CN105440047B - Mouth mountain ketone compound and preparation method thereof, pharmaceutical composition and purposes - Google Patents
Mouth mountain ketone compound and preparation method thereof, pharmaceutical composition and purposes Download PDFInfo
- Publication number
- CN105440047B CN105440047B CN201410280756.6A CN201410280756A CN105440047B CN 105440047 B CN105440047 B CN 105440047B CN 201410280756 A CN201410280756 A CN 201410280756A CN 105440047 B CN105440047 B CN 105440047B
- Authority
- CN
- China
- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- tumour
- cancer
- 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.)
- Expired - Fee Related
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 11
- -1 ketone compound Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 23
- 239000003814 drug Substances 0.000 claims abstract description 16
- 230000036541 health Effects 0.000 claims abstract description 12
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims abstract description 10
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims abstract description 10
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 8
- 201000005202 lung cancer Diseases 0.000 claims abstract description 8
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 8
- 208000019065 cervical carcinoma Diseases 0.000 claims abstract description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 229940126062 Compound A Drugs 0.000 claims description 22
- 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 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 239000000284 extract Substances 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 230000002829 reductive effect Effects 0.000 claims description 6
- 238000010898 silica gel chromatography Methods 0.000 claims description 6
- 238000004809 thin layer chromatography Methods 0.000 claims description 6
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 5
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 5
- 201000010881 cervical cancer Diseases 0.000 claims description 5
- 238000010828 elution Methods 0.000 claims description 5
- 238000000926 separation method Methods 0.000 claims description 5
- 239000002027 dichloromethane extract Substances 0.000 claims description 4
- 239000012141 concentrate Substances 0.000 claims description 3
- 241001597008 Nomeidae Species 0.000 claims description 2
- 239000000651 prodrug Substances 0.000 abstract description 15
- 229940002612 prodrug Drugs 0.000 abstract description 15
- 229940079593 drug Drugs 0.000 abstract description 10
- 230000002265 prevention Effects 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 8
- 210000004881 tumor cell Anatomy 0.000 description 8
- 239000007788 liquid Substances 0.000 description 6
- 239000000825 pharmaceutical preparation Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 230000022131 cell cycle Effects 0.000 description 4
- 239000000470 constituent Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 229940041181 antineoplastic drug Drugs 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- PFUUALWTCREXES-UHFFFAOYSA-N Cowaxanthone Natural products COc1cc2C(=O)c3c(O)c(C=C(/C)CCCC=C(C)C)c(O)cc3Oc2cc1O PFUUALWTCREXES-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 241001051053 Garcinia cowa Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 108010019160 Pancreatin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- VEGUCVDYIMCIAZ-RIYZIHGNSA-N cowaxanthone Chemical compound O1C2=CC(O)=C(C\C=C(/C)CCC=C(C)C)C(O)=C2C(=O)C2=C1C=C(O)C(OC)=C2 VEGUCVDYIMCIAZ-RIYZIHGNSA-N 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 2
- 229960005420 etoposide Drugs 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 229940055695 pancreatin Drugs 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)=CCc(c(Oc(c1c(c(C*=C(C)C)c2C)O)c2O)c(cc2)C1=O)c2O Chemical compound CC(C)=CCc(c(Oc(c1c(c(C*=C(C)C)c2C)O)c2O)c(cc2)C1=O)c2O 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 230000004668 G2/M phase Effects 0.000 description 1
- 241000593508 Garcinia Species 0.000 description 1
- 241000598860 Garcinia hanburyi Species 0.000 description 1
- 235000000885 Garcinia xanthochymus Nutrition 0.000 description 1
- 241000832224 Hypericaceae Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 244000283207 Indigofera tinctoria Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001529246 Platymiscium Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000006382 Ribonucleases Human genes 0.000 description 1
- 108010083644 Ribonucleases Proteins 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 229930003427 Vitamin E Natural products 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000012470 diluted sample Substances 0.000 description 1
- 208000022602 disease susceptibility Diseases 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012894 fetal calf serum Substances 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 229940117709 gamboge Drugs 0.000 description 1
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 238000004019 gradient elution chromatography Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to mouth mountain ketone compound and preparation method thereof, pharmaceutical composition and purposes, it is related to native compound field, the noval chemical compound for having the following structure formula or its pharmaceutically acceptable salt obtained, hydrate or prodrug and preparation method thereof, pharmaceutical composition and purposes can be extracted more particularly to two kinds from Yun Shuzhong：
Description
Technical field
The present invention relates to native compound fields, more particularly to a kind of mouthful of xanthones compounds and preparation method thereof, medicine
Compositions and purposes.
Background technology
Malignant tumour is current threat human health and the principal disease of life.In most of developed countries, tumour is only
Inferior to the second largest cause of death of cardiovascular disease.Tumour is also to seriously endanger the major disease of the health of our people, and China swells
Tumor research is also paid attention to by government, and control tumour has become one of China's health strategy emphasis.
The therapy of tumour includes surgical operation and chemicotherapy.The outstanding problem of the antitumor drug of Present clinical application
It is efficient low, poor selectivity (toxicity is big) and to the insensitive of resistant tumors.In addition, recurrence and transfer are also oncotherapy
Difficult point.Therefore, research selectivity is good, curative effect is high, target spot is clear and the antitumor drug without side-effects to non-target organ is
The great research topic of pharmacy worker.
Yun Shu (Garcinia cowa Roxb.) is the plant of Hypericaceae Garcinia.It is distributed in Andaman, Central-South
The peninsula, Bangladesh, India, Malay Archipelago and China's Mainland the ground such as Yunnan.
Invention content
The purpose of the present invention, which is intended to provide two kinds, to extract the antitumoral compounds and preparation method thereof obtained from Yun Shuzhong
And purposes.
Specifically, there is provided a kind of compound A or its pharmaceutically acceptable salt, water for the first aspect of the present invention
Object or prodrug are closed, the compound A can be extracted from Yun Shuzhong and be obtained and have following structural (I)：
The second aspect of the present invention is a kind of compound B or its pharmaceutically acceptable salt, hydrate or prodrug, described
Compound B can be extracted from Yun Shuzhong and be obtained and have following structural (II)：
For the third aspect of the present invention there is provided a kind of preparation method of above compound, the method includes walking as follows
Suddenly：
A) cloud tree is extracted first with acetone soak, acetone extract is then concentrated under reduced pressure to no acetone taste, then use dichloro
Methane extracts concentrate, and dichloromethane extract liquor is concentrated under reduced pressure and obtains medicinal extract；
B) silica gel column chromatography separation is carried out to gained medicinal extract：1 is pressed with dichloromethane and methanol:0~0:1 volume ratio is formed
Mixed solution carry out gradient elution, thin-layer chromatography detection, collect the fraction containing target compound；
C) reversed-phase silica gel column chromatography separation is carried out to collected fraction：65 are pressed with methanol and water:35~90:10 volume
Mixed solution than formation carries out gradient elution, and thin-layer chromatography detection is collected the fraction containing target compound, concentrated, dry.
There is provided a kind of pharmaceutical composition of anti-curing oncoma, the composition includes treatment to be had the fourth aspect of the present invention
The above compound of effect amount or its pharmaceutically acceptable salt, hydrate or prodrug.
In a preferred example, the tumour is one or more in cervical carcinoma, cancer of pancreas and lung cancer.
For the fifth aspect of the present invention there is provided a kind of health products of anti-curing oncoma, the health products include on a effective amount of
State compound or its pharmaceutically acceptable salt, hydrate or prodrug：
In a preferred example, the tumour is one or more in cervical carcinoma, cancer of pancreas and lung cancer.
There is provided above compound or its pharmaceutically acceptable salt, hydrate or prodrugs for the sixth aspect of the present invention
Application in preparing tumor cell Cycle Arrest derivant.
In a preferred example, the tumour cell be selected from Hela cervical cancer cells, PANC-1 human pancreas cancer cell strains and
It is one or more in A549 Non-small cell lung carcinoma cells.
The present invention also provides above compound or its pharmaceutically acceptable salt, hydrate or prodrugs to prepare prevention
Treatment tumour drug or the application in health products.
In a preferred example, the tumour is one or more in cervical carcinoma, cancer of pancreas and lung cancer.
The details of various aspects of the present invention will be able to detailed description in subsequent chapters and sections.By hereafter and claim
Description, the features of the present invention, purpose and advantage will become apparent from.
Specific implementation mode
The appearance of the present invention is had been surprisingly found that based on such a：The two kinds of new mouth mountain ketone chemical combination extracted from Yun Shuzhong
Object A and B can significantly inhibit the growth of kinds of tumor cells and the cell cycle of inducible tumour cell blocks.Therefore,
Compound A and B are expected to be developed into a kind of drug or health products prevented or treat tumour.
In turn, present invention firstly provides a kind of compound A with following structural (I) and with following structural
(II) compound B：
The present invention also provides the corresponding all pharmaceutically acceptable salt of above compound, hydrate or prodrugs.This
A little salt can by part (for example, amido) positively charged in compound with it is negatively charged (for example, trifluoro with opposite-sign
Acetic acid) it is formed；Or by part (for example, carboxyl) negatively charged in compound and positive charge (for example, sodium, potassium, calcium, magnesium) shape
At.Compound can contain there are one nonaromatic double bond, have one or more asymmetric centers.So these compounds
Racemic mixture, individual enantiomter, individual diastereoisomer, diastereoisomer mixing can be used as
Object, cis or trans isomers exist.All these isomers are all expected.It is described " before the compound of the present invention
Medicine " is often referred to a kind of substance, after being applied with method appropriate, can be metabolized or chemically react in subject's body and change
At the compound or its salt of the present invention.
The above compound of the present invention can be by conventional method such as alcohol extracting, chromatography of this field etc. from gamboge platymiscium such as cloud
It sets to extract in (Garcinia cowa Roxb.) etc. and obtain, also can buy or utilize marketable material by commercial sources, pass through
Traditional compound synthesis method synthesis in the prior art obtains.Those skilled in the art can according to existing known technology
With the above compound of the synthesis present invention.Synthesis the present invention above compound can further by column chromatography, efficiently
The modes such as liquid chromatography or crystallization are further purified.
Synthesize chemical improvement, protection functional group methodology (protection or deprotection) is helpful to synthesizing application to close object
, and it is well known in the prior art technology, such as R.Larock, Comprehensive Organic
Transformations,VCH Publishers(1989)；T.W.Greene and P.G.M.Wuts,Protective
Groups in Organic Synthesis,3rdEd.,John Wiley and Sons(1999)；L.Fieser and
M.Fieser,Fieser and Fieser’s Reagents for Organic Synthesis,John Wiley and
Sons(1994)；and L.Paquette,ed.,Encyclopedia of Reagents for Organic Synthesis,
There is disclosure in John Wiley and Sons (1995).
Above compound or its pharmaceutically acceptable salt, the hydrate or prodrug of the present invention can effectively inhibit more
The growth of kind tumour cell, so the above compound or its pharmaceutically acceptable salt of the present invention, hydrate or prodrug can be used
In the drug and health products that prepare anti-curing oncoma.
The present invention also provides a kind of pharmaceutical composition, which includes the compound of the present invention A or compound
B or its pharmaceutically acceptable salt, hydrate or prodrug, with pharmaceutically acceptable carrier, which can be used for preventing
Curing oncoma.
The present invention also provides a kind of pharmaceutical preparation, which includes the compound of the present invention A or compound B, or
Its pharmaceutically acceptable salt, hydrate or prodrug, the pharmaceutical preparation can be used for treating tumour.
The compound of the present invention A or compound B or its pharmaceutically acceptable salt, hydrate or prodrug in composition or
Content such as 0.0001-50wt% in pharmaceutical preparation；Preferable 0.001-30wt%；More preferably 0.01-20wt%.
Therapeutically effective amount (can generate people and/or animal function or active and can be received by people and/or animal
Amount) the compound of the present invention A or compound B and pharmaceutically acceptable carrier (be used for the carrier of therapeutic administratp, they this
Body is not necessary active constituent, and does not have excessive toxicity after applying) pharmaceutical preparation can be formed, these pharmaceutical preparations can
To be prepared into oral preparation, injection, tablet, powder preparation, capsule, dispersible tablet, sustained release preparation etc..
The dosage of the pharmaceutical composition of the present invention of therapeutically effective amount is appointed between 0.001-500mg/kg body weight/days
What dosage within above range is all the effective quantity of the pharmaceutical composition of the present invention.Preferably, medicine group of the invention
The dosage of object is closed between 0.005-300mg/kg body weight/days；It is furthermore preferred that the present invention pharmaceutical composition dosage between
Between 0.0l-100mg/kg body weight/days." therapeutically effective amount " can be used for the single drug or drug combination of relevant disease
Treatment.One of skill in the art is it is understood that the dosage when being actually administered can be higher or lower than above-mentioned dosage range.For
" therapeutically effective amount " of certain an object (such as mammal-people) and specific therapeutic scheme can be influenced by factors, including institute
With the compound of the present invention A or the drug activity of compound B or its prodrug, the age of administration object, weight, ordinary circumstance, property
Not, diet, administration time, disease susceptibility, disease process and the judgement etc. for accepting doctor for medical treatment." treatment " refer to
Body (symptom containing tumour, with tumour or the omen with tumour) the compound of the present invention A or compound B is given, with
It treats, mitigate, slowing down, changing, curing, influencing, improving its tumour, the omen of the symptom of tumour or tumour.
The compound of the present invention A or compound B or its pharmaceutically acceptable salt, hydrate or prodrug or combinations thereof object
Or its pharmaceutical preparation can be by the way that approach are administered in oral, intravenous, intramuscular, subcutaneous, nasal cavity, in rectum etc..Solid carrier
Such as：Starch, lactose, phosphoric acid glycol, microcrystalline cellulose, brown sugar and white bole, and liquid carrier is such as：It is sterile water, polyethylene glycol, non-
Ionic surfactant and edible oil (such as corn oil, peanut oil and sesame oil), as long as being suitble to characteristic and the institute of active constituent
The specific administration mode needed.It also can be advantageously by including e.g., seasoning preparing adjuvant usually used in pharmaceutical composition
Agent, pigment, preservative and antioxidant such as vitamin E, vitamin C, BHT and BHA.
These reactive compounds also can parenteral or intraperitoneal administration.Also surfactant (such as hydroxyl can properly mixed
Propyl cellulose) water in prepare solution or the suspension of these reactive compounds (as free alkali or pharmaceutically acceptable salt)
Liquid.Dispersion liquid can also be prepared in glycerine, polyethylene glycol and its mixture in the oil.Under conventional storage and use condition,
Containing preservative to prevent the growth of microorganism in these preparations.
Medicament forms suitable for injection include：Aseptic aqueous solution or dispersion liquid and aseptic powder (are used for extemporaneous preparation of sterile
Injection or dispersion liquid).In all situations, these forms must be sterile and must be that fluid is discharged with being easy to syringe
Fluid.It must be stable under conditions of manufacture and storage, and must be able to prevent pollution and the shadow of microorganism such as bacterium and fungi
It rings.Carrier can be solvent or decentralized medium, wherein containing as water, alcohol, they properly mix object and vegetable oil.
The details of various aspects of the present invention will be able to detailed description in subsequent chapters and sections.By hereafter and claim
Description, the features of the present invention, purpose and advantage will become apparent from.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise all percentage, ratio, ratio or number is pressed
Weight meter.
Unless otherwise defined, all professional and scientific terms used in text and meaning known to one skilled in the art
Justice is identical.In addition, any method and material similar or impartial to described content can be applied to the method for the present invention.Wen Zhong
The preferred implement methods and materials are for illustrative purposes only.
The feature that the features described above or embodiment that the present invention mentions are mentioned can be in any combination.Patent specification is taken off
All features shown can be used in combination with any composition form, and each feature disclosed in specification any can provide phase
The alternative characteristics substitution of same, impartial or similar purpose.Therefore it is only impartial or similar except having special instruction, revealed feature
The general example of feature.
Embodiment one prepares and identifies noval chemical compound A and B sterling
A) cloud tree is extracted with acetone soak, it is cloud tree cloud tree medicinal material matter to be extracted to impregnate the acetone volume used every time
5 times of amount impregnate a week every time, altogether soak extraction 3 times；Merge acetone soak extracting solution, is concentrated under reduced pressure into no acetone taste；It adopts
Concentrate is extracted with dichloromethane 4 times, and dichloromethane extract liquor is concentrated under reduced pressure and obtains medicinal extract；
B) gained medicinal extract is detached using silica gel column chromatography：1 is pressed with dichloromethane and methanol:0-0:1 volume ratio is formed
Mixed solution carry out gradient elution, thin-layer chromatography detection, collect the fraction containing noval chemical compound A or B；
C) inverted silica gel column chromatography separation is carried out to collected fraction：15 are pressed with methanol and water:35-90:10 body
Product carries out gradient elution than the mixed solution of formation, and the fraction containing noval chemical compound A or B is collected in thin-layer chromatography detection；
D) HPLC purifying noval chemical compounds A or B are used：Using waters2535Series, chromatographic column Xbridge Prep
C18OBD column (19 × 250mm, 5 μm), eluent are with acetonitrile and water by 25:The mixed solution that 75 volume ratio is formed,
And also contain 0.1wt% trifluoroacetic acids (TFA), flow velocity 16ml/min in mixed solution.It is 12.1 minutes to collect retention time
Compound A and retention time be 15.6 minutes compound B.
The Structural Identification data of compound A：
Cowaxanthone I(1)
HRESI-MS：393.1326；
UV(MeOH)：334 (3.15) λ max (log ε), 58 (4.45) nm；
IR(KBr)：ν max3440,2973,2919,1647,1633,1587,1442,1288,1188,1122cm–1；
H1-NMR(600MHz in CD3OD) and13C-NMR(150MHz in CD3OD) data are shown in Table 1.
The Structural Identification data of compound B：
Cowaxanthone J(2)
HRESI-MS：395.1486
UV(MeOH)：327 (3.20) λ max (log ε), 253 (4.61) nm；
IR(KBr)：ν max3419,2919,1649,1608,1585,1284,1207,1159cm–1；
H1-NMR(600MHz in CD3) and C OD13-NMR(150MHz in DMSO-d6) data are shown in Table 1.
Table 1 compound A's and compound B1H-NMR、13C-NMR data
Embodiment two, the external activity that noval chemical compound A and B are verified using mtt assay
Growth inhibition effects of the detection noval chemical compound A or B to kinds of tumor cells on a cellular level.
Experiment material：
Human tumor cell line and its culture：Hela cervical cancer cells, PANC-1 human pancreas cancer cell strains, A549 people are non-small thin
Born of the same parents' lung cancer cell line and HL-7702 human liver cell strains etc. are purchased from OEG cell research institute of the Chinese Academy of Sciences.Cell is in containing 10% tire ox
In RPMI-1640 (Gibco) culture medium of serum (Gibco), in 37 DEG C, 5%CO2Under the conditions of cultivate.
Noval chemical compound A and B are prepared and are purified as described in Example 1；Other reagents：MTT and DMSO etc. is Sigma public affairs
Take charge of product.
Experimental method：
Noval chemical compound A and B measures the cytotoxicity of above-mentioned various tumor cell strains by mtt assay.It is as follows：
1. sample preparation：Noval chemical compound A or B are dissolved respectively in moon DMSO, the solution of a concentration of 1mg/ml is obtained；
2. cell is suspended in after pancreatin digests and washs in the RPMI-1640 culture mediums containing 10% fetal calf serum, through tire
Disk indigo plant dyes exclusive method meter or cell number, and adjusts cell suspending liquid density to 1 × 105Cell/ml.
3. in flat 96 orifice plate, 100 microlitres of cells are added per hole, total number of cells are 1 × 10 in every hole4.In 37 DEG C,
5%CO2Overnight incubation in cell incubator.
4. 5 microlitres are added per hole with the diluted sample of cell growth medium, make reaction final concentration be respectively 0,0.3,1,
3,10,30 and 100ug/ml.DMSO through corresponding amount is added in the cell of not dosing as a contrast, is not added with containing for drug and DMSO
Cell hole is as background.Every is done three parallel laboratory tests.
5. by dosing cell in 37 DEG C, 5%CO248 hours are kept the temperature in cell incubator.
6. 10ul5mg/ml MTT solution is added in per hole, continue to keep the temperature 3-4 hours in the incubator.
7. cell plates are centrifuged 15 minutes in 1000rpm, vacuum sucks culture solution, is centrifuged after 150ul PBS washings are added
And carefully suck solution.
8. 150ul DMSO are added per hole, it are placed on shaking table and are shaken 15 minutes with 150rpm, the first hairpin crystal of generation is made to fill
Divide dissolving.Measure 492nm absorbance values.
9. calculating comparative survival rate of cells after noval chemical compound A or B are handled according to absorbance value.
Comparative survival rate of cells=(absorbance value-background absorbance of drug-treated group)/(light of DMSO processing groups is inhaled
Receipts value-background absorbance)
Cytotoxicity (the IC of table 2 noval chemical compound pair, three kinds of cancer strains50(μM))
From table 2：Noval chemical compound A or B is to Hela cervical cancer cells, PANC-1 human pancreas cancer cell strains and A549 people
The growth of non-small cell lung cancer cell strain all has obvious inhibiting effect, is better than positive control drug Etoposide (etoposide),
Antitumor activity is notable, it is expected to be used to prepare anti-tumor medicinal preparation as active constituent, have prospect in medicine.
Embodiment three, the activity that the cell cycle is influenced using flow cytometry verification noval chemical compound A and B
Logarithmic growth phase HeLa cervical cancer cells are with 1 × 106/ mL is inoculated in 6 orifice plates, and inoculation volume is 2ml, sets 37
DEG C, 5%CO2It is cultivated for 24 hours in incubator；The experimental group (15,5,1.67 μM) of cell controls group and 3 concentration is set respectively；Culture is for 24 hours
After draw culture solution, pancreatin digestion is added, PBS is used in combination to wash once；After 4 DEG C of 70% ethyl alcohol of addition fixes 30 minutes, with PBS rinses
And RNase (10 μ g/ml) is added, 37 DEG C are incubated 15 minutes；Propidium iodide (propidium iodide) is eventually adding to be used in combination
FACSCalibur (BD, the U.S.) detects the cell cycle.Testing result is shown in Table 3.
Influences of the 3 noval chemical compound A and B of table to Hela cell cycles
From table 3：Compound A can induce the HeLa cell S phases and block, and function and effect are improved in concentration dependent.Chemical combination
Object B can induce HeLa cell blocks in the G2/M phases, and antitumor activity is notable.It is both expected to be used to prepare as active constituent anti-
Tumor drug formulation has prospect in medicine.
Many aspects according to the present invention have done elaboration as above.However, it should be understood that without departing from spirit of that invention
Under the premise of, those skilled in the art can carry out it equivalent change and modification, and the change and modification equally fall into the application
The coverage area of appended claims.
Claims (7)
1. a kind of compound A or its pharmaceutically acceptable salt, which is characterized in that the compound A can be extracted from Yun Shuzhong and be obtained
It obtains and there is following structural (I)：
2. a kind of compound B or its pharmaceutically acceptable salt, which is characterized in that the compound B can be extracted from Yun Shuzhong and be obtained
It obtains and there is following structural (II)：
3. a kind of preparation method of compound as claimed in claim 1 or 2, which is characterized in that the method includes walking as follows
Suddenly：
A) cloud tree is extracted first with acetone soak, acetone extract is then concentrated under reduced pressure to no acetone taste, then use dichloromethane
Concentrate is extracted, dichloromethane extract liquor is concentrated under reduced pressure and obtains medicinal extract；
B) silica gel column chromatography separation is carried out to gained medicinal extract：1 is pressed with dichloromethane and methanol:0~0:1 volume ratio is formed mixed
It closes solution and carries out gradient elution, the fraction containing target compound is collected in thin-layer chromatography detection；
C) reversed-phase silica gel column chromatography separation is carried out to collected fraction：65 are pressed with methanol and water:35~90:10 volume ratio shape
At mixed solution carry out gradient elution, thin-layer chromatography detection is collected the fraction containing target compound, is concentrated, dry.
4. a kind of pharmaceutical composition of anti-curing oncoma, which is characterized in that the composition includes therapeutically effective amount as right is wanted
Seek the compound or its pharmaceutically acceptable salt described in 1 or 2；The tumour in cervical carcinoma, cancer of pancreas and lung cancer one
Kind is a variety of.
5. a kind of health products of anti-curing oncoma, which is characterized in that the health products include a effective amount of such as claims 1 or 2 institute
The compound stated or its pharmaceutically acceptable salt, the one kind or more of the tumour in cervical carcinoma, cancer of pancreas and lung cancer
Kind.
6. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt are preparing Hela cervical cancer cell cells
Application in Cycle Arrest derivant.
7. compound as claimed in claim 1 or 2 or its pharmaceutically acceptable salt are preparing the medicine for preventing or treating tumour
Application in object or health products, the tumour are one or more in cervical carcinoma, cancer of pancreas and lung cancer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410280756.6A CN105440047B (en) | 2014-06-20 | 2014-06-20 | Mouth mountain ketone compound and preparation method thereof, pharmaceutical composition and purposes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410280756.6A CN105440047B (en) | 2014-06-20 | 2014-06-20 | Mouth mountain ketone compound and preparation method thereof, pharmaceutical composition and purposes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105440047A CN105440047A (en) | 2016-03-30 |
| CN105440047B true CN105440047B (en) | 2018-10-23 |
Family
ID=55550738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410280756.6A Expired - Fee Related CN105440047B (en) | 2014-06-20 | 2014-06-20 | Mouth mountain ketone compound and preparation method thereof, pharmaceutical composition and purposes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105440047B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557815A (en) * | 2004-01-15 | 2004-12-29 | 复旦大学 | Isopentenyl xanthone compounds and their use in the preparation of antitumor medicines |
| CN101112370A (en) * | 2006-07-25 | 2008-01-30 | 复旦大学 | Extract of valid target in cudrania tricuspidata total flavone and method for preparing the same |
| CN101856351A (en) * | 2010-05-28 | 2010-10-13 | 暨南大学 | Composition and use thereof in preparation of RXR receptor transcription inhibitor |
| CN102516219A (en) * | 2011-10-28 | 2012-06-27 | 沈阳药科大学 | Halogenated polyhydroxy xanthene derivatives, preparation method and use thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8618125B2 (en) * | 2011-01-14 | 2013-12-31 | Heptiva LLC | Composition comprising hepatic therapeutic active for treating liver diseases, certain cancers and liver health maintenance |
-
2014
- 2014-06-20 CN CN201410280756.6A patent/CN105440047B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1557815A (en) * | 2004-01-15 | 2004-12-29 | 复旦大学 | Isopentenyl xanthone compounds and their use in the preparation of antitumor medicines |
| CN101112370A (en) * | 2006-07-25 | 2008-01-30 | 复旦大学 | Extract of valid target in cudrania tricuspidata total flavone and method for preparing the same |
| CN101856351A (en) * | 2010-05-28 | 2010-10-13 | 暨南大学 | Composition and use thereof in preparation of RXR receptor transcription inhibitor |
| CN102516219A (en) * | 2011-10-28 | 2012-06-27 | 沈阳药科大学 | Halogenated polyhydroxy xanthene derivatives, preparation method and use thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105440047A (en) | 2016-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101045046B (en) | Use of Brazil hemoatoxy type compound for preparing antineoplastic | |
| TWI648257B (en) | Compounds from antrodia camphorata, method for preparing the same and use thereof | |
| CN102516344B (en) | Compound with antitumor activity and preparation method and application thereof | |
| CN102908340B (en) | Isolicoflavonol-containing antitumor drug and application thereof | |
| CN105440047B (en) | Mouth mountain ketone compound and preparation method thereof, pharmaceutical composition and purposes | |
| CN107324999B (en) | Naphthoquinone dimer and preparation method and application thereof | |
| CN109867649B (en) | Biflavonoid compound and preparation method and application thereof | |
| CN105541858B (en) | Xanthone class compounds and preparation method thereof, composition and purposes | |
| WO2016107471A1 (en) | Stat3 and erk signal pathway inhibitor and use thereof | |
| CN101317835B (en) | Application of cantharidin and its derivant in preparing sensitization medicament for tumour chemotherapy | |
| CN115025088A (en) | Application of decalin pyridone alkaloid and pharmaceutical composition thereof | |
| CN102210668B (en) | Application of cantharidin and derivants thereof in preparation of tumor chemotherapy sensitivity enhancing medicine | |
| CN101948453A (en) | Novel NEO-clerodane typed diterpene compound and application thereof | |
| CN105769863A (en) | Application of Tipranavir in anti-cancer drug and anti-cancer drug | |
| CN106727603A (en) | Application of the DEMETHYLZEYLASTERAL in the medicine for preparing treatment cancer of pancreas | |
| CN105477068B (en) | Preparation method and application of active site of mulberry branch and leaf | |
| CN105541631B (en) | Raw element A (spiratisanin A) of meadow sweet Ah Ti and preparation method thereof and the application on medicine | |
| CN106188179B (en) | Sharp leaf vacation Radix Gentianae extract, compound and pharmaceutical composition with anti-diarrhea effect | |
| CN105462980B (en) | HTERT gene antisenses oligonucleotides, pharmaceutical composition and application | |
| CN104257641B (en) | A kind of C36Polyacetylene compound and preparation thereof and application | |
| CN110812479A (en) | Gallic acid and EGFR target antibody composition and application thereof in lung cancer | |
| CN110934877A (en) | Perergosterol and EGFR target antibody composition and application thereof in head and neck squamous cell carcinoma | |
| JP6660301B2 (en) | Novel compound, its production method and its use | |
| CN109223762A (en) | Glabrene is preparing the application in anticancer drug | |
| CN109867657B (en) | Dihydroxydibenzo [ b, f ] [1,5] dioxacin ring compound, preparation method, pharmaceutical composition and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20181023 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |