CN116283717A - 一种藁本内酯衍生物及其制备方法和应用 - Google Patents
一种藁本内酯衍生物及其制备方法和应用 Download PDFInfo
- Publication number
- CN116283717A CN116283717A CN202310019255.1A CN202310019255A CN116283717A CN 116283717 A CN116283717 A CN 116283717A CN 202310019255 A CN202310019255 A CN 202310019255A CN 116283717 A CN116283717 A CN 116283717A
- Authority
- CN
- China
- Prior art keywords
- compound
- ligustilide
- nmr
- inflammatory
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- IQVQXVFMNOFTMU-FLIBITNWSA-N (Z)-ligustilide Chemical class C1CC=CC2=C1C(=C/CCC)/OC2=O IQVQXVFMNOFTMU-FLIBITNWSA-N 0.000 title claims abstract description 49
- 238000002360 preparation method Methods 0.000 title claims description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- IQVQXVFMNOFTMU-DHZHZOJOSA-N Z-ligustilide Natural products C1CC=CC2=C1C(=C/CCC)\OC2=O IQVQXVFMNOFTMU-DHZHZOJOSA-N 0.000 claims abstract description 39
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 5
- 125000001424 substituent group Chemical group 0.000 claims abstract 2
- -1 cyano, hydroxyl Chemical group 0.000 claims description 46
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000001072 heteroaryl group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000012453 solvate Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims 2
- 230000002503 metabolic effect Effects 0.000 claims 1
- 239000002207 metabolite Substances 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- 229940002612 prodrug Drugs 0.000 claims 1
- 239000000651 prodrug Substances 0.000 claims 1
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 abstract description 37
- 229960000905 indomethacin Drugs 0.000 abstract description 19
- 239000003814 drug Substances 0.000 abstract description 13
- 229940124599 anti-inflammatory drug Drugs 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 8
- 229940126115 compound 4f Drugs 0.000 abstract description 7
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 abstract description 5
- 229960003957 dexamethasone Drugs 0.000 abstract description 5
- 239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
- 150000002611 lead compounds Chemical class 0.000 abstract 2
- 238000000034 method Methods 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 22
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 15
- 230000000694 effects Effects 0.000 description 13
- 239000002158 endotoxin Substances 0.000 description 12
- 229920006008 lipopolysaccharide Polymers 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 230000028327 secretion Effects 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 230000002757 inflammatory effect Effects 0.000 description 8
- 230000005764 inhibitory process Effects 0.000 description 8
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 6
- YLLRPQWLASQXSI-UHFFFAOYSA-N 3-(4b,8a,9,9a-tetrahydro-4aH-pyrido[2,3-b]indol-4-ylamino)phenol Chemical compound Oc1cccc(NC2=CC=NC3NC4C=CC=CC4C23)c1 YLLRPQWLASQXSI-UHFFFAOYSA-N 0.000 description 6
- 102000004889 Interleukin-6 Human genes 0.000 description 6
- 108090001005 Interleukin-6 Proteins 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 6
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 102000003777 Interleukin-1 beta Human genes 0.000 description 5
- 108090000193 Interleukin-1 beta Proteins 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- WNZQDUSMALZDQF-UHFFFAOYSA-N 2-benzofuran-1(3H)-one Chemical compound C1=CC=C2C(=O)OCC2=C1 WNZQDUSMALZDQF-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 2
- RQJDUEKERVZLLU-UHFFFAOYSA-N 4-Hydroxybenzylamine Chemical compound NCC1=CC=C(O)C=C1 RQJDUEKERVZLLU-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PRDBLLIPPDOICK-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl]methanamine Chemical group NCC1=CC=C(C(F)(F)F)C=C1 PRDBLLIPPDOICK-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- YWKVMGDEOUPQGN-UHFFFAOYSA-N ethyl 2-[4-[2-(3-hydroxy-1-azabicyclo[2.2.2]octan-3-yl)ethynyl]phenyl]acetate Chemical compound C1=CC(CC(=O)OCC)=CC=C1C#CC1(O)C(CC2)CCN2C1 YWKVMGDEOUPQGN-UHFFFAOYSA-N 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 150000003951 lactams Chemical group 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- KDDNKZCVYQDGKE-UHFFFAOYSA-N (2-chlorophenyl)methanamine Chemical compound NCC1=CC=CC=C1Cl KDDNKZCVYQDGKE-UHFFFAOYSA-N 0.000 description 1
- LRFWYBZWRQWZIM-UHFFFAOYSA-N (2-fluorophenyl)methanamine Chemical compound NCC1=CC=CC=C1F LRFWYBZWRQWZIM-UHFFFAOYSA-N 0.000 description 1
- PXJACNDVRNAFHD-UHFFFAOYSA-N (2-methoxyphenyl)methanamine Chemical compound COC1=CC=CC=C1CN PXJACNDVRNAFHD-UHFFFAOYSA-N 0.000 description 1
- KRIWIRSMQRQYJG-DLBZAZTESA-N (2s,3s)-3-[[7-(benzylamino)-3-propan-2-ylpyrazolo[1,5-a]pyrimidin-5-yl]amino]butane-1,2,4-triol Chemical compound C=1C(N[C@@H](CO)[C@H](O)CO)=NC2=C(C(C)C)C=NN2C=1NCC1=CC=CC=C1 KRIWIRSMQRQYJG-DLBZAZTESA-N 0.000 description 1
- BJFPYGGTDAYECS-UHFFFAOYSA-N (3-chlorophenyl)methanamine Chemical compound NCC1=CC=CC(Cl)=C1 BJFPYGGTDAYECS-UHFFFAOYSA-N 0.000 description 1
- QVSVMNXRLWSNGS-UHFFFAOYSA-N (3-fluorophenyl)methanamine Chemical compound NCC1=CC=CC(F)=C1 QVSVMNXRLWSNGS-UHFFFAOYSA-N 0.000 description 1
- GRRIMVWABNHKBX-UHFFFAOYSA-N (3-methoxyphenyl)methanamine Chemical compound COC1=CC=CC(CN)=C1 GRRIMVWABNHKBX-UHFFFAOYSA-N 0.000 description 1
- WKHABRRJMGVELW-UHFFFAOYSA-N (3-phenylphenyl)methanamine Chemical compound NCC1=CC=CC(C=2C=CC=CC=2)=C1 WKHABRRJMGVELW-UHFFFAOYSA-N 0.000 description 1
- LPNRUMVKXCLEBE-JXVRESAISA-L (3r)-4-[[(e)-2-[5-ethyl-4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethenyl]-oxidophosphoryl]-3-hydroxybutanoate Chemical compound CCC1=C(C=2C=CC=CC=2)N=C(C(C)C)C(\C=C\P([O-])(=O)C[C@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 LPNRUMVKXCLEBE-JXVRESAISA-L 0.000 description 1
- XRNVSPDQTPVECU-UHFFFAOYSA-N (4-bromophenyl)methanamine Chemical compound NCC1=CC=C(Br)C=C1 XRNVSPDQTPVECU-UHFFFAOYSA-N 0.000 description 1
- USTCFIRCUNVNNM-UHFFFAOYSA-N (4-ethoxyphenyl)methanamine Chemical compound CCOC1=CC=C(CN)C=C1 USTCFIRCUNVNNM-UHFFFAOYSA-N 0.000 description 1
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- HMTSWYPNXFHGEP-UHFFFAOYSA-N (4-methylphenyl)methanamine Chemical compound CC1=CC=C(CN)C=C1 HMTSWYPNXFHGEP-UHFFFAOYSA-N 0.000 description 1
- RMSPOVPGDBDYKH-UHFFFAOYSA-N (4-phenylphenyl)methanamine Chemical compound C1=CC(CN)=CC=C1C1=CC=CC=C1 RMSPOVPGDBDYKH-UHFFFAOYSA-N 0.000 description 1
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 1
- PNHBRYIAJCYNDA-VQCQRNETSA-N (4r)-6-[2-[2-ethyl-4-(4-fluorophenyl)-6-phenylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(CC)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 PNHBRYIAJCYNDA-VQCQRNETSA-N 0.000 description 1
- QVBVQHTXLPNXEY-ZMFCMNQTSA-N (4r)-6-[2-[4-(4-fluorophenyl)-6-phenyl-2-propan-2-ylpyridin-3-yl]ethyl]-4-hydroxyoxan-2-one Chemical compound C([C@H](O)C1)C(=O)OC1CCC=1C(C(C)C)=NC(C=2C=CC=CC=2)=CC=1C1=CC=C(F)C=C1 QVBVQHTXLPNXEY-ZMFCMNQTSA-N 0.000 description 1
- QOLHWXNSCZGWHK-BWBORTOCSA-N (6r,7r)-1-[(4s,5r)-4-acetyloxy-5-methyl-3-methylidene-6-phenylhexyl]-4,7-dihydroxy-6-(11-phenoxyundecylcarbamoyloxy)-2,8-dioxabicyclo[3.2.1]octane-3,4,5-tricarboxylic acid Chemical compound C([C@@H](C)[C@H](OC(C)=O)C(=C)CCC12[C@@H]([C@@H](OC(=O)NCCCCCCCCCCCOC=3C=CC=CC=3)C(O1)(C(O)=O)C(O)(C(O2)C(O)=O)C(O)=O)O)C1=CC=CC=C1 QOLHWXNSCZGWHK-BWBORTOCSA-N 0.000 description 1
- CDLZUDXUPFCTRJ-UHFFFAOYSA-N 1,1-di(propan-2-yl)hydrazine Chemical compound CC(C)N(N)C(C)C CDLZUDXUPFCTRJ-UHFFFAOYSA-N 0.000 description 1
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 description 1
- YHXKXVFQHWJYOD-UHFFFAOYSA-N 1-biphenyl-2-ylmethanamine Chemical compound NCC1=CC=CC=C1C1=CC=CC=C1 YHXKXVFQHWJYOD-UHFFFAOYSA-N 0.000 description 1
- PDJZOFLRRJQYBF-UHFFFAOYSA-N 4-(aminomethyl)-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(CN)C=C1 PDJZOFLRRJQYBF-UHFFFAOYSA-N 0.000 description 1
- LFIWXXXFJFOECP-UHFFFAOYSA-N 4-(aminomethyl)benzonitrile Chemical compound NCC1=CC=C(C#N)C=C1 LFIWXXXFJFOECP-UHFFFAOYSA-N 0.000 description 1
- LIDUGWDLSDKCLM-CSKARUKUSA-N 4-[[3-[[[(e)-6,6-dimethylhept-2-en-4-ynyl]-ethylamino]methyl]phenoxy]methyl-dimethylsilyl]benzonitrile Chemical compound CC(C)(C)C#C/C=C/CN(CC)CC1=CC=CC(OC[Si](C)(C)C=2C=CC(=CC=2)C#N)=C1 LIDUGWDLSDKCLM-CSKARUKUSA-N 0.000 description 1
- 241000208173 Apiaceae Species 0.000 description 1
- 229940126559 Compound 4e Drugs 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 229940125907 SJ995973 Drugs 0.000 description 1
- ZSKQIFWUTUZAGF-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC=C1C(F)(F)F ZSKQIFWUTUZAGF-UHFFFAOYSA-N 0.000 description 1
- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125872 compound 4d Drugs 0.000 description 1
- 229940125880 compound 4j Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- BJZJDEOGMBZSLE-UHFFFAOYSA-N cyclohexane;hydrate Chemical compound O.C1CCCCC1 BJZJDEOGMBZSLE-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- XZMHJYWMCRQSSI-UHFFFAOYSA-N n-[5-[2-(3-acetylanilino)-1,3-thiazol-4-yl]-4-methyl-1,3-thiazol-2-yl]benzamide Chemical compound CC(=O)C1=CC=CC(NC=2SC=C(N=2)C2=C(N=C(NC(=O)C=3C=CC=CC=3)S2)C)=C1 XZMHJYWMCRQSSI-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
Abstract
本发明属于医药领域，公开了一类藁本内酯衍生物及其抗炎药物的应用。所述的藁本内酯结构衍生物如式I所示，
式I中，其中R1基团为苄基上各个位置取代基，选自以下任意一种：2′‑F、3′‑F、4′‑F、2′‑Cl、3′‑Cl、4′‑Cl、4′‑Br、4′‑CN2′‑CF3、3′‑CF3、4′‑CF3、2′‑OCH3、3′‑OCH3、4′‑OCH3、4′‑OCH2CH32′‑Ph、3′‑Ph、4′‑Ph、4′‑OH、4′‑CH3、
本发明以藁本内酯为母核，在N‑1位引入苄基为基础，设计并合成了一系列藁本内酯类衍生物，所得化合物大都具有优秀的抗炎活性。与临床常用的抗炎药物吲哚美辛和地塞米松相比，先导化合物4f的抗炎活性优于临床常用药，修饰后的4f结构高效稳定，具有开发为新型抗炎药物的潜力。
Description
技术领域
本发明属于医药领域，特别涉及一类藁本内酯衍生物及其制备方法在抗炎药物中的应用。
背景技术
炎症是身体的一种保护性反应，但持续的炎症反应会损害组织，甚至导致功能丧失、肿瘤和死亡。遗憾的是，目前临床所用的抗炎药普遍具有选择性差以及临床上应用副作用明显，限制了传统抗炎药的临床应用，需要开发新的抗炎药。藁本内酯(ligustilide)是从传统伞形科中药当归中分离获得的具有较强抗炎止痛的中药提取物，但由于藁本内酯化学性质不稳定，其C-3位连接的丁烯基易被环境中的光、热以及酶等氧化或降解，成药性较差。因此，设计了一系列结构稳定具有抗炎抑制活性的藁本内酯类化合物，作为潜在的抗炎药物具有良好的应用场景，有助于提升临床抗炎治疗的效果。
发明内容
本发明所要解决的技术问题是提供一种具有抗炎抑制活性的藁本内酯类化合物，该衍生物能够通过抑制NF-κB和MAPK信号通路发挥其抗炎作用，且效果显著。
本发明解决上述技术问题的方案如下：
一种具有抗炎抑制活性的藁本内酯类化合物，该化合物的化学结构如下式(I)所示，
其中R1基团为氢、卤素、2-8碳原子烷基、环烷烃基、烷氧基、氰基、羟基、胺基、芳基、杂芳基、异丙基中的一种：
2′-F、3′-F、4′-F、2′-C1、3′-C1、4′-C1、4′-Br、4′-CN
2′-CF3、3′-CF3、4′-CF3、2′-OCH3、3′-OCH3、4′-OCH3、4′-OCH2CH3
2′-Ph、3′-Ph、4′-Ph、4′-OH、4′-CH3 
优选的，本发明所述的藁本内酯类衍生物，具有如表1所示的化学结构：
表1化合物的结构与命名
一种上述藁本内酯衍生物的制备方法，具体包括以下步骤：
(1.1)将苯酞、含正丁基锂的环己烷水溶液在溶剂中进行反应，反应结束后得到的反应液经纯化即得化合物1；
(1.2)将化合物1、液氨和Na置于溶剂中反应，得到的反应液经纯化所得到化合物2；
(1.3)将化合物2、吡啶、甲磺酰氯置于溶剂中反应，得到的反应液经纯化所得到化合物3；
(1.4)化合物3与胺在溶剂中加热回流反应，得到的反应液经纯化得到化合物4a-4v。
此合成路线为：
上述的藁本内酯类化合物在制备抗炎药物中的应用。
所述的药物指包含藁本内酯类化合物或其药用盐和溶剂化物中的至少一种。
所述的药物还包含一种或多种药学上可接受的载体或赋形剂。
本发明相对于现有技术，具有如下的优点及有益效果：
(1)本发明以藁本内酯作为母核，进行修饰和改造，设计合成了一系列化学性质稳定的藁本内酯类化合物，并应用于抗炎药物的开发中，其中改造后的藁本内酯衍生物内酰胺环上连接的基团为对三氟甲基苄胺(4f)时，优于阳性对照化合物，可有效的降低细胞炎症因子的产生。
(2)开发了新型高效稳定的藁本内酯衍生物4f，具有开发为新型抗炎药物的潜力。
附图说明
图1是不同浓度化合物4f、吲哚美辛、藁本内酯作用细胞24h后，对RAW264.7细胞中ROS表达的影响。
具体实施方式
实施例中所用试剂如无特殊说明均可从市场常规购得。
实施例1：3-(1-羟基丁基)苯并呋喃酮(化合物1)的制备
把二异丙胺溶入于四氢呋喃中，-78℃，用Ar保护，并保持搅拌，然后慢慢地滴加含正丁基锂的环己烷水溶液(含正丁基锂 0.015 mol)，待溶剂滴加完成后，以继续反应约10min，制备了二异丙基氨基铵的水溶液。减温至-70 ℃，然后慢慢地滴加含苯酞(C8H6O2，0.01mol)的THF溶液(滴加时间约20
min)，此时反应液里生成亮黄色的沉淀，溶液滴加结束后，继续反应15min。缓慢滴加正丁醛(0.015mol)，溶液滴加结束后，继续反应20min。加入碎冰块3g，持续20min，终止反应。升温至室温，加入4mL H2O，在Ar保护下真空浓缩，去除反应体系中残余的有机溶剂，然后用HCl调pH至3，用30mL×3的乙酸乙酯萃取，然后合并有机相，用MgSO4充分干燥后再抽滤，在Ar保护环境下真空浓缩，获得黄色的粘稠油状物，产率90％。1H NMR(400MHz,CDCl3)δ7.83(d,J＝7.6Hz,1H),7.60(t,J＝7.3Hz,1H),7.53(d,J＝7.6Hz,1H),7.47(t,J＝7.3Hz,1H),5.33(dd,J＝11.0,4.1Hz,1H),4.01–3.82(m,1H),1.52(q,J＝12.2,10.3Hz,3H),1.41–1.29(m,1H),0.87(t,J＝7.0Hz,3H).13C NMR(101MHz,CDCl3)δ170.60,147.08,134.00,129.41,126.58,125.77,123.18,83.59,72.56,34.50,18.76,13.88.
实施例2：3-(1-羟基丁基)-4,5二氢异苯并呋喃(化合物2)的制备
将1置于三口烧杯中，用少许四氢呋喃溶化后，接着加液氨。-50℃用Ar保护，先一边搅拌一边加异丙醇，接着再慢慢加切碎的Na(0.15mol)，此时溶液颜色呈深蓝色，随后保持在室温下继续反应6h。缓慢加入NH4Cl固体，直至溶液的深蓝色全部消退为止。接着再慢慢谨慎地加入H2O，反应体系温度上升至室温后真空浓缩，最后蒸出反应溶液残存的NH3，用3mol/L的HCl调节水层的pH至1，用30mL×3乙醚萃取后合并有机相，接着用30
mL×3饱和的NaCl液洗，直至流出水层为中性。用MgSO4充分干燥后抽滤，在Ar保护下真空浓缩，得到棕红色的粘稠油状产品产率60％，有中药香味。1H NMR(400MHz,CDCl3)δ6.18(dt,J＝9.7,2.1Hz,1H),5.94(dt,J＝9.3,4.4Hz,1H),4.90(dd,J＝19.9,3.6Hz,1H),3.86(dq,J＝10.0,5.6,4.9Hz,1H),2.69–2.50(m,2H),2.43(dtt,J＝15.2,7.1,2.8Hz,2H),1.65–1.35(m,5H),0.93(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ171.59,159.83,129.44,126.09,117.17,85.89,72.41,34.86,22.74,22.49,21.59,19.28,14.31.
实施例3：藁本内酯(化合物3)的制备
将化合物2用CH2Cl2溶解，-15℃，Ar保护，搅拌状态下，滴加吡啶(0.03mol)，滴加结束后反应10min。缓慢地滴加甲磺酰氯溶液(0.013mol)，滴加结束后继续反应10min，自然升温至室温，Ar保护，40℃以下真空浓缩去CH2Cl2。向体系中补加20mL吡啶，Ar保护，加热回流反应40min，降温至0℃，用3mol/L的HCl调节其pH至1，升温至室温，用30mL×3乙醚萃取后合并有机相，接着用30mL×3饱和的NaCl液洗，直至流出水层为中性。用MgSO4充分干燥后抽滤，在Ar保护下真空浓缩，在避光条件下用冷冻的丙酮-石油醚溶剂进行色谱柱层析，得到棕红色的粘稠油状，产率：55％，产品有浓烈的中药香味。1H NMR(400MHz,CDCl3)δ6.22(d,J＝9.6Hz,1H),5.93(dt,J＝9.1,4.2Hz,1H),5.15(t,J＝8.0Hz,1H),2.53(t,J＝9.6Hz,2H),2.44–2.35(m,2H),2.31(q,J＝7.6Hz,2H),1.44(h,J＝7.4Hz,2H),0.89(t,J＝7.4Hz,3H).13C NMR(101MHz,CDCl3)δ167.67,148.61,147.08,129.90,124.05,117.17,112.94,28.16,22.45,18.57,13.81.
实施例4：制备3-丁基-2-(4-氯苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4a)
以中间体藁本内酯(100mg，0.53mmol)和对氯苄胺(211mg，1.5mmol)原料，于室温下，用5mL的无水四氢呋喃溶解0.53mmol的藁本内酯，接着加入用2mL的无水四氢呋喃溶解对氯苄胺(1.5mmol)。混合物在60℃下反应12h，反应结束后，将混合物在真空下浓缩成残渣，加入50mL石油醚，混合成均相溶液。放置12
h后，产物结晶过滤。粗品在石油醚和丙酮(5：1)的混合溶剂进行重结晶，得4a为白色固体，产率：65％。1H NMR(400MHz,CDCl3)δ7.39–7.31(m,2H),7.27(dd,J＝7.9,5.9Hz,2H),6.26(dt,J＝9.5,2.0Hz,1H),5.92(dt,J＝9.7,4.0Hz,1H),4.54(d,J＝15.3Hz,1H),4.33(d,J＝15.2Hz,1H),3.16(s,1H),2.63–2.47(m,1H),2.43(dddd,J＝11.5,7.8,3.8,1.9Hz,2H),2.35–2.24(m,1H),1.78–1.62(m,3H),1.02(dddd,J＝13.3,9.0,7.5,6.1Hz,1H),0.90–0.68(m,2H),0.65(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ168.79,137.25,133.12,130.08,129.03,128.83,128.46,117.25,92.17,41.09,33.41,25.20,22.78,22.22,18.61,13.65.HRMS(ESI)of compound 4a:calcd.for C19H22ClNO2[M+H]+＝332.1339,found[M+H]+＝332.1421.
实施例5：制备2-(4-溴苄基)-3-丁基-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4b)
以中间体藁本内酯(100mg，0.53mmol)和对溴苄胺(279mg，1.5mmol)原料，合成方法同化合物4a，得4b为白色固体，产率：58％。1H NMR(400MHz,CDCl3)δ7.44–7.38(m,2H),7.29(d,J＝8.4Hz,2H),6.25(dt,J＝9.6,2.0Hz,1H),5.92(dt,J＝9.6,4.1Hz,1H),4.52(d,J＝15.3Hz,1H),4.30(d,J＝15.3Hz,1H),3.24(s,1H),2.64–2.49(m,1H),2.43(dddd,J＝11.6,7.8,3.9,1.8Hz,2H),2.37–2.22(m,1H),1.79–1.63(m,3H),1.07–0.93(m,1H),0.90–0.68(m,2H),0.65(t,J＝7.2Hz,3H),0.57–0.43(m,1H).13C NMR(101MHz,CDCl3)δ168.81,152.33,137.76,131.42,130.44,128.99,128.82,121.20,117.24,92.17,41.14,33.43,25.20,22.78,22.23,18.62,13.66.HRMS(ESI)of compound 4b:calcd.for C19H22BrNO2[M+H]+＝375.0834,found[M+H]+＝376.0913.
实施例6：制备3-丁基-2-(4-氟苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4c)
以中间体藁本内酯(100mg，0.53mmol)和对氟苄胺(187mg，1.5mmol)原料，合成方法同化合物4a，得4c为白色固体，产率：63％。1H NMR(400MHz,CDCl3)δ7.43–7.37(m,2H),7.02–6.94(m,2H),6.27(dt,J＝9.4,1.9Hz,1H),5.93(dt,J＝9.8,4.0Hz,1H),4.55(d,J＝15.2Hz,1H),4.36(d,J＝15.2Hz,1H),2.97(s,1H),2.62–2.50(m,1H),2.43(dddd,J＝9.8,8.2,4.0,2.2Hz,2H),2.36–2.24(m,1H),1.76–1.70(m,2H),1.02(ddt,J＝13.3,8.9,6.8Hz,1H),0.92–0.79(m,1H),0.80–0.69(m,1H),0.65(t,J＝7.3Hz,3H),0.52(dddd,J＝22.2,13.0,10.0,5.9Hz,1H).13C NMR(101MHz,CDCl3)δ168.68,152.04,134.56,130.40,130.32,129.17,128.78,117.28,115.24,115.02,92.16,41.03,33.40,25.21,22.79,22.21,18.58,13.65.HRMS(ESI)of compound 4c:calcd.for C19H22 FNO2[M+H]+＝316.3884,found[M+H]+＝316.1707.
实施例7：制备3-丁基-3-羟基-2-(4-甲氧基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4d)
以中间体藁本内酯(100mg，0.53mmol)和对甲氧基苄胺(205mg，1.5mmol)原料，合成方法同化合物4a，得4d为白色固体，产率：52％。1H NMR(400MHz,CDCl3)δ7.32(d,J＝8.2Hz,2H),6.80(dd,J＝7.0,4.4Hz,2H),6.27–6.18(m,1H),5.88(dt,J＝9.4,4.1Hz,1H),4.57(d,J＝15.1Hz,1H),4.19(d,J＝15.1Hz,1H),4.06(s,1H),3.76(s,3H),2.61–2.46(m,1H),2.45–2.35(m,2H),2.34–2.17(m,1H),1.68(dd,J＝9.4,7.2Hz,2H),0.93(ddd,J＝13.5,10.5,6.2Hz,1H),0.78–0.62(m,2H),0.58(t,J＝7.1Hz,3H),0.43(ddt,J＝19.4,13.6,6.9Hz,1H).13C NMR(101MHz,CDCl3)δ168.94,158.79,152.57,130.94,130.00,128.77,128.49,117.39,113.67,92.22,55.32,41.06,33.58,25.14,22.77,22.21,18.61,13.67.HRMS(ESI)of compound 4d:calcd.for C20H25NO3[M+H]+＝327.1834,found[M+H]+＝328.1919.
实施例8：制备4-(3-丁基-3-羟基-1-氧代-1，3，4，5-四氢-2H-异吲哚-2-基)苯甲腈(化合物4e)
以中间体藁本内酯(100mg，0.53mmol)和对氰基苄胺(198mg，1.5mmol)原料，合成方法同化合物4a，得4e为白色固体，产率：61％。1H NMR(400MHz,CDCl3)δ7.65–7.55(m,3H),7.55–7.47(m,2H),6.24(dt,J＝9.6,1.9Hz,1H),5.93(dt,J＝9.5,4.0Hz,1H),4.55(d,J＝15.5Hz,1H),4.42(d,J＝15.6Hz,1H),3.27–3.21(m,1H),2.61–2.24(m,4H),1.71(dddd,J＝38.7,14.0,11.9,4.6Hz,2H),1.34–1.23(m,0H),1.11–0.93(m,1H),0.93–0.69(m,2H),0.66(d,J＝7.1Hz,2H),0.66–0.56(m,1H),0.59–0.45(m,1H).13C NMR(101MHz,CDCl3)δ168.84,152.36,144.19,132.21,129.35,129.25,129.09,118.72,117.08,111.10,92.08,41.48,33.41,25.22,22.75,22.20,18.66,13.68.HRMS(ESI)of compound 4e:calcd.forC20H22N2O2[M+H]+＝323.1681,found[M+H]+＝323.1807.
实施例9：制备3-丁基-3-羟基-2-(4-三氟甲基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4f)
以中间体藁本内酯(100mg，0.53mmol)和对三氟甲基苄胺(262mg，1.5mmol)原料，合成方法同化合物4a，得4f为白色固体，产率：60％。1H NMR(400MHz,CDCl3)δ7.54(d,J＝2.7Hz,4H),6.27(d,J＝9.7Hz,1H),5.94(dt,J＝9.0,4.2Hz,1H),4.63(d,J＝15.3Hz,1H),4.41(d,J＝15.3Hz,1H),3.17(d,J＝4.9Hz,1H),2.58–2.50(m,1H),2.44(td,J＝9.9,9.5,3.6Hz,2H),2.36–2.25(m,1H),1.91–1.51(m,4H),0.99(h,J＝8.2,7.2Hz,1H),0.74(dh,J＝10.6,6.1,4.9Hz,2H),0.61(t,J＝7.0Hz,3H),0.47(dh,J＝17.6,6.8,5.4Hz,1H).13C NMR(101MHz,CDCl3)δ168.86,152.37,142.77,129.03,128.96,128.94,125.37,125.33,125.29,125.26,117.19,92.18,41.34,33.42,25.21,22.76,22.17,18.62,13.56.HRMS(ESI)of compound 4f:calcd.for C20H22F3NO2[M+H]＝366.1605,found[M+H]+＝366.1660.
实施例10：制备3-丁基-3-羟基-2-(2-三氟甲基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4g)
以中间体藁本内酯(100mg，0.53mmol)和邻三氟甲基苄胺(262mg，1.5mmol)原料，合成方法同化合物4a，得4g为白色固体，产率：52％。1H NMR(400MHz,CDCl3)δ7.64(d,J＝7.9Hz,1H),7.56–7.44(m,2H),7.34(t,J＝7.6Hz,1H),6.34(dd,J＝9.7,2.1Hz,1H),5.98(dt,J＝9.4,4.3Hz,1H),4.85(d,J＝16.7Hz,1H),4.62(d,J＝16.6Hz,1H),2.62–2.43(m,3H),2.35(p,J＝5.5,4.7Hz,2H),1.74(td,J＝8.2,7.2,3.1Hz,2H),1.39–1.24(m,1H),1.08(dq,J＝13.8,7.0Hz,1H),0.98–0.73(m,3H),0.69(td,J＝7.2,1.9Hz,3H).13C NMR(101MHz,CDCl3)δ156.53,151.59,131.00,129.32,128.58,128.41,126.56,121.06,117.47,110.53,91.78,55.54,35.67,33.72,25.53,22.83,22.39,18.66,13.81.HRMS(ESI)of compound4g:calcd.for C20H22F3NO2[M+H]+＝366.1605,found[M+H]+＝366.1688.
实施例11：制备3-丁基-3-羟基-2-(3-三氟甲基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4h)
以中间体藁本内酯(100mg，0.53mmol)和间三氟甲基苄胺(262mg，1.5mmol)原料，合成方法同化合物4a，得4h为白色固体，产率：56％。1H NMR(400MHz,CDCl3)δ7.65(d,J＝7.4Hz,2H),7.53(d,J＝7.8Hz,1H),7.43(t,J＝7.8Hz,1H),6.30(dd,J＝9.8,2.2Hz,1H),5.95(dt,J＝9.5,4.4Hz,1H),4.65(d,J＝15.3Hz,1H),4.44(dd,J＝15.4,1.8Hz,1H),2.82(d,J＝1.7Hz,1H),2.60–2.51(m,1H),2.50–2.39(m,2H),2.38–2.24(m,1H),1.80–1.68(m,2H),1.01(dp,J＝13.9,7.0Hz,1H),0.79(ttd,J＝16.6,11.3,9.8,4.5Hz,2H),0.63(dd,J＝8.0,6.2Hz,3H),0.51(td,J＝13.9,13.0,6.6Hz,1H).13C NMR(101MHz,CDCl3)δ168.76,152.11,139.74,132.21,129.18,128.97,128.91,125.26,125.22,124.17,124.13,117.24,92.13,41.39,33.40,25.25,22.78,22.13,18.60,13.57.HRMS(ESI)of compound 4h:calcd.for C20H22F3NO2[M+H]+＝366.1605,found[M+H]+＝366.1674.
实施例12：制备2-(1，1'-联苯]-4-基甲基)-3-丁基-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4i)
以中间体藁本内酯(100mg，0.53mmol)和对苯基苄胺(274mg，1.5mmol)原料，合成方法同化合物4a，得4i为白色固体，产率：41％。1H NMR(400MHz,CDCl3)δ7.54(dd,J＝21.1,6.0Hz,6H),7.44(t,J＝7.5Hz,2H),7.35(t,J＝7.3Hz,1H),6.35–6.27(m,1H),5.94(dt,J＝9.2,4.2Hz,1H),4.65(d,J＝15.2Hz,1H),4.41(d,J＝15.1Hz,1H),3.20(s,1H),2.65–2.51(m,1H),2.45(td,J＝10.6,4.2Hz,2H),2.39–2.24(m,1H),1.76(t,J＝8.3Hz,2H),1.08–0.87(m,1H),0.75(ddt,J＝23.1,15.1,7.8Hz,2H),0.61(t,J＝7.1Hz,3H),0.58–0.51(m,1H).13C NMR(101MHz,CDCl3)δ168.81,152.25,140.96,140.32,137.77,129.16,129.08,128.76,128.71,127.24,127.14,127.08,117.39,92.27,41.45,33.47,25.26,22.82,22.22,18.62,13.71.HRMS(ESI)of compound 4i:calcd.For C25H27NO2[M+H]+＝374.2042,found[M+H]+＝374.2119.
实施例13：制备3-丁基-3-羟基-2-(4-羟基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4j)
以中间体藁本内酯(100mg，0.53mmol)和对羟基苄胺(184mg，1.5mmol)原料，合成方法同化合物4a，得4j为白色固体，产率：68％。1H NMR(400MHz,CDCl3)δ7.48(d,J＝7.6Hz,1H),7.31–7.18(m,1H),6.99–6.83(m,2H),6.29(dd,J＝9.8,2.0Hz,1H),5.91(dt,J＝9.2,4.3Hz,1H),4.68(d,J＝15.3Hz,1H),4.44(d,J＝15.3Hz,1H),3.90(d,J＝1.6Hz,3H),3.17(s,1H),2.62–2.50(m,1H),2.49–2.39(m,2H),2.38–2.25(m,1H),1.95–1.84(m,1H),1.77(td,J＝13.3,12.6,5.4Hz,1H),1.06(ddq,J＝35.5,13.8,7.0Hz,2H),0.85–0.77(m,1H),0.74(t,J＝7.3Hz,3H),0.67(t,J＝7.2Hz,1H).13C NMR(101MHz,CDCl3)δ156.53,151.59,131.00,129.32,128.58,128.41,126.56,121.06,117.47,110.53,91.78,55.54,35.67,33.72,25.53,22.83,22.39,18.66,13.81.HRMS(ESI)of compound 4j:calcd.for C19H23NO3[M+H]+＝314.1678,found[M+H]+＝314.1758.
实施例14：制备3-丁基-3-羟基-2-(4-甲基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4k)
以中间体藁本内酯(100mg，0.53mmol)和对甲基基苄胺(181mg，1.5mmol)原料，合成方法同化合物4a，得4k为白色固体，产率：59％。1H NMR(400MHz,Chloroform-d)δ7.35–7.27(m,2H),7.10(d,J＝7.7Hz,2H),6.28(dt,J＝9.5,1.9Hz,1H),5.91(dt,J＝9.7,4.1Hz,1H),4.54(d,J＝15.1Hz,1H),4.36(d,J＝15.1Hz,1H),2.60–2.49(m,1H),2.43(ddt,J＝13.2,6.3,2.0Hz,2H),2.32(s,3H),1.73(ddd,J＝10.3,5.6,3.8Hz,2H),1.44–1.16(m,1H),1.00(dddd,J＝12.9,8.8,7.4,5.9Hz,1H),0.85–0.66(m,2H),0.63(t,J＝7.3Hz,3H),0.59–0.45(m,1H).13C NMR(101MHz,Chloroform-d)δ168.69,152.08,136.87,135.67,129.10,128.99,128.64,128.60,117.41,92.22,41.48,33.41,25.21,22.81,22.22,21.05,18.58,13.65.HRMS(ESI)of compound 4k:calcd.for C20H25NO2[M+H]+＝312.1885,found[M+H]+＝312.1964
实施例15：制备3-丁基-3-羟基-2-(4-异丙基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4l)
以中间体藁本内酯(100mg，0.53mmol)和对异丙基苄胺(225mg，1.5mmol)原料，合成方法同化合物4a，得4l为白色固体，产率：67％。1H NMR(400MHz,Chloroform-d)δ7.38–7.31(m,2H),7.19–7.10(m,2H),6.29(dt,J＝9.5,2.0Hz,1H),5.91(dt,J＝9.7,4.1Hz,1H),4.61(d,J＝15.0Hz,1H),4.33(d,J＝15.1Hz,1H),3.01(s,1H),2.88(p,J＝6.9Hz,1H),2.60–2.49(m,1H),2.43(ddt,J＝12.9,6.1,1.9Hz,2H),2.36–2.21(m,1H),1.75–1.69(m,2H),1.23(d,J＝6.9Hz,6H),0.95(tdd,J＝11.2,7.5,5.4Hz,1H),0.76–0.63(m,2H),0.59(t,J＝6.9Hz,3H),0.54–0.41(m,1H).13C NMR(101MHz,Chloroform-d)δ168.65,152.02,148.02,136.07,129.10,128.78,128.59,126.38,117.43,92.23,41.44,33.85,33.42,25.26,24.05,23.98,22.81,22.15,18.55,13.75.HRMS(ESI)of compound 4l:calcd.forC22H29NO2[M+H]+＝340.2198,found[M+H]+＝340.2284
实施例16：制备3-丁基-2-(4-二甲基氨基苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4m)
以中间体藁本内酯(100mg，0.53mmol)和4-二甲氨基苄胺(231mg，1.5mmol)原料，合成方法同化合物4a，得4m为白色固体，产率：43％。1H NMR(400MHz,Chloroform-d)δ7.33–7.26(m,2H),6.66(d,J＝8.1Hz,2H),6.27(dt,J＝9.6,2.0Hz,1H),5.90(dt,J＝8.8,4.1Hz,1H),4.47–4.28(m,2H),3.06(s,1H),2.90(s,6H),2.61–2.47(m,1H),2.42(tdd,J＝8.9,4.2,1.9Hz,2H),2.33–2.22(m,1H),1.73–1.68(m,2H),1.04(ddd,J＝21.2,11.2,6.8Hz,1H),0.86(tt,J＝13.3,7.0Hz,2H),0.66(t,J＝7.3Hz,3H),0.61–0.54(m,1H).13C NMR(101MHz,Chloroform-d)δ168.49,151.85,129.72,129.17,128.41,126.82,117.50,112.75,92.16,41.22,40.84,33.49,25.25,22.83,22.29,18.55,13.77,1.03.HRMS(ESI)ofcompound 4m:calcd.for C21H28N2O2[M+H]+＝341.2151,found[M+H]+＝341.2230
实施例17：制备3-丁基-2-(4-乙氧基苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4n)
以中间体藁本内酯(100mg，0.53mmol)和对乙氧基苄胺(205mg，1.5mmol)原料，合成方法同化合物4a，得4n为白色固体，产率：54％。1H NMR(400MHz,Chloroform-d)δ7.37–7.32(m,2H),6.82(dq,J＝9.6,3.1,2.5Hz,2H),6.28(dt,J＝9.6,1.9Hz,1H),5.92(dt,J＝9.6,4.1Hz,1H),4.43(q,J＝15.1Hz,2H),4.01(q,J＝7.0Hz,2H),2.59–2.48(m,2H),2.43(ddt,J＝11.9,6.4,2.1Hz,2H),2.35–2.23(m,1H),1.81–1.72(m,2H),1.41(t,J＝7.0Hz,4H),1.28(s,1H),1.10–0.98(m,1H),0.90(tt,J＝13.7,6.4Hz,1H),0.74(dt,J＝13.2,5.7Hz,1H),0.68(t,J＝7.3Hz,3H),0.63–0.58(m,1H).13C NMR(101MHz,Chloroform-d)δ158.18,151.70,130.79,129.93,129.31,128.64,117.39,114.37,92.16,63.49,41.17,33.36,25.25,22.83,22.26,18.55,14.81,13.74.HRMS(ESI)of compound 4n:calcd.forC21H27NO3[M+H]+＝342.1991,found[M+H]+＝342.2055.
实施例18：制备3-丁基-2-(2-氯苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4o)
以中间体藁本内酯(100mg，0.53mmol)和邻氯苄胺(211mg，1.5mmol)原料，合成方法同化合物4a，得4o为白色固体，产率：57％。1H NMR(400MHz,CDCl3)δ7.50(ddd,J＝18.8,7.4,3.0Hz,1H),7.38–7.27(m,1H),7.19(td,J＝8.4,7.2,4.3Hz,2H),6.31(d,J＝9.8Hz,1H),5.95(dt,J＝9.5,4.0Hz,1H),4.78(d,J＝16.0Hz,1H),4.57(d,J＝15.9Hz,1H),2.73(s,1H),2.62–2.51(m,1H),2.50–2.40(m,2H),2.39–2.26(m,1H),1.86–1.51(m,5H),1.28(s,1H),1.06(dh,J＝12.8,6.5,5.8Hz,1H),0.90(dp,J＝21.4,6.3,5.6Hz,2H),0.83–0.73(m,1H),0.69(t,J＝7.4Hz,3H).13C NMR(101MHz,CDCl3)δ168.86,152.18,136.03,132.82,130.46,129.35,129.17,128.86,128.49,126.98,117.30,92.06,38.52,33.32,25.39,22.82,22.30,18.68,13.69.HRMS(ESI)of compound 4o:calcd.for C19H22 Cl NO2[M+H]+＝332.1339,found[M+H]+＝332.1421.
实施例19：制备3-丁基-2-(2-氟苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4p)
以中间体藁本内酯(100mg，0.53mmol)和邻氟苄胺(187mg，1.5mmol)原料，合成方法同化合物4a，得4p为白色固体，产率：52％。1H NMR(400MHz,CDCl3)δ7.64–7.48(m,2H),7.31–7.20(m,2H),7.08(dq,J＝17.0,8.9,7.9Hz,3H),6.29(dt,J＝9.5,2.2Hz,1H),5.93(dt,J＝8.9,4.1Hz,1H),4.74–4.61(m,1H),4.60–4.49(m,1H),2.62(d,J＝2.9Hz,1H),2.58–2.49(m,1H),2.44(tdd,J＝9.3,3.9,2.1Hz,2H),2.37–2.26(m,1H),1.88–1.75(m,2H),1.43–1.27(m,1H),1.06(dp,J＝20.7,7.1Hz,1H),1.00–0.85(m,2H),0.68(t,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ168.71,151.94,131.37,129.05,128.97,128.78,125.59,125.44,124.28,117.31,115.32,115.10,91.98,34.19,33.12,25.38,22.81,22.28,18.59,13.71.HRMS(ESI)of compound 4p:calcd.for C19H22 FNO23[M+H]+＝316.3884,found[M+H]+＝316.1730.
实施例20：制备3-丁基-3-羟基-2-(2-甲氧基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4q)
以中间体藁本内酯(100mg，0.53mmol)和邻甲氧基苄胺(205mg，1.5mmol)原料，合成方法同化合物4a，得4q为白色固体，产率：63％。1H NMR(400MHz,CDCl3)δ7.65(d,J＝7.4Hz,2H),7.53(d,J＝7.8Hz,1H),7.43(t,J＝7.8Hz,1H),6.30(dd,J＝9.8,2.2Hz,1H),5.95(dt,J＝9.5,4.4Hz,1H),4.65(d,J＝15.3Hz,1H),4.44(dd,J＝15.4,1.8Hz,1H),2.82(d,J＝1.7Hz,1H),2.60–2.51(m,1H),2.50–2.39(m,2H),2.38–2.24(m,1H),1.80–1.68(m,2H),1.01(dp,J＝13.9,7.0Hz,1H),0.79(ttd,J＝16.6,11.3,9.8,4.5Hz,2H),0.63(dd,J＝8.0,6.2Hz,3H),0.51(td,J＝13.9,13.0,6.6Hz,1H).13C NMR(101MHz,CDCl3)δ168.65,159.65,152.03,140.30,129.40,128.68,120.94,117.39,114.05,112.92,92.19,55.26,41.74,33.43,25.31,22.81,22.23,18.59,13.70.HRMS(ESI)of compound 4q:calcd.forC20H25NO3[M+H]+＝328.1834,found[M+H]+＝328.1915.
实施例21：制备2-(1，1'-联苯]-2-基甲基)-3-丁基-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物r)
以中间体藁本内酯(100mg，0.53mmol)和邻苯基苄胺(274mg，1.5mmol)原料，合成方法同化合物4a，得4r为白色固体，产率：41％。1H NMR(400MHz,CDCl3)δ7.39(d,J＝4.9Hz,1H),7.32–7.12(m,3H),6.27(dd,J＝9.7,2.1Hz,1H),5.93(dt,J＝10.0,4.1Hz,1H),4.56(d,J＝15.3Hz,1H),4.32(d,J＝15.3Hz,1H),3.22(s,1H),2.62–2.50(m,1H),2.49–2.38(m,2H),2.37–2.22(m,1H),1.79–1.59(m,4H),1.01(tq,J＝8.0,5.4,2.9Hz,1H),0.88–0.68(m,2H),0.65(t,J＝7.1Hz,3H),0.53(tdd,J＝16.4,13.1,6.3Hz,2H).13C NMR(101MHz,CDCl3)δ168.85,152.41,140.73,134.20,129.66,128.97,128.84,128.64,127.45,126.81,117.27,92.17,41.23,33.44,25.26,22.77,22.20,18.63,13.69.HRMS(ESI)of compound 4r:calcd.for C25H27NO2[M+H]+＝374.2042,found[M+H]+＝374.2118.
实施例22：制备3-丁基-2-(3-氯苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物s)
以中间体藁本内酯(100mg，0.53mmol)和间氯苄胺(211mg，1.5mmol)原料，合成方法同化合物4a，得4s为白色固体，产率：68％。1H NMR(400MHz,CDCl3)δ7.30–7.14(m,1H),7.03–6.89(m,2H),6.84–6.71(m,1H),6.34–6.19(m,1H),5.93(dtt,J＝10.8,4.6,2.2Hz,1H),4.54(d,J＝15.2Hz,1H),4.40(dd,J＝15.1,7.2Hz,1H),3.79(q,J＝2.3Hz,3H),2.91–2.78(m,1H),2.61–2.48(m,1H),2.49–2.38(m,2H),2.37–2.23(m,1H),1.81–1.70(m,2H),1.02(dq,J＝13.8,6.9Hz,1H),0.84(dq,J＝13.2,6.9Hz,1H),0.78–0.68(m,1H),0.69–0.62(m,3H),0.62–0.52(m,1H).13C NMR(101MHz,CDCl3)δ168.65,159.65,152.03,140.30,129.40,128.68,120.94,117.39,114.05,112.92,92.19,55.26,41.74,33.43,25.31,22.81,22.23,18.59,13.70.HRMS(ESI)of compound 4s:calcd.for C19H22ClNO2[M+H]+＝332.1339,found[M+H]+＝332.1422.
实施例23：制备3-丁基-2-(3-氟苄基)-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4t)
以中间体藁本内酯(100mg，0.53mmol)和间氟苄胺(187mg，1.5mmol)原料，合成方法同化合物4a，得4t为白色固体，产率：56％。1H NMR(400MHz,CDCl3)δ7.30–7.20(m,2H),7.13–7.01(m,2H),6.25(dt,J＝9.5,1.9Hz,1H),5.89(dt,J＝9.6,3.9Hz,1H),3.70(ddd,J＝13.8,9.5,5.4Hz,1H),3.33(ddd,J＝13.9,9.3,6.6Hz,1H),3.11(ddd,J＝13.0,9.4,6.8Hz,1H),2.98(ddd,J＝13.9,9.3,5.4Hz,1H),2.55–2.25(m,4H),2.07(s,1H),1.96–1.78(m,2H),1.35–1.25(m,3H),0.95–0.90(m,1H),0.88(d,J＝7.3Hz,3H).13C NMR(101MHz,CDCl3)δ168.45,151.50,131.25,131.20,129.39,128.66,128.30,128.22,124.10,117.25,115.47,115.25,91.68,38.79,33.00,28.70,25.44,22.81,22.46,18.63,13.90,1.03.HRMS(ESI)of compound 4t:calcd.for C19H22FNO2[M+H]+＝316.3884,found[M+H]+＝316.1713.
实施例24：制备3-丁基-3-羟基-2-(3-甲氧基苄基)-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4u)
以中间体藁本内酯(100mg，0.53mmol)和间甲氧基苄胺(205mg，1.5mmol)原料，合成方法同化合物4a，得4u为白色固体，产率：63％。1H NMR(400MHz,CDCl3)δ7.65(d,J＝7.4Hz,2H),7.53(d,J＝7.8Hz,1H),7.43(t,J＝7.8Hz,1H),6.30(dd,J＝9.8,2.2Hz,1H),5.95(dt,J＝9.5,4.4Hz,1H),4.65(d,J＝15.3Hz,1H),4.44(dd,J＝15.4,1.8Hz,1H),2.82(d,J＝1.7Hz,1H),2.60–2.51(m,1H),2.50–2.39(m,2H),2.38–2.24(m,1H),1.80–1.68(m,2H),1.01(dp,J＝13.9,7.0Hz,1H),0.79(ttd,J＝16.6,11.3,9.8,4.5Hz,2H),0.63(dd,J＝8.0,6.2Hz,3H),0.51(td,J＝13.9,13.0,6.6Hz,1H).13C NMR(101MHz,CDCl3)δ168.65,159.65,152.03,140.30,129.40,128.68,120.94,117.39,114.05,112.92,92.19,55.26,41.74,33.43,25.31,22.81,22.23,18.59,13.70.HRMS(ESI)of compound 4u calcd.forC20H25NO3[M+H]+＝328.1834,found[M+H]+＝328.1911.
实施例25：制备2-(1，1'-联苯]-3-基甲基)-3-丁基-3-羟基-2，3，4，5-四氢-1H-异吲哚-1-酮(化合物4v)
以中间体藁本内酯(100mg，0.53mmol)和间苯基苄胺(274mg，1.5mmol)原料，合成方法同化合物4a，得4v为白色固体，产率：43％。1H NMR(400MHz,CDCl3)δ7.68–7.54(m,3H),7.42(ddt,J＝34.5,14.8,7.6Hz,6H),6.31(d,J＝9.7Hz,1H),5.93(dt,J＝9.1,4.3Hz,1H),4.68(d,J＝15.1Hz,1H),4.47(d,J＝15.0Hz,1H),2.86(d,J＝2.0Hz,1H),2.62–2.49(m,1H),2.49–2.38(m,2H),2.37–2.25(m,1H),1.75(tq,J＝14.0,7.6,4.7Hz,2H),1.29(s,1H),0.99(dt,J＝14.7,7.5Hz,1H),0.75(ddd,J＝22.9,12.7,6.3Hz,2H),0.63–0.57(m,3H).13CNMR(101MHz,CDCl3)δ168.69,152.05,141.39,139.28,129.18,128.86,128.75,128.73,127.72,127.47,127.32,127.20,126.10,117.41,92.25,41.81,33.44,25.30,22.81,22.20,18.59,13.70.HRMS(ESI)of compound 4v:calcd.for C25H27NO2[M+H]+＝374.2042,found[M+H]+＝374.2123.
实施例26：Griess试剂法检测化合物对LPS诱导NO释放的抑制作用
实验方法：该试验中所用的RAW264.7细胞生长状态需要良好，种板密度为2.5×104/孔种于96孔板中。24h后加入配置好的药物，浓度为10μM，每个浓度设六个复孔，加药体积为200μL，同时设置空白组(只有培养基)和对照组(加脂多糖LPS)。3h后加入LPS(1μg/mL)，LPS作用48h后取细胞上清液检测NO含量。NO在水和体液内很易氧化而形成NO2-,在酸性条件下NO2-和Griess试剂进行化学反应得到重氮物质。重氮化合物再与对萘基乙烯基二胺进行耦合化学反应。这个化学反应过程生成的物质含量与NO含量之间有线性关系，所以可以在540nm处用酶标仪进行定量测定。实验结果：抑制NO生成活性结果见表1和2。
表1目标化合物对于LPS诱导的RAW264.7细胞分泌NO产生的影响。用10μM的化合物预处理RAW264.7细胞3h后，用LPS(1μg/mL)刺激48h。数据为三次实验的平均值±SD(n＞3)。
表2化合物抑制RAW264.7分泌NO的IC50，用不同浓度的化合物预处理RAW264.7细胞3h后，用LPS(1μg/mL)刺激48h.数据为三次实验的平均值±SD(n＞3)
实验结果：蒿本内酯的内酯环变为内酰胺环时，化合物稳定性增加，在苄基作为提高藁本内酯类衍生物活性的有效基团的基础上，当将N-1位苄基中苯环连接基团替换为三氟甲基时，所得到化合物4f、4g活性均优于阳性对照。当三氟甲基连接于苯环的对位时，化合物抑制NO活性有显著提升，因此对位三氟甲基为最优连接基团。其抑制NO的IC50为1.61±0.11μM优于两种阳性对照药吲哚美辛IC50(2.81±0.06μM)和地塞米松IC50(2.22±0.02μM)。
实施例27：ELISA法测定化合物对于炎症因子IL-1β、TNF-α和IL-6的影响
实验方法：RAW264.7细胞的种板密度为2.5×105/孔种于24孔板中，每个实验组设6个复孔，培养过夜。第二天，加药预处理2h后，加入LPS＝1μg/mL，同时设立空白组(只有细胞培养液)与对照组(细胞培养液和LPS)。24h后吸取细胞上清液。
选取NO抑制率较高的苗头化合物4f进行酶联免疫吸附测定法(ELISA)检测其对促炎症因子IL-1β、TNF-α和IL-6的实验探究。地塞米松作为阳性对照。用ELISA试剂盒根据实验步骤测定所有样品中炎症因子IL-1β、TNF-α和IL-6含量，计算对应的化合物抑制炎症因子生成的IC50，实验结果如表3所示。
表3 6种化合物抑制LPS诱导RAW264.7细胞分泌IL-1β、TNF-α和IL-6的IC50
实验结果：根据表3的实验结果可得出，苗头化合物4f呈现出优于阳性对照地塞米松的抗炎活性，其有效的抑制了IL-1β炎症因子的分泌，IC50为18.22±0.12nM，有效抑制了TNF-α炎症因子的分泌，IC50为6.2±0.02μM，同时还抑制了IL-6炎症因子的分泌，IC50为2.61±0.31μM。此外，我们还发现4r的抗炎活性同样优于阳性对照地塞米松，抑制炎症因子IL-1β分泌的IC50为556.76±0.35nM，抑制TNF-α分泌的IC50为10.85±0.14μM，抑制IL-6分泌的IC50为3.34±0.12μM，以上实验结果表示该系列衍生物具有优秀的抗炎作用。
实施例28：检测化合物对于ROS的抑制作用
实验方法：将RAW264.7巨噬细胞(2.5×105细胞/孔)接种到黑色96孔细胞培养板中并培养12h。将细胞用测试化合物预处理1h，然后与1mg/mL LPS共孵育24h。除去培养基并用PBS洗涤；加入100mL DCFH-DA，在不含FBS的培养基中稀释至终浓度为100mM，并在37℃下培养30分钟。除去培养基，每孔加入100mL PBS，用酶标仪在485nm激发波长和520nm发射波长下检测荧光。实验结果如附图1所示。
实验结果：通过ROS试剂盒检测化合物对LPS诱导的RAW264.7细胞分泌ROS的影响。结果表明，化合物4f、吲哚美辛、藁本内酯均能抑制LPS诱导RAW264.7细胞分泌ROS。但化合物4f(IC50＝1.44μM)抑制效果稍优于吲哚美辛(IC50＝2.47μM)和藁本内酯(IC50＝3.44μM)。
Claims (4)
1.一类藁本内酯衍生物，其特征在于具有如式I所示的化学结构：
其中R1基团为苄基上各个位置取代基，具体为氢、卤素、2-8碳原子烷基、环烷烃基、烷氧基、氰基、羟基、胺基、芳基、杂芳基、异丙基中的一种：
2′-F、3′-F、4′-F、2′-Cl、3′-Cl、4′-Cl、4′-Br、4′-CN
2′-CF3、3′-CF3、4′-CF3、2′-OCH3、3′-OCH3、4′-OCH3、4′-OCH2CH3
2′-Ph、3′-Ph、4′-Ph、4′-OH、4′-CH3、
2.根据权利要求1所述的藁本内酯类衍生物，其特征在于具有如下所示的化学结构：
表1化合物的结构与命名
3.权利要求1或者2所述的一种具有抗炎抑制活性的藁本内酯类化合物在制备抗炎抑制剂中的应用。
4.根据权利要求3所述的应用，其特征在于，所述的抗炎抑制剂由权利要求1所述的一种具有抗炎抑制活性的藁本内酯类化合物和医学上可接受的变异构体、内消旋体、外消旋体、立体异构体、代谢产物、代谢前体、前药或溶剂化物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310019255.1A CN116283717A (zh) | 2023-01-06 | 2023-01-06 | 一种藁本内酯衍生物及其制备方法和应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310019255.1A CN116283717A (zh) | 2023-01-06 | 2023-01-06 | 一种藁本内酯衍生物及其制备方法和应用 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116283717A true CN116283717A (zh) | 2023-06-23 |
Family
ID=86796705
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310019255.1A Pending CN116283717A (zh) | 2023-01-06 | 2023-01-06 | 一种藁本内酯衍生物及其制备方法和应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116283717A (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020082260A1 (en) * | 2000-12-13 | 2002-06-27 | Kevin Richard Guertin | Isoindolin-1-one glucokinase activators |
| CN109053546A (zh) * | 2018-07-05 | 2018-12-21 | 中国科学院兰州化学物理研究所 | 一种苯酞类衍生物及其制备方法和应用 |
| CN109939108A (zh) * | 2019-05-08 | 2019-06-28 | 广东药科大学 | 藁本环丙内酰胺在制备防治急、慢性肝损伤和肝纤维化药物中的应用 |
| CN115108964A (zh) * | 2022-05-30 | 2022-09-27 | 成都陈泷张科技有限责任公司 | 一种苯酞类衍生物、制备方法及应用 |
-
2023
- 2023-01-06 CN CN202310019255.1A patent/CN116283717A/zh active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020082260A1 (en) * | 2000-12-13 | 2002-06-27 | Kevin Richard Guertin | Isoindolin-1-one glucokinase activators |
| CN109053546A (zh) * | 2018-07-05 | 2018-12-21 | 中国科学院兰州化学物理研究所 | 一种苯酞类衍生物及其制备方法和应用 |
| CN109939108A (zh) * | 2019-05-08 | 2019-06-28 | 广东药科大学 | 藁本环丙内酰胺在制备防治急、慢性肝损伤和肝纤维化药物中的应用 |
| CN115108964A (zh) * | 2022-05-30 | 2022-09-27 | 成都陈泷张科技有限责任公司 | 一种苯酞类衍生物、制备方法及应用 |
Non-Patent Citations (1)
| Title |
|---|
| FERENC CSENDE ET AL.: "Design and synthesis of some isoindoline derivatives as analogs of the active antiinflammatory Indoprofen", 《 ARKIVOC》, vol. 2, 31 December 2013 (2013-12-31), pages 378 - 388 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU625068B2 (en) | New beta-carbolines, their bio-isosteric benzofuran and benzothiophene analogues having cytostatic properties | |
| DE69726876T2 (de) | Anthranilsäure-derivate als modulatoren der multidrug resistenz. | |
| CA1330661C (en) | N-(pyridinyl)-1h-indol-1-amines, a process for their preparation and their use as medicaments | |
| Verotta et al. | Synthesis and antinociceptive activity of chimonanthines and pyrrolidinoindoline-type alkaloids | |
| CN102356082A (zh) | 作为抗癌剂的3,3'-螺吲哚满酮衍生物 | |
| US5202243A (en) | Method of hydroxylating 3-[2-(benzoxazol-2-yl)ethyl]-5-ethyl-6-methyl-2-(1H)-pyridinone by incubation with liver slices | |
| Kondo et al. | Enantioselective construction of a polyhydroxylated pyrrolidine skeleton from 3-vinylaziridine-2-carboxylates: synthesis of (+)-DMDP and a potential common intermediate for (+)-hyacinthacine A1 and (+)-1-epi-australine | |
| DE102006012548A1 (de) | Substituierte Chromanol-Derivate und ihre Verwendung | |
| WO2013127356A1 (zh) | 左旋吡喹酮的合成方法 | |
| WO2021139741A1 (zh) | 大麻二酚衍生物及其制备方法和在医药上的应用 | |
| CN115141195B (zh) | 一种nuak抑制剂及其用途 | |
| CN102264738A (zh) | 螺吲哚满酮吡啶衍生物 | |
| CN103641827B (zh) | 中氮茚衍生物及其合成方法和应用 | |
| US6034243A (en) | Intermediates in the synthesis of (±)-camptothecin and related compounds and synthesis thereof | |
| Monfray et al. | A new asymmetric synthesis of 2, 6-cis-disubstituted 4-methylenepiperidines: total synthesis of (+)-alkaloid 241D and (+)-isosolenopsin A | |
| CN112250688B (zh) | 一类7-氮杂苯并呋喃衍生物及其在抗肿瘤药物中的应用 | |
| WO2006134955A1 (ja) | １，２－ジ（環式基）置換ベンゼン誘導体 | |
| KR20100119819A (ko) | Ｈｄｌ-콜레스테롤 상승제로서 3-트라이플루오로메틸-피라진-2-카복실산 아미드 유도체 | |
| US4094987A (en) | 2-(3-m-hydroxy-phenyl-1-substituted-3-pyrrolidinyl)-ethanols | |
| CN116283717A (zh) | 一种藁本内酯衍生物及其制备方法和应用 | |
| Zhang et al. | Novel asymmetric total synthesis of the natural (+)-6-epicastanospermine | |
| Bellina et al. | Synthetic applications of 3, 4-dihalo-2 (5H)-furanones: A formal total synthesis of nostoclides I and II | |
| FR2477149A1 (fr) | Nouveaux derives de carbostyrile, leur procede de preparation et leur application en therapeutique | |
| CN116444425A (zh) | 微管蛋白-src双靶点抑制剂 | |
| CN110343109B (zh) | 一种二氢蝶啶酮-磺酰胺类衍生物及其药学上可接受的盐、其制备方法及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |