽子结构结合，所以其在RNA翻译过程中发挥着不可替代的调控作用。在正常细胞中，eIF4E的活性被限制，这些肿瘤相关mRNA的转录得到抑制；而在肿瘤细胞或组织中，eIF4E的高表达或过度活化会引起这些mRNA转录水平的上调。在多种肿瘤和肿瘤细胞株中均检测到了eIF4E表达水平的上调，其中包括结肠癌、乳腺癌、膀胱癌、肺癌、前列腺癌、胃癌、霍奇经淋巴瘤和成神经细胞瘤。而在临床上，MNK激酶与eIF4E表达上调或过度激活往往伴随着耐药以及不良预后。更为重要的是，虽然MNKs是eIF4E调控的肿瘤形成的必不可少的条件，但抑制MNKs活性并不会影响正常细胞和动物的存活与生长。所以，通过小分子药物抑制MNKs是一种极具前景的肿瘤治疗手段。
eIF4E作为一个重要的翻译限速因子，MNK/eIF4E信号通路能够影响多种趋化因子、细胞因子以及免疫检查点蛋白的合成，进而调控免疫应答。MNK激酶抑制剂能够显著降低肿瘤细胞表面PD-L1的含量，而对PD-L1mRNA的表达无影响，同时MNK抑制剂能够降低激活性T细胞表面免疫检查点蛋白PD-1、TIM-3和LAG3的表达。肿瘤异种移植模型结果也证实，MNK激酶抑制剂能够降低小鼠体内50％的PD-L1含量，并且MNK抑制剂对PD-L1高表达的肿瘤模型更为敏感。同时，MNK激酶抑制剂能够显著增强细胞毒CD8+T细胞的功能，抑制激活的调节性T细胞的分化，并促进中央记忆T细胞的形成。在小鼠结肠癌同种移植模型中，MNK抑制剂几乎完全抑制肿瘤的增殖。而在停药29天后再次接种相同的肿瘤，在不给药的情况下，小鼠的肿瘤增殖依旧得到了完全的控制。这也从侧面反映了MNK抑制剂能够激活模型鼠持久的抗肿瘤免疫应答。
随着近几年对MNKs结构及功能了解的深入，陆续有多个MNK抑制剂得到了报道，其中BAY1143269、Tomivosertib和ETC-206陆续进入了临床。在小鼠异种移植模型中，BAY1143269、Tomivosertib以及ETC-206均能够显著地抑制瘤块的生长，并延长小鼠的生存期。从已经公布的I期临床结果来看，Tomivosertib和ETC-206均能够显著降低病人体内eIF4E的磷酸化水平，并表现出初步的症状缓解。而目前临床结果也进一步证实，在体内条件下，MNK抑制剂能够通过调节肿瘤微环境发挥抗肿瘤效果。随着对MNK/eIF4E通路了解的不断深入，基于该通路的抑制剂开发将在靶向治疗和肿瘤免疫疗法中发挥更为重要作用。
综上所述，本领域迫切需要开发新的MNK激酶抑制剂。
发明内容
本发明的目的是开发一种新的MNK激酶抑制剂。
本发明的第一方面，提供了一种通式(I)所示的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物：
其中，
X为S或O；
R1和R2各自独立地选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基、-CN、-OR、-SR、-N(R)2、-NO2、-COR、-CO2R、-CON(R)2、-CONROR、-SOR、-SO2R、-SO2N(R)2、-OCOR、-NRCOR、-NRSO2R或-NRCON(R)2；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
各个R各自独立选自氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
R3为H，或具有-NR4R5所示的结构，其中，R4和R5各自独立地选自下组：氢、取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
其中，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷胺基、-C(O)C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、C3-C8环烷基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、C1-C6烷氧基。
在另一优选例中，所述的X为O。
在另一优选例中，所述的R1和R2各自独立地为取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基。
在另一优选例中，所述的-NR1R2具有如下所示的结构：
其中，Y选自下组：无(即化学键)、O、S、NR6、或CHR6；
所述的R6选自下组：C1-C6烷基、C1-C6烷胺基、-C(O)C1-C6烷基、氨基、具有1-3个选自N、S和O的杂原子的5-10元杂环基。
在另一优选例中，所述的化合物具有如下式II所示的结构：
在另一优选例中，所述的化合物选自I-1至I-20。
本发明的第二方面，提供了一种药物组合物，所述药物组合物包括：(i)治疗有效量的本发明第一方面所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的一种或多种，以及(ii)药学上可接受的载体或赋形剂。
在另一优选例中，所述药物组合物具有选自下组的制剂形式：片剂、丸剂、颗粒剂、膜剂、滴丸、胶囊剂、注射剂、软胶囊、乳剂、脂质体、冻干粉、高分子微球，或者聚乙二醇衍生物。
在另一优选例中，所述的药物组合物用于治疗与MNK的活性或表达量相关的疾病或病症。
在另一优选例中，所述的MNK为MNK1或MNK2。
本发明的第三方面，提供了一种如本发明第一方面所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的用途，其用于制备治疗或预防与MNK的活性或表达量相关的疾病或病症的药物组合物。
在另一优选例中，所述的疾病为癌症。
在另一优选例中，所述的癌症选自下组：白血病，淋巴瘤，霍奇金病，骨髓瘤、急性淋巴细胞白血病、急性粒细胞白血病、极性早幼粒细胞白血病、慢性淋巴细胞白血病、慢性粒细胞白血病、慢性嗜中性粒细胞白血病、极性未分化细胞白血病、退行发育性大细胞性淋巴瘤、成人T细胞ALL、伴有三谱系脊髓发育不良的AML、混合型谱系白血病、脊髓发育不良综合征、骨髓增生异常、多发性骨髓瘤和脊髓肉瘤、慢性淋巴细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤或慢性淋巴细胞白血病、套细胞淋巴瘤、纵膈(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤。
本发明的第四方面，提供了一种如本发明第一方面所述的式(I)化合物的制备方法，所述方法包括步骤：
在金属钯催化剂(优选为Pd(PPh3)4或Pd(dppf)Cl2)催化下，用式7化合物与
进行偶联反应，得到目标化合物(I)。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
具体实施方式
本发明人经过长期而深入的研究，发现了一类对MNK激酶(优选为MNK1和MNK2)具有优异的抑制效果的新型化合物。该化合物可以作为活性成分，用于制备治疗与MNK激酶活性或表达量相关的疾病的药物组合物。在此基础上，发明人完成了本发明。
定义
如本文所用，术语“烷基”包括直链或支链的烷基。例如C1-C8烷基表示具有1-8个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基等。
如本文所用，术语“C3-C8环烷基”指具有3-8个碳原子的环烷基。其可以是单环，例如环丙基、环丁基、环戊基、环己基、或类似基团。也可以是双环形式，例如桥环或螺环形式。
如本文所用，术语“C1-C6烷氧基”是指具有1-6个碳原子的直链或支链的烷氧基；例如，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基等。
如本文所用，术语“10-20元芳基”是指具有10-20个碳原子的芳基，例如，萘基、蒽基、菲基或类似基团。
如本文所用，术语“具有1-3个选自下组N、S和O的杂原子的5-12元杂芳基”指具有5-10个原子的且其中1-3个原子为选自下组N、S和O的杂原子的环状芳香基团。其可以是单环，也可以是稠环形式。具体的实例可以为吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、吡咯基、吡唑基、咪唑基、(1,2,3)-三唑基以及(1,2,4)-三唑基、四唑基、呋喃基、噻吩基、异恶唑基、噻唑基、恶唑基等。
本发明所述的基团除非特别说明是“取代的或未取代的”，否则本发明的基团均可被选自下组的取代基所取代：卤素、腈基、硝基、羟基、氨基、C1-C6烷基-胺基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、卤代C1-C6烷基、卤代C2-C6烯基、卤代C2-C6炔基、卤代C1-C6烷氧基、烯丙基、苄基、C6-C12芳基、C1-C6烷氧基-C1-C6烷基、C1-C6烷氧基-羰基、苯氧羰基、C2-C6炔基-羰基、C2-C6烯基-羰基、C3-C6环烷基-羰基、C1-C6烷基-磺酰基等。
如本文所用，“卤素”或“卤原子”指F、Cl、Br、和I。更佳地，卤素或卤原子选自F、Cl和Br。“卤代的”是指被选自F、Cl、Br、和I的原子所取代。
除非特别说明，本发明所描述的结构式意在包括所有的同分异构形式(如对映异构，非对映异构和几何异构体(或构象异构体))：例如含有不对称中心的R、S构型，双键的(Z)、(E)异构体等。因此，本发明化合物的单个立体化学异构体或其对映异构体、非对映异构体或几何异构体(或构象异构体)的混合物都属于本发明的范围。
如本文所用，术语“互变异构体”表示具有不同能量的结构同分异构体可以超过低能垒，从而互相转化。比如，质子互变异构体(即质子移变)包括通过质子迁移进行互变，如1H-吲唑与2H-吲唑。化合价互变异构体包括通过一些成键电子重组而进行互变。
如本文所用，术语“溶剂合物”是指本发明化合物与溶剂分子配位形成特定比例的配合物。
如本文所用，术语“水合物”是指本发明化合物与水进行配位形成的配合物。
如本文所用，术语“药学上可接受的盐”包括式(I)化合物与下列酸形成的酸加成盐：盐酸、氢溴酸、硫酸、硝酸、磷酸、甲酸、乙酸、三氟乙酸、乳酸、草酸、己二酸、戊二酸、丙二酸、马来酸、琥珀酸、富马酸、酒石酸、柠檬酸、棕榈酸、苯甲酸、甲磺酸、对甲苯磺酸、水杨酸、苯基乙酸、杏仁酸，此外还包括无机碱的酸式盐。
活性成分
本发明合成了一系列结构通式(I)所述的化合物或其立体异构体、几何异构体、互变异构体及其药学上可接受的盐、水合物、前药或溶剂合物：
其中，
X为S或O；
R1和R2各自独立地选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基、-CN、-OR、-SR、-N(R)2、-NO2、-COR、-CO2R、-CON(R)2、-CONROR、-SOR、-SO2R、-SO2N(R)2、-OCOR、-NRCOR、-NRSO2R或-NRCON(R)2；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
各个R各自独立选自氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
R3为H，或具有-NR4R5所示的结构，其中，R4和R5各自独立地选自下组：氢、取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
其中，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷胺基、-C(O)C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、C3-C8环烷基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、C1-C6烷氧基。
优选地，本发明式(I)所示的化合物选自下表1中的化合物：
表1.化合物结构
式(I)化合物的制备
本发明所述的式(I)化合物可以通过以下步骤进行制备：
从化合物1和2出发，经过关环、与甲氧羰基苯硼酸偶联、溴代、水解、与相应的胺缩合再偶联得到目标化合物。具体的说，所述制备方法包括如下步骤：
1.以2-氨基5-溴吡啶1和溴代乙醛缩二乙醇2为原料，在氢溴酸中关环得到化合物3；
2.化合物3在Pd(PPh3)4或Pd(dppf)Cl2催化作用下与甲氧基羰基苯硼酸偶联得到化合物4；
3.化合物4在N-溴代丁二酰亚胺作用下溴代得到化合物5；
4.化合物5在氢氧化锂作用下水解得到化合物6；
5.化合物6在缩合剂EDCI/HOBT或HATU作用下与相应的胺缩合得到化合物7。
6.化合物7在Pd(PPh3)4或Pd(dppf)Cl2催化作用下与苯并呋喃-2-硼酸或苯并噻吩-2-硼酸偶联得到目标化合物(I)；
其中，以上X、R1和R2的定义如前所述。
药物组合物和施用方法
由于本发明化合物具有优异的MNK激酶的抑制活性，因此本发明化合物及其各种晶型，药学上可接受的无机或有机盐，水合物或溶剂合物，以及含有本发明化合物为主要活性成分的药物组合物可用于预防和/或治疗(稳定、减轻或治愈)MNK激酶活性或表达量相关疾病(例如，结直肠癌，胃癌，甲状腺癌，肺癌，白血病，B细胞淋巴瘤，T细胞淋巴瘤，毛细胞淋巴瘤，霍奇金淋巴瘤，非霍奇金淋巴瘤，伯基特淋巴瘤，胰腺癌，黑素瘤，多发性骨髓瘤，脑癌，CNS癌，肾癌，前列腺癌，卵巢癌、乳腺癌、不受控制的细胞生长、增殖和/或存活、不适宜的细胞免疫应答、不适宜的细胞炎症应答、白血病和骨髓增生异常综合征、恶性淋巴瘤、头颈部肿瘤、肺肿瘤和肺转移瘤、胸部肿瘤、非小细胞肿瘤和小细胞肺肿瘤、胃肠肿瘤、内分泌肿瘤、乳房和其他妇科肿瘤、泌尿系肿瘤、肾、膀胱和前列腺肿瘤、皮肤肿瘤、肉瘤、肿瘤转移、神经变性病症)。
本发明的药物组合物包含安全有效量范围内的本发明化合物及药学上可以接受的赋形剂或载体。其中“安全有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明化合物/剂，更佳地，含有10-200mg本发明化合物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物(例如其他抗肿瘤或抗炎症药物)联合给药。
联合给药时，所述药物组合物还包括与一种或多种(2种，3种，4种，或更多种)其他药学上可接受的化合物(例如其他抗肿瘤或抗炎症药物)。该其他药学上可接受的化合物中的一种或多种(2种，3种，4种，或更多种)可与本发明的化合物同时、分开或顺序地用于预防和/或治疗MNK激酶活性或表达量相关疾病。
使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，为达到所需结果，每千克每24小时给药的式(I)化合物的总量为约0.01-800mg，优选的总量为0.1-80mg/kg。如果必要，以几次单剂量的形式给药。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。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。除非另外说明，否则百分比和份数按重量计算。除另有定义或说明，本文中所使用的所有专业与科学用语与本领域技术熟练人员所熟悉的意义相同。
实施例1
(4-(3-(苯并噻吩-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮(I-1)
步骤1：6-溴咪唑并[1,2-a]吡啶的制备
将2-氨基-6-溴吡啶(3g，17.34mmol)溶于30mL乙醇和18mL水的混合溶液中，加入溴代乙醛缩二乙醇(5.13g，26.01mmol)和48％氢溴酸水溶液(3mL)，升温至100℃反应8h。TLC板监测反应完全后，冷却反应液至室温后减压浓缩，加入100mL水，乙酸乙酯萃取，合并有机相后用饱和食盐水洗，有机相用无水硫酸钠干燥，过滤减压浓缩，残留物经柱层析分离，得到白色固体粉末2.98g，为中间体6-溴咪唑并[1,2-a]吡啶，收率87.2％。
1H NMR(300MHz,DMSO-d6)δ:8.92(s,1H),7.93(s,1H),7.61(s,1H),7.56(d,J＝9.6Hz,1H),7.33(dd,J＝9.5,1.8Hz,1H).
步骤2：4-(咪唑并[1,2-a]吡啶基-6-基)苯甲酸甲酯的制备
将6-溴咪唑并[1,2-a]吡啶(2.5g，12.69mmol)溶于45mL1,4-二氧六环和4.5mL水的混合溶液中，加入4-甲氧羰基苯硼酸(2.74g，15.23mmol)和三水磷酸钾(8.45g，31.72mmol)，以氮气充分置换反应装置内的空气，室温搅拌15min，加入四三苯基膦钯(0.73g，0.63mmol)，以氮气充分置换反应装置内的空气，室温继续搅拌15min后升温至95℃反应8h。TLC板监测反应完全后，冷却反应液至室温，硅藻土滤去不溶物，滤液减压浓缩，残留物经柱层析分离，得到白色固体2.6g，为中间体4-(咪唑并[1,2-a]吡啶基-6-基)苯甲酸甲酯，收率为81.2％。
1H NMR(300MHz,DMSO-d6)δ:9.08(s,1H),8.07(d,J＝8.4Hz,2H),7.99(s,1H),7.89(d,J＝8.4Hz,2H),7.69–7.62(m,3H),3.89(s,3H).
步骤3：4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯甲酸甲酯的制备
将4-(咪唑并[1,2-a]吡啶基-6-基)苯甲酸甲酯(2.6g，10.31mmol)溶于48mL乙腈和16mL二氯甲烷的混合溶液中，加入N-溴代丁二酰亚胺(2.38g，13.40mmol)，室温下搅拌反应8h。TLC板监测反应完全后，减压浓缩，加入100mL水，二氯甲烷萃取，合并有机相后用饱和食盐水洗，有机相用无水硫酸钠干燥，过滤减压浓缩，残留物经柱层析分离，得到黄色固体粉末3.1g，为中间体4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯甲酸甲酯，收率为90.8％。
1H NMR(300MHz,CDCl3)δ:8.34(s,1H),8.24–8.11(m,2H),7.75(d,J＝9.4Hz,1H),7.68(dd,J＝5.4,2.8Hz,3H),7.54(dd,J＝9.4,1.8Hz,1H),3.96(s,3H).
步骤4：4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯甲酸的制备
将4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯甲酸甲酯(1.89g，5.71mmol)溶于20mL四氢呋喃和10mL甲醇的混合溶液中，缓慢滴加10mL LiOH(1.09g，45.66mmol)水溶液中，室温下搅拌4h。TLC板监测反应完全后，减压浓缩，加入20mL水稀释，缓慢滴加1M盐酸，将pH调至2～3，有大量白色固体析出，过滤收集滤饼，水洗，烘干得白色固体1.75g，为中间体4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯甲酸，收率为96.7％。
步骤5：(4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮
将4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯甲酸(360mg，1.14mmol)溶于3mL N,N-二甲基甲酰胺，依次加入吗啉(119mg，1.36mmol)、EDCI(261mg，1.36mmol)、HOBT(184mg，1.36mmol)、三乙胺(138mg，1.36mmol)和DMAP(14mg，0.11μmol)，升温至40℃反应8h。TLC板监测反应完全后，加入200mL二氯甲烷稀释，饱和食盐水洗(20mL×3)，有机相用无水硫酸钠干燥，过滤减压浓缩，残留物经柱层析(二氯甲烷/甲醇＝100/1～100/3)分离，得到黄色固体粉末356mg，为中间体(4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮，收率为81.2％。
1H NMR(300MHz,CDCl3)δ8.32(s,1H),7.72(dd,J＝21.1,8.4Hz,4H),7.55(dd,J＝13.8,9.4Hz,3H),3.67(d,J＝47.9Hz,8H).
步骤6：(4-(3-(苯并噻吩-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮(I-1)的制备
将(4-(3-溴咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮(110mg，0.26mmol)溶于2mL1,4-二氧六环和0.2mL水的混合溶液中，加入苯并噻吩-2-硼酸(61mg，0.34mmol)和三水磷酸钾(138mg，0.52mmol)，以氮气充分置换反应装置内的空气，室温搅拌15min，加入四三苯基膦钯(30mg，26μmol)，以氮气充分置换反应装置内的空气，室温继续搅拌15min后升温至95℃反应8h。TLC板监测反应完全后，冷却反应液至室温，硅藻土滤去不溶物，滤液减压浓缩，残留物经柱层析分离，得到白色固体粉末55mg，(4-(3-(苯并噻吩-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮，收率为43.9％。
1H NMR(300MHz,CDCl3)δ(ppm):8.75(s,1H),7.97–7.79(m,4H),7.66(d,J＝9.0Hz,2H),7.55(d,J＝7.3Hz,4H),7.49–7.34(m,2H),3.74(s,8H)；MS:found m/z[M+H]+440.05,calcd.m/z[M]439.14.
实施例2
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮(I-2)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮。
1H NMR(300MHz,DMSO-d6)δ:9.01(s,1H),8.22(s,1H),7.99–7.84(m,3H),7.85–7.67(m,3H),7.66–7.49(m,3H),7.43–7.27(m,2H),3.64(s,8H)；MS:found m/z[M+H]+424.01,calcd.m/z[M]423.16.
实施例3
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-甲基哌嗪-1-基)甲酮(I-3)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-甲基哌嗪-1-基)甲酮。
1H NMR(300MHz,DMSO-d6)δ(ppm):9.01(s,1H),8.22(s,1H),7.89(t,J＝7.9Hz,3H),7.74(dd,J＝23.3,7.1Hz,3H),7.63–7.47(m,3H),7.41–7.26(m,2H),3.53(d,J＝42.9Hz,4H),2.34(s,4H),2.22(s,3H)；MS:found m/z[M+H]+437.19,calcd.m/z[M]436.19.
实施例4
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(哌啶基)甲酮(I-4)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):9.30(s,1H),9.09(s,1H),8.24(s,1H),8.07(d,J＝7.1Hz,2H),7.75–7.63(m,2H),7.59(d,J＝7.3Hz,2H),7.48–7.31(m,2H),7.29(s,1H),7.17(s,1H),3.76(s,2H),3.45(s,2H),1.67(d,J＝33.8Hz,6H)；MS:found m/z[M+H]+422.06,calcd.m/z[M]421.18.
实施例5
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(N,N-二甲基胺基)甲酮(I-5)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(N,N-二甲基胺基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.95(s,1H),8.12(s,1H),7.84(d,J＝8.8Hz,1H),7.68(s,3H),7.60(d,J＝5.7Hz,4H),7.34(t,J＝6.4Hz,2H),7.05(s,1H),3.17(s,3H),3.10(s,3H)；MS:found m/z[M+H]+382.10,calcd.m/z[M]381.15.
实施例6
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吡咯烷基)甲酮(I-6)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吡咯烷基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.94(s,1H),8.12(s,1H),7.85(d,J＝8.9Hz,1H),7.76–7.54(m,6H),7.40–7.28(m,2H),7.05(s,1H),3.71(t,J＝6.7Hz,2H),3.53(t,J＝6.5Hz,2H),1.99(ddd,J＝18.9,13.2,7.5Hz,4H)；MS:found m/z[M+H]+408.22,calcd.m/z[M]407.16.
实施例7
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-乙酰基哌嗪-1-基)甲酮(I-7)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-乙酰基哌嗪-1-基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.93(s,1H),8.10(s,1H),7.83(d,J＝9.3Hz,1H),7.70(dd,J＝6.4,1.9Hz,2H),7.68–7.62(m,1H),7.57(tt,J＝8.2,6.1Hz,4H),7.33(ddd,J＝14.6,7.1,1.4Hz,2H),7.03(s,1H),3.62(d,J＝32.4Hz,8H),2.15(s,3H)；MS:found m/z[M+H]+465.26,calcd.m/z[M]464.18.
实施例8
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-二甲氨基哌啶基)甲酮(I-8)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-二甲氨基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.92(s,1H),8.10(s,1H),7.81(d,J＝9.3Hz,1H),7.72–7.52(m,7H),7.34(dd,J＝14.6,6.1Hz,2H),7.03(s,1H),4.79(s,1H),3.92(s,1H),3.02(s,2H),2.53(t,J＝10.9Hz,1H),2.32(d,J＝22.8Hz,6H),1.96(s,2H),1.57(d,J＝9.9Hz,2H)；MS:found m/z[M+H]+465.32,calcd.m/z[M]464.22.
实施例9
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-甲基哌啶基)甲酮(I-9)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-甲基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.95(s,1H),8.12(s,1H),7.86(d,J＝9.3Hz,1H),7.73–7.45(m,7H),7.35(t,J＝7.9Hz,2H),7.06(s,1H),4.72(s,1H),3.82(s,1H),2.95(d,J＝71.1Hz,2H),2.09(s,2H),1.74(d,J＝36.4Hz,3H),1.02(d,J＝6.2Hz,3H)；MS:found m/z[M+H]+436.28,calcd.m/z[M]435.19.
实施例10
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-异丙基哌嗪-1-基)甲酮(I-10)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-异丙基哌嗪-1-基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.94(s,1H),8.12(s,1H),7.83(d,J＝9.3Hz,1H),7.68(t,J＝7.8Hz,3H),7.59(q,J＝6.6Hz,4H),7.35(dd,J＝13.9,6.6Hz,2H),7.05(s,1H),3.71(d,J＝93.4Hz,4H),2.80(dt,J＝13.1,6.5Hz,1H),2.60(d,J＝33.0Hz,4H),1.10(d,J＝6.5Hz,6H)；MS:found m/z[M+H]+465.26,calcd.m/z[M]464.22.
实施例11
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-哌啶基哌啶基)甲酮(I-11)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-哌啶基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.94(s,1H),8.12(s,1H),7.83(d,J＝9.3Hz,1H),7.67(dd,J＝10.3,4.9Hz,3H),7.59(dd,J＝12.3,8.3Hz,4H),7.42–7.30(m,2H),7.05(s,1H),4.81(s,1H),3.92(s,1H),3.08(s,1H),2.82(s,1H),2.57(s,5H),1.88(s,4H),1.63(d,J＝4.9Hz,6H)；MS:found m/z[M+H]+505.22,calcd.m/z[M]504.25.
实施例12
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-吗啉基哌啶基)甲酮(I-12)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-吗啉基哌啶基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.94(s,1H),8.12(s,1H),7.82(d,J＝9.8Hz,1H),7.63(dt,J＝17.9,8.1Hz,6H),7.45–7.30(m,2H),7.05(s,1H),4.78(s,2H),3.94(s,1H),3.76(s,4H),3.02(d,J＝58.3Hz,2H),2.56(d,J＝26.5Hz,4H),2.47(s,1H),1.96(s,2H),1.56(s,2H)；MS:found m/z[M+H]+507.10,calcd.m/z[M]506.23.
实施例13
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐(I-13)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(哌嗪基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):8.94(s,1H),8.12(s,1H),7.82(d,J＝9.8Hz,1H),7.63(dt,J＝17.9,8.1Hz,6H),7.45–7.30(m,2H),7.05(s,1H),6.51(s,1H),3.55(s,4H),3.45(s,4H)；MS:found m/z[M+H]+423.16,calcd.m/z[M]422.17.
实施例14
(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-氨基哌啶基)甲酮三氟乙酸盐(I-14)
可通过与实施例1中类似的方法制备(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(4-氨基哌啶基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):9.03(s,1H),8.23(s,1H),7.91(dd,J＝14.0,8.8Hz,3H),7.80(dd,J＝9.4,1.6Hz,1H),7.72(t,J＝6.8Hz,2H),7.61(s,1H),7.54(d,J＝8.2Hz,2H),7.41–7.28(m,2H),6.85(s,2H),4.47(s,1H),3.72(s,1H),3.22(s,2H),2.96(s,1H),1.92(s,2H),1.43(s,2H)；MS:found m/z[M+H]+437.26,calcd.m/z[M]436.19.
实施例15
(R)-(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(3-氨基哌啶基)甲酮三氟乙酸盐(I-15)
可通过与实施例1中类似的方法制备(R)-(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(3-氨基哌啶基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):8.94(s,1H),8.12(s,1H),7.82(d,J＝9.8Hz,1H),7.63(dt,J＝17.9,8.1Hz,6H),7.45–7.30(m,2H),7.05(s,1H),4.28(d,J＝46.0Hz,2H),3.13–2.80(m,3H),1.95(s,1H),1.71(s,1H),1.48(s,2H)；MS:found m/z[M+H]+437.13,calcd.m/z[M]436.19.
实施例16
(S)-(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(3-氨基哌啶基)甲酮三氟乙酸盐(I-16)
可通过与实施例1中类似的方法制备(S)-(4-(3-(苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(3-氨基哌啶基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):9.03(s,1H),8.23(s,1H),7.92(d,J＝8.2Hz,3H),7.81(d,J＝9.4Hz,1H),7.72(t,J＝7.0Hz,2H),7.62(s,1H),7.57(d,J＝8.0Hz,2H),7.43–7.28(m,2H),4.27(d,J＝46.0Hz,2H),3.10–2.78(m,3H),1.94(s,1H),1.69(s,1H),1.45(s,2H)；MS:found m/z[M+H]+437.13,calcd.m/z[M]436.19.
实施例17
(4-(3-(7-吗啉基苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮(I-17)
可通过与实施例1中类似的方法制备(7-异丙基苯并呋喃-2-基)硼酸(4-(3-(7-吗啉基苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):8.98(s,1H),8.15(s,1H),7.86(d,J＝7.7Hz,1H),7.70(d,J＝6.5Hz,2H),7.65–7.52(m,3H),7.28(s,2H),7.05(s,1H),6.85(d,J＝7.7Hz,1H),3.90(d,J＝3.5Hz,4H),3.68(d,J＝53.0Hz,8H),3.39(d,J＝3.5Hz,4H)；MS:found m/z[M+H]+509.37,calcd.m/z[M]508.21.
实施例18
(4-(3-(7-(哌嗪-1基)苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮三氟乙酸盐(I-18)
可通过与实施例1中类似的方法制备(4-(3-(7-(哌嗪-1基)苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮三氟乙酸盐。
1H NMR(300MHz,CDCl3)δ(ppm):9.92(s,2H),8.99(s,1H),8.22(s,1H),8.14(d,J＝7.4Hz,1H),7.75(d,J＝9.5Hz,1H),7.67(d,J＝6.1Hz,2H),7.60(d,J＝9.1Hz,2H),7.36(d,J＝7.4Hz,1H),7.29(s,1H),7.15(s,1H),6.88(d,J＝7.1Hz,1H),3.81(s,4H),3.64(d,J＝32.1Hz,8H),3.27(s,4H)；MS:found m/z[M+H]+508.27,calcd.m/z[M]507.23.
实施例19
(4-(3-(7-哌啶基苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮(I-19)
可通过与实施例1中类似的方法制备(4-(3-(7-哌啶基苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮。
1H NMR(300MHz,CDCl3)δ(ppm):9.04(s,1H),8.11(s,1H),7.83(d,J＝9.3Hz,1H),7.72(d,J＝8.1Hz,2H),7.61–7.54(m,3H),7.28(s,1H),7.02(s,1H),6.86(d,J＝6.5Hz,1H),3.76(s,8H),3.34(s,4H),1.78(d,J＝4.1Hz,4H),1.63(dd,J＝10.7,5.5Hz,2H)；MS:found m/z[M+H]+507.30,calcd.m/z[M]506.23.
实施例20
(4-(3-(7-(二甲氨基)苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮(I-20)
可通过与实施例1中类似的方法制备(4-(3-(7-(二甲氨基)苯并呋喃-2-基)咪唑并[1,2-a]吡啶基-6-基)苯基)(吗啉基)甲酮。
1H NMR(300MHz,DMSO-d6)δ(ppm):9.07(s,1H),8.24(s,1H),7.95–7.75(m,5H),7.59(d,J＝8.2Hz,2H),7.52(s,1H),7.15(dd,J＝6.7,3.7Hz,2H),3.63(s,8H),3.08(s,6H)；MS:found m/z[M+H]+467.14,calcd.m/z[M]466.2.
生物活性测试例1激酶水平测试
以下是本发明化合物对MNK1和MNK2酶活的抑制活性。利用ADP-Glo激酶测试试剂盒(Promega,catalog No.V6930)，筛选化合物活性。所有激酶反应均在HEPES反应缓冲液(15mM HEPES pH7.4，20mM NaCl2，1mM EGTA，10mMMgCl2，0.1mg/mL BGG和0.02％Tween-20)中进行。最终MNK1反应液包含10nM MNK1(Carna，catalog No.02-145)、100μM多肽底物(TATKSGSTTKNR，Genscript)、300μM ATP和不同浓度化合物；最终MNK2反应液包含3nM MNK1(Carna，catalog No.02-146)、50μM多肽底物(TATKSGSTTKNR，Genscript)、10μM ATP和不同浓度化合物。各反应中最终DMSO浓度为1％。具体实施方法为：
384孔板每孔加入4μL蛋白溶液，再加入2μL化合物溶液，1000rpm离心5min，摇床上室温孵育10min；
每孔加入4μL底物混合物(多肽底物和ATP)，1000rpm离心5min，摇床上室温孵育60min；
每孔加入10μL ADP-Glo试剂，1000rpm离心5min，摇床上室温孵育40min(避光)；
每孔加入20μL Detection试剂，1000rpm离心5min，摇床上室温孵育40min(避光)；
使用多功能酶标仪冷发光模块读取RLU(Relative luminescence unit)值。信号强度用以表征MNK酶的活性强度，并利用化合物稀释的8个浓度来计算实现50％酶活抑制所需的化合物浓度(IC50)。(实验结果见表2)
表2.化合物对MNK1和MNK2酶活的抑制活性
从上述结果中可见，本发明的化合物对于MNK1和MNK2均有优异的抑制活性。
生物活性测试例2肝微粒稳定性测试
选用Tolbutamide为参比化合物。具体方法如下：
配置0.1M K3PO4(pH7.4)缓冲液及3×NADPH储存液(6mM，5mg/mL)，并在37℃水浴锅中预热；
受试化合物及参比化合物spiking solution的配置：将5μL化合物储备液(10nM)加入到95μL乙腈中；
1.5μM spiking solution in microsomes(0.75mg/mL)的配置：将1.5μL spikingsolution和18.75μL肝微粒溶液(20mg/mL)加入到479.75μL K3PO4缓冲液中；
取30μL spiking solution in microsomes加入到多孔板中，并在37℃条件下孵育5min；
每孔加入15μL NADPH储存液开始反应，并计时；
分别在0min、5min、15min、30min和45min加入150μL含IS的乙腈溶液，终止反应；
振荡10min后6000rpm离心15min；每孔取80μL上清LC/MS检测，计算T1/2。
(实验结果见表3)
表3.化合物肝微粒体稳定性
从上述结果中可见，本发明的化合物在肝微粒体模型中具有良好的代谢稳定性。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.通式(I)所示的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物：
其中，
X为S或O；
R1和R2各自独立地选自下组：氢、卤素、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基、-CN、-OR、-SR、-N(R)2、-NO2、-COR、-CO2R、-CON(R)2、-CONROR、-SOR、-SO2R、-SO2N(R)2、-OCOR、-NRCOR、-NRSO2R或-NRCON(R)2；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
各个R各自独立选自氢、取代或未取代的C1-C6烷基、取代或未取代的C3-C8环烷基、取代或未取代的C6-C10芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂芳基、取代或未取代的具有1-3个选自N、S和O的杂原子的5-10元杂环基；
R3为H，或具有-NR4R5所示的结构，其中，R4和R5各自独立地选自下组：氢、取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基；
其中，所述的“取代”是指被选自下组的一个或多个(例如2个、3个、4个等)取代基所取代：卤素、C1-C6烷基、卤代的C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷氧基、C1-C6烷胺基、-C(O)C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、氧代、-CN、羟基、氨基、羧基、未取代或被一个或多个取代基取代的选自下组的基团：C6-C10芳基、C3-C8环烷基、具有1-3个选自N、S和O的杂原子的5-10元杂芳基、具有1-3个选自N、S和O的杂原子的5-10元杂环基；所述的取代基选自下组：卤素、C1-C6烷氧基。
2.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的X为O。
3.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的R1和R2各自独立地为取代或未取代的C1-C6烷基；或R1和R2与其相连的N原子同形成取代或未取代的5-6元杂环基。
4.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的化合物具有如下式II所示的结构：
5.如权利要求1所述的化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药及其水合物或溶剂合物，其特征在于，所述的化合物选自下组：
6.一种药物组合物，其特征在于，所述药物组合物包括：(i)治疗有效量的权利要求1-5中任一所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的一种或多种，以及(ii)药学上可接受的载体或赋形剂。
7.如权利要求6所述的药物组合物，其特征在于，所述的药物组合物用于治疗与MNK的活性或表达量相关的疾病或病症。
8.如权利要求1-5任一所述的式(I)化合物，或其立体异构体、几何异构体、互变异构体、其药学上可接受的盐、其前药、水合物或溶剂合物的用途，其特征在于，所述的化合物用于制备治疗或预防与MNK的活性或表达量相关的疾病或病症的药物组合物。
9.如权利要求8所述的用途，其特征在于，所述的疾病为癌症。
10.如权利要求1-5任一所述的式(I)化合物的制备方法，其特征在于，所述方法包括步骤：
在金属钯催化剂(优选为Pd(PPh3)4或Pd(dppf)Cl2)催化下，用式7化合物与
进行偶联反应，得到目标化合物(I)。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910430268.1A CN111978318A (zh) | 2019-05-22 | 2019-05-22 | 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910430268.1A CN111978318A (zh) | 2019-05-22 | 2019-05-22 | 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111978318A true CN111978318A (zh) | 2020-11-24 |
Family
ID=73436038
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910430268.1A Pending CN111978318A (zh) | 2019-05-22 | 2019-05-22 | 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111978318A (zh) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009144395A1 (fr) * | 2008-03-21 | 2009-12-03 | Sanofi-Aventis | DÉRIVÉS POLYSUBSTITUES DE 2-HETEROARYL-6-PHENYL-IMIDAZO[1,2- α]PYRIDINES, LEUR PRÉPARATION ET LEUR APPLICATION EN THÉRAPEUTIQUE |
| WO2014138692A1 (en) * | 2013-03-07 | 2014-09-12 | Califia Bio, Inc. | Mixed lineage kinase inhibitors and method of treatments |
-
2019
- 2019-05-22 CN CN201910430268.1A patent/CN111978318A/zh active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009144395A1 (fr) * | 2008-03-21 | 2009-12-03 | Sanofi-Aventis | DÉRIVÉS POLYSUBSTITUES DE 2-HETEROARYL-6-PHENYL-IMIDAZO[1,2- α]PYRIDINES, LEUR PRÉPARATION ET LEUR APPLICATION EN THÉRAPEUTIQUE |
| WO2014138692A1 (en) * | 2013-03-07 | 2014-09-12 | Califia Bio, Inc. | Mixed lineage kinase inhibitors and method of treatments |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN114901661B (zh) | 新型K-Ras G12C抑制剂 | |
| CN113454081B (zh) | 咪唑并吡啶基化合物及其用于治疗增生性疾病的用途 | |
| JP6940039B2 (ja) | Ｐａｒｐ阻害剤の製造方法、結晶型、及びその使用 | |
| WO2018157856A1 (zh) | 酰胺类衍生物抑制剂及其制备方法和应用 | |
| WO2016026445A1 (zh) | 作为fgfr激酶抑制剂的吲唑类化合物及其制备和应用 | |
| WO2001083456A1 (en) | Condensed heteroaryl derivatives | |
| TWI794294B (zh) | 吡唑衍生化合物及其用途 | |
| CN112672997A (zh) | 哒嗪酮衍生物 | |
| WO2006070943A1 (ja) | 縮合イミダゾール化合物およびその用途 | |
| TW200916458A (en) | Heterocyclic compounds and methods of use thereof | |
| WO2020038460A1 (zh) | 一种新型的喹啉衍生物抑制剂 | |
| WO2020078362A1 (zh) | 一类咪唑并芳环类化合物的制备和应用 | |
| CN104045642A (zh) | 含嘧啶或吡啶的稠环化合物及其作为抗肿瘤药物的应用 | |
| JP2019038848A (ja) | 白血病を予防および治療するためのマレイミド誘導体の使用 | |
| CN115515589A (zh) | Ulk1/2抑制剂及其使用方法 | |
| JPWO2016039398A1 (ja) | 含窒素複素環誘導体、神経保護剤及び癌治療用医薬組成物 | |
| KR20240009929A (ko) | Parp 억제제로서 치환된 융합 이환 화합물 및 이의 용도 | |
| CN111978325B (zh) | 咪唑并哒嗪类mnk1/mnk2激酶抑制剂及其制备方法和应用 | |
| CN111978317A (zh) | 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 | |
| CN111978318A (zh) | 咪唑并吡啶类mnk1/mnk2激酶抑制剂及其制备方法和应用 | |
| CN108117551B (zh) | 取代(1H-吡唑[3,4-b]吡啶)脲类化合物及其抗肿瘤用途 | |
| CN106565599A (zh) | 2‑氨甲基吡啶基烟酰胺类化合物及其制备方法和应用 | |
| CN114805371B (zh) | 含2-氨基嘧啶大环类化合物及其制备方法和用途 | |
| CN112625027B (zh) | 杂环衍生物及其用途 | |
| HK40058867A (zh) | 咪唑幷吡啶基化合物及其用於治疗增生性疾病的用途 |
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 | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20220525 Address after: Tong Xiang, Gulou District of Nanjing city of Jiangsu Province, No. 24 210009 Applicant after: CHINA PHARMACEUTICAL University Address before: 201800 room 131, building 3, No. 1101, Huyi Road, Jiading District, Shanghai Applicant before: Shanghai daoentropy Biotechnology Co.,Ltd. Applicant before: SHANGHAI MEDICILON Inc. |
|
| TA01 | Transfer of patent application right | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20201124 |
|
| WD01 | Invention patent application deemed withdrawn after publication |