WO2016095249A1 - 20(R)-人参皂苷Rg3多酰基化衍生物、制备及其应用 - Google Patents
20(R)-人参皂苷Rg3多酰基化衍生物、制备及其应用 Download PDFInfo
- Publication number
- WO2016095249A1 WO2016095249A1 PCT/CN2014/094726 CN2014094726W WO2016095249A1 WO 2016095249 A1 WO2016095249 A1 WO 2016095249A1 CN 2014094726 W CN2014094726 W CN 2014094726W WO 2016095249 A1 WO2016095249 A1 WO 2016095249A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- ginsenoside
- anhydride
- chloride
- process according
- cancer
- Prior art date
Links
- RWXIFXNRCLMQCD-CZIWJLDFSA-N (20R)-ginsenoside Rg3 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1CC[C@]2(C)[C@H]3C[C@@H](O)[C@H]4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@@H]4[C@](C)(O)CCC=C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RWXIFXNRCLMQCD-CZIWJLDFSA-N 0.000 title claims abstract description 69
- XIRZPICFRDZXPF-GCIIHGAUSA-N 20(R)-Ginsenoside Rg3 Natural products CC(=CCC[C@](C)(O)[C@H]1CC[C@]2(C)[C@@H]1[C@H](O)C[C@@H]3[C@@]4(C)CC[C@H](O[C@@H]5O[C@H](CO)[C@@H](O)[C@H](O)[C@H]5O[C@H]6O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]6O)C(C)(C)[C@@H]4[C@@H](O)C[C@@]23C)C XIRZPICFRDZXPF-GCIIHGAUSA-N 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 230000000259 anti-tumor effect Effects 0.000 claims abstract description 12
- 206010028980 Neoplasm Diseases 0.000 claims description 28
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 239000000243 solution Substances 0.000 claims description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- 238000005886 esterification reaction Methods 0.000 claims description 11
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 10
- 201000005202 lung cancer Diseases 0.000 claims description 10
- 208000020816 lung neoplasm Diseases 0.000 claims description 10
- 208000005016 Intestinal Neoplasms Diseases 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 201000002313 intestinal cancer Diseases 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 8
- 206010017758 gastric cancer Diseases 0.000 claims description 8
- 201000011549 stomach cancer Diseases 0.000 claims description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- YWGHUJQYGPDNKT-UHFFFAOYSA-N hexanoyl chloride Chemical compound CCCCCC(Cl)=O YWGHUJQYGPDNKT-UHFFFAOYSA-N 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- PKHMTIRCAFTBDS-UHFFFAOYSA-N hexanoyl hexanoate Chemical compound CCCCCC(=O)OC(=O)CCCCC PKHMTIRCAFTBDS-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- XGISHOFUAFNYQF-UHFFFAOYSA-N pentanoyl chloride Chemical compound CCCCC(Cl)=O XGISHOFUAFNYQF-UHFFFAOYSA-N 0.000 claims description 2
- DUCKXCGALKOSJF-UHFFFAOYSA-N pentanoyl pentanoate Chemical compound CCCCC(=O)OC(=O)CCCC DUCKXCGALKOSJF-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 229940086066 potassium hydrogencarbonate Drugs 0.000 claims description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 230000001644 anti-hepatocarcinoma Effects 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 229930182494 ginsenoside Natural products 0.000 description 21
- 229940089161 ginsenoside Drugs 0.000 description 21
- 238000012360 testing method Methods 0.000 description 21
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 239000013642 negative control Substances 0.000 description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 206010027476 Metastases Diseases 0.000 description 11
- 238000002347 injection Methods 0.000 description 11
- 239000007924 injection Substances 0.000 description 11
- 230000009401 metastasis Effects 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- AEDDIBAIWPIIBD-ZJKJAXBQSA-N mangiferin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=C(O)C=C(OC=2C(=CC(O)=C(O)C=2)C2=O)C2=C1O AEDDIBAIWPIIBD-ZJKJAXBQSA-N 0.000 description 10
- 230000000694 effects Effects 0.000 description 9
- 238000011081 inoculation Methods 0.000 description 9
- 241000699660 Mus musculus Species 0.000 description 8
- 239000006285 cell suspension Substances 0.000 description 8
- 238000011580 nude mouse model Methods 0.000 description 8
- 239000000843 powder Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 201000007270 liver cancer Diseases 0.000 description 6
- 208000014018 liver neoplasm Diseases 0.000 description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-M octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- YWQSXCGKJDUYTL-UHFFFAOYSA-N Mangiferin Natural products CC(CCC=C(C)C)C1CC(C)C2C3CCC4C(C)(C)CCCC45CC35CCC12C YWQSXCGKJDUYTL-UHFFFAOYSA-N 0.000 description 5
- 238000013401 experimental design Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 229940043357 mangiferin Drugs 0.000 description 5
- 230000000144 pharmacologic effect Effects 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 210000000952 spleen Anatomy 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 238000007920 subcutaneous administration Methods 0.000 description 5
- 210000000683 abdominal cavity Anatomy 0.000 description 4
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 238000011355 in situ vaccination Methods 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- JUJWROOIHBZHMG-RALIUCGRSA-N pyridine-d5 Chemical compound [2H]C1=NC([2H])=C([2H])C([2H])=C1[2H] JUJWROOIHBZHMG-RALIUCGRSA-N 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RWXIFXNRCLMQCD-JBVRGBGGSA-N (20S)-ginsenoside Rg3 Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1CC[C@]2(C)[C@H]3C[C@@H](O)[C@H]4[C@@]([C@@]3(CC[C@H]2C1(C)C)C)(C)CC[C@@H]4[C@@](C)(O)CCC=C(C)C)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O RWXIFXNRCLMQCD-JBVRGBGGSA-N 0.000 description 3
- 238000011740 C57BL/6 mouse Methods 0.000 description 3
- XIRZPICFRDZXPF-UHFFFAOYSA-N Ginsenoside Rg3 Natural products CC(C)=CCCC(C)(O)C1CCC(C2(CC(O)C3C4(C)C)C)(C)C1C(O)CC2C3(C)CCC4OC1OC(CO)C(O)C(O)C1OC1OC(CO)C(O)C(O)C1O XIRZPICFRDZXPF-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012295 chemical reaction liquid Substances 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000265 homogenisation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- VTTIDPAZLXIGNF-UHFFFAOYSA-N octadecyl butanoate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)CCC VTTIDPAZLXIGNF-UHFFFAOYSA-N 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000013268 sustained release Methods 0.000 description 3
- 239000012730 sustained-release form Substances 0.000 description 3
- XULPLJSODQQHPH-UHFFFAOYSA-N Bergenin Natural products OCC1OC2C(OC(=O)c3cc(O)c(CO)c(O)c23)C(O)C1O XULPLJSODQQHPH-UHFFFAOYSA-N 0.000 description 2
- YWJXCIXBAKGUKZ-HJJNZUOJSA-N Bergenin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@H]2C3=C(O)C(OC)=C(O)C=C3C(=O)O[C@@H]21 YWJXCIXBAKGUKZ-HJJNZUOJSA-N 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 235000002789 Panax ginseng Nutrition 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- -1 diol saponin Chemical class 0.000 description 2
- 239000002662 enteric coated tablet Substances 0.000 description 2
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229940100688 oral solution Drugs 0.000 description 2
- 229940100692 oral suspension Drugs 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000005507 spraying Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- PFTAWBLQPZVEMU-DZGCQCFKSA-N (+)-catechin Chemical compound C1([C@H]2OC3=CC(O)=CC(O)=C3C[C@@H]2O)=CC=C(O)C(O)=C1 PFTAWBLQPZVEMU-DZGCQCFKSA-N 0.000 description 1
- LSHVYAFMTMFKBA-PZJWPPBQSA-N (+)-catechin-3-O-gallate Chemical compound O([C@H]1CC2=C(O)C=C(C=C2O[C@@H]1C=1C=C(O)C(O)=CC=1)O)C(=O)C1=CC(O)=C(O)C(O)=C1 LSHVYAFMTMFKBA-PZJWPPBQSA-N 0.000 description 1
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- 241000208340 Araliaceae Species 0.000 description 1
- 235000004936 Bromus mango Nutrition 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 208000001382 Experimental Melanoma Diseases 0.000 description 1
- 208000006552 Lewis Lung Carcinoma Diseases 0.000 description 1
- 240000007228 Mangifera indica Species 0.000 description 1
- 235000014826 Mangifera indica Nutrition 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 235000009184 Spondias indica Nutrition 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002001 anti-metastasis Effects 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- ADRVNXBAWSRFAJ-UHFFFAOYSA-N catechin Natural products OC1Cc2cc(O)cc(O)c2OC1c3ccc(O)c(O)c3 ADRVNXBAWSRFAJ-UHFFFAOYSA-N 0.000 description 1
- 235000005487 catechin Nutrition 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229950001002 cianidanol Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001784 detoxification Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000000105 evaporative light scattering detection Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- LVJJFMLUMNSUFN-UHFFFAOYSA-N gallocatechin gallate Natural products C1=C(O)C=C2OC(C=3C=C(O)C(O)=CC=3)C(O)CC2=C1OC(=O)C1=CC(O)=C(O)C(O)=C1 LVJJFMLUMNSUFN-UHFFFAOYSA-N 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000013415 human tumor xenograft model Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- OSFBJERFMQCEQY-UHFFFAOYSA-N propylidene Chemical compound [CH]CC OSFBJERFMQCEQY-UHFFFAOYSA-N 0.000 description 1
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 108010048734 sclerotin Proteins 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011973 solid acid Substances 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 150000003521 tetracyclic triterpenoids Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- SWGJCIMEBVHMTA-UHFFFAOYSA-K trisodium;6-oxido-4-sulfo-5-[(4-sulfonatonaphthalen-1-yl)diazenyl]naphthalene-2-sulfonate Chemical compound [Na+].[Na+].[Na+].C1=CC=C2C(N=NC3=C4C(=CC(=CC4=CC=C3O)S([O-])(=O)=O)S([O-])(=O)=O)=CC=C(S([O-])(=O)=O)C2=C1 SWGJCIMEBVHMTA-UHFFFAOYSA-K 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J17/005—Glycosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
Definitions
- the present invention belongs to the field of medicinal chemistry, and in particular, the present invention relates to a 20(R)-ginsenoside Rg3 polyacylated derivative, a process for the preparation thereof, and a pharmacological action of such a derivative in antitumor action.
- 20(R)-ginsenoside Rg3 is a tetracyclic triterpenoid ginseng diol saponin monomer isolated and purified from red ginseng. It was firstly isolated from Korean red ginseng by Japanese scholar Beichuan Xun in 1980. Its molecular formula is C. 42 H 72 O 13 , relative molecular weight 784.3.
- the efficacy of ginsenoside Rg3 includes synergistic detoxification, improvement of qi deficiency syndrome, and improvement of immunity.
- studies have shown that ginsenoside Rg3 can inhibit the proliferation, invasion and metastasis of tumor cells, and can induce apoptosis of liver cancer cells, prostate cancer cells, leukemia cells, cervical cancer cells.
- 20(R)-ginsenoside Rg3 has a large molecular structure, and 20(R)-ginsenoside Rg3 is insoluble in large polar solvents such as water, and is not soluble in small polar or non-polar solvents such as petroleum ether and chloroform;
- BCS Biopharmaceutics Classification System
- the technical problem to be solved by the present invention is to prepare a 20(R)-ginsenoside Rg3 polyacylated derivative by a chemical synthesis method.
- the present invention provides a synthetic 20(R)-ginsenoside Rg3 polyacylated derivative which utilizes 20(R)-ginsenoside Rg3 as a lead compound and utilizes an acylation reaction.
- the mother's hydroxyl group is blocked to enhance the lipophilicity, and the oil-water separation coefficient is changed, which is beneficial to the intestinal absorption, thereby improving the therapeutic effect.
- the present invention also provides a process for preparing 20(R)-ginsenoside Rg3 polyacylated derivative, which has mild reaction conditions and is suitable for industrial scale-up production.
- the present invention provides a 20(R)-ginsenoside Rg3 polyacylated derivative represented by the formula (I),
- the present invention provides a pharmaceutical composition comprising the 20(R)-ginsenoside Rg3 polyacylated derivative of the present invention.
- Biological as well as pharmaceutically acceptable excipients.
- a pharmaceutically acceptable excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, carrier, pH adjuster, ionic strength modifier, sustained release or controlled release agent, encapsulating material or other formulation excipient.
- the carrier used may be adapted to the corresponding administration form, and may be formulated into an injection, a lyophilized powder for injection, a spray, an oral solution, an oral suspension, a tablet, a capsule, or the like, which is known to those skilled in the art.
- Formulations such as enteric-coated tablets, pills, powders, granules, sustained release or delayed release.
- the 20(R)-ginsenoside Rg3 polyacylated derivative of the first aspect of the invention is administered by injection or by digestive tract, and therefore, the pharmaceutical composition of the present invention is preferably an injection or a preparation for administration via the digestive tract. That is, excipients suitable for administration by injection and transgestive administration are particularly preferred.
- administered by the digestive tract refers to a mode of administration of a pharmaceutical preparation through the digestive tract of a patient, including oral, intragastric, and enema administration, preferably oral, as may be known to those skilled in the art.
- the auxiliary materials are formulated into an oral solution, an oral suspension, a tablet, a capsule, an enteric-coated tablet, a pill, a powder, a granule, a sustained release or a delayed release release; wherein the preparation for injection administration is mainly an injection and a powder injection.
- Another aspect of the invention provides a process for the preparation of a 20(R)-ginsenoside Rg3 polyacylated derivative comprising the steps of:
- the organic solvent in the step 1) is selected from triethylamine or anhydrous pyridine, preferably anhydrous pyridine; and the acylating reagent in the step 2) is an acid chloride or an acid anhydride.
- the acid chloride is selected from acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride or hexanoyl chloride;
- the anhydride is selected from acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride or hexanoic anhydride.
- reaction temperature of the esterification reaction in the step 2) is from 80 to 100 °C.
- esterification reaction takes 2-5 hours.
- the acylating agent was added to a 20(R)-ginsenoside Rg3 solution at room temperature.
- the temperature is from 15 to 35 °C.
- the base in step 3 is selected as an inorganic base.
- the inorganic base is selected from sodium carbonate, potassium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably sodium hydrogencarbonate.
- the added water described in step 3) is ice water, i.e. water having a water temperature of 0 ° C, and the esterification reaction is quenched.
- the 20(R)-ginsenoside Rg3 polyacylated derivative is subjected to the recrystallization described in step 4) using a water/methanol system.
- the present invention provides a use of a 20(R)-ginsenoside Rg3 polyacylated derivative for the preparation of an antitumor, anticancer drug.
- the present invention provides a 20(R)-ginsenoside Rg3 polyacylated derivative in the preparation of anti-multiple animal solid tumors, anti-human lung cancer, anti-breast cancer, anti-gastric cancer, anti-intestinal cancer, anti-liver drugs. application.
- the invention has the advantages that the preparation method of the 20(R)-ginsenoside Rg3 polyacylated derivative of the invention is easy to control, the comprehensive yield of the product is high, and it is suitable for industrial large-scale production.
- the invention is further described by the following examples, which are intended to illustrate the invention and are not to be construed as limiting.
- the reagents and raw materials in the examples can be obtained through commercial channels. If there are any defects, the organic synthesis guide, the guidelines of the drug regulatory agency, and the manufacturer's instructions of the corresponding instruments and reagents can be referred to.
- reaction liquid was poured into ice water, and the pH was adjusted to 7 with a saturated aqueous sodium hydrogencarbonate solution, and a large amount of white solid was precipitated.
- reaction solution was poured into ice water with saturated sodium bicarbonate.
- the aqueous solution was adjusted to a pH of 7, and a large amount of white solid precipitated.
- reaction liquid was poured into ice water, and the pH was adjusted to 7 with a saturated aqueous sodium hydrogencarbonate solution, and a large amount of white solid was precipitated.
- reaction liquid was poured into ice water, and the pH was adjusted to 7 with a saturated aqueous sodium hydrogencarbonate solution, and a large amount of white solid was precipitated.
- 20R-ginsenoside Rg3 octadecanoate (3g) is a white solid, soluble in water and ethanol.
- the 10% H 2 SO 4 -ethanol reagent was sprayed on a TLC plate (the chromatographic solution was chloroform/methanol 5:1, Rf was 0.4).
- m/z [M+Na] was 1602.2 and the molecular weight was 1570.
- CX Positive control injection cyclophosphamide
- MMC mitomycin for injection
- Tumor source human breast cancer Bcap-37 model, human lung cancer A549 model, human intestinal cancer LOVO model, human gastric cancer MGC model and human liver cancer QGY are used as the tumor source for the second generation or more; mouse B16 melanoma cells, mice The Lewis lung cancer model and the mouse sarcoma S180 model were all maintained by the pharmacology room of Shanghai Pharmaceutical Industry Research Institute.
- the source nude mice were provided by the Experimental Animal Center of the Chinese Academy of Sciences of Shanghai, with the certificate number: SCXK 2003-0003.
- C57BL/6 and Kunming mice were provided by the experimental animal group of the Pharmacology Laboratory of Shanghai Pharmaceutical Industry Research Institute.
- the nude mice were 6 weeks old, and the Kunming mice and C57BL/6 mice were 18-22 grams.
- Both sexes are male and female, and the same gender is used for each batch of experiments.
- Dosage setting 20(R)-ginsenoside Rg3 octaacetyl ester, 20(R)-ginsenoside Rg3 octadecanoate, 20(R)-ginsenoside Rg3 octadecanoate (0.3mg/kg/d), medium (0.06mg/kg/d), low dose (0.012mg/kg/d) group.
- Dosing regimen Oral administration, 2 times a day; human tumor model and cell model of cell inoculation po ⁇ 14bid; mouse tumor inoculation model po ⁇ 10bid regimen treatment.
- Test control Negative control: 5% CMC-Na was administered in the same volume as the test group, and the administration schedule was the same as the test group; positive control: cyclophosphamide CTX 30 mg/kg, MMC 2 mg/kg, and 5 Fu 30 mg/kg intraperitoneally or intravenously. The drug was taken once a day for seven days.
- the vigorous growth of the tumor source was prepared by homogenization to prepare a cell suspension of about 1 to 2 ⁇ 10 7 /ml; 0.2 ml/mouse was inoculated under the corresponding host sputum, and the next day was administered according to the experimental design.
- the animals in each group were sacrificed in about three weeks.
- the tumors were weighed and the tumor inhibition rate was calculated according to the following formula:
- Tumor inhibition rate% [(control group average tumor weight-average tumor weight of administration group)/control group average tumor weight] ⁇ 100%
- the human tumor xenograft model is operated the same, but the feed, litter, cage and contact equipment used should be used after autoclaving, and the nude mice are placed in a laminar flow rack.
- the life extension rate of the tumor-bearing host was calculated according to the following formula:
- Life extension rate% average survival days of the administration group/average survival days of the control group ⁇ 100%
- B16 mouse melanoma culture cells in logarithmic growth phase were prepared under aseptic conditions to prepare a cell suspension of about 2.5 ⁇ 10 5 /ml, and 0.2 ml/mouse was inoculated into the tail vein of C57BL/6 mice. The drug was administered. Three weeks later, the animals in each group were sacrificed. The lungs of each group were dissected. The number of colonies transferred from each lung was measured. The average number of colonies in each group was calculated according to the following formula:
- Tumor inhibition rate% [(the average number of colonies in the control group - the average number of colonies in the administration group) / the average number of colonies in the control group) ⁇ 100%
- the LOVO intestinal cancer culture cells in the logarithmic growth phase were taken under aseptic conditions, and about 1.8 ⁇ 10 7 /ml cell suspension was diluted with RPMI1640 medium for use.
- the mice were placed in cages and placed in a laminar flow rack. The next day, according to the experimental design, the mortality of each group of mice was observed and recorded, and the statistical life extension rate was compared with the negative control group.
- the second-generation QGY tumor source was obtained by vigorous growth, and a cell suspension of about 1-2 ⁇ 10 7 /ml was prepared by homogenization method 1:6, and the homogenate was filtered through a 100-mesh stainless steel mesh.
- Nude mice were routinely sterilized, anesthetized in the mid-abdominal sacral process to open the skin and abdominal cavity, expose the liver, and inject 0.05 ml of cell suspension into the liver parenchyma with an imported 28 ga 1/2 ml syringe, close the abdominal cavity, suture the abdominal cavity and skin layer by layer. .
- the nude mice were placed in a laminar flow rack, and the feed, litter, cages, and instruments in contact were used after autoclaving. The next day, according to the experimental design, the survival time of each group of animals was observed within 45 days, and compared with the negative control group, the life extension rate was counted.
- the test results in Table 1-2 show that ginsenoside Rg3-octadecanoate, ginsenoside Rg3-octadecanoate, and ginsenoside Rg3-octaacetate inhibit tumor growth in mouse and human tumor solid tumor models.
- the inhibitory rate of the best efficacy group was more than 70%, which was significantly different from the invisible control group (p ⁇ 0.01).
- Ginsenoside Rg3-octadecanoate, ginsenoside Rg3-octadecanoate, ginsenoside Rg3-octaacetate The anti-tumor test results of mouse melanin B16, S180, Lewis lung cancer metastasis model and human lung cancer metastasis model are shown in Table 3-6.
- the test results of Tables 7-9 show that the ginsenoside Rg3-octadecanoate, ginsenoside Rg3-octadecanoate and ginsenoside Rg3-octaacetate of the present invention can significantly prolong the gastric cancer and human intestinal cancer
- the survival time of human liver cancer has obvious effects on prolonging the life rate.
- the high-dose group of ginsenoside Rg3-octadecanoate, ginsenoside Rg3-octadecanoate and ginsenoside Rg3-octaacetate has obvious prolonged life effects on human gastric cancer, human intestinal cancer and human liver cancer. And more than the positive drug group; the effect of the low dose group on prolonging the life rate is comparable to the positive control drug.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
Claims (10)
- 一种如权利要求1所述的20(R)-人参皂苷Rg3多酰基化衍生物的制备方法,其特征在于,包括如下顺序进行的步骤:1)将20(R)-人参皂苷Rg3溶于有机溶剂,制得20(R)-人参皂苷Rg3溶液;2)加入酰化试剂,进行酯化反应;3)加入水淬灭反应,用碱调节混合溶液的pH值为7;4)过滤、重结晶即得。
- 如权利要求2所述的制备方法,其特征在于步骤1)所述有机溶剂选择三乙胺或无水吡啶,优选为无水吡啶。
- 如权利要求2所述的制备方法,其特征在于步骤2)所述酰化试剂为酰氯或酸酐。
- 如权利要求4所述的制备方法,其特征在于所述酰氯选择乙酰氯、丙酰氯、丁酰氯、戊酰氯或己酰氯;所述酸酐选择乙酸酐、丙酸酐、丁酸酐、戊酸酐或己酸酐。
- 如权利要求2所述的制备方法,其特征在于步骤2)中所述酯化反应的反应温度为80-100℃。
- 权利要求2所述的制备方法,其特征在于步骤3)中所述碱选择无机碱。
- 如权利要求7所述的制备方法,其特征在于所述无机碱选择碳酸钠、碳酸钾、碳酸氢钠或碳酸氢钾。
- 如权利要求1所述的20(R)-人参皂苷Rg3多酰基化衍生物在制备抗肿瘤、抗癌药物中的应用。
- 如权利要求1所述的20(R)-人参皂苷Rg3多酰基化衍生物在制备抗多种动物实体瘤、抗人体肺癌、抗乳腺癌、抗胃癌、抗肠癌、抗肝癌药物中的应用。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR1020177018133A KR102010484B1 (ko) | 2014-12-17 | 2014-12-23 | 20(r)-진세노사이드 rg3 다중아실화 유도체, 이의 제조, 및 용도 |
AU2014414533A AU2014414533B2 (en) | 2014-12-17 | 2014-12-23 | 20(R)-ginsenoside Rg3 multiacylated derivative, preparation, and application thereof |
RU2017124917A RU2673885C1 (ru) | 2014-12-17 | 2014-12-23 | Полиацилированные производные 20(r)-гинзенозида rg3, их получение и применение |
JP2017530148A JP6415725B2 (ja) | 2014-12-17 | 2014-12-23 | ポリアシル化20(R)−ジンセノサイドRg3誘導体、その調製方法及びその応用 |
ES14908284T ES2786092T3 (es) | 2014-12-17 | 2014-12-23 | Derivado multiacilado del 20(R)ginsenósido Rg3, preparación y aplicación del mismo |
CA2971365A CA2971365C (en) | 2014-12-17 | 2014-12-23 | 20(r)-ginsenoside rg3 polyacylated derivatives, preparation and application thereof |
EP14908284.4A EP3235826B1 (en) | 2014-12-17 | 2014-12-23 | 20(r)-ginsenoside rg3 multiacylated derivative, preparation, and application thereof |
US15/536,301 US9969766B2 (en) | 2014-12-17 | 2014-12-23 | 20(R)-ginsenoside Rg3 polyacylated derivatives, preparation and application thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN2014107851724 | 2014-12-17 | ||
CN201410785172.4A CN105753923B (zh) | 2014-12-17 | 2014-12-17 | 20(R)‑人参皂苷Rg3多酰基化衍生物、制备及其应用 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016095249A1 true WO2016095249A1 (zh) | 2016-06-23 |
Family
ID=56125703
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2014/094726 WO2016095249A1 (zh) | 2014-12-17 | 2014-12-23 | 20(R)-人参皂苷Rg3多酰基化衍生物、制备及其应用 |
Country Status (10)
Country | Link |
---|---|
US (1) | US9969766B2 (zh) |
EP (1) | EP3235826B1 (zh) |
JP (1) | JP6415725B2 (zh) |
KR (1) | KR102010484B1 (zh) |
CN (1) | CN105753923B (zh) |
AU (1) | AU2014414533B2 (zh) |
CA (1) | CA2971365C (zh) |
ES (1) | ES2786092T3 (zh) |
RU (2) | RU2673885C1 (zh) |
WO (1) | WO2016095249A1 (zh) |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005116042A1 (en) * | 2004-05-29 | 2005-12-08 | Myung Hwan Park | Treatment and prevention of cancer with new ginsenoside derivatives |
US20060014704A1 (en) * | 2004-07-16 | 2006-01-19 | Landry Donald W | Compounds and their preparation for the treatment of Alzheimer's disease by inhibiting beta-amyloid peptide production |
CN102603847A (zh) * | 2010-11-18 | 2012-07-25 | 吉林农业大学 | 人参皂苷Rh2脂肪酸酯类化合物制备方法及其医药用途 |
CN102775461A (zh) * | 2012-07-02 | 2012-11-14 | 云南农业大学 | 一种20(r)-人参皂苷的制备方法 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR0169536B1 (ko) * | 1996-02-27 | 1999-01-15 | 손경식 | 신규한 인삼 사포닌, 그의 제조방법 및 이를 유효성분으로 하는 항종양제 |
JP2008506686A (ja) * | 2004-07-16 | 2008-03-06 | ザ トラスティーズ オブ コロンビア ユニバーシティ イン ザ シティ オブ ニューヨーク | ベータ−アミロイドペプチドの形成を阻害することによるアルツハイマー病治療用化合物及び製造 |
TWI373473B (en) * | 2005-09-02 | 2012-10-01 | Otsuka Pharma Co Ltd | Anticancer agent |
JP4740938B2 (ja) * | 2007-12-27 | 2011-08-03 | ダイセル化学工業株式会社 | 6位高アセチル化セルロースジアセテート及びその製造方法 |
CN102603848A (zh) * | 2011-01-24 | 2012-07-25 | 吉林农业大学 | 人参皂苷Rh2脂肪酸双酯的制备方法及其医药用途 |
-
2014
- 2014-12-17 CN CN201410785172.4A patent/CN105753923B/zh active Active
- 2014-12-23 ES ES14908284T patent/ES2786092T3/es active Active
- 2014-12-23 KR KR1020177018133A patent/KR102010484B1/ko active IP Right Grant
- 2014-12-23 AU AU2014414533A patent/AU2014414533B2/en active Active
- 2014-12-23 WO PCT/CN2014/094726 patent/WO2016095249A1/zh active Application Filing
- 2014-12-23 US US15/536,301 patent/US9969766B2/en active Active
- 2014-12-23 RU RU2017124917A patent/RU2673885C1/ru active
- 2014-12-23 JP JP2017530148A patent/JP6415725B2/ja active Active
- 2014-12-23 EP EP14908284.4A patent/EP3235826B1/en active Active
- 2014-12-23 CA CA2971365A patent/CA2971365C/en active Active
-
2018
- 2018-10-17 RU RU2018136587A patent/RU2695380C1/ru active
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005116042A1 (en) * | 2004-05-29 | 2005-12-08 | Myung Hwan Park | Treatment and prevention of cancer with new ginsenoside derivatives |
US20060014704A1 (en) * | 2004-07-16 | 2006-01-19 | Landry Donald W | Compounds and their preparation for the treatment of Alzheimer's disease by inhibiting beta-amyloid peptide production |
CN102603847A (zh) * | 2010-11-18 | 2012-07-25 | 吉林农业大学 | 人参皂苷Rh2脂肪酸酯类化合物制备方法及其医药用途 |
CN102775461A (zh) * | 2012-07-02 | 2012-11-14 | 云南农业大学 | 一种20(r)-人参皂苷的制备方法 |
Non-Patent Citations (1)
Title |
---|
See also references of EP3235826A4 * |
Also Published As
Publication number | Publication date |
---|---|
JP2017537932A (ja) | 2017-12-21 |
US20170327529A1 (en) | 2017-11-16 |
US9969766B2 (en) | 2018-05-15 |
CA2971365A1 (en) | 2016-06-23 |
EP3235826B1 (en) | 2020-02-05 |
KR20170087513A (ko) | 2017-07-28 |
JP6415725B2 (ja) | 2018-10-31 |
EP3235826A4 (en) | 2018-08-15 |
ES2786092T3 (es) | 2020-10-08 |
AU2014414533A1 (en) | 2017-07-20 |
CN105753923A (zh) | 2016-07-13 |
CA2971365C (en) | 2019-03-19 |
EP3235826A1 (en) | 2017-10-25 |
CN105753923B (zh) | 2017-09-29 |
AU2014414533B2 (en) | 2019-02-21 |
RU2695380C1 (ru) | 2019-07-23 |
KR102010484B1 (ko) | 2019-08-13 |
RU2673885C1 (ru) | 2018-12-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US9321804B2 (en) | Synthesis and use of anti-tumor drug LQC-Y | |
CN101045046B (zh) | 巴西苏木素类化合物在制备抗肿瘤药物中的用途 | |
CN1793132A (zh) | 环黄芪醇类衍生物以及用途 | |
WO2005040189A1 (en) | Novel dammarane sapogenins and their use as anti-cancer agents | |
Qu et al. | Novel 25-hydroxyprotopanaxadiol derivatives incorporating chloroacetyl chloride and their anti-tumor evaluation | |
JP6356218B2 (ja) | 抗腫瘍活性を有する7−α−[9−(4,4,5,5,5−ペンタフルオロペンチルスルフィニル)ノニル]−エストラ−1,3,5(10)−トリエン−3,17β−ジオールのエステル誘導体及びその調製方法 | |
CN107200769B (zh) | 一种具有防治肿瘤转移作用的救必应酸衍生物 | |
RU2695380C1 (ru) | Полиацилированные производные 20(r)-гинзенозида rg3, их получение и применение | |
EP2452681B1 (en) | SALTS OF 13a-(S)-DEOXYTYLOPHORININE, PREPARATION METHODS AND PHARMACEUTICAL COMPOSITIONS AND USES THEREOF | |
Yuan et al. | Non-protein amino acid derivatives of 25-methoxylprotopanaxadiol/25-hydroxyprotopanaxadioland their anti-tumour activity evaluation | |
CN108341850B (zh) | 皂苷衍生物及其药物组合物和应用 | |
CN115626946B (zh) | 一种桦木醇-卡洛芬衍生物及其自组装纳米颗粒和在制备抗肺癌药物中的用途 | |
Zhang et al. | Synthesis of oleandrin derivatives and their cytotoxic activity | |
CN114940696B (zh) | 一种川楝素衍生物及其在乳腺癌治疗中的应用 | |
CN115558012B (zh) | 一种薯蓣皂苷元-丹参素衍生物及其自组装纳米颗粒和制备方法及用途 | |
CN102838652B (zh) | 一种具有抗恶性肿瘤作用的齐墩果酸衍生物及其制备方法和用途 | |
CN101830958A (zh) | 20(R)-25-乙氧基-达玛烷-3β,12β,20-三醇及其制备方法 | |
CN107011352A (zh) | 白坚木碱二聚体与其药物组合物及其制备方法和应用 | |
WO2016095248A1 (zh) | 20(R)-人参皂苷Rg3衍生物、制备方法及其应用 | |
CN103254266B (zh) | 甾体锌金属配合物及其制备方法和在制备抗胃癌药物中的应用 | |
PT1572715E (pt) | Compostos de esteróides com actividade anti-tumor | |
CN104098646A (zh) | 纤细薯蓣皂苷衍生物及其抗肿瘤活性应用 | |
CN113773356A (zh) | 一种胡黄连苷ii衍生物及其制备方法和应用 | |
CN102659895A (zh) | 甾体生物碱盐酸盐及其制备方法和用途 | |
CN101875682A (zh) | 人参皂苷元20(R)-甲氧基-达玛烷-3β,12β,25-三醇及其制备方法和医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14908284 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2017530148 Country of ref document: JP Kind code of ref document: A |
|
REEP | Request for entry into the european phase |
Ref document number: 2014908284 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15536301 Country of ref document: US |
|
ENP | Entry into the national phase |
Ref document number: 2971365 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20177018133 Country of ref document: KR Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2017124917 Country of ref document: RU Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2014414533 Country of ref document: AU Date of ref document: 20141223 Kind code of ref document: A |