TWI508967B - 螺-吲哚酮mdm2拮抗劑 - Google Patents
螺-吲哚酮mdm2拮抗劑 Download PDFInfo
- Publication number
- TWI508967B TWI508967B TW099138770A TW99138770A TWI508967B TW I508967 B TWI508967 B TW I508967B TW 099138770 A TW099138770 A TW 099138770A TW 99138770 A TW99138770 A TW 99138770A TW I508967 B TWI508967 B TW I508967B
- Authority
- TW
- Taiwan
- Prior art keywords
- group
- optionally substituted
- hydrogen
- compound
- alkyl
- Prior art date
Links
- 102000012199 E3 ubiquitin-protein ligase Mdm2 Human genes 0.000 title description 42
- 239000005557 antagonist Substances 0.000 title description 7
- 101150024228 mdm2 gene Proteins 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 206
- 239000001257 hydrogen Substances 0.000 claims description 173
- 229910052739 hydrogen Inorganic materials 0.000 claims description 173
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 82
- 150000002431 hydrogen Chemical class 0.000 claims description 82
- 206010028980 Neoplasm Diseases 0.000 claims description 73
- 150000003839 salts Chemical class 0.000 claims description 69
- 238000000034 method Methods 0.000 claims description 50
- 125000000217 alkyl group Chemical group 0.000 claims description 46
- 201000011510 cancer Diseases 0.000 claims description 46
- 239000003814 drug Substances 0.000 claims description 45
- 239000002246 antineoplastic agent Substances 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 33
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 32
- 239000000460 chlorine Substances 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 13
- 230000003463 hyperproliferative effect Effects 0.000 claims description 13
- PIGFYZPCRLYGLF-UHFFFAOYSA-N Aluminum nitride Chemical compound [Al]#N PIGFYZPCRLYGLF-UHFFFAOYSA-N 0.000 claims description 12
- 125000001153 fluoro group Chemical group F* 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 206010039491 Sarcoma Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 208000032839 leukemia Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 4
- 208000026310 Breast neoplasm Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 206010060862 Prostate cancer Diseases 0.000 claims description 4
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 3
- 206010025323 Lymphomas Diseases 0.000 claims description 3
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 201000005202 lung cancer Diseases 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 3
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 208000034578 Multiple myelomas Diseases 0.000 claims description 2
- 201000000582 Retinoblastoma Diseases 0.000 claims description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 2
- 206010017758 gastric cancer Diseases 0.000 claims description 2
- 206010024627 liposarcoma Diseases 0.000 claims description 2
- 201000000050 myeloid neoplasm Diseases 0.000 claims description 2
- 201000011549 stomach cancer Diseases 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 2
- 229910052801 chlorine Inorganic materials 0.000 claims 2
- 210000004027 cell Anatomy 0.000 description 102
- -1 amino acid esters Chemical class 0.000 description 98
- UNXQGBMZYKHQCO-NVHWNKAKSA-N (2'r,3s,3'r,5'r)-6-chloro-3'-(3-chlorophenyl)-n-[(3s)-3,4-dihydroxybutyl]-5'-(2,2-dimethylpropyl)-5-fluoro-2-oxospiro[1h-indole-3,4'-pyrrolidine]-2'-carboxamide Chemical compound C1([C@H]2[C@@H](N[C@@H]([C@@]22C3=CC(F)=C(Cl)C=C3NC2=O)CC(C)(C)C)C(=O)NCC[C@H](O)CO)=CC=CC(Cl)=C1 UNXQGBMZYKHQCO-NVHWNKAKSA-N 0.000 description 72
- 239000000203 mixture Substances 0.000 description 70
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 70
- 125000000547 substituted alkyl group Chemical group 0.000 description 68
- 238000005481 NMR spectroscopy Methods 0.000 description 65
- 125000001072 heteroaryl group Chemical group 0.000 description 65
- 102100025064 Cellular tumor antigen p53 Human genes 0.000 description 63
- 101000721661 Homo sapiens Cellular tumor antigen p53 Proteins 0.000 description 63
- 125000003107 substituted aryl group Chemical group 0.000 description 63
- 235000002639 sodium chloride Nutrition 0.000 description 60
- 239000012453 solvate Substances 0.000 description 51
- 230000006907 apoptotic process Effects 0.000 description 48
- 108050002772 E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 41
- 229940002612 prodrug Drugs 0.000 description 38
- 239000000651 prodrug Substances 0.000 description 38
- 230000005855 radiation Effects 0.000 description 38
- 241001465754 Metazoa Species 0.000 description 35
- 239000012819 MDM2-Inhibitor Substances 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- 125000004433 nitrogen atom Chemical group N* 0.000 description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 27
- 108090000623 proteins and genes Proteins 0.000 description 27
- 241000700159 Rattus Species 0.000 description 26
- 125000000623 heterocyclic group Chemical group 0.000 description 25
- 235000018102 proteins Nutrition 0.000 description 25
- 102000004169 proteins and genes Human genes 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 24
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 125000003710 aryl alkyl group Chemical group 0.000 description 23
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 23
- IDKAKZRYYDCJDU-YJRDPZTCSA-N (2'r,3s,3's,5'r)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-n-(4-hydroxycyclohexyl)-2-oxospiro[1h-indole-3,4'-pyrrolidine]-2'-carboxamide Chemical compound C1([C@H]2[C@@H](N[C@@H]([C@@]22C3=CC=C(Cl)C=C3NC2=O)CC(C)(C)C)C(=O)NC2CCC(O)CC2)=CC=CC(Cl)=C1F IDKAKZRYYDCJDU-YJRDPZTCSA-N 0.000 description 22
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 22
- 230000003228 microsomal effect Effects 0.000 description 21
- 238000001228 spectrum Methods 0.000 description 21
- 125000005330 8 membered heterocyclic group Chemical group 0.000 description 20
- 241000282414 Homo sapiens Species 0.000 description 20
- 208000035475 disorder Diseases 0.000 description 20
- 229940079593 drug Drugs 0.000 description 20
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 19
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- 238000001959 radiotherapy Methods 0.000 description 17
- 238000004885 tandem mass spectrometry Methods 0.000 description 17
- 125000001188 haloalkyl group Chemical class 0.000 description 16
- 239000002243 precursor Substances 0.000 description 16
- 125000001424 substituent group Chemical group 0.000 description 16
- 125000003118 aryl group Chemical group 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000002207 metabolite Substances 0.000 description 15
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 14
- 108010091356 Tumor Protein p73 Proteins 0.000 description 14
- 230000003993 interaction Effects 0.000 description 14
- 239000003446 ligand Substances 0.000 description 14
- 210000001853 liver microsome Anatomy 0.000 description 14
- 230000002503 metabolic effect Effects 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 13
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 230000025084 cell cycle arrest Effects 0.000 description 13
- 238000004440 column chromatography Methods 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 239000003112 inhibitor Substances 0.000 description 13
- 239000011734 sodium Substances 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 208000024891 symptom Diseases 0.000 description 13
- 229940124597 therapeutic agent Drugs 0.000 description 13
- 230000001225 therapeutic effect Effects 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- 102100030018 Tumor protein p73 Human genes 0.000 description 12
- 125000004104 aryloxy group Chemical group 0.000 description 12
- 230000001939 inductive effect Effects 0.000 description 12
- 150000002500 ions Chemical class 0.000 description 12
- 125000005017 substituted alkenyl group Chemical group 0.000 description 12
- 102000003390 tumor necrosis factor Human genes 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 230000010261 cell growth Effects 0.000 description 10
- 229940127089 cytotoxic agent Drugs 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 10
- 230000002401 inhibitory effect Effects 0.000 description 10
- 238000001990 intravenous administration Methods 0.000 description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 125000004414 alkyl thio group Chemical group 0.000 description 9
- 229940041181 antineoplastic drug Drugs 0.000 description 9
- 125000000392 cycloalkenyl group Chemical group 0.000 description 9
- 230000001976 improved effect Effects 0.000 description 9
- 238000000338 in vitro Methods 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 125000004426 substituted alkynyl group Chemical group 0.000 description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 229940076005 apoptosis modulator Drugs 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 230000001965 increasing effect Effects 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- 125000000565 sulfonamide group Chemical group 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 7
- 229940083338 MDM2 inhibitor Drugs 0.000 description 7
- 108700012411 TNFSF10 Proteins 0.000 description 7
- 102100024598 Tumor necrosis factor ligand superfamily member 10 Human genes 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000008346 aqueous phase Substances 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- 238000013461 design Methods 0.000 description 7
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 7
- 238000005805 hydroxylation reaction Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 210000004881 tumor cell Anatomy 0.000 description 7
- BBQJVCVEWSBWBN-UHFFFAOYSA-N 3-methylbut-3-enoxymethylbenzene Chemical compound CC(=C)CCOCC1=CC=CC=C1 BBQJVCVEWSBWBN-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002671 adjuvant Substances 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
- 125000000304 alkynyl group Chemical group 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000036983 biotransformation Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 6
- 150000001768 cations Chemical class 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 230000006698 induction Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 229940043355 kinase inhibitor Drugs 0.000 description 6
- 210000001589 microsome Anatomy 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 6
- 230000036470 plasma concentration Effects 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 5
- 241000282472 Canis lupus familiaris Species 0.000 description 5
- 108020004414 DNA Proteins 0.000 description 5
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 5
- 101000610604 Homo sapiens Tumor necrosis factor receptor superfamily member 10B Proteins 0.000 description 5
- 101000611023 Homo sapiens Tumor necrosis factor receptor superfamily member 6 Proteins 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 5
- 102100040112 Tumor necrosis factor receptor superfamily member 10B Human genes 0.000 description 5
- 102100040403 Tumor necrosis factor receptor superfamily member 6 Human genes 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 5
- OPGPYIKNRCXNQY-UHFFFAOYSA-N benzyl 3-oxocyclobutane-1-carboxylate Chemical compound C1C(=O)CC1C(=O)OCC1=CC=CC=C1 OPGPYIKNRCXNQY-UHFFFAOYSA-N 0.000 description 5
- 230000027455 binding Effects 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 150000003857 carboxamides Chemical class 0.000 description 5
- 230000030833 cell death Effects 0.000 description 5
- 229960002949 fluorouracil Drugs 0.000 description 5
- 230000003211 malignant effect Effects 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 5
- 230000001235 sensitizing effect Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 230000008093 supporting effect Effects 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- 238000001262 western blot Methods 0.000 description 5
- 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 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 4
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 4
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 230000000692 anti-sense effect Effects 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 230000022131 cell cycle Effects 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 239000011248 coating agent Substances 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 238000006356 dehydrogenation reaction Methods 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 239000008298 dragée Substances 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 229940014259 gelatin Drugs 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- ROPLCSFPUPWHGJ-UHFFFAOYSA-N hydroxycyanamide Chemical compound ONC#N ROPLCSFPUPWHGJ-UHFFFAOYSA-N 0.000 description 4
- 125000005350 hydroxycycloalkyl group Chemical group 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 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 4
- 239000007788 liquid Substances 0.000 description 4
- 239000007937 lozenge Substances 0.000 description 4
- 108010082117 matrigel Proteins 0.000 description 4
- 230000001575 pathological effect Effects 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 230000036515 potency Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000009758 senescence Effects 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WYWHKKSPHMUBEB-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 230000009385 viral infection Effects 0.000 description 4
- 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
- 241000283690 Bos taurus Species 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 101001015963 Homo sapiens E3 ubiquitin-protein ligase Mdm2 Proteins 0.000 description 3
- 101000610605 Homo sapiens Tumor necrosis factor receptor superfamily member 10A Proteins 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 206010036790 Productive cough Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 102100040113 Tumor necrosis factor receptor superfamily member 10A Human genes 0.000 description 3
- 102100022203 Tumor necrosis factor receptor superfamily member 25 Human genes 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000001640 apoptogenic effect Effects 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 3
- 229960001467 bortezomib Drugs 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000973 chemotherapeutic effect Effects 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 229960004316 cisplatin Drugs 0.000 description 3
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 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
- 230000007547 defect Effects 0.000 description 3
- 229960003957 dexamethasone Drugs 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 238000009510 drug design Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229960000390 fludarabine Drugs 0.000 description 3
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 3
- 229960002074 flutamide Drugs 0.000 description 3
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229960002584 gefitinib Drugs 0.000 description 3
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 208000014829 head and neck neoplasm Diseases 0.000 description 3
- 102000055302 human MDM2 Human genes 0.000 description 3
- RNIXSZHNJLUJGC-UHFFFAOYSA-N hydroxy(nitro)cyanamide Chemical compound N#CN(O)[N+]([O-])=O RNIXSZHNJLUJGC-UHFFFAOYSA-N 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000005917 in vivo anti-tumor Effects 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- FABUFPQFXZVHFB-CFWQTKTJSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@H](C)C(=O)C(C)(C)[C@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-CFWQTKTJSA-N 0.000 description 3
- 229960002014 ixabepilone Drugs 0.000 description 3
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 229960004857 mitomycin Drugs 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 239000002674 ointment Substances 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 201000008968 osteosarcoma Diseases 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 239000012188 paraffin wax Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 102000005962 receptors Human genes 0.000 description 3
- 108020003175 receptors Proteins 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 210000003802 sputum Anatomy 0.000 description 3
- 208000024794 sputum Diseases 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- 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 2
- 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 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- 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 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- GPWHFPWZAPOYNO-UHFFFAOYSA-N 3,3-dimethylbutan-1-amine Chemical group CC(C)(C)CCN GPWHFPWZAPOYNO-UHFFFAOYSA-N 0.000 description 2
- XMTQQYYKAHVGBJ-UHFFFAOYSA-N 3-(3,4-DICHLOROPHENYL)-1,1-DIMETHYLUREA Chemical compound CN(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XMTQQYYKAHVGBJ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 235000019489 Almond oil Nutrition 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 102100027308 Apoptosis regulator BAX Human genes 0.000 description 2
- 108050006685 Apoptosis regulator BAX Proteins 0.000 description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 108010006654 Bleomycin Proteins 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- OJRUSAPKCPIVBY-KQYNXXCUSA-N C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N Chemical compound C1=NC2=C(N=C(N=C2N1[C@H]3[C@@H]([C@@H]([C@H](O3)COP(=O)(CP(=O)(O)O)O)O)O)I)N OJRUSAPKCPIVBY-KQYNXXCUSA-N 0.000 description 2
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 102000011727 Caspases Human genes 0.000 description 2
- 108010076667 Caspases Proteins 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- 101150065749 Churc1 gene Proteins 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 2
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 108010092160 Dactinomycin Proteins 0.000 description 2
- 101100441092 Danio rerio crlf3 gene Proteins 0.000 description 2
- 102000000541 Defensins Human genes 0.000 description 2
- 108010002069 Defensins Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 description 2
- 102100026693 FAS-associated death domain protein Human genes 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000971171 Homo sapiens Apoptosis regulator Bcl-2 Proteins 0.000 description 2
- 101000911074 Homo sapiens FAS-associated death domain protein Proteins 0.000 description 2
- 101000679921 Homo sapiens Tumor necrosis factor receptor superfamily member 21 Proteins 0.000 description 2
- 101000679903 Homo sapiens Tumor necrosis factor receptor superfamily member 25 Proteins 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- 206010024612 Lipoma Diseases 0.000 description 2
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 2
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 2
- 229930192392 Mitomycin Natural products 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 229930012538 Paclitaxel Natural products 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 241000282320 Panthera leo Species 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical compound OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 2
- 102100038239 Protein Churchill Human genes 0.000 description 2
- 102100022419 RPA-interacting protein Human genes 0.000 description 2
- 108090000829 Ribosome Inactivating Proteins Proteins 0.000 description 2
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 101150009046 Tnfrsf1a gene Proteins 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 2
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 2
- 108050002568 Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 2
- 102100022205 Tumor necrosis factor receptor superfamily member 21 Human genes 0.000 description 2
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- 230000001919 adrenal effect Effects 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 239000008168 almond oil Substances 0.000 description 2
- JKOQGQFVAUAYPM-UHFFFAOYSA-N amifostine Chemical compound NCCCNCCSP(O)(O)=O JKOQGQFVAUAYPM-UHFFFAOYSA-N 0.000 description 2
- 239000003098 androgen Substances 0.000 description 2
- 230000033115 angiogenesis Effects 0.000 description 2
- MWPLVEDNUUSJAV-UHFFFAOYSA-N anthracene Chemical compound C1=CC=CC2=CC3=CC=CC=C3C=C21 MWPLVEDNUUSJAV-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 229940124650 anti-cancer therapies Drugs 0.000 description 2
- 230000000340 anti-metabolite Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000011319 anticancer therapy Methods 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 229940100197 antimetabolite Drugs 0.000 description 2
- 239000002256 antimetabolite Substances 0.000 description 2
- 239000004599 antimicrobial Substances 0.000 description 2
- 230000009925 apoptotic mechanism Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000003943 azolyl group Chemical group 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 229960000997 bicalutamide Drugs 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229960001561 bleomycin Drugs 0.000 description 2
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 230000005907 cancer growth Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 150000001767 cationic compounds Chemical class 0.000 description 2
- 238000010822 cell death assay Methods 0.000 description 2
- 230000003915 cell function Effects 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000007385 chemical modification Methods 0.000 description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125797 compound 12 Drugs 0.000 description 2
- 229940126543 compound 14 Drugs 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000003246 corticosteroid Substances 0.000 description 2
- 229960001334 corticosteroids Drugs 0.000 description 2
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 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 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 229960003901 dacarbazine Drugs 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 125000004990 dihydroxyalkyl group Chemical group 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 239000005712 elicitor Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 239000000328 estrogen antagonist Substances 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 239000003925 fat Substances 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 239000010685 fatty oil Substances 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 2
- 108010074605 gamma-Globulins Proteins 0.000 description 2
- 210000004051 gastric juice Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 0.000 description 2
- QBKSWRVVCFFDOT-UHFFFAOYSA-N gossypol Chemical compound CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 QBKSWRVVCFFDOT-UHFFFAOYSA-N 0.000 description 2
- 208000024908 graft versus host disease Diseases 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 2
- XXSMGPRMXLTPCZ-UHFFFAOYSA-N hydroxychloroquine Chemical compound ClC1=CC=C2C(NC(C)CCCN(CCO)CC)=CC=NC2=C1 XXSMGPRMXLTPCZ-UHFFFAOYSA-N 0.000 description 2
- 230000033444 hydroxylation Effects 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 238000009169 immunotherapy Methods 0.000 description 2
- 229940051026 immunotoxin Drugs 0.000 description 2
- 239000002596 immunotoxin Substances 0.000 description 2
- 230000002637 immunotoxin Effects 0.000 description 2
- 231100000608 immunotoxin Toxicity 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 230000002757 inflammatory effect Effects 0.000 description 2
- 229910001411 inorganic cation Inorganic materials 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 230000009545 invasion Effects 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 206010028417 myasthenia gravis Diseases 0.000 description 2
- 208000029974 neurofibrosarcoma Diseases 0.000 description 2
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000000174 oncolytic effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000003791 organic solvent mixture Substances 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000010287 polarization Effects 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000000159 protein binding assay Methods 0.000 description 2
- 239000002534 radiation-sensitizing agent Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 229960003440 semustine Drugs 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- VSIVTUIKYVGDCX-UHFFFAOYSA-M sodium;4-[2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)tetrazol-2-ium-5-yl]benzene-1,3-disulfonate Chemical compound [Na+].COC1=CC([N+]([O-])=O)=CC=C1[N+]1=NC(C=2C(=CC(=CC=2)S([O-])(=O)=O)S([O-])(=O)=O)=NN1C1=CC=C([N+]([O-])=O)C=C1 VSIVTUIKYVGDCX-UHFFFAOYSA-M 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000013222 sprague-dawley male rat Methods 0.000 description 2
- 208000003265 stomatitis Diseases 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000002511 suppository base Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 208000011580 syndromic disease Diseases 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229960003087 tioguanine Drugs 0.000 description 2
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 2
- 229950002376 tirapazamine Drugs 0.000 description 2
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 2
- 229960000977 trabectedin Drugs 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- MMHDBUJXLOFTLC-WOYTXXSLSA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2s)-1-acetylpyrrolidine-2-carbonyl]amino]-3-(1h-imidazol-5-yl)propanoyl]amino]-3-hydroxypropanoyl]amino]-3-sulfanylpropanoyl]amino]butanediamide Chemical compound CC(=O)N1CCC[C@H]1C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(N)=O)CC1=CN=CN1 MMHDBUJXLOFTLC-WOYTXXSLSA-N 0.000 description 1
- MHFUWOIXNMZFIW-WNQIDUERSA-N (2s)-2-hydroxypropanoic acid;n-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1h-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide Chemical compound C[C@H](O)C(O)=O.C1CN(C)CCN1C1=CC(NC2=NNC(C)=C2)=NC(SC=2C=CC(NC(=O)C3CC3)=CC=2)=N1 MHFUWOIXNMZFIW-WNQIDUERSA-N 0.000 description 1
- XBLHJWMODQPUON-LBPRGKRZSA-N (2s)-2-methyl-4-phenylmethoxybutane-1,2-diol Chemical compound OC[C@](O)(C)CCOCC1=CC=CC=C1 XBLHJWMODQPUON-LBPRGKRZSA-N 0.000 description 1
- PSVUJBVBCOISSP-SPFKKGSWSA-N (2s,3r,4s,5s,6r)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1O[C@@H](OP(=O)(NCCCl)NCCCl)[C@H](O)[C@@H](O)[C@@H]1O PSVUJBVBCOISSP-SPFKKGSWSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 description 1
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 1
- ZGNLFUXWZJGETL-YUSKDDKASA-N (Z)-[(2S)-2-amino-2-carboxyethyl]-hydroxyimino-oxidoazanium Chemical compound N[C@@H](C\[N+]([O-])=N\O)C(O)=O ZGNLFUXWZJGETL-YUSKDDKASA-N 0.000 description 1
- YFKBXYGUSOXJGS-UHFFFAOYSA-N 1,3-Diphenyl-2-propanone Chemical compound C=1C=CC=CC=1CC(=O)CC1=CC=CC=C1 YFKBXYGUSOXJGS-UHFFFAOYSA-N 0.000 description 1
- PVCULFYROUOVGJ-UHFFFAOYSA-N 1-[2-chloroethyl(methylsulfonyl)amino]-3-methyl-1-methylsulfonylurea Chemical compound CNC(=O)N(S(C)(=O)=O)N(S(C)(=O)=O)CCCl PVCULFYROUOVGJ-UHFFFAOYSA-N 0.000 description 1
- KMICWMXRUOETFR-UHFFFAOYSA-N 1-[4-[2-(diethylamino)ethoxy]phenyl]-3-phenylpropan-1-one Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(=O)CCC1=CC=CC=C1 KMICWMXRUOETFR-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- TYNKREVQBXDBSZ-UHFFFAOYSA-N 1-nitroso-7,9-dihydro-3H-purine-2,6,8-trione Chemical compound N(=O)N1C(=O)NC=2NC(=O)NC=2C1=O TYNKREVQBXDBSZ-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- MXHRCPNRJAMMIM-SHYZEUOFSA-N 2'-deoxyuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-SHYZEUOFSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- AHDSRXYHVZECER-UHFFFAOYSA-N 2,4,6-tris[(dimethylamino)methyl]phenol Chemical compound CN(C)CC1=CC(CN(C)C)=C(O)C(CN(C)C)=C1 AHDSRXYHVZECER-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- XARVANDLQOZMMJ-CHHVJCJISA-N 2-[(z)-[1-(2-amino-1,3-thiazol-4-yl)-2-oxo-2-(2-oxoethylamino)ethylidene]amino]oxy-2-methylpropanoic acid Chemical compound OC(=O)C(C)(C)O\N=C(/C(=O)NCC=O)C1=CSC(N)=N1 XARVANDLQOZMMJ-CHHVJCJISA-N 0.000 description 1
- FOMKFBXHAKRALK-UHFFFAOYSA-N 2-[4-[(2-bromoethylamino)methyl]-2-nitroimidazol-1-yl]ethanol Chemical compound OCCN1C=C(CNCCBr)N=C1[N+]([O-])=O FOMKFBXHAKRALK-UHFFFAOYSA-N 0.000 description 1
- PBUUPFTVAPUWDE-UGZDLDLSSA-N 2-[[(2S,4S)-2-[bis(2-chloroethyl)amino]-2-oxo-1,3,2lambda5-oxazaphosphinan-4-yl]sulfanyl]ethanesulfonic acid Chemical compound OS(=O)(=O)CCS[C@H]1CCO[P@](=O)(N(CCCl)CCCl)N1 PBUUPFTVAPUWDE-UGZDLDLSSA-N 0.000 description 1
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 1
- 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 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- IJRKANNOPXMZSG-SSPAHAAFSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O.OC(=O)CC(O)(C(O)=O)CC(O)=O IJRKANNOPXMZSG-SSPAHAAFSA-N 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- GLPDBPGNFRRABU-UHFFFAOYSA-N 2-methylbenzenecarboximidamide Chemical compound CC1=CC=CC=C1C(N)=N GLPDBPGNFRRABU-UHFFFAOYSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical compound CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- 229940080296 2-naphthalenesulfonate Drugs 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 1
- 150000004959 2-nitroimidazoles Chemical class 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- AXRCEOKUDYDWLF-UHFFFAOYSA-N 3-(1-methyl-3-indolyl)-4-[1-[1-(2-pyridinylmethyl)-4-piperidinyl]-3-indolyl]pyrrole-2,5-dione Chemical compound C12=CC=CC=C2N(C)C=C1C(C(NC1=O)=O)=C1C(C1=CC=CC=C11)=CN1C(CC1)CCN1CC1=CC=CC=N1 AXRCEOKUDYDWLF-UHFFFAOYSA-N 0.000 description 1
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-Methylquinoline Natural products C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-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
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- CCRNCEKMSVYFLU-UHFFFAOYSA-N 4,5-dinitro-1h-imidazole Chemical class [O-][N+](=O)C=1N=CNC=1[N+]([O-])=O CCRNCEKMSVYFLU-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 1
- YUCBLVFHJWOYDN-PPIALRKJSA-N 4-[(r)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]-1-[(r)-[(2r,4r,5s)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@@H](OC=3C4=CC=CC=C4C(O[C@@H]([C@@H]4N5CC[C@@H]([C@@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-PPIALRKJSA-N 0.000 description 1
- BKTRENAPTCBBFA-UHFFFAOYSA-N 4-[2-(4-hydroxy-3-phenylphenyl)propan-2-yl]-2-phenylphenol Chemical compound C=1C=C(O)C(C=2C=CC=CC=2)=CC=1C(C)(C)C(C=1)=CC=C(O)C=1C1=CC=CC=C1 BKTRENAPTCBBFA-UHFFFAOYSA-N 0.000 description 1
- 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- 125000004539 5-benzimidazolyl group Chemical group N1=CNC2=C1C=CC(=C2)* 0.000 description 1
- FHIDNBAQOFJWCA-UAKXSSHOSA-N 5-fluorouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 FHIDNBAQOFJWCA-UAKXSSHOSA-N 0.000 description 1
- KUEFXPHXHHANKS-UHFFFAOYSA-N 5-nitro-1h-1,2,4-triazole Chemical compound [O-][N+](=O)C1=NC=NN1 KUEFXPHXHHANKS-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 108010075480 ADI PEG20 Proteins 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- ZGCSNRKSJLVANE-UHFFFAOYSA-N Aglycone-Rebeccamycin Natural products N1C2=C3NC4=C(Cl)C=CC=C4C3=C(C(=O)NC3=O)C3=C2C2=C1C(Cl)=CC=C2 ZGCSNRKSJLVANE-UHFFFAOYSA-N 0.000 description 1
- 108010012934 Albumin-Bound Paclitaxel Proteins 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- MXPOCMVWFLDDLZ-NSCUHMNNSA-N Apaziquone Chemical compound CN1C(\C=C\CO)=C(CO)C(C2=O)=C1C(=O)C=C2N1CC1 MXPOCMVWFLDDLZ-NSCUHMNNSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 108010037003 Buserelin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- 0 CC=CCCN1C*OCC1 Chemical compound CC=CCCN1C*OCC1 0.000 description 1
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 206010008874 Chronic Fatigue Syndrome Diseases 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 241000723346 Cinnamomum camphora Species 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- PXXNTAGJWPJAGM-VCOUNFBDSA-N Decaline Chemical class C=1([C@@H]2C3)C=C(OC)C(OC)=CC=1OC(C=C1)=CC=C1CCC(=O)O[C@H]3C[C@H]1N2CCCC1 PXXNTAGJWPJAGM-VCOUNFBDSA-N 0.000 description 1
- 101710088341 Dermatopontin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 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 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000320368 Eucryphia cordifolia Species 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 241000237858 Gastropoda Species 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 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
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- XYZZKVRWGOWVGO-UHFFFAOYSA-N Glycerol-phosphate Chemical compound OP(O)(O)=O.OCC(O)CO XYZZKVRWGOWVGO-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 208000001204 Hashimoto Disease Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101500025915 Homo sapiens Angiostatin Proteins 0.000 description 1
- 101100369992 Homo sapiens TNFSF10 gene Proteins 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 208000010159 IgA glomerulonephritis Diseases 0.000 description 1
- 206010021263 IgA nephropathy Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 102100039064 Interleukin-3 Human genes 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- MLFKVJCWGUZWNV-UHFFFAOYSA-N L-alanosine Natural products OC(=O)C(N)CN(O)N=O MLFKVJCWGUZWNV-UHFFFAOYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 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
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- GDBQQVLCIARPGH-UHFFFAOYSA-N Leupeptin Natural products CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N GDBQQVLCIARPGH-UHFFFAOYSA-N 0.000 description 1
- 108010000817 Leuprolide Proteins 0.000 description 1
- UPYKUZBSLRQECL-UKMVMLAPSA-N Lycopene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1C(=C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=C)CCCC2(C)C UPYKUZBSLRQECL-UKMVMLAPSA-N 0.000 description 1
- JEVVKJMRZMXFBT-XWDZUXABSA-N Lycophyll Natural products OC/C(=C/CC/C(=C\C=C\C(=C/C=C/C(=C\C=C\C=C(/C=C/C=C(\C=C\C=C(/CC/C=C(/CO)\C)\C)/C)\C)/C)\C)/C)/C JEVVKJMRZMXFBT-XWDZUXABSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 241000204031 Mycoplasma Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- ACFIXJIJDZMPPO-NNYOXOHSSA-J NADPH(4-) Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP([O-])(=O)OP([O-])(=O)OC[C@@H]2[C@H]([C@@H](OP([O-])([O-])=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-J 0.000 description 1
- KTDZCOWXCWUPEO-UHFFFAOYSA-N NS-398 Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1CCCCC1 KTDZCOWXCWUPEO-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- 108010066154 Nuclear Export Signals Proteins 0.000 description 1
- JZTPOMIFAFKKSK-UHFFFAOYSA-N O-phosphonohydroxylamine Chemical compound NOP(O)(O)=O JZTPOMIFAFKKSK-UHFFFAOYSA-N 0.000 description 1
- 229960005524 O6-benzylguanine Drugs 0.000 description 1
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- SUDAHWBOROXANE-VIFPVBQESA-N PD 0325901-Cl Chemical compound OC[C@H](O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-VIFPVBQESA-N 0.000 description 1
- 239000009820 PHY 906 Substances 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 102000029797 Prion Human genes 0.000 description 1
- 108091000054 Prion Proteins 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 229940079156 Proteasome inhibitor Drugs 0.000 description 1
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 1
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 239000012083 RIPA buffer Substances 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- QEHOIJJIZXRMAN-UHFFFAOYSA-N Rebeccamycin Natural products OC1C(O)C(OC)C(CO)OC1N1C2=C3NC4=C(Cl)C=CC=C4C3=C3C(=O)NC(=O)C3=C2C2=CC=CC(Cl)=C21 QEHOIJJIZXRMAN-UHFFFAOYSA-N 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- YJDYDFNKCBANTM-QCWCSKBGSA-N SDZ PSC 833 Chemical compound C\C=C\C[C@@H](C)C(=O)[C@@H]1N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C(=O)[C@H](C(C)C)NC1=O YJDYDFNKCBANTM-QCWCSKBGSA-N 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 206010068771 Soft tissue neoplasm Diseases 0.000 description 1
- 208000021712 Soft tissue sarcoma Diseases 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 108700011582 TER 286 Proteins 0.000 description 1
- 108010000449 TNF-Related Apoptosis-Inducing Ligand Receptors Proteins 0.000 description 1
- 102000002259 TNF-Related Apoptosis-Inducing Ligand Receptors Human genes 0.000 description 1
- JACAAXNEHGBPOQ-LLVKDONJSA-N Talampanel Chemical compound C([C@H](N(N=1)C(C)=O)C)C2=CC=3OCOC=3C=C2C=1C1=CC=C(N)C=C1 JACAAXNEHGBPOQ-LLVKDONJSA-N 0.000 description 1
- LGGHDPFKSSRQNS-UHFFFAOYSA-N Tariquidar Chemical compound C1=CC=CC2=CC(C(=O)NC3=CC(OC)=C(OC)C=C3C(=O)NC3=CC=C(C=C3)CCN3CCC=4C=C(C(=CC=4C3)OC)OC)=CN=C21 LGGHDPFKSSRQNS-UHFFFAOYSA-N 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
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 208000024313 Testicular Neoplasms Diseases 0.000 description 1
- 206010057644 Testis cancer Diseases 0.000 description 1
- QHOPXUFELLHKAS-UHFFFAOYSA-N Thespesin Natural products CC(C)c1c(O)c(O)c2C(O)Oc3c(c(C)cc1c23)-c1c2OC(O)c3c(O)c(O)c(C(C)C)c(cc1C)c23 QHOPXUFELLHKAS-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000005485 Thrombocytosis Diseases 0.000 description 1
- 108010078233 Thymalfasin Proteins 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 1
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 1
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 1
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 208000006593 Urologic Neoplasms Diseases 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 208000033559 Waldenström macroglobulinemia Diseases 0.000 description 1
- 208000008383 Wilms tumor Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- DFYPFJSPLUVPFJ-QJEDTDQSSA-N [(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[5-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl] [(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methyl hydrogen phosphate Chemical compound Cc1cn([C@H]2C[C@H](OP(O)(=O)OC[C@H]3O[C@H](C[C@@H]3OP(O)(=O)OC[C@H]3O[C@H](C[C@@H]3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)[C@@H](COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)O[C@H]3C[C@@H](O[C@@H]3COP(O)(=O)OC3CC(OC3CO)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)O2)c(=O)[nH]c1=O DFYPFJSPLUVPFJ-QJEDTDQSSA-N 0.000 description 1
- FKCMADOPPWWGNZ-YUMQZZPRSA-N [(2r)-1-[(2s)-2-amino-3-methylbutanoyl]pyrrolidin-2-yl]boronic acid Chemical compound CC(C)[C@H](N)C(=O)N1CCC[C@H]1B(O)O FKCMADOPPWWGNZ-YUMQZZPRSA-N 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- IBXPAFBDJCXCDW-MHFPCNPESA-A [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].Cc1cn([C@H]2C[C@H](O)[C@@H](COP([S-])(=O)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3COP([O-])(=S)O[C@H]3C[C@@H](O[C@@H]3CO)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3cnc4c3nc(N)[nH]c4=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O IBXPAFBDJCXCDW-MHFPCNPESA-A 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 108010011755 acetyl-prolyl-histidyl-seryl-cysteinyl-asparaginamide Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 201000005188 adrenal gland cancer Diseases 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 229950005033 alanosine Drugs 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 1
- 229960003437 aminoglutethimide Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940046836 anti-estrogen Drugs 0.000 description 1
- 230000001833 anti-estrogenic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 229940125648 antineoplastic drug candidate Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 229950002465 apaziquone Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 229950003462 atiprimod Drugs 0.000 description 1
- SERHTTSLBVGRBY-UHFFFAOYSA-N atiprimod Chemical compound C1CC(CCC)(CCC)CCC11CN(CCCN(CC)CC)CC1 SERHTTSLBVGRBY-UHFFFAOYSA-N 0.000 description 1
- 208000019493 atypical carcinoid tumor Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- FZIZEIAMIREUTN-UHFFFAOYSA-N azane;cerium(3+) Chemical compound N.[Ce+3] FZIZEIAMIREUTN-UHFFFAOYSA-N 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229960003094 belinostat Drugs 0.000 description 1
- NCNRHFGMJRPRSK-MDZDMXLPSA-N belinostat Chemical compound ONC(=O)\C=C\C1=CC=CC(S(=O)(=O)NC=2C=CC=CC=2)=C1 NCNRHFGMJRPRSK-MDZDMXLPSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 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
- 229940050390 benzoate Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- ASZMLLYVWJJPMZ-UHFFFAOYSA-N benzyl 3-[tert-butyl(dimethyl)silyl]oxy-3-methylcyclobutane-1-carboxylate Chemical compound C1C(O[Si](C)(C)C(C)(C)C)(C)CC1C(=O)OCC1=CC=CC=C1 ASZMLLYVWJJPMZ-UHFFFAOYSA-N 0.000 description 1
- AFFVTFZFBYSFES-UHFFFAOYSA-N benzyl 3-hydroxy-3-methylcyclobutane-1-carboxylate Chemical compound C1C(C)(O)CC1C(=O)OCC1=CC=CC=C1 AFFVTFZFBYSFES-UHFFFAOYSA-N 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
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- ACFIXJIJDZMPPO-UHFFFAOYSA-N beta-NADPH Natural products C1=CCC(C(=O)N)=CN1C1C(O)C(O)C(COP(O)(=O)OP(O)(=O)OCC2C(C(OP(O)(O)=O)C(O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000003592 biomimetic effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229960005539 bryostatin 1 Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- CUWODFFVMXJOKD-UVLQAERKSA-N buserelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](COC(C)(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 CUWODFFVMXJOKD-UVLQAERKSA-N 0.000 description 1
- 229960002719 buserelin Drugs 0.000 description 1
- 229960002092 busulfan Drugs 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
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 1
- 235000020964 calcitriol Nutrition 0.000 description 1
- 239000011612 calcitriol Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229960000846 camphor Drugs 0.000 description 1
- 229930008380 camphor Natural products 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 229940088954 camptosar Drugs 0.000 description 1
- OJLHWPALWODJPQ-QNWVGRARSA-N canfosfamide Chemical compound ClCCN(CCCl)P(=O)(N(CCCl)CCCl)OCCS(=O)(=O)C[C@H](NC(=O)CC[C@H](N)C(O)=O)C(=O)N[C@@H](C(O)=O)C1=CC=CC=C1 OJLHWPALWODJPQ-QNWVGRARSA-N 0.000 description 1
- 229950000772 canfosfamide Drugs 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- OWIUPIRUAQMTTK-UHFFFAOYSA-N carbazic acid Chemical compound NNC(O)=O OWIUPIRUAQMTTK-UHFFFAOYSA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 238000002701 cell growth assay Methods 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- HZCWPKGYTCJSEB-UHFFFAOYSA-N chembl118841 Chemical compound C12=CC(OC)=CC=C2NC2=C([N+]([O-])=O)C=CC3=C2C1=NN3CCCN(C)C HZCWPKGYTCJSEB-UHFFFAOYSA-N 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 229940044683 chemotherapy drug Drugs 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
- 229950009003 cilengitide Drugs 0.000 description 1
- AMLYAMJWYAIXIA-VWNVYAMZSA-N cilengitide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](C(C)C)N(C)C(=O)[C@H]1CC1=CC=CC=C1 AMLYAMJWYAIXIA-VWNVYAMZSA-N 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 239000000571 coke Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000004148 curcumin Substances 0.000 description 1
- 235000012754 curcumin Nutrition 0.000 description 1
- 229940109262 curcumin Drugs 0.000 description 1
- 238000011461 current therapy Methods 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- BALGDZWGNCXXES-UHFFFAOYSA-N cyclopentane;propanoic acid Chemical compound CCC(O)=O.C1CCCC1 BALGDZWGNCXXES-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 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
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- UFULAYFCSOUIOV-UHFFFAOYSA-O cysteaminium Chemical compound [NH3+]CCS UFULAYFCSOUIOV-UHFFFAOYSA-O 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 229960000975 daunorubicin Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 229940026692 decadron Drugs 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 229940027008 deltasone Drugs 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 201000001981 dermatomyositis Diseases 0.000 description 1
- MXHRCPNRJAMMIM-UHFFFAOYSA-N desoxyuridine Natural products C1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 MXHRCPNRJAMMIM-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000001840 diploid cell Anatomy 0.000 description 1
- 235000021186 dishes Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- HKXBNHCUPKIYDM-CGMHZMFXSA-N doxercalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C HKXBNHCUPKIYDM-CGMHZMFXSA-N 0.000 description 1
- 229960000413 doxercalciferol Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 206010013781 dry mouth Diseases 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- HKSZLNNOFSGOKW-UHFFFAOYSA-N ent-staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 HKSZLNNOFSGOKW-UHFFFAOYSA-N 0.000 description 1
- 229950002189 enzastaurin Drugs 0.000 description 1
- 230000008995 epigenetic change Effects 0.000 description 1
- YJGVMLPVUAXIQN-UHFFFAOYSA-N epipodophyllotoxin Natural products COC1=C(OC)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YJGVMLPVUAXIQN-UHFFFAOYSA-N 0.000 description 1
- UFNVPOGXISZXJD-XJPMSQCNSA-N eribulin Chemical compound C([C@H]1CC[C@@H]2O[C@@H]3[C@H]4O[C@H]5C[C@](O[C@H]4[C@H]2O1)(O[C@@H]53)CC[C@@H]1O[C@H](C(C1)=C)CC1)C(=O)C[C@@H]2[C@@H](OC)[C@@H](C[C@H](O)CN)O[C@H]2C[C@@H]2C(=C)[C@H](C)C[C@H]1O2 UFNVPOGXISZXJD-XJPMSQCNSA-N 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical compound CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 229950000484 exisulind Drugs 0.000 description 1
- 238000011347 external beam therapy Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229950003662 fenretinide Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- YLQWCDOCJODRMT-UHFFFAOYSA-N fluoren-9-one Chemical compound C1=CC=C2C(=O)C3=CC=CC=C3C2=C1 YLQWCDOCJODRMT-UHFFFAOYSA-N 0.000 description 1
- 238000002875 fluorescence polarization Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229950011423 forodesine Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 229950001109 galiximab Drugs 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960003297 gemtuzumab ozogamicin Drugs 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 102000054767 gene variant Human genes 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 229940045109 genistein Drugs 0.000 description 1
- 235000006539 genistein Nutrition 0.000 description 1
- TZBJGXHYKVUXJN-UHFFFAOYSA-N genistein Natural products C1=CC(O)=CC=C1C1=COC2=CC(O)=CC(O)=C2C1=O TZBJGXHYKVUXJN-UHFFFAOYSA-N 0.000 description 1
- ZCOLJUOHXJRHDI-CMWLGVBASA-N genistein 7-O-beta-D-glucoside Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C(C=3C=CC(O)=CC=3)=COC2=C1 ZCOLJUOHXJRHDI-CMWLGVBASA-N 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229950011595 glufosfamide Drugs 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 102000006602 glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical class C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229930000755 gossypol Natural products 0.000 description 1
- 229950005277 gossypol Drugs 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 230000003676 hair loss Effects 0.000 description 1
- 201000009277 hairy cell leukemia Diseases 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 230000009931 harmful effect Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 235000008216 herbs Nutrition 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- HHXHVIJIIXKSOE-QILQGKCVSA-N histrelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC(N=C1)=CN1CC1=CC=CC=C1 HHXHVIJIIXKSOE-QILQGKCVSA-N 0.000 description 1
- 229960002193 histrelin Drugs 0.000 description 1
- 108700020746 histrelin Proteins 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- HYFHYPWGAURHIV-UHFFFAOYSA-N homoharringtonine Natural products C1=C2CCN3CCCC43C=C(OC)C(OC(=O)C(O)(CCCC(C)(C)O)CC(=O)OC)C4C2=CC2=C1OCO2 HYFHYPWGAURHIV-UHFFFAOYSA-N 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960004171 hydroxychloroquine Drugs 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- HIFJCPQKFCZDDL-ACWOEMLNSA-N iloprost Chemical compound C1\C(=C/CCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)C(C)CC#CC)[C@H](O)C[C@@H]21 HIFJCPQKFCZDDL-ACWOEMLNSA-N 0.000 description 1
- 229960002240 iloprost Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- IWKXDMQDITUYRK-KUBHLMPHSA-N immucillin H Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)N[C@H]1C1=CNC2=C1N=CNC2=O IWKXDMQDITUYRK-KUBHLMPHSA-N 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 239000003022 immunostimulating agent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- SETFNECMODOHTO-UHFFFAOYSA-N indisulam Chemical compound C1=CC(S(=O)(=O)N)=CC=C1S(=O)(=O)NC1=CC=CC2=C1NC=C2Cl SETFNECMODOHTO-UHFFFAOYSA-N 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 230000006882 induction of apoptosis Effects 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 206010022498 insulinoma Diseases 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940117681 interleukin-12 Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000010262 intracellular communication Effects 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- NICJCIQSJJKZAH-AWEZNQCLSA-N irofulven Chemical compound O=C([C@@]1(O)C)C2=CC(C)=C(CO)C2=C(C)C21CC2 NICJCIQSJJKZAH-AWEZNQCLSA-N 0.000 description 1
- 229950005254 irofulven Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 235000014705 isoleucine Nutrition 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008274 jelly Substances 0.000 description 1
- 229960004125 ketoconazole Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229960004942 lenalidomide Drugs 0.000 description 1
- GOTYRUGSSMKFNF-UHFFFAOYSA-N lenalidomide Chemical compound C1C=2C(N)=CC=CC=2C(=O)N1C1CCC(=O)NC1=O GOTYRUGSSMKFNF-UHFFFAOYSA-N 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 229950001845 lestaurtinib Drugs 0.000 description 1
- 235000005772 leucine Nutrition 0.000 description 1
- 208000002741 leukoplakia Diseases 0.000 description 1
- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
- 108010052968 leupeptin Proteins 0.000 description 1
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 1
- 229960004338 leuprorelin Drugs 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- DHMTURDWPRKSOA-RUZDIDTESA-N lonafarnib Chemical compound C1CN(C(=O)N)CCC1CC(=O)N1CCC([C@@H]2C3=C(Br)C=C(Cl)C=C3CCC3=CC(Br)=CN=C32)CC1 DHMTURDWPRKSOA-RUZDIDTESA-N 0.000 description 1
- 229950001750 lonafarnib Drugs 0.000 description 1
- 235000012680 lutein Nutrition 0.000 description 1
- 239000001656 lutein Substances 0.000 description 1
- 229960005375 lutein Drugs 0.000 description 1
- KBPHJBAIARWVSC-RGZFRNHPSA-N lutein Chemical compound C([C@H](O)CC=1C)C(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\[C@H]1C(C)=C[C@H](O)CC1(C)C KBPHJBAIARWVSC-RGZFRNHPSA-N 0.000 description 1
- ORAKUVXRZWMARG-WZLJTJAWSA-N lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C ORAKUVXRZWMARG-WZLJTJAWSA-N 0.000 description 1
- 235000012661 lycopene Nutrition 0.000 description 1
- 239000001751 lycopene Substances 0.000 description 1
- 229960004999 lycopene Drugs 0.000 description 1
- OAIJSZIZWZSQBC-GYZMGTAESA-N lycopene Chemical compound CC(C)=CCC\C(C)=C\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C=C(/C)CCC=C(C)C OAIJSZIZWZSQBC-GYZMGTAESA-N 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 201000000564 macroglobulinemia Diseases 0.000 description 1
- 229950000547 mafosfamide Drugs 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CCERQOYLJJULMD-UHFFFAOYSA-M magnesium;carbanide;chloride Chemical compound [CH3-].[Mg+2].[Cl-] CCERQOYLJJULMD-UHFFFAOYSA-M 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- 229960003151 mercaptamine Drugs 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229940087646 methanolamine Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 235000006109 methionine Nutrition 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- SIVLENRHVVVPKJ-UHFFFAOYSA-N methyl 4-chloro-3-[(2-methoxy-7-oxo-8h-pyrido[2,3-d]pyrimidine-6-carbonyl)amino]benzoate Chemical compound COC(=O)C1=CC=C(Cl)C(NC(=O)C=2C(NC3=NC(OC)=NC=C3C=2)=O)=C1 SIVLENRHVVVPKJ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 description 1
- 229960000282 metronidazole Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 229960000350 mitotane Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- JFOHFDSMPQIOES-UHFFFAOYSA-N motexafin Chemical compound C1=NC2=CC(OCCOCCOCCOC)=C(OCCOCCOCCOC)C=C2N=CC(C(=C2CCCO)C)=NC2=CC(C(CC)=C2CC)=NC2=CC2=C(CCCO)C(C)=C1N2 JFOHFDSMPQIOES-UHFFFAOYSA-N 0.000 description 1
- 229950011637 motexafin Drugs 0.000 description 1
- 239000002324 mouth wash Substances 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 description 1
- KWQWWUXRGIIBAS-UHFFFAOYSA-N n-[2-(4-hydroxyanilino)pyridin-3-yl]-4-methoxybenzenesulfonamide;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=CN=C1NC1=CC=C(O)C=C1 KWQWWUXRGIIBAS-UHFFFAOYSA-N 0.000 description 1
- YZOQZEXYFLXNKA-UHFFFAOYSA-N n-[4-(4-amino-2-ethylimidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide Chemical compound C1=CC=CC2=C(N(C(CC)=N3)CCCCNS(C)(=O)=O)C3=C(N)N=C21 YZOQZEXYFLXNKA-UHFFFAOYSA-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
- UMJJGDUYVQCBMC-UHFFFAOYSA-N n-ethyl-n'-[3-[3-(ethylamino)propylamino]propyl]propane-1,3-diamine Chemical compound CCNCCCNCCCNCCCNCC UMJJGDUYVQCBMC-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- BUIMWOLDCCGZKZ-UHFFFAOYSA-N n-hydroxynitramide Chemical compound ON[N+]([O-])=O BUIMWOLDCCGZKZ-UHFFFAOYSA-N 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
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical class [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-M naphthalene-2-sulfonate Chemical compound C1=CC=CC2=CC(S(=O)(=O)[O-])=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-M 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 229950009793 naptumomab estafenatox Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 201000008026 nephroblastoma Diseases 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000030147 nuclear export Effects 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 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
- 229960002230 omacetaxine mepesuccinate Drugs 0.000 description 1
- HYFHYPWGAURHIV-JFIAXGOJSA-N omacetaxine mepesuccinate Chemical compound C1=C2CCN3CCC[C@]43C=C(OC)[C@@H](OC(=O)[C@@](O)(CCCC(C)(C)O)CC(=O)OC)[C@H]4C2=CC2=C1OCO2 HYFHYPWGAURHIV-JFIAXGOJSA-N 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000004279 orbit Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- HFHZKZSRXITVMK-UHFFFAOYSA-N oxyphenbutazone Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 HFHZKZSRXITVMK-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 208000021255 pancreatic insulinoma Diseases 0.000 description 1
- 229960001972 panitumumab Drugs 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
- 208000003154 papilloma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 229940097097 pediapred Drugs 0.000 description 1
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- JRKICGRDRMAZLK-UHFFFAOYSA-L peroxydisulfate Chemical compound [O-]S(=O)(=O)OOS([O-])(=O)=O JRKICGRDRMAZLK-UHFFFAOYSA-L 0.000 description 1
- 229960002087 pertuzumab Drugs 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000008063 pharmaceutical solvent Substances 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 238000002732 pharmacokinetic assay Methods 0.000 description 1
- 239000012071 phase 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
- DYUMLJSJISTVPV-UHFFFAOYSA-N phenyl propanoate Chemical compound CCC(=O)OC1=CC=CC=C1 DYUMLJSJISTVPV-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- ISWRGOKTTBVCFA-UHFFFAOYSA-N pirfenidone Chemical compound C1=C(C)C=CC(=O)N1C1=CC=CC=C1 ISWRGOKTTBVCFA-UHFFFAOYSA-N 0.000 description 1
- 229960003073 pirfenidone Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- PEZPMAYDXJQYRV-UHFFFAOYSA-N pixantrone Chemical compound O=C1C2=CN=CC=C2C(=O)C2=C1C(NCCN)=CC=C2NCCN PEZPMAYDXJQYRV-UHFFFAOYSA-N 0.000 description 1
- 229960004403 pixantrone Drugs 0.000 description 1
- 229940072689 plaquenil Drugs 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 150000003058 platinum compounds Chemical class 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229960001237 podophyllotoxin Drugs 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- YVCVYCSAAZQOJI-UHFFFAOYSA-N podophyllotoxin Natural products COC1=C(O)C(OC)=CC(C2C3=CC=4OCOC=4C=C3C(O)C3C2C(OC3)=O)=C1 YVCVYCSAAZQOJI-UHFFFAOYSA-N 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- VJZLQIPZNBPASX-OJJGEMKLSA-L prednisolone sodium phosphate Chemical compound [Na+].[Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 VJZLQIPZNBPASX-OJJGEMKLSA-L 0.000 description 1
- 229940096111 prelone Drugs 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 1
- 239000003207 proteasome inhibitor Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000006920 protein precipitation Effects 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 230000005588 protonation Effects 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000000191 radiation effect Effects 0.000 description 1
- 239000000718 radiation-protective agent Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229940124553 radioprotectant Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 229950007649 ranpirnase Drugs 0.000 description 1
- 108010061338 ranpirnase Proteins 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 230000036647 reaction Effects 0.000 description 1
- 229960005567 rebeccamycin Drugs 0.000 description 1
- INSACQSBHKIWNS-QZQSLCQPSA-N rebeccamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](OC)[C@@H](CO)O[C@H]1N1C2=C3N=C4[C](Cl)C=CC=C4C3=C3C(=O)NC(=O)C3=C2C2=CC=CC(Cl)=C21 INSACQSBHKIWNS-QZQSLCQPSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- OAKGNIRUXAZDQF-TXHRRWQRSA-N retaspimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(O)C1=CC(O)=C2NCC=C OAKGNIRUXAZDQF-TXHRRWQRSA-N 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- OHRURASPPZQGQM-GCCNXGTGSA-N romidepsin Chemical compound O1C(=O)[C@H](C(C)C)NC(=O)C(=C/C)/NC(=O)[C@H]2CSSCC\C=C\[C@@H]1CC(=O)N[C@H](C(C)C)C(=O)N2 OHRURASPPZQGQM-GCCNXGTGSA-N 0.000 description 1
- 229960003452 romidepsin Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- 235000021003 saturated fats Nutrition 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000002453 shampoo Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 238000012421 spiking Methods 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 1
- CGPUWJWCVCFERF-UHFFFAOYSA-N staurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(OC)O1 CGPUWJWCVCFERF-UHFFFAOYSA-N 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000005156 substituted alkylene group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- MVGSNCBCUWPVDA-MFOYZWKCSA-N sulindac sulfone Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)(=O)=O)C=C1 MVGSNCBCUWPVDA-MFOYZWKCSA-N 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229950010637 talabostat Drugs 0.000 description 1
- 108010009573 talabostat Proteins 0.000 description 1
- 229950004608 talampanel Drugs 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 229950007866 tanespimycin Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229950005890 tariquidar Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 108091035539 telomere Proteins 0.000 description 1
- 102000055501 telomere Human genes 0.000 description 1
- 210000003411 telomere Anatomy 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 206010043554 thrombocytopenia Diseases 0.000 description 1
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)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)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 1
- 229960004231 thymalfasin Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- ZCIHMQAPACOQHT-ZGMPDRQDSA-N trans-isorenieratene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/c1c(C)ccc(C)c1C)C=CC=C(/C)C=Cc2c(C)ccc(C)c2C ZCIHMQAPACOQHT-ZGMPDRQDSA-N 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 229960005526 triapine Drugs 0.000 description 1
- AYNNSCRYTDRFCP-UHFFFAOYSA-N triazene Chemical compound NN=N AYNNSCRYTDRFCP-UHFFFAOYSA-N 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-O trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=[NH+]C(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-O 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229950010938 valspodar Drugs 0.000 description 1
- 108010082372 valspodar Proteins 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000006444 vascular growth Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000010455 vermiculite Substances 0.000 description 1
- 229910052902 vermiculite Inorganic materials 0.000 description 1
- 235000019354 vermiculite Nutrition 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- 229950001212 volociximab Drugs 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- ZFNVDHOSLNRHNN-UHFFFAOYSA-N xi-3-(4-Isopropylphenyl)-2-methylpropanal Chemical compound O=CC(C)CC1=CC=C(C(C)C)C=C1 ZFNVDHOSLNRHNN-UHFFFAOYSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- ZPFVQKPWGDRLHL-ZLYBXYBFSA-N zosuquidar trihydrochloride Chemical compound Cl.Cl.Cl.C([C@H](COC=1C2=CC=CN=C2C=CC=1)O)N(CC1)CCN1C1C2=CC=CC=C2[C@H]2C(F)(F)[C@H]2C2=CC=CC=C12 ZPFVQKPWGDRLHL-ZLYBXYBFSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- 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 or sparfloxacin
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/20—Spiro-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
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- 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
- C07D495/10—Spiro-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 Table
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Toxicology (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本發明係於美國國家衛生研究院資助之Grant Nos. CA121279;CA069568;與CA097248下進行。美國政府具有本發明之特定權利。
本發明提供醫藥化學領域中之化合物、組成物、及方法。本發明提供之化合物與組成物係有關作為p53與MDM2間相互作用拮抗劑用之螺-吲哚酮類,及其作為治療癌症與其他疾病之治療劑之用途。
侵犯性癌細胞表現型乃多種基因及表觀基因改變,導致細胞內傳訊路徑鬆綁之結果(Ponder,Nature 411
:336(2001))。癌細胞典型地無法執行細胞凋亡程式及由於正常細胞凋亡機制缺損而缺乏適當細胞凋亡被認為是癌症之特徵(Loweet al
.,Carcinogenesis 21
:485(2000))。由於正常細胞凋亡機制缺損使癌細胞無力執行細胞凋亡程式,常與對化學治療、輻射抗性增加、或免疫治療誘發之細胞凋亡相關。不同起因的人類癌症由於細胞凋亡缺損導致對目前治療流程之原發或後天抗性係當前癌症治療之主要問題(Loweet al
.,Carcinogenesis 21
:485(2000);Nicholson,Nature 407
:810(2000))。因此,針對增進癌症病患存活率與生活品質之新穎分子標靶專一性抗癌療法設計與開發之當前及未來之努力應包括專一性地以癌細胞對細胞凋亡之抗性為目標之策略。
p53腫瘤抑制因子在細胞週期進展、衰老、及細胞凋亡之調控上扮演核心角色(Vogelsteinet al., Nature 408
:307(2000);Goberdhan,Cancer Cell 7
:505(2005))。MDM2與p53為自動調控反饋迴路之一部分(Wuet al.,Genes Dev. 7
:1126(1993))。MDM2被p53與MDM2轉錄活化,接著,經由至少三個機制抑制p53活性(Wuet al.,Genes Dev. 7
:1126(1993)。第一,MDM2蛋白直接結合於p53交替活化功能部位,因而抑制p53傳介之交替活化;第二,MDM2蛋白含有核輸出信號序列,與p53結合後,誘導p53之核輸出,防止p53與標的DNAs結合。第三,MDM2蛋白為E3泛素連接酶,與p53結合後,能促進p53降解。
過去雖已成功地設計出MDM2之高親和性肽系抑制劑(Garcia-Echeverriaet al.,Med. Chem. 43
:3205(2000)),然而由於其細胞滲透性及活體內生物利用性差,彼等抑制劑並非適當之治療分子。儘管製藥業界精深努力,惟在鑑定有效力、非肽小分子抑制劑上,高量篩選策略之成功仍極有限。因此,業界對於p53-MDM2相互作用之非肽、似藥物之小分子抑制劑有所需求。
p53與MDM2相互作用之結構基礎已經由x射線結晶學被建立(Kussieet al.,Science 274
:948(1996))。
p53-MDM2相互作用之螺-吲哚酮系拮抗劑見述於美國專利案7,759,383 B2與7,737,174 B2。
本發明慮及使罹患癌症之動物暴露於治療有效量之增加p53與p53相關蛋白(例如,p63、p73)功能藥物(例如,小分子)可抑制癌細胞或支持細胞之生長。於若干具體實例中,本文提供之化合物抑制p53或p53相關蛋白與MDM2或MDM2相關蛋白(例如,MDMX)間之相互作用。抑制p53或p53相關蛋白與MDM2或MDM2相關蛋白間之相互作用可抑制癌細胞或支持細胞之生長及/或使得該等細胞成為對癌症治療藥物或輻射療法之誘發細胞死亡活性更為敏感之族群。於若干具體實例中,本文提供之抑制劑藉由干擾通常會促進p53降解之p53-MDM2相互作用而延長p53之半衰期。本文提供之化合物於呈單一療法投與以於癌細胞中誘發衰老、細胞生長抑制、細胞凋亡及/或細胞週期停止時,或與附加製劑[例如其他誘發細胞死亡或細胞週期中斷之癌症治療藥物或輻射療法(組合療法)]暫時關聯投與時,在治療多種癌症類型上,能符合未滿足之需求,俾使相較於單僅以癌症治療藥物或輻射療法處理的動物之對應比例細胞,有極大比例之癌細胞或支持細胞對執行細胞凋亡程式敏感。
於若干具體實例中,相較於單獨以化合物或抗癌藥物/輻射處理之動物,以治療有效量之一或多種本文提供之化合物與抗癌劑處理之動物產生較大之抗腫瘤活性及臨床優勢。換言之,由於本文提供之化合物可降低表現p53或p53相關蛋白細胞之細胞凋亡門檻,於組合使用一或多種本文提供之化合物時,回應抗癌藥物/輻射之細胞凋亡誘發活性而成功執行細胞凋亡程式之細胞比例將增加。替代地,本文提供之化合物可用於提供較低、因而較少毒性及更可容忍之抗癌藥物及/或輻射劑量之投與,而產生與單獨抗癌藥物/輻射習用劑量相同之腫瘤反應/臨床優勢。由於所有被認可的抗癌藥物與輻射處理之劑量為已知,因此本文提供之本發明化合物、組成物、與方法可與一或多種被認可之抗癌藥物及/或輻射處理一起使用。又,由於本文提供之化合物至少部分可藉由激發p53與p53相關蛋白之促細胞凋亡及/或細胞週期-抑制活性而作用,癌細胞與支持細胞暴露於治療有效量之化合物可暫時與細胞回應抗癌藥物或輻射療法以執行細胞凋亡程式之企圖相配合。因此,於若干具體實例中,投與本文提供之化合物或組成物組合其他已知抗癌藥物提供特別有效之治療方法。
於其他具體實例中,本文所提供之p53或p53相關蛋白和MDM2與MDM2相關蛋白間相互作用之抑制劑可能經由抑制劑導使正常細胞細胞週期停止之能力,而可保護正常(例如,非過度增殖)細胞免受特定化學治療劑與輻射之毒性作用。舉例而言,本文提供之抑制劑可於含有野生型或功能性p53(及/或野生型或功能性p53相關蛋白)之細胞中引致細胞週期停止,而對含有突變、刪除、或者不具功能性或功能性較小的p53(及/或突變、刪除、或者不具功能性或功能性較小的p53相關蛋白)之癌細胞不具效力或效力較小。與本文提供之抑制劑組合投與時,藉由容許使用化學治療劑或處理之較高劑量或較長時間之處理而不增加此等處理之毒性副作用,此差別性保護效力可能提供更有效之癌症治療。
申請人已發現,本文提供之特定螺-吲哚酮類展現意想不到之似藥物性質組合。此等意想不到之組合包括,例如,二或多種活體外效力、活體內效力、活體外肝微粒體穩定性、合乎所需之吸收、分佈、代謝、及排泄(ADME)性質。舉例而言,相較於已知之p53-MDM2相互作用拮抗劑,本文提供之特定螺-吲哚酮對於例如利用活體外肝微粒體穩定性及/或活體內藥物動力學測定之代謝降解更具抗性,及/或展現增進之活體內效力。
申請人亦已發現,可代謝裂解之基團可用於增加母分子之水溶性。因此,於若干具體實例中,相較於其母分子,本文提供之螺-吲哚酮類係具有增進水溶性之有用前驅藥物。
於若干具體實例中,本文提供之螺-吲哚酮類具下式I:
式中:R1a
、R1b
、R1c
、與R1d
係獨立地選自包括氫、鹵素、羥基、胺基、硝基、氰基、烷氧基、芳氧基、視需要經取代之烷基、鹵烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之環烯基、視需要經取代之芳基、視需要經取代之雜芳基、羧醯胺基、與磺醯胺基之組群;R2
係選自包括視需要經取代之與芳基視需要經取代之雜芳基之組群;R3
係選自包括視需要經取代之烷基、視需要經取代之(環烷基)烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之環烯基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R4
係選自包括氫與視需要經取代之C1
-C6
烷基之組群;R5
係選自包括下文諸式之組群:
式中:R6a
與R6b
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R7
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R8a
與R8b
各自獨立地選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;或R8a
與R8b
和與彼等連接之碳一起形成視需要經取代之3至8員環烷基;W1
係選自包括-OR9a
與-NR9b
R9c
之組群;R9a
為氫;R9b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R9d
、與-CONR9e
R9f
之組群;R9c
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R9b
與R9c
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R9d
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R9e
與R9f
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R9e
與R9f
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;W2
係選自包括-OR10
與-NR11a
R11b
之組群;惟當W1
為-OR9a
及W2
為-OR10
時,則R7
、R8a
、與R8b
至少一者不為氫;R10
為氫;或R9a
與R10
有一者為氫,另一者為可代謝裂解之基團;R11a
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R11c
、與-CONR11d
R11e
之組群;R11b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R11a
與R11b
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R11c
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R11d
與R11e
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R11d
與R11e
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;n為1、2、3、4、或5;R12a
、R12b
、R12c
與R12d
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R13
係選自包括氫與視需要經取代之C1
-C6
烷基之組群;R14
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;Z係選自包括-OR15
與-NR16a
R16b
之組群;或Z與R14
一起形成羰基,亦即,C=O基團;R15
係選自包括氫與可代謝裂解之基團之組群;R16a
係選自包括-SO2
R16c
與-CONR16d
R16e
之組群;R16b
係選自包括氫與視需要經取代之烷基之組群;R16c
係選自包括視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R16d
與R16e
各自獨立地選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R16d
與R16e
和與彼等連接之氮原子一起形成4至8員雜環;o為1、2、或3;p為0、1、2、或3;R17a
、R17b
、R17c
與R17d
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R18
係選自包括氫與視需要經取代之C1
-C6
烷基之組群;R19
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R20
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R21a
與R21b
各自為氫;或R21a
與R21b
有一者為氫,另一者為可代謝裂解之基團;q為0、1、2、或3;r為1、2、或3;R22a
、R22b
、R22c
、與R22d
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R23
係選自包括氫與視需要經取代之C1
-C6
烷基之組群;R24
係選自包括-SO2
R24a
與-CONR24b
R24c
之組群;R24a
係選自包括視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R24b
與R24c
各自獨立地選自包括氫、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R24b
與R24c
和與彼等連接之氮原子一起形成4至8員雜環;s與t各自獨主立地為1、2、或3;X係選自包括O、S、與NR'
之組群;Y係選自包括O、S、與NR"
之組群;R'
係選自包括氫、視需要經取代之烷基、芳烷基、與視需要經取代之環烷基之組群;R"
係選自包括氫、視需要經取代之烷基、芳烷基、與視需要經取代之環烷基之組群;及代表單鍵或雙鍵;或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,或具下述結構式之化合物:
或其醫藥上可接受之鹽、溶劑合物、或前驅藥物。
於若干具體實例中,本文提供之化合物抑制p53或p53相關蛋白與MDM2或MDM2相關蛋白間之相互作用。
於若干具體實例中,本文提供之化合物含有可代謝裂解之基團。特別是,於若干具體實例中,本文提供之化合物含有可用於連接可代謝裂解基團之羥基環烷基側鏈之羥基基團。適當之可代謝裂解基團包括,惟不限於,胺基酸酯類或磷酸酯類。
於若干具體實例中,本文提供之化合物在含有功能性p53或p53相關蛋白之細胞中可用於誘發衰老、細胞週期停止及/或細胞凋亡。本文亦提供使用本文提供之化合物使細胞對附加製劑(例如衰老、細胞凋亡及/或細胞週期停止之誘發劑)敏化之方法。在以化學治療劑處理之前,本文提供之化合物亦可經由誘發細胞週期停止而用於提供對正常細胞之化學保護。於一具體實例中,使正常細胞對化學治療劑或處理具抗性之方法包括使細胞與一或多種本文提供之化合物接觸。於一具體實例中,保護具有過度增殖疾病動物中之正常細胞免受化學治療劑或處理的毒性副作用之方法包括投與該動物本文提供之化合物。本文係提供治療、改善、或預防由於對正常細胞投與化學治療劑引致之失調症、副作用、或症狀之方法,該方法包括投與進行化療之動物本文提供之化合物。由化療引致之此等失調症及症狀之實例包括,惟不限於,黏膜炎、口腔炎、口乾、胃腸失調、及脫髮。
本文提供之化合物可用於治療、改善、或預防失調症,例如受誘發凋亡細胞死亡影響者,例如,其特徵為細胞凋亡失調之失調症,包括過度增殖疾病例如癌症。於特定具體實例中,化合物可用於治療、改善、或預防其特徵為對癌症療法具抗性之癌症(例如,具化療抗性、輻射抗性、激素抗性等之彼等癌細胞)。於其他具體實例中,化合物可用於治療其特徵為表現功能性p53或p53相關蛋白之過度增殖疾病。於其他具體實例中,本文提供之化合物可藉由誘發正常(例如,非過度增殖)細胞中之細胞週期停止而用於保護彼等細胞免受化學治療劑與處理之毒性副作用。
於一具體實例中,係提供醫藥組成物。該等醫藥組成物可於醫藥上可接受之載體中含有一或多種本文提供之化合物。
於一具體實例中,係提供套組。該等套組可包含一或多種本文提供之化合物及投與動物該化合物之用法說明。該等套組可視需要含有其他治療劑,例如,抗癌劑或細胞凋亡調控劑。
本文提供之抑制p53或p53相關蛋白與MDM2或MDM2相關蛋白間相互作用之化合物。藉由抑制MDM2或MDM2相關蛋白對p53或p53相關蛋白之負面影響,彼等化合物使細胞對細胞凋亡及/或細胞週期停止之誘發劑敏化。於若干具體實例中,本文提供之化合物誘發細胞凋亡及/或細胞週期停止。因此,本文亦提供使細胞對細胞凋亡及/或細胞週期停止之誘發劑敏化之方法,及於細胞中誘發細胞凋亡及/或細胞週期停止之方法。於若干具體實例中,彼等方法包括使細胞與一或多種本文提供之化合物單獨或組合附加製劑(例如,細胞凋亡誘發劑或細胞週期干擾劑)接觸。
本文亦提供治療、改善、或預防病患之失調症之方法,該方法包括投與病患一或多種本文提供之化合物與附加製劑(例如,細胞凋亡誘發劑)。此等失調症包括其特徵為細胞凋亡失調之病症及其特徵為表現功能性p53或p53相關蛋白之細胞增殖之病症。於其他具體實例中,係提供保護動物之正常(例如,非過度增殖)細胞免受化學治療劑與處理之毒性副作用之方法。彼等方法包括投與該動物一或多種本文提供之化合物。
本文所用“抗癌劑”一詞係指用於治療過度增殖疾病例如癌症[例如,於哺乳動物(如人類)中]之任何治療劑(例如,化學治療化合物及/或分子治療化合物)、反義療法、輻射療法、或手術治療。
本文所用“前驅藥物”一詞係指母“藥物”分子之藥理上不具活性之衍生物,其需於目標生理系統內生物轉化(例如,無論自發性或酵素性)以釋放、或轉化(例如,酵素性、生理性、機械性、電磁性)前驅藥物成為活性藥物。前驅藥物之設計係用以克服與穩定性、水溶性、毒性、缺乏專一性、或受限之生物利用性相關之問題。例示之前驅藥物由活性藥物分子本身與化學掩蓋基團(例如,可逆地抑制該藥物之活性之基團)組成。若干前驅藥物為化合物之變化或衍生物,其具有於代謝條件下可裂解之基團。前驅藥物可使用此項技藝中已知之方法,以母化合物容易地予以製備,彼等方法見述於例如A Textbook of Drug Design and Development,Krogsgaard-Larsen and H. Bundgaard(eds.),Gordon & Breach,1991,特別是第5章:"Design and Applications of Prodrugs";Design of Prodrugs,H. Bundgaard(ed.),Elsevier,1985;Prodrugs: Topical and Ocular Drug Delivery,K. B. Sloan(ed.),Marcel Dekker,1998;Methods in Enzymology,K. Widder et al.(eds.),Vol. 42,Academic Press,1985,particularly pp. 309-396;Burger's Medicinal Chemistry and Drug Discovery,5th Ed.,M. Wolff(ed.),John Wiley & Sons,1995,particularly Vol. 1 and pp. 172-178 and pp. 949-982;Pro-Drugs as Novel Delivery Systems,T. Higuchi and V. Stella(eds.),Am. Chem. Soc.,1975;與Bioreversible Carriers in Drug Design,E. B. Roche(ed.),Elsevier,1987。
當例示之前驅藥物於生理條件下進行溶劑分解作用或進行酵素降解或其他生化轉化反應(例如,磷酸化反應、氫化反應、脫氫反應、醣化反應)時,即成為具活體內或活體外醫藥活性。前驅藥物通常提供水溶性、組織相容性、或於哺乳類生物中延時釋放等優點(參見例如,Bundgard,Design of Prodrugs,pp.
7-9,21-24,Elsevier,Amsterdam(1985);與Silverman,The Organic Chemistry of Drug Design and Drug Action,pp.
352-401,Academic Press,San Diego,CA(1992))。常見之前驅藥物包括酸衍生物例如以母酸與適當醇(例如,低級烷醇)反應製備之酯類或使母醇與適當羧酸(例如,胺基酸)反應製備之酯類、使母酸化合物與胺反應製備之醯胺類、使鹼性基團反應形成醯化鹼衍生物(例如,低級烷基醯胺)、或含磷之衍生物例如磷酸、膦酸、與胺基磷酸酯類包括環狀磷酸酯、膦酸酯、與胺基磷酸酯,參見,例如,US 2007/0249564 A1。
本文所用"可代謝裂解之基團"一詞係指經由代謝程序可自母分子裂解並以氫置換之基團。含有可代謝裂解基團之特定化合物可為前驅藥物,亦即,彼等於藥理上不具活性。含有可代謝裂解基團之其他特定化合物可為p53與MDM2間相互作用之拮抗劑。於此情形下,彼等化合物可具有母分子之更多、更少、或相等之活性。可代謝裂解基團之實例包括自胺基酸衍生者(參見,例如,US 2006/0241017 A1;US 2006/0287244 A1;與WO 2005/046575 A2)或含磷化合物(參見,例如,U.S. 2007/0249564 A1),如反應圖式1所示。
本文所用“醫藥上可接受之鹽”一詞係指本文提供之化合物於目標動物(例如,哺乳動物)中生理上可容忍之任何鹽(例如,利用與酸或鹼反應製得)。本文提供之化合物之鹽可衍生自無機或有機酸與鹼。酸之實例包括,惟不限於,鹽酸、氫溴酸、硫酸、硝酸、過氯酸、反丁烯二酸、順丁烯二酸、磷酸、乙醇酸、乳酸、柳酸、琥珀酸、對甲苯磺酸、酒石酸、乙酸、檸檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸、磺酸、萘-2-磺酸、苯磺酸等。其他酸,例如草酸,其本身雖非於醫藥上可接受,惟可用於製造於獲得本文提供之化合物及其醫藥上可接受之酸加成鹽時作為中間體用之鹽類。
鹼之實例包括,惟不限於,鹼金屬(例如,鈉)氫氧化物、鹼土金屬(例如,鎂)氫氧化物、氨、與式NW4 +
(式中W為C1-4
烷基)之化合物等。
鹽之實例包括,惟不限於:乙酸鹽、己二酸鹽、海藻酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、環戊烷丙酸鹽、二葡萄糖酸鹽、十二基硫酸鹽、乙磺酸鹽、反丁烯二酸鹽、葡萄糖庙酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氯鹽、溴鹽、碘鹽、2-羥基乙磺酸鹽、乳酸鹽、順丁烯二酸鹽、甲磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、草酸鹽、雙羥萘酸、果凍酸鹽、過硫酸鹽、苯丙酸鹽、苦味酸鹽、三甲基乙酸、丙酸鹽、琥珀酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽、十一酸鹽等。鹽之其他實例包括與適當陽離子例如Na+
、NH4 +
、與NW4 +
(式中W為C1-4
烷基)化合之本文提供化合物之陰離子等。供治療用途時,本文提供之化合物之鹽被認為於醫藥上可接受。然而,不是醫藥上可接受的酸與鹼之鹽亦可,舉例而言,於醫藥上可接受之化合物之製備或純化上找到用途。
本文所用"溶劑合物"一詞係指本文提供之化合物與一或多種溶劑分子(無論有機或無機)之物理結合。此物理結合常包括氫鍵。於特定情況下,溶劑合物能予以單離;舉例而言,於一或多種溶劑合物分子納入結晶固體之結晶格子中時。"溶劑合物"涵蓋溶液相及孤立之溶劑合物。溶劑合物之實例包括水合物、乙醇合物、與甲醇合物。
本文所用"醫藥上可接受之單價陽離子"一詞係指無機陽離子例如,惟不限於,鹼金屬離子例如Na+
與K+
,以及有機陽離子例如,惟不限於,銨與經取代之銨離子例如NH4 +
、NHMe3 +
、NH2
Me2 +
、NHMe3 +
與NMe4 +
。
本文所用"醫藥上可接受之二價陽離子"一詞係指無機陽離子例如,惟不限於,鹼土金屬陽離子例如Ca2+
與Mg2+
。
醫藥上可接受之單價與二價陽離子之實例詳述於例如Bergeet al. J. Pharm. Sci.,66
:1-19(1997)。
本文所用“治療有效量”一詞係指足以導使改善失調症之一或多種症狀、或防止失調症進展、或使失調症復原之治療劑(包括本文提供之化合物與組成物物質)之量。舉例而言,關於癌症之治療,於一具體實例中,治療有效量可意指降低腫瘤生長速率、減少腫瘤質量、降低轉移數量、使腫瘤進展時間增加、增加腫瘤細胞凋亡、或增加存活時間至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%、至少90%、至少95%、或至少100%之治療劑量。
本文所用“敏化”一詞係指,經由投與第一治療劑(例如,本文提供之化合物),使動物或動物中之細胞對第二治療劑之生物效應(例如,促進或阻止細胞功能方面包括,惟不限於,細胞分裂、細胞生長、增殖、侵入、血管生成、壞死、或細胞凋亡)更敏感、或更靈敏。第一劑對標的細胞之敏化效力可由投與及未投與第一劑下,投與第二劑所觀察預期生物效應(例如,促進或阻止細胞功能方面包括,惟不限於,細胞生長、增殖、侵入、血管生成、或細胞凋亡)之差異予以測定。相較於缺乏第一劑下之反應,敏化細胞之反應可增加至少約10%、至少約20%、至少約30%、至少約40%、至少約50%、至少約60%、至少約70%、至少約80%、至少約90%、至少約100%、至少約150%、至少約200%、至少約250%、至少300%、至少約350%、至少約400%、至少約450%、或至少約500%。
本文所用"細胞凋亡失調"一詞係指細胞經由細胞凋亡進行細胞死亡的能力之任何偏差。細胞凋亡失調與多種症狀相關或被其誘發,該等症狀之非限制實例包括,自體免疫失調[例如,全身性紅斑狼瘡、類風濕關節炎、移植物抗宿主疾病、重症肌無力、或休格倫氏(Sjgren)症候群]、慢性炎性症狀[例如,牛皮癬、氣喘或克隆氏(Crohn)症]、過度增殖失調(例如,腫瘤、B細胞淋巴瘤、或T細胞淋巴瘤)、病毒感染(例如,皰疹、乳頭狀瘤、或HIV)、及其他症狀例如骨關節炎與動脈粥狀硬化症。應注意的是,當失調係由病毒感染誘發或與其相關時,在發生或觀察到失調當時,可能可檢測出或無法檢測出病毒感染。亦即,病毒引發之失調甚至可能於病毒感染症狀消失後才發生。
本文所用"功能性p53"一詞係指以正常、高量或低量表現之野生型p53及保留野生型p53之至少約5%活性(例如,至少約10%、約20%、約30%、約40%、約50%、或更多野生型活性)之p53變異株或對偶基因變異體。
本文所用"p53相關蛋白"一詞係指與p53具有至少25%序列同源性、具有腫瘤抑制因子活性、及被與MDM2或MDM2相關蛋白相互作用抑制之蛋白質。p53相關蛋白之實例包括,惟不限於,p63與p73。
本文所用"MDM2相關蛋白"一詞係指與MDM2具有至少25%序列同源性、及抑制p53或p53相關蛋白或與其相互作用之蛋白質。MDM2相關蛋白之實例包括,惟不限於,MDMX。本文所用"衰老"一詞係指非癌二倍體細胞喪失分裂能力,及部分特徵為端粒失去功能或縮短之現象。
本文所用“過度增殖疾病”一詞係指動物之局部族群增殖細胞不受正常生長一般侷限所控制之任何症狀。過度增殖失調症之實例包括腫瘤、贅瘤、淋巴瘤、白血病等。贅瘤若未經受侵入或轉移則被認為是良性,若經受侵入或轉移則為惡性。“轉移性”細胞意指細胞會侵入鄰近之身體結構。增生係涉及組織或器官之細胞數增加而結構或功能無顯著變化之細胞增殖形式。組織變形係經控制之細胞生長形式,其中一類型之完全分化細胞替換另一類型之分化細胞。
經活化之淋巴樣細胞常導致自體免疫失調或慢性炎性症狀。本文所用“自體免疫失調”一詞係指生物產生認定該生物本身之分子、細胞或組織之抗體或免疫細胞之任何症狀。自體免疫失調之非限制實例包括自體免疫性溶血性貧血、自體免疫性肝炎、柏格氏(Berger)症或IgA腎病、口炎性腹瀉、慢性疲勞症候群、克隆氏症、皮肌炎、纖維肌痛、移植物抗宿主疾病、葛瑞夫氏(Grave)症、橋本氏(Hashimoto)甲狀腺炎、自發性血小板缺乏紫斑症、扁平苔蘚、多發性硬化症、重症肌無力、皮癬、風濕熱、風濕性關節炎、硬皮症、休格倫氏症候群、全身性紅斑狼瘡、第1型糖尿病、潰瘍性結腸炎、白斑病等。
本文所用“腫瘤疾病”一詞係指良性(非癌性)或惡性(癌性)細胞之任何異常生長。
本文所用"正常細胞"一詞係指未經受異常生長或分裂之細胞。正常細胞為非癌性,且不屬於任何過度增殖疾病或失調。
本文所用“抗腫瘤劑”一詞係指阻止目標(例如,惡性)贅瘤增殖、生長、或擴散之任何化合物。
本文所用“預防”與“防止”等詞係指減少動物中病理細胞(例如,過度增殖或腫瘤細胞)之出現。預防可能是徹底的,例如,使患者之病理細胞完全不存在;也可能是部分的,俾使相較於未以一或多種本文提供化合物處理,患者病理細胞較少出現。
本文所用"細胞凋亡調控劑"一詞係指涉及調控(例如,抑制、減少、增加、促進)細胞凋亡之製劑。細胞凋亡調控劑之實例包括含有死亡功能部位(例如,惟不限於,Fas/CD95、TRAMP、TNF RI、DR1、DR2、DR3、DR4、DR5、DR6、FADD、與RIP)之蛋白質。細胞凋亡調控劑之其他實例包括,惟不限於,TNFα、Fas配體、針對Fas/CD95與其他TNF家族受體之抗體、TRAIL(亦為所謂Apo2配體或Apo2L/TRAIL)、針對TRAIL-R1或TRAIL-R2之抗體、Bcl-2、p53、BAX、BAD、Akt、CAD、PI3激酶、PP1、與半胱天冬酶等蛋白質。調控劑概括地包括TNF家族受體與TNF家族配體之促效劑及拮抗劑。細胞凋亡調控劑可為水溶性或膜結合(例如配體或受體)。細胞凋亡調控劑包括為細胞凋亡之誘發劑者,例如TNF或TNF相關配體,特別是TRAMP配體、Fas/CD95配體、TNFR-1配體、或TRAIL。
本文所用"醫藥上可接受之載體"或"醫藥上可接受之賦形劑"涵蓋任何標準醫藥載體、溶劑、界面活性劑、或賦形劑。適當之醫藥上可接受之賦形劑包括水性賦形劑與非水性賦形劑。標準醫藥載體及其調配物見述於Remington's Pharmaceutical Sciences,Mack Publishing Co.,Easton,PA,19th ed. 1995。
本文所用“烷基”一詞本身或其他基團之一部分係指具有一至八個碳或指定碳數(例如,C1
-C18
意指1至18個碳)之直鏈或分支鏈飽和脂族烴。於一具體實例中,烷為C1
-C10
烷基。於其他具體實例中,烷基為C1
-C6
烷基。於其他具體實例中,烷基為C1
-C4
烷基。烷基之實例包括甲基、乙基、正丙基、異丙基、正丁基、第二丁基、異丁基、第三丁基、正戊基、正己基、異己基、正庚基、4,4-二甲基戊基、正辛基、2,2,4-三甲基戊基、壬基、癸基等。
本文所用"視需要經取代之烷基"一詞本身或其他基團之一部分意指如上文界定之烷基係未經取代或者被一、二或三個獨立地選自羥基(亦即,-OH)、硝基(亦即,-NO2
)、氰基(亦即,-CN)、視需要經取代之環烷基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基或磺醯胺基之取代基取代。於一具體實例中,視需要經取代之烷基被兩個取代基取代。於其他具體實例中,視需要經取代之烷基被一個取代基取代。於其他具體實例中,取代基係選自羥基(亦即,羥烷基)、視需要經取代之環烷基(亦即,(環烷基)烷基)、或胺基(亦即,胺烷基)。視需要經取代之烷基之實例包括-CH2
OCH3
、-CH2
CH2
NH2
、-CH2
CH2
NH(CH3
)、-CH2
CH2
CN、-CH2
SO2
CH3
、羥甲基、羥乙基、羥丙基等。
本文所用"伸烷基"一詞本身或其他基團之一部分係指含有一、二、三、四、或多個鄰接亞甲基之二價烷基。伸烷基之實例包括-(CH2
)-、-(CH2
)2
-、-(CH2
)3
-、-(CH2
)4
-等。
本文所用"視需要經取代之伸烷基"一詞本身或其他基團之一部分意指如上文界定之伸烷基係未經取代或被一、二、三、或四個獨立地選自包括視需要經取代之C1
-C6
烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群之取代基取代。於一具體實例中,視需要經取代之C1
-C6
烷基為甲基。於一具體實例中,視需要經取代之芳基為視需要被一或兩個鹵基取代之苯基。視需要經取代之伸烷基之實例包括-CH(CH3
)-、-C(CH3
)2
-、-CH2
CH(CH3
)-、-CH2
CH(CH3
)CH2
-、-CH2
CH(Ph)CH2
-、-CH(CH3
)CH(CH3
)-等。
本文所用"鹵烷基"一詞本身或其他基團之一部分係指具有一至六個鹵基取代基之如上文界定之烷基。於一具體實例中,鹵烷基具有一、二或三個鹵基取代基。鹵烷基之實例包括三氟甲基、-CH2
CH2
F等。
本文所用"羥烷基"一詞本身或其他基團之一部分係指具有一個羥基取代基之如上文界定之烷基。羥烷基之實例包括羥甲基、羥乙基、羥丙基等。
本文所用“二羥烷基”一詞本身或其他基團之一部分係指具有兩個羥基取代基之如上文界定之烷基。二羥烷基之實例包括-CH2
CH2
CCH3
(OH)CH2
OH、-CH2
CH2
CH(OH)CH(CH3)OH、CH2
CH(CH2
OH)2
、-CH2
CH2
CH(OH)C(CH3)2
OH、-CH2
CH2
CCH3
(OH)CH(CH3
)OH等,包括其立體異構物。
本文所用"羥基環烷基"一詞本身或其他基團之一部分係指具有至少一個(例如,一或兩個)羥基取代基之如下文界定之視需要經取代之環烷基。羥基環烷基之實例包括:
等,包括其立體異構物。
本文所用"視需要經取代之(環烷基)烷基"一詞本身或其他基團之一部分係指具有視需要經取代之環烷基(如下文所界定)取代基之視需要經取代之如上文界定之烷基。視需要經取代之(環烷基)烷基之實例包括:
等,包括其立體異構物。
本文所用"芳烷基"一詞本身或其他基團之一部分係指具有一、二或三個視需要經取代之芳基取代基之視需要經取代之如上文界定之烷基。於一具體實例中,芳烷基具有兩個視需要經取代之芳基取代基。於其他具體實例中,芳烷基具有一個視需要經取代之芳基取代基。於其他具體實例中,芳烷基為芳基(C1
-C4
烷基)。於其他具體實例中,芳基(C1
-C4
烷基)具有兩個視需要經取代之芳基取代基。於其他具體實例中,芳基(C1
-C4
烷基)具有一個視需要經取代之芳基取代基。芳烷基之實例包括,例如,苄基、苯乙基、(4-氟苯基)乙基、苯丙基、二苯甲基(亦即,Ph2
CH-)、二苯乙基(Ph2
CHCH2
-)等。
本文所用"環烷基"一詞本身或其他基團之一部分係指含具有三至十二個或指定碳數之碳原子之一至三個環之飽和及部分不飽和(含有一或兩個雙鍵)環狀烴基(亦即,C3
-C12
環烷基)。於一具體實例中,環烷基具有一個環。於其他具體實例中,環烷基為C3
-C6
環烷基。環烷基之實例包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、降基、十氫萘、金剛烷基等。
本文所用“視需要經取代之環烷基”一詞本身或其他基團之一部分意指如上文界定之環烷基係未經取代或被一、二或三個獨立地選自鹵基、硝基、氰基、羥基、胺基、視需要經取代之烷基、鹵烷基、羥烷基、胺烷基、芳烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之炔基、視需要經取代之芳基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基或磺醯胺基之取代基取代。"視需要經取代之環烷基"一詞亦意指如上文界定之環烷基可稠合於視需要經取代之芳基。視需要經取代之環烷基之實例包括等。
本文所用"烯基"一詞本身或其他基團之一部分係指含有一、二或三個碳-碳雙鍵之如上文界定之烷基。於一具體實例中,烯基具有一個碳-碳雙鍵。烯基之實例包括-CH=CH2
、-CH2
CH=CH2
、-CH2
CH2
CH=CH2
、-CH2
CH2
CH=CHCH3
等。
本文所用"視需要經取代之烯基"一詞本身或其他基團之一部分意指如上文界定之烯基係未經取代或被一、二或三個獨立地選自鹵基、硝基、氰基、羥基、胺基、視需要經取代之烷基、鹵烷基、羥烷基、芳烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之炔基、視需要經取代之芳基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基或磺醯胺基之取代基取代。視需要經取代之烯基之實例包括-CH=CHPh、-CH2
CH=CHPh等。
本文所用"環烯基"一詞本身或其他基團之一部分係指含有一、二或三個碳-碳雙鍵之如上文界定之環烷基。於一具體實例中,環烯基具有一個碳-碳雙鍵。環烯基之實例包括環戊烯基、環己烯基等。
本文所用"視需要經取代之環烯基"一詞本身或其他基團之一部分意指如上文界定之環烯基係未經取代或被一、二或三個獨立地選自鹵基、硝基、氰基、羥基、胺基、視需要經取代之烷基、鹵烷基、羥烷基、芳烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之炔基、視需要經取代之芳基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基或磺醯胺基之取代基取代。
本文所用"炔基"一詞本身或其他基團之一部分係指含有一至三個碳-碳三鍵之如上文界定之烷基。於一具體實例中,炔基具有一個碳-碳三鍵。炔基之實例包括-C≡CH、-C≡CCH3
、-CH2
C≡CH、-CH2
CH2
C≡CH與-CH2
CH2
C≡CCH3
。
本文所用"視需要經取代之炔基"一詞本身或其他基團之一部分意指如上文界定之炔基係未經取代或被一、二或三個獨立地選自鹵基、硝基、氰基、羥基、胺基、視需要經取代之烷基、鹵烷基、羥烷基、芳烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之炔基、視需要經取代之芳基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基或磺醯胺基之取代基取代。視需要經取代之炔基之實例包括-C≡CPh、-CH2
C≡CPh等。
本文所用"芳基"一詞本身或其他基團之一部分係指具有六至十四個碳原子之單環與雙環芳族環系(亦即,C6
-C14
芳基)例如苯基(縮寫為Ph)、1-萘基與2-萘基等。
本文所用“視需要經取代之芳基”一詞本身或其他基團之一部分意指如上文界定之芳基係未經取代或被一至五個獨立地選自鹵基、硝基、氰基、羥基、胺基、視需要經取代之烷基、鹵烷基、羥烷基、芳烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之炔基、視需要經取代之芳基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基或磺醯胺基之取代基取代。於一具體實例中,視需要經取代之芳基為視需要經取代之苯基。於一具體實例中,視需要經取代之苯基具有四個取代基。於其他具體實例中,視需要經取代之苯基具有三個取代基。於其他具體實例中,視需要經取代之苯基具有兩個取代基。於其他具體實例中,視需要經取代之苯基具有一個取代基。經取代之芳基之實例包括2-甲基苯基、2-甲氧苯基、2-氟苯基、2-氯苯基、2-溴苯基、3-甲基苯基、3-甲氧苯基、3-氟苯基、3-氯苯基、4-甲基苯基、4-乙基苯基、4-甲氧苯基、4-氟苯基、4-氯苯基、2,6-二-氟苯基、2,6-二-氯苯基、2-甲基-3-甲氧苯基、2-乙基-3-甲氧苯基、3,4-二-甲氧苯基、3,5-二-氟苯基、3,5-二-甲基苯基與3,5-二甲氧-4-甲基苯基、2-氟-3-氯苯基、3-氯-4-氟苯基等。視需要經取代之芳基一詞意欲包括具有稠合之視需要經取代之環烷基及稠合之視需要經取代之雜環之基團;其實例包括等。
本文所用"雜芳基"一詞本身或其他基團之一部分係指具有五至十四個碳原子(亦即,C5
-C14
雜芳基)及一、二、三或四個獨立地選自包括氧、氮與硫之組群之雜原子之單環與雙環芳族環系。於一具體實例中,雜芳基具有三個雜原子。於一具體實例中,雜芳基具有兩個雜原子。於一具體實例中,雜芳基具有一個雜原子。雜芳基之實例包括1-吡咯基、2-吡咯基、3-吡咯基、2-咪唑基、4-咪唑基、吡基、2-唑基、4-唑基、5-唑基、3-異唑基、4-異唑基、5-異唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、嘌呤基、2-苯并咪唑基、4-苯并咪唑基、5-苯并咪唑基、2-苯并噻唑基、4-苯并噻唑基、5-苯并噻唑基、5-吲哚基、3-吲唑基、4-吲唑基、5-吲唑基、1-異喹啉基、5-異喹啉基、2-喹啉基、5-喹啉基、2-喹啉基、3-喹啉基、6-喹啉基等。雜芳基一詞意欲包括可能之N-氧化物。N-氧化物之實例包括吡啶基N-氧化物等。
本文所用"視需要經取代之雜芳基"一詞本身或其他基團之一部分意指如上文界定之雜芳基係未經取代或被一至四個、典型地為一或兩個獨立地選自鹵基、硝基、氰基、羥基、胺基、視需要經取代之烷基、鹵烷基、羥烷基、芳烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之炔基、視需要經取代之芳基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基或磺醯胺基之取代基取代。於一具體實例中,視需要經取代之雜芳基具有一個取代基。於其他具體實例中,取代基為視需要經取代之芳基、芳烷基、或視需要經取代之烷基。於其他具體實例中,取代基為視需要經取代之苯基。任何可用之碳或氮原子均可經取代。視需要經取代之雜芳基之實例包括
等。
本文所用"雜環"一詞本身或其他基團之一部分係指含具有二至十二個碳原子與一或兩個氧、硫或氮原子之一至三個環之飽和及部分不飽和(含有一或兩個雙鍵)環狀基團(亦即,C2
-C12
雜環)。雜環可視需要經由碳或氮原子連接於分子之其餘部分。雜環基之實例包括等。
本文所用“視需要經取代之雜環”一詞本身或其他基團之一部分意指如上文界定之雜環係未經取代或被一至四個獨立地選自鹵基、硝基、氰基、羥基、胺基、視需要經取代之烷基、鹵烷基、羥烷基、芳烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之炔基、視需要經取代之芳基、視需要經取代之雜芳基、視需要經取代之雜環、烷氧基、芳氧基、芳烷氧基、烷硫基、羧醯胺基、磺醯胺基、-CORc
、-SO2
Rd
、-N(Re
)CORf
、-N(Re
)SO2
Rg
或-N(Re
)C=N(Rh
)-胺基[其中Rc
為氫、視需要經取代之烷基、視需要經取代之芳基、或視需要經取代之雜芳基;Rd
為視需要經取代之烷基、視需要經取代之芳基、或視需要經取代之雜芳基;Re
為氫、視需要經取代之烷基、視需要經取代之芳基、或視需要經取代之雜芳基;Rf
為氫、視需要經取代之烷基、視需要經取代之芳基、或視需要經取代之雜芳基;Rg
為視需要經取代之烷基、視需要經取代之芳基、或視需要經取代之雜芳基;及Rh
為氫、-CN、視需要經取代之烷基、視需要經取代之芳基、或視需要經取代之雜芳基]之取代基取代。取代可發生於任何可用之碳或氮原子上。經取代之雜環基之實例包括
等。視需要經取代之雜環可稠合於芳基基團以提供如上述之視需要經取代之芳基。
本文所用"烷氧基"一詞本身或其他基團之一部分係指連接於末端氧原子之鹵烷基、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之烯基或視需要經取代之炔基。烷氧基之實例包括甲氧基、第三丁氧基、-OCH2
CH=CH2
等。
本文所用"芳氧基"一詞本身或其他基團之一部分係指連接於末端氧原子之視需要經取代之芳基。芳氧基之實例包括苯氧基等。
本文所用"芳烷氧基"一詞本身或其他基團之一部分係指連接於末端氧原子之芳烷基。芳烷氧基之實例包括苄氧基等。
本文所用"烷硫基"一詞本身或其他基團之一部分係指連接於末端硫原子之鹵烷基、芳烷基、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之烯基或視需要經取代之炔基。烷硫基之實例包括-SCH3
等。
本文所用"鹵基"或"鹵素"等詞本身或其他基團之一部分係指氟基、氯基、溴基或碘基。於一具體實例中,鹵基為氟基或氯基。
本文所用"胺基"一詞本身或其他基團之一部分係指具式-NRa
Rb
之基團,式中Ra
與Rb
獨立地為氫、鹵烷基、芳烷基、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之雜環、視需要經取代之芳基或視需要經取代之雜芳基;或Ra
與Rb
和與彼等連接之氮原子一起形成四至七員視需要經取代之雜環。胺基之實例包括-NH2
、-N(H)CH3
、-N(CH3
)2
、N(H)CH2
CH3
、N(CH2
CH3
)、-N(H)CH2
Ph等。
本文所用"羧醯胺基"一詞本身或其他基團之一部分係指具式-CO-胺基之基團。羧醯胺基之實例包括-CONH2
、-CON(H)CH3
、-CON(H)Ph、-CON(H)CH2
CH2
Ph、-CON(CH3
)2
、CON(H)CHPh2
等。
本文所用"磺醯胺基"一詞本身或其他基團之一部分係指具式-SO2
-胺基之基團。磺醯胺基之實例包括-SO2
NH2
、-SO2
N(H)CH3
、-SO2
N(H)Ph等。
本文所用"約"一詞意指所述數值±10%。因此,"約10"意指9至11。
特定之本發明化合物可能呈包括光學異構物及構形異構物(或構形物)之立體異構物存在。本發明涵蓋所有立體異構物,包括呈單一個別立體異構物製劑與各者之富集製劑二者,及該等立體異構物之消旋混合物以及根據熟習此項技藝人士悉知之方法分離之個別非鏡像異構物與鏡像異構物。
於特定具體實例中,係提供具下式I之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中R1a
、R1b
、R1c
、與R1d
係獨立地選自包括氫、鹵素、羥基、胺基、硝基、氰基、烷氧基、芳氧基、視需要經取代之烷基、鹵烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之環烯基、視需要經取代之芳基、視需要經取代之雜芳基、羧醯胺基、與磺醯胺基之組群;R2
係選自包括視需要經取代之與芳基視需要經取代之雜芳基之組群;R3
係選自包括視需要經取代之烷基、視需要經取代之(環烷基)烷基、視需要經取代之環烷基、視需要經取代之烯基、視需要經取代之環烯基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R4
係選自包括氫與視需要經取代之烷基之組群;R5
係選自下述組群:
式中:R6a
與R6b
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R7
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R8a
與R8b
各自獨立地選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;或R8a
與R8b
和與彼等連接之碳一起形成視需要經取代之3至8員環烷基;W1
係選自包括-OR9a
與-NR9b
R9c
之組群;R9a
為氫;R9b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R9d
、與-CONR9e
R9f
之組群;R9c
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R9b
與R9c
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R9d
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R9e
與R9f
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R9e
與R9f
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;W2
係選自包括-OR10
與-NR11a
R11b
之組群;惟當W1
為-OR9a
及W2
為-OR10
時,則R7
、R8a
、與R8b
至少一者不為氫;R10
為氫;或R9a
與R10
有一者為氫,另一者為可代謝裂解之基團;R11a
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R11c
、與-CONR11d
R11e
之組群;R11b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R11a
與R11b
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R11c
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R11d
與R11e
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R11d
與R11e
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;n為1、2、3、4、或5;R12a
、R12b
、R12c
與R12d
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R13
係選自包括氫與視需要經取代之C1
-C6
烷基之組群;R14
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;Z係選自包括-OR15
與-NR16a
R16b
之組群;或Z與R14
一起形成羰基,亦即,C=O基團;R15
係選自包括氫與可代謝裂解之基團之組群;R16a
係選自包括-SO2
R16c
與-CONR16d
R16e
之組群;R16b
係選自包括氫與視需要經取代之烷基之組群;R16c
係選自包括視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R16d
與R16e
各自獨立地選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R16d
與R16e
和與彼等連接之氮原子一起形成4至8員雜環;o為1、2、或3;p為0、1、2、或3;R17a
、R17b
、R17c
與R17d
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R18
係選自包括氫與視需要經取代之C1
-C6
烷基之組群;R19
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R20
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R21a
與R21b
各自為氫;或R21a
與R21b
有一者為氫,另一者為可代謝裂解之基團;q為0、1、2、或3;r為1、2、或3;R22a
、R22b
、R22c
、與R22d
各自獨立地選自包括氫與視需要經取代之C1
-C6
烷基之組群;R23
係選自包括氫與視需要經取代之C1
-C6
烷基之組群;R24
係選自包括-SO2
R24a
與-CONR24b
R24c
之組群;R24a
係選自包括視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R24b
與R24c
各自獨立地選自包括氫、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R24b
與R24c
和與彼等連接之氮原子一起形成4至8員雜環;s與t各自獨主立地為1、2、或3;X係選自包括O、S、與NR'
之組群;Y係選自包括O、S、與NR"
之組群;R'
係選自包括氫、視需要經取代之烷基、芳烷基、與視需要經取代之環烷基之組群;R"
係選自包括氫、視需要經取代之烷基、芳烷基、與視需要經取代之環烷基之組群;及代表單鍵或雙鍵;或具下述結構式之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
於特定具體實例中,係有關代表單鍵或雙鍵之式I
化合物。
於特定具體實例中,式I化合物係立體異構物混合物,例如,非鏡像異構物及/或鏡像異構物之混合物,例如,消旋混合物。於另一該等具體實例中,化合物為非鏡像異構物之混合物。於另一該等具體實例中,化合物為鏡像異構物之混合物。於特別之具體實例中,化合物為單一鏡像異構物。
於特定具體實例中,R5
係選自包括R5-1
與R5-2
之組群。於特別之具體實例中,R5
為R5
-2及Z為-OH。
於特定具體實例中,係提供具下式Ia
之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中R1a
、R1b
、R1c
、R1d
、R2
、R3
、R4
、R5
、X、與Y具有如上文式I
中敘述之意義。
於特定具體實例中,係提供具下式Ib
之化合物或其互變異構物、或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中R1a
、R1b
、R1c
、R1d
、R2
、R3
、R4
、R5
、X、與Y具有如上文式I
中敘述之意義。
於特定具體實例中,係提供具下式II
至XVII
之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中R1a
、R1b
、R1c
、R1d
、R2
、R3
、R4
、R5
、X、與Y具有如上文式I
中敘述之意義。
於若干具體實例中,係提供式II
化合物,其中R1a
、R1b
、R1c
、R1d
、R2
、R3
、R4
、R5
、X、與Y具有如上文有關式I
敘述之意義;或其醫藥上可接受之鹽、溶劑合物、或前驅藥物。
於特定具體實例中,係提供式I
至XVII
之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物。於若干具體實例中,係提供式II
化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中:
a) R1a
、R1b
、R1c
、與R1d
係獨立地選自包括氫、氟基、與氯基之組群;
b) R1a
與R1d
為氫;R1b
係選自包括氫與氟基之組群;及R1c
係選自包括氟基與氯基之組群;
c) R2
為視需要經取代之苯基;
d) R3
係選自包括視需要經取代之烷基、視需要經取代之(環烷基)烷基、與視需要經取代之環烷基之組群;
e) R4
為氫;
f) X為NH;
g) X為O;
h) X為S;
i) Y為O;
j) Y為S;
k) Y為NH;或
l) X與Y為NH;
或其任何組合。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-1
;R6a
與R6b
為氫;R7
為C1
-C4
烷基;R8a
與R8b
為氫;W為-OR10
,R9
與R10
為氫;及n為2。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-1
;R6a
與R6b
為氫;R7
為C1
-C4
烷基;R8a
與R8b
為氫;W為-NR11a
R11b
,R9
為氫;及n為2。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-1
;R6a
與R6b
為氫;R7
為C1
-C4
烷基;R8a
與R8b
為氫;W為-OR10
,R9
與R10
有一者為氫,另一者為可代謝裂解之基團;及n為2。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-2
;R12a
、R12b
、R12c
、與R12d
各自為氫;R13
為氫;Z為-OR15
及R15
為氫;o為1或2;及p為1或2。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-2
;R12a
、R12b
、R12c
、與R12d
各自為氫;R13
為氫;Z為-NR16a
R16b
;o為1或2;及p為1或2。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-2
;R12a
、R12b
、R12c
、與R12d
各自為氫;R13
為氫;Z為-OR15
及R15
為可代謝裂解之基團;o為1或2;及p為1或2。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-3
;R17a
、R17b
、R17c
、與R17d
各自為氫;R18
、R19
、與R20
為氫;R21a
與R21b
為氫;及q與r為1。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
為R5-3
;R17a
、R17b
、R17c
、與R17d
各自為氫;R18
、R19
、與R20
為氫;R21a
與R21b
有一者為氫,另一者為可代謝裂解之基團;及q與r為1。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R2
為具式R2-1
之視需要經取代之芳基:
R25a
、R25b
、R25c
、R25d
、與R25e
各自獨立地選自包括氫、鹵素、羥基、硝基、胺基、氰基、烷氧基、視需要經取代之烷基、鹵烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群。於特別之具體實例中,R25a
係選自包括氫與氟基之組群;R25b
為氯基;R25c
係選自包括氫與氟基之組群;及R25d
與R25e
為氫。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物;其中R5
係選自下述組群:
包括其立體異構物,例如,鏡像異構物,式中:R7
為視需要經取代之C1
-C4
烷基;R9a
與R10
各自為氫;或R9a
與R10
有一者為氫,另一者為可代謝裂解之基團;R9b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R9d
、與-CONR9e
R9f
之組群;R9c
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R9b
與R9c
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R9d
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R9e
與R9f
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R9e
與R9f
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R11a
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R11c
、與-CONR11d
R11e
之組群;R11b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R11a
與R11b
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R11c
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R11d
與R11e
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R11d
與R11e
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R14
係選自包括氫、C1
-C4
烷基、或C3
-C6
環烷基之組群;R15
為氫或可代謝裂解之基團;R16a
係選自包括之-SO2
R16c
與-CONR16d
R之組群;R16c
係選自包括視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R16d
與R16e
各自獨立地選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R16d
與R16e
和與彼等連接之氮原子一起形成4至8員雜環;R19
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R20
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R21a
與R21b
各自為氫;或R21a
與R21b
有一者為氫,另一者為可代謝裂解之基團;R24
係選自包括-SO2
R24a
與-CONR24b
R24c
之組群;R24a
係選自包括視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;及R24b
與R24c
各自獨立地選自包括氫、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R24b
與R24c
和與彼等連接之氮原子一起形成4至8員雜環。
於特定具體實例中,R5
係選自包括R5-5、R5-6、R5-10、R5-11、R5-12、R5-13、
與R5-14
之組群。
於特定具體實例中,R5
係選自包括R5-10
與R5-12
之組群,R14
為氫或甲基及R15
為氫。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R5
係選自下述組群:
式中:R7
係選自包括甲基、乙基、丙基、異丙基、與環丙基之組群;及R8a
與R8b
各自獨立地選自包括氫、甲基、乙基、丙基、異丙基、與環丙基之組群。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R5
係選自下述組群:
式中:R7
係選自包括甲基、乙基、丙基、異丙基、與環丙基之組群;R8a
與R8b
各自獨立地選自包括氫、甲基、乙基、丙基、異丙基、與環丙基之組群;R9d
係選自包括甲基、三氟甲基、乙基、丙基、異丙基、與環丙基之組群;及R11c
係選自包括甲基、三氟甲基、乙基、丙基、異丙基、與環丙基之組群。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R5
係選自下述組群:
式中:R7
係選自包括甲基、乙基、丙基、異丙基、與環丙基之組群;R8a
與R8b
各自獨立地選自包括氫、甲基、乙基、丙基、異丙基、與環丙基之組群;R9e
係選自包括甲基、三氟甲基、乙基、丙基、異丙基、與環丙基之組群;及R11d
係選自包括甲基、三氟甲基、乙基、丙基、異丙基、與環丙基之組群。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R5
係選自下述組群:
式中:R14
係選自包括甲基、乙基、丙基、異丙基、與環丙基之組群;及R19
與R20
各自獨立地選自包括氫、甲基、乙基、丙基、異丙基、與環丙基之組群。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R5
係選自下述組群:
式中:R14
係選自包括甲基、乙基、丙基、異丙基、與環丙基之組群;及R16c
係選自包括甲基、三氟甲基、乙基、丙基、異丙基、與環丙基之組群。
於特定具體實例中,係提供式II化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R5
係選自下述組群:
式中:R14
係選自包括甲基、乙基、丙基、異丙基、與環丙基之組群;及R16d
係選自包括甲基、三氟甲基、乙基、丙基、異丙基、與環丙基之組群。
於另一具體實例中,係提供具下式XVIIIa
之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中:R1b
與R1c
係獨立地選自包括氫、氟基、與氯基之組群;R3
係選自包括視需要經取代之烷基、視需要經取代之(環烷基)烷基、與視需要經取代之環烷基之組群;R26a
,R26b
、與R26c
係獨立地選自包括群氫、氟基、與氯基之組群;及R27
係選自下述組群:
式中:R7
為視需要經取代之C1
-C4
烷基;W2
係選自包括-OR10
與-NR11a
R11b
之組群;R9a
與R10
各自為氫;或R9a
與R10
有一者為氫,另一者為可代謝裂解之基團;R11a
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R11c
、與-CONR11d
R11e
之組群;R11b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R11a
與R11b
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R11c
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R11d
與R11e
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R11d
與R11e
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R14
係選自包括氫、視需要經取代之C1
-C4
烷基、與視需要經取代之環烷基之組群;Z係選自包括-OR15
與-NR16a
R16b
之組君與R15
係選自包括氫與可代謝裂解之基團之組群;R16a
係選自包括-SO2
R16c
與-CONR16d
R16e
之組群;R16b
係選自包括氫與視需要經取代之烷基之組群;R16c
係選自包括視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;R16d
與R16e
各自獨立地選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R16d
與R16e
和與彼等連接之氮原子一起形成4至8員雜環;R19
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R20
係選自包括氫、視需要經取代之C1
-C6
烷基、與視需要經取代之環烷基之組群;R21a
與R21b
各自為氫;或R21a
與R21b
有一者為氫,另一者為可代謝裂解之基團。
於另一具體實例中,係提供具下式XVIIIb
之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中R1b
、R1b
、R3
、R26a
、R26b
、R26c
、與R27
具有如上文式XVIIIa
中敘述之意義。
於另一具體實例中,係提供具下式XVIIIc
之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中R1b
、R1b
、R3
、R26a
、R26b
、R26c
、與R27
具有如上文式XVIIIa
中敘述之意義。
於特定具體實例中,R27
係選自包括R27-2
、R27-3
、R27-5
、R27-6
、R27-8
、R27-9
、R27-11
、R27-12
、R27-14
、R27-15
、R27-16
、R27-17
、R27-19
、R27-20
、R27-21
、R27-22
、R2-24
、R27-25
、R27-27
、R27-29
、R27-30
、R27-31
、與R27-32
之組群。於特定具體實例中,R27
係選自包括R27-2
、R27-3
、R27-5
、與R27-6
、R27-8
、R27-9
、R27-14
、R27-15
、R27-16
、及R27-17
之組群。於特定具體實例中,R27
為羥基環烷基。
於特定具體實例中,R9a
為氫;W2
為OH;Z為OH;R7
為C1
-C4
烷基,例如,甲基、乙基、丙基、或異丙基、或環丙基;R14
、R19
、與R20
各自獨主立地為氫、C1
-C4
烷基,例如,甲基、乙基、丙基、或異丙基、或環丙基;及R21a
與R21b
各自為氫。
於特定具體實例中,R9a
為氫、R7
為氫、C1
-C4
烷基、或環丙基;W2
為-NHR11a
;R11a
為C1
-C4
烷基,例如,甲基、三氟甲基、乙基、丙基、或異丙基、或環丙基;R14
為氫、C1
-C4
烷基,例如,甲基、乙基、丙基、或異丙基、或環丙基;Z為-NHSO2
R16c
或-NHCONHR16d
;及R16c
與R16d
各自獨主立地為視需要經取代之C1
-C4
烷基,例如,甲基、三氟甲基、乙基、丙基、或異丙基、或環丙基。
於特定具體實例中,係提供具下式XIX
至XXXIV
之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
式中R1b
、R1c
、R3
、R26a
、R26b
、R26c
、與R27
具有如上文有關式XVIIIa
敘述之意義。
於特定具體實例中,係提供式XIX之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R1b
、R1c
、R3
、R26a
、R26b
、R26c
、與R27
具有如上文有關式XVIIIa
敘述之意義。
於特定具體實例中,係提供式XIX之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R27
係選自下述組群:
式中:R7
為C1
-C4
烷基;R9a
與R10
為氫;或R9a
與R10
有一者為氫,另一者為可代謝裂解之基團;R11a
與R11b
各自獨立地選自包括氫、視需要經取代之C1
-C4
烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R11a
與R11b
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R14
係選自包括氫與C1
-C4
烷基之組群;R15
為氫或可代謝裂解之基團;及R16a
係選自包括-SO2
R16c
與-CONR16d
R16e
之組群;R16c
係選自包括視需要經取代之C1
-C4
烷基或環丙基之組群;R16d
與R16e
各自獨立地選自包括氫、視需要經取代之C1
-C4
烷基或環丙基之組群;或R16d
與R16e
和與彼等連接之氮原子一起形成4至8員雜環。
於特定具體實例中,係提供式XIX之化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物,其中R27
係選自下述組群:
式中:R7
為視需要經取代之C1
-C4
烷基;W2
係選自包括-ORl0
與-NRlla
Rllb
之組群;R9a
與R10
各自為氫;或R9a
與Rl0
有一者為氫,另一者為可代謝裂解之基團;R1la
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、視需要經取代之雜芳基、-SO2
R11c
、與-CONR11d
R11e
之組群;R11b
係選自包括氫、視需要經取代之烷基、視需要經取代之環烷基、視需要經取代之芳基、與視需要經取代之雜芳基之組群;或R11a
與R11b
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環;R11c
係選自包括視需要經取代之烷基與視需要經取代之環烷基之組群;R11d
與R11e
各自獨立地選自包括氫、視需要經取代之烷基、與視需要經取代之環烷基之組群;或R11d
與R11e
和與彼等連接之氮原子一起形成視需要經取代之4至8員雜環。
於特定具體實例中,係提供式XIX之化合物,其中R27
係選自下述組群:
於特定具體實例中,係提供式XIX之化合物,其中R27
係選自下述組群:
式中R11a
與R11b
和與彼等連接之氮一起形成5或6員視需要經取代之雜環。
於特定具體實例中,係提供式XIX之化合物,其中R27
係選自下述組群:
式中:R14
係選自包括氫與C1-
C4
烷基之組群;及R15
為可代謝裂解之基團。
於特定具體實例中,係提供式II
與XIX
之化合物,其中R15
為選自下述組群之可代謝裂解之基團:
式中:R28a
與R28b
各自獨立地選自包括氫、視需要經取代之烷基、與芳烷基之組群;R29a
與R29b
各自選自包括氫與視需要經取代之烷基之組群;v為1、2、3、或4;及R30a
與R30b
各自選自包括氫、視需要經取代之烷基、芳烷基、視需要經取代之芳基、與醫藥上可接受之單價陽離子之組群;或R30a
與R30b
一起代表醫藥上可接受之二價陽離子或視需要經取代之伸烷基。
於特定具體實例中,R15
為天然或非天然胺基酸之殘基。於另一具體實例中,R15
為甘胺酸、異白胺酸、丙胺酸、白胺酸、天冬醯胺、離胺酸、天冬胺酸、甲硫胺酸、半胱胺酸、苯丙胺酸、麩胺酸、蘇胺酸、麩醯胺,色胺酸、纈胺酸、脯胺酸、絲胺酸、酪胺酸、精胺酸、與組胺酸之殘基。
於特定具體實例中,係提供式II
與XIX
之化合物,其中R3
為C1
-C10
烷基。
於特定具體實例中,係提供式II
與XIX
之化合物,其中R3
係選自包括-CH2
C(CH3
)3
、-CH2
C(CH3
)2
CH2
CH3
、-CH2
C(CH3
)2
CH2
CH2
CH3
、-CH2
C(CH3
)2
CH2
CH2
CH2
CH3
、-CH2
C(CH2
CH3
)2
CH3
、與-CH2
C(CH3
)2
CH2
CH(CH3
)2
之組群。於特定具體實例中,R3
為-CH2
C(CH3
)3
。
於特定具體實例中,係提供具下述結構式之式I化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
("Ms"=-SO2
CH3
)。
於特定具體實例中,係提供具下述結構式之式I
化合物或其醫藥上可接受之鹽、溶劑合物、或前驅藥物:
("Ms"=-SO2
CH3
)。
於特定具體實例中,係提供具下述結構式之式I
化合物或其醫藥上可接受之鹽或溶劑合物,該等結構對含有為前驅藥物之可代謝裂解之胺基酸酯類或磷酸酯類:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
於特定具體實例中,係提供具下述結構式之化合物或其醫藥上可接受之鹽或溶劑合物:
結合闡明可製備本文提供化合物之方法之下述合成反應圖示,將更為瞭解本文提供之化合物與製法。起始物質可自商業來源獲得或可利用熟習此項技藝者已知之已為大家接受之文獻方法製備。一般熟習此項技藝者將顯見,藉由替換下文所示合成中之適當試劑與製劑,即可合成上文界定之化合物。
式Ia
中Y為NH之化合物可如反應圖示2與3所述合成。
式Ia
化合物可利用此項技藝中悉知之掌性解析法(例如,掌性管柱層析法)進行分離,得到式II
至XVII
之化合物。用於掌性解析之適當掌性管柱包括,例如,DaicelOD-H、DaicelAD-H與Regis Technologies ULMO掌性管柱。亦可能進行其他掌性解析法。式II
至XVII
之化合物亦可利用不對稱合成法製備。舉例而言,式II
中Y為NH之化合物可如先前所述(參見美國專利案7,759,383 B2、7,737,174 B2、與Ding et al.,J. Am. Chem. Soc. 127
:10130-10131(2005))(反應圖示4),藉使用不對稱1,3-偶極環加成反應為關鍵步驟予以合成。
簡言之,化合物A與醛B反應,得到C。化合物C與醛E及化合物D反應,得到F(式I
中R"為芳烷基之化合物)。以Pb(OAc)4
或CAN處理F,得到式II
化合物中Y為NH之化合物。
於若干具體實例中,本文提供之化合物於單獨使用或回應附加之細胞凋亡誘發信號時,誘發細胞週期停止及/或細胞凋亡,以及增強細胞週期停止及/或細胞凋亡之誘發作用。因此,一般認為彼等化合物使細胞敏化而誘發細胞週期停止及/或細胞凋亡(彼等細胞包括對該等誘發刺激具抗性之細胞)。藉由抑制p53或p53相關蛋白與MDM2或MDM2相關蛋白間之相互作用,本文提供之化合物可於經由誘發細胞凋亡被治療、改善、或預防之任何失調症中用以誘發細胞凋亡。於一具體實例中,彼等抑制劑可於含有功能性p53或p53相關蛋白之細胞中用以誘發細胞凋亡。
於另一具體實例中,本發明係有關以本文提供之化合物組合一或多種附加細胞凋亡調控劑,以調控細胞凋亡。細胞凋亡調控劑之實例包括,惟不限於,Fas/CD95、TRAMP、TNFRI、DR1、DR2、DR3、DR4、DR5、DR6、FADD、RIP、TNFα、Fas配體、TRAIL、針對TRAIL-R1或TRAIL-R2之抗體、Bc1-2、p53、BAX、BAD、Akt、CAD、PI3激酶、PP1、與半胱天冬酶等蛋白質;亦包括涉及細胞凋亡開始、決定及退化階段之其他製劑。細胞凋亡調控劑之實例包括其活性、存在、或濃度變化可調控患者之細胞凋亡之製劑。細胞凋亡調控劑包括細胞凋亡誘發劑,例如TNF或TNF相關配體,特別是TRAMP配體、Fas/CD95配體、TNFR-1配體、或TRAIL。
於若干具體實例中,本文提供之組成物及方法係用於治療動物(例如,哺乳物動病患包括,惟不限於,人類與獸醫動物)病變之細胞、組織、器官、或病理症狀及/或疾病狀況。就此而言,多種疾病和病變均能使用本發明方法與組成物治療或預防。彼等疾病與症狀之非限制實例包括,惟不限於,乳癌、前列腺癌、淋巴瘤、皮膚癌、胰臟癌、結腸癌、黑色素瘤、惡性黑色素瘤、卵巢癌、腦癌、原發性腦癌、頭頸癌、神經膠質瘤、神經膠母細胞瘤、肝癌、膀胱癌、非小細胞肺癌、頭或頸癌、乳癌、卵巢癌、肺癌、小細胞肺癌、威爾姆氏(Wilms)腫瘤、子宮頸癌、睪丸癌、膀胱癌、胰臟癌、胃癌、結腸癌、前列腺癌、泌尿道癌、甲狀腺癌、食道癌、骨髓瘤、多發性骨髓瘤、腎上腺癌、腎細胞癌、子宮內膜癌、腎上腺皮質癌、惡性胰島素瘤、惡性類癌瘤、絨毛膜癌、蕈狀肉芽腫、惡性高血鈣症、子宮頸增生、白血病、急性淋巴性白血病、慢性淋巴性白血病(CLL)包括B-CLL、急性骨髓性白血病、慢性骨髓性白血病、慢性顆粒球性白血病、急性顆粒球性白血病、髮樣細胞白血病、神經母細胞瘤、肉瘤例如脂肉瘤惡性纖維組織細胞瘤、骨肉瘤、尤文氏(Ewing)肉瘤、平滑肌肉瘤、與橫紋肌肉瘤、卡波西氏(Kaposi)肉瘤、紅血球過多症、實質性血小板增多症、霍奇金氏(Hodgkin)症、非霍奇金氏淋巴瘤、軟組織肉瘤例如脂肪瘤、與惡性神經鞘瘤、骨原肉瘤、原發性巨球蛋白血症、與視網膜胚細胞瘤等;T及B細胞傳介之自體免疫疾病;炎性疾病;感染;過度增殖疾病;AIDS;退化性症狀、血管疾病等。於若干具體實例中,正在治療之癌細胞具轉移性。於另一具體實例中,正在治療之癌細胞對其他抗癌劑具抗性。
於若干具體實例中,本文提供之組成物及方法係用於治療表現功能性或野生型p53或p53相關蛋白之癌症。於若干具體實例中,本文提供之組成物及方法係用於治療表現增量MDM2或MDM2相關蛋白之癌症。
於若干具體實例中,本文提供之方法、化合物、與組成物可用於治療有肉瘤(包括,例如,脂肉瘤、惡性纖維組織細胞瘤、骨肉瘤、與橫紋肌肉瘤)之病患。於若干具體實例中,本文提供之方法、化合物、與組成物可用於治療有軟組織腫瘤(包括,例如,尤文氏肉瘤、平滑肌肉瘤、脂肪瘤、與惡性神經鞘瘤)之病患。於若干具體實例中,本文提供之方法、化合物、與組成物可用於治療有肺癌、乳癌、肝癌、或結腸癌症之病患。於若干具體實例中,本文提供之方法、化合物、與組成物可用於治療有B細胞慢性淋巴性白血病與急性骨髓性白血病之病患。
於若干具體實例中,適於以本文提供之組成物及方法治療之感染包括,惟不限於,由病毒、細菌、真菌、黴漿菌、普里昂蛋白等引起之感染。
於若干具體實例中,係提供投與有效量本文提供化合物與至少一種附加治療劑(包括,惟不限於,化療抗癌劑、細胞凋亡調控劑、抗微生物劑、抗病毒劑、抗真菌劑、與消炎劑)及/或治療技術(例如,手術治療、及/或輻射療法)之方法。於特別之具體實例中,附加治療劑為抗癌劑。
有一些適當治療劑或抗癌劑被考慮於本文提供之方法中使用。確實,本文提供之方法可包括,惟不限於,投與許多治療劑例如:細胞凋亡誘發劑;多核苷酸(例如,反義、核糖酶、siRNA);多肽類(例如,酵素與抗體);生物模擬物(例如,棉子酚或BH3模擬物);與Bcl-2家族蛋白結合(例如,寡聚或複合)之製劑例如Bax;生物鹼類;烷化劑;抗腫瘤抗生素;抗代謝物;激素類;鉑化合物;單株或多株抗體(例如,與抗癌藥物接合之抗體、毒素、防禦素)、毒素;放射核種;生物反應修飾劑(例如,干擾素(例如,IFN-α)與介白素(例如,IL-2));授受性免疫治療劑;造血生長因子;腫瘤細胞分化誘發劑(例如,全反式視黃酸);基因治療試劑(例如,反義療法試劑與核苷酸);腫瘤疫苗;血管生成抑制劑;蛋白酶體抑制劑:NF-KB調節劑;抗-CDK化合物;HDAC抑制劑等。治療劑之許多其他實例例如適用於與所揭示化合物共投與之化療化合物與抗癌療法均為熟習此項技藝者已知。
於特定具體實例中,抗癌劑包含誘發或刺激細胞凋亡之製劑。誘發或刺激細胞凋亡之製劑包括,例如,與DNA相互作用或修飾DNA(例如利用插入、交聯、烷化、或者傷害或化學修飾DNA)之製劑。細胞凋亡誘發劑包括,惟不限於,輻射(例如,X射線、γ射線、UV);腫瘤壞死因子(TNF)相關因子(例如,TNF家族受體蛋白、TNF家族配體、TRAIL、針對TRAIL-R1或TRAIL-R2之抗體);激酶抑制劑(例如,表皮生長因子受體(EGFR)激酶抑制劑)。附加抗癌劑包括:血管生長因子受體(VGFR)激酶抑制劑、纖維母細胞生長因子受體(FGFR)激酶抑制劑、血小板衍生之生長因子受體(PDGFR)激酶抑制劑、與Bcr-Abl激酶抑制劑(例如GLEEVEC));反義分子;抗體(例如,HERCEPTIN衍生之RITUXAN、ZEVALIN、與AVASTIN);抗雌激素劑(例如,雷洛昔芬(raloxifene)、與他莫昔芬(tamoxifen));抗雄激素劑(例如,氟他胺(flutamide)、白卡陸他胺(bicalutamide)、柔沛(finasteride)、胺基格魯米特(aminoglutethamide)、酮康唑(ketoconazole)、與皮質類固醇);環加氧酶2(COX-2)抑制劑(例如,塞勒昔布(celecoxib)、美洛昔康(meloxicam)、NS-398、與非類固醇抗炎性藥物(NSAIDs));抗炎性藥物(例如,保泰松(butazolidin)、DECADRON、DELTASONE、地塞米松(dexamethasone)、地塞米松口服劑、DEXONE、HEXADROL、羥基氯奎寧、METICORTEN、ORADEXON、ORASONE、羥基保泰松、PEDIAPRED、丁二苯吡唑二酮、PLAQUENIL、去氫皮質醇、強體松、PRELONE、與TANDEARIL);及癌症化療藥物(例如,伊立替康(irinotecan)(CAMPTOSAR)、CPT-11、氟達拉濱(fludarabine)(FLUDARA)、達卡巴(dacarbazine)(DTIC)、地塞米松、米托蒽醌(mitoxantrone)、MYLOTARG、VP-16、順鉑、卡鉑、奧沙利鉑(oxaliplatin)、5-FU、多索紅黴素(doxorubicin)、吉西他濱(gemcitabine)、硼替左米(bortezomib)、吉非替尼(gefitinib)、貝瓦滋單抗(bevacizumab)、TAXOTERE或TAXOL);細胞傳訊分子;腦胺類與細胞介素類;星形孢菌素等。
於又其他具體實例中,本文提供之組成物及方法包括一或多種本文提供之化合物與至少一種選自烷化劑、抗代謝物、與天然產物(例如,草本植物與其他植物及/或動物衍生之化合物)之抗過度增殖或抗腫瘤劑。
適用於本發明組成物與方法之烷化劑包括,惟不限於:1)氮芥類(例如,雙氯乙基甲胺、環磷醯胺、異環磷醯胺(ifosfamide)、黴法蘭(melphalan)(L-sarcolysin);及苯丁酸氮芥(chlorambucil));2)伸乙亞胺類與甲基三聚氰胺類(例如,六甲基三聚氰胺與噻替哌(thiotepa));3)烷基磺酸酯(例如,馬利蘭(busulfan));4)亞硝基脲類(例如,亞硝基脲氮芥(carmustine)(BCNU);洛莫司汀(lomustine)(CCNU);司莫司汀(semustine)(甲基-CCNU);及鏈佐星(streptozocin)(鏈佐菌素));及5)三氮烯類(例如,達卡巴(DTIC;二甲基三氮烯咪唑甲醯胺)。
於若干具體實例中,適用於本發明組成物與方法之抗代謝物包括,惟不限於:1)葉酸類似物(例如,胺甲喋呤(amethopterin));2)嘧啶類似物(例如,氟尿嘧啶(5-氟尿嘧啶;5-FU)、氟尿苷(氟脫氧尿苷;FudR)、與阿糖胞苷(胞嘧啶阿拉伯糖苷));及3)嘌呤類似物(例如,巰基嘌呤(6-巰基嘌呤;6-MP)、硫鳥嘌呤(6-硫鳥嘌呤;TG)、與戊史塔汀(pentostatin)(2’-脫氧可福黴素(coformycin))。
於又進一步之具體實例中,適用於本發明組成物與方法之化學治療劑包括,惟不限於:1)長春花生物鹼類(例如,長春花鹼(VLB)、長春新鹼);2)鬼臼毒素(例如,依托泊苷(etoposide)與天尼泊苷(teniposide));3)抗生素(例如,更生黴素(放線菌素D)、道諾紅菌素(道諾黴素;紅比黴素)、多索紅黴素、博來黴素(bleomycin)、普卡黴素(plicamycin)(光神黴素)、與絲裂黴素(絲裂黴素C));4)酵素(例如,L-天冬醯胺酶);5)生物反應修飾劑(例如,干擾素-α);6)鉑配位錯合物(例如,順鉑(順式DDP)與卡鉑);7)蒽二酮類(例如,米托蒽醌);8)經取代之脲類(例如,羥基脲);9)甲基肼衍生物(例如,甲基苄肼(N-甲基肼;MIH));10)腎上腺皮質抑制劑(例如,米托坦(mitotane)(o,p’-DDD)與胺基導眠能(aminoglutethimide));11)腎上腺皮質類固醇(例如,強體松);12)黃體素類(例如,己酸羥孕酮、乙酸甲羥孕酮、與乙酸甲地孕酮);13)雌激素類(例如,己烯雌酚與乙烯雌二醇);14)抗雌激素類(例如,他莫昔芬(tamoxifen));15)雄激素類(例如,丙酸睪固酮與氟羥甲基睪酮);16)抗雄激素類(例如,氟他胺);與17)釋放促性腺激素之激素類似物(例如,柳培林(leuprolide))。
慣常於癌症治療情況中使用之任何溶瘤劑均可於本發明組成物與方法中尋得用途。舉例而言,美國食品藥物管理局(U.S.F.D.A)有一套美國核准使用之溶瘤劑處方。與U.S.F.D.A.對等之國際機構亦有一套類似處方。表1提供美國核准使用之抗腫瘤劑之實例列表。熟習此項技藝者將察知,就例示製劑而言,所有美國核准的化療劑要求之“產品標籤”均敘述所核准之症狀、用藥資訊、毒性數據等。
抗癌劑進一步包括已被確認具抗癌活性之化合物;其實例包括,惟不限於,3-AP、12-O-十四醯基巴豆醇-13-乙酸酯、17AAG、852A、ABI-007、ABR-217620、ABT-751、ADI-PEG20、AE-941、AG-013736、AGRO100、阿拉諾新(alanosine)、A毫克706、抗體G250、抗癌物質(antineoplastons)、AP23573、阿帕濟胱(apaziquone)、APC8015、阿替莫德(atiprimod)、ATN-161、阿曲生坦(atrasenten)、阿扎胞苷(azacitidine)、BB-10901、BCX-1777、貝瓦滋單抗、BG00001、比卡魯胺(bicalutamide)、BMS 247550、硼替左米、苔蘚抑素(bryostatin)-1、布舍瑞林(buserelin)、骨化三醇(calcitriol)、CCI-779、CDB-2914、頭孢克肟(cefixime)、西妥昔單抗(cetuximab)、CG0070、西侖吉肽(cilengitide)、克羅拉濱(clofarabine)、磷酸考布他汀(combretastatin) A4、CP-675,206、CP-724,714、CpG 7909、薑黃素、地西他濱(decitabine)、DENSPM、多舍骨化醇(doxercalciferol)、E7070、E7389、ecteinascidin 743、乙丙昔羅(efaproxiral)、依氟鳥胺酸(eflornithine)、EKB-569、因扎托雷(enzastaurin)、爾洛替尼(erlotinib)、依昔舒林(exisulind)、維甲醯酚胺(fenretinide)、福拉匹醇(flavopiridol)、氟達拉濱、氟他胺、福莫司汀(fotemustine)、FR901228、G17DT、加利昔單抗(galiximab)、吉非替尼、雀異黃酮(genistein)、葡磷醯胺(glufosfamide)、GTI-2040、組胺瑞林(histrelin)、HKI-272、高三尖杉酯鹼(homoharringtonine)、HSPPC-96、hu14.18-介白素-2融合蛋白、HuMax-CD4、伊洛前列素(iloprost)、咪喹莫特(imiquimod)、因福昔單抗(infliximab)、介白素-12、IPI-504、伊洛福芬(irofulven)、伊沙匹隆(ixabepilone)、拉帕替尼(lapatinib)、雷那竇邁(lenalidomide)、來他替尼(lestaurtinib)、柳培林、LMB-9免疫毒素、洛那法尼(lonafarnib)、路尼昔單抗(luniliximab)、馬磷醯胺(mafosfamide)、MB07133、MDX-010、MLN2704、單株抗體3F8、單株抗體J591、莫特沙芬(motexafin)、MS-275、MVA-MUC1-IL2、尼魯米特(nilutamide)、硝基喜樹鹼、諾拉曲特(nolatrexed)二鹽酸鹽、諾瓦得士(nolvadex)、NS-9、O6-苄基鳥嘌呤、奧利默森(oblimersen)鈉、ONYX-015、歐瑞佛單抗(或egovomab)、OSI-774、帕尼單抗(panitumumab)、伯爾定(paraplatin)、PD-0325901、培美曲塞(pemetrexed)、PHY906、吡格列酮(pioglitazone)、吡非尼酮(pirfenidone)、匹杉瓊(pixantrone)、PS-341、PSC833、PXD101、吡唑并吖啶、R115777、RAD001、豹蛙酶(ranpirnase)、蝴蝶黴素(rebeccamycin)類似物、重組人血管生成抑制素、rhuMab 2C4、羅格列酮(rosiglitazone)、魯比替康(rubitecan)、S-1、S-8184、沙鉑(satraplatin)、S B-、15992、SGN-0010、SGN-40、索拉非尼(sorafenib)、SR31747A、ST1571、SU011248、辛二醯苯胺羥肟酸、蘇拉明(suramin)、他拉泊芬(talabostat)、他拉帕奈(talampanel)、塔利奇大(tariquidar)、特西羅莫司(temsirolimus)、TGFa-PE38免疫毒素、沙利竇邁(thalidomide)、胸腺法新(thymalfasin)、替吡法尼(tipifarnib)、替拉扎明(tirapazamine)、TLK286、他比特定(trabectedin)、葡萄糖醛酸三甲曲沙(trimetrexate)、TroVax、UCN-1、丙戊酸、長春氟寧(vinflunine)、VNP40101M、伏洛昔單抗(volociximab)、伏利諾他(vorinostat)、VX-680、ZD1839、ZD6474、齊留通(zileuton)、與唑喹達(zosuquidar)三鹽酸鹽。
關於抗癌劑與其他治療劑更詳細之說明,熟習此項技藝者可參照任何指導性簡介包括,惟不限於,Physician's Desk Reference及Goodman and Gilman's"Pharmaceutical Basis of Therapeutics"tenth edition,Eds. Hardmanet al
.,2002。
於若干具體實例中,本文提供之方法包含投與一或多種本文提供之化合物加上輻射療法。本文提供之方法不受限於用以傳送治療輻射劑量至動物之類型、用量、或傳送及投與系統。舉例而言,動物可能接受光子輻射療法、粒子束輻射療法、其他類型輻射療法、及其組合。於若干具體實例中,係使用線性加速器傳送輻射至動物。於又其他具體實例中,係使用伽瑪刀傳送輻射。
輻射來源對動物而言可為外部或內部。外部輻射療法最為常見,係涉及使用例如線性加速器引導高能量輻射光束穿過皮膚至腫瘤部位。在輻射光束定位於腫瘤部位之同時,正常、健康組織之暴露幾乎不可能避免。然而,動物對外部輻射之耐受性通常良好。內部輻射療法涉及於體內腫瘤部位或靠近腫瘤部位植入輻射發射源(例如小珠、金屬線、丸狀物、膠囊、顆粒等),包括使用專一性地針對癌細胞(例如,使用附著於癌細胞結合配體之顆粒)之傳送系統。此等植入劑可於處理後移除,或不具活性地留在體內。內部輻射療法之類型包括,惟不限於,近距離輻射療法、組織間輻射、腔內輻射、輻射免疫療法等。
動物可視需要接受輻射增敏劑(例如,甲硝唑(metronidazole)、米索硝唑(misonidazole)、動脈內Budr、靜脈內碘基脫氧尿苷(IudR)、硝基咪唑、5-經取代之-4-硝基咪唑、2H-異吲哚二酮類、[[(2-溴乙基)-胺基]甲基]-硝基-1H-咪唑-1-乙醇、硝基苯胺衍生物、DNA親和性低氧選擇性細胞毒素、鹵化之DNA配體、1,2,4苯并三氧化物、2-硝基咪唑衍生物、含氟之硝基唑衍生物、苯甲醯胺、菸鹼醯胺、吖啶-插入劑、5-硫四唑衍生物、3-硝基-1,2,4-三唑、4,5-二硝基咪唑衍生物、羥化之德卟啉類(texaphrins)、順鉑、絲裂黴素、替拉扎明、亞硝基脲、巰基嘌呤、胺甲喋呤、氟尿嘧啶、博來黴素、長春鹼、卡鉑、依匹紅黴素、多索紅黴素、環磷醯胺、長春地辛(vindesine)、依托泊苷、太平洋紫杉醇、加熱(高溫)等);輻射防護劑(例如,半胱胺、胺烷基二氫硫代磷酸酯類、阿米福汀(WR 2721)、IL-1、IL-6等)。輻射增敏劑促進殺死腫瘤細胞;輻射防護劑保護健康組織免受輻射之有害效應。
動物可施行任何類型之輻射,只要輻射劑量動物可容忍而無不可接受之負面效應即可。輻射療法之適當類型包括,例如,電離(電磁)輻射療法(例如,X射線或伽瑪射線)或粒子束輻射療法(例如,高線性能量輻射)。電離輻射係界定為由具有足夠能量以產生電離[亦即,得到或失去電子(見述於,例如,U.S. 5,770,581,其全部內容併入本文以資參考)]之粒子或光子構成之放射。輻射效應至少部分可由臨床醫師調控。於一具體實例中,輻射劑量係將最大標靶細胞暴露分成幾部分,以減少毒性。
於一具體實例中,投與動物之總輻射劑量為約.01戈雷(Gray)(Gy)至約100 Gy。於另一具體實例中,整個療程投與約10 Gy至約65 Gy(例如,約15 Gy、20 Gy、25 Gy、30 Gy、35 Gy、40 Gy、45 Gy、50 Gy、55 Gy、或60 Gy)。雖然於若干具體實例中,可於一天療程投與全部輻射劑量,惟較理想為將總劑量分成幾部分於數天之內投與。較合意地為,於至少約3天,例如,至少5、7、10、14、17、21、25、28、32、35、38、42、46、52、或56天(約1至8週)之療程間施行輻射治療。因此,輻射日劑量將成為大約1至5 Gy(例如,約1 Gy、1.5 Gy、1.8 Gy、2 Gy、2.5 Gy、2.8 Gy、3 Gy、3.2 Gy、3.5 Gy、3.8 Gy、4 Gy、4.2 Gy、或4.5 Gy)、或1至2 Gy(例如,1.5至2 Gy)。輻射日劑量必須足以引致破壞標靶細胞。若延伸一段期間,於一具體實例中,並未每天施行輻射,因而容許動物休息,俾使實現治療效果。例如,就每週之治療而言,合意地連續5天施行輻射,不施行2天,因而容許每週有2天休息。然而,視動物之反應及任何可能副作用而定,輻射之施行可為1天/週、2天/週、3天/週、4天/週、5天/週、6天/週、或全部7天/週。輻射治療可於治療期間任何時候開始進行。於一具體實例中,輻射於第1週或第2週開始進行,並於治療期之剩餘期間施行。舉例而言,於治療例如實體腫瘤之為期6週之治療期中,輻射係於第1至6週或第2至6週施行。替代地,於為期5週之治療期中,輻射係於第1至5週或第2至5週施行。然而,彼等例示之輻射治療施行療程不擬對本文提供之方法構成侷限。
抗微生物治療劑亦可與本文提供之化合物組合作為治療劑用。可消除、抑制、或者減弱微生物功能之任何製劑,以及被認為具有此等活性之任何製劑均可使用。抗微生物劑包括,惟不限於,單獨或組合使用之天然與合成之抗生素、抗體、抑制蛋白(例如,防禦素)、反義核酸、膜破壞劑等。的確,任何類型之抗生素均可使用,包括,惟不限於,抗細菌劑、抗病毒劑、抗真菌劑等。
於本文提供之方法之若干具體實例中,一或多種本文提供之化合物與一或多種治療劑或抗癌劑係於一或多個下述條件下對動物進行投與:不同週期性、不同持續時間、不同濃度、利用不同投與途徑等。於若干具體實例中,化合物係於投與治療劑或抗癌劑之前(例如,投與治療劑或抗癌劑0.5、1、2、3、4、5、10、12、或18小時、1、2、3、4、5、或6天、或1、2、3、或4週之前)進行投與。於若干具體實例中,化合物係於投與治療劑或抗癌劑之後(例如,投與抗癌劑0.5、1、2、3、4、5、10、12、或18小時、1、2、3、4、5、或6天、或1、2、3、或4週之後)進行投與。於若干具體實例中,化合物與治療劑或抗癌劑係同時惟依不同時間表投與,例如,化合物係每天投與而治療劑或抗癌劑之投與為每週一次、每兩週一次、每三週一次、或每四週一次。於另一具體實例中,化合物之投與為每週一次,而治療劑或抗癌劑之投與為每天、每週一次、每兩週一次、每三週一次、或每四週一次。
於若干具體實例中,本文提供之組成物含有其量為有效達成其意指用途之一或多種本文提供之化合物。雖然個別需要不同,惟各成分有效量最適範圍之決定屬此項技藝範圍之內。通常,對進行治療回應誘發細胞凋亡之失調症之哺乳動物(例如人類)而言,每天每公斤體重之口服劑量為0.0025至50毫克化合物,或對等量之其醫藥上可接受之鹽。於一具體實例中,係經口投與約0.01至約25毫克/公斤,以治療、改善、或預防該等失調症。肌內注射時,其劑量通常為口服劑量之約一半。舉例而言,適當之肌內劑量為約0.0025至約25毫克/公斤、或約0.01至約5毫克/公斤。
單位口服劑量可含有約0.01至約1000毫克,例如,約0.1至約100毫克之化合物。單位劑量可呈各含約0.1至約10毫克,方便地為約0.25至50毫克化合物或其溶劑合物之一或多個錠劑或膠囊,每天投與一或多次。
於局部調配劑中,化合物可能以每克載體約0.01至100毫克之濃度存在。於一具體實例中,化合物係以約0.07至1.0毫克/毫升,例如,約0.1至0.5毫克/毫升,及於一具體實例中,約0.4毫克/毫升之濃度存在。
除了投與呈未加工的化學藥劑之化合物外,本文提供之化合物可呈醫藥製劑之一部分進行投與。於若干具體實例中,醫藥製劑可包含一或多種醫藥上可接受之載體、賦形劑、及/或輔助劑。於若干具體實例中,該一或多種載體、賦形劑、與輔助劑有助於化合物加工成為醫藥上可使用之製劑。該等製劑,特別是可口服或局部投與及可用於一種投與類型之彼等製劑,例如錠劑、糖衣錠、緩釋型菱形錠劑與膠囊、漱口藥水與漱劑、凝膠、液體懸浮劑、頭髮漂洗劑、髮膠、洗髮精及可經直腸投與之製劑,例如栓劑,以及靜脈內輸注、注射、局部或經口投與用之適當溶液,含有約0.01至99%,於一具體實例中約0.25至75%之活性化合物,連同一或多種載體、賦形劑、及/或輔助劑。
本文提供之醫藥組成物可投與可體驗本文提供化合物之有利效應之任何病患。此等病患中最重要的為哺乳動物,例如,人類,惟本文提供之方法與組成物不擬如此受限。其他病患包括獸醫動物(牛、羊、豬、馬、狗、貓等)。
化合物及其醫藥組成物可利用達成其意指用途之任何方式投與。舉例而言,可經由非經腸、皮下、靜脈內、肌內、腹膜內、經皮膚、頰、鞘內、顱內、鼻內局部途徑進行投與。替代地,或同時,可利用經由口途徑投與。投與劑量視接受者之年齡、健康、與體重、同時治療之種類(若有的話)、治療頻率、及期望效應之性質而定。
本文提供之醫藥製劑係利用習知之混合、粒化、糖衣錠製造、溶解、或凍乾等程序製造。因此,供口服用之醫藥製劑可利用結合活性化合物與固體賦形劑,如果需要或必要,則於添加適當輔助劑後,視需要研磨所得混合物及加工該粒劑混合物,製得錠劑或糖衣錠核心。
適當賦形劑為,詳言之,填充劑如醣類例如乳糖或蔗糖、甘露糖醇或山梨糖醇、纖維素製劑及/或磷酸鈣類例如磷酸三鈣或磷酸氫鈣、以及黏合劑如澱粉糊狀物,使用例如玉米澱粉、小麥澱粉、稻米澱粉、馬鈴薯澱粉、明膠、黃蓍膠、甲基纖維素、羥丙甲基纖維素、羧甲基纖維素鈉、及/或聚乙烯吡咯啶酮。若需要,則可添加崩解劑例如上述澱粉以及羧甲基-澱粉、交聯聚乙烯吡咯啶酮、洋菜、或海藻酸或其鹽例如海藻酸鈉。輔助劑可為適當之流動調控劑與潤滑劑。適當之輔助劑包括,例如,矽石、滑石、硬脂酸或其鹽例如硬脂酸鎂硬脂酸鈣、及/或聚乙二醇。糖衣錠核心備有需要時對胃液具抗性之適當塗層。欲達此目的,可使用濃縮之醣溶液,其中視需要含有阿拉伯膠、滑石、聚乙烯吡咯啶酮、聚乙二醇及/或二氧化鈦、塗料溶液及適當有機溶劑或溶劑混合物。為了產生對胃液具抗性之塗層,係使用適當纖維素製劑例如乙醯基纖維素酞酸酯或羥丙基甲基-纖維素酞酸酯之溶液。錠劑或糖衣錠塗層中可添加染料或色料,舉例而言,以識別活性化合物劑量組合或確認。
可口服用之其他醫藥製劑包括以明膠製成之推進式膠囊,以及以明膠與塑化劑例如甘油或山梨糖醇製成之密封之軟膠囊。推進式膠囊可含呈顆粒形式之活性化合物,其中可摻和填充劑例如乳糖、黏合劑例如澱粉、及/或潤滑劑例如滑石或硬脂酸鎂及視需要之安定劑。軟膠囊於一具體實例中係使活性化合物溶解或懸浮於適當液體例如脂肪油、或液態石蠟中;此外,可添加安定劑。
可經直腸使用之可能醫藥製劑包括例如栓劑,其係由一或多種活性化合物與栓劑基底之組合物組成。適當之栓劑基底為,例如,天然或合成之三酸甘油酯類、或鏈烷烴。此外,亦可能使用由活性化合物與基底之組合物組成之明膠直腸膠囊。可能之基底材料包括,例如,液態三酸甘油酯類、聚乙二醇類、或鏈烷烴。
供非經腸投與用之適當調配劑包括呈水溶性形式之活性化合物水性溶液,例如,水溶性鹽類與鹼溶液。此外,可投與呈適當油性注射懸浮劑之活性化合物懸浮劑。適當之親脂性溶劑或賦形劑包括脂肪油類例如芝麻油、或合成之脂肪酸酯類例如油酸乙酯或三酸甘油酯類或聚乙二醇-400。水性注射懸浮劑可含增加懸浮劑黏性之物質包括例如羧甲基纖維素鈉、山梨糖醇、及/或葡聚糖。視需要,懸浮劑中亦可含有安定劑。
本文提供之局部組成物於一具體實例中係利用選擇適當載體調配為油類、霜劑、洗劑、軟膏等。適當之載體包括植物油或礦物油、白石蠟脂(白軟石蠟)、分支鏈脂肪或油脂、動物脂肪及高分子量醇(大於C12
)。載體可為其中活性成分可溶解者;亦可包括乳化劑、安定劑、濕潤劑與抗氧化劑,以及需要時,給予顏色或香味之製劑。附加地,於彼等局部調配劑中可使用皮膚滲透增進劑;此等增進劑之實例見述於美國專利案3,989,816與4,444,762。
調配軟膏時,可使活性成分於植物油例如杏仁油中之溶液與溫軟之石蠟混合,然後令混合物冷卻。此等軟膏之典型實例為包含約30重量%杏仁油及約70重量%白軟石蠟者。於適當高分子量醇例如丙二醇或聚乙二醇中溶解活性成分,可方便地製備洗液。
下述實例係說明而非限制本文提供之化合物、組成物、與方法。於臨床治療上通常遇到之各種條件與參數之其他適當修飾及調整為熟習此項技藝者所顯見及隸屬本文提供之方法、化合物、與組成物之精神與範圍之內。
美國專利案7,759,383 B2與7,737,174 B2揭示包括MI-219(AT-219)、MI-319與MI-147(圖示1)之MDM2抑制劑。
為了進一步探討MI-219、MI-147、與MI-319作為臨床開發之潛在抗癌候選藥物,乃進行一系列實驗,以評估其代謝及藥物動力學性質。
於活體外,使MI-219、MI-147與MI-319和人類、大鼠及狗微粒體一起培育顯示,此三種化合物各個濃度均相當迅速地下降(表2)。彼等數據暗示MI-219、MI-147與MI-319於活體外被大鼠、狗及人類微粒體頗為迅速地代謝。
MI-219於Sprague Dawley公大鼠中之藥物動力學研究(PK)顯示,MI-219具口服生物利用性(表3至4)。舉例而言,經口投與劑量25毫克/公斤之MI-219後,MI-219之Cmax(最大血漿濃度)與Tmax平均±SD值分別為3751.78±1067.86微克/公斤、0.58±0.38小時;MI-219之AUC(0-∞)(曲線下方面積)與半衰期(T)平均±SD值分別為7689.94±325.86小時*微克/公斤與1.43±0.09小時。MI-219之血漿濃度下降頗為迅速,從時間點1小時之2957奈克/毫升,成為時間點4小時之224奈克/毫升,進一步成為時間點6小時之103奈克/毫升。使用25毫克/公斤口服給藥及5毫克/公斤IV給藥為基準,所計算大鼠中MI-219之生物利用性為65.45±2.77%。
MI-219於ICR小鼠中之PK研究顯示,MI-219於小鼠中具口服生物利用性(表5至7)。50毫克/公斤口服給藥下,MI-219於時間點2小時達到8469奈克/毫升之最大濃度(Cmax),AUC為8469±2381小時*微克/公斤。MI-219之濃度於3小時、5小時及9小時分別為3077±2296、378±128與121±133奈克/毫升。所計算MI-219於小鼠中之口服生物利用性(F)為54.9±19.0%。
MI-219於比格(Beagle)獵犬中之PK研究顯示,MI-219於該等犬中具口服生物利用性(表8至11)。10毫克/公斤口服給藥下,MI-219於時間點1小時達到2893±726奈克/毫升之最大濃度(Cmax),AUC為7947±2396小時*微克/公斤。MI-219之濃度於時間點2、3、4、6及8小時分別為1500±599、759±314、483±152、327±147、178±92奈克/毫升。所計算MI-219於該等犬中之口服生物利用性(F)為22.8%。
MI-219於狒狒(Cynomolgus Monkeys)中之PK研究顯示,MI-219於狒狒中具口服生物利用性(表12-13)。50毫克/公斤口服給藥下,MI-219於3.3小時達到1257±837之最大濃度(Cmax)(利用曲線擬合法),AUC為8199±5717小時*微克/公斤。MI-219之濃度於時間點4、6、8與24小時分別為1121.42±951.73、796.07±703.14、341.82±273.89與17.60±7.21。所計算MI-219於狒狒中之口服生物利用性(F)為13.89%。
於具有SJSA-1與LnCAP人類異種移植腫瘤之小鼠中,為期2週之MI-219之200-300毫克/公斤每天或一天兩次之口服投與,確實有效抑制腫瘤生長(Shangaryet al
. 2008,PNAS)。SJSA-1細胞係衍生自經診斷具有原始多能股骨肉瘤之病患之原發性腫瘤。SJSA-1細胞懷有MDM2基因之擴增作用。LnCAP細胞係衍生自經診斷為前列腺癌病患之轉移性腫瘤之對雄激素敏感之人類前列腺腺癌細胞。彼等數據顯示MI-219為具口服活性之MDM2抑制劑。
彼等代謝及PK研究亦揭示,MI-219為很快地被代謝。因此,MI-219之進一步化學修飾以改善其代謝及PK參數可獲得為透過以人類MDM2及p53之活化為目標而用於治療人類癌症與其他症狀之較佳候選藥物之新穎MDM2抑制劑。
本文係提供抑制p53-MDM2相互作用之新穎化合物。本文提供之化合物尤其具有增進之代謝穩定性及/或藥物動力學性質與口服生物利用性。
活體外使用人類與大鼠微粒體及活體內使用大鼠進行精深研究以測定MI-219之代謝作用。
試樣製備:肝微粒體中代謝物培育:
於37℃,磷酸鹽緩衝液中,使MI-219(或其他化合物)與集中之肝微粒體一起培育。0.4毫升混合物溶液中,化合物、HLM、β-NADPH、磷酸鹽緩衝液與毫克Cl2
之最終濃度分別為20-50 μM、1毫克/毫升、1 mM、0.1 M與3.3 mM。MeOH在培育混合物中之百分比保持小於0.2%(v/v)。培育試樣60分鐘,以1.2毫升冰冷乙腈終止反應使蛋白質沉澱。蛋白質沉澱後,使用煮沸微粒體(100℃ 5分鐘)或受阻之(spiking) MI-219製備兩個不同對照組。接著於14,000 rpm使試樣離心5分鐘。上澄液利用LC/MS/MS進行分析。
大鼠血漿中之代謝物:以5毫克/公斤劑量,對Sprague-Dawley公大鼠(n=6,重量範圍200至220克)進行MI-219之靜脈內注射。注射後0.166、0.5、1、2、4、6、8、與24小時,於乙醚輕輕麻醉下,自大鼠眼窩採血液試樣置入含肝素抗凝血劑之微離心管中。於4℃,13000 rpm下,將血液離心5分鐘以採集血漿,至分析前於-80±10℃冷凍保存。
以LC-MS/MS篩選及確認代謝物:將MI-219與其他化合物注射入質譜儀內以獲得其MS、MS2
與MS3
光譜。根據彼等質譜間之相似性及差異性,提出質子化MI-219與數個前導化合物可能之裂解路徑。使用包括40個常見生物轉化程序之代謝物ID軟體(Applied Biosystems),選定三個具特徵之產物離子以產生240個離子通道供MRM篩選。為了搜尋所有代謝物,亦進行兩個其他掃描模式,EMS完整掃描及前驅體掃描。惟有於試樣中檢測出而於所有對照組試樣中不存在之成分被視為係可能之代謝物。為鑑定可能之代謝物,將試樣及對照組注入LC-MS上,供EPI與MS3
掃描以獲得其MS2
與MS3
光譜。根據代謝物之MS2
、MS3
光譜及提出之MI-219與其他化合物之裂解路徑,進行代謝物確認。
圖13A-D顯示質子化MI-219、MI-142、MI-63與MI-708B之MS/MS光譜。根據彼等MS/MS光譜與例如m/z
496、419、363、320、285、188等主要產物離子之MS3
光譜,提出質子化MI-219之裂解路徑(反應圖示5)。藉由追蹤MI-219衍生物之功能性基團,獲得所提出裂解之支撐證據。產物離子之質量偏移存在與否可提供該產物離子之結構資訊。
圖14A-B顯示去質子化MI-219與MI-142之MS/MS光譜。此二化合物之MS/MS光譜中均檢測出產物離子m/z
306。MI-219於m/z
243之產物離子及MI-142於m/
z 257之產物離子暗示MI-219於m/z
306及243之產物離子係由於切割吡咯啶環而產生。藉由比較MI-219諸代謝物與MI-219之主要產物離子,可試驗性地說明MI-219之諸代謝物。
圖15B顯示M1之MS/MS光譜。m/z
419、363、320與285之存在暗示代謝位置不在核心結構。相較於MI-219之m/z
188與106,產物離子於m/z 186與104之檢測具有2 Da之質量偏移,暗示脫氫反應發生於側鏈上。為了證實M1之結構,乃藉由氧化MI-219之任一羥基基團,合成兩個酮化合物;發現此二化合物可相互轉換。圖15A與15C顯示,合成之化合物展現相同之HPLC駐留時間與質譜圖示,暗示M1係衍生自MI-219一羥基基團之氧化。
圖16顯示大鼠中MI-219與M1之血漿濃度。此二化合物之清除率相似。
除了M1之外,於層析圖4.76分鐘處檢測出分子量567 Da之另一代謝物(M2)。圖17顯示質子化M2(A)與去質子化M2(B)之MS/MS光譜。相較於MI-219,M2顯示16 Da之質量偏移,暗示該生物轉化可能為羥化反應。圖17A中m/z
419與320不存在,暗示該羥化反應發生於核心結構。圖17B中m/z
306與259存在,表示羥化反應發生於MI-219之m/z
243部分;因此推斷羥化反應發生於3,3-二甲基丁-1-胺部分。從m/z
568至m/z
452,喪失116 Da係歸因於羥化3,3-二甲基丁-1-胺基基團之消除。此116 Da之基團喪失亦於其他MI-219類似物(例如MI-773、MI-519-63與MI-519-64)之羥化代謝物中被檢測出,將於後文討論。胺之羥化反應被預期有助於N-C鍵之均裂。因此,羥基基團被分派至吡咯啶環之胺。
除了M1與M2外,針對人類肝微粒體培育中MI-219之其他6個代謝物進行試驗性確認;其可能結構、層析駐留時間、特有產物離子及峰面積列於表14。
諸代謝研究因而確定MI-219中之最初代謝位置在其“尾部”。再者,由於兩個其他有希望之MDM2抑制劑,MI-147與MI-319,亦含有相同之二醇尾部,其尾部也很容易被迅速代謝。本文提供之化合物包含具有不同尾部之新穎MDM2抑制劑,可提供增進之代謝穩定性。此外,為了藥物開發之目的,業界高度期望獲得不僅具有增進代謝穩定性,亦具有良好口服生物利用性之新穎MDM2抑制劑。
直接修飾“二醇”尾部,導使產生一系列新穎化合物,例如,MI-519-24、MI-519-28、MI-519-29、MI-519-31、與MI-758。結合實驗顯示,彼等新穎類似物以良好親和性與MDM2結合(表19A)。再者,與其作用機制一致地,彼等亦於具有野生型p53之腫瘤細胞株中有效地抑制細胞生長,及對具有突變或缺失p53之腫瘤細胞株顯示選擇性。
微粒體穩定性研究顯示,相較於大鼠肝微粒體中之MI-219,MI-758、MI-519-24、MI-519-28與MI-519-29具有增進之穩定性;相較於人類肝微粒體中之MI-219,MI-758與MI-519-28亦具有增進之穩定性。彼等數據表示,相同化合物之微粒體穩定性於大鼠及人類微粒體間可能大為不同(表15)。
亦針對含有不同“尾部”基團之類似物(圖示2)進行研究,以進一步檢驗何種尾部於大鼠或人類肝微粒體中較穩定。彼等類似物之微粒體穩定性數據摘述於表16。此微粒體穩定性數據顯示,相較於MI-219,MI-122與MI-126具有增進之大鼠微粒體穩定性。
根據增進之微粒體穩定性,設計及合成一系列新穎類似物(圖示3)。微粒體穩定性試驗顯示,相較於MI-219,MI-519-40、MI-519-43與MI-763具有增進之微粒體穩定性;而數種其他類似物與MI-219具有可比較或較低之微粒體穩定性(表17)。
由於業界高度期望獲得具口服生物利用性之化合物,因此評估數種MDM2抑制劑於大鼠中之藥物動力學性質;此數據摘述於表18。很遺憾地,相較於MI-219具有增進微粒體穩定性之MI-122、MI-126、MI-519-24、MI-519-28與MI-519-29於大鼠中具有遠不如AT-219之口服藥物動力學參數。有一例外為MI-758,其顯示良好之口服生物利用性及藥物動力學參數。彼等數據表示,難以設計出具有增進微粒體穩定性及口服給藥時之良好藥物動力學性質之MDM2抑制劑。引人關注的是,微粒體穩定性不如MI-219之MI-225具有良好口服生物利用性。
根據彼等數據,乃提出為了使MDM2抑制劑達成良好口服生物利用性,以電荷中性之“尾部”較佳。再者,MI-225之微粒體穩定性雖然不如MI-219,惟達成良好口服生物利用性。因此,製備含有連接著羥基基團作為“尾部"的4、5與6員環之一些化合物。
生物測試顯示,未預期地,羥基之構型在細胞活性上扮演重要角色。舉例而言,於具有野生型p53之多種癌細胞株中抑制細胞生長時,MI-519-60較其表異構物MI-519-63更具效力,MI-519-64較其表異構物MI-519-65更具效力(表19A)。
微粒體穩定性研究顯示,雖然MI-519-51在人類與大鼠肝微粒體中之穩定性均不如MI-219,MI-773在人類肝微粒體中較MI-219更穩定,MI-519-63則具有與MI-219可相較之微粒體穩定性(表21至24)。
針對MI-519-51與MI-773進行藥物動力學研究,其數據摘述於表25至26。PK數據顯示,於靜脈內及口服給藥途徑中,雖然MI-519-51所有PK參數均不如MI-219,惟MI-773具有比MI-219增進之PK參數。例如,相同劑量下,MI-773於兩種給藥途徑之AUC值較MI-219高2倍。彼等數據表示,MI-773於大鼠之靜脈內及口服兩種給藥途徑中,具有良好藥物動力學概況及良好口服生物利用性。再者,MI-519-51與MI-773間,其藥物動力學參數之主要差異無法根據其化學結構預測。
為了有助於設計新穎之MDM2抑制劑以進一步改善其整體PK概況,乃針對MI-773與MI-519-63進行代謝研究。
針對人類肝微粒體培育中MI-773之主要代謝物進行確認。圖18A-D顯示質子化MI-773與MI-773三個代謝物(M1、M2與M3)之MS/MS光譜。如M1與M2之MS/MS光譜所示,m/z
419與320之存在暗示脫氫與羥化未發生於核心結構。相較於質子化MI-773之m/z 116,m/z
114之存在質量偏移2 Da,表示代謝位置位於環己烷側鏈上。MI-773與M1之化學結構示於圖示4。
探討MI-519-63於人類肝微粒體培育中之生物轉化路徑。於質子化MI-519-63與M1之MS/MS光譜(圖19A-C)中,m
/z
419、363、320與285之檢測表示脫氫反應發生於環丁烷側鏈,此由檢測M1之產物離子之m
/z
112(相較於MI-519-63之之產物離子之m
/z
114,顯示質量偏移2 Da)而獲得進一步證實。M2之MS/MS光譜顯現與MI-773-M3和MI219-M2之MS/MS光譜非常相似之圖示;因而推斷羥化反應發生於吡咯啶環之胺。所提供之MI-519-63之生物轉化示於圖示5。
圖示5. MI-519-63於人類肝微粒體培育中之生物轉化路徑
本文提供之化合物包括螺-吲哚酮MDM2抑制劑,係根據MI-773與MI-519-63之彼等代謝研究所設計。
結合與細胞研究顯示,儘管MI-519-64與MI-519-65以高親和性結合於人類MDM2蛋白,且於具有野生型p53之癌細胞株中有效地抑制癌細胞生長,惟MI-519-64之效力比MI-519-65強數倍。
微粒體穩定性研究顯示,MI-519-64具有較MI-519-63增進之微粒體穩定性(表22至24)。
由於MI-773與MI-519-63中之羥基可代謝得到酮,因此探討以磺醯胺基置換此羥基作為產生具有增進微粒體穩定性及/或良好口服生物利用性之MDM2抑制劑之方式(見MI-771與MI-772)。
結合與細胞研究顯示,儘管MI-771與MI-772均以高親和性結合於人類MDM2蛋白,且於具有野生型p53之癌細胞株中有效地抑制癌細胞生長,惟MI-772之效力比MI-771強數倍。
微粒體穩定性研究顯示,MI-772非常穩定,比MI-773以及MI-219更穩定許多(表21與23)。令人驚訝的是,MI-771之微粒體穩定性很差(表21與23)。未預期地,MI-772及其表異構物MI-771之微粒體穩定性數據顯示-NHSO2
Me基團之構型對於彼等化合物之微粒體穩定性具有重大影響。
於大鼠中之藥物動力學研究顯示,MI-772於大鼠之靜脈內及口服兩種給藥途徑中具有很長之半衰期(表25與26)及適度之口服生物利用性。相較之下,MI-771於靜脈內及口服兩種給藥途徑中之藥物動力學概況很差。因此,MI-771與MI-772中-NHSO2
Me基團之構型對其藥物動力學概況具有重大影響。
1
H NMR(300 MHz,CD3
OD)δ7.72(d,J
=8.5 Hz,1H),7.32-7.21(m,3H),7.08(d,J
=7.7 Hz,1H),6.87(d,J
=6.0 Hz,1H),5.25(d,J
=11.2 Hz,1H),4.50-4.47(m,1H),4.11(d,J
=11.2 Hz,1H),4.05-3.97(m,2H),3.67-3.38(m,2H),2.61-2.56(m,2H),1.92(dd,J
=15.5,8.2 Hz,1H),1.20(dd,J
=15.5,2.0 Hz,1H),0.92(s,9H);MS(ESI)m/z
550[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.70(m,1H),7.31-7.02(m,4H),6.88-6.83(m,1H),5.28(d,J
=11.3 Hz,1H),4.48-4.45(m,1H),4.18-4.13(m,1H),3.75-3.72(m,2H),3.36-3.31(m,1H),3.05-3.03(m,1H),2.83-2.76(m,1H),1.92(dd,J
=15.4,8.4 Hz,1H),1.65-1.53(2H),1.36(s,9H),1.17(d,J
=15.4 Hz,1H),0.92(s,9H);MS(ESI)m/z
607[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.68(d,J
=8.5 Hz,1H),7.32-7.20(m,3H),7.08(d,J
=7.7 Hz,1H),6.87(d,J
=6.0 Hz,1H),5.20(d,J
=11.2 Hz,1H),4.38(d,J
=7.8 Hz,1H),4.24-4.20(m,2H),4.08(d,J
=11.2 Hz,1H),2.19-2.12(m,1H),1.90-1.70(m,3H),1.53-1.48(m,2H),1.39-1.31(m,1H),1.20-1.16(m,1H),0.91(s,9H);MS(ESI)m/z
548[M+H]+
。
1
H NMR(300 MHz,CD3OD)δ7.70(d,J=8.5 Hz,1H),7.33-7.21(m,3H),7.09(d,J=7.6 Hz,1H),6.87(d,J=6.0 Hz,1H),5.27(d,J=11.2 Hz,1H),4.56(s,1H),4.46-4.44(m,1H),4.15(d,J=11.2 Hz,1H),3.75-3.65(4H),3.42-3.28(m,2H),3.15(m,3H),2.30-2.05(m,2H),1.90(dd,J=15.4,8.5 Hz,1H)。
1
H NMR(300 MHz,CD3
OD)δ7.55(d,J
=8.7 Hz,1H),7.23-7.14(m,2H),7.08(s,1H),7.02-6.99(m,1H),6.85(d,J
=6.2 Hz,1H),4.87(d,J
=11.0 Hz,1H),4.27-4.24(m,1H),4.11-4.06(m,1H),3.50-3.47(m,1H),3.40-3.32(m,2H),3.19-3.16(m,1H),1.58-1.48(m,3H),1.12-1.04(m,4H),0.92(s,9H);MS(ESI)m/z
566[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.68(d,J
=8.5 Hz,1H),7.31-7.20(m,3H),7.10-7.08(m,1H),6.86(d,J
=6.0 Hz,1H),5.26(d,J
=11.2 Hz,1H),5.10-5.03(m,1H),4.50(m,1H),4.40-4.37(m,1H),4.16(d,J
=11.2 Hz,1H),3.63-3.51(m,4H),3.44-3.32(m,3H),2.21-2.18(m,1H),2.01-1.95(m,1H),1.89(dd,J
=15.4,8.6 Hz,1H),1.18-1.03(m,1H),0.92(s,9H);MS(ESI)m/z
577[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.53(m,1H),7.27-7.17(m,2H),7.07(s,1H),7.00-6.98(m,1H),6.86(d,J
=6.2 Hz,1H),4.98(d,J
=12.4 Hz,1H),4.45-4.41(m,1H),4.10(d,J
=12.4 Hz,1H),3.85-3.81(m,1H),3.28-3.22(m,1H),3.04-2.96(m,1H),2.33-2.29(m,1H),1.74(dd,J
=15.2,7.3 Hz,1H),1.64-1.51(m,2H),1.30-1.21(m,3H),0.90(s,9H);MS(ESI)m
/z
578[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.71(d,J
=8.5 Hz,1H),7.33-7.22(m,3H),7.08(d,J
=7.6 Hz,1H),6.87(d,J
=6.0 Hz,1H),5.26(d,J
=11.3 Hz,1H),4.49-4.46(m,1H),4.10(d,J
=11.3 Hz,1H),3.85-3.78(m,2H),3.33-3.22(m,1H),3.00-2.93(m,1H),2.31-2.28(m,1H),1.92(dd,J
=15.5,8.2 Hz,1H),1.60-1.52(m,2H),1.28-1.18(m,3H),0.92(s,9H);MS(ESI)m
/z
578[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.68(d,J
=8.5 Hz,1H),7.33-7.24(m,3H),7.10(d,J
=7.7 Hz,1H),6.87(d,J
=6.0 Hz,1H),5.28(d,J
=11.2 Hz,1H),4.44(m,1H),4.11(d,J
=11.2 Hz,1H),1.90(dd,J
=15.5,8.3 Hz,1H),1.20(dd,J
=15.5,2.0 Hz,1H),0.92(s,9H);MS(ESI)m/z
464[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.57-7.54(m,2H),7.46-7.40(m,1H),7.22-7.14(m,2H),6.81(d,J
=1.8 Hz,1H),5.34(d,J
=11.4 Hz,1H),4.66(d,J
=11.4 Hz,1H),4.55-4.52(m,1H),3.60(m,2H),3.32-3.26(m,2H),3.03-2.93(m,4H),2.11-1.81(m,7H),1.15(dd,J
=15.4,1.7 Hz,1H),0.90(s,9H);MS(ESI)m/z
575[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.63-7.57(m,2H),7.46-7.41(m,1H),7.23-7.14(m,2H),6.81(m,1H),5.30(d,J
=11.3 Hz,1H),4.64(d,J
=11.3 Hz,1H),4.50(d,J
=8.3 Hz,1H),3.43-3.19(m,4H),2.94-2.75(m,4H),1.95-1.71(m,8H),1.53-1.43(m,1H),1.14(d,J
=15.2 Hz,1H),0.92(s,9H);MS(ESI )m/z
589[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.60-7.55(m,2H),7.44-7.39(m,1H),7.20-7.15(m,2H),6.80(d,J
=1.8 Hz,1H),5.33(d,J
=11.4 Hz,1H),4.64(d,J
=11.4 Hz,1H),4.48(d,J
=7.1 Hz,1H),3.72-3.64(m,1H),3.55-3.52(m,5H),3.38-3.30(m,6H),2.95(s,3H),1.93(dd,J
=15.3,8.6 Hz,1H),1.13(d,J
=15.3 Hz,1H),0.90(s,9H);MS(ESI)m/z
654[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.58-7.55(m,2H),7.45-7.39(m,1H),7.22-7.14(m,2H),6.80(d,J
=1.8 Hz,1H),5.29(d,J
=11.3 Hz,1H),4.60(d,J
=11.3 Hz,1H),4.50(dd,J
=8.6,1.9 Hz,1H),1.88(dd,J
=15.4,8.4 Hz,1H),1.15(dd,J
=15.4,1.9 Hz,1H),0.90(s,9H);MS(ESI)m/z
464[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.54(d,J
=8.1 Hz,1H),7.36-7.31(m,1H),7.15-7.12(m,1H),7.02-6.91(m,2H),6.81-6.80(m,1H),4.98(d,J
=11.9 Hz,1H),4.47(d,J
=11.8 Hz,1H),4.41-4.37(m,1H),4.22-4.19(m,2H),2.18-2.08(m,1H),1.85-1.49(m,5H),1.37-1.33(m,1H),1.14(dd,J
=15.2,3.6 Hz,1H),0.91(s,9H);MS(ESI)m/z
548[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.63-7.56(m,2H),7.45-7.40(m,1H),7.21-7.14(m,2H),6.82(m,1H),5.19(d,J
=11.3 Hz,1H),4.59(d,J
=11.3 Hz,1H),4.54-4.51(m,1H),4.35-4.32(m,1H),4.24-4.21(m,1H),2.02-1.85(m,3H),1.73-1.63(m,2H),1.51(m,1H),1.19-1.14(m,1H),1.09-1.04(m,1H),0.90(s,9H);MS(ESI)m/z
548[M+H]+
。
(MI-519-63之表異構物)
1
H NMR(300 MHz,CD3
OD)δ7.61-7.56(m,1H),7.41-7.36(m,1H),7.23-7.18(m,1H),6.88(m,1H),6.80-6.76(m,1H),6.66-6.60(m,1H),4.82-4.77(m,1H),4.43-4.15(m,2H),4.05-3.80(m,2H),3.75-3.51(m,3H),2.35-2.09(m,1H),1.88(dd,J=15.0,8.0 Hz,1H),1.24-1.18(m,1H),0.82(s,9H);MS(ESI) m/z 534[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.63-7.57(m,2H),7.44-7.39(m,1H),7.21-7.15(m,2H),6.81(m,1H),5.26(d,J
=10.9 Hz,1H),4.75-4.73(m,1H),4.64(d,J
=11.4 Hz,1H),4.52-4.50(m,1H),3.98-3.94(m,1H),3.75-3.60(m,1H),3.55-3.52(m,1H),3.46-3.42(m,1H),3.31-3.13(m,1H),2.31-2.20(m,1H),1.95-1.87(m,3H),1.80-1.50(m,1H),1.18-1.13(m,1H),0.90(s,9H);MS(ESI)m/z
593[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.57-7.53(m,1H),7.41-7.38(m,1H),7.22-7.17(m,1H),6.87-6.82(m,3H),5.02(d,J
=10.1 Hz,1H),4.44(d,J
=10.1 Hz,1H),4.11(dd,J
=7.4,2.8 Hz,1H),3.41-3.36(m,1H),3.12-3.07(m,1H),1.97(dd,J
=15.2,7.5 Hz,1H),1.32(dd,J
=15.2,2.9 Hz,1H),1.07(s,3H),0.98(s,3H),0.90(s,9H);MS(ESI)m/z
536[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.55-7.51(m,1H),7.43-7.38(m,1H),7.24-7.18(m,1H),6.88(m,1H),6.81(m,1H),6.79-6.73(m,1H),4.93(d,J
=9.7 Hz,1H),4.40(d,J
=9.7 Hz,1H),4.11(dd,J
=7.7,2.7 Hz,1H),3.98-3.93(m,1H),3.87-3.32(m,1H),2.72-2.56(m,2H),2.03-1.87(m,2H),1.77-1.71(m,1H),1.25(dd,J
=15.4,2.6 Hz,1H),0.89(s,9H);MS(ESI)m/z
534[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.58-7.55(m,1H),7.38-7.35(m,1H),7.21-7.16(m,1H),6.87(s,1H),6.82-6.78(m,2H),5.08(d,J
=10.0 Hz,1H),4.45(d,J
=10.0 Hz,1H),4.17-4.07(m,2H),3.78(s,2H),2.68-2.58(m,2H),2.44-2.40(m,1H),2.30-2.27(m,1H),1.98(dd,J
=15.4,7.7 Hz,1H),1.58(s,1H),1.26(dd,J
=15.4,2.5 Hz,1H),0.82(s,9H);MS(ESI)m/z
464[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.62-7.57(m,1H),7.41-7.35(m,1H),7.22-7.17(m,1H),6.88(s,1H),6.79(m,2H),5.11(d,J
=10.1 Hz,1H),4.47(d,J
=10.1 Hz,1H),4.19(dd,J
=7.6,2.6 Hz,1H),4.07-4.02(m,1H),3.82(s,2H),2.87-2.74(m,2H),2.22-2.18(m,1H),2.07-1.96(m,2H),1.27(dd,J
=15.3,2.6 Hz,1H),0.82(s,9H);MS(ESI)m
/z
591[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.58-7.53(m,1H),7.44-7.39(m,1H),7.26-7.21(m,1H),6.90-6.89(m,1H),6.80-6.77(m,1H),6.60(d,J
=8.1 Hz,1H),5.00(d,J
=9.0 Hz,1H),4.50-4.40(m,2H),4.08(d,J
=5.5 Hz,1H),3.43-3.32(m,2H),3.17-3.06(m,2H),1.96(dd,J
=15.2,7.9 Hz,1H),1.18(dd,J
=15.2,1.9 Hz,1H),0.83(s,9H);MS(ESI)m
/z
532[M+H]+
。
1
H NMR(300 MHz,CD3
OD)δ7.65(d,J
=8.4 Hz,1H),7.29(d,J
=7.8 Hz,1H),7.27(s,1H),7.21(t,J
=7.8 Hz,1H),7.04(d,J
=7.5 Hz,1H),6.83(d,J
=6.0 Hz,1H),5.27(d,J
=11.4 Hz,1H),4.41(d,J
=6.6 Hz,1H),4.10(d,J
=11.4 Hz,1H),3.39-3.53(m,1H),3.11-3.22(m,1H),3.00(s,4H),2.53(s,4H),2.41(dd,J
=6.6,12.0 Hz,1H),1.86(dd,J
=8.1,15.3 Hz,1H),1.09-1.38(m,2H),0.93(s,9H)。
1
H NMR(300 MHz,CD3
OD)δ7.66(d,J
=8.4 Hz,1H),7.15-7.33(m,3H),7.05(d,J
=7.5 Hz,1H),6.81(d,J
=6.0 Hz,1H),5.31(d,J
=11.4 Hz,1H),4.44(dd,J
=1.8,8.4 Hz,1H),4.12(d,J
=11.4 Hz,1H),3.33-3.45(m,1H),3.18(dd,J
=7.5,14.7 Hz,4H),2.95-3.10(m,1H),2.80(s,3H),2.66(dd,J
=7.5,13.8 Hz,4H),2.46(dd,J
=6.6,12.6 Hz,2H),1.88(dd,J
=8.4,15.3 Hz,1H),1.23-1.38(m,1H),0.85(s,9H)。
1
H NMR (300 MHz,CD3
OD)δ7.68(d,J
=8.4 Hz,1H),7.13-7.30(m,3H),7.04(d,J
=7.2 Hz,1H),6.84(d,J
=6.0 Hz,1H),5.32(d,J
=11.4 Hz,1H),4.41(dd,J
=1.8,8.4 Hz,1H),4.11(d,J
=11.4 Hz,1H),3.31-3.46(m,1H),3.16(dd,J
=7.5,14.7 Hz,4H),2.95-3.10(m,1H),2.78(s,3H),2.67(dd,J
=7.5,14.1 Hz,4H),2.46(dd,J
=6.6,12.6 Hz,2H),2.09-2.38(m,2H),1.67-1.78(m,1H),1.23-1.38(m,1H),0.86(s,9H)。
1
H NMR(300 MHz,CD3
OD)δ7.70(d,J
=8.4 Hz,1H),7.58(t,J
=7.2 Hz,1H),7.42(t,J
=7.5 Hz,1H),7.18(t,J
=8.1 Hz,1H),6.88(d,J
=6.0 Hz,1H),5.31(d,J
=11.4 Hz,1H),4.67(d,J
=11.4 Hz,1H),4.48(d,J
=7.8 Hz,1H),3.52-3.80(m,2H),3.00-3.48(m,6H),1.95-2.30(m,4H),1.93(dd,J
=8.4,15.3 Hz,1H),1.13(d,J
=15.6 Hz,1H),0.92(s,9H)。
1
H NMR(300 MHz,CD3
OD)δ7.71(d,J
=8.1 Hz,1H),7.60(t,J
=7.2 Hz,1H),7.45(t,J
=6.9 Hz,1H),7.21(t,J
=7.8 Hz,1H),6.89(d,J
=6.0 Hz,1H),5.30(d,J
=11.4 Hz,1H),4.66(d,J
=11.4 Hz,1H),4.52(d,J
=8.1 Hz,1H),3.55-3.80(m,2H),3.18-3.46(m,2H),2.82-3.15(m,4H),1.74-2.33(m,7H),1.16(d,J
=15.6 Hz,1H),0.92(s,9H)。
1
H NMR(300 MHz,CD3
OD)δ7.71(d,J
=8.7 Hz,1H),7.59(t,J
=6.6 Hz,1H),7.44(t,J
=6.9 Hz,1H),7.20(t,J
=8.1 Hz,1H),6.88(d,J
=6.0 Hz,1H),5.28(d,J
=11.4 Hz,1H),4.65(d,J
=11.4 Hz,1H),4.52(d,J
=8.4 Hz,1H),3.55-3.70(m,2H),3.08-3.27(m,4H),2.88-3.08(m,2H),1.98-2.28(m,5H),1.91(dd,J
=8.4,15.3 Hz,1H),1.40-1.65(m,4H),1.15(d,J
=15.3 Hz,1H),0.91(s,9H),0.82(d,J
=9.9 Hz,1H)。
1
H NMR(300 MHz,CD3
OD)δ8.33(d,J
=7.5 Hz,1H),7.45(t,J
=6.9 Hz,1H),7.34(t,J
=7.8 Hz,1H),7.15(t,J
=8.7 Hz,1H),6.83(d,J
=1.5 Hz,1H),6.75(dd,J
=1.8,8.1 Hz,1H),6.66(d,J
=8.1 Hz,1H),4.79(d,J
=9.9 Hz,1H),4.32(d,J
=9.6 Hz,1H),3.99(d,J
=5.4 Hz,1H),3.55-3.70(m,1H),3.05-3.20(m,1H),2.89(s,3H),1.78-2.06(m,4H),1.67(d,J
=12.6 Hz,1H),1.15-1.45(m,6H),0.86(d,J
=6.3 Hz,1H),0.78(s,9H)。
1
H NMR(300 MHz,CD3
OD)δ8.31(d,J
=7.8 Hz,1H),7.46(t,J
=6.9 Hz,1H),7.34(t,J
=7.8 Hz,1H),7.15(t,J
=8.7 Hz,1H),6.83(d,J
=1.5 Hz,1H),6.75(dd,J
=1.8,8.1 Hz 1H),6.66(d,J
=8.1 Hz,1H),4.79(d,J
=9.9 Hz,1H),4.32(dJ
=9.6 Hz,1H),3.99(d,J
=5.4 Hz,1H),3.55-3.70(m,1H),3.05-3.20(m,1H),2.89(s,3H),1.78-2.06(m,4H),1.67(d,J
=12.6 Hz,1H),1.15-1.45(m,6H),0.86(d,J
=6.3 Hz,1H),0.78(s,9H)。
1
H NMR(300 MHz,CD3
OD)δ7.48(t,J
=6.6 Hz,1H),7.35(t,J
=6.9 Hz,1H),7.16(t,J
=7.8 Hz,1H),6.83(d,J
=1.8 Hz,1H),6.75(dd,J
=1.8,8.1 Hz,1H),6.65(d,J
=8.1 Hz,1H),4.33(d,J
=9.3 Hz,1H),4.02(d,J
=5.4 Hz,1H),3.70-3.88(m,1H),3.62(d,J
=12.3 Hz,1H),3.53(d,J
=12.9 Hz,1H),2.77(s,3H),2.65-2.90(m,2H),1.79-2.06(m,2H),1.65-1.78(m,1H),1.47-1.63(m,1H),1.32-1.47(m,1H),1.10-1.24(m,1H),0.86(d,J
=6.0 Hz,1H),0.78(s,9H),0.76(d,J
=11.7 Hz,1H)。
1
H NMR(300 MHz,CD3
OD)δ8.53(d,J
=7.5 Hz,1H),7.55(t,J
=7.5 Hz,1H),7.39(t,J
=7.2 Hz,1H),7.19(t,J
=8.1 Hz,1H),6.88(s,1H),6.82(s,2H),5.04(d,J
=9.9 Hz,1H),4.46(d,J
=9.9 Hz,1H),4.20(dd,J
=2.7,7.2 Hz,1H),3.73-4.05(m,2H),3.07-3.22(m,2H),2.86(dd,J
=13.8,26.1 Hz,2H),2.03(dd,J
=7.2,15.3 Hz,1H),1.78-1.96(m,2H),1.56-1.68(m,1H),1.16-1.53(m,3H),1.10(t,J
=7.2 Hz,3H),0.90(d,J
=4.5 Hz,1H),0.82(s,9H),0.80(d,J
=12.9Hz,1H)。
1
H NMR(300 MHz,MeOH-d4): 7.50-7.36(m,1H),7.24-7.10(m,2H),6.88-6.76(m,3H),5.12(d,J
=10.17 Hz,1H),4.49(d,J
=10.17 Hz,1H),4.23(dd,J
=6.83,2.09 Hz,1H),3.98-3.83(m,1H),2.49-2.36(m,1H),2.36-2.22(m,1H),2.10-1.96(m,2H),1.94-1.82(m,1H),1.35-1.28(m,1H),1.29(s,3H),0.80(s,9H);13
C NMR(75 MHz,MeOH-d4): 108.1,166.0,145.4,136.9,127.9,126.1(t,J C-F
=5.6 Hz),125.4,123.4 118.8(d,J C-F
=17.3 Hz),112.0,67.4,64.5,63.7,61.6,49.5,45.6,45.5,42.4,38.5,30.9,29.5,27.6;ESI-MS:C28
H33 35
ClF2
N3
O3
[M+H]+
之計算值:532.2179,實測值:532.42。
1
H NMR(300 MHz,MeOH-d4): 8.84(d,J
=6.80 Hz,1H),7.58(t,J=6.80 Hz,1H),7.39(t,J
=7.11 Hz,1H),7.22(t,J
=7.80 Hz,1H),6.88(dd,J
=9.81,7.80 Hz,1H),6.78(d,J
=10.13,6.63 Hz,1H),5.11(d,J
=10.37 Hz,1H),4.48(d,J
=10.37 Hz,1H),4.21(d,J
=10.37 Hz,1H),4.21(dd,J
=7.32,2.66 Hz,1H),3.95-3.75(m,1H),2.46-2.22(m,2H),2.12-1.96(m,2H),1.94-1.80(m,1H),1.34-1.28(m,1),1.29(s,3H),0.81(s,9H);13
C NMR(75 MHz,MeOH-d4): 180.2,169.2,132.2,128.7(d,J C-F
=2.2 Hz),126.5(d,J C-F
=4.6 Hz),124.7(dd,J C-F
=33.5,19.2 Hz),122.6(d,J C-F
=18.1 Hz),101.5(d,J C-F
=23.0 Hz),67.4,64.4,63.5,61.9,49.8,45.6,45.5,42.4,38.6,30.9,29.5,27.6;ESI-MS:C28
H32 35
ClF3
N3
O3
[M+H]+
之計算值:550.2084,實測值:550.33。
1
H NMR(300 MHz,MeOH-d4): 7.68-7.54(m,1H),7.38-7.26(m,1H),7.22-7.12(m,1H),6.90-6.76(m,1H),6.70-6.60(m,1H),6.56-6.42(m,1H),5.30-5.20(m,1H),4.49(d,J
=10.03 Hz,1H),4.25(dd,J
=71.9,2.39 Hz,1H),4.00-3.82(m,1H),2.50-2.21(m,2H),2.18-2.00(m,2H),1.98-1.82(m,1H),1.40-1.30(m,1H),1.28(s,3H),0.79(s,9H);13
C NMR(75 MHz,MeOH-d4):180.6,165.1(d,J C-F
=246.7 Hz),166.1,157.7(d,J C-F
=247.9 Hz),145.6(d,J C-F
=12.0 Hz),132.0,128.6,128.2(d,J C-F
=10.2 Hz),126.3(d,J C-F
=4.5 Hz),125.0(d,J C-F
=14.0 Hz),122.4(d,J C-F
=18.4 Hz),122.3,109.8(d,J C-F
=23.2 Hz),99.9(d,J C-F
=27.8 Hz),67.4,64.5,63.5,61.5,49.2,45.6,45.5,42.3,38.4,30.9,29.5,27.5;ESI-MS:C28
H33 35
ClF2
N3
O3
[M-CH]+
之計算值:532.2179,實測值:532.42。
1
H NMR(300 MHz,MeOH-d4):7.28-7.10(m,5H),6.92-6.84(m,1H),6.80-6.76(m,1H),5.40-5.20(m,1H),5.08(d,J
=10.96 Hz,1H),4.40-4.20(m,1H),3.90-3.60(m,1H),2.50-2.30(m,1H),2.30-2.15(m,1H),2.15-2.00(m,2H),1.90-1.75(m,1H),1.57(dd,J
=15.3,3.71 Hz,1H),1.25(s,3H),0.79(s,9H);13
C NMR(75 MHz,MeOH-d4):180.0,165.9,144.7,136.7,136.6,135.8,131.3,130.1,129.8,128.1,128.1,126.8,123.5,112.0,67.4,64.3,64.0,62.2,57.2,45.7,45.6,42.7,38.3,31.0,29.6,27.5;ESI-MS:C28
H34 35
Cl2
N3
O3
[M+H]+
之計算值:530.1977,實測值:530.50。
1
H NMR(300 MHz,MeOH-d4): 7.40-7.00(m,5H),6.80-6.40(m,1H),5.60-5.00(m,2H),4.60-4.20(m,1H),4.00-3.80(m,1H),2.60-2.40(m,1H),2.40-2.20(m,1H),2.20-2.00(m,2H),2.00-1.80(m,1H),1.70-1.50(m,1H),1.28(s,3H),0.83(s,9H);13
C NMR(75 MHz,MeOH-d4): 180.0,165.8,160.0-145.0(m,2×Csp2
-F),136.5,135.9,131.4,130.0,129.9,128.0,124.1(d,J C-F
=6.3 Hz),119.1,116.7(d,J C-F
=20.4 Hz),101.4(d,J C-F
=23.0 Hz),67.4,64.2,63.8,62.5,57.4,45.6,45.5,42.7,38.3,31.0,29.5,27.5;ESI-MS:C28
H33 35
ClF2
N3
O3
[M+H]+
之計算值:532.2179,實測值:532.42。
1
H NMR(300 MHz,MeOH-d4): 7.50-7.30(m,2H),7.20-7.10(m,1H),6.90-6.70(m,3H),5.00-4.70(m,1H),4.36(d,J
=9.76 Hz,1H),4.05-3.96(m,1H),3.70-3.50(m,1H),1.94(dd,J
=14.98,7.30 Hz,1H),1.80-1.00(m,8H),1.16(s,3H),0.90-0.70(m,1H),0.80(s,9H);ESI-MS:C30
H37 35
Cl2
FN3
O3
[M+H]+
之計算值:576.2196,實測值:576.58。
1
H NMR(300 MHz,MeOH-d4): 7.50-7.30(m,2H),7.25-7.10(m,1H),6.85-6.70(m,3H),5.00-4.70(m,1H),4.32(d,J
=9.69 Hz,1H),4.10-3.95(m,1H),3.85-3.70(m,1H),2.00-1.80(m,2H),1.75-1.20(m,7H),1.13(s,3H),0.95-0.75(m,1H),0.81(s,9H);ESI-MS:C30
H37 35
Cl2
FN3
O3
[M+H]+
之計算值:576.2196,實測值:576.58。
1
H NMR(300 MHz,MeOH-d4): 7.36-7.25(m,1H),7.24-7.11(m,2H),6.86(d,J
=1.8 Hz,1H),6.80(dd,J
=1.8,8.1 Hz,1H),6.72(d,J
=8.1 Hz,1H),4.82(d,J
=9.6 Hz,1H),4.36(d,J
=9.6 Hz,1H),4.04(dd,J
=2.4,7.4 Hz,1H),3.74-3.56(m,1H),3.56-3.40(m,1H),2.05-1.78(m,5H),1.75-1.59(m,1H),1.43-1.04(m,5H),0.81(s,9H);ESI-MS:C29
H35
ClF2
N3
O3
(M+H)+
之計算值需要546.23,實測值為546.58。
1
H NMR(300 MHz,MeOH-d4): 8.3
8(d,J
=7.7 Hz,1H),7.54
(t,J
=6.7 Hz,1H),7.40(d,J
=7.1 Hz,1H),7.20(t,J
=7.9 Hz,1H),6.93(d,J
=6.1 Hz,1H),6.86(d,J
=8.7 Hz,1H),4.45(d,J
=10.3 Hz,1H),4.13(dd,J
=2.8,7.5 Hz,1H),3.77-3.55(m,1H),3.55-3.42(m,1H),2.09-1.71(m,4H),1.70-1.56(m,1H),1.45-1.02(m,5H),0.82(s,9H);ESI-MS:C29
H34
Cl2
F2
N3
O3
(M+H)+
之計算值需需要580.19,實測值為580.67。
1
H NMR(300 MHz,MeOH-d4): 7.49(t,J=7.2 Hz,1H),7.45-7.38(m,1H),7.22(t,J=8.0 Hz,1H),6.85-6.68(m,2H),4.80(d,J=9.8 Hz,1H),4.36(d,J=9.9 Hz,1H),4.01(dd,J=2.4,7.6 Hz,1H),3.74-3.57(m,1H),3.55-3.39(m,1H),2.04-1.77(m,4H),1.74-1.59(m,1H),1.44-1.04(m,5H),0.90(d,J=4.5 Hz,1H),0.82(s,9H);ESI-MS:C29
H34
ClF3
N3
O3
(M+H)+
之計算值需要564.22,實測值為564.58。
1
H NMR(300 MHz,MeOH-d4):7.49(t,J=7.2 Hz,1H),7.45-7.38(m,1H),7.22(t,J=8.0 Hz,1H),6.85-6.68(m,2H),4.80(d,J=9.8 Hz,1H),4.36(d,J=9.9 Hz,1H),4.01(dd,J=2.4,7.6 Hz,1H),3.74-3.57(m,1H),3.55-3.39(m,1H),2.04-1.77(m,4H),1.74-1.59(m,1H),1.44-1.04(m,5H),0.90(d,J=4.5 Hz,1H),0.82(s,9H);ESI-MS:C29
H35
ClF2
N3
O3
(M+H)+
之計算值需要546.23,實測值為546.58。
1
H NMR(300 MHz,MeOH-d4): 8.36(d,J
=7.0 Hz,1H),7.59(d,J
=8.1 Hz,1H),7.4
1-7.11(m,4H),7.04(d,J
=7.6 Hz,1H),6.78(d,J
=1.8 Hz,1H),5.19(d,J
=11.3 Hz,1H),4.44(J
=8.1 Hz,1H),4.07(d,J
=11.3 Hz,1H),3.74-3.53(m,1H),3.53-3.37(m,1
H),2.08-1.
83
(m,3H
),
1.83-1.6
9(m,1H),1.61-1.44(m,1H),1.44-1.08(m,4H),1.07-0.72(m,1H),0.88(s,9H);ESI-MS:C29
H36
Cl2
N3
O3
(M+H)+
之計算值需要544.21,實測值為544.67。
1
H NMR(300 MHz,MeOH-d4/DMSO-d6): 10.15(s,1H),7.76(d,J=8.2 Hz,1H),7.22(s,1H),7.17-7.00(m,3H),6.94(d,J=7.1 Hz,1H),6.81(d,J=6.0 Hz,1H),4.42(d,J=8.3 Hz,1H),4.09(d,J=3.0 Hz,1H),3.79(d,J=8.3 Hz,1H),3.73-3.49(m,2H),3.35(d,J=9.5 Hz,1H),2.10-1.84(m,4H),1.52-1.11(m,5H),0.87(s,9H);13C NMR(75 MHz,MeOH-d4/DMSO-d6): 177.1,172.4,153.6(d,JC-F
=242.7 Hz),138.7,138.5(d,JC-F
=2.4 Hz),133.2,129.0,127.544,127.541(d,JC-F
=6.7 Hz),126.8,126.5,119.7(d,JC-F
=19.2 Hz),111.3,110.4(d,JC-F
=24.1 Hz),68.4,66.6,65.7,64.0,58.6,46.8,42.2,33.26,33.20,30.4,30.2,29.7,29.5;ESI-MS:C29
H35
Cl2
FN3
O3
(M+H)+之計算值需要562.20,實測值為562.67。
1
H NMR(300 MHz,MeOH-d4): 7.47(t,J
=6.7 Hz,1H),7.42-7.33(m,1H),7.18(t,J
=7.7 Hz,1H),6.87(d,J
=1.8 Hz,1H),6.78(dd,J
=1.8,8.1 Hz,1H
),6.70(d,J
=8.1 Hz,1
H),4.40(d,J
=9.7 Hz,1H),4.11(dd,J
=2.5,7.6 Hz,1H),2.77-2.65(m,1H),1.99(dd,J
=7.6,15.3 Hz,1H),1.
24(dd,J
=2.5,15.3 Hz,1H),0.92-0.62(m,2H),0.81(s,9H),0.56-0.30(m,2H);ESI-MS:C26
H29
Cl2
FN3
O2
(M+H)+
之計算值需要504.16,實測值為504.58。
1
H NMR(300 MHz,CD3
OD): 7.597(d,J
=8.73 Hz,1H),7.30-7.10(m,3H),7.10-7.00(m,1H),6.84(d,J
=6.14 Hz,1H),5.35(d,J
=12.85 Hz,1H),4.40(dd,J
=7.62,3.80 Hz,1H),4.15(d,J
=12.92 Hz,1H),1.71(dd,J
=15.32,7.68 Hz,1H),1.12(dd,J
=15.32,3.79 Hz,1H),0.92(s,9H);ESI-MS:C23
H24 35
Cl2
FN2
O3
[M+H]+
之計算值:465.1148,實測值:465.50。
1
H NMR(300 MHz,CD3
OD): 7.67(d,J
=8.41 Hz,1H),7.35-7.18(m,3H),7.10-7.00(m,1H),6.87(d,J
=6.03 Hz,1H),5.62(d,J
=12.10 Hz,1H),4.42(dd,J
=8.54,1.92 Hz,1H),4.30-4.15(m,2H),4.23(d,J
=12.00 Hz,1H),1.96(dd,J
=15.44,8.61 Hz,1H),1.24-1.15(m,1H),1.13(t,J
=7.13 Hz,3H),0.91(s,9H);ESI-MS:C25
H28 35
Cl2
FN2
O3
[M+H]+
之計算值:493.1461,實測值:493.30。
1
H NMR(300 MHz,CD3
OD): 7.45-7.34(m,1H),7.26-7.12(m,1H),7.04-6.93(m,1H),6.90(d,J
=1.80 Hz,1H),6.65(dd,J
=8.08,1.80 Hz,1H),4.41(d,J
=9.25 Hz,1H),3.96(quint,J
=8.13 Hz,1H),2.51-2.07(m,2H),2.40-2.20(m,2H),1.88(dd,J
=14.20,9.91 Hz,1H),1.32(s,3H),1.20-0.80(m,1H),0.88(s,9H);13
C NMR(75 MHz,CD3
OD): 181.3,172.9(d,J C-F
=266.9 Hz),168.6,162.7,145.3,135.8,131.7,130.7(d,J C-F
=38.6 Hz),126.2(d,J C-F
=4.5 Hz),126.1,123.6,122.9,122.7,111.4,78.4,67.7,63.4,46.0,45.8,44.3,38.0,31.4,30.2,27.6;ESI-MS:C28
H31 35
Cl2
FN3
O3
[M+H]+
之計算值:546.1727,實測值:546.50。
1
H NMR(300 MHz,CD3
OD): 7.60-7.45(m,1H),7.45-7.35(m,1H),7.22(t,J
=7.96 Hz,1H),6.90(d,J
=1.80 Hz,1H),6.75(dd,J
=8.14,1.92 Hz,1H),6.41(d,J
=8.13 Hz,1H),5.07(d,J
=8.40 Hz,1H),4.39(d,J
=8.40 Hz,1H),4.01(dd,J
=7.76,2.17 Hz,1H),1.95(dd,J
=15.35,7.83 Hz,1H),1.12(dd,J
=15.35,2.17 Hz,1H),0.82(s,9H);ESI-MS:C23
H24 35
Cl2
FN2
O3
[M+H]+
之計算值:465.1148,實測值:465.42。
ESI-MS:C28
H32 35
Cl2
F3
N4
O2
[M+H]+
之計算值:583.1854,實測值:583.42。
1
H NMR(300 MHz,CD3
OD): 7.64-7.54(m,1H),7.42-7.60(m,1H),7.26-7.18(m,1H),6.88(s,1H),6.80-6.70(m,1H),6.50-6.40(m,1H),5.20-5.00(m,1H),4.80-4.30(m,4H),4.30-4.10(m,2H),4.10-4.00(m,1H),3.98(s,3H),1.90(dd,J
=14.96,7.33 Hz,1H),1.11(d,J
=14.96 Hz,1H),0.81(s,9H);ESI-MS:C27
H32 35
Cl2
FN4
O2
[M+H]+
之計算值:533.1886,實測值:533.58。
ESI-MS:C28
H33 35
Cl2
F2
N4
O2
[M+H]+
之計算值:565.1949,實測值:565.42。
H NMR(300 MHz,CD3
OD): 7.50-7.40(m,1H),7.40(m,1H),7.20-7.10(m,1H),6.85(d,J
=1.40 Hz,1H),6.84-6.72(m,2H),5.00-4.80(m,1H),4.45(d,J
=10.10 Hz,1H),4.02(t,J
=6.61 Hz,1H),3.90(quintet,J
=8.07 Hz,1H),2.50-2.25(m,2H),2.10-1.82(m,3H),1.81-1.31(m,8H),1.30(s,3H),1.10-0.91(m,1H),0.91-0.81(m 1H);ESI-MS:C29
H33 35
Cl2
FN3
O3
[M+H]+
之計算值:560.1883,實測值:560.50。
1
H NMR(300 MHz,CD3
OD): 7.45-7.31(m,2H),7.20-7.11(m,1H),6.86-6.82(m,1H),6.81-6.78(m,2H),4.90-4.80(m,1H),4.45(d,J=10.33 Hz,1H),4.10-3.95(m,1H),3.70-3.60(m,1H),3.50-3.40(m,1H),2.10-1.05(m,17H),1.05-0.95(m,1H),0.95-0.80(m,1H);ESI-MS:C30
H35 35
Cl2
FN3
O3
[M+H]+
之計算值:574.2040,實測值:574.58。
1
H NMR(300 MHz,CD3
OD): 7.78(d,J=6.92 Hz,1H),7.56-7.42(m,2H),6.90(d,J
=1.89 Hz,1H),6.68(dd,J
=8.15,1.84 Hz,1H),6.03(dd,J
=8.13,3.66 Hz,1H),4.80-4.70(m,1H),4.58(d,J
=5.51 Hz,1H),4.10-3.70(m,7H),3.54(dt,J
=15.10,5.20 Hz,2H),3.40-3.20(m,3H),1.79(ddd,J
=14.60,8.49,1.59 Hz,1H),1.00-0.80(m,1H),0.81(s,9H);ESI-MS:C29
H36 35
Cl3
N4
O3
[M+H]+
之計算值:593.1853,實測值:593.75。
1
H NMR(300 MHz,CD3
OD): 7.80-7.72(m,1H),7.50-7.38(m,2H),6.87(d,J
=1.81 Hz,1H),6.71(dd,J
=8.16,1.81 Hz,1H),6.52-6.40(m,1H),4.96-4.80(m,1H),4.62(d,J
=8.69 Hz,1H),4.10-3.95(m,1H),3.70-3.55(m,1H),3.50-3.45(m,1H),2.00-1.80(m,3H),1.80-1.60(m,1H),1.40-1.00(m,5H),0.95-0.85(m,1H),0.80(s,9H);ESI-MS:C29
H35 35
Cl3
N3
O3
[M+H]+
之計算值:578.1744,實測值:578.75。
使用重組人類His-標記之MDM2蛋白(殘基1至118)與螢光標記之p53系肽,以最佳化、靈敏及定量之螢光偏振系(FP系)結合分析法測定MDM2抑制劑之結合親和性。
螢光探針之設計係根據先前報導之高親和性p53系擬肽化合物(5-FAM-βAla-βAla-Phe-Met-Aib-pTyr-(6-Cl-LTrp)-Glu-Ac3c-Leu-Asn-NH2(SEQ ID NO: 1))(Garca-Echeverraet al
.,J. Med. Chem. 43
: 3205-3208(2000))。此標記之肽稱為PMDM6-F。從飽和曲線測定PMDM6-F與重組MDM2蛋白之Kd
值。於黑色、圓底之Dynex 96槽盤中進行MDM2蛋白之連續兩倍稀釋,添加濃度1nM之PMDM6-F肽。於下述緩衝液中進行測定:100 mM磷酸鉀、pH 7.5;100微克/毫升牛伽瑪球蛋白;0.02%疊氮化鈉、0.01% Triton X-100),培育3小時後,使用ULTRA READER(Tecan U.S. Inc.,Research Triangle Park,NC)測量偏振值。使用非線性迴歸法,將諸mP值擬合於S形劑量-反應曲線(斜率可變)中,測得IC50
值為1.40 nM±0.25。Kd
值之計算係使用等式:Kd
值=IC50
-L0/2;L0/2為游離配體(PMDM6-F)之濃度。由於所用PMDM6-F之最終濃度為1nM,因此L0/2為0.5 nM。
使用測試化合物於DMSO中之系列稀釋液進行劑量相依、競爭性結合實驗。於黑色、圓底之Dynex 96槽盤中,添加於分析法緩衝液(100 mM磷酸鉀、pH 7.5;100微克/毫升牛伽瑪球蛋白;0.02疊氮化鈉、0.01% Triton X-100)中之5微升測試化合物試樣與預先培育之MDM2蛋白(10 nM)及PMDM6-F肽(1 nM),使最終容積為125微升。於各個測定中,對照組包括MDM2蛋白與PMDM6-F(相當於0%抑制)、單僅PMDM6-F肽(相當於100%抑制作用)。培育3小時後,測量偏振值。IC50
值,亦即50%結合肽被置換之抑制劑濃度,係使用非線性最小平方分析,從製圖中決定。使用GRAPHPAD PRISM軟體(GraphPad Software,Inc.,San Diego,CA)進行曲線擬合。如表19A-D所呈現,本文提供之化合物為強力MDM2拮抗劑。表19A-D所示呈游離鹼之化合物係呈游離鹼或呈CF3
CO2
H(TFA)或HCl鹽進行測試。通常,化合物之游離鹼與鹽型間被預期具可相較之分析反應。
同源HCT-116結腸癌細胞株為Prof. Bert Vogeltein(Johns Hopkins,Baltimore,MD)所饋贈,係維持於含有10% FBS之McCoy's 5A培養基中。所有其他細胞株係得自ATCC(Manassas,VA),係維持於含有10% FBS之RPMI-1640培養基中。
以每槽2-3×103
個細胞之密度,將細胞接種於具有化合物之96槽平底細胞培養盤中,培育4天。經濃度漸增之測試化合物處理後,利用WST-8(2-(2-甲氧基-4-硝苯基)-3-(4-硝苯基)-5-(2,4-二磺苯基)-2H-四銼一鈉鹽(Dojindo Molecular Technologies Inc.,Gaithersburg,Maryland)測定細胞生長抑制率。添加最終濃度10%之WST-8至各槽,於37℃培育培養盤2至3小時。使用TECAN ULTRA Reader測定試樣於450奈米處之吸光率。使用GraphPad Prism軟體(GraphPad Software,La Jolla,CA 92037,USA),藉由比較未處理細胞及經化合物處理細胞之吸光率計算抑制50%細胞生長之化合物濃度(IC50
)。此分析法之結果呈現於表19A-D。
使用錐蟲藍染色法進行細胞死亡測定。於所示化合物存在及不存在下處理細胞。漂浮與黏著之細胞均以錐蟲藍染色。染成藍色之細胞或形態不健康之細胞均評分為死細胞。顯微鏡下三個不同區域各計數至少100個細胞。
如圖1所示,本文提供之MDM2抑制劑於具有野生型p53之SJSA-1癌細胞中誘發細胞死亡。
進行西方墨點分析時,使細胞溶於冰冷之RIPA緩衝液中:20 mM Tris-HCl(pH 7.5)、150 mM NaCl、1 mM EDTA、1 mM EGTA、1%脫氧膽酸鈉、2.5 mM焦磷酸鈉、1 mMb-甘油磷酸鹽、1mM正釩酸鈉與1微克/毫升亮肽素。以西方墨點分析檢測整個細胞溶解液中之蛋白質,使用下述抗體:抗p53(DO-1株)、抗MDM2(SMP-14株)、抗p21(SX118株)、抗β-肌動蛋白(AC-40株)與甘油醛-3-磷酸脫氫酶(GAPDH;接合HRP)。如圖2至4所示,本文提供之MDM2抑制劑於此分析法中具活性。
使用大鼠及/或人類肝微粒體測定本文提供之諸MDM2抑制劑之活體外穩定性,如表20至24所示。
於大鼠中,針對MDM2抑制劑進行藥物動力學研究。為了比較,亦研究MDM2抑制劑AT-219。如圖5與6所示,及表25與26所摘述,本文提供之MDM2抑制劑於大鼠中具大有可為之ADME性質。特別是,MI-773展現高口服生物利用性;MI-772展現長血漿半衰期。MI-774,MI-773之胺基酸酯前驅藥物,亦具有良好口服生物利用性。值得注意的是,進行MI-774之藥物動力學評估時,測定MI-773之濃度。
使用胰蛋白酶(0.05%)-EDTA(0.53mM)(GIBCOTM
,Invitrogen Corp.)收取SJSA-1腫瘤細胞,添加生長培養基,將細胞置於冰上。使細胞試樣與錐蟲藍(Trypan Blue)(GIBCOTM
,Invitrogen Corp.)1:1混合,於血球計上計數以測定活/死細胞。細胞以1X PBS(GIBCOTM
,Invitrogen Corp.)洗滌一次,使其再懸浮於PBS中。製備Matrigel注射劑時,細胞於PBS中洗滌後,使其再懸浮於PBS與Matrigel(BD Biosciences,Invitrogen Corp.)之1:1冰冷混合物中,使最終Matrigel蛋白質濃度為5毫克/毫升。以Matrigel將SJSA-1腫瘤(0.1毫升中5 x 106
個細胞)接種入C.B-17 SCID小鼠中。使用27號針將細胞從皮下注入各小鼠腹部部位。
使用測徑器二維測量在小鼠中生長之腫瘤大小。腫瘤體積(毫米)=(AxB2)/2,其中A與B分別為腫瘤之長與寬(單位為毫米)。處理期間,每週測量腫瘤體積與體重三次。處理終止後,每週至少測量腫瘤體積(圖7、9與11)與體重(圖8、10與12)一次。繼續飼養小鼠60天以進一步觀察腫瘤生長及毒性。
處理開始之前,讓腫瘤生長至體積為60至140立方毫米,此時供給腫瘤之血管應已建立。將腫瘤大小在可接受範圍內之小鼠隨機分為實驗化合物處理組(每組8隻小鼠)及對照組(每組10隻小鼠)。實驗化合物供口服用,每天一次,為期2至3週。對照組單只接受賦形劑(10% PEG 400:3% Cremophor:87% PBS)。MDM2抑制劑對SJSA-1腫瘤之活體內效力之統計分析呈現於表27至29。
彼等數據表明本發明特定MDM2抑制劑(特別是MI-519-63、MI-773與MI-519-64)之良好活體內效力,動物體重未明顯減少。
步驟1:3-酮基環丁烷甲酸苄酯(2)
添加BnBr至化合物1
與K2
CO3
於150毫升乙腈之混合物中。於室溫攪拌混合物24小時,過濾固體。去除溶劑,殘留物利用管柱層析法進行純化,得到化合物2
。
步驟2:3-羥基-3-甲基環丁烷甲酸苄酯(3與4)
於-78℃,逐滴添加MeMgCl之THF溶液至化合物2
之乙醚溶液中,此混合物於相同溫度攪拌半小時。TCL監測顯示起始物質消失後,添加NH4
Cl水溶液以終止反應。水相以乙酸乙酯萃取三次,合併之有機相以鹽水洗滌,乾燥(Na2
SO4
)。過濾固體,去除溶劑。殘留物利用管柱層析法進行純化,得到化合物3
與4
(5:1,根據TLC分析)。
步驟3:3-(第三丁基二甲基矽烷氧基)-3-甲基環丁烷甲酸苄酯(5與6)
於化合物3
與4
之DMF(10毫升)混合物中,添加咪唑與TBSCl,所得混合物於80℃攪拌30小時。冷卻至室溫後,添加水,水相以乙酸乙酯萃取三次。合併之有機相以鹽水洗滌,乾燥(Na2
SO4
)。過濾固體,去除溶劑。殘留物利用管柱層析法進行純化,得到化合物5
與6
。
步驟4:3-(第三丁基二甲基矽烷氧基)-3-甲基環丁烷甲酸(7與8)
於化合物5
與6
之異丙醇混合物中,添加Pd/C。所得混合物於1大氣壓氫氣下攪拌1小時。TLC顯示起始物質消失,過濾固體。去除溶劑,得到化合物7
與8
。
步驟5:3-(第三丁基二甲基矽烷氧基)-3-甲基環丁基胺基甲
酸苄酯9與10
於化合物7
與8
和Et3
N之丙酮0℃攪拌溶液中,逐滴添加ClCOOEt。所得混合物於0℃攪拌30分鐘。添加NaN3
之水溶液,所得混合物於0℃再攪拌20分鐘。添加水,水相以乙酸乙酯萃取三次。合併之有機相以鹽水洗滌,乾燥(Na2
SO4
)。去除溶劑,使殘留物溶於甲苯中。添加苄醇與NaHCO3
。所得混合物於80℃攪拌2小時。去除所有溶劑,殘留物利用管柱層析法進行純化,製得兩個異構物9
與10
(比率5:1)。
步驟6:3-(第三丁基二甲基矽烷氧基)-3-甲基環丁胺(11)
於主要異構物9
與NaHCO3
之異丙醇混合物中,添加Pd/C,所得混合物於1大氣壓氫氣下攪拌1小時。過濾固體,去除溶劑,得到化合物11
。
步驟7:3-(第三丁基二甲基矽烷氧基)-3-甲基環丁胺(12)
於次要異構物10
與NaHCO3
之異丙醇混合物中,添加Pd/C,所得混合物於1大氣壓氫氣下攪拌1小時。過濾固體,去除溶劑,得到化合物12
。
步驟8:MI-519-64
於化合物11
之THF溶液中,添加化合物13
,攪拌所得溶液隔夜。去除溶劑,使如此得到之殘留物溶於CH3
CN/H2
O(1:1)中。添加CAN,攪拌反應混合物30分鐘。添加水,水相以乙酸乙酯萃取三次。乾燥(Na2
SO4
)合併之有機層,過濾,濃縮。殘留物於矽膠上利用管柱層析法進行純化,得到化合物14
。使化合物14
溶於甲醇中,添加12MHCl水溶液,於室溫攪拌反應混合物1小時。去除溶劑,殘留物利用HPLC進行純化,得到呈TFA鹽之MI-519-64
。1
H NMR(300 MHz,CD3
OD)δ7.54-7.52(m,1H),7.42-7.38(m,1H),7.23-7.18(m,1H),6.88-6.75(m,3H),5.04(d,J
=9.9 Hz,1H),4.45(d,J
=9.9 Hz,1H),4.19-4.16(m,1H),3.92-3.89(m,1H),2.42-2.11(m,2H),2.10-1.87(m,3H),1.32-1.24(m,4H),0.82(s,9H);MS(ESI)m
/z
548[M+H]+
。
步驟9:MI-519-65
於化合物12
之THF溶液中,添加化合物13
,攪拌所得溶液隔夜。去除溶劑,使殘留物溶於CH3
CN/H2
O(1:1)中。添加CAN,攪拌反應混合物30分鐘。添加水,水相以乙酸乙酯萃取三次。乾燥(Na2
SO4
)合併之有機層,過濾,濃縮。殘留物於矽膠上利用管柱層析法進行純化,得到化合物15
。使化合物15
溶於甲醇中,添加12M HCl水溶液,於室溫攪拌反應混合物1小時。去除溶劑,殘留物利用HPLC進行純化,得到呈TFA鹽之MI-519-65
。1
H NMR(300 MHz,CD3
OD)δ7.50(m,1H),7.44-7.38(m,1H),7.24-7.20(m,1H),6.89-6.88(m,1H),6.80(m,1H),6.71(m,1H),4.91-4.88(m,1H),4.40-4.36(m,2H),4.10-4.06(m,1H),2.41-2.33(m,2H),2.07-1.87(m,3H),1.25-1.21(m,4H),0.82(s,9H);MS(ESI)m/z 548[M+H]+
。
步驟1:((3-甲基丁-3-烯氧基)甲基)苯(1)
添加BnBr至於冰浴中冷卻之醇與NaH之DMF混合物中。此混合物於室溫攪拌隔夜,過濾固體。去除溶劑,殘留物利用管柱層析法進行純化,得到化合物1
。
步驟2:(S)-4-(苄氧基)-2-甲基丁烷-1,2-二醇(2)
添加化合物1
至於冰浴中冷卻之AD-mix-α之tBuOH/H2
O(1:1)溶液中。TCL監測顯示起始物質消失後,藉添加Na2
SO3
終止反應。水相以乙酸乙酯萃取三次,合併之有機相以鹽水洗滌,乾燥(Na2
SO4
)。過濾固體,去除溶劑。殘留物利用管柱層析法進行純化,得到化合物2
。
步驟3:(S)-4-(2-(苄氧基)乙基)-2,2,4-三甲基-1,3-二
茂烷(3)
於化合物2
與2,2-二甲氧丙烷之DCM混合物中,添加p-TSA。TCL監測顯示起始物質消失後,添加NaHCO3
水溶液,然後以乙酸乙酯萃取三次。合併之有機相以鹽水洗滌,乾燥(Na2
SO4
)。過濾固體,去除溶劑。殘留物利用管柱層析法進行純化,得到化合物3
。
步驟4:(S)-2-(2,2,4-三甲基-1,3-二
茂烷-4-基)乙醇(4)
於3
之MeOH溶液中,添加Pd/C。所得混合物於1大氣壓氫氣下攪拌隔夜。TLC顯示起始物質消失,過濾固體。去除溶劑,得到化合物4
。
步驟5:4-甲基苯磺酸(S)-2-(2,2,4-三甲基-1,3-二
茂烷-4-基)乙酯(5)
於化合物4
與Et3
N之DCM溶液中,逐滴添加TsCl。所得混合物於0℃攪拌30分鐘。過濾固體,去除溶劑。殘留物利用管柱層析法進行純化,得到化合物5
。
步驟6:(S)-N-苄基-2-(2,2,4-三甲基-,,3-二
茂烷-4-基)乙胺(6)
回流加熱5
與BnNH2
之THF溶液隔夜。去除溶劑。殘留物利用管柱層析法進行純化,得到化合物6
。
步驟7:(S)-2-(2,2,4-三甲基-1,3-二
茂烷-4-基)乙胺(7)
於6
之MeOH溶液中,添加Pd/C。所得混合物於1大氣壓氫氣下攪拌隔夜。TLC顯示起始物質消失,過濾固體。去除溶劑,得到化合物7
。
步驟8:MI-758(11)
於化合物7
之THF溶液中,添加化合物8
,攪拌所得溶液隔夜。去除溶劑,使殘留物溶於CH3
CN/H2
O(1:1)中。添加CAN,攪拌反應混合物5分鐘。添加K2
CO3
,水相以乙酸乙酯萃取三次。乾燥(Na2
SO4
)合併之有機層,過濾,濃縮。殘留物於矽膠上利用管柱層析法進行純化,得到化合物11
。使化合物11
溶於二烷中,添加4M HCl之二烷溶液,於室溫攪拌反應混合物0.5小時。去除溶劑,殘留物利用HPLC進行純化,得到呈TFA鹽之MI-758
。1
H NMR(300 MHz,CD3
OD)δ8.44(s,1H),7.72(d,J=8.4 Hz,1H),7.19-7.36(m,3H),7.09(d,J=7.5 Hz,1H),6.89(d,J=6.0 Hz,1H),5.28(d,J=11.1 Hz,1H),4.50(d,J=6.6 Hz,1H),4.16(d,J=11.1 Hz,1H),3.30(s,2H),1.94(dd,J=8.4,15.3 Hz,1H),1.47-1.68(m,2H),1.18(d,J=15.6 Hz,1H),1.07(s,3H),0.93(s,9H)。
於吲哚酮1
(4.19克,25毫莫耳)之甲醇(50毫升)攪拌溶液中,添加醛2
(3.96克,25毫莫耳)與哌啶(2.45毫升,25毫莫耳)。於室溫攪拌反應混合物3小時,收集黃色沉澱,相繼以甲醇、己烷、與乙醚洗滌,乾燥,得到化合物3
(6.25克,81%產率)。
步驟2
於化合物3
(6.25克,21毫莫耳)之甲苯(75毫升)溶液中,添加化合物4
(5.43克,21毫莫耳)、化合物5
(2.15克,21毫莫耳)與4分子篩(4克)。回流加熱反應混合物隔夜,過濾。蒸發濾液,殘留物利用矽膠急驟管柱層析法(正己烷/乙酸乙酯=9:1至5:1)進行純化,得到化合物6
(8.78克,65%產率)。
步驟3
於室溫攪拌化合物6
(965毫克,1.5毫莫耳)與胺7
(346毫克,3毫莫耳)之5毫升THF溶液2天,減壓去除溶劑。殘留物利用矽膠急驟管柱層析法(正己烷/乙酸乙酯=1:1至1:4)進行純化,得到化合物8
(819毫克,72%產率)。
步驟4
於化合物8
(800毫克,1.05毫莫耳)之CH3
CN(8毫升)、H2
O(4毫升)與丙酮(4毫升)冰浴冷卻溶液中,添加CAN(銨鈰)(1.15克,2.1毫莫耳)。利用TLC監測反應進展。於所有起始物質消失(大約5分鐘)時,添加100毫克NaHCO3
粉末,以50毫升乙酸乙酯稀釋反應混合物。有機相以無水Na2
SO4
乾燥,過濾,濃縮。殘留物利用矽膠急驟管柱層析法(二氯甲烷/甲醇/三乙胺=200:1:1至200:10:1)進行純化,得到(2'R
,3S
,4'S
,5'R
)-6-氯-4'-(3-氯-2-氟苯基)-N
-((反式-4-羥基環己基)-2'-新戊基-2-酮基螺[吲哚啉-3,3'-吡咯啶]-5'-甲醯胺(MI-773
)(402毫克,68%產率)。1
H NMR(300 MHz,CD3
OD)δ7.50(t,J
=6.3 Hz,1H),7.39(t,J
=6.9 Hz,1H),7.19(t,J
=7.8 Hz,1H),6.88(d,J
=1.8 Hz,1H),6.81(dd,J
=1.8,8.1 Hz,1H),6.75(d,J
=8.1 Hz,1H),4.40(d,J
=9.6 Hz,1H),4.10(dd,J
=2.7,7.5 Hz,1H),3.58-3.78(m,1H),3.36-3.58(m,2H),1.75-2.10(m,4H),1.15-1.45(m,4H),0.90(d,J
=5.4 Hz,1H),0.83(s,9H),0.81(d,J
=11.4 Hz,1H)。
經完整敘述本文提供之方法、化合物、及組成物物質後,熟習此項技藝者將瞭解在寬廣及對等範圍之條件、調配劑、及其他參數下同樣可進行而不影響本文或其任何具體實例提供之方法、化合物、與組成物之範圍。本文引用之所有專利案、專利申請案與公告案,其全部內容均併入本文以資參考。
圖1係顯示於具有野生型p53之SJSA-1癌細胞中利用諸MDM2抑制劑誘發細胞死亡之條形圖。
圖2係顯示於具有野生型p53之SJSA-1癌細胞中利用諸MDM2抑制劑誘發p53活化之西方墨點分析圖示。
圖3係顯示於具有野生型p53之SJSA-1癌細胞中利用諸MDM2抑制劑誘發p53活化之西方墨點分析圖示。
圖4係顯示於具有野生型p53之SJSA-1癌細胞中利用諸MDM2抑制劑誘發p53活化之西方墨點分析圖示。
圖5係顯示於大鼠中靜脈(IV)注射諸MDM2抑制劑後,血漿濃度vs.時間曲線之線形圖。
圖6係顯示於大鼠中進行諸MDM2抑制劑口服給藥後,血漿濃度vs.時間曲線之線形圖。
圖7係顯示諸MDM2抑制劑於小鼠SJSA-1異種移植模式中之活體內抗腫瘤活性之線形圖。
圖8係顯示於小鼠中投與諸MDM2抑制劑後,動物重量之線形圖。
圖9係顯示諸MDM2抑制劑於小鼠SJSA-1異種移植模式中之活體內抗腫瘤活性之線形圖。
圖10係顯示於小鼠中投與諸MDM2抑制劑後,動物重量之線形圖。
圖11係顯示諸MDM2抑制劑於小鼠SJSA-1異種移植模式中之活體內抗腫瘤活性之線形圖。
圖12係顯示於小鼠中投與諸MDM2抑制劑後,動物重量之線形圖。
圖13A-D分別為質子化MI-219、MI-142、MI-63與MI-708B之四MS/MS光譜。
圖14A-B分別為去質子化MI-219與MI-142之二MS/MS光譜。
圖15A-D為於大鼠血漿中之M1(A與B)及合成M1(C與D)之四LC-MS層析圖與MS/MS光譜。
圖16係顯示於大鼠中MI-219與M1血漿濃度之線形圖。
圖17A-B係質子化M2(A)與去質子化M2(B)之二MS/MS光譜。
圖18A-D係質子化MI-773與M1、M2與M3三代謝物之四MS/MS光譜。
圖19A-C係質子化MI-519-63與其代謝物M1與M2之三MS/MS光譜。
Claims (12)
- 一種具下式I 之化合物或其醫藥上可接受之鹽:
- 根據申請範圍第1項之化合物或其醫藥上可接受之鹽,該化合物具下式II :
- 根據申請範圍第2項之化合物或其醫藥上可接受之鹽,該化合物具下式XIX :
- 根據申請專利範圍第3項之化合物或其醫藥上可接受之鹽,其中R3 為-CH2 C(CH3 )3 。
- 根據申請範圍第2項之化合物或其醫藥上可接受之鹽,該化合物係選自由下列組成之組群:
- 根據申請專利範圍第5項之化合物或其醫藥上可接受之鹽,其係為
- 一種醫藥組成物,其包含根據申請專利範圍第1至6項中任一項之化合物或其醫藥上可接受之鹽與醫藥上可接受之載體。
- 一種根據申請專利範圍第1至6項之任一項之化合物或醫藥上可接受之鹽之用途,其用於製造供治療癌症之醫藥品。
- 根據申請專利範圍第8項之用途,其中該癌症係選自由黑色素瘤、肺癌、肉瘤、結腸癌、前列腺癌、絨毛膜癌、乳癌、視網膜胚細胞瘤、胃癌、急性骨髓性白血病、淋巴癌、多發性骨髓瘤、及白血病組成之群組。
- 根據申請專利範圍第9項之用途,其中該癌症係選自由脂肉瘤及骨髓瘤組成之群組。
- 一種根據申請專利範圍第1至6項中任一項之化合物或醫藥上可接受之鹽之用途,其係用於製造供治療具有過度增殖疾病且正以抗癌劑進行治療之病患的醫藥品。
- 一種套組,其包含根據申請專利範圍第1至6項中之任一項之化合物及投與具有癌症的病患該化合物之用法說明。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26068509P | 2009-11-12 | 2009-11-12 | |
US26366209P | 2009-11-23 | 2009-11-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
TW201129570A TW201129570A (en) | 2011-09-01 |
TWI508967B true TWI508967B (zh) | 2015-11-21 |
Family
ID=43974649
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
TW099138770A TWI508967B (zh) | 2009-11-12 | 2010-11-11 | 螺-吲哚酮mdm2拮抗劑 |
Country Status (28)
Country | Link |
---|---|
US (3) | US8518984B2 (zh) |
EP (1) | EP2499145B1 (zh) |
JP (1) | JP2013510860A (zh) |
KR (1) | KR20120099462A (zh) |
CN (2) | CN104876938A (zh) |
AR (1) | AR079026A1 (zh) |
AU (1) | AU2010319595B2 (zh) |
BR (1) | BR112012011317A2 (zh) |
CA (1) | CA2780547C (zh) |
CL (1) | CL2012001250A1 (zh) |
CO (1) | CO6501131A2 (zh) |
CR (1) | CR20120313A (zh) |
DO (1) | DOP2012000131A (zh) |
EC (1) | ECSP12011943A (zh) |
GT (1) | GT201200147A (zh) |
IL (1) | IL219706A (zh) |
MA (1) | MA33815B1 (zh) |
MX (1) | MX2012005507A (zh) |
NI (1) | NI201200083A (zh) |
NZ (1) | NZ600430A (zh) |
PE (1) | PE20121282A1 (zh) |
RU (1) | RU2553269C2 (zh) |
TN (1) | TN2012000161A1 (zh) |
TW (1) | TWI508967B (zh) |
UA (1) | UA107814C2 (zh) |
UY (1) | UY33029A (zh) |
WO (1) | WO2011060049A2 (zh) |
ZA (1) | ZA201203323B (zh) |
Families Citing this family (56)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8889632B2 (en) | 2007-01-31 | 2014-11-18 | Dana-Farber Cancer Institute, Inc. | Stabilized p53 peptides and uses thereof |
EP2142562B1 (en) | 2007-03-28 | 2013-07-03 | President and Fellows of Harvard College | Stitched polypeptides |
BR112012011317A2 (pt) | 2009-11-12 | 2019-09-24 | Univ Michigan Regents | antagonistas espiro-oxindóis de mdm2 |
US8088815B2 (en) * | 2009-12-02 | 2012-01-03 | Hoffman-La Roche Inc. | Spiroindolinone pyrrolidines |
JP2013523820A (ja) * | 2010-04-09 | 2013-06-17 | ザ、リージェンツ、オブ、ザ、ユニバーシティ、オブ、ミシガン | 疾患を処置する際に使用するためのmdm2阻害剤のバイオマーカー |
RU2582678C2 (ru) | 2010-08-13 | 2016-04-27 | Эйлерон Терапьютикс, Инк. | Пептидомиметические макроциклы |
US8680132B2 (en) | 2010-11-12 | 2014-03-25 | The Regents Of The University Of Michigan | Spiro-oxindole MDM2 antagonists |
SG10201601802YA (en) * | 2011-03-10 | 2016-04-28 | Daiichi Sankyo Co Ltd | Dispiropyrrolidine derivatives |
CN103717605B (zh) | 2011-05-11 | 2016-05-18 | 密执安州立大学董事会 | 螺-羟吲哚mdm2拮抗剂 |
RU2639523C2 (ru) | 2011-10-18 | 2017-12-21 | Эйлерон Терапьютикс, Инк. | Пептидомиметические макроциклы и их применение |
US9937178B2 (en) | 2011-12-07 | 2018-04-10 | Duke University | Methods of identifying and using MDM2 inhibitors |
EP2819688A4 (en) | 2012-02-15 | 2015-10-28 | Aileron Therapeutics Inc | TRIAZOL AND THIOETHER-COUPLED PEPTIDOMIMETIC MACROCYCLES |
CA2862038C (en) | 2012-02-15 | 2021-05-25 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles |
TWI586668B (zh) | 2012-09-06 | 2017-06-11 | 第一三共股份有限公司 | 二螺吡咯啶衍生物之結晶 |
KR20150082307A (ko) | 2012-11-01 | 2015-07-15 | 에일러론 테라퓨틱스 인코포레이티드 | 이치환 아미노산 및 이의 제조 및 사용 방법 |
BR112015013611A2 (pt) | 2012-12-20 | 2017-11-14 | Merck Sharp & Dohme | composto, e, composição farmacêutica |
CN103739566B (zh) * | 2014-01-24 | 2016-01-20 | 中国人民解放军第三军医大学 | 含有磺酰胺的手性五元并环骨架化合物及制备方法和用途 |
CN111718354A (zh) * | 2014-04-17 | 2020-09-29 | 密歇根大学董事会 | Mdm2抑制剂和使用其的治疗方法 |
CN103992334A (zh) * | 2014-05-29 | 2014-08-20 | 中国人民解放军第二军医大学 | 吲哚酮螺四氢硫代吡喃类抗肿瘤衍生物及其制备方法 |
WO2016001376A1 (en) | 2014-07-03 | 2016-01-07 | Boehringer Ingelheim International Gmbh | New spiro[3h-indole-3,2´-pyrrolidin]-2(1h)-one compounds and derivatives as mdm2-p53 inhibitors |
WO2016028391A2 (en) * | 2014-08-18 | 2016-02-25 | Hudson Biopharma Inc. | Spiropyrrolidines as mdm2 inhibitors |
JP6412753B2 (ja) * | 2014-09-19 | 2018-10-24 | 日本テルペン化学株式会社 | 抗菌活性を持つ化合物、およびその製造方法 |
JP6408318B2 (ja) * | 2014-09-19 | 2018-10-17 | 日本テルペン化学株式会社 | 抗菌活性を持つ化合物、およびその製造方法 |
US10471120B2 (en) | 2014-09-24 | 2019-11-12 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
US10905739B2 (en) | 2014-09-24 | 2021-02-02 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and formulations thereof |
WO2016147205A1 (en) * | 2015-03-13 | 2016-09-22 | Council Of Scientific & Industrial Research | Novel substituted 3-spirophosphoryl pyrazole-2-oxindoles as anti-infectives and process for the synthesis thereof |
EP3294318A4 (en) | 2015-03-20 | 2019-04-03 | Aileron Therapeutics, Inc. | PEPTIDOMIMETIC MACROCYCLES AND USES THEREOF |
WO2017044633A1 (en) | 2015-09-10 | 2017-03-16 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles as modulators of mcl-1 |
US9962380B2 (en) | 2015-09-23 | 2018-05-08 | Wisconsin Alumni Research Foundation | Methods for treating cognitive deficits associated with fragile X syndrome |
GB201517216D0 (en) | 2015-09-29 | 2015-11-11 | Cancer Res Technology Ltd And Astex Therapeutics Ltd | Pharmaceutical compounds |
GB201517217D0 (en) | 2015-09-29 | 2015-11-11 | Astex Therapeutics Ltd And Cancer Res Technology Ltd | Pharmaceutical compounds |
JP6602470B2 (ja) * | 2015-10-09 | 2019-11-06 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Mdm2−p53阻害薬としてのスピロ[3h−インドール−3,2‘−ピロリジン]−2(1h)−オン化合物及び誘導体 |
RU2743432C2 (ru) | 2016-04-06 | 2021-02-18 | Дзе Риджентс Оф Дзе Юниверсити Оф Мичиган | Деструкторы белка mdm2 |
US10759808B2 (en) | 2016-04-06 | 2020-09-01 | The Regents Of The University Of Michigan | Monofunctional intermediates for ligand-dependent target protein degradation |
ES2858151T3 (es) | 2016-05-20 | 2021-09-29 | Hoffmann La Roche | Conjugados de PROTAC-anticuerpo y procedimientos de uso |
GB201704965D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
GB201704966D0 (en) | 2017-03-28 | 2017-05-10 | Astex Therapeutics Ltd | Pharmaceutical compounds |
US9822128B1 (en) | 2017-06-01 | 2017-11-21 | King Saud University | Substituted spirooxindoles |
CN107312115B (zh) * | 2017-06-22 | 2020-06-12 | 北京理工大学 | 一种双吲哚稀土金属催化剂、制备方法及应用 |
CN109988070B (zh) * | 2017-12-29 | 2022-07-26 | 南京富润凯德生物医药有限公司 | 反式-1-羟基-1-(三氟甲基)-3-氨基环丁烷盐酸盐的中间体及制备方法和应用 |
KR101857408B1 (ko) | 2018-02-28 | 2018-05-14 | 경북대학교 산학협력단 | 탈모 예방 또는 치료용 조성물 |
AU2019356772A1 (en) | 2018-10-08 | 2021-04-01 | The Regents Of The University Of Michigan | Small molecule MDM2 protein degraders |
GB201919219D0 (en) | 2019-12-23 | 2020-02-05 | Otsuka Pharma Co Ltd | Cancer biomarkers |
CN115776887A (zh) | 2020-03-19 | 2023-03-10 | 凯麦拉医疗公司 | Mdm2降解剂和其用途 |
TW202214248A (zh) | 2020-08-27 | 2022-04-16 | 日商大塚製藥股份有限公司 | 使用mdm2拮抗劑的癌症療法之生物標記 |
CN116829571A (zh) | 2020-11-23 | 2023-09-29 | 英安塔制药有限公司 | 新型螺旋吡咯烷衍生的抗病毒药物 |
GB202103080D0 (en) | 2021-03-04 | 2021-04-21 | Otsuka Pharma Co Ltd | Cancer biomarkers |
CN117337327A (zh) * | 2021-04-24 | 2024-01-02 | 通用测序技术公司 | 用于单分子检测的纳米火车 |
WO2022235605A1 (en) | 2021-05-04 | 2022-11-10 | Enanta Pharmaceuticals, Inc. | Novel macrocyclic antiviral agents |
WO2023056069A1 (en) | 2021-09-30 | 2023-04-06 | Angiex, Inc. | Degrader-antibody conjugates and methods of using same |
US11919910B2 (en) | 2021-11-12 | 2024-03-05 | Enanta Pharmaceuticals, Inc. | Spiropyrrolidine derived antiviral agents |
WO2023086352A1 (en) | 2021-11-12 | 2023-05-19 | Enanta Pharmaceuticals, Inc. | Novel spiropyrrolidine derived antiviral agents |
US11858945B2 (en) | 2021-11-12 | 2024-01-02 | Enanta Pharmaceuticals, Inc. | Alkyne-containing antiviral agents |
US11993600B2 (en) | 2021-12-08 | 2024-05-28 | Enanta Pharmaceuticals, Inc. | Saturated spirocyclics as antiviral agents |
US20230295175A1 (en) * | 2022-03-18 | 2023-09-21 | Enanta Pharmaceuticals, Inc. | Processes for the preparation of substituted spirooxindole derivatives |
US11944604B1 (en) | 2023-03-10 | 2024-04-02 | King Saud University | Nanoformulation of spriooxindole and methods for treating hepatocellular carcinoma |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080125430A1 (en) * | 2006-08-30 | 2008-05-29 | The Regents Of The University Of Michigan | New small molecule inhibitors of mdm2 and the uses thereof |
Family Cites Families (74)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3219661A (en) * | 1962-12-14 | 1965-11-23 | Warner Lambert Pharmaceutical | Spirooxindole and spirodehydroindole alkaloids and process therefor |
GB1056537A (en) | 1963-07-16 | 1967-01-25 | Smith Kline French Lab | Improvements in or relating to crystalline alkaloids of mitragyna citiata and compositions thereof |
JPS444986Y1 (zh) | 1966-10-20 | 1969-02-24 | ||
US3989816A (en) | 1975-06-19 | 1976-11-02 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacycloheptan-2-ones |
US4444762A (en) | 1980-04-04 | 1984-04-24 | Nelson Research & Development Company | Vehicle composition containing 1-substituted azacyclopentan-2-ones |
JPH044986A (ja) | 1990-04-20 | 1992-01-09 | Nippon Stainless Steel Co Ltd | ニッケル・ステンレス鋼クラッド材の製造方法 |
US6605712B1 (en) | 1990-12-20 | 2003-08-12 | Arch Development Corporation | Gene transcription and ionizing radiation: methods and compositions |
RU2084449C1 (ru) | 1994-03-02 | 1997-07-20 | Всероссийский научный центр по безопасности биологически активных веществ | 1-бензил-2-оксотриптамин гидрохлорид и его производные, обладающие гепатозащитной активностью |
US5773455A (en) | 1996-06-28 | 1998-06-30 | Biomeasure, Incorporated | Inhibitors of prenyl transferases |
US7083983B2 (en) | 1996-07-05 | 2006-08-01 | Cancer Research Campaign Technology Limited | Inhibitors of the interaction between P53 and MDM2 |
EP0989856B1 (de) * | 1997-01-20 | 2010-05-12 | IMMODAL PHARMAKA GESELLSCHAFT m.b.H. | Verfahren und stoffe zur freisetzung eines wachstumsfaktors aus endothelzellen, und nach dem verfahren freigesetzter wachstumsfaktor sowie seine verwendung |
AU9307098A (en) | 1997-09-08 | 1999-03-29 | Arqule, Inc. | Spiro{pyrrolidine-2,3'-oxindole} compounds and methods of use |
US7125659B1 (en) | 1998-08-20 | 2006-10-24 | Chugai Seiyaku Kabushiki Kaisha | Method and screening candidate compounds for drug against tumor |
US7205404B1 (en) | 1999-03-05 | 2007-04-17 | Metabasis Therapeutics, Inc. | Phosphorus-containing prodrugs |
US6831155B2 (en) | 1999-12-08 | 2004-12-14 | President And Fellows Of Harvard College | Inhibition of p53 degradation |
CN1182083C (zh) | 2001-10-08 | 2004-12-29 | 廖宜芳 | 一种杀虫灭菌的配位肥及其制造方法 |
RU2305095C2 (ru) | 2001-12-18 | 2007-08-27 | Ф.Хоффманн-Ля Рош Аг | Цис-2,4,5-трифенилимидазолины и фармацевтическая композиция на их основе |
RU2312101C2 (ru) | 2001-12-18 | 2007-12-10 | Ф.Хоффманн-Ля Рош Аг | Цис-имидазолины в качестве ингибиторов mdm2 |
JP4023184B2 (ja) | 2002-03-11 | 2007-12-19 | 昭和電工株式会社 | 発光体粒子及びその製造方法並びにその用途 |
US7514579B2 (en) | 2002-06-13 | 2009-04-07 | Johns Hopkins University | Boronic chalcone derivatives and uses thereof |
US20040171035A1 (en) | 2002-11-08 | 2004-09-02 | Irm Llc | Methods and compositions for modulating P53 transcription factor |
US20050227932A1 (en) | 2002-11-13 | 2005-10-13 | Tianbao Lu | Combinational therapy involving a small molecule inhibitor of the MDM2: p53 interaction |
CA2514374A1 (en) | 2003-02-13 | 2004-09-02 | Government Of The United States Of America, As Represented By The Secret Ary, Department Of Health And Human Services | Deazaflavin compounds and methods of use thereof |
US6916833B2 (en) | 2003-03-13 | 2005-07-12 | Hoffmann-La Roche Inc. | Substituted piperidines |
US7132421B2 (en) | 2003-06-17 | 2006-11-07 | Hoffmann-La Roche Inc. | CIS-imidazoles |
US7425638B2 (en) | 2003-06-17 | 2008-09-16 | Hoffmann-La Roche Inc. | Cis-imidazolines |
AU2004289174B2 (en) | 2003-07-29 | 2011-05-19 | Signature R&D Holdings, Lcc | Amino acid prodrugs |
US8173840B2 (en) | 2003-07-29 | 2012-05-08 | Signature R&D Holdings, Llc | Compounds with high therapeutic index |
US7589233B2 (en) | 2003-07-29 | 2009-09-15 | Signature R&D Holdings, Llc | L-Threonine derivatives of high therapeutic index |
US7829742B2 (en) | 2003-12-22 | 2010-11-09 | Johns Hopkins University | Boronic acid aryl analogs |
WO2005097820A1 (en) | 2004-04-06 | 2005-10-20 | Korea Research Institute Of Bioscience And Biotechnology | Peptides for inhibiting mdm2 function |
TWI350168B (en) | 2004-05-07 | 2011-10-11 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
KR20080027969A (ko) | 2004-05-18 | 2008-03-28 | 에프. 호프만-라 로슈 아게 | 신규 cis-이미다졸린 |
GB0419481D0 (en) | 2004-09-02 | 2004-10-06 | Cancer Rec Tech Ltd | Isoindolin-1-one derivatives |
US7834016B2 (en) | 2004-09-22 | 2010-11-16 | Janssen Pharmaceutica Nv | Inhibitors of the interaction between MDM2 and p53 |
WO2006091646A2 (en) * | 2005-02-22 | 2006-08-31 | The Regents Of The University Of Michigan | Small molecule inhibitors of mdm2 and uses thereof |
US7759383B2 (en) * | 2005-02-22 | 2010-07-20 | The Regents Of The University Of Michigan | Small molecule inhibitors of MDM2 and the uses thereof |
US8236963B2 (en) | 2005-05-24 | 2012-08-07 | Merck Serono Sa | Tricyclic spiro derivatives as CRTH2 modulators |
US7576082B2 (en) * | 2005-06-24 | 2009-08-18 | Hoffman-La Roche Inc. | Oxindole derivatives |
US7495007B2 (en) * | 2006-03-13 | 2009-02-24 | Hoffmann-La Roche Inc. | Spiroindolinone derivatives |
ES2350504T3 (es) * | 2006-03-13 | 2011-01-24 | F. Hoffmann-La Roche Ag | Derivados de espiroindolinona. |
AU2007228782B2 (en) | 2006-03-22 | 2012-09-06 | Janssen Pharmaceutica N.V. | Inhibitors of the interaction between MDM2 and p53 |
EA016145B1 (ru) | 2006-08-30 | 2012-02-28 | Дзе Риджентс Оф Дзе Юниверсити Оф Мичиган | Новые низкомолекулярные ингибиторы mdm2 и их применение |
US8222288B2 (en) | 2006-08-30 | 2012-07-17 | The Regents Of The University Of Michigan | Small molecule inhibitors of MDM2 and the uses thereof |
US8002528B2 (en) * | 2006-09-18 | 2011-08-23 | Emerson Climate Technologies, Inc. | Compressor assembly having vibration attenuating structure |
CN101516366B (zh) * | 2006-09-21 | 2012-05-30 | 霍夫曼-拉罗奇有限公司 | 作为抗癌剂的羟吲哚衍生物 |
US7638548B2 (en) * | 2006-11-09 | 2009-12-29 | Hoffmann-La Roche Inc. | Spiroindolinone derivatives |
CN101605798A (zh) | 2006-12-14 | 2009-12-16 | 第一三共株式会社 | 咪唑并噻唑衍生物 |
WO2008106507A2 (en) | 2007-02-27 | 2008-09-04 | University Of South Florida | Mdm2/mdmx inhibitor peptide |
AR065860A1 (es) | 2007-03-29 | 2009-07-08 | Novartis Ag | 3-imidazolil-indoles para el tratamiento de enfermedades proliferativas |
US7625895B2 (en) | 2007-04-12 | 2009-12-01 | Hoffmann-Le Roche Inc. | Diphenyl-dihydro-imidazopyridinones |
WO2008130614A2 (en) | 2007-04-20 | 2008-10-30 | University Of Pittsburg-Of The Commonwealth System Of Higher Education | Selective and dual-action p53/mdm2/mdm4 antagonists |
US7553833B2 (en) * | 2007-05-17 | 2009-06-30 | Hoffmann-La Roche Inc. | 3,3-spiroindolinone derivatives |
US7834179B2 (en) * | 2007-05-23 | 2010-11-16 | Hoffmann-La Roche Inc. | Spiroindolinone derivatives |
JP5438008B2 (ja) | 2007-09-21 | 2014-03-12 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | MDM2とp53の間の相互作用の阻害剤 |
RU2360914C1 (ru) * | 2007-10-31 | 2009-07-10 | Государственное образовательное учреждение высшего профессионального образования "Пермский государственный университет" | Анальгетическое средство |
CZ301561B6 (cs) | 2007-12-04 | 2010-04-14 | Výzkumný ústav živocišné výroby, v. v. i. | Prostredek pro prevenci a potlacování kokcidióz |
US8134001B2 (en) * | 2007-12-14 | 2012-03-13 | Hoffmann-La Roche Inc. | Spiroindolinone derivatives |
US7776875B2 (en) * | 2007-12-19 | 2010-08-17 | Hoffman-La Roche Inc. | Spiroindolinone derivatives |
US7723372B2 (en) * | 2008-03-19 | 2010-05-25 | Hoffman-La Roche Inc. | Spiroindolinone derivatives |
JPWO2009151069A1 (ja) | 2008-06-12 | 2011-11-17 | 第一三共株式会社 | 4,7−ジアザスピロ[2.5]オクタン環構造を有するイミダゾチアゾール誘導体 |
GB0811643D0 (en) | 2008-06-25 | 2008-07-30 | Cancer Rec Tech Ltd | New therapeutic agents |
US7928233B2 (en) * | 2009-02-10 | 2011-04-19 | Hoffmann-La Roche Inc. | Spiroindolinone pyridine derivatives |
US8076482B2 (en) * | 2009-04-23 | 2011-12-13 | Hoffmann-La Roche Inc. | 3,3′-spiroindolinone derivatives |
BR112012011317A2 (pt) * | 2009-11-12 | 2019-09-24 | Univ Michigan Regents | antagonistas espiro-oxindóis de mdm2 |
US8088815B2 (en) * | 2009-12-02 | 2012-01-03 | Hoffman-La Roche Inc. | Spiroindolinone pyrrolidines |
US8288431B2 (en) | 2010-02-17 | 2012-10-16 | Hoffmann-La Roche Inc. | Substituted spiroindolinones |
WO2011106650A2 (en) | 2010-02-27 | 2011-09-01 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Novel p53-mdm2/p53-mdm4 antagonists to treat proliferative disease |
JP2013523820A (ja) * | 2010-04-09 | 2013-06-17 | ザ、リージェンツ、オブ、ザ、ユニバーシティ、オブ、ミシガン | 疾患を処置する際に使用するためのmdm2阻害剤のバイオマーカー |
US8217044B2 (en) * | 2010-04-28 | 2012-07-10 | Hoffmann-La Roche Inc. | Spiroindolinone pyrrolidines |
US20120046306A1 (en) | 2010-08-18 | 2012-02-23 | David Joseph Bartkovitz | Substituted Heteroaryl Spiropyrrolidine MDM2 Antagonists |
US20120071499A1 (en) | 2010-09-20 | 2012-03-22 | Xin-Jie Chu | Substituted Spiro[3H-Indole-3,6'(5'H)-[1H]Pyrrolo[1,2c]Imidazole-1',2(1H,2'H)-diones |
US8680132B2 (en) * | 2010-11-12 | 2014-03-25 | The Regents Of The University Of Michigan | Spiro-oxindole MDM2 antagonists |
CN103717605B (zh) | 2011-05-11 | 2016-05-18 | 密执安州立大学董事会 | 螺-羟吲哚mdm2拮抗剂 |
-
2010
- 2010-11-10 BR BR112012011317A patent/BR112012011317A2/pt not_active IP Right Cessation
- 2010-11-10 JP JP2012538940A patent/JP2013510860A/ja active Pending
- 2010-11-10 PE PE2012000616A patent/PE20121282A1/es not_active Application Discontinuation
- 2010-11-10 NZ NZ600430A patent/NZ600430A/en not_active IP Right Cessation
- 2010-11-10 CN CN201510186334.7A patent/CN104876938A/zh active Pending
- 2010-11-10 WO PCT/US2010/056197 patent/WO2011060049A2/en active Application Filing
- 2010-11-10 CN CN201080061294.9A patent/CN102712650B/zh not_active Expired - Fee Related
- 2010-11-10 KR KR1020127015095A patent/KR20120099462A/ko not_active Application Discontinuation
- 2010-11-10 MX MX2012005507A patent/MX2012005507A/es active IP Right Grant
- 2010-11-10 AU AU2010319595A patent/AU2010319595B2/en not_active Ceased
- 2010-11-10 UA UAA201207063A patent/UA107814C2/uk unknown
- 2010-11-10 EP EP10830642.4A patent/EP2499145B1/en not_active Not-in-force
- 2010-11-10 RU RU2012124056/04A patent/RU2553269C2/ru not_active IP Right Cessation
- 2010-11-10 CA CA2780547A patent/CA2780547C/en not_active Expired - Fee Related
- 2010-11-11 TW TW099138770A patent/TWI508967B/zh not_active IP Right Cessation
- 2010-11-12 UY UY0001033029A patent/UY33029A/es not_active Application Discontinuation
- 2010-11-12 AR ARP100104201A patent/AR079026A1/es unknown
- 2010-11-12 US US12/945,511 patent/US8518984B2/en not_active Expired - Fee Related
-
2012
- 2012-04-04 TN TNP2012000161A patent/TN2012000161A1/en unknown
- 2012-05-03 NI NI201200083A patent/NI201200083A/es unknown
- 2012-05-07 ZA ZA2012/03323A patent/ZA201203323B/en unknown
- 2012-05-09 IL IL219706A patent/IL219706A/en not_active IP Right Cessation
- 2012-05-10 DO DO2012000131A patent/DOP2012000131A/es unknown
- 2012-05-11 CL CL2012001250A patent/CL2012001250A1/es unknown
- 2012-05-11 GT GT201200147A patent/GT201200147A/es unknown
- 2012-06-01 EC ECSP12011943 patent/ECSP12011943A/es unknown
- 2012-06-08 CR CR20120313A patent/CR20120313A/es unknown
- 2012-06-11 MA MA34958A patent/MA33815B1/fr unknown
- 2012-06-12 CO CO12098587A patent/CO6501131A2/es active IP Right Grant
-
2013
- 2013-07-17 US US13/944,587 patent/US8877796B2/en not_active Expired - Fee Related
-
2014
- 2014-09-12 US US14/485,054 patent/US9079913B2/en not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080125430A1 (en) * | 2006-08-30 | 2008-05-29 | The Regents Of The University Of Michigan | New small molecule inhibitors of mdm2 and the uses thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
TWI508967B (zh) | 螺-吲哚酮mdm2拮抗劑 | |
JP6251301B2 (ja) | スピロ−オキシインドールmdm2アンタゴニスト | |
TWI535723B (zh) | 螺-吲哚酮mdm2拮抗劑 | |
JP6909323B2 (ja) | Mdm2阻害剤及びそれを使用する治療方法 | |
WO2016187544A1 (en) | Compositions and methods for treating and preventing cancer | |
WO2020123670A1 (en) | Small molecule inhibitors of the androgen receptor activity and/or expression and uses thereof | |
OA16409A (en) | Spiro-oxindole MDM2 antagonists. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
MM4A | Annulment or lapse of patent due to non-payment of fees |