CN101305998B - Use of aryl-3-substituted carbonyl pyridone compound - Google Patents
Use of aryl-3-substituted carbonyl pyridone compound Download PDFInfo
- Publication number
- CN101305998B CN101305998B CN2008100630180A CN200810063018A CN101305998B CN 101305998 B CN101305998 B CN 101305998B CN 2008100630180 A CN2008100630180 A CN 2008100630180A CN 200810063018 A CN200810063018 A CN 200810063018A CN 101305998 B CN101305998 B CN 101305998B
- Authority
- CN
- China
- Prior art keywords
- bimodal
- unimodal
- compound
- dimethoxyphenyl
- aryl
- 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 carbonyl pyridone compound Chemical class 0.000 title description 12
- 239000003814 drug Substances 0.000 claims abstract description 31
- 208000032839 leukemia Diseases 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- SBBCTVDKWRLARY-UHFFFAOYSA-N 3-(oxomethylidene)pyridin-2-one Chemical class O=C=C1C=CC=NC1=O SBBCTVDKWRLARY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 47
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- 241001597008 Nomeidae Species 0.000 claims description 4
- 230000001772 anti-angiogenic effect Effects 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims 1
- 210000004027 cell Anatomy 0.000 abstract description 44
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 239000002246 antineoplastic agent Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 8
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 7
- 238000000338 in vitro Methods 0.000 abstract description 7
- 230000012010 growth Effects 0.000 abstract description 6
- 230000002401 inhibitory effect Effects 0.000 abstract description 5
- 210000004881 tumor cell Anatomy 0.000 abstract description 5
- 201000010099 disease Diseases 0.000 abstract description 4
- 208000019420 lymphoid neoplasm Diseases 0.000 abstract 1
- 230000002902 bimodal effect Effects 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 28
- 239000007787 solid Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 17
- 238000001953 recrystallisation Methods 0.000 description 15
- 206010028980 Neoplasm Diseases 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000011282 treatment Methods 0.000 description 9
- 238000000354 decomposition reaction Methods 0.000 description 8
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 8
- 210000002751 lymph Anatomy 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 210000001185 bone marrow Anatomy 0.000 description 6
- 230000003013 cytotoxicity Effects 0.000 description 6
- 231100000135 cytotoxicity Toxicity 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000003556 assay Methods 0.000 description 5
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 5
- 229960004316 cisplatin Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000001472 cytotoxic effect Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 4
- DQXKOHDUMJLXKH-PHEQNACWSA-N (e)-n-[2-[2-[[(e)-oct-2-enoyl]amino]ethyldisulfanyl]ethyl]oct-2-enamide Chemical compound CCCCC\C=C\C(=O)NCCSSCCNC(=O)\C=C\CCCCC DQXKOHDUMJLXKH-PHEQNACWSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- 239000000427 antigen Substances 0.000 description 3
- 102000036639 antigens Human genes 0.000 description 3
- 108091007433 antigens Proteins 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 3
- 230000002607 hemopoietic effect Effects 0.000 description 3
- 210000000265 leukocyte Anatomy 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 208000037920 primary disease Diseases 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 231100000167 toxic agent Toxicity 0.000 description 3
- 239000003440 toxic substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 230000000118 anti-neoplastic effect Effects 0.000 description 2
- JSKFWUPVIZYJMR-UDOAKELVSA-N bmy-27557 Chemical compound O=C1N(CCN(CC)CC)C(=O)C(C2=C3[CH]C=CC(Cl)=C3NC2=C23)=C1C2=C1C=CC=C(Cl)[C]1N3[C@@H]1O[C@H](CO)[C@@H](OC)[C@H](O)[C@H]1O JSKFWUPVIZYJMR-UDOAKELVSA-N 0.000 description 2
- 238000010322 bone marrow transplantation Methods 0.000 description 2
- 244000309466 calf Species 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- 229940080856 gleevec Drugs 0.000 description 2
- HAVJATCHLFRDHY-JZTSUELASA-N harringtonine Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@](O)(CCC(C)(C)O)CC(=O)OC)[C@@H]4C2=CC2=C1OCO2 HAVJATCHLFRDHY-JZTSUELASA-N 0.000 description 2
- 229960002411 imatinib Drugs 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 150000004885 piperazines Chemical class 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- INSACQSBHKIWNS-QZQSLCQPSA-N rebeccamycin Chemical class O[C@@H]1[C@@H](O)[C@H](OC)[C@@H](CO)O[C@H]1N1C2=C3N=C4[C](Cl)C=CC=C4C3=C3C(=O)NC(=O)C3=C2C2=CC=CC(Cl)=C21 INSACQSBHKIWNS-QZQSLCQPSA-N 0.000 description 2
- 229960005567 rebeccamycin Drugs 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 description 1
- XPDSXKIDJNKIQY-UHFFFAOYSA-N 1-cyclohexylpiperazine Chemical class C1CCCCC1N1CCNCC1 XPDSXKIDJNKIQY-UHFFFAOYSA-N 0.000 description 1
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 1
- 206010000830 Acute leukaemia Diseases 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 108010024976 Asparaginase Proteins 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- HXWDNCGKKYUTTH-UHFFFAOYSA-N CN(N1CC=CC=2C=CC=NC12)C Chemical compound CN(N1CC=CC=2C=CC=NC12)C HXWDNCGKKYUTTH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical class C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- HAVJATCHLFRDHY-UHFFFAOYSA-N Harringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HAVJATCHLFRDHY-UHFFFAOYSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 239000003817 anthracycline antibiotic agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 229960003272 asparaginase Drugs 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000009096 combination chemotherapy Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000013210 evaluation model Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- 239000004519 grease Substances 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229960004130 itraconazole Drugs 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004799 sedative–hypnotic effect Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006203 subcutaneous dosage form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229960000820 zopiclone Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides aryl-3-substituted carbonyl-pyridinones and the application of medicine salts thereof to the preparation of anti-neoplastic drugs, and main relates to 6-aryl-3-substituted carbonyl-pyridinones and the medicine salts thereof. 6-aryl-3-substituted carbonyl-pyridinone derivatives provided by the invention have obvious growth inhibitory activity to promyelocytic leukemia cells cultured in vitro (HL-60) and mouse lymphoid tumor cell strains (P388D1); therefore, the 6-aryl-3-substituted carbonyl-pyridinone derivatives have the expectable purpose of being used as the drugs for treating the correlative tumorous diseases of leukemia.
Description
Technical field
The invention belongs to pharmaceutical chemistry and area of pharmacology, particularly, the present invention relates to the purposes that a class 6-aryl-3-substituted carbonyl-pyridinone chemical compound is used to prepare antitumor drug and pharmaceutical composition.Test through pharmacologically active, this compounds has the activity of remarkable inhibition In vitro culture people promyelocytic leukemia cell (HL-60) and mouse lymph sample tumor cell strain (P388D1) growth, can expect as anti-treating leukemia and related neoplasms disease medicament purposes thereof.
Background technology
Leukemia (leukemia) is commonly called as leukemia, be one of domestic ten big malignant tumor occurred frequently, the malignant disease that belongs to hemopoietic system, comparatively different with cancers in general is, its pathogenesis still is certain class cell abnormality proliferation in bone marrow or other hemopoietic tissue in the hemopoietic tissue, and further invade each viscera tissue in the human body, cause the normal hematopoiesis cell to be suppressed, the symptom of Chan Shenging generally includes fever clinically, hemorrhage, anemia and liver, the situation of spleen and lymphadenectasis, can be divided into acute and chronic leukemia according to the tumor development situation, if classified by paracytic source, individual beamlets is divided into bone marrow and lymph corpuscle leukemia more again again.Acute lymphoblastic (lymphoblast) leukemia is a kind of life-threatening disease, can grow under its normal condition for lymphocytic cell cancerates, and replace the normal cell in the bone marrow rapidly.This type acute lymphoblastic leukemia is the modal malignant tumor of child, accounts for 25% of the whole tumors of child below 15 years old.Involve 3～5 years old child more, also involve teenager, lessly involve the adult.The associating chemotherapy of treatment multiple medications commonly used, the medicine of each dosage is given in a couple of days or several weeks repeatedly.The Combination chemotherapy medication has oral prednisone, weekly vincristine, and vein gives anthracycline antibiotics or asparaginase.Chronic myelocytic (marrow, bone marrow, granulocytic) leukemia is that bone marrow the marrow being invaded by pathogen malignant change of cell produces a large amount of unusual granulocytic a kind of diseases.Primary disease can involve the crowd of any age and sex, but more rare in child below 10 years old.The treatment of chronic lymphocytic leukemia can merge bone marrow transplantation by the high dose chemotherapy and achieve the goal.Hydroxyurea is the most frequently used chemotherapeutics of primary disease as oral medicine.Busulfan is also helpful to primary disease, but because its serious toxic action is general only as the short-term medication.Yet leukocyte has surface antigen, be (the Human Leukocyte Antigen of Human leukocyte antigen, HLA), if do not run into close family members of blood relationship or the close bone marrow donor of other HLA, because repel considering of factor, usually do not advise accepting bone marrow transplantation, and only based on chemotherapy.In the middle of the leukemic medicine of many treatments, the pill Gleevec (being called STI-571 or imatinib again) of the chronic myeloid leukemia of treatment (CML) of U.S. food and UNDCP (FDA) approval listing is evident in efficacy.As if yet the variability of cancerous cell (Heterogeneity) but overcomes the influence that this medicine brings, take this medicine more for a long time, more is easy to generate the JEG-3 to this medical instrument resistance, and this also so once becomes one of problem of the anxious desire solution of scientist.
Except the novel targets of the antitumor action of domestic and international concern and the new type antineoplastic medicine development at the too many levels effect of mechanism, traditional cytotoxicity antitumor drug is still in the treatment of cancer and the common indispensable first-line treatment measure of using of means such as radiotherapy.The task of pharmaceutical chemistry research worker is in this regard: constantly seek the cell toxicant compounds that leukemia cell line is had growth inhibitory activity, as lead compound, strive for finding the anti-cancer agent of more efficient, low toxicities, such as the treatment leukemia medicaments of finding from one generation to the next such as harringtonine, and constantly make progress.The industry cell toxicant class antineoplastic new material just under study for action that national cancer institute NCI announces has manyly have been finished clinical experiment nearly or has come into the market, and it is effective to be used for the treatment of mouse leukemia as the Rebeccamycin Analogue (NSC 655649) of Bristol Myers Squibb development; The guanine metabolism agent interfering (NSC 686673) that Glaxo Wellcome releases is used for the treatment of leukemia, t cell lymphoma etc.Illustrate that all cell toxicant class anti-leukemia medicine still has market and definite curative effect comparatively widely.Leukemia cell line pharmacodynamics evaluation model commonly used is P388, P388/ADR, CCRF, CEM, K562, MolT4, HL-60 etc.
Piperazine compounds has pharmacologically active widely, medication as usual: sedative hypnotic (Zopiclone), phosphodiesterase gamma inhibitors (Sildenafil), antimicrobial drug (Enoxacin, Ciprofloxacin) and antifungal agent (Ketoconazole, itraconazole).In early days, piperazine and piperazine derivative thereof have carried out extensive studies [Groszkowski as antitumor drug, S. etc., J.Med.Chem.1968,11,621.], many in recent years antitumor drug that are used for contain piperazine fragment [Westwell, A.D.Drug Discovery Today 2003,8,229; Boschelli, D.H. etc., J.Med.Chem.2001,44,3965].
Summary of the invention
The object of the present invention is to provide a class aryl-3-substituted carbonyl-pyridinone chemical compound and officinal salt thereof the purposes in the preparation antitumor drug, relate generally to a class 6-aryl-3-substituted carbonyl-pyridinone chemical compound and an officinal salt thereof.6-aryl-3-substituted carbonyl-pyridinone derivant provided by the invention has significant growth inhibitory activity for In vitro culture people promyelocytic leukemia cell (HL-60) and mouse lymph sample tumor cell strain (P388D1), illustrates that such 6-aryl-3-substituted carbonyl-pyridinone derivant has the purposes that can expect as anti-treating leukemia related neoplasms disease medicament.
This compounds is selected from:
Compound I-1.3-(4-cyclohexyl piperazine carbonyl)-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-2.3-[4-(4-fluorophenyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-3.3-[4-(2-methoxyphenyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-4.3-[4-(3, the 4-dichloro benzyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-5.3-[4-(3, the 4-Dichlorobenzene base) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-6.3-(4-cyclopentyl-based piperazine carbonyl)-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-7.3-[4-(2-pyrimidine radicals) piperazine carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-8.3-[4-(3, the 4-dimethoxy-benzyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-9.3-[4-(3, the 4-dichloro benzyl) piperazine carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-10.N-benzyl-6-(3, the 4-Dimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3 amide;
Compound I-11.3-(trans-4-benzyl-2,5-lupetazin carbonyl)-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-12.N-(4-benzyl piepridine base)-6-(3, the 4-Dimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3 amide;
Compound I-13.3-[is trans-4-(3,4,5-trimethoxy benzyl)-2, and 5-lupetazin carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-14.3-[is trans-4-(4-luorobenzyl)-2, and 5-lupetazin carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones.
Usefulness of the present invention is: the prepared above-mentioned 6-aryl-3-substituted carbonyl-pyridinone chemical compound of the present invention has important biological, in vitro tests shows that such chemical compound with pyridone structure has growth inhibitory activity for In vitro culture people promyelocytic leukemia cell (HL-60) and mouse lymph sample tumor cell strain (P388D1), can expect as control related neoplasms disease medicament purposes.
The specific embodiment
The present invention is further described in conjunction with the embodiments.Embodiment has provided the synthetic and dependency structure appraising datum of representative noval chemical compound.Mandatory declaration, following embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1:The preparation of starting material A (3, the 4-dimethoxy-acetophenone):
Starting material A
Catechol (11.0 grams, 0.1 mole) is dissolved in 150 milliliters of acetone, adds potassium carbonate (27.6 grams, 0.20 mole) and dimethyl sulfate (12.6 grams, 0.1 mole)); Back flow reaction 10 hours, TLC shows and to react completely, filter, with ethyl acetate filter wash cake, concentrate the grease crude product, get o-dimethoxybenzene (12.1 grams, yield 81%) through too short silica gel column chromatography.
O-dimethoxybenzene (13.8 grams, 0.1 mole) is dissolved in 150 milliliters of dichloromethane, adds anhydrous chlorides of rase zinc powder (26.8 grams, 0.20 mole) then, drip acetic anhydride (15.3 grams, 0.15 mole) down at-15 ℃; After dropwising, reaction slowly was raised to room temperature reaction 12 hours, then reactant was carefully poured in 600 milliliters of frozen water, used ethyl acetate extraction 3 times; Organic facies anhydrous magnesium sulfate drying, filtering and concentrating get the yellow oil crude product, get starting material A (3, the 4-dimethoxy-acetophenone) through too short silica gel column chromatography, 15.3 grams, yield 85%; White solid, fusing point: 41～43 ℃; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm) 2.56 (unimodal, 3H, COCH
3), 3.93 (unimodal, 3H, OCH
3), 3.95 (unimodal, 3H, OCH
3), 6.89 (bimodal, 1H, J=8.4Hz, H-5), 7.52 (unimodal, 1H, H-2), 7.57 (bimodal, 1H, J=8.4Hz, H-6).
Embodiment 2:The preparation of starting material B (2, the 5-dimethoxy-acetophenone):
Identical with the method for embodiment 1, to be raw material, get starting material B (2, the 5-dimethoxy-acetophenone), colorless oil to biphenol (11.0 grams, 0.1 mole).Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm) 2.62 (unimodal, 3H, COCH
3), 3.77 (unimodal, 3H, OCH
3), 3.79 (unimodal, 3H, OCH
3), 6.89 (bimodal, 1H, J=8.4Hz, H-4), 7.03 (bimodal, 1H, J=8.4Hz, H-3), 7.30 (unimodal, 1H, H-6).
Embodiment 3:Intermediate compound III a[3-cyano group-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones] preparation:
Compound III a
With sodium metal (2.76 grams, 120 mMs) add in 250 milliliters of ether, drip 1 milliliter of ethanol, under ice bath, drip starting material A (3, the 4-dimethoxy-acetophenone) (100 mM) and Ethyl formate (150 mM) mixture, after dropwising, mixture stirred after 15 minutes, was warmed up to room temperature reaction 1 hour, remove ether under reduced pressure after, solid mixture adds cyanoacetamide (12.6 grams, 150 mMs) and water (400 milliliters).After mixture refluxed 8 hours, acidifying with acetic acid was used in cooling, filter xanchromatic solid, after the drying, head product recrystallization from ethanol obtains intermediate compound III a[3-cyano group-6-(3, the 4-Dimethoxyphenyl)-and the 2H-pyridin-2-ones]: yield: 56%, faint yellow solid; Fusing point＞250 ℃; R
f(methylene chloride 20: 1) 0.46; Proton nmr spectra
1H-NMR (400MHz, deuterated dimethyl sulfoxide, δ ppm): 3.82 (unimodal, MeO-4 '), 6.69 (bimodal, 1H, J=7.2Hz, H-5), 7.05 (bimodal, 2H, J=8.4Hz, H-3 ', 5 '), 7.79 (bimodal, 2H, J=8.4Hz, H-2 ', 6 '), 8.06 is (bimodal, 1H, J=7.2Hz, H-4); Electrospray Mass Spectrometry MS (ESI), m/e:257 ([M+1]
+).
Embodiment 4:Intermediate compound III b[3-cyano group-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones] preparation:
Identical with the method for embodiment 3, be raw material with starting material B, get intermediate compound III b[3-cyano group-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones]: yield: 46%, faint yellow solid; Fusing point＞250 ℃; R
f(methylene chloride 20: 1) 0.45; Electrospray Mass Spectrometry MS (ESI), m/e:257 ([M+1]
+).
Embodiment 5:Midbody compound IVa[6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones-3-carboxylic acid] preparation:
Compound III a[3-cyano group-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones] (10 mM) spend the night in ethanol water (ethanol/water=1/1) (50 milliliters) reflux of 25%KOH, and after the cooling, mixture is with the HCl neutralization of 6N.Xanchromatic solid precipitation filters, and gets thick product compound IVa[6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones-3-carboxylic acid with a spot of washing with alcohol filter cake]: white solid; Fusing point＞250 ℃; R
f(methylene chloride 5: 1) 0.20.
Embodiment 6:Midbody compound IVb[6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones-3-carboxylic acid] preparation:
Identical with the method for embodiment 5, with compound III b[3-cyano group-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones] be raw material, get compound IV b[6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones-3-carboxylic acid]: white solid; Fusing point＞250 ℃; R
f(methylene chloride 5: 1) 0.25.
Embodiment 7:The preparation of Compound I-1 (3-(4-cyclohexyl piperazine carbonyl)-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones)
With compound IV b[6-(2, the 5-Dimethoxyphenyl)-and 2H-pyridin-2-ones-3-carboxylic acid] (0.1 mM) be dissolved in 5 milliliters of dichloromethane, add 10 milligrams of 4-N successively, N-dimethylamino naphthyridine (DMAP), 41 milligrams of dicyclohexylcarbodiimides (DCC) and 60 milligrams of 1-cyclohexyl piperazines, mixture stirring at room 12 hours, after the filtration, remove solvent under reduced pressure, silica gel column chromatography (methylene chloride: 30/1), obtain white solid, fusing point: 198～199 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.54; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 1.73～2.20 (multiplet, 10H, H-9 ', 10 ', 11 ', 12 ', 13 '), 2.99 is (wide unimodal, 5H, H-4 ', 6 ', 8 '), 3.17 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.85 (unimodal, 3H, MeO-5 "), 3.88 (unimodal; 3H, MeO-2 "), 4.00 (wide unimodal, 2H, H-3 ' a, 7 ' a), 6.69 (bimodal, 2H, J=7.2Hz, H-5), 7.09～7.13 (multiplet, 3H, J=7.2Hz, H-3 ", 4 " and, 6 "); 7.82 (bimodal, 1H, J=7.2Hz, H-4); Electrospray Mass Spectrometry MS (ESI), relative abundance m/e:426 (M+1)
+
Prepare the chemical compound shown in the table one (I) according to similar approach with above embodiment:
Table one:
OMe representation methoxy (OCH wherein
3); What list below is the physicochemical data of each chemical compound in the table: I-2.3-[4-(4-fluorophenyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 215 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/methanol: 10/1) 0.43; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.08 (wide unimodal, 2H, H-4 ' b, 6 ' b), 3.17 (wide unimodal brs, 2H, H-4 ' a, 6 ' a), 3.56 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.81 is (unimodal, 3H, MeO-5 "), 3.88 (unimodal, 3H, MeO-2); 3.92 (wide unimodal, 2H, H-3 ' a, 7 ' a), 6.57 (bimodal; 1H, J=7.2Hz, H-5), 6.88-6.99 (multiplet, 6H; H-9 ', 10 ', 12 ', 13 '; 3 ", 4 "), 7.08 (unimodal, 1H; H-6 "), 7.75 (bimodal, 1H, J=7.2Hz, H-4), 11.10 (wide unimodal, 1H, H-1).
I-3.3-[4-(2-methoxyphenyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 218～220 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/methanol: 10/1) 0.33;
1Proton nmr spectra H-NMR (400MHz, deuterochloroform, δ ppm): 3.03 (wide unimodal, 2H, H-4 ' b, 6 ' b), 3.11 (wide unimodal, 2H, H-4 ' a, 6 ' a), 3.57 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.80 is (unimodal, 3H, MeO-5 "), 3.86 (unimodal, 6H, MeO-2 ", 9 '), 3.97 (wide unimodal, 2H, H-3 ' a, 7 ' a), 6.55 (bimodal, 1H, J=7.2Hz, H-5), 6.87～7.01 (multiplets, 6H, H-10 ', 11 ', 12 ', 13 ', 3 ", 4 "), 7.08 (unimodal, 1H, H-6 "), 7.73 (bimodal, 1H, J=7.2Hz; H-4), 11.10 (wide unimodal, 1H, H-1).
I-4.3-[4-(3, the 4-dichloro benzyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 205～207 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.32; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.40 (wide unimodal, 2H, H-4 ' b, 6 ' b), 2.49 (wide unimodal, 2H, H-4 ' a, 6 ' a), 3.39 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.43 is (unimodal, 2H, H-8 '), 3.77 (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.84 (unimodal, 3H, MeO-5 "), 3.87 (unimodal; 6H, MeO-2 "), 6.53 (bimodal, 1H, J=7.2Hz, H-5), and 6.95-7.01 (multiplet, 2H, H-3 ", 4 "), 7.08 (bimodal, 1H, J=2.4Hz, H-6 "), 7.15 (bimodal; 1H, J=8.4Hz, H-14 '), 7.37 (bimodal, 1H; J=8.4Hz, H-13 '), 7.43 (bimodal, 1H, J=2.0Hz; H-10 '), 7.69 (bimodal, 1H, J=7.2Hz; H-4), 10.93 (wide unimodal, 1H, H-1).
I-5.3-[4-(3, the 4-Dichlorobenzene base) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 217 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/methanol: 10/1) 0.40; Proton nmr spectra
1H-NMR (400MHz, deuterated dimethyl sulfoxide DMSO-d
6, δ ppm): 3.28 (wide unimodal, 4H, H-4 ', 6 '), 3.43 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.73 is (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.78 (unimodal, 3H, MeO-5 "), 3.79 (unimodal, 6H, MeO-2 "), 6.46 is (wide unimodal, 1H, H-5), 6.97 (double doublet, 1H, J=2.4,8.8Hz, H-13 '), 7.03 (unimodal, 1H, H-9 '), 7.05～7.11 (multiplet, 2H, H-3 ", 4 "), 7.17 is (bimodal, 1H, J=2.8Hz, H-6 "), 7.42 (bimodal, 1H; J=8.8Hz, H-12 '), 7.59 (bimodal, 1H, J=7.2Hz; H-4), 11.86 (wide unimodal, 1H, H-1).
I-6.3-(4-cyclopentyl-based piperazine carbonyl)-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 197～199 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.38; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 1.41～1.86 (multiplet, 8H, H-9 ', 10 ', 11 ', 12 '), 2.54 (multiplet, 5H, H-4 ', 6 ', 8 '), 3.46 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.82 (wide unimodal, 5H, MeO-5 "; 3 ' a, 7 ' a), 3.90 (unimodal, 3H, MeO-2 "), 6.53 (bimodal, 2H, J=7.2Hz, H-5), 6.98 (double doublet, 3H, J=12.0,10.0Hz, H-3 ", 4 "), 7.08 (unimodal, 1H, H-6 "), 7.70 (bimodal, 1H, J=7.2Hz; H-4), 10.47 (wide unimodal, 1H, H-1).
I-7.3-[4-(2-pyrimidine radicals) piperazine carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, white solid, fusing point: 227 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/methanol: 10/1) 0.33; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.53 (multiplet, 6H, H-4 ', 6 ', 3 ' b, 7 ' b), 3.82 (wide unimodal, 5H, MeO-3 ", 3 ' a, 7 ' a), 3.90 (unimodal; 3H, MeO-4 "), 6.69 (bimodal, 2H, J=7.2Hz, H-5), 7.06 (bimodal, 1H, J=8.0Hz, H-5 "), 7.36～7.41 (multiplet, 3H; H-2 ", 6 ", 11 '), 7.62 (bimodal, 1H, J=7.2Hz; H-4), 8.37 (bimodal, 2H, J=4.8Hz, H-10 ', 12 ').
I-8.3-[4-(3, the 4-dimethoxy-benzyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 200～201 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.56; Proton nmr spectra
1H-NMR (400MHz, deuterated dimethyl sulfoxide DMSO-d
6, δ ppm): 2.41 (wide unimodal, 4H, H-4 ', 6 '), 3.28 (wide unimodal, 2H, H-3 ' b, 7 ' b), 3.46 is (unimodal, 2H, H-8 '), 3.61 (wide unimodal, 2H, H-3 ' a, 7 ' a), 3.77～3.79 (multiplet, 12H, MeO-2 ", 5 ", 11 ', 12 '), 6.44 (bimodal, 1H, J=7.2Hz, H-5), 6.83 (bimodal, 1H, J=7.2Hz, H-14 '), 6.89～6.92 (multiplet, 2H, H-10 ', 4 "); 7.02～7.10 (multiplet, 3H, H-3 ", 6 "; 13 '), 7.52 (bimodal, 1H, J=7.2Hz; H-4), 11.71 (wide unimodal, 1H, H-1).
I-9.3-[4-(3, the 4-dichloro benzyl) piperazine carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones: faint yellow solid, fusing point: 200～202 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.43; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 2.64 (triplet, 4H, J=4.8Hz, H-4 ', 6 '), 3.34 (triplet, 4H, J=4.8Hz, H-3 ', 7 '), 3.85 (unimodal, 3H, MeO-3 "); 3.87 (unimodal, 3H, MeO-4 "), 3.92 (unimodal, 2H, H-8 '), 6.49 (bimodal, 1H, J=7.2Hz, H-5), (6.92 bimodal, 1H, J=8.8Hz, H-14 '), 7.07～7.12 (multiplets, 3H, H-10 ', 2 ", 5 "), 7.18 (unimodal, 1H, J=8.0Hz, H-6 "); 7.30 (bimodal, 1H, J=8.8Hz, H-13 '); 7.58 (bimodal, 1H, J=7.2Hz, H-4).
I-10.N-benzyl-6-(3, the 4-Dimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3 amide: white solid, fusing point: 176～177 ℃ (ethyl alcohol recrystallization), R
f(chloroform/methanol: 10/1) 0.56; Proton nmr spectra
1H-NMR (400MHz, deuterochloroform, δ ppm): 3.77 (unimodal, 3H, MeO-3 "), 3.94 (unimodal; 3H, MeO-4 "), 4.63 (unimodal, 2H, J=6.0Hz, H-3 '), 6.71 (bimodal, 1H, J=7.6Hz, H-5), 6.78 (bimodal, 1H, J=8.8Hz, H-5 "), 7.17～7.35 (multiplet, 7H, H-5 '～～9 ', 2 ", 6 "), 8.64 (bimodal, 1H, J=7.6Hz, H-4), 9.89 (bimodal; 1H, J=6.0Hz, H-2 '), 12.67 (wide unimodal, 1H, H-1).
I-11.3-(trans-4-benzyl-2,5-lupetazin carbonyl)-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 228 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/ethyl acetate: 3/1) 0.16; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 0.93 (bimodal, 3H, J=6.4Hz, 6 '-Me), 1.13 (bimodal, 3H, J=6.0Hz, 3 '-Me), 1.84 (multiplet, 1H, H-4 ' b), 2.23 (multiplet, 1H, H-7 ' b), 2.66 (multiplet, 4H, H-3 ', 6 '), 2.79 (multiplet, 1H, H-4 ' a), 2.90 (double doublet, 1H, J=12.0,6.0Hz, H-7 ' a), 3.30 (bimodal, 1H, J=15.2Hz, H-8 ' b), 3.54 (bimodal, 1H, J=12.0Hz, H-8 ' a), 3.91 (unimodal, 3H, MeO-3 "), 3.95 (unimodal; 3H, MeO-4 "), 6.48 (bimodal, 1H, J=7.2Hz, H-5), 6.95 (bimodal, 1H, J=8.8Hz, H-5 "); 7.27～7.34 (multiplet, 7H, H-10 '～14 ', 2 " and, 6 "); 7.57 (bimodal, 1H, J=7.2Hz, H-4).
I-12.N-(4-benzyl piepridine base)-6-(3, the 4-Dimethoxyphenyl)-2-oxo-1,2-dihydropyridine-3 amide: yellow solid, fusing point: 219 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/methanol: 20/1) 0.12; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 1.46 (triplet, 2H, J=10.0Hz, H-4 ' b, 8 ' b), 1.93 (bimodal, 2H, J=10.8Hz, H-4 ' a, 8 ' a), 2.12 (multiplet, 2H, H-5 ' b, 7 ' b), 2.72 (wide bimodal, 2H, H-5 ' a, 7 ' a), (3.46 wide unimodal, 2H, H-9 '), 3.84 (unimodal, 3H, MeO-3 "), 3.94 (unimodal, 3H, MeO-4 "), 3.98 is (wide unimodal, 1H, H-3 '), 6.69 (bimodal, 1H, J=7.2Hz, H-5), 6.96 (bimodal, 1H, J=8.4Hz, H-5 "); 7.15 (bimodal, 1H, J=1.6Hz, H-2 "), 7.26～7.32 (multiplets, 6H, H-11 '～15 ', 6 "), 8.60 (bimodal, 1H; J=7.6Hz, H-4), 9.40 (bimodal, 1H, J=7.6Hz; H-2 '), 11.67 (wide bimodal, 1H, H-1).
I-13.3-[is trans-4-(3,4,5-trimethoxy benzyl)-2, and 5-lupetazin carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones: faint yellow solid, fusing point: 225 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/ethyl acetate: 3/1) 0.13; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 0.92 (multiplet, 3H, 6 '-Me), 1.30 (multiplets, 3H, 3 '-Me), and 1.61 (multiplet, 2H, H-6 '), 2.22 is (wide bimodal, 1H, H-4 '), 2.69 (bimodal, 2H, J=12.0Hz, H-3 '), 3.01 (wide unimodal, 1H, 6.0Hz, H-7 '), 3.33 (bimodal, 1H, J=13.2Hz, H-8 ' b), 3.56 is (bimodal, 1H, J=13.6Hz, H-8 ' a), 3.84 (unimodal, 9H, MeO-11 '～13 '), 3.94 (unimodal, 3H, MeO-3 "), 3.96 (unimodal; 3H, MeO-4 "), 6.50 (bimodal, 1H, J=7.6Hz, H-5), 6.59 (unimodal, 2H, H-10 ', 14 '), 6.96 (bimodal, 1H, J=8.8Hz, H-5 "), 7.27～7.29 (multiplet; 2H, H-2 ", 6 "), 7.56 (bimodal, 1H; J=7.6Hz, H-4), 11.95 (wide bimodal, 1H, H-1).
I-14.3-[is trans-4-(4-luorobenzyl)-2, and 5-lupetazin carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones: white solid, fusing point: 203 ℃ of (decomposition) (ethyl alcohol recrystallizations), R
f(chloroform/ethyl acetate: 3/1) 0.15; Proton nmr spectra
1H NMR (400MHz, deuterochloroform, δ ppm): 0.94 (multiplet, 3H, 6 '-Me), 1.26 (multiplet, 3H, 3 '-Me), 1.61 (multiplet, 2H, H-6 '), 2.17 (wide bimodal, 1H, H-4 '), 2.75 is (bimodal, 2H, J=10.0Hz, H-3 '), 2.96 (wide unimodal, 1H, H-7 '), 3.38 (bimodal, 1H, J=13.6Hz, H-8 ' is b), 3.55 (bimodal, 1H, J=13.6Hz, H-8 ' a), 3.84 is (unimodal, 9H, MeO-11 '～13 '), 3.95 (unimodal, 3H, MeO-3 "); 3.97 (unimodal, 3H, MeO-4 "), 6.52 (bimodal, 1H, J=7.6Hz, H-5), 6.96～7.00 (multiplet, 3H, H-11 ', 13 ', 5 "), 7.23～7.30 (multiplet, 4H; H-10 ', 14 ', 2 ", 6 "); 7.58 (bimodal, 1H, J=7.6Hz, H-4).
The prepared above-mentioned 6-aryl-3-substituted carbonyl-pyridinone chemical compound of the present invention has important biological, in vitro tests shows that such chemical compound with pyridone structure has growth inhibitory activity for In vitro culture people promyelocytic leukemia cell (HL-60) and mouse lymph sample tumor cell strain (P388D1), can expect as control related neoplasms disease medicament purposes.
The prepared compound or pharmaceutically acceptable salt thereof of the present invention can combine with adjuvant or carrier pharmaceutically commonly used, prepares the pharmaceutical composition with anticancer usage.Aforementioned pharmaceutical compositions can adopt injection, tablet, capsule, paster, the subcutaneous dosage forms such as burying agent of planting, or other adopt controlled release, slow release formulation and the nanometer formulation of known theory and technology preparation.
Embodiment further specifies the present invention below by pharmacology.Embodiment has provided the part activity data of representative compounds.Mandatory declaration, following pharmacology embodiment is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Pharmacology embodiment 1: the cytotoxic activity of Compound I-7 pair people's promyelocytic leukemia cell
People's promyelocytic leukemia cell (HL-60) cell contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter streptomycin with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 1 * 10
4Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of humid air.
The assay method of cell survival rate is with improveing MTT (3-(4,5-dimethylthiazole-2)-2,5-diphenyl tetrazole bromine salt) method.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I that will newly join-7 joins in each hole with Concentraton gradient respectively, makes that the ultimate density of chemical compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of humid air, add 150 microlitre dimethyl sulfoxines in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Half-inhibition concentration (the IC of Compound I-7 pair HL-60 cell wherein
50) obtain by dose effect curve.Experimental result shows, the IC of Compound I-7
50Be 27.2 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of HL-60 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 7.9 μ M.
This experiment shows that this type of 6-aryl-3-substituted carbonyl-pyridinone chemical compound has stronger cytotoxicity to the HL-60 cell, might develop into the new medicine with anti-people's promyelocytic leukemia and related neoplasms effect.
Pharmacology embodiment 2: the cytotoxic activity of Compound I-3 pair people's promyelocytic leukemia cell
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 1.
Compound I-3 couple people's promyelocytic leukemia cell (HL-60) cell 503nhibiting concentration (IC wherein
50) obtain by dose effect curve.The IC of Compound I-3
50Be 24.9 μ M; And the positive control cisplatin is to the 503nhibiting concentration IC of HL-60 cell
50Be 7.9 μ M.
Experiment conclusion: this experiment shows that further this type of 6-aryl-3-substituted carbonyl-pyridinone chemical compound has stronger cytotoxicity to people's promyelocytic leukemia cell, might develop into the new medicine with the effect of anti-BM form leukemia and related neoplasms effect.
Pharmacology embodiment 3: the cytotoxic activity of Compound I-7 pair mouse lymph sample oncocyte
Mouse lymph sample oncocyte (P388D1) contains 10% calf serum, 100U/ ml penicillin and 100U/ milliliter streptomycin with RPMI 1640 culture medium culturings in the culture medium.Cell is with every hole 5 * 10
3Individual density is inoculated in 96 orifice plates, at 37 ℃, and 5%CO
2Cultivated 24 hours in the incubator of humid air.
The assay method of cell survival rate is with improveing mtt assay.Cell is after 24 hours hatch, and the dimethyl sulfoxide solution of the Compound I that will newly join-7 joins in each hole with Concentraton gradient respectively, makes that the ultimate density of chemical compound is respectively 100 mcg/ml, 50 mcg/ml, 25 mcg/ml, 5 mcg/ml in the hole.After 72 hours, add the normal saline solution of 10 microlitre MTT (5 mg/ml), continue at 37 ℃ 5%CO again
2Cultivated 3 hours in the incubator of humid air, add 150 microlitre dimethyl sulfoxines in every hole, the MTT crystal Jia Za (formazan) that the vibration dissolving generates, formed Jia Za microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample OD value for contrast OD value.Half-inhibition concentration (the IC of Compound I-7 pair P388D1 cell wherein
50) obtain by dose effect curve.
Compound I-7 couple P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of Compound I-7
50Be 38.2 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of P388D1 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 7.7 μ M.
This experiment shows that this type of 6-aryl-3-substituted carbonyl-pyridinone chemical compound has stronger cytotoxicity to the P388D1 cell, might develop into the new medicine with antiangiogenic quasi-leukemia and related neoplasms effect.
Pharmacology embodiment 4: the cytotoxic activity of Compound I-9 pair mouse lymph sample tumor
The mensuration of cell survival rate is with improveing mtt assay, concrete grammar such as pharmacology embodiment 3.
Compound I-9 couple P388D1 cell half-inhibition concentration IC
50Obtain by dose effect curve.Experimental result shows, the IC of Compound I-9
50Be 36.5 μ M.
As positive control, DDP is to the 503nhibiting concentration IC of P388D1 cell with antitumor one line medication cisplatin (DDP) in this test
50Be 7.7 μ M.
This experiment shows that further this type of 6-aryl-3-substituted carbonyl-pyridinone chemical compound has stronger cytotoxicity to the P388D1 cell, might develop into the new medicine with antiangiogenic quasi-leukemia and related neoplasms effect.
These compound or pharmaceutically acceptable salt thereofs of the present invention can with antitumor drug that has now gone on the market such as platinum medicine cisplatin (DDP), camptothecine irinotecan (Irinatecan, CPT-11), the vinca alkaloids medicine loses carbon vincaleucoblastine (Vinorebine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), the harringtonine analog derivative, Rebeccamycin Analogue (NSC 655649), guanine metabolism agent interfering (NSC 686673), Gleevec etc. unite use, prepare and have tumor growth and suppress active cytotoxicity compositions, can be used for treating tumor disease, especially leukemia and related neoplasms disease thereof.
Claims (2)
1. an aryl-3-substituted carbonyl-pyridinone derivant and pharmaceutically useful salt thereof the application in the antiangiogenic quasi-leukemia medicine of preparation is characterized by the aryl-3-substituted carbonyl-pyridinone derivant and is selected from following structure:
Compound I-3.3-[4-(2-methoxyphenyl) piperazine carbonyl]-6-(2, the 5-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-7.3-[4-(2-pyrimidine radicals) piperazine carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones;
Compound I-9.3-[4-(3, the 4-dichloro benzyl) piperazine carbonyl]-6-(3, the 4-Dimethoxyphenyl)-2H-pyridin-2-ones.
2. application according to claim 1 is characterized in that: the dosage form of described medicine is selected injection, tablet or capsule for use.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100630180A CN101305998B (en) | 2008-07-04 | 2008-07-04 | Use of aryl-3-substituted carbonyl pyridone compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100630180A CN101305998B (en) | 2008-07-04 | 2008-07-04 | Use of aryl-3-substituted carbonyl pyridone compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101305998A CN101305998A (en) | 2008-11-19 |
| CN101305998B true CN101305998B (en) | 2010-11-17 |
Family
ID=40122834
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100630180A Expired - Fee Related CN101305998B (en) | 2008-07-04 | 2008-07-04 | Use of aryl-3-substituted carbonyl pyridone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101305998B (en) |
-
2008
- 2008-07-04 CN CN2008100630180A patent/CN101305998B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101305998A (en) | 2008-11-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107849022A (en) | Substituted quinazoline compound and its application method | |
| CN108779097A (en) | Include the quinazoline compound and its application method of the 2- substitutions of substituted heterocycle | |
| EP2168964B1 (en) | Azaindole-indole coupled derivatives, preparation methods and uses thereof | |
| EP3444250A1 (en) | Fgfr4 inhibitor, preparation method therefor, and applications thereof | |
| CN102875560B (en) | 5-substituted tetrandrine compound and application thereof in preparing anticarcinogen sensitizer | |
| CN107382966B (en) | Piperlongumine-ligustrazine heterocomplex, preparation method and medical application | |
| EP3498707A1 (en) | Fgfr4 inhibitor and preparation method and use thereof | |
| CN104557940A (en) | BCR-ABL kinase inhibitor and application thereof | |
| CN103420990B (en) | 7-oxygen, sulphur or azepine substituted cumarin and derivative thereof and purposes | |
| CN101434600A (en) | Curcumin piperidone analog and use thereof in anti-tumor medicament | |
| CN101332198B (en) | Pharmaceutical use of 6-aryl-3-substituted carbonyl pyridine compound | |
| CN102627685B (en) | Nitric oxide-donating glutathione compound, preparation method and medical purpose thereof | |
| CN102153508B (en) | 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone and application of the 3,5-(E)-dibenzylidene-N-cyclopropyl piperidine-4-ketone in preparing antitumour drugs | |
| Liu et al. | Discovery of novel tacrine derivatives as potent antiproliferative agents with CDKs inhibitory property | |
| CN103214456A (en) | Benzimidazole compound with antitumour activity as well as preparation method and application thereof | |
| CN101305998B (en) | Use of aryl-3-substituted carbonyl pyridone compound | |
| CN103130632A (en) | 1-substituted benzylidene-2-naphthalenone derivative, preparation method thereof and use thereof | |
| US20140249312A1 (en) | [1,3]dioxolo[4,5-g]quinoline-6(5h)thione and [1,3]dioxolo[4,5-g][1,2,4]triazolo[1,5-a]quinoline derivatives as inhibitors of the late sv40 factor (lsf) for use in treating cancer | |
| CN115160277A (en) | Apigenin derivative and application thereof | |
| CN101317845B (en) | Pharmaceutical use of 6-aryl substituted pyridine compounds | |
| CN109096194B (en) | Biguanide derivative, pharmaceutical composition, preparation method and application | |
| CN101230015B (en) | Substituted cinnamic acid derivatives containing amine substituent group and tumor cytotoxicity thereof | |
| KR20210146296A (en) | Triazolopyrimidines based on thymine nucleic acid base and method for producing the same | |
| CN101284007B (en) | Pharmaceutical use of aryl group substituted pyridone derivates in preparing medicine for tumour | |
| CN111039940B (en) | Aurora A kinase inhibitor, 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 | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20101117 Termination date: 20110704 |