CN116693583A - Aconitin analogue, preparation method and application thereof - Google Patents
Aconitin analogue, preparation method and application thereof Download PDFInfo
- Publication number
- CN116693583A CN116693583A CN202310106645.2A CN202310106645A CN116693583A CN 116693583 A CN116693583 A CN 116693583A CN 202310106645 A CN202310106645 A CN 202310106645A CN 116693583 A CN116693583 A CN 116693583A
- Authority
- CN
- China
- Prior art keywords
- compound
- acid
- organic solvent
- water
- tetrahydrofuran
- 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
- XFSBVAOIAHNAPC-NPVHKAFCSA-N aconitin Chemical class O([C@H]1[C@]2(O)C[C@H]3[C@@]45[C@H]6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-NPVHKAFCSA-N 0.000 title claims abstract description 15
- 238000002360 preparation method Methods 0.000 title claims description 24
- 239000003814 drug Substances 0.000 claims abstract description 46
- 229940079593 drug Drugs 0.000 claims abstract description 36
- 229930182470 glycoside Natural products 0.000 claims abstract description 17
- 150000002338 glycosides Chemical class 0.000 claims abstract description 16
- 241000173529 Aconitum napellus Species 0.000 claims abstract description 12
- 229940023019 aconite Drugs 0.000 claims abstract description 12
- 206010019280 Heart failures Diseases 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 62
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 49
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- 239000003960 organic solvent Substances 0.000 claims description 34
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 23
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 20
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical group IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 18
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 18
- 230000009471 action Effects 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 239000012351 deprotecting agent Substances 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 12
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 11
- 229910017604 nitric acid Inorganic materials 0.000 claims description 11
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 9
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical group CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 9
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 8
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 8
- 229940126062 Compound A Drugs 0.000 claims description 8
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 8
- 239000002808 molecular sieve Substances 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 8
- 230000003177 cardiotonic effect Effects 0.000 claims description 7
- 229940125898 compound 5 Drugs 0.000 claims description 7
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 7
- LHJCZOXMCGQVDQ-UHFFFAOYSA-N tri(propan-2-yl)silyl trifluoromethanesulfonate Chemical compound CC(C)[Si](C(C)C)(C(C)C)OS(=O)(=O)C(F)(F)F LHJCZOXMCGQVDQ-UHFFFAOYSA-N 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical group OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical group OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 4
- BJEIBBWKRCNBIL-UHFFFAOYSA-M FC(S(=O)(=O)[O-])(F)F.C[Si+](C)C Chemical compound FC(S(=O)(=O)[O-])(F)F.C[Si+](C)C BJEIBBWKRCNBIL-UHFFFAOYSA-M 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- CBEQRNSPHCCXSH-UHFFFAOYSA-N iodine monobromide Chemical compound IBr CBEQRNSPHCCXSH-UHFFFAOYSA-N 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical group [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Chemical group 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- 239000003223 protective agent Substances 0.000 claims description 4
- 239000002516 radical scavenger Substances 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- STMPXDBGVJZCEX-UHFFFAOYSA-N triethylsilyl trifluoromethanesulfonate Chemical compound CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F STMPXDBGVJZCEX-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical group [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 3
- 150000002952 aconitine derivatives Chemical class 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000004327 boric acid Substances 0.000 claims description 3
- 230000002107 myocardial effect Effects 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 claims description 2
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 claims description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical group [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000001012 protector Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 32
- 238000005728 strengthening Methods 0.000 abstract description 10
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000006257 total synthesis reaction Methods 0.000 abstract description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical group NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 42
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 33
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- 229960003638 dopamine Drugs 0.000 description 21
- 241000700159 Rattus Species 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000005406 washing Methods 0.000 description 15
- 230000004217 heart function Effects 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 239000011734 sodium Substances 0.000 description 14
- 238000010828 elution Methods 0.000 description 13
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical group [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 11
- 230000002861 ventricular Effects 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 9
- 239000013641 positive control Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000000006 Nitroglycerin Substances 0.000 description 7
- 238000010790 dilution Methods 0.000 description 7
- 239000012895 dilution Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 229960003711 glyceryl trinitrate Drugs 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 230000007423 decrease Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 230000010412 perfusion Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 241000132521 Erigeron Species 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 229940090044 injection Drugs 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical class C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 210000000709 aorta Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 230000003205 diastolic effect Effects 0.000 description 3
- 229960001149 dopamine hydrochloride Drugs 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 230000035488 systolic blood pressure Effects 0.000 description 3
- XFSBVAOIAHNAPC-UHFFFAOYSA-N Aconitin Natural products CCN1CC(C(CC2OC)O)(COC)C3C(OC)C(C(C45)(OC(C)=O)C(O)C6OC)C1C32C4CC6(O)C5OC(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-UHFFFAOYSA-N 0.000 description 2
- 241001013934 Erigeron breviscapus Species 0.000 description 2
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000035487 diastolic blood pressure Effects 0.000 description 2
- 229940005482 dopamine injection Drugs 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- QRUBYZBWAOOHSV-UHFFFAOYSA-M silver trifluoromethanesulfonate Chemical compound [Ag+].[O-]S(=O)(=O)C(F)(F)F QRUBYZBWAOOHSV-UHFFFAOYSA-M 0.000 description 2
- 239000011550 stock solution Substances 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
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- XFSBVAOIAHNAPC-XTHSEXKGSA-N 16-Ethyl-1alpha,6alpha,19beta-trimethoxy-4-(methoxymethyl)-aconitane-3alpha,8,10alpha,11,18alpha-pentol, 8-acetate 10-benzoate Chemical compound O([C@H]1[C@]2(O)C[C@H]3[C@@]45C6[C@@H]([C@@]([C@H]31)(OC(C)=O)[C@@H](O)[C@@H]2OC)[C@H](OC)[C@@H]4[C@]([C@@H](C[C@@H]5OC)O)(COC)CN6CC)C(=O)C1=CC=CC=C1 XFSBVAOIAHNAPC-XTHSEXKGSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- 241001671653 Aconitum carmichaelii Species 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 102000004631 Calcineurin Human genes 0.000 description 1
- 108010042955 Calcineurin Proteins 0.000 description 1
- 241000223782 Ciliophora Species 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 241000218201 Ranunculaceae Species 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 229940039750 aconitine Drugs 0.000 description 1
- STDXGNLCJACLFY-UHFFFAOYSA-N aconitine Natural products CCN1CC2(COC)C(O)CC(O)C34C5CC6(O)C(OC)C(O)C(OC(=O)C)(C5C6OC(=O)c7ccccc7)C(C(OC)C23)C14 STDXGNLCJACLFY-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 1
- 229960002327 chloral hydrate Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 125000003563 glycoside group Chemical group 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 241000411851 herbal medicine Species 0.000 description 1
- JCDRZCWRRLKLTB-UHFFFAOYSA-N hydron;4-[2-(methylamino)ethyl]benzene-1,2-diol;chloride Chemical compound Cl.CNCCC1=CC=C(O)C(O)=C1 JCDRZCWRRLKLTB-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 210000005240 left ventricle Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229940114657 nitroglycerin 0.5 mg Drugs 0.000 description 1
- 231100000989 no adverse effect Toxicity 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000009966 trimming Methods 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12
-
- 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)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Cardiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a aconitin analogue with a heart strengthening effect, which provides a new choice for clinical medication of heart strengthening and heart failure resistance; meanwhile, the invention also provides a synthesis method of the aconite glycoside analogue, and the total synthesis way of the aconite glycoside analogue is enriched.
Description
Technical Field
The invention belongs to the field of compound synthesis, and particularly relates to a aconitine analogue, a preparation method and application thereof.
Background
Radix Aconiti lateralis is processed product of radix Aconiti lateralis (Aconitum carmichaelii) of Ranunculaceae, and is mainly produced in Sichuan river oil, shaanxi Han and Yunnan Lijiang. Radix Aconiti lateralis is widely used as a well-known traditional Chinese medicine in China, japan, southeast Asia and the like for restoring yang, rescuing from adverse effects, dispelling cold, relieving pain and the like (Chinese pharmacopoeia, 2010 edition one, page 177).
The action of strengthening heart is one of the main actions of Fu Zi. The reported cardiotonic ingredients found from aconite include racemic norlindera root base (chem. Pharm. Bull.1976,24,178), methyldopamine hydrochloride (Planta medical, 1979,35,150), salvinorine (pharmaceutical journal, 1982,17,792), uracil (natural product research and development, 1997,9,30), aconitoside (Chinese herbal medicine, 2004,35,964; chinese invention patent CN 100386338C), chinese wuning (chinese patent CN 102146057B), and the like.
The aconite glycoside (fuziside) is a glycoside compound with remarkable cardiotonic activity, which is separated from aconite carmichaeli, and the structure is presumed to be shown as a formula I at present. Experiments prove that the aconitine has the function of improving the content of the calcineurin in the rat body. Because the content of the aconitin in the plant body is very low, the source is limited, and the chemical synthesis method is expected to efficiently prepare the compound and the derivative with a new structure, and has important significance for solving the source problem and discovering novel cardiotonic active drugs.
Disclosure of Invention
The invention aims to provide a aconitin analogue, a preparation method and application thereof.
The invention provides a aconitin analogue, which has a structure shown in a formula I:
wherein R is NH 2 OR OR ', R' is a nitro, phosphate, sulfate OR borate group;
R 1 、R 2 independently selected from H orAnd R is 1 、R 2 And not H at the same time.
Further, R' is nitro.
Further, R 1 Is H, R 2 Is thatOr R is 1 Is->R 2 H.
Further, the aconitin analogues have the structure shown in formula II:
further, it has any one of the following structures:
the invention also provides a preparation method of the aconitin analogue, which comprises the following steps:
(1) The compound A and the silyl ether protective agent react in an organic solvent under the action of alkali to prepare an intermediate, and the intermediate is further reacted with the compound B under the action of an accelerator and a catalyst after water removal to obtain a silyl ether protective group-protected compound C;
(2) The compound C reacts in an organic solvent under the action of a deprotection agent a to obtain a compound D;
(3) Reacting the compound D in an organic solvent under the action of a deprotection agent b to obtain a aconitine analogue shown in a formula I; the reaction formula is as follows:
wherein R is a 、R b Independently selected from silyl ether protecting groups orAnd R is a 、R b Not both a silyl ether protecting group;
R a ’、R b ' each independently selected from H orAnd R is a ’、R b ' not both H;
bz is benzoyl and STol is p-toluenesulfonyl.
Further, the molar ratio of the compound A to the silyl ether protectant and the alkali in the step (1) is 1 (1-1.5) (1.5-2.5), preferably 1:1.2:2;
the mol ratio of the intermediate to the compound B, the promoter and the catalyst is 1 (1-2): (2-4): (0.1-0.5), preferably 1:1.5:3:0.2;
the silyl ether protectant is: TIPSOTf, TBSOTf, TESOTf or TBDPSOTf, preferably TIPSOTf; the silyl ether protecting group is TIPS, TBS, TES or TBDPS, preferably TIPS;
and/or the base is triethylamine, pyridine, p-dimethylaminopyridine, lutidine, imidazole, DBU or tetramethylpiperidine, preferably triethylamine;
and/or the organic solvent is dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, toluene or diethyl ether, preferably dichloromethane;
and/or the accelerator is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or iodine bromide, preferably N-iodosuccinimide;
and/or the catalyst is silver trifluoromethane sulfonate, trimethylsilicon trifluoromethane sulfonate or trifluoromethane sulfonic acid, preferably silver trifluoromethane sulfonate;
and/or the water removal is water removal by adding 4A molecular sieve.
Further, the molar ratio of the compound C and the deprotection agent a in the step (2) is as follows: 1 (0.05-0.1), preferably 1 (0.7-0.8);
the organic solvent is a mixed solvent of tetrahydrofuran and water, tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water; preferably, the organic solvent is a mixed solvent of tetrahydrofuran and water in a volume ratio of 1:1;
and/or the deprotecting agent a is trifluoroacetic acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid, preferably trifluoroacetic acid.
Further, the molar ratio of the compound D to the deprotecting agent b in the step (3) is: 1 (4-8), preferably 1 (4-5);
the organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran, preferably methanol;
and/or the deprotecting agent a is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium methoxide.
Further, the reaction conditions of the compound A and the silyl ether protectant in the step (1) are as follows: adding alkali at 0-5 ℃ for 5-15 min, then dripping a silyl ether protective agent for reacting for 20-40 min, and then heating to 20-30 ℃ for reacting for 8-14 h;
the reaction conditions of the intermediate and the compound B are as follows: the intermediate reacts with the compound B in an organic solvent for 10min at minus 30 to minus 50 ℃, then the accelerant is added for 20 to 40min, the catalyst is added, and the temperature is raised to 0 to 5 ℃ for 8 to 14h.
Further, the reaction conditions of step (2) are: after trifluoroacetic acid is added at 0-5 ℃, the mixture reacts for 8-14 h at 30-50 ℃.
Further, the reaction conditions of step (3) are: reacting for 3-5 h at 20-30 ℃.
Further, the intermediate in step (1) is purified by the following method before reacting with compound B: extracting with dichloromethane, washing with water, washing with saturated saline, drying, concentrating, and purifying by silica gel column chromatography;
the compound C in the step (2) is purified by the following method before being reacted with the deprotection agent a: saturated Na 2 S 2 O 3 Washing the solution, extracting with dichloromethane, washing with water, washing with saturated saline, drying, concentrating, and purifying by silica gel column chromatography;
the compound D in the step (3) is purified by the following method before being reacted with the deprotection agent b: the pH value is regulated to 6.5-7.5, the extraction is performed by ethyl acetate, the washing is performed by water, the washing is performed by saturated saline water, and the purification is performed by silica gel column chromatography after the drying and concentration.
Further, in the above preparation method, when R is OR', the compound a is prepared according to the following method steps:
(1') reacting the compound B with the compound 2 in an organic solvent under the action of an accelerator, a catalyst and a water remover to obtain a compound 3;
(2') reacting the compound 3 in an organic solvent under the action of acid to obtain a compound 4;
(3 ') reacting compound 4 with compound R' -OH in an acid anhydride to obtain compound 5;
(4') reacting compound 5 with a deprotecting agent in an organic solvent to give compound 6;
(5') reacting the compound 6 with the compound 1 in an organic solvent under the action of a catalyst to obtain a compound A;
the reaction formula is as follows:
wherein STol is p-toluenesulfonyl, bz is benzoyl, ph is phenyl, and R' is nitro, phosphate, sulfate, sulfite or borate.
Further, the molar ratio of the compound B to the compound 2, the promoter and the catalyst in the step (1') is as follows: 1 (1-2): (0.05-0.15), preferably 1:1.5:1.5:0.1; the mass ratio of the compound B to the water scavenger is 1 (0.5-3), preferably 1:1;
the organic solvent is dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, toluene or diethyl ether, preferably dichloromethane;
and/or the accelerator is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or iodine bromide, preferably N-iodosuccinimide;
and/or the catalyst is silver trifluoromethane sulfonate, trimethylsilicon trifluoromethane sulfonate or trifluoromethane sulfonic acid, preferably silver trifluoromethane sulfonate;
and/or the water scavenger is a 4A molecular sieve.
Further, the molar ratio of the compound 3 to the acid in the step (2') is 1 (0.01-0.05), preferably 1 (0.03-0.04);
the acid is hydrochloric acid, trifluoroacetic acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid, preferably hydrochloric acid;
the organic solvent is tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of tetrahydrofuran and water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water, preferably tetrahydrofuran.
Further, the mass-to-volume ratio of the compound 4 to the compound R '-OH in the step (3') is as follows: (1-5) g, 1mL;
the anhydride is acetic anhydride and the R' -OH is nitric acid, phosphoric acid, sulfuric acid, sulfurous acid or boric acid, preferably nitric acid.
Further, the molar ratio of compound 5 to the deprotecting agent in step (4') is: 1 (4-5), preferably 1:4.5;
the organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran, preferably methanol;
and/or the deprotecting agent is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium methoxide.
Further, the molar ratio of the compound 6, the compound 1 and the catalyst in the step (5') is 1 (2-3): (0.05-0.15), preferably 1:2.5:0.1;
the catalyst is D-camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, and preferably D-camphorsulfonic acid;
the organic solvent is acetone, dichloromethane, chloroform or tetrahydrofuran, preferably acetone.
Further, the reaction condition in the step (1') is that the compound B and the compound 2 react in an organic solvent at the temperature of 0-5 ℃ for 10min, then the accelerant is added for 20-40 min, the catalyst is added, and the temperature is raised to 20-30 ℃ for 2-4 h.
Further, the reaction condition of the step (2') is that after the compound 3 is added with acid at the temperature of 0-5 ℃, the temperature is raised to 20-30 ℃ for 2-4 hours.
Further, the reaction condition in the step (3 ') is that the compound 4 and R' -OH react for 15 to 35 minutes at the temperature of between 0 and 5 ℃, and then the temperature is raised to between 20 and 30 ℃ for 2 to 4 hours.
Further, the reaction condition of the step (4') is 20-30 ℃ for 1-3 h.
Further, the reaction condition in the step (5') is 20-30 ℃ for 3-5 h.
Further, the products after each of the steps (1 ') to (5') are purified by silica gel column chromatography.
The invention also provides application of the compound in medicaments for strengthening heart and/or resisting heart failure.
Further, the above-mentioned drugs are drugs for enhancing myocardial contractility.
The invention also provides a heart-strengthening medicine, which is a preparation prepared by taking the compound as an active ingredient and adding pharmaceutically acceptable auxiliary materials.
The invention has the beneficial effects that: the invention provides a new aconitin analogue with heart strengthening effect, and provides a new choice for clinical medication of heart strengthening and heart failure resistance; meanwhile, the invention also provides a synthesis method of the aconitin analogue, and the chemical synthesis approach of the aconitin analogue is enriched.
The term of the invention: TIPSOTf refers to triisopropyltriflate (CAS: 1328887-45-1); TIPS finger-SiPr 3 The protecting group Pr refers to isopropyl.
TBSOTf refers to t-butyldisilyl triflate (CAS: 69739-34-0); TBS means a tertiary butyl dimethylsilyl protecting group;
TESOTf refers to triethylsilicon trifluoromethane sulfonic acid (CAS: 79271-56-0); TES finger-SiEt 3 Protecting group Et is ethyl.
TBDPSOTf refers to tert-butyldiphenyl triflate; TBDPS means t-BuPh 2 Si-group, t-Bu is tert-butyl and Ph is phenyl.
DBU refers to 1, 8-diazabicyclo [5.4.0] undec-7-ene.
The term "nitric acid, phosphoric acid, sulfuric acid, sulfurous acid or boric acid" as used herein refers to a pure acid in a liquid state or a highly concentrated aqueous solution thereof. For example, the high-concentration nitric acid solution (concentrated nitric acid) means an aqueous nitric acid solution having a concentration of 8mol/L or more, and preferably an aqueous nitric acid solution having a concentration of 8mol/L or more.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Detailed Description
The raw materials and equipment used in the invention are all known products and are obtained by purchasing commercial products.
The K-H solutions used in the present invention were formulated and the concentrations are shown in the following table.
Rats used for the isolated cardiac function experiments were: healthy SD rats, about 250g in weight, are used as both male and female. Provided by university of Sichuan animal experiment center, animal qualification number: SCXK (Chuan) 2018-026.
EXAMPLE 1 Synthesis of aconite glycoside analogues of the invention
The synthetic route is as follows:
preparation of compound 3: 1 (30 g,42.7 mmol) and 2 (11.5 g,64.1 mmol) were dissolved in dry dichloromethane (450 mL) followed by the addition of 4A molecular sieves (30 g). After stirring the reaction solution at 0℃for 10 minutes, NIS (14.4 g,64.1 mmol) was added. After the addition was completed, stirring was continued at this temperature for 30 minutes, agOTf (1.1 g,4.3 mmol) was added. After the addition, the reaction solution was slowly warmed from 0℃to room temperature. After 3h of reaction, et 3 The reaction was quenched by N and the molecular sieves were filtered off. Saturated Na is used for filtrate 2 S 2 O 3 Solution washing, dichloromethane (200 mL. Times.2) extraction, washing with water and saturated brine, anhydrous MgSO 4 And (5) drying. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE: ea=10:1 to 5:1 gradient elution) to afford 3 as a white foam (23.7 g, 73%).
1 H NMR(400MHz,Chloroform-d)δ8.11–8.03(m,4H),7.94(dd,J＝12.8,7.2Hz,4H),7.56–7.45(m,6H),7.37–7.25(m,11H),6.10–6.02(m,1H),5.67(d,J＝5.4Hz,1H),5.65(s,1H),5.57(d,J＝11.6Hz,2H),4.85–4.79(m,1H),4.74(d,J＝5.3Hz,2H),4.42(d,J＝11.8Hz,2H),4.09(t,J＝11.9Hz,2H),3.71(s,1H).
13 C NMR(100MHz,CDCl 3 )δ166.09,165.77,165.69,165.39,138.18,133.39,133.36,133.22,133.07,130.05,129.95,129.84,129.70,129.46,129.03,128.92,128.41,128.37,128.32,128.22,126.21,105.07,101.43,82.28,81.80,70.46,70.32,69.40,68.82,63.31
HRMS(ESI):m/z calcd.For C 44 H 38 O 12 [M+Na] + 781.2255,found 781.2259.
Preparation of Compound 4: 3 (23.7 g,31.2 mmol) was dissolved in tetrahydrofuran (450 mL) followed by the addition of 4M HCl (300 mL) at 0deg.C. After the addition, the reaction solution was slowly warmed from 0℃to room temperature. After 3h of reaction, saturated NaHCO was slowly added at 0deg.C 3 The pH of the solution was adjusted to about 7. Ethyl acetate (300 mL. Times.2) extraction, washing with water and saturated brine, anhydrous MgSO 4 And (5) drying. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE: ea=2:1 to 1:2 gradient elution) to give white foamy solid 4 (15.5 g, 74%).
1 H NMR(400MHz,Chloroform-d)δ8.08(d,J＝7.6Hz,2H),8.00(dd,J＝11.5,7.8Hz,4H),7.92(d,J＝8.0Hz,2H),7.59–7.51(m,4H),7.46–7.29(m,8H),6.00–5.96(m,1H),5.73(dd,J＝5.7,1.8Hz,1H),5.52(s,1H),5.49(d,J＝1.8Hz,1H),4.82(dd,J＝5.5,4.1Hz,1H),4.77(d,J＝4.7Hz,1H),4.72(dd,J＝11.9,6.7Hz,1H),3.93–3.89(m,1H),3.81–3.66(m,4H).
13 C NMR(100MHz,CDCl 3 )δ166.18,166.13,165.65,165.56,133.66,133.38,133.21,129.95,129.88,129.75,129.44,129.30,128.74,128.52,128.47,128.41,106.50,83.28,81.01,80.97,70.21,63.08,63.05,62.39.
HRMS(ESI):m/z calcd.For C 37 H 34 O 12 [M+Na] + 693.1942,found 693.1938.
Preparation of compound 5: 4 (15.5 g,23.1 mmol) was dissolved in acetic anhydride (200 mL) followed by slow dropwise addition of concentrated HNO3 solution (10 mL in 200mL acetic anhydride) under ice bath. After the addition was completed, the reaction mixture was stirred at 0℃for 20 minutes, and then slowly warmed to room temperature. After 2.5h of reaction, saturated NaHCO3 solution was slowly added at 0deg.C to adjust the pH to about 7. Extraction with ethyl acetate (200X 2), water and saturated salineWashing, anhydrous MgSO 4 And (5) drying. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE: ea=8:1 to 6:1 gradient elution) to afford 5 as a white foam (15.3 g, 87%).
1 H NMR(400MHz,Chloroform-d)δ8.08(d,J＝7.5Hz,2H),8.03(d,J＝7.5Hz,2H),7.98(d,J＝7.7Hz,2H),7.88(d,J＝7.5Hz,2H),7.60–7.52(dd,4H),7.46–7.22(m,8H),6.07–6.03(m,1H),5.66(d,J＝6.3Hz,1H),5.48(s,1H),5.45(s,1H),4.80–4.72(m,3H),4.70–4.58(m,4H),4.39–4.30(m,1H). 13 C NMR(100MHz,CDCl 3 )δ166.06,165.67,165.58,165.46,133.62,133.53,133.33,133.15,129.96,129.87,129.85,129.67,129.42,129.32,128.73,128.51,128.47,128.43,128.35,105.37,82.55,81.97,77.21,70.89,70.29,70.16,69.81,63.23.
HRMS(ESI):m/z calcd.For C 37 H 32 N 2 O 16 [M+Na] + 783.1644,found783.1641.
Preparation of Compound 6: 5 (15.3 g,20.1 mmol) was dissolved in methanol (400 mL) followed by NaOMe (4.9 g,90.6 mmol). After the addition, stirring at room temperature. After 2 hours of reaction, the pH of the reaction solution was adjusted to about 7 with an activated cation exchange resin. After suction filtration and concentration of the filtrate in vacuo, the crude product was purified by silica gel column chromatography (DCM: meoh=10:1 to 7:1 gradient elution) to give white foamy solid 6 (5.9 g, 86%).
1 H NMR(400MHz,DMSO-d 6 )δ5.37(d,J＝6.0Hz,1H),5.11(d,J＝5.4Hz,1H),4.91(d,J＝1.6Hz,1H),4.73(dd,J＝11.6,4.0Hz,1H),4.66(d,J＝4.8Hz,2H),4.61(dd,J＝12.2,6.0Hz,2H),4.52(t,J＝5.9Hz,1H),4.26–4.21(m,1H),3.88–3.81(m,1H),3.80–3.72(m,2H),3.54–3.48(m,1H),3.40–3.32(m,2H).
13 C NMR(100MHz,DMSO)δ108.20,83.01,82.61,77.07,72.71,72.46,70.39,70.07,63.36.
HRMS(ESI):m/z calcd.For C 9 H 16 N 2 O 12 [M+Na] + 367.0601,found367.0598.
Preparation of compound 7: 6 (5.9 g,17.1 mmol) was dissolved in dry acetone (150 mL) followed by the addition of 2, 2-dimethoxypropane (5.3 m)L,42.9 mmol) and D-CSA (0.4 g,1.7 mmol). After the addition, stirring at room temperature. After 4h of reaction, et was added 3 The reaction was quenched with N, concentrated directly in vacuo, and the crude product was purified by silica gel column chromatography (PE: ea=2:1 to 1:1.5 gradient elution) to give 7 (6.4 g, 97%) as a pale yellow oil.
1 H NMR(400MHz,Chloroform-d)δ5.18(s,1H),4.77(s,2H),4.70(dd,J＝12.0,4.1Hz,1H),4.63(dd,J＝12.2,4.8Hz,1H),4.53(dd,J＝12.2,5.4Hz,1H),4.45(dd,J＝11.8,7.2Hz,1H),4.37–4.31(m,2H),4.19(t,J＝1.3Hz,1H),4.15–4.06(m,2H),4.01–3.91(m,2H),1.40(d,J＝8.7Hz,6H).
13 C NMR(100MHz,CDCl 3 )δ110.30,108.54,86.38,78.53,78.28,75.43,71.07,70.03,69.82,65.57,25.50,25.44.
HRMS(ESI):m/z calcd.For C 12 H 20 N 2 O 12 [M+Na] + 407.0908,found407.0912.
Preparation of compounds 8 and 9: 7 (4.9 g,12.7 mmol) was dissolved in dry dichloromethane (100 mL) followed by the addition of triethylamine (Et) at 0deg.C 3 N) (3.5 mL,25.5 mmol). After the addition was completed, the reaction mixture was stirred at this temperature for 10 minutes, and triisopropylsilyl triflate (TIPSOTf) (4.1 mL,15.3 mmol) was slowly added dropwise. After the addition was completed, the reaction mixture was stirred for 30 minutes and then slowly warmed to room temperature. The reaction was quenched by addition of saturated NH4Cl solution overnight. Dichloromethane (60 mL. Times.2) extraction, washing with water and saturated brine, anhydrous MgSO 4 And (5) drying. After concentration in vacuo, the crude product was chromatographed on a column of silica gel (PE: ea=7:1 to 2:1 gradient elution) to give 4.1g of a pale yellow oily mixture.
The above mixture (4.1 g,7.6 mmol) and 1 (8.0 g,11.4 mmol) were dissolved in dry dichloromethane (150 mL) followed by the addition of 4A molecular sieve (5 g). After stirring the reaction at-40℃for 10 minutes, NIS (5.1 g,22.8 mmol) was added. After the addition was completed, stirring was continued at this temperature for 30 minutes, silver trifluoromethane sulfonate (AgOTf) (0.4 g,1.5 mmol) was added. After the addition, the reaction solution was slowly raised from-40℃to 0 ℃. The reaction was carried out overnight with Et 3 The reaction was quenched by N and the molecular sieves were filtered off. Saturated Na is used for filtrate 2 S 2 O 3 Washing the solution, extracting with dichloromethane (100 mL. Times.2)Washing with water and saturated saline, anhydrous MgSO 4 And (5) drying. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE: ea=9:1 to 5:1 gradient elution) to give yellow foamy solid 8 (2.4 g,19%,2 steps) and yellow foamy solid 9 (4.8 g,37%,2 steps).
Compound 8:
1 H NMR(400MHz,Chloroform-d)δ8.09–8.00(m,4H),7.98–7.90(m,4H),7.56–7.49(m,3H),7.45–7.30(m,9H),6.05–6.01(m,1H),5.71–5.62(m,1H),5.53(s,1H),5.42(s,1H),5.40–5.30(m,1H),4.81(dd,J＝11.6,4.6Hz,1H),4.75–4.67(m,2H),4.65–4.60(m,1H),4.57–4.49(m,2H),4.46–4.37(m,1H),4.31(dd,J＝6.2,3.4Hz,1H),4.27–4.22(m,1H),4.09–4.02(m,2H),3.95–3.85(m,2H),3.50(s,1H),1.39(s,3H),1.34(s,3H),1.11–1.06(m,3H),1.05(d,J＝4.8Hz,18H).
13 C NMR(100MHz,CDCl 3 )δ166.05,165.55,165.52,165.11,133.56,133.47,133.37,133.19,129.92,129.86,129.71,129.33,128.45,128.40,109.54,107.29,106.03,90.95,83.22,81.91,81.87,77.59,74.68,71.06,70.42,70.33,70.21,65.55,63.06,26.27,25.48,17.91,17.88.
HRMS(ESI):m/z calcd.For C 55 H 66 N 2 O 21 Si[M+Na] + 1141.3819,found1141.3817.
compound 9:
1 H NMR(400MHz,Chloroform-d)δ8.07–8.02(m,4H),7.99–7.89(m,4H),7.60–7.48(m,4H),7.42(t,J＝7.8Hz,2H),7.38–7.30(m,6H),6.05–6.01(m,1H),5.67(dd,J＝4.9,1.1Hz,1H),5.50(d,J＝1.2Hz,1H),5.44(s,1H),5.13(s,1H),4.78(dd,J＝12.0,4.2Hz,1H),4.74–4.67(m,2H),4.58(dd,J＝11.8,4.0Hz,1H),4.53(dd,J＝12.1,4.9Hz,1H),4.48–4.39(m,3H),4.36–4.25(m,2H),4.21(dd,J＝6.3,4.1Hz,1H),4.04(dd,J＝4.0,0.9Hz,1H),3.95(dd,J＝8.4,7.0Hz,1H),3.89(dd,J＝8.3,6.3Hz,1H),1.42(s,3H),1.31(s,3H),1.12–1.06(m,3H),1.03(d,J＝5.5Hz,18H).
13 C NMR(100MHz,CDCl 3 )δ165.98,165.60,165.54,165.22,133.56,133.43,133.26,133.08,129.92,129.89,129.81,129.67,129.45,129.41,128.90,128.75,128.44,128.39,128.34,109.91,108.20,105.74,85.31,84.64,82.04,82.00,80.83,75.58,70.97,70.78,70.49,69.16,65.49,63.35,26.39,25.14,17.72,11.89.
HRMS(ESI):m/z calcd.For C 55 H 66 N 2 O 21 Si[M+Na] + 1141.3819,found1141.3817.
preparation of compound 10: 9 (4.8 g,4.2 mmol) was dissolved in tetrahydrofuran-water mixed solution (48 mL, 1:1) followed by slow dropwise addition of CF at 0deg.C 3 COOH (24 mL). After the addition, the reaction was stirred at 40 ℃. The reaction was carried out overnight and saturated NaHCO was added 3 The pH of the solution was adjusted to about 7. Ethyl acetate (40 mL. Times.2) extraction, washing with water and saturated brine, anhydrous MgSO 4 And (5) drying. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE: ea=1.5:1 to PE: ea=1:2.5 gradient elution) to afford 10 as a white foam solid (3.1 g, 80%).
1 H NMR(400MHz,Chloroform-d)δ8.12–8.02(m,4H),8.00–7.94(m,2H),7.91–7.83(m,2H),7.65–7.55(m,1H),7.55–7.48(m,3H),7.44(t,J＝7.6Hz,2H),7.39–7.27(m,6H),6.14–6.10(m,1H),5.61(dd,J＝5.4,0.9Hz,1H),5.52(d,J＝1.6Hz,1H),5.50(s,1H),5.15(s,1H),4.79(dd,J＝11.8,4.1Hz,1H),4.76–4.65(m,2H),4.54(dd,J＝11.7,4.5Hz,1H),4.50–4.40(m,2H),4.36–4.25(m,4H),4.23–4.18(m,1H),3.98(s,1H),3.78–3.368(m,2H).
13 C NMR(100MHz,CDCl 3 )δ166.62,165.73,165.66,165.54,133.60,133.46,133.30,129.92,129.84,129.77,129.70,129.28,129.22,128.85,128.62,128.46,128.42,128.40,107.89,106.05,84.96,84.11,82.13,81.92,78.53,77.55,71.19,70.75,70.42,70.05,69.34,63.94,63.76.
HRMS(ESI):m/z calcd.For C 43 H 42 N 2 O 21 [M+Na] + 945.2172,found945.2174.
Preparation of Compound 11: 10 (2.9 g,3.1 mmol) was dissolved in methanol (100 mL) followed by NaOMe (0.76 g,14.1 mmol). After the addition, stirring at room temperature. After 4 hours of reaction, the pH of the reaction solution was adjusted to about 7 with an activated cation exchange resin. Suction filtration, vacuum concentration of filtrate, and passing of crude product through positive reactionChromatography on silica gel (DCM: meOH: H) 2 O=15:5:1 elution) and reverse direction silica gel column chromatography (H 2 O: meoh=5:1 elution) to give 11 (1.48 g, 93%) as a white solid after lyophilization.
1 H NMR(400MHz,D 2 O)δ5.21(s,1H),5.13(d,J＝1.6Hz,1H),4.86(dd,J＝12.4,4.0Hz,1H),4.77–4.65(m,3H),4.47–4.42(m,1H),4.23(dd,J＝1.9,1.1Hz,1H),4.18–4.10(m,3H),4.08(dd,J＝6.7,3.9Hz,1H),3.96–3.92(m,2H),3.86–3.82(m,1H),3.69(qd,J＝11.6,6.0Hz,4H).
13 C NMR(100MHz,D 2 O)δ107.30,106.99,83.04,83.01,82.71,81.25,79.35,76.53,71.65,70.96,70.44,70.36,62.84,62.81.
HRMS(ESI):m/z calcd.For C 15 H 26 N 2 O 17 [M+Na] + 529.1123,found529.1126.
Preparation of Compound 12: 8 (2.4 g,2.1 mmol) of a tetrahydrofuran-water mixed solution (24 mL, 1:1) was dissolved, followed by slowly dropping CF at 0 ℃ 3 COOH (12 mL). After the addition, the reaction was stirred at 40 ℃. The reaction was carried out overnight and saturated NaHCO was added 3 The pH of the solution was adjusted to about 7. Ethyl acetate (20 mL. Times.2) extraction, washing with water and saturated brine, anhydrous MgSO 4 And (5) drying. After concentration in vacuo, the crude product was purified by silica gel column chromatography (PE: ea=1.5:1 to 1:2.5 gradient elution) to afford 12 (1.6 g, 82%) as a white foam.
1 H NMR(400MHz,Chloroform-d)δ8.10–7.95(m,6H),7.90–7.84(m,2H),7.60–7.49(m,4H),7.45–7.24(m,8H),6.06–6.02(m,1H),5.67(dd,J＝5.2,1.1Hz,1H),5.51(s,1H),5.45(d,J＝1.3Hz,1H),5.28(d,J＝0.9Hz,1H),4.84(dd,J＝11.8,4.5Hz,1H),4.75–4.65(m,2H),4.59–4.54(m,2H),4.52–4.43(m,2H),4.33–4.26(m,1H),4.21(dd,J＝3.6,1.3Hz,1H),4.19–4.14(m,1H),4.06–4.03(m,1H),3.88–3.83(m,1H),3.77–3.71(m,2H),3.30(s,1H),2.66(s,1H),2.44(s,1H).
13 C NMR(100MHz,CDCl 3 )δ165.17,164.96,164.66,164.62,132.67,132.39,132.27,128.95,128.90,128.88,128.72,128.37,128.28,127.73,127.49,127.46,127.43,105.08,105.01,86.95,83.34,81.61,80.70,76.10,75.08,70.14,70.02,69.63,69.22,69.14,62.88,62.18.
HRMS(ESI):m/z calcd.For C 43 H 42 N 2 O 21 [M+Na] + 945.2172,found945.2171.
Preparation of Compound 13: 12 (1.4 g,1.5 mmol) was dissolved in methanol (50 mL) followed by NaOMe (0.37 g,6.8 mmol). After the addition, stirring at room temperature. After 4 hours of reaction, the pH of the reaction solution was adjusted to about 7 with an activated cation exchange resin. Suction filtration, concentration of the filtrate in vacuo, and chromatography of the crude product on a forward silica gel column (DCM: meOH: H) 2 O=15:5:1 elution) and reverse direction silica gel column chromatography (H 2 O: meoh=5:1 elution) to give 13 as a white solid (0.69 g, 90%) after lyophilization.
1 H NMR(400MHz,D 2 O)δ5.29(s,1H),5.17(d,J＝1.2Hz,1H),4.85(dd,J＝12.4,4.0Hz,1H),4.77(d,J＝3.9Hz,1H),4.72(dd,J＝12.8,5.9Hz,2H),4.46–4.41(m,1H),4.23(dd,J＝6.6,2.9Hz,1H),4.13–4.06(m,3H),4.03–3.97(m,2H),3.88–3.83(m,2H),3.77–3.60(m,4H).
13 C NMR(100MHz,D 2 O)δ107.14,105.81,87.26,83.31,82.65,81.22,76.65,75.33,71.71,71.07,70.67,70.56,70.22,62.79,62.74.
HRMS(ESI):m/z calcd.For C 15 H 26 N 2 O 17 [M+Na] + 529.1123,found529.1122.
The following experiments prove the beneficial effects of the invention.
Experimental example 1 in vitro frog heart Experimental results of the aconite glycoside analog of the invention
1. Experimental method
The heart strengthening effect of the compounds 6, 11, 14, 16 and 17 prepared in the embodiment 1 of the invention and the positive drug ciliate are verified and compared through an in vitro frog heart experiment.
2. Experimental results
As shown in Table 1
TABLE 1 results of in vitro frog heart experiments
It can be seen that both compounds 11, 13 have excellent cardiotonic activity.
Experimental example 2 Effect of the aconitin analog of the present invention on rat isolated cardiac Functions
1. Test method
1.1 grouping of animals
Healthy SD rats were randomly divided into 19 groups, each with 3 positive drug control groups, comprising: a desacetyl erigeron glycoside injection group (0.015 mg), a dopamine injection group (0.075 mg) and a nitroglycerin injection group (0.15 mg); the other compound 13 drug groups are respectively: 0.075mg, 0.15mg, 0.3mg, 0.6mg,1.25mg,2.5mg, 5mg, 10mg dose group, and compound 11 drug group, respectively: a dose group of 0.075mg, 0.15mg, 0.3mg, 0.6mg,1.25mg,2.5mg, 5mg, 10 mg.
1.2 pharmaceutical formulation
1.2.1 configuration of Compound 13 drug
1ml of a crude drug solution (5 mg/ml) of the compound 13 is taken, and K-H solution is added in a continuous double dilution mode to obtain 2.5mg/ml, 2.5mg/m, 1.25mg/ml, 0.625mg/ml, 0.3mg/ml, 0.15mg/ml and 0.075mg/ml of liquid medicine respectively. The liquid medicine with each concentration is administered according to the dosage of 0.3 ml/time.
1.2.2 preparation of Compound 11 drug
1ml of a stock solution (5 mg/ml) of the compound 11 is taken, and K-H solution is added in a continuous double dilution mode to obtain 2.5mg/ml, 2.5mg/m, 1.25mg/ml, 0.625mg/ml, 0.3mg/ml, 0.15mg/ml and 0.075mg/ml of liquid medicine respectively. The liquid medicine with each concentration is administered according to the dosage of 0.3 ml/time.
1.2.3 preparation of De-acetyl-Maohuaoside injection group
Taking 1ml of crude liquid (0.2 mg/ml) of the desacetyl erigeron breviscapus injection, adding 3ml of K-H liquid, and fully and uniformly mixing to obtain the 4-time dilution of the desacetyl erigeron breviscapus injection0.05mg/ml) 0.3ml of each dose.
1.2.4 preparation of dopamine injection
1 μl of dopamine hydrochloride injection stock solution (10 mg/ml) is taken, 9999 μl of K-H solution is added, and the mixture is fully mixed to obtain 1 μg/ml. Taking 1ml of dopamine hydrochloride injection (1 mug/ml), adding K3ml of H solution, and fully and uniformly mixing to obtain0.25μg/ml0.3ml of the composition is administered each time.
1.2.5 preparation of nitroglycerin injection
Taking 1ml of the original solution (5 mg/ml) of the nitroglycerin injection, adding 9ml of K-H solution, and fully and uniformly mixing to obtain 10-time dilution of the nitroglycerin0.5mg/ml) 0.3ml of each dose.
1.3 observations index:
the Heart Rate (HR), left Ventricular Systolic Pressure (LVSP), left Ventricular Diastolic Pressure (LVDP), left ventricular pressure difference (DeltaLVP), left Ventricular End Diastolic Pressure (LVEDP), left ventricular pressure change rate (+/-dp/dtmax), epicardial electrogram and other indexes are collected.
1.4Langendorff in vitro heart perfusion method
Selecting SD rats with weight of 250-400g, injecting 2.5% chloral hydrate 1-1.5ml+1% heparin 1ml (or other anesthetic) into abdominal cavity for general anesthesia, fixing, opening chest, exposing heart rapidly, lifting, crossing aorta at 0.5-1.5 cm distance from aortic root, immediately placing K-H liquid at about 4deg.C to stop heart, lightly pressing heart to squeeze blood in coronary artery several times, lifting heart, trimming superfluous tissue at bottom of heart, and cutting right atrium (facilitating perfusion liquid outflow). The broken end of the aorta is clamped by using ophthalmic forceps, and is hung on a Langendorff in-vitro heart perfusion device, the device is fixed, a water stop clamp is opened, and constant-pressure (8.33 kPa) constant-temperature (37 ℃) K-H liquid is reversely poured into coronary circulation through the aorta, so that the heart recovery rate is realized. After stabilization, cardiac function indicators were recorded (three replicates were recorded over 1 minute, and an average was taken). The individual isolated hearts were then started to be administered in groups, and the previous indices were recorded by observation.
1.4 statistical method
Test based on animal response to each dose, effective safe doses were determined, and each group was statistically processed to mean ± standard deviation from 6 effective animal data taken from the dose groupThe inter-group t-test was performed using SPSS13.0 statistical software, with a test level α=0.05.
2. Test results
2.1 Effect of Compound 13 drug on rat isolated cardiac function
The effect of compound 13 on rat isolated cardiac function results are shown in tables 1-1 and 1-2.
TABLE 1-1
/>
TABLE 1-2
The results show that the compound 13 has no obvious effect on the isolated heart perfusion heart rate of rats (P > 0.05) after the administration of each dose group, positive control group, i.e. the deacetylated eriocidin group, the dopamine group and the nitroglycerin group, compared with the heart rate before the administration of the isolated heart; there was also no significant difference in the effect of compound 13 dose groups on heart rate (P > 0.05) compared to the positive drug control groups.
The LVSP was very significantly elevated (P < 0.01) in all 8 dose groups of compound 13; the positive drug control group also obviously increases LVSP (P < 0.05) after the administration of dopamine hydrochloride and desacetyl erigeron, and the nitroglycerin obviously decreases LVSP (P > 0.05) after the administration; compound 13 increased LVSP more significantly (P < 0.05) than the positive control group dopamine, desacetyl-pilin.
The results show that the compound 13 has a well-defined effect of enhancing myocardial contractility and is more obvious than dopamine and desacetyl erigeron glycoside. The left ventricular systolic pressure was increased by 71.5% even at low concentrations (0.075 mg).
The results also show that the compound 13 has no obvious effect on LVEDP after administration (P > 0.05) in different concentration administration groups and positive drug control drug groups, namely, the deacetylated hairy glycoside, the dopamine and the nitroglycerin are respectively compared with the LVEDP before the respective isolated perfusion heart administration; compound 13 was also not significantly affected by LVEDP (P > 0.05) at different concentrations compared to the positive control groups. The left ventricular end-diastole pressure reflects mainly the diastolic function of the left ventricle. The above results demonstrate that compound 13, while enhancing LVSP, has no adverse effect on ventricular diastolic function as does a drug that enhances LVSP, such as dopamine, desacetyl-maohexadine, etc.
Further, compared with the pre-administration ratio, the compound 13, the positive drug control group, the deacetyl-Maohuaside and the dopamine obviously improve the maximum rising rate (+dp/dtmax) of the left indoor pressure of the isolated heart of the rat after the administration (P is less than 0.05-0.01); in particular compound 13 achieved a +dp/dtmax increase rate of 125% (P < 0.01) even at low concentrations (0.075 mg); whereas the +dp/dtmax after nitroglycerin administration of the other positive control drug was not significantly altered (P > 0.05); compared with the ratio of the desacetyl-pilin and the dopamine, the concentration of the compound 13 is similar to that of the dopamine, and the effect is more obvious than that of the desacetyl-pilin (P < 0.05).
Further, the compound 13, the positive drug control group, the deacetyl-Maohaloside and the dopamine all increase the maximum decrease rate (-dp/dtmax) of the left indoor pressure after the administration, namely the absolute value is obviously or obviously increased (P is less than 0.05-0.01); comparison between the different dose groups of compound 13, no significant difference in-dp/dtmax increases; similar in intensity to dopamine and desacetylbrin; the absolute value of-dp/dtmax was significantly decreased (P < 0.05) after administration of nitroglycerin. The maximum rate of decrease (-dp/dtmax) of left indoor pressure is one of the indicators reflecting left ventricular diastolic function. The faster the dp/dtmax decrease rate, the more pronounced the effect on improving cardiac function.
The above results indicate that each dose group of compound 13 showed a significant improvement in cardiac function.
2.2 Effect of Compound 11 drug on rat isolated cardiac function
The effect of compound 11 on rat isolated cardiac function results are shown in tables 2-1 and 2-2.
TABLE 2-1
TABLE 2-2
/>
The results show that compared with the heart rate before administration, the compound 11 has no obvious effect on the isolated heart perfusion heart rate of rats (P > 0.05) in each dose group, positive control group, and after administration of the compound 11, the positive control group, and the dopamine group; the ratio between the dose groups of compound 11, the dose groups did not significantly differ in the heart rate effect (P > 0.05); there was also no significant difference in the effect of compound 11 dose groups on heart rate (P > 0.05) compared to the positive drug control groups.
The compound 11 has the advantages that the LVSP (P < 0.05-0.01) is obviously or obviously increased in the 8-dose group, the positive drug control group dopamine and the desacetyl erigeron glycoside, and especially, the compound 11 can increase the left ventricular systolic pressure by more than 1 time even at a low concentration (0.075 mg); the ratio of each dose group of compound 11, the effect of increasing LVSP of each dose group is not significantly different, i.e. as the concentration of compound 11 increases, LVSP does not have a tendency to increase with the increase of the concentration of drug; compared with the positive drug control group dopamine and deacetyl-hairy glycoside, the compound 11 has more obvious LVSP increasing effect; whereas nitroglycerin significantly reduced LVSP (P > 0.05) after administration.
Further, compared with the pre-administration ratio, the compound 11 has no obvious effect (P > 0.05) on LVEDP after the administration of each dose group, the positive drug control group, the desacetylbrin group, the dopamine group and the nitroglycerin group; the ratio between the dose groups of compound 11, no significant difference in the effect of each dose group on LVEDP (P > 0.05); the ratio of the administration group with different concentrations to the dopamine group, the desacetyl erigeron glycoside group and the nitric acid Gan Youzu of each positive medicine control group has no obvious difference (P is more than 0.05) on the LVEDP.
Further, compared with the pre-administration ratio, the compound 11, the positive drug control group, the deacetyl-Maohuaside and the dopamine obviously improve the maximum rising rate (+dp/dtmax) of the left indoor pressure of the isolated heart of the rat after the administration (P is less than 0.05-0.01); in particular compound 11 increased the +dp/dtmax ramp rate to 157% (P < 0.01) even at low concentrations (0.075 mg); the ratio between the dose groups of compound 11, no significant difference in effect on +dp/dtmax for each dose (P > 0.05); compared with the ratio of the desacetyl-pilin and the dopamine, the concentration of the compound 11 is similar to that of the dopamine, and the effect is more obvious than that of the desacetyl-pilin (P is less than 0.05); whereas the +dp/dtmax after nitroglycerin administration of the other positive control drug was not significantly altered (P > 0.05);
further, the compound 11, the positive drug control group, and the desacetyl-maohexaside and the dopamine all increase the maximum decrease rate (-dp/dtmax) of the left indoor pressure after the administration, namely the absolute value increase is obvious or obvious (P < 0.05-0.01); compared with the different dose groups of the compound 11, the-dp/dtmax rate intensity has no obvious difference, namely the effect of the compound 11 on the-dp/dtmax is not obviously increased along with the increase of the concentration of the drug; the effect of each dose of compound 11 on-dp/dtmax was similar to that of the positive control drug dopamine, deacetyl-hairy glycoside; the absolute value of-dp/dtmax was significantly decreased (P < 0.05) after administration of nitroglycerin.
Taken together, the results show that both compound 13 and compound 11 have very significant effects in increasing LVSP, +dp/dtmax. Compound 11 showed more pronounced LVSP enhancement and also showed more pronounced +dp/dtmax elevation than compound 13. Both compound 13 and compound 11 had no significant effect on rat isolated cardiac left ventricular end-diastolic pressure (LVEDP), but both significantly accelerated the-dp/dtmax decline rate. Taken together, both compound 13 and compound 11 significantly improved rat isolated cardiac function without significantly affecting heart rate, with compound 11 acting more significantly.
Therefore, the compound 13 and the compound 11 have similar or obvious effects with the positive control medicine deacetyl-hirsutin and dopamine which can also promote the heart function.
Experimental example 3 effective concentration of the aconitin analog of the present invention on the influence of rat isolated cardiac Functions
From the results of Experimental example 2, it was found that compound 13 and compound 11 have a strong cardiotonic effect of only 0.075mg/ml (1/8-fold), and therefore, further pharmacodynamic tests were conducted to greatly reduce the drug concentration.
Preliminary test results after the compound 11 compound is greatly diluted show that the diluted concentration of the compound 11 compound reaches 0.024 mug/mlFold) still has weaker effect, but has no obvious difference with KH buffer ratio; the concentration reaches 0.0048 mug/ml (& lt/EN)>Fold) the difference between the indices of heart function is less pronounced than KH buffer. The results are shown in Table 3-1 and Table 3-2.
Preliminary test results of the compound 13 with a large dilution concentration show that the dilution concentration of the compound 13 reaches 0.015 mug/mlFold), but there is no obvious difference from KH buffer results; the dilution concentration reaches 0.0075 mug/ml ()>Double) the effect is basically lost, and the indexes of heart function are basically not different from KH buffer solution. The results are shown in Table 3-1 and Table 3-2.
TABLE 3-1
TABLE 3-2
The above results demonstrate that ineffective concentrations of compound 11 on isolated rat hearts may be at 0.0048. Mu.g/mlMultiple) to 0.024. Mu.g/ml (& lt/EN)>Multiple) interval, the minimum effective concentration is 0.024 mug/ml%Multiple) of the total area. The ineffective concentration of compound 13 on heart action of isolated rats may be 0.0075 mug/mlMultiple) to 0.015. Mu.g/ml (/ -for)>Multiple) of the interval; and the minimum effective concentration is also 0.015. Mu.g/ml ()>Multiple) of the total area. Namely, the compound of the present invention can also exhibit a cardiotonic effect at a relatively low concentration.
In conclusion, the invention provides a novel aconitin analogue with heart strengthening effect, and provides a novel choice for clinical medicines with heart strengthening and heart failure resisting effects; meanwhile, the invention also provides a synthesis method of the aconite glycoside analogue, and the total synthesis way of the aconite glycoside analogue is enriched.
Claims (10)
1. A aconite glycoside analogue, characterized in that it has the structure shown in formula I:
wherein R is NH 2 OR OR ', R' is nitro, phosphate OR sulfateA group, a sulfite group or a borate group;
R 1 、R 2 independently selected from H orAnd R is 1 、R 2 And not H at the same time.
2. The aconite glycoside analog of claim 1, wherein R' is nitro.
3. The aconitin analog according to claim 1 or 2, which has the structure shown in formula II:
preferably any one of the following structures:
4. a process for the preparation of a aconite glycoside analogue as claimed in any one of claims 1 to 3, comprising the steps of:
(1) The compound A and the silyl ether protective agent react in an organic solvent under the action of alkali to prepare an intermediate, and the intermediate is further reacted with the compound B under the action of an accelerator and a catalyst after water removal to obtain a silyl ether protective group-protected compound C;
(2) The compound C reacts in an organic solvent under the action of a deprotection agent a to obtain a compound D;
(3) Reacting the compound D in an organic solvent under the action of a deprotection agent b to obtain a aconitine analogue shown in a formula I; the reaction formula is as follows:
wherein R is a 、R b Independently selected from silyl ether protecting groups orAnd R is a 、R b Not both a silyl ether protecting group;
R a ’、R b ' each independently selected from H orAnd R is a ’、R b ' not both H;
bz is benzoyl and STol is p-toluenesulfonyl.
5. The preparation method according to claim 4, wherein the molar ratio of the compound A to the silyl ether protector to the alkali in the step (1) is 1 (1-1.5): (1.5-2.5), preferably 1:1.2:2;
the mol ratio of the intermediate to the compound B, the promoter and the catalyst is 1 (1-2): (2-4): (0.1-0.5), preferably 1:1.5:3:0.2;
the silyl ether protectant is: TIPSOTf, TBSOTf, TESOTf or TBDPSOTf, preferably TIPSOTf; the silyl ether protecting group is TIPS, TBS, TES or TBDPS, preferably TIPS;
and/or the base is triethylamine, pyridine, p-dimethylaminopyridine, lutidine, imidazole, DBU or tetramethylpiperidine, preferably triethylamine;
and/or the organic solvent is dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, toluene or diethyl ether, preferably dichloromethane;
and/or the accelerator is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or iodine bromide, preferably N-iodosuccinimide;
and/or the catalyst is silver trifluoromethane sulfonate, trimethylsilicon trifluoromethane sulfonate or trifluoromethane sulfonic acid, preferably silver trifluoromethane sulfonate;
and/or the water removal is water removal by adding a 4A molecular sieve;
the reaction conditions of the compound A and the silyl ether protectant are as follows: adding alkali at 0-5 ℃ for 5-15 min, then dripping a silyl ether protective agent for reacting for 20-40 min, and then heating to 20-30 ℃ for reacting for 8-14 h;
the reaction conditions of the intermediate and the compound B are as follows: the intermediate reacts with the compound B in an organic solvent for 10min at minus 30 to minus 50 ℃, then the accelerant is added for 20 to 40min, the catalyst is added, and the temperature is raised to 0 to 5 ℃ for 8 to 14h.
6. The process of claim 4, wherein the molar ratio of compound C to deprotecting agent a in step (2) is: 1 (0.05-0.1), preferably 1 (0.7-0.8);
the organic solvent is a mixed solvent of tetrahydrofuran and water, tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water; preferably, the organic solvent is a mixed solvent of tetrahydrofuran and water in a volume ratio of 1:1;
and/or the deprotecting agent a is trifluoroacetic acid, hydrochloric acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid, preferably trifluoroacetic acid;
the reaction conditions are as follows: after trifluoroacetic acid is added at 0-5 ℃, the mixture reacts for 8-14 h at 30-50 ℃.
7. The process according to claim 4, wherein the molar ratio of compound D to deprotecting agent b in step (3) is: 1 (4-8), preferably 1 (4-5);
the organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran, preferably methanol;
and/or the deprotecting agent a is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium methoxide;
the reaction conditions are as follows: reacting for 3-5 h at 20-30 ℃.
8. The preparation method according to any one of claims 4 to 7, wherein R is OR', and the compound a is prepared according to the following method steps:
(1') reacting the compound B with the compound 2 in an organic solvent under the action of an accelerator, a catalyst and a water remover to obtain a compound 3;
(2') reacting the compound 3 in an organic solvent under the action of acid to obtain a compound 4;
(3 ') reacting compound 4 with compound R' -OH in an acid anhydride to obtain compound 5;
(4') reacting compound 5 with a deprotecting agent in an organic solvent to give compound 6;
(5') reacting the compound 6 with the compound 1 in an organic solvent under the action of a catalyst to obtain a compound A;
the reaction formula is as follows:
wherein STol is p-toluenesulfonyl, bz is benzoyl, ph is phenyl, and R' is nitro, phosphate, sulfate, sulfite or borate.
9. The method according to claim 8, wherein the molar ratio of the compound B to the compound 2, the promoter and the catalyst in the step (1') is: 1 (1-2): (0.05-0.15), preferably 1:1.5:1.5:0.1; the mass ratio of the compound B to the water scavenger is 1 (0.5-3), preferably 1:1;
the organic solvent is dichloromethane, 1, 2-dichloroethane, chloroform, tetrahydrofuran, toluene or diethyl ether, preferably dichloromethane;
and/or the accelerator is N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or iodine bromide, preferably N-iodosuccinimide;
and/or the catalyst is silver trifluoromethane sulfonate, trimethylsilicon trifluoromethane sulfonate or trifluoromethane sulfonic acid, preferably silver trifluoromethane sulfonate;
and/or the water scavenger is a 4A molecular sieve;
the reaction conditions are that the compound B and the compound 2 react in an organic solvent for 10min at the temperature of 0-5 ℃, then the accelerant is added for 20-40 min, the catalyst is added, and the temperature is raised to 20-30 ℃ for 2-4 h;
the molar ratio of the compound 3 to the acid in the step (2') is 1 (0.01-0.05), preferably 1 (0.03-0.04);
the acid is hydrochloric acid, trifluoroacetic acid, sulfuric acid, trifluoromethanesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid or camphorsulfonic acid, preferably hydrochloric acid;
the organic solvent is tetrahydrofuran, methanol, ethanol, acetone, a mixed solvent of tetrahydrofuran and water, a mixed solvent of methanol and water, a mixed solvent of ethanol and water, or a mixed solvent of acetone and water, preferably tetrahydrofuran;
the reaction condition is that after the compound 3 is added with acid at 0-5 ℃, the temperature is raised to 20-30 ℃ for reaction for 2-4 h;
the mass-volume ratio of the compound 4 to the compound R '-OH in the step (3') is as follows: (1-5) g, 1mL;
the anhydride is acetic anhydride, and the R' -OH is nitric acid, phosphoric acid, sulfuric acid, sulfurous acid or boric acid, preferably nitric acid;
the reaction condition is that after the compound 4 and R' -OH react for 15-35 min at 0-5 ℃, the temperature is raised to 20-30 ℃ for 2-4 h;
the molar ratio of the compound 5 to the deprotection agent in the step (4') is as follows: 1 (4-5), preferably 1:4.5;
the organic solvent is methanol, ethanol, isopropanol, tert-butanol or tetrahydrofuran, preferably methanol;
and/or the deprotecting agent is sodium methoxide, potassium tert-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide or potassium carbonate, preferably sodium methoxide;
the reaction condition is that the reaction is carried out for 1 to 3 hours at the temperature of 20 to 30 ℃;
the molar ratio of the compound 6, the compound 1 and the catalyst in the step (5') is 1 (2-3): (0.05-0.15), preferably 1:2.5:0.1;
the catalyst is D-camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and p-toluenesulfonic acid, and preferably D-camphorsulfonic acid;
the organic solvent is acetone, dichloromethane, chloroform or tetrahydrofuran, preferably acetone;
the reaction condition is that the reaction is carried out for 3 to 5 hours at the temperature of 20 to 30 ℃.
10. Use of a compound according to any one of claims 1 to 3 in a cardiotonic and/or anti-heart-failure medicament; preferably, the drug is a drug that enhances myocardial contractility.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2022102123674 | 2022-03-04 | ||
| CN202210212367 | 2022-03-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116693583A true CN116693583A (en) | 2023-09-05 |
Family
ID=87843964
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310106645.2A Pending CN116693583A (en) | 2022-03-04 | 2023-02-13 | Aconitin analogue, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116693583A (en) |
-
2023
- 2023-02-13 CN CN202310106645.2A patent/CN116693583A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101014607B (en) | Polysulfated glycosides and salts thereof | |
| US6117844A (en) | Method and composition for antiviral therapy | |
| TW201623208A (en) | Compounds from antrodia camphorata, method for preparing the same and use thereof | |
| CN107963987B (en) | A stachydrine derivative, its preparation method and application in preparing medicine for treating cardiovascular disease and cerebrovascular disease | |
| CN114573600A (en) | Preparation method and application of four diterpenoid components with function of activating latent HIV | |
| CN115894418B (en) | Mongolian artelactone A-F and pharmaceutical composition thereof, and preparation method and application thereof | |
| CN116693583A (en) | Aconitin analogue, preparation method and application thereof | |
| US7727965B2 (en) | C-glycosylisoflavones having alkylaminoalkoxyl substituent, preparation and use of the same | |
| CN107383150B (en) | A kind of compound and its preparation method and application with antihepatitis activity | |
| WO2005116042A1 (en) | Treatment and prevention of cancer with new ginsenoside derivatives | |
| EP3398596A1 (en) | Ingenol compounds and use thereof in anti-hiv latency treatment | |
| AU777920B2 (en) | Beta-D-5-thioxylose derivatives, preparation method and therapeutic use | |
| KR100564383B1 (en) | Process for preparing ginsenoside derivatives | |
| CN102584846B (en) | Curcumenol derivatives resisting influenza A(H1N1) virus | |
| EP2628485A1 (en) | New use of chemical ingredients in cynomorium as phytoestrogen | |
| CN112409443B (en) | Proteborl derivative, preparation method thereof and application thereof in preparation of medicines for treating cardiovascular and cerebrovascular diseases | |
| CN104876942B (en) | isosorbide mononitrate hemihydrate | |
| JPS62265223A (en) | Avermectin as growth promotor | |
| KR100516647B1 (en) | Hypoglycemic composition | |
| CN107857754B (en) | A kind of compound and its application in preparing preventing/treating medicine for treating rheumatoid arthritis | |
| WO2001049293A1 (en) | A lower toxicity and anti-inflammatory and anti-exudation pharmaceutical composition | |
| JP2006513178A (en) | Novel α-glucosidase inhibitors and their synthesis from natural sources | |
| CN110407789B (en) | Medicine for preventing and treating osteoporosis and preparation method thereof | |
| CN106188179B (en) | Sharp leaf vacation Radix Gentianae extract, compound and pharmaceutical composition with anti-diarrhea effect | |
| WO2023160302A1 (en) | C19 diterpene alkaloid, preparation method therefor and application thereof |
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 |