TR201615186A2 - (E) -1- (4-CINNAMOYLPHENYL) -1H-PYROL-2,5-DIONE DERIVATIVES WITH ANTICANSEROGEN ACTIVITY - Google Patents
(E) -1- (4-CINNAMOYLPHENYL) -1H-PYROL-2,5-DIONE DERIVATIVES WITH ANTICANSEROGEN ACTIVITY Download PDFInfo
- Publication number
- TR201615186A2 TR201615186A2 TR2016/15186A TR201615186A TR201615186A2 TR 201615186 A2 TR201615186 A2 TR 201615186A2 TR 2016/15186 A TR2016/15186 A TR 2016/15186A TR 201615186 A TR201615186 A TR 201615186A TR 201615186 A2 TR201615186 A2 TR 201615186A2
- Authority
- TR
- Turkey
- Prior art keywords
- formula
- molecule
- cancer
- molecules
- organic
- Prior art date
Links
- -1 4-CINNAMOYLPHENYL Chemical class 0.000 title claims description 10
- 230000000694 effects Effects 0.000 title description 8
- 238000000034 method Methods 0.000 claims abstract description 18
- 239000000203 mixture Substances 0.000 claims abstract description 12
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- 239000003814 drug Substances 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000000126 substance Substances 0.000 claims description 14
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 claims description 10
- 235000005513 chalcones Nutrition 0.000 claims description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 239000004480 active ingredient Substances 0.000 claims description 9
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 8
- 239000013543 active substance Substances 0.000 claims description 7
- 150000007530 organic bases Chemical class 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- DQFBYFPFKXHELB-VAWYXSNFSA-N trans-chalcone Chemical compound C=1C=CC=CC=1C(=O)\C=C\C1=CC=CC=C1 DQFBYFPFKXHELB-VAWYXSNFSA-N 0.000 claims description 6
- 229940086542 triethylamine Drugs 0.000 claims description 6
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 5
- 230000003217 anti-cancerogenic effect Effects 0.000 claims description 5
- 108010006654 Bleomycin Proteins 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229960001561 bleomycin Drugs 0.000 claims description 4
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 claims description 4
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 claims description 3
- 230000002001 anti-metastasis Effects 0.000 claims description 3
- 239000003005 anticarcinogenic agent Substances 0.000 claims description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 3
- 229960005420 etoposide Drugs 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- 239000002244 precipitate Substances 0.000 claims description 3
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 claims description 3
- 229960000624 procarbazine Drugs 0.000 claims description 3
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 claims description 2
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- JARCFMKMOFFIGZ-UHFFFAOYSA-N 4,6-dioxo-n-phenyl-2-sulfanylidene-1,3-diazinane-5-carboxamide Chemical compound O=C1NC(=S)NC(=O)C1C(=O)NC1=CC=CC=C1 JARCFMKMOFFIGZ-UHFFFAOYSA-N 0.000 claims description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 claims description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 claims description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 2
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 claims description 2
- YJQPYGGHQPGBLI-UHFFFAOYSA-N Novobiocin Natural products O1C(C)(C)C(OC)C(OC(N)=O)C(O)C1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-UHFFFAOYSA-N 0.000 claims description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 claims description 2
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 claims description 2
- 229960002092 busulfan Drugs 0.000 claims description 2
- 229960004562 carboplatin Drugs 0.000 claims description 2
- 190000008236 carboplatin Chemical compound 0.000 claims description 2
- 229960005243 carmustine Drugs 0.000 claims description 2
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 claims description 2
- 229960004630 chlorambucil Drugs 0.000 claims description 2
- 229960002436 cladribine Drugs 0.000 claims description 2
- 229960003901 dacarbazine Drugs 0.000 claims description 2
- 229960004679 doxorubicin Drugs 0.000 claims description 2
- 229960000390 fludarabine Drugs 0.000 claims description 2
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 claims description 2
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 claims description 2
- 229960004783 fotemustine Drugs 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 claims description 2
- 229960001101 ifosfamide Drugs 0.000 claims description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims description 2
- 229960004961 mechlorethamine Drugs 0.000 claims description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 2
- 229960001924 melphalan Drugs 0.000 claims description 2
- 229960000485 methotrexate Drugs 0.000 claims description 2
- QXYYYPFGTSJXNS-UHFFFAOYSA-N mitozolomide Chemical compound N1=NN(CCCl)C(=O)N2C1=C(C(=O)N)N=C2 QXYYYPFGTSJXNS-UHFFFAOYSA-N 0.000 claims description 2
- 229950005967 mitozolomide Drugs 0.000 claims 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 claims description 2
- 229960000801 nelarabine Drugs 0.000 claims description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 2
- 229960002950 novobiocin Drugs 0.000 claims description 2
- YJQPYGGHQPGBLI-KGSXXDOSSA-N novobiocin Chemical compound O1C(C)(C)[C@H](OC)[C@@H](OC(N)=O)[C@@H](O)[C@@H]1OC1=CC=C(C(O)=C(NC(=O)C=2C=C(CC=C(C)C)C(O)=CC=2)C(=O)O2)C2=C1C YJQPYGGHQPGBLI-KGSXXDOSSA-N 0.000 claims description 2
- 239000003791 organic solvent mixture Substances 0.000 claims description 2
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 claims description 2
- 229960002340 pentostatin Drugs 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 claims description 2
- 229960005205 prednisolone Drugs 0.000 claims description 2
- 229960003440 semustine Drugs 0.000 claims description 2
- 229960001052 streptozocin Drugs 0.000 claims description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 claims description 2
- 229960004964 temozolomide Drugs 0.000 claims description 2
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 2
- 229960001278 teniposide Drugs 0.000 claims description 2
- 229960001196 thiotepa Drugs 0.000 claims description 2
- 229960004528 vincristine Drugs 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical group ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 claims 3
- 229960004397 cyclophosphamide Drugs 0.000 claims 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 claims 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 claims 1
- 229960004176 aclarubicin Drugs 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 claims 1
- 229960000928 clofarabine Drugs 0.000 claims 1
- 238000001914 filtration Methods 0.000 claims 1
- 229960002247 lomustine Drugs 0.000 claims 1
- 229910052697 platinum Inorganic materials 0.000 claims 1
- 239000011343 solid material Substances 0.000 claims 1
- 238000009472 formulation Methods 0.000 abstract description 2
- ZJTXBNPJEYRAAZ-IZZDOVSWSA-N 1-[4-[(e)-3-phenylprop-2-enoyl]phenyl]pyrrole-2,5-dione Chemical class C=1C=C(N2C(C=CC2=O)=O)C=CC=1C(=O)\C=C\C1=CC=CC=C1 ZJTXBNPJEYRAAZ-IZZDOVSWSA-N 0.000 abstract 1
- 238000011275 oncology therapy Methods 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 42
- 201000011510 cancer Diseases 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 201000010099 disease Diseases 0.000 description 12
- 230000000118 anti-neoplastic effect Effects 0.000 description 11
- 239000002552 dosage form Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 7
- 201000009030 Carcinoma Diseases 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229940124597 therapeutic agent Drugs 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 150000001789 chalcones Chemical class 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 206010009944 Colon cancer Diseases 0.000 description 3
- 208000008839 Kidney Neoplasms Diseases 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 206010060862 Prostate cancer Diseases 0.000 description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 3
- 206010038389 Renal cancer Diseases 0.000 description 3
- 206010041067 Small cell lung cancer Diseases 0.000 description 3
- 201000000053 blastoma Diseases 0.000 description 3
- 208000029742 colonic neoplasm Diseases 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 201000008184 embryoma Diseases 0.000 description 3
- 150000002430 hydrocarbons Chemical class 0.000 description 3
- 201000010982 kidney cancer Diseases 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 208000000587 small cell lung carcinoma Diseases 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010008342 Cervix carcinoma Diseases 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 206010058314 Dysplasia Diseases 0.000 description 2
- 206010025323 Lymphomas Diseases 0.000 description 2
- 206010029260 Neuroblastoma Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- 208000000453 Skin Neoplasms Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 201000010881 cervical cancer Diseases 0.000 description 2
- 150000001788 chalcone derivatives Chemical class 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 150000002215 flavonoids Chemical class 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 201000010536 head and neck cancer Diseases 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 206010041823 squamous cell carcinoma Diseases 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 201000008827 tuberculosis Diseases 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- GVSPXQVUXHMUMA-MDWZMJQESA-N (e)-3-(3,5-ditert-butyl-4-hydroxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one Chemical compound C1=CC(OC)=CC=C1C(=O)\C=C\C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 GVSPXQVUXHMUMA-MDWZMJQESA-N 0.000 description 1
- ARXKVVRQIIOZGF-UHFFFAOYSA-N 1,2,4-butanetriol Chemical compound OCCC(O)CO ARXKVVRQIIOZGF-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- WOVKYSAHUYNSMH-RRKCRQDMSA-N 5-bromodeoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(Br)=C1 WOVKYSAHUYNSMH-RRKCRQDMSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010051999 Anogenital dysplasia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 1
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 229920004518 DION® Polymers 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010061934 Salivary gland cancer Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 1
- 208000004354 Vulvar Neoplasms Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000003969 blast cell Anatomy 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 108091092356 cellular DNA Proteins 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 230000002498 deadly effect Effects 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000003221 ear drop Substances 0.000 description 1
- 229940047652 ear drops Drugs 0.000 description 1
- 235000018927 edible plant Nutrition 0.000 description 1
- 239000007938 effervescent tablet Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 201000005619 esophageal carcinoma Diseases 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 150000002214 flavonoid derivatives Chemical class 0.000 description 1
- VVIAGPKUTFNRDU-ABLWVSNPSA-N folinic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-ABLWVSNPSA-N 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 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 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 208000029824 high grade glioma Diseases 0.000 description 1
- 201000000284 histiocytoma Diseases 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229930013032 isoflavonoid Natural products 0.000 description 1
- 150000003817 isoflavonoid derivatives Chemical class 0.000 description 1
- 235000012891 isoflavonoids Nutrition 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- 201000011614 malignant glioma Diseases 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- 239000007912 modified release tablet Substances 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 201000011682 nervous system cancer Diseases 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 201000003804 salivary gland carcinoma Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000006200 vaporizer Substances 0.000 description 1
- 229940065658 vidaza Drugs 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 239000012224 working solution Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
- C07D207/452—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Mevcut buluş formül 1 ile gösterilen (e)-1-(4-sinnamoilfenil)-1H-pirol-2,5-dion türevlerine, bu moleküllerin hazırlanma yöntemlerine, bu molekülleri içeren formülasyonlara ve bu moleküllerin kanser tedavisinde kullanımına ilişkindir.The present invention relates to (e) -1- (4-cinnamoylphenyl) -1H-pyrrole-2,5-dione derivatives represented by formula 1, methods of preparation of these molecules, formulations containing these molecules and the use of these molecules in cancer therapy.
Description
TARIFNAME ANTIKANSEROJEN ETKINLIGE SAHIP OLAN (EH-(4- SINNAMOILFENILl-lH-PIROL-2,5-DION TUREVLERI Mevcut bUIUs formül 1 ile gösterilen (Ej-l-(4-sinnamoilfenil)-1H-pirol-2,S-dion türevlerine, bu moleküllerin hazirlanma yöntemlerine, bu molekülleri içeren formülasyonlara ve bu moleküllerin kanser tedavisinde kullanimina iliskindir. DESCRIPTION WITH ANTI-CANCEROGEN ACTIVITY (EH-(4- SINNAMOILFENILl-1H-PIROL-2,5-DION DERIVATIVES The present bUIUs are represented by formula 1 (Ej-1-(4-cinnamoylphenyl)-1H-pyrrole-2,S-dione derivatives, preparation methods of these molecules, It is about formulations and the use of these molecules in cancer treatment.
Bilinen Teknik Hem dogal hem de sentetik bilesikler olan kalkonlar, flavonoid ailesine üye bilesiklerdir ve genis bir biyolojik aktivite spektrumuna sahiptirler. Known Technique Chalcones, both natural and synthetic compounds, are members of the flavonoid family. compounds and have a broad spectrum of biological activity.
Kalkonlar, yenilebilir bitkilerde bol miktarda bulunan flavonoid ve izoflavonoidlerin öncüsü sayilirlar. Bu yüzden, son yillarda kalkon ve türevleri yogun bir ilgi odagi OImUS ve özellikle biyolojik aktivite üzerine çok sayida çalisma yapilmistir. Chalcones are flavonoids and isoflavonoids that are abundant in edible plants. are considered pioneers. Therefore, chalcone and its derivatives have been the focus of intense attention in recent years. Numerous studies have been conducted on OImUS and especially on biological activity.
Bir ketovinil grubuna sahip çok sayida bilesigin önemli derecede biyolojik aktivite gösterdigi iyi bilinen bir gerçektir. Kalkonlar da ketovinil grubu içeren bilesikler arasindadir ve gösterdikleri biyolojik aktiviteden dolayi bu tür bilesikler üzerine yapilan çalismalarin sayisi gün geçtikçe artmaktadir. Significant biological activity of many compounds with a ketovinyl group It is a well known fact. Compounds containing ketovinyl groups in chalcones and on such compounds due to their biological activity. The number of studies carried out is increasing day by day.
Lin ve arkadaslari bir dizi kalkon ve flavonoid türevinin, öldürücü ve bulasici bir hastalik olan tüberküloza karsi aktivitelerini incelemisler ve yüksek oranda aktivite gösterdigini tespit etmislerdir. Lin et al. reported that a series of chalcone and flavonoid derivatives have been found to be a deadly and contagious disease. examined its activities against tuberculosis and found that it showed high activity. they did.
Literatürde, bitkilerden izole elde edilen kalkon türevleri içerisinde 4 pozisyonunda hidroksi grubu ve sülfoamino yapisinin enzimlerde inhibitör etki gösterdigi ve bu bilesiklerin ilaç olarak kullanildigi bildirilmistir. In the literature, in the chalcone derivatives isolated from plants, hydroxy in the 4 position group and sulfoamino structure showed inhibitory effect on enzymes and these compounds has been reported to be used.
Bunun yani sira literatürde kalkon türevleri çesitli moleküllerin diyabet, hipertansiyon. malarya, obezite, tüberküloz, gut rahatSizIiklarinin tedavisinde endike oldugu ve ayrica antiparazitik, antihistaminik, antioksidan, antifungal, antibakteriyel, antianjiyojenik, antispazmodik, antiaritmik etki gösterdigi de belirlenmistir. Kalkon türevi moleküllerin etkinlik gösterebilecegi diger hastaliklar da arastirilmaktadir. In addition, in the literature, chalcone derivatives are used in diabetes, hypertension and various molecules. It is indicated for the treatment of malaria, obesity, tuberculosis, gout and also antiparasitic, antihistamine, antioxidant, antifungal, antibacterial, antiangiogenic, It has also been determined that it has antispasmodic and antiarrhythmic effects. Chalcone-derived molecules Other diseases in which it may be effective are also being investigated.
Son yillarda oldukça yayginlasan kanser gibi neoplastik hastaliklarin tedavisinde karsilasilan en büyük sorunlardan biri tedavi esnasinda kemoterapide kullanilan ilaca karsi hastanin bagisiklik gelistirmesi ve kanserli hücrelerin tedaviye ragmen artmaya devam etmesidir. encountered in the treatment of neoplastic diseases such as cancer, which have become quite common in recent years. One of the biggest problems is the patient's resistance to the drug used in chemotherapy during treatment. immune enhancement and cancer cells continue to increase despite treatment.
Ayrica antineoplastik etki sahibi moleküllerin bir ç0gunun son derece toksik olmasi ve hastada önemli yan etilere neden olmasi da bu alanda ilaç gelistirilmesini zorlastirmaktadir. In addition, many of the molecules with antineoplastic effects are extremely toxic and The fact that it causes significant side effects in the patient also complicates the development of drugs in this area.
Bu tür moleküllerin kullaniminda karsilasilan bir diger problem antineoplastik etki gösterdigi tespit edilen moleküllerin bazilarinin bu etkilerini ancak çok yüksek dozlar kullanildiginda göstermesi ve bunun sonucu olarak da çok sayida yan etkiye neden olmasidir. Another problem encountered in the use of such molecules is that they have an antineoplastic effect. These effects of some of the detected molecules can only be achieved when very high doses are used. and, as a result, cause many side effects.
Bu durum çok sayida ve farkli özelliklerde antineoplastik molekül alternatiflerine ihtiyaç duyulmasina neden olmaktadir. This situation requires a large number of antineoplastic molecule alternatives with different properties. causes it to be heard.
Bulusun Amaci Mevcut buIUsun amaci kanser tedavisinde kullanilacak yeni moleküller gelistirmektir. Purpose of the Invention The aim of the present invention is to develop new molecules to be used in cancer treatment.
Mevcut bUIUSun bir diger amaci toksik etkiye sahip olmayan antineoplastik etkili ajanlarin gelistirilmedir. Another aim of the current bUIUS is non-toxic antineoplastic effect. agents are developed.
BUIUSun bir diger amaci düsük dozlarda da yüksek etkinlik gösteren antineoplastik etkili veya bir diger deyisle antikansinojenik ajanlarin gelistirilmesidir. Another aim of BUIUS is antineoplastic agents that show high efficacy at low doses. It is the development of effective or, in other words, anticarcinogenic agents.
Bulusun Detayli Açiklamasi BUIUS sahipleri yaptiklari çalismalar neticesinde formül 1 ile gösterilen genel yapiya sahip kalkon türevi moleküllerin antineoplastik özellige sahip olduklarini bulmuslardir. Detailed Description of the Invention As a result of the work they have done, BUIUS owners have achieved the general structure shown by formula 1. that chalcone-derived molecules have antineoplastic properties. they have found.
Buna göre bUIUSun bir özelligi neoplastik hastaliklarin tedavisinde kullanima uygun formül I ile gösterilen kalkon türevi moleküllerdir. Accordingly, a feature of bUIUS is suitable for use in the treatment of neoplastic diseases. They are chalcone-derived molecules represented by formula I.
Burada R= m-OCHg-Ph, O-CHg-Ph, m-CHg-Ph, o-CI-Ph, m-Br-Ph, Furan'dan oIUSan bir grubun içerisinden seçilir. where R= m-OCHg-Ph, O-CHg-Ph, m-CHg-Ph, o-CI-Ph, m-Br-Ph, oIUSan from Furan selected from a group.
Formül 1 ile gösterilen bilesiklerin genel kimyasal ismi (El-l-(4-sinnam0ilfenill-lH- piroI-2,5-dion türevleridir. Mevcut bulus kapsaminda bu molekülleri genel olarak ifade etmek için “formül 1”, ve/veya “(El-l-(4-sinnamoilfenil]-1H-pirol-2,5-dion türevleri” veya “formül 1 ile gösterilen moleküller" veya “bUIUSa uygun moleküller” terimleri birbiri ile degisebilir sekilde kullanilabilir. The general chemical name of the compounds represented by formula 1 (E-1-(4-cinnam0ylphenyl-1H-) pyrroI-2,5-dione derivatives. In the context of the present invention, these molecules are generally “formula 1”, and/or “(El-1-(4-cinnamoylphenyl]-1H-pyrrole-2,5-dione) to denote derivatives” or “molecules represented by formula 1” or “molecules suitable for bUIUS” terms can be used interchangeably.
Mevcut bulusun tercih edilen bir uygulamasinda antineoplastik hastaliklarin tedavisinde kullanima uygun molekül formül la ile gösterilmektedir. In a preferred embodiment of the present invention, antineoplastic diseases The molecule suitable for use in the treatment is indicated by the formula Ia.
Formül la bilesiginin kimyasal adi (El-l-(4-(3-(3-met0ksifenilll akriloillfenill-lH-pirol- 2,5-di0n'dur. Mevcut bUiUS kapsaminda bu molekülü ifade etmek Için “la”, “formül la" ve/veya “(E)-1-(4-(3-(3-met0ksifenilll akriloillfenill-lH-pirol-2,5-di0n" terimleri birbiri ile degisebilir sekilde kullanilmaktadir. Chemical name of the compound of formula la (E-1-(4-(3-(3-methoxyphenyl)acryloylphenylphenyl-1H-pyrrole- 2,5-di0n. To denote this molecule within the scope of the current bUiUS, “la”, “formula la" and/or the terms "(E)-1-(4-(3-(3-methoxyphenyl)acryloylphenylphenyl-1H-pyrrole-2,5-di0n" are used interchangeably.
Mevcut buIUSun tercih edilen bir uygulamasinda antineoplastik hastaliklarin tedavisinde kullanima uygun molekül formül lb ile gösterilmektedir. In a preferred application of the present invention, antineoplastic diseases The molecule suitable for use in the treatment is indicated by the formula lb.
Formül lb bilesiginin kimyasal adi (E)-1-(4-(3-(0-metillakriloil)feniI)-1H-piroI-2,5- dion”dur. Mevcut bUIUS kapsaminda bu molekülü ifade etmek için “1b”, “formül lb” ve/veya "(El-l-(4-(3-(o-metillakriloillfenill-lH-piroI-2,5-di0n" terimleri birbiri ile degisebilir sekilde kullanilmaktadir. Chemical name of the compound of formula Ib (E)-1-(4-(3-(0-methyllacryloyl)phenyl)-1H-pyrroI-2,5- dion". “1b”, “formula lb” to denote this molecule under the current bUIUS and/or the terms "(E-1-(4-(3-(o-methyllacryloylphenylphenyl-1H-pyrrole-2,5-diOn") are interchangeable used interchangeably.
Mevcut buIUSun tercih edilen bir uygulamasinda antineoplastik hastaliklarin tedavisinde kullanima uygun molekül formül lc ile gösterilmektedir. In a preferred application of the present invention, antineoplastic diseases The molecule suitable for use in the treatment is shown with the formula lc.
Formül lc bilesiginin kimyasal adi (El-l-(4-(3-(m-metillakriIoiIlfenil)-1H-pirol-2,5- dionidur. Mevcut bulus kapsaminda bu molekülü ifade etmek için “lc”, “formül lc” ve/veya "(EJ-l-(4-(3-(m-metillakriloillfeniIJ-lH-piroI-2,5-di0n" terimleri birbiri ile degisebilir sekilde kullanilmaktadir. Chemical name of the compound of formula Ic (E-1-(4-(3-(m-methyllacryloylphenyl)-1H-pyrrole-2,5- is dioni. "lc", "formula lc" to denote this molecule in the context of the present invention and/or the terms "(EJ-1-(4-(3-(m-methyllacryloylphenylphenylJ-1H-pyrroI-2,5-diOn") are interchangeable used interchangeably.
Mevcut bUiUSun tercih edilen bir uygulamasinda antineoplastik hastaliklarin tedavisinde kullanima uygun molekül formül 1d ile gösterilmektedir. Treatment of antineoplastic diseases in a preferred application of the current buUiUS The molecule suitable for use in the treatment is shown with formula 1d.
Formül 1d bilesiginin kimyasal adi (El-l-(4-(3-(2-kl0r0fenillakriloillfeniIl-lH-piroI-2,5- dion'dur. Mevcut bUiUS kapsaminda bu molekülü ifade etmek için “1d", “formül 1d“ ve/veya “(El-1-(4-(3-(2-klorofenillakriloillfenill-lH-piroI-2,5-dion" terimleri birbiri ile degisebilir sekilde kullanilmaktadir. Chemical name of the compound of formula 1d (E-1-(4-(3-(2-chlorophenylphenylacryloylphenylphenyl-1H-pyrrole-2,5-) is dion. “1d”, “formula 1d” to express this molecule in the current bUiUS and/or the terms "(E-1-(4-(3-(2-chlorophenylacryloylphenylphenyl-1H-pyrrole-2,5-dione") are interchangeable used interchangeably.
Mevcut bUIUSun tercih edilen bir uygulamasinda antineoplastik hastaliklarin tedavisinde kullanima uygun molekül formül le ile gösterilmektedir. In a preferred embodiment of the present bUIUS, antineoplastic diseases The molecule suitable for use in the treatment is shown with the formula le.
Formül le bilesiginin kimyasal adi (El-l-(4-(3-(3-br0mofenill akriloillfenill-lH-pirol- 2,5-di0n'dur. Mevcut bulus kapsaminda bu molekülü ifade etmek için le”, “formül le” ve/veya “(El-l-(4-(3-(3-br0mofenill akriloillfenill-lH-piroI-2,5-dion" terimleri birbiri ile degisebilir sekilde kullanilmaktadir. Chemical name of the compound of formula I (E-1-(4-(3-(3-br0mophenyl)acryloylphenylphenyl-1H-pyrrole- 2,5-di0n. In the context of the present invention, to express this molecule le”, “formula le” and/or “(El-1-(4-(3-(3-br0mophenylacryloylphenylphenyl-1H-pyrroI-2,5-dione") are interchangeable used interchangeably.
Mevcut buIUSun tercihedilen bir uygulamasinda antineoplastik hastaliklarin tedavisinde kullanima uygun molekül formül lf ile gösterilmektedir. In a preferred application of the present invention, antineoplastic diseases The molecule suitable for use in the treatment is shown with the formula lf.
Formül lf bilesiginin kimyasal adi (Ei-l-(4-(3-(furan-2-iliakriIoilifenili-lH-pirol-2,5- dion'dur. Mevcut buIUS kapsaminda bu molekülü ifade etmek için “lf”, “formül lf” ve/veya “(E)-1-(4-(3-(furan-2-Iliakriloillfenil)-1H-pirol-2,5-di0n" terimleri birbiri Ile degisebilir sekilde kullanilmaktadir. Chemical name of the compound of formula I (Ei-1-(4-(3-(furan-2-iliacryIoiphenylenyl-1H-pyrrole-2,5-) is dion. “lf”, “formula lf” to denote this molecule in the current IUS and/or the terms "(E)-1-(4-(3-(furan-2-ylacryloylphenyl)-1H-pyrrole-2,5-di0n"' used interchangeably.
Mevcut bulusun bir bakima Formül la ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. In a way, the present invention refers to the molecule denoted by Formula la. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Mevcut bUiUSLIn bir bakima Formül lb ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. The present bUiUSLI is somewhat related to the molecule represented by Formula lb. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Mevcut buIUSun bir bakima Formül lc ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasmda kullanilmaSina, bu ilaCin bilinen terapötik ajanlarla beraber kullanilmasma iliskindir. The present invention is, in a way, the molecule represented by Formula lc. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, This is related to the use of this medicine in combination with known therapeutic agents.
Mevcut buIUSun bir bakima Formül 1d ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. The present invention is somewhat related to the molecule represented by Formula 1d. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Mevcut bUiUsLln bir bakima Formül le ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu ilacin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. The present bUiUsLln is in a way the molecule represented by Formula le, the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, relates to the use of this drug with known therapeutic agents.
Mevcut bulusun bir bakima Formül lf ile gösterilen moleküle, bu molekülün elde edilmesinde kullanilan yönteme, bu molekülün kanser tedavisinde kullanilmasina, bu molekülün kanser tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanilmasina, bu iIaCin bilinen terapötik ajanlarla beraber kullanilmasina iliskindir. In a way, the present invention refers to the molecule represented by Formula If. the method used in the treatment of cancer, the use of this molecule in the treatment of cancer, to use the molecule in the preparation of a drug to be used in the treatment of cancer, This relates to the use of this drug with known therapeutic agents.
Mevcut bulusa uygun formül 1 ile gösterilen moleküllerin hayli etkin antikarsinojenik özellige sahip olduklari yapilan testlerde ortaya çikarilmistir. Bu bUlUSun diger kanser ilaçlarina göre avantaji; düsük dozda etki göstermesi ve saglikli hücrelere daha az toksik olmasidir. Molecules of formula 1 according to the present invention are highly active anticarcinogenic It has been revealed in the tests that they have this feature. Other cancers of this invention advantage over drugs; low-dose effect and less damage to healthy cells it is toxic.
Bir diger açidan bUlUS, formül 1 ile gösterilen bilesiklerin hazirlanmasinda kullanilacak bir yönteme iliskin olup, söz konusu yöntem asagidaki adimlari içerir; (i) Maleik anhidrit (formül 2) organik solvent ile çözülür, (ii) Elde edilen karisima Formül 3 ile gösterilen kalkon türevi madde eklenir, ki burada R = m-OCHg-Ph, O-CHg-Ph, m-CHg-Ph, o-CI-Ph, m-Br-Ph, furan'dan 0IUSan bir grubun içerisinden seçilir (iii) OIUSan karisima organik baz ilave edilerek reflüks sicakliginda karistirilmaya devam edilir, (iv) Reaksiyon sonunda organik solvent uzaklastirilir, (v) Elde edilen kati madde bir organik alkol içerisinde çözülür ve buz banyosuna aktarilarak çökmesi saglanir, (vi) Çökelti süzülür ve organik alkol/organik solvent karisimindan kristallendirilerek formül I elde edilir. On the other hand, the invention is used in the preparation of the compounds represented by formula 1. It relates to a method to be used, which method includes the following steps; (i) Maleic anhydride (formula 2) is dissolved with organic solvent, (ii) The chalcone-derived substance shown by Formula 3 is added to the resulting mixture, wherein R = m-OCHg-Ph, O-CHg-Ph, m-CHg-Ph, o-CI-Ph, m-Br-Ph from furan 0IUSan is selected from a group (iii) OIUSan is mixed at reflux temperature by adding organic base to the mixture. continues, (iv) At the end of the reaction, the organic solvent is removed, (v) The resulting solid is dissolved in an organic alcohol and placed in an ice bath. it is transferred and collapsed, (vi) The precipitate is filtered and crystallized from an organic alcohol/organic solvent mixture. formula I is obtained.
Burada kullanilan “organik solvent” ifadesi C1-C10 hidrokarbon veya ikame edilmis Ci-Cio hidrokarbon yapidaki bilesikleri tanimlamaktadir. Mevcut bulus kapsaminda organik solvent, bunlarla kisitli olmamakla beraber, asetik asit, aseton, asetonitril, benzen, l-butanol, 2-butanol, 2-butanone, t-bütil alkol, karbon tetrklorür, klorobenzen, kloroform, siklohekzan, 1,2-dikloroetan, dietilenglikol, dietileter, dimetil formamid, dimetil sülfoksit, 1-4 dioksan, etanol, etil asetat, etilen glikol, gliserin, heptan, hekzan, metanol, metilen klorür, N-metil-Z-pirolidon, nitrometan, pentan, l-propanol, 2-propanol, piridin, tetrahidrofuran, tolüen, trietil amin'den 0IUsan grubun içerisinden seçilebilir. Bulusun tercih edilen bir uygulamasinda organik solvent, benzen, tolüen, hegzan, metilen klorür'den OIUSan bir grubun içerisinden seçilir. BUIUSun özellikle tercih edilen bir uygulamasinda organik solvent olarak tolüen ve/veya hegzan kullanilir. The term "organic solvent" as used herein is C1-C10 hydrocarbon or substituted Ci-Cio describes compounds of hydrocarbon structure. Within the scope of the present invention organic solvent, including but not limited to acetic acid, acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone, t-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform, cyclohexane, 1,2-dichloroethane, diethyleneglycol, diethylether, dimethyl formamide, dimethyl sulfoxide, 1-4 dioxane, ethanol, ethyl acetate, ethylene glycol, glycerin, heptane, hexane, methanol, methylene chloride, N-methyl-Z-pyrrolidone, nitromethane, from pentane, 1-propanol, 2-propanol, pyridine, tetrahydrofuran, toluene, triethyl amine 0IUsan can be selected from within the group. In a preferred embodiment of the invention, organic from a group consisting of solvent, benzene, toluene, hexane, methylene chloride is selected. As an organic solvent in a particularly preferred application of BUIUS toluene and/or hexane is used.
Burada kullanilan “organik alkol" ifadesi doymus bir karbon atomuna bagli -OH grubuna sahip olan Ci-Cio hidrokarbon bilesiklerini ifade etmektedir. BUIUSun bir uygulamasinda organik alkol, bunlarla kisitli olmamakla beraber, l-butanol, 2- butanol, t-bütil alkol, etanol, metanol, 1-pr0panol, 2-propanol, diethylene glycol, ethylene glycol, 1,4-butandiol, 1,2,4-butantriol'den olusan bir grubun içerisinden seçilir. BuluSun tercih edilen bir uygulamasinda organik alkol etanol, metanol, 1- propanol'den olusan bir grubun içerisinden seçilir. BuIUSun özellikle tercih edilen bir uygulamasinda organik alkol olarak etanol kullanilir. The expression "organic alcohol" as used herein is -OH bonded to a saturated carbon atom. refers to the Ci-Cio hydrocarbon compounds having the group. BUIUS is a organic alcohol in its application, including but not limited to 1-butanol, 2- butanol, t-butyl alcohol, ethanol, methanol, 1-propanol, 2-propanol, diethylene glycol, From a group consisting of ethylene glycol, 1,4-butanediol, 1,2,4-butantriol is selected. In a preferred embodiment of the invention, organic alcohol ethanol, methanol, 1- selected from the group consisting of propanol. BuIUS is a particularly preferred Ethanol is used as organic alcohol in its application.
Bulus kapsaminda kullanilan organik baz, piridin, metil amin, trietil amin, imidazole, benzimidazole, fenil aminden olusan bir grubun içerisinden seçilebilir olmakla beraber bunlarla sinirli degildir. BUIUSUl'l tercih edilen bir uygulamasinda organik baz BUIUSun tercih edilen bir uygulamasinda (i) adiminda organik solvent olarak tolüen, iii) adiminda organik baz olarak trietil amin, (vl adiminda organik alkol olarak etanol (vi) organik solvent olarak hegzan ve organik alkol olarak etanol kullanilir. The organic base used within the scope of the invention is pyridine, methyl amine, triethyl amine, imidazole, benzimidazole can be selected from a group consisting of phenyl amine, but but not angry with them. In a preferred embodiment of BUIUSUL, the organic base In a preferred application of BUIUS, toluene as an organic solvent in step (i), triethyl amine as organic base in step iii), ethanol as organic alcohol in step vl (vi) hexane as organic solvent and ethanol as organic alcohol.
BuIUSun bir diger açidan Formül 1 ile gösterilen moleküllerin antikanser veya benzer özellikte ilaçlarin verilmesini gerektiren çesitli hastaliklarin tedavisinde kullanimina iliskindir. In another respect, the molecules represented by Formula 1 are anticancer or similar. It is used in the treatment of various diseases that require the administration of drugs. is related.
Bulusun bir diger açidan Formül 1 ile gösterilen moleküllerin antikanser veya benzer özellikte ilaçlarin verilmesini gerektiren çesitli hastaliklarin tedavisinde kullanilacak bir ilacin hazirlanmasinda kullanimina iliskindir. In another aspect of the invention, the molecules represented by Formula 1 are anticancer or similar. It will be used in the treatment of various diseases that require the administration of drugs in particular. It is related to its use in the preparation of a drug.
BUIUSun bir bakima formül 1 ile gösterilen moleküllerin kanserin tedavisinde ilaç BUIUS bir diger açindan formül 1 ile gösterilen moleküllerin kanserin tedavisinde kullanilmaya uygun bir ilacin üretiminde kullanilmasidir. BUIUS is a drug in the treatment of cancer, in a way the molecules represented by the formula 1 BUIUS is another aspect of the molecules shown with formula 1 in the treatment of cancer. is to be used in the production of a drug suitable for use.
Burada kullanilan sekliyle, "tedavi" ya da "tedavi etme" Ifadeleri bir rahatsizlik tarafindan tehdit edilen ya da bir rahatsizliga sahip bir denekte patolojik bir rahatsizligi karakterize eden en az bir semptomun engellenmesini, azaltilmasini, hafifletilmesini, iyilestirilmesini ya da bloke edilmesini ifade etmektedir. Farkli kanser türlerine iliskin sinirlayiCi olmayan bir liste asagida verilmektedir: karsinomlar, kati dokularin karsinomlari, skuamöz hücreli karsinomlar, adenokarsinomlar, sakromlar, gliyomlar, yüksek dereceli gliyomlar, blastomlar, nöroblastomlar, plazmasitomlar, histiositomlar, melanomlar, adenomlar, hipoksik tümörler, miyelomlar, metastatik kanserler ya da genel anlamda kanserler. Burada açiklanan bilesiklerin tedavisinde kullanilabilecegi spesifik kanser örnekleri arasinda ise B hücreli Ienfoma, T hücreli lenfoma, mikozis fungoides, Hodgkin Hastaligi, mesane kanseri, beyin kanseri, sinir sistemi kanseri, bas ve boyun kanseri, bas ve boynun skuamöz hücreli karsinomlari, böbrek kanseri, küçük hücreli akciger kanseri ve küçük hücreli olmayan akciger kanseri benzeri akciger kanserleri, nöroblastom/gliyoblastom, yumurtalik kanseri, pankreas kanseri, prostat kanseri, deri kanseri, karaciger kanseri, melanom, agzin, bOgazin, yemek borusunun skuamöz hücreli karsinomu, kolon kanseri, rahim agzi kanseri, rahim agzi karsinomu, gögüs kanseri ve epitelyal kanser, böbrek kanseri, genitoüriner kanser, pulmoner kanser, yemek borusu karsinomu, bas ve boyun karsinomu, kalin bagirsak kanseri, hemotopoietik kanserler; testis kanseri; kolon ve Rektal kanserler, prostat kanseri ya da pankreas kanseri sayilabilir. As used herein, the Expressions "treat" or "treat" are a sign of discomfort. a pathological condition in a subject threatened by or having a disorder prevention or reduction of at least one symptom that characterizes the disorder, refers to alleviation, improvement or blocking. Different The following is a non-limiting list of cancer types: carcinomas, carcinomas of solid tissues, squamous cell carcinomas, adenocarcinomas, sacromas, gliomas, high-grade gliomas, blastomas, neuroblastomas, plasmacytomas, histiocytomas, melanomas, adenomas, hypoxic tumors, myelomas, metastatic cancers or cancers in general. Here Examples of specific cancers for which the compounds described can be used to treat B-cell lymphoma, T-cell lymphoma, mycosis fungoides, Hodgkin's Disease, bladder cancer, brain cancer, nervous system cancer, head and neck cancer, head and squamous cell carcinomas of the neck, kidney cancer, small cell lung cancer and lung cancers such as non-small cell lung cancer, neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, liver cancer, melanoma, mouth, throat, squamous esophagus cell carcinoma, colon cancer, cervical cancer, cervical carcinoma, breast cancer and epithelial cancer, kidney cancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma, head and neck carcinoma, colon cancer, hematopoietic cancers; testicular cancer; colon and rectal cancers, prostate cancer or can also be considered pancreatic cancer.
BUIUS konusu formül 1 Ile gösterilen moleküller ayrica servikal ve anal displazileri, diger displaziler, agir displaziler, hiperplazi, tipik olmayan hiperplazi ve neoplazi benzeri kanser öncesi rahatSizliklarin tedavisi için de kullanilabilir. Molecules shown with the formula 1 in the subject of BUIUS also cause cervical and anal dysplasias, other dysplasias, severe dysplasias, hyperplasia, atypical hyperplasia and neoplasia It can also be used for the treatment of similar pre-cancer ailments.
Asagidaki örneklerde de gösterildigi üzere formül 1 ile gösterilen mevcut bulusa uygun moleküller in-vitro ortamda C6 (Siçan Beyin Tümörü) hücre hatlarinda, saglikli hücrelerle karsilastirmali olarak denenmistir. Bunun sonucunda bilesiklerin kullanilan ilaçlara göre düsük dozlarda daha etkin oldugu tespit edilmistir. The current invention represented by formula 1 as illustrated in the examples below suitable molecules in-vitro in C6 (Rat Brain Tumor) cell lines, tested in comparison with healthy cells. As a result, the compounds It has been found that it is more effective at low doses than the drugs used.
Mevcut bUIUS kapsaminda kullanilan “kanser" ifadesi habis (malign) tümörlere veya kontrolsüz hücre büyümesi ile karakterize olan bir fizyolojik duruma isaret eder. The term “cancer” used in the current bUIUS refers to malignant tumors or refers to a physiological state characterized by uncontrolled cell growth.
Kanser örnekleri karsinoma, lenfoma, blastoma sarkoma ve lösemiyi içermekte olup bunlarla sinirli degildir. Examples of cancer include carcinoma, lymphoma, blastoma sarcoma, and leukemia. not angry with them.
Karsinoma, burada kullanildigi sekliyle, epitel hücrelerden OIUsan bir kanser türünü ifade etmektedir. Carcinoma, as used herein, is a type of cancer that originates from epithelial cells. means.
Lenfoma, burada kullanildigi sekliyle, lenfositlerden gelisen bir kanser türünü anlatmaktadir. Lymphoma, as used herein, is a type of cancer that develops from lymphocytes. it tells.
Blastoma, burada kullanildigi sekliyle, blast hücre adiyla da bilinen öncü hücrelerden gelisen bir kanser türünü anlatmaktadir. Blastoma, as used herein, is one of the progenitor cells, also known as blast cells. describes a developing type of cancer.
Sarkoma, burada kullanildigi sekliyle, mezenkimal kökenli degismis hücrelerden kaynaklanan kanser türünü anlatmaktadir. Sarcoma, as used herein, consists of altered cells of mesenchymal origin. describes the type of cancer caused.
Lösemi, burada kullanildigi sekliyle, kemik iliginde baslayan ve yüksek sayida anormal akyuvar hücresi 0IUSumuna neden olan kanser türünü ifade etmektedir. Leukemia, as used herein, is bone marrow-onset and high-number refers to the type of cancer that causes abnormal white blood cell 0IUS.
Kanser türlerine ait daha özel örnekler meme kanseri, prostat kanseri, kolorektal kanser, deri kanseri, küçük hücreli akciger kanseri, küçük hücreli olmayan akciger kanseri, mezotelyom, gastrointestinal kanser, pankreas kanseri, gliyoblastom, vulva kanseri, rahim agzi kanseri, endometriyal karsinom, yumurtalik kanseri, karaciger kanseri, hepatom, mesane kanseri, böbrek kanseri, tükürük bezi karsinomu, tiroid kanseri ve çesitli bas ve boyun kanserlerini içerir. More specific examples of cancer types are breast cancer, prostate cancer, colorectal cancer, skin cancer, small cell lung cancer, non-small cell lung cancer, mesothelioma, gastrointestinal cancer, pancreatic cancer, glioblastoma, vulva cancer, cervical cancer, endometrial carcinoma, ovarian cancer, liver cancer, hepatoma, bladder cancer, kidney cancer, salivary gland carcinoma, thyroid cancer and various head and neck cancers.
Burada açiklanan sekliyle bu buIUSun konusu formül 1'e uygun moleküller kanserin tedavisi ve/veya kanser hastaligindan korumada kullanim alani bulmaktadir. Bu baglamda, bUIUS konusu formül 1'e uygun moleküller bir farmasötik bilesim seklinde uygulanacaktir. Molecules conforming to formula 1, the subject of this invention, as described herein, It finds use in the treatment and/or prevention of cancer. This In this context, the molecules according to the formula 1 subject to bUIUS are in the form of a pharmaceutical composition. will be applied.
Bir diger açidan mevcut buIUS formül 1 ile gösterilen moleküller ile birlikte en az bir farmasötik olarak kabul edilebilir eksipiyan içeren farmasötik bilesimlere iliskindir. On the other hand, these IUS present molecules with the formula 1 together with at least one relates to pharmaceutical compositions containing pharmaceutically acceptable excipients.
Söz konusu farmasötik bilesimler bu bilesimin hastaya uygulanmasi açisindan tercih edilen yönteme bagli olarak herhangi bir uygun formda olabilir. Said pharmaceutical compositions are preferred in terms of administration of this composition to the patient. It may take any suitable form depending on the method used.
BUIUS konusu farmasötik bilesimler formül 1 ile gösterilen moleküllere ilave olarak en az bir adet ikinci bir etken madde içerebilirler. In addition to the molecules indicated by formula 1, the pharmaceutical compositions of BUIUS are the most they may contain at least one second active ingredient.
Mevcut bUIUSa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerde bu etken maddeye ilave olarak en az bir diger etken madde antikanserojen ve/veya antimetastatik etki gösteren etken maddeler içerisinden seçilebilir. Ikinci etken madde formül 1 ile gösterilen moleküllerle beraber formüle edilebilecegi gibi formül 1 ile gösterilen moleküllerden ayri sekilde formüle edilip beraber kullanima uygun paketlerde satisa sunulabilir. Pharmaceutical containing molecules of formula 1 according to the present BUIUS In addition to this active ingredient in the compositions, at least one other active ingredient Among the active substances with anticarcinogenic and / or antimetastatic effects can be selected. The second active ingredient is formulated together with the molecules indicated by formula 1. can be formulated separately from the molecules indicated by formula 1 and It can be offered for sale in packages suitable for use together.
Formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerde bu etken maddeye ilave olarak en az bir diger etken madde kullanilmasi durumunda ikinci etken madde, cycl0phosphamide, methotrexate, S-fluorouracil, doxorubicin, cycloph05phamide, mustine, vincristine, procarbazine, prednisolone, bleomycin, dacarbazine, bleomycin, etoposide, cisplatin, epirubicin, capecitabine, folinic acid, oxaliplatin, carboplatin, mechloramine, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methyl urea, carmustine, Iomustine, semustine, fotemustine, streptozotocin, mitozolomide, temozolomide, thiotepa, mytomycin, procarbazine, cytarabine, gemcitabine, decitabine, vidaza, fludarabine, nelarabine, cladribine, clofarabinei pentostatin, etoposide, teniposide, novobiocin, merbarone, aclarubicinfden 0IUSan bir grubun içerisinden seçilebilir. Mevcut bUIUSa uygun moleküller Yukarida sayilan ajanlardan en az biri ile veya iki veya daha fazla ajanla kombine halde kullanilabilirler. In pharmaceutical compositions containing molecules represented by formula 1, this active ingredient In addition, if at least one other active substance is used, the second active substance, cycl0phosphamide, methotrexate, S-fluorouracil, doxorubicin, cycloph05phamide, mustine, vincristine, procarbazine, prednisolone, bleomycin, dacarbazine, bleomycin, etoposide, cisplatin, epirubicin, capecitabine, folinic acid, oxaliplatin, carboplatin, mechloramine, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methyl urea, carmustine, Iomustine, semustine, fotemustine, streptozotocin, mitozolomide, temozolomide, thiotepa, mytomycin, procarbazine, cytarabine, gemcitabine, decitabine, vidaza, fludarabine, nelarabine, cladribine, clofarabinei pentostatin, A group of 0IUSan from etoposide, teniposide, novobiocin, merbarone, aclarubicinf can be selected from. Molecules suitable for the present bUIUS they may be used with at least one or in combination with two or more agents.
Mevcut bUIUSa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerde bu etken madde 1 mcm/kg ile 1000 mg/kg araliginda bir dozda kullanilabilir. Pharmaceutical containing molecules of formula 1 according to the present BUIUS In compositions, this active ingredient is administered at a dose of 1 mcm/kg to 1000 mg/kg. can be used.
Mevcut bUIUSa görei formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler kombine halde, simültane olarak, sirali olarak veya ayri ayri bir veya daha fazla baska terapötik aktif madde, örnegin kanser tedavisinde kullanilan aktif maddelerle birlikte verilebilir. Pharmaceutical compositions containing the molecules represented by formula 1 according to the present BUIUS in combination, simultaneously, sequentially or separately, in one or more other therapeutically active substance, for example in combination with active substances used in the treatment of cancer can be given.
Mevcut bUIUSa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler kati veya SiVi dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present BUIUS They can be formulated in solid or liquid dosage forms.
Mevcut bulusa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler agiz yoluyla alima uygun dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention They can be formulated in dosage forms suitable for oral administration.
Mevcut bUIUSa göre, formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler agiz yoluyla alima uygun dozaj formlarinda formüle edilmesi durumunda söz konusu dozaj formu tablet, kapsül, salinimi degistirilmis tablet, salinimi uzatilmis tablet, agizda dagilan tablet, dil alti tablet, efervesan tablet, sivi solüsyon, sivi süspansy0n`dan oIUSan bir grubun içerisinden seçilebilir. Pharmaceutical compositions containing molecules of formula 1 according to the present BUIUS If formulated in dosage forms suitable for oral administration, dosage form tablet, capsule, modified release tablet, extended release tablet, mouth dispersing tablet, sublingual tablet, effervescent tablet, liquid solution, liquid It can be selected from a group of suspensions.
Mevcut bUIUSa göre formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler inhalasyon yoluyla alima uygun dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present BUIUS They may be formulated in dosage forms suitable for inhalation.
Mevcut buIUSa göre formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerin inhalasyon yoluyla alima uygun dozaj formlarinda formüle edilmesi durumunda söz konusu dozaj formu aerosol, inhaler, nebulizer, vaporizör'den olusan bir grubun içerisinden seçilebilir. Pharmaceutical compositions containing molecules of formula 1 according to the present invention If formulated in dosage forms suitable for inhalation, The dosage form in question is a group consisting of aerosol, inhaler, nebulizer, vaporizer. can be selected from.
Mevcut bulusa göre formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler enjeksiyon yoluyla alima uygun dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention They may be formulated in dosage forms suitable for administration by injection.
Mevcut bUIUSa göre formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerin enjeksiyon yoluyla alima uygun dozaj formlarinda formüle edilmesi durumunda söz konusu dozaj formu deri içi, kas içi, damar içi, karin için uygulamaya uygun dozaj formlarindan birinde formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present BUIUS when formulated in dosage forms suitable for administration by injection. The dosage form in question is suitable for intradermal, intramuscular, intravenous, abdominal application. They can be formulated in one of the following forms.
Mevcut bulusa uygun formül 1 ile gösterilen molekülleri içeren farmasötik bilesimler deri yoluyla alima uygun dozaj formlarinda formüle edilebilirler. Pharmaceutical compositions containing molecules of formula 1 according to the present invention They may be formulated in dosage forms suitable for transdermal administration.
Mevcut bulusa uygun formül 1 ile gösterilen molekülleri içeren farmasötik bilesimlerin deri yoluyla alima uygun dozaj formlarinda formüle edilmesi durumunda krem, jel, losyon, merhem, kulak damlasi, göz damlasi, transdermal flaster'den OlUSan bir grubun içerisinden seçilebilir. Pharmaceutical containing molecules of formula 1 according to the present invention when the compositions are formulated in dosage forms suitable for transdermal administration Composed of cream, gel, lotion, ointment, ear drops, eye drops, transdermal patch can be selected from a group.
BUIUS sahipleri bUIUSa uygun formül 1 ile gösterilen moleküllerin yapisini teyit eden verileri, molekülün üretim yöntemine iliskin örnekleri ve bulusa uygun molekülün antikanserojen etkisini kanitlayan deneysel verileri bu basvuruda dikkatinize sunmaktadir. Sunulan tüm bu veriler ve teknigin bilinen durumu dikkate alindiginda bulusa uygun formül 1 ile gösterilen moleküllerin teknigin bilinen durumunda daha önce açiklanmamis olan yeni moleküller oldugu ve yapilan deneylerde de gösterildigi üzere bulus konusu moleküllerin teknigin bilinen durumunda var olan antikanserojen özellikteki moleküllerden hem daha etkili oldugu hem de daha düsük toksisiteye sahip oldugu görülmekte bu baglamda mevcut bUIUSa uygun moleküllerin yeni oldugu ve teknigin bilinen durumunu asarak bUIUS basamagina sahip oldugu gösterilmektedir. BUIUS holders confirming the structure of the molecules shown with formula 1 according to bUIUS data, examples of the method of manufacture of the molecule, and the molecule according to the invention. We bring to your attention the experimental data proving its anticarcinogenic effect in this application. offers. Considering all these data presented and the state of the art, The molecules represented by the formula 1 according to the invention are more in the state of the art. It has been shown that there are new molecules that have not been explained before and it has been shown in the experiments. Anticarcinogens existing in the state of the art of the molecules of the invention, such as It has both more effective and lower toxicity than molecules with In this context, it is seen that the molecules suitable for the current bUIUS are new and It is shown to have the bUIUS step, surpassing the state of the art.
Simdi bUlUS sadece örnek amaçli olan ve bu bUIUsun kapsamini herhangi bir sekilde kisitlar olarak yorumlanmamasi gereken asagidaki örneklere atifta bulunularak açiklanacaktir. Now the bUlUS is for illustrative purposes only and does not in any way extend the scope of this bIU. with reference to the following examples, which should not be construed as constraints. will be disclosed.
ORNEKLER Ornek 1: (E)-1-(4-sinnamoilfenil)-1H-pir0I-2,5-dion (Formül I) Türevlerinin Sentezi Için Genel Yöntem karistirildi. Daha sonra bu karisima kalkon türevi (0.5 9, 0.002 mol] madde (3) eklenip üzerine 15 damla trietilamin ilave edilerek reflüks islemi baslatildi. Reaksiyon belli araliklarla TLC ile takip edildi. Reaksiyon 24 saat sonunda bitirildi. Toluen evaparatörde uzaklastirildi ve kati kiSim etanol de çözülerek hazirlanan buz banyosuna döküldü. 3 saatin sonunda süzülen çökelek etanol ile çözülerek etanol/hegzan karisiminda kristallendirildi. EXAMPLES Example 1: Derivatives of (E)-1-(4-cinnamoylphenyl)-1H-pyrOI-2,5-dione (Formula I) General Method for Synthesis mixed up. Then, the chalcone derivative (0.5 9, 0.002 mol] substance (3) is added to this mixture. The reflux process was started by adding 15 drops of triethylamine on it. The reaction is periodically Followed by TLC. The reaction was finished after 24 hours. Toluene was removed in the evaporator and the solid was dissolved in ethanol and poured into the prepared ice bath. after 3 hours The filtered precipitate was dissolved with ethanol and crystallized in an ethanol/hexane mixture.
Reflü ks N 2 O 24 saat C& R: m-OCH3-Ph, o-CH3-Ph, m-CH3-Ph, o-Cl-Ph, m-Br-Ph, Furan Sema 1: Formül 1 ile gösterilen moleküllerin sentez yöntemi. Reflux N 2 O 24 hours C& R: m-OCH3-Ph, o-CH3-Ph, m-CH3-Ph, o-Cl-Ph, m-Br-Ph, Furan Scheme 1: Synthesis method of molecules represented by formula 1.
Bütün bilesiklerin safliklari spektroskopik olarak kontrol edildi. NMR spektrumlari; Bruker 400 MHz 1H ve 13C NMR'sinde Gaziosmanpasa Üniversitesinde alindi. Çözücü olarak CDCILDMSO kullanildi. Elde edilen NMR spektrum verileri yapilar ile uyum içerisindedir. The purity of all compounds was checked spectroscopically. NMR spectra; Bruker Obtained at 400 MHz 1H and 13C NMR at Gaziosmanpasa University. As a solvent CDCILDMSO was used. The obtained NMR spectrum data are in good agreement with the structures.
Formül 1 ile gösterilen moleküllerin erime noktalari elektrotermal erime noktasi tayin cihaziyla belirlendi. BUIUSa uygun formül 1 ile gösterilen moleküllerin IR ölçümlerinde örnekler KBr ile hazirlanip ölçümler Transform lnfrared Spectrometer (JASCO FT/IR-430) cihazindan Gaziosmanpasa Üniversitesinde alindi. The melting points of the molecules represented by formula 1 are determined by the electrothermal melting point. determined by the device. In the IR measurements of the molecules shown with formula 1 in accordance with BUIUS samples were prepared with KBr and measurements were made with Transform Infrared Spectrometer (JASCO FT/IR-430) The device was taken from Gaziosmanpasa University.
Yukarida detaylari verilen sekilde karakterize edilen bUIUSa uygun her bir molekülün karakterizasyon bilgisi asagida verilmektedir. 1H NMR (, 7.59 (d, (El-l-(4-(3-(0-metillakriloillfeniI)-lH-pir0I-2,5-dion (lbl: Sari renkli kristal Verim= % 76, 1H NMR (, 7.57-7.55 (El-l-(4-(3-(m-metiIlakriloillfenill-lH-piroI-2,5-dion (lc): Kahve renkli kristal Verim = % 74, E.N= 138-140°C 1H NMR (, 7.80 (d, (El-l-(4-(3-(2-klor0feniIlakriloillfenill-lH-pirol-2,5-dion (1d): Kahve renkli kristal Verim= % 83, E.N= 138-142 °C 1H NMR (, (EJ-l-(4-(3-(3-bromofenil) akriloillfenil)-1H-pir0I-2,5-dion (le): Sari renkli kristal Verim: (El-l-(4-(3-(furan-2-il)akril0il)fenil)-1H-pirol-2,5-dion (lf): Sari renkli kristal Verim= % 80, E.N= 187-190 °C Bulus kapsaminda test edilen maddelerin antiproliferatif aktivitesinin (antikanser aktivitesi) ve IC50 konsantrasyonlarinin belirlenmesi için hücresel DNA miktarinin tespitini saglayan kolorimetrik BrDU (S-bromo-Z'-deoksiüridinl Cell ELISA kiti (Roche) kullanilmistir. Bu amaçla, hazirlanan hücre stogundan 100 ul hücre süspansiyonu 96 kuyucuklu steril hücre kültür plakalarinin ilgili kuyucuklarina triplike olacak sekilde pipetlenir. Hücre kontrolü için besi yeri, negatif kontrol için çözücü madde (çözücü kontrol, genellikle DMSOJ, pozitif kontrol için uygun bir antikanser bilesik (5-Flor0urasil, Sigma F6627l test maddesi ile ayni Kuyucuklardaki son hacim 200 pl olacak sekilde besi yeri ile tamamlanir ve 37C, %5 C02 ortami saglayan bir inkübatörde 24 saat inkübe edilir. Each molecule suitable for the bUIUS characterized as detailed above Characterization information is given below. 1H NMR (, 7.59 (d, (El-1-(4-(3-(0-methyllacryloylphenyl)-1H-pyrOI-2,5-dione (lbl: Yellow crystal Yield= 76%, 1H NMR (, 7.57-7.55 (El-1-(4-(3-(m-methyllacriloylphenylphenyl-1H-pyrroI-2,5-dione (lc): Brown crystal Yield = % 74, M.N= 138-140°C 1H NMR (, 7.80 (d, (El-1-(4-(3-(2-chlorophenyl-lacryloylphenylphenyl-1H-pyrrole-2,5-dione (1d): Brown crystal Yield= 83%, M.N= 138-142 °C 1H NMR (, (EJ-1-(4-(3-(3-bromophenyl) acryloylphenyl)-1H-pyrOI-2,5-dione (le): Yellow crystal Yield: (El-1-(4-(3-(furan-2-yl)acrylOyl)phenyl)-1H-pyrrole-2,5-dione (lf): Yellow crystal Yield= % 80, M.N= 187-190 °C The antiproliferative activity (anticancer activity) of the substances tested within the scope of the invention and quantification of cellular DNA for determination of IC50 concentrations. A colorimetric BrDU (S-bromo-Z'-deoxyuridine Cell ELISA kit (Roche) was used. This For this purpose, 100 µl of the cell suspension from the prepared cell stock was used in 96-well sterile cells. It is pipetted in triplicate into the corresponding wells of the culture plates. For cell control medium, solvent for negative control (solvent control, usually DMSOJ, positive an appropriate anticancer compound for control (5-Fluorouracil, same as Sigma F6627l test substance The final volume in the wells is made up with 200 pl medium and 37°C, 5% CO2. It is incubated for 24 hours in an incubator that provides the environment.
Inkübasyondan sonra hücreler üzerine göre BrDU isaretleme solüsyonundan 10 uL/kuyu olacak sekilde eklenir ve hücreler 37 derecede 2 saat yeniden inkübe edilir. Daha sonra platelerdeki medyum aspire edilerek isaretleme solüsyonunu ortamdan uzaklastirilir, filtre kagidina blotlanarak Sivi kalintisi alinir ve hücreler 60 derecede 1 saat bekletilerek kurutulur. 10 µL/well of BrDU labeling solution based on cells after incubation and the cells are re-incubated at 37 degrees for 2 hours. Later on The media on the plates is aspirated and the marking solution is removed from the environment, the filter Liquid residue is taken by blotting on the paper and the cells are dried at 60 degrees for 1 hour.
Kurutulan hücrelere, 200 uL/kuyu olacak sekilde FixDenat solüsyonu eklenir ve 15 ila 25 derecede 30 dakika inkübe edilir. FixDenat hem hücreleri sabitler hem de DNA'yi denatüre eder, böylece anti-BrdU-POD antikorlari DNA*ya girmis BrdU'ya rahatça ulasabilir. FixDenat solution at 200 µL/well is added to the dried cells and 15 to 25 incubated for 30 minutes. FixDenat both fixes cells and denatures DNA. Thus, anti-BrdU-POD antibodies can easily reach the BrdU that has entered the DNA.
Inkübasyondan sonra FixDenat solüsyonu aspirasyon ve blotlamayla uzaklastirilir. Hücreler üzerine Anti-BrdU-POD çalisma solüsyonu 100 uL/kuyu olacak sekilde eklenir ve 22 derecede yaklasik 90 dakika inkübe edilir. Daha sonra plateler blotlanarak antikor konjugesi uzaklastirilir ve kuyular 200 ila 300 uL/kuyu olacak sekilde yikama solüsyonuyla üç kez yikanir. Sonra yikama solüsyonu dökülerek ve blotlamayla uzaklastirilir ve 100 uL/kuyu olacak sekilde substrat solüsyonu eklenir. Renk olusuncaya kadar 22 derecede 30 dakika inkübe edilir. Son olarak her bir kuyucuga 25 uL 1M sülfürik asit (durdurma solüsyonu) eklenir ve bir çalkalayici üzerinde 300 rpm'de yaklasik 1 dakika boyunca mikroplate inkübe edilir. Daha sonra bir ELIZA okuyucusu (Ryto, China] kullanarak plakalardaki hücrelerin proliferasyon miktari hücre kültür medyumunun 450 nm'deki absorbansi ölçülerek belirlenir. After incubation, the FixDenat solution is removed by aspiration and blotting. cells 100 µL/well of the Anti-BrdU-POD working solution was added onto it and 22 incubated for approximately 90 minutes. The plates are then blotted and antibody conjugated removed and wells washed three times with 200 to 300 µL/well of wash solution. is washed. The wash solution is then removed by pouring and blotting and 100 µL/well substrate solution is added. 30 minutes at 22 degrees until color develops is incubated. Finally, add 25 µL of 1M sulfuric acid (stop solution) to each well. added and incubated the microplate for approximately 1 minute at 300 rpm on a shaker. is done. Then, using an ELIZA reader (Ryto, China], cells in the plates The amount of proliferation is determined by measuring the absorbance of the cell culture medium at 450 nm.
Sonuçlar % hücre inhibisyonu olarak rapor edilmekte olup, çözücü ile muamele edilmis hücrelerin optik densitesi %100 olarak kabul edilecektir. Buna göre % inhibisyon [l-(A test maddesi /A çözücü kontrol) X 100 formülüne göre hesaplanacaktir. Deney sonuçlari 3 kanser hücre hatti kullanilarak yapilmis 3 ayri testin ortalamasi seklinde ifade edilmistir.Results are reported as % cell inhibition, not treated with solvent. The optical density of the cells will be considered as 100%. Accordingly, % inhibition [1-(A test substance /A solvent control) will be calculated according to the formula X 100. Experiment results 3 cancer expressed as the average of 3 separate tests performed using a cell line.
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2016/15186A TR201615186A2 (en) | 2016-10-26 | 2016-10-26 | (E) -1- (4-CINNAMOYLPHENYL) -1H-PYROL-2,5-DIONE DERIVATIVES WITH ANTICANSEROGEN ACTIVITY |
| PCT/TR2017/050521 WO2018226178A2 (en) | 2016-10-26 | 2017-10-25 | (e)-1-(4-cinnamoyl-phenyl)-1 h-pyrrole-2,5-dione derivatives having anti-cancerogenic efficiency |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR2016/15186A TR201615186A2 (en) | 2016-10-26 | 2016-10-26 | (E) -1- (4-CINNAMOYLPHENYL) -1H-PYROL-2,5-DIONE DERIVATIVES WITH ANTICANSEROGEN ACTIVITY |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR201615186A2 true TR201615186A2 (en) | 2017-02-21 |
Family
ID=64567447
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TR2016/15186A TR201615186A2 (en) | 2016-10-26 | 2016-10-26 | (E) -1- (4-CINNAMOYLPHENYL) -1H-PYROL-2,5-DIONE DERIVATIVES WITH ANTICANSEROGEN ACTIVITY |
Country Status (2)
| Country | Link |
|---|---|
| TR (1) | TR201615186A2 (en) |
| WO (1) | WO2018226178A2 (en) |
-
2016
- 2016-10-26 TR TR2016/15186A patent/TR201615186A2/en unknown
-
2017
- 2017-10-25 WO PCT/TR2017/050521 patent/WO2018226178A2/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018226178A2 (en) | 2018-12-13 |
| WO2018226178A3 (en) | 2019-03-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Vicini et al. | Synthesis and antiproliferative activity of benzo [d] isothiazole hydrazones | |
| Kumar et al. | Hypoxia-directed and activated theranostic agent: Imaging and treatment of solid tumor | |
| Zhu et al. | Design, synthesis, and evaluation of chalcone analogues incorporate α, β-Unsaturated ketone functionality as anti-lung cancer agents via evoking ROS to induce pyroptosis | |
| Sun et al. | Discovery of a series of 1, 3, 4-oxadiazole-2 (3H)-thione derivatives containing piperazine skeleton as potential FAK inhibitors | |
| CN107257800A (en) | The method that target protein is degraded is induced by bifunctional molecule | |
| CN109422733A (en) | One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades | |
| Chipoline et al. | Molecular mechanism of action of new 1, 4-naphthoquinones tethered to 1, 2, 3-1H-triazoles with cytotoxic and selective effect against oral squamous cell carcinoma | |
| CA2950305A1 (en) | Texaphyrin-pt(iv) conjugates and compositions for use in overcoming platinum resistance | |
| Volodina et al. | Thiophene-2-carboxamide derivatives of anthraquinone: A new potent antitumor chemotype | |
| CN106957315B (en) | N- replaces benzenesulfonyl-azaindole oxybenzamide class compound and its prepares the purposes of drug | |
| WO2015096640A1 (en) | Thiazolyl-containing rapamycin derivative and application thereof | |
| Tang et al. | Novel cytisine derivatives exert anti-liver fibrosis effect via PI3K/Akt/Smad pathway | |
| Zeng et al. | Selective stabilization of multiple promoter G-quadruplex DNA by using 2-phenyl-1H-imidazole-based tanshinone IIA derivatives and their potential suppressing function in the metastatic breast cancer | |
| Li et al. | Synthesis and biological evaluation of novel alkylated polyamine analogues as potential anticancer agents | |
| de la Cueva-Alique et al. | Biological evaluation of water soluble arene Ru (II) enantiomers with amino-oxime ligands | |
| Dai et al. | Synthesis and biological evaluation of naphthalimide-polyamine conjugates modified by alkylation as anticancer agents through p53 pathway | |
| Ji et al. | A novel triazolonaphthalimide induces apoptosis and inhibits tumor growth by targeting DNA and DNA-associated processes | |
| CN108676009B (en) | Pyrimidine derivatives as HER2 tyrosine kinase inhibitors and uses thereof | |
| Metwally et al. | Structure–activity relationship investigation of methoxy substitution on anticancer pyrimido [4, 5-c] quinolin-1 (2 H)-ones | |
| CN104829671B (en) | The gemcitabine of NO donator types/FTA/ furazans conjugate and preparation method and purposes | |
| Hoang et al. | Design, synthesis and evaluation the bioactivities of novel 1, 3-dimethyl-6-amino-1H-indazole derivatives as anticancer agents | |
| CN101816649A (en) | Preparation method of 2,3-indolediketone-3-oxime and application in prevention and control of cancer | |
| TR201615186A2 (en) | (E) -1- (4-CINNAMOYLPHENYL) -1H-PYROL-2,5-DIONE DERIVATIVES WITH ANTICANSEROGEN ACTIVITY | |
| CN104144919A (en) | Condensation product of theanine derivative and carboxylic acid coumarin derivative, intermediate of the condensation product, method for preparing same, and use thereof | |
| Tala et al. | Design and synthesis of potent antitumor water-soluble phenyl N-mustard-benzenealkylamide conjugates via a bioisostere approach |