CN114874172A - Oridonin derivative, preparation method and medical application thereof - Google Patents
Oridonin derivative, preparation method and medical application thereof Download PDFInfo
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- CN114874172A CN114874172A CN202210751697.0A CN202210751697A CN114874172A CN 114874172 A CN114874172 A CN 114874172A CN 202210751697 A CN202210751697 A CN 202210751697A CN 114874172 A CN114874172 A CN 114874172A
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- oridonin
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- SDHTXBWLVGWJFT-XKCURVIJSA-N oridonin Chemical class C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12[C@@H](O)CCC(C)(C)[C@H]1[C@H](O)[C@@]3(O)OC2 SDHTXBWLVGWJFT-XKCURVIJSA-N 0.000 title claims abstract description 58
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- CAQAFLRZJHXSIS-UHFFFAOYSA-N oridonin Natural products CC1(C)C=CC(O)C23COC(O)(C(O)C12)C45C(O)C(CCC34)C(=C)C5=O CAQAFLRZJHXSIS-UHFFFAOYSA-N 0.000 claims abstract description 38
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 10
- -1 oridonin compound Chemical class 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 201000010099 disease Diseases 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 6
- 229940124599 anti-inflammatory drug Drugs 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 77
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000003054 catalyst Substances 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 11
- 238000010898 silica gel chromatography Methods 0.000 claims description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 102000000874 Pyrin Domain-Containing 3 Protein NLR Family Human genes 0.000 claims description 8
- 108010001946 Pyrin Domain-Containing 3 Protein NLR Family Proteins 0.000 claims description 8
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 claims description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 238000000926 separation method Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- 238000005303 weighing Methods 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- ZZAKLGGGMWORRT-UHFFFAOYSA-N 1-methylsulfonylpiperazine Chemical compound CS(=O)(=O)N1CCNCC1 ZZAKLGGGMWORRT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 239000004643 cyanate ester Substances 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 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
- 239000000203 mixture Substances 0.000 claims description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 102000003777 Interleukin-1 beta Human genes 0.000 abstract description 5
- 108090000193 Interleukin-1 beta Proteins 0.000 abstract description 5
- 238000000338 in vitro Methods 0.000 abstract description 5
- 230000002757 inflammatory effect Effects 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 125000000466 oxiranyl group Chemical group 0.000 description 15
- 238000001035 drying Methods 0.000 description 10
- 238000005406 washing Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 3
- 101000588302 Homo sapiens Nuclear factor erythroid 2-related factor 2 Proteins 0.000 description 3
- 102100031701 Nuclear factor erythroid 2-related factor 2 Human genes 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RRNGFPNDTJUIGS-UHFFFAOYSA-N (3,4-dichlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(Cl)C(Cl)=C1 RRNGFPNDTJUIGS-UHFFFAOYSA-N 0.000 description 2
- VKHHBEKDPDCZIC-UHFFFAOYSA-N (3-chloro-4-fluorophenyl) carbamate Chemical compound C(N)(OC1=CC(=C(C=C1)F)Cl)=O VKHHBEKDPDCZIC-UHFFFAOYSA-N 0.000 description 2
- SHXGGYLLZCCNAX-UHFFFAOYSA-N (3-chlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=CC(Cl)=C1 SHXGGYLLZCCNAX-UHFFFAOYSA-N 0.000 description 2
- CCENBZDJMALWCH-UHFFFAOYSA-N (4-chlorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(Cl)C=C1 CCENBZDJMALWCH-UHFFFAOYSA-N 0.000 description 2
- JPPPAMSLRGOAOW-UHFFFAOYSA-N (4-cyanophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(C#N)C=C1 JPPPAMSLRGOAOW-UHFFFAOYSA-N 0.000 description 2
- ANJYDSPMBISEHY-UHFFFAOYSA-N (4-fluorophenyl) carbamate Chemical compound NC(=O)OC1=CC=C(F)C=C1 ANJYDSPMBISEHY-UHFFFAOYSA-N 0.000 description 2
- NIHHYKUHSZFXTC-UHFFFAOYSA-N (4-methoxyphenyl) carbamate Chemical compound COC1=CC=C(OC(N)=O)C=C1 NIHHYKUHSZFXTC-UHFFFAOYSA-N 0.000 description 2
- RHNSSYGTJAAVCR-UHFFFAOYSA-N (4-methylphenyl)carbamic acid Chemical compound CC1=CC=C(NC(O)=O)C=C1 RHNSSYGTJAAVCR-UHFFFAOYSA-N 0.000 description 2
- MUAUTBNKPSNTFM-UHFFFAOYSA-N 2-phenylethyl carbamate Chemical compound NC(=O)OCCC1=CC=CC=C1 MUAUTBNKPSNTFM-UHFFFAOYSA-N 0.000 description 2
- KUPJXBSBRGRTKB-UHFFFAOYSA-N 3-chloropropyl carbamate Chemical compound NC(=O)OCCCCl KUPJXBSBRGRTKB-UHFFFAOYSA-N 0.000 description 2
- VETXQJLDLLEFBI-UHFFFAOYSA-N 4-methylsulfonylpiperazine-1-carboxylic acid Chemical compound CS(=O)(=O)N1CCN(C(O)=O)CC1 VETXQJLDLLEFBI-UHFFFAOYSA-N 0.000 description 2
- AEDANDOCUNOLBS-UHFFFAOYSA-N 4-phenylpiperazine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCN1C1=CC=CC=C1 AEDANDOCUNOLBS-UHFFFAOYSA-N 0.000 description 2
- 241001646826 Isodon rubescens Species 0.000 description 2
- JCPLZLUJLOCUOG-UHFFFAOYSA-N [4-(trifluoromethyl)phenyl] carbamate Chemical compound NC(=O)OC1=CC=C(C(F)(F)F)C=C1 JCPLZLUJLOCUOG-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- GABQKHQNXWNJJJ-UHFFFAOYSA-N diphenylcarbamic acid Chemical compound C=1C=CC=CC=1N(C(=O)O)C1=CC=CC=C1 GABQKHQNXWNJJJ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- APRJFNLVTJWEPP-UHFFFAOYSA-M n,n-diethylcarbamate Chemical compound CCN(CC)C([O-])=O APRJFNLVTJWEPP-UHFFFAOYSA-M 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- RIXVESSVKLKKFV-UHFFFAOYSA-N piperazine-1,4-dicarboxylic acid Chemical compound OC(=O)N1CCN(C(O)=O)CC1 RIXVESSVKLKKFV-UHFFFAOYSA-N 0.000 description 2
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 description 2
- 229930185378 rubescensin Natural products 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- IVZWRQBQDVHDNG-UHFFFAOYSA-N (-)-Kauran; alpha-Dihydrokauren Natural products C1CC2C3(C)CCCC(C)(C)C3CCC22CC(C)C1C2 IVZWRQBQDVHDNG-UHFFFAOYSA-N 0.000 description 1
- ZWWKXEXFVYBART-UHFFFAOYSA-N 2,5-diisocyanato-5-methylcyclohexa-1,3-diene Chemical compound O=C=NC1(C)CC=C(N=C=O)C=C1 ZWWKXEXFVYBART-UHFFFAOYSA-N 0.000 description 1
- UAIUNKRWKOVEES-UHFFFAOYSA-N 3,3',5,5'-tetramethylbenzidine Chemical compound CC1=C(N)C(C)=CC(C=2C=C(C)C(N)=C(C)C=2)=C1 UAIUNKRWKOVEES-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009692 acute damage Effects 0.000 description 1
- 206010069351 acute lung injury Diseases 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000023402 cell communication Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 238000003570 cell viability assay Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229930001567 kaurane Natural products 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- DWLVWMUCHSLGSU-UHFFFAOYSA-M n,n-dimethylcarbamate Chemical compound CN(C)C([O-])=O DWLVWMUCHSLGSU-UHFFFAOYSA-M 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 206010034674 peritonitis Diseases 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229930002348 tetracyclic diterpenoid Natural products 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
-
- 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
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- 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)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an oridonin derivative which is a novel compound; the invention also provides a preparation method and medical application of the oridonin compound, and the method has the advantages of rich raw material sources, simple reaction process operation and cheap and easily obtained reagents. The prepared novel oridonin derivative has similar effect with oridonin. In vitro anti-inflammatory tests of LPS and ATP induced THP-M cells showed that: the oridonin derivative can obviously inhibit the generation of inflammatory factors IL-1 beta, has better activity than oridonin and positive drugs CY-09, shows better anti-inflammatory action, and can be applied to the preparation of anti-inflammatory drugs for treating NLRP 3-related diseases.
Description
Technical Field
The invention belongs to the technical field of chemical medicine, particularly relates to oridonin, and particularly relates to an oridonin derivative and a preparation method thereof, and also discloses medical application of the oridonin derivative.
Background
Oridonin is a compound extracted from Rabdosia rubescens (Rabdosia rubescens)s (Hemsl.) Hara) to obtain the kaurane tetracyclic diterpenoid compound. Oridonin (structural formula is shown in formula I, and is called Ori hereinafter) with chemical name of (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5,6, 14-tetrahydroxy-4, 4-dimethyl-8-methylene decahydro-6, 11b- (epoxy-methyl-bridge) -6a, 9-methylcyclohepta [ a)]Naphthalene-7 (8H) -one, formula: c 20 H 28 O 6 Molecular weight 364.44.
The in vivo and in vitro anti-inflammatory experiments of the existing oridonin show that: oridonin can target NLRP3 through carbon, thereby affecting NLRP3-NEK7 interaction, and inhibiting generation of inflammatory factor IL-1 beta. In vivo activity studies find that the medicament has good treatment effect on NLRP3 related diseases, such as peritonitis, arthritis and type 2 diabetes. (reference: He H, Jiang H, Yun C, et al., Oridonin is a equivalent NLRP3 inhibitor with strong anti-inflammatory activity [ J ]. Nature Communications,2018,9(1): 2550-.
There are also reports in the literature that [ Yang H, Lv H, Li H, et al, Oridonin protects LPS-induced acid lung by modulating Nrf2-mediated oxidative stress and Nrf2-independent NLRP3 and NF-. kappa.B pathways [ J ]. Cell Communication and Signaling,2019,17(1):62-77.] oridonin exerts anti-inflammatory effects by inhibiting Nrf2-mediated oxidative stress and NLRP3 and NF-. kappa.B Signaling pathways, and in the LPS-induced acute lung injury model, oridonin alleviates LPS-induced histopathological changes, inhibits MPO and MDA in mouse lung tissues, while increasing GSH and OSD production, thus having important therapeutic effects on acute injury of the lung.
It can be seen that oridonin and oridonin derivatives are hot spots in the development of new drugs, and have great potential in the research and development of drugs for treating diseases related to NLRP 3.
Disclosure of Invention
The invention aims to provide an oridonin derivative, which is a novel oridonin derivative compound, and further provides a preparation method of the oridonin derivative.
Another object of the invention is to provide the use of such compounds in the treatment of NLRP3 related diseases.
The invention discloses an oridonin derivative, which has a structure shown in a formula II:
when R is 1 ＝H，R 2 Is the following group:
(A) aromatic hydrocarbons: phenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, benzyl, phenethyl;
(B) alkane: ethyl, propyl, isopropyl, heptyl, hexyl, cyclohexyl, allyl, 3-chloropropyl;
R 1 ，R 2 is the following group: morpholine, pyrrolidine, piperidine, piperazine, 4-phenylpiperazine, 4-methanesulfonyl piperazine, diphenyl, Boc-piperazine, diethylamino, dimethylamino.
Among the compounds having the general formula II, preferred compounds are:
II 1: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl p-tolylcarbamate;
II 2: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4-methoxyphenyl) carbamate;
II 3: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohept [ a ] naphthalen-14-yl (4-fluorophenyl) carbamate;
II 4: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4-chlorophenyl) carbamate;
II 5: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (3-chlorophenyl) carbamate;
II 6: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethyl bridge) -6a, 9-methylcyclohept [ a ] naphthalen-14-yl (3, 4-dichlorophenyl) carbamate;
II 7: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohept [ a ] naphthalen-14-yl (3-chloro-4-fluorophenyl) carbamate;
II 8: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4- (trifluoromethyl) phenyl) carbamate;
II 9: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4-cyanophenyl) carbamate;
II 10: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohept [ a ] naphthalen-14-ylbenzylcarbamate;
II 11: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl phenethylcarbamate;
II 12: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalene-14-ethylcarbamate;
II 13: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohept [ a ] naphthalen-14-yl allylcarbamate;
II 14: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohept [ a ] naphthalen-14-ylcyclohexylcarbamate;
II 15: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecane-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-ylcyclopentylcarbamate;
II 16: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-ylbutylcarbamate;
II 17: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (3-chloropropyl) carbamate;
II 18: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien-14-ylmorpholine-4-carboxylate;
II 19: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-ylpyrrolidine-1-carboxylate;
II 20: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-ylpiperidine-1-carboxylate;
II 21: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl 4-phenylpiperazine-1-carboxylate;
II 22: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecane-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-yl diethyl carbamate;
II 23: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien-14-yl 4-methanesulfonylpiperazine-1-carboxylate;
II 24: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-yldimethylcarbamate;
II 25: 1- (tert-butyl) 4- ((1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl) piperazine-1, 4-dicarboxylate;
II 26: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-yl diphenylcarbamate.
The preparation of a compound of formula II according to claim 1 according to the present invention can be obtained by the following process:
the method comprises the following steps:
weighing oridonin, dissolving in a solvent (1mmol/2mL), adding isocyanate under low-temperature stirring, wherein the ratio of the mole number of the oridonin to the mole number of the cyanate ester is 1: 1 to 1.5, and adding the mixture of the raw materials in a molar ratio of 1 to 3: 1, stirring the catalyst for reaction under the protection of nitrogen, wherein the reaction temperature is-10-30 ℃, TLC (thin layer chromatography) detection is carried out until the raw materials disappear, a solvent system is evaporated to dryness to obtain a crude product, and silica gel column chromatography separation (dichloromethane: methanol: 30: 1) or thin layer preparation is carried out to obtain the compound of the general formula II;
wherein the catalyst is any one of triethylamine and N, N-diisopropylethylamine;
the solvent is one of tetrahydrofuran, toluene, dichloromethane and chloroform.
The method 2 comprises the following steps:
weighing oridonin, dissolving in a solvent (1mmol/2mL), adding DMAP and a catalyst, adding azoic chloride under low-temperature stirring, wherein the ratio of the mole number of the oridonin to the mole number of the azoic chloride is 1: 1 to 1.5, wherein the ratio of the mole number of the oridonin to the mole number of the DMAP is 1: 1 to 1.5, wherein the molar ratio of the oridonin to the catalyst is 1: 1-3, stirring and reacting under the protection of nitrogen, wherein the reaction temperature is-10-30 ℃, TLC (thin-layer chromatography) detection is carried out until the raw materials disappear, a solvent system is evaporated to dryness to obtain a crude product, and silica gel column chromatography separation (dichloromethane: methanol is 30: 1) or thin-layer preparation is carried out to obtain the compound of the general formula II;
wherein the catalyst is any one of triethylamine and N, N-diisopropylethylamine;
the solvent is one of tetrahydrofuran, toluene, dichloromethane and chloroform.
The method 3 comprises the following steps:
weighing oridonin, dissolving in solvent (1mmol/2mL), adding catalyst, adding p-nitrophenyl chloroformate under low-temperature stirring, wherein the ratio of the mole number of the oridonin to the mole number of the p-nitrophenyl chloroformate is 1: 1 to 1.5, wherein the molar ratio of the oridonin to the catalyst is 1: 1-4, detecting by TLC until the oridonin disappears, and then adding secondary amine, wherein the ratio of the mole number of the oridonin to the mole number of the secondary amine is 1: 1-5, stirring for reaction at the temperature of-10-30 ℃, evaporating a solvent system to dryness after the reaction is completed to obtain a crude product, and performing silica gel column chromatography separation (dichloromethane: methanol is 30: 1) or thin layer preparation to obtain the compound of the general formula II;
wherein the catalyst is any one of triethylamine and N, N-diisopropylethylamine;
the solvent is one of tetrahydrofuran, toluene, dichloromethane and chloroform.
The invention has the positive effects that:
discloses a series of oridonin derivatives and a preparation method thereof, which are novel compound substances; the derivative of the invention adopts an ELISA method to determine the in vitro anti-inflammatory experiment of THP-M cells induced by LPS and ATP, and the result shows that the tested compounds can obviously inhibit the generation of inflammatory factors IL-1 beta, the activity of the derivative is superior to that of oridonin and positive drug CY-09, and the derivative shows better anti-inflammatory action. Can be applied to the preparation of anti-inflammatory drugs for treating NLRP3 related diseases; the method for preparing the oridonin derivative is simple, high in purity, low in cost and suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, which do not limit the present invention in any way, and any modifications or changes that can be easily made by a person skilled in the art to the present invention will fall within the scope of the claims of the present invention without departing from the technical solution of the present invention.
Example 1
II 1: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl p-tolylcarbamate;
oridonin (50.00mg) was placed in 10mL of anhydrous dichloromethane, p-tolylene isocyanate (21.89mg) and TEA (37.4. mu.L) were slowly added dropwise while cooling on ice, and the ice bath was removed and stirred at 25 ℃ for 12-15 hours under nitrogen. TCL detection reaction until the material disappeared, extraction with dichloromethane (3X 10mL) three times, saturated NaCl (2X 10mL) solution after washing, anhydrous Na 2 SO 4 Drying, filtering under reduced pressure, and spin-drying to obtain crude product. Purification by silica gel chromatography using methanol/dichloromethane (40: 1) as eluent gave compound II 1;
1 H NMR(400MHz,DMSO)δ9.48(s,1H),7.34(d,J＝6.9Hz,2H),7.05(d,J＝7.6Hz,2H),6.01(s,1H),5.96(d,J＝10.0Hz,1H),5.77(s,1H),5.66(s,1H),5.57(s,1H),4.44(s,1H),4.12(d,J＝10.2Hz,1H),3.87(d,J＝10.2Hz,1H),3.56–3.45(m,1H),3.35–3.30(m,1H),3.13(d,J＝9.6Hz,1H),2.57–2.52(m,1H),2.22(s,3H),2.19–2.07(m,1H),1.95–1.86(m,1H),1.76–1.64(m,1H),1.59–1.40(m,3H),1.36–1.11(m,3H),1.01(s,3H),0.99(s,3H)。
example 2
II 2: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4-methoxyphenyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(400MHz,DMSO)δ9.42(s,1H),7.37(d,J＝7.4Hz,2H),6.84(d,J＝8.0Hz,2H),6.02(s,1H),5.96(d,J＝10.0Hz,1H),5.76(s,1H),5.66(s,1H),5.55(s,1H),4.44(s,1H),4.11(d,J＝10.0Hz,1H),3.87(d,J＝10.0Hz,1H),3.69(s,3H),3.56–3.47(m,1H),3.35–3.29(m,1H),3.13(d,J＝9.2Hz,1H),2.58–2.52(m,1H),2.20–2.05(m,1H),1.92(dd,J＝11.9,4.0Hz,1H),1.77–1.64(m,1H),1.57–1.40(m,3H),1.36–1.12(m,3H),1.01(s,3H),0.99(s,3H)。
example 3
II 3: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohept [ a ] naphthalen-14-yl (4-fluorophenyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ9.59(s,1H),7.48(s,2H),7.10(t,J＝8.4Hz,2H),6.02(s,1H),5.95(d,J＝10.1Hz,1H),5.81(s,1H),5.69(s,1H),5.67(s,1H),4.45(d,J＝5.1Hz,1H),4.11(d,J＝10.2Hz,1H),3.86(d,J＝10.2Hz,1H),3.52(dd,J＝10.0,6.8Hz,1H),3.36–3.33(m,1H),3.12(d,J＝9.8Hz,1H),2.57–2.51(m,1H),2.17–2.08(m,1H),1.91(dd,J＝12.8,5.6Hz,1H),1.74–1.67(m,1H),1.55–1.42(m,3H),1.34–1.29(m,1H),1.25–1.18(m,1H),1.16(d,J＝6.7Hz,1H),1.01(s,3H),0.99(s,3H)。
example 4
II 4: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4-chlorophenyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ9.68(s,1H),7.50(d,J＝7.7Hz,2H),7.30(d,J＝8.4Hz,2H),6.02(s,1H),5.95(d,J＝10.1Hz,1H),5.83(s,1H),5.75(s,1H),5.67(s,1H),4.45(d,J＝5.1Hz,1H),4.11(d,J＝10.1Hz,1H),3.86(d,J＝10.1Hz,1H),3.52(dd,J＝10.1,6.8Hz,1H),3.36–3.33(m,1H),3.11(d,J＝9.8Hz,1H),2.56–2.51(m,1H),2.18–2.07(m,1H),1.90(dd,J＝12.7,5.8Hz,1H),1.75–1.68(m,1H),1.55–1.41(m,3H),1.33–1.29(m,1H),1.26–1.18(m,1H),1.15(d,J＝6.7Hz,1H),1.01(s,3H),0.99(s,3H)。
example 5
II 5: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (3-chlorophenyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ9.69(s,1H),7.62(s,1H),7.33(d,J＝7.0Hz,1H),7.23(t,J＝8.0Hz,1H),6.98(d,J＝7.8Hz,1H),5.99(s,1H),5.90(d,J＝10.2Hz,1H),5.82(s,1H),5.76(s,1H),5.64(s,1H),4.41(d,J＝5.1Hz,1H),4.08(d,J＝10.2Hz,1H),3.83(d,J＝10.2Hz,1H),3.50(dd,J＝10.1,6.9Hz,1H),3.35–3.32(m,1H),3.08(d,J＝9.8Hz,1H),2.52–2.48(m,1H),2.13–2.04(m,1H),1.86(dd,J＝12.9,5.6Hz,1H),1.72–1.66(m,1H),1.52–1.38(m,3H),1.30–1.25(m,1H),1.21–1.15(m,1H),1.12(d,J＝6.8Hz,1H),0.97(s,3H),0.96(s,3H)。
example 6
II 6: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethyl bridge) -6a, 9-methylcyclohept [ a ] naphthalen-14-yl (3, 4-dichlorophenyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ9.83(s,1H),7.83(s,1H),7.51(d,J＝8.7Hz,1H),7.41(s,1H),6.02(s,1H),5.93(d,J＝10.3Hz,1H),5.88(d,J＝11.6Hz,2H),5.67(s,1H),4.45(d,J＝5.1Hz,1H),4.11(d,J＝10.2Hz,1H),3.86(d,J＝10.2Hz,1H),3.53(dd,J＝10.1,6.9Hz,1H),3.34(d,J＝5.3Hz,1H),3.10(d,J＝9.7Hz,1H),2.56–2.51(m,1H),2.15–2.05(m,1H),1.89(dd,J＝12.9,5.7Hz,1H),1.75–1.69(m,1H),1.55–1.41(m,3H),1.34–1.29(m,1H),1.25–1.18(m,1H),1.15(d,J＝6.8Hz,1H),1.01(s,3H),0.99(s,3H)。
example 7
II 7: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-Trihydroxyl-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (Oxymethyl) -6a, 9-methylcyclohepto [ a ] Naphthalen-14-yl (3-chloro-4-fluorophenyl) carbamate
The preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ9.70(s,1H),7.72(s,1H),7.40–7.24(m,2H),5.99(s,1H),5.91(d,J＝10.2Hz,1H),5.82(s,2H),5.64(s,1H),4.43(d,J＝5.1Hz,1H),4.08(d,J＝10.1Hz,1H),3.83(d,J＝10.4Hz,1H),3.50(dd,J＝9.9,7.0Hz,1H),3.34–3.28(m,1H),3.07(d,J＝9.8Hz,1H),2.52–2.48(m,1H),2.12–2.02(m,1H),1.86(dd,J＝12.8,5.6Hz,1H),1.72–1.66(m,1H),1.51–1.38(m,3H),1.30–1.24(m,1H),1.21–1.15(m,1H),1.12(d,J＝6.8Hz,1H),0.97(s,3H),0.96(s,3H)。
example 8
II 8: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4- (trifluoromethyl) phenyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ9.92(s,1H),7.68(d,J＝8.3Hz,2H),7.61(d,J＝8.5Hz,2H),6.02(s,1H),5.94(d,J＝10.2Hz,1H),5.85(d,J＝16.4Hz,2H),5.67(s,1H),4.46(d,J＝5.1Hz,1H),4.12(d,J＝10.2Hz,1H),3.86(d,J＝10.2Hz,1H),3.53(dd,J＝10.1,6.9Hz,1H),3.37–3.33(m,1H),3.12(d,J＝9.8Hz,1H),2.56–2.51(m,1H),2.16–2.07(m,1H),1.90(dd,J＝12.8,5.7Hz,1H),1.75–1.69(m,1H),1.55–1.41(m,3H),1.33–1.28(m,1H),1.24–1.18(m,1H),1.15(d,J＝6.7Hz,1H),1.00(s,3H),0.99(s,3H)。
example 9
II 9: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (4-cyanophenyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ9.99(s,1H),7.71(d,J＝8.7Hz,2H),7.68–7.63(m,2H),6.02(s,1H),5.92(d,J＝10.3Hz,1H),5.89(d,J＝6.8Hz,2H),5.67(s,1H),4.44(d,J＝5.1Hz,1H),4.11(d,J＝10.1Hz,1H),3.85(d,J＝10.1Hz,1H),3.52(dd,J＝10.2,6.9Hz,1H),3.38–3.36(m,1H),3.11(d,J＝9.8Hz,1H),2.56–2.51(m,1H),2.16–2.05(m,1H),1.89(dd,J＝12.8,5.8Hz,1H),1.76–1.69(m,1H),1.55–1.41(m,3H),1.33–1.28(m,1H),1.25–1.18(m,1H),1.15(d,J＝6.7Hz,1H),1.00(s,3H),0.99(s,3H)。
example 10
II 10: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohept [ a ] naphthalen-14-ylbenzylcarbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.85(t,J＝5.8Hz,1H),7.31(t,J＝7.2Hz,2H),7.22(t,J＝7.9Hz,3H),6.01–5.93(m,2H),5.63(s,1H),5.60(s,1H),5.32(s,1H),4.47(d,J＝4.9Hz,1H),4.15(d,J＝5.6Hz,2H),4.07(d,J＝10.2Hz,1H),3.85(d,J＝10.1Hz,1H),3.40–3.31(m,2H),3.10(d,J＝9.6Hz,1H),2.49–2.43(m,1H),2.15–2.05(m,1H),1.90(dd,J＝12.1,5.4Hz,1H),1.69–1.60(m,1H),1.53–1.41(m,3H),1.33–1.28(m,1H),1.23–1.17(m,1H),1.14(d,J＝6.1Hz,1H),1.00(s,3H),0.97(s,3H)。
example 11
II 11: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl phenethylcarbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.43(t,J＝5.6Hz,1H),7.27(t,J＝7.5Hz,2H),7.21–7.14(m,3H),5.96(d,J＝10.7Hz,2H),5.62(s,1H),5.54(s,1H),5.18(s,1H),4.46(d,J＝5.0Hz,1H),4.07(d,J＝10.3Hz,1H),3.86(d,J＝10.2Hz,1H),3.62–3.52(m,1H),3.34(dt,J＝11.0,5.4Hz,1H),3.23–3.17(m,1H),3.15–3.09(m,1H),3.07(d,J＝9.9Hz,1H),2.72–2.62(m,2H),2.49–2.42(m,1H),2.16–2.06(m,1H),1.90(dd,J＝12.6,5.9Hz,1H),1.67–1.60(m,1H),1.54–1.39(m,3H),1.33–1.28(m,1H),1.23–1.16(m,1H),1.14(d,J＝6.4Hz,1H),1.00(s,3H),0.95(s,3H)。
example 12
II 12: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalene-14-ethylcarbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.31(s,1H),5.96(d,J＝8.9Hz,2H),5.62(s,1H),5.55(s,1H),5.19(s,1H),4.46(s,1H),4.07(d,J＝10.2Hz,1H),3.85(d,J＝10.2Hz,1H),3.40–3.31(m,2H),3.08(d,J＝9.6Hz,1H),2.99–2.94(m,2H),2.49–2.39(m,1H),2.16–2.06(m,1H),1.90(dd,J＝12.0,5.6Hz,1H),1.68–1.60(m,1H),1.54–1.37(m,3H),1.34–1.27(m,1H),1.24–1.16(m,1H),1.13(d,J＝5.8Hz,1H),0.99(s,3H),0.96(s,6H)。
example 13
II 13: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclohept [ a ] naphthalen-14-yl allylcarbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.51(t,J＝5.8Hz,1H),5.99–5.94(m,2H),5.79–5.71(m,1H),5.62(s,1H),5.57(s,1H),5.23(s,1H),5.08(d,J＝17.2Hz,1H),5.03(d,J＝10.3Hz,1H),4.46(d,J＝5.1Hz,1H),4.07(d,J＝10.3Hz,1H),3.85(d,J＝10.3Hz,1H),3.57(t,J＝4.8Hz,2H),3.50–3.48(m,1H),3.34(dt,J＝10.9,5.3Hz,1H),3.09(d,J＝9.8Hz,1H),2.48–2.43(m,1H),2.16–2.07(m,1H),1.91(dd,J＝12.6,5.9Hz,1H),1.67–1.61(m,1H),1.54–1.39(m,3H),1.33–1.28(m,1H),1.22–1.16(m,1H),1.14(d,J＝6.4Hz,1H),1.00(s,3H),0.97(s,3H)。
example 14
II 14: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohept [ a ] naphthalen-14-ylcyclohexylcarbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.27(d,J＝7.7Hz,1H),5.96–5.91(m,2H),5.60(s,1H),5.50(s,1H),5.11(s,1H),4.40(d,J＝5.0Hz,1H),4.04(d,J＝10.3Hz,1H),3.82(d,J＝10.2Hz,1H),3.44(dd,J＝9.6,6.5Hz,1H),3.33–3.29(m,1H),3.22–3.15(m,1H),3.07(d,J＝9.9Hz,1H),2.46–2.40(m,1H),2.14–2.05(m,1H),1.89(dd,J＝12.5,6.0Hz,1H),1.68(s,2H),1.64–1.57(m,3H),1.52–1.46(m,2H),1.45–1.36(m,2H),1.30–1.26(m,1H),1.23–1.15(m,3H),1.12–1.02(m,4H),0.97(s,3H),0.94(s,3H)。
example 15
II 15: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecane-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-ylcyclopentylcarbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.39(s,1H),6.04–5.92(m,2H),5.64(s,1H),5.54(s,1H),5.13(s,1H),4.43(s,1H),4.08(d,J＝6.0Hz,1H),3.86(d,J＝6.4Hz,1H),3.78–3.70(m,1H),3.53–3.43(m,1H),3.33–3.25(m,1H),3.11(d,J＝5.2Hz,1H),2.50–2.42(m,1H),2.17–2.08(m,1H),1.97–1.88(m,1H),1.79–1.71(m,2H),1.68–1.41(m,8H),1.39–1.29(m,3H),1.25–1.13(m,2H),1.01(s,3H),0.98(s,3H)。
example 16
II 16: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethyl bridge) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-ylbutyl carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.32(t,J＝5.5Hz,1H),5.97(s,1H),5.95(d,J＝9.7Hz,1H),5.63(s,1H),5.55(d,J＝8.4Hz,1H),5.18(s,1H),4.43(d,J＝5.0Hz,1H),4.07(d,J＝10.3Hz,1H),3.85(d,J＝10.3Hz,1H),3.48(dd,J＝9.6,6.5Hz,1H),3.35–3.31(m,1H),3.09(d,J＝9.9Hz,1H),2.93(dd,J＝13.0,6.6Hz,2H),2.48–2.43(m,1H),2.17–2.07(m,1H),1.91(dd,J＝12.6,5.9Hz,1H),1.68–1.59(m,1H),1.54–1.48(m,1H),1.47–1.39(m,2H),1.37–1.28(m,3H),1.26–1.17(m,3H),1.14(d,J＝6.4Hz,1H),1.00(s,3H),0.97(s,3H),0.84(t,J＝7.3Hz,3H)。
example 17
II 17: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl (3-chloropropyl) carbamate;
the preparation method is the same as that of example 1;
1 H NMR(600MHz,dmso)δ7.35(t,J＝5.6Hz,1H),5.97(s,1H),5.94(d,J＝9.9Hz,1H),5.63(s,1H),5.59(s,1H),5.30(s,1H),4.43(d,J＝5.0Hz,1H),4.07(d,J＝10.3Hz,1H),3.85(d,J＝10.3Hz,1H),3.60(t,J＝6.4Hz,2H),3.49(dd,J＝9.7,6.7Hz,1H),3.36–3.32(m,1H),3.12–2.98(m,3H),2.48–2.42(m,1H),2.14–2.05(m,1H),1.89(dd,J＝12.6,5.7Hz,1H),1.84–1.78(m,2H),1.68–1.61(m,1H),1.54–1.40(m,3H),1.33–1.28(m,1H),1.24–1.16(m,1H),1.14(d,J＝6.4Hz,1H),1.00(s,3H),0.97(s,3H)。
example 18
II 18: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien-14-ylmorpholine-4-carboxylate;
placing rubescensin (60.00mg) and TEA (91.2 μ L) in 10mL anhydrous dichloromethane, slowly adding p-nitrophenyl chloroformate (39.82mg) under ice bath, stirring for 6-8 hr at 25 deg.C under nitrogen protection, detecting by TCL until the raw materials disappear, adding morpholine (43.12 μ L), extracting with dichloromethane (3 × 10mL) for three times after reaction is completed, washing with saturated NaCl (2 × 10mL), and adding anhydrous Na 2 SO 4 Drying, filtering under reduced pressure, and spin-drying to obtain crude product; purification by silica gel chromatography using methanol/dichloromethane (40: 1) as eluent gave compound II 18;
1 H NMR(400MHz,DMSO)δ6.04–5.90(m,3H),5.64(s,1H),5.60(s,1H),4.42(s,1H),4.06(d,J＝9.9Hz,1H),3.84(d,J＝9.9Hz,1H),3.57–3.42(m,5H),3.35–3.05(m,5H),3.02(d,J＝9.4Hz,1H),2.48–2.41(m,1H),2.14–1.98(m,1H),1.83(d,J＝12.9Hz,1H),1.74–1.63(m,1H),1.56–1.38(m,3H),1.35–1.11(m,3H),1.01(s,3H),0.99(s,3H)。
example 19
II 19: (1S,4aR,5S,6S,6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (oxiranyl) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-ylpyrrolidine-1-carboxylate.
The preparation method is the same as that of example 18;
1 H NMR(400MHz,DMSO)δ5.96(d,J＝12.0Hz,2H),5.70(s,1H),5.60(s,2H),4.41(s,1H),4.07(d,J＝9.9Hz,1H),3.84(d,J＝9.8Hz,1H),3.55–3.45(m,1H),3.29–3.24(m,1H),3.24–3.12(m,2H),3.02(d,J＝9.4Hz,1H),2.96–2.86(m,1H),2.48–2.40(m,1H),2.14–1.98(m,1H),1.84(d,J＝12.8Hz,1H),1.71(s,5H),1.58–1.39(m,3H),1.36–1.11(m,4H),1.00(s,3H),0.98(s,3H)。
example 20
II 20: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-ylpiperidine-1-carboxylate;
the preparation method is the same as that of example 18;
1 H NMR(400MHz,DMSO)δ6.08–5.88(m,2H),5.81(s,1H),5.58(s,2H),4.41(s,1H),4.06(d,J＝9.2Hz,1H),3.84(d,J＝9.0Hz,1H),3.51(d,J＝7.1Hz,1H),3.22(s,3H),3.10(s,1H),3.01(d,J＝8.6Hz,1H),2.47–2.37(m,1H),2.14–1.98(m,1H),1.91–1.79(m,1H),1.74–1.61(m,1H),1.58–1.08(m,13H),1.01(s,3H),0.99(s,3H)。
example 21
II 21: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl 4-phenylpiperazine-1-carboxylate;
the preparation method is the same as that of example 18;
1 H NMR(600MHz,dmso)δ7.21(t,J＝7.9Hz,2H),6.92(d,J＝8.2Hz,2H),6.79(t,J＝7.2Hz,1H),6.00(s,2H),5.95(d,J＝10.2Hz,1H),5.67(s,1H),5.62(s,1H),4.43(d,J＝5.1Hz,1H),4.07(d,J＝10.2Hz,1H),3.84(d,J＝10.2Hz,1H),3.58–3.42(m,3H),3.35–2.96(m,8H),2.49–2.44(m,1H),2.12–2.02(m,1H),1.85(dd,J＝12.9,5.6Hz,1H),1.73–1.66(m,1H),1.55–1.40(m,3H),1.33–1.28(m,1H),1.23–1.17(m,1H),1.13(d,J＝6.8Hz,1H),1.00(s,3H),0.99(s,3H).。
example 22
II 22: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecane-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-yl diethyl carbamate;
the preparation method is the same as that of example 18;
1 H NMR(600MHz,dmso)δ5.98(s,1H),5.96(d,J＝10.3Hz,1H),5.83(s,1H),5.60(s,1H),5.57(s,1H),4.43(d,J＝5.0Hz,1H),4.07(d,J＝10.2Hz,1H),3.84(d,J＝10.2Hz,1H),3.52(dd,J＝10.0,6.8Hz,1H),3.35–3.25(m,2H),3.21–3.09(m,2H),3.01(d,J＝9.9Hz,1H),2.87(dd,J＝13.6,6.6Hz,1H),2.49–2.41(m,1H),2.12–2.02(m,1H),1.85(dd,J＝12.8,5.7Hz,1H),1.71–1.65(m,1H),1.54–1.40(m,3H),1.33–1.29(m,1H),1.24–1.17(m,1H),1.14(d,J＝6.7Hz,1H),1.01(s,6H),0.99(s,3H),0.88(t,J＝5.6Hz,3H)。
example 23
II 23: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien-14-yl 4-methanesulfonylpiperazine-1-carboxylate;
placing oridonin (200.00mg) and TEA (366.98 μ L) in 10mL anhydrous dichloromethane, slowly adding p-nitrophenyl chloroformate (87.56mg) under ice bath, stirring at 25 deg.C under nitrogen for 6-8 hr, detecting by TCL until the raw materials disappear, adding piperazine (155 μ L), reacting completely, and adding dichloromethaneAlkane (3X 10mL) extraction three times, saturated NaCl (2X 10mL) solution after washing, anhydrous Na 2 SO 4 Drying, filtering under reduced pressure, and spin-drying to obtain crude product. Purification by silica gel chromatography using methanol/dichloromethane (20: 1) as eluent gave the title compound. The title compound (50mg) was dissolved in DCM, TEA (43.75. mu.L) was added, stirred for 15min in ice bath, MsCl (10. mu.L) was added, and after stirring for 4-6 h at 25 ℃ under nitrogen, TCL detected reaction until the material disappeared, extracted three times with dichloromethane (3X 10mL), washed with saturated NaCl (2X 10mL), and then anhydrous Na 2 SO 4 Drying, filtering under reduced pressure, and spin-drying to obtain crude product. Purification by silica gel chromatography using methanol/dichloromethane (40: 1) as eluent gave II 23;
1 H NMR(600MHz,dmso)δ5.98(s,1H),5.93(s,1H),5.89(d,J＝10.3Hz,1H),5.62(s,1H),5.55(s,1H),4.38(d,J＝5.1Hz,1H),4.00(d,J＝10.2Hz,1H),3.77(d,J＝10.2Hz,1H),3.57–3.40(m,3H),3.30–2.86(m,8H),2.79(s,3H),2.43–2.37(m,1H),2.04–1.95(m,1H),1.78(dd,J＝12.9,5.6Hz,1H),1.65–1.59(m,1H),1.48–1.34(m,3H),1.27–1.22(m,1H),1.18–1.11(m,1H),1.07(d,J＝6.7Hz,1H),0.94(s,3H),0.92(s,3H)。
example 24
II 24: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadiene [ a ] naphthalen-14-yl dimethylcarbamate;
the preparation method is the same as that of example 18;
1 H NMR(600MHz,dmso)δ5.97(d,J＝10.6Hz,2H),5.84(s,1H),5.59(s,1H),5.57(s,1H),4.42(d,J＝5.1Hz,1H),4.06(d,J＝10.2Hz,1H),3.83(d,J＝10.3Hz,1H),3.51(dd,J＝10.0,6.8Hz,1H),3.36–3.31(m,1H),3.00(d,J＝9.9Hz,1H),2.75(s,3H),2.67(s,3H),2.48–2.42(m,1H),2.12–2.02(m,1H),1.85(dd,J＝12.8,5.7Hz,1H),1.70–1.64(m,1H),1.55–1.40(m,3H),1.33–1.28(m,1H),1.23–1.16(m,1H),1.13(d,J＝6.7Hz,1H),1.00(s,3H),0.98(s,3H)。
example 25
II 25: 1- (tert-butyl) 4- ((1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclohepta [ a ] naphthalen-14-yl) piperazine-1, 4-dicarboxylate;
the preparation method is the same as that of example 18;
1 H NMR(600MHz,dmso)δ5.97(d,J＝8.3Hz,2H),5.91(d,J＝10.2Hz,1H),5.61(s,1H),5.58(s,1H),4.40(d,J＝5.1Hz,1H),4.03(d,J＝10.2Hz,1H),3.80(d,J＝10.1Hz,1H),3.48(dd,J＝10.1,6.9Hz,1H),3.33–2.94(m,10H),2.46–2.40(m,1H),2.02(dt,J＝21.5,13.5Hz,1H),1.81(dd,J＝12.9,5.7Hz,1H),1.69–1.62(m,1H),1.52–1.39(m,3H),1.35(s,9H),1.30–1.25(m,1H),1.20–1.14(m,1H),1.10(d,J＝6.8Hz,1H),0.97(s,3H),0.96(s,3H)。
example 26
II 26: (1S,4aR,5S, 6aR,9S,11bS,14R) -1,5, 6-trihydroxy-4, 4-dimethyl-8-methylene-7-oxododecahydro-1H-6, 11b- (epoxymethano) -6a, 9-methylcyclopentadien [ a ] naphthalen-14-yl diphenylcarbamate;
placing rubescensin (50.00mg), TEA (37.4 μ L) and DMAP (20.08mg) in 10mL of anhydrous dichloromethane, slowly adding dibenzoylchloride (38.09mg) in ice bath, stirring overnight at 25 ℃ under nitrogen protection, detecting by TCL until the raw materials disappear, extracting with dichloromethane (3X 10mL) for three times after the reaction is completed, washing with saturated NaCl (2X 10mL), and adding anhydrous Na 2 SO 4 Drying, filtering under reduced pressure, and spin-drying to obtain crude product. Purification by silica gel chromatography using methanol/dichloromethane (40: 1) as eluent gave compound II 25;
1 H NMR(600MHz,dmso)δ7.22(qd,J＝14.8,7.5Hz,10H),5.84(d,J＝10.3Hz,1H),5.80(s,1H),5.79(s,1H),5.51(s,1H),5.48(s,1H),4.41(d,J＝5.1Hz,1H),4.07(d,J＝10.2Hz,1H),3.84(d,J＝10.2Hz,1H),3.49(dd,J＝10.2,7.0Hz,1H),3.32–3.28(m,1H),3.08(d,J＝9.8Hz,1H),2.48–2.40(m,1H),2.08–1.97(m,1H),1.80(dd,J＝12.8,5.5Hz,1H),1.74–1.66(m,1H),1.53–1.39(m,3H),1.33–1.26(m,1H),1.23–1.15(m,1H),1.09(d,J＝6.8Hz,1H),1.00(s,3H),0.98(s,3H).
experimental example 1
Cell viability assay for in vitro compounds of interest
THP-1 cells in good suspended state were resuspended in 1640 full culture medium containing 100ng/L PMA (cell density about 10) 6 mL), and inoculated into a 96-well plate at 100. mu.L per well, incubated in an incubator for 48 hours to stimulate the differentiation of THP-1 into THP-M. The supernatant was aspirated, washed twice with PBS, and a blank group and a dosing group of a concentration gradient were set at 100. mu.L per well for 24 hours. Add 10. mu.L cck8 reagent per well and incubate at 37 ℃ for 0.5-4 hours until the color turns orange. Absorbance at 450nm was measured with a microplate reader. Cell viability was calculated from absorbance values.
Experimental example 2
Effect of in vitro target Compounds on the production of the inflammatory factor IL-1 beta
The THP-1 cells are stimulated by PMA (100ng/mL) for 48 hours and then are differentiated into THP-M; after the medicine is prepared by a 1640 basic culture medium, cell supernatant is discarded, and a target compound (with the final concentration of 1 mu M), Ori (with the final concentration of 1 mu M) and CY-09 (with the final concentration of 8 mu M) are respectively added for incubation for 1h, and then LPS (with the final concentration of 1 mu g/mL) and ATP (with the final concentration of 5mM) are used for stimulation for 4.5h and 0.5 h; cell culture supernatants were collected, centrifuged at 13000rpm for 5min to remove dead cells, and the supernatants were used for ELISA assay. Diluting the supernatant, adding 100 mu L of diluted supernatant into a detection hole coated with an antibody in advance, setting a plurality of holes, adding 50 mu L of Biotinylated antibody, mixing uniformly, reacting for 3 hours at room temperature after closing the plate, adding Streptavidin-HRP working solution after washing for 3 times, incubating for 20 minutes at room temperature, adding TMB substrate after washing for 3 times, developing for 5-30 minutes at room temperature in a dark place, measuring an OD value at the wavelength of 450nm, and calculating the IL-1 beta concentration in the sample according to a corresponding regression equation (see Table 1):
table 1.
Note: results are expressed as mean ± Standard Deviation (SD) (n ═ 3).
Claims (6)
1. An oridonin derivative is characterized in that the derivative has a structure shown in a formula II:
when R is 1 ＝H，R 2 Is the following group:
(A) aromatic hydrocarbons: phenyl, 4-chlorophenyl, 3, 4-dichlorophenyl, 3-chloro-4-fluorophenyl, 4-methoxyphenyl, 4-methylphenyl, 4-cyanophenyl, 4-trifluoromethylphenyl, benzyl, phenethyl;
(B) alkane: ethyl, propyl, isopropyl, heptyl, hexyl, cyclohexyl, allyl;
R 1 ，R 2 is the following group:
morpholine, pyrrolidine, piperidine, piperazine, 4-phenylpiperazine, 4-methanesulfonyl piperazine, diphenyl, Boc-piperazine, diethylamino, dimethylamino.
2. The use of the oridonin derivative of claim 1 in the preparation of anti-inflammatory drugs.
3. The use of the oridonin derivatives of claim 1 in the preparation of a medicament for the treatment of NLRP3 related diseases.
4. The method for preparing the oridonin derivative of claim 1, comprising the steps of: the method comprises the following steps:
weighing oridonin, dissolving in a solvent (1mmol/2mL), adding isocyanate under low-temperature stirring, wherein the ratio of the mole number of the oridonin to the mole number of the cyanate ester is 1: 1 to 1.5, and adding the mixture of the raw materials in a molar ratio of 1 to 3: 1, stirring the catalyst for reaction under the protection of nitrogen, wherein the reaction temperature is-10-30 ℃, TLC (thin layer chromatography) detection is carried out until the raw materials disappear, a solvent system is evaporated to dryness to obtain a crude product, and silica gel column chromatography separation (dichloromethane: methanol: 30: 1) or thin layer preparation is carried out to obtain the compound of the general formula II;
wherein the catalyst is any one of triethylamine and N, N-diisopropylethylamine;
the solvent is one of tetrahydrofuran, toluene, dichloromethane and chloroform.
5. The method for preparing the oridonin derivative of claim 1, comprising the steps of:
weighing oridonin, dissolving in a solvent (1mmol/2mL), adding DMAP and a catalyst, adding azoic chloride under low-temperature stirring, wherein the ratio of the mole number of the oridonin to the mole number of the azoic chloride is 1: 1 to 1.5, wherein the ratio of the mole number of the oridonin to the mole number of the DMAP is 1: 1 to 1.5, wherein the molar ratio of the oridonin to the catalyst is 1: 1-3, stirring and reacting under the protection of nitrogen, wherein the reaction temperature is-10-30 ℃, TLC (thin-layer chromatography) detection is carried out until the raw materials disappear, a solvent system is evaporated to dryness to obtain a crude product, and silica gel column chromatography separation (dichloromethane: methanol is 30: 1) or thin-layer preparation is carried out to obtain the compound of the general formula II;
wherein the catalyst is any one of triethylamine and N, N-diisopropylethylamine;
the solvent is one of tetrahydrofuran, toluene, dichloromethane and chloroform.
6. The method for preparing the oridonin derivative of claim 1, comprising the steps of:
weighing oridonin, dissolving in solvent (1mmol/2mL), adding catalyst, adding p-nitrophenyl chloroformate under low temperature stirring, wherein the ratio of the mole number of the oridonin to the mole number of the p-nitrophenyl chloroformate is 1: 1 to 1.5, the molar ratio of the oridonin to the catalyst is 1: 1-4, detecting by TLC until the oridonin disappears, and then adding secondary amine, wherein the ratio of the mole number of the oridonin to the mole number of the secondary amine is 1: 1-5, stirring for reaction at the temperature of-10-30 ℃, evaporating a solvent system to dryness after the reaction is completed to obtain a crude product, and performing silica gel column chromatography separation (dichloromethane: methanol is 30: 1) or thin layer preparation to obtain the compound of the general formula II;
wherein the catalyst is any one of triethylamine and N, N-diisopropylethylamine;
the solvent is one of tetrahydrofuran, toluene, dichloromethane and chloroform.
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| CN105503894A (en) * | 2012-01-21 | 2016-04-20 | 杭州本生药业有限公司 | 1-oxo/acylated-14-acylated Oridonin derivative and preparation method and application thereof |
| CN108299458A (en) * | 2017-12-28 | 2018-07-20 | 青岛海洋生物医药研究院股份有限公司 | Oridonin derivative and its preparation method and application |
| CN110151749A (en) * | 2018-02-13 | 2019-08-23 | 中国科学技术大学 | Application of the Oridonin in the drug of preparation prevention or treatment NLRP3 inflammation corpusculum related disease |
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| CN105503894A (en) * | 2012-01-21 | 2016-04-20 | 杭州本生药业有限公司 | 1-oxo/acylated-14-acylated Oridonin derivative and preparation method and application thereof |
| CN108299458A (en) * | 2017-12-28 | 2018-07-20 | 青岛海洋生物医药研究院股份有限公司 | Oridonin derivative and its preparation method and application |
| CN110151749A (en) * | 2018-02-13 | 2019-08-23 | 中国科学技术大学 | Application of the Oridonin in the drug of preparation prevention or treatment NLRP3 inflammation corpusculum related disease |
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| LEI PANG 等: "Development of novel oridonin analogs as specifically targeted NLRP3 inflammasome inhibitors for the treatment of dextran sulfate sodium-induced colitis" * |
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