CN112745284A - Natural chalcone derivative and preparation method and application thereof - Google Patents
Natural chalcone derivative and preparation method and application thereof Download PDFInfo
- Publication number
- CN112745284A CN112745284A CN202011584817.XA CN202011584817A CN112745284A CN 112745284 A CN112745284 A CN 112745284A CN 202011584817 A CN202011584817 A CN 202011584817A CN 112745284 A CN112745284 A CN 112745284A
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- Prior art keywords
- halogen
- substituted
- independently selected
- alkoxy
- 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.)
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- 238000002360 preparation method Methods 0.000 title claims abstract description 47
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 91
- 102000003777 Interleukin-1 beta Human genes 0.000 claims abstract description 23
- 108090000193 Interleukin-1 beta Proteins 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 206010061218 Inflammation Diseases 0.000 claims abstract description 13
- 230000004054 inflammatory process Effects 0.000 claims abstract description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 6
- 201000009961 allergic asthma Diseases 0.000 claims abstract description 6
- 208000006673 asthma Diseases 0.000 claims abstract description 6
- 239000003112 inhibitor Substances 0.000 claims abstract description 6
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims abstract description 6
- 208000007920 Neurogenic Inflammation Diseases 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 183
- 150000002367 halogens Chemical class 0.000 claims description 183
- 125000001424 substituent group Chemical group 0.000 claims description 88
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 78
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 67
- -1 hydroxy, amino Chemical group 0.000 claims description 62
- 125000003545 alkoxy group Chemical group 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 50
- 125000001544 thienyl group Chemical group 0.000 claims description 40
- 150000002431 hydrogen Chemical class 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 20
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 19
- 125000003342 alkenyl group Chemical group 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 14
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 125000004076 pyridyl group Chemical group 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 229910052701 rubidium Inorganic materials 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 206010003246 arthritis Diseases 0.000 claims description 2
- 206010009887 colitis Diseases 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 208000035475 disorder Diseases 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 14
- 201000010099 disease Diseases 0.000 abstract description 10
- 206010059447 Allergic colitis Diseases 0.000 abstract description 4
- 206010061430 Arthritis allergic Diseases 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 82
- 238000006243 chemical reaction Methods 0.000 description 81
- 239000011734 sodium Substances 0.000 description 46
- 239000011541 reaction mixture Substances 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 44
- 239000000543 intermediate Substances 0.000 description 39
- 230000002829 reductive effect Effects 0.000 description 38
- 239000002904 solvent Substances 0.000 description 38
- 239000000047 product Substances 0.000 description 37
- 238000005160 1H NMR spectroscopy Methods 0.000 description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- 238000010898 silica gel chromatography Methods 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- 238000001035 drying Methods 0.000 description 13
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 229910001868 water Inorganic materials 0.000 description 12
- 150000003254 radicals Chemical class 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 125000004432 carbon atom Chemical group C* 0.000 description 8
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 8
- 239000011259 mixed solution Substances 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 6
- 235000005513 chalcones Nutrition 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 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 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 4
- 239000005695 Ammonium acetate Substances 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- 229910002666 PdCl2 Inorganic materials 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 4
- 229940043376 ammonium acetate Drugs 0.000 description 4
- 235000019257 ammonium acetate Nutrition 0.000 description 4
- 239000012964 benzotriazole Substances 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- KOFLVDBWRHFSAB-UHFFFAOYSA-N 1,2,4,5-tetrahydro-1-(phenylmethyl)-5,9b(1',2')-benzeno-9bh-benz(g)indol-3(3ah)-one Chemical compound C1C(C=2C3=CC=CC=2)C2=CC=CC=C2C23C1C(=O)CN2CC1=CC=CC=C1 KOFLVDBWRHFSAB-UHFFFAOYSA-N 0.000 description 3
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000004327 boric acid Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- DANUORFCFTYTSZ-UHFFFAOYSA-N epinigericin Natural products O1C2(C(CC(C)(O2)C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)C)C(C)C(OC)CC1CC1CCC(C)C(C(C)C(O)=O)O1 DANUORFCFTYTSZ-UHFFFAOYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- DANUORFCFTYTSZ-BIBFWWMMSA-N nigericin Chemical compound C([C@@H]1C[C@H]([C@H]([C@]2([C@@H](C[C@](C)(O2)C2O[C@@](C)(CC2)C2[C@H](CC(O2)[C@@H]2[C@H](C[C@@H](C)[C@](O)(CO)O2)C)C)C)O1)C)OC)[C@H]1CC[C@H](C)C([C@@H](C)C(O)=O)O1 DANUORFCFTYTSZ-BIBFWWMMSA-N 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 3
- LLLBDLDNTMMZHL-UHFFFAOYSA-N 1-benzofuran-5-carbaldehyde Chemical compound O=CC1=CC=C2OC=CC2=C1 LLLBDLDNTMMZHL-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- BKLJUYPLUWUEOQ-UHFFFAOYSA-N 6-bromopyridin-2-amine Chemical compound NC1=CC=CC(Br)=N1 BKLJUYPLUWUEOQ-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 2
- MEWLFMBVEMOTCW-UHFFFAOYSA-N COC(C1=C2C=CO1)=CC(CN(C(C=C)=O)C(C=C1)=CC=C1F)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(CN(C(C=C)=O)C(C=C1)=CC=C1F)=C2OC MEWLFMBVEMOTCW-UHFFFAOYSA-N 0.000 description 2
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 2
- 239000012124 Opti-MEM Substances 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940109262 curcumin Drugs 0.000 description 2
- 239000004148 curcumin Substances 0.000 description 2
- 235000012754 curcumin Nutrition 0.000 description 2
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- QMATYTFXDIWACW-UHFFFAOYSA-N 1-(2-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC=C1F QMATYTFXDIWACW-UHFFFAOYSA-N 0.000 description 1
- HCEKGPAHZCYRBZ-UHFFFAOYSA-N 1-(3-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(F)=C1 HCEKGPAHZCYRBZ-UHFFFAOYSA-N 0.000 description 1
- ZDPAWHACYDRYIW-UHFFFAOYSA-N 1-(4-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(F)C=C1 ZDPAWHACYDRYIW-UHFFFAOYSA-N 0.000 description 1
- ABXGMGUHGLQMAW-UHFFFAOYSA-N 1-[3-(trifluoromethyl)phenyl]ethanone Chemical compound CC(=O)C1=CC=CC(C(F)(F)F)=C1 ABXGMGUHGLQMAW-UHFFFAOYSA-N 0.000 description 1
- VUGQIIQFXCXZJU-UHFFFAOYSA-N 3,4,5-trimethoxyacetophenone Chemical compound COC1=CC(C(C)=O)=CC(OC)=C1OC VUGQIIQFXCXZJU-UHFFFAOYSA-N 0.000 description 1
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 description 1
- KKLCYBZPQDOFQK-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CC=C1 KKLCYBZPQDOFQK-UHFFFAOYSA-N 0.000 description 1
- FFZHICFAHSDFKZ-UHFFFAOYSA-N 4,4,5,5-tetramethyl-2-thiophen-2-yl-1,3,2-dioxaborolane Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=CS1 FFZHICFAHSDFKZ-UHFFFAOYSA-N 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
- BIFWGDWGCZLCHF-UHFFFAOYSA-N 4-bromo-2,5-dimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=C(OC)C=C1Br BIFWGDWGCZLCHF-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- CEYBVHFSZZQISA-UHFFFAOYSA-N 7-hydroxy-5-methoxy-2-methylchromen-4-one Chemical compound O1C(C)=CC(=O)C2=C1C=C(O)C=C2OC CEYBVHFSZZQISA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910015845 BBr3 Inorganic materials 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- RCDMPSONLWIIFW-VOTSOKGWSA-N COC(C1=C2C=CO1)=CC(/C=C/C(C(C=C1OC)=CC(OC)=C1OC)=O)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(/C=C/C(C(C=C1OC)=CC(OC)=C1OC)=O)=C2OC RCDMPSONLWIIFW-VOTSOKGWSA-N 0.000 description 1
- XBWHVRMBOAUOSX-BQYQJAHWSA-N COC(C1=C2C=CO1)=CC(/C=C/C(C(C=CC=C1)=C1F)=O)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(/C=C/C(C(C=CC=C1)=C1F)=O)=C2OC XBWHVRMBOAUOSX-BQYQJAHWSA-N 0.000 description 1
- HMTMRULJRDVGGW-VOTSOKGWSA-N COC(C1=C2C=CO1)=CC(/C=C/C(C1=CC(C(F)(F)F)=CC=C1)=O)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(/C=C/C(C1=CC(C(F)(F)F)=CC=C1)=O)=C2OC HMTMRULJRDVGGW-VOTSOKGWSA-N 0.000 description 1
- CYQVBTYJAMECEL-VOTSOKGWSA-N COC(C1=C2C=CO1)=CC(/C=C/C(C1=CC(F)=CC=C1)=O)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(/C=C/C(C1=CC(F)=CC=C1)=O)=C2OC CYQVBTYJAMECEL-VOTSOKGWSA-N 0.000 description 1
- KBXSRGLERODXDN-CMDGGOBGSA-N COC(C1=C2C=CO1)=CC(/C=C/C(C1=CC=CC=C1)=O)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(/C=C/C(C1=CC=CC=C1)=O)=C2OC KBXSRGLERODXDN-CMDGGOBGSA-N 0.000 description 1
- WCEVIRNBGPCVRM-VAWYXSNFSA-N COC(C1=C2C=CO1)=CC(/C=C/C(C1=NC(C3=CC=CC=C3)=CC=C1)=O)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(/C=C/C(C1=NC(C3=CC=CC=C3)=CC=C1)=O)=C2OC WCEVIRNBGPCVRM-VAWYXSNFSA-N 0.000 description 1
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- SIAVMCUTCCXEPZ-FPYGCLRLSA-N COC(C1=C2C=CO1)=CC(/C=C/C(NC(C=C1)=CC=C1F)=O)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(/C=C/C(NC(C=C1)=CC=C1F)=O)=C2OC SIAVMCUTCCXEPZ-FPYGCLRLSA-N 0.000 description 1
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- ZMRSTGKXYCAKJQ-UHFFFAOYSA-N COC(C1=C2C=CO1)=CC(CN(C(C=C)=O)C1=CC=CC=C1)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(CN(C(C=C)=O)C1=CC=CC=C1)=C2OC ZMRSTGKXYCAKJQ-UHFFFAOYSA-N 0.000 description 1
- HUIZMVKDRXAPEL-UHFFFAOYSA-N COC(C1=C2C=CO1)=CC(CN(C(C=C)=O)C1=NC(Br)=CC=C1)=C2OC Chemical compound COC(C1=C2C=CO1)=CC(CN(C(C=C)=O)C1=NC(Br)=CC=C1)=C2OC HUIZMVKDRXAPEL-UHFFFAOYSA-N 0.000 description 1
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- 241001098027 Callerya speciosa Species 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
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- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000005882 aldol condensation reaction Methods 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
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- 239000007864 aqueous solution Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000003181 biological factor Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 150000001788 chalcone derivatives Chemical class 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WMSPXQIQBQAWLL-UHFFFAOYSA-N cyclopropanesulfonamide Chemical compound NS(=O)(=O)C1CC1 WMSPXQIQBQAWLL-UHFFFAOYSA-N 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- YDVNLQGCLLPHAH-UHFFFAOYSA-N dichloromethane;hydrate Chemical compound O.ClCCl YDVNLQGCLLPHAH-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- HNQIVZYLYMDVSB-UHFFFAOYSA-N methanesulfonimidic acid Chemical compound CS(N)(=O)=O HNQIVZYLYMDVSB-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- 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]
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- C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C311/01—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms
- C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C311/09—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton the carbon skeleton being further substituted by at least two halogen atoms
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- C07C311/14—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
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- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/40—Radicals substituted by oxygen atoms
- C07D307/46—Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
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- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides a natural chalcone derivative and a preparation method and application thereof, belonging to the technical field of chemical medicines. The natural chalcone derivative is a compound shown in a formula (I), or a salt, a stereoisomer or a hydrate thereof. The derivative has obvious inhibitory activity to IL-1 beta, can effectively inhibit the release of IL-1 beta, and has an inhibitory effect even superior to that of a compound with a similar structure in the prior art. Of these, compounds 19, 27, 30, 32 and 40 had the best inhibitory effect on IL-1 β. The derivative can be used as an IL-1 beta inhibitor, is used for preparing medicaments for treating inflammation and inflammation related diseases, such as preparing medicaments for treating diseases such as neurogenic inflammation, Alzheimer disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and the like, and has good application prospect.
Description
Technical Field
The invention belongs to the technical field of chemical medicines, and particularly relates to a natural chalcone derivative, and a preparation method and application thereof.
Background
The inflammatory reaction is one of the important defense mechanisms of the body against tissue cell damage caused by physical, chemical, immune or biological factors, and is also the basic pathological process for the development of various diseases, including Alzheimer's disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and other important diseases.
Chalcone and derivatives thereof are products of aromatic aldehyde ketone subjected to cross aldol condensation, and are important organic synthesis intermediates for synthesizing various natural compounds. The chalcone has great flexibility of molecular structure and can combine with different receptors, so that the chalcone has wide biological activity, such as tumor resistance, oxygen radical inhibition and elimination, inflammation resistance, virus resistance and the like.
A natural chalcone with certain inhibition effect on IL-1 beta can be separated from natural plant of Millettia speciosa. However, the activity of the compound has yet to be further improved so as to have potential clinical anti-inflammatory application value.
Disclosure of Invention
In order to solve the problems, the invention provides a natural chalcone derivative and a preparation method and application thereof.
The present invention provides a compound represented by formula (I), or a salt thereof, or a stereoisomer thereof, or a hydrate thereof:
wherein,
The dotted line is a bond or nothing;
when the dotted line is a bond, X is selected from-CRa-or-N-; when the dotted line is absent, X is selected from-CRaRb-or-NRa-;
Ra、RbEach independently selected from hydrogen, hydroxy, a and RcSubstituted 5-to 10-membered aryl or substituted a RcA substituted 5-to 10-membered heteroaryl;
a is 0, 1, 2 or 3;
Rceach independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 10-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R3、R4、R5、R6each independently selected from hydrogen, substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, halogen or cyano; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C8Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdQuiltb number of ReSubstituted 5-to 10-membered aryl or substituted b ReA substituted 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdEach independently selected from substituted or unsubstituted C1~C8Alkyl, halogen or 3-to 8-membered cycloalkyl; the substituent of the alkyl is halogen;
R2selected from hydroxy, C2~C8Alkynyl, by n R7Substituted 5-to 10-membered aryl, substituted with n R7Substituted 5-to 10-membered heteroaryl, 3-to 8-membered cycloalkyl or-NR8R9;
n is 0, 1, 2 or 3;
R7each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 10-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R8、R9are independently selected from hydrogen, hydroxyl and m R10Substituted 5-to 10-membered aryl or substituted with m R10A substituted 5-to 10-membered heteroaryl;
m is 0, 1, 2 or 3;
R10each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 8-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
when the dotted line is null, X is-CH2-,R2When it is phenyl, R3、R4Not hydrogen at the same time.
Further, the air conditioner is provided with a fan,
The dotted line is a bond or nothing;
when the dotted line is a bond, X is selected from-CRa-or-N-; when the dotted line is absent, X is selected from-CRaRb-or-NRa-;
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4、R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O)(O)Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
preferably, the first and second electrodes are formed of a metal,
when the dotted line is a bond, X is selected from-CH-or-N-; when the dotted line is absent, X is selected from-CH2-or-NRa-。
Further, the compound is a compound represented by the formula (II):
wherein,
X is selected from-CRaRb-or-NRa-;
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4、R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
preferably, the first and second electrodes are formed of a metal,
x is selected from-CH2-or-NRa-。
Further, the compound is a compound represented by the formula (III):
wherein,
R3、R4、R5、R6Are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen.
Further, the compound is a compound represented by the formula (IV):
wherein,
R3、R4are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (V):
wherein,
R3、R4are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (VI):
wherein,
R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen.
Further, the compound is a compound represented by the formula (VII):
wherein,
R3、R4are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (VIII):
wherein,
R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (IX):
wherein,
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
alternatively, the compound is a compound represented by formula (X):
wherein,
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-to 6-membered cycloalkyl, trifluoromethyl.
Further, the compound is one of the following compounds:
the invention also provides application of the compound or the salt thereof, or the stereoisomer thereof, or the hydrate thereof in preparing the IL-1 beta inhibitor.
The invention also provides the application of the compound, or the salt, the stereoisomer or the hydrate thereof in preparing medicaments for treating inflammation and inflammation-related diseases;
preferably, the medicament is a medicament for treating neurogenic inflammation, alzheimer's disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis.
The invention also provides a medicament which is a preparation prepared by taking the compound, or the salt thereof, or the stereoisomer thereof, or the hydrate thereof as an active ingredient and adding pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
In the invention, the room temperature is 25 +/-5 ℃; the overnight period was 12. + -.2 h.
The compounds and derivatives provided in the present invention may be named according to the IUPAC (international union of pure and applied chemistry) or CAS (chemical abstracts service, Columbus, OH) naming system.
Definitions of terms used in connection with the present invention: the initial definitions provided herein for a group or term apply to that group or term throughout the specification unless otherwise indicated; for terms not specifically defined herein, the meanings that would be given to them by a person skilled in the art are to be given in light of the disclosure and the context.
"substituted" means that a hydrogen atom in a molecule is replaced by a different atom or molecule.
The structures of the compounds in the invention are all structures capable of stably existing.
The minimum and maximum carbon atom contents of the hydrocarbon groups in the present invention are indicated by prefixes, e.g. prefix (C)a~Cb) Alkyl indicates any alkyl group containingAlkyl of "a" to "b" carbon atoms. Thus, for example, C1~C10The alkyl refers to a straight chain or branched chain alkyl containing 1-10 carbon atoms; c1~C8The alkoxy group is an alkoxy group having 1 to 8 carbon atoms; c2~C10The alkenyl group means an alkenyl group having 2 to 10 carbon atoms; c2~C10The alkynyl group means an alkynyl group having 2 to 10 carbon atoms.
The cycloalkyl refers to a carbon ring which does not contain double bonds and heteroatoms, the cycloalkyl can be monocyclic, condensed rings, bridged rings or spiro rings, and the 3-8-membered cycloalkyl refers to the carbon ring containing 3-8 carbon atoms.
Aryl in the present invention means a carbocyclic ring containing at least one double bond and no heteroatom, and the aryl may be monocyclic, fused, bridged or spiro, such as phenyl, naphthyl, anthracenyl and the like; the 6-to 10-membered aromatic group means that the carbon ring contains 6 to 10 carbon atoms.
Heteroaryl in the present invention refers to a carbocyclic ring containing at least one double bond and containing a heteroatom, which heteroatom aromatic group may be monocyclic, fused, bridged or spiro ring, the heteroatom is selected from O, S or N, the number of heteroatoms is 1, 2, 3, 4, 5 or 6, which heteroaryl group may be selected from benzoheterocyclyl; the 5-to 10-membered hetero-atom aromatic group means that the sum of the number of hetero atoms and carbon atoms in the carbon ring is 5 to 10.
In the present invention, halogen is fluorine, chlorine, bromine or iodine.
The invention provides a natural chalcone derivative which has obvious inhibitory activity on IL-1 beta, can effectively inhibit the release of the IL-1 beta, and has an inhibitory effect even superior to that of a compound with a similar structure in the prior art. Of these, compounds 19, 27, 30, 32 and 40 had the best inhibitory effect on IL-1 β. The derivative can be used as an IL-1 beta inhibitor, is used for preparing medicaments for treating inflammation and inflammation related diseases, such as preparing medicaments for treating diseases such as neurogenic inflammation, Alzheimer disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and the like, and has good application prospect.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and obtained by purchasing commercially available products. To facilitate the subsequent description of the exemplary synthetic routes and methods, the abbreviations for some of the starting materials or reagents used in the examples are given in Table 1 below.
TABLE 1 abbreviations for some of the starting materials or reagents used in the examples
Reagent | Abbreviations |
Ethyl acetate | EtOAc |
Methanol | MeOH |
Ethanol | EtOH |
N, N-dimethylformamide | DMF |
Hydrochloric acid | HCl |
Anhydrous sodium sulfate | Na2SO4 |
Potassium carbonate | K2CO3 |
Nitrogen gas | N2 |
Petroleum ether | PE |
Methylene dichloride | DCM |
Water (W) | H2O |
Sodium bicarbonate | NaHCO3 |
Dimethyl sulfoxide | DMSO |
Sodium sulfate | Na2SO4 |
Trifluoroacetic acid | TFA |
Boron tribromide | BBr3 |
Triethylamine | Et3N |
4-dimethylaminopyridine | DMAP |
1, 3-bis (diphenylphosphino) propane | DPPP |
EXAMPLE 1 preparation of (E) -3- (4, 7-Dimethoxybenzofuran-5-yl) -1-phenyl-prop-2-en-1-one
Step 1: preparation of intermediate 1
Commercially available QINLIN (1equiv, furochromone, CAS number: 82-02-0) was stirred in 10mL of distilled water for 10min at room temperature, 10mL of an aqueous solution prepared by slowly adding potassium hydroxide (6equiv) dropwise, followed by stirring at 120 ℃ for 9-11h, and the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature, the reaction solution was extracted three times with DCM (50mL), and the organic layer was collected and Na anhydrous2SO4After drying and concentration under reduced pressure to remove the solvent, purification by silica gel column chromatography gave yellow solid 1 (intermediate 1).1H NMR(400MHz,CDCl3)δ13.09(s,1H),7.50(d,J=2.3Hz,1H),6.90(d,J=2.4Hz,1H),4.14(s,3H),4.04(s,3H),2.73(s,3H).Exact mass calcd for C12H12O5[M+H]+:236.0685;found 236.0681.
Step 2: preparation of intermediate 2
Intermediate 1(1equiv) and DMAP (1.5equiv) were dissolved in 15mL DCM and trifluoromethanesulfonic anhydride (Tf) was slowly added dropwise at 0 deg.C2O,4.5equiv), after the addition was complete, the reaction was stirred at 0 ℃ for 10min, then at room temperature for 3-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to give compound 2 (intermediate 2) as a pale yellow oil.1H NMR(400MHz,CDCl3)δ7.71(d,J=2.2Hz,1H),6.97(d,J=2.2Hz,1H),4.20(s,3H),4.04(s,3H),2.59(s,3H).Exact mass calcd for C13H11F3O7S[M+H]+:368.0178;found 368.0172.
And step 3: preparation of intermediate 3
Mixing intermediate 2(1equiv) and PdCl2(dppf) (0.1equiv) and DPPP (1.5equiv) were dissolved in 10mL DMF, triethylamine (3equiv) and formic acid (2equiv) were added dropwise at room temperature, the reaction mixture was heated at 60 ℃ for 1-2h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, extracted three times with ethyl acetate (50mL), and the organic layer was collected and washed with anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain white solid 3 (intermediate 3).1H NMR(400MHz,CDCl3)δ7.64(d,J=2.2Hz,1H),7.25(s,1H),6.97(d,J=2.2Hz,1H),4.07(s,3H),4.00(s,3H),2.70(s,3H).Exact mass calcd for C12H12O4[M+H]+:220.0736;found 220.0732.
And 4, step 4: preparation of intermediate 4
Intermediate 3(1equiv) was dissolved in a mixed solution of 10mL of distilled water and 10mL of 1, 4-dioxane, and 25mL of NaOCl was added. The mixture was stirred at 120 ℃ for 3-4h and the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature, the reaction mixture was poured into 125mL of distilled water, the pH was adjusted to 2 with concentrated hydrochloric acid solution, a white solid was precipitated, filtered under suction, washed with anhydrous ether, and dried under vacuum to give white solid 4 (intermediate 4).1H NMR(400MHz,DMSO-d6)δ12.64(s,1H),7.96(d,J=2.2Hz,1H),7.12(s,1H),7.09(d,J=2.2Hz,1H),3.86(s,3H),3.85(s,3H).Exact mass calcd for C11H10O5[M+H]+:222.0528;found 222.0523.
And 5: preparation of intermediate 5
Intermediate 4(1equiv) was dissolved in 15mL of anhydrous THF, lithium aluminum hydride (1.5equiv) was added slowly at 0 deg.C, the reaction mixture was stirred at room temperature for 3-4h, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was poured into 125mL of ice water, suction-filtered, the filtrate was extracted with ethyl acetate (50mL) three times, and the organic layer was collected and Na anhydrous2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain white solid 5 (intermediate 5).1H NMR(400MHz,DMSO-d6)δ7.97(d,J=2.2Hz,1H),7.12(d,J=2.2Hz,1H),7.00(s,1H),4.62(s,2H),3.95(s,3H),3.93(s,3H).Exact mass calcd for C11H12O4[M+H]+:208.0736;found 208.0734.
Step 6: preparation of intermediate 6
Intermediate 5(1equiv) was dissolved in 15mL toluene, manganese dioxide (5equiv) was added and the reaction mixture was stirred at 120 ℃ for 6-8h, and the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature, and the reaction mixture was concentrated under reduced pressure to remove the solvent, followed by purification by silica gel column chromatography to give white solid 6 (intermediate 6).1H NMR(400MHz,DMSO-d6)δ10.28(s,1H),8.04(d,J=2.2Hz,1H),7.31(d,J=2.2Hz,1H),7.08(s,1H),4.07(s,3H),3.86(s,3H).Exact mass calcd for C11H10O4[M+H]+:206.0579;found 206.0575.
And 7: preparation of Compound A1
Intermediate 6(1equiv) and acetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A1.1H NMR(400MHz,CDCl3)δ8.22(d,J=15.8Hz,1H),8.08–8.01(m,2H),7.62(d,J=2.2Hz,1H),7.60–7.54(m,1H),7.49(d,J=15.8Hz,1H),7.54–7.48(m,2H),7.05(s,1H),6.95(d,J=2.2Hz,1H),4.04(d,J=5.1Hz,6H).13C NMR(101MHz,CDCl3)δ191.18,148.23,147.54,145.13,142.11,140.48,138.75,132.69,128.71,128.71,128.66,128.66,121.83,121.63,120.90,105.49,105.12,61.65,56.67.Exact mass calcd for C19H16O4Na,331.0946;[M+Na]+:331.0940.
EXAMPLE 2 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (3',4',5' -trimethoxyphenyl) -prop-2-en-1-one
The method comprises the following specific steps:
intermediate 6(1equiv) and 3',4',5' -trimethoxyacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A2.1H NMR(400MHz,DMSO-d6)δ8.14(d,J=15.7Hz,1H),8.04(d,J=2.2Hz,1H),7.86(d,J=15.7Hz,1H),7.51(s,1H),7.42(s,2H),7.26(d,J=2.3Hz,1H),4.05(s,3H),4.03(s,3H),3.92(s,6H),3.79(s,3H).13C NMR(101MHz,DMSO-d6)δ188.75,153.38,153.38,148.00,147.38,146.50,142.41,141.92,139.02,133.85,121.58,120.99,120.37,106.79,106.29,106.19,105.96,61.69,60.70,57.06,56.75,56.54.Exact mass calcd for C22H22O7[M+Na]+:421.1264;found 421.1251.
EXAMPLE 3 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (3' -trifluoromethylphenyl) -prop-2-en-1-one
The method comprises the following specific steps:
intermediate 6(1equiv) and 3' -trifluoromethylacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. Completion of the reactionThereafter, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A3.1H NMR(400MHz,CDCl3)δ8.27(s,1H),8.23(d,J=15.8Hz,1H1H),8.20(d,J=7.8Hz,1H),7.84(d,J=7.8Hz,1H),7.67(d,J=7.7Hz,1H),7.63(d,J=2.3Hz,1H),7.46(d,J=15.8Hz,1H),7.05(s,1H),6.96(d,J=2.2Hz,1H),4.06(d,J=2.1Hz,6H).13C NMR(101MHz,CDCl3)δ189.81,148.40,147.75,145.08,142.03,141.71,139.22,131.67,131.32,129.23,128.91,125.38,122.49,121.38,120.96,120.35,105.42,105.13,60.62,54.92..Exact mass calcd for C20H15F3O4[M+Na]+:399.0820;found 399.0817.
EXAMPLE 4 preparation of (E) -3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (2' -fluorophenyl) -prop-2-en-1-one
The method comprises the following specific steps:
intermediate 6(1equiv) and 2' -fluoroacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A4.1H NMR(400MHz,CDCl3)δ8.16(dd,J=15.8,1.8Hz,1H),7.81(td,J=7.5,1.9Hz,1H),7.61(d,J=2.2Hz,1H),7.55-7.48(m,1H),7.36(dd,J=15.9,2.7Hz,1H),7.26-7.24(m,1H),7.17(dd,J=9.7,8.2Hz,1H),7.02(s,1H),6.93(d,J=2.2Hz,1H),4.03(d,J=3.3Hz,6H).13C NMR(101MHz,CDCl3)δ189.58,162.34(159.83),148.26,147.57,145.01,142.01,140.45,133.65(133.57),131.01(130.99),125.09,125.03,124.48,121.46,120.59,116.58(116.36),105.35,104.87,61.58,56.44.Exact mass calcd for C19H15FO4[M+Na]+:349.0852;found 349.0851.
EXAMPLE 5 preparation of (E) -3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (3' -fluorophenyl) -prop-2-en-1-one
The method comprises the following specific steps:
intermediate 6(1equiv) and 3' -fluoroacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A5.1H NMR(400MHz,CDCl3)δ8.24(d,J=15.8Hz,1H),7.81(dt,J=7.8,1.2Hz,1H),7.71(ddd,J=9.5,2.7,1.6Hz,1H),7.62(d,J=2.2Hz,1H),7.50(dd,J=8.1,5.5Hz,1H),7.44(d,J=15.8Hz,1H),7.29(ddd,J=8.3,2.6,0.9Hz,1H),7.04(s,1H),6.95(d,J=2.2Hz,1H),4.05(d,J=1.8Hz,6H).13C NMR(101MHz,CDCl3)δ189.64,164.12(161.66),148.31,147.61,145.05,141.99,141.14,140.79(140.73),130.26(130.18),124.20,121.40,121.03,120.47,119.63(119.42),115.44(115.22),105.41,104.98,61.50,56.54.Exact mass calcd for C19H15FO4[M+Na]+:349.0852;found 349.0857.
Examples 6 to 27
The synthesis methods of other natural chalcone derivatives are the same as those in examples 1-5, except that the types of the aromatic methyl ketone are changed. The aromatic methyl ketone starting material, the structural formula of the obtained compound and the nuclear magnetic results of the obtained compound are shown in table 2.
TABLE 2 raw materials for preparing compounds, structural formula of the obtained compounds and nuclear magnetic results of the compounds
EXAMPLE 28 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (6-phenylpyridin-2-yl) -prop-2-en-1-one
The method comprises the following specific steps:
mixing compound A12(1equiv), pinacol phenylboronate (1.2equiv), PdCl2(dppf) (0.1equiv), potassium carbonate (2equiv) in a mixed solution of 7mL dioxane, 3mL ethanol and 4mL water, N2The reaction mixture was stirred at 80 ℃ for 1-2 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A28.1H NMR(400MHz,CDCl3)δ8.69(d,J=3.5Hz,2H),8.42(d,J=15.8Hz,1H),8.44–8.36(m,2H),8.20(d,J=4.4Hz,2H),7.88(d,J=2.2Hz,1H),7.79(d,J=15.8Hz,1H),7.82 7.69(m,3H),7.46(s,1H),7.22(d,J=2.2Hz,1H),4.33(s,6H).13C NMR(101MHz,CDCl3)δ189.92,156.40,154.47,148.45,147.60,145.03,142.04,140.11,138.86,137.95,129.52,128.97,128.97,127.11,127.11,123.35,121.58,121.41,121.34,120.78,105.51,105.33,61.72,56.55.Exact mass calcd for C24H19NO4[M+Na]+:408.1212;found 408.1214.
EXAMPLE 29 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1- (6-thienylpyridin-2-yl) -prop-2-en-1-one
The method comprises the following specific steps:
mixing compound A12(1equiv), thiophene-2-boronic acid pinacol ester (1.2equiv), PdCl2(dppf) (0.1equiv), potassium carbonate (2equiv) in a mixed solution of 7mL dioxane, 3mL ethanol and 4mL water, N2Under protection, the reaction mixture is stirred for 1-2 hours at 80 DEG CThe reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A29.1H NMR(400MHz,CDCl3)δ8.15(d,J=3.3Hz,2H),7.79(dd,J=7.4,1.2Hz,1H),7.60(t,J=7.7Hz,1H),7.56(dd,J=7.9,1.2Hz,1H),7.40(dd,J=3.7,1.1Hz,1H),7.36(d,J=2.2Hz,1H),7.19(dd,J=5.0,1.1Hz,1H),6.97(s,1H),6.89(dd,J=5.1,3.7Hz,1H),6.70(d,J=2.2Hz,1H),3.83(d,J=4.3Hz,6H).13C NMR(101MHz,CDCl3)δ189.22,154.01,151.69,148.39,147.48,144.92,144.59,141.95,139.89,137.76,128.25,128.13,125.04,121.48,121.27,121.27,120.89,120.40,105.43,105.13,61.64,56.36.Exact mass calcd for C22H17NO4S[M+Na]+:417.0776;found 417.0764.
EXAMPLE 30 preparation of (E) -3- (4-bromo-2, 5-dimethoxyphenyl) -1- (4-fluorophenyl) -prop-2-en-1-one
The method comprises the following specific steps:
commercially available 4-bromo-2, 5-dimethoxybenzaldehyde (1equiv) and 4-fluoroacetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A30.1H NMR(400MHz,CDCl3)δ8.33–8.28(m,2H),8.25(d,J=15.8Hz,1H),7.83(d,J=15.8Hz,1H),7.46–7.41(m,3H),7.38(s,1H),4.16(d,J=11.4Hz,6H).13C NMR(101MHz,CDCl3)δ189.51,164.44,153.50,150.37,139.95,134.81,131.32,131.23,123.62,123.16,117.12,115.96,115.74,115.23,112.44,57.11,56.51.Exact mass calcd for C17H14BrFO3Na,387.0008;[M+Na]+:387.0006.
EXAMPLE 31 preparation of (E) -3- (2,5-2' -methyl- [1,1' -biphenyl ] -4-yl) -1- (4' -fluorophenyl) -prop-2-en-1-one
The method comprises the following specific steps:
mixing compound A30(1equiv), methylbenzene-2-boric acid (1.2equiv), PdCl2(dppf) (0.1equiv), potassium carbonate (2equiv) in a mixed solution of 7mL dioxane, 3mL ethanol and 4mL water, N2The reaction mixture was stirred at 80 ℃ for 1-2 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A31.1H NMR(400MHz,CDCl3)δ8.07(d,J=15.8Hz,1H),8.05–7.99(m,2H),7.57(d,J=15.8Hz,1H),7.25–7.19(m,3H),7.18–7.09(m,4H),6.74(s,1H),3.83(s,3H),3.73(s,3H),2.13(s,3H).13C NMR(101MHz,CDCl3)δ189.79,166.89(164.36),153.33,150.89,140.78,138.03,136.83,135.01,134.97,131.31,131.22,129.95,129.75,127.97,125.73,123.19,122.60,115.90,115.69,114.82,111.59,56.31,56.31,20.07.Exact mass calcd for C24H21FO3Na,399.1372;[M+Na]+:399.1371.
The synthesis methods of examples 32 to 40 were the same as in example 31 except that the type of boric acid was changed. The boric acid species, structural formula of the obtained compound and nuclear magnetic results of the obtained compound are shown in table 3.
TABLE 3 raw materials for preparing compounds, structural formula of the obtained compounds and nuclear magnetic results of the compounds
EXAMPLE 41 (E) -N- (4-fluorophenyl) -3-oxoprop-1-en-1-yl) -2, 5-dimethoxyphenylmethanesulfonamide
The method comprises the following specific steps:
compound A30(1equiv), methylsulfonamide (1.2equiv), [ Pd (allyl) Cl]2(0.1equiv), t-BuXPhos (0.13equiv), Potassium carbonate (2equiv) in 7mL 2-methyltetrahydrofuran, N2The reaction mixture was stirred at 80 ℃ for 8-10 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A41.1H NMR(400MHz,DMSO)δ8.18–8.12(m,2H),8.06(d,J=15.2Hz,1H),7.43(d,J=15.2Hz,1H),7.36–7.29(m,2H),7.16(s,1H),6.90(s,1H),3.73(d,J=10.3Hz,6H),2.68(s,3H).13C NMR(101MHz,DMSO)δ186.84,165.70(163.22),155.64,146.09,140.47,135.71,130.93,130.84,129.72,115.58,115.37,112.88,109.42,109.18,100.52,55.88,55.58,48.52.Exact mass calcd for C18H18FNO5SNa,402.0787;[M+Na]+:402.0783.
EXAMPLE 42 (E) -N- (4-fluorophenyl) -3-oxoprop-1-en-1-yl) -2, 5-dimethoxyphenylcyclopropanesulfonamide
The method comprises the following specific steps:
compound A30(1equiv), cyclopropanesulfonamide (1.2equiv), [ Pd (allyl) Cl]2(0.1equiv), t-BuXPhos (0.13equiv), Potassium carbonate (2equiv) in 7mL 2-methyltetrahydrofuran, N2The reaction mixture was stirred at 80 ℃ for 8-10 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A42.1H NMR(400MHz,CDCl3)δ8.03(d,J=15.8Hz,1H),8.08–7.97(m,2H),7.52(d,J=15.8Hz,1H),7.28(s,1H),7.17(t,J=8.6Hz,2H),7.11(s,1H),3.91(d,J=4.9Hz,6H),2.57–2.47(m,1H),1.23(dd,J=6.8,4.8Hz,2H),0.99(dd,J=7.9,3.2Hz,2H).Exact mass calcd for C20H20FNO5SNa,428.0944;[M+Na]+:428.0949.
EXAMPLE 43 (E) -N- (4-fluorophenyl) -3-oxoprop-1-en-1-yl) -2, 5-dimethoxyphenyl trifluoromethanesulfonamide
The method comprises the following specific steps:
compound A30(1equiv), trifluoromethylsulfonamide (1.2equiv), [ Pd (allyl) Cl]2(0.1equiv), t-BuXPhos (0.13equiv), Potassium carbonate (2equiv) in 7mL 2-methyltetrahydrofuran, N2The reaction mixture was stirred at 80 ℃ for 8-10 hours under protection and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product A43.1H NMR(400MHz,MeOD-d4)δ8.12(d,J=15.7Hz,1H),8.19–8.05(m,2H),7.67(d,J=15.7Hz,1H),7.32(s,1H),7.30–7.21(m,2H),7.13(s,1H),3.87(d,J=2.9Hz,6H).Exact mass calcd for C18H15F4NO5SNa,456.0505;[M+Na]+:456.0503.
EXAMPLE 44 preparation of (E) -3- (benzofuran-5-yl) -1-phenyl-prop-2-en-1-one
The method comprises the following specific steps:
commercially available 1-benzofuran-5-carbaldehyde (1equiv) and acetophenone (1.2equiv) were dissolved in 15mL of methanol, 3mL of 3M NaOH solution was added dropwise, the reaction mixture was stirred at room temperature for 4-5h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was neutralized with 5% HCl, extracted with ethyl acetate, and the organic phase was washed with water and anhydrous Na2SO4After drying and concentration under reduced pressure to remove the solvent, the product was purified by silica gel column chromatography to obtain product A44.1H NMR(400MHz,CDCl3)δ8.34–8.26(m,2H),8.20(d,J=15.8Hz,1H),8.14(d,J=1.8Hz,1H),7.92(d,J=2.3Hz,1H),7.89–7.70(m,6H),7.07(d,J=2.3Hz,1H).13C NMR(101MHz,CDCl3)δ190.63,156.36,146.25,145.53,138.51,132.81,130.13,128.73,128.73,128.60,128.60,128.28,124.71,122.35,121.12,112.14,106.94.Exact mass calcd for C17H12F4O2Na,271.0735;[M+Na]+:271.0729.
EXAMPLE 45 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1-phenyl-propan-1-one
The method comprises the following specific steps:
1 particle of zinc particles (0.3g) and ammonium acetate (2equiv) were dissolved in a mixed solution of 5mL of distilled water and 5mL of ethanol, stirred at normal temperature for 30min, Compound A1(1equiv) was added to the reaction system, stirred at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B1.1H NMR(400MHz,CDCl3)δ8.25(dd,J=8.4,1.4Hz,2H),7.83(d,J=2.1Hz,1H),7.82–7.76(m,1H),7.71(dd,J=8.3,7.0Hz,2H),7.12(d,J=2.2Hz,1H),6.92(s,1H),4.23(d,J=2.0Hz,6H),3.56(dd,J=8.8,6.7Hz,2H),3.37(dd,J=8.6,6.8Hz,2H).Exact mass calcd for C19H18O4[M+Na]+:333.1103;found 333.1102.
EXAMPLE 46 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (4' -fluorophenyl) -propan-1-one
The method comprises the following specific steps:
1 zinc pellet (0.3g) and ammonium acetate (2equiv) were dissolved in 5mLTo a mixed solution of distilled water and 5mL of ethanol, stirring was carried out at normal temperature for 30min, Compound A19(1equiv) was added to the reaction system, stirring was carried out at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B2.1H NMR(400MHz,CDCl3)δ8.30–8.24(m,2H),7.84(d,J=2.2Hz,1H),7.38(dd,J=9.6,7.7Hz,2H),7.12(d,J=2.2Hz,1H),6.91(s,1H),4.23(d,J=2.9Hz,6H),3.53(dd,J=8.7,6.7Hz,2H),3.36(dd,J=8.8,6.6Hz,2H).Exact mass calcd for C19H17FO4[M+Na]+:351.1009;found 351.1004.
EXAMPLE 47 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (3' -trifluoromethylphenyl) -propan-1-one
The method comprises the following specific steps:
1 particle of zinc particles (0.3g) and ammonium acetate (2equiv) were dissolved in a mixed solution of 5mL of distilled water and 5mL of ethanol, stirred at normal temperature for 30min, Compound A3(1equiv) was added to the reaction system, stirred at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B3.1H NMR(400MHz,CDCl3)δ8.49(s,1H),8.42(d,J=7.8Hz,1H),8.07(d,J=7.8Hz,1H),7.88–7.84(m,1H),7.84(d,J=2.0Hz,1H),7.13(dd,J=2.3,1.0Hz,1H),6.92(s,1H),4.23(t,J=1.5Hz,6H),3.58(t,J=7.7Hz,2H),3.38(dd,J=8.5,6.7Hz,2H).13C NMR(101MHz,CDCl3)δ198.51,144.64,144.54,144.43,141.35,137.37,131.26,129.43,129.40,129.27,125.44,125.07(125.03),122.37,121.14,108.57,104.66,60.74,56.51,40.35,25.56.Exact mass calcd for C20H17F3O4Na,401.0979;[M+Na]+:401.0979.
EXAMPLE 48 preparation of 3- (4, 7-Dimethoxybenzofuran-5-yl) -1- (3' -aminophenyl) -propan-1-one
The method comprises the following specific steps:
1 particle of zinc particles (0.3g) and ammonium acetate (2equiv) were dissolved in a mixed solution of 5mL of distilled water and 5mL of ethanol, stirred at normal temperature for 30min, Compound A12(1equiv) was added to the reaction system, stirred at 55 ℃ for 5 to 8 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain product B4.1H NMR(400MHz,CDCl3)δ7.30(d,J=2.2Hz,1H),7.25(t,J=7.7Hz,1H),7.08(dd,J=12.7,7.7Hz,2H),6.57(d,J=2.2Hz,1H),6.36(s,1H),3.72(s,3H),3.67(s,3H),2.70–2.53(m,2H),1.73(dtd,J=13.9,8.5,5.4Hz,2H).Exact mass calcd for C18H16BrNO4Na,412.0160;[M+Na]+:412.0162.
EXAMPLE 49 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1-N-phenylacrylamide
The method comprises the following specific steps:
dissolving compound A25(1equiv), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (1.5equiv), and triethylamine (1.5equiv) in 10mL of DMF, stirring at room temperature for 30min, and adding aniline(1.2equiv) was dissolved in a small amount of DMF and slowly dropped into the reaction system, stirred at room temperature for 1-2 hours, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C1.1H NMR(400MHz,CDCl3)δ7.85(d,J=15.6Hz,1H),7.38(d,J=7.9Hz,2H),7.34(d,J=2.2Hz,1H),7.21(s,1H),7.09(t,J=7.9Hz,2H),6.87(t,J=7.4Hz,1H),6.66(d,J=2.3Hz,2H),6.34(d,J=15.7Hz,1H),3.74(d,J=4.8Hz,6H).Exact mass calcd for C19H17NO4Na,346.1055;[M+Na]+:346.1056.
EXAMPLE 50 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1-N- (4' -fluorophenyl) -acrylamide
The method comprises the following specific steps:
compound a25(1equiv), 2- (7-benzotriazole oxide) -N, N '-tetramethylurea Hexafluorophosphate (HATU) (1.5equiv), triethylamine (1.5equiv) were dissolved in 10mL DMF, stirred at room temperature for 30min, 4' -fluoroaniline (1.2equiv) was dissolved in a small amount of DMF and then slowly dropped into the reaction system, stirred at room temperature for 1-2h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C2.1H NMR(400MHz,DMSO-d6)δ7.84(d,J=2.2Hz,1H),7.73(d,J=15.8Hz,1H),7.59–7.53(m,2H),7.04(d,J=2.3Hz,1H),7.00(t,J=8.9Hz,2H),6.93(s,1H),6.65(d,J=15.8Hz,1H),3.81(d,J=12.8Hz,6H).Exact mass calcd for C19H16FNO4[M+Na]+:364.0961;found 364.0961.
EXAMPLE 51 preparation of (E) -3- (4, 7-dimethoxybenzofuran-5-yl) -1-N- (3' -trifluoromethylphenyl) -acrylamide
The method comprises the following specific steps:
compound a25(1equiv), 2- (7-benzotriazole oxide) -N, N '-tetramethylurea Hexafluorophosphate (HATU) (1.5equiv), triethylamine (1.5equiv) were dissolved in 10mL DMF, stirred at room temperature for 30min, 3' -trifluoromethylaniline (1.2equiv) was dissolved with a small amount of DMF and then slowly dropped into the reaction system, stirred at room temperature for 1-2h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C3.1H NMR(400MHz,CDCl3)δ8.14(d,J=15.7Hz,1H),7.95(s,1H),7.84(d,J=8.2Hz,1H),7.61(d,J=2.2Hz,1H),7.52–7.44(m,2H),7.38(d,J=7.9Hz,1H),6.94(d,J=2.2Hz,1H),6.92(s,1H),6.58(d,J=15.6Hz,1H),4.02(d,J=5.6Hz,6H).Exact mass calcd for C20H16F3NO4Na:414.0929;[M+Na]+:414.0934.
EXAMPLE 52 preparation of (E) -N- (6-bromopyridin-2-yl) -3- (4, 7-dimethoxybenzofuran-5-yl) -acrylamide
The method comprises the following specific steps:
dissolving compound A25(1equiv), 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (1.5equiv) and triethylamine (1.5equiv) in 10mL of DMF, stirring at room temperature for 30min, dissolving 2-amino-6-bromopyridine (1.2equiv) in a small amount of DMF, slowly dropping into the reaction system, stirring at room temperature for 1-2h, monitoring reverse reaction by TLCShould be used. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product C4.1H NMR(400MHz,CDCl3)δ8.75(dd,J=4.5,1.4Hz,1H),8.50(d,J=16.1Hz,1H),8.45(dd,J=8.4,1.4Hz,1H),7.65(d,J=2.2Hz,1H),7.46(dd,J=8.4,4.5Hz,1H),7.00(s,1H),6.98(d,J=2.2Hz,1H),6.77(d,J=16.1Hz,1H),4.09(s,3H),4.05(s,3H).13C NMR(101MHz,CDCl3)δ163.47,151.85,149.00,146.99,145.36,142.18,141.16,135.25,129.69,120.95,119.11,116.07,109.41,105.79,105.52,105.00,61.58,56.61.Exact mass calcd for C18H15BrN2O4Na:425.0113;[M+Na]+:425.0114.
EXAMPLE 53 preparation of N- ((4, 7-Dimethoxybenzofuran-5-yl) methyl) -N-phenylacrylamide
Step 1: preparation of intermediate 7
The intermediate 6(1equiv) and aniline (1.2equiv) were dissolved in 10mL DCM, 1mL glacial acetic acid and anhydrous sodium sulfate (1.5equiv) were added, stirring was carried out at room temperature for 1h, suction filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the solid obtained by spin-drying was dissolved in 10mL methanol, sodium cyanoborohydride (2.5equiv) was slowly added under ice bath, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and then purified by silica gel column chromatography to obtain intermediate 7.1H NMR(400MHz,CDCl3)δ7.56(d,J=2.2Hz,1H),7.32–7.27(m,3H),7.04–6.99(m,2H),6.90(s,1H),6.78(d,J=2.2Hz,1H),5.56(t,J=5.5Hz,2.1Hz,1H),5.16(s,2H),3.96(s,3H),3.51(s,3H)
Step 2: preparation of Compound D1
The intermediate 7(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise under ice bath, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D1.1H NMR(400MHz,CDCl3)δ7.56(d,J=2.2Hz,1H),7.32–7.27(m,3H),7.04–6.99(m,2H),6.90(s,1H),6.78(d,J=2.2Hz,1H),6.45(dd,J=16.8,2.1Hz,1H),6.05(dd,J=16.8,10.3Hz,1H),5.56(dd,J=10.3,2.1Hz,1H),5.16(s,2H),3.96(s,3H),3.51(s,3H).13C NMR(101MHz,CDCl3)δ165.79,145.23,144.97,144.36,144.36,141.71,129.31,129.31,128.83,128.57,127.82,127.77,122.30,120.69,108.12,104.87,60.67,56.50,56.47,46.50.Exact mass calcd for C20H19NO4Na:360.1212;[M+Na]+360.1204.
EXAMPLE 54 preparation of N- ((4, 7-dimethoxybenzofuran-5-yl) methyl) -N- (4-fluorophenyl) -acrylamide
Step 1: preparation of intermediate 8
The intermediate 6(1equiv) and 4-fluoroaniline (1.2equiv) were dissolved in 10mL of DCM, 1mL of glacial acetic acid and anhydrous sodium sulfate (1.5equiv) were added, stirring was carried out at room temperature for 1h, suction filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the solid obtained by spin-drying was dissolved in 10mL of methanol, sodium cyanoborohydride (2.5equiv) was slowly added under ice bath, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then purified by silica gel column chromatography to obtain intermediate 8.1H NMR(400MHz,CDCl3)δ7.82(d,J=2.2Hz,1H),7.26–7.20(m,4H),7.12(s,1H),7.04(d,J=2.2Hz,1H),5.30(t,J=5.4Hz,1H),5.37(s,2H),4.21(s,3H),3.81(s,3H).Exact mass calcd for C17H16FNO3Na:324.1012;[M+Na]+324.1015.
Step 2: preparation of Compound D2
The intermediate 8(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise under ice bath, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D2.1H NMR(400MHz,CDCl3)δ7.82(d,J=2.2Hz,1H),7.26–7.20(m,4H),7.12(s,1H),7.04(d,J=2.2Hz,1H),6.70(dd,J=16.8,2.1Hz,1H),6.26(dd,J=16.8,10.3Hz,1H),5.83(dd,J=10.3,2.0Hz,1H),5.37(s,2H),4.21(s,3H),3.81(s,3H).13C NMR(101MHz,CDCl3)δ165.79,163.06(160.59),145.31,145.06,144.46,141.73,137.64,130.33,130.25,128.54,128.14,121.89,120.63,116.31,116.08,108.18,104.89,60.67,56.53,46.50.Exact mass calcd for C20H18FNO4Na:378.1118;[M+Na]+378.1115.
EXAMPLE 55 preparation of N- ((4, 7-Dimethoxybenzofuran-5-yl) methyl) -N- (4-fluorophenyl) -acrylamide
Step 1: preparation of intermediate 9
Dissolving intermediate 6(1equiv) and 3-trifluoromethylaniline (1.2equiv) in 10mL DCM, adding 1mL glacial acetic acid and anhydrous sodium sulfate (1.5equiv), stirring at room temperature for 1h, vacuum filtering, concentrating the filtrate under reduced pressure to remove solvent, dissolving the solid obtained in 10mL methanol, ice-cooling, and removing solventNext, sodium cyanoborohydride (2.5equiv) was added slowly, stirred for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the solvent was removed by concentration under reduced pressure, and then purified by silica gel column chromatography to obtain intermediate 9.1H NMR(500MHz,CDCl3)δ7.56–7.50(m,2H),7.40(t,J=7.9Hz,1H),7.34(s,1H),7.14(d,J=7.9Hz,1H),6.85(s,1H),6.77(d,J=2.2Hz,1H),5.43(t,J=5.5Hz,1H),5.13(s,2H),3.93(s,3H),3.56(s,3H).Exact mass calcd for C18H16F3NO3Na:374.0980;[M+Na]+374.0981.
Step 2: preparation of Compound D3
Intermediate 9(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise while cooling on ice, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D3.1H NMR(400MHz,CDCl3)δ7.56–7.50(m,2H),7.40(t,J=7.9Hz,1H),7.34(s,1H),7.14(d,J=7.9Hz,1H),6.85(s,1H),6.77(d,J=2.2Hz,1H),6.46(dd,J=16.7,2.0Hz,1H),5.98(t,J=13.5Hz,1H),5.60(dd,J=10.3,1.9Hz,1H),5.13(s,2H),3.93(s,3H),3.56(s,3H).Exact mass calcd for C21H18F3NO4Na:428.1086;[M+Na]+:428.1080.
EXAMPLE 56 preparation of N- (6-bromopyridin-2-yl) -N- ((4, 7-dimethoxybenzofuran-5-yl) methyl) -acrylamide
Step 1: preparation of intermediate 10
The intermediate 6(1equiv) and 2-amino-6-bromopyridine (1.2equiv) were dissolved in 10mL of DCM, 1mL of glacial acetic acid and anhydrous sodium sulfate (1.5equiv) were added, stirring was carried out at room temperature for 1h, suction filtration was carried out, the filtrate was concentrated under reduced pressure to remove the solvent, the solid obtained by spin-drying was dissolved in 10mL of methanol, sodium cyanoborohydride (2.5equiv) was slowly added under ice bath, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and then purified by silica gel column chromatography to obtain intermediate 10.1H NMR(400MHz,CDCl3)δ7.80(d,J=2.2Hz,1H),7.73(t,J=7.8Hz,1H),7.58(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),7.14(s,1H),7.06(d,J=2.2Hz,1H),5.43(t,J=5.5Hz,1H),5.56(s,2H),4.19(s,3H),4.08(s,3H).Exact mass calcd for C16H15BrN2O3Na:385.0164;[M+Na]+:385.0168.
Step 2: preparation of Compound D4
The intermediate 10(1equiv) and triethylamine (1.5equiv) were dissolved in 10mL of Dichloromethane (DCM), acryloyl chloride (2equiv) was slowly added dropwise under ice bath, after the addition was completed, stirring was carried out for 2-3h, and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, and then purified by silica gel column chromatography to obtain a product D4.1H NMR(400MHz,CDCl3)δ7.80(d,J=2.2Hz,1H),7.73(t,J=7.8Hz,1H),7.58(d,J=7.8Hz,1H),7.34(d,J=7.8Hz,1H),7.14(s,1H),7.06(d,J=2.2Hz,1H),6.72(dd,J=16.7,2.0Hz,1H),6.58(dd,J=16.7,10.2Hz,1H),5.94(dd,J=10.2,2.0Hz,1H),5.56(s,2H),4.19(s,3H),4.08(s,3H).Exact mass calcd for C19H17BrN2O4Na:439.0269;[M+Na]+:439.0272.
The advantageous effects of the present invention are demonstrated by specific test examples below.
Test example 1 pharmacological test of the Compound of the present invention
The invention also provides a pharmacological activity screening experiment of the partial compounds, namely an in-vitro IL-1 beta inhibition experiment. THP-1 is a human myeloid leukemia monocyte originally derived from acute monocytic leukemia patients. THP-1 is an acute monocytic leukemia cell line commonly used in various laboratories, and is an ideal cell for researching immunity and inflammation.
Materials: LPS, nigericin, PMA.
Preparation of the compound: 1) preparing a compound into a mother solution of 10mmol/L by using 100% DMSO; 2) preparing LPS into 1mg/ml mother solution by using Opti-MEM; 3) preparing Nigericin into 10mM mother liquor by using absolute ethyl alcohol; 4) PMA was prepared as a stock solution at 100. mu.g/ml in 100% DMSO.
The method comprises the following steps: THP-1 cells (3X 10)3) The cells were inoculated in 48-well plates and cultured with PMA (100ng/ml) for 24 hours, then the medium was changed to Opti-MEM and treated with LPS (concentration 1mg/ml) for 3 hours, then with 2. mu.M of the compound for 40min, and finally with nigericin (concentration 10mM) for 40min, and the supernatant was collected. IL-1. beta. was detected in the supernatant by ELISA kit.
Reading and recording the raw data of each hole, and performing corresponding conversion on the raw data.
As a result: table 4 shows the inhibitory activity of the compounds of the present invention on IL-1 β, wherein at 2 μ M, the inhibition rate > 80% is indicated as "+++", the inhibition rate < 50% < 80% is indicated as "+++", and the inhibition rate < 50% is indicated as "+".
TABLE 4 inhibitory Activity of Compounds of the present invention on IL-1 beta
The structural formula of curcumin is as follows:the structural formula of chalcone is:control compound 1 and control compound 2 are known compounds, and control compound 1 has the formula:control compound 2 has the structural formula:
as can be seen from table 4 above: the compound of the invention has obvious inhibitory activity to IL-1 beta, can effectively inhibit the release of IL-1 beta, and has the inhibitory effect even better than that of compounds such as curcumin, chalcone, a control compound 1, a control compound 2 and the like. Of these, compounds 19, 27, 30, 32 and 40 had the best inhibitory effect on IL-1 β. The compound can be used for preparing IL-1 beta inhibitor and treating diseases related to IL-1 beta.
In conclusion, the invention provides a natural chalcone derivative, which has obvious inhibitory activity on IL-1 beta, can effectively inhibit the release of IL-1 beta, and has an inhibitory effect even superior to that of a compound with a similar structure in the prior art. Of these, compounds 19, 27, 30, 32 and 40 had the best inhibitory effect on IL-1 β. The derivative can be used as an IL-1 beta inhibitor, is used for preparing medicaments for treating inflammation and inflammation related diseases, such as preparing medicaments for treating diseases such as neurogenic inflammation, Alzheimer disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis and the like, and has good application prospect.
Claims (10)
1. A compound represented by the formula (I), or a salt thereof, or a stereoisomer thereof, or a hydrate thereof:
wherein,
The dotted line is a bond or nothing;
when the dotted line is a bond, X is selected from-CRa-or-N-; when the dotted line is absent, X is selected from-CRaRb-or-NRa-;
Ra、RbEach independently selected from hydrogen, hydroxy, a and RcSubstituted 5-to 10-membered aryl or substituted a RcA substituted 5-to 10-membered heteroaryl;
a is 0, 1, 2 or 3;
Rceach independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 10-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R3、R4、R5、R6each independently selected from hydrogen, substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, halogen or cyano; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C8Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted 5-to 10-membered aryl or substituted b ReA substituted 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdEach independently selected from substituted or unsubstituted C1~C8Alkyl, aryl, heteroaryl, and heteroaryl,Halogen or 3-to 8-membered cycloalkyl; the substituent of the alkyl is halogen;
R2selected from hydroxy, C2~C8Alkynyl, by n R7Substituted 5-to 10-membered aryl, substituted with n R7Substituted 5-to 10-membered heteroaryl, 3-to 8-membered cycloalkyl or-NR8R9;
n is 0, 1, 2 or 3;
R7each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 10-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
R8、R9are independently selected from hydrogen, hydroxyl and m R10Substituted 5-to 10-membered aryl or substituted with m R10A substituted 5-to 10-membered heteroaryl;
m is 0, 1, 2 or 3;
R10each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, 5-to 8-membered aryl or 5-to 10-membered heteroaryl; the substituent of the alkyl is halogen; the substituent of the alkoxy is halogen;
when the dotted line is null, X is-CH2-,R2When it is phenyl, R3、R4Not hydrogen at the same time.
2. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that:
The dotted line is a bond or nothing;
when the dotted line is a bond, X is selected from-CRa-or-N-; when the dotted line is absent, X is selected from-CRaRb-or-NRa-;
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4、R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
preferably, the first and second electrodes are formed of a metal,
when the dotted line is a bond, X is selected from-CH-or-N-; when the dotted line is absent, X is selected from-CH2-or-NRa-。
3. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that: the compound is represented by a formula (II):
wherein,
X is selected from-CRaRb-or-NRa-;
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4、R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
preferably, the first and second electrodes are formed of a metal,
x is selected from-CH2-or-NRa-。
4. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that: the compound is represented by a formula (III):
wherein,
R3、R4、R5、R6Are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen.
5. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that: the compound is represented by a formula (IV):
wherein,
R3、R4are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (V):
wherein,
R3、R4are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (VI):
wherein,
R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-to 6-membered cycloalkyl, trifluoromethylA group;
n is 0, 1, 2 or 3;
R7are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen.
6. The compound according to claim 1, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, characterized in that: the compound is represented by a formula (VII):
wherein,
R3、R4are respectively and independently selectedFrom hydrogen, C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (VIII):
wherein,
R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-6 membered cycloalkyl, trifluoromethyl;
m is 0, 1, 2 or 3;
R10are each independently selected from C1~C8Alkyl, trifluoromethyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, phenyl or thienyl; the substituent of the alkoxy is halogen;
alternatively, the compound is of formula (IX):
wherein,
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R3、R4are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
alternatively, the compound is a compound represented by formula (X):
wherein,
a is 0, 1, 2 or 3;
Rcare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, trifluoromethyl, cyano, halogen, hydroxy or amino;
R5、R6are respectively and independently selected from hydrogen and C1~C8Alkyl, methoxy, halogen, cyano or trifluoromethyl;
R11each independently selected from substituted or unsubstituted C1~C8Alkyl, substituted or unsubstituted C2~C4Alkenyl, substituted or unsubstituted C1~C8Alkoxy, cyano, halogen, hydroxy, amino, -NHS (O) RdB are provided with ReSubstituted phenyl, substituted by b ReSubstituted pyridyl, thienyl, furyl; the substituent of the alkyl is halogen; the substituent of the alkenyl is halogen; the substituent of the alkoxy is halogen;
b is 0, 1, 2 or 3;
Reare each independently selected from C1~C8Alkyl radical, C1~C8Alkoxy, halogen, -S (O) Rdor-NHS (O) Rd;
RdAre each independently selected from C1~C8Alkyl, 3-to 6-membered cycloalkyl, trifluoromethyl.
8. use of a compound according to any one of claims 1 to 7, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, for the preparation of an IL-1 β inhibitor.
9. Use of a compound according to any one of claims 1 to 7, or a salt thereof, or a stereoisomer thereof, or a hydrate thereof, for the preparation of a medicament for the treatment of inflammation and inflammation-related disorders;
preferably, the medicament is a medicament for treating neurogenic inflammation, alzheimer's disease, systemic lupus erythematosus, atherosclerosis, allergic asthma, arthritis, colitis.
10. A medicament, characterized by: the compound is a preparation prepared from the compound or the salt thereof, the stereoisomer thereof or the hydrate thereof as an active ingredient and pharmaceutically acceptable auxiliary materials or auxiliary ingredients.
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