CN111788183A - 用于抑制tnik的杂环融合苯基化合物及其医疗用途 - Google Patents
用于抑制tnik的杂环融合苯基化合物及其医疗用途 Download PDFInfo
- Publication number
- CN111788183A CN111788183A CN201980015875.XA CN201980015875A CN111788183A CN 111788183 A CN111788183 A CN 111788183A CN 201980015875 A CN201980015875 A CN 201980015875A CN 111788183 A CN111788183 A CN 111788183A
- Authority
- CN
- China
- Prior art keywords
- pyrazol
- benzo
- amino
- compound
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 125000000623 heterocyclic group Chemical group 0.000 title claims description 21
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 17
- 230000002401 inhibitory effect Effects 0.000 title abstract description 18
- 101000662997 Homo sapiens TRAF2 and NCK-interacting protein kinase Proteins 0.000 title abstract 2
- 102100037671 TRAF2 and NCK-interacting protein kinase Human genes 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 156
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 62
- 150000003839 salts Chemical class 0.000 claims abstract description 48
- 201000011510 cancer Diseases 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 38
- 239000000126 substance Substances 0.000 claims abstract description 24
- 239000000203 mixture Substances 0.000 claims abstract description 22
- -1 and Chemical compound 0.000 claims description 49
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 21
- 206010009944 Colon cancer Diseases 0.000 claims description 18
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 16
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 16
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 14
- 125000005605 benzo group Chemical group 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 10
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 10
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 10
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 9
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 9
- 206010017758 gastric cancer Diseases 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 201000011549 stomach cancer Diseases 0.000 claims description 9
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 8
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 claims description 7
- ASSKVPFEZFQQNQ-UHFFFAOYSA-N 2-benzoxazolinone Chemical compound C1=CC=C2OC(O)=NC2=C1 ASSKVPFEZFQQNQ-UHFFFAOYSA-N 0.000 claims description 7
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 201000007270 liver cancer Diseases 0.000 claims description 7
- 208000014018 liver neoplasm Diseases 0.000 claims description 7
- 229930192474 thiophene Natural products 0.000 claims description 7
- TZOYXRMEFDYWDQ-UHFFFAOYSA-N 3,4-dihydro-1h-quinolin-2-one Chemical compound C1=CC=C2NC(=O)CCC2=C1 TZOYXRMEFDYWDQ-UHFFFAOYSA-N 0.000 claims description 6
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 6
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims description 6
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 5
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 claims description 5
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 claims description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 claims description 5
- QRCGFTXRXYMJOS-UHFFFAOYSA-N 4h-1,4-benzoxazin-3-one Chemical compound C1=CC=C2NC(=O)COC2=C1 QRCGFTXRXYMJOS-UHFFFAOYSA-N 0.000 claims description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 5
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 claims description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 4
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 claims description 3
- MFJCPDOGFAYSTF-UHFFFAOYSA-N 1H-isochromene Chemical compound C1=CC=C2COC=CC2=C1 MFJCPDOGFAYSTF-UHFFFAOYSA-N 0.000 claims description 3
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical compound C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 claims description 3
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 claims description 3
- PRZZTRULFLCGBS-UHFFFAOYSA-N 3H-isochromene Chemical compound C1=CC=CC2=CCOC=C21 PRZZTRULFLCGBS-UHFFFAOYSA-N 0.000 claims description 3
- ZQHIKNXKPKDNJA-UHFFFAOYSA-N 6-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-3,4-dihydro-1H-quinolin-2-one Chemical compound OC1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2CCC(NC2=CC=1)=O ZQHIKNXKPKDNJA-UHFFFAOYSA-N 0.000 claims description 3
- RACWNJQJHCSCLU-UHFFFAOYSA-N 6-[[5-(4-phenylmethoxyphenyl)-1H-pyrazol-3-yl]amino]-3,4-dihydro-1H-quinolin-2-one Chemical compound C(C1=CC=CC=C1)OC1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2CCC(NC2=CC=1)=O RACWNJQJHCSCLU-UHFFFAOYSA-N 0.000 claims description 3
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 claims description 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 3
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 3
- DMSMPAJRVJJAGA-UHFFFAOYSA-N benzo[d]isothiazol-3-one Chemical compound C1=CC=C2C(=O)NSC2=C1 DMSMPAJRVJJAGA-UHFFFAOYSA-N 0.000 claims description 3
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 claims description 3
- 208000032839 leukemia Diseases 0.000 claims description 3
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims description 3
- CSNIZNHTOVFARY-UHFFFAOYSA-N 1,2-benzothiazole Chemical compound C1=CC=C2C=NSC2=C1 CSNIZNHTOVFARY-UHFFFAOYSA-N 0.000 claims description 2
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 claims description 2
- YHMYGUUIMTVXNW-UHFFFAOYSA-N 1,3-dihydrobenzimidazole-2-thione Chemical compound C1=CC=C2NC(S)=NC2=C1 YHMYGUUIMTVXNW-UHFFFAOYSA-N 0.000 claims description 2
- PDQRQJVPEFGVRK-UHFFFAOYSA-N 2,1,3-benzothiadiazole Chemical compound C1=CC=CC2=NSN=C21 PDQRQJVPEFGVRK-UHFFFAOYSA-N 0.000 claims description 2
- JGQPSDIWMGNAPE-UHFFFAOYSA-N 2,1-benzothiazole Chemical compound C1=CC=CC2=CSN=C21 JGQPSDIWMGNAPE-UHFFFAOYSA-N 0.000 claims description 2
- FZKCAHQKNJXICB-UHFFFAOYSA-N 2,1-benzoxazole Chemical compound C1=CC=CC2=CON=C21 FZKCAHQKNJXICB-UHFFFAOYSA-N 0.000 claims description 2
- LDZYRENCLPUXAX-UHFFFAOYSA-N 2-methyl-1h-benzimidazole Chemical compound C1=CC=C2NC(C)=NC2=C1 LDZYRENCLPUXAX-UHFFFAOYSA-N 0.000 claims description 2
- KGWNRZLPXLBMPS-UHFFFAOYSA-N 2h-1,3-oxazine Chemical class C1OC=CC=N1 KGWNRZLPXLBMPS-UHFFFAOYSA-N 0.000 claims description 2
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical class N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 claims description 2
- ZYGYULIGJXJLRW-UHFFFAOYSA-N 4-methyl-1h-indazole Chemical compound CC1=CC=CC2=C1C=NN2 ZYGYULIGJXJLRW-UHFFFAOYSA-N 0.000 claims description 2
- APLVPBUBDFWWAD-UHFFFAOYSA-N 4-methylquinolin-2(1H)-one Chemical compound C1=CC=C2C(C)=CC(=O)NC2=C1 APLVPBUBDFWWAD-UHFFFAOYSA-N 0.000 claims description 2
- HMMPHXCOTBASBC-UHFFFAOYSA-N 6-methyl-1h-indazole Chemical compound CC1=CC=C2C=NNC2=C1 HMMPHXCOTBASBC-UHFFFAOYSA-N 0.000 claims description 2
- DYESOCDTCOTWKJ-UHFFFAOYSA-N N-[5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-1H-indol-5-amine Chemical compound COC1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2C=CNC2=CC=1 DYESOCDTCOTWKJ-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 claims description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 2
- 150000003248 quinolines Chemical class 0.000 claims description 2
- HJPABNQVBRJZGO-UHFFFAOYSA-N 2-fluoro-4-[3-(1H-indazol-5-ylamino)-1H-pyrazol-5-yl]phenol Chemical compound N1N=CC2=CC(=CC=C12)NC1=NNC(=C1)C1=CC(=C(C=C1)O)F HJPABNQVBRJZGO-UHFFFAOYSA-N 0.000 claims 2
- DRHMBWYRNLIICS-UHFFFAOYSA-N 4-[3-(1H-indazol-5-ylamino)-1H-pyrazol-5-yl]phenol Chemical compound N1N=CC2=CC(=CC=C12)NC1=NNC(=C1)C1=CC=C(C=C1)O DRHMBWYRNLIICS-UHFFFAOYSA-N 0.000 claims 2
- BJCMQWVCSXXBSZ-UHFFFAOYSA-N 4-methyl-6-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]-1H-quinolin-2-one Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2C(=CC(NC2=CC=1)=O)C BJCMQWVCSXXBSZ-UHFFFAOYSA-N 0.000 claims 2
- FUFJJRBBUSPEQN-UHFFFAOYSA-N 5-[[5-(3-fluoro-4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-1,3-dihydroindol-2-one Chemical compound FC=1C=C(C=CC=1O)C1=CC(=NN1)NC=1C=C2CC(NC2=CC=1)=O FUFJJRBBUSPEQN-UHFFFAOYSA-N 0.000 claims 2
- DBPJGNASQBRYCG-UHFFFAOYSA-N 6-[[5-(4-imidazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]-3,4-dihydro-1H-quinolin-2-one Chemical compound N1(C=NC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2CCC(NC2=CC=1)=O DBPJGNASQBRYCG-UHFFFAOYSA-N 0.000 claims 2
- FMODLHMRSPQXGM-UHFFFAOYSA-N 6-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]-3,4-dihydro-1H-quinolin-2-one Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2CCC(NC2=CC=1)=O FMODLHMRSPQXGM-UHFFFAOYSA-N 0.000 claims 2
- KDMLBQLDHLHSPL-UHFFFAOYSA-N 7-[[5-(4-hydroxyphenyl)-1H-pyrazol-3-yl]amino]-4H-1,4-benzoxazin-3-one Chemical compound OC1=CC=C(C=C1)C1=CC(=NN1)NC=1C=CC2=C(OCC(N2)=O)C=1 KDMLBQLDHLHSPL-UHFFFAOYSA-N 0.000 claims 2
- KCKGSMRODNFDQP-UHFFFAOYSA-N 7-[[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]-4H-1,4-benzoxazin-3-one Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC=1C=CC2=C(OCC(N2)=O)C=1 KCKGSMRODNFDQP-UHFFFAOYSA-N 0.000 claims 2
- IJLYKUPJZHTQFS-UHFFFAOYSA-N N-[5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-1H-indazol-5-amine Chemical compound COC1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2C=NNC2=CC=1 IJLYKUPJZHTQFS-UHFFFAOYSA-N 0.000 claims 2
- HCHUIDZUTWOFOR-UHFFFAOYSA-N N-[5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]-1H-indazol-5-amine Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=CC(=NN1)NC=1C=C2C=NNC2=CC=1 HCHUIDZUTWOFOR-UHFFFAOYSA-N 0.000 claims 2
- PVTXJGJDOHYFOX-UHFFFAOYSA-N 2h-1,4-benzoxazine Chemical class C1=CC=C2N=CCOC2=C1 PVTXJGJDOHYFOX-UHFFFAOYSA-N 0.000 claims 1
- QCXGJTGMGJOYDP-UHFFFAOYSA-N 4-methyl-1h-benzimidazole Chemical compound CC1=CC=CC2=C1N=CN2 QCXGJTGMGJOYDP-UHFFFAOYSA-N 0.000 claims 1
- YAPBGONDNJGPLF-UHFFFAOYSA-N 6-[[4-fluoro-5-(4-pyrazol-1-ylphenyl)-1H-pyrazol-3-yl]amino]-3,4-dihydro-1H-quinolin-2-one Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C1=C(C(=NN1)NC=1C=C2CCC(NC2=CC=1)=O)F YAPBGONDNJGPLF-UHFFFAOYSA-N 0.000 claims 1
- LBSNKWDBZPJRFG-UHFFFAOYSA-N N-[5-(4-methoxyphenyl)-1H-pyrazol-3-yl]-1H-indazol-6-amine Chemical compound COC1=CC=C(C=C1)C1=CC(=NN1)NC1=CC=C2C=NNC2=C1 LBSNKWDBZPJRFG-UHFFFAOYSA-N 0.000 claims 1
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 claims 1
- NBGMRMDAEWWFIR-UHFFFAOYSA-N imidazole-2-thione Chemical class S=C1N=CC=N1 NBGMRMDAEWWFIR-UHFFFAOYSA-N 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 23
- 230000002265 prevention Effects 0.000 abstract description 9
- 125000000217 alkyl group Chemical group 0.000 description 42
- 210000004027 cell Anatomy 0.000 description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000008194 pharmaceutical composition Substances 0.000 description 18
- 201000010099 disease Diseases 0.000 description 17
- 239000002552 dosage form Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 239000003112 inhibitor Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 108091000080 Phosphotransferase Proteins 0.000 description 13
- 102000020233 phosphotransferase Human genes 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000002904 solvent Substances 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 229910052799 carbon Inorganic materials 0.000 description 10
- 208000035475 disorder Diseases 0.000 description 10
- 125000001424 substituent group Chemical group 0.000 description 10
- 239000002246 antineoplastic agent Substances 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 229940041181 antineoplastic drug Drugs 0.000 description 8
- 238000002648 combination therapy Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 239000011324 bead Substances 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000000021 kinase assay Methods 0.000 description 6
- 238000007911 parenteral administration Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical class C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- 229910003827 NRaRb Inorganic materials 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 125000004663 dialkyl amino group Chemical group 0.000 description 4
- 125000001188 haloalkyl group Chemical group 0.000 description 4
- 201000005787 hematologic cancer Diseases 0.000 description 4
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 239000004615 ingredient Substances 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 238000013268 sustained release Methods 0.000 description 4
- 239000012730 sustained-release form Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000588724 Escherichia coli Species 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 241000288906 Primates Species 0.000 description 3
- 238000011529 RT qPCR Methods 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000003570 cell viability assay Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000003111 delayed effect Effects 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- 230000009826 neoplastic cell growth Effects 0.000 description 3
- 150000004893 oxazines Chemical class 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- CZWWCTHQXBMHDA-UHFFFAOYSA-N 3h-1,3-thiazol-2-one Chemical compound OC1=NC=CS1 CZWWCTHQXBMHDA-UHFFFAOYSA-N 0.000 description 2
- NTPLXRHDUXRPNE-UHFFFAOYSA-N 4-methoxyacetophenone Chemical compound COC1=CC=C(C(C)=O)C=C1 NTPLXRHDUXRPNE-UHFFFAOYSA-N 0.000 description 2
- LLXJPNQWAGNDDN-UHFFFAOYSA-N 7-amino-2,4-dihydro-1h-isoquinolin-3-one Chemical compound C1C(=O)NCC2=CC(N)=CC=C21 LLXJPNQWAGNDDN-UHFFFAOYSA-N 0.000 description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 2
- 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 2
- 206010059352 Desmoid tumour Diseases 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000005777 Lupus Nephritis Diseases 0.000 description 2
- 206010027476 Metastases Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 206010039710 Scleroderma Diseases 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102000013814 Wnt Human genes 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 229960000397 bevacizumab Drugs 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229940000425 combination drug Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 201000006827 desmoid tumor Diseases 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 238000004520 electroporation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012091 fetal bovine serum Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 description 2
- 231100000854 focal segmental glomerulosclerosis Toxicity 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[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 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 230000009401 metastasis Effects 0.000 description 2
- 208000037819 metastatic cancer Diseases 0.000 description 2
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 2
- 125000002757 morpholinyl group Chemical group 0.000 description 2
- 230000001613 neoplastic effect Effects 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- 125000003566 oxetanyl group Chemical group 0.000 description 2
- 239000006201 parenteral dosage form Substances 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 208000005069 pulmonary fibrosis Diseases 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 150000003254 radicals Chemical class 0.000 description 2
- 201000002793 renal fibrosis Diseases 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 210000000130 stem cell Anatomy 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 125000004963 sulfonylalkyl group Chemical group 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 2
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 2
- 125000004001 thioalkyl group Chemical group 0.000 description 2
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- YXTKHLHCVFUPPT-YYFJYKOTSA-N (2s)-2-[[4-[(2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid;(1r,2r)-1,2-dimethanidylcyclohexane;5-fluoro-1h-pyrimidine-2,4-dione;oxalic acid;platinum(2+) Chemical compound [Pt+2].OC(=O)C(O)=O.[CH2-][C@@H]1CCCC[C@H]1[CH2-].FC1=CNC(=O)NC1=O.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 YXTKHLHCVFUPPT-YYFJYKOTSA-N 0.000 description 1
- MEJYDZQQVZJMPP-ULAWRXDQSA-N (3s,3ar,6r,6ar)-3,6-dimethoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound CO[C@H]1CO[C@@H]2[C@H](OC)CO[C@@H]21 MEJYDZQQVZJMPP-ULAWRXDQSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- UKLWWIPJQMYGIB-UNOMPAQXSA-N (Z)-3-(1H-indol-5-ylamino)-1-(4-methoxyphenyl)-3-methylsulfanylprop-2-en-1-one Chemical compound N1C=CC2=CC(=CC=C12)N/C(=C/C(=O)C1=CC=C(C=C1)OC)/SC UKLWWIPJQMYGIB-UNOMPAQXSA-N 0.000 description 1
- VQUUGQMOOHOVHS-UHFFFAOYSA-N 1-(4-methoxyphenyl)-3,3-bis(methylsulfanyl)prop-2-en-1-one Chemical compound COC1=CC=C(C(=O)C=C(SC)SC)C=C1 VQUUGQMOOHOVHS-UHFFFAOYSA-N 0.000 description 1
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 1
- GCKMFJBGXUYNAG-UHFFFAOYSA-N 17alpha-methyltestosterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C)(O)C1(C)CC2 GCKMFJBGXUYNAG-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- ZCBIFHNDZBSCEP-UHFFFAOYSA-N 1H-indol-5-amine Chemical compound NC1=CC=C2NC=CC2=C1 ZCBIFHNDZBSCEP-UHFFFAOYSA-N 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 1
- LYTMVABTDYMBQK-UHFFFAOYSA-N 2-benzothiophene Chemical compound C1=CC=CC2=CSC=C21 LYTMVABTDYMBQK-UHFFFAOYSA-N 0.000 description 1
- NYHNVHGFPZAZGA-UHFFFAOYSA-N 2-hydroxyhexanoic acid Chemical compound CCCCC(O)C(O)=O NYHNVHGFPZAZGA-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 150000000463 2H-chromenes Chemical class 0.000 description 1
- HLMABMJBEJCRQD-UHFFFAOYSA-N 2h-benzo[b][1,4]oxazine Chemical compound C1=C[C]2N=CCOC2=C=C1 HLMABMJBEJCRQD-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-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
- GEDVWGDBMPJNEV-UHFFFAOYSA-N 6-bromo-1h-benzimidazole Chemical compound BrC1=CC=C2N=CNC2=C1 GEDVWGDBMPJNEV-UHFFFAOYSA-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
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- SFYABQXMXHCEAK-UHFFFAOYSA-N 7-nitro-2,4-dihydro-1H-isoquinolin-3-one Chemical compound [O-][N+](=O)c1ccc2CC(=O)NCc2c1 SFYABQXMXHCEAK-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 229940126638 Akt inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229940124290 BCR-ABL tyrosine kinase inhibitor Drugs 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 102000016289 Cell Adhesion Molecules Human genes 0.000 description 1
- 108010067225 Cell Adhesion Molecules Proteins 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- ITRJWOMZKQRYTA-RFZYENFJSA-N Cortisone acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)CC2=O ITRJWOMZKQRYTA-RFZYENFJSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-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
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 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 description 1
- 241000283953 Lagomorpha Species 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 229940124647 MEK inhibitor Drugs 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 150000007945 N-acyl ureas Chemical class 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229940124611 PDK1 inhibitor Drugs 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical group [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 108010066684 Proto-Oncogene Proteins A-raf Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 229910006069 SO3H Inorganic materials 0.000 description 1
- 108010087230 Sincalide Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- 101150069360 TNIK gene Proteins 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229940124674 VEGF-R inhibitor Drugs 0.000 description 1
- 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- IAJILQKETJEXLJ-RSJOWCBRSA-N aldehydo-D-galacturonic acid Chemical class O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-RSJOWCBRSA-N 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 239000003886 aromatase inhibitor Substances 0.000 description 1
- 229940046844 aromatase inhibitors Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- 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 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- NMMPMZWIIQCZBA-UHFFFAOYSA-M chloropalladium(1+);dicyclohexyl-[2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane;2-phenylethanamine Chemical compound [Pd+]Cl.NCCC1=CC=CC=[C-]1.CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 NMMPMZWIIQCZBA-UHFFFAOYSA-M 0.000 description 1
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 1
- 150000001854 cinnolines Chemical class 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 229940035811 conjugated estrogen Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 229960003290 cortisone acetate Drugs 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin 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(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000532 dioxanyl group Chemical group 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- 239000012149 elution buffer Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- QTTMOCOWZLSYSV-QWAPEVOJSA-M equilin sodium sulfate Chemical compound [Na+].[O-]S(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4C3=CCC2=C1 QTTMOCOWZLSYSV-QWAPEVOJSA-M 0.000 description 1
- 230000008029 eradication Effects 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000000328 estrogen antagonist Substances 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000005713 exacerbation Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 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 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- JYEFSHLLTQIXIO-SMNQTINBSA-N folfiri regimen Chemical compound FC1=CNC(=O)NC1=O.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.C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 JYEFSHLLTQIXIO-SMNQTINBSA-N 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
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000021472 generally recognized as safe Nutrition 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- XLXSAKCOAKORKW-UHFFFAOYSA-N gonadorelin Chemical class C1CCC(C(=O)NCC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)CNC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 XLXSAKCOAKORKW-UHFFFAOYSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000000232 haloalkynyl group Chemical group 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 238000002868 homogeneous time resolved fluorescence Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002700 inhibitory effect on cancer Effects 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 150000002576 ketones Chemical group 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 229960001756 oxaliplatin Drugs 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
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical compound O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- 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 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 description 1
- 229940032159 propylene carbonate Drugs 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 239000003197 protein kinase B inhibitor Substances 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003252 quinoxalines Chemical class 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 125000006413 ring segment Chemical group 0.000 description 1
- PSJMMTZCYKGHJA-UHFFFAOYSA-N s-methyl prop-2-enethioate Chemical compound CSC(=O)C=C PSJMMTZCYKGHJA-UHFFFAOYSA-N 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008137 solubility enhancer Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- GLBQVJGBPFPMMV-UHFFFAOYSA-N sulfilimine Chemical compound S=N GLBQVJGBPFPMMV-UHFFFAOYSA-N 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 125000005555 sulfoximide group Chemical group 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 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 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- NJRXVEJTAYWCQJ-UHFFFAOYSA-N thiomalic acid Chemical compound OC(=O)CC(S)C(O)=O NJRXVEJTAYWCQJ-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 208000013076 thyroid tumor Diseases 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- HHJUWIANJFBDHT-KOTLKJBCSA-N vindesine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(N)=O)N4C)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 HHJUWIANJFBDHT-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 235000016804 zinc Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Oncology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明提供了对TNIK有抑制性且具有特定化学结构的化合物或其在药学上可接受的盐。本发明也提供一种包含所述化合物或其在药学上可接受的盐的组成物。本发明亦提供一种所述化合物、其盐类或是包含所述化合物或其在药学上可接受的盐的所述组成物的用于治疗或预防癌症的医疗用途。本发明并且提供一种治疗或预防癌症的方法,所述方法包含:将所述化合物、其盐类或是包含所述化合物或其盐类的所述组成物施予至需要这样的治疗或预防的一患者。
Description
技术领域
本发明主张2018年2月7日于大韩民国申请的专利申请第10-2018-0015161号的优先权,上述申请的所有内容通过引用被并入本文中。
本发明是关于具有抑制Traf2-及Nck-互动激酶(TNIK)的一活性的一组化合物。本发明也关于包含所述化合物的药学组成物。本发明关于使用所述化合物的,对治疗特定疾病,包括癌症或肿瘤有用的方法。亦即,本发明是关于根据本发明的这些化合物用于治疗或预防癌症或肿瘤的医疗用途。
背景技术
众所周知的是,Traf2-及Nck-互动激酶(TNIK)的抑制剂对治疗癌症是有用的(例如,美国专利申请公布第2010/0216795号)。更具体地,众所周知的是TNIK在大肠直肠癌、乳癌、脑瘤、胃癌、肝癌、卵巢癌等癌症当中是过度活跃的(J.S.Boehm等人,Cell 129,1065-1079,2007年)。特定地,TNIK在大肠直肠癌的生长中扮演一重要角色,且TNIK据报是能够控制大肠直肠癌中的异常Wnt信息传递的一标的物(Cancer Res 2010;70:5024-5033)。TNIK基因在7%的胃癌病患的组织样本中是过度表现的,且TNIK据报是治疗胃癌的新标的(Oncogenesis 2014,3,e89)。此外,据报TNIK与慢性粒细胞性血癌(chronic myelogenousleukemia)中的血癌干细胞的增殖与分化有关(临床研究期刊2012 122 624)。除了这些癌症或肿瘤外,肝细胞癌(hepatocellular carcinoma)、硬纤维瘤(desmoid tumor)、髓母细胞瘤(medulloblastoma)(小儿脑瘤)、威尔姆氏瘤(Wilms tumor)(小儿肾癌)、甲状腺瘤及其它癌症或肿瘤与异常Wnt信息传递相关,且因此用于这些疾病的药物可以基于TNIK抑制而被发展。
因此,抑制TNIK的药物阻断TNIK信息传递的途径,藉此抑制癌症的增殖、存活及血管新生。抑制TNIK的药物因此被预期作为治疗癌症的药物是有用的(见PCT国际公布号第WO2010-100431号及WO2009-030890号)。
与此同时,TNIK抑制据报在治疗慢性阻塞性肺病(chronic obstructivepulmonary disease,COPD)、狼疮肾炎(lupus nephritis)、糖尿病性肾病(diabeticnephropathy)、局灶节段性肾小球硬化症(focal segmental glomerulosclerosis)、肾纤维化(renal fibrosis)、肺纤维化(Pulmonary fibrosis)、硬皮症(scleroderma)等疾病上是有用的。
因此,TNIK抑制剂被预期在治疗或预防各种疾病,包括发炎性疾病以及癌症上是有效的。
发明揭露:
技术问题:
因此本发明的一个目标是要提供一种具有抑制TNIK(Traf2-及Nck-互动激酶)的活性的化合物、包含所述化合物作为一有效药剂的药学组成物及所述化合物用于治疗或预防癌症的医疗用途。
本发明的另一目标是提供一种用于治疗或缓解癌症的方法,所述方法包含:对需要治疗、缓解或预防癌症的一患者施用根据本发明的抑制TNIK活性的一化合物。
本发明的又一目标是提供一种通过共同施予与其它抗癌药物展现协同作用的一化合物、包含所述化合物作为一有效药剂的药学组成物及所述化合物用于治疗或预防癌症的医疗用途。
本发明的再一目标是提供一种用于治疗或缓解癌症的方法,所述方法包含:同时地或连续地或对需要治疗、缓解或预防癌症的一患者施用抑制TNIK活性的一化合物及具有其他机制的抗癌药物。
技术解决方案:
发明内容
为了达成所述目标,在一实施例中,提供了一种化合物或其在药学上可接受的盐,所述化合物具有如化学式1的结构:
[化学式1]
在所述化学式1中:
W是取代的或未取代的,芳香环、杂芳基或融合的杂芳基,
R1是H或F,
R2是具有未取代的或可选地取代的-C1-6卤代烷基、-C1-6烷基、卤素或-C1-6烷氧基的杂环融合苯基,其中所述杂环是与所述苯基的两个相邻的碳原子融合。
在另一实施例中,提供了一种药用组成物,所述组成物包含:化学式1的一化合物或其在药学上可接受的盐,及一药学上可接受的载体或添加物。
在各种实施例中,所述药用组成物进一步包含一种或更多种额外的药学活性药剂。
在又一实施例中,提供了一种用于治疗一病症的方法,所述方法包含:将化学式1的一化合物或其在药学上可接受的盐的一治疗有效量施予一患者,其中要被治疗的所述病症包括但不限于:癌症,比如大肠直肠癌、乳癌、脑瘤、胃癌、肝癌、卵巢癌、肺癌、胃肠道癌、血癌或黑色素瘤,肿瘤形成(neoplasia)或肿瘤。根据本发明的化学式1的所述化合物或其药学上可接受的盐通过以癌症干细胞为目标,在预防肿瘤的远端转移(metastasis)及复发上也是有用的。亦即,提供了化学式1的所述化合物或其药学上可接受的盐用于治疗或预防上文所提及的疾病的医疗用途。
在各种实施例中,所述方法包含:施用本发明的所述化合物或其盐与其它药学上具活性的化合物的组合药剂。亦即,提供了组合药剂的一种用于治疗或预防上文所述的疾病的医疗用途,所述组合药剂包含本发明的所述化合物或其药学上可接受的盐及其它活性药剂。
上文的所述化合物、所述药学组成物及它们的医疗用途在下文的具体实施方式中被更完整地描述。
详细描述:
下文的描述在本质上仅是示例性的,且并非意在限制本发明、应用或使用。
定义:
在本揭示中被使用的通用词汇为了清楚起见而在此被界定。
本说明书可互换地使用“取代基”(substituent)、“自由基”(radical)、“基团”(group)、“部分”(moiety)及“片段”(fragment)等词汇。
如本文中所使用地,“患者”一词意指一动物,优选地是一哺乳类,比如一非灵长类(例如,牛、马、羊、猪、鸡、火鸡、鹌鹑、猫、狗、小鼠、大鼠、兔或天竺鼠)或一灵长类(例如,猴及人类),最优选地是一人类。
如本文中所使用的,“烷基”一词意指饱和直链或分支非环状碳氢化合物,除非内文明显另有指示,具有自1个至10个碳原子。“低级烷”意指具有自1个至4个碳原子的烷基。代表性的饱和直链烷基包括-甲基、-乙基、-正丙基、-正丁基、-正戊基、-正己基、-正庚基、-正辛基、-正壬基及-正癸基;而饱和分支烷基包括-异丙基、-仲丁基、-异丁基、-叔丁基、-异戊基、2-甲基丁基、3-甲基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基丁基、2,3-二甲基戊基、2,4-二甲基戊基、2,3-二甲基己基、2 4-二甲基己基、2,5-二甲基己基、2,2-二甲基戊基、2,2-二甲基己基、3,3-二甲基戊基、3,3-二甲基己基、4,4-二甲基己基、2-乙基戊基、3-乙基戊基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、2-甲基-4-乙基戊基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2-甲基-4-乙基己基、2,2-二乙基戊基、3,3-二乙基己基、2,2-二乙基己基、3,3-二乙基己基等。
如本文中所使用的,若“C1-6”一词被使用,它意指碳原子的数量是自1至6。举例而言,C1-6烷基意指一个烷基,所述烷基的碳数为自1至6的任何整数。
“卤素”及“卤基”等词意指氟、氯、溴或碘。
如本文中所使用的,“卤代烷基”、“卤代烷氧基”、“卤代烯基”或“卤代炔基”等词汇分别意指一烷基、烷氧基、烯基或炔基,其中的一个或更多个氢原子被卤素原子取代。举例而言,卤代烷基包含-CF3、-CHF2、-CH2F、-CBr3、-CHBr2、-CH2Br、-CC13、-CHC12、-CH2CI、-CI3、-CHI2、-CH2I、-CH2-CF3、-CH2-CHF2、-CH2-CH2F、-CH2-CBr3、-CH2-CHBr2、-CH2-CH2Br、-CH2-CC13、-CH2-CHC12、-CH2-CH2CI、-CH2-CI3、-CH2-CHI2及-CH2-CH2I等,其中烷基及卤素如上文所述。
“烷酰基”或“酰基”等词汇意指一-C(O)烷基,其中烷基已在上文中定义。所述-C(O)烷基包含-C(O)CH3、-C(O)CH2CH3、-C(O)(CH2)2CH3、-C(O)(CH2)3CH3、-C(O)(CH2)4CH3及-C(O)(CH2)5CH3等。
“烷酰氧基”或“酰氧基”等词汇意指一-OC(O)烷基,其中烷基已在上文中定义。所述-OC(O)烷基包含-OC(O)CH3、-OC(O)CH2CH3、-OC(O)(CH2)2CH3、-OC(O)(CH2)3CH3、-OC(O)(CH2)4CH3及-OC(O)(CH2)5CH3等。
“烷氧基”一词意指一-O-(烷)基,其中烷基已在上文中定义。所述-O-(烷)基包含-OCH3、-OCH2CH3、-O(CH2)2CH3、-O(CH2)3CH3、-O(CH2)4CH3及-O(CH2)5CH3等。
“低级烷氧”一词意指-O-(低级烷),其中烷基是如在上文中所定义。
“芳香基”一词意指含有自5个至10个环原子的碳环芳香基团。代表性的示例包括,但不限于苯基、甲苯基、茬基、萘基、四氢萘基、蒽基、芴基、茚基和蓝烃基。一碳环芳香基团可以是未经取代的或可选地经取代的。
“芳氧基”一词是RO-,其中R是如上文所定义的芳香基。“芳硫基”是RS-,其中R是如上文所定义的芳香基。
“环烷基”一词意指一单环或多环饱和环,所述环具有碳原子及氢原子且并不具有碳-碳多键。环烷基团的数个示例包括但不限于(C3-C7)环烷基团,包括环丙基、环丁基、环戊基、环己基及环庚基。一环烷基团可以是未经取代的或可选地是经取代的。在一实施例中,所述环烷基团是一单环或双环。
“单烷基氨基”一词意指-NH(烷基),其中烷基是如在上文中所定义,所述单烷基氨基比如-NHCH3、-NHCH2CH3、-NH(CH2)2CH3、-NH(CH2)3CH3、-NH(CH2)4CH3及-NH(CH2)5CH3等。
“二烷基氨基”一词意指-N(烷基)(烷基),其中每个烷基个别地是如在上文中所定义的烷基。所述二烷基氨基包括-N(CH3)2、-N(CH2CH3)2、-N((CH2)2CH3)2及-N(CH3)(CH2CH3)等。
“烷基氨基”意指如上文中所定义的单烷基氨基或二烷基氨基。
“羧基”及“羧”等词意指-COOH。
“氨基烷基”一词意指-(烷基)-NH2,其中烷基是如在上文中所定义。所述氨基烷基包括-CH2-NH2、-(CH2)2-NH2、-(CH2)3-NH2、-(CH2)-NH2及-(CH2)5-NH2等。
“单烷基氨基烷基”一词意指-(烷基)-NH(烷基),其中每个烷基个别地是在上文中所定义的烷基。所述单烷基氨基烷基包括-CH2-NH-CH3、-CH2-NHCH2CH3、-CH2-NH(CH2)2CH3、-CH2-NH(CH2)3CH3、-CH2-NH(CH2)4CH3、-CH2-NH(CH2)5CH3及-(CH2)2-NH-CH3等。
“杂芳基”一词意指5个至10个原子的芳香杂环,所述芳香杂环具有至少一个选自于氮、氧及硫的杂原子(heteroatom)并含有至少1个碳原子。所述芳香杂环包括单环及双环系统两者。代表性的杂芳基是三唑基、四唑基、恶二唑基、吡啶基、呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、喹啉基、吡咯基、吲哚基、恶唑基、苯并恶唑基、咪唑基、苯并咪唑基、噻唑基、苯并噻唑基、异恶唑基、吡唑基、异噻唑基、哒嗪基、嘧啶碱基、吡嗪基、三嗪基、肉桂基、酞嗪基、喹唑啉基、嘧啶基、氧杂环丁烷基、氮杂吡啶基、哌嗪基、吗啉基、二恶烷基、硫杂环丁烷基及恶唑基。
“杂环”一词意指一个5至7个原子的单环杂环,或7至10个原子的双环杂环,所述杂环是饱和的或未饱和的,并包含自1个至4个杂原子,所述数个杂原子是独立地选自于氮、氧及硫,且在所述杂环中,所述氮及硫杂原子可以选择性地是经氧化的,且所述氮杂原子可以选择性地被四元化(quatemized)。所述杂环包括双环,在所述双环中上述的杂环中的任何杂环被融合到一苯环。所述杂环可以经由任何杂原子或碳原子而被附加。杂环,包括杂芳基是如上文中所定义。代表性的杂环包括吗啉基、吡咯二壬基、吡咯烷基、哌啶基、乙内酰脲基、戊内酰胺基、环氧乙烷基、氧杂环丁烷基、四氢呋喃基、四氢吡喃基、四氢吡啶基、四氢伯啶基、四氢噻吩基、四氢硫吡喃基、四氢嘧啶基、四氢噻吩基及四氢硫吡喃基。
“融合到苯基的杂环”一词意指一杂环,所述杂环在所述苯环的两个相邻的碳原子处被连接到所述苯环,其中杂环如上文中所定义。
“羟烷基”一词意指烷基,其中烷基如上文中所定义。所述烷基有一个或更多个氢原子被羟基取代。所述羟烷基包括-CH2OH、-CH2CH OH、-(CH)CH OH、-(CH2)3CH2OH、-(CH2)4CH2OH、-(CH2)5CH2OH、-CH(OH)-CH3及-CH2CH(OH)CH3等。
“磺酰基”一词意指-SO3H。
“磺酰基烷基”一词意指-SO2-(烷基)。其中烷基如上文中所定义。所述磺酰基烷基包括SO2-CH3、-SO2-CH2CH3、-SO2-(CH2)2CH3、-SO2-(CH2)3CH3、-SO2-(CH2)4CH3及-SO2-(CH2)5CH3等。
“亚磺酰基烷基”一词意指-SO-(烷基)。其中烷基如上文中所定义。所述亚磺酰基烷基包括SO-CH3、-SO-CH2CH3、-SO-(CH2)2CH3、-SO-(CH2)3CH3、-SO-(CH2)4CH3及-SO-(CH2)5CH3等。
“硫代烷基”一词意指-S-(烷基),其中烷基如上文中所定义。所述硫代烷基包括-S-CH3、-S-CH2CH3、-S-(CH2)2CH3、-S-(CH2)3CH3、-S-(CH2)4CH3及-S-(CH2)5CH3等。
如本文中所使用的,“经取代的”一词意指任何上述基团(亦即,烷基,芳香基,杂芳基,杂环或环烷基),其中被取代的所述部分的至少一个氢原子被一个取代基取代。在一实施例中,被取代的所述基团的每个碳原子是被不多于两个取代基取代。在另一实施例中,被取代的所述基团的每个碳原子是被不多于一个取代基取代。在酮取代基的案例中,两个氢原子被一个氧取代,所述氧经由一个双键被连接到所述碳。除非特别界定,取代基包括卤素、羟基、(低级)烷基、卤代烷基、单烷基氨基或二烷基氨基、芳香基、杂环、-NO2、-NRaRb、-NRaC(=O)Rb、-NRaC(=O)NRaRb、-NRaC(=O)ORb、-NRaSO2Rb、-ORa、-CN、-C(=O)Ra、-C(=O)ORa、-C(=O)NRaRb、-OC(=O)Ra、-OC(=O)ORa、-OC(=O)NRaRb、-NRaSO2Rb、-PO3Ra、-PO(ORa)(ORb)、-SO2Ra、-S(O)Ra、-SO(N)Ra(例如,亚砜亚胺)、-(Ra)S=NRb(例如,硫亚胺)及-SRa,其中Ra及Rb是相同或不同的且个别的氢、卤素、胺、烷基、卤代烷基、芳香基或杂环,或其中Ra及Rb连同它们所附着的氮原子形成一杂环。基于它们所附着的原子,Ra及Rb可以是复数的。
如本文中所使用的,“药学上可接受的(数种)盐”一词意指制备自根据本发明的活性化合物的盐,视乎这些化合物的特定取代基,所述盐是以相对非毒性的酸或碱及活性化合物制备。当所述化合物具有一相对酸性的基团时,碱盐(base-added salts)可以通过将所述中性化合物与一足量的所欲的碱及一纯溶剂或惰性溶剂接触而被获得。适宜的药学上可接受的碱加成盐包括但不限于钠盐、钾盐、钙盐、铝盐、有机铵盐、镁盐等。当所述化合物具有一相对碱性的基团时,酸盐(acid-added salts)可以通过将所述中性化合物与一足量的所欲的酸及纯溶剂或惰性溶剂接触而被获得。适宜的药学上可接受的酸加成盐包括衍生自非毒性有机酸及非毒性无机酸的盐,所述非毒性有机酸包括但不限于乙酸、丙酸、异丁酸、草酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、杏仁酸、苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸、甲磺酸等,且所述非毒性无机酸包括但不限于盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、碘化氢及亚磷酸等。并且所述盐包括胺基酸的盐,比如精氨酸盐或其类似物。且所述盐亦包括有机酸,比如葡萄醣醛酸或半乳醣醛酸的类似物。此发明的一些特定化合物具有碱性及酸性功能两者,可供化合物以具有一碱性或酸性部分的(加成)盐的转化。盐的其它示例在本领域中的众所周知的文章中被揭示。举例而言,Remington's Pharmaceutical Sciences,第18版,Mack Publishing,Easton PA,1990年或Remington:.The Science and Practice of Pharmacy,第19版被揭示于Mack Publishing,Easton PA,1995年当中。
如在本文中所使用的,“有效量”一词包含足以摧毁、改变、控制或移除一原发性的、区域性的或转移的癌细胞或癌组织;延迟或最小化癌症的扩散;或在癌症、一瘤形成疾患或肿瘤的治疗或管理中提供一治疗上的益处的本发明的一化合物的量。一“有效量”亦包括足以导致癌症或肿瘤性细胞的死亡的本发明的一化合物的量。一“有效量”亦包括足以在体外或体内抑制或减少TNIK活性的本发明的一化合物的量。
如在本文中所使用的,“预防性有效量”一词意指一化合物的足以在一患者中预防癌症复发或扩散或癌症的发生的量,所述患者包括但不限于对癌症易感或先前暴露于一致癌物者。
如本文中所使用的,“肿瘤性的”一词意指一细胞或组织(例如,一肿瘤)的一异常生长,所述细胞或组织可能是良性的或癌性的。
如本文中所使用的,“预防”一词包括预防一患者中的癌症的复发、扩散或发生。
如本文中所使用的,“治疗”一词包括原发性的、区域性的或转移的癌组织的根除、移除、改变或控制;及包括最小化或延迟癌症的扩散。
如本文中所使用的,“此/本发明的化合物”一词包括任何化学式1的(数种)化合物,以及其笼合物(clathrates)、水合物、溶合物(solvates)或多晶形物(polymorphs)。并且,即便“此/本发明的化合物”一词并未提及其药学上可接受的盐,本词汇包含所述化合物的盐。在一实施例中,本发明的化合物包括立体化学上纯净的(stereo-chemically pure)化合物,例如,基本上无其它立体异构物(例如,大于85%异构物过量值、大于90%异构物过量值、大于95%异构物过量值、大于97%异构物过量值或大于99%异构物过量值)的化合物。亦即,若根据本发明的化学式1的所述化合物或其盐是互变异构物(tautomericisomers)及/或立体异构物(例如,几何异构物及构象异构物),如此的经分离异构物及它们的混合物亦被包括在本发明的范围内。若本发明的所述化合物或其盐在它们的的结构中具有一不对称碳,它们的活性光学异构物及它们的消旋混合物也被包括在本发明的范围内。
如在本文中被使用的,“多晶形物”一词意指本发明的一化合物或其复合物的固态晶体型态。同一化合物的不同多晶形物可以展现出不同的物理、化学及/或光谱学性质。不同的物理性质包括但不限于稳定度(例如,对热或光的稳定度)、可压缩性及密度(在配方及产品制造中是重要的)及溶解率(溶解率可影响生物利用率)。稳定度的差异可缘于化学反应性(例如,差别氧化,比如一剂型在由一多晶形组成时比起由另一多晶形组成时变色得更快速)或力学特性(例如,药片在储存时随着动力学上受偏好的一多晶形转变至热动力学上更稳定的多晶形而崩解)或两者(例如,一多晶形的药片在高湿度下更易崩解)的改变。多晶形的不同物理性质可能影响它们的加工。举例而言,一种多晶形可能由于,举例而言,其粒子的形状或尺寸分布,而比另一种多晶形更可能形成溶合物或可能更难以过滤或洗去杂质。
如本文中所使用的,“溶合物”一词意指根据本发明的一化合物或其盐,所述化合物或其盐进一步包含一溶剂的一化学计量(stoichiometric)的或非化学计量的量,所述溶剂被分子间非共价力所局限。优选的溶剂是挥发性的,非毒性的及/或在微量施予给人类时是可接受的。
如本文中所使用的,“水合物”一词意指根据本发明的一化合物或其盐,所述化合物进一步包含水的一化学计量的或非化学计量的量,所述水被分子间非共价力所局限。
如本文中所使用的,“笼合物”一词意指处于一晶格形态的一化合物或其盐,所述晶格包含当中困有一宾分子(例如,一溶剂或水)的空间(例如,孔道)。
若任何化合物(药物前体)在于体内分解后产生本发明的所述化合物或其盐,则这样的化合物被包含在本发明中。如本文中所使用的及除非另外指示的,“药物前体”一词意指一化合物,所述化合物可以水解、氧化或者在生物性条件下(体外或体内)反应以提供一活性化合物,特别是本发明的一化合物。药物前体的数个示例包括但不限于,一化合物的代谢物,所述化合物包括可生物水解的部分,比如可生物水解的酰胺、可生物水解的酯、可生物水解的氨基甲酸酯、可生物水解的碳酸盐、可生物水解的酰脲及可生物水解的磷酸盐类似物。优选地,具有羧基官能基团的化合物的药物前体是羧酸的低级烷基酯。所述羧酸酯通过酯化在分子上的任何羧酸部分而被便利地形成。药物前体典型地可以使用周知的方法,比如由Burger's Medicinal Chemistry and Drug Discovery第六版(Donald J.Abraham编,2001年,Wiley)及Design and Application of Prodrugs(H.Bundgaard编,1985年,Harwood Academic Publishers Gmfh)所描述的方法而被制备。
如在本文中被使用的,“经纯化”一词意指当被分离后,被分离物是大于90%纯净、在一实施例中大于95%纯净、在另一实施例中大于99%纯净及在又一实施例中大于99.9%纯净。
“氢化”一词意指单一一个-H原子(H)且可以被与符号“H”或“氢”一词互换地使用。
若一取代基是被描述为“可选地经取代的”,所述取代基可以是(1)未被取代的或(2)被取代的。若一个可取代的位置是未经取代的,默认的取代基是一氢自由基。
如本文中所使用的,单数型“一”(a)及“一”(an)可以包括复数所指物,除非上下文明显另有指示。
“药学上可接受的”一词意指适宜用在药用制剂中,一般地被认为对那样的使用而言是安全的,被一国家或州政府的一主管机关正式认可用于那样的用途,或者被列在南韩或美国药典或其它普遍认可的药典中供用在动物,及更特定地用于人类。
本发明的化合物:
提供了一种化学式1的化合物或其在药学上可接受的盐:
[化学式1]
在所述化学式1中:
W是取代的或未取代的,芳香环、杂芳基或融合的杂芳基,
R1是H或F,
R2是具有未取代的或可选地取代的-C1-6卤代烷基、-C1-6烷基、卤素或-C1-6烷氧基的杂环融合苯基,其中所述杂环是与所述苯基的两个相邻的碳原子融合。
所述杂环融合苯基包括吲哚啉、3H-吲哚、1H-吲哚、2H-异吲哚、1H-吲唑、苯并咪唑、苯并呋喃、异苯并呋喃、苯并[c]噻吩、苯并[b]噻吩、苯并[d]异恶唑、苯并[c]异恶唑、苯并[d]异噻唑、苯并[c]异噻唑、苯并[d]恶唑、苯并[d]噻唑、苯并[c][1,2,5]噻二唑、1,2-苯并异噻唑-3(2H)-酮、1,2,3,4-四氢喹啉、1,2-二氢喹啉、1,2-二氢异喹啉、喹啉、异喹啉、喹喔啉、酞嗪、喹唑啉、噌啉、2H-色烯、1H-异色烯、3H-异色烯、2H-色烯-2-酮、2H-苯并[e][1,2]恶嗪、2H-苯并[e][1,3]恶嗪、2H-苯并[b][1,4]恶嗪、喹啉-2(1H)-酮、异喹啉-1(2H)-酮、1,3-二氢-2H-苯并[d]咪唑-2-酮、3,4-二氢喹啉-2(1H)-酮、吲哚啉-2-酮、苯并[b][1,4]恶嗪-3(4H)-酮、苯并[d]恶唑-2(3H)-酮、1H-苯并[d]咪唑、1,3-二氢-2H-苯并[d]咪唑-2-硫酮,及苯并[d]噻唑-2(3H)-酮。
在又一实施例中,优选地,
在所述化学式1中:
W是取代的或未取代的,苯基、吡啶基、噻吩、噻唑、吡咯、苯并噻吩、吲哚、恶唑、吡唑、咪唑、嘧啶、苯并吡唑、苯并噻唑、苯并恶唑、苯并咪唑或苯并噻吩,
R1是H或F,
R2是具有未取代或取代的-C1-6卤代烷基、-C1-6烷基、卤素或-C1-6烷氧基的:吲哚啉、3H-吲哚、1H-吲哚、2H-异吲哚、1H-吲唑、苯并咪唑、苯并呋喃、异苯并呋喃、苯并[c]噻吩、苯并[b]噻吩、苯并[d]异恶唑、苯并[c]异恶唑、苯并[d]异噻唑、苯并[c]异噻唑、苯并[d]恶唑、苯并[d]噻唑、苯并[c][1,2,5]噻二唑、1,2-苯并异噻唑-3(2H)-酮、1,2,3,4-四氢喹啉、1,2-二氢喹啉、1,2-二氢异喹啉、喹啉、异喹啉、喹喔啉、酞嗪、喹唑啉、噌啉、2H-色烯、1H-异色烯、3H-异色烯、2H-色烯-2-酮、2H-苯并[e][1,2]恶嗪、2H-苯并[e][1,3]恶嗪、2H-苯并[b][1,4]恶嗪、喹啉-2(1H)-酮、异喹啉-1(2H)-酮、1,3-二氢-2H-苯并[d]咪唑-2-酮、3,4-二氢喹啉-2(1H)-酮、吲哚啉-2-酮、苯并[b][1,4]恶嗪-3(4H)-酮、苯并[d]恶唑-2(3H)-酮、1H-苯并[d]咪唑、1,3-二氢-2H-苯并[d]咪唑-2-硫酮,或苯并[d]噻唑-2(3H)-酮。
在又一实施例中,更优选地,
在所述化学式1中:
W是取代的或未取代的苯基、吡啶基、噻吩、噻唑、吡咯、苯并噻吩或吲哚,
R1是H或F、
R2是1H-吲哚、1H-吲唑、1,3-二氢-2H-苯并[d]咪唑-2-酮、3,4-二氢喹啉-2(1H)-酮、吲哚啉-2-酮、苯并[b][1,4]恶嗪-3(4H)-酮、苯并[d]恶唑-2(3H)-酮、2-甲基-1H-苯并[d]咪唑、4-甲基喹啉-2(1H)-酮、1,3-二氢-2H-苯并[d]咪唑-2-硫酮、苯并[d]噻唑-2(3H)-酮、4-甲基-1H-吲唑、6-甲基-1H-吲唑、4-甲基-1H-苯并[d]咪唑,或6-甲基-1H-苯并[d]咪唑,或1H-苯并[d]咪唑。
发明者已合成并评量了许多化合物以找出具有良好TNIK抑制活性并对TNIK具有高选择性,藉此对癌细胞具有良好抑制效果且对正常细胞具有低副作用的化合物。最后,本发明的所述化合物被识别为适于本发明的目标。
本发明的化合物的非限定性的示例包括下方的表1的化合物及其药学上可接受的盐
[表1]
优选地,本发明的化合物被选择于下方的表2中。
[表2]
在又一实施例中,提供了一种药用组成物,所述组成物包含:化学式1的一化合物或其在药学上可接受的盐的一治疗有效量,及一药学上可接受的载体。
在又一实施例中,提供了一种药用组成物,所述组成物包含:化学式1的一化合物或其在药学上可接受的盐的一治疗有效量、一药学上可接受的载体及一活性药用成分的一治疗有效量,所述活性药用成分并非本发明的所述化合物,及是选自于由细胞抑制药物、血管生成抑制剂、激酶抑制剂、细胞素阻断剂及细胞黏附分子抑制剂的抑制剂组成的群组。
在另一实施例中,提供了一种用于治疗一疾病或病症的方法,所述方法包含:将化学式1的一化合物或其在药学上可接受的盐的一治疗有效量施予需要的一患者,其中所述疾病或病症是选自于由癌症、肿瘤形成或肿瘤所组成的群组。所述癌症、肿瘤形成或肿瘤包括大肠直肠癌、乳癌、脑瘤、胃癌、肝癌、卵巢癌、肺癌、胃肠道癌、血癌或黑色素瘤。在另一实施例中,所述患者是一人类。在另一实施例中,所述疾病或病症是大肠直肠癌。
亦即,提供了化学式1或其药学上可接受的盐的一种医疗用途,其中所述化学式1或其药学上可接受的盐是被用作一有效药剂。在一实施例中,所述医疗用途是用于治疗或预防上文中描述的所述疾病或病症。
根据本发明的所述化合物的医疗用途及治疗方法:
本发明进一步提供数种通过施予具有或易感于一疾病或病症的一患者上文所描述的一种或更多种化合物的一治疗有效量而治疗所述患者中的所述疾病或病症的方法。在一实施例中,所述治疗是预防性治疗。在另一实施例中,所述治疗是舒缓治疗(palliativetreatment)。在另一实施例中,所述治疗是修复性治疗(restorative treatment)。
1.疾病或病症
本发明的用于抑制TNIK活性的化合物对治疗或预防各种病症(举例而言,对于抗肿瘤)是有用的。所述化合物可以被用于抑制或阻碍TNIK活性,及被用于治疗一肿瘤或癌症,或被用于预防这样的疾病的恶化。因此,本发明提供了一种用于抑制或阻碍一细胞中的TNIK活性的方法,其中所述细胞被与本发明的一化合物的一有效量接触。在一实施例中,这样的细胞是存在于一患者(举例而言,癌症病患)中。在另一实施例中,提供了一种使用根据本发明的所述化合物治疗一患者中的癌症或预防一患者中的肿瘤的增生的医疗用途。本发明的所述方法包含:施予需要治疗或预防的一患者一药学组成物,所述药学组成物含有TNIK抑制剂的一治疗上的或预防上有效的量。
在一实施例中,提供了一种用于抑制或阻断一肿瘤或癌症细胞中的TNIK活性的方法。举例而言,本发明被用于抑制一细胞,比如大肠直肠癌细胞、乳癌细胞、脑瘤细胞、胃癌细胞、肝癌细胞、卵巢癌细胞、肺癌细胞、胃肠道癌细胞、血癌细胞或黑色素瘤细胞中的TNIK活性。在此方法中,本发明提供了一种用于在一患者中抑制细胞,特别是肿瘤细胞或癌细胞的生长或增生的方法。在此方法中,所述肿瘤细胞是存在于体内。本发明的所述化合物可以以本文中所描述的药学组成物的一形态被施予至所述患者。
在另一实施例中,提供了一种用于治疗或预防一患者中的一癌症或肿瘤的方法。所述癌症包括,但不限于大肠直肠癌、乳癌、脑瘤、胃癌、肝癌、卵巢癌、肺癌、胃肠道癌、血癌或黑色素瘤。所述方法包含施予需要治疗的一患者所述化合物的一足够的量,亦即,本发明的所述化合物的一治疗性的量。
2.患者
根据本发明的适宜被治疗的患者包括哺乳类患者。根据本发明的哺乳类包括,但不限于人类、犬、猫、牛、山羊、马、绵羊、猪、囓齿动物、兔形目、灵长类等,并包括在子宫内的(in utero)哺乳类。患者可以属于任一性别及可以处于任何发育阶段。
在一实施例中,适宜根据本发明而被治疗的患者是人类。
3.施予及给药
本发明的所述化合物一般地是以一治疗上有效的量被施予。
本发明的所述化合物可以以任何适宜的途径,以适应那样的一途径的一药学组成物的形态,并以对所意图的治疗而言有效的一剂量被施予。一有效剂量典型地是以单一或分开的剂量,在约0.001毫克至约100毫克每公斤体重每天,优选地约0.01至约50毫克/公斤/天的范围内。视乎年龄、物种及被治疗的疾病或病症,低于此范围的下限的剂量水平可能是适宜的。在其它案例中,更大的剂量可以被使用而无有害副作用。较大的剂量也可以被分为数个较小剂量,以供在一天当中施予。用于决定适宜剂量的方法在本发明所属的技艺中是周知的。举例而言,雷明顿:药学的科学与实践(Remington:The Science andPractice of Pharmacy),第20版,Mack Publishing Co,2000年可以被使用。
药学组成物、剂型及施予途径:
对于上文中提及的疾病或病症的治疗,本文中所描述的所述化合物或其药学上可接受的盐可以如下地被施予:
口服:
本发明的所述化合物可以被经口施予,包括通过吞服,而使所述化合物进入胃肠道,或自口直接被吸收进入血流中(颊或舌下施予)。
适宜用于口服的组成物包括固态、液态、胶状或粉末状处方,且具有比如药片、锭剂(lozenge)、胶囊、颗粒(granule)或粉末的一剂型。
用于口服的组成物可以被调剂为立即或修改释放(modified release),包括延迟或持续释放,可选地具有肠溶膜衣(enteric coating)。
液态剂型可以包括溶液、糖浆及悬浮液,所述溶液、糖浆及悬浮液可以在软质或硬质胶囊中被使用。如此剂型可以包括一药学上可接受的载体,举例而言,水、酒精、聚乙二醇,纤维素或油。所述剂型可以亦包含一种或更多种乳化剂及/或悬浮剂。
在一药片剂型中,存在的所述药剂的量可以是依所述剂型的重量计自约0.05%至约95%,更典型地依所述剂型的重量计自约2%至约50%。此外,药片可以含有一崩解剂(disintegrant),所述崩解剂按重量计包含所述剂型的自约0.5%至约35%,更典型地包含所述剂型的自约2%至约25%。崩解剂的数个示例包括但不限于:乳糖、淀粉、羟乙酸淀粉钠、交聚维酮、交联羧甲基纤维素钠、麦芽糊精或其混合物。
适宜用于一药片中的润滑剂可以以依重量计自约0.1%至约5%的量存在,且包括但不限于滑石、二氧化硅、硬脂酸、硬脂酸钙、锌或镁、硬脂富马酸钠等。
适宜用于一药片中的结合剂包括但不限于明胶、聚乙二醇、糖、树胶、淀粉、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素等。适宜用于一药片中的稀释剂包括但不限于甘露醇、木糖醇、乳糖、右旋糖、蔗糖、山梨糖醇、微晶纤维素及淀粉。
适宜用于一药片中的增溶剂(solubilizers)可以以依重量计自约0.1%至约3%的量存在,并包括但不限于聚山梨酯、月桂基硫酸钠、十二烷基硫酸钠、碳酸丙烯酯、二甘醇单乙醚、二甲基异山梨醇、聚乙二醇(天然或氢化)蓖麻油、HCORTM(Nikkol)、油酸酯、GelucireTM、辛酸/辛酸单/二甘油酯、山梨糖醇酐脂肪酸酯及Solutol HSTM。
非消化道施予(Parenteral Administration):
本发明的化合物可以被直接施予进入血流、肌肉或内脏中。用于非消化道施予的适宜方式包括静脉内施予、肌内施予、皮下动脉内施予、腹膜内施予、脊髓鞘内施予、颅内施予等。适合用于非消化道施予的装置包括注射器(包括针头及无针头注射器)及输液方法。
用于非消化道施予的组成物可以被调剂为立即或修改释放,包括延迟或持续释放。
多数非消化道剂型是水溶液,所述水溶液含有赋形剂,包括盐、缓冲剂及等渗透剂。
非消化道剂型也可以以一脱水型态(例如,通过冷冻干燥)或作为消毒非水溶液溶液而被制备。这些剂型可以与一适宜载体,比如无菌水一同被使用。溶解度增进剂也可以在非消化道施予溶液的制备中被使用。
局部施予:
本发明的化合物可以被局部地被施予到皮肤或被透皮地(transdermally)施予。用于此局部施予的剂型可以包含乳液、溶液、乳霜、凝胶、水凝胶、软膏(ointments)、泡沫、植入物、贴剂(patches)等。用于局部施予剂型的药学上可接受的载体可以包括水、酒精、矿物油、甘油、聚乙二醇等。局部施予也可以通过电穿孔(electroporation)、离子电泳法(iontophoresis)、超声波透入法(phonophoresis)等被执行。
用于典型的施予的组成物可以被调剂为立即或修改释放,包括延迟或持续释放。
关于制备药用组成物的参考:
用于制备用于治疗或预防一疾病或病症的药用组成物的方法在本发明所属的领域中是周知的。举例而言,基于药物赋形剂手册(第7版)、雷明顿:药学的科学与实践(第20版)、药学技术百科全书(第3版)或缓释及控释药物递送系统(1978年),药学上可接受的赋形剂、载体、添加物等可以被选择并与本发明的所述化合物混合以制造所述药用组成物。
组合与组合疗法:
本发明的所述化合物可以被单独地,或与其它药学活性化合物组合使用,以治疗病症,例如在上文中所描述的病症。本发明的所述(数种)化合物及其它(数种)药学活性化合物可以同时地(以相同剂型或以个别的剂型)或接续地被施予。因此,在一实施例中,本发明包含用于治疗一病症的方法。所述方法是通过将本发明的一种或更多种化合物及一种或更多种额外的药学活性化合物的治疗上有效的量施予一患者。
在另一实施例中,提供了一种药学组成物,所述药学组成物包含:本发明的一种或更多种化合物、一种或更多种额外的药学活性化合物及药学上可接受的一载体。
在另一实施例中,所述一种或更多种额外的药学活性化合物是一抗癌药物。举例而言,所述抗癌药物是EGFR激酶抑制剂、MEK抑制剂、VEGFR抑制剂、抗VEGFR2抗体、KDR抗体、AKT抑制剂、PDK-1抑制剂、PI3K抑制剂、c-kit/Kdr酪胺酸激酶抑制剂、Bcr-Abl酪胺酸激酶抑制剂、VEGFR2抑制剂、PDGFR-β抑制剂、KIT抑制剂、Flt3酪胺酸激酶抑制剂、PDGF受体家族抑制剂、Flt3酪胺酸激酶抑制剂、RET酪胺酸激酶受体家族抑制剂、VEGF-3受体拮抗剂、Raf蛋白激酶家族抑制剂、血管新生抑制剂、Erb2抑制剂、mTOR抑制剂、IGF-1R抗体、NFkB抑制剂、蛋白酶体抑制剂、化学疗法药剂或葡萄糖减降剂。
在一实施例中,在所述组合药物及/或组合疗法中与本发明的所述(数种)化合物一起被使用的一活性药剂是一抗癌药物。亦即,本发明的所述(数种)化合物可以被同时地或接续地被施予正服用一种或更多种抗癌药物的一患者。这样的抗癌药物包括,但不限于烷基化剂比如氮芥、苯丁酸氮芥、癌得星、异环磷酰胺、美法仑、噻替哌及白消安;抗代谢剂比如甲氨蝶呤、5-氟脲嘧啶、阿糖胞苷(ara-C)、5-氮杂胞苷、6-巯基嘌呤、6-硫鸟嘌呤及磷酸氟达拉滨磷;抗肿瘤抗生素比如阿霉素、亚德里亚霉素、柔红霉素、放线菌素、博来霉素、丝裂霉素C、普卡霉素、伊达比星及米托蒽醌;长春花生物碱及鬼臼素比如长春新碱、长春碱、长春地辛、依托泊苷和替尼泊苷;亚硝脲类比如卡氮芥、洛莫斯汀、斯莫斯汀及炼脲霉素;合成剂比如达卡巴仁、六甲基三聚氰胺、羟基脲、米托坦丙卡巴肼、顺铂(cisplatin)、顺氯氨铂(cisplatinum)及卡铂;皮质类固醇(乙酸可的松、氢化可的松、泼尼松、泼尼松龙、甲基泼尼松龙及地塞米松)、雌激素(二乙基己烯雌酚、雌二醇、酯化雌激素、共轭雌激素、氯烯雌醚)、孕酮(乙酸甲羟孕酮、羟已酸孕酮、乙酸甲地孕酮)、抗雌激素剂(它莫西芬)、芳香化酶抑制剂(氨鲁米特)、雄激素(丙酸睾酮)、甲基睾酮、氟羟甲睾丸酮、睾内酯、抗雄激素(氟他胺)、LHRH类似物(醋酸亮丙瑞林)和用于前列腺癌的激素(酮康唑)。
在一实施例中,在所述组合药剂及/或组合疗法中与本发明的所述(数种)化合物一同被使用的一活性药剂是用于大肠直肠癌的一药物。在另一实施例中,用于大肠直肠癌的所述药物是基于FOLFOX或FOLFIRI方案(regimens),所述药物包括5-FU、亚叶酸、奥沙利铂、抗癌妥或其组合物。在一常规标准疗法中,所述组合疗法是与西妥昔单抗(cetuximab)及/或贝伐单抗(bevacizumab)一同被使用。当本发明的所述化合物是被与其它抗大肠癌药物一同被使用时,本发明的所述化合物可以通过注射而被局部地施予以治疗非侵袭性大肠癌。
当所述数种药物在治疗组合中被使用时,治疗上有效的剂量将改变。组合治疗进一步包含:周期性治疗,所述周期性治疗在不同的时间开始及停止,以帮助所述病患的临床管理。在任何情况下,所述多种治疗性药剂(其中一种是如本文中所描述的一TNIK抑制剂)是以任何顺序被施予或甚至同时被施予。若是同时施予,所述多种治疗性药剂可选地以一单一,统一的形式,或以多种形式(仅作为示例,作为一单一的药丸或作为两个分开的药丸)被提供。
在一些实施例中,所述数种治疗性药剂中的一种是以多个剂量被给予,或者所述数种治疗性药剂中的两种皆是以多剂量被给予。若非同时,所述多个剂量之间的时间可选地自多于零周至少于十二周间变化。
此外,所述组合方法、组成物及配方并不限于仅两种药剂的使用,多种治疗性组合的使用也是被设想到的。应被了解的是,用于治疗、预防或缓解冀求纾解的所述(数种)病症的剂量方案是根据各种因素而可选地被修改的。这些因素包括所述患者遭受的疾患,以及所述患者的年龄、体重、性别、饮食及身体状况。因此,在一些实施例中,实际被采用的剂量方案广幅地变化,并且因此脱离本文中所提出的所述剂量方案。
组成本文中所揭示的所述组合疗法的所述药用成分可选地是一经组合的剂型,或为分离剂型,所述分离剂型意在随后被同时施予。组成所述组合疗法的所述药用成分可选地也是接续地被施予的,而每个药剂皆是通过要求两步骤施予的一方案而被施予。所述两步骤施予方案可选地要求所述活性药剂的接续施予或所述不同活性药剂的空间分隔施予。在所述多个施予步骤间的时间段的范围是自数分钟至数小时,视每个药用成分的性质,比如所述药用成分的效价(potency)、可溶性、生物利用性、血浆半衰期及动力学特质而定。目标分子浓度的昼夜周期变化可选地被用于决定最佳的剂量区间。
有益效果:
本发明提供了一种通过抑制TNIK活性而具有各种药学效果的化合物、一种具有所述化合物作为一有效药剂的药学组成物、一种所述化合物的医疗用途,特别是用于治疗癌症的医疗用途及一种治疗或预防方法,所述治疗或预防方法包含:将所述化合物施予需要这样的治疗或预防的一患者。本发明的所述化合物及其药学上可接受的盐具有良好的安全性及对TNIK的高选择性,且因此展现出作为一药物的优越性质。
具体实施方式
下文中,本发明相当详细地被描述,并有示例以帮助本领域的一般技术人员了解本发明。然而,以下的示例是以例示性的方式被提供且并非意在限制本发明的范围。明显的是,各种改变可以在不脱离本发明的精神及范围或者牺牲其所有材料优势的情况下被作出。
制备本发明的化合物:
下文中所使用的反应物及溶剂是购自奥德里奇化学公司(Aldrich ChemicalCo.)(美国威斯康辛州密尔瓦基)。1H-NMR光谱是以Bruker Avance300百万赫兹、BrukerAvance III HD 300百万赫兹、Bruker Avance 500百万赫兹NMR光谱仪等评量。
下文中,描述了本发明的一些化合物的例示性合成示例,且其它化合物可以以不同起始材料或反应材料,以类似于下文中所描述的方法的方法被制备。
合成示例1:N-(5-(4-甲氧苯基)-1H-吡唑-3-基)-1H-吲哚-5-胺的制备
步骤1.1-(4-甲氧苯基)-3,3-二(甲硫)丙-2-烯-1-酮
4-甲氧基苯乙酮(10.0公克,66.6毫莫耳)及苯(220毫升)于室温下在一个500毫升圆烧瓶中被混合。在使用一冰浴冷却后,NaH(5.32公克,133.0毫莫耳,2.0化学当量)被缓慢添加并被搅拌5分钟。二硫化碳(6.0毫升,99.9毫莫耳,1.5化学当量)被缓慢添加并在室温下被搅拌5分钟,接着碘甲烷(12.4毫升,199.8毫莫耳,3.0化学当量)被缓慢添加并在室温下被搅拌5分钟。其后,N,N-二甲基乙酰胺(13毫升,139.9毫莫耳,2.1化学当量)被缓慢添加并在室温下搅拌3小时。在所述反应结束后,H2O为了骤冷(quenching)而被添加,且所述反应物被以EtOAc.萃取。所述有机溶剂层被以MgSO4干燥并在真空中被浓缩。其后,它被以Et2O过滤以提供作为黄色固体的所述化合物(6.97公克)(产率:41%)。
步骤2.(Z)-3-((1H-吲哚-5-基)氨基)-1-(4-甲氧苯基)-3-(甲硫)丙-2-烯-1-酮
在步骤1中被制备的1-(4-甲氧苯基)-3,3-二(甲硫)丙-2-烯-1-酮(127毫克,0.5毫莫耳)及甲苯(5毫升)被添加到供微波反应的一小瓶(vial)中,接着被搅拌。接着BF3.OEt2(13微升,0.1毫莫耳,0.2化学当量)被添加,接着5-氨基吲哚(100毫克,0.75毫莫耳,1.5化学当量)被添加。其后,所述反应混合物在反流下被反应24小时。在所述反应结束后,所述溶剂被以一旋转蒸发器(rotavapor)移除且剩余的反应物被以MeOH过滤以提供作为一棕色固体的所述化合物(65公克)(产率:38%)。
步骤3.N-(5-(4-甲氧苯基)-1H-吡唑-3-基)-1H-吲哚-5-胺
在步骤2中制备的(Z)-3-((1H-吲哚-5-基)氨基)-1-(4-甲氧苯基)-3-(甲硫)丙-2-烯-1-酮(54毫克,0.16毫莫耳)、t-BuOH(3毫升)及AcOH(10微升)被加入一个50毫升圆烧瓶中并搅拌。水合肼(10微升,0.24毫莫耳,1.5化学当量)被添加并在反流下反应20小时。在所述反应结束后,溶剂被以一旋转蒸发器移除,且被以H2O(50毫升)及EtOAc(50毫升x3)萃取,接着所述有机溶剂层被以MgSO4干燥并在真空中被浓缩。其后,所述反应物被以硅胶柱色层分析(EtOAc:Hex)分离以提供作为黄色固体的所述化合物(42毫克)(产率:86%)。
1H-NMR(500百万赫兹,DMSO-d6)δ10.71(s,-NH),8.21(s,1H),7.66(d,2H,J=8.1赫兹),7.62(s,1H),7.32(d,1H,J=8.5赫兹),7.09(s,1H),7.02(d,2H,8.2赫兹),6.85(d,1H,J=8.6赫兹),3.80(s,3H)。
合成示例2:6-((5-(4-(苄氧基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮的制备
步骤1.7-硝基-1,4-二氢异喹啉-3(2H)-酮
3,4-二氢-2-(1H)-喹啉酮(2.94公克,20.0毫莫耳)及H2SO4(60毫升)被加入一个250毫升圆烧瓶中并在室温下被搅拌。在使用一冰浴冷却后,H2O(30毫升)被添加且HNO3(2.1毫升,30.0毫莫耳,1.5化学当量)被逐滴添加,接着所述反应混合物在室温下被搅拌30分钟。在所述反应结束后,冰水被添加,接着所述反应物被以H2O(50毫升)及EtOAc(50毫升x3)萃取。所述有机溶剂层被以MgSO4干燥并在真空中被浓缩。其后,所述反应物被以EtOAc过滤以提供所述化合物(2.5公克)(产率:65%)。
步骤2.7-氨基-1,4-二氢异喹啉-3(2H)-酮
7-硝基-1,4-二氢异喹啉-3(2H)-酮(2.5公克,13.0毫莫耳,1.0化学当量)及THF/MeOH(50/50毫升)于室温下在一个250毫升圆烧瓶中被搅拌。Pd/C(500毫克,20重量百分率)被添加且在室温下被搅拌24小时。Pd/C(250毫克,10重量百分率)被进一步添加且在室温下被搅拌12小时。在所述反应结束后,Pd/C被以一硅藻土滤器移除且溶剂被以一旋转蒸发器移除。所述反应物接着被以硅胶柱色层分析(EtOAc:Hex)分离以提供所述化合物(1.35公克)(产率:64%)。
步骤3.6-((5-(4-(苄氧基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮
1-(4-苄氧基)苯基)-3,3-二(甲硫)丙-2-烯-1-酮(660毫克,2.0毫莫耳)及甲苯(10毫升)在一个MW小瓶(MW vial)中被搅拌。BF3.OEt2(50微升,0.4毫莫耳,0.2化学当量)及步骤2中制备的7-氨基-1,4-二氢异喹啉-3(2H)-酮(487毫克,3.0毫莫耳,1.5化学当量)被加到所述小瓶并于120度反应24小时。在所述反应结束后,溶剂被以一旋转蒸发器移除,且所述反应物被以H2O(50毫升)及EtOAc(50毫升x3)萃取。所述有机溶剂层被以MgSO4干燥并在真空中被浓缩。t-BuOH(10毫升)、AcOH(75微升)及水合肼(150微升,3.0毫莫耳,1.5化学当量)被添加并在反流下反应24小时。在所述反应结束后,溶剂被以一旋转蒸发器移除,且被以H2O(50毫升)及EtOAc(50毫升x3)萃取。所述有机溶剂层被以MgSO4干燥并在真空中被浓缩。其后,硅胶柱色层分析(EtOAc:Hex)分离所述化合物(2步骤,307毫克)(产率:37%)。
1H NMR(300百万赫兹,氯仿-d)δ7.96(d,J=8.9赫兹,2H),7.85(s,1H),7.50-7.32(m,5H),7.13(d,J=8.3赫兹,2H),7.05(d,J=8.9赫兹,2H),6.80(d,J=8.0赫兹,1H),6.15(s,1H),5.15(s,2H),3.01(t,J=7.5赫兹,2H),2.73-2.61(m,2H),2.52(s,3H)。
合成示例3:6-((5-(4-羟苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮的制备
6-((5-(4-(苄氧基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氫喹啉-2(1H)-酮(300毫克,0.73毫莫耳)及EtOAc/THF/MeOH(20/20/20毫升)于室温下在一个100毫升圆烧瓶中被搅拌。Pd/C(60毫克,20重量百分率)被添加且在室温下被搅拌24小时。在所述反应结束后,Pd/C被以一硅藻土垫(celite pad)移除且溶剂被以一旋转蒸发器移除。其后,硅胶柱色层分析(DCM:MeOH)分离所述化合物(21毫克)(产率:9%)。
1H NMR(300百万赫兹,DMSO-d6)δ12.12(s,1H),9.80(s,1H),9.65(s,1H),8.18(s,1H),7.51(d,J=8.6赫兹,2H),7.21(s,1H),7.13–7.04(m,1H),6.80(d,J=8.6赫兹,2H),6.69(d,J=8.5赫兹,1H),6.02(s,1H),2.80(t,J=7.5赫兹,2H),2.39(t,J=7.4赫兹,2H)。
合成示例4:N-(5-(4-氟苯基)-1H-吡唑-3-基)-1H-苯并[d]咪唑-6-胺的制备
XPhos Pd G1(5莫耳百分率,0.0113毫莫耳,5.4毫克)、XPhos(7莫耳百分率,0.0158毫莫耳,11.6毫克)、NaOtBu(2.1化学当量,0.475毫莫耳,45毫克)、吡唑胺(1.0化学当量,0.226莫耳,40毫克)、6-溴苯并咪唑(1.2化学当量,0.271毫莫耳,53毫克)及脱气t-BuOH(4毫升)被加入一个微波小瓶中。微波辐照于150度执行1小时。在被冷却到室温后,所述反应混合物被以冷乙醚清洗并过滤以提供所述化合物(20毫克)(产率:30%)。
1H NMR(300百万赫兹,CDCl 3)δ7.98(s,1H),7.76(d,J=1.8赫兹,1H),7.57-7.50(m,2H),7.46(s,1H),7.36(dd,J=8.6,1.8赫兹,1H),7.06(t,J=8.7赫兹,2H),5.87(s,1H)。
本发明的化合物是使用上文所述的方法通过调整起始原料及/或中间产物而合成的。1H NMR测试的结果被写在下方的表3中。
[表3]
化合物的评量
1.抑制TNIK活性的效力,使用qPCR的体外TNIK激酶试验
对于多数试验,激酶标记T7噬菌体品系在衍生自BL21品系的一大肠杆菌(E.coli)宿主中被于24孔分隔盘(24-well blocks)中平行地培养。所述大肠杆菌被培养至指数期并被来自一冷冻存货的T7噬菌体感染(多重感染率=0.4),并且在32度震荡培养直到(90至150分钟)。溶胞物质被离心(6,000x g)并过滤(0.2微米)以移除细胞碎屑。剩余的激酶在HEK-293细胞中被制造并接着被以供qPCR侦测的DNA进行标记。披覆以链霉亲和素(Streptavidin)的磁珠(magnetic beads)在室温下被以生物素化的小分子配位体(ligands)处理30分钟以产生用于激酶试验的亲和树脂(affinity resins)。所述被配位化的磁珠被以过量生物素组断(blocked)并以阻断缓冲液(SeaBlock(Pierce),1%BSA、0.05%Tween 20,1毫体积莫耳浓度(mM)DTT)清洗以移除未连结的配位体并减少非特定噬菌体连结。连结反应通过在1x连结缓冲液(20%SeaBlock、0.17x PBS、0.05%Tween 20,6毫体积莫耳浓度DTT)中结合激酶、被配位化的亲和磁珠及测试化合物而组成。测试化合物被制备为于100%DMSO中的40x储备并被直接稀释进入所述试验。所有反应以0.04毫升的一最终体积在聚丙烯384孔盘中被执行。
所述试验盘在室温下震荡培养1小时且所述亲和磁珠被以清洗缓冲液(1x PBS,0.05%Tween 20)清洗。所述磁珠接着被重新悬浮在洗脱缓冲液(elution buffer)(1xPBS、0.05%Tween 20、0.5微体积莫耳浓度(μM)非生物素化亲和配位体)中并在室温下震荡培养30分钟。在洗脱液中的所述激酶浓度被以qPCR测量。
结果被展示在以下的表4中。
[表4]
化合物号码 | 在1微体积莫耳浓度的活性(%) |
1 | 16 |
2 | 21 |
3 | 7 |
4 | 8 |
如在上方的表4中所展示的,本发明的化合物在抑制TNIK活性上是非常有效的。
2.抑制TNIK活性的效力,使用ADP-GloTM激酶试验系统的体外TNIK激酶试验
化合物的抑制性质被以TNIK激酶酵素系统及来自Promega公司的萤光ADP-GloTM激酶试验,根据制造商的方案而被评量。被测化合物被与TNIK激酶培养。反应在10微升激酶缓冲液中于37度被执行30分钟,所述激酶缓冲液被增补以含有2微升ATP、2微升MBP蛋白及2微升TNIK的反应混合物。反应的条件被提供在表5中。在激酶反应后,5微升的所述反应混合物被转移至384孔试验盘(Greiner,纯白低结合盘)。接下来,5微升的ADP-Glo试剂被添加到每个孔中并于37度培养30分钟。在45分钟后,10微升激酶侦测试剂被添加至每个孔且萤光讯号在于37度培养30分钟后被以SpectraMax M5e微盘读仪(Microplate Reader)(MolecularDevices,加州,门洛帕克)侦测。IC50值使用GraphPad Prism软体(GraphPad SoftwareInc.,美国,加州,拉荷亚)而被计算,以决定套组表现。在截止点试验(cut-off assay)中,所述化合物对TNIK激酶的抑制活性被表示为一指定浓度的抑制剂的激酶抑制活性百分比。所述化合物对TNIK激酶的IC50值被计算,一对数浓度反应曲线(log-concentration-response curve)符合一个四参数逻辑方程(logistic化学当量uation)并表现抑制百分比对所述化合物浓度的对数值的剂量依赖曲线。
将被用于体外TNIK激酶抑制试验的所述反应的条件被显示在表5中。
[表5]
体外TNIK激酶试验(HTRF)的结果被展示在下方的表6及表7中。
[表6]
[表7]
化合物号码 | 于1微体积莫耳浓度时的抑制(%) |
2 | 99 |
3 | 79 |
6 | 96 |
8 | 88 |
9 | 98 |
10 | 99 |
11 | 94 |
12 | 93 |
13 | 90 |
14 | 97 |
18 | 99 |
19 | 97 |
3.抑制癌细胞的效力,使用结肠癌细胞株
1)细胞培养
人类结肠癌细胞株SW480(目录号CCL-228)及SW620(目录号CCL-227)获得自美国典型培养物保藏中心(American Type Culture Collection(ATCC)),并被保持在增补以10%胎牛血清(FBS)(Thermo Fisher Scientific Inc.,麻萨诸塞州,沃尔瑟姆)、100单位/毫升盘尼西林及100微克/毫升链霉素(Gibco,马里兰州,盖瑟斯堡)的DMEM(Thermo FisherScientific Inc.,美国,马萨诸塞州,沃尔瑟姆)中。细胞于37度在5%CO2中被生长以供汇合(confluence)。
2)细胞存活力试验
细胞存活力使用Cell Counting Kit-8(Dojindo Molecular Technologies)而被测量。SW480及SW620细胞(2.5×104细胞/孔)被播种在96孔盘中并培养24小时。在所述培养后,所述细胞被暴露于经连续稀释的化合物(0.1、0.3、1、3、10及30微体积莫耳浓度),所述化合物在含有0.1%FBS的100微升无苯酚DMEM培养基中。48小时后,添加了每孔10微升的CCK-8试剂并在37度培养1小时。光学密度于450纳米处使用一微盘读仪(Bio-RadLaboratories,加州赫拉克勒斯)而被测量。所述IC50值使用GraphPad Prism软体(GraphPadSoftware Inc.,美国,加州,拉荷亚)而被计算,以决定套组表现。实验以3重复被进行。
使用SW620细胞的细胞存活力试验的结果被展示在下方的表8中。
[表8]
化合物号码 | IC<sub>50</sub>(微体积莫耳浓度)SW620 |
2 | 1.2 |
12 | 13 |
18 | 3.4 |
使用SW480细胞的细胞存活力试验的结果被展示在下方的表9中。
[表9]
化合物號碼 | IC<sub>50</sub>(微体积莫耳浓度)SW480 |
2 | 4.5 |
18 | 21 |
所有被提及的文件通过引用被并入本文中,如同被写在本文中。当引介本发明或本发明的示例性实施例的元素时,冠词“一(a)”、“一(an)”、“所述(the)”及“所述(said)”是意在意指有一个或更多个所述元素。“包含(comprising)”、“包括(including)”及“具有(having)”等词汇是意在作为含括性的且意指除了被列出的元素外可以有额外的元素。虽然本发明参照特定实施例而被描述,这些实施例的细节不应被视为限制。
Claims (12)
2.如权利要求1所述的化合物,其特征在于:在所述化学式1中:
W是取代的或未取代的苯基、吡啶基、噻吩、噻唑、吡咯、苯并噻吩、吲哚、恶唑、吡唑、咪唑、嘧啶、苯并吡唑、苯并噻唑、苯并恶唑、苯并咪唑或苯并噻吩,
R1是H或F,
R2是具有未取代或取代的-C1-6卤代烷基、-C1-6烷基、卤素或-C1-6烷氧基的:吲哚啉、3H-吲哚、1H-吲哚、2H-异吲哚、1H-吲唑、苯并咪唑、苯并呋喃、异苯并呋喃、苯并[c]噻吩、
苯并[b]噻吩、苯并[d]异恶唑、苯并[c]异恶唑、
苯并[d]异噻唑、苯并[c]异噻唑、苯并[d]恶唑、
苯并[d]噻唑、苯并[c][1,2,5]噻二唑、
1,2-苯并异噻唑-3(2H)-酮、1,2,3,4-四氢喹啉、
1,2-二氢喹啉、1,2-二氢异喹啉、喹啉、异喹啉、
喹喔啉、酞嗪、喹唑啉、噌啉、2H-色烯、
1H-异色烯、3H-异色烯、2H-色烯-2-酮、
2H-苯并[e][1,2]恶嗪、2H-苯并[e][1,3]恶嗪、
2H-苯并[b][1,4]恶嗪、喹啉-2(1H)-酮、异喹啉-1(2H)-酮、
1,3-二氢-2H-苯并[d]咪唑-2-酮、
3,4-二氢喹啉-2(1H)-酮、吲哚啉-2-酮、
苯并[b][1,4]恶嗪-3(4H)-酮、苯并[d]恶唑-2(3H)-酮、
1H-苯并[d]咪唑、1,3-二氢-2H-苯并[d]咪唑-2-硫酮,或
苯并[d]噻唑-2(3H)-酮。
3.如权利要求2所述的化合物,其特征在于:在所述化学式1中:
W是取代的或未取代的苯基、吡啶基、噻吩、噻唑、吡咯、苯并噻吩或吲哚,
R1是H或F、
R2是1H-吲哚、1H-吲唑、
1,3-二氢-2H-苯并[d]咪唑-2-酮、
3,4-二氢喹啉-2(1H)-酮、吲哚啉-2-酮、
苯并[b][1,4]恶嗪-3(4H)-酮、苯并[d]恶唑-2(3H)-酮、
2-甲基-1H-苯并[d]咪唑,4-甲基喹啉-2(1H)-酮、
1,3-二氢-2H-苯并[d]咪唑-2-硫酮、
苯并[d]噻唑-2(3H)-酮、4-甲基-1H-吲唑、
6-甲基-1H-吲唑,4-甲基-1H-苯并[d]咪唑,或
6-甲基-1H-苯并[d]咪唑或1H-苯并[d]咪唑。
4.如权利要求1所述的化合物,其特征在于:所述化合物是
N-(5-(4-甲氧苯基)-1H-吡唑-3-基)-1H-吲哚-5-胺、
N-(5-(4-甲氧苯基)-1H-吡唑-3-基)-1H-吲唑-5-胺、
5-((5-(4-甲氧苯基)-1H-吡唑-3-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-酮、
N-(5-(4-甲氧苯基)-1H-吡唑-3-基)-1H-吲唑-6-胺、
6-((5-(4-(苄氧基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮、
6-((5-(4-羟苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮、
6-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮、
5-((5-(3-氟-4-羟苯基)-1H-吡唑-3-基)氨基)吲哚啉-2-酮、
6-((5-(4-(1H-咪唑-1-基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮、
N-(5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)-1H-吲唑-5-胺、
4-(3-((1H-吲唑-5-基)氨基)-1H-吡唑-5-基)苯酚、
4-(3-((1H-吲唑-5-基)氨基)-1H-吡唑-5-基)-2-氟苯酚、
7-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮、
7-((5-(4-羟苯基)-1H-吡唑-3-基)氨基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮、
5-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)苯并[d]恶唑-2(3H)-酮、
N-(5-(4-氟苯基)-1H-吡唑-3-基)-1H-苯并[d]咪唑-6-胺、
6-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-4-甲基喹啉-2(1H)-酮、
N-(5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)-2-甲基-1H-苯并[d]咪唑-5-胺、
5-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-硫酮、
6-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)苯并[d]噻唑-2(3H)-酮,或
6-((5-(4-(1H-吡唑-1-基)苯基)-4-氟-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮。
5.如权利要求4所述的化合物,其特征在于:所述化合物是
N-(5-(4-甲氧苯基)-1H-吡唑-3-基)-1H-吲唑-5-胺、
6-((5-(4-羟苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮、
6-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮、
5-((5-(3-氟-4-羟苯基)-1H-吡唑-3-基)氨基)吲哚啉-2-酮、
6-((5-(4-(1H-咪唑-1-基)苯基)-1H-吡唑-3-基)氨基)-3,4-二氢喹啉-2(1H)-酮、
N-(5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)-1H-吲唑-5-胺、
4-(3-((1H-吲唑-5-基)氨基)-1H-吡唑-5-基)苯酚、
4-(3-((1H-吲唑-5-基)氨基)-1H-吡唑-5-基)-2-氟苯酚、
7-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮、
7-((5-(4-羟苯基)-1H-吡唑-3-基)氨基)-2H-苯并[b][1,4]恶嗪-3(4H)-酮、
5-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)苯并[d]恶唑-2(3H)-酮、
N-(5-(4-氟苯基)-1H-吡唑-3-基)-1H-苯并[d]咪唑-6-胺、
6-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-4-甲基喹啉-2(1H)-酮、
N-(5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)-2-甲基-1H-苯并[d]咪唑-5-胺、
5-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)-1,3-二氢-2H-苯并[d]咪唑-2-硫酮,或
6-((5-(4-(1H-吡唑-1-基)苯基)-1H-吡唑-3-基)氨基)苯并[d]噻唑-2(3H)-酮。
6.一种组成物,其特征在于:所述组成物包含:如权利要求1至5中任一项所述的一化合物或其在药学上可接受的盐;及一药学上可接受的载体。
7.一种用于治疗或预防癌症的组成物,其特征在于:所述组成物包含:作为一有效药剂的如权利要求1至5中任一项所述的一化合物或其在药学上可接受的盐。
8.如权利要求7所述的组成物,其特征在于:所述癌症是大肠直肠癌、乳癌、脑瘤、胃癌、肝癌、卵巢癌、肺癌、胃肠道癌、血癌或黑色素瘤。
9.如权利要求8所述的组成物,其特征在于:所述癌症是大肠直肠癌。
10.一种用于治疗或预防癌症的方法,其特征在于:所述方法包含:将如权利要求1至5中任一项所述的一化合物或其在药学上可接受的盐的一治疗有效量施予需要的一患者。
11.如权利要求10所述的方法,其特征在于:所述癌症是大肠直肠癌、乳癌、脑瘤、胃癌、肝癌、卵巢癌、肺癌、胃肠道癌、血癌或黑色素瘤。
12.如权利要求11所述的方法,其特征在于:所述癌症是大肠直肠癌。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR20180015161 | 2018-02-07 | ||
KR10-2018-0015161 | 2018-02-07 | ||
PCT/KR2019/001403 WO2019156438A1 (en) | 2018-02-07 | 2019-01-31 | Hetero ring-fused phenyl compounds for inhibiting tnik and medical uses thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111788183A true CN111788183A (zh) | 2020-10-16 |
CN111788183B CN111788183B (zh) | 2024-02-23 |
Family
ID=67549456
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201980015875.XA Active CN111788183B (zh) | 2018-02-07 | 2019-01-31 | 用于抑制tnik的杂环融合苯基化合物及其医疗用途 |
Country Status (4)
Country | Link |
---|---|
US (1) | US11447469B2 (zh) |
EP (1) | EP3749647B1 (zh) |
CN (1) | CN111788183B (zh) |
WO (1) | WO2019156438A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111788183B (zh) | 2018-02-07 | 2024-02-23 | 韩国化学硏究院 | 用于抑制tnik的杂环融合苯基化合物及其医疗用途 |
JP7260718B2 (ja) * | 2019-11-29 | 2023-04-18 | メッドシャイン ディスカバリー インコーポレイテッド | ジアザインドール誘導体及びそのChk1阻害剤としての使用 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8299108B2 (en) * | 2002-03-29 | 2012-10-30 | Novartis Ag | Substituted benzazoles and methods of their use as inhibitors of raf kinase |
US7521560B2 (en) | 2004-06-29 | 2009-04-21 | Rigel Pharmaceuticals, Inc. | 2-substituted quinoline compounds and their uses |
WO2009030890A1 (en) | 2007-09-03 | 2009-03-12 | University Court Of The University Of Dundee | Pyrimidine compounds for the treatment of cancer, septic shock and/or primary open angle glaucoma |
US20100216795A1 (en) | 2008-12-01 | 2010-08-26 | Tesshi Yamada | Tnik inhibitor and the use |
US20100137386A1 (en) | 2008-12-01 | 2010-06-03 | Tesshi Yamada | Tnik inhibitor and the use |
EP2398791A1 (en) * | 2009-02-18 | 2011-12-28 | Amgen, Inc | INDOLE/BENZIMIDAZOLE COMPOUNDS AS mTOR KINASE INHIBITORS |
GB0903759D0 (en) | 2009-03-04 | 2009-04-15 | Medical Res Council | Compound |
KR101663277B1 (ko) | 2015-03-30 | 2016-10-06 | 주식회사 녹십자 | TNIK, IKKε 및 TBK1 억제제로서의 피라졸계 유도체 및 이를 포함하는 약학적 조성물 |
KR101943256B1 (ko) | 2016-05-04 | 2019-01-29 | 이노베이티브 크라이오제닉 시스템즈, 인크. | 가스 소비 부재에 가연성 가스를 급송하고 상기 가연성 가스를 액화하기 위한 설비 |
CN111836801B (zh) * | 2018-02-07 | 2024-02-02 | 韩国化学硏究院 | 用于抑制tnik的化合物及其医疗用途 |
CN111788183B (zh) | 2018-02-07 | 2024-02-23 | 韩国化学硏究院 | 用于抑制tnik的杂环融合苯基化合物及其医疗用途 |
-
2019
- 2019-01-31 CN CN201980015875.XA patent/CN111788183B/zh active Active
- 2019-01-31 US US16/967,825 patent/US11447469B2/en active Active
- 2019-01-31 WO PCT/KR2019/001403 patent/WO2019156438A1/en unknown
- 2019-01-31 EP EP19750420.2A patent/EP3749647B1/en active Active
Non-Patent Citations (1)
Title |
---|
REGISTRY: "RN1257090-91-7", 《STN COLUMBU》 * |
Also Published As
Publication number | Publication date |
---|---|
CN111788183B (zh) | 2024-02-23 |
EP3749647C0 (en) | 2023-09-27 |
US11447469B2 (en) | 2022-09-20 |
WO2019156438A1 (en) | 2019-08-15 |
EP3749647B1 (en) | 2023-09-27 |
EP3749647A1 (en) | 2020-12-16 |
EP3749647A4 (en) | 2021-11-24 |
US20210047300A1 (en) | 2021-02-18 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6464139B2 (ja) | ブロモドメイン含有タンパク質の阻害のための方法および組成物 | |
TWI473792B (zh) | New quinoline compounds and their use | |
CN111836801B (zh) | 用于抑制tnik的化合物及其医疗用途 | |
JP6087954B2 (ja) | キノリン類およびシンノリン類化合物、およびその使用 | |
CA2544186A1 (en) | Inhibition of fgfr3 and treatment of multiple myeloma with benzimidazole quinolinones | |
TW200307535A (en) | Therapeutic agent for cancer | |
JP2013224299A (ja) | 4−アミノ−5−フルオロ−3−[6−(4−メチルピペラジン−1イル)−1h−ベンズイミダゾール−2−イル]−1h−キノリン−2−オン乳酸塩の結晶およびその他の形態 | |
CZ20021746A3 (cs) | Nové sloučeniny | |
JP2008056692A (ja) | イソチアゾール−4−カルボキサミドの塩及びそれらの抗増殖過剰剤としての使用 | |
TW200819434A (en) | 1-(het)aryl-3-[hetaryl-piperidin-4-yl]-thioureas as modulators of the EP2 receptor | |
EP2539327A1 (en) | Oxadiazole compounds, their preparation and use | |
BR112020008499A2 (pt) | composição farmacêutica para prevenir ou tratar leucemia mieloide aguda ou câncer de mama metastático | |
AU2018226922A1 (en) | Urea-substituted aromatic ring-linked dioxane-quinazoline and -linked dioxane-quinoline compounds, preparation method therefor and use thereof | |
CN111788183B (zh) | 用于抑制tnik的杂环融合苯基化合物及其医疗用途 | |
JP7181565B2 (ja) | Yap-tead結合を阻害する化合物、およびそれを有効成分として含有する癌の予防または治療用医薬組成物 | |
WO2018157730A1 (zh) | 脲取代的芳环连二噁烷并喹唑啉与连二噁烷并喹啉类化合物及其制备方法与应用 | |
KR20230106610A (ko) | 치료제로서의 석시네이트 및 이의 결정 형태 | |
JP2021527071A (ja) | Epac阻害剤としてのチエノ[2,3−b]ピリジン誘導体及びその医薬用途 | |
KR101920163B1 (ko) | 항암용 약학 조성물 | |
WO2023284838A1 (zh) | Aak1抑制剂及其用途 | |
KR20230114646A (ko) | 벤조다이옥세인 유도체 화합물 및 이의 의약 용도 | |
TW201702223A (zh) | 吲哚酮衍生物及其醫藥用途與製法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |