JP2017532377A - インドリノン化合物及びその使用 - Google Patents
インドリノン化合物及びその使用 Download PDFInfo
- Publication number
- JP2017532377A JP2017532377A JP2017538916A JP2017538916A JP2017532377A JP 2017532377 A JP2017532377 A JP 2017532377A JP 2017538916 A JP2017538916 A JP 2017538916A JP 2017538916 A JP2017538916 A JP 2017538916A JP 2017532377 A JP2017532377 A JP 2017532377A
- Authority
- JP
- Japan
- Prior art keywords
- group
- alkyl
- compound
- cell
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 36
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims description 124
- 206010028980 Neoplasm Diseases 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 46
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 210000004027 cell Anatomy 0.000 claims description 43
- 108090000623 proteins and genes Proteins 0.000 claims description 24
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 23
- 201000011510 cancer Diseases 0.000 claims description 20
- 239000012453 solvate Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 230000004927 fusion Effects 0.000 claims description 16
- 241000282414 Homo sapiens Species 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 101001077417 Gallus gallus Potassium voltage-gated channel subfamily H member 6 Proteins 0.000 claims description 11
- 101001010792 Homo sapiens Transcriptional regulator ERG Proteins 0.000 claims description 11
- 101150025421 ETS gene Proteins 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 9
- 102100030334 Friend leukemia integration 1 transcription factor Human genes 0.000 claims description 9
- 101001062996 Homo sapiens Friend leukemia integration 1 transcription factor Proteins 0.000 claims description 9
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 238000001727 in vivo Methods 0.000 claims description 9
- 210000004881 tumor cell Anatomy 0.000 claims description 9
- 102100039563 ETS translocation variant 1 Human genes 0.000 claims description 8
- 101000813729 Homo sapiens ETS translocation variant 1 Proteins 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 8
- 208000005017 glioblastoma Diseases 0.000 claims description 8
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 8
- 206010006187 Breast cancer Diseases 0.000 claims description 7
- 208000026310 Breast neoplasm Diseases 0.000 claims description 7
- 102100039578 ETS translocation variant 4 Human genes 0.000 claims description 7
- 101000813747 Homo sapiens ETS translocation variant 4 Proteins 0.000 claims description 7
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 208000002495 Uterine Neoplasms Diseases 0.000 claims description 7
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 206010046766 uterine cancer Diseases 0.000 claims description 7
- 238000000338 in vitro Methods 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 5
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 101000893493 Homo sapiens Protein flightless-1 homolog Proteins 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000004614 tumor growth Effects 0.000 claims description 3
- 125000002393 azetidinyl group Chemical group 0.000 claims description 2
- 125000004069 aziridinyl group Chemical group 0.000 claims description 2
- 230000010261 cell growth Effects 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 230000002147 killing effect Effects 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 206010008342 Cervix carcinoma Diseases 0.000 claims 1
- 102100022807 Potassium voltage-gated channel subfamily H member 2 Human genes 0.000 claims 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims 1
- 201000010881 cervical cancer Diseases 0.000 claims 1
- -1 Indolinone derivative compounds Chemical class 0.000 abstract description 35
- 239000003112 inhibitor Substances 0.000 abstract description 22
- 230000005764 inhibitory process Effects 0.000 abstract description 7
- 108700037122 EWS-FLI fusion Proteins 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003556 assay Methods 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- 239000007787 solid Substances 0.000 description 46
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- 239000000203 mixture Substances 0.000 description 40
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 239000003814 drug Substances 0.000 description 18
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 230000005945 translocation Effects 0.000 description 15
- 108090000740 RNA-binding protein EWS Proteins 0.000 description 14
- 239000000243 solution Substances 0.000 description 14
- 102000004229 RNA-binding protein EWS Human genes 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 229940124597 therapeutic agent Drugs 0.000 description 12
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 238000002571 electroretinography Methods 0.000 description 11
- 239000003826 tablet Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 101710164022 ATP-dependent RNA helicase A Proteins 0.000 description 10
- 102100030088 ATP-dependent RNA helicase A Human genes 0.000 description 10
- 102100029983 Transcriptional regulator ERG Human genes 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 10
- 238000003818 flash chromatography Methods 0.000 description 10
- 210000003494 hepatocyte Anatomy 0.000 description 10
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- NUXYYWOWNFEMNH-UHFFFAOYSA-N 4,7-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC=C(Cl)C2=C1NC(=O)C2=O NUXYYWOWNFEMNH-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 206010039491 Sarcoma Diseases 0.000 description 9
- 108091023040 Transcription factor Proteins 0.000 description 9
- 102000040945 Transcription factor Human genes 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 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
- 102000043276 Oncogene Human genes 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000001990 intravenous administration Methods 0.000 description 8
- 239000003755 preservative agent Substances 0.000 description 8
- 150000003384 small molecules Chemical class 0.000 description 8
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 230000014509 gene expression Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 108091008819 oncoproteins Proteins 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 239000011780 sodium chloride Substances 0.000 description 7
- 239000004094 surface-active agent Substances 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- 239000002562 thickening agent Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 238000012369 In process control Methods 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 230000000692 anti-sense effect Effects 0.000 description 6
- 239000001768 carboxy methyl cellulose Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 201000010536 head and neck cancer Diseases 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 238000010965 in-process control Methods 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 210000001853 liver microsome Anatomy 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- XOLOINUNYGPTGM-UHFFFAOYSA-N 3-[2-[4-(aziridin-1-yl)phenyl]-2-oxoethyl]-4,7-dichloro-3-hydroxy-1H-indol-2-one Chemical compound N1(CC1)C1=CC=C(C=C1)C(CC1(C(NC2=C(C=CC(=C12)Cl)Cl)=O)O)=O XOLOINUNYGPTGM-UHFFFAOYSA-N 0.000 description 5
- ZWHNLSHDLKIXOG-UHFFFAOYSA-N 4,7-dichloro-3-[2-(4-cyclopropylphenyl)-2-oxoethyl]-3-hydroxy-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(O)CC(=O)C1=CC=C(C=C1)C1CC1 ZWHNLSHDLKIXOG-UHFFFAOYSA-N 0.000 description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 5
- 108020004459 Small interfering RNA Proteins 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 5
- 239000000969 carrier Substances 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 239000008121 dextrose Substances 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 102000037865 fusion proteins Human genes 0.000 description 5
- 108020001507 fusion proteins Proteins 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 230000002503 metabolic effect Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000003380 propellant Substances 0.000 description 5
- 230000004850 protein–protein interaction Effects 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000008107 starch Substances 0.000 description 5
- 235000019698 starch Nutrition 0.000 description 5
- 229940032147 starch Drugs 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 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 4
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- MWAUGZLJRYZZBX-UHFFFAOYSA-N 3-[2-[4-(azetidin-1-yl)phenyl]-2-oxoethyl]-4,7-dichloro-3-hydroxy-1H-indol-2-one Chemical compound N1(CCC1)C1=CC=C(C=C1)C(CC1(C(NC2=C(C=CC(=C12)Cl)Cl)=O)O)=O MWAUGZLJRYZZBX-UHFFFAOYSA-N 0.000 description 4
- FDPMWMDIYFGVKV-UHFFFAOYSA-N 4,7-dichloro-3-[2-(4-cyclopropyl-2-fluorophenyl)-2-oxoethyl]-3-hydroxy-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(O)CC(=O)C1=C(C=C(C=C1)C1CC1)F FDPMWMDIYFGVKV-UHFFFAOYSA-N 0.000 description 4
- GRWSVPKRYXCYOR-UHFFFAOYSA-N 4,7-dichloro-3-[2-(4-cyclopropyl-3-fluorophenyl)-2-oxoethyl]-3-hydroxy-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(O)CC(=O)C1=CC(=C(C=C1)C1CC1)F GRWSVPKRYXCYOR-UHFFFAOYSA-N 0.000 description 4
- RXWACXOOCXIXNH-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-(4-methylsulfonylphenyl)-2-oxoethyl]-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(=O)C1=CC=C(C=C1)S(=O)(=O)C)O RXWACXOOCXIXNH-UHFFFAOYSA-N 0.000 description 4
- IFNZYWIIFKZQGE-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-oxo-2-(4-propan-2-ylphenyl)ethyl]-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(=O)C1=CC=C(C=C1)C(C)C)O IFNZYWIIFKZQGE-UHFFFAOYSA-N 0.000 description 4
- GPQBOHJABMHCFO-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-oxo-2-(4-pyrrolidin-1-ylphenyl)ethyl]-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(C1=CC=C(C=C1)N1CCCC1)=O)O GPQBOHJABMHCFO-UHFFFAOYSA-N 0.000 description 4
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- 208000034951 Genetic Translocation Diseases 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 4
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 4
- 229940126543 compound 14 Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 230000000670 limiting effect Effects 0.000 description 4
- 230000014759 maintenance of location Effects 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000002207 metabolite Substances 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000002685 pulmonary effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 239000004055 small Interfering RNA Substances 0.000 description 4
- 239000003381 stabilizer Substances 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 239000003981 vehicle Substances 0.000 description 4
- WRVQGDJMGIOYIH-UHFFFAOYSA-N 4,7-dichloro-3-[1-[4-(dimethylamino)phenyl]-1-oxopropan-2-yl]-3-hydroxy-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(O)C(C(=O)C1=CC=C(C=C1)N(C)C)C WRVQGDJMGIOYIH-UHFFFAOYSA-N 0.000 description 3
- GRTALIAHGOGFFG-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-oxo-2-(4-pyrazol-1-ylphenyl)ethyl]-1H-indol-2-one Chemical compound N1(N=CC=C1)C1=CC=C(C=C1)C(CC1(C(NC2=C(C=CC(=C12)Cl)Cl)=O)O)=O GRTALIAHGOGFFG-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 208000018084 Bone neoplasm Diseases 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 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 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-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 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 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 3
- 241000124008 Mammalia Species 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 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 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- 239000002246 antineoplastic agent Substances 0.000 description 3
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 3
- 230000027455 binding Effects 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229910052805 deuterium Inorganic materials 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 229960004679 doxorubicin Drugs 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 3
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 125000001183 hydrocarbyl group Chemical group 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000003018 immunosuppressive agent Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 229960001375 lactose Drugs 0.000 description 3
- 238000012417 linear regression Methods 0.000 description 3
- 239000002502 liposome Substances 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000000346 nonvolatile oil Substances 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 2
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- RUZGTGOJKZKIRY-UHFFFAOYSA-N 4,7-dichloro-3-[2-(3,4-difluorophenyl)-2-oxoethyl]-3-hydroxy-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(O)CC(=O)C1=CC(=C(C=C1)F)F RUZGTGOJKZKIRY-UHFFFAOYSA-N 0.000 description 2
- LLHHTBOKWOSBTN-UHFFFAOYSA-N 4,7-dichloro-3-[2-(3-fluoro-4-pyrrolidin-1-ylphenyl)-2-oxoethyl]-3-hydroxy-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(O)CC(=O)C1=CC(=C(C=C1)N1CCCC1)F LLHHTBOKWOSBTN-UHFFFAOYSA-N 0.000 description 2
- OWXWAMRNUNTHDE-UHFFFAOYSA-N 4,7-dichloro-3-[2-[4-(dimethylamino)-1-bicyclo[2.2.2]octanyl]-2-oxoethyl]-3-hydroxy-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(O)CC(=O)C12CCC(CC1)(CC2)N(C)C OWXWAMRNUNTHDE-UHFFFAOYSA-N 0.000 description 2
- AXZMPODJSDUCNK-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-(2-oxo-2-pyridin-2-ylethyl)-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(C1=NC=CC=C1)=O)O AXZMPODJSDUCNK-UHFFFAOYSA-N 0.000 description 2
- QXRVDKZVLJNUCH-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-(2-oxo-2-pyridin-3-ylethyl)-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(C=1C=NC=CC=1)=O)O QXRVDKZVLJNUCH-UHFFFAOYSA-N 0.000 description 2
- FMNLLFVLZIDTKK-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-(2-oxo-2-pyridin-4-ylethyl)-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(C1=CC=NC=C1)=O)O FMNLLFVLZIDTKK-UHFFFAOYSA-N 0.000 description 2
- WNBJOKCPNXEIDK-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-(4-hydroxyphenyl)-2-oxoethyl]-1h-indol-2-one Chemical compound C1=CC(O)=CC=C1C(=O)CC1(O)C(C(Cl)=CC=C2Cl)=C2NC1=O WNBJOKCPNXEIDK-UHFFFAOYSA-N 0.000 description 2
- FYLQWZMGGSHBJC-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-(4-methoxy-1-bicyclo[2.2.2]octanyl)-2-oxoethyl]-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(=O)C12CCC(CC1)(CC2)OC)O FYLQWZMGGSHBJC-UHFFFAOYSA-N 0.000 description 2
- NMNYDURLPKIKSG-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-(4-methoxycyclohexyl)-2-oxoethyl]-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)Cl)=O)(CC(=O)C1CCC(CC1)OC)O NMNYDURLPKIKSG-UHFFFAOYSA-N 0.000 description 2
- IVNZDFWTFASZGV-UHFFFAOYSA-N 4,7-dichloro-3-hydroxy-3-[2-(4-morpholin-4-ylphenyl)-2-oxoethyl]-1h-indol-2-one Chemical compound O=C1NC(C(=CC=C2Cl)Cl)=C2C1(O)CC(=O)C(C=C1)=CC=C1N1CCOCC1 IVNZDFWTFASZGV-UHFFFAOYSA-N 0.000 description 2
- QEEXPXYUNRERGH-UHFFFAOYSA-N 4-chloro-7-fluoro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-indol-2-one Chemical compound ClC1=C2C(C(NC2=C(C=C1)F)=O)(CC(=O)C1=CC=C(C=C1)OC)O QEEXPXYUNRERGH-UHFFFAOYSA-N 0.000 description 2
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical compound O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 description 2
- OIVLITBTBDPEFK-UHFFFAOYSA-N 5,6-dihydrouracil Chemical compound O=C1CCNC(=O)N1 OIVLITBTBDPEFK-UHFFFAOYSA-N 0.000 description 2
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 2
- 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 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 2
- 108010087230 Sincalide Proteins 0.000 description 2
- 206010041067 Small cell lung cancer Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-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
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 102100031989 Transmembrane protease serine 2 Human genes 0.000 description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 235000011054 acetic acid Nutrition 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
- 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 2
- 238000001994 activation Methods 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001413 amino acids Chemical class 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
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 239000003719 aurora kinase inhibitor Substances 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- CUFNKYGDVFVPHO-UHFFFAOYSA-N azulene Chemical compound C1=CC=CC2=CC=CC2=C1 CUFNKYGDVFVPHO-UHFFFAOYSA-N 0.000 description 2
- 229960000686 benzalkonium chloride Drugs 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- BPKIGYQJPYCAOW-FFJTTWKXSA-I calcium;potassium;disodium;(2s)-2-hydroxypropanoate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].C[C@H](O)C([O-])=O BPKIGYQJPYCAOW-FFJTTWKXSA-I 0.000 description 2
- 229940077731 carbohydrate nutrients Drugs 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 230000003833 cell viability Effects 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 239000012649 demethylating agent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229960001259 diclofenac Drugs 0.000 description 2
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 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 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 230000009368 gene silencing by RNA Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000003979 granulating agent Substances 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 229960003444 immunosuppressant agent Drugs 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000004005 microsphere Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 210000000496 pancreas Anatomy 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 159000000001 potassium salts Chemical class 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 2
- 229960004919 procaine Drugs 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000007901 soft capsule Substances 0.000 description 2
- 239000008347 soybean phospholipid Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 238000004808 supercritical fluid chromatography Methods 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 0.000 description 2
- 108091006106 transcriptional activators Proteins 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 230000004565 tumor cell growth Effects 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- ASGMFNBUXDJWJJ-JLCFBVMHSA-N (1R,3R)-3-[[3-bromo-1-[4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl]pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N,1-dimethylcyclopentane-1-carboxamide Chemical compound BrC1=NN(C2=NC(=NC=C21)N[C@H]1C[C@@](CC1)(C(=O)NC)C)C1=CC=C(C=C1)C=1SC(=NN=1)C ASGMFNBUXDJWJJ-JLCFBVMHSA-N 0.000 description 1
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- IZUAHLHTQJCCLJ-UHFFFAOYSA-N (2-chloro-1,1,2,2-tetrafluoroethyl) hypochlorite Chemical compound FC(F)(Cl)C(F)(F)OCl IZUAHLHTQJCCLJ-UHFFFAOYSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 description 1
- ASWBNKHCZGQVJV-UHFFFAOYSA-N (3-hexadecanoyloxy-2-hydroxypropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(O)COP([O-])(=O)OCC[N+](C)(C)C ASWBNKHCZGQVJV-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- ZYZCALPXKGUGJI-DDVDASKDSA-M (e,3r,5s)-7-[3-(4-fluorophenyl)-2-phenyl-5-propan-2-ylimidazol-4-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C=1C=C(F)C=CC=1N1C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C(C)C)N=C1C1=CC=CC=C1 ZYZCALPXKGUGJI-DDVDASKDSA-M 0.000 description 1
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- BBVIDBNAYOIXOE-UHFFFAOYSA-N 1,2,4-oxadiazole Chemical compound C=1N=CON=1 BBVIDBNAYOIXOE-UHFFFAOYSA-N 0.000 description 1
- YGTAZGSLCXNBQL-UHFFFAOYSA-N 1,2,4-thiadiazole Chemical compound C=1N=CSN=1 YGTAZGSLCXNBQL-UHFFFAOYSA-N 0.000 description 1
- KTZQTRPPVKQPFO-UHFFFAOYSA-N 1,2-benzoxazole Chemical compound C1=CC=C2C=NOC2=C1 KTZQTRPPVKQPFO-UHFFFAOYSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 description 1
- SNKAWJBJQDLSFF-NVKMUCNASA-N 1,2-dioleoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/CCCCCCCC SNKAWJBJQDLSFF-NVKMUCNASA-N 0.000 description 1
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 1
- CIISBYKBBMFLEZ-UHFFFAOYSA-N 1,2-oxazolidine Chemical compound C1CNOC1 CIISBYKBBMFLEZ-UHFFFAOYSA-N 0.000 description 1
- LKLLNYWECKEQIB-UHFFFAOYSA-N 1,3,5-triazinane Chemical compound C1NCNCN1 LKLLNYWECKEQIB-UHFFFAOYSA-N 0.000 description 1
- BGJSXRVXTHVRSN-UHFFFAOYSA-N 1,3,5-trioxane Chemical compound C1OCOCO1 BGJSXRVXTHVRSN-UHFFFAOYSA-N 0.000 description 1
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 1
- SILNNFMWIMZVEQ-UHFFFAOYSA-N 1,3-dihydrobenzimidazol-2-one Chemical compound C1=CC=C2NC(O)=NC2=C1 SILNNFMWIMZVEQ-UHFFFAOYSA-N 0.000 description 1
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- IVJFXSLMUSQZMC-UHFFFAOYSA-N 1,3-dithiole Chemical compound C1SC=CS1 IVJFXSLMUSQZMC-UHFFFAOYSA-N 0.000 description 1
- QVFHFKPGBODJJB-UHFFFAOYSA-N 1,3-oxathiane Chemical compound C1COCSC1 QVFHFKPGBODJJB-UHFFFAOYSA-N 0.000 description 1
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JBYHSSAVUBIJMK-UHFFFAOYSA-N 1,4-oxathiane Chemical compound C1CSCCO1 JBYHSSAVUBIJMK-UHFFFAOYSA-N 0.000 description 1
- CPRVXMQHLPTWLY-UHFFFAOYSA-N 1,4-oxathiine Chemical compound O1C=CSC=C1 CPRVXMQHLPTWLY-UHFFFAOYSA-N 0.000 description 1
- OHNZLHGFLNFUHB-UHFFFAOYSA-N 1-(4-cyclopropyl-2-fluorophenyl)ethanone Chemical compound CC(=O)C1=C(F)C=C(C=C1)C1CC1 OHNZLHGFLNFUHB-UHFFFAOYSA-N 0.000 description 1
- HGBWKKQBETZKDB-UHFFFAOYSA-N 1-(4-cyclopropyl-3-fluorophenyl)ethanone Chemical compound FC1=CC(C(=O)C)=CC=C1C1CC1 HGBWKKQBETZKDB-UHFFFAOYSA-N 0.000 description 1
- SWHHCKFQUJBPPQ-UHFFFAOYSA-N 1-(4-cyclopropylphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1C1CC1 SWHHCKFQUJBPPQ-UHFFFAOYSA-N 0.000 description 1
- WNRFELFKDNNURJ-UHFFFAOYSA-N 1-(4-pyrrolidin-1-ylphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1N1CCCC1 WNRFELFKDNNURJ-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- AHHKQUNYVVUSNT-UHFFFAOYSA-N 1-[4-(azetidin-1-yl)phenyl]ethanone Chemical compound C1=CC(C(=O)C)=CC=C1N1CCC1 AHHKQUNYVVUSNT-UHFFFAOYSA-N 0.000 description 1
- LIMPBKNXJWAFBM-UHFFFAOYSA-N 1-[4-(aziridin-1-yl)phenyl]ethanone Chemical compound C1=CC(C(=O)C)=CC=C1N1CC1 LIMPBKNXJWAFBM-UHFFFAOYSA-N 0.000 description 1
- HUDYANRNMZDQGA-UHFFFAOYSA-N 1-[4-(dimethylamino)phenyl]ethanone Chemical compound CN(C)C1=CC=C(C(C)=O)C=C1 HUDYANRNMZDQGA-UHFFFAOYSA-N 0.000 description 1
- GDBAYICEBDZUNM-UHFFFAOYSA-N 1-[4-(methylamino)phenyl]ethanone Chemical compound CNC1=CC=C(C(C)=O)C=C1 GDBAYICEBDZUNM-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- 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
- CUCJJMLDIUSNPU-UHFFFAOYSA-N 1-oxidopiperidin-1-ium Chemical compound [O-][NH+]1CCCCC1 CUCJJMLDIUSNPU-UHFFFAOYSA-N 0.000 description 1
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- JECYNCQXXKQDJN-UHFFFAOYSA-N 2-(2-methylhexan-2-yloxymethyl)oxirane Chemical compound CCCCC(C)(C)OCC1CO1 JECYNCQXXKQDJN-UHFFFAOYSA-N 0.000 description 1
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 1
- BCHZICNRHXRCHY-UHFFFAOYSA-N 2h-oxazine Chemical compound N1OC=CC=C1 BCHZICNRHXRCHY-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-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
- MRUWJENAYHTDQG-UHFFFAOYSA-N 4H-pyran Chemical compound C1C=COC=C1 MRUWJENAYHTDQG-UHFFFAOYSA-N 0.000 description 1
- UCZQXJKDCHCTAI-UHFFFAOYSA-N 4h-1,3-dioxine Chemical group C1OCC=CO1 UCZQXJKDCHCTAI-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
- 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
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 108020005544 Antisense RNA Proteins 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229940123877 Aurora kinase inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- ISMDILRWKSYCOD-GNKBHMEESA-N C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O Chemical compound C(C1=CC=CC=C1)[C@@H]1NC(OCCCCCCCCCCCNC([C@@H](NC(C[C@@H]1O)=O)C(C)C)=O)=O ISMDILRWKSYCOD-GNKBHMEESA-N 0.000 description 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 1
- 125000005915 C6-C14 aryl group Chemical group 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 206010073140 Clear cell sarcoma of soft tissue Diseases 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- 229940126639 Compound 33 Drugs 0.000 description 1
- 229940127007 Compound 39 Drugs 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(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)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 1
- 108010036949 Cyclosporine Proteins 0.000 description 1
- 230000004568 DNA-binding Effects 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 101150029838 ERG gene Proteins 0.000 description 1
- 102000040848 ETS family Human genes 0.000 description 1
- 108091071901 ETS family Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920000569 Gum karaya Polymers 0.000 description 1
- 244000043261 Hevea brasiliensis Species 0.000 description 1
- 102000003964 Histone deacetylase Human genes 0.000 description 1
- 108090000353 Histone deacetylase Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000864670 Homo sapiens ATP-dependent RNA helicase A Proteins 0.000 description 1
- 108090000144 Human Proteins Proteins 0.000 description 1
- 102000003839 Human Proteins Human genes 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 102000012011 Isocitrate Dehydrogenase Human genes 0.000 description 1
- 108010075869 Isocitrate Dehydrogenase Proteins 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- HRNLUBSXIHFDHP-UHFFFAOYSA-N N-(2-aminophenyl)-4-[[[4-(3-pyridinyl)-2-pyrimidinyl]amino]methyl]benzamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC1=NC=CC(C=2C=NC=CC=2)=N1 HRNLUBSXIHFDHP-UHFFFAOYSA-N 0.000 description 1
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 description 1
- XJLXINKUBYWONI-NNYOXOHSSA-N NADP zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-NNYOXOHSSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 208000019802 Sexually transmitted disease Diseases 0.000 description 1
- 206010071051 Soft tissue mass Diseases 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 241000934878 Sterculia Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-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
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 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
- 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 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229940023476 agar Drugs 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229960001097 amifostine Drugs 0.000 description 1
- 239000012491 analyte Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229960004977 anhydrous lactose Drugs 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- 239000003212 astringent agent Substances 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 238000000889 atomisation Methods 0.000 description 1
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 1
- 229960002170 azathioprine Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 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
- 229960003094 belinostat Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 239000003613 bile acid Substances 0.000 description 1
- 239000003833 bile salt Substances 0.000 description 1
- 229940093761 bile salts Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229910000394 calcium triphosphate Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229960001631 carbomer Drugs 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- VDANGULDQQJODZ-UHFFFAOYSA-N chloroprocaine Chemical class CCN(CC)CCOC(=O)C1=CC=C(N)C=C1Cl VDANGULDQQJODZ-UHFFFAOYSA-N 0.000 description 1
- 229960002023 chloroprocaine Drugs 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical class C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 229960001265 ciclosporin Drugs 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 201000000292 clear cell sarcoma Diseases 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000003184 complementary RNA Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125878 compound 36 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940127573 compound 38 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 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
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 238000007405 data analysis Methods 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
- 230000007423 decrease Effects 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000013461 design 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
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 229940043237 diethanolamine Drugs 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 description 1
- SNQXJPARXFUULZ-UHFFFAOYSA-N dioxolane Chemical compound C1COOC1 SNQXJPARXFUULZ-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 210000005081 epithelial layer Anatomy 0.000 description 1
- 210000003617 erythrocyte membrane Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 150000002244 furazanes Chemical class 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000003208 gene overexpression Methods 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000003306 harvesting Methods 0.000 description 1
- GLDSKRNGVVYJAB-DQSJHHFOSA-N hesperadin Chemical compound C12=CC(NS(=O)(=O)CC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 GLDSKRNGVVYJAB-DQSJHHFOSA-N 0.000 description 1
- 102000046803 human DHX9 Human genes 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 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
- 239000000017 hydrogel Substances 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000010494 karaya gum Nutrition 0.000 description 1
- 239000000231 karaya gum Substances 0.000 description 1
- 229940039371 karaya gum Drugs 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 231100001252 long-term toxicity Toxicity 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 230000003228 microsomal effect Effects 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
- 229960004857 mitomycin Drugs 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229950007812 mocetinostat Drugs 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 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
- 239000002088 nanocapsule Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 229920003052 natural elastomer Polymers 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 229940042880 natural phospholipid Drugs 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229920001194 natural rubber Polymers 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 239000007764 o/w emulsion Substances 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
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 108091008820 oncogenic transcription factors Proteins 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229940127084 other anti-cancer agent Drugs 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229960005184 panobinostat Drugs 0.000 description 1
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000008010 parenteral excipient Substances 0.000 description 1
- RFWLACFDYFIVMC-UHFFFAOYSA-D pentacalcium;[oxido(phosphonatooxy)phosphoryl] phosphate Chemical compound [Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O.[O-]P([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O RFWLACFDYFIVMC-UHFFFAOYSA-D 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- JTHRRMFZHSDGNJ-UHFFFAOYSA-N piperazine-2,3-dione Chemical compound O=C1NCCNC1=O JTHRRMFZHSDGNJ-UHFFFAOYSA-N 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- 230000029983 protein stabilization Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- DNXIASIHZYFFRO-UHFFFAOYSA-N pyrazoline Chemical compound C1CN=NC1 DNXIASIHZYFFRO-UHFFFAOYSA-N 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000022532 regulation of transcription, DNA-dependent Effects 0.000 description 1
- 235000009566 rice Nutrition 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
- OHRURASPPZQGQM-UHFFFAOYSA-N romidepsin Natural products O1C(=O)C(C(C)C)NC(=O)C(=CC)NC(=O)C2CSSCCC=CC1CC(=O)NC(C(C)C)C(=O)N2 OHRURASPPZQGQM-UHFFFAOYSA-N 0.000 description 1
- 108010091666 romidepsin Proteins 0.000 description 1
- 239000005060 rubber Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229930182490 saponin Natural products 0.000 description 1
- 150000007949 saponins Chemical class 0.000 description 1
- 235000017709 saponins Nutrition 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 231100001251 short-term toxicity Toxicity 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 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
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 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 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
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 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
- 239000012178 vegetable wax Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 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
- 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
- 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
- 230000007279 water homeostasis Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
- A61K31/403—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 carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Physical Education & Sports Medicine (AREA)
- Neurology (AREA)
- Reproductive Health (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Diabetes (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本出願は、米国仮出願第62/062086号(発明の名称「インドリノン化合物及びその使用」、2014年10月9日出願)の利益を主張するものである。その内容は、本明細書に参考として組み込まれる。
本明細書で使用される全ての技術的及び科学的用語は、特に定義がない限り、当業者が通常理解しているものと同じ意味を有する。本明細書で引用される全ての特許、出願、公開出願、及び他の公開物は、特に規定がない限り、もっぱら参考として組み込まれている。本明細書の用語について複数の定義がある場合には、特に規定がない限り、該セクションにおける定義を優先する。
第1の局面において、式(I)で表される化合物、もしくは、その立体異性体、その薬学的に許容される塩、又はその溶媒和物が提供される。
R1、R2、R3、及びR4は、それぞれ独立して、H、Cl、−CN、及び−CF3からなる群より選ばれ、
Aは、H及びC1−6アルキルからなる群より選ばれ、
Dは、−OH及び−O(C1−6アルキル)からなる群より選ばれ、
R5及びR6は、それぞれ独立して、H、F、及びC1−6アルキルからなる群より選ばれるか、もしくは、置換又は非置換のシクロアルキル環を一緒になって形成しており、
R12は、独立して、C3−8シクロアルキル及び
R1、R2、R3、及びR4は、それぞれ独立して、H及びClからなる群より選ばれ、
R7、R8、R10、及びR11は、それぞれ独立して、H及びハロゲンからなる群より選ばれ、
R9は、独立して、C3−8シクロアルキル及びC3−8ヘテロシクロアルキルからなる群より選ばれる。
一般に、好適な実施形態に係る阻害剤を、静脈内又は皮下の単位剤形で投与することが好ましいが、他の投与経路も考えられる。考えられる投与経路としては、経口、非経口、静脈内、及び皮下が含まれるが、これらに限定されない。好適な実施形態に係る阻害剤は、例えば経口投与等のための液体製剤に製剤化することができる。適切な剤形には、懸濁剤、シロップ剤、エリキシル剤等が含まれる。経口投与のための特に好適な単位剤形には、錠剤及びカプセル剤が含まれる。単位剤形は、1日1回投与するように構成されることが特に好ましいが、特定の実施形態において、1日2回又はそれ以上の回数で投与するように構成されることが望ましい場合もある。
好適な実施形態に係る化合物は、キットの形で、医師又は他の医療専門家による投与に提供される。キットは、適切な医薬組成物における化合物の収納容器、及び対象に医薬組成物を投与するための使用説明を収容するパッケージである。また、キットは、例えば、本明細書に記載される肉腫の治療に現在使用されている化学療法薬等の1つ又はそれ以上の付加的治療薬を任意に含んでもよい。例えば、1つ又はそれ以上の付加的化学療法薬と組み合わせて、好適な実施形態に係る化合物が含まれる1つ又はそれ以上の組成物を含有するキットを提供することができる。また、好適な実施形態に係る阻害剤が含まれる医薬組成物と付加的治療薬とを分割するキットを提供することができる。キットは、順次又は連続投与のために、個別投与量の好ましい実施形態に係る化合物を含んでもよい。キットは、1つ以上の診断ツール及び使用説明を任意に含んでもよい。キットは、例えば注射器などの適切な送達デバイスを、阻害剤及び他の任意の治療薬を投与するための使用説明とともに含んでもよい。キットは、それに含まれる一部又は全ての治療薬の保管、再構成(必要な場合)、及び投与のための使用説明を任意に含んでもよい。キットは、対象への投与回数に相応する複数の容器を含んでもよい。
本明細書で提供されるいくつかの実施形態は、ユーイング肉腫ファミリー腫瘍(ESFT)を治療する方法に関する。ESFTは、特有の融合タンパク質であるEWS−FLI1を含む。ESFTは、3歳〜40歳の患者に影響を与え、ほとんどの場合10代の患者に発生する。ESFTの由来となる発生学的細胞型は不明であるにもかかわらず、腫瘍は骨に近接して成長する場合が多いが、軟組織塊として発生する可能性もある。転位性ESFTを呈する患者の75%〜80%は、高用量の化学療法にもかかわらず、5年以内に死亡することになる一方、局所腫瘍を呈する患者のうち40%を超える患者は、再発性疾患を発症するとともに、これらの患者の大部分は、ESFTで死亡することになる(Grier HE,Krailo MD,Tarbell NJ,et al.Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone.N Engl J Med 2003;348(8):694−701)。これらの患者の生存率は、用量強化化学治療(dose−intensifyingchemotherapy)後でも、過去20年間に改善していない。生存率を改善し、治療関連死亡率を減少させるために、好適な実施形態で提供されるような、ESFT患者を治療するための新規標的戦略を使用することができる。
本明細書で提供される特定の化合物、組成物、及び方法を、例えば表1に示されるような転座遺伝子融合からなる腫瘍又は腫瘍細胞、例えば、ユーイング肉腫、前立腺癌、膠芽細胞腫、急性骨髄性白血病、乳癌、頭部及び頸部癌、黒色腫、非小細胞肺癌、卵巣癌、及び子宮癌といった、多数の疾患の治療のために使用することができる。本明細書で提供される方法のいくつかの実施形態には、細胞の増殖を阻害する方法が含まれる。いくつかの実施形態において、該細胞はETS遺伝子を過剰発現する。いくつかの実施形態において、過剰発現したETS遺伝子には、FLI1、ERG、ETV1、又はETV4が含まれる。いくつかの実施形態において、該細胞はETS融合遺伝子からなる。いくつかの実施形態において、該ETS融合遺伝子には、FLI1、ERG、ETV1、及びETV4等のETS遺伝子が含まれる。
白色固体
融点:149〜151℃
1H−NMR(DMSO,400MHz): d 10.93(s,1H),7.86(d,2H,J=9.2Hz),7.26(d,1H,J=8.8Hz),6.98(d,2H,J=8.8Hz),6.86(d,1H,J=8.4Hz),6.39(s,1H),4.31(d,1H,J=18.0Hz),3.80(s,3H),3.61(d,1H,J=18.0Hz)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.28(s,3H),3.81(d,1H,J=16Hz),4.42(d,1H,J=16Hz),6.53(s,1H),6.92(d,1H,J=8Hz),7.32(d,1H,J=8Hz),8.05(d,2H,J=8Hz),8.17(d,2H,J=8Hz),11.04(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 2.16(s,4H),3.64(d,1H,J=16Hz),4.32(d,1H,J=16Hz),6.41(s,1H),6.89(d,1H,J=8Hz),7.05(d,2H,J=8Hz),7.30(d,1H,J=8Hz),7.80(d,2H,J=8Hz),10.95(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 1.21(d,6H,J=4Hz),2.95(m,1H),3.69(d,1H,J=16Hz),4.39(d,1H,J=16Hz),6.45(s,1H),6.90(d,1H,J=8Hz),7.29(d,1H,J=8Hz),7.38(d,2H,J=8Hz),7.85(d,2H,J=8Hz),10.98(s,1H)
1H−NMR(DMSO−d6,400MHz): d 1.48(d,3H,J=8Hz),3.00(s,6H),4.78(m,1H),6.35(s,1H),6.66(d,2H,J=8Hz),6.76(d,1H,J=8Hz),7.17(d,1H,J=8Hz),7.69(d,2H,J=8Hz),10.74(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 0.76(m,2H),1.06(m,2H),2.0(m,1H),3.65(d,1H,J=16Hz),4.35(d,1H,J=16Hz),6.43(s,1H),6.89(d,1H,J=8Hz),7.19(d,2H,J=8Hz),7.30(d,1H,J=8Hz),7.79(d,2H,J=8Hz),10.97(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.72(d,1H,J=16Hz),4.41(d,1H,J=16Hz),6.47(s,1H),6.62(d,1H,J=4Hz),6.90(d,1H,J=8Hz),7.31(d,1H,J=8Hz),7.84,(d,1H,J=4H),7.99(d,2H,J=8Hz),8.06(d,2H,J=8Hz),8.66(d,1H,J=4Hz),10.98(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 1.96(m,4H),3.30(m,4H),3.65(d,1H,J=16Hz),4.29(d,1H,J=16Hz),6.34(s,1H),6.53(d,2H,J=8Hz),6.88(d,1H,J=8Hz),7.28(d,1H,J=8Hz),7.72(d,2H,J=8Hz),10.97(s,1H)
次の条件による予備検討方法
RegisCellカラム L:250mm,IS:50mm,粒子径:5μm、移動相:メタノール/CO2,比率:35/65、検出波長:254nm、フロー速度:325g/min、共溶媒フロー速度:113.75ml/min、溶解度:メタノール1000mL中19.72g,濃度:0.020g/ml、注入容量:25.00ml,総量:0.500g/injection、収量(+):9.73g,旋光度:+247(20℃)、収量(−):9.26g
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.78(d,1H,J=16Hz),4.41(d,1H,J=16Hz),6.51(s,1H),6.90(d,1H,J=8Hz),7.31(d,1H,J=8Hz),7.56(s,2H),7.91(d,2H,J=8Hz),8.11(d,2H,J=8Hz),10.98(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 1.91(m,4H),3.46(m,4H),3.57(d,1H,J=16Hz),4.27(d,1H,J=16Hz),6.36(s,1H),6.71(t,1H,J=4Hz,J=8Hz),7.29(d,1H,J=8Hz),7.46(d,1H,J=8Hz),7.61(d,1H,J=4Hz),7.64(d,1H,J=8Hz),11.01(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 2.32(m,2H),3.51(d,1H,J=16Hz),3.95(m,4H),4.30(d,1H,J=16Hz),6.35(s,1H),6.36(d,2H,J=8Hz),6.87(d,1H,J=8Hz),7.28(d,1H,J=8Hz),7.73(d,2H,J=8Hz),10.89(s,1H)
生成色固体
1H−NMR(CDCl3,400MHz): d 1.24(m,4H),1.92(m,2H),2.08(m,2H),2.32(m,1H),3.06(m,1H),3.26(s,3H),3.33(d,1H,J=16Hz),3.69(s,1H),3.70(d,1H,J=16Hz),6.91(d,1H,J=8Hz),7.20(d,1H,J=8Hz),7.61(s,1H)
生成色固体
1H−NMR(CDCl3,400MHz): d 1.59(m,12H),3.16(s,3H),3.22(d,H,J=16Hz),3.58(s,1H),4.14(d,1H,J=16Hz),6.90(d,1H,J=8Hz),7.23(d,1H,J=8Hz),7.67(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 1.59(m,12H),2.5(s,3H),3.18(d,1H,J=16Hz),3.85(d,1H,J=16Hz),6.31(s,1H),6.90(d,1H,J=8Hz),7.30(d,1H,J=8Hz),10.95(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 0.83(m,2H),1.08(m,2H),2.11(m,1H),3.68(d,1H,J=16Hz),4.34(d,1H,J=16Hz),6.43(s,1H),6.90(d,1H,J=8Hz),7.11(m,1H),7.30(d,1H,J=8Hz),7.60(d,1H,J=8Hz),7.68(d,1H,J=8Hz),10.96(s,1H)
LCスクリーニング カラム:AD−H,250mm×4.6mm,5μm,ヘキサン/エタノール(65/35),1.5ml/min,注入容量:10.0μl,圧力:102.9bar、ピーク1 リテンションタイム:5.40min,幅:0.171min,面積:4502.21,面積%:50.08、ピーク2 リテンションタイム:7.23min,幅:0.239min,面積:4488.43,面積%:49.92
生成色固体
1H−NMR(DMSO−d6,400MHz): d 0.82(m,2H),1.07(m,2H),2.01(m,1H),3.66(d,1H,J=16Hz),4.26(d,1H,J=16Hz),6.44(s,1H),6.91(d,1H,J=8Hz),7.01(m,2H),7.31(d,1H,J=8Hz),7.57(m,1H),10.96(s,1H)
LCスクリーニング カラム:RegisCell,250mm×4.6mm,5μm,ヘキサン/IPA(80/20),1.5ml/min,注入容量:2.0μl,圧力:51.5bar、ピーク1 リテンションタイム:5.16min,幅:0.238min,面積:3716.20,面積%:49.78、ピーク2 リテンションタイム:6.49min,幅:0.324min,面積:3749.55,面積%:50.22
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.63(d,1H,J=16Hz),3.84(s,3H),4.36(d,1H,J=16Hz),6.38(s,1H),6.88(d,1H,J=8Hz),7.02(d,2H,J=8Hz),7.16(m,1H),7.89(d,2H,J=8Hz),11.01(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.28(m,4H),3.53(d,1H,J=16Hz),3.71(m,4H),4.33(d,1H,J=16Hz),6.37(s,1H),6.87(d,1H,J=8Hz),6.97(d,2H,J=8Hz),7.30(d,1H,J=8Hz),7.77(d,2H,J=8Hz),10.95(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.78(d,1H,J=16Hz),4.39(d,1H,J=16Hz),6.53(s,1H),6.92(d,1H,J=8Hz),7.32(d,1H,J=8Hz),7.79(d,2H,J=4Hz),8.80(d,2H,J=4Hz),11.03(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.78(d,1H,J=16Hz),4.39(d,1H,J=16Hz),6.50(s,1H),6.90(d,1H,J=8Hz),7.30(d,1H,J=8Hz),7.57(m,1H),8.28(d,1H,J=4Hz),8.80(d,1H,J=4Hz),9.09(s,1H),11.03(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.78(d,1H,J=16Hz),4.68(d,1H,J=16Hz),6.50(s,1H),6.90(d,1H,J=8Hz),7.30(d,1H,J=8Hz),7.70(d,1H,J=4Hz),7.81(d,1H,J=4Hz),7.98(m,1H),8.76(s,1H),11.01(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.74(d,1H,J=16Hz),4.42(d,1H,J=16Hz),6.49(s,1H),6.92(d,1H,J=8Hz),7.31(d,1H,J=8Hz),7.57(s,1H),7.95(d,2H,J=8Hz),7.97(d,2H,J=8Hz),8.10(s,1H),11.01(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.60(d,1H,J=16Hz),4.30(d,1H,J=16Hz),6.39(s,1H),6.82(d,2H,J=8Hz),6.90(d,1H,J=8Hz),7.30(d,1H,J=8Hz),7.80(d,2H,J=8Hz),10.45(s,1H),10.93(s,1H)
生成色固体
1H−NMR(DMSO−d6,400MHz): d 3.70(d,1H,J=16Hz),4.37(d,1H,J=16Hz),6.48(s,1H),6.91(d,1H,J=8Hz),7.30(d,1H,J=8Hz),7.56(m,1H),7.96(m,1H),8.01(m,1H),11.01(s,1H)
表2に示す特定化合物の生物活性を確認した。
CCK−8キット(Sigma−Aldrich;St Louis,MO)を用いた修飾テトラゾリウム塩アッセイにより、ヒト腫瘍細胞増殖の阻害を測定した。腫瘍細胞(5000〜7500/ウェル)を96ウェルプレートに播種し、4〜5時間にわたって接着させた。化合物を段階的に希釈し、0.02〜5μMの濃度で3種添加した。DMSOをビヒクルコントロールとして含ませた。化合物の存在下、細胞を3日間インキュベートした。インキュベーション後、各ウェルにCCK−8試薬を添加し、2〜4時間インキュベートした。波長450nmにおける分光光度測定により、生細胞を定量した。以下のとおり、各サンプルの生存率(%)をA450値から算出した。
生存率(%)=(サンプルのA450値/DNSO処理細胞のA450値×100)
細胞生存率を50%阻害した濃度をIC50と定義した。SKES細胞(ユーイング肉腫細胞株)を用いて、特定化合物のIC50活性を判定した。以下の表3に結果を纏める。以下の表4に示す細胞株を用いて、特定化合物のIC50活性を判定した。
化合物1:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物2:
SKES:B; A4573:B; TC71:B; LNCap:B; PC3:A; MDA−MB−231:B; MCF7:A; BxPC3:B; 及び PANC1:A
化合物3:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物4:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物5:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物6:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物7:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物8:
SKES:B; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物9:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物10:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物11:
SKES:B; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物12:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物13:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物14:
SKES:B; A4573:B; TC71:B; LNCap:B; PC3:A; MDA−MB−231:B; MCF7:A; BxPC3:B; 及び PANC1:A
化合物15:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物16:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物17:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物18:
SKES:B; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物19:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物20:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物21:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物22:
SKES:B; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物23:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物24:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物25:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物26:
SKES:B; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物27:
SKES:B; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物28:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物29:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物30:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物31:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物32:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物33:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物34:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物35:
SKES:A; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物36:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C.
化合物37:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物38:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
化合物39:
SKES:C; A4573:C; TC71:C; LNCap:C; PC3:C; MDA−MB−231:C; MCF7:C; BxPC3:C; 及び PANC1:C
NADPH再生系及び標準プロトコルを用い、特定化合物の代謝活性を肝ミクロソームでアッセイした。要約すると、単離したヒト、ラット、イヌ、又はマウスの肝ミクロソームで化合物をインキュベートした。96ウェルプレートにおいて、NADPH再生系(β−ニコチンアミドアデニンジヌクレオチドリン酸、イソクエン酸、及びイソクエン酸脱水素酵素)の添加によって反応を開始させた。5分、10分、20分、30分、及び60分の時点で、冷アクリロニトリルで反応系を急冷し、振盪し、4000rpmで20分間にわたって遠心分離した。検出された分析化合物を含む上澄みをLC/MS/MSを用いて解析した。条件は次のとおりである。
LC:Shimadzu LC 20−AD
MS:API4000
オートサンプラー:CTC PAL
使用カラム:CHIRALPAK AS−RH 150*4.6mm,5μm Part No.ASRHCD−KK008、及び、Ace 5 Phenyl,50×2.1mm,Part No.ACE−125−0502
データ解析:下記一次速度論の方程式を用いてT1/2及びCLを算出
Ct=C0*e−kt
Ct=(1/2)*C0
T1/2=(ln2)/k=0.693/k
CL=Vd*k
Vd=2mL/mg
以下の表5〜8に結果を纏める。表5〜8において、R2は速度定数を決定するための線形回帰の相関係数、T1/2は半減期、NCFは補因子なしである。
特定化合物について、ヒト肝ミクロソーム及びヒト肝細胞で、半減期及びクリアランス率をアッセイした。5%CO2で、95%に加湿されたインキュベーターにおいて、ヒト肝ミクロソーム(又はヒト肝細胞)の存在下で化合物をインキュベートし、反応を開始させた。各時点(0分、5分、15分、30分、60分、及び90分)で反応を停止させ、ボルテックス及び遠心分離を行った。LC/MS/MS解析まで上澄みを凍結させた。以下の表9及び表10に、各々ヒト肝ミクロソーム及びヒト肝細胞についての結果を纏める。
インビボにおける静脈内投与及び経口投与での特定化合物について、特定の薬物動態パラメータを決定した。要約すると、化合物を処方し、急速静脈内投与、持続静脈内投与、又は経口投与を行った。24時間にわたって複数時点で血液を採取し、プラズマを得た。LC/MS/MSを用い、親(母体)についてプラズマを解析した。特定化合物について、特定パラメータを2回得た。以下の表15に、ラット又はイヌにおける化合物14の持続投与試験の結果を纏める。以下の表16に、BALB/cマウス又はSprague Dawleyラットにおける試験の結果を纏める。
Claims (21)
- 式(I):
R1、R2、R3、及びR4は、それぞれ独立して、H、Cl、−CN、及び−CF3からなる群より選ばれ、
Aは、H及びC1−6アルキルからなる群より選ばれ、
Dは、−OH及び−O(C1−6アルキル)からなる群より選ばれ、
R5及びR6は、それぞれ独立して、H、F、及びC1−6アルキルからなる群より選ばれるか、もしくは、置換又は非置換のシクロアルキル環を一緒になって形成しており、
R12は、独立して、C3−8シクロアルキル及び
で表される構造を有する化合物、もしくは、その立体異性体、その薬学的に許容される塩、又はその溶媒和物。 - 前記R9は、アジリジニル、アゼチジニル、ピロリジニル、及びモルホリノリルからなる群より選ばれる、請求項1に記載の化合物。
- 前記R9は、イソプロピル及びシクロプロピルからなる群より選ばれる、請求項1に記載の化合物。
- 式(Ia):
R1、R2、R3、及びR4は、それぞれ独立して、H及びClからなる群より選ばれ、
R7、R8、R10、及びR11は、それぞれ独立して、H及びハロゲンからなる群より選ばれ、
R9は、独立して、C3−8シクロアルキル及びC3−8ヘテロシクロアルキルからなる群より選ばれる)
で表される構造を有する、請求項1に記載の化合物、もしくは、その立体異性体、その薬学的に許容される塩、又はその溶媒和物。 - 前記R1及びR4は、Clであり、前記R2及びR3は、Hである、請求項1〜4のいずれか1つに記載の化合物。
-
-
-
-
-
-
-
- 請求項1〜12のいずれか1つに記載の化合物と、薬学的に許容される担体とからなる、医薬組成物。
- 細胞の増殖を阻害する方法であって、
前記細胞は、ETS遺伝子を過剰発現させるか、又はETS融合遺伝子からなり、
前記細胞を、有効量の、請求項1〜13のいずれか1つに記載の化合物に接触させることからなる、方法。 - 前記ETS遺伝子又は前記ETS融合遺伝子は、FLI1、ERG、ETV1、及びETV4からなる群より選ばれる、請求項14に記載の方法。
- 腫瘍細胞を殺傷する、又は腫瘍細胞の増殖を阻害する方法であって、
前記細胞を、有効量の、請求項1〜13のいずれか1つに記載の化合物に接触させることからなる、方法。 - 前記細胞は、哺乳動物のものである、請求項14〜16のいずれか1つに記載の方法。
- 前記細胞は、ヒトのものである、請求項14〜17のいずれか1つに記載の方法。
- 前記細胞は、インビトロのものである、請求項14〜18のいずれか1つに記載の方法。
- 前記細胞は、インビボのものである、請求項14〜18のいずれか1つに記載の方法。
- 前記細胞は、癌細胞であり、
前記癌は、ユーイング肉腫、前立腺癌、膠芽細胞腫、急性骨髄性白血病、乳癌、頭部癌、頸部癌、黒色腫、非小細胞肺癌、卵巣癌、及び子宮癌からなる群より選ばれる、請求項14〜20のいずれか1つに記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201462062086P | 2014-10-09 | 2014-10-09 | |
US62/062,086 | 2014-10-09 | ||
PCT/US2015/054533 WO2016057698A1 (en) | 2014-10-09 | 2015-10-07 | Indolinone compounds and uses thereof |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019223835A Division JP6795861B2 (ja) | 2014-10-09 | 2019-12-11 | インドリノン化合物及びその使用 |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2017532377A true JP2017532377A (ja) | 2017-11-02 |
JP2017532377A5 JP2017532377A5 (ja) | 2018-09-13 |
JP6654197B2 JP6654197B2 (ja) | 2020-02-26 |
Family
ID=54337916
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017538916A Active JP6654197B2 (ja) | 2014-10-09 | 2015-10-07 | インドリノン化合物及びその使用 |
JP2019223835A Active JP6795861B2 (ja) | 2014-10-09 | 2019-12-11 | インドリノン化合物及びその使用 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019223835A Active JP6795861B2 (ja) | 2014-10-09 | 2019-12-11 | インドリノン化合物及びその使用 |
Country Status (14)
Country | Link |
---|---|
US (5) | US9604927B2 (ja) |
EP (1) | EP3204376B1 (ja) |
JP (2) | JP6654197B2 (ja) |
KR (1) | KR102482197B1 (ja) |
CN (2) | CN111777596A (ja) |
AR (1) | AR102222A1 (ja) |
AU (2) | AU2015328121B2 (ja) |
CA (1) | CA2961781C (ja) |
EA (1) | EA032644B1 (ja) |
IL (2) | IL251498B (ja) |
MX (1) | MX2017003589A (ja) |
NZ (1) | NZ730585A (ja) |
TW (2) | TWI750782B (ja) |
WO (1) | WO2016057698A1 (ja) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NZ723971A (en) | 2012-04-12 | 2018-01-26 | Univ Georgetown | Methods and compositions for treating ewings sarcoma family of tumors |
CN111777596A (zh) | 2014-10-09 | 2020-10-16 | 英克特诺治疗公司 | 吲哚酮化合物及其用途 |
CN109219594B (zh) * | 2016-03-31 | 2022-10-11 | 英克特诺治疗公司 | 吲哚啉类似物及其用途 |
CA3029851A1 (en) * | 2016-07-29 | 2018-02-01 | Oncternal Therapeutics, Inc. | Uses of indoline compounds such as tk216 for the treatment of cancer |
CN110818611B (zh) * | 2018-08-13 | 2023-01-24 | 中国科学院上海药物研究所 | 一类吲哚酮类化合物、其制备方法、药物组合物和用途 |
US20240139153A1 (en) * | 2020-09-17 | 2024-05-02 | Oklahoma Medical Research Foundation | Inhibition of Endothelial ETS Family Transcription Factors Promotes Flow-Dependent Ocular Vessel Regression |
CN113456631B (zh) * | 2021-08-06 | 2022-06-21 | 徐州医科大学 | 一种靶向acsl1的小分子药物及其在治疗子宫内膜癌中的应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008083326A2 (en) * | 2006-12-29 | 2008-07-10 | Georgetown University | Targeting of ews-fli1 as anti-tumor therapy |
WO2010042225A2 (en) * | 2008-10-10 | 2010-04-15 | Dana Farber Cancer Institute | Chemical modulators of pro-apoptotic bax and bcl-2 polypeptides |
WO2010083505A1 (en) * | 2009-01-19 | 2010-07-22 | The Trustees Of The University Of Pennsylvania | Method of treating cancer using a survivin inhibitor |
WO2013155341A1 (en) * | 2012-04-12 | 2013-10-17 | Georgetown University | Methods and compositions for treating ewings sarcoma family of tumors |
Family Cites Families (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA1288436C (en) | 1983-07-22 | 1991-09-03 | David Paul Hesson | Phenylquinolinecarboxylic acids and derivatives as antitumor agents |
JP2002531498A (ja) | 1998-12-04 | 2002-09-24 | ニューロサーチ、アクティーゼルスカブ | イオンチャネル活性剤としてのイサチン誘導体の使用方法 |
CN1155572C (zh) | 2001-01-19 | 2004-06-30 | 中国人民解放军军事医学科学院毒物药物研究所 | 吲哚类衍生物及其抗肿瘤用途 |
US20030157486A1 (en) | 2001-06-21 | 2003-08-21 | Graff Jonathan M. | Methods to identify signal sequences |
JP4584987B2 (ja) | 2004-04-30 | 2010-11-24 | アルニラム ファーマスーティカルズ インコーポレイテッド | C5修飾ピリミジンを含むオリゴヌクレオチド |
AR056317A1 (es) * | 2005-04-20 | 2007-10-03 | Xenon Pharmaceuticals Inc | Compuestos de oxindol y composicion farmaceutica |
WO2006117414A1 (es) | 2005-04-29 | 2006-11-09 | Proyecto De Biomedicina Cima, S.L. | Modelo animal no humano de sarcoma |
WO2008046083A2 (en) | 2006-10-12 | 2008-04-17 | Xenon Pharmaceuticals Inc. | Use of oxindole compounds as therapeutic agents |
US8232310B2 (en) | 2006-12-29 | 2012-07-31 | Georgetown University | Targeting of EWS-FLI1 as anti-tumor therapy |
EP2154966B1 (en) | 2007-04-20 | 2013-08-21 | The Research Foundation Of State University Of New York | Benzimidazoles and pharmaceutical compositions thereof |
US8377992B2 (en) | 2007-10-22 | 2013-02-19 | The Wistar Institute | TRBD-binding effectors and methods for using the same to modulate telomerase activity |
AP2011005690A0 (en) | 2008-10-21 | 2011-06-30 | Onyx Therapeutics Inc | Combination therapy with peptide epoxyketones. |
WO2012078519A2 (en) | 2010-12-06 | 2012-06-14 | Numerate, Inc. | 3-acylidene-2-oxoindole derivatives for inhibition of transglutaminase 2 |
CN102516152B (zh) | 2011-12-12 | 2014-12-10 | 华东师范大学 | 一种α-二氟羰基取代的手性叔醇类化合物及其合成方法和应用 |
WO2013151981A1 (en) | 2012-04-02 | 2013-10-10 | Gradalis, Inc. | Ewing's sarcoma bifunctional shrna design |
WO2014015153A2 (en) * | 2012-07-20 | 2014-01-23 | Star Biotechnology, Llc | Compositions and methods for treating ewing's sarcoma and other disorders related to ews-fli1 |
US11285169B2 (en) * | 2013-03-13 | 2022-03-29 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Methods for modulating chemotherapeutic cytotoxicity |
CN103435606A (zh) * | 2013-08-22 | 2013-12-11 | 中国药科大学 | CDK2与GSK3β双重抑制剂及用途 |
CN103613580B (zh) * | 2013-09-03 | 2016-02-10 | 遵义医学院 | 用于抗肿瘤药物的3-羟基吲哚-2-酮类化合物或其药学上能够接受的盐 |
KR20160065986A (ko) | 2013-10-24 | 2016-06-09 | 조지타운 유니버시티 | 암 치료용 방법 및 조성물 |
RU2646758C2 (ru) | 2013-12-05 | 2018-03-07 | Ф. Хоффманн-Ля Рош Аг | Гетероарил пиридоны и азапиридоны с электрофильной функциональностью |
WO2015160868A1 (en) | 2014-04-16 | 2015-10-22 | Signal Pharmaceuticals, Llc | Methods for treating cancer using tor kinase inhibitor combination therapy |
CN111777596A (zh) | 2014-10-09 | 2020-10-16 | 英克特诺治疗公司 | 吲哚酮化合物及其用途 |
CN109219594B (zh) | 2016-03-31 | 2022-10-11 | 英克特诺治疗公司 | 吲哚啉类似物及其用途 |
CA3029851A1 (en) * | 2016-07-29 | 2018-02-01 | Oncternal Therapeutics, Inc. | Uses of indoline compounds such as tk216 for the treatment of cancer |
-
2015
- 2015-10-07 CN CN202010495279.0A patent/CN111777596A/zh active Pending
- 2015-10-07 US US14/877,708 patent/US9604927B2/en active Active
- 2015-10-07 AU AU2015328121A patent/AU2015328121B2/en active Active
- 2015-10-07 EA EA201790445A patent/EA032644B1/ru unknown
- 2015-10-07 NZ NZ730585A patent/NZ730585A/en unknown
- 2015-10-07 WO PCT/US2015/054533 patent/WO2016057698A1/en active Application Filing
- 2015-10-07 CA CA2961781A patent/CA2961781C/en active Active
- 2015-10-07 KR KR1020177012523A patent/KR102482197B1/ko active IP Right Grant
- 2015-10-07 EP EP15784237.8A patent/EP3204376B1/en active Active
- 2015-10-07 JP JP2017538916A patent/JP6654197B2/ja active Active
- 2015-10-07 CN CN201580054973.6A patent/CN107108580B/zh active Active
- 2015-10-07 MX MX2017003589A patent/MX2017003589A/es unknown
- 2015-10-08 TW TW109129160A patent/TWI750782B/zh active
- 2015-10-08 TW TW104133287A patent/TWI705054B/zh active
- 2015-10-09 AR ARP150103264A patent/AR102222A1/es unknown
-
2016
- 2016-11-21 US US15/357,933 patent/US9895352B2/en active Active
- 2016-11-21 US US15/357,876 patent/US9987251B2/en active Active
-
2017
- 2017-04-02 IL IL251498A patent/IL251498B/en unknown
-
2018
- 2018-05-07 US US15/973,110 patent/US20180256546A1/en not_active Abandoned
-
2019
- 2019-12-11 JP JP2019223835A patent/JP6795861B2/ja active Active
-
2020
- 2020-01-29 AU AU2020200631A patent/AU2020200631B2/en active Active
-
2021
- 2021-06-23 IL IL284322A patent/IL284322B2/en unknown
-
2022
- 2022-06-02 US US17/830,668 patent/US20220288023A1/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008083326A2 (en) * | 2006-12-29 | 2008-07-10 | Georgetown University | Targeting of ews-fli1 as anti-tumor therapy |
WO2010042225A2 (en) * | 2008-10-10 | 2010-04-15 | Dana Farber Cancer Institute | Chemical modulators of pro-apoptotic bax and bcl-2 polypeptides |
WO2010083505A1 (en) * | 2009-01-19 | 2010-07-22 | The Trustees Of The University Of Pennsylvania | Method of treating cancer using a survivin inhibitor |
WO2013155341A1 (en) * | 2012-04-12 | 2013-10-17 | Georgetown University | Methods and compositions for treating ewings sarcoma family of tumors |
Non-Patent Citations (7)
Title |
---|
BECERRA D; INSUASTY B; COBO J; GLIDEWELL C: "HYDROGEN-BONDING PATTERNS IN 3-ALKYL-3-HYDROXYINDOLIN-2-ONES", ACTA CRYSTALLOGRAPHICA SECTION C. CRYSTAL STRUCTURE COMMUNICATIONS, vol. VOL:66, NR:2, JPN5017008807, 22 January 2010 (2010-01-22), DK, pages 79 - 86, ISSN: 0004040916 * |
FILE REGISTRY ON STN, RN 309928-53-8, ENTERED STN: 20 DEC 2000, JPN7019003261, ISSN: 0004128943 * |
HOSSEIN PAJOUHESH; ET AL: "POTENTIAL ANTICONVULSANTS VI: CONDENSATION OF ISATINS WITH CYCLOHEXANONE AND OTHER CYCLIC KETONES", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. VOL:72, NR:3, JPN5017008820, 1983, pages 318 - 321, ISSN: 0004040914 * |
NAGLE A A; REDDY S A; ET AL: "3-(2-OXOETHYLIDENE)INDOLIN-2-ONE DERIVATIVES ACTIVATE NRF2 AND INHIBIT NF-κB: POTENTIAL 以下備考", CHEMMEDCHEM, vol. VOL:9, NR:8, JPN5017008796, 2014, pages 1763 - 1774, ISSN: 0004040918 * |
PAJOUHESH H; PARSON R AND POPP F D: "SYNTHESIS OF 3-HYDROXY-3-PHENACYLOXINDOLE ANALOGS", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. VOL:68, NR:4, JPN5017008821, 1979, pages 519 - 520, ISSN: 0004040913 * |
SURESH ALLU; ET AL: "ENANTIOSELECTIVE ORGANOCATALYTIC ALDOL REACTION OF UNACTIVATED KETONES WITH ISATINS", TETRAHEDRON LETTERS, vol. VOL:52, NR:32, JPN5017008804, 11 May 2011 (2011-05-11), NL, pages 4080 - 4083, ISSN: 0004040915 * |
WEN-BING CHEN; ET AL: "CATALYST-FREE ALDOL CONDENSATION OF KETONES AND ISATINS UNDER MILD REACTION CONDITIONS 以下備考", GREEN CHEMISTRY, vol. VOL:11, NR:9, JPN5017008809, 2009, GB, pages 1465 - 1476, ISSN: 0004040917 * |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6795861B2 (ja) | インドリノン化合物及びその使用 | |
JP6345301B2 (ja) | ユーイング肉腫ファミリー腫瘍を治療するための方法及び組成物 | |
JP6864379B2 (ja) | インドール類似体及びその使用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20170518 |
|
RD01 | Notification of change of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7426 Effective date: 20170517 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180731 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180731 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20190509 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190528 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190806 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191008 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191211 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200114 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200129 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6654197 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |