CN113501826A - 作为tdp2的抑制剂的呋喃并喹啉二酮 - Google Patents
作为tdp2的抑制剂的呋喃并喹啉二酮 Download PDFInfo
- Publication number
- CN113501826A CN113501826A CN202110013140.2A CN202110013140A CN113501826A CN 113501826 A CN113501826 A CN 113501826A CN 202110013140 A CN202110013140 A CN 202110013140A CN 113501826 A CN113501826 A CN 113501826A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- substituted
- pharmaceutically acceptable
- 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.)
- Pending
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 25
- 101000760781 Homo sapiens Tyrosyl-DNA phosphodiesterase 2 Proteins 0.000 title description 17
- 102100024578 Tyrosyl-DNA phosphodiesterase 2 Human genes 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 140
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 201000011510 cancer Diseases 0.000 claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 20
- 150000003254 radicals Chemical class 0.000 claims description 39
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 229910052736 halogen Inorganic materials 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 33
- -1 hydroxy, amino Chemical group 0.000 claims description 25
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 20
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 19
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 239000013543 active substance Substances 0.000 claims description 16
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 101710183280 Topoisomerase Proteins 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 229960004679 doxorubicin Drugs 0.000 claims description 7
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 7
- 229960005420 etoposide Drugs 0.000 claims description 7
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 6
- CTSPAMFJBXKSOY-UHFFFAOYSA-N ellipticine Chemical compound N1=CC=C2C(C)=C(NC=3C4=CC=CC=3)C4=C(C)C2=C1 CTSPAMFJBXKSOY-UHFFFAOYSA-N 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 5
- 206010018338 Glioma Diseases 0.000 claims description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 5
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 4
- 206010039491 Sarcoma Diseases 0.000 claims description 4
- 125000003282 alkyl amino group Chemical group 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 238000006467 substitution reaction Methods 0.000 claims description 4
- WDXXEUARVHTWQF-ZYMOGRSISA-N 3-hydroxy-2-[(1r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C(CCCCC)=CC(=O)C([C@H]2C(CCC(C)=C2)C(C)=C)=C1O WDXXEUARVHTWQF-ZYMOGRSISA-N 0.000 claims description 3
- 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 claims description 3
- 206010003571 Astrocytoma Diseases 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 3
- 208000032612 Glial tumor Diseases 0.000 claims description 3
- ZIXGXMMUKPLXBB-UHFFFAOYSA-N Guatambuinine Natural products N1C2=CC=CC=C2C2=C1C(C)=C1C=CN=C(C)C1=C2 ZIXGXMMUKPLXBB-UHFFFAOYSA-N 0.000 claims description 3
- 208000033833 Myelomonocytic Chronic Leukemia Diseases 0.000 claims description 3
- 206010033128 Ovarian cancer Diseases 0.000 claims description 3
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 3
- SUYXJDLXGFPMCQ-INIZCTEOSA-N SJ000287331 Natural products CC1=c2cnccc2=C(C)C2=Nc3ccccc3[C@H]12 SUYXJDLXGFPMCQ-INIZCTEOSA-N 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 claims description 3
- 229960001220 amsacrine Drugs 0.000 claims description 3
- GIXWDMTZECRIJT-UHFFFAOYSA-N aurintricarboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=CC1=C(C=1C=C(C(O)=CC=1)C(O)=O)C1=CC=C(O)C(C(O)=O)=C1 GIXWDMTZECRIJT-UHFFFAOYSA-N 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 claims description 3
- 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 claims description 3
- 229960000975 daunorubicin Drugs 0.000 claims description 3
- 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 claims description 3
- 229960001156 mitoxantrone Drugs 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 claims description 3
- 229960001278 teniposide Drugs 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 201000006462 myelodysplastic/myeloproliferative neoplasm Diseases 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 206010038038 rectal cancer Diseases 0.000 claims description 2
- 201000001275 rectum cancer Diseases 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 9
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 3
- 206010004593 Bile duct cancer Diseases 0.000 claims 1
- 208000026900 bile duct neoplasm Diseases 0.000 claims 1
- 125000001589 carboacyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 8
- VXRAAUKUZQYZRW-UHFFFAOYSA-N 3'-N'-Acetylfusarochromanone Chemical compound O1C(C)(C)CC(=O)C2=C(N)C(C(=O)CC(CO)NC(=O)C)=CC=C21 VXRAAUKUZQYZRW-UHFFFAOYSA-N 0.000 abstract description 4
- 230000002062 proliferating effect Effects 0.000 abstract description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 84
- 239000007787 solid Substances 0.000 description 61
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 230000015572 biosynthetic process Effects 0.000 description 51
- 238000003786 synthesis reaction Methods 0.000 description 51
- 238000002360 preparation method Methods 0.000 description 44
- 239000007858 starting material Substances 0.000 description 40
- 239000011734 sodium Substances 0.000 description 32
- 239000000243 solution Substances 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- 125000000217 alkyl group Chemical group 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 17
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 125000006413 ring segment Chemical group 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 101000760764 Homo sapiens Tyrosyl-DNA phosphodiesterase 1 Proteins 0.000 description 9
- 102100024579 Tyrosyl-DNA phosphodiesterase 1 Human genes 0.000 description 8
- 239000000872 buffer Substances 0.000 description 8
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
- 238000003556 assay Methods 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 101150107801 Top2a gene Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- 125000004430 oxygen atom Chemical group O* 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 102000007405 tyrosyl-DNA phosphodiesterase Human genes 0.000 description 5
- 108020005400 tyrosyl-DNA phosphodiesterase Proteins 0.000 description 5
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 101100483248 Drosophila melanogaster gkt gene Proteins 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 229920001213 Polysorbate 20 Polymers 0.000 description 4
- 101150041808 TDP1 gene Proteins 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 4
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 206010006187 Breast cancer Diseases 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000282887 Suidae Species 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 229940127093 camptothecin Drugs 0.000 description 3
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000012453 solvate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 3
- 229960000303 topotecan Drugs 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 2
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 2
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 2
- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-phenylethanol Chemical compound OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- BGAJNPLDJJBRHK-UHFFFAOYSA-N 3-[2-[5-(3-chloro-4-propan-2-yloxyphenyl)-1,3,4-thiadiazol-2-yl]-3-methyl-6,7-dihydro-4h-pyrazolo[4,3-c]pyridin-5-yl]propanoic acid Chemical compound C1=C(Cl)C(OC(C)C)=CC=C1C1=NN=C(N2C(=C3CN(CCC(O)=O)CCC3=N2)C)S1 BGAJNPLDJJBRHK-UHFFFAOYSA-N 0.000 description 2
- GRFNBEZIAWKNCO-UHFFFAOYSA-N 3-pyridinol Chemical compound OC1=CC=CN=C1 GRFNBEZIAWKNCO-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IKHKJYWPWWBSFZ-UHFFFAOYSA-N 4-[[4-(diethylamino)phenyl]-(4-diethylazaniumylidenecyclohexa-2,5-dien-1-ylidene)methyl]benzene-1,3-disulfonate;hydron Chemical compound C1=CC(N(CC)CC)=CC=C1C(C=1C(=CC(=CC=1)S([O-])(=O)=O)S(O)(=O)=O)=C1C=CC(=[N+](CC)CC)C=C1 IKHKJYWPWWBSFZ-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 229940126639 Compound 33 Drugs 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 241000282326 Felis catus Species 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 101150098265 TDP2 gene Proteins 0.000 description 2
- 101150041570 TOP1 gene Proteins 0.000 description 2
- 102220541225 Transmembrane glycoprotein NMB_N14Y_mutation Human genes 0.000 description 2
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 2
- YRKCREAYFQTBPV-UHFFFAOYSA-N acetylacetone Chemical compound CC(=O)CC(C)=O YRKCREAYFQTBPV-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical group C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- UDSAIICHUKSCKT-UHFFFAOYSA-N bromophenol blue Chemical compound C1=C(Br)C(O)=C(Br)C=C1C1(C=2C=C(Br)C(O)=C(Br)C=2)C2=CC=CC=C2S(=O)(=O)O1 UDSAIICHUKSCKT-UHFFFAOYSA-N 0.000 description 2
- WERYXYBDKMZEQL-UHFFFAOYSA-N butane-1,4-diol Chemical compound OCCCCO WERYXYBDKMZEQL-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- 238000004296 chiral HPLC Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 208000005017 glioblastoma Diseases 0.000 description 2
- 238000011194 good manufacturing practice Methods 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 102000057216 human TDP2 Human genes 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 244000144972 livestock Species 0.000 description 2
- 239000012160 loading buffer Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L magnesium chloride Substances [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 230000002071 myeloproliferative effect Effects 0.000 description 2
- 108020004707 nucleic acids Proteins 0.000 description 2
- 150000007523 nucleic acids Chemical class 0.000 description 2
- 102000039446 nucleic acids Human genes 0.000 description 2
- 229940054534 ophthalmic solution Drugs 0.000 description 2
- 239000002997 ophthalmic solution Substances 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
- 150000002894 organic compounds Chemical class 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 125000002071 phenylalkoxy group Chemical group 0.000 description 2
- 125000003884 phenylalkyl group Chemical group 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 230000008439 repair process Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 150000003568 thioethers Chemical class 0.000 description 2
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 1
- VIJSPAIQWVPKQZ-BLECARSGSA-N (2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-4-methylpentanoyl]amino]-4,4-dimethylpentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(C)=O VIJSPAIQWVPKQZ-BLECARSGSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- YQOLEILXOBUDMU-KRWDZBQOSA-N (4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2-chlorophenyl)pentanoic acid Chemical compound CC1=C(C2=C(C=CC(=C2)Br)N=C1N3CCCC3)C(=O)NC[C@H](CCC(=O)O)C4=CC=CC=C4Cl YQOLEILXOBUDMU-KRWDZBQOSA-N 0.000 description 1
- 125000006766 (C2-C6) alkynyloxy group Chemical group 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- UVNPEUJXKZFWSJ-LMTQTHQJSA-N (R)-N-[(4S)-8-[6-amino-5-[(3,3-difluoro-2-oxo-1H-pyrrolo[2,3-b]pyridin-4-yl)sulfanyl]pyrazin-2-yl]-2-oxa-8-azaspiro[4.5]decan-4-yl]-2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@@](=O)N[C@@H]1COCC11CCN(CC1)c1cnc(Sc2ccnc3NC(=O)C(F)(F)c23)c(N)n1 UVNPEUJXKZFWSJ-LMTQTHQJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- SVPKNMBRVBMTLB-UHFFFAOYSA-N 2,3-dichloronaphthalene-1,4-dione Chemical compound C1=CC=C2C(=O)C(Cl)=C(Cl)C(=O)C2=C1 SVPKNMBRVBMTLB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- ISPYQTSUDJAMAB-UHFFFAOYSA-N 2-chlorophenol Chemical compound OC1=CC=CC=C1Cl ISPYQTSUDJAMAB-UHFFFAOYSA-N 0.000 description 1
- TZPPDWDHNIMTDQ-UHFFFAOYSA-N 2-dimethoxyphosphorylethanol Chemical compound COP(=O)(OC)CCO TZPPDWDHNIMTDQ-UHFFFAOYSA-N 0.000 description 1
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 1
- CHZCERSEMVWNHL-UHFFFAOYSA-N 2-hydroxybenzonitrile Chemical compound OC1=CC=CC=C1C#N CHZCERSEMVWNHL-UHFFFAOYSA-N 0.000 description 1
- GCPJQRYMHLEJQY-UHFFFAOYSA-N 2-methyl-4,9-dioxofuro[2,3-g]quinoline-3-carboxylic acid Chemical compound CC1=C(C2=C(C(C=3C=CC=NC=3C2=O)=O)O1)C(=O)O GCPJQRYMHLEJQY-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- QRPDBJLLBPNMHY-UHFFFAOYSA-N 3-acetyl-2-methylfuro[2,3-g]quinoline-4,9-dione Chemical compound C(C)(=O)C1=C(OC=2C(C=3C=CC=NC=3C(C=21)=O)=O)C QRPDBJLLBPNMHY-UHFFFAOYSA-N 0.000 description 1
- JLWNNRDCASDTPO-UHFFFAOYSA-N 3-acetyl-2-methylfuro[3,2-g]quinoline-4,9-dione Chemical compound C(C)(=O)C1=C(OC2=C1C(C=1C=CC=NC=1C2=O)=O)C JLWNNRDCASDTPO-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- DHXNZYCXMFBMHE-UHFFFAOYSA-N 3-bromopropanoic acid Chemical compound OC(=O)CCBr DHXNZYCXMFBMHE-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical compound OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 description 1
- AODMJIOEGCBUQL-UHFFFAOYSA-N 3-ethynylphenol Chemical compound OC1=CC=CC(C#C)=C1 AODMJIOEGCBUQL-UHFFFAOYSA-N 0.000 description 1
- SGHBRHKBCLLVCI-UHFFFAOYSA-N 3-hydroxybenzonitrile Chemical compound OC1=CC=CC(C#N)=C1 SGHBRHKBCLLVCI-UHFFFAOYSA-N 0.000 description 1
- WSGYTJNNHPZFKR-UHFFFAOYSA-N 3-hydroxypropanenitrile Chemical compound OCCC#N WSGYTJNNHPZFKR-UHFFFAOYSA-N 0.000 description 1
- 125000005925 3-methylpentyloxy group Chemical group 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- WYFCZWSWFGJODV-MIANJLSGSA-N 4-[[(1s)-2-[(e)-3-[3-chloro-2-fluoro-6-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-(4-methyl-2-oxopiperazin-1-yl)-3,4-dihydro-1h-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound O=C1CN(C)CCN1C1=CC=CC2=C1CCN(C(=O)\C=C\C=1C(=CC=C(Cl)C=1F)N1N=NN=C1)[C@@H]2C(=O)NC1=CC=C(C(O)=O)C=C1 WYFCZWSWFGJODV-MIANJLSGSA-N 0.000 description 1
- GZFGOTFRPZRKDS-UHFFFAOYSA-N 4-bromophenol Chemical compound OC1=CC=C(Br)C=C1 GZFGOTFRPZRKDS-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- KECCFSZFXLAGJS-UHFFFAOYSA-N 4-methylsulfonylphenol Chemical compound CS(=O)(=O)C1=CC=C(O)C=C1 KECCFSZFXLAGJS-UHFFFAOYSA-N 0.000 description 1
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 1
- XFJBGINZIMNZBW-CRAIPNDOSA-N 5-chloro-2-[4-[(1r,2s)-2-[2-(5-methylsulfonylpyridin-2-yl)oxyethyl]cyclopropyl]piperidin-1-yl]pyrimidine Chemical compound N1=CC(S(=O)(=O)C)=CC=C1OCC[C@H]1[C@@H](C2CCN(CC2)C=2N=CC(Cl)=CN=2)C1 XFJBGINZIMNZBW-CRAIPNDOSA-N 0.000 description 1
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 1
- TUWOPVCIIBKUQS-UHFFFAOYSA-N 6,7-dichloroquinoline-5,8-dione Chemical compound C1=CC=C2C(=O)C(Cl)=C(Cl)C(=O)C2=N1 TUWOPVCIIBKUQS-UHFFFAOYSA-N 0.000 description 1
- KDAPICORIPPFII-UHFFFAOYSA-N 6-(2-hydroxyethyl)-2-methyl-4,9-dioxofuro[2,3-g]quinoline-3-carboxylic acid Chemical compound Cc1oc2c(c1C(O)=O)C(=O)c1nc(CCO)ccc1C2=O KDAPICORIPPFII-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000011691 Burkitt lymphomas Diseases 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- KQLDDLUWUFBQHP-UHFFFAOYSA-N Cordycepin Natural products C1=NC=2C(N)=NC=NC=2N1C1OCC(CO)C1O KQLDDLUWUFBQHP-UHFFFAOYSA-N 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- LOFDXZJSDVCYAS-UHFFFAOYSA-N Ethyl 3-furoate Chemical compound CCOC(=O)C=1C=COC=1 LOFDXZJSDVCYAS-UHFFFAOYSA-N 0.000 description 1
- GKKZMYDNDDMXSE-UHFFFAOYSA-N Ethyl 3-oxo-3-phenylpropanoate Chemical compound CCOC(=O)CC(=O)C1=CC=CC=C1 GKKZMYDNDDMXSE-UHFFFAOYSA-N 0.000 description 1
- 244000239659 Eucalyptus pulverulenta Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 229940123414 Folate antagonist Drugs 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 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
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 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
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- RNVYQYLELCKWAN-RXMQYKEDSA-N [(4r)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@@H](CO)O1 RNVYQYLELCKWAN-RXMQYKEDSA-N 0.000 description 1
- RNVYQYLELCKWAN-YFKPBYRVSA-N [(4s)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol Chemical compound CC1(C)OC[C@H](CO)O1 RNVYQYLELCKWAN-YFKPBYRVSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 125000003302 alkenyloxy group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000005133 alkynyloxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 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
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 229950011260 betanaphthol Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 125000005392 carboxamide group Chemical group NC(=O)* 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 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
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 230000024321 chromosome segregation Effects 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125844 compound 46 Drugs 0.000 description 1
- 229940127271 compound 49 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 229910000366 copper(II) sulfate Inorganic materials 0.000 description 1
- OFEZSBMBBKLLBJ-BAJZRUMYSA-N cordycepin Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)C[C@H]1O OFEZSBMBBKLLBJ-BAJZRUMYSA-N 0.000 description 1
- OFEZSBMBBKLLBJ-UHFFFAOYSA-N cordycepine Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)CC1O OFEZSBMBBKLLBJ-UHFFFAOYSA-N 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([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
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000010217 densitometric analysis Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229960001484 edetic acid Drugs 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- LIJHQCSZRUQOGG-UHFFFAOYSA-N ethyl 2-methyl-4,9-dioxofuro[2,3-g]quinoline-3-carboxylate Chemical compound CC1=C(C2=C(C(C=3C=CC=NC=3C2=O)=O)O1)C(=O)OCC LIJHQCSZRUQOGG-UHFFFAOYSA-N 0.000 description 1
- DOQJAKRLELECTO-UHFFFAOYSA-N ethyl 2-methyl-4,9-dioxofuro[3,2-g]quinoline-3-carboxylate Chemical compound CC1=C(C=2C(C=3C=CC=NC=3C(C=2O1)=O)=O)C(=O)OCC DOQJAKRLELECTO-UHFFFAOYSA-N 0.000 description 1
- HCGPBZIHEJAWRD-UHFFFAOYSA-N ethyl 4,9-dioxo-2-phenylfuro[2,3-g]quinoline-3-carboxylate Chemical compound O=C1C2=C(C(C=3C=CC=NC1=3)=O)OC(=C2C(=O)OCC)C1=CC=CC=C1 HCGPBZIHEJAWRD-UHFFFAOYSA-N 0.000 description 1
- KZWPWZFXESKAJG-UHFFFAOYSA-N ethyl 4,9-dioxo-2-phenylfuro[3,2-g]quinoline-3-carboxylate Chemical compound O=C1C=2C=CC=NC=2C(C2=C1C(=C(O2)C1=CC=CC=C1)C(=O)OCC)=O KZWPWZFXESKAJG-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000003722 extracellular fluid Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 102000046366 human TDP1 Human genes 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 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
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound 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 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- 229940045996 isethionic acid Drugs 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
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 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
- 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
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical group O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- KRMVXLWZDYZILN-UHFFFAOYSA-N methyl 2-acetamido-3-(4-hydroxyphenyl)propanoate Chemical compound COC(=O)C(NC(C)=O)CC1=CC=C(O)C=C1 KRMVXLWZDYZILN-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- UMRZSTCPUPJPOJ-KNVOCYPGSA-N norbornane Chemical group C1C[C@H]2CC[C@@H]1C2 UMRZSTCPUPJPOJ-KNVOCYPGSA-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
- 238000011275 oncology therapy Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005554 pyridyloxy group Chemical group 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 125000000714 pyrimidinyl 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
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 201000011096 spinal cancer Diseases 0.000 description 1
- 208000014618 spinal cord cancer Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 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
- 230000002381 testicular Effects 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004001 thioalkyl group Chemical group 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- NLIVDORGVGAOOJ-MAHBNPEESA-M xylene cyanol Chemical compound [Na+].C1=C(C)C(NCC)=CC=C1C(\C=1C(=CC(OS([O-])=O)=CC=1)OS([O-])=O)=C\1C=C(C)\C(=[NH+]/CC)\C=C/1 NLIVDORGVGAOOJ-MAHBNPEESA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/08—Aza-anthracenes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/92—Naphthofurans; Hydrogenated naphthofurans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
Abstract
本发明涉及作为TDP2的抑制剂的呋喃并喹啉二酮。本发明公开了式I的化合物及其药学上可接受的盐。本文公开了变量X1、X2和R1‑4。所述化合物可用于治疗癌症和相关的增生性疾病。还公开了含有式I化合物的药物组合物以及包含给药式I化合物的治疗方法。
Description
本申请是申请日为2016年1月8日的题为“作为TDP2的抑制剂的呋喃并喹啉二酮”的中国专利申请No.201680014742.7的分案申请。
政府支持声明
本发明部分得到了国立卫生研究院(National Institutes of Health)的政府支持。政府对本发明具有一定的权利。
相关申请的引用
本申请要求2015年1月8日提交的美国临时申请号62/100968的优先权,其通过引用以其整体并入本文。
技术领域
本申请涉及作为TDP2的抑制剂的呋喃并喹啉二酮及其药学上可接受的盐。本申请还涉及该呋喃并喹啉二酮用于治疗癌症和相关的增生性疾病的用途。
背景技术
拓扑异构酶(Topoisomerase)是用于松弛超螺旋DNA所必需的酶的家族,其是转录、复制和染色体分离所需的。拓扑异构酶切割超螺旋核酸,其减轻扭转应变,然后重新连接切割的链。拓扑异构酶在DNA复制中的重要作用使这些酶成为癌症治疗的主要靶标。拓扑异构酶抑制剂,如用于拓扑异构酶1(Top1)的喜树碱(camptothecin)和拓扑替康(topotecan),以及用于拓扑异构酶2(Top2)的依托泊苷(etoposide)和多柔比星(doxorubicin),捕获拓扑异构酶-DNA切割复合物,由此防止复制并引发由细胞凋亡带来的破坏。
酪氨酰-DNA磷酸二酯酶(TDP)在被捕获的拓扑异构酶-DNA切割复合物的修复中起重要作用。TDP存在两种形式:TDP1,用于分解捕获的Top1-DNA切割复合物,和TDP2,用于分解Top2-DNA切割复合物。
由于TDP可以修复广谱的核酸损伤,TDP的抑制是治疗性治疗癌症的有吸引力的靶标,可能作为唯一的治疗剂。还已经注意到,TDP2缺乏可以增强Top2抑制剂在具有缺陷性细胞检查点的细胞中的抗增生活性,因此,TDP2抑制剂作为与Top2的抑制剂(如依托泊苷(etoposide)和多柔比星(doxorubicin))的组合疗法,可以提供协同效应。可以预计,使用Top1的抑制剂和TDP1的抑制剂具有相似的协同效应。因此,鉴定TDP1和/或TDP2的有效抑制剂在提供治疗癌症的新方法中将是重要的。
发明内容
本文描述的是TDP2的抑制剂、它们的制造方法、含有所述化合物的组合物、和使用所述化合物的方法。在第一方面,提供了式I的化合物以及式I化合物的药学上可接受的盐,
在式I中,符合以下条件。
X1是N或CR5。
X2是N或CR6。
X1或X2中的至少一种是N。
R1是羟基、C1-C6烷基、C1-C6烷氧基、C2-C6烯氧基、C2-C6炔氧基、或C3-C7环烷氧基,其中R1的烷基、烯基、或炔基部分中的一个或多个亚甲基单元可选地或独立地被-O-、-S-或-N(R7)-替换,并且除了羟基之外的R1在每次出现时被0-3个独立地选自卤素、羟基、氰基、=N、=NOR7、-CO2H、-(CO)-O-C1-C6烷基、-C(O)NR7R8和-W-P(O)YR9ZR10的取代基取代。
或者R1可以是-O-A-B,其中O是氧原子。
A是由键、1至6个碳的亚烷基链或亚苯基组成的接头。
B是苯基、或具有1、2或3个独立地选自N、O和S的环原子的5或6元杂环,其中B用独立地从卤素、羟基、氰基、氨基、-SH、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烷酰基、C1-C6硫代烷基、C1-C6卤代烷基、C1-C6卤代烷氧基、-(C0-C6烷基)环烷基、-(C0-C6烷基)CO2H、-(C0-C6烷基)-(CO)-O-C1-C6烷基、-(C0-C6烷基)C(O)NR7R8、-(C0-C6烷基)NR7C(O)R8、-(C1-C6烷基)烷氧基、-(C1-C6烷基)OH、-(C0-C6烷基)NR7R8、-SO2-C1-C6烷基和-(C0-C6烷基)-W-P(O)YR9ZR10选择的0-3个取代基取代。
Y1是O、NH或S。
Y2是N或CR2。
R2是氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、-(C0-C6烷基)环烷基、-(C0-C6烷基)NR7R8或苯基,除了氢和羟基之外的每个R2在每次出现时被独立地从卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基中选择的0至3个基团取代。
或者,R2是基团-J-Q,其中J是1至4个碳的亚烷基接头,其中任何的-CH2-基团可选地被-C(O)O-、-C(O)NH-、-C(O)NR11或-C(O)-替换。
Q是C1-C6烷基、C1-C6烷基氨基、芳基或杂芳基,它们的每一个是未被取代的或被独立地从卤素、羟基、氨基、氰基、C1-C4烷基、C1-C4烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基中选择的一个或多个基团取代。
W、Y和Z在每次出现时独立地是键或O。
R3、R4、R5和R6在每次出现时独立地选自氢、卤素、氰基、氨基、C1-C6烷基、-(C0-C6烷基)环烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基。
R7、R8、R9和R10在每次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、-(C0-C6烷基)环烷基和C1-C6卤代烷基,并且键合到相同氮原子的任何R7和R8可以结合在一起形成4-至7-元杂环烷基,该杂环烷基被0至2个从羟基、卤素、C1-C4烷基、C1-C4烷氧基和C2-C4烷酰基中选择的取代基取代。
R11是C1-C6烷基或C1-C6烷基氨基。
其中化合物不是:
还公开了包含式I的化合物或盐以及药学上可接受的载体的药物组合物。
还公开了治疗对TDP2抑制有响应的病症的方法,包含以下步骤:向需要其的患者给药化合物或其盐。
还公开了治疗癌症(包括胶质瘤(glioma)(成胶质细胞瘤(glioblastoma,恶性胶质瘤))、急性髓性白血病(acute myelogenous leukemia)、急性骨髓性白血病(acutemyeloid leukemia)、骨髓增生异常(myelodysplastic)/骨髓增生性(myeloproliferative)肿瘤、肉瘤、慢性骨髓单核细胞性白血病、非霍奇金淋巴瘤、星形细胞瘤、黑素瘤、非小细胞肺癌、小细胞肺癌、子***、直肠癌、卵巢癌、胆管癌(cholangiocarcinomas)、软骨肉瘤或结肠癌)的方法,包含向需要此种治疗的患者给药治疗有效量的式I的化合物或盐。
具体实施方式
术语
使用标准术语描述化合物。除非另有定义,本文使用的所有技术和科学术语具有与本发明所属领域的技术人员通常理解的相同的含义。
术语“一个/一种(a)”和“一个/一种(an)”不表示数量的限制,而是表示存在至少一个所引用的项目。术语“或”是指“和/或”。术语“包含(comprising)”、“具有(having)”、“包括(including)”和“含有(containing)”应被解释为开放式的术语(即,意味着“包括,但不限于”)。
除非本文另有说明,否则数值范围的陈述仅仅意在作为单独地指代落入该范围内的每个单独值的简写方法,并且将每个单独的值并入本说明书中,如同在本文中单独列举一样。所有范围的端点都包括在该范围内并可独立组合。
本文所述的所有方法可以以适当的顺序进行,除非本文另有说明或以其他方式明确地与上下文相矛盾。任何和所有示例或示例性语言(例如“诸如”)的使用仅旨在更好地说明本发明,并且不对本发明的范围构成限制,除非另有说明。说明书中的任何语言都不应被解释为表示任何非要求保护的元素对于本文所用的本发明的实践是必要的。除非另有定义,本文使用的技术和科学术语具有与本公开技术领域的技术人员通常理解的相同的含义。
此外,本公开涵盖其中将来自所列权利要求中的一个或多个的一个或多个限制、要素、条款和描述性术语引入到另一权利要求中的所有变化、组合和排列。例如,从属于另一个权利要求的任何权利要求可被修改,以包括从属于相同基础权利要求的任何其他权利要求中发现的一个或多个限制。当元素以列表形式呈现时,例如以马库什组形式呈现,所述元素的每个子组也被公开,并且可以从该组中移除任何元素。
所有化合物都被理解为包括在化合物中出现的原子的所有可能的同位素。同位素包括具有相同原子序数但质量数不同的那些原子。作为一般实例但不限于,氢的同位素包括氚和氘,碳的同位素包括11C、13C和14C。
式I包括式I的所有药学上可接受的盐。
开放式术语“包含”包括中间物(intermediate)和封闭式术语“基本由……组成”和“由……组成”。
术语“取代的”表示指定的原子或基团上的任何一个或多个氢被从所指定组中选择的基团替代,前提是不超过指定原子的正常价态。当取代基是氧基(即=O)时,那么该原子上的2个氢被替代。当芳族部分被氧基取代时,芳环被相应的部分不饱和的环取代。例如,被氧基取代的吡啶基是吡啶酮。仅当取代基和/或变量的组合产生稳定的化合物或有用的合成中间体时,这些组合才被允许。稳定的化合物或稳定的结构意味着化合物足够坚固,可以从反应混合物中分离出来,并且随后被配制成有效的治疗剂。
可以存在于“可选取代的”位置上的合适基团包括但不限于例如卤素、氰基、羟基、氨基、硝基、氧基、叠氮基、烷酰基(诸如C2-C6烷酰基,如酰基等(-(CO)烷基));甲酰胺基;烷基甲酰胺;烷基、烷氧基、烷基硫基(包括具有一个或多个硫醚键的那些)、烷基亚磺酰基(包括具有一个或多个亚磺酰基键的那些)、烷基磺酰基(包括具有一个或多个磺酰基键的那些)、单-和二-氨基烷基(包括具有一个或多个N原子的基团),所有上述可选的烷基取代基中的一个或多个亚甲基可以被氧或-NH-替代并且具有约1至约8个、约1至约6个或1至约4个碳原子,环烷基;苯基;苯基烷基,苄基是一个示例性的苯基烷基,苯基烷氧基,苄氧基是一个示例性的苯基烷氧基。烷基硫基和烷氧基分别通过硫或氧原子附接到它们取代的位置。
不在两个字母或符号之间的破折号(“-”)用来指示取代基的附接点。
“烷基”包括具有指定数目的碳原子的支链和直链饱和脂族烃基,通常为1至约8个碳原子。在本文中使用的术语C1-C6烷基指示具有1、2、3、4、5或6个碳原子的烷基。其它实施方案包括具有1至8个碳原子,1至4个碳原子或1或2个碳原子的烷基,例如C1-C8烷基、C1-C4烷基和C1-C2烷基。当在本文中C0-Cn烷基连同其它基团使用时,例如指示的基团-C0-C2烷基(苯基),在这种情况下,苯基通过单共价键直接连接(C0烷基)或通过具有指定数目碳原子的烷基链附接,在这种情况下为1、2、3或4个碳原子。烷基还可以通过其它基团诸如杂原子附接,如在-O-C0-C4烷基(C3-C7环烷基)中。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、3-甲基丁基、叔丁基、正戊基和仲戊基。
“烯基”是支链或直链脂族烃基,其具有可以沿具有指定数目碳原子的链上的任何稳定点处发生的一个或多个碳-碳双键。烯基的实例包括但不限于乙烯基和丙烯基。
“炔基”是指支链或直链脂族烃基,其具有可以沿具有指定数目碳原子的链的任何稳定点发生的一个或多个双碳-碳三链。
“烷氧基”是指如上定义的具有指定数目碳原子的烷基通过氧桥(-O-)共价地键合到其取代的基团。烷氧基的实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、2-丁氧基、叔丁氧基、正戊氧基、2-戊氧基、3-戊氧基、异戊氧基、新戊氧基、正己氧基、2-己氧基、3-己氧基和3-甲基戊氧基。类似地,“烷基硫基”或“硫代烷基”是指如上定义的具有指定数目碳原子的烷基通过硫桥(-S-)共价地键合到其取代的基团。类似地,“烯氧基”、“炔氧基”和“环烷氧基”是指烯基、炔基和环烷基在每种情况下通过氧桥(-O-)共价地键合到其取代的基团。
“烷酰基”是指如上定义的具有指定数目碳原子的烷基通过酮基(-C(O)-)共价地键合到其取代的基团。酮基的碳被包括在所述烷酰基中的碳原子的数目中,即C2烷酰基是-C(O))CH3。
“亚烷基”是一个或多个亚甲基的链,每个末端具有连接点,使得它可以连接另外两个基团,即亚烷基是-(CH2)n-。
“环烷基”是具有指定数目的碳原子通常为3至约7个碳原子的饱和烃环基团。环烷基的例子包括环丙基、环丁基、环戊基或环己基以及桥接(bridged)或笼式(caged)饱和环基团,例如降冰片烷或金刚烷。“-(C0-Cn烷基)环烷基”是通过单共价键(C0)或通过具有1至n个碳原子的亚烷基接头附接到其取代的位置的环烷基。
“卤代”或“卤素”是指氟代、氯代、溴代或碘代。
“杂芳基”是具有指定数目环原子的稳定单环芳族环,所述环原子中含有1至3个或在一些实施方案中为1至2个选自N、O和S的杂原子,其余环原子为碳;或为含有至少一个5至7元芳族环的稳定双环或三环***,该5至7元芳族环含有1至3个或在一些实施方案中为1至2个选自N、O和S的杂原子,其余环原子为碳。单环杂芳基通常具有5至7个环原子。在一些实施方案中,双环杂芳基是9至10元杂芳基,即含有9或10个环原子的基团,其中一个5-至7-元芳环与第二芳族或非芳族环稠合。当杂芳基中S和O原子的总数超过1时,这些杂原子彼此不相邻。优选杂芳基中S和O原子的总数不大于2。特别优选芳族杂环中S和O原子的总数不大于1。杂芳基包括但不限于恶唑基、哌嗪基、吡喃基、吡嗪基、吡唑并嘧啶基、吡唑基、吡啶嗪基(pyridizinyl)、吡啶基、嘧啶基、吡咯基、喹啉基、四唑基、噻唑基、噻吩基吡唑基、噻吩基、***基、苯并[d]恶唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并恶二唑基、二氢苯并二氧炔基(dihydrobenzodioxynyl)、呋喃基、咪唑基、吲哚基和异恶唑基。
“杂环”是具有指定数目环原子的饱和、不饱和或芳族环状基团,其含有1至约3个选自N、O和S的杂原子,其余的环原子为碳。杂环基的实例包括哌嗪基和噻唑基。
“杂环烷基”是具有指定数目环原子的饱和环状基团,其含有1至约3个选自N、O和S的杂原子,其余的环原子为碳。杂环烷基的实例包括四氢呋喃基和吡咯烷基。
“卤代烷基”是指具有指定数目碳原子的支链和直链烷基,其被1个或更多个卤素原子取代,通常最多达到最大允许数量的卤素原子。卤代烷基的实例包括但不限于三氟甲基、二氟甲基、2-氟乙基和五氟乙基。
“卤代烷氧基”是通过氧桥(醇基的氧)连接的如上所定义的卤代烷基。
“亚苯基”是具有两个不同附接点的苯环,以便可以连接两个其他基团,即亚苯基是-(C6H4)-。附接点可以彼此是邻位、间位或对位。
“药物组合物”是指包含至少一种活性剂(例如式I的化合物或盐)和至少一种其它物质(例如载体)的组合物。药物组合物达到了人或非人类药物的U.S.FDA GMP(良好生产规范)标准。
“载体(carrier)”是指施用活性化合物的稀释剂、赋形剂或运载体(vehicle)。“药学上可接受的载体”是指物质例如赋形剂、稀释剂或运载体,其可用于制备通常是安全的、无毒的且既不在生物学上也不在其它方面不合需要的药物组合物,并且包括兽医用途以及人类药物用途中可接受的载体。“药学上可接受的载体”包括一种和多于一种这样的载体。
“患者”是指需要医学治疗的人或非人动物。医学治疗可以包括治疗现有病症,如疾病或病症或诊断治疗。在一些实施方案中,患者是人类患者。
“提供”是指给予、给药、销售、分发、转让(为了利润或不是)、制造、混合或分配。
“治疗(treatment)”或“治疗了(treating)”是指以足以可测地降低任何癌症症状、减慢癌症进展或引起癌症消退的量向患者提供活性化合物。在某些实施方案中,可以在患者出现疾病症状之前开始治疗癌症。
药物组合物的“治疗有效量”是指当向患者给药时,有效于提供治疗益处例如改善症状、降低癌症进展或引起癌症消退的量。
显著变化是任何可检测的变化,其在统计学显著性的标准参数检验如Student'sT检验中具有统计学显著性,其中p<0.05。
化学描述
式I的化合物可以含有一个或多个不对称元素,例如立体中心、立体轴等,例如不对称碳原子,使得化合物可以以不同的立体异构形式存在。这些化合物可以是例如外消旋体或光学活性形式。对于具有两个或更多个不对称元素的化合物,这些化合物可以附加地是非对映异构体的混合物。对于具有不对称中心的化合物,涵盖了纯形式的所有光学异构体及其混合物。在这些情况下,单一的对映异构体(即光学活性形式)可以通过不对称合成、从光学纯的前体合成或通过拆分外消旋体来获得。外消旋体的拆分也可以例如通过常规方法(如在拆分剂存在下结晶)或通过使用例如手性HPLC柱的色谱法来完成。无论用于获得它们的方法如何,本文考虑了所有形式。
可以单独地采用或组合采用活性剂的所有形式(例如溶剂化物、光学异构体、对映体形式、多晶型物、游离化合物和盐)。
术语“手性”是指具有镜像配偶体(mirror image partner)的无重叠能力(non-superimposability)的性质的分子。
“立体异构体”是具有相同化学构成的化合物,但在原子或基团的空间排列方面不同。
“非对映异构体”是具有两个或多个手性中心的立体异构体,并且其分子不是彼此的镜像。非对映异构体具有不同的物理性质,例如熔点、沸点、光谱性质和反应性。非对映异构体的混合物可以在高分辨率分析程序(例如电泳、在拆分剂存在下的结晶、或使用例如手性HPLC柱的色谱法)下分离。
“对映异构体”是指化合物的两种立体异构体,它们是彼此不重叠的镜像。对映异构体的50:50混合物称为外消旋混合物或外消旋体,其在化学反应或过程中没有立体选择性或立体特异性的情况下可能出现。
本文使用的立体化学定义和惯例大体遵循S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;和Eliel,E.and Wilen,S.,Stereochemistry of Organic Compounds(1994)John Wiley&Sons,Inc.,New York。许多有机化合物以光学活性形式存在,即它们具有旋转平面偏振光的平面的能力。在描述光学活性化合物时,前缀D和L或R和S用于表示分子绕其手性中心的绝对构型。前缀d和l或(+)和(-)用于指示化合物对平面偏振光的旋转的符号,(-)和l是指该化合物是左旋的。具有(+)或d前缀的化合物是右旋的。
“外消旋混合物”或“外消旋体”是两种对映体物质的等摩尔(或50:50)混合物,其没有光学活性。外消旋混合物在化学反应或过程中没有立体选择性或立体特异性的情况下可能出现。
“药学上可接受的盐”包括所公开的化合物的衍生物,其中母体化合物通过制备该母体化合物的无机和有机、无毒的酸或碱加成盐而被改性。本发明化合物的盐,可以通过常规化学方法,由含有碱性或酸性部分的母体化合物合成。通常,这些盐可以通过使游离酸形式的这些化合物与化学计量量的适当碱(例如Na、Ca、Mg或K氢氧化物、碳酸盐、碳酸氢盐等)反应来制备,或者通过使游离碱形式的这些化合物与化学计量量的适当酸反应来制备。这种反应通常在水中或在有机溶剂或在两者的混合物中进行。通常,在可行的情况下,使用非水介质如醚、乙酸乙酯、乙醇、异丙醇或乙腈。本发明化合物的盐还包括所述化合物的溶剂化物和所述化合物的盐的溶剂化物。
药学上可接受的盐的实例包括但不限于,碱性残基如胺的矿物酸或有机酸盐;酸性残基如羧酸的碱或有机盐;等等。药学上可接受的盐包括例如由无毒的无机或有机酸形成的母体化合物的常规无毒盐和季铵盐。例如,常规的无毒酸盐包括衍生自无机酸如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的那些盐;以及由诸如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸(pamoic)、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、甲磺酸、乙磺酸(esylic)、苯磺酸(besylic)、对氨基苯磺酸(sulfanilic)、2-乙酰氧基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、羟乙磺酸(isethionic)、HOOC-(CH2)n-COOH(其中n为0-4)等有机酸制备的盐。额外的适合的盐的列举可以例如在G.Steffen Paulekuhn,et al.,Journal of Medicinal Chemistry 2007,50,6665和Handbook of Pharmaceutically Acceptable Salts:Properties,Selection andUse,P.Heinrich Stahl and Camille G.Wermuth,Editors,Wiley-VCH,2002中找到。
TDP2抑制剂
本文公开了抑制TDP2的分子。
除了在发明内容章节中示出的式I的化合物之外,本公开还包括其中变量例如A、B、X1、X2、W、Y、Z、R1至R10携带以下定义的化合物。本公开包括这些定义的所有组合,只要能够得到稳定的化合物结果即可。本公开包括以下特定的式(I)的实施方案。
本公开包括式IA和IB的化合物及其盐。
R1是羟基、C1-C8烷氧基或–O-(C0-C6烷基)环烷基,其中R1的烷氧基或烷基部分中的一个或多个亚甲基单元可选地且独立地被-O-或-N(R7)-替代,并且R1在每次出现时被0-3个独立地从羟基、卤素、氰基、-CO2H、-(CO)-O-C1-C6烷基和-W-P(O)YR9ZR10中选择的取代基取代;或者R1是-O-A-B。
B是苯基或具有1、2或3个氮环原子的5或6元杂芳基,其中B可选地被0-3个独立地从卤素、羟基、氰基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C2-C6烷酰基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、-(C0-C6烷基)环烷基、-(C0-C6烷基)CO2H,-(C0-C6烷基)-(CO)-O-C1-C6烷基、-(C1-C6烷基)烷氧基、-(C1-C6烷基)OH,-SO2-C1-C6烷基和-(C0-C6烷基)-W-P(O)YR9ZR10中选择的取代基取代。
R2是卤素、C1-C6烷基、C1-C6卤代烷基、或-(C0-C6烷基)环烷基、或苯基,所述苯基在每次出现时被0至3个独立的从卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基中选择的基团取代。
(B)R3和R4均为氢。
(C)R2是C1-C6烷基、C1-C6卤代烷基、-(C0-C6烷基)环烷基、或苯基,所述苯基在每次出现时被0至3个独立地从卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基中选择的基团取代。(D)R1被至少一个-W-P(O)YR9ZR10取代基取代;并且
W是键,并且Y和Z均为O。
(E)R2是甲基或苯基。
(F)X1是N且X2是CH。
(G)X1是CH且X2是N。
(H)R1是C1-C8烷氧基。
R1是苯氧基或吡啶氧基,它们的每一个可选地被0-3个独立地从卤素、羟基、氰基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、-(C0-C6烷基)环烷基、-(C0-C6烷基)CO2H、-(C0-C6烷基)-(CO)-O-C1-C6烷基、-(C1-C6烷基)烷氧基、-(C1-C6烷基)OH、-SO2-C1-C6烷基和-(C0-C6烷基)-W-P(O)YR9ZR10中选择的取代基取代。
(I)R1是烷氧基,其中R1的烷基部分中的一个或多个亚甲基单元可选地被-O-或-N(R7)-替代,并且R1被1至3个独立地选自羟基和-WP(O)YR9ZR10的取代基取代;其中W是键;并且Y和Z均为O。
(J)R1是-O-A-B。
(K)R1是-O-A-B;
A是键或1至3个碳原子的亚烷基链;并且
B是苯基或吡啶基,其可选地被0-3个独立地从卤素、羟基、氰基、C1-C4烷基、C1-C4烷氧基、C2-C4烷酰基、C1-C2卤代烷基、C1-C2卤代烷氧基、-(C0-C2烷基)-(CO)-O-C1-C6烷基、-(C0-C2烷基)C(O)NR7R8、-(C0-C2烷基)NR7C(O)R8、-(C1-C6烷基)OH和-SO2-C1-C2烷基中选择的取代基取代。
(L)R1是-O-A-B;
A是键;并且
B是苯基,其被一个选自羟基、卤素和氰基的取代基取代。
(M)R1是-O-A-B;并且
B是***基、吡唑基、咪唑基、噻吩基、二氧杂环戊基(dioxylanyl)、吗啉基、哌嗪基或哌啶基;所述B的每一个被0-3个独立地从卤素、羟基、氰基、氨基、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C2-C6烷酰基、C1-C2卤代烷基、C1-C2卤代烷氧基、-(C0-C6烷基)CO2H、-(C0-C6烷基)-(CO)-O-C1-C6烷基、-(C0-C6烷基)C(O)NR7R8、-(C0-C6烷基)NR7C(O)R8、-(C1-C6烷基)OH、-(C0-C6烷基)NR7R8和-SO2-C1-C6烷基中选择的取代基取代;其中R7和R8是氢或C1-C4烷基。
(N)R2是氢、卤素、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基、C1-C6卤代烷氧基、-(C0-C6烷基)环烷基、-(C0-C6烷基)NR7R8或苯基,除了氢和卤素之外的每个R2在每次出现时被0至3个独立地从卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基中选择的基团取代。
(O)R2是
其中n是1、2、3或4;
J1是O、NH、NR11;
Q1是C1-C6烷基或C1-C6烷基氨基-;
R12不存在或是1或更多个独立地选自羟基、卤素、氨基或氰基的取代基;并且
R13不存在或是1或2个独立地选自C1-C4烷基和单-或二-C1-C6烷基氨基的取代基。
本公开包括一种实施方案,其是包含式I的化合物或盐以及药学上可接受的载体的药物组合物。
药物制剂
本文公开的化合物可以作为纯化学品给药,但优选作为药物组合物给药。因此,本公开提供药物组合物,其包含Tdp1抑制剂的化合物或药学上可接受的盐(诸如式I的化合物)以及至少一种药学上可接受的载体。所述药物组合物/组合可以含有式I的化合物或盐作为唯一的活性剂,但优选含有至少一种附加的活性剂。在某些实施方案中,优选的是,所述附加的活性剂是选自喜树碱、伊立替康和拓扑替康的化合物或其盐。在某些实施方案中,所述附加活性剂是依托泊苷、替尼泊苷、多柔比星、柔红霉素、米托蒽醌、安吖啶、玫瑰树碱、金精三羧酸和3-羟基-2-[(1R)-6-异丙烯基-3-甲基-环己-2-烯-1-基]-5-戊基-1,4-苯醌(HU-331)。在某些实施方案中,所述药物组合物是在单位剂型中含有约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg或约200mg至约600mg的式I的化合物以及可选的约0.1mg至约2000mg、约10mg至约1000mg、约100mg至约800mg或约200mg至约600mg的附加活性剂的剂量形式。所述药物组合物还可以包括一定摩尔比的Tdp1抑制剂的化合物(诸如式I的化合物)和附加活性剂。例如,所述药物组合物可以含有式I的TDP2抑制剂与附加活性剂的摩尔比为约0.5:1、约1:1、约2:1、约3:1或约1.5:1至约4:1。
本文公开的化合物可以在含有常规药学上可接受的载体的剂量单位配方中,通过口服、局部、胃肠外、通过吸入或喷雾、舌下、经皮、经颊给药、直肠、作为眼用溶液或其他方式来给药。药物组合物可以配制成任何药学上可用的形式,例如作为气溶胶、霜剂、凝胶、丸剂、胶囊、片剂、糖浆、透皮贴剂或眼用溶液。一些剂型,例如片剂和胶囊,被细分成适当尺寸的含有适量的活性组分的单位剂量,例如达到所需目的的有效量。
载体包括赋形剂和稀释剂,并且必须具有足够高的纯度和足够低的毒性,使其适合于给药到被治疗的患者中。载体可以是惰性的,或者它可以具有其自身的药物益处。与化合物一起使用的载体的量,足以提供用于每单位剂量的化合物给药的实际量的材料。
载体类别包括但不限于粘合剂、缓冲剂、着色剂、稀释剂、崩解剂、乳化剂、调味剂、助流剂、润滑剂、防腐剂、稳定剂、表面活性剂、压片剂和润湿剂。一些载体可以列示在多于一个类别中,例如植物油在一些配方中可以用作润滑剂,而在其它配方中可以用作稀释剂。示例性的药学上可接受的载体包括糖、淀粉、纤维素、粉状黄蓍胶、麦芽、明胶;滑石粉和植物油。可选的活性剂可以包含在药物组合物中,其基本上不干扰本发明化合物的活性。
所述药物组合物/组合可以被配制为用于口服给药。这些组合物可以含有0.1至99重量%(wt.%)的式I的化合物,并且通常至少约5wt.%的式I的化合物。一些实施方案含有约25wt.%至约50wt.%或约5wt.%至约75wt.%的式I的化合物。
治疗方法
式I的化合物或其盐以及包含所述化合物的药物组合物可用于治疗癌症,包括在体内引起肿瘤消退。治疗癌症或引起肿瘤消退的方法包括,向需要这种治疗的患者提供治疗有效量的式I化合物。在一个实施方案中,患者是哺乳动物,更具体地是人。本公开还提供了治疗非人类患者例如伴侣动物(例如,猫、狗和家畜)的方法。药物组合物的治疗有效量可以是足以抑制癌症或癌性肿瘤进展的量;或导致癌症或癌性肿瘤的消退的量。
治疗有效量的本文所述的化合物或药物组合物当给药到患者中时还将提供充足浓度的式I的化合物。充足浓度是患者体内为预防或抵抗病症所必要的化合物的浓度。这样的量可以通过实验来确定,例如通过测定化合物的血液浓度,或理论上通过计算生物利用度来确定。
治疗方法包括提供一定剂量量的式I的化合物给患者。每一千克体重每天约0.1mg至约140mg的每种化合物的剂量水平,可用于治疗上述病症(每个患者每天约0.5mg至约7g)。可以与载体材料组合以产生单一剂型的化合物的量将取决于所治疗的患者和特定给药方式而变化。剂量单位形式通常含有约1mg至约500mg的每种活性化合物。在某些实施方案中,每天向患者提供25mg至500mg或25mg至200mg的式I的化合物。剂量的频率也可以根据所使用的化合物和所治疗的特定疾病而变化。然而,为了治疗大多数疾病和病症,可以使用每日4次或更少的剂量方案,并且在某些实施方案中,使用每日1或2次的剂量方案。
式I化合物可用于治疗癌症并引起肿瘤消退,包括癌性肿瘤。在某些实施方案中,患者患有细胞增生性病症或疾病。细胞增生性病症可以是癌症、肿瘤(癌性或良性)、肿瘤(neoplasm)、新生血管形成或黑素瘤。用于治疗的癌症包括固体癌和散播性癌症。可以通过本文提供的方法治疗的示例性固体癌(肿瘤)包括例如肺癌,、***癌、乳腺癌、肝癌、结肠癌、乳腺癌、肾癌、胰腺癌、脑癌、皮肤癌包括恶性黑素瘤和Kaposi肉瘤、睾丸或卵巢癌、癌、肉瘤和肾癌(肾细胞)。可用式I化合物治疗的癌症也包括膀胱癌、乳腺癌、结肠癌、子宫内膜癌、肺癌、支气管癌、黑素瘤、非霍奇金淋巴瘤、血液癌、胰腺癌、***癌、甲状腺癌、脑或脊髓癌以及白血病。示例性散播性癌症包括白血病或淋巴瘤,包括霍奇金病、多发性骨髓瘤和套细胞淋巴瘤(mantle cell lymphoma)(MCL)、慢性淋巴细胞性白血病(CLL)、T细胞白血病、多发性骨髓瘤和伯基特氏淋巴瘤。本文特别包括通过向患者提供式I化合物来治疗癌症的方法,其中所述癌症是实体瘤或散播性癌症。
进一步包括的是通过向患者提供式I的化合物以治疗癌症的方法,其中所述癌症选自胶质瘤(glioma)(成胶质细胞瘤(glioblastoma,恶性胶质瘤))、急性髓性白血病、急性骨髓性白血病、骨髓增生异常/骨髓增生性肿瘤、肉瘤、慢性骨髓单核细胞性白血病、非霍奇金淋巴瘤、星形细胞瘤、黑素瘤、非小细胞肺癌、小细胞肺癌、子***、直肠癌、卵巢癌、胆管癌(cholangiocarcinomas)、软骨肉瘤或结肠癌。
然而,应当理解的是,用于任何特定患者的具体剂量水平将取决于多种因素,包括使用的具体化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、给药途径和***速率、药物组合以及接受治疗的特定疾病的严重程度。
式I的化合物可以单独给药(即,方案的唯一治疗剂)来治疗或预防疾病和病症,例如不期望的细胞增生、癌症和/或肿瘤生长,或者可以与另一种活性剂组合给药。一种或多种式I化合物可以与一种或多种其他化学治疗剂的方案协调给药,例如抗肿瘤药物,例如烷基化剂(例如氮芥、苯丁酸氮芥、环磷酰胺、苯丙氨酸氮芥或异环磷酰胺),抗代谢药如叶酸拮抗剂(例如氨甲喋呤),嘌呤拮抗剂(例如6-巯基嘌呤)或嘧啶拮抗剂(例如5-氟尿嘧啶)。可以与一种或多种式I化合物配合使用的化学治疗剂的其它非限制性例子包括紫杉烷和拓扑异构酶抑制剂。此外,活性治疗剂的其它非限制性实例包括生物制剂,例如单克隆抗体或IgG嵌合分子,它们通过特异性结合与癌症相关的信号转导途径中的受体或配体来实现其治疗效果(例如针对CD20的治疗性抗体(例如利妥昔单抗)或针对VEGF的治疗性抗体(例如贝伐单抗))。
本文提供的治疗方法也可用于治疗除人之外的哺乳动物,包括用于兽医应用,例如治疗马和家畜例如公牛、绵羊、奶牛、山羊、猪等,以及宠物(伴侣动物)如狗和猫。
对于诊断或研究应用,各种各样的哺乳动物将是合适的受试者,包括啮齿动物(例如小鼠、大鼠、仓鼠)、兔、灵长类动物和猪诸如近交系猪等。此外,对于诸如体外诊断和研究应用的体外应用,上述受试者的体液(例如血液、血浆、血清、细胞间质液、唾液、粪便和尿液)和细胞以及组织样品将适于使用。
在一个实施方案中,本发明提供了一种在被鉴定为需要这种治疗的患者中治疗癌症病症的方法,该方法包括向患者提供有效量的式I化合物。本文提供的式I的化合物或盐可以单独给药,或者可以与一种或多种其它活性剂组合给药。
在一个实施方案中,治疗癌症的方法可以附加地包含确定对Tdp2抑制响应的癌症。
在一个实施方案中,治疗癌症的方法可以附加地包含向需要此种治疗的患者给药式I的化合物与一种或多种额外的化合物,其中所述额外的化合物的至少一种是已知为拓扑异构酶2的抑制剂的活性剂。
在一个实施方案中,治疗癌症的方法可以附加地包含向需要此种治疗的患者给药治疗有效量的式I的化合物或盐与一种或多种额外的化合物,其中至少一种额外地化合物是选自依托泊苷、替尼泊苷、多柔比星、柔红霉素、米托蒽醌、安吖啶、玫瑰树碱、金精三羧酸和3-羟基-2-[(1R)-6-异丙烯基-3-甲基-环己-2-烯-1-基]-5-戊基-1,4-苯醌(HU-331)中的活性剂。
在其它实施方案中,所述癌症是可以使用Top2抑制剂治疗的癌症,其中TDP2抑制剂作为与Top2的抑制剂(例如依托泊苷和多柔比星)的联合治疗,可以提供协同效应。
实施例
缩写
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
DMSO 二甲基亚砜
DTT 二硫苏糖醇
EDTA 乙二胺四乙酸
ESI 电喷雾离子化
HPLC 高效液相色谱
HRMS 高分辨率质谱
NMR 核磁共振
THF 四氢呋喃
WCE 全细胞提取物
一般方法
使用的试剂和溶剂是商业无水级的。如果没有提及,它们未经进一步纯化即使用。柱色谱在硅胶(200-300目)上进行。1H NMR光谱是在Bruker AVANCE III400 MHz光谱仪上使用四甲基硅烷作为内部参照来记录的。质谱是在Agilent 6120(四极LCMS)质谱仪上分析的。高分辨率质谱是在SHIMADZU LCMS-IT-TOF质谱仪上分析的。HPLC分析方法采用SHIMADZU LC-20AB具有SPD-M20A检测器的液相色谱***。分析方法条件包括PhenomenexC18柱(4.6x250mm,5.0um)并且在1mL/min流速下使用在pH 3.0NaH2PO4缓冲水溶液中的25%甲醇至75%甲醇的线性递度进行洗脱。使用在220nm下的UV峰面积确定纯度。HPLC方法A使用具有0.1%TFA的H2O缓冲液,方法B使用pH 6的磷酸盐缓冲盐水缓冲液,方法C使用pH 3的磷酸盐缓冲盐水缓冲液。
实施例
以下方案提供了用于制备式I化合物的一般方法,
实施例1.化合物1和2的合成
向MeCN(30ml)中6,7-二氯喹啉-5,8-二酮(0.46g,2mmol)的黄色溶液中,加入乙酰乙酸乙酯(0.26ml,2.2mmol)和K2CO3(1.10g,8mmol)。将所得溶液搅拌并回流6小时。反应完成后,将反应溶液冷却至室温,减压浓缩。通过硅胶柱色谱纯化目标产物。
2-甲基-4,9-二氧代-4,9-二氢呋喃并[3,2-g]喹啉-3-羧酸乙酯(1),黄色固体。1HNMR(400MHz,CDCl3)δ9.04(d,J=4.8Hz,1H),8.54(d,J=8.0Hz,1H),7.67(dd,J=7.6,4.7Hz,1H),4.46(q,J=7.1Hz,2H),2.76(s,3H),1.46(t,J=6.7Hz,3H).HRMS(ESI)m/z:284.0574计算为C15H10NO5284.0564.
2-甲基-4,9-二氧代-4,9-二氢呋喃并[2,3-g]喹啉-3-羧酸乙酯(2),黄色固体。1HNMR(400MHz,CDCl3)δ9.06(d,J=4.0Hz,1H),8.54(d,J=7.6Hz,1H),7.70(dd,J=7.6,4.7Hz,1H),4.44(q,J=6.7Hz,2H),2.76(s,3H),1.48(t,J=7.2Hz,3H).HRMS(ESI)m/z:284.0551计算为C15H10NO5 284.0564.
实施例2.化合物8和9的合成
根据制备1,使用乙酰丙酮作为原料得到目标产品8和9。
3-乙酰基-2-甲基呋喃并[3,2-g]喹啉-4,9-二酮(8),黄色固体。1H NMR(400MHz,CDCl3)δ9.07(dd,J=4.7,1.7Hz,1H),8.54(dd,J=7.9,1.7Hz,1H),7.73(dd,J=7.9,4.7Hz,1H),2.79(s,3H),2.70(s,3H).HRMS(ESI)m/z:256.0593[M+H]+,已计算为C14H10NO4256.0604.
3-乙酰基-2-甲基呋喃并[2,3-g]喹啉-4,9-二酮(9),黄色固体。1H NMR(400MHz,CDCl3)δ9.07(d,J=4.5Hz,1H),8.55(dd,J=7.8,1.2Hz,1H),7.73(dd,J=7.8,4.7Hz,1H),2.81(s,3H),2.70(s,3H)。HRMS(ESI)m/z:256.0613[M+H]+,计算为C14H10NO4 256.0604.
实施例3.化合物3的合成
根据制备1,使用2,3-二氯萘-1,4-二酮作为原料,得到目标产物3(2-甲基-4,9-二氧代-4,9-二氢萘并[2,3-b]呋喃-3-羧酸乙酯),黄色固体。1H NMR(400MHz,CDCl3)δ8.23-8.16(m,2H),7.76-7.74(m,2H),4.45(q,J=7.1Hz,1H),2.72(s,3H),1.45(t,J=7.1Hz,3H).HRMS(ESI)m/z:307.0590[M+Na]+,计算为C16H12O5Na 307.0577.
实施例4.化合物29和30的合成
根据制备1,使用3-氧代-3-苯基丙酸乙酯作为原料,得到目标产物29和30。
4,9-二氧代-2-苯基-4,9-二氢呋喃并[3,2-g]喹啉-3-羧酸乙酯(29),黄色固体。1H NMR(400MHz,CDCl3)δ9.08(dd,J=4.6,1.6Hz,1H),8.53(dd,J=7.9,1.6Hz,1H),8.21-7.84(m,2H),7.72(dd,J=7.9,4.7Hz,1H),7.60-7.42(m,3H),4.51(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H).HRMS(ESI)m/z:348.0865[M+H]+,计算为C20H14NO5 348.0866.
4,9-二氧代-2-苯基-4,9-二氢呋喃并[2,3-g]喹啉-3-羧酸乙酯(30),黄色固体。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.7,1.7Hz,1H),8.58(dd,J=7.9,1.7Hz,1H),8.00-7.95(m,2H),7.72(dd,J=7.9,4.7Hz,1H),7.52-7.49(m,3H),4.53(q,J=7.1Hz,2H),1.46(t,J=7.1Hz,3H).HRMS(ESI)m/z:348.0887[M+H]+,计算为C20H14NO5 348.0866.
实施例5.制备2:化合物7的合成
向MeOH或异丙醇(300ml)中2(1.10g,4mmol)的溶液中,加入K2CO3的水溶液(15%,30ml)。将反应溶液回流12小时。过滤出沉淀并溶解在水(500ml)中。使用盐酸(2N)将水溶液酸化至pH 3,并且使用DCM萃取(100ml x 3)。使用无水MgSO4干燥有机溶液并减压浓缩。将所得固体在MeOH中重结晶,得到目标化合物黄色固体7。
2-甲基-4,9-二氧代-4,9-二氢呋喃并[2,3-g]喹啉-3-羧酸(7)。1H NMR(400MHz,CDCl3)δ9.12(dd,J=4.7,1.7Hz,1H),8.59(dd,J=7.9,1.7Hz,1H),7.82(dd,J=7.9,4.7Hz,1H),2.93(s,3H).
实施例6.制备3:化合物10的合成
在室温下,向在新蒸馏氯仿(20ml)中化合物7(65mg,0.25mmol)和三乙胺(0.07ml,0.5mmol)的红色溶液中,逐滴加入亚硫酰二氯(thionyl chloride)(1.25ml)。将混合物搅拌并回流5小时。然后将反应溶液冷却至室温。在减压下蒸发溶剂。将残余物减压收集(contain)一段时间以除去大部分残留的亚硫酰二氯,得到橙色固体残余物。将得到的残余物溶解于新蒸馏氯仿(10ml)中,并且将其逐滴加入到在新蒸馏氯仿(30ml)中4-(二甲基氨基)吡啶(35mg,0.3mmol)和乙二醇(0.3mmol)的溶液中。将反应混合物回流3小时,并冷却至室温。在减压下蒸发溶剂。通过硅胶柱色谱法纯化目标产物。
2-羟基乙基-2-甲基-4,9-二氧代-4,9-二氢呋喃并[2,3-g]喹啉-3-羧酸酯(10),黄色固体。1H NMR(400MHz,CDCl3)δ9.08(d,J=3.2Hz,1H),8.56(d,J=7.6Hz,1H),7.73(dd,J=7.4,4.4Hz,1H),4.49(t,J=4.4Hz,2H),4.00(t,J=4,4Hz,2H),2.80(s,3H).HRMS(ESI)m/z:300.0499[M-H]-,计算为C15H10NO6 300.0514.
实施例7.化合物11的合成
根据制备3,使用丙二醇作为原料,得到目标黄色固体11。1H NMR(400MHz,CDCl3)δ9.06(d,J=3.3Hz,1H),8.54(d,J=7.0Hz,1H),7.71(dd,J=7.6,4.7Hz,1H),4.55(t,J=5.9Hz,2H),3.91(t,J=5.9Hz,2H),2.77(s,3H),2.09(五重峰,J=5.8Hz,2H).HRMS(ESI)m/z:314.0653[M-H]-,计算为C16H12NO6 314.0670.
实施例8.化合物12的合成
根据制备3,使用间二羟基苯作为原料,得到目标黄色固体12。1H NMR(400MHz,DMSO)δ9.81(s,1H),9.03(d,J=3.1Hz,1H),8.49(d,J=7.2Hz,1H),7.87(dd,J=6.6,4.9Hz,1H),7.31-7.26(m,1H),6.88-6.68(m,3H),2.76(s,3H).HRMS(ESI)m/z:348.0499[M-H]-,计算为C19 H10NO6348.0514.
实施例9.化合物13的合成
根据制备3,使用邻二羟基苯作为原料,得到目标黄色固体13。1H NMR(400MHz,DMSO)δ9.81(s,1H),9.03(d,J=3.9Hz,1H),8.49(d,J=7.7Hz,1H),7.87(dd,J=7.6,4.7Hz,1H),7.23(d,J=7.8Hz,1H),7.16(t,J=7.6Hz,1H),7.00(d,J=7.9Hz,1H),6.90(t,J=7.5Hz,1H),2.80(s,3H).HRMS(ESI)m/z:C19 H10NO6 348.0514[M-H]-,计算为348.0512.
实施例10.化合物14的合成
根据制备3,使用苯酚作为原料,得到目标黄色固体14。1H NMR(400MHz,DMSO)δ9.03(dd,J=4.7,1.7Hz,1H),8.49(dd,J=7.9,1.7Hz,1H),7.87(dd,J=7.9,4.7Hz,1H),7.62-7.46(m,2H),7.44-7.29(m,3H),2.78(s,3H).HRMS(ESI)m/z:332.0563[M-H]-,计算为C19H10NO5 332.0564.
实施例11.化合物15的合成
根据制备3,使用苯酚作为原料,得到目标黄色固体15。1H NMR(400MHz,CDCl3)δ9.08(dd,J=4.7,1.7Hz,1H),8.55(dd,J=7.9,1.7Hz,1H),7.73(dd,J=7.9,4.7Hz,1H),4.47(d,J=5.2Hz,2H),4.19-4.17(m,1H),3.83-3.74(m,2H),2.80(s,3H).HRMS(ESI)m/z:330.0604[M-H]-,计算为C16H12NO7 330.0619.
实施例12.化合物16的合成
根据制备3,使用苯胺作为原料,得到目标黄色固体16。1H NMR(400MHz,DMSO)δ11.10(s,1H),9.06(d,J=3.2Hz,1H),8.51(dd,J=7.8,1.5Hz,1H),7.91(dd,J=7.7,4.7Hz,1H),7.77-7.75(m,2H),7.44-7.40(m,2H),7.18-7.14(m,1H),2.78(s,3H).HRMS(ESI)m/z:331.0723[M-H]-,计算为C19H11N2O4 331.0724.
实施例13.化合物17的合成
根据制备3,使用间氯苯胺作为原料,得到目标黄色固体17。1H NMR(400MHz,DMSO)δ11.19(s,1H),9.07(d,J=3.2Hz,1H),8.51(dd,J=7.8,1.5Hz,1H),7.96(s,1H),7.92(dd,J=7.7,4.7Hz,1H),7.59(d,J=8.2Hz,1H),7.45(t,J=8.1Hz,1H),7.23(d,J=7.8Hz,1H),2.76(s,3H).HRMS(ESI)m/z:367.0501[M+H]+,计算为C19H12N2O4Cl 367.0480.
实施例14.化合物18的合成
根据制备3,使用邻氨基苯酚作为原料,得到目标黄色固体18。1H NMR(400MHz,DMSO)δ11.11(s,1H),10.02(s,1H),9.05(d,J=3.3Hz,1H),8.49(d,J=6.7Hz,1H),8.18(d,J=7.8Hz,1H),7.90(dd,J=7.7,4.7Hz,1H),7.01-6.93(m,2H),6.82(t,J=7.3Hz,1H),2.83(s,3H).HRMS(ESI)m/z:347.0656[M-H]-,计算为C19H11N2O5 347.0673.
实施例15.化合物19的合成
根据制备3,使用对甲氧基苯胺作为原料,得到目标红色固体19。1H NMR(400MHz,DMSO)δ11.00(s,1H),9.07(d,J=3.3Hz,1H),8.50(dd,J=7.8,1.6Hz,1H),7.91(dd,J=7.7,4.7Hz,1H),7.67(d,J=9.0Hz,2H),6.99(d,J=9.0Hz,2H),3.77(s,3H),2.77(s,3H).HRMS(ESI)m/z:361.0817[M-H]-,计算为C20H13N2O5 361.0830.
实施例16.化合物20的合成
根据制备3,使用乙胺为原料,得到目标黄色固体20。1H NMR(400MHz,CDCl3)δ9.52(s,1H),9.08(d,J=3.3Hz,1H),8.56(d,J=7.4Hz,1H),7.76(dd,J=7.7,4.7Hz,1H),3.50(q,J=6.5Hz,2H),2.93(s,3H),1.34(t,J=7.2Hz,3H).HRMS(ESI)m/z:307.0699[M+Na]+,计算为C15H12N2O4Na307.0689.
实施例17.化合物22的合成
根据制备3,使用2-羟基乙基膦酸二甲酯作为原料,得到目标黄色固体22。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.6,1.6Hz,1H),8.54(dd,J=7.9,1.6Hz,1H),7.71(dd,J=7.9,4.7Hz,1H),4.64-4.58(m,2H),3.80(s,3H),3.77(s,3H),2.77(s,3H),2.54–2.39(m,2H).HRMS(ESI)m/z:392.0538[M-H]-,计算为C17H15NO8P 392.0541.
实施例18.化合物23的合成
根据制备3,使用以间氯酚为原料,得到目标黄色固体23。1H NMR(400MHz,CDCl3)δ9.07(dd,J=4.6,1.6Hz,1H),8.56(dd,J=7.9,1.6Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),7.52(s,1H),7.39-7.35(m,2H),7.30-7.26(m,1H),2.83(s,1H).HRMS(ESI)m/z:368.0341[M+H]+,计算为C19H11NO5Cl 368.0320.
实施例19.化合物24的合成
根据制备3,使用邻氯酚为原料,得到目标黄色固体24。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.6,1.6Hz,1H),8.56(dd,J=7.9,1.7Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),7.53-7.49(m,2H),7.38(td,J=7.8,1.5Hz,1H),7.29-7.25(m,1H),2.85(s,3H).HRMS(ESI)m/z:368.0335[M+H]+,计算为C19H10NO5Cl 368.0320.
实施例20.化合物25的合成
根据制备3,使用2-萘酚作为原料,得到目标黄色固体25。1H NMR(400MHz,CDCl3)δ9.07(d,J=4.6Hz,1H),8.56(d,J=7.8Hz,1H),7.94-9.86(m,4H),7.72(dd,J=7.9,4.6Hz,1H),7.60(dd,J=8.8,2.2Hz,1H),7.55-7.41(m,2H),2.86(s,3H).HRMS(ESI)m/z:382.0706[M-H]-,计算为C23H12NO5 382.0721.
实施例21.化合物26的合成
根据制备3,使用3-羟基苄腈作为材料,得到目标黄色固体26。1H NMR(400MHz,CDCl3)δ9.08(dd,J=4.7,1.7Hz,1H),8.57(dd,J=7.9,1.7Hz,1H),7.82(s,1H),7.79-7.75(m,1H),7.74(dd,J=7.9,4.7Hz,1H),7.66-7.48(m,2H),2.84(s,3H).HRMS(ESI)m/z:359.0679[M+H]+,计算为C20H11N2O5 359.0662.
实施例22.化合物27的合成
根据制备3,使用对氯苯酚作为材料,得到目标黄色固体27。1H NMR(400MHz,CDCl3)δ9.07(dd,J=4.6,1.6Hz,1H),8.56(dd,J=7.9,1.6Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),7.41(br,s,4H),2.82(s,3H).HRMS(ESI)m/z:368.0334[M+H]+,计算为C19H11NO5Cl368.0320.
实施例23.化合物28的合成
根据制备3,使用3-羟基吡啶作为原料,得到目标黄色固体28。1H NMR(400MHz,CDCl3)δ9.08(dd,J=4.7,1.7Hz,1H),8.77(d,J=2.5Hz,1H),8.58-8.55(m,2H),7.87(ddd,J=8.3,2.7,1.4Hz,1H),7.73(dd,J=7.9,4.7Hz,1H),7.43(dd,J=8.3,4.8Hz,1H),2.85(s,3H).HRMS(ESI)m/z:335.0673[M+H]+,计算为C18H11N2O5 335.0662.
实施例24.化合物31的合成
根据制备3,使用4-溴苯酚作为原料,得到目标黄色固体31。1H NMR(400MHz,CDCl3)δ9.07(dd,J=4.7,1.7Hz,1H),8.56(dd,J=7.9,1.7Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),7.56(d,J=8.8Hz,2H),7.36(d,J=8.8Hz,2H),2.82(s,3H).HRMS(ESI)m/z:411.9820和413.9865[M+H]+,计算为C19H11NO5 Br 411.9815和413.9797.
实施例25.化合物32的合成
根据制备例3,使用3-乙炔基苯酚作为原料,得到目标黄色固体32。1H NMR(400MHz,CDCl3)δ9.07(dd,J=4.6,1.5Hz,1H),8.56(dd,J=7.9,1.7Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),7.60(s,1H),7.50-7.34(m,3H),3.12(s,1H),2.83(s,3H).HRMS(ESI)m/z:380.0543[M+Na]+,计算为C21H11NO5Na 380.0529.
实施例26.化合物35的合成
根据制备例3,使用丁烷-1,4-二醇作为原料,得到目标黄色固体35。1H NMR(400MHz,CDCl3)δ9.06(d,J=3.5Hz,1H),8.54(dd,J=7.8,1.1Hz,1H),7.71(dd,J=7.8,4.6Hz,1H),4.43(t,J=6.4Hz,2H),3.75(t,J=6.3Hz,2H),2.76(s,3H),2.00-1.92(m,2H),1.85-1.78(m,2H).HRMS(ESI)m/z:352.0810[M+Na]+,计算为C17H15NO6Na 352.0792.
实施例27.化合物36的合成
根据制备3,使用2,2'-氧二乙醇作为原料,得到目标黄色固体36。1H NMR(400MHz,CDCl3)δ9.05(dd,J=4.7,1.7Hz,1H),8.53(dd,J=7.9,1.7Hz,1H),7.71(dd,J=7.9,4.7Hz,1H),4.54(t,J=4.6Hz,2H),3.93(t,J=4.8Hz,2H),3.79(t,J=4.4Hz,2H),3.70(t,J=4.4Hz,2H),2.76(s,3H).HRMS(ESI)m/z:368.0752[M+Na]+,计算为C17H15NO7Na368.0741.
实施例28.化合物37的合成
根据制备3,使用(R)-(2,2-二甲基-1,3-二氧戊环-4-基)甲醇作为原料,得到目标黄色固体37。1H NMR(400MHz,CDCl3)δ9.09(dd,J=4.6,1.6Hz,1H),8.57(dd,J=7.8,1.5Hz,1H),7.75(dd,J=7.8,4.7Hz,1H),4.48(d,J=4.7Hz,2H),4.19(m,1H),3.85-3.76(m,2H),2.81(s,3H).
实施例29.化合物38和45的合成
根据制备3,使用(S)-(2,2-二甲基-1,3-二氧戊环-4-基)甲醇作为原料,得到两种黄色固体38和45。
38:1H NMR(400MHz,CDCl3)δ8.99(dd,J=4.7,1.7Hz,1H),8.47(dd,J=7.9,1.7Hz,1H),7.64(dd,J=7.9,4.7Hz,1H),4.54-4.46(m,1H),4.36(dd,J=11.0,5.4Hz,1H),4.30(dd,J=11.0,6.5Hz,1H),4.19(dd,J=8.7,6.3Hz,1H),3.94(dd,J=8.7,5.4Hz,1H),2.70(s,3H),1.37(s,3H),1.31(s,3H).HRMS(ESI)m/z:394.0909[M+Na]+,计算为C19H17NO7Na394.0897.
45:1H NMR(400MHz,CDCl3)δ9.01(dd,J=4.7,1.7Hz,1H),8.48(dd,J=7.9,1.7Hz,1H),7.66(dd,J=7.9,4.7Hz,1H),4.40(d,J=5.2Hz,2H),4.14-4.08(m,1H),3.76-3.63(m,2H),2.73(s,3H).HRMS(ESI)m/z:354.0596[M+Na]+,计算为C16H13NO7Na 354.0584.
实施例30.化合物39的合成
根据制备3,使用苯甲醇作为原料,得到目标黄色固体39。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.6,1.6Hz,1H),8.53(dd,J=7.9,1.6Hz,1H),7.69(dd,J=7.8,4.7Hz,1H),7.58-7.56(m,2H),7.42-7.37(m,2H),7.35-7.31(m,1H),5.42(s,2H),2.73(s,3H).HRMS(ESI)m/z:370.0704[M+Na]+,计算为C20H13NO5Na 370.0686.
实施例31.化合物40的合成
根据制备3,使用2-苯基乙醇作为原料,得到目标黄色固体40。1H NMR(400MHz,CDCl3)δ9.07(dd,J=4.7,1.7Hz,1H),8.54(dd,J=7.9,1.7Hz,1H),7.70(dd,J=7.9,4.7Hz,1H),7.33-7.28(m,4H),7.25-7.20(m,1H),4.60(t,J=7.3Hz,2H),3.19(t,J=7.3Hz,2H),2.65(s,3H).HRMS(ESI)m/z:384.0864[M+Na]+,计算为C21H15NO5Na 384.0842.
实施例32.化合物58的合成
根据制备例3,使用戊-1,5-二醇作为原料,得到目标黄色固体45。1H NMR(400MHz,CDCl3)δ9.05(dd,J=4.7,1.7Hz,1H),8.53(dd,J=7.9,1.7Hz,1H),7.70(dd,J=7.9,4.7Hz,1H),4.40(t,J=6.5Hz,2H),3.71(t,J=6.1Hz,2H),2.76(s,3H),1.93-1.85(m,2H),1.73-1.55(m,4H).HRMS(ESI)m/z:366.0966[M+Na]+,计算为C18H17NO6Na 366.0948.
实施例33.化合物46的合成
根据制备3,使用2-羟基乙酸作为原料,得到目标黄色固体46。1H NMR(400MHz,MeOD)δ8.95(dd,J=4.7,1.6Hz,1H),8.58(dd,J=7.9,1.6Hz,1H),7.84(dd,J=7.9,4.8Hz,1H),4.07(s,2H),2.78(s,3H).HRMS(ESI)m/z:338.0283[M+Na]+,计算为C15H9NO7Na338.0271.
实施例34.化合物47的合成
根据制备3,使用三氟乙醇作为原料,得到目标黄色固体47。1H NMR(400MHz,CDCl3)δ9.07(dd,J=4.7,1.7Hz,1H),8.54(dd,J=7.9,1.7Hz,1H),7.71(dd,J=7.9,4.7Hz,1H),4.77(q,J=8.3Hz,2H),2.78(s,3H).HRMS(ESI)m/z:362.0266[M+Na]+,计算为C15H8NO5F3Na362.0247.
实施例35.化合物48的合成
根据制备3,使用3-羟基丙腈作为原料,得到目标黄色固体48。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.6,1.6Hz,1H),8.54(dd,J=7.9,1.7Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),4.60(t,J=6.5Hz,2H),2.99(t,J=6.5Hz,2H),2.78(s,3H).
实施例36.化合物49的合成
根据制备3,使用苯并[d][1,3]二氧杂环戊烯(dioxol)-5-醇作为原料,得到目标黄色固体49。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.7,1.7Hz,1H),8.55(dd,J=7.9,1.7Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),6.97(d,J=2.3Hz,1H),6.89(dd,J=8.4,2.3Hz,1H),6.82(d,J=8.4Hz,1H),6.01(s,2H),2.81(s,2H).
实施例37.化合物43的合成
根据制备例3,使用丙-2-炔-1-醇作为原料,得到目标黄色固体43。1H NMR(400MHz,CDCl3)δ9.06(d,J=4.5Hz,1H),8.54(d,J=7.7Hz,1H),7.70(dd,J=7.8,4.6Hz,1H),4.50(t,J=7.0Hz,2H),2.88-2.64(m,5H),2.02(t,J=2.6Hz,1H).HRMS(ESI)m/z:332.0544[M+Na]+,计算为C17H11NO5Na 332.0529.
实施例38.化合物44的合成
根据制备3,使用4-(甲基磺酰基)苯酚作为原料,得到目标黄色固体44。1H NMR(400MHz,CDCl3)δ9.10(dd,J=4.7,1.7Hz,1H),8.59(dd,J=7.9,1.7Hz,1H),8.11-8.03(m,2H),7.76(dd,J=7.9,4.7Hz,1H),7.76-7.63(m,2H),3.11(s,3H),2.86(s,3H).HRMS(ESI)m/z:434.0334[M+H]+,计算为C20H13NO7SNa 434.0305.
实施例39.化合物50的合成
根据制备3,使用2-羟基苄腈作为原料,得到目标黄色固体50。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.7,1.7Hz,1H),8.57(dd,J=7.9,1.7Hz,1H),7.92-7.61(m,4H),7.42(td,J=7.5,1.4Hz,1H),2.87(s,3H).HRMS(ESI)m/z:381.0503[M+Na]+,计算为C20H10N2O5Na381.0482.
实施例40.化合物51的合成
根据制备3,使用4-羟基苄腈作为原料,得到目标黄色固体51。1H NMR(400MHz,CDCl3)δ9.08(dd,J=4.7,1.7Hz,1H),8.57(dd,J=7.9,1.7Hz,1H),7.76(d,J=8.8Hz,1H),7.74(dd,J=7.0,3.7Hz,2H),7.63(d,J=8.8Hz,2H),2.84(s,3H).HRMS(ESI)m/z:381.0496[M+Na]+,计算为C20H10N2O5Na 381.0482.
实施例41.化合物52的合成
根据制备3,使用N-乙酰基-L-酪氨酸甲基酯作为材料,得到目标黄色固体52。1HNMR(400MHz,CDCl3)δ9.06(dd,J=4.7,1.7Hz,1H),8.56(dd,J=7.9,1.7Hz,1H),7.72(dd,J=7.9,4.7Hz,1H),7.38(d,J=8.5Hz,2H),7.17(d,J=8.5Hz,2H),5.98(d,J=7.5Hz,1H),4.91(dt,J=7.7,5.7Hz,1H),3.75(s,3H),3.17(dd,J=5.6,3.4Hz,2H),2.82(s,3H),2.02(s,3H).ESI/MS m/z:477.1[M+H]+.
实施例42.化合物53和54的合成
根据制备3,使用3-溴丙醇作为原料,得到目标黄色固体53。1H NMR(400MHz,CDCl3)δ9.06(dd,J=4.7,1.7Hz,1H),8.54(dd,J=7.9,1.7Hz,1H),7.70(dd,J=7.9,4.7Hz,1H),4.54(t,J=5.8Hz,2H),3.75(t,J=5.4Hz,2H),2.78(s,3H),2.45-2.36(m,2H).HRMS(ESI)m/z:377.9996和380.0005[M+H]+,计算为C16H12NO5Br 377.9972和379.9953.
在80℃下将吡啶(5ml)中53(20mg,0.05mmol)溶液加热8小时。然后,将反应溶液冷却至室温,加入***(5ml)。过滤沉淀,并且分别用醚(10ml)和乙酸乙酯(5ml)洗涤,得到目标黄色固体54。1H NMR(400MHz,MeOD)δ9.20(d,J=5.6Hz,2H),9.02(dd,J=4.7,1.6Hz,1H),8.64-8.60(m,2H),8.18(t,J=7.2Hz,2H),7.89(dd,J=7.9,4.8Hz,1H),5.08(t,J=7.4Hz,2H),4.46(t,J=5.6Hz,2H),2.74(s,3H),2.64-2.48(m,2H).HRMS(ESI)m/z:377.1149[M-Br]+,计算为C21H17N2O5 377.1132.
实施例43.化合物55的合成
将在THF(10ml)中的53(20mg,0.05mmol)和N,N-二甲基-4-氨基吡啶(62mg,0.5mmol)溶液回流8小时。然后,将反应溶液冷却至室温,并且加入醚(20ml)。过滤出沉淀,并且分别使用醚(10ml)和乙酸乙酯(5ml)洗涤,得到目标黄色固体55。1H NMR(400MHz,MeOD)δ9.01(dd,J=4.7,1.5Hz,1H),8.61(dd,J=7.9,1.5Hz,1H),8.35(d,J=7.7Hz,2H),7.89(dd,J=7.9,4.8Hz,1H),7.01(d,J=7.7Hz,2H),4.57(t,J=7.0Hz,2H),4.40(t,J=5.6Hz,2H),3.21(s,6H),2.74(s,3H),2.45-2.31(m,2H).HRMS(ESI)m/z:420.1555[M-Br]+,计算为C23H22N3O5420.1554.
实施例44.制备4:化合物33的合成
向MeCN(20ml)中3-溴丙酸(152mg,1mmol)的溶液中,加入NaN3(130mg,2mmol)。将溶液回流8小时。将反应溶液减压浓缩,得到白色固体。将得到的白色固体溶解于水(5ml)中,并且分别加入化合物32(60mg,0.17mmol)、CuSO4(3mg)、抗坏血酸钠(2.5mg)和DMF(5ml)。将溶液加热至80℃3小时。然后,将反应溶液冷却到室温,并且加入水(50ml)。使用CH2Cl2(20ml x 2)萃取得到的悬浮液。使用水(10ml x 3)和饱和盐水溶液(10ml x 2)洗涤合并的有机溶液。减压浓缩有机溶液,通过硅胶柱色谱纯化,得到目标黄色固体33。1H NMR(400MHz,DMSO)δ12.54(s,1H),9.04(dd,J=4.6,1.6Hz,1H),8.68(s,1H),8.50(dd,J=7.9,1.6Hz,1H),7.89(dd,J=7.9,4.7Hz,1H),7.85(d,J=1.9Hz,1H),7.82(d,J=7.8Hz,1H),7.60(t,J=7.9Hz,1H),7.35(dd,J=8.1,1.4Hz,1H),4.63(t,J=6.7Hz,2H),2.97(t,J=6.7Hz,2H),2.81(s,3H).HRMS(ESI)m/z:471.0920[M-H]-,计算为C24H15N4O7 471.0946.
实施例45.化合物34的合成
根据制备4,使用3-溴丙醇作为原料,得到目标黄色固体34。1H NMR(400MHz,CDCl3)δ9.08(dd,J=4.7,1.7Hz,1H),8.58(dd,J=7.9,1.7Hz,1H),7.93(s,1H),7.85-7.82(m,2H),7.74(dd,J=7.9,4.7Hz,1H),7.52(t,J=7.9Hz,1H),7.44-7.37(m,1H),4.61(t,J=6.7Hz,2H),3.72(t,J=5.8Hz,2H),2.85(s,3H),2.21(五重峰,J=6.2Hz,2H).HRMS(ESI)m/z:457.1138[M-H]-,计算为C24H17N4O6 457.1154.
实施例46.化合物42的合成
根据制备4,使用化合物43作为材料,得到目标黄色固体42。1H NMR(400MHz,CDCl3)δ8.99(dd,J=4.8,1.4Hz,1H),8.65(dd,J=7.9,1.5Hz,1H),8.19(s,1H),7.83(dd,J=7.9,4.8Hz,1H),4.78(t,J=5.6Hz,2H),4.70(t,J=5.0Hz,2H),3.24(t,J=5.0Hz,2H),2.92(t,J=5.6Hz,2H),2.79(s,2H).HRMS(ESI)m/z:423.0923[M-H]-,计算为C20H15N4O7 423.0946.
实施例47.化合物56的合成
根据42的合成,使用3-溴丙醇作为原料,得到目标黄色固体56。1H NMR(400MHz,CDCl3)δ9.02(d,J=4.5Hz,1H),8.57(dd,J=7.9,1.6Hz,1H),7.98(s,1H),7.75(dd,J=7.9,4.7Hz,1H),4.70(t,J=5.6Hz,2H),4.58(t,J=5.6Hz,2H),3.68(t,J=5.8Hz,2H),3.27(t,J=5.6Hz,2H),2.76(s,3H),2.15(五重峰,J=6Hz,2H).HRMS(ESI)m/z:433.1142[M+Na]+,计算为C20H18N4O6Na 433.1119.
实施例48.化合物7-Na盐的合成
向乙醇(10ml)中7(52mg,0.20mmol)的溶液中,逐滴加入乙醇(5ml)中NaOH(8mg,0.2mmol)的溶液。在室温下将溶液搅拌30分钟。过滤出沉淀物,用乙醇(1ml x 2)洗涤并且干燥,得到目标黄色固体7-Na盐。
实施例49.化合物33-Na盐的合成
根据7-Na盐的合成,使用化合物33作为原料,得到目标黄色固体33-Na盐。
实施例50.化合物57的合成
将在乙醇(10ml)中2(72mg,0.25mmol)、盐酸羟胺(52mg,0.75mmol)和K2CO3(52mg,0.375mmol)的溶液搅拌并且回流1.5h。在减压下浓缩反应溶液。所得固体通过硅胶柱色谱纯化,得到目标黄色固体57。1H NMR(400MHz,CDCl3)δ8.76-8.74(m,2H),7.76(dd,J=8.0,5.0Hz,1H),4.42(q,J=7.1Hz,2H),2.64(s,3H),1.41(t,J=7.1Hz,3H).
实施例51.额外的化合物
以下化合物可以通过实施例1-50所示的方法制备。制备特定化合物所需的试剂和反应条件的常规变化对于本领域技术人员将是显而易见的。
实施例52.全细胞提取物TDP1测定
收集、洗涤并离心用于补充有人类TDP1(hTDP1)的Tdp1(TDP1-/-)的DT40敲除细胞(1x107)。然后将细胞团粒重新悬浮于100μL CellLytic M细胞裂解试剂(SIGMA-AldrichC2978)中。在冰上15分钟后,将裂解物以12,000g离心10分钟,并将上清液转移到新管中。使用Nanodrop分光光度计(Invitrogen)确定蛋白质浓度,并且将全细胞提取物存储在-80℃下。将含有3′-磷酸酪氨酸(N14Y)的5′-[32P]-标记的单链DNA寡核苷酸,在室温下,在含有50mM Tris HCl,pH 7.5、80mM KCl、2mM EDTA、1mM DTT、40μg/mL BSA和0.01%Tween-20的WCE缓冲液中,在存在或不存在抑制剂的条件下,使用4μg/mL全细胞提取物在1nM下温育15分钟。通过添加1体积的凝胶加载缓冲液[99.5%(v/v)甲酰胺、5mM EDTA、0.01%(w/v)二甲苯蓝(xylene cyanol)和0.01%(w/v)溴酚蓝]终止反应。以12分钟间隔,将样品以多次载荷进行16%变性PAGE。将凝胶干燥并且暴露于PhosphorImager屏(GE Healthcare)。使用Typhoon 8600(GE Healthcare)扫描凝胶图像,并且使用ImageQuant软件(GE Healthcare)进行光密度分析。
实施例53.重组TDP1测定
在室温下,在WCE缓冲液(参见实施例51)中,在不存在或存在抑制剂的条件下,使用10pM重组TDP1在1nM下将N14Y DNA底物温育15分钟。当指示时,在含有1X PBS,pH 7.4、80mM KCl和0.01%Tween-20的HTS测定缓冲液中进行平行反应。然后,类似于WCE TDP1测定(实施例51),分析样品。
实施例54.重组TDP2测定
如先前所描述的(实施例52),使用下列修改进行TDP2反应。在室温下,在含有50mMTris-HCl,pH 7.5、80mM KCl、5mM MgCl2、0.1mM EDTA、1mM DTT、40μg/mL BSA和0.01%Tween 20的缓冲液中,在不存在或存在抑制剂的条件下,使用25pM重组人类TDP2在1nM下将18链节单链寡核苷酸DNA底物(α32P-虫草素(cordycepin)-3’-标记的)温育15分钟。类似于WCE和重组TDP1反应(参见实施例52和53),终止并处理反应。
实施例55.全细胞提取物TDP2测定
收集、洗涤并离心用于补充有人类TDP2(hTDP2)的Tdp1(TDP1-/-)的DT40敲除细胞(1x107)。然后将细胞团粒裂解并与hTDP1提取物类似地存储(参见上文)。在室温下,在含有50mM Tris HCl,pH 7.5、80mM KCl、5mM MgCl2、2mM EDTA、1mM DTT、40μg/mL BSA和0.01%Tween-20的WCE缓冲液中,在不存在或存在抑制剂的条件下,使用4μg/mL全细胞提取物,在1nM下将18链节单链寡核苷酸温育15分钟。通过加入1体积的凝胶加载缓冲液[99.5%(v/v)甲酰胺、5mM EDTA、0.01%(w/v)二甲苯蓝和0.01%(w/v)溴酚蓝]终止反应。然后,类似于hTDP1全细胞提取物(实施例51),处理并运行样品。
实施例56.额外的化合物
表1示出了化合物1至44和额外的化合物59-74的化合物。所有的化合物均是通过实施例1至50中示出的方法制备的。使用本领域技术人员显而易见的起始材料和反应条件的常规变化,来制备表1中公开的具体化合物。4星“****”用于指示IC50≤1微摩尔的化合物,3星“***”指示1微摩尔<IC50≤12微摩尔的化合物,2星“**”指示12微摩尔<IC50≤37微摩尔的化合物,一星“*”指示37微摩尔<IC50≤111微摩尔的化合物,并且0指示IC50>111微摩尔的化合物。使用标准Tdp2抑制测定法,例如实施例53的测定法,来确定化合物的IC50。LC方法在“一般方法”部分中给出。
Claims (16)
1.一种式I的化合物或其药学上可接受的盐,
其中
X1是N或CR5;
X2是N或CR6;并且
X1或X2中的至少一个是N;
R1是羟基或C1-C6烷氧基,其中所述C1-C6烷氧基中的一个或多个亚甲基单元可选地并独立地被-O-、-S-或-N(R7)-替换,并且除了羟基之外的R1在每次出现时被0-3个独立地选自卤素、羟基、氰基、=N、=NOR7、-CO2H、-(CO)-O-C1-C6烷基、-C(O)NR7R8和-W-P(O)YR9ZR10中的取代基取代;或者
Y1是O、NH或S;
Y2是N或C-R2;
R2是卤素、C1-C6卤代烷基、C1-C6卤代烷氧基、-(C0-C6烷基)环烷基、-(C0-C6烷基)NR7R8或苯基,除了卤素之外的每个R2在每次出现时被0至3个独立地选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基中的基团取代;或
R2是基团-J-Q,其中J是1至4碳的亚烷基接头,其中任何的-CH2-基团可选地被-C(O)O-、-C(O)NH-、-C(O)NR11或-C(O)-替换;
Q是C1-C6烷基、C1-C6烷基氨基、芳基或杂芳基,它们的每一个是未被取代的或被一个或多个独立地选自卤素、羟基、氨基、氰基、C1-C4烷基、C1-C4烷氧基、C1-C2卤代烷基和C1-C2卤代烷氧基中的基团取代;W、Y和Z在每次出现时独立地为键或O;
R3、R4、R5和R6在每次出现时独立地选自氢、卤素、氰基、氨基、C1-C6烷基、-(C0-C6烷基)环烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基;
R7、R8、R9和R10在每次出现时独立地选自氢、C1-C6烷基、C2-C6烯基、-(C0-C6烷基)环烷基和C1-C6卤代烷基,并且连接到相同氮原子的任何R7和R8可以一起形成4-至7-元杂环烷基,所述4-至7-元杂环烷基被0至2个选自羟基、卤素、C1-C4烷基、C1-C4烷氧基和C2-C4烷酰基中的取代基取代;并且
R11是C1-C6烷基或C1-C6烷基氨基。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中Y2是N。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中Y1是O且Y2是N。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其中
Y2是N
R1是C1-C8烷氧基,其中所述C1-C8烷氧基中的一个或多个亚甲基单元可选地且独立地被-O-或-N(R7)-替换,并且R1在每次出现时被0-3个独立地选自羟基、卤素、氰基、-CO2H、-(CO)-O-C1-C6烷基和-W-P(O)YR9ZR10中的取代基取代;或
R2是卤素、C1-C6卤代烷基、-(C0-C6烷基)环烷基或苯基,所述苯基在每次出现时被0至3个独立地选自卤素、羟基、C1-C6烷基、C1-C6烷氧基、C1-C6卤代烷基和C1-C6卤代烷氧基中的基团取代。
5.根据权利要求1所述的化合物或其药学上可接受的盐,其中R2是基团-J-Q。
7.根据权利要求1所述的化合物或其药学上可接受的盐,其中
R1被至少一个-W-P(O)YR9ZR10取代基取代;并且
W是键;并且Y和Z均为O。
8.根据权利要求1所述的化合物或其药学上可接受的盐,其中Y2是C-R2,R1是C1-C8烷氧基且R2是C1-C6卤代烷基。
9.根据权利要求1所述的化合物或其药学上可接受的盐,其中
R1是烷氧基,其中一个或多个亚甲基单元被-O-或-N(R7)-替换并且R1被1至3个独立地选自羟基和-WP(O)YR9ZR10的取代基取代;其中W是键;并且Y和Z均为O。
12.一种包含权利要求1所述的化合物或其药学上可接受的盐以及药学上可接受的载体的药物组合物。
13.权利要求1-11中任一项所述的化合物或其药学上可接受的盐在治疗需要这种治疗的患者的癌症中的用途。
14.权利要求1-11中任一项所述的化合物或其药学上可接受的盐在联合一种或多种额外的化合物治疗需要这种治疗的患者的癌症中的用途,其中所述额外的化合物的至少一种是已知为拓扑异构酶2的抑制剂的活性剂。
15.根据权利要求14所述的用途,其中至少一种所述额外的化合物是选自依托泊苷、替尼泊苷、多柔比星、柔红霉素、米托蒽醌、安吖啶、玫瑰树碱、金精三羧酸和3-羟基-2-[(1R)-6-异丙烯基-3-甲基-环己-2-烯-1-基]-5-戊基-1,4-苯醌中的活性剂。
16.根据权利要求13-15中任一项所述的用途,其中所述癌症是胶质瘤、急性髓性白血病、急性骨髓性白血病、骨髓增生异常/骨髓增生性肿瘤、肉瘤、慢性骨髓单核细胞性白血病、非霍奇金淋巴瘤、星形细胞瘤、黑素瘤、非小细胞肺癌、小细胞肺癌、子***、直肠癌、卵巢癌、胆管癌、软骨肉瘤或结肠癌。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562100968P | 2015-01-08 | 2015-01-08 | |
US62/100,968 | 2015-01-08 | ||
CN201680014742.7A CN107635991B (zh) | 2015-01-08 | 2016-01-08 | 作为tdp2的抑制剂的呋喃并喹啉二酮 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680014742.7A Division CN107635991B (zh) | 2015-01-08 | 2016-01-08 | 作为tdp2的抑制剂的呋喃并喹啉二酮 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113501826A true CN113501826A (zh) | 2021-10-15 |
Family
ID=55300777
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680014742.7A Active CN107635991B (zh) | 2015-01-08 | 2016-01-08 | 作为tdp2的抑制剂的呋喃并喹啉二酮 |
CN202110013140.2A Pending CN113501826A (zh) | 2015-01-08 | 2016-01-08 | 作为tdp2的抑制剂的呋喃并喹啉二酮 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201680014742.7A Active CN107635991B (zh) | 2015-01-08 | 2016-01-08 | 作为tdp2的抑制剂的呋喃并喹啉二酮 |
Country Status (6)
Country | Link |
---|---|
US (2) | US10906914B2 (zh) |
EP (1) | EP3242881B1 (zh) |
CN (2) | CN107635991B (zh) |
AU (1) | AU2016205137B2 (zh) |
CA (1) | CA2973484A1 (zh) |
WO (1) | WO2016112304A1 (zh) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10906914B2 (en) * | 2015-01-08 | 2021-02-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Furoquinolinediones as inhibitors of TDP2 |
US10617706B2 (en) | 2018-02-05 | 2020-04-14 | Regents Of The University Of Minnesota | Compounds for cancer chemotherapeutic sensitization |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1887884A (zh) * | 2006-07-14 | 2007-01-03 | 中山大学 | 喹啉二酮衍生物及其在制备抗菌药物中的应用 |
CN101182321A (zh) * | 2007-12-11 | 2008-05-21 | 中山大学 | 中氮茚并氮杂萘醌类衍生物及其制备方法与抗癌应用 |
KR20090013664A (ko) * | 2007-08-01 | 2009-02-05 | 충북대학교 산학협력단 | 신규한 인돌다이온 유도체 화합물 및 이를 함유하는혈관평활근세포 이상 증식성 질환의 예방 또는 치료용약제학적 조성물 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS63196576A (ja) | 1987-02-10 | 1988-08-15 | Tetsuo Ikegawa | フラルナフトキノン誘導体と制癌剤及びその製造方法 |
TW252136B (zh) | 1992-10-08 | 1995-07-21 | Ciba Geigy | |
JP3530650B2 (ja) | 1995-09-26 | 2004-05-24 | 京セラミタ株式会社 | 電子写真感光体 |
JP2001097860A (ja) | 1999-09-29 | 2001-04-10 | Japan Science & Technology Corp | 抗薬剤耐性菌剤と抗クラミジア剤 |
ES2423800T3 (es) | 2003-03-28 | 2013-09-24 | Novartis Vaccines And Diagnostics, Inc. | Uso de compuestos orgánicos para la inmunopotenciación |
WO2008052352A1 (en) | 2006-11-03 | 2008-05-08 | The University Of British Columbia | Substituted quinone indoleamine 2,3-dioxygenase (ido) inhibitors and syntheses and uses therefor |
SI2200431T1 (sl) | 2007-09-10 | 2016-10-28 | Boston Biomedical, Inc. | Sestave in metode za zdravljenje raka |
CN103153975B (zh) | 2010-08-24 | 2016-01-20 | 杭州益尔生物科技有限公司 | 用于疾病治疗的新型萘醌 |
JP2014511384A (ja) | 2011-03-04 | 2014-05-15 | ゾウシャン ハイジョンジョウ シンシェン ファーマシューティカルズ カンパニー リミテッド | 疾患治療のための4,9−ジヒドロキシ−ナフト[2,3−b]フランの新規エステル |
WO2013166618A1 (en) | 2012-05-08 | 2013-11-14 | Zhoushan Haizhongzhou Xinsheng Pharmaceuticals Co., Ltd. | PRODRUGS OF 4,9-DIHYDROXY-NAPHTHO[2,3-b]FURANS FOR CIRCUMVENTING CANCER MULTIDRUG RESISTANCE |
WO2015151490A1 (ja) * | 2014-03-31 | 2015-10-08 | 大日本住友製薬株式会社 | 新規な三環性キノン誘導体 |
US10906914B2 (en) * | 2015-01-08 | 2021-02-02 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Furoquinolinediones as inhibitors of TDP2 |
-
2016
- 2016-01-08 US US15/542,560 patent/US10906914B2/en active Active
- 2016-01-08 AU AU2016205137A patent/AU2016205137B2/en active Active
- 2016-01-08 CN CN201680014742.7A patent/CN107635991B/zh active Active
- 2016-01-08 WO PCT/US2016/012672 patent/WO2016112304A1/en active Application Filing
- 2016-01-08 CA CA2973484A patent/CA2973484A1/en active Pending
- 2016-01-08 CN CN202110013140.2A patent/CN113501826A/zh active Pending
- 2016-01-08 EP EP16703001.4A patent/EP3242881B1/en active Active
-
2021
- 2021-01-11 US US17/146,327 patent/US20210139492A1/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1887884A (zh) * | 2006-07-14 | 2007-01-03 | 中山大学 | 喹啉二酮衍生物及其在制备抗菌药物中的应用 |
KR20090013664A (ko) * | 2007-08-01 | 2009-02-05 | 충북대학교 산학협력단 | 신규한 인돌다이온 유도체 화합물 및 이를 함유하는혈관평활근세포 이상 증식성 질환의 예방 또는 치료용약제학적 조성물 |
CN101182321A (zh) * | 2007-12-11 | 2008-05-21 | 中山大学 | 中氮茚并氮杂萘醌类衍生物及其制备方法与抗癌应用 |
Non-Patent Citations (5)
Title |
---|
"Chemical Abstract RN,RN:1508279-60-4", 《STN ON THE WEB REGISTRY数据库》 * |
SUH, MYUNG EUN: "Cytotoxic effects of pyridino[2, 3-f]indole-4, 9-diones on human tumor cell lines", 《BIOLOGICAL & PHARMACEUTICAL BULLETIN》, pages 1 * |
SUH, MYUNG-EUN ETAL: "Synthesis of 1N-alkyl-2-amino-3-ethoxycarbonyl-pyridino[2, 3-f]indole-4, 9- dione derivatives (I)", 《 YAKHAK HOECHI 》, pages 575 - 581 * |
SUH, MYUNG-EUN: "Synthesis of 1-alkyl-2-methyl-3-(ethoxycarbonyl)pyrido[2, 3-f]indole-4, 9- dione derivatives", 《YAKHAK HOECHI》, pages 19 - 24 * |
YANNI, AMAL S.: "Synthesis and application of some new quinolinofurandione derivatives as bactericides", 《JOURNAL OF THE INDIAN CHEMICAL SOCIETY》, pages 777 - 9 * |
Also Published As
Publication number | Publication date |
---|---|
US20210139492A1 (en) | 2021-05-13 |
EP3242881B1 (en) | 2020-04-29 |
CN107635991A (zh) | 2018-01-26 |
EP3242881A1 (en) | 2017-11-15 |
WO2016112304A1 (en) | 2016-07-14 |
CN107635991B (zh) | 2021-01-01 |
US20180009822A1 (en) | 2018-01-11 |
US10906914B2 (en) | 2021-02-02 |
AU2016205137A1 (en) | 2017-08-03 |
AU2016205137B2 (en) | 2020-01-30 |
CA2973484A1 (en) | 2016-07-14 |
WO2016112304A8 (en) | 2016-09-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2971872C (en) | Mutant idh1 inhibitors useful for treating cancer | |
CA2736097C (en) | Carbazole compounds for inhibition of nf-kb activity | |
US20230099858A1 (en) | Pyridopyrimidine derivatives as kras inhibitors | |
CN109745316B (zh) | 用于治疗癌症的联合治疗 | |
EP3088397B1 (en) | Compounds that abrogate the cell cycle g2 checkpoint for use in the treatment of cancer | |
WO2021113595A1 (en) | Phosphorus derivatives as kras inhibitors | |
CN109641887B (zh) | 可用作用于治疗癌症的突变idh1抑制剂的噻唑衍生物 | |
CN109983016B (zh) | 嘧啶并[5,4-b]吲嗪或嘧啶并[5,4-b]吡呤化合物、其制备方法及用途 | |
WO2013013614A1 (zh) | 4-(3-杂芳基芳基氨基)喹唑啉和1-(3-杂芳基芳基氨基)异喹啉作为Hedgehog通路抑制剂及其应用 | |
JP2021519828A (ja) | ジアリール大員環化合物、医薬組成物及びその用途 | |
WO2017198196A1 (zh) | 具有抗肿瘤活性的喹啉衍生物 | |
Mashayekhi et al. | Synthesis, antimycobacterial and anticancer activity of novel indole-based thiosemicarbazones | |
CN109843874A (zh) | 作为parp1、parp2和/或微管蛋白的抑制剂可用于治疗癌症的酞嗪衍生物 | |
US20210139492A1 (en) | Furoquinolinediones as inhibitors of tdp2 | |
US20210332046A1 (en) | Nicotinic acetylcholine receptor silent agonists | |
JP7423655B2 (ja) | キノリル含有化合物、医薬組成物およびその使用 | |
KR101505783B1 (ko) | 신규한 피롤로피리디닐옥시페닐아미드 유도체 및 이의 용도 | |
CN106117182A (zh) | 喹唑啉‑n‑苯乙基四氢异喹啉类化合物及其制备方法和应用 | |
CN115427407A (zh) | 一种新型n-杂环bet溴结构域抑制剂、其制备方法及医药用途 | |
CN108341774B (zh) | 取代的喹啉酮类抑制剂 | |
US20150259331A1 (en) | Protozoan parasite growth inhibitors | |
RU2803116C2 (ru) | Хинолинил-содержащее соединение и его фармацевтическая композиция и применение | |
CN111808080B (zh) | 取代的吡啶或嘧啶化合物、其制备方法及其在医药上的应用 | |
US20240002365A1 (en) | Pyridazine and 1,2,4-triazine derivatives as fgfr kinase inhibitors | |
RU2801302C2 (ru) | Производные циклического иминопиримидина в качестве ингибиторов киназ |
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 |