WO2014191726A1 - Chemical compounds - Google Patents
Chemical compounds Download PDFInfo
- Publication number
- WO2014191726A1 WO2014191726A1 PCT/GB2014/051607 GB2014051607W WO2014191726A1 WO 2014191726 A1 WO2014191726 A1 WO 2014191726A1 GB 2014051607 W GB2014051607 W GB 2014051607W WO 2014191726 A1 WO2014191726 A1 WO 2014191726A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- methyl
- fluoro
- pyrido
- indol
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 317
- 150000003839 salts Chemical class 0.000 claims abstract description 172
- 238000011282 treatment Methods 0.000 claims abstract description 104
- 238000000034 method Methods 0.000 claims abstract description 98
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 42
- 239000000203 mixture Substances 0.000 claims description 124
- 206010028980 Neoplasm Diseases 0.000 claims description 119
- 241001465754 Metazoa Species 0.000 claims description 58
- 201000011510 cancer Diseases 0.000 claims description 55
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 50
- 239000003795 chemical substances by application Substances 0.000 claims description 48
- DFBDRVGWBHBJNR-BBNFHIFMSA-N (e)-3-[3,5-difluoro-4-[(1r,3r)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H](N2CC(C)(C)F)C)=C(F)C=C(\C=C\C(O)=O)C=C1F DFBDRVGWBHBJNR-BBNFHIFMSA-N 0.000 claims description 47
- 230000000259 anti-tumor effect Effects 0.000 claims description 41
- 239000003814 drug Substances 0.000 claims description 31
- 239000003085 diluting agent Substances 0.000 claims description 27
- 230000002265 prevention Effects 0.000 claims description 16
- 239000003963 antioxidant agent Substances 0.000 claims description 15
- 235000006708 antioxidants Nutrition 0.000 claims description 15
- 210000000481 breast Anatomy 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 12
- 230000003078 antioxidant effect Effects 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- 239000002738 chelating agent Substances 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- IOPRLAHXDGSIHG-NAUGMMEESA-N (e)-3-[3-fluoro-4-[2-[(2s)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1h-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1=2NC3=CC=CC=C3C=2CC(C)(C)N(C[C@@H](CF)C)C1C1=CC=C(\C=C\C(O)=O)C=C1F IOPRLAHXDGSIHG-NAUGMMEESA-N 0.000 claims description 4
- DFBDRVGWBHBJNR-NYKMLEKOSA-N (e)-3-[4-[(1r,3r)-1-deuterio-2-(2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3h-pyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoic acid Chemical compound C1([C@@]2(C3=C(C4=CC=CC=C4N3)C[C@@H](C)N2CC(C)(C)F)[2H])=C(F)C=C(\C=C\C(O)=O)C=C1F DFBDRVGWBHBJNR-NYKMLEKOSA-N 0.000 claims description 4
- STVQFMFTCUMADM-XGMWYDOHSA-N (e)-3-[3,5-difluoro-4-[(1r,3r)-2-[(2s)-3-fluoro-2-methylpropyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](C)N2C[C@@H](CF)C)=C(F)C=C(\C=C\C(O)=O)C=C1F STVQFMFTCUMADM-XGMWYDOHSA-N 0.000 claims description 3
- HYPDMBONKGTBLC-NVEBTIFVSA-N (e)-3-[4-[(1r,3r)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@H](N2CC(C)(C)F)C)=CC=C(\C=C\C(O)=O)C=C1 HYPDMBONKGTBLC-NVEBTIFVSA-N 0.000 claims description 3
- CLDCRFJRMORRTI-IEGMAYJBSA-N (e)-3-[4-[(1r,3r)-2-[(2s)-3-fluoro-2-methylpropyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H](C)N2C[C@@H](CF)C)=CC=C(\C=C\C(O)=O)C=C1 CLDCRFJRMORRTI-IEGMAYJBSA-N 0.000 claims description 3
- WRHLOSDZEZAYKX-WFSDQYTKSA-N (e)-3-[4-[2-[(2s)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1h-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1=2NC3=CC=CC=C3C=2CC(C)(C)N(C[C@@H](CF)C)C1C1=CC=C(\C=C\C(O)=O)C=C1 WRHLOSDZEZAYKX-WFSDQYTKSA-N 0.000 claims description 3
- AKZLESYLLLKGNZ-MDZDMXLPSA-N (e)-3-[3,5-difluoro-4-[2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-4,9-dihydro-1h-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1=2NC3=CC=CC=C3C=2CC(C)(C)N(CC(C)(F)C)C1C1=C(F)C=C(\C=C\C(O)=O)C=C1F AKZLESYLLLKGNZ-MDZDMXLPSA-N 0.000 claims description 2
- XTDHJGCTXMSPCY-RSEBSXLISA-N (e)-3-[3,5-difluoro-4-[2-[(2s)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1h-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1=2NC3=CC=CC=C3C=2CC(C)(C)N(C[C@@H](CF)C)C1C1=C(F)C=C(\C=C\C(O)=O)C=C1F XTDHJGCTXMSPCY-RSEBSXLISA-N 0.000 claims description 2
- RZLKPYCEHAUODL-SDNWHVSQSA-N (e)-3-[4-[2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-4,9-dihydro-1h-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C1=2NC3=CC=CC=C3C=2CC(C)(C)N(CC(C)(F)C)C1C1=CC=C(\C=C\C(O)=O)C=C1 RZLKPYCEHAUODL-SDNWHVSQSA-N 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 55
- 230000008569 process Effects 0.000 abstract description 21
- 230000002062 proliferating effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 126
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 124
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 118
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 112
- 239000000243 solution Substances 0.000 description 112
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 108
- 239000007787 solid Substances 0.000 description 106
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 94
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 72
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 70
- 238000006243 chemical reaction Methods 0.000 description 62
- 239000000047 product Substances 0.000 description 60
- 102100038595 Estrogen receptor Human genes 0.000 description 59
- 108090000623 proteins and genes Proteins 0.000 description 58
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 53
- 108010038795 estrogen receptors Proteins 0.000 description 53
- 235000019439 ethyl acetate Nutrition 0.000 description 51
- 239000000377 silicon dioxide Substances 0.000 description 51
- 239000003112 inhibitor Substances 0.000 description 47
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 46
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 45
- 210000004027 cell Anatomy 0.000 description 43
- 150000007523 nucleic acids Chemical class 0.000 description 43
- 241000282414 Homo sapiens Species 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 41
- 239000000523 sample Substances 0.000 description 41
- 239000012043 crude product Substances 0.000 description 40
- 238000003199 nucleic acid amplification method Methods 0.000 description 38
- 208000026310 Breast neoplasm Diseases 0.000 description 37
- 230000003321 amplification Effects 0.000 description 37
- 230000035772 mutation Effects 0.000 description 36
- 239000011541 reaction mixture Substances 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000010410 layer Substances 0.000 description 32
- 238000004519 manufacturing process Methods 0.000 description 32
- 102000039446 nucleic acids Human genes 0.000 description 32
- 108020004707 nucleic acids Proteins 0.000 description 32
- 238000004587 chromatography analysis Methods 0.000 description 31
- 230000000694 effects Effects 0.000 description 31
- 229960005419 nitrogen Drugs 0.000 description 30
- 239000007858 starting material Substances 0.000 description 29
- 238000007792 addition Methods 0.000 description 28
- 206010006187 Breast cancer Diseases 0.000 description 27
- -1 endogenous ligand E2 Chemical class 0.000 description 27
- 229910052757 nitrogen Inorganic materials 0.000 description 27
- 239000000725 suspension Substances 0.000 description 27
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 26
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 238000004458 analytical method Methods 0.000 description 26
- 238000010828 elution Methods 0.000 description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 26
- 238000003752 polymerase chain reaction Methods 0.000 description 26
- 108020004414 DNA Proteins 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 23
- 239000002585 base Substances 0.000 description 23
- 102000005962 receptors Human genes 0.000 description 23
- 108020003175 receptors Proteins 0.000 description 23
- 210000004881 tumor cell Anatomy 0.000 description 23
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 22
- 101150051821 era gene Proteins 0.000 description 21
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 238000001514 detection method Methods 0.000 description 19
- 239000002552 dosage form Substances 0.000 description 19
- 235000018102 proteins Nutrition 0.000 description 19
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 18
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 18
- 238000003556 assay Methods 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 18
- 239000000262 estrogen Substances 0.000 description 18
- 239000000463 material Substances 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000004480 active ingredient Substances 0.000 description 17
- 238000001914 filtration Methods 0.000 description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 108091007960 PI3Ks Proteins 0.000 description 16
- 102000038030 PI3Ks Human genes 0.000 description 16
- 239000003886 aromatase inhibitor Substances 0.000 description 16
- 229940002612 prodrug Drugs 0.000 description 16
- 239000000651 prodrug Substances 0.000 description 16
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- JUSFANSTBFGBAF-IRXDYDNUSA-N 3-[2,4-bis[(3s)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(C=2N=C3N=C(N=C(C3=CC=2)N2[C@H](COCC2)C)N2[C@H](COCC2)C)=C1 JUSFANSTBFGBAF-IRXDYDNUSA-N 0.000 description 14
- 229940119564 Selective estrogen receptor downregulator Drugs 0.000 description 14
- 239000000090 biomarker Substances 0.000 description 14
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 239000002953 phosphate buffered saline Substances 0.000 description 14
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 14
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 14
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 201000010099 disease Diseases 0.000 description 13
- 239000012065 filter cake Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 238000009396 hybridization Methods 0.000 description 13
- 238000001819 mass spectrum Methods 0.000 description 13
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 13
- 238000002560 therapeutic procedure Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 229940122815 Aromatase inhibitor Drugs 0.000 description 12
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 12
- 239000013059 antihormonal agent Substances 0.000 description 12
- 230000002401 inhibitory effect Effects 0.000 description 12
- 108020001756 ligand binding domains Proteins 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 230000004083 survival effect Effects 0.000 description 12
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 12
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 11
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 11
- 108091028043 Nucleic acid sequence Proteins 0.000 description 11
- 230000014509 gene expression Effects 0.000 description 11
- 239000003446 ligand Substances 0.000 description 11
- 229940124302 mTOR inhibitor Drugs 0.000 description 11
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 11
- 229960004390 palbociclib Drugs 0.000 description 11
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 11
- 239000000546 pharmaceutical excipient Substances 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- PBIVLMHOKZWHEW-LLVKDONJSA-N 2-fluoro-N-[(2R)-1-(1H-indol-3-yl)propan-2-yl]-2-methylpropan-1-amine Chemical compound C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(C)F PBIVLMHOKZWHEW-LLVKDONJSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
- 108091034117 Oligonucleotide Proteins 0.000 description 10
- 238000013459 approach Methods 0.000 description 10
- 238000001727 in vivo Methods 0.000 description 10
- 238000005259 measurement Methods 0.000 description 10
- 230000007246 mechanism Effects 0.000 description 10
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 10
- 238000002953 preparative HPLC Methods 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 239000003643 water by type Substances 0.000 description 10
- 108700028369 Alleles Proteins 0.000 description 9
- VWUXBMIQPBEWFH-WCCTWKNTSA-N Fulvestrant Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3[C@H](CCCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F)CC2=C1 VWUXBMIQPBEWFH-WCCTWKNTSA-N 0.000 description 9
- 206010033128 Ovarian cancer Diseases 0.000 description 9
- 206010061535 Ovarian neoplasm Diseases 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 230000027455 binding Effects 0.000 description 9
- 150000002148 esters Chemical class 0.000 description 9
- 239000000284 extract Substances 0.000 description 9
- 239000003102 growth factor Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- GDGULTXZDPTNNZ-NSCUHMNNSA-N methyl (E)-3-(3,5-difluoro-4-formylphenyl)prop-2-enoate Chemical compound COC(=O)\C=C\c1cc(F)c(C=O)c(F)c1 GDGULTXZDPTNNZ-NSCUHMNNSA-N 0.000 description 9
- 239000002773 nucleotide Substances 0.000 description 9
- 125000003729 nucleotide group Chemical group 0.000 description 9
- 230000037361 pathway Effects 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 230000004044 response Effects 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- 229960001603 tamoxifen Drugs 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 9
- 206010014759 Endometrial neoplasm Diseases 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 210000003679 cervix uteri Anatomy 0.000 description 8
- 210000004696 endometrium Anatomy 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 210000001672 ovary Anatomy 0.000 description 8
- 230000000144 pharmacologic effect Effects 0.000 description 8
- 239000003755 preservative agent Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 230000019491 signal transduction Effects 0.000 description 8
- 230000011664 signaling Effects 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- OJFXAMILNHYNSV-UHFFFAOYSA-N (2-fluoro-2-methylpropyl) trifluoromethanesulfonate Chemical compound CC(C)(F)COS(=O)(=O)C(F)(F)F OJFXAMILNHYNSV-UHFFFAOYSA-N 0.000 description 7
- 229940123150 Chelating agent Drugs 0.000 description 7
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 7
- DIBNGUKFUWYBBI-SCSAIBSYSA-N [(2S)-3-fluoro-2-methylpropyl] trifluoromethanesulfonate Chemical compound C[C@H](CF)COS(=O)(=O)C(F)(F)F DIBNGUKFUWYBBI-SCSAIBSYSA-N 0.000 description 7
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 150000001413 amino acids Chemical class 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 230000001413 cellular effect Effects 0.000 description 7
- 239000007857 degradation product Substances 0.000 description 7
- 230000001419 dependent effect Effects 0.000 description 7
- 238000009261 endocrine therapy Methods 0.000 description 7
- 229940011871 estrogen Drugs 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 229960002258 fulvestrant Drugs 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- NERYNBJQGGYORQ-OCFXUSKDSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)cc(F)c1[C@H]1N(CC(C)(C)F)[C@H](C)Cc2c1[nH]c1ccccc12 NERYNBJQGGYORQ-OCFXUSKDSA-N 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 102000054765 polymorphisms of proteins Human genes 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 239000012258 stirred mixture Substances 0.000 description 7
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- QSQQQURBVYWZKJ-MRVPVSSYSA-N (2r)-1-(1h-indol-3-yl)propan-2-amine Chemical compound C1=CC=C2C(C[C@H](N)C)=CNC2=C1 QSQQQURBVYWZKJ-MRVPVSSYSA-N 0.000 description 6
- QZKOBFIEGIQDMU-MYSGNRETSA-N (E)-3-[3,5-difluoro-4-[(3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-3,4-dihydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C([C@H]([N+]=1CC(C)(C)F)C)c(c2c(cccc2)[nH]2)c2C=1c1c(F)cc(\C=C\C([O-])=O)cc1F QZKOBFIEGIQDMU-MYSGNRETSA-N 0.000 description 6
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 6
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 6
- 101000882584 Homo sapiens Estrogen receptor Proteins 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 235000001014 amino acid Nutrition 0.000 description 6
- 230000001028 anti-proliverative effect Effects 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 235000010323 ascorbic acid Nutrition 0.000 description 6
- 239000011668 ascorbic acid Substances 0.000 description 6
- 229960005070 ascorbic acid Drugs 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
- 238000006731 degradation reaction Methods 0.000 description 6
- 230000003828 downregulation Effects 0.000 description 6
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 6
- HXWNOZFHDDAZHY-JLHYYAGUSA-N methyl (E)-3-[4-(3,3-dimethyl-1,2,4,9-tetrahydropyrido[3,4-b]indol-1-yl)phenyl]prop-2-enoate Chemical compound c1cc(/C=C/C(=O)OC)ccc1C1NC(C)(C)Cc2c1[nH]c1ccccc12 HXWNOZFHDDAZHY-JLHYYAGUSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000012163 sequencing technique Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 238000013518 transcription Methods 0.000 description 6
- 230000035897 transcription Effects 0.000 description 6
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 6
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 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 5
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 5
- 239000008186 active pharmaceutical agent Substances 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000001740 anti-invasion Effects 0.000 description 5
- 230000015556 catabolic process Effects 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- 230000002354 daily effect Effects 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000004255 ion exchange chromatography Methods 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 108020004999 messenger RNA Proteins 0.000 description 5
- 239000002207 metabolite Substances 0.000 description 5
- SSQOQBIRCYAJOF-GPTGHKLOSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)cc(F)c1[C@H]1N(CC(C)(F)CO)[C@H](C)Cc2c1[nH]c1ccccc12 SSQOQBIRCYAJOF-GPTGHKLOSA-N 0.000 description 5
- SRUXXGKYHYNBQK-ZHACJKMWSA-N methyl (E)-3-[3,5-difluoro-4-[2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)cc(F)c1C1N(CC(C)(C)F)C(C)(C)Cc2c1[nH]c1ccccc12 SRUXXGKYHYNBQK-ZHACJKMWSA-N 0.000 description 5
- GHGYNJBXDGPRCE-NTCAYCPXSA-N methyl (E)-3-[4-[2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound c1cc(/C=C/C(=O)OC)ccc1C1N(CC(C)(C)F)C(C)(C)Cc2c1[nH]c1ccccc12 GHGYNJBXDGPRCE-NTCAYCPXSA-N 0.000 description 5
- KVXMLLMZXPRPNG-VOTSOKGWSA-N methyl (e)-3-(4-formylphenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(C=O)C=C1 KVXMLLMZXPRPNG-VOTSOKGWSA-N 0.000 description 5
- 230000001617 migratory effect Effects 0.000 description 5
- 102000004196 processed proteins & peptides Human genes 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000004853 protein function Effects 0.000 description 5
- 239000002002 slurry Substances 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
- 229940063683 taxotere Drugs 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 5
- 238000012546 transfer Methods 0.000 description 5
- 239000003039 volatile agent Substances 0.000 description 5
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 4
- VQDNMKWCOYVVJH-UHFFFAOYSA-N 2-fluoro-2-methylpropan-1-ol Chemical compound CC(C)(F)CO VQDNMKWCOYVVJH-UHFFFAOYSA-N 0.000 description 4
- FUVRFVXIQBDLOF-UHFFFAOYSA-N 3-(oxan-2-yloxy)propanoic acid Chemical compound OC(=O)CCOC1CCCCO1 FUVRFVXIQBDLOF-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 101150041968 CDC13 gene Proteins 0.000 description 4
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 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 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 230000001594 aberrant effect Effects 0.000 description 4
- 229940022682 acetone Drugs 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 229940046844 aromatase inhibitors Drugs 0.000 description 4
- 125000003435 aroyl group Chemical group 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 239000002178 crystalline material Substances 0.000 description 4
- 238000012217 deletion Methods 0.000 description 4
- 230000037430 deletion Effects 0.000 description 4
- 238000000113 differential scanning calorimetry Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000012156 elution solvent Substances 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000796 flavoring agent Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 238000004949 mass spectrometry Methods 0.000 description 4
- FOIUBWMGMCVSEG-UQVHDOFVSA-N methyl (E)-3-[3,5-difluoro-4-[2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)cc(F)c1C1N(C[C@H](C)CF)C(C)(C)Cc2c1[nH]c1ccccc12 FOIUBWMGMCVSEG-UQVHDOFVSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 229920001184 polypeptide Polymers 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- DMEUDSHBHKHLPD-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=C=C[N]1 DMEUDSHBHKHLPD-UHFFFAOYSA-N 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000007894 restriction fragment length polymorphism technique Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 4
- 229940001584 sodium metabisulfite Drugs 0.000 description 4
- 235000010262 sodium metabisulphite Nutrition 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- 230000003442 weekly effect Effects 0.000 description 4
- ZVURTQUPKQRQTE-VXGBXAGGSA-N (2S)-3-fluoro-N-[(2R)-1-(1H-indol-3-yl)propan-2-yl]-2-methylpropan-1-amine Chemical compound C[C@H](CF)CN[C@H](C)Cc1c[nH]c2ccccc12 ZVURTQUPKQRQTE-VXGBXAGGSA-N 0.000 description 3
- LSRHFWSNUFIKER-SMZGMGDZSA-N (4-bromo-2,6-difluorophenyl)-dideuteriomethanol Chemical compound [2H]C([2H])(O)c1c(F)cc(Br)cc1F LSRHFWSNUFIKER-SMZGMGDZSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- LLBNXYIFLJLUEA-ZRKZCGFPSA-N 2-fluoro-3-[[(2R)-1-(1H-indol-3-yl)propan-2-yl]amino]-2-methylpropan-1-ol Chemical compound C[C@H](Cc1c[nH]c2ccccc12)NCC(C)(F)CO LLBNXYIFLJLUEA-ZRKZCGFPSA-N 0.000 description 3
- GUASKKAHCKSDBG-UICOGKGYSA-N 4-bromo-1-deuterio-2,6-difluorocyclohexa-2,4-diene-1-carbaldehyde Chemical compound BrC1=CC(C(C=O)(C(=C1)F)[2H])F GUASKKAHCKSDBG-UICOGKGYSA-N 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 3
- 108020004635 Complementary DNA Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000053602 DNA Human genes 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102100029951 Estrogen receptor beta Human genes 0.000 description 3
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 3
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 239000000443 aerosol Substances 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 125000005907 alkyl ester group Chemical group 0.000 description 3
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 229940054051 antipsychotic indole derivative Drugs 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000003115 biocidal effect Effects 0.000 description 3
- 239000003139 biocide Substances 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052796 boron Inorganic materials 0.000 description 3
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 230000002860 competitive effect Effects 0.000 description 3
- 230000000295 complement effect Effects 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000008380 degradant Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229910001873 dinitrogen Inorganic materials 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- 235000003599 food sweetener Nutrition 0.000 description 3
- 239000001530 fumaric acid Substances 0.000 description 3
- 230000009036 growth inhibition Effects 0.000 description 3
- 238000000265 homogenisation Methods 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 238000002513 implantation Methods 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 150000002475 indoles Chemical class 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 3
- 239000011976 maleic acid Substances 0.000 description 3
- 150000002688 maleic acid derivatives Chemical class 0.000 description 3
- 239000001630 malic acid Substances 0.000 description 3
- 235000011090 malic acid Nutrition 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 230000001394 metastastic effect Effects 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- PZDAYFVEJZGUGR-UKSOIIMHSA-N methyl (E)-3-[3,5-difluoro-4-[(1R,3R)-2-[(2S)-3-fluoro-2-methylpropyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)cc(F)c1[C@H]1N(C[C@H](C)CF)[C@H](C)Cc2c1[nH]c1ccccc12 PZDAYFVEJZGUGR-UKSOIIMHSA-N 0.000 description 3
- LXIXGEWZONJSJR-UHICZHLJSA-N methyl (E)-3-[3-fluoro-4-[2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)ccc1C1N(C[C@H](C)CF)C(C)(C)Cc2c1[nH]c1ccccc12 LXIXGEWZONJSJR-UHICZHLJSA-N 0.000 description 3
- WIQOMMQZANAFJX-CMDGGOBGSA-N methyl (E)-3-[4-(3,3-dimethyl-1,2,4,9-tetrahydropyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)cc(F)c1C1NC(C)(C)Cc2c1[nH]c1ccccc12 WIQOMMQZANAFJX-CMDGGOBGSA-N 0.000 description 3
- HUDKDIKGLTVYKQ-AEFTVVLGSA-N methyl (E)-3-[4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound c1cc(/C=C/C(=O)OC)ccc1[C@H]1N(CC(C)(C)F)[C@H](C)Cc2c1[nH]c1ccccc12 HUDKDIKGLTVYKQ-AEFTVVLGSA-N 0.000 description 3
- DNPUONKJPGDDLL-HZYYTIRMSA-N methyl (E)-3-[4-[(1R,3R)-2-[(2S)-3-fluoro-2-methylpropyl]-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound c1cc(/C=C/C(=O)OC)ccc1[C@H]1N(C[C@H](C)CF)[C@H](C)Cc2c1[nH]c1ccccc12 DNPUONKJPGDDLL-HZYYTIRMSA-N 0.000 description 3
- OGJPPELUWHAGOO-ORYVFASXSA-N methyl (E)-3-[4-[(1S,3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound c1cc(/C=C/C(=O)OC)ccc1[C@@H]1N[C@H](C)Cc2c1[nH]c1ccccc12 OGJPPELUWHAGOO-ORYVFASXSA-N 0.000 description 3
- UVRSSTMRVVBLAO-CDBFJARXSA-N methyl (E)-3-[4-[2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound c1cc(/C=C/C(=O)OC)ccc1C1N(C[C@H](C)CF)C(C)(C)Cc2c1[nH]c1ccccc12 UVRSSTMRVVBLAO-CDBFJARXSA-N 0.000 description 3
- AAGYNMFEAPYSEX-HWKANZROSA-N methyl (e)-3-(3-fluoro-4-formylphenyl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(C=O)C(F)=C1 AAGYNMFEAPYSEX-HWKANZROSA-N 0.000 description 3
- 238000010369 molecular cloning Methods 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 230000020477 pH reduction Effects 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 230000007115 recruitment Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 230000008261 resistance mechanism Effects 0.000 description 3
- 238000012552 review Methods 0.000 description 3
- 238000013207 serial dilution Methods 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000011343 solid material Substances 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 239000001117 sulphuric acid Substances 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 239000007916 tablet composition Substances 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 3
- 238000005292 vacuum distillation Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- HRPXBIFMRWNHRU-SCSAIBSYSA-N (2S)-3-fluoro-2-methylpropan-1-ol Chemical compound C[C@@H](CO)CF HRPXBIFMRWNHRU-SCSAIBSYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- XTDHJGCTXMSPCY-JTPUKKJKSA-N (E)-3-[3,5-difluoro-4-[(1R)-2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound FC=1C=C(C=C(C1[C@H]1N(C(CC2=C1NC1=CC=CC=C21)(C)C)C[C@@H](CF)C)F)/C=C/C(=O)O XTDHJGCTXMSPCY-JTPUKKJKSA-N 0.000 description 2
- BDVPOTANVYJGJS-FLVTYSTMSA-N (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-3-hydroxy-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound c1([C@H]2N([C@@H](Cc3c2[nH]c2ccccc23)C)CC(C)(F)CO)c(F)cc(\C=C\C(O)=O)cc1F BDVPOTANVYJGJS-FLVTYSTMSA-N 0.000 description 2
- JWOHBPPVVDQMKB-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-4-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC(C(O)=O)CC1 JWOHBPPVVDQMKB-UHFFFAOYSA-N 0.000 description 2
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- RVGLEPQPVDUSOJ-UHFFFAOYSA-N 2-Methyl-3-hydroxypropanoate Chemical compound COC(=O)CCO RVGLEPQPVDUSOJ-UHFFFAOYSA-N 0.000 description 2
- HUHGPYXAVBJSJV-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyethyl)-1,3,5-triazinan-1-yl]ethanol Chemical compound OCCN1CN(CCO)CN(CCO)C1 HUHGPYXAVBJSJV-UHFFFAOYSA-N 0.000 description 2
- UYEMGAFJOZZIFP-UHFFFAOYSA-N 3,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC(O)=C1 UYEMGAFJOZZIFP-UHFFFAOYSA-N 0.000 description 2
- UQELSASGYKYYDA-UHFFFAOYSA-N 3-amino-6-bromo-n'-(2,2-dimethylpropanoyl)pyrazine-2-carbohydrazide Chemical compound CC(C)(C)C(=O)NNC(=O)C1=NC(Br)=CN=C1N UQELSASGYKYYDA-UHFFFAOYSA-N 0.000 description 2
- QMHDHIQYBCUNPW-UHFFFAOYSA-N 3-amino-6-bromopyrazine-2-carbohydrazide Chemical compound NNC(=O)C1=NC(Br)=CN=C1N QMHDHIQYBCUNPW-UHFFFAOYSA-N 0.000 description 2
- CZGVAISJIQNQEJ-UHFFFAOYSA-N 4-bromo-2,6-difluorobenzaldehyde Chemical compound FC1=CC(Br)=CC(F)=C1C=O CZGVAISJIQNQEJ-UHFFFAOYSA-N 0.000 description 2
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 241000283707 Capra Species 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 238000000018 DNA microarray Methods 0.000 description 2
- 230000004568 DNA-binding Effects 0.000 description 2
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 2
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 238000009007 Diagnostic Kit Methods 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 239000004150 EU approved colour Substances 0.000 description 2
- 102400001368 Epidermal growth factor Human genes 0.000 description 2
- 101800003838 Epidermal growth factor Proteins 0.000 description 2
- 108010007005 Estrogen Receptor alpha Proteins 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 229940123457 Free radical scavenger Drugs 0.000 description 2
- 101001010910 Homo sapiens Estrogen receptor beta Proteins 0.000 description 2
- 206010061598 Immunodeficiency Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- 125000002842 L-seryl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])O[H] 0.000 description 2
- 102000003960 Ligases Human genes 0.000 description 2
- 108090000364 Ligases Proteins 0.000 description 2
- 108091054455 MAP kinase family Proteins 0.000 description 2
- 102000043136 MAP kinase family Human genes 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-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
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 2
- 238000012408 PCR amplification Methods 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- 108091000080 Phosphotransferase Proteins 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
- 206010036790 Productive cough Diseases 0.000 description 2
- 108091008611 Protein Kinase B Proteins 0.000 description 2
- 108020004682 Single-Stranded DNA Proteins 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 102100023132 Transcription factor Jun Human genes 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 108090000848 Ubiquitin Proteins 0.000 description 2
- 102000044159 Ubiquitin Human genes 0.000 description 2
- 229930003427 Vitamin E Natural products 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 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
- 239000013543 active substance Substances 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 230000008485 antagonism Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- 239000012911 assay medium Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000012472 biological sample Substances 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 229940098773 bovine serum albumin Drugs 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 2
- 235000011092 calcium acetate Nutrition 0.000 description 2
- 239000001639 calcium acetate Substances 0.000 description 2
- 229960005147 calcium acetate Drugs 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 125000001589 carboacyl group Chemical group 0.000 description 2
- 210000000748 cardiovascular system Anatomy 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000002050 diffraction method Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 2
- 230000002222 downregulating effect Effects 0.000 description 2
- 238000001647 drug administration Methods 0.000 description 2
- 238000009510 drug design Methods 0.000 description 2
- 229960001484 edetic acid Drugs 0.000 description 2
- 230000002357 endometrial effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940116977 epidermal growth factor Drugs 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 229940087861 faslodex Drugs 0.000 description 2
- 238000002866 fluorescence resonance energy transfer Methods 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 238000001502 gel electrophoresis Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 238000001415 gene therapy Methods 0.000 description 2
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 2
- 230000007274 generation of a signal involved in cell-cell signaling Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- 238000005342 ion exchange Methods 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 235000019136 lipoic acid Nutrition 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- PCLAJCSDDSUXMO-PKNBQFBNSA-N methyl (E)-3-[4-(3,3-dimethyl-1,2,4,9-tetrahydropyrido[3,4-b]indol-1-yl)-3-fluorophenyl]prop-2-enoate Chemical compound Fc1cc(/C=C/C(=O)OC)ccc1C1NC(C)(C)Cc2c1[nH]c1ccccc12 PCLAJCSDDSUXMO-PKNBQFBNSA-N 0.000 description 2
- NERYNBJQGGYORQ-HMICBJMASA-N methyl (E)-3-[4-[(1R,3R)-1-deuterio-2-(2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-1-yl]-3,5-difluorophenyl]prop-2-enoate Chemical compound c1([C@]2(N([C@H](C)Cc3c2[nH]c2ccccc23)CC(C)(C)F)[2H])c(F)cc(\C=C\C(=O)OC)cc1F NERYNBJQGGYORQ-HMICBJMASA-N 0.000 description 2
- OGJPPELUWHAGOO-XUDMUCCWSA-N methyl (E)-3-[4-[(1R,3R)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoate Chemical compound c1cc(/C=C/C(=O)OC)ccc1[C@H]1N[C@H](C)Cc2c1[nH]c1ccccc12 OGJPPELUWHAGOO-XUDMUCCWSA-N 0.000 description 2
- YBWXLHHUFCDASG-UHFFFAOYSA-N methyl 3-(oxan-2-yloxy)propanoate Chemical compound COC(=O)CCOC1CCCCO1 YBWXLHHUFCDASG-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 230000004899 motility Effects 0.000 description 2
- 229950004847 navitoclax Drugs 0.000 description 2
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 2
- 102000006255 nuclear receptors Human genes 0.000 description 2
- 108020004017 nuclear receptors Proteins 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000004031 partial agonist Substances 0.000 description 2
- 239000013610 patient sample Substances 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 235000011007 phosphoric acid Nutrition 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000001766 physiological effect Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000004237 preparative chromatography Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 208000037821 progressive disease Diseases 0.000 description 2
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 description 2
- 230000000069 prophylactic effect Effects 0.000 description 2
- 235000010388 propyl gallate Nutrition 0.000 description 2
- 239000000473 propyl gallate Substances 0.000 description 2
- 229940075579 propyl gallate Drugs 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000000700 radioactive tracer Substances 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 229940044551 receptor antagonist Drugs 0.000 description 2
- 239000002464 receptor antagonist Substances 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 102220197815 rs1057519714 Human genes 0.000 description 2
- 102220197818 rs1057519717 Human genes 0.000 description 2
- 102220080548 rs141368794 Human genes 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000007790 scraping Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000003802 sputum Anatomy 0.000 description 2
- 208000024794 sputum Diseases 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 229960002663 thioctic acid Drugs 0.000 description 2
- MGSRCZKZVOBKFT-UHFFFAOYSA-N thymol Chemical compound CC(C)C1=CC=C(C)C=C1O MGSRCZKZVOBKFT-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 235000019165 vitamin E Nutrition 0.000 description 2
- 229940046009 vitamin E Drugs 0.000 description 2
- 239000011709 vitamin E Substances 0.000 description 2
- 235000012431 wafers Nutrition 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 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 1
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 1
- RLJZAVNBCCJJHJ-TWURYWFSSA-N (E)-3-(4-deuteriocarbonyl-3,5-difluorophenyl)prop-2-enoic acid Chemical compound [2H]C(=O)c1c(F)cc(\C=C\C(O)=O)cc1F RLJZAVNBCCJJHJ-TWURYWFSSA-N 0.000 description 1
- AKZLESYLLLKGNZ-HBRDYDSTSA-N (E)-3-[3,5-difluoro-4-[(1R)-2-(2-fluoro-2-methylpropyl)-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound c1([C@@H]2c3[nH]c4ccccc4c3CC(N2CC(C)(F)C)(C)C)c(F)cc(\C=C\C(O)=O)cc1F AKZLESYLLLKGNZ-HBRDYDSTSA-N 0.000 description 1
- DFBDRVGWBHBJNR-UIUOXSNXSA-N (E)-3-[3,5-difluoro-4-[(1S,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound c1([C@@H]2N([C@@H](Cc3c2[nH]c2ccccc23)C)CC(C)(C)F)c(F)cc(\C=C\C(O)=O)cc1F DFBDRVGWBHBJNR-UIUOXSNXSA-N 0.000 description 1
- DFBDRVGWBHBJNR-MELHEWHKSA-N (E)-3-[3,5-difluoro-4-[(3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-1,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C([C@H](N1CC(C)(C)F)C)c(c2c(cccc2)[nH]2)c2C1c1c(F)cc(\C=C\C(O)=O)cc1F DFBDRVGWBHBJNR-MELHEWHKSA-N 0.000 description 1
- SSQFNKWKMVSXTM-CMDGGOBGSA-N (E)-3-[3,5-difluoro-4-[2-(2-fluoro-2-methylpropyl)-3-methylpyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound CC(F)(C)C[n+]1c(C)cc(c2c(cccc2)[nH]2)c2c1-c1c(F)cc(\C=C\C([O-])=O)cc1F SSQFNKWKMVSXTM-CMDGGOBGSA-N 0.000 description 1
- IOPRLAHXDGSIHG-GZFWLVPGSA-N (E)-3-[3-fluoro-4-[(1R)-2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound FC=1C=C(C=CC1[C@H]1N(C(CC2=C1NC1=CC=CC=C21)(C)C)C[C@@H](CF)C)/C=C/C(=O)O IOPRLAHXDGSIHG-GZFWLVPGSA-N 0.000 description 1
- WRHLOSDZEZAYKX-DMPFGEPASA-N (E)-3-[4-[(1R)-2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound FC[C@H](CN1[C@@H](C=2NC3=CC=CC=C3C2CC1(C)C)C1=CC=C(C=C1)/C=C/C(=O)O)C WRHLOSDZEZAYKX-DMPFGEPASA-N 0.000 description 1
- BRTCOEODQMFPJW-ICRPVFISSA-N (Z)-but-2-enedioate (E)-3-[3,5-difluoro-4-[(1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-2-ium-1-yl]phenyl]prop-2-enoic acid Chemical compound [O-]C(=O)\C=C/C([O-])=O.c1([C@H]2[NH+]([C@@H](Cc3c2[nH]c2ccccc23)C)CC(C)(C)F)c(F)cc(\C=C\C(O)=O)cc1F.c1([C@H]2[NH+]([C@@H](Cc3c2[nH]c2ccccc23)C)CC(C)(C)F)c(F)cc(\C=C\C(O)=O)cc1F BRTCOEODQMFPJW-ICRPVFISSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- GJJVAFUKOBZPCB-ZGRPYONQSA-N (r)-3,4-dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2h-1-benzopyran-6-ol Chemical class OC1=CC=C2OC(CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-ZGRPYONQSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- AKYNGEZSGVHBML-UHFFFAOYSA-N 1-[4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl-1,2,4-triazol-3-yl]piperidin-1-yl]-3-(oxan-2-yloxy)propan-1-one Chemical compound CCN1N=C(C2CCN(CC2)C(=O)CCOC2OCCCC2)N=C1C(N=1)=CN=C(N)C=1C1=NN=C(C(C)(C)C)O1 AKYNGEZSGVHBML-UHFFFAOYSA-N 0.000 description 1
- 102100038028 1-phosphatidylinositol 3-phosphate 5-kinase Human genes 0.000 description 1
- 108040005121 1-phosphatidylinositol-4-phosphate 5-kinase activity proteins Proteins 0.000 description 1
- PGZVFRAEAAXREB-UHFFFAOYSA-N 2,2-dimethylpropanoyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OC(=O)C(C)(C)C PGZVFRAEAAXREB-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- 108020005065 3' Flanking Region Proteins 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- XTDHJGCTXMSPCY-FXBVVIMESA-N 3-[3,5-difluoro-4-[2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C[C@@H](CN1C(C2=C(CC1(C)C)C3=CC=CC=C3N2)C4=C(C=C(C=C4F)C=CC(=O)O)F)CF XTDHJGCTXMSPCY-FXBVVIMESA-N 0.000 description 1
- WRHLOSDZEZAYKX-SMFUYQKNSA-N 3-[4-[2-[(2S)-3-fluoro-2-methylpropyl]-3,3-dimethyl-4,9-dihydro-1H-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid Chemical compound C[C@@H](CN1C(C2=C(CC1(C)C)C3=CC=CC=C3N2)C4=CC=C(C=C4)C=CC(=O)O)CF WRHLOSDZEZAYKX-SMFUYQKNSA-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
- UOQHWNPVNXSDDO-UHFFFAOYSA-N 3-bromoimidazo[1,2-a]pyridine-6-carbonitrile Chemical compound C1=CC(C#N)=CN2C(Br)=CN=C21 UOQHWNPVNXSDDO-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
- UPCARQPLANFGQJ-UHFFFAOYSA-N 4-bromo-2-fluorobenzaldehyde Chemical compound FC1=CC(Br)=CC=C1C=O UPCARQPLANFGQJ-UHFFFAOYSA-N 0.000 description 1
- ZRYZBQLXDKPBDU-UHFFFAOYSA-N 4-bromobenzaldehyde Chemical compound BrC1=CC=C(C=O)C=C1 ZRYZBQLXDKPBDU-UHFFFAOYSA-N 0.000 description 1
- SGOOQMRIPALTEL-UHFFFAOYSA-N 4-hydroxy-N,1-dimethyl-2-oxo-N-phenyl-3-quinolinecarboxamide Chemical compound OC=1C2=CC=CC=C2N(C)C(=O)C=1C(=O)N(C)C1=CC=CC=C1 SGOOQMRIPALTEL-UHFFFAOYSA-N 0.000 description 1
- 108020005029 5' Flanking Region Proteins 0.000 description 1
- AOFGEQOSHGYUFK-UHFFFAOYSA-N 5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carbonitrile Chemical compound O1C(C(C)(C)C)=NN=C1C1=NC(C#N)=CN=C1N AOFGEQOSHGYUFK-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000012827 ATM inhibitor Substances 0.000 description 1
- 239000012103 Alexa Fluor 488 Substances 0.000 description 1
- 239000012110 Alexa Fluor 594 Substances 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 102000012936 Angiostatins Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 101100463130 Arabidopsis thaliana PDK gene Proteins 0.000 description 1
- 101100028391 Arabidopsis thaliana PI4KB1 gene Proteins 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 241000937413 Axia Species 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 102000036365 BRCA1 Human genes 0.000 description 1
- 108700020463 BRCA1 Proteins 0.000 description 1
- 101150072950 BRCA1 gene Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- 229940124291 BTK inhibitor Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 102000008169 Co-Repressor Proteins Human genes 0.000 description 1
- 108010060434 Co-Repressor Proteins Proteins 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 102000000311 Cytosine Deaminase Human genes 0.000 description 1
- 108010080611 Cytosine Deaminase Proteins 0.000 description 1
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 1
- CIWBSHSKHKDKBQ-DUZGATOHSA-N D-araboascorbic acid Natural products OC[C@@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-DUZGATOHSA-N 0.000 description 1
- 230000005778 DNA damage Effects 0.000 description 1
- 231100000277 DNA damage Toxicity 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- RPWFJAMTCNSJKK-UHFFFAOYSA-N Dodecyl gallate Chemical compound CCCCCCCCCCCCOC(=O)C1=CC(O)=C(O)C(O)=C1 RPWFJAMTCNSJKK-UHFFFAOYSA-N 0.000 description 1
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 1
- 208000006402 Ductal Carcinoma Diseases 0.000 description 1
- 241001269524 Dura Species 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 101150064205 ESR1 gene 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
- 108010041356 Estrogen Receptor beta Proteins 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 241000400611 Eucalyptus deanei Species 0.000 description 1
- 108700024394 Exon Proteins 0.000 description 1
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 description 1
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 108091008683 G protein-coupled steroid receptors Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 102100038942 Glutamate receptor ionotropic, NMDA 3A Human genes 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 239000007821 HATU Substances 0.000 description 1
- 108010027992 HSP70 Heat-Shock Proteins Proteins 0.000 description 1
- 102000018932 HSP70 Heat-Shock Proteins Human genes 0.000 description 1
- 108010033152 HSP90 Heat-Shock Proteins Proteins 0.000 description 1
- 102000007011 HSP90 Heat-Shock Proteins Human genes 0.000 description 1
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 1
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 102100024025 Heparanase Human genes 0.000 description 1
- 108090000100 Hepatocyte Growth Factor Proteins 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 108091027305 Heteroduplex Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 1
- 101001034652 Homo sapiens Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000864800 Homo sapiens Serine/threonine-protein kinase Sgk1 Proteins 0.000 description 1
- 101000617830 Homo sapiens Sterol O-acyltransferase 1 Proteins 0.000 description 1
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 1
- 241000243251 Hydra Species 0.000 description 1
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 1
- 229940127590 IRAK4 inhibitor Drugs 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- 102000000588 Interleukin-2 Human genes 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000004388 Interleukin-4 Human genes 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108091092195 Intron Proteins 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 108091082332 JAK family Proteins 0.000 description 1
- 238000003109 Karl Fischer titration Methods 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 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
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 229910010084 LiAlH4 Inorganic materials 0.000 description 1
- 230000037364 MAPK/ERK pathway Effects 0.000 description 1
- 108700041567 MDR Genes Proteins 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 101710150918 Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- 108010006519 Molecular Chaperones Proteins 0.000 description 1
- QPCDCPDFJACHGM-UHFFFAOYSA-N N,N-bis{2-[bis(carboxymethyl)amino]ethyl}glycine Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(=O)O)CCN(CC(O)=O)CC(O)=O QPCDCPDFJACHGM-UHFFFAOYSA-N 0.000 description 1
- ZKGNPQKYVKXMGJ-UHFFFAOYSA-N N,N-dimethylacetamide Chemical compound CN(C)C(C)=O.CN(C)C(C)=O ZKGNPQKYVKXMGJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000004497 NIR spectroscopy Methods 0.000 description 1
- 102000008052 Nitric Oxide Synthase Type III Human genes 0.000 description 1
- 108010075520 Nitric Oxide Synthase Type III Proteins 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 102000004459 Nitroreductase Human genes 0.000 description 1
- 108020004485 Nonsense Codon Proteins 0.000 description 1
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 239000004677 Nylon Substances 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- BELBBZDIHDAJOR-UHFFFAOYSA-N Phenolsulfonephthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2S(=O)(=O)O1 BELBBZDIHDAJOR-UHFFFAOYSA-N 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 108010076986 Phytochelatins Proteins 0.000 description 1
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 description 1
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 1
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 1
- 108030005449 Polo kinases Proteins 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940124158 Protease/peptidase inhibitor Drugs 0.000 description 1
- 102100027584 Protein c-Fos Human genes 0.000 description 1
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 108091030071 RNAI Proteins 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 102100021993 Sterol O-acyltransferase 1 Human genes 0.000 description 1
- 101000697584 Streptomyces lavendulae Streptothricin acetyltransferase Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000017274 T cell anergy Effects 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 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
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 102000006601 Thymidine Kinase Human genes 0.000 description 1
- 108020004440 Thymidine kinase Proteins 0.000 description 1
- 239000005844 Thymol Substances 0.000 description 1
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 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 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 102000018478 Ubiquitin-Activating Enzymes Human genes 0.000 description 1
- 108010091546 Ubiquitin-Activating Enzymes Proteins 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 1
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 1
- 102000004504 Urokinase Plasminogen Activator Receptors Human genes 0.000 description 1
- 108010042352 Urokinase Plasminogen Activator Receptors Proteins 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 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
- 102000003970 Vinculin Human genes 0.000 description 1
- 108090000384 Vinculin Proteins 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229940045942 acetone sodium bisulfite Drugs 0.000 description 1
- ZIQPQYFSSSHQBP-UHFFFAOYSA-N acetyl 2,3-dihydroxypropanoate Chemical compound CC(=O)OC(=O)C(O)CO ZIQPQYFSSSHQBP-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 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
- 125000005042 acyloxymethyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 238000000246 agarose gel electrophoresis Methods 0.000 description 1
- GZCGUPFRVQAUEE-KVTDHHQDSA-N aldehydo-D-mannose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O GZCGUPFRVQAUEE-KVTDHHQDSA-N 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004849 alkoxymethyl group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 238000007844 allele-specific PCR Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 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 1
- 230000004075 alteration Effects 0.000 description 1
- 239000004411 aluminium Substances 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
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 229960002932 anastrozole Drugs 0.000 description 1
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003432 anti-folate effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 230000002137 anti-vascular effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940127074 antifolate Drugs 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 239000003080 antimitotic agent Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010385 ascorbyl palmitate Nutrition 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 239000003719 aurora kinase inhibitor Substances 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 238000000998 batch distillation Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 238000010256 biochemical assay Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- OWMVSZAMULFTJU-UHFFFAOYSA-N bis-tris Chemical compound OCCN(CCO)C(CO)(CO)CO OWMVSZAMULFTJU-UHFFFAOYSA-N 0.000 description 1
- CWBHKBKGKCDGDM-UHFFFAOYSA-N bis[(2,2,2-trifluoroacetyl)oxy]boranyl 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OB(OC(=O)C(F)(F)F)OC(=O)C(F)(F)F CWBHKBKGKCDGDM-UHFFFAOYSA-N 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 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
- 230000004097 bone metabolism Effects 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 150000001746 carotenes Chemical class 0.000 description 1
- 235000005473 carotenes Nutrition 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000000423 cell based assay Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000006721 cell death pathway Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 238000002701 cell growth assay Methods 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 210000005266 circulating tumour cell Anatomy 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229940046044 combinations of antineoplastic agent Drugs 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- PMSVVUSIPKHUMT-UHFFFAOYSA-N cyanopyrazine Chemical compound N#CC1=CN=CC=N1 PMSVVUSIPKHUMT-UHFFFAOYSA-N 0.000 description 1
- 239000002875 cyclin dependent kinase inhibitor Substances 0.000 description 1
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000640 dactinomycin Drugs 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 238000013481 data capture Methods 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
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- 210000004443 dendritic cell Anatomy 0.000 description 1
- CFCUWKMKBJTWLW-UHFFFAOYSA-N deoliosyl-3C-alpha-L-digitoxosyl-MTM Natural products CC=1C(O)=C2C(O)=C3C(=O)C(OC4OC(C)C(O)C(OC5OC(C)C(O)C(OC6OC(C)C(O)C(C)(O)C6)C5)C4)C(C(OC)C(=O)C(O)C(C)O)CC3=CC2=CC=1OC(OC(C)C1O)CC1OC1CC(O)C(O)C(C)O1 CFCUWKMKBJTWLW-UHFFFAOYSA-N 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- 229940061607 dibasic sodium phosphate Drugs 0.000 description 1
- QMSICYQQZWUMHX-UHFFFAOYSA-N diethyl 2-fluoro-2-methylpropanedioate Chemical compound CCOC(=O)C(C)(F)C(=O)OCC QMSICYQQZWUMHX-UHFFFAOYSA-N 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- LVXHNCUCBXIIPE-UHFFFAOYSA-L disodium;hydrogen phosphate;hydrate Chemical compound O.[Na+].[Na+].OP([O-])([O-])=O LVXHNCUCBXIIPE-UHFFFAOYSA-L 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 235000010386 dodecyl gallate Nutrition 0.000 description 1
- 239000000555 dodecyl gallate Substances 0.000 description 1
- 229940080643 dodecyl gallate Drugs 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 229960004679 doxorubicin Drugs 0.000 description 1
- 229950004203 droloxifene Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000464 effect on transcription Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- 229940034984 endocrine therapy antineoplastic and immunomodulating agent Drugs 0.000 description 1
- 239000006274 endogenous ligand Substances 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 230000004076 epigenetic alteration Effects 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- XBRDBODLCHKXHI-UHFFFAOYSA-N epolamine Chemical compound OCCN1CCCC1 XBRDBODLCHKXHI-UHFFFAOYSA-N 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 235000010350 erythorbic acid Nutrition 0.000 description 1
- 239000004318 erythorbic acid Substances 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229940125641 estrogen receptor degrader Drugs 0.000 description 1
- 102000015694 estrogen receptors Human genes 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- OCLXJTCGWSSVOE-UHFFFAOYSA-N ethanol etoh Chemical compound CCO.CCO OCLXJTCGWSSVOE-UHFFFAOYSA-N 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- CJRQQJKWNULSFQ-UHFFFAOYSA-N ethyl 2-fluoro-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)F CJRQQJKWNULSFQ-UHFFFAOYSA-N 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 239000011536 extraction buffer Substances 0.000 description 1
- 210000005002 female reproductive tract Anatomy 0.000 description 1
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 150000005699 fluoropyrimidines Chemical class 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000004052 folic acid antagonist Substances 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 229950005309 fostamatinib Drugs 0.000 description 1
- GKDRMWXFWHEQQT-UHFFFAOYSA-N fostamatinib Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3N=C4N(COP(O)(O)=O)C(=O)C(C)(C)OC4=CC=3)C(F)=CN=2)=C1 GKDRMWXFWHEQQT-UHFFFAOYSA-N 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 238000003205 genotyping method Methods 0.000 description 1
- 210000004602 germ cell Anatomy 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000003505 heat denaturation Methods 0.000 description 1
- 108010037536 heparanase Proteins 0.000 description 1
- VNDHXHMRJVTMTK-WZVRVNPQSA-H hexasodium 4-[[(1S,3R,5R,6S,8R,10R,11S,13R,15R,16S,18R,20R,21S,23R,25R,26S,28R,30R,31S,33R,35R,36R,37R,38R,39R,40R,41R,42R,43R,44R,45R,46R,47R,48R,49R)-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecahydroxy-10-(hydroxymethyl)-15,20,25,30,35-pentakis(4-sulfonatobutoxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-5-yl]methoxy]butane-1-sulfonate Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3COCCCCS([O-])(=O)=O)O[C@H]1[C@H](O)[C@H]2O VNDHXHMRJVTMTK-WZVRVNPQSA-H 0.000 description 1
- 229920001903 high density polyethylene Polymers 0.000 description 1
- 239000004700 high-density polyethylene Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 102000011941 human estrogen receptor alpha Human genes 0.000 description 1
- 229960001330 hydroxycarbamide Drugs 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 208000026278 immune system disease Diseases 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010949 in-process test method Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 229940028885 interleukin-4 Drugs 0.000 description 1
- 230000037041 intracellular level Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N ipa isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229940026239 isoascorbic acid Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 238000011005 laboratory method Methods 0.000 description 1
- 229940099563 lactobionic acid Drugs 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- 229960003881 letrozole Drugs 0.000 description 1
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 238000007834 ligase chain reaction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 108010026228 mRNA guanylyltransferase Proteins 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- 230000008774 maternal effect Effects 0.000 description 1
- 229960004961 mechlorethamine Drugs 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- BCVXHSPFUWZLGQ-UHFFFAOYSA-N mecn acetonitrile Chemical compound CC#N.CC#N BCVXHSPFUWZLGQ-UHFFFAOYSA-N 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960004296 megestrol acetate Drugs 0.000 description 1
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 1
- 229960003194 meglumine Drugs 0.000 description 1
- 229960003987 melatonin Drugs 0.000 description 1
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- GDGULTXZDPTNNZ-QZZYGYPJSA-N methyl (E)-3-(4-deuteriocarbonyl-3,5-difluorophenyl)prop-2-enoate Chemical compound [2H]C(=O)c1c(F)cc(\C=C\C(=O)OC)cc1F GDGULTXZDPTNNZ-QZZYGYPJSA-N 0.000 description 1
- CNXSIRHOIFRMOB-UHFFFAOYSA-N methyl 3-amino-6-bromopyrazine-2-carboxylate Chemical compound COC(=O)C1=NC(Br)=CN=C1N CNXSIRHOIFRMOB-UHFFFAOYSA-N 0.000 description 1
- JBXJLZRTTCGLNR-UHFFFAOYSA-N methyl 4-bromo-2,6-difluorobenzoate Chemical compound COC(=O)C1=C(F)C=C(Br)C=C1F JBXJLZRTTCGLNR-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical compound COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940064639 minipress Drugs 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- FPMHLFVZAFVGAF-UHFFFAOYSA-N n',5-diamino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazine-2-carboximidamide Chemical compound O1C(C(C)(C)C)=NN=C1C1=NC(C(\N)=N\N)=CN=C1N FPMHLFVZAFVGAF-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- XTEGVFVZDVNBPF-UHFFFAOYSA-N naphthalene-1,5-disulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1S(O)(=O)=O XTEGVFVZDVNBPF-UHFFFAOYSA-N 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 108020001162 nitroreductase Proteins 0.000 description 1
- 229960003301 nivolumab Drugs 0.000 description 1
- 230000008298 non-genomic mechanism Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 108091008589 nuclear estrogen receptors Proteins 0.000 description 1
- 239000002853 nucleic acid probe Substances 0.000 description 1
- 229920001778 nylon Polymers 0.000 description 1
- 235000010387 octyl gallate Nutrition 0.000 description 1
- 239000000574 octyl gallate Substances 0.000 description 1
- NRPKURNSADTHLJ-UHFFFAOYSA-N octyl gallate Chemical compound CCCCCCCCOC(=O)C1=CC(O)=C(O)C(O)=C1 NRPKURNSADTHLJ-UHFFFAOYSA-N 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 229960001972 panitumumab Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000008775 paternal effect Effects 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229960000639 pazopanib Drugs 0.000 description 1
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229960003330 pentetic acid Drugs 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 229960003531 phenolsulfonphthalein Drugs 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 230000029279 positive regulation of transcription, DNA-dependent Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229960003975 potassium Drugs 0.000 description 1
- 239000001508 potassium citrate Substances 0.000 description 1
- 229960002635 potassium citrate Drugs 0.000 description 1
- QEEAPRPFLLJWCF-UHFFFAOYSA-K potassium citrate (anhydrous) Chemical compound [K+].[K+].[K+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O QEEAPRPFLLJWCF-UHFFFAOYSA-K 0.000 description 1
- 235000011082 potassium citrates Nutrition 0.000 description 1
- 229940093932 potassium hydroxide Drugs 0.000 description 1
- RWPGFSMJFRPDDP-UHFFFAOYSA-L potassium metabisulfite Chemical compound [K+].[K+].[O-]S(=O)S([O-])(=O)=O RWPGFSMJFRPDDP-UHFFFAOYSA-L 0.000 description 1
- 229940043349 potassium metabisulfite Drugs 0.000 description 1
- 235000010263 potassium metabisulphite Nutrition 0.000 description 1
- 101150063097 ppdK gene Proteins 0.000 description 1
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 102000003998 progesterone receptors Human genes 0.000 description 1
- 108090000468 progesterone receptors Proteins 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 229960000380 propiolactone Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 230000004063 proteosomal degradation Effects 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- NPCOQXAVBJJZBQ-UHFFFAOYSA-N reduced coenzyme Q9 Natural products COC1=C(O)C(C)=C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)C(O)=C1OC NPCOQXAVBJJZBQ-UHFFFAOYSA-N 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- QBERHIJABFXGRZ-UHFFFAOYSA-M rhodium;triphenylphosphane;chloride Chemical compound [Cl-].[Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 QBERHIJABFXGRZ-UHFFFAOYSA-M 0.000 description 1
- ATCCIZURPPEVIZ-SCSAIBSYSA-N roche ester Chemical compound COC(=O)[C@H](C)CO ATCCIZURPPEVIZ-SCSAIBSYSA-N 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 229960003522 roquinimex Drugs 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229940095743 selective estrogen receptor modulator Drugs 0.000 description 1
- 239000000333 selective estrogen receptor modulator Substances 0.000 description 1
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940083608 sodium hydroxide Drugs 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
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- YNJORDSKPXMABC-UHFFFAOYSA-N sodium;2-hydroxypropane-2-sulfonic acid Chemical compound [Na+].CC(C)(O)S(O)(=O)=O YNJORDSKPXMABC-UHFFFAOYSA-N 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 230000003019 stabilising effect Effects 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000001119 stannous chloride Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 102000005969 steroid hormone receptors Human genes 0.000 description 1
- 108020003113 steroid hormone receptors Proteins 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000009044 synergistic interaction Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 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
- CEVFURZBPWQHGC-UHFFFAOYSA-N tert-butyl 4-[5-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-1-ethyl-1,2,4-triazol-3-yl]piperidine-1-carboxylate Chemical compound CCN1N=C(C2CCN(CC2)C(=O)OC(C)(C)C)N=C1C(N=1)=CN=C(N)C=1C1=NN=C(C(C)(C)C)O1 CEVFURZBPWQHGC-UHFFFAOYSA-N 0.000 description 1
- ZWGAMKKFKDCCIF-UHFFFAOYSA-N tert-butyl 4-[[(e)-[amino-[5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]methylidene]amino]carbamoyl]piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)N\N=C(/N)C1=CN=C(N)C(C=2OC(=NN=2)C(C)(C)C)=N1 ZWGAMKKFKDCCIF-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960000790 thymol Drugs 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 235000010384 tocopherol Nutrition 0.000 description 1
- 229930003799 tocopherol Natural products 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 229960001295 tocopherol Drugs 0.000 description 1
- 229930003802 tocotrienol Natural products 0.000 description 1
- 239000011731 tocotrienol Substances 0.000 description 1
- 229940068778 tocotrienols Drugs 0.000 description 1
- 235000019148 tocotrienols Nutrition 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229940038773 trisodium citrate Drugs 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
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 229940040064 ubiquinol Drugs 0.000 description 1
- QNTNKSLOFHEFPK-UPTCCGCDSA-N ubiquinol-10 Chemical compound COC1=C(O)C(C)=C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)C(O)=C1OC QNTNKSLOFHEFPK-UPTCCGCDSA-N 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- 241001515965 unidentified phage Species 0.000 description 1
- 238000011870 unpaired t-test Methods 0.000 description 1
- 229940116269 uric acid Drugs 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000010200 validation analysis Methods 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
- 229960001183 venetoclax Drugs 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000011995 wilkinson's catalyst Substances 0.000 description 1
- UTODFRQBVUVYOB-UHFFFAOYSA-P wilkinson's catalyst Chemical compound [Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)(C=1C=CC=CC=1)[Rh+](P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 UTODFRQBVUVYOB-UHFFFAOYSA-P 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 150000003739 xylenols Chemical class 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
Classifications
-
- 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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/13—Dicarboxylic acids
- C07C57/145—Maleic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the invention concerns certain novel indole derivatives, or
- the invention also concerns processes for the manufacture of said indole derivatives, pharmaceutical compositions containing them and their use in therapeutic methods, for example in the manufacture of medicaments for use in the prevention or treatment of cancers in a warm-blooded animal such as man, including use in the prevention or treatment of cancer.
- the present invention also relates to indole derivatives that are selective down- regulators of the estrogen receptor.
- Estrogen receptor alpha (ERa, ESR1, NR3A) and estrogen receptor beta (ER , ESR2, NR3b) are steroid hormone receptors which are members of large nuclear receptor family. Structured similarly to all nuclear receptors, ERa is composed of six functional domains (named A-F) (Dahlman-Wright, et al., Pharmacol. Rev., 2006, 58:773-781) and is classified as a ligand-dependent transcription factor because after its association with the specific ligand, the female sex steroid hormone 17b estradiol (E2), the complex binds to genomic sequences, named Estrogen Receptor Elements (ERE) and interacts with co- regulators to modulate the transcription of target genes.
- A-F six functional domains
- E2 the female sex steroid hormone 17b estradiol
- E2 the complex binds to genomic sequences, named Estrogen Receptor Elements (ERE) and interacts with co- regulators
- the ERa gene is located on 6q25.1 and encodes a 595AA protein and multiple isoforms can be produced due to alternative splicing and translational start sites.
- the receptor contains an N-terminal (A/B) domain, a hinge (D) domain that links the C and E domains and a C-terminal extension (F domain). While the C and E domains of ERa and ERb are quite conserved (96% and 55% amino acid identity respectively) conservation of the A/B, D and F domains is poor (below 30% amino acid identity).
- ERs Both receptors are involved in the regulation and development of the female reproductive tract and in addition play roles in the central nervous system, cardiovascular system and in bone metabolism.
- the genomic action of ERs occurs in the nucleus of the cell when the receptor binds EREs directly (direct activation or classical pathway) or indirectly (indirect activation or non-classical pathway).
- ERs are associated with heat shock proteins, Hsp90 and Hsp70, and the associated chaperone machinery stabilizes the ligand binding domain (LBD) making it accessible to ligand.
- LBD ligand binding domain
- Liganded ER dissociates from the heat shock proteins leading to a conformational change in the receptor that allows dimerisation, DNA binding, interaction with co- activators or co-repressors and modulation of target gene expression.
- AP-1 and Sp-1 are alternative regulatory DNA sequences used by both isoforms of the receptor to modulate gene expression.
- ER does not interact directly with DNA but through associations with other DNA bound transcription factors e.g. c-Jun or c-Fos (Kushner et al., Pure Applied Chemistry 2003, 75: 1757-1769).
- c-Jun or c-Fos DNA bound transcription factors
- the precise mechanism whereby ER affects gene transcription is poorly understood but appears to be mediated by numerous nuclear factors that are recruited by the DNA bound receptor.
- the recruitment of co-regulators is primarily mediated by two protein surfaces, AF2 and AF1 which are located in E-domain and the A/B domain respectively.
- AF1 is regulated by growth factors and its activity depends on the cellular and promoter environment whereas AF2 is entirely dependent on ligand binding for activity.
- the two domains can act independently, maximal ER transcriptional activity is achieved through synergistic interactions via the two domains (Tzukerman, et al., Mol. Endocrinology, 1994, 8:21-30).
- ERs are considered transcription factors they can also act through non-genomic mechanisms as evidenced by rapid ER effects in tissues following E2 administration in a timescale that is considered too fast for a genomic action.
- ERa has been shown to have ligand independent activity through AF-1 which has been associated with stimulation of MAPK through growth factor signalling e.g. insulin like growth factor 1 (IGF-1) and epidermal growth factor (EGF).
- IGF-1 insulin like growth factor 1
- EGF epidermal growth factor
- Activity of AF-1 is dependent on phosphorylation of Serl 18 and an example of cross-talk between ER and growth factor signalling is the phosphorylation of Ser 118 by MAPK in response to growth factors such as IGF-1 and EGF (Kato, et al., Science, 1995, 270: 1491- 1494).
- SERMs selective estrogens receptor modulators
- tamoxifen have the ability to act as both receptor agonists and antagonists depending on the cellular and promoter context as well as the ER isoform targeted.
- tamoxifen acts as an antagonist in breast but acts as a partial agonist in bone, the cardiovascular system and uterus. All SERMs appear to act as AF2 antagonists and derive their partial agonist characteristics through AFl.
- a second group fulvestrant being an example, are classified as full antagonists and are capable of blocking estrogen activity via the complete inhibition of AFl and AF2 domains through induction of a unique conformation change in the ligand binding domain (LBD) on compound binding which results in complete abrogation of the interaction between helix 12 and the remainder of the LBD, blocking co-factor recruitment (Wakeling, et al., Cancer Res., 1991, 51:3867-3873; Pike, et al., Structure, 2001, 9: 145-153).
- LBD ligand binding domain
- Intracellular levels of ERa are down-regulated in the presence of E2 through the ubiquitin/proteosome (Ub/26S) pathway.
- Polyubiquitinylation of liganded ERa is catalysed by at least three enzymes; the ubiquitin-activating enzyme El activated ubiquitin is conjugated by E2 with lysine residues through an isopeptide bond by E3 ubiquitin ligase and polyubiquitinated ERa is then directed to the proteosome for degradation.
- ER-dependent transcription regulation and proteosome-mediated degradation of ER are linked (Lonard, et al., Mol.
- ER and/or progesterone receptors implying the hormone dependence of these tumour cells for growth.
- Other cancers such as ovarian and endometrial are also thought to be dependent on ERa signalling for growth.
- Therapies for such patients can inhibit ER signalling either by antagonising ligand binding to ER e.g. tamoxifen which is used to treat early and advanced ER positive breast cancer in both pre and post menopausal setting; antagonising and down-regulating ERa e.g.
- fulvestrant which is used to treat breast cancer in women which have progressed despite therapy with tamoxifen or aromatase inhibitors; or blocking estrogen synthesis e.g.
- aromatase inhibitors which are used to treat early and advanced ER positive breast cancer. Although these therapies have had an enormously positive impact on breast cancer treatment, a considerable number of patients whose tumours express ER display de novo resistance to existing ER therapies or develop resistance to these therapies over time.
- Several distinct mechanism have been described to explain resistance to first-time tamoxifen therapy which mainly involve the switch from tamoxifen acting as an antagonist to an agonist, either through the lower affinity of certain co-factors binding to the tamoxifen- ERa complex being off-set by over-expression of these co-factors, or through the formation of secondary sites that facilitate the interaction of the tamoxifen- ERa complex with co-factors that normally do not bind to the complex.
- Resistance could therefore arise as a result of the outgrowth of cells expressing specific co-factors that drive the tamoxifen- ERa activity.
- growth factor signalling pathways directly activate the ER receptor or co-activators to drive cell proliferation independently of ligand signalling.
- ESR1 mutations in ESR1 have been identified as a possible resistance mechanism in metastatic ER-positive patient derived tumour samples and patient-derived xenograft models (PDX) at frequencies varying from 17-25%. These mutations are predominantly, but not exclusively, in the ligand-binding domain leading to mutated functional proteins; examples of the amino acid changes include Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn and Asp538Gly, with changes at amino acid 537 and 538 constituting the majority of the changes currently described. These mutations have been undetected previously in the genomes from primary breast samples characterised in the Cancer Genome Atlas database.
- the compounds of the invention have been found to possess potent anti-tumour activity, being useful in inhibiting the uncontrolled cellular proliferation which arises from malignant disease.
- the compounds of the invention provide an anti-tumour effect by, as a minimum, acting as SERDs.
- R 1 and FT 2 are each independently H or F;
- R is H or methyl
- R 4 is H and R 5 is F;
- R 4 is F and R 5 is H.
- the compounds of formula (I) have one, two or three chiral centres and the invention encompasses pure chiral forms or mixtures thereof in any proportion.
- the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques.
- a particular enantiomer or diasteroeisomer of a compound described herein may be more active than other enantiomers or diastereoisomers of the same compound.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof which is a single enantiomer being in an enantiomeric excess (%ee) of > 95, > 98% or > 99%.
- the single enantiomer is present in an enantiomeric excess (%ee) of > 99%.
- a pharmaceutical composition which comprises a compound of the Formula (I), which is a single enantiomer being in an enantiomeric excess (%ee) of > 95, > 98% or > 99% or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
- the single enantiomer is present in an enantiomeric excess (%ee) of > 99%.
- diastereoisomer being in an diastereomeric excess (%de) of > 95, > 98% or > 99%.
- the single diastereoisomer is present in an diastereomeric excess (%de) of > 99%.
- a pharmaceutical composition which comprises a compound of the Formula (I), which is a single diastereoisomer being in an diastereomeric excess (%de) of > 95, > 98% or > 99% or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
- the single diastereoisomer is present in an diastereomeric excess (%de) of > 99%.
- the compound of Formula (I) is a compound of Formula
- the compound of Formula (I) is a compound of Formula (IB):
- Example 2 the compound of Example 1, (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l- yl)phenyl)acrylic acid, is an example of a compound of Formula (IA).
- Some compounds of Formula (I) may be crystalline and may have more than one crystalline form. It is to be understood that the present invention encompasses any crystalline or amorphous form, or mixtures thereof, which form possesses properties useful in SERD activity, it being well known in the art how to determine efficacy of a crystalline or amorphous form for the SERD activity by the standard tests described hereinafter.
- crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction (hereinafter XRPD) analysis, Differential Scanning Calorimetry (hereinafter DSC), Thermal Gravimetric Analysis (hereinafter TGA), Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy.
- XRPD X-Ray Powder Diffraction
- DSC Differential Scanning Calorimetry
- TGA Thermal Gravimetric Analysis
- DRIFT Diffuse Reflectance Infrared Fourier Transform
- NIR Near Infrared
- solution and/or solid state nuclear magnetic resonance spectroscopy solution and/or solid state nuclear magnetic resonance spectroscopy.
- Karl Fischer analysis Karl Fischer analysis.
- Example 7 exhibits crystallinity and one crystalline form has been identified.
- a further aspect of the invention is Form A of (E)-3-(4-(2-((S)-3- fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l- yl)phenyl) acrylic acid (Example 7).
- crystalline form, Form A of Example 7 which has an X-ray powder diffraction pattern substantially the same as the X- ray powder diffraction pattern shown in Figure 1.
- Example 1 also shows crystallinity.
- Form B of (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro- lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid which has an X-ray powder diffraction pattern substantially the same as the X-ray powder diffraction pattern shown in Figure 2.
- the degree of crystallinity is conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90% and more preferably greater than about 95%. Most preferably the degree of crystallinity is greater than about 98%.
- the present invention relates to a crystalline form of Example 1 Form B
- the material is preferably substantially free of other crystalline forms or amorphous material.
- substantially free we mean conveniently greater than about 60%, more conveniently greater than about 80%, preferably greater than about 90%, more preferably greater than about 95% and most preferably greater than about 98% of single polymorph.
- 2-theta values of the X-ray powder diffraction patterns may vary slightly from one machine to another or from one sample to another, and so the values quoted are not to be construed as absolute.
- an X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment or machine used).
- intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions. Therefore it should be understood that the crystalline Forms of the present invention described above, unless otherwise stated, are not limited to the crystals that provide X-ray powder diffraction patterns identical to the X-ray powder diffraction pattern shown in the relevant Figures, and any crystals providing X-ray powder diffraction patterns substantially the same as those shown in these Figures fall within the scope of the present invention.
- a person skilled in the art of X-ray powder diffraction is able to judge the substantial identity of X-ray powder diffraction patterns.
- a measurement error of a diffraction angle in an X-ray powder diffractogram is approximately plus or minus 0.2° 2-theta, and such degree of a
- Particular compounds of the invention are each of the Examples, each of which provides a further independent aspect of the invention.
- Further particular compounds of the invention are pharmaceutically-acceptable salt(s) of each of the Examples, each of which provides a further independent aspect of the invention.
- a further feature is any of the scopes defined herein with the proviso that specific Examples, such as Example 1, 2, 3 etc. are individually disclaimed.
- the present invention encompasses any racemic, optically-active, polymorphic or stereoisomeric form, or mixtures thereof, which form possesses properties useful as SERDs, it being well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, by enzymatic resolution, by biotransformation, or by chromatographic separation using a chiral stationary phase) and how to determine efficacy as SERDs by the standard tests described hereinafter.
- the present invention is intended to include all isotopes of atoms occurring in the present compounds.
- Isotopes will be understood to include those atoms having the same atomic number but different mass numbers.
- isotopes of hydrogen include tritium and deuterium.
- isotopes of carbon include 13 C and 14 C.
- a deuterated version of Example 1 is described in Example 10.
- a suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, an alkali or alkaline earth metal salt such as a sodium, calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine,
- a pharmaceutically-acceptable salt of a compound of Formula (I) is a salt with a metal cation, an ammonium salt or a salt with an organic base.
- a further suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I).
- a suitable pharmaceutically-acceptable salt of a compound of the Formula (I) may also be, for example, an acid-addition salt of a compound of the Formula (I), for example an acid-addition salt with a strong inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric or trifluoroacetic acid.
- Other potential suitable pharmaceutically- acceptable salt of a compound of the Formula (I) may also be as described below for Example 1.
- a pharmaceutically-acceptable salt of a compound of Formula (I) is an acid-addition salt.
- Example 1 ((E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid) to form crystalline salts.
- the following acids and bases were tried:
- hydroxyethylpyrrolidine magnesium acetate, meglumine, piperazine, potassium hydroxide, sodium hydroxide, t-butylamine, triethanolamine,
- Tris(hydroxymethyl)aminomethane Tris
- N,N-diethylethanolamine Tris(hydroxymethyl)aminomethane
- isolatable solid salts were not always obtainable, or not obtainable in crystalline form in the experimental conditions employed.
- Preferred salts of Example 1 include those which may be isolated in crystalline form, for example, benzene sulfonic acid salt (besylate salt), succinic acid salt (succinate salt) and maleic acid salt (maleate salt).
- suitable salts of Example 1 may include besylate, succinate and maleate.
- a suitable salt of Example 1 may be the maleate salt, which is described in Example 11.
- co-crystal refers to a multicomponent system in which there exists a host API (active pharmaceutical ingredient) molecule or molecules and a guest (or co-former) molecule or molecules.
- a host API active pharmaceutical ingredient
- a guest or co-former
- both the API molecule and the guest (or co-former) molecule exist as a solid at room temperature when alone in their pure form (in order to distinguish the co-crystal from solvates or hydrates). Salts, in which significant or complete proton exchange occurs between the API molecule and the guest molecule, are excluded from this particular definition.
- co-crystal the API and co-former molecules interact by hydrogen bonding and possibly other non-covalent interactions.
- Pharmaceutically acceptable co-formers include neutral molecules such as nicotinamide, resorcinol and xylenols, as well as ionisable molecules such as oxalic acid, 3,5-dihydroxybenzoic acid and isoquinoline (the extent of proton exchange determining whether a salt or co-crystal is formed). It may be noted that a co-crystal may itself form solvates, including hydrates.
- a suitable pharmaceutically-acceptable solvate of a compound of the Formula (I) also forms an aspect of the present invention.
- a suitable pharmaceutically-acceptable solvate is, for example, a hydrate such as a hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate or an alternative quantity thereof.
- a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) also forms an aspect of the present invention.
- the compounds of the invention may be administered in the form of a prodrug, which is a compound that is broken down in the human or animal body to release a compound of the invention.
- a pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention.
- a pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in-vivo cleavable ester derivatives that may be formed at a carboxy group in a compound of the Formula (I).
- the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound.
- a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.
- pro-drug Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.
- a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I that possesses a carboxy group is, for example, an in vivo cleavable ester thereof.
- An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid.
- Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-buty ⁇ , (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters,
- 2-oxo-l,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (l-6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.
- a suitable pharmaceutically-acceptable pro-drug of a compound of the Formula I which have a carboxy group is for example an in vivo cleavable amide such as a
- N-Ci_ 6 alkyl and N,N-di-(Ci_ 6 alkyl)amide such as N-methyl, N-ethyl, N-propyl, N,N- dimethyl, N-ethyl-N-methyl or N,N-diethylamide.
- the in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).
- Example 14A and B Two isomeric active metabolites of Example 1 have been identified from in- vitro human systems as shown below (where the isomers are diastereomeric as a result of both configurations existing at the carbon marked with a *), and synthesis of both isomers is set out in Examples 14A and B herein:
- novel compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of R 1 and R 2 , has any of the meanings defined hereinbefore or in the following statements:
- R 1 is hydrogen. In another aspect R 1 is fluoro.
- R 2 is hydrogen. In another aspect R 2 is fluoro.
- both R 1 and R2 are hydrogen. In another aspect both R 1 and R2 are fluoro. In another aspect R 1 is hydrogen and R 2 is fluoro.
- R 3 is hydrogen. In another aspect R 3 is methyl.
- R 4 is hydrogen and R 5 is fluoro. In another aspect R 5 is hydrogen and R 4 is fluoro.
- Particular compounds of the invention are, for example, the compounds of the Formula (I) that are disclosed within the Examples that are set out hereinafter.
- a particular compound of the invention is a compound of the Formula (I) selected from any one of the following :-
- a further particular compound of the invention is a compound of the Formula (I) selected from any one of the following :-
- a particular pharmaceutically-acceptable salt of the invention is (lR,3R)-l- ⁇ 4-[(E) 2-carboxyethenyl]-2,6-difluorophenyl ⁇ -2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro- lH-beta-carbolin-2-ium maleate.
- Another aspect of the present invention provides a process for preparing a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof.
- a suitable process is illustrated by the following representative process variants in which, unless otherwise stated, R 1 to R 5 have any of the meanings defined hereinbefore.
- Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
- Compounds of formula (I) are conveniently made by hydrolysis of an ester derivative of formula (II), wherein R 6 is (1-6C) alkyl, such as methyl. Hydrolysis is conveniently carried out in the presence of base such as using sodium hydroxide in a suitable solvent (such as aqueous THF and MeOH (or another similar alcohol), or such as an aqueous alcohol for example aqueous isopropanol) and a suitable temperature, conveniently room temperature.
- a suitable solvent such as aqueous THF and MeOH (or another similar alcohol), or such as an aqueous alcohol for example aqueous isopropanol
- Compounds of formula (IV) may be prepared by reaction of a compound of formula (VIII) with an alkyl acrylate ester (such as methyl acrylate when R 6 is methyl) under conditions known in the art for a Heck reaction; that is in the presence of an aryl phosphine (eg tri-o-tolylphosphine), a palladium catalyst (such as palladium (II) acetate and base (such as triethylamine) in a suitable solvent (such as DMA) and at a suitable temperature (eg 80 °C).
- an alkyl acrylate ester such as methyl acrylate when R 6 is methyl
- an alkyl acrylate ester such as methyl acrylate when R 6 is methyl
- a Heck reaction that is in the presence of an aryl phosphine (eg tri-o-tolylphosphine), a palladium catalyst (such as palladium (II) acetate and base (such as
- Compounds of formula (V) may be prepared by reaction of a compound of formula (VII) with a compound of formula (IV) using conditions similar to those described for the reaction of compounds of formulae (III) and (IV) above.
- Compounds of formula (VI) where LG is triflate may be prepared as shown below in Schemes 1 and 2.
- Other compound of formula (VI) where LG is other than triflate may be prepared by similar methods known in the art.
- Step 1 Fluorinating agent, e.g. N,N-diethyl-l, 1,2,3,3, 3-hexafluoropropan-l- amine/DCM/RT, then reducing agent, e.g. lithium aluminium hydride/THF/RT
- Step 2 Trifluoromethane sulfonic anhydride/base, e.g. 2,6-lutidine/DCM/0°C
- Step 1 Reducing agent, e.g. lithium aluminium hydride/ether/0°C
- Step 2 Trifluoromethane sulfonic anhydride/base, e.g. 2,6-lutidine/DCM/-10°C
- stereoselective reactions may be used to obtain the desired isomers.
- stereochemistry may be adjusted by suitable means, such as by epimerisation from cis to trans isomers via acidification of an intermediate with protected amine group as illustrated in Example 4 herein (and described for example in J. Org. Chem. 2009, 74, 2771-2779).
- a pharmaceutically-acceptable salt of a compound of the Formula (I) When a pharmaceutically-acceptable salt of a compound of the Formula (I) is required it may be obtained by, for example, reaction of said compound with a suitable base.
- a pharmaceutically-acceptable pro-drug of a compound of the Formula (I) When a pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is required, it may be obtained using a conventional procedure.
- an in vivo cleavable ester of compound of the Formula (I) may be obtained by, for example, reaction of a compound of the Formula (I) containing a carboxy group with a pharmaceutically- acceptable alcohol. Further information on pro-drugs has been provided hereinbefore.
- a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group, an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or i-butoxycarbonyl group
- arylmethoxycarbonyl group for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
- the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
- an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
- an acyl group such as a i-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
- a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
- a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
- the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
- an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
- a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
- an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as
- a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a i-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
- a base such as sodium hydroxide
- a i-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
- the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
- Estrogen Receptor Alpha Ligand binding domain ER alpha - LBD (GST)
- GST Estrogen Receptor Alpha Ligand binding domain
- TR-FRET Time-Resolved Fluorescence Resonance Energy Transfer
- a suitable fluorophore Fluormone ES2, Product code P2645
- recombinant human Estrogen Receptor alpha ligand binding domain Product code PV4543
- the assay principle is that ER alpha -LBD (GST) is added to a fluorescent ligand to form a receptor/fluorophore complex.
- a terbium-labelled anti- GST antibody (Product code PV3551) is used to indirectly label the receptor by binding to its GST tag, and competitive binding is detected by a test compounds' ability to displace the fluorescent ligand resulting in a loss of TR-FRET signal between the Tb-anti-GST antibody and the tracer.
- the assay was performed as follows with all reagent additions carried out using the Beckman Coulter BioRAPTR FRD microfluidic workstation:-
- the Echo 550 is a liquid handler that uses acoustic technology to perform direct microplate-to-microplate transfers of DMSO compound solutions and the system can be programmed to transfer multiple small nL volumes of compound from the different source plate wells to give the desired serial dilution of compound in the assay which is then back-filled to normalise the DMSO concentration across the dilution range.
- TR-FRET dose response data obtained with each compound was exported into a suitable software package (such as Origin or Genedata) to perform curve fitting analysis.
- Competitive ER alpha binding was expressed as an IC 5 0 value. This was determined by calculation of the concentration of compound that was required to give a 50% reduction in tracer compound binding to ER alpha-LBD.
- Estrogen Receptor (ER) numbers was assessed in a cell based immuno-fluorescence assay using the MCF-7 human ductal carcinoma breast cell line.
- MCF-7 cells were revived directly from a cryovial (approx 5 x 10 6 cells) in Assay Medium (phenol red free Dulbecco's Modified Eagle's medium
- DMEM fetal calf serum
- Assay Medium a density of 3.75xl0 4 cells per ml and 40 ⁇ 1 per well added to transparent bottomed, black, tissue culture treated 384 well plates (Costar, No. 3712) using a Thermo Scientific Matrix WellMate or Thermo
- Multidrop Following cell seeding, plates were incubated overnight at 37 C, 5% C0 2 (Liconic carousel incubator). Test data was generated using the LabCyte Echo® model 555 compound reformatter which is part of an automated workcell (Integrated Echo 2 workcell). lOmM compound stock solutions of the test compounds were used to generate a 384 well compound dosing plate (Labcyte P-05525-CV1). 40 ⁇ 1 of each of the lOmM compound stock solutions was dispensed into the first quadrant well and then 1: 100 stepwise serial dilutions in DMSO were performed using a Hydra II (MATRIX UK) liquid handling unit to give 40ul of diluted compound into quadrant wells 2 (O.
- the system can be programmed to transfer volumes as low as 2.5 nL in multiple increments between microplates and in so doing generates a serial dilution of compound in the assay plate which is then back-filled to normalise the DMSO concentration across the dilution range.
- Compounds were dispensed onto the cell plates with a compound source plate prepared as above producing a 12pt duplicate 3 ⁇ to 3pM dose range with 3 fold dilutions and one final 10 fold dilution using the Integrated Echo 2 workcell.
- the maximum signal control wells were dosed with DMSO to give a final concentration of 0.3% and the minimum signal control wells were dosed with Faslodex® to give a final concentration of
- PBS/Proclin PBS with a Biocide preservative
- BioTek platewasher 40 ⁇ 1 of PBS/Proclin was then added to all wells and the plates stored at 4°C.
- the fixing method described above was carried out on the Integrated Echo 2 workcell. Immuno staining was performed using an automated AutoElisa workcell.
- the PBS/Proclin was aspirated from all wells and the cells permeabilised with 40 ⁇ 1 PBS containing 0.5% TweenTM 20 (v/v) for 1 hour at room temperature.
- the plates were washed three times in 250 ⁇ 1 of PBS/0.05% (v/v) Tween 20 with Proclin (PBST with a Biocide preservative) and then 20 ⁇ 1 of ERa (SP1) Rabbit monoclonal antibody (Thermofisher) 1: 1000 in PBS/TweenTM/3% (w/v) Bovine Serum Albumin was added.
- the plates were incubated overnight at 4°C (Liconic carousel incubator) and then washed three times in 250 ⁇ 1 of PBS/0.05%) (v/v) TweenTM 20 with Proclin (PBST).
- the plates were then incubated with 20 ⁇ 1 ⁇ 11 of a goat anti-rabbit IgG AlexaFluor 594 or goat anti-rabbit AlexaFluor 488 antibody (Molecular Probes) with Hoechst at 1:5000 in PBS/TweenTM/3% (w/v) Bovine Serum Albumin for lhr at room temperature.
- the plates were then washed three times in 250 ⁇ 1 of PBS/0.05% (v/v) TweenTM 20 with Proclin (PBST with a Biocide preservative). 20 ⁇ 1 of PBS was added to each well and the plates covered with a black plate seal and stored at 4°C before being read.
- Example 1 In-vivo xenograft study with Example 1 as single agent and in combination with an mTQR inhibitor.
- MCF7 cells (5 x 10 6 cells suspended in 100 ⁇ of RPMI cell medium) were implanted subcutaneously in the hind flank of immuno-compromised (SCID) mice the day after each mouse was surgically implanted with a 0.5 mg/21 day oestrogen pellet (Innovative Research, USA). Tumours were measured twice weekly and changes in tumour volume and growth inhibition were determined by bilateral Vernier calliper measurement (length x width) where length was taken to be the longest diameter across the tumour and width the corresponding perpendicular. Tumour volume was calculated using the formula (length x width) x (length x width) x ⁇ /6). Tumours were measured 13 days after cell implantation to allow randomisation of mice into test groups. Treatment with compounds began the day after (i.e. 14 days after cell implantation).
- the mTOR inhibitor AZD2014 was dosed to different groups of mice at 15 mg/kg once daily every day orally (p.o.) at a volume of 0.1 ml per lOg.
- Example 1 was dosed at 5 mg/kg once daily orally at 0.1 ml/lOg.
- One group of animals was dosed with vehicle p.o. to act as a control.
- Nine mice per group were used for active agents for the control group.
- HCC1428 LTED cells (1 x 10 6 ) were implanted subcutaneously in the hind flank of female immuno-compromised NSG mice (Jackson Labs, USA) that had undergone overectomy. Tumours were measured twice weekly and changes in tumour volume and growth inhibition were determined by bilateral Vernier calliper measurement (length x width) where length was taken to be the longest diameter across the tumour and width the corresponding perpendicular. Tumour volume was calculated using the formula (length x width) x (length x width) x (71/6). Tumours were measured once weekly after cell implantation until the average size reached 150 mm at which point the mice were placed into randomised test groups, each group containing 10 mice.
- Example 1 Treatment with compounds began the day after (day 62 in this study) and once weekly tumour measurement continued.
- Example 1 was dosed 25 mg/kg once daily every day orally (p.o.) at a volume of 0.1 ml per lOg.
- Another group of animals was dosed with vehicle p.o. to act as a control.
- control treated tumours grew on average by 220 mm (using geometric mean values) while tumours from mice treated by Example 1 decreased in size by 46 mm representing a 121% inhibition of tumour growth (P ⁇ 0.001 by unpaired t-test).
- tumours samples were harvested 24hrs post final dose of vehicle or example 1 treatment and snap frozen in liquid nitrogen.
- tumour fragments were added to 700ul of
- Invitrogen Cell Extraction buffer FNN0011 with added Sigma Phosphatase inhibitors (No. 2 (P5726) and 3 (P0044) 1 in 100 dilution) and Roche Complete (11836145001) protease inhibitor (1 tablet per 50 mis), ImM dithiothreitol (DTT) in 2ml sample tubes on wt ice.
- Homogenisation of the sample was done using a Mixermill (level 27/sec) and 3 x 2 mins cycles of homogenisation. Samples were spun briefly to ascertain complete homogenisation of the tumours. Homogenate was sonicated for 10 seconds and then spun down at top speed (13000rpm) centrifuge for 15 mins. Levels of protein in the supernatent were measured and approx 45ug of protein were run on a 15 well Bis-Tris Gels (4-12% Gels) using standard methods. Following protein separation and transfer onto
- a pharmaceutical composition which comprises a compound of the Formula (I), or a
- Suitable pharmaceutically-acceptable excipients for a tablet formulation include, for example, inert diluents, granulating and disintegrating agents, binding agents, lubricating agents, preservative agents and anti-oxidants.
- inert diluents for example, inert diluents, granulating and disintegrating agents, binding agents, lubricating agents, preservative agents and anti-oxidants.
- compositions for oral use may alternatively be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil.
- Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, dispersing or wetting agents.
- the aqueous suspensions may also contain one or more preservatives, anti-oxidants, colouring agents, flavouring agents, and/or sweetening agents.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil or in a mineral oil.
- the oily suspensions may also contain a thickening agent.
- Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
- compositions of the invention may also be in the form of oil-in-water emulsions.
- the oily phase may be a vegetable oil or a mineral oil or a mixture of any of these.
- the emulsions may also contain sweetening, flavouring and preservative agents.
- Syrups and elixirs may be formulated with sweetening agents, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
- compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
- a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent system.
- Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
- Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.
- Dry powder inhalers may also be suitable.
- the pharmaceutical composition described above comprises the compound of Example 1 [(E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid], or a pharmaceutically acceptable salt thereof.
- the compound of Example 1 is present in its polymorph described herein as crystalline Form B.
- the degradation product referred to which is (R,E)-3-(3,5-difluoro-4-(2-(2-fluoro- 2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l-yl)phenyl)acrylate, has the following structure:
- Example 1 [(E)-3-(3,5-difluoro-4-((lR,3R)-2-(2- fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l- yl)phenyl)acrylic acid] by autooxidation in air via a free radical chain mechanism.
- this degradation product is not believed to have significant SERD activity.
- This compound could also be referred to as (E)-3-[3,5-difluoro-4-[(3R)-2-(2-fluoro- 2-methyl-propyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l-yl]phenyl]prop-2- enoate and a synthetic method for making it is given in Example 13.
- control of the formation of degradation products is essential to the safe production and storage of pharmaceuticals.
- certain compounds may degrade on storage, even after formulation into a pharmaceutical composition, and that such degradation may in some instances be controlled by the use of appropriate excipients in the pharmaceutical composition and/or by appropriate packaging of the final product.
- compositions of (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid, or a pharmaceutically-acceptable salt thereof, include a compound which acts as an anti-oxidant.
- Anti-oxidant compounds which are suitable for use in pharmaceutical compositions are known in the art, and include, for example, acetone sodium bisulfite; alpha lipoic acid; alpha tocopherol; ascorbic acid; ascorbyl palmitate; butylated hydroxyanisole; butylated hydroxy toluene; carotenes; citric acid monohydrate; dodecyl gallate; erythorbic acid; fumaric acid; glutathione; histidine; hypophosphorous acid; lactobionic acid; lipoic acid; malic acid; melatonin; methionine; d-mannose; monothioglycerol; octyl gallate; potassium metabisulfite; propionic acid; propyl gallate; sodium ascorbate; sodium bisulfite; sodium formaldehyde sulfoxylate; sodium metabisulfite; sodium sulfite; sodium thiosulfate;
- stannous chloride sulfur dioxide; thymol; tocopherol; tocotrienols; ubiquinol; uric acid; vitamin E; and vitamin E polyethylene glycol succinate.
- Such compounds may exert their anti-oxidant effect by a variety of mechanisms, and one or more of these mechanisms may be more effective than others for any particular compound.
- a chelating agent such as for example EDTA
- metal-chelating agents include, for example, betadex sulfobutyl ether sodium; calcium acetate; citric acid monohydrate; cyclodextrins; disodium edetate; edetic acid; fumaric acid; galactose; glutamic acid; histidine; hydroxypropyl betadex; malic acid; pentetic acid; phytochelatin; poly(methyl vinyl ether/maleic anhydride); potassium citrate; sodium citrate dihydrate; sodium phosphate, dibasic; sodium phosphate, monobasic; tartaric acid; and trehalose.
- compositions containing sodium metabisulfite appeared to be less stable than those with no anti-oxidant, after four weeks storage under a number of different heat and humidity conditions.
- compositions containing ascorbic acid appeared to be the most stable after 4 weeks storage under a number of different heat and humidity conditions (as determined by Liquid Chromatography analysis, eg UHPLC).
- suitable additives for formulations comprising the compound of Example 1 include using excipients with a low metal content, excipients with a low peroxide content, excipients such as mannitol which is a free-radical scavenger as well as a filler.
- excipients with a low metal content include using excipients with a low peroxide content, excipients such as mannitol which is a free-radical scavenger as well as a filler.
- the process of production of such a formulation may also impact stability.
- ensuring intimate mixing of the active ingredient with stability- inducing excipients may be important in ensuring maximum stabilisation.
- Intimate mixing may be influenced by, for example, mixing speed, particle sizes and wet or dry
- An active ingredient may be granulated with an antioxidant and then mixed with other excipients.
- Antioxidants may also be added to any coating on the outside of a pharmaceutical composition.
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, in association with at least one pharmaceutically-acceptable diluents or carrier.
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, and also comprising an anti-oxidant.
- ascorbic acid may be used as the anti-oxidant.
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, and also comprising a metal chelating agent.
- EDTA may be used as a metal chelating agent.
- composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, an anti-oxidant and optionally further comprising a metal chelating agent.
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, in association with at least one pharmaceutically-acceptable diluent or carrier, wherein the composition contains less than 5% w/w of (R,E)-3-(3,5-difluoro-4- (2-(2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l- yl)phenyl) acrylate .
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, in association with at least one pharmaceutically-acceptable diluent or carrier, wherein the composition contains less than 2% w/w of (R,E)-3-(3,5-difluoro-4- (2-(2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l- yl)phenyl) acrylate .
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, in association with at least one pharmaceutically-acceptable diluent or carrier, wherein the composition contains less than 1% w/w of (R,E)-3-(3,5-difluoro-4- (2-(2-nuoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l- yl)phenyl) acrylate .
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, in association with at least one pharmaceutically-acceptable diluent or carrier, wherein the composition contains less than 0.5% w/w of (R,E)-3-(3,5-difluoro- 4-(2-(2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l- yl)phenyl) acrylate .
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, in association with at least one pharmaceutically-acceptable diluents or carrier, wherein the composition contains less than 0.1% w/w of (R,E)-3-(3,5- difluoro-4-(2-(2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2- ium- 1 -yl)phenyl) acrylate .
- a pharmaceutical composition comprising (E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9- tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid or a pharmaceutically- acceptable salt thereof, in association with at least one pharmaceutically-acceptable diluents or carrier, wherein the composition contains less than 0.05% w/w of (R,E)-3-(3,5- difluoro-4-(2-(2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2- ium- 1 -yl)phenyl) acrylate .
- composition is described as containing less than 5% w/w, 2%w/w, l%w/w, 0.5% w/w, 0.1%w/w or 0.05% w/w of (R,E)-3-(3,5-difluoro-4-(2- (2-fluoro-2-methylpropyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l- yl)phenyl)acrylate
- this is intended to mean percentage weight for weight in comparison to the weight of (E)-3-(3,5-difluoro-4- ((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol- l-yl)phenyl)acrylic acid present in the composition.
- the degradation product (R,E)-3-(3,5-difluoro-4-(2-(2-fluoro-2-methylpropyl)-3- methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-2-ium-l-yl)phenyl)acrylate may therefore be used as a reference marker or reference standard in analytical techniques such as HPLC to monitor the stability of the compound of Example 1 or pharmaceutical compositions containing it.
- the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
- oral administration to humans will generally require, for example, from 1 mg to 2 g of active agent (more suitably from lOOmg to 2g, for example from 250 mg to 1.8g, such as from 500mg to 1.8g, particularly from 500mg to 1.5g, conveniently from 500mg to lg) to be administered compounded with an appropriate and convenient amount of excipients which may vary from about 3 to about 98 percent by weight of the total composition.
- unit dosage forms will contain about 10 mg to 0.5 g of a compound of this invention, although a unit dosage form may contain up to lg. Conveniently, a single solid dosage form may contain between 1 and 300mg of active ingredient.
- the size of the dose for therapeutic or prophylactic purposes of compounds of the present invention will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
- a daily dose in the range for example, 1 mg/kg to 100 mg/kg body weight is received, given if required in divided doses.
- lower doses will be administered when a parenteral route is employed.
- a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will generally be used.
- a dose in the range for example, 1 mg/kg to 25 mg/kg body weight will be used.
- Oral administration is however preferred, particularly in tablet form.
- pharmaceutically-acceptable salts thereof are administered as tablets comprising lOmg to lOOmg of the compound of Formula (I) (or a pharmaceutically-acceptable salt thereof), wherein one or more tablets are administered as required to achieve the desired dose.
- signalling through ERa causes tumourigenesis by one or more of the effects of mediating proliferation of cancer and other cells, mediating angiogenic events and mediating the motility, migration and invasiveness of cancer cells.
- the compounds of the present invention possess potent anti-tumour activity which it is believed is obtained by way of antagonism and down-regulation of ERa that is involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the invasiveness and migratory ability of metastasising tumour cells.
- the compounds of the present invention may be of value as anti-tumour agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of tumour growth and survival and to inhibition of metastatic tumour growth.
- the compounds of the present invention may be of value as anti-proliferative and anti-invasive agents in the containment and/or treatment of solid tumour disease.
- the compounds of the present invention may be useful in the prevention or treatment of those tumours which are sensitive to inhibition of ERa and that are involved in the signal transduction steps which lead to the proliferation and survival of tumour cells and the migratory ability and invasiveness of metastasising tumour cells.
- the compounds of the present invention may be useful in the prevention or treatment of those tumours which are mediated alone or in part by antagonism and down-regulation of ERa, i.e. the compounds may be used to produce an ERa inhibitory effect in a warm blooded animal in need of such treatment.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and/or treatment of solid tumour disease.
- a method for producing an anti-proliferative effect in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a method for producing an anti-invasive effect by the containment and/or treatment of solid tumour disease in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the prevention or treatment of cancer in a warm blooded animal such as man.
- a method for the prevention or treatment of cancer in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the prevention or treatment of solid tumour disease in a warm blooded animal such as man.
- a method for the prevention or treatment of solid tumour disease in a warm blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in the prevention or treatment of those tumours which are sensitive to inhibition of ERa that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of ERa that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells.
- a method for the prevention or treatment of those tumours which are sensitive to inhibition of ERa that are involved in the signal transduction steps which lead to the proliferation, survival, invasiveness and migratory ability of tumour cells which comprises administering to said animal an effective amount of a compound of the Formula (I), or a pharmaceutically- acceptable salt thereof, as defined hereinbefore.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore for use in providing an inhibitory effect on ERa.
- a method for providing an inhibitory effect on ERa which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a method for providing a selective inhibitory effect on ERa which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- the compounds of the present invention are shown to be potent estrogen receptor binders and reduce cellular levels of ERa and may therefore be useful in the treatment of estrogen sensitive diseases or conditions (including diseases that have developed resistance to endocrine therapies), i.e. for use in the treatment of cancer of the breast and gynaecological cancers (including endometrial, ovarian and cervical) and cancers expressing ERa mutated proteins which may be de novo mutations or have arisen as a result of treatment with a prior endocrine therapy such as an aromatase inhibitor.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof as defined herein before for use in the treatment of breast or gynaecological cancers.
- a method for treating breast or gynaecological cancers which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a method for treating cancer of the breast, endometrium, ovary or cervix which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a method for treating breast cancer which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a method for treating breast cancer wherein the cancer has developed resistance to one or more other endocrine therapies, which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof as defined herein before in the manufacture of a medicament for use in the treatment of breast or gynaecological cancers.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof as defined herein before in the manufacture of a medicament for use in the treatment of cancer of the breast, endometrium, ovary or cervix.
- the cancer to be treated is breast cancer.
- the breast cancer is Estrogen Receptor +ve (ER+ve).
- the compound of Formula (I) is dosed in combination with another anticancer agent, such as an anti-hormonal agent as defined herein.
- a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined herein before for use in the treatment of ER+ve breast cancer is provided.
- a method for treating ER+ve breast cancer which comprises administering an effective amount of a compound of the Formula (I), or a pharmaceutically-acceptable salt thereof, as defined hereinbefore.
- the in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I).
- the present invention therefore also contemplates a method for inhibiting ER-a in a patient, comprising administering to a patient an amount of the a compound of Formula (I), or a pharmaceutically-acceptable salt thereof, effective in inhibiting ER-a in the patient.
- the present invention therefore also contemplates a method for inhibiting ER-a in a patient, comprising administering to a patient an amount of a compound of Formula (I), or a pharmaceutic ally- acceptable salt thereof, effective in inhibiting ER-a in the patient.
- Example 1 a suitable compound of the formula (I) is Example 1, or a pharmaceutically-acceptable salt thereof.
- Example 1 is in crystalline form B as described herein.
- the anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the invention, conventional surgery or radiotherapy or chemotherapy.
- Such chemotherapy may include one or more of the following categories of anti-tumour agents :-
- antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cis-platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblast
- antihormonal agents such as antioestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane);
- antioestrogens for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene
- progestogens for example megestrol acetate
- aromatase inhibitors for example as anastrozole, letrozole, vorazole and exemestane
- kinase inhibitors examples include the anti-erbB2 antibody trastuzumab [HerceptinTM], the anti-EGFR antibody panitumumab, the anti-EGFR antibody cetuximab [Erbitux, C225] and tyrosine kinase inhibitors including inhibitors of the erbB receptor family, such as epidermal growth factor family receptor (EGFR/erbB l) tyrosine kinase inhibitors such as gefitinib or erlotinib, erbB2 tyrosine kinase inhibitors such as lapatinib, and mixed erbl/2 inhibitors such as afatanib; similar strategies are available for other classes of growth factors and their receptors, for
- modulators which target signalling proteins in the PI3 -kinase signalling pathway for example, inhibitors of PI3 -kinase isoforms such as ⁇ 3 ⁇ - ⁇ / ⁇ / ⁇ and ser / thr kinases such as AKT, mTOR (such as AZD2014), PDK, SGK, PI4K or PIP5K; also included are inhibitors of serine/threonine kinases not listed above, for example raf inhibitors such as vemurafenib, MEK inhibitors such as selumetinib (AZD6244), Abl inhibitors such as imatinib or nilotinib, Btk inhibitors such as ibrutinib, Syk inhibitors such as fostamatinib, aurora kinase inhibitors (for example AZDl 152), inhibitors of other ser/thr kinases such as JAKs, STATs and IRAK4, and
- antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as sorafenib, axitinib, pazopanib, sunitinib and vandetanib (and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ 3 function and angio statin)];
- vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab (AvastinTM) and for example, a VEGF receptor tyrosine kinase inhibitor such as sorafenib, axitinib, pazopanib, sunitinib and vandetanib (and compounds that work by other mechanisms (for example linomide
- vascular damaging agents such as Combretastatin A4
- anti-invasion agents for example c-Src kinase family inhibitors like (dasatinib, J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase] ;
- immunotherapy approaches including for example ex-vivo and in- vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.
- cytokines such as interleukin 2, interleukin 4 or granulocyte
- PD-1 e.g. BMS-936558
- CTLA4 e.g. ipilimumab and tremelimumab
- (xi) gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy.
- GDEPT gene-directed enzyme pro-drug therapy
- a combination suitable for use in the treatment of cancer comprising compounds of the present invention as defined herein or a pharmaceutically acceptable salt thereof and another anti-tumour agent, in particular any one of the anti tumour agents listed under (i) - (xi) above.
- the anti-tumour agent listed under (i)-(xi) above is the standard of care for the specific cancer to be treated; the person skilled in the art will understand the meaning of "standard of care”.
- the compound of the present invention is Example 1, or a pharmaceutically-acceptable salt thereof.
- compounds of the present invention or a pharmaceutically acceptable salt thereof in combination with another anti-tumour agent in particular an anti-tumour agent selected from one listed under (i) - (xi) herein above.
- Example 1 [(E)-3-(3,5- Difluoro-4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH- pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid] or a pharmaceutically acceptable salt thereof in combination with another anti-tumour agent, in particular an anti-tumour agent selected from one listed under (i) - (xi) herein above.
- compounds of the present invention or a pharmaceutically acceptable salt thereof in combination with another anti- tumour agent in particular an anti-tumour agent selected from one listed under (i) above.
- Example 1 or a pharmaceutically acceptable salt thereof in combination with any one of the anti-tumour agents listed under (i) above.
- a combination suitable for use in the treatment of cancer comprising compounds of the present invention as defined hereinbefore or a pharmaceutically acceptable salt thereof and a taxoid, such as for example taxol or taxotere, conveniently taxotere.
- a suitable compound of the invention in combination with a taxoid, such as for example taxol or taxotere, conveniently taxotere is Example 1, or a pharmaceutically-acceptable salt thereof.
- a combination suitable for use in the treatment of cancer comprising compounds of the present invention as defined herein before or a pharmaceutically acceptable salt thereof and any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above.
- Example 1 or a pharmaceutically acceptable salt thereof and any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above.
- Example 1 or a pharmaceutically acceptable salt thereof and an mTOR inhibitor, such as AZD2014 (see for example WO2008/023161).
- Example 1 a pharmaceutically-acceptable salt thereof and a PDKa-inhibitor, such as those PI3K ⁇ / ⁇ inhibitors in our co-pending PCT application PCT/GB2014/050163.
- Example 3 is the compound l-(4-(5-(5-amino-6-(5-tert- butyl-l,3,4-oxadiazol-2-yl)pyrazin-2-yl)-l-ethyl-lH-l,2,4-triazol-3-yl)piperidin-l-yl)-3- hydroxypropan-l-one, or a pharmaceutically-acceptable salt thereof.
- a process to make Example 3 of PCT/GB2014/050163 is set out in Reference Example 1 herein.
- Example 1 or a pharmaceutically acceptable salt thereof and palbociclib.
- Example 1 a pharmaceutically acceptable salt thereof, with an anti-tumour agent listed in (ii) above, or an mTOR inhibitor (such as AZD2014), or a PI3K-a inhibitor (such as those PI3K ⁇ / ⁇ inhibitors in our copending PCT application PCT/GB2014/050163, particularly Example 3 therein) or palbociclib, is suitable for use in the treatment of breast or gynaecological cancers, such as cancer of the breast, endometrium, ovary or cervix, particularly breast cancer, such as ER+ve breast cancer.
- an anti-tumour agent listed in (ii) above or an mTOR inhibitor (such as AZD2014), or a PI3K-a inhibitor (such as those PI3K ⁇ / ⁇ inhibitors in our copending PCT application PCT/GB2014/050163, particularly Example 3 therein) or palbociclib, is suitable for use in the treatment of breast or gynaecological cancers, such as
- the compounds of the present invention are dosed once daily.
- a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above, in association with a pharmaceutically acceptable diluent or carrier.
- a pharmaceutical composition which comprises Example 1 [(E)-3-(3,5-difluoro-4-((lR,3R)-2-(2-fluoro-2- methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylic acid] or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above, in association with a pharmaceutically acceptable diluent or carrier.
- a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above in association with a pharmaceutically acceptable diluent or carrier.
- a pharmaceutical composition which comprises Example 1 or a pharmaceutically acceptable salt thereof and any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above; in association with a pharmaceutically acceptable diluent or carrier.
- a pharmaceutical composition comprising Example 1 or a pharmaceutically acceptable salt thereof and an mTOR inhibitor, such as AZD2014 (see for example WO2008/023161); in association with a pharmaceutically acceptable diluent or carrier.
- an mTOR inhibitor such as AZD2014 (see for example WO2008/023161)
- a pharmaceutical composition comprising Example 1, or a pharmaceutically-acceptable salt thereof and a PDKa- inhibitor, such as those PI3K ⁇ / ⁇ inhibitors in our co-pending PCT application PCT/GB2014/050163, in association with a pharmaceutically acceptable diluent or carrier.
- a suitable PI3K ⁇ / ⁇ inhibitor is Example 3 from PCT/GB2014/050163, as described hereinbefore.
- Example 1 In a further aspect of the invention there is provided a pharmaceutical composition
- a pharmaceutical composition comprising Example 1 or a pharmaceutically acceptable salt thereof and palbociclib in association with a pharmaceutically acceptable diluent or carrier.
- a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above, in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.
- a pharmaceutical composition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.
- a pharmaceutical composition which comprises Example 1 or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above, in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.
- a pharmaceutical composition which comprises Example 1 or a pharmaceutically acceptable salt thereof and any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above; in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.
- a pharmaceutical composition comprising Example 1 or a pharmaceutically acceptable salt thereof and an mTOR inhibitor, such as AZD2014 (see for example WO2008/023161); in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.
- an mTOR inhibitor such as AZD2014 (see for example WO2008/023161)
- Example 1 a pharmaceutical composition
- a pharmaceutical composition comprising Example 1, or a pharmaceutically-acceptable salt thereof and a PDKa- inhibitor, such as those PI3K ⁇ / ⁇ inhibitors in our co-pending PCT application
- PCT/GB2014/050163 in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.
- a suitable PI3K ⁇ / ⁇ inhibitor is Example 3 from PCT/GB2014/050163, as described hereinbefore.
- Example 1 In a further aspect of the invention there is provided a pharmaceutical composition
- a pharmaceutical composition comprising Example 1 or a pharmaceutically acceptable salt thereof and palbociclib in association with a pharmaceutically acceptable diluent or carrier for use in treating cancer.
- Example 1 or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above, in the manufacture of a medicament for use in cancer in a warm-blooded animal, such as man.
- a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal, such as man.
- Example 1 or a pharmaceutically acceptable salt thereof in combination with any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above; in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal, such as man.
- Example 1 or a pharmaceutically acceptable salt thereof in combination with an mTOR inhibitor, such as AZD2014 (see for example WO2008/023161); in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal, such as man.
- an mTOR inhibitor such as AZD2014 (see for example WO2008/023161)
- Example 1 or a pharmaceutically-acceptable salt thereof in combination with a PDKa-inhibitor, such as those PI3K ⁇ / ⁇ inhibitors in our co-pending PCT application PCT/GB2014/050163, in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal, such as man.
- a suitable PI3K ⁇ / ⁇ inhibitor is Example 3 from
- Example 1 or a pharmaceutically acceptable salt thereof in combination with palbociclib in the
- an anti-tumour agent listed in (ii) above or an mTOR inhibitor (such as AZD2014), or a PI3K-a inhibitor (such as those PI3K ⁇ / ⁇ inhibitors in our co-pending PCT application PCT/GB2014/050163, particularly Example 3 therein)
- a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above.
- a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Example 1 or a
- a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above.
- a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Example 1 or a pharmaceutically acceptable salt thereof in combination with any one of antihormonal agents listed under (ii) above, for example any one of the anti-oestrogens listed in (ii) above, or for example an aromatase inhibitor listed in (ii) above.
- a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Example 1 or a pharmaceutically acceptable salt thereof in combination with an mTOR inhibitor, such as AZD2014 (see for example WO2008/023161).
- an mTOR inhibitor such as AZD2014
- a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Example 1, or a pharmaceutically - acceptable salt thereof in combination with a PDKa-inhibitor, such as those PI3K ⁇ / ⁇ inhibitors in our co-pending PCT application PCT/GB2014/050163.
- a suitable PI3K ⁇ / ⁇ inhibitor is Example 3 from PCT/GB2014/050163, as described hereinbefore.
- a method of treating cancer in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of Example 1 or a pharmaceutically acceptable salt thereof in combination with palbociclib.
- the above methods of treating cancer are methods for the treatment of breast or gynaecological cancers, such as cancer of the breast, endometrium, ovary or cervix, particularly breast cancer, such as ER+ve breast cancer.
- breast or gynaecological cancers such as cancer of the breast, endometrium, ovary or cervix, particularly breast cancer, such as ER+ve breast cancer.
- kits comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above.
- kits comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) or (ii) herein above.
- a kit comprising:
- an anti-tumour agent selected from one listed under (i) - (xi) herein above in a second unit dosage form;
- a kit comprising:
- Example 1 or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) - (xi) herein above.
- Example 1 or a pharmaceutically acceptable salt thereof in combination with an anti-tumour agent selected from one listed under (i) or (ii) herein above.
- a kit comprising:
- Example 1 or a pharmaceutically acceptable salt thereof in a first unit dosage form; b) an anti-tumour agent selected from one listed under (i) - (xi) herein above in a second unit dosage form; and
- a kit comprising:
- Example 1 or a pharmaceutically acceptable salt thereof in a first unit dosage form; b) an anti-tumour agent selected from one listed under (i) - (ii) herein above in a second unit dosage form; and
- a kit comprising:
- Example 1 or a pharmaceutically acceptable salt thereof in a first unit dosage form
- an anti-tumour agent selected from AZD2014, a PDKa-inhibitor (such as those PI3K ⁇ / ⁇ inhibitors in our co-pending PCT application PCT/GB2014/050163) and palbociclib in a second unit dosage form
- AZD2014 a PDKa-inhibitor
- palbociclib a second unit dosage form
- Combination therapy as described above may be added on top of standard of care therapy typically carried out according to its usual prescribing schedule.
- the compounds of the Formula (I) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit ER-a. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
- Another aspect of the present invention is based on identifying a link between the status of the gene encoding ERa and potential susceptibility to treatment with a compound of Formula (I).
- ERa gene status may indicate that a patient is less likely to respond to exisiting hormone therapy (such as aromatase inhibitors), in part at least because some ERa mutations are though to arise as resistance mechanisms to existing treatments.
- a SERD particularly a SERD which can be administered orally in potentially larger doses without excessive inconvenince, may then advantageously be used to treat patentients with ERa mutations who may be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients for treatment with a compound of Formula (I), particularly cancer patients.
- the present invention relates to patient selection tools and methods (including personalised medicine).
- the selection is based on whether the tumour cells to be treated possess wild-type or mutant ERa gene.
- the ERa gene status could therefore be used as a biomarker to indicate that selecting treatment with a SERD may be advantageous.
- compounds of the formula (I) as described herein are thought to be similarly active against wild-type and mutant ERa genes, at least those mutations in ERa gene identified at the date of filing this application.
- Patient selection biomarkers that identify the patients most likely to respond to one agent over another are ideal in the treatment of cancer, since they reduce the unnecessary treatment of patients with non-responding tumours to the potential side effects of such agents.
- a biomarker can be described as "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention".
- a biomarker is any identifiable and measurable indicator associated with a particular condition or disease where there is a correlation between the presence or level of the biomarker and some aspect of the condition or disease (including the presence of, the level or changing level of, the type of, the stage of, the susceptibility to the condition or disease, or the responsiveness to a drug used for treating the condition or disease). The correlation may be qualitative, quantitative, or both qualitative and quantitative.
- a biomarker is a compound, compound fragment or group of compounds. Such compounds may be any compounds found in or produced by an organism, including proteins (and peptides), nucleic acids and other compounds.
- Biomarkers may have a predictive power, and as such may be used to predict or detect the presence, level, type or stage of particular conditions or diseases (including the presence or level of particular microorganisms or toxins), the susceptibility (including genetic susceptibility) to particular conditions or diseases, or the response to particular treatments (including drug treatments). It is thought that biomarkers will play an increasingly important role in the future of drug discovery and development, by improving the efficiency of research and development programs. Biomarkers can be used as diagnostic agents, monitors of disease progression, monitors of treatment and predictors of clinical outcome. For example, various biomarker research projects are attempting to identify markers of specific cancers and of specific cardiovascular and immunological diseases. It is believed that the development of new validated biomarkers will lead both to significant reductions in healthcare and drug development costs and to significant improvements in treatment for a wide variety of diseases and conditions.
- a biomarker may be required.
- the marker may be measurable in surrogate and tumour tissues. Ideally these markers will also correlate with efficacy and thus could ultimately be used for patient selection.
- the technical problem underlying this aspect of the present invention is the identification of means for stratification of patients for treatment with a compound of Formula (I).
- the technical problem is solved by provision of the embodiments
- Tumours which contain wild type ERa are believed to be susceptible to treatment with a compound of formula (I), for example as a first-line treatment. Tumours may also respond to treatment with a compound of formula (I) as a second-line, third-line or subsequent therapy and this may be useful, in particular, where the tumours contain mutant ERa and may thus be resistant to existing therapies such as AIs. A higher dosage of a compound of formula (I) may be required in the resistant setting than in wild type tumours).
- the invention provides a method of determining sensitivity of cells to a compound of Formula (I).
- the method comprises determining the status of ERa gene in said cells.
- a cell is defined as sensitive to a compound of Formula (I) if it inhibits the increase in cell number in a cell growth assay (either through inhibition of cell proliferation and /or through increased cell death). Methods of the invention are useful for predicting which cells are more likely to respond to a compound of Formula (I) by growth inhibition.
- a sample "representative of the tumour” can be the actual tumour sample isolated, or may be a sample that has been further processed, e.g. a sample of PCR amplified nucleic acid from the tumour sample.
- Allele refers to a particular form of a genetic locus, distinguished from other forms by its particular nucleotide or amino acid sequence.
- Amplification reactions are nucleic acid reactions which result in specific amplification of target nucleic acids over non-target nucleic acids.
- the polymerase chain reaction (PCR) is a well known amplification reaction.
- Cancer is used herein to refer to neoplastic growth arising from cellular transformation to a neoplastic phenotype. Such cellular transformation often involves genetic mutation.
- Gene is a segment of DNA that contains all the information for the regulated biosynthesis of an RNA product, including a promoter, exons, introns, and other sequence elements which may be located within 5' or 3' flanking regions (not within the transcribed portions of the gene) that control expression.
- Gene status refers to whether the gene is wild type or not (i.e. mutant).
- Label refers to a composition capable of producing a detectable signal indicative of the presence of the target polynucleotide in an assay sample. Suitable labels include radioisotopes, nucleotide chromophores, enzymes, substrates, fluorescent molecules, chemiluminescent moieties, magnetic particles, bioluminescent moieties, and the like. As such, a label is any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means.
- Non- synonymous variation refers to a variation (variance) in or overlapping the coding sequence of a gene that result in the production of a distinct (altered) polypeptide sequence. These variations may or may not affect protein function and include missense variants (resulting in substitution of one amino acid for another), nonsense variants (resulting in a truncated polypeptide due to generation of a premature stop codon) and insertion/deletion variants.
- “Synonymous variation” refers to a variation (variance) in the coding sequence of a gene that does not affect sequence of the encoded polypeptide. These variations may affect protein function indirectly (for example by altering expression of the gene), but, in the absence of evidence to the contrary, are generally assumed to be innocuous.
- Nucleic acid refers to single stranded or double stranded DNA and RNA molecules including natural nucleic acids found in nature and/or modified, artificial nucleic acids having modified backbones or bases, as are known in the art.
- Primer refers to a single stranded DNA oligonucleotide sequence capable of acting as a point of initiation for synthesis of a primer extension product which is complementary to the nucleic acid strand to be copied.
- the length and sequence of the primer must be such that they are able to prime the synthesis of extension products.
- a typical primer contains at least about 7 nucleotides in length of a sequence substantially complementary to the target sequence, but somewhat longer primers are preferred. Usually primers contain about 15-26 nucleotides, but longer or shorter primers may also be employed.
- Polymorphic site is a position within a locus at which at least two alternative sequences are found in a population.
- Polymorphism refers to the sequence variation observed in an individual at a polymorphic site. Polymorphisms include nucleotide substitutions, insertions, deletions and microsatellites and may, but need not, result in detectable differences in gene expression or protein function. In the absence of evidence of an effect on expression or protein function, common polymorphisms, including non-synonomous variants, are generally considered to be included in the definition of wild-type gene sequence. A catalog of human polymorphisms and associated annotation, including validation, observed frequencies, and disease association, is maintained by NCBI (dbSNP:
- polymorphism when used in the context of solid state form of a compound, that is the crystalline or amorphous nature of a compound. The skilled person will understand the intended meaning by its context.
- Probe refers to single stranded sequence-specific oligonucleotides which have a sequence that is exactly complementary to the target sequence of the allele to be detected.
- Response is defined by measurements taken according to Response Evaluation Criteria in Solid Tumours (RECIST) involving the classification of patients into two main groups: those that show a partial response or stable disease and those that show signs of progressive disease.
- “Stringent hybridisation conditions” refers to an overnight incubation at 42°C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulphate, and 20 pg/ml denatured, sheared salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65 °C.
- “Survival” encompasses a patients' overall survival and progression-free survival.
- OS Global System for disease
- PFS progression-free survival
- a method for selecting a patient for treatment with a compound of Formula (I) comprising providing a tumour cell containing sample from a patient; determining whether the ERa gene in the patient's tumour cell containing sample is wild type or mutant; and selecting a patient for treatment with a compound of Formula (I) based thereon.
- the method may include or exclude the actual patient sample isolation step.
- a method for selecting a patient for treatment with a compound of Formula (I) comprising determining whether the ERa gene in a tumour cell containing sample previously isolated from the patient is wild type or mutant; and selecting a patient for treatment with a compound of Formula (I) based thereon.
- the patient is selected for treatment with a compound of Formula (I) if the tumour cell DNA has a mutant ERa gene.
- a patient whose tumour cell DNA possesses a wild type ERa gene is selected for treatment with a compound of Formula (I).
- a gene status of wild-type is meant to indicate normal or appropriate expression of the gene and normal function of the encoded protein.
- mutant status is meant to indicate expression of a protein with altered function, consistent with the known roles of mutant ERa genes in cancer (as described herein). Any number of genetic or epigenetic alterations, including but not limited to mutation, amplification, deletion, genomic rearrangement, or changes in methylation profile, may result in a mutant status. However, if such alterations nevertheless result in appropriate expression of the normal protein, or a functionally equivalent variant, then the gene status is regarded as wild-type.
- variants that typically would not result in a functional mutant gene status include synonomous coding variants and common polymorphisms (synonymous or non-synonymous).
- gene status can be assessed by a functional assay, or it may be inferred from the nature of detected deviations from a reference sequence.
- the wild-type or mutant status of the ERa gene is determined by the presence or absence of non-synonymous nucleic acid variations in the genes. Observed non- synonymous variations corresponding to known common polymorphisms with no annotated functional effects do not contribute to a gene status of mutant.
- splice site variations that decrease recognition of an intron/exon junction during processing of pre- mRNA to mRNA. This can result in exon skipping or the inclusion of normally intronic sequence in spliced mRNA (intron retention or utilization of cryptic splice junctions). This can, in turn, result in the production of aberrant protein with insertions and/or deletions relative to the normal protein.
- the gene has a mutant status if there is a variant that alters splice site recognition sequence at an intron/exon junction.
- ESR1 ESR1 gene status, i.e. whether a particular ESRlgene is wild type or mutant, based on comparison of DNA or protein sequence with wild type.
- genes and mRNA sequences disclosed for ERa gene are representative sequences. In normal individuals there are two copies of each gene, a maternal and paternal copy, which will likely have some sequence differences, moreover within a population there will exist numerous allelic variants of the gene sequence.
- Other sequences regarded as wild type include those that possess one or more synonymous changes to the nucleic acid sequence (which changes do not alter the encoded protein sequence), non-synonymous common polymorphisms (e.g. germ-line polymorphisms) which alter the protein sequence but do not affect protein function, and intronic non- splice- site sequence changes.
- the gene status of ERa can be determined by determination of the nucleic acid sequence. This could be via direct sequencing of the full-length gene or analysis of specific sites within the gene, e.g. commonly mutated sites.
- the patient's sample to be tested for the gene status can be any tumour tissue or tumour-cell containing sample obtained or obtainable from the individual.
- the test sample is conveniently a sample of blood, mouth swab, biopsy, or other body fluid or tissue obtained from an individual.
- Particular examples include: circulating tumour cells, circulating DNA in the plasma or serum, cells isolated from the ascites fluid of ovarian cancer patients, lung sputum for patients with tumours within the lung, a fine needle aspirate from a breast cancer patient, urine, peripheral blood, a cell scraping, a hair follicle, a skin punch or a buccal sample.
- test sample may equally be a nucleic acid sequence corresponding to the sequence in the test sample, that is to say that all or a part of the region in the sample nucleic acid may firstly be amplified using any convenient technique e.g. polymerase chain reaction (PCR), before analysis.
- the nucleic acid may be genomic DNA or fractionated or whole cell RNA.
- the RNA is whole cell RNA and is used directly as the template for labelling a first strand cDNA using random primers or poly A primers.
- the nucleic acid or protein in the test sample may be extracted from the sample according to standard methodologies (see Green & Sambrook, Eds., Molecular Cloning: A Laboratory Manual, (2012, 4th edition, Vol. 1-3, ISBN
- the diagnostic methods of the invention can be undertaken using a sample previously taken from the individual or patient. Such samples may be preserved by freezing or fixed and embedded in formalin-paraffin or other media. Alternatively, a fresh tumour cell containing sample may be obtained and used.
- tumours for treatment with a compound of Formula (I) have been described hereinbefore.
- mutant ERa nucleic acids can be employed, in the context of the present invention, to select drug treatment. Since mutations in these genes occur at the DNA level, the methods of the invention can be based on detection of mutations or variances in genomic DNA, as well as transcripts and proteins themselves. It can be desirable to confirm mutations in genomic DNA by analysis of transcripts and/or polypeptides, in order to ensure that the detected mutation is indeed expressed in the subject.
- allelic variation requires a mutation discrimination technique, optionally an amplification reaction (such as one based on polymerase chain reaction) and optionally a signal generation system.
- mutation detection techniques available in the art and these may be used in combination with a signal generation system, of which there are numerous available in the art.
- Many methods for the detection of allelic variation are reviewed by Nollau et al., Clin. Chem., 1997, 43, 1114-1120; Anderson SM. Expert Rev Mol Diagn., 2011, 11, 635- 642; Meyerson M.
- determining the presence or absence of a particular variance or plurality of variances in the ERa gene in a patient with cancer can be performed in a variety of ways. Such tests are commonly performed using DNA or RNA collected from biological samples, e.g., tissue biopsies, urine, stool, sputum, blood, cells, tissue scrapings, breast aspirates or other cellular materials, and can be performed by a variety of methods including, but not limited to, PCR, hybridization with allele-specific probes, enzymatic mutation detection, chemical cleavage of mismatches, mass spectrometry or DNA sequencing, including minisequencing.
- biological samples e.g., tissue biopsies, urine, stool, sputum, blood, cells, tissue scrapings, breast aspirates or other cellular materials
- methods including, but not limited to, PCR, hybridization with allele-specific probes, enzymatic mutation detection, chemical cleavage of mismatches, mass spectrometry or DNA sequencing, including minis
- Suitable mutation detection techniques include amplification refractory mutation system (ARMSTM), amplification refractory mutation system linear extension (ALEXTM), competitive oligonucleotide priming system (COPS), Taqman, Molecular Beacons, restriction fragment length polymorphism (RFLP), and restriction site based PCR and fluorescence resonance energy transfer (FRET) techniques.
- ARMSTM amplification refractory mutation system
- ALEXTM amplification refractory mutation system linear extension
- COPS competitive oligonucleotide priming system
- RFLP restriction fragment length polymorphism
- FRET fluorescence resonance energy transfer
- the method employed for determining the nucleotide(s) within a biomarker gene is selected from: allele-specific amplification (allele specific PCR) - such as amplification refractory mutation system (ARMS), sequencing, allelic discrimination assay, hybridisation, restriction fragment length polymorphism (RFLP) or oligonucleotide ligation assay (OLA).
- allele-specific amplification allele specific PCR
- ARMS amplification refractory mutation system
- allelic discrimination assay hybridisation
- RFLP restriction fragment length polymorphism
- OLA oligonucleotide ligation assay
- hybridization with allele specific probes can be conducted by: (1) allele specific oligonucleotides bound to a solid phase (e.g. glass, silicon, nylon membranes) with the labelled sample in solution, for example as in many DNA chip applications; or, (2) bound sample (often cloned DNA or PCR amplified DNA) and labelled oligonucleotides in solution (either allele specific or short so as to allow
- Diagnostic tests may involve a panel of variances, often on a solid support, which enables the simultaneous determination of more than one variance.
- Such hybridization probes are well known in the art (see, e.g., Green & Sambrook, Eds., Molecular Cloning: A Laboratory Manual, (2012, 4th edition, Vol. 1-3, ISBN
- the detection of the presence or absence of at least one mutation provides for contacting ERa nucleic acid containing a putative mutation site with at least one nucleic acid probe.
- the probe preferentially hybridizes with a nucleic acid sequence including a variance site and containing complementary nucleotide bases at the variance site under selective hybridization conditions.
- Hybridization can be detected with a detectable label using labels known to one skilled in the art. Such labels include, but are not limited to radioactive, fluorescent, dye, and enzymatic labels.
- the detection of the presence or absence of at least one mutation provides for contacting ERa nucleic acid containing a putative mutation site with at least one nucleic acid primer.
- the primer preferentially hybridizes with a nucleic acid sequence including a variance site and containing complementary nucleotide bases at the variance site under selective hybridization conditions.
- Oligonucleotides used as primers for specific amplification may carry the complementary nucleotide base to the mutation of interest in the centre of the molecule (so that amplification depends on differential hybridization; see, e.g., Gibbs, et al., 1989. Nucl. Acids Res., 17, 2437-248) or at the extreme 3'-terminus of one primer where, under appropriate conditions, mismatch can prevent, or reduce polymerase extension (see, e.g., Prossner, 1993, Tibtech, 11 238).
- the detection of the presence or absence of at least one mutation comprises sequencing at least one nucleic acid sequence and comparing the obtained sequence with the known wild type nucleic acid sequence.
- the presence or absence of at least one mutation comprises mass spectrometric determination of at least one nucleic acid sequence.
- the detection of the presence or absence of at least one nucleic acid variance comprises performing a polymerase chain reaction (PCR).
- the target nucleic acid sequence containing the hypothetical variance is amplified and the nucleotide sequence of the amplified nucleic acid is determined.
- Determining the nucleotide sequence of the amplified nucleic acid comprises sequencing at least one nucleic acid segment.
- amplification products can be analyzed using any method capable of separating the amplification products according to their size, including automated and manual gel electrophoresis, and the like.
- Mutations in genomic nucleic acid are advantageously detected by techniques based on mobility shift in amplified nucleic acid fragments. For instance, Chen et al., Anal Biochem 1996, 239,, 61-9, describe the detection of single-base mutations by a competitive mobility shift assay. Moreover, assays based on the technique of Marcelino et al.,
- capillary heteroduplex analysis may be used to detect the presence of mutations based on mobility shift of duplex nucleic acids in capillary systems as a result of the presence of mismatches.
- nucleic acids for analysis from samples generally requires nucleic acid amplification.
- Many amplification methods rely on an enzymatic chain reaction (such as a polymerase chain reaction, a ligase chain reaction, or a self-sustained sequence replication) or from the replication of all or part of the vector into which it has been cloned.
- the amplification according to the invention is an exponential amplification, as exhibited by for example the polymerase chain reaction.
- PCR polymerase chain reaction
- LAR ligase amplification reaction
- GAS transcription-based amplification system
- GAWTS genomic amplification with transcript sequencing
- NASBA nucleic acid sequence-based amplification
- PCR Polymerase Chain Reaction
- PCR is a nucleic acid amplification method described inter alia in U.S. Pat. Nos. 4,683,195 and 4,683,202.
- PCR consists of repeated cycles of DNA polymerase generated primer extension reactions.
- the target DNA is heat denatured and two oligonucleotides, which bracket the target sequence on opposite strands of the DNA to be amplified, are hybridised. These oligonucleotides become primers for use with DNA polymerase.
- the DNA is copied by primer extension to make a second copy of both strands. By repeating the cycle of heat denaturation, primer hybridisation and extension, the target DNA can be amplified a million fold or more in about two to four hours.
- PCR is a molecular biology tool, which must be used in conjunction with a detection technique to determine the results of amplification.
- An advantage of PCR is that it increases sensitivity by amplifying the amount of target DNA by 1 million to 1 billion fold in approximately 4 hours.
- PCR can be used to amplify any known nucleic acid in a diagnostic context (Mok et al., Gynaecologic Oncology, 1994, 52: 247-252,).
- An allele specific amplification technique such as Amplification Refractory Mutation System (ARMSTM) (Newton et al., Nucleic Acids Res., 1989, 17, 2503-2516) can also be used to detect single base mutations. Under the appropriate PCR amplification conditions a single base mismatch located at the 3 '-end of the primer is sufficient for preferential amplification of the perfectly matched allele (Newton et al., 1989, supra), allowing the discrimination of closely related species.
- the basis of an amplification system using the primers described above is that oligonucleotides with a mismatched 3'-residue will not function as primers in the PCR under appropriate conditions. This amplification system allows genotyping solely by inspection of reaction mixtures after agarose gel electrophoresis.
- Analysis of amplification products can be performed using any method capable of separating the amplification products according to their size, including automated and manual gel electrophoresis, mass spectrometry, and the like.
- the present invention also provides predictive and diagnostic kits comprising degenerate primers to amplify a target nucleic acid in the ERa gene and instructions comprising; amplification protocol and analysis of the results.
- the kit may alternatively also comprise buffers, enzymes, and containers for performing the amplification and analysis of the amplification products.
- the kit may also be a component of a screening, or diagnostic kit comprising other tools such as DNA microarrays, or other supports.
- the kit also provides one or more control templates, such as nucleic acids isolated from normal tissue sample, and/or a series of samples representing different variances in the reference genes.
- control templates such as nucleic acids isolated from normal tissue sample, and/or a series of samples representing different variances in the reference genes.
- the kit provides two or more primer pairs, each pair capable of amplifying a different region of the reference (ERa) gene (each region a site of potential variance) thereby providing a kit for analysis of expression of several gene variances in a biological sample in one reaction or several parallel reactions.
- ERa reference gene
- Primers in the kits may be labelled, for example fluorescently labelled, to facilitate detection of the amplification products and consequent analysis of the nucleic acid variances.
- the kit may also allow for more than one variance to be detected in one analysis.
- a combination kit will therefore comprise of primers capable of amplifying different segments of the reference gene.
- the primers may be differentially labelled, for example using different fluorescent labels, so as to differentiate between the variances.
- the invention provides a method of treating a patient suffering from cancer comprising: determining the mutant or wild type status of the ERa gene in the patient' s tumour cells and if the ERa gene is mutant, administering to the patient an effective amount of a compound of Formula (I).
- Pharmacological effectiveness refers to the ability of the treatment to result in a desired biological effect in the patient.
- Physiological safety refers to the level of toxicity, or other adverse physiological effects at the cellular, organ and/or organism level (often referred to as side-effects) resulting from administration of the treatment. "Less effective” means that the treatment results in a therapeutically significant lower level of pharmacological effectiveness and/or a therapeutically greater level of adverse physiological effects.
- a compound of Formula (I) or a pharmaceutically-acceptable salt thereof to treat a cancer patient whose tumour cells have been identified as possessing a mutant ERa gene.
- the compound of Formula (I) is Example 1.
- a compound of Formula (I) or a pharmaceutically-acceptable salt thereof for treating cancers with tumour cells identified as harbouring mutant ERa gene is Example 1.
- a method of treating cancers with tumour cells identified as harbouring mutant ERa gene comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically- acceptable salt thereof.
- the compound of Formula (I) is Example 1.
- the invention relates to pharmaceutical composition
- a compound of Formula (I) for use in the prevention and treatment of cancer with tumour cells identified as harbouring a mutant ERa gene.
- the compound of Formula (I) is Example 1.
- mutant forms of ERa determined/identified are at all positions across the gene.
- tumours such as breast cancer
- particular mutant forms of ERa determined/identified are those at positions Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn and Asp538Gly.
- Figure 1 shows an X-Ray Powder Diffraction Pattern of Example 7 Form A
- Figure 2 shows an X-Ray Powder Diffraction Pattern of Example 1 Form B
- Figure 3 shows DSC Thermogram of Example 1 Form B
- Figure 4 shows X-Ray Powder Diffraction Pattern of Example 1 Form A
- Figure 5 shows TGA Thermogram of Example 1 Form A
- Figure 6 shows X-Ray Powder Diffraction Pattern of Example 1 Form C
- FIG. 7 shows TGA Thermogram of Example 1 Form C
- Figure 8 shows an X-Ray Powder Diffraction Pattern of Example 11
- Figure 9 shows a DSC trace of Example 11.
- Figure 10 shows the results of an MCF-7 xenograft study with Example 1 and AZD2014.
- Figures 11 and 12 show the results of an HCC1428 long term estrogen deprived (LTED) xenograft efficacy study with Example 1.
- the column used was Waters Acquity HSS T3 1.8 ⁇ 2.1 x50 mm
- the column used was Waters Acquity BEH 1.7 ⁇ 2.1x50mm
- LCMS was carried out using a Waters Alliance HT (2795) fitted with a Waters ZQ ESCi mass spectrometer and a Phenomenex Gemini -NX (50x2. lmm 5 ⁇ ) column at a flow rate of l.lml/min 95% A to 95%B over 4 min with a 0.5 min hold.
- the modifier is kept at a constant 5% C (50:50 acetonitrile:water 0.1% formic acid) or D (50:50 acetonitrile:water 0.1% ammonium hydroxide (0.88 SG) depending on whether it is an acidic or basic method.
- the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
- the surface planarity of the sample may also have a small effect.
- the diffraction pattern data presented are not to be taken as absolute values;
- the X-ray powder diffractogram was determined by mounting a sample of the crystalline material on a Panalytical single silicon crystal (SSC) wafer mount and spreading out the sample into a thin layer with the aid of a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a copper long-fine focus tube operated at 45kV and 40mA with a wavelength of 1.5418 angstroms. The X-ray beam was passed through a 0.04rad soller slit, then an automatic variable divergence slit set at 20mm and finally a 20mm beam mask.
- SSC Panalytical single silicon crystal
- the reflected radiation was directed through a 20mm antiscatter slit and a 0.04rad soller slit.
- the sample was exposed for 1.905 seconds per 0.0025067° 2-theta increment (continuous scan mode) over the range 2 degrees to 40 degrees 2-theta in theta-theta mode.
- the running time was 3 minutes and 36 seconds.
- the instrument was equipped X-Celerator detector. Control and data capture was by means of a Dell Pentium 4HT Workstation operating with X'Pert Industry software.
- the filtrate was returned to the reactor vessel.
- the filter and filtrate collection vessel were washed with isopropanol (700 ml) and the washings were added to the reactor vessel.
- the reaction mixture was agitated and water (1.75 L) was added.
- Concentrated hydrochloric acid (37% w/w, 165 ml, 1.92 mol) was charged to the vessel. Further hydrochloric acid (21.5 ml) was added to the vessel to adjust the pH between 4.0 and 4.5.
- the solution was heated to 50°C. Water (1.92 L) added to the vessel over 1 hour maintaining the internal temperature between 50-53°C.
- the jacket temperature was raised to 70°C to maintain the reactor temperature in this range during the addition.
- the mixture self seeded and started to crystallise.
- the mixture was held at 50-52°C for 1.5 hours (jacket set temperature 58°C).
- the resulting yellow suspension was cooled to 5°C (jacket temperature) over 6 hours.
- the slurry was held at 5°C (jacket temperature) for 11 hrs.
- the resultant yellow solid was isolated by filtration.
- the cake was pasted with a spatula to prevent cracking of the cake.
- the vessel was washed with water (1.05 L). The washings were used to wash the cake.
- Example 1 An alternative method for synthesising Example 1, which results in formation of Form B crystalline material, is as follows:
- the reaction mixture was diluted with water (250 ml), the pH adjusted to pH4 with cone, hydrochloric acid (27.28ml, 317.63 mmol) and the mixture heated to 50°C. Further water (225 ml) was added over 30 minutes, maintaining the temperature above 45 °C. During the addition, the material began to crystallise. The mixture was cooled from 50°C to 5°C over 5 hours then the suspension was held at 0°C for a further 11 hours. The yellow solid was isolated by filtration.
- crystalline form B of Example 1 isolated from isopropanol/water mixture.
- a process for isolation of crystalline form B of Example 1 which comprises hydrolysis of (E)-methyl 3-(3,5-difluoro- 4-((lR,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4- b]indol-l-yl)phenyl)acrylate in isopropyl alcohol and base, followed by acidification and isolation of crystalline product from aqueous isopropanol.
- Example 1 Form B is characterised in providing at least one of the following 2 ⁇ values measured using CuKa radiation: 8.4 and 10.9.
- Example 1 Form B is characterised in providing an X-ray powder diffraction pattern, substantially as shown in Figure 2.
- Ten X-Ray powder diffraction peaks are shown in Table A:
- Example 1 shows it to be a high melting solid with an endotherm showing onset of melting at 188.6°C ( Figure 3).
- Example 1 shows degradation through the melt which may lead to variation in melting onset, thus the value of 188.6°C should not be taken as absolute.
- Example 1 Two solvated forms of Example 1 have also been observed.
- Form A is a methyl tertiary butyl ether mono-solvate.
- the X-ray powder diffraction pattern is shown in Figure 4.
- TGA shows an associated weight loss of 14.7% w/w between 55-150°C ( Figure 5).
- a theoretical loss for a mono methyl tertiary butyl ether solvate is calculated to be 16.6%.
- Form C is an Acetone mono- solvate
- the X-ray powder diffraction pattern is shown in Figure 6.
- TGA shows an associated weight loss of 10.0% w/w 50-150°C %.
- Figure 7 The theoretical loss for a mono-acetone solvate is calculated to be 11.0%.
- 2,6-Difluoro-4-bromobenzaldehyde 1000 g, 4.39 mol
- l,l-bis(di-tert- butylphosphino)ferrocene palladium dichloride 57.2 g; 87.76 mmol
- Tetra-n-butylammonium chloride 122 g, 438.97 mmol
- dimethylacetamide 5 L
- Phosphonics SPM32 Scavenger (1050 g, 1050 mol) was added to the vessel and the mixture was stirred for 3 days at 25°C.
- the solid material was removed by filtration.
- the cake was washed with ethanol (5L) and the combined filtrates were concentrated under reduced pressure to afford a solid.
- the solid was dissolved in ethanol (9 L) and the solution was agitated in a 20 L vessel.
- the solution was heated to 50°C.
- a solution of sodium bisulfite (460 g, 4.42 mol) in water (2.5 L) was added over 30 minutes. A thick slurry resulted which was stirred for 4 hours at 50°C.
- the slurry was cooled to 20°C over 2 hours.
- a solution of potassium carbonate (0.916 kg, 6.63 mol) in water (3.3 L) was added to the mixture. The mixture was stirred for 10 minutes before the agitator was switched off and the layers were allowed to separate. The aqueous layer was removed and discarded. Water (3.3 L) was charged to the reactor. The mixture was agitated for 10 minutes then allowed to stand for 10 minutes. The lower aqueous phase was removed and the organic layer was allowed to stand at room temperature overnight. The batch was heated to 80°C. Heptane (4.61 L) was added to the hot solution over 35 minutes. The stirred mixture was held at approximately 80°C for 1 hour. The mixture was cooled to 30°C over 2 hours during which time the product crystallised.
- Example 1 Alternative preparation of Example 1: ( ⁇ )-3-(3,5- ⁇ -4-((1 ⁇ ,3 )-2-(2- ⁇ -2- methylpropyl)-3-methyl-2 ⁇ 3 ,9-tetrahvdro-lH-pyrido[3,4-b1indol-l-yl)phenyl)acrylic acid
- the pH of the aqueous was adjusted to -6.5 by addition of 2N HC1 solution, then the solution was extracted with diethyl ether (3 x 150 ml). The combined organics were dried over Na 2 S0 4 and concentrated.
- the crude product was purified by flash silica chromatography, elution gradient 0 to 20% methanol in DCM which afforded a yellow solid. Attempted trituration with acetone/heptane failed due to higher than expected solubility.
- the solvents were removed to give a yellow solid which was triturated in isohexane (50 ml) with a few drops of diethyl ether, the resulting solid was filtered off and dried to give crude product (11.14 g) as a yellow powder.
- the solid was dissolved in ethanol (100 ml), under nitrogen and in the dark. The solution was then evaporated to 5mBar using a vacuum pump at 62°C in the dark. This procedure was repeated twice and the resulting resulting yellow glass scratched with a spatula into a fine powder and subjected to 5mBar using a vacuum pump at 62°C for 60 min, to afford a yellow powder. The powder was then left in a vacuum oven over P 2 O 5 at 62°C at 300 mBar overnight to afford the title product (9.77 g, 89 %) as a pale yellow solid.
- Trifluoromethanesulfonic anhydride (12.06 ml, 71.24 mmol), followed by 2,6-lutidine (11.42 ml, 81.42 mmol) were added to a solution of 2-fluoro-2-methylpropan-l-ol (6.25 g, 67.85 mmol) in DCM (146 ml) at -10 °C.
- the reaction was stirred for 1 hr, then washed with 2N HC1 (2 x 100ml) and saturated NaHC0 3 solution (2 x 100ml). The organic phase was then dried over Na 2 S0 4 and concentrated to give 2-fluoro-2-methylpropyl
- This intermediate may be purified by vacuum distillation. Analysis by DSC showed the material had the potential to self heat. For reasons of process safety a wiped film evaporator or similar may be preferable to a batch distillation.
- the desired product was eluted from the column using 7M NH 3 /methanol and pure fractions were evaporated to dryness to afford a brown solid.
- the crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the title product (7.52 g, 68.0 %) as a yellow solid.
- Fractions containing the desired product were eluted from the column using 7M NH 3 /methanol and pure fractions were evaporated to dryness to afford a yellow solid.
- the crude product was purified by preparative HPLC (Waters SunFire column, 5 ⁇ silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness and then loaded onto SCX-2 column and eluted with 7N ammonia in methanol to afford the title product (63.0 mg, 21.02 %) as a yellow solid.
- reaction mixture was diluted with DCM (60 ml), and washed sequentially with 1M HC1 (3 x 100 ml), saturated sodium bicarbonate solution (100 ml) and saturated brine (50 ml).
- 1M HC1 3 x 100 ml
- saturated sodium bicarbonate solution 100 ml
- saturated brine 50 ml
- the organic layer was dried over Na 2 S0 4 , filtered and evaporated to near dryness.
- the solution was filtered through a plug of silica and washed through with DCM (50 ml) and
- the reaction mixture was evaporated to dryness and redissolved in DCM (500 ml), and washed sequentially with saturated NaHC0 3 (300 ml x 2), 2M NaOH (aq) (300 ml), water (300 ml), and saturated brine (300 ml).
- the organic layer was dried over MgS0 4 , filtered and evaporated to afford crude product.
- the crude product was purified by flash silica chromatography, elution gradient 1 to 7% methanol in DCM.
- the reaction mixture was evaporated to dryness and redissolved in DCM (100 ml), and washed sequentially with 1M citric acid (100 ml), water (100 ml), and saturated brine (100 ml).
- the organic layer was dried over MgS0 4 , filtered and evaporated to afford crude product.
- the crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane.
- Trifluoroacetic acid (5.59 ml, 75.29 mmol) was added to (E)-methyl 3-(4-((lS,3R)-2-allyl- 3-methyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylate (9.7 g, 25.10 mmol) in DCM (100 ml) at 20°C under nitrogen. The resulting solution was stirred at 20 °C for 3 days. The reaction mixture was diluted cautiously with saturated NaHC0 3 solution (250 ml), and the DCM layer washed sequentially with water (250 ml) and saturated brine (250 ml).
- reaction mixtures were combined and evaporated to dryness and redissolved in DCM (200 ml) and saturated NaHC0 3 solution (200 ml) added.
- the organic layer was washed sequentially with water (200 ml) and saturated brine (200 ml) before being dried over MgS0 4 , filtered and evaporated to afford crude product.
- the crude product was purified by flash silica chromatography, elution gradient 0 to 5% methanol in DCM.
- the resulting aqueous solution was acidified to pH 6 with 2M HC1.
- the resulting aqueous suspension was extracted with DCM (500 ml) (adding brine to help separate the emulsion which formed), filtered through a phase- separating paper, dried over MgS0 4 then filtered through celite and evaporated to afford ⁇ 3.5g of a pale yellow solid.
- the crude product was treated with diethyl ether/DCM (1: 1, 150 ml) and sonicated. The fine suspension which formed was passed through a pad of silica ( ⁇ 100g) and the silica was eluted with diethyl ether ( ⁇ 2 L).
- racemic material was purified by preparative HPLC (Chiralpak OD column, 20 ⁇ silica, 100 mm diameter, 250 mm length), Heptane:IPA 50:50. Fractions containing the desired compounds were evaporated to dryness to afford (E)-methyl 3-(4-(3,3-dimethyl- 2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l-yl)phenyl)acrylate (isomer 1, first eluted, 30.3 g, 93 %) and (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-lH-pyrido[3,4-b]indol-l- yl)phenyl)acrylate (isomer 2, second eluted, 28.2 g, 86 %).
- the mixture was concentrated to a volume such that all of the organic solvent had been removed, diluted with water (50 ml), acidified with dilute HCl to pH 6 and extracted with ethyl acetate (2 x 50 ml). The extracts were combined and evaporated under reduced pressure. The residue was purified by preparative HPLC (Chiralpak IA column, 20 ⁇ silica, 20 mm diameter, 250 mm length), HeptaneTPA 90: 10, 0.2% acetic acid at 80 ml / min.
- the mixture was heated at 60°C for 4 hours, then stirred at ambient temperature for 12 hours.
- the mixture was partitioned between ethyl acetate (25 ml) and water (25 ml).
- the aqueous layer was extracted with ethyl acetate (2 x 25 ml) and the extracts combined with the organic layer.
- the combined extracts were evaporated under vacuum.
- the residue was purified by flash silica chromatography, elution solvent 10% EtOAc in heptane.
- This compound could alternatively be named (E)-3-[4-[(lR,3R)-l-deuterio-2-(2-fluoro-2- methyl-propyl)-3-methyl-4,9-dihydro-3H-pyrido[3,4-b]indol-l-yl]-3,5-difluoro- phenyl] acrylic acid.
- Lithium borodeuteride (0.497 g, 17.25 mmol) was added portionwise to a solution of methyl 4-bromo-2,6-difluorobenzoate (2.89 g, 11.5 mmol) in THF (46.0 ml). The reaction was heated to 50 °C for 2 hours. After cooling, (30ml) 2N HC1 was carefully added. The layers were separated, and the aqueous was extracted with EtOAc (2x50ml). The combined organics were washed with brine, dried (MgS0 4 ) and concentrated to afford (4-bromo-2,6- difluoro-phenyl)-dideuterio-methanol (2.250 g, 87 %) as a white solid.
- Dess-Martin reagent (4.98 g, 11.73 mmol) was added to (4-bromo-2,6-difluoro-phenyl)- dideuterio-methanol (2.20 g, 9.78 mmol) in DCM (39.1 ml) at room temperature. The reaction was stirred for 1 hour, then was quenched by addition of (50ml) sat. NaHC0 3 containing 10% sodium thiosulfate. The layers were separated and the aqueous phase was extracted with DCM (2x50ml). The organics were dried (MgS0 4 ) and concentrated, then the crude product was purified by flash silica chromatography, elution gradient 0 to 25% EtOAc in heptane.
- (2R)-l-(lH-indol-3-yl)propan-2-amine (3.81 kg, 21.21 moles) was added to a 100 L glass lined jacketed vessel under an atmosphere of nitrogen.
- 1,4-dioxane (23 L) was added, and the agitator was switched on.
- Diisopropylethylamine (5.55 L; 31.82 moles) was added to the stirred suspension followed by (2-fluoro-2-methyl-propyl)trifluoromethanesulfonate (5.55 kg, 23.77 moles).
- 1,4-Dioxane (4 L) was added to the vessel, and the mixture was heated to 75 °C. Heating was continued for 24 hours before cooling the mixture to 25 °C.
- compositions of Example 1 were manufactured at the 75g scale using a wet granulation process.
- the active ingredient, mannitol, microcrystalline cellulose and sodium starch glycolate were weighed in the quantities tabulated below and transferred to a Diosna Pl-6mixer-granulator and mixed (with chopping) at 600rpm for 6 minutes.
- Composition A mixing was continued while 30mL water was added in two aliquots at a rate of approximately lmL per second, pausing mixing in between aliquots, while for Composition B a solution prepared by stirring the required amounts of EDTA and ascorbic acid with 20mL water at 50°C for 20 minutes (protected from light) was added using an analogous process, the second aliquot in this case comprising approximately lOmL of rinse liquor.
- Wet mixing was continued for a total of 1.5 minutes. The wet granules were passed through a 1.5mm screen then dried under vacuum at 50 - 60°C to a moisture content of ⁇ 2%w/w.
- granules were milled using a 1mm screen then mixed with the lubricant for 5 minutes at 32rpm using a Turbula blender.
- Tablets containing lOmg of the active ingredient were formed by compressing the granules to a nominal lOOmg compression weight using a Riva Mini-press equipped with 6mm normal concave tooling.
- compositions A and B with regard to degradant formation were evaluated for tablets packed in induction sealed 75cc HDPE bottles or exposed to the atmosphere in petri dishes, stored in the dark, under controlled temperature and humidity as tabulated below. It is apparent that Composition B, which contains both a chelating agent and anti-oxidant, is more stable to chemical degradation than Composition A which is a standard tablet formulation. Stability of exemplary compositions with regard to Degradant formation (%)
- reaction mixture was cooled and purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5 ⁇ silica, 50 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH 3 ) and MeCN as eluents.
- Fractions containing the desired compound were evaporated to dryness to afford (E)-3-[3,5-difluoro-4-[2-(2-fluoro-2-methyl-propyl)-3-methyl-9H-pyrido[3,4-b]indol-2- ium-l-yl]phenyl]prop-2-enoate (0.047 g, 9.40 %) as an orange solid.
- Example 14A Preparation of (E)-3-[3,5-difluoro-4-[(lR ⁇ 3 )-2-(2-fluoro-3-hydroxy- l-methyl-propyP-S-methyl-l ⁇ -tetrahydropyrido ⁇ -blindol-l-yllphenyllprop-l- enoic acid (Isomer 1)
- the aqueous was adjusted to pH 6 by addition of 2M HCl, and the layers were separated.
- the aqueous layer was extracted with EtOAc, then the combined organics were dried (MgS0 4 ) and concentrated in vacuo.
- the crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.
- Example 14B Preparation of ( ⁇ )-3- ⁇ 3,5- ⁇ -4- ⁇ (1 ⁇ ,3 ⁇ )-2-(2- ⁇ -3- ⁇ ( ⁇ - l-methyl-propyP-S-methyl-l ⁇ -tetrahydropyrido ⁇ -blindol-l-yllphenyllprop-l- enoic acid (Isomer 2)
- the aqueous was adjusted to pH 6 by addition of 2M HCl, and the layers were separated.
- the aqueous layer was extracted with EtOAc, then the combined organics were dried (MgS0 4 ) and concentrated in vacuo.
- the crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM.
- Trifluoromethanesulfonic anhydride (1.151 ml, 6.80 mmol) was added to a solution of 2- fluoro-2-methylpropane-l,3-diol (0.70 g, 6.47 mmol) in DCM (17.85 ml) at 0 °C, followed by 2,6-lutidine (0.908 ml, 7.77 mmol). The reaction was allowed to warm to room temperature over 30 min, then was washed with 2M HC1. The organic phase was passed through a phase separator cartridge and concentrated in vacuo.
- the mixture was held at 50°C overnight during which time a precipitate formed.
- the solid material was isolated by filtration and washed with water and acetonitrile. This material still contained minor impurities from the previous stage and required further purification. The material was dissolved in
- the reaction mixture was stirred at 60°C for 5.5h then at 50°C overnight.
- the reaction mixture was cooled to 0°C and the solid was filtered off.
- the product was slurried in water (250 mL) for 20 min at room temperature, filtered off, washed with water (3x40 mL) and dried at 50°C in vacuo.
- the methanol liquors were concentrated and the resulting solid was slurried in water (0.6 L) for 20 min at room temperature.
- the solid was isolated by filtration and washed with water (3x100 mL).
- the filter cake was slurried for a second time in water (0.5 L) for a further 20 minutes.
- the product was isolated by filtration, washed with water (100 mL) and dried at 50°C in vacuo.
- This material was further purified by slurrying in heptane (7.5 rel vols) for 1 hour. The mixture was filtered, pulled dry on the filter, and dried at 50°C in a vacuum oven overnight to afford l-(4-(5-(5-amino-6-(5-tert-butyl-l,3,4-oxadiazol-2-yl)pyrazin-2-yl)-l-ethyl-lH- l,2,4-triazol-3-yl)piperidin-l-yl)-3-hydroxypropan-l-one (102.5g) as Form B.
- Form B may also be made by slurrying Form A in MeCN without seeding.
- Form A or B may also be converted to Form C as follows:
- Form C may also be converted to Form B as follows:
- Form C (377.8 g portion 1) in MIBK (7900 mL) was heated to 110-115 °C to give a solution.
- the solution was allowed to cool to 97-103 °C and immediately polish filtered into a 50L vessel containing a seed of Form B (0.8 g) in acetonitrile (8220 mL) stirring at -15 °C.
- the temperature in the 50 L vessel was maintained between -15 and 25 °C by means of jacket cooling.
- Three further portions of the compound dissolved in MIBK were added by a similar method.
- To the resulting slurry was added a seed of form B (0.8 g) and the mixture was then stirred at 10- 20 °C overnight.
- tert-butyl 4-(5-(5-amino-6-(5-tert-butyl-l,3,4-oxadiazol-2-yl)pyrazin-2-yl)-lH-l,2,4- triazol-3-yl)piperidine-l-carboxylate was prepared as follows:
- a stream of nitrogen gas was passed through a solution of 5-bromo-3-(5-tert-butyl-l,3,4- oxadiazol-2-yl)pyrazin-2-amine (89.35 g, 239.75 mmol) in DMA (1.2 L) for 20 minutes.
- Dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (11.43 g, 23.98 mmol), tris(dibenzylideneacetone)dipalladium(0) (5.49 g, 5.99 mmol), zinc (1.568 g, 23.98 mmol) and dicyanozinc (16.89 g, 143.85 mmol) were added sequentially to the stirred mixture.
- the mixture was heated to 100°C and stirred for 1 hour.
- the mixture was cooled and partitioned between DCM (3 L) and water (1L).
- the black mixture was filtered through celite and the organic layer was separated. The solution was washed with water then brine.
- the N-Boc-isonipecotic acid may be made in situ as follows: Isonipecotic acid (858g, 3.74mol) was dissolved in DMA (25.3L) and 4-methylmorpholine (393mL, 3.74mol) added. Stirred for 5 mins and isobutyl chloroformate (489mL, 3.74mol) added. The reaction mixture was stirred at 25°C for 2h and cooled to 15°C before (Z)-5- amino-6-(5-tert-butyl- 1 ,3 ,4-oxadiazol-2-yl)pyrazine-2-carbohydrazonamide (940g, 3.4mol) was added portionwise over 10 mins.
- reaction mixture was stirred for l-2h at 15°C.
- Water (20.5L) was added portionwise over lh and stirred for a further lh before being filtered.
- the filtercake was then washed with water (4 x 4L) and pulled dry on the filter before being dried in a vacuum oven at 50°C until dry to give the desired product.
- reaction mixture was stirred at 100°C for 1.5 hours (suspension) then held at 80°C overnight (solution formed after overnight hold).
- the resulting solution was concentrated under reduced pressure, then diluted with toluene, evaporated to dryness, taken up with toluene and concentrated again.
- the residual oil was mixed with some ethyl acetate and concentrated to dryness.
- a solid crystallised from solution which was triturated with MTBE (200 mL) and isolated by filtration.
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
Claims
Priority Applications (27)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AP2015008858A AP2015008858A0 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
PL14727036T PL3004090T3 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
SG11201509393VA SG11201509393VA (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
EP14727036.7A EP3004090B1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
CN201480028785.1A CN105229004B (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
MEP-2017-292A ME02892B (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
DK14727036.7T DK3004090T3 (en) | 2013-05-28 | 2014-05-27 | CHEMICAL COMPOUNDS |
RS20171304A RS56678B1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
JP2016516235A JP6286031B2 (en) | 2013-05-28 | 2014-05-27 | Compound |
CA2911859A CA2911859A1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
ES14727036.7T ES2654161T3 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
AU2014272856A AU2014272856B2 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
KR1020157036820A KR20160013198A (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
RU2015151502A RU2664109C2 (en) | 2013-05-28 | 2014-05-27 | Tetrahydropyrido[3,4-b]indole derivatives useful in treatment of cancer |
MA38620A MA38620B1 (en) | 2013-05-28 | 2014-05-27 | Compound (e) -3- (4 - ((3r) -3-methyl-2-propyl-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indol-1-yl) phenyl ) acrylic acid for the treatment or prevention of breast cancer |
BR112015029455A BR112015029455A8 (en) | 2013-05-28 | 2014-05-27 | chemical compounds, use, methods and compositions for cancer prevention or treatment |
LTEP14727036.7T LT3004090T (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
TN2015000516A TN2015000516A1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
SI201430531T SI3004090T1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
MX2015016428A MX361538B (en) | 2013-05-28 | 2014-05-27 | Chemical compounds. |
EP17196495.0A EP3360875A1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
IL242559A IL242559B (en) | 2013-05-28 | 2015-11-12 | Chemical compounds |
PH12015502615A PH12015502615B1 (en) | 2013-05-28 | 2015-11-24 | Chemical compounds |
CR20150629A CR20150629A (en) | 2013-05-28 | 2015-11-30 | CHEMICAL COMPOUNDS |
HK16111116.8A HK1222859A1 (en) | 2013-05-28 | 2016-09-22 | Chemical compounds |
HRP20171961TT HRP20171961T1 (en) | 2013-05-28 | 2017-12-18 | Chemical compounds |
CY20181100009T CY1120474T1 (en) | 2013-05-28 | 2018-01-03 | CHEMICAL COMPOUNDS |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361827951P | 2013-05-28 | 2013-05-28 | |
US61/827,951 | 2013-05-28 | ||
US201361915685P | 2013-12-13 | 2013-12-13 | |
US61/915,685 | 2013-12-13 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP17196495.0A Previously-Filed-Application EP3360875A1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014191726A1 true WO2014191726A1 (en) | 2014-12-04 |
Family
ID=50841880
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2014/051607 WO2014191726A1 (en) | 2013-05-28 | 2014-05-27 | Chemical compounds |
Country Status (35)
Country | Link |
---|---|
US (4) | US9155727B2 (en) |
EP (2) | EP3004090B1 (en) |
JP (1) | JP6286031B2 (en) |
KR (1) | KR20160013198A (en) |
CN (1) | CN105229004B (en) |
AP (1) | AP2015008858A0 (en) |
AU (1) | AU2014272856B2 (en) |
BR (1) | BR112015029455A8 (en) |
CA (1) | CA2911859A1 (en) |
CL (1) | CL2015003491A1 (en) |
CR (1) | CR20150629A (en) |
CY (1) | CY1120474T1 (en) |
DK (1) | DK3004090T3 (en) |
DO (1) | DOP2015000274A (en) |
ES (1) | ES2654161T3 (en) |
HK (1) | HK1222859A1 (en) |
HR (1) | HRP20171961T1 (en) |
HU (1) | HUE035738T2 (en) |
IL (1) | IL242559B (en) |
LT (1) | LT3004090T (en) |
ME (1) | ME02892B (en) |
MX (1) | MX361538B (en) |
NI (1) | NI201500167A (en) |
PE (1) | PE20160874A1 (en) |
PH (1) | PH12015502615B1 (en) |
PL (1) | PL3004090T3 (en) |
PT (1) | PT3004090T (en) |
RS (1) | RS56678B1 (en) |
RU (1) | RU2664109C2 (en) |
SG (1) | SG11201509393VA (en) |
SI (1) | SI3004090T1 (en) |
TN (1) | TN2015000516A1 (en) |
TW (1) | TWI653235B (en) |
UY (1) | UY35590A (en) |
WO (1) | WO2014191726A1 (en) |
Cited By (69)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016097072A1 (en) | 2014-12-18 | 2016-06-23 | F. Hoffmann-La Roche Ag | TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF |
WO2016146591A1 (en) * | 2015-03-16 | 2016-09-22 | Astrazeneca Ab | Combination treatment |
WO2016202161A1 (en) * | 2015-06-16 | 2016-12-22 | 江苏恒瑞医药股份有限公司 | Piperidine derivative and preparation method and pharmaceutical use thereof |
WO2017024318A1 (en) | 2015-08-06 | 2017-02-09 | Dana-Farber Cancer Institute, Inc. | Targeted protein degradation to attenuate adoptive t-cell therapy associated adverse inflammatory responses |
WO2017059139A1 (en) | 2015-10-01 | 2017-04-06 | Olema Pharmaceuticals, Inc. | TETRAHYDRO-1H-PYRIDO[3,4-b]INDOLE ANTI-ESTROGENIC DRUGS |
WO2017080338A1 (en) * | 2015-11-12 | 2017-05-18 | 浙江海正药业股份有限公司 | Acrylic acid derivative, preparation method and use in medicine thereof |
WO2017100712A1 (en) | 2015-12-09 | 2017-06-15 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
WO2017107754A1 (en) | 2015-12-22 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Benzopiperidine derivative, preparation method thereof and medical use thereof |
WO2017136688A1 (en) | 2016-02-05 | 2017-08-10 | Inventisbio Inc. | Selective estrogen receptor degraders and uses thereof |
WO2017172957A1 (en) | 2016-04-01 | 2017-10-05 | Kalyra Pharmaceuticals, Inc. | Estrogen receptor modulators |
WO2017197055A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Heterocyclic degronimers for target protein degradation |
WO2017197046A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | C3-carbon linked glutarimide degronimers for target protein degradation |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
WO2017216280A1 (en) | 2016-06-16 | 2017-12-21 | F. Hoffmann-La Roche Ag | TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF |
US9873671B2 (en) | 2014-01-16 | 2018-01-23 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
WO2018019793A1 (en) | 2016-07-25 | 2018-02-01 | Astrazeneca Ab | N-(2-(4-((1r,3r)-3-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine derivatives and related compounds as selective down-regulators of the estrogen receptor for treating cancer |
US9884818B2 (en) | 2013-05-17 | 2018-02-06 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US9895349B2 (en) | 2013-04-03 | 2018-02-20 | Janssen Sciences Ireland Us | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
CN107814798A (en) * | 2016-09-14 | 2018-03-20 | 四川科伦博泰生物医药股份有限公司 | 3 substitutional crylic acid class compounds and its production and use |
WO2018129387A1 (en) | 2017-01-06 | 2018-07-12 | G1 Therapeutics, Inc. | Combination therapy for the treatment of cancer |
US10071961B2 (en) | 2013-10-23 | 2018-09-11 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10077239B2 (en) | 2015-09-29 | 2018-09-18 | Novira Therapeutics, Inc. | Crystalline forms of a hepatitis B antiviral agent |
US10125135B2 (en) | 2016-04-20 | 2018-11-13 | Astrazeneca Ab | Chemical compounds |
US10125094B2 (en) | 2013-02-28 | 2018-11-13 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
US10131663B2 (en) | 2016-10-24 | 2018-11-20 | Astrazeneca Ab | Chemical compounds |
US10160743B2 (en) | 2013-05-17 | 2018-12-25 | Janssen Sciences Ireland Uc | Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
WO2019006393A1 (en) | 2017-06-29 | 2019-01-03 | G1 Therapeutics, Inc. | Morphic forms of git38 and methods of manufacture thereof |
US10196376B2 (en) | 2011-12-21 | 2019-02-05 | Novira Therapeutics, Inc. | Hepatitis B antiviral agents |
US10208011B2 (en) | 2017-02-10 | 2019-02-19 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
US10213420B2 (en) | 2014-02-05 | 2019-02-26 | Novira Therapeutics, Inc. | Combination therapy for treatment of HBV infections |
US10221173B2 (en) | 2017-01-30 | 2019-03-05 | Astrazeneca Ab | Chemical compounds |
WO2019079569A1 (en) | 2017-10-18 | 2019-04-25 | Novartis Ag | Compositions and methods for selective protein degradation |
JP2019514930A (en) * | 2016-04-29 | 2019-06-06 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | Targeted measure of transcriptional activity related to hormone receptors |
WO2019123367A1 (en) | 2017-12-21 | 2019-06-27 | Astrazeneca Ab | Compounds and their use in treating cancer |
JP2019521982A (en) * | 2016-06-16 | 2019-08-08 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Heteroaryl estrogen receptor modulators and uses thereof |
US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
US10441589B2 (en) | 2016-04-15 | 2019-10-15 | Novira Therapeutics, Inc. | Combinations and methods comprising a capsid assembly inhibitor |
US10450270B2 (en) | 2013-07-25 | 2019-10-22 | Janssen Sciences Ireland Uc | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10537580B2 (en) | 2015-03-19 | 2020-01-21 | Novira Therapeutics, Inc. | Azocane and azonane derivatives and methods of treating hepatitis B infections |
US10676429B2 (en) | 2012-08-28 | 2020-06-09 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
WO2020132561A1 (en) | 2018-12-20 | 2020-06-25 | C4 Therapeutics, Inc. | Targeted protein degradation |
US10703747B2 (en) | 2016-10-24 | 2020-07-07 | The Board of Directors of the University of Illinois | Benzothiophene-based selective mixed estrogen receptor downregulators |
WO2020219742A1 (en) | 2019-04-24 | 2020-10-29 | Novartis Ag | Compositions and methods for selective protein degradation |
US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10954234B2 (en) | 2018-06-21 | 2021-03-23 | Genentech, Inc. | Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use |
US10973801B2 (en) | 2018-03-14 | 2021-04-13 | Janssen Sciences Ireland Unlimited Company | Capsid assembly modulator dosing regimen |
WO2021091819A1 (en) * | 2019-11-04 | 2021-05-14 | Recurium Ip Holdings, Llc | Salts and forms of an estrogen receptor modulator |
WO2021127561A1 (en) | 2019-12-20 | 2021-06-24 | C4 Therapeutics, Inc. | Isoindolinone and indazole compounds for the degradation of egfr |
WO2021139756A1 (en) | 2020-01-10 | 2021-07-15 | 江苏恒瑞医药股份有限公司 | Tricyclic tetrahydroisoquinoline derivative, preparation method therefor and application thereof in medicine |
US11078193B2 (en) | 2014-02-06 | 2021-08-03 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
EP3858835A1 (en) | 2016-07-01 | 2021-08-04 | G1 Therapeutics, Inc. | Pyrimidine-based antiproliferative agents |
US11096931B2 (en) | 2019-02-22 | 2021-08-24 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
WO2021253380A1 (en) * | 2020-06-19 | 2021-12-23 | InventisBio Co., Ltd. | Oral formulations and uses thereof |
US11278532B2 (en) | 2019-08-06 | 2022-03-22 | Recurium Ip Holdings, Llc | Estrogen receptor modulators for treating mutants |
US11311609B2 (en) | 2017-02-08 | 2022-04-26 | Dana-Farber Cancer Institute, Inc. | Regulating chimeric antigen receptors |
US11339162B1 (en) | 2020-12-23 | 2022-05-24 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
WO2022109395A2 (en) | 2020-11-23 | 2022-05-27 | Sanofi | Panel of er regulated genes for use in monitoring endocrine therapy in breast cancer |
US11491148B2 (en) | 2019-05-06 | 2022-11-08 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
US11547762B2 (en) | 2016-10-05 | 2023-01-10 | Genentech, Inc. | Methods for preparing antibody drug conjugates |
WO2023280309A1 (en) | 2021-07-09 | 2023-01-12 | 江苏恒瑞医药股份有限公司 | Salt types of tricyclic tetrahydro isoquinoline derivative |
EP3969050A4 (en) * | 2019-05-14 | 2023-11-01 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
WO2023221123A1 (en) * | 2022-05-20 | 2023-11-23 | Olema Pharmaceuticals, Inc. | Crystalline forms of an estrogen receptor antagonist |
US11834458B2 (en) | 2021-03-23 | 2023-12-05 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
WO2024030968A1 (en) | 2022-08-03 | 2024-02-08 | Brystol-Myers Squibb Company | Compounds for modulating ret protein |
US11903931B2 (en) | 2018-12-24 | 2024-02-20 | InventisBio Co., Ltd. | Salts of selective estrogen receptor degraders |
US11952349B2 (en) | 2019-11-13 | 2024-04-09 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
WO2024097980A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein inhibitors |
WO2024097989A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein degraders |
US12006314B2 (en) | 2021-05-03 | 2024-06-11 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017197904A2 (en) * | 2016-05-08 | 2017-11-23 | 上海诚妙医药科技有限公司 | New crystal forms of palbociclib, and preparation method and use therefor |
CN109415361B (en) * | 2016-06-29 | 2022-03-08 | 浙江海正药业股份有限公司 | Acrylic acid derivative, preparation method thereof and application thereof in medicine |
WO2018130124A1 (en) * | 2017-01-11 | 2018-07-19 | 南京圣和药业股份有限公司 | Tricyclic compound as selective estrogen receptor down-regulator and use thereof |
WO2018130123A1 (en) * | 2017-01-11 | 2018-07-19 | 南京圣和药业股份有限公司 | Pentacyclic compound as selective estrogen receptor down-regulator and use thereof |
CN108864080B (en) * | 2017-05-09 | 2021-10-15 | 南京圣和药业股份有限公司 | Tetracyclic compounds as selective estrogen receptor down-regulating agents and application thereof |
WO2018233591A1 (en) * | 2017-06-20 | 2018-12-27 | 江苏恒瑞医药股份有限公司 | Salt of benzopiperidine derivative and crystal form thereof, and method for preparing salt and crystal form thereof |
EA038160B1 (en) * | 2017-11-30 | 2021-07-15 | Астразенека Аб | Estrogen receptor modulators |
CN109867659A (en) * | 2017-12-04 | 2019-06-11 | 江苏恒瑞医药股份有限公司 | The preparation method of benzo piperidine derivatives |
CN112041294B (en) * | 2018-02-23 | 2024-02-20 | 晶体工程智能研究中心 | Co-crystals of panthenol and compositions comprising said co-crystals |
TW202016084A (en) * | 2018-05-30 | 2020-05-01 | 大陸商迪哲(江蘇)醫藥有限公司 | Selective estrogen receptor downregulators and uses thereof |
AU2019299221A1 (en) | 2018-07-03 | 2021-02-04 | The Board Of Trustees Of The University Of Illinois | Activators of the unfolded protein response |
EP4192439A1 (en) * | 2020-08-05 | 2023-06-14 | Aizant Drug Research Solutions Private Limited | Solid dosage forms of palbociclib |
CA3226156A1 (en) * | 2021-07-08 | 2023-01-12 | Olema Pharmaceuticals, Inc. | Methods of treating estrogen receptor-associated diseases |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005070930A2 (en) * | 2004-01-23 | 2005-08-04 | Chiron Corporation | Tetrahydrocarboline compounds as anticancer agents |
US20100003324A1 (en) * | 2008-07-03 | 2010-01-07 | Osteogenex Inc. | Vinpocetine and eburn amonine derivatives for promoting bone growth |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
WO1997039748A1 (en) | 1996-04-19 | 1997-10-30 | Novo Nordisk A/S | Modulators of molecules with phosphotyrosine recognition units |
FR2778404B1 (en) * | 1998-05-06 | 2000-06-30 | Hoechst Marion Roussel Inc | DERIVATIVES OF DIHYDRO OR TETRAHYDRONAPHTALENE, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
GB9814414D0 (en) | 1998-07-03 | 1998-09-02 | Celltech Therapeutics Ltd | Chemical compounds |
ES2287016T3 (en) | 1999-04-28 | 2007-12-16 | Sanofi-Aventis Deutschland Gmbh | DERIVATIVES OF DIARIL-ACID AS LIGANDS OF THE PPAR RECEIVER. |
FR2796644B1 (en) * | 1999-07-23 | 2001-09-07 | Adir | NOVEL BETA-CARBOLINE DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
HUP0300894A3 (en) * | 2000-03-15 | 2008-05-28 | Sanofi Aventis Deutschland | Substituted beta-carbolines, process for their preparation, pharmaceutical compositions containing them and their use |
US6720331B2 (en) | 2001-04-03 | 2004-04-13 | National Sun Yat-Sen University | 1-substituted 1,2,3,4-tetrahydro-β-carboline and 3,4-dihydro-β-carboline and analogs as antitumor agents |
AU2003205630A1 (en) | 2002-01-18 | 2003-07-30 | The Genetics Company Inc. | Beta-secretase inhibitors |
DE60322869D1 (en) | 2002-04-22 | 2008-09-25 | Univ Johns Hopkins | MODULATORS OF HEDGEHOG SIGNALING PATCHES, COMPOSITIONS AND RELATED USES |
TWI329111B (en) | 2002-05-24 | 2010-08-21 | X Ceptor Therapeutics Inc | Azepinoindole and pyridoindole derivatives as pharmaceutical agents |
US20050004164A1 (en) | 2003-04-30 | 2005-01-06 | Caggiano Thomas J. | 2-Cyanopropanoic acid amide and ester derivatives and methods of their use |
JP4671123B2 (en) | 2003-06-23 | 2011-04-13 | 小野薬品工業株式会社 | New tricyclic heterocyclic compounds |
AU2004261627C1 (en) * | 2003-07-28 | 2009-02-05 | Smithkline Beecham Corporation | Cycloalkylidene compounds as modulators of estrogen receptor |
DE10335725A1 (en) | 2003-08-05 | 2005-03-03 | Bayer Cropscience Gmbh | Safener based on aromatic-aliphatic carboxylic acid derivatives |
DE602005006539D1 (en) * | 2004-03-11 | 2008-06-19 | Actelion Pharmaceuticals Ltd | TETRAHYDROPYRIDOINDOLDERIVATE |
US8076352B2 (en) | 2004-03-15 | 2011-12-13 | Ptc Therapeutics, Inc. | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
GB0422057D0 (en) | 2004-10-05 | 2004-11-03 | Astrazeneca Ab | Novel compounds |
US20060094747A1 (en) | 2004-10-28 | 2006-05-04 | The Institute For Pharmaceutical Discovery, L.L.C. | Substituted carboxylic acids |
JP2008520683A (en) | 2004-11-18 | 2008-06-19 | ジ インスチチュート フォー ファーマシューティカル ディスカバリー、エルエルシー | Heterocyclylbiphenyl derivatives as protein tyrosine phosphatase inhibitors |
AU2006214319A1 (en) | 2005-02-14 | 2006-08-24 | Miikana Therapeutics, Inc. | Fused heterocyclic compounds useful as inhibitors of histone deacetylase |
EP1863810A4 (en) * | 2005-03-22 | 2010-03-31 | Astrazeneca Ab | NOVEL TETRAHYDRO-1H-PYRIDO [4,3-b] INDOLE DERIVATIVES AS CB1' RECEPTOR LIGANDS |
US20070032385A1 (en) | 2005-06-20 | 2007-02-08 | Dunetz Joshua R | Sustainable chemical processes |
CA2652235A1 (en) | 2006-05-09 | 2007-11-22 | Hemaquest Pharmaceuticals, Inc. | Methods for treating blood disorders |
LT2057156T (en) | 2006-08-23 | 2017-05-25 | Kudos Pharmaceuticals Limited | 2-methylmorpholine pyrido-,pyrazo- and pyrimido-pyrimidine derivatives as mtor inhibitors |
CA2662218A1 (en) | 2006-08-29 | 2008-03-06 | Reinnervate Limited | Retinoid compounds and their use |
WO2008124838A1 (en) | 2007-04-10 | 2008-10-16 | University Of Maryland, Baltimore | Compounds that inhibit human dna ligases and methods of treating cancer |
US20100249234A1 (en) | 2007-04-10 | 2010-09-30 | Uwm Research Foundation, Inc. | Methods of reducing virulence in bacteria |
US20100158858A1 (en) | 2007-04-13 | 2010-06-24 | Liangxian Cao | Administration of carboline derivatives useful in the treatment of cancer and other diseases |
JP2010533712A (en) | 2007-07-19 | 2010-10-28 | メルク・シャープ・エンド・ドーム・コーポレイション | Betacarboline derivatives as antidiabetic compounds |
TW201028414A (en) | 2009-01-16 | 2010-08-01 | Merck Sharp & Dohme | Oxadiazole beta carboline derivatives as antidiabetic compounds |
WO2010107485A1 (en) | 2009-03-17 | 2010-09-23 | The Trustees Of Columbia University In The City Of New York | E3 ligase inhibitors |
WO2010138706A1 (en) | 2009-05-27 | 2010-12-02 | Ptc Therapeutics, Inc. | Methods for treating breast cancer |
US9351964B2 (en) * | 2009-05-27 | 2016-05-31 | Ptc Therapeutics, Inc. | Methods for treating cancer and non-neoplastic conditions |
US9434747B2 (en) | 2011-02-18 | 2016-09-06 | Medivation Technologies, Inc. | Methods of treating diabetes |
WO2013022740A2 (en) | 2011-08-05 | 2013-02-14 | Corning Incorporated | Gpr35 ligands and the uses thereof |
-
2014
- 2014-05-27 PL PL14727036T patent/PL3004090T3/en unknown
- 2014-05-27 CN CN201480028785.1A patent/CN105229004B/en not_active Expired - Fee Related
- 2014-05-27 MX MX2015016428A patent/MX361538B/en active IP Right Grant
- 2014-05-27 SI SI201430531T patent/SI3004090T1/en unknown
- 2014-05-27 DK DK14727036.7T patent/DK3004090T3/en active
- 2014-05-27 CA CA2911859A patent/CA2911859A1/en not_active Abandoned
- 2014-05-27 ES ES14727036.7T patent/ES2654161T3/en active Active
- 2014-05-27 WO PCT/GB2014/051607 patent/WO2014191726A1/en active Application Filing
- 2014-05-27 AU AU2014272856A patent/AU2014272856B2/en not_active Ceased
- 2014-05-27 PE PE2015002429A patent/PE20160874A1/en active IP Right Grant
- 2014-05-27 PT PT147270367T patent/PT3004090T/en unknown
- 2014-05-27 US US14/287,332 patent/US9155727B2/en not_active Expired - Fee Related
- 2014-05-27 UY UY0001035590A patent/UY35590A/en not_active Application Discontinuation
- 2014-05-27 LT LTEP14727036.7T patent/LT3004090T/en unknown
- 2014-05-27 EP EP14727036.7A patent/EP3004090B1/en active Active
- 2014-05-27 JP JP2016516235A patent/JP6286031B2/en not_active Expired - Fee Related
- 2014-05-27 AP AP2015008858A patent/AP2015008858A0/en unknown
- 2014-05-27 ME MEP-2017-292A patent/ME02892B/en unknown
- 2014-05-27 SG SG11201509393VA patent/SG11201509393VA/en unknown
- 2014-05-27 TW TW103118498A patent/TWI653235B/en not_active IP Right Cessation
- 2014-05-27 HU HUE14727036A patent/HUE035738T2/en unknown
- 2014-05-27 RS RS20171304A patent/RS56678B1/en unknown
- 2014-05-27 KR KR1020157036820A patent/KR20160013198A/en not_active Application Discontinuation
- 2014-05-27 EP EP17196495.0A patent/EP3360875A1/en not_active Withdrawn
- 2014-05-27 TN TN2015000516A patent/TN2015000516A1/en unknown
- 2014-05-27 RU RU2015151502A patent/RU2664109C2/en active
- 2014-05-27 BR BR112015029455A patent/BR112015029455A8/en not_active Application Discontinuation
-
2015
- 2015-08-31 US US14/840,342 patent/US9616050B2/en active Active
- 2015-11-11 DO DO2015000274A patent/DOP2015000274A/en unknown
- 2015-11-12 IL IL242559A patent/IL242559B/en not_active IP Right Cessation
- 2015-11-24 PH PH12015502615A patent/PH12015502615B1/en unknown
- 2015-11-27 NI NI201500167A patent/NI201500167A/en unknown
- 2015-11-27 CL CL2015003491A patent/CL2015003491A1/en unknown
- 2015-11-30 CR CR20150629A patent/CR20150629A/en unknown
-
2016
- 2016-09-22 HK HK16111116.8A patent/HK1222859A1/en not_active IP Right Cessation
-
2017
- 2017-02-28 US US15/445,000 patent/US10130617B2/en not_active Expired - Fee Related
- 2017-12-18 HR HRP20171961TT patent/HRP20171961T1/en unknown
-
2018
- 2018-01-03 CY CY20181100009T patent/CY1120474T1/en unknown
- 2018-10-12 US US16/158,527 patent/US20190038607A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005070930A2 (en) * | 2004-01-23 | 2005-08-04 | Chiron Corporation | Tetrahydrocarboline compounds as anticancer agents |
US20100003324A1 (en) * | 2008-07-03 | 2010-01-07 | Osteogenex Inc. | Vinpocetine and eburn amonine derivatives for promoting bone growth |
Non-Patent Citations (1)
Title |
---|
YA-CHING SHEN ET AL: "The Preparation and Evaluation of 1-Substituted 1,2,3,4-Tetrahydro- and 3,4-Dihydro-[beta]-carboline Derivatives as Potential Antitumor Agents", CHEMICAL & PHARMACEUTICAL BULLETIN, vol. 53, no. 1, 1 January 2005 (2005-01-01), pages 32 - 36, XP055126371, ISSN: 0009-2363, DOI: 10.1248/cpb.53.32 * |
Cited By (145)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10196376B2 (en) | 2011-12-21 | 2019-02-05 | Novira Therapeutics, Inc. | Hepatitis B antiviral agents |
US10995064B2 (en) | 2012-08-28 | 2021-05-04 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
US10676429B2 (en) | 2012-08-28 | 2020-06-09 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
US10125094B2 (en) | 2013-02-28 | 2018-11-13 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
US10941113B2 (en) | 2013-02-28 | 2021-03-09 | Janssen Sciences Ireland Uc | Sulfamoyl-arylamides and the use thereof as medicaments for the treatment of hepatitis B |
US9895349B2 (en) | 2013-04-03 | 2018-02-20 | Janssen Sciences Ireland Us | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10398677B2 (en) | 2013-04-03 | 2019-09-03 | Janssen Sciences Ireland Uc | N-phenyl-carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10457638B2 (en) | 2013-05-17 | 2019-10-29 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10160743B2 (en) | 2013-05-17 | 2018-12-25 | Janssen Sciences Ireland Uc | Sulphamoylthiophenamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US9884818B2 (en) | 2013-05-17 | 2018-02-06 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10450270B2 (en) | 2013-07-25 | 2019-10-22 | Janssen Sciences Ireland Uc | Glyoxamide substituted pyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10377709B2 (en) | 2013-10-23 | 2019-08-13 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10071961B2 (en) | 2013-10-23 | 2018-09-11 | Janssen Sciences Ireland Uc | Carboxamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10392349B2 (en) | 2014-01-16 | 2019-08-27 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
US9873671B2 (en) | 2014-01-16 | 2018-01-23 | Novira Therapeutics, Inc. | Azepane derivatives and methods of treating hepatitis B infections |
US10632112B2 (en) | 2014-02-05 | 2020-04-28 | Novira Therapeutics, Inc. | Combination therapy for treatment of HBV infections |
US10213420B2 (en) | 2014-02-05 | 2019-02-26 | Novira Therapeutics, Inc. | Combination therapy for treatment of HBV infections |
US11078193B2 (en) | 2014-02-06 | 2021-08-03 | Janssen Sciences Ireland Uc | Sulphamoylpyrrolamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US10966963B2 (en) | 2014-12-18 | 2021-04-06 | Genentech, Inc. | Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof |
WO2016097072A1 (en) | 2014-12-18 | 2016-06-23 | F. Hoffmann-La Roche Ag | TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF |
EP3760623A1 (en) | 2014-12-18 | 2021-01-06 | F. Hoffmann-La Roche AG | Tetrahydro-pyrido[3,4-b]indole estrogen receptor modulators and uses thereof |
WO2016146591A1 (en) * | 2015-03-16 | 2016-09-22 | Astrazeneca Ab | Combination treatment |
US10537580B2 (en) | 2015-03-19 | 2020-01-21 | Novira Therapeutics, Inc. | Azocane and azonane derivatives and methods of treating hepatitis B infections |
CN107406457B (en) * | 2015-06-16 | 2019-02-01 | 江苏恒瑞医药股份有限公司 | Piperidine derivatives, preparation method and its application in medicine |
RU2730508C2 (en) * | 2015-06-16 | 2020-08-24 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Piperidine derivative, a method for production thereof and pharmaceutical use thereof |
CN107406457A (en) * | 2015-06-16 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | Piperidine derivatives, its preparation method and its application in medicine |
JP2018521988A (en) * | 2015-06-16 | 2018-08-09 | ジエンス ヘンルイ メデイシンカンパニー リミテッドJiangsu Hengrui Medicine Co.,Ltd. | Piperidine derivatives, production method thereof and pharmaceutical use |
US10385060B2 (en) | 2015-06-16 | 2019-08-20 | Jiangsu Hengrui Medicine Co., Ltd. | Piperidine derivative and preparation method and pharmaceutical use thereof |
TWI714600B (en) * | 2015-06-16 | 2021-01-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | Piperidine derivatives of ammonia sulfonyl, preparation method and medical use thereof |
WO2016202161A1 (en) * | 2015-06-16 | 2016-12-22 | 江苏恒瑞医药股份有限公司 | Piperidine derivative and preparation method and pharmaceutical use thereof |
AU2016279330B2 (en) * | 2015-06-16 | 2020-05-14 | Jiangsu Hengrui Medicine Co., Ltd. | Piperidine derivative and preparation method and pharmaceutical use thereof |
US10087191B2 (en) | 2015-06-16 | 2018-10-02 | Jiangsu Hengrui Medicine Co., Ltd. | Piperidine derivative and preparation method and pharmaceutical use thereof |
US10875876B2 (en) | 2015-07-02 | 2020-12-29 | Janssen Sciences Ireland Uc | Cyclized sulfamoylarylamide derivatives and the use thereof as medicaments for the treatment of hepatitis B |
US11293023B2 (en) | 2015-08-06 | 2022-04-05 | Dana-Farber Cancer Institute, Inc. | Tunable endogenous protein degradation |
WO2017024318A1 (en) | 2015-08-06 | 2017-02-09 | Dana-Farber Cancer Institute, Inc. | Targeted protein degradation to attenuate adoptive t-cell therapy associated adverse inflammatory responses |
US11046954B2 (en) | 2015-08-06 | 2021-06-29 | Dana-Farber Cancer Institute, Inc. | Targeted protein degradation to attenuate adoptive T-cell therapy associated adverse inflammatory responses |
US10077239B2 (en) | 2015-09-29 | 2018-09-18 | Novira Therapeutics, Inc. | Crystalline forms of a hepatitis B antiviral agent |
JP2018530549A (en) * | 2015-10-01 | 2018-10-18 | オレマ ファーマシューティカルズ インク. | Tetrahydro-1H-pyrido [3,4-b] indole antiestrogenic drug |
WO2017059139A1 (en) | 2015-10-01 | 2017-04-06 | Olema Pharmaceuticals, Inc. | TETRAHYDRO-1H-PYRIDO[3,4-b]INDOLE ANTI-ESTROGENIC DRUGS |
US10624878B2 (en) | 2015-10-01 | 2020-04-21 | Olema Pharmaceuticals, Inc. | Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs |
CN108366996B (en) * | 2015-10-01 | 2021-04-09 | 奥列马制药公司 | tetrahydro-1H-pyridine [3,4-b ] indole antiestrogens |
US10292971B2 (en) | 2015-10-01 | 2019-05-21 | Olema Pharmaceuticals, Inc. | Tetrahydro-1H-pyrido[3,4-b]indole anti-estrogenic drugs |
US11229630B2 (en) | 2015-10-01 | 2022-01-25 | Olema Pharmaceuticals, Inc. | Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs |
US11672785B2 (en) | 2015-10-01 | 2023-06-13 | Olema Pharmaceuticals, Inc. | Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs |
RU2745742C1 (en) * | 2015-10-01 | 2021-03-31 | Олема Фармасьютикалз, Инк. | Tetrahydro-1h-pyrido[3,4-b]indole anti-estrogenic drugs |
EP3912680A1 (en) | 2015-10-01 | 2021-11-24 | Olema Pharmaceuticals, Inc. | Tetrahydro-1h-pyrido[3,4-b]indole anti-estrogenic drugs |
AU2021206861B2 (en) * | 2015-10-01 | 2023-02-02 | Olema Pharmaceuticals, Inc. | Tetrahydro-1H-pyrido(3,4-b)indole anti-estrogenic drugs |
CN108366996A (en) * | 2015-10-01 | 2018-08-03 | 奥列马制药公司 | Tetrahydrochysene -1H- pyridines [3,4-b] indoles antiestrogen |
KR102099159B1 (en) * | 2015-11-12 | 2020-04-10 | 쯔지앙 하이썬 파머슈티컬 컴퍼니, 리미티드 | Acrylic acid derivatives, methods for their preparation and methods of use in medicine |
KR20180080245A (en) * | 2015-11-12 | 2018-07-11 | 쯔지앙 하이썬 파머슈티컬 컴퍼니, 리미티드 | Acrylic Acid Derivatives, Their Preparation and Their Use in Medicine |
US10519148B2 (en) | 2015-11-12 | 2019-12-31 | Zhejiang Hisun Pharmaceutical Co., Ltd. | Acrylic acid derivative, preparation method and use in medicine thereof |
WO2017080338A1 (en) * | 2015-11-12 | 2017-05-18 | 浙江海正药业股份有限公司 | Acrylic acid derivative, preparation method and use in medicine thereof |
JP2018535216A (en) * | 2015-11-12 | 2018-11-29 | 浙江海正薬業股▲ふん▼有限公司Zhejiang Hisun Pharmaceutical CO.,LTD. | Acrylic acid derivatives, process for preparation and use thereof as pharmaceuticals |
CN107428758A (en) * | 2015-11-12 | 2017-12-01 | 浙江海正药业股份有限公司 | Acrylate derivative, its preparation method and its purposes in medicine |
TWI615393B (en) * | 2015-11-12 | 2018-02-21 | Zhejiang Hisun Pharm Co Ltd | Acrylic derivative, preparation method thereof and use thereof in medicine |
CN107428758B (en) * | 2015-11-12 | 2020-08-04 | 浙江海正药业股份有限公司 | Acrylic acid derivative, preparation method and medical application thereof |
US10377735B2 (en) | 2015-12-09 | 2019-08-13 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US11072595B2 (en) | 2015-12-09 | 2021-07-27 | The Board of Trustees of lhe University of Illinois | Benzothiophene-based selective estrogen receptor downregulator compounds |
US10807964B2 (en) | 2015-12-09 | 2020-10-20 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
WO2017100712A1 (en) | 2015-12-09 | 2017-06-15 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
WO2017100715A1 (en) | 2015-12-09 | 2017-06-15 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulator compounds |
US10118910B2 (en) | 2015-12-09 | 2018-11-06 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US11447461B2 (en) | 2015-12-09 | 2022-09-20 | The Board Of Trustees Of The University Of Illinois | Benzothiophene-based selective estrogen receptor downregulators |
US10398689B2 (en) | 2015-12-22 | 2019-09-03 | Jiangsu Hengrui Medicine Co., Ltd. | Benzopiperidine derivative, preparation method thereof and medical use thereof |
WO2017107754A1 (en) | 2015-12-22 | 2017-06-29 | 江苏恒瑞医药股份有限公司 | Benzopiperidine derivative, preparation method thereof and medical use thereof |
EP3411034A4 (en) * | 2016-02-05 | 2019-08-28 | Inventisbio Inc. | Selective estrogen receptor degraders and uses thereof |
JP2019504890A (en) * | 2016-02-05 | 2019-02-21 | インベンティスバイオ インコーポレイテッド | Selective estrogen receptor degradation agent and use thereof |
WO2017136688A1 (en) | 2016-02-05 | 2017-08-10 | Inventisbio Inc. | Selective estrogen receptor degraders and uses thereof |
KR20180104161A (en) * | 2016-02-05 | 2018-09-19 | 인벤티스바이오 인크. | Selective Estrogen Receptor Release and Uses Thereof |
US11014936B2 (en) | 2016-02-05 | 2021-05-25 | Inventisbio Llc | Selective estrogen receptor degraders and uses thereof |
KR102479822B1 (en) | 2016-02-05 | 2022-12-21 | 인벤티스바이오 엘엘씨 | Selective estrogen receptor degraders and their uses |
US10647724B2 (en) | 2016-02-05 | 2020-05-12 | Inventisbio Inc. | Selective estrogen receptor degraders and uses thereof |
AU2017213614B2 (en) * | 2016-02-05 | 2022-09-01 | Inventisbio Llc | Selective estrogen receptor degraders and uses thereof |
JP2019515026A (en) * | 2016-04-01 | 2019-06-06 | ゼノ ロイアルティー アンド マイルストーンズ リミテッド ライアビリティー カンパニー | Estrogen receptor modulators |
KR20190002478A (en) * | 2016-04-01 | 2019-01-08 | 제노 로얄티즈 앤 마일스톤즈, 엘엘씨 | Estrogen receptor modulator |
US10959989B2 (en) | 2016-04-01 | 2021-03-30 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
TWI746535B (en) * | 2016-04-01 | 2021-11-21 | 美商瑞卡瑞恩Ip控股有限責任公司 | Estrogen receptor modulators |
WO2017172957A1 (en) | 2016-04-01 | 2017-10-05 | Kalyra Pharmaceuticals, Inc. | Estrogen receptor modulators |
AU2017242027B2 (en) * | 2016-04-01 | 2020-10-08 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
US11065234B2 (en) | 2016-04-01 | 2021-07-20 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
US11065233B2 (en) | 2016-04-01 | 2021-07-20 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
JP2021176911A (en) * | 2016-04-01 | 2021-11-11 | リキュリウム アイピー ホールディングス リミテッド ライアビリティー カンパニー | Estrogen receptor controlling medicine |
RU2738646C2 (en) * | 2016-04-01 | 2020-12-15 | РЕКЬЮРИУМ АйПи ХОЛДИНГС, ЛЛС | Estrogen receptor modulators |
KR102401841B1 (en) | 2016-04-01 | 2022-05-25 | 리커리엄 아이피 홀딩스, 엘엘씨 | estrogen receptor modulators |
US11129834B2 (en) | 2016-04-15 | 2021-09-28 | Novira Therapeutics, Inc. | Combinations and methods comprising a capsid assembly inhibitor |
US10441589B2 (en) | 2016-04-15 | 2019-10-15 | Novira Therapeutics, Inc. | Combinations and methods comprising a capsid assembly inhibitor |
US10125135B2 (en) | 2016-04-20 | 2018-11-13 | Astrazeneca Ab | Chemical compounds |
US11459617B2 (en) | 2016-04-29 | 2022-10-04 | Board Of Regents, The University Of Texas System | Targeted measure of transcriptional activity related to hormone receptors |
JP2019514930A (en) * | 2016-04-29 | 2019-06-06 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | Targeted measure of transcriptional activity related to hormone receptors |
JP7131773B2 (en) | 2016-04-29 | 2022-09-06 | ボード オブ リージェンツ,ザ ユニバーシティ オブ テキサス システム | A targeted measure of transcriptional activity associated with hormone receptors |
WO2017197055A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Heterocyclic degronimers for target protein degradation |
WO2017197046A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | C3-carbon linked glutarimide degronimers for target protein degradation |
WO2017197036A1 (en) | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Spirocyclic degronimers for target protein degradation |
JP2019521982A (en) * | 2016-06-16 | 2019-08-08 | エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト | Heteroaryl estrogen receptor modulators and uses thereof |
WO2017216280A1 (en) | 2016-06-16 | 2017-12-21 | F. Hoffmann-La Roche Ag | TETRAHYDRO-PYRIDO[3,4-b]INDOLE ESTROGEN RECEPTOR MODULATORS AND USES THEREOF |
JP7018026B2 (en) | 2016-06-16 | 2022-02-09 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Heteroarylestrogen receptor modulator and its use |
EP3858835A1 (en) | 2016-07-01 | 2021-08-04 | G1 Therapeutics, Inc. | Pyrimidine-based antiproliferative agents |
WO2018019793A1 (en) | 2016-07-25 | 2018-02-01 | Astrazeneca Ab | N-(2-(4-((1r,3r)-3-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indol-1-yl)phenoxy)ethyl)propan-1-amine derivatives and related compounds as selective down-regulators of the estrogen receptor for treating cancer |
US10149839B2 (en) | 2016-07-25 | 2018-12-11 | Astrazeneca Ab | Chemical compounds |
CN107814798A (en) * | 2016-09-14 | 2018-03-20 | 四川科伦博泰生物医药股份有限公司 | 3 substitutional crylic acid class compounds and its production and use |
CN107814798B (en) * | 2016-09-14 | 2020-11-03 | 四川科伦博泰生物医药股份有限公司 | 3-substituted acrylic acid compound and preparation method and application thereof |
US11547762B2 (en) | 2016-10-05 | 2023-01-10 | Genentech, Inc. | Methods for preparing antibody drug conjugates |
US10961241B2 (en) | 2016-10-24 | 2021-03-30 | Astrazeneca Ab | Chemical compounds |
US10703747B2 (en) | 2016-10-24 | 2020-07-07 | The Board of Directors of the University of Illinois | Benzothiophene-based selective mixed estrogen receptor downregulators |
US10590130B2 (en) | 2016-10-24 | 2020-03-17 | Astrazeneca Ab | Chemical compounds |
US10131663B2 (en) | 2016-10-24 | 2018-11-20 | Astrazeneca Ab | Chemical compounds |
WO2018129387A1 (en) | 2017-01-06 | 2018-07-12 | G1 Therapeutics, Inc. | Combination therapy for the treatment of cancer |
US11364222B2 (en) | 2017-01-06 | 2022-06-21 | G1 Therapeutics, Inc. | Combination therapy for treatment of cancer |
US11046689B2 (en) | 2017-01-30 | 2021-06-29 | Astrazeneca Ab | Selective estrogen receptor down-regulators |
US10221173B2 (en) | 2017-01-30 | 2019-03-05 | Astrazeneca Ab | Chemical compounds |
US10590132B2 (en) | 2017-01-30 | 2020-03-17 | Astrazeneca Ab | Selective estrogen receptor down-regulators |
US11311609B2 (en) | 2017-02-08 | 2022-04-26 | Dana-Farber Cancer Institute, Inc. | Regulating chimeric antigen receptors |
EP4119552A1 (en) | 2017-02-08 | 2023-01-18 | Dana-Farber Cancer Institute, Inc. | Regulating chimeric antigen receptors |
US10633362B2 (en) | 2017-02-10 | 2020-04-28 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
US10981887B2 (en) | 2017-02-10 | 2021-04-20 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
US10208011B2 (en) | 2017-02-10 | 2019-02-19 | G1 Therapeutics, Inc. | Benzothiophene estrogen receptor modulators |
WO2019006393A1 (en) | 2017-06-29 | 2019-01-03 | G1 Therapeutics, Inc. | Morphic forms of git38 and methods of manufacture thereof |
WO2019079569A1 (en) | 2017-10-18 | 2019-04-25 | Novartis Ag | Compositions and methods for selective protein degradation |
WO2019123367A1 (en) | 2017-12-21 | 2019-06-27 | Astrazeneca Ab | Compounds and their use in treating cancer |
US10973801B2 (en) | 2018-03-14 | 2021-04-13 | Janssen Sciences Ireland Unlimited Company | Capsid assembly modulator dosing regimen |
US11780834B2 (en) | 2018-06-21 | 2023-10-10 | Genentech, Inc. | Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3-fluoropropyl)azetidin-3- yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use |
US10954234B2 (en) | 2018-06-21 | 2021-03-23 | Genentech, Inc. | Solid forms of 3-((1R,3R)-1-(2,6-difluoro-4-((1-(3- fluoropropyl)azetidin-3-yl)amino)phenyl)-3-methyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)-2,2-difluoropropan-1-ol and processes for preparing fused tricyclic compounds comprising a substituted phenyl or pyridinyl moiety, including methods of their use |
WO2020132561A1 (en) | 2018-12-20 | 2020-06-25 | C4 Therapeutics, Inc. | Targeted protein degradation |
US11903931B2 (en) | 2018-12-24 | 2024-02-20 | InventisBio Co., Ltd. | Salts of selective estrogen receptor degraders |
US11096931B2 (en) | 2019-02-22 | 2021-08-24 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
WO2020219742A1 (en) | 2019-04-24 | 2020-10-29 | Novartis Ag | Compositions and methods for selective protein degradation |
US11491148B2 (en) | 2019-05-06 | 2022-11-08 | Janssen Sciences Ireland Unlimited Company | Amide derivatives useful in the treatment of HBV infection or HBV-induced diseases |
US11826430B2 (en) | 2019-05-14 | 2023-11-28 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
EP3969050A4 (en) * | 2019-05-14 | 2023-11-01 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
US11278532B2 (en) | 2019-08-06 | 2022-03-22 | Recurium Ip Holdings, Llc | Estrogen receptor modulators for treating mutants |
WO2021091819A1 (en) * | 2019-11-04 | 2021-05-14 | Recurium Ip Holdings, Llc | Salts and forms of an estrogen receptor modulator |
US11952349B2 (en) | 2019-11-13 | 2024-04-09 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
WO2021127561A1 (en) | 2019-12-20 | 2021-06-24 | C4 Therapeutics, Inc. | Isoindolinone and indazole compounds for the degradation of egfr |
WO2021139756A1 (en) | 2020-01-10 | 2021-07-15 | 江苏恒瑞医药股份有限公司 | Tricyclic tetrahydroisoquinoline derivative, preparation method therefor and application thereof in medicine |
WO2021253380A1 (en) * | 2020-06-19 | 2021-12-23 | InventisBio Co., Ltd. | Oral formulations and uses thereof |
WO2022109395A2 (en) | 2020-11-23 | 2022-05-27 | Sanofi | Panel of er regulated genes for use in monitoring endocrine therapy in breast cancer |
US11999728B2 (en) | 2020-12-23 | 2024-06-04 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
US11339162B1 (en) | 2020-12-23 | 2022-05-24 | Recurium Ip Holdings, Llc | Estrogen receptor modulators |
US11834458B2 (en) | 2021-03-23 | 2023-12-05 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
US12006314B2 (en) | 2021-05-03 | 2024-06-11 | Nuvation Bio Inc. | Anti-cancer nuclear hormone receptor-targeting compounds |
WO2023280309A1 (en) | 2021-07-09 | 2023-01-12 | 江苏恒瑞医药股份有限公司 | Salt types of tricyclic tetrahydro isoquinoline derivative |
WO2023221123A1 (en) * | 2022-05-20 | 2023-11-23 | Olema Pharmaceuticals, Inc. | Crystalline forms of an estrogen receptor antagonist |
WO2024030968A1 (en) | 2022-08-03 | 2024-02-08 | Brystol-Myers Squibb Company | Compounds for modulating ret protein |
WO2024097989A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein degraders |
WO2024097980A1 (en) | 2022-11-04 | 2024-05-10 | Bristol-Myers Squibb Company | Ret-ldd protein inhibitors |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10130617B2 (en) | Chemical compounds | |
EP3640251B1 (en) | 6,7,8,9-tetrahydro-3h-pyrazolo[4,3-f]isoquinoline derivatives useful in the treatment of cancer | |
EP2948447B1 (en) | Chemical compounds | |
US20180021316A1 (en) | Chemical compounds | |
US10125135B2 (en) | Chemical compounds | |
EP3494116B1 (en) | Estrogen receptor modulators | |
WO2017182495A1 (en) | Indazole derivatives that down-regulate the estrogen receptor and possess anti-cancer activity |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 201480028785.1 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 14727036 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2911859 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 242559 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 002429-2015 Country of ref document: PE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12015502615 Country of ref document: PH |
|
WWE | Wipo information: entry into national phase |
Ref document number: IDP00201507687 Country of ref document: ID Ref document number: 38620 Country of ref document: MA |
|
ENP | Entry into the national phase |
Ref document number: 2014272856 Country of ref document: AU Date of ref document: 20140527 Kind code of ref document: A |
|
ENP | Entry into the national phase |
Ref document number: 2016516235 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: MX/A/2015/016428 Country of ref document: MX |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: CR2015-000629 Country of ref document: CR |
|
REEP | Request for entry into the european phase |
Ref document number: 2014727036 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2014727036 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2015/1441.1 Country of ref document: KZ |
|
REG | Reference to national code |
Ref country code: BR Ref legal event code: B01A Ref document number: 112015029455 Country of ref document: BR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 15302397 Country of ref document: CO |
|
ENP | Entry into the national phase |
Ref document number: 2015151502 Country of ref document: RU Kind code of ref document: A Ref document number: 20157036820 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: A201511399 Country of ref document: UA |
|
ENP | Entry into the national phase |
Ref document number: 112015029455 Country of ref document: BR Kind code of ref document: A2 Effective date: 20151125 |