CN106188069B - Purposes of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound as tumor cell proliferation inhibitor - Google Patents
Purposes of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound as tumor cell proliferation inhibitor Download PDFInfo
- Publication number
- CN106188069B CN106188069B CN201610591881.8A CN201610591881A CN106188069B CN 106188069 B CN106188069 B CN 106188069B CN 201610591881 A CN201610591881 A CN 201610591881A CN 106188069 B CN106188069 B CN 106188069B
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- salt
- pyrazolos
- amino
- 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
- -1 [1,2,4] triazole compound Chemical class 0.000 title claims abstract description 25
- 230000004663 cell proliferation Effects 0.000 title abstract description 4
- 239000003112 inhibitor Substances 0.000 title abstract description 4
- 210000004881 tumor cell Anatomy 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 20
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 16
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical class C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 claims description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 150000002431 hydrogen Chemical class 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- 235000002597 Solanum melongena Nutrition 0.000 claims description 5
- 244000061458 Solanum melongena Species 0.000 claims description 5
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 claims description 5
- 235000011167 hydrochloric acid Nutrition 0.000 claims description 5
- 238000006722 reduction reaction Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- 239000005711 Benzoic acid Substances 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 235000010233 benzoic acid Nutrition 0.000 claims description 4
- 235000015165 citric acid Nutrition 0.000 claims description 4
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 229940126214 compound 3 Drugs 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 239000001630 malic acid Substances 0.000 claims description 4
- 235000011090 malic acid Nutrition 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- 235000011007 phosphoric acid Nutrition 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000011975 tartaric acid Substances 0.000 claims description 4
- 235000002906 tartaric acid Nutrition 0.000 claims description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- 238000001514 detection method Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims description 2
- DZGCGKFAPXFTNM-UHFFFAOYSA-N ethanol;hydron;chloride Chemical compound Cl.CCO DZGCGKFAPXFTNM-UHFFFAOYSA-N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 208000005718 Stomach Neoplasms Diseases 0.000 claims 1
- 239000003610 charcoal Substances 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 210000000981 epithelium Anatomy 0.000 claims 1
- 239000000835 fiber Substances 0.000 claims 1
- 206010017758 gastric cancer Diseases 0.000 claims 1
- 235000013372 meat Nutrition 0.000 claims 1
- 201000011549 stomach cancer Diseases 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 3
- YCWSUKQGVSGXJO-NTUHNPAUSA-N nifuroxazide Chemical group C1=CC(O)=CC=C1C(=O)N\N=C\C1=CC=C([N+]([O-])=O)O1 YCWSUKQGVSGXJO-NTUHNPAUSA-N 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 230000000259 anti-tumor effect Effects 0.000 description 11
- 238000000034 method Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 5
- 229960005537 combretastatin A-4 Drugs 0.000 description 5
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 125000003831 tetrazolyl group Chemical group 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 238000012449 Kunming mouse Methods 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 230000007059 acute toxicity Effects 0.000 description 2
- 231100000403 acute toxicity Toxicity 0.000 description 2
- 229940009456 adriamycin Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007928 intraperitoneal injection Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 150000003852 triazoles Chemical class 0.000 description 2
- KLVQAIJZDCCJRZ-UHFFFAOYSA-N 2h-1,3,4-thiadiazine Chemical compound C1SC=CN=N1 KLVQAIJZDCCJRZ-UHFFFAOYSA-N 0.000 description 1
- ILUSBJDVXKZYEP-UHFFFAOYSA-N 4-(aminomethyl)oxan-4-ol;hydrochloride Chemical compound Cl.NCC1(O)CCOCC1 ILUSBJDVXKZYEP-UHFFFAOYSA-N 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 238000007445 Chromatographic isolation Methods 0.000 description 1
- 201000008808 Fibrosarcoma Diseases 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000124033 Salix Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- 229940122530 Tubulin polymerization inhibitor Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- PJANXHGTPQOBST-QXMHVHEDSA-N cis-stilbene Chemical class C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to pharmaceutical technology field, is related to a kind of 3,6 diaryl 1HPyrazolo [5,1 c] [1,2,4] triazole compound and application thereof, exactly, is related to application of such compound as tumor cell proliferation inhibitor in terms of anti-tumor drug is prepared.The structure of the compound is as follows：The definition of each substituent is as described in claims and specification.
Description
Technical field
The invention belongs to pharmaceutical technology field, is related to one kind 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] three nitrogen
Azole compounds and application thereof, exactly, be related to such compound as tumor cell proliferation inhibitor prepare it is antitumor
Medicine in terms of application.
Background technology
Malignant tumour is to threaten human health and the serious disease of life, is one of main lethal cause of disease in China.Find
New drug with discovery treatment and pre- preventing tumor is the hot research direction of our times.
Combretastatin A-4 (CA-4) are that isolated cis-stilbene class from the willow of South Africa is naturally produced
Thing, its chemical name are (Z) -2- methoxyl groups -5- (3,4,5- trimethoxy styryl) phenol.CA-4 is tubulin polymerization
Inhibitor, is presented very strong suppression proliferative activity o f tumor, due to its poorly water-soluble, prodrug CA-4 phosphate ester salts has been made
(CA-4P), and to enter phase iii clinical trial conceptual phase.It is current that antitumor activity is carried out using CA-4 as lead compound
There are a large amount of reports, but the noval chemical compound of most of synthesis is not enough protruded in the presence of activity or toxicity is larger or synthesis is relatively more tired
The shortcomings of difficult.Five-ring heterocycles and hexa-member heterocycle class compound are as CA-4 analogs it has been reported that representative change
Compound structure is as follows.(relevant report referring to：Lu Y.,et al.Journal of Medicinal Chemistry,
2009,52,1701；Chen J.J.,et al.Journal of Medicinal Chemistry,2010,53,7414；Xiao
M.,et al.Journal of Medicinal Chemistry,2013,56,3318；Romagnoli R.,et
al.Journal of Medicinal Chemistry,2011,54,5144；Lu Y.,et al.Journal of
Medicinal Chemistry,2014,57,7355；Hwang D.J.,et al.ACS Medicinal Chemistry
Letter,2015,6,993.)
Five-ring heterocycles of the present invention and five-ring heterocycles, that is, 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] three
Nitrogen azole compounds have not yet to see report as the research of active compound for anti tumor.
The content of the invention
It is an object of the invention to design, synthesize the Combretastatin with good proliferative activity o f tumor
The analogue of A-4, the i.e. CA-4 of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound are similar
Thing；Show good result in the antitumor activity test in vivo and in vitro of prepared compound.
The target product possible constructions general formula I of the present invention is represented：
Present invention is preferably related to the compounds of formula I being defined as follows：
Wherein, in general formula I, R2-R4For C1-C6Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C6Alkyl,
C1-C6Alkyl oxy, nitro, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino.
Present invention is preferably related to the compounds of formula I being defined as follows：
Wherein, R in general formula I2-R4For C1-C4Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C4Alkyl,
C1-C4Alkyl oxy, nitro, amino, C1-C4Alkyl amino, two C1-C4Alkyl amino.
Present invention is preferably related to the compounds of formula I being defined as follows：
Wherein, in general formula I, R2-R4For C1-C3Alkyl oxy, R1、R5、R6It is each independently hydrogen, fluorine, chlorine, bromine, iodine, C1-
C3Alkyl, C1-C3Alkyl oxy, nitro, amino, C1-C3Alkyl amino, two C1-C3Alkyl amino.
Present invention is preferably related to the compounds of formula I being defined as follows：
Wherein, in general formula I, R2-R4For C1-C3Alkyl oxy, R1、R5、R6It is each independently hydrogen, chlorine, C1-C3Alkyl,
C1-C3Alkyl oxy, nitro, amino.
Present invention is preferably related to the compounds of formula I being defined as follows：
Wherein, in general formula I, R2-R4For methoxyl group, R1、R5、R6Be each independently hydrogen, chlorine, methyl, methoxyl group, nitro,
Amino.
The present invention compound further include derivative shown in structure above formed it is pharmaceutically acceptable nontoxic
Salt and its hydrate, these pharmaceutically acceptable nontoxic salts include the salt that the derivative is formed with acid.The acid can be with
For hydrochloric acid, sulfuric acid, hydrobromic acid, the inorganic acid of phosphoric acid or selected from acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid
Organic acid.The hydration number of the hydrate is any real number in 0~16.
Currently preferred part of compounds structure is as follows：
Compound 1
3- (3,4,5- trimethoxyphenyls) -6- (4- aminomethyl phenyls) -1H- pyrazolos [5,1-c] [1,2,4] triazole
Compound 2
3- (3,4,5- trimethoxyphenyls) -6- (4- chlorphenyls) -1H- pyrazolos [5,1-c] [1,2,4] triazole
Compound 3
3- (3,4,5- trimethoxyphenyls) -6- (4- methoxyphenyls) -1H- pyrazolos [5,1-c] [1,2,4] triazole
Compound 4
3- (3,4,5- trimethoxyphenyls) -6- (3- nitro -4- methoxyphenyls) -1H- pyrazolos [5,1-c] [1,2,
4] triazole
Compound 5
3- (3,4,5- trimethoxyphenyls) -6- (3- amino-4-methoxyls phenyl) -1H- pyrazolos [5,1-c] [1,2,
4] triazole
3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound of invention can be according to following anti-
Route is answered to synthesize to obtain：
The compound A substituted accordingly is added in eggplant type bottle, makees solvent reaction 2h, TLC detection raw material with acetic anhydride
After disappearance, reaction solution is poured into frozen water and is stirred, the solid filtration drying of precipitation, then returns it with concentrated hydrochloric acid-ethanol system
Stream；After question response is complete, ethanol is evaporated, adds ethyl acetate, is washed, is evaporated after organic layer is dried with anhydrous sodium sulfate, obtains end
Product B, yield 69-84%.
Wherein, 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole chemical combination containing amino in compound
Thing can be prepared by the compound containing nitro in corresponding compound through reduction reaction, and reducing agent is anhydrous ferric trichloride/hydration
Hydrazine/activated carbon system.
Embodiment
It will be helpful to understand the present invention by following examples, but present disclosure is not limited to example.
Agents useful for same of the present invention is commercially available, microwave model CEM-discover-sp used, Ultrasound Instrument KQ-
400KDB type high power numerical control supersonic cleaning devices (Kunshan Ultrasonic Instruments Co., Ltd.), nuclear magnetic resoance spectrum is by AVANCE-
400th, Bruker ARX-300, Bruker ARX-400, Bruker ARX-600 fourier transform NMRs spectrometer measure,
Mass spectrum is measured by Brukee Esqure 2000, Shimadzu GCMS-QP5050A types mass spectrograph.
Embodiment 1：3- (3,4,5- trimethoxyphenyls) -6- (4- aminomethyl phenyls) -1H- pyrazolos [5,1-c] [1,2,4]
The preparation of triazole (compound 1)：
By 3- (3,4,5- trimethoxyphenyls) -6- (4- aminomethyl phenyls)-[1,2,4] triazole simultaneously [3,4-b] [1,3,4]
Thiadiazine 0.40g (1mmol) is added in 50ml eggplant type bottles, after making solvent reaction 2h, TLC detection raw material disappearance with acetic anhydride,
Reaction solution is poured into frozen water and is stirred, the solid filtration drying of precipitation, is then added into 50ml eggplant type bottles, with 20ml second
Alcohol dissolves, and adds 1ml concentrated hydrochloric acids, back flow reaction 2h；After question response is complete, ethanol is evaporated, adds ethyl acetate, is washed, by organic layer
It is evaporated after being dried with anhydrous sodium sulfate, chromatographic process purifying, obtains compound 1；Red brown solid, yield：81%.M.p.:119-
122℃；1H-NMR(600MHz,CDCl3):δ 9.73 (s, 1H), 7.88 (s, 2H), 7.82 (d, J=8.0Hz, 2H), 7.25 (d, J
=8.0Hz, 2H), 6.02 (s, 1H), 4.01 (s, 6H), 3.94 (s, 3H), 2.40 (s, 3H)；13C-NMR(150MHz,CDCl3):
δ160.1,153.4(2C),148.4,139.5,139.4,138.4,130.9,129.3(2C),126.0(2C),121.1,
103.8(2C),75.0,60.9,56.2(2C),21.3；ESI-MS:M/z=365.3 [M+H]+,387.3[M+Na]+。
Embodiment 2：3- (3,4,5- trimethoxyphenyls) -6- (4- chlorphenyls) -1H- pyrazolos [5,1-c] [1,2,4] three
The preparation of nitrogen azoles (compound 2)：
In addition to using corresponding raw material, with the identical method prepare compound 2 of embodiment 1；Red solid, yield：
82%.M.p.:150-151℃；1H-NMR(600MHz,CDCl3):δ 9.65 (s, 1H), 7.86 (s, 2H), 7.85 (d, J=
8.4Hz, 2H), 7.41 (d, J=8.4Hz, 2H), 6.05 (s, 1H), 4.02 (s, 6H), 3.94 (s, 3H)；13C-NMR(150MHz,
CDCl3):δ158.7,153.4(2C),148.4,139.7,139.4,134.3,132.3,128.8(2C),127.3(2C),
120.9,103.8(2C),75.3,60.9,56.2(2C)；ESI-MS:M/z=385.0 [M+H]+,407.1[M+Na]+。
Embodiment 3：3- (3,4,5- trimethoxyphenyls) -6- (4- methoxyphenyls) -1H- pyrazolos [5,1-c] [1,2,
4] preparation of triazole (compound 3)：
In addition to using corresponding raw material, with the identical method prepare compound 3 of embodiment 1；Red solid, yield：
84%.M.p.:146-147℃；1H-NMR(600MHz,CDCl3):δ 9.89 (s, 1H), 7.87 (s, 2H), 7.86 (d, J=
8.7Hz, 2H), 6.97 (d, J=8.7Hz, 2H), 5.98 (s, 1H), 4.01 (s, 6H), 3.93 (s, 3H), 3.86 (s, 3H)；13C-
NMR(150MHz,CDCl3):δ159.9,159.8,153.4(2C),148.4,139.5,139.3,127.3(2C),126.5,
121.2,114.0(2C),103.8(2C),74.6,60.9,56.2(2C),55.3；ESI-MS:M/z=381.3 [M+H]+。
Embodiment 4：3- (3,4,5- trimethoxyphenyls) -6- (3- nitro -4- methoxyphenyls) -1H- pyrazolos [5,1-
C] [1,2,4] triazole (compound 4) preparation：
In addition to using corresponding raw material, with the identical method prepare compound 4 of embodiment 1；Yellow solid, yield：
76%.M.p.:149-151℃；1H-NMR(400MHz,DMSO-d6):δ 13.23 (s, 1H), 8.41 (d, J=2.0Hz, 1H),
8.25 (dd, J=8.8Hz, J=2.0Hz, 1H), 7.80 (s, 2H), 7.44 (d, J=8.8Hz, 1H), 6.50 (s, 1H), 3.97
(s,3H),3.93(s,6H),3.76(s,3H)；13C-NMR(100MHz,DMSO-d6):δ156.7,153.7(2C),152.3,
149.2,139.9,139.4,137.8,131.7,126.9,122.3,121.5,115.2,103.6(2C),75.7,60.7,
57.3,56.4(2C)；ESI-MS:M/z=426.1 [M+H]+,448.1[M+Na]+。
Embodiment 5：3- (3,4,5- trimethoxyphenyls) -6- (3- amino-4-methoxyls phenyl) -1H- pyrazolos [5,1-
C] [1,2,4] triazole (compound 5) preparation：
0.26g (0.5mmol) compound 4 is added in 50mL eggplant type bottles, adds activated carbon 20mg and ferric trichloride
20mg makees catalyst, makees solvent with absolute ethyl alcohol, 80% hydrazine hydrate 0.1mL of lower dropwise addition is stirred, when back flow reaction 3 is small；TLC is detected
After completion of the reaction, activated carbon is filtered to remove, absolute ethyl alcohol is evaporated, adds water, is extracted with ethyl acetate, organic layer is merged dry
Dry, vacuum distillation obtains crude product, and chromatographic isolation obtains compound 5；Red brown solid, yield：69%.M.p.:135-137℃；1H-
NMR(600MHz,CDCl3):δ 9.86 (s, 1H), 7.85 (s, 2H), 7.31 (s, 2H), 6.84 (d, J=8.8Hz, 1H), 5.95
(s,1H),4.00(s,6H),3.92(s,3H),3.89(s,3H)；ESI-MS:M/z=396.4 [M+H]+。
Embodiment 6：The anti tumor activity in vitro test of the compound of the present invention
External activity test method and result are as follows：
Wherein, select CA-4 and the clinical common antitumor drug adriamycin (ADM) of document report real for positive control
Test group.
Antitumor activity body outer screening test -1
Screening technique：Tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell line：BGC823 cell line SGC-7901cell line
Action time：72h
- 1 is shown in Table to the inhibiting rate (%) of tumour growth under each 10 μ g/mL dosage of compound.
Antitumor activity body outer screening test -2
Screening technique：Tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell line：Human oral cavity epithelial cancer cell line KB cell line
Action time：72h
- 1 is shown in Table to the inhibiting rate (%) of tumour growth under each 10 μ g/mL dosage of compound.
Antitumor activity body outer screening test 3
Screening technique：Tetrazolium (micoculture tetrozolium, MTT) reduction method
Cell line：Human fibrosarcoma cell strain HT-1080cell line
Action time：72h
- 1 is shown in Table to the inhibiting rate (%) of tumour growth under each 10 μ g/mL dosage of compound.
Embodiment 7：Antitumor activity test in the animal body of the compound of the present invention
The preferable compound 2 of selection external activity and compound 5 have carried out antitumor activity in animal body and have tested, mould used
Type is mouse S-180 sarcoma models, and positive control medicine is clinical common antitumor drug fluorouracil
(Fluorouracil)。
Experimental method：18-22 grams of female KM mouse and the S-180 knurl kinds of well-grown 7-11 days are selected, by knurl group
Cell suspension is woven into, it is subcutaneous to be seeded to right side of mice armpit, about 1.0-2.0 × 106Cell/only, when inoculation 24 is small after it is random
Divide cage, continuous 7 days of intraperitoneal injection.Animal is put to death when 24 is small after drug withdrawal, is weighed, knurl weight, each group is calculated and is averaged knurl weight, press
Equation below obtains tumor control rate and carries out t inspections.
Tumor control rate=[(blank control group be averaged knurl weight-treatment group be averaged knurl weight)/(blank control group is averaged knurl
Weight)] × 100%
Experimental result is shown in Table -2.
Embodiment 8：Acute toxicity preliminary test in the animal body of the compound of the present invention
The preferable compound 2 of antitumor activity and compound 5 have carried out acute toxicity survey in animal body in selection animal body
Examination.
Each 10 of 18-22 grams of female KM mouse is selected, respectively intraperitoneal injection compound 2,5 each 500mg/ of compound
After kg, there is autogenic movement suppression, writhing, and to the suppression of body weight increase, food ration, water intake, but have no dead mouse.Stop
After the medicine a few days, surviving animals recover normal.The LD of intraperitoneal administration50Value is more than 500mg/kg.
Table -1
Table -2
Claims (13)
1. 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compounds and its salt of general formula I：
Wherein, in general formula I, R2-R4For C1-C6Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C6Alkyl, C1-C6
Alkyl oxy, nitro, amino, C1-C6Alkyl amino, two C1-C6Alkyl amino.
2. compound and its salt described in claim 1,
Wherein, in general formula I, R2-R4For C1-C4Alkyl oxy, R1、R5、R6It is each independently hydrogen, halogen, C1-C4Alkyl, C1-C4
Alkyl oxy, nitro, amino, C1-C4Alkyl amino, two C1-C4Alkyl amino.
3. compound and its salt described in claim 1 or 2,
Wherein, in general formula I, R2-R4For C1-C3Alkyl oxy, R1、R5、R6It is each independently hydrogen, fluorine, chlorine, bromine, iodine, C1-C3Alkane
Base, C1-C3Alkyl oxy, nitro, amino, C1-C3Alkyl amino, two C1-C3Alkyl amino.
4. compound and its salt described in claim 1 or 2,
Wherein, in general formula I, R2-R4For methoxyl group, R1、R5、R6It is each independently hydrogen, chlorine, methyl, methoxyl group, nitro, amino.
5. compound and its salt described in claim 3,
Wherein, in general formula I, R2-R4For methoxyl group, R1、R5、R6It is each independently hydrogen, chlorine, methoxyl group, amino.
6. compound according to claim 1 and its salt, are selected from：
Compound 1
3- (3,4,5- trimethoxyphenyls) -6- (4- aminomethyl phenyls) -1H- pyrazolos [5,1-c] [1,2,4] triazole
Compound 2
3- (3,4,5- trimethoxyphenyls) -6- (4- chlorphenyls) -1H- pyrazolos [5,1-c] [1,2,4] triazole
Compound 3
3- (3,4,5- trimethoxyphenyls) -6- (4- methoxyphenyls) -1H- pyrazolos [5,1-c] [1,2,4] triazole
Compound 4
3- (3,4,5- trimethoxyphenyls) -6- (3- nitro -4- methoxyphenyls) -1H- pyrazolos [5,1-c] [1,2,4] three
Nitrogen azoles
Compound 5
3- (3,4,5- trimethoxyphenyls) -6- (3- amino-4-methoxyls phenyl) -1H- pyrazolos [5,1-c] [1,2,4] three
Nitrogen azoles.
7. compound and its salt according to claim 1,2,5 or 6 any one, it is characterised in that：The salt is should
Compound and the salt that is formed of acid, the acid is hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid,
Benzoic acid, malic acid.
8. compound according to claim 3 and its salt, it is characterised in that：The salt is formed by the compound and acid
Salt, the acid for hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
9. compound according to claim 4 and its salt, it is characterised in that：The salt is formed by the compound and acid
Salt, the acid for hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, acetic acid, citric acid, oxalic acid, tartaric acid, benzoic acid, malic acid.
10. the preparation method of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound shown in formula B, its
It is characterized in that：
The compound A substituted accordingly is added in eggplant type bottle, makees solvent reaction with acetic anhydride, after TLC detection raw materials disappear,
Reaction solution is poured into frozen water and is stirred, the solid filtration drying of precipitation, then flows back it with concentrated hydrochloric acid-ethanol system；Treat anti-
After having answered, ethanol is evaporated, adds ethyl acetate, is washed, is evaporated after organic layer is dried with anhydrous sodium sulfate, obtains end-product B；Its
In, R5、R6As claimed in claim 1；
Wherein, 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound containing amino can in compound
Prepared by the compound containing nitro in corresponding compound through reduction reaction, reducing agent is anhydrous ferric trichloride/hydrazine hydrate/work
Property charcoal system.
11. a kind of pharmaceutical composition, comprising the compound described in claim 1-9 any one and its salt and pharmaceutically acceptable
Carrier.
12. 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole any one of claim 1-9
Application of the pharmaceutical composition in antitumor drug is prepared described in compound and its salt or claim 11.
13. application as claimed in claim 12, it is characterised in that the tumour is stomach cancer, oral epithelium cancer or fiber meat
Knurl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610591881.8A CN106188069B (en) | 2016-07-26 | 2016-07-26 | Purposes of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound as tumor cell proliferation inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610591881.8A CN106188069B (en) | 2016-07-26 | 2016-07-26 | Purposes of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound as tumor cell proliferation inhibitor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106188069A CN106188069A (en) | 2016-12-07 |
| CN106188069B true CN106188069B (en) | 2018-05-08 |
Family
ID=57495038
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610591881.8A Expired - Fee Related CN106188069B (en) | 2016-07-26 | 2016-07-26 | Purposes of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound as tumor cell proliferation inhibitor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106188069B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113929635B (en) * | 2021-11-09 | 2023-08-22 | 沈阳药科大学 | 1, 6-diphenyl-1H-benzo [ d ] [1,2,3] triazole compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008069500A1 (en) * | 2006-12-07 | 2008-06-12 | Amorepacific Corporation | Triazolopyridazine derivatives having inhibitory activity against acetyl-coa carboxylase |
| WO2009094205A2 (en) * | 2008-01-23 | 2009-07-30 | Cytovia, Inc. | 3-aryl-6-aryl-7h-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| CN102020648A (en) * | 2011-01-14 | 2011-04-20 | 南京英派药业有限公司 | 3-aryl-6-aryl-[1,2,4] triazol [4,3-b] pyridazine taken as cell proliferation inhibitor and application of cell proliferation inhibitor |
-
2016
- 2016-07-26 CN CN201610591881.8A patent/CN106188069B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008069500A1 (en) * | 2006-12-07 | 2008-06-12 | Amorepacific Corporation | Triazolopyridazine derivatives having inhibitory activity against acetyl-coa carboxylase |
| WO2009094205A2 (en) * | 2008-01-23 | 2009-07-30 | Cytovia, Inc. | 3-aryl-6-aryl-7h-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines and analogs as activators of caspases and inducers of apoptosis and the use thereof |
| CN102020648A (en) * | 2011-01-14 | 2011-04-20 | 南京英派药业有限公司 | 3-aryl-6-aryl-[1,2,4] triazol [4,3-b] pyridazine taken as cell proliferation inhibitor and application of cell proliferation inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106188069A (en) | 2016-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108524482B (en) | Use of 2- (substituted phenylamino) benzoic acid FTO inhibitors for treating leukemia | |
| Cao et al. | Synthesis, acute toxicities, and antitumor effects of novel 9-substituted β-carboline derivatives | |
| JP7030093B2 (en) | How to make an oxathiadin-like compound | |
| CN103961340B (en) | A kind of LSD1 inhibitor and its application | |
| JP7123417B2 (en) | Anxiolytic deuterium compound and its medicinal use | |
| CN114195814B (en) | Hydroxy naphthalenone-phenylboronic acid compound, preparation method and application | |
| CN106188069B (en) | Purposes of 3,6- diaryl -1H- pyrazolos [5,1-c] [1,2,4] triazole compound as tumor cell proliferation inhibitor | |
| CN106008557B (en) | 3,6- diaryl-[1,2,4] triazole simultaneously purposes of [3,4-b] [1,3,4] thiadiazole compound as tumor cell proliferation inhibitor | |
| CN110922415B (en) | Synthesis and application of novel anti-tumor active compound | |
| CA2847971C (en) | Stilbenoid compounds as inhibitors for squamous carcinoma and hepatoma and uses thereof | |
| CN113735814B (en) | Myrtle ketone compound and application thereof in preparation of anti-influenza virus drugs | |
| CN106188068A (en) | 3,6 diaryl [1,2,4] triazole also [4,3 b] pyridazine compound and purposes | |
| CN112679492B (en) | Berberine derivative, preparation method and application thereof | |
| CN106243130B (en) | 3,6- diaryl-[1,2,4] triazole simultaneously [3,4-b] [1,3,4] diazthines compound and application thereof | |
| CN107162982A (en) | Imidazole compounds with anticancer activity and derivatives thereof | |
| CN102746212B (en) | Beta-elemene indole derivative, preparation and application thereof | |
| CN103601684B (en) | 5-arylseleno benzimidazoles compound and uses thereof | |
| KR20010070381A (en) | Anti-cancer agent containing naphthoquinone compound | |
| CN107325052A (en) | Imidazole ester compounds with anticancer activity and derivatives thereof | |
| CN106220582B (en) | n, 4-diaryl thiazole-2-amine compound and application thereof as tumor cell proliferation inhibitor | |
| Yeşilada et al. | Synthesis, Anti‐inflammatory and Analgesic Synthesis, Anti‐inflammatory and Analgesic New 4 (3H)‐Quinazolinone Derivatives | |
| WO2016184122A1 (en) | Pyrazoles compounds | |
| CN103483291B (en) | 4,5-diaryl-1,3-selenazoles compounds and its production and use | |
| JP5489026B2 (en) | Novel antibacterial and anticancer compounds, their preparation and drug composition | |
| CN102766109B (en) | 2,3-diaryl thiazolidine-4-one/-thioketone compounds, oxides thereof and use 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 | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180508 |