CN1964970B - Iap的抑制剂 - Google Patents
Iap的抑制剂 Download PDFInfo
- Publication number
- CN1964970B CN1964970B CN2005800186137A CN200580018613A CN1964970B CN 1964970 B CN1964970 B CN 1964970B CN 2005800186137 A CN2005800186137 A CN 2005800186137A CN 200580018613 A CN200580018613 A CN 200580018613A CN 1964970 B CN1964970 B CN 1964970B
- Authority
- CN
- China
- Prior art keywords
- methylamino
- phenyl
- pyrrolidyl
- cyclohexyl
- propionic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000003112 inhibitor Substances 0.000 title description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 204
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 70
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 59
- -1 tetrazyl Chemical group 0.000 claims description 57
- 125000003118 aryl group Chemical group 0.000 claims description 44
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 13
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- FATAVLOOLIRUNA-UHFFFAOYSA-N formylmethyl Chemical group [CH2]C=O FATAVLOOLIRUNA-UHFFFAOYSA-N 0.000 claims 18
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 7
- 150000003851 azoles Chemical class 0.000 claims 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims 4
- VTDXVLNCQSBLMT-XZZVZQAVSA-N (2s)-n-[(1s)-1-cyclohexyl-2-oxo-2-[(2s)-2-(3-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(OC=3C=CC=CC=3)C=CC=2)CCCCC1 VTDXVLNCQSBLMT-XZZVZQAVSA-N 0.000 claims 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 2
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 2
- KMEYYKLNJDBCPU-FIKGOQFSSA-N (2s)-2-(methylamino)-n-[(2s)-1-oxo-1-[(2s)-2-(3-phenoxyphenyl)pyrrolidin-1-yl]propan-2-yl]propanamide Chemical compound CN[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C1=CC=CC(OC=2C=CC=CC=2)=C1 KMEYYKLNJDBCPU-FIKGOQFSSA-N 0.000 claims 1
- KVGQXXNSQRRKHI-RJWMVNQGSA-N (2s)-n-[(1s)-1-cyclohexyl-2-oxo-2-[(2s)-2-(2-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C(=CC=CC=2)OC=2C=CC=CC=2)CCCCC1 KVGQXXNSQRRKHI-RJWMVNQGSA-N 0.000 claims 1
- XMLVJVXHBBMNCZ-XZZVZQAVSA-N (2s)-n-[(1s)-1-cyclohexyl-2-oxo-2-[(2s)-2-(4-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=CC(OC=3C=CC=CC=3)=CC=2)CCCCC1 XMLVJVXHBBMNCZ-XZZVZQAVSA-N 0.000 claims 1
- LVMGRCRBRDPJCO-LQGLAIQGSA-N (2s)-n-[(1s)-1-cyclopentyl-2-oxo-2-[(2s)-2-(3-phenoxyphenyl)pyrrolidin-1-yl]ethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(OC=3C=CC=CC=3)C=CC=2)CCCC1 LVMGRCRBRDPJCO-LQGLAIQGSA-N 0.000 claims 1
- VOQNQDGSABNMPI-XZZVZQAVSA-N (2s)-n-[(1s)-2-[(2s)-2-(3-benzoylphenyl)pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2C=C(C=CC=2)C(=O)C=2C=CC=CC=2)CCCCC1 VOQNQDGSABNMPI-XZZVZQAVSA-N 0.000 claims 1
- ZPDHHIXSFRFHSN-HSQYWUDLSA-N (2s)-n-[(1s)-2-[(2s)-2-(4-benzoyl-1,3-thiazol-2-yl)pyrrolidin-1-yl]-1-cyclohexyl-2-oxoethyl]-2-(methylamino)propanamide Chemical compound C1([C@H](NC(=O)[C@H](C)NC)C(=O)N2[C@@H](CCC2)C=2SC=C(N=2)C(=O)C=2C=CC=CC=2)CCCCC1 ZPDHHIXSFRFHSN-HSQYWUDLSA-N 0.000 claims 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 1
- 125000003226 pyrazolyl group Chemical group 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 125000004306 triazinyl group Chemical group 0.000 claims 1
- 125000001425 triazolyl group Chemical group 0.000 claims 1
- 108091007065 BIRCs Proteins 0.000 abstract description 14
- 102000055031 Inhibitor of Apoptosis Proteins Human genes 0.000 abstract 2
- 101710156605 Diablo homolog, mitochondrial Proteins 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 126
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 103
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 88
- 239000000203 mixture Substances 0.000 description 79
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 235000019439 ethyl acetate Nutrition 0.000 description 49
- 125000000217 alkyl group Chemical group 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- 239000000460 chlorine Substances 0.000 description 39
- 238000003756 stirring Methods 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 38
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 32
- 201000010099 disease Diseases 0.000 description 31
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
- 229910052760 oxygen Inorganic materials 0.000 description 29
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 29
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 28
- 125000000753 cycloalkyl group Chemical group 0.000 description 28
- 238000000034 method Methods 0.000 description 28
- 238000000746 purification Methods 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000007788 liquid Substances 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- 206010028980 Neoplasm Diseases 0.000 description 23
- 239000012043 crude product Substances 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 229910052717 sulfur Inorganic materials 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 21
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- 238000010790 dilution Methods 0.000 description 20
- 239000012895 dilution Substances 0.000 description 20
- 239000000284 extract Substances 0.000 description 19
- 238000005406 washing Methods 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 17
- 102100033189 Diablo IAP-binding mitochondrial protein Human genes 0.000 description 16
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 16
- 125000000623 heterocyclic group Chemical group 0.000 description 16
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 16
- 239000000741 silica gel Substances 0.000 description 16
- 229910002027 silica gel Inorganic materials 0.000 description 16
- 229960001866 silicon dioxide Drugs 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 101710101225 Diablo IAP-binding mitochondrial protein Proteins 0.000 description 15
- 239000003814 drug Substances 0.000 description 15
- 230000006907 apoptotic process Effects 0.000 description 14
- 238000003818 flash chromatography Methods 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 13
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 13
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 13
- 238000000605 extraction Methods 0.000 description 13
- 230000002062 proliferating effect Effects 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 239000008194 pharmaceutical composition Substances 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 11
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 11
- 125000004433 nitrogen atom Chemical group N* 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 108091000080 Phosphotransferase Proteins 0.000 description 10
- 229940024606 amino acid Drugs 0.000 description 10
- 235000001014 amino acid Nutrition 0.000 description 10
- 150000001413 amino acids Chemical class 0.000 description 10
- 102000020233 phosphotransferase Human genes 0.000 description 10
- 239000012266 salt solution Substances 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229930182817 methionine Natural products 0.000 description 8
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 102000003916 Arrestin Human genes 0.000 description 7
- 108090000328 Arrestin Proteins 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 208000034578 Multiple myelomas Diseases 0.000 description 7
- 206010035226 Plasma cell myeloma Diseases 0.000 description 7
- 230000001028 anti-proliverative effect Effects 0.000 description 7
- 201000011510 cancer Diseases 0.000 description 7
- 150000001721 carbon Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 6
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 description 6
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 6
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003545 alkoxy group Chemical group 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 150000004646 arylidenes Chemical group 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 229940022353 herceptin Drugs 0.000 description 6
- 229940043355 kinase inhibitor Drugs 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 125000001624 naphthyl group Chemical group 0.000 description 6
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 6
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 6
- 230000009467 reduction Effects 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 238000010792 warming Methods 0.000 description 6
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 5
- 102000011727 Caspases Human genes 0.000 description 5
- 108010076667 Caspases Proteins 0.000 description 5
- 102100037024 E3 ubiquitin-protein ligase XIAP Human genes 0.000 description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 5
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 5
- 108700031544 X-Linked Inhibitor of Apoptosis Proteins 0.000 description 5
- 125000001118 alkylidene group Chemical group 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 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 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 5
- 229950010895 midostaurin Drugs 0.000 description 5
- 239000000825 pharmaceutical preparation Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 229940121649 protein inhibitor Drugs 0.000 description 5
- 239000012268 protein inhibitor Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 5
- QSUXZIPXYDQFCX-JTQLQIEISA-N (2s)-2-cyclohexyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]acetic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)C1CCCCC1 QSUXZIPXYDQFCX-JTQLQIEISA-N 0.000 description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 4
- 229940122815 Aromatase inhibitor Drugs 0.000 description 4
- 206010006187 Breast cancer Diseases 0.000 description 4
- 208000026310 Breast neoplasm Diseases 0.000 description 4
- 102000004039 Caspase-9 Human genes 0.000 description 4
- 108090000566 Caspase-9 Proteins 0.000 description 4
- 102000001301 EGF receptor Human genes 0.000 description 4
- 108060006698 EGF receptor Proteins 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- 108010069236 Goserelin Proteins 0.000 description 4
- 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 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 4
- 108090000301 Membrane transport proteins Proteins 0.000 description 4
- 102000003939 Membrane transport proteins Human genes 0.000 description 4
- 102000029749 Microtubule Human genes 0.000 description 4
- 108091022875 Microtubule Proteins 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 4
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 4
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 125000000539 amino acid group Chemical group 0.000 description 4
- 239000003886 aromatase inhibitor Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 210000000170 cell membrane Anatomy 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 239000000328 estrogen antagonist Substances 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 230000004927 fusion Effects 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 210000004688 microtubule Anatomy 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 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 4
- 108010014186 ras Proteins Proteins 0.000 description 4
- 102000016914 ras Proteins Human genes 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000001291 vacuum drying Methods 0.000 description 4
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 3
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 3
- YJZSUCFGHXQWDM-UHFFFAOYSA-N 1-adamantyl 4-[(2,5-dihydroxyphenyl)methylamino]benzoate Chemical compound OC1=CC=C(O)C(CNC=2C=CC(=CC=2)C(=O)OC23CC4CC(CC(C4)C2)C3)=C1 YJZSUCFGHXQWDM-UHFFFAOYSA-N 0.000 description 3
- XKTYXVDYIKIYJP-UHFFFAOYSA-N 3h-dioxole Chemical compound C1OOC=C1 XKTYXVDYIKIYJP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OGWKCGZFUXNPDA-CFWMRBGOSA-N 5j49q6b70f 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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 OGWKCGZFUXNPDA-CFWMRBGOSA-N 0.000 description 3
- OGSPWJRAVKPPFI-UHFFFAOYSA-N Alendronic Acid Chemical compound NCCCC(O)(P(O)(O)=O)P(O)(O)=O OGSPWJRAVKPPFI-UHFFFAOYSA-N 0.000 description 3
- 229940097396 Aminopeptidase inhibitor Drugs 0.000 description 3
- 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 3
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 3
- GAGWJHPBXLXJQN-UORFTKCHSA-N Capecitabine Chemical compound C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](C)O1 GAGWJHPBXLXJQN-UORFTKCHSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 3
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 3
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 3
- 206010016654 Fibrosis Diseases 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- 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 3
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 3
- BLCLNMBMMGCOAS-URPVMXJPSA-N Goserelin Chemical compound C([C@@H](C(=O)N[C@H](COC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NNC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 BLCLNMBMMGCOAS-URPVMXJPSA-N 0.000 description 3
- 101710113864 Heat shock protein 90 Proteins 0.000 description 3
- 102100034051 Heat shock protein HSP 90-alpha Human genes 0.000 description 3
- 108010033040 Histones Proteins 0.000 description 3
- 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 3
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 3
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 229940079156 Proteasome inhibitor Drugs 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- IIDJRNMFWXDHID-UHFFFAOYSA-N Risedronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CC1=CC=CN=C1 IIDJRNMFWXDHID-UHFFFAOYSA-N 0.000 description 3
- 102000013275 Somatomedins Human genes 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 108010017842 Telomerase Proteins 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- DKJJVAGXPKPDRL-UHFFFAOYSA-N Tiludronic acid Chemical compound OP(O)(=O)C(P(O)(O)=O)SC1=CC=C(Cl)C=C1 DKJJVAGXPKPDRL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940100198 alkylating agent Drugs 0.000 description 3
- 239000002168 alkylating agent Substances 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229960003437 aminoglutethimide Drugs 0.000 description 3
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 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 3
- 230000001772 anti-angiogenic effect Effects 0.000 description 3
- 239000000051 antiandrogen Substances 0.000 description 3
- 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 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 3
- 238000009395 breeding Methods 0.000 description 3
- 230000001488 breeding effect Effects 0.000 description 3
- 230000000711 cancerogenic effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 229960004562 carboplatin Drugs 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- ACSIXWWBWUQEHA-UHFFFAOYSA-N clodronic acid Chemical compound OP(O)(=O)C(Cl)(Cl)P(O)(O)=O ACSIXWWBWUQEHA-UHFFFAOYSA-N 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- 229960005167 everolimus Drugs 0.000 description 3
- 230000004761 fibrosis Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229960004421 formestane Drugs 0.000 description 3
- OSVMTWJCGUFAOD-KZQROQTASA-N formestane Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1O OSVMTWJCGUFAOD-KZQROQTASA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 3
- 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 3
- 229960002989 glutamic acid Drugs 0.000 description 3
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 3
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 3
- 229940088013 hycamtin Drugs 0.000 description 3
- 229960000908 idarubicin Drugs 0.000 description 3
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 3
- 229960001101 ifosfamide Drugs 0.000 description 3
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.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 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 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 3
- 150000002632 lipids Chemical class 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 206010061289 metastatic neoplasm Diseases 0.000 description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 description 3
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 3
- 229960001156 mitoxantrone Drugs 0.000 description 3
- FMWOIXMBYLSGDY-UHFFFAOYSA-N n,4,4-trimethoxy-n-methylbutanamide Chemical compound COC(OC)CCC(=O)N(C)OC FMWOIXMBYLSGDY-UHFFFAOYSA-N 0.000 description 3
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 description 3
- 125000004430 oxygen atom Chemical group O* 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].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.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- LBKJNHPKYFYCLL-UHFFFAOYSA-N potassium;trimethyl(oxido)silane Chemical compound [K+].C[Si](C)(C)[O-] LBKJNHPKYFYCLL-UHFFFAOYSA-N 0.000 description 3
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 3
- 239000003207 proteasome inhibitor Substances 0.000 description 3
- 150000003217 pyrazoles Chemical class 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 229960004622 raloxifene Drugs 0.000 description 3
- 229910052701 rubidium Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004434 sulfur atom Chemical group 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
- 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 3
- 229960001278 teniposide Drugs 0.000 description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 229940100445 wheat starch Drugs 0.000 description 3
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 3
- 229960000641 zorubicin Drugs 0.000 description 3
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin 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)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 3
- NBRQRXRBIHVLGI-OWXODZSWSA-N (4as,5ar,12ar)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C(C2=O)[C@@H]1C[C@@H]1[C@@]2(O)C(O)=C(C(=O)N)C(=O)C1 NBRQRXRBIHVLGI-OWXODZSWSA-N 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products 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 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- UMGQVUWXNOJOSJ-KMHUVPDISA-N (e)-2-cyano-3-(3,4-dihydroxyphenyl)-n-[(1r)-1-phenylethyl]prop-2-enamide Chemical compound N([C@H](C)C=1C=CC=CC=1)C(=O)C(\C#N)=C\C1=CC=C(O)C(O)=C1 UMGQVUWXNOJOSJ-KMHUVPDISA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 2
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 2
- OQEBBZSWEGYTPG-UHFFFAOYSA-N 3-aminobutanoic acid Chemical compound CC(N)CC(O)=O OQEBBZSWEGYTPG-UHFFFAOYSA-N 0.000 description 2
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 2
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 2
- 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 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- 102000004400 Aminopeptidases Human genes 0.000 description 2
- 108090000915 Aminopeptidases Proteins 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 229940122361 Bisphosphonate Drugs 0.000 description 2
- DSDUSPFAABXQOQ-UHFFFAOYSA-N BrC(=N)C=C Chemical compound BrC(=N)C=C DSDUSPFAABXQOQ-UHFFFAOYSA-N 0.000 description 2
- NYWMQLNNNSQZRT-UHFFFAOYSA-N C(=O)OCC.C=N.C=N.C=N.C=N Chemical compound C(=O)OCC.C=N.C=N.C=N.C=N NYWMQLNNNSQZRT-UHFFFAOYSA-N 0.000 description 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical group NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 2
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 2
- 229940124087 DNA topoisomerase II inhibitor Drugs 0.000 description 2
- 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 2
- 108090000371 Esterases Proteins 0.000 description 2
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 229940124226 Farnesyltransferase inhibitor Drugs 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- 102400000932 Gonadoliberin-1 Human genes 0.000 description 2
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 2
- 102100024025 Heparanase Human genes 0.000 description 2
- 101500026183 Homo sapiens Gonadoliberin-1 Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 229940124761 MMP inhibitor Drugs 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 108050008598 Phosphoesterases Proteins 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 2
- 229940123582 Telomerase inhibitor Drugs 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 2
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 2
- 239000000317 Topoisomerase II Inhibitor Substances 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 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 2
- MBWMAMDHYSTWKY-UHFFFAOYSA-N [K].C[SiH](C)C Chemical compound [K].C[SiH](C)C MBWMAMDHYSTWKY-UHFFFAOYSA-N 0.000 description 2
- AIWRTTMUVOZGPW-HSPKUQOVSA-N abarelix Chemical compound C([C@@H](C(=O)N[C@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)N(C)C(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 AIWRTTMUVOZGPW-HSPKUQOVSA-N 0.000 description 2
- 229960002184 abarelix Drugs 0.000 description 2
- 108010023617 abarelix Proteins 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 229940062527 alendronate Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 125000005038 alkynylalkyl group Chemical group 0.000 description 2
- 230000006229 amino acid addition Effects 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000001640 apoptogenic effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000000889 atomisation Methods 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N benzyl-alpha-carboxylic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000008512 biological response Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 150000004663 bisphosphonates Chemical class 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 230000005587 bubbling Effects 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 239000003183 carcinogenic agent Substances 0.000 description 2
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 229960002286 clodronic acid Drugs 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 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 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- 229960003603 decitabine Drugs 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- OTKJDMGTUTTYMP-UHFFFAOYSA-N dihydrosphingosine Natural products CCCCCCCCCCCCCCCC(O)C(N)CO OTKJDMGTUTTYMP-UHFFFAOYSA-N 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 102000015694 estrogen receptors Human genes 0.000 description 2
- 108010038795 estrogen receptors Proteins 0.000 description 2
- 230000001076 estrogenic effect Effects 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 229960004585 etidronic acid Drugs 0.000 description 2
- 229960000255 exemestane Drugs 0.000 description 2
- 239000004744 fabric Substances 0.000 description 2
- 229950011548 fadrozole Drugs 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 229960002258 fulvestrant Drugs 0.000 description 2
- 229910021485 fumed silica Inorganic materials 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutanoic acid Natural products NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- ZTQSADJAYQOCDD-UHFFFAOYSA-N ginsenoside-Rd2 Natural products C1CC(C2(CCC3C(C)(C)C(OC4C(C(O)C(O)C(CO)O4)O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC(C(C(O)C1O)O)OC1COC1OCC(O)C(O)C1O ZTQSADJAYQOCDD-UHFFFAOYSA-N 0.000 description 2
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 2
- 229960001442 gonadorelin Drugs 0.000 description 2
- 229960002913 goserelin Drugs 0.000 description 2
- 208000014829 head and neck neoplasm Diseases 0.000 description 2
- 239000003481 heat shock protein 90 inhibitor Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 108010037536 heparanase Proteins 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 229940079322 interferon Drugs 0.000 description 2
- 229960004768 irinotecan Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 229960003881 letrozole Drugs 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- 229940124302 mTOR inhibitor Drugs 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 229950010159 nemorubicin Drugs 0.000 description 2
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 2
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 description 2
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229940026778 other chemotherapeutics in atc Drugs 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 229960001756 oxaliplatin Drugs 0.000 description 2
- 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 2
- 229960003978 pamidronic acid Drugs 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- DTUQWGWMVIHBKE-UHFFFAOYSA-N phenylacetaldehyde Chemical compound O=CCC1=CC=CC=C1 DTUQWGWMVIHBKE-UHFFFAOYSA-N 0.000 description 2
- 229960003424 phenylacetic acid Drugs 0.000 description 2
- 239000003279 phenylacetic acid Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 125000004344 phenylpropyl group Chemical group 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003009 phosphonic acids Chemical class 0.000 description 2
- 125000004193 piperazinyl group Chemical group 0.000 description 2
- 150000003053 piperidines Chemical class 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- AXPUQAAUHKSVKR-UHFFFAOYSA-N prop-2-enimidamide Chemical compound NC(=N)C=C AXPUQAAUHKSVKR-UHFFFAOYSA-N 0.000 description 2
- 208000023958 prostate neoplasm Diseases 0.000 description 2
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229960000759 risedronic acid Drugs 0.000 description 2
- 229950008902 safingol Drugs 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 229960002930 sirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 2
- OTKJDMGTUTTYMP-ZWKOTPCHSA-N sphinganine Chemical compound CCCCCCCCCCCCCCC[C@@H](O)[C@@H](N)CO OTKJDMGTUTTYMP-ZWKOTPCHSA-N 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- HKSZLNNOFSGOKW-FYTWVXJKSA-N staurosporine Chemical class C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@H](NC)[C@@H](OC)[C@]4(C)O1 HKSZLNNOFSGOKW-FYTWVXJKSA-N 0.000 description 2
- 150000003431 steroids Chemical class 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 229960001603 tamoxifen Drugs 0.000 description 2
- 229940120982 tarceva Drugs 0.000 description 2
- 239000003277 telomerase inhibitor Substances 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 229960005324 tiludronic acid Drugs 0.000 description 2
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- 229960003048 vinblastine Drugs 0.000 description 2
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.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 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 2
- 229960004982 vinblastine sulfate Drugs 0.000 description 2
- 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 2
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.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=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 2
- 229960004276 zoledronic acid Drugs 0.000 description 2
- GZIFEOYASATJEH-VHFRWLAGSA-N δ-tocopherol Chemical compound OC1=CC(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-VHFRWLAGSA-N 0.000 description 2
- DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- IYLGZMTXKJYONK-ACLXAEORSA-N (12s,15r)-15-hydroxy-11,16-dioxo-15,20-dihydrosenecionan-12-yl acetate Chemical compound O1C(=O)[C@](CC)(O)C[C@@H](C)[C@](C)(OC(C)=O)C(=O)OCC2=CCN3[C@H]2[C@H]1CC3 IYLGZMTXKJYONK-ACLXAEORSA-N 0.000 description 1
- RTCUCQWIICFPOD-VIFPVBQESA-N (1s)-1-naphthalen-1-ylethanamine Chemical compound C1=CC=C2C([C@@H](N)C)=CC=CC2=C1 RTCUCQWIICFPOD-VIFPVBQESA-N 0.000 description 1
- QIXDRLIEARGEQY-ZETCQYMHSA-N (2s)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]butanoic acid Chemical compound CC[C@@H](C(O)=O)N(C)C(=O)OC(C)(C)C QIXDRLIEARGEQY-ZETCQYMHSA-N 0.000 description 1
- VEVRNHHLCPGNDU-MUGJNUQGSA-N (2s)-2-amino-5-[1-[(5s)-5-amino-5-carboxypentyl]-3,5-bis[(3s)-3-amino-3-carboxypropyl]pyridin-1-ium-4-yl]pentanoate Chemical compound OC(=O)[C@@H](N)CCCC[N+]1=CC(CC[C@H](N)C(O)=O)=C(CCC[C@H](N)C([O-])=O)C(CC[C@H](N)C(O)=O)=C1 VEVRNHHLCPGNDU-MUGJNUQGSA-N 0.000 description 1
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- GSQOBTOAOGXIFL-LFIBNONCSA-N (e)-2-cyano-3-(3,4-dihydroxyphenyl)-n-(3-phenylpropyl)prop-2-enamide Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCCCC1=CC=CC=C1 GSQOBTOAOGXIFL-LFIBNONCSA-N 0.000 description 1
- GWCNJMUSWLTSCW-SFQUDFHCSA-N (e)-2-cyano-3-(3,4-dihydroxyphenyl)-n-(4-phenylbutyl)prop-2-enamide Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCCCCC1=CC=CC=C1 GWCNJMUSWLTSCW-SFQUDFHCSA-N 0.000 description 1
- HKHOVJYOELRGMV-XYOKQWHBSA-N (e)-2-cyano-3-(3,4-dihydroxyphenyl)-n-phenylprop-2-enamide Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NC1=CC=CC=C1 HKHOVJYOELRGMV-XYOKQWHBSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- 150000000177 1,2,3-triazoles Chemical class 0.000 description 1
- WQONPSCCEXUXTQ-UHFFFAOYSA-N 1,2-dibromobenzene Chemical compound BrC1=CC=CC=C1Br WQONPSCCEXUXTQ-UHFFFAOYSA-N 0.000 description 1
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- VRVRKVMNULDZPO-UHFFFAOYSA-N 1,3-oxazole;1,3-thiazole Chemical compound C1=COC=N1.C1=CSC=N1 VRVRKVMNULDZPO-UHFFFAOYSA-N 0.000 description 1
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- JHTPBGFVWWSHDL-UHFFFAOYSA-N 1,4-dichloro-2-isothiocyanatobenzene Chemical compound ClC1=CC=C(Cl)C(N=C=S)=C1 JHTPBGFVWWSHDL-UHFFFAOYSA-N 0.000 description 1
- YQRRFIKLPFQWAO-UHFFFAOYSA-N 1-(2,3-dihydro-1h-inden-1-yloxy)-2,3-dihydro-1h-indene Chemical compound C1CC2=CC=CC=C2C1OC1C2=CC=CC=C2CC1 YQRRFIKLPFQWAO-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 description 1
- QSSXJPIWXQTSIX-UHFFFAOYSA-N 1-bromo-2-methylbenzene Chemical compound CC1=CC=CC=C1Br QSSXJPIWXQTSIX-UHFFFAOYSA-N 0.000 description 1
- VOXZDWNPVJITMN-ZBRFXRBCSA-N 17β-estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 VOXZDWNPVJITMN-ZBRFXRBCSA-N 0.000 description 1
- XWIYUCRMWCHYJR-UHFFFAOYSA-N 1h-pyrrolo[3,2-b]pyridine Chemical compound C1=CC=C2NC=CC2=N1 XWIYUCRMWCHYJR-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- SIQBPWRTJNBBER-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-2-benzazepine Chemical compound C1CCNCC2=CC=CC=C21 SIQBPWRTJNBBER-UHFFFAOYSA-N 0.000 description 1
- SYOANZBNGDEJFH-UHFFFAOYSA-N 2,5-dihydro-1h-triazole Chemical compound C1NNN=C1 SYOANZBNGDEJFH-UHFFFAOYSA-N 0.000 description 1
- UEJJHQNACJXSKW-UHFFFAOYSA-N 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C1CCC(=O)NC1=O UEJJHQNACJXSKW-UHFFFAOYSA-N 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N 2-Aminobutanoic acid Natural products CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 1
- VTJXFTPMFYAJJU-UHFFFAOYSA-N 2-[(3,4-dihydroxyphenyl)methylidene]propanedinitrile Chemical compound OC1=CC=C(C=C(C#N)C#N)C=C1O VTJXFTPMFYAJJU-UHFFFAOYSA-N 0.000 description 1
- OYIFNHCXNCRBQI-UHFFFAOYSA-N 2-aminoadipic acid Chemical compound OC(=O)C(N)CCCC(O)=O OYIFNHCXNCRBQI-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- AUQKXXDHDKEBEY-UHFFFAOYSA-N 2-methylbutan-2-yl carbamate Chemical compound CCC(C)(C)OC(N)=O AUQKXXDHDKEBEY-UHFFFAOYSA-N 0.000 description 1
- RUXRFDVEVQNQMF-UHFFFAOYSA-N 2-methylpropyl 3,5-ditert-butyl-4-hydroxybenzoate Chemical compound CC(C)COC(=O)C1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 RUXRFDVEVQNQMF-UHFFFAOYSA-N 0.000 description 1
- XABCFXXGZPWJQP-UHFFFAOYSA-N 3-aminoadipic acid Chemical compound OC(=O)CC(N)CCC(O)=O XABCFXXGZPWJQP-UHFFFAOYSA-N 0.000 description 1
- BZFKSWOGZQMOMO-UHFFFAOYSA-N 3-chloropropan-1-amine Chemical compound NCCCCl BZFKSWOGZQMOMO-UHFFFAOYSA-N 0.000 description 1
- QSFREBZMBNRGOK-UHFFFAOYSA-N 4-[(2,5-dihydroxyphenyl)methylamino]benzoic acid methyl ester Chemical compound C1=CC(C(=O)OC)=CC=C1NCC1=CC(O)=CC=C1O QSFREBZMBNRGOK-UHFFFAOYSA-N 0.000 description 1
- DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- NMUSYJAQQFHJEW-UHFFFAOYSA-N 5-Azacytidine Natural products O=C1N=C(N)N=CN1C1C(O)C(O)C(CO)O1 NMUSYJAQQFHJEW-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- RXGJTUSBYWCRBK-UHFFFAOYSA-M 5-methylphenazinium methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC=C2[N+](C)=C(C=CC=C3)C3=NC2=C1 RXGJTUSBYWCRBK-UHFFFAOYSA-M 0.000 description 1
- XZNDNNJBHFICJB-UHFFFAOYSA-N 6-fluoro-6-methylcyclohexa-2,4-dien-1-amine Chemical compound CC1(F)C=CC=CC1N XZNDNNJBHFICJB-UHFFFAOYSA-N 0.000 description 1
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-HQCWYSJUSA-N 7-hydroxystaurosporine Chemical compound N([C@H](O)C1=C2C3=CC=CC=C3N3C2=C24)C(=O)C1=C2C1=CC=CC=C1N4[C@H]1C[C@@H](NC)[C@@H](OC)[C@]3(C)O1 PBCZSGKMGDDXIJ-HQCWYSJUSA-N 0.000 description 1
- PBCZSGKMGDDXIJ-UHFFFAOYSA-N 7beta-hydroxystaurosporine Natural products C12=C3N4C5=CC=CC=C5C3=C3C(O)NC(=O)C3=C2C2=CC=CC=C2N1C1CC(NC)C(OC)C4(C)O1 PBCZSGKMGDDXIJ-UHFFFAOYSA-N 0.000 description 1
- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical class N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 description 1
- ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 7h-pyrrolo[2,3-h]quinoline Chemical compound C1=CN=C2C(C=CN3)=C3C=CC2=C1 ZIUYHTQZEPDUCZ-UHFFFAOYSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 229940122531 Anaplastic lymphoma kinase inhibitor Drugs 0.000 description 1
- 229940088872 Apoptosis inhibitor Drugs 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- JBTHDRKOFQEAEX-PUUVEUEGSA-N CCC(CC)[C@@H](C(N(CCC1)[C@@H]1c1cc(N(CCO)c2ccccc2)ccc1)=O)NC([C@H](C)NC)=O Chemical compound CCC(CC)[C@@H](C(N(CCC1)[C@@H]1c1cc(N(CCO)c2ccccc2)ccc1)=O)NC([C@H](C)NC)=O JBTHDRKOFQEAEX-PUUVEUEGSA-N 0.000 description 1
- VVHCBXPUGLFOEJ-KDQQNUDCSA-N C[C@@H](C(N[C@@H](C1CCCCC1)C(N(CCC1)[C@@H]1C(/C=C(/Cc1ccccc1)\C=C/C)=C)=O)=O)NC Chemical compound C[C@@H](C(N[C@@H](C1CCCCC1)C(N(CCC1)[C@@H]1C(/C=C(/Cc1ccccc1)\C=C/C)=C)=O)=O)NC VVHCBXPUGLFOEJ-KDQQNUDCSA-N 0.000 description 1
- OFGXRVARKSIROZ-QXWFJRNPSA-N C[C@@H](C(N[C@@H](C1CCCCC1)C(N(CCC1)[C@@H]1c1cc(Oc2ccccc2)ncc1)=O)=O)NC Chemical compound C[C@@H](C(N[C@@H](C1CCCCC1)C(N(CCC1)[C@@H]1c1cc(Oc2ccccc2)ncc1)=O)=O)NC OFGXRVARKSIROZ-QXWFJRNPSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 102000003952 Caspase 3 Human genes 0.000 description 1
- 108090000397 Caspase 3 Proteins 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- ZCGXPIUEMOPXOG-UHFFFAOYSA-N ClC1=C(C2=C(N=C(N2)S(=O)(=O)O)C=C1)C1=CC=CC=C1 Chemical compound ClC1=C(C2=C(N=C(N2)S(=O)(=O)O)C=C1)C1=CC=CC=C1 ZCGXPIUEMOPXOG-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 108010037464 Cyclooxygenase 1 Proteins 0.000 description 1
- 108010037462 Cyclooxygenase 2 Proteins 0.000 description 1
- GZIFEOYASATJEH-UHFFFAOYSA-N D-delta tocopherol Natural products OC1=CC(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 GZIFEOYASATJEH-UHFFFAOYSA-N 0.000 description 1
- 230000035131 DNA demethylation Effects 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 208000002699 Digestive System Neoplasms Diseases 0.000 description 1
- 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 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.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 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 1
- XOZIUKBZLSUILX-SDMHVBBESA-N Epothilone D Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C XOZIUKBZLSUILX-SDMHVBBESA-N 0.000 description 1
- UKCVAQGKEOJTSR-UHFFFAOYSA-N Fadrozole hydrochloride Chemical compound Cl.C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 UKCVAQGKEOJTSR-UHFFFAOYSA-N 0.000 description 1
- 102000018233 Fibroblast Growth Factor Human genes 0.000 description 1
- 108050007372 Fibroblast Growth Factor Proteins 0.000 description 1
- 238000001159 Fisher's combined probability test Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 101710113436 GTPase KRas Proteins 0.000 description 1
- 102100039788 GTPase NRas Human genes 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 206010061183 Genitourinary tract neoplasm Diseases 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 229920002971 Heparan sulfate Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- 101000871228 Homo sapiens Diablo IAP-binding mitochondrial protein Proteins 0.000 description 1
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 1
- 101000624643 Homo sapiens M-phase inducer phosphatase 3 Proteins 0.000 description 1
- 101000580039 Homo sapiens Ras-specific guanine nucleotide-releasing factor 1 Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000037147 Hypercalcaemia Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- 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
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- LPGWZGMPDKDHEP-HLTPFJCJSA-N Leurosine Chemical compound C([C@]1([C@@H]2O1)CC)N(CCC=1C3=CC=CC=C3NC=11)C[C@H]2C[C@]1(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 LPGWZGMPDKDHEP-HLTPFJCJSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- 229940123917 Lipid kinase inhibitor Drugs 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 102100023330 M-phase inducer phosphatase 3 Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 1
- 229910017976 MgO 4 Inorganic materials 0.000 description 1
- 108010058682 Mitochondrial Proteins Proteins 0.000 description 1
- 102000006404 Mitochondrial Proteins Human genes 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 description 1
- GPVKLYONJSSZFL-UHFFFAOYSA-N NSC 750259 Natural products CCC(C)C=CC(O)C(O)C(O)C(OC)C(=O)NC1CCCCNC1=O GPVKLYONJSSZFL-UHFFFAOYSA-N 0.000 description 1
- XXHMLEKZHYDRMK-JTQLQIEISA-N N[C@H](C(=O)OC(=O)OC(C)(C)C)C1CCCCC1 Chemical compound N[C@H](C(=O)OC(=O)OC(C)(C)C)C1CCCCC1 XXHMLEKZHYDRMK-JTQLQIEISA-N 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- MSHZHSPISPJWHW-UHFFFAOYSA-N O-(chloroacetylcarbamoyl)fumagillol Chemical compound O1C(CC=C(C)C)C1(C)C1C(OC)C(OC(=O)NC(=O)CCl)CCC21CO2 MSHZHSPISPJWHW-UHFFFAOYSA-N 0.000 description 1
- GKXFUKMATXVYEL-UHFFFAOYSA-N O1C=NC2=C1C=CC=C2.N2C=CC1=CC=C3C(=C21)C=CC=C3 Chemical compound O1C=NC2=C1C=CC=C2.N2C=CC1=CC=C3C(=C21)C=CC=C3 GKXFUKMATXVYEL-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 description 1
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 108010065954 SMAC peptide Proteins 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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 208000005250 Spontaneous Fractures Diseases 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- JXAGDPXECXQWBC-LJQANCHMSA-N Tanomastat Chemical compound C([C@H](C(=O)O)CC(=O)C=1C=CC(=CC=1)C=1C=CC(Cl)=CC=1)SC1=CC=CC=C1 JXAGDPXECXQWBC-LJQANCHMSA-N 0.000 description 1
- 229940123237 Taxane Drugs 0.000 description 1
- 108091033399 Telomestatin Proteins 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
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 241000534944 Thia Species 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 239000006035 Tryptophane Substances 0.000 description 1
- 229940122530 Tubulin polymerization inhibitor Drugs 0.000 description 1
- 102100037236 Tyrosine-protein kinase receptor UFO Human genes 0.000 description 1
- 108090000848 Ubiquitin Proteins 0.000 description 1
- 102000044159 Ubiquitin Human genes 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 208000008385 Urogenital Neoplasms Diseases 0.000 description 1
- BTKMJKKKZATLBU-UHFFFAOYSA-N [2-(1,3-benzothiazol-2-yl)-1,3-benzothiazol-6-yl] dihydrogen phosphate Chemical compound C1=CC=C2SC(C3=NC4=CC=C(C=C4S3)OP(O)(=O)O)=NC2=C1 BTKMJKKKZATLBU-UHFFFAOYSA-N 0.000 description 1
- ODEDPKNSRBCSDO-UHFFFAOYSA-N [2-(hexadecylsulfanylmethyl)-3-methoxypropyl] 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCSCC(COC)COP([O-])(=O)OCC[N+](C)(C)C ODEDPKNSRBCSDO-UHFFFAOYSA-N 0.000 description 1
- VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 229940037127 actonel Drugs 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- REWIJITZQJASKD-UHFFFAOYSA-N adamantane;benzoic acid Chemical class OC(=O)C1=CC=CC=C1.C1C(C2)CC3CC1CC2C3 REWIJITZQJASKD-UHFFFAOYSA-N 0.000 description 1
- 239000003470 adrenal cortex hormone Substances 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 125000005037 alkyl phenyl group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- SHGAZHPCJJPHSC-YCNIQYBTSA-N all-trans-retinoic acid Chemical compound OC(=O)\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-YCNIQYBTSA-N 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical group 0.000 description 1
- 159000000013 aluminium salts Chemical class 0.000 description 1
- 229910000329 aluminium sulfate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000002927 anti-mitotic effect Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 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
- 239000000158 apoptosis inhibitor Substances 0.000 description 1
- 230000005775 apoptotic pathway Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 229940078010 arimidex Drugs 0.000 description 1
- 229940087620 aromasin Drugs 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 229950004810 atamestane Drugs 0.000 description 1
- PEPMWUSGRKINHX-TXTPUJOMSA-N atamestane Chemical compound C1C[C@@H]2[C@@]3(C)C(C)=CC(=O)C=C3CC[C@H]2[C@@H]2CCC(=O)[C@]21C PEPMWUSGRKINHX-TXTPUJOMSA-N 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 108010023337 axl receptor tyrosine kinase Proteins 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 1
- 229950001858 batimastat Drugs 0.000 description 1
- 229930195545 bengamide Natural products 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
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- 229960005539 bryostatin 1 Drugs 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 description 1
- 229960001921 calcium levofolinate Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 description 1
- 229940088954 camptosar Drugs 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
- 230000003327 cancerostatic effect Effects 0.000 description 1
- 229950002826 canertinib Drugs 0.000 description 1
- OMZCMEYTWSXEPZ-UHFFFAOYSA-N canertinib Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC(OCCCN3CCOCC3)=C(NC(=O)C=C)C=C12 OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 229940047495 celebrex Drugs 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000004637 cellular stress Effects 0.000 description 1
- ZGHQGWOETPXKLY-XVNBXDOJSA-N chembl77030 Chemical compound NC(=S)C(\C#N)=C\C1=CC=C(O)C(O)=C1 ZGHQGWOETPXKLY-XVNBXDOJSA-N 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960001338 colchicine Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
- OMFXVFTZEKFJBZ-HJTSIMOOSA-N corticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OMFXVFTZEKFJBZ-HJTSIMOOSA-N 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 235000010389 delta-tocopherol Nutrition 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- FSIRXIHZBIXHKT-MHTVFEQDSA-N edatrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CC(CC)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FSIRXIHZBIXHKT-MHTVFEQDSA-N 0.000 description 1
- 229950006700 edatrexate Drugs 0.000 description 1
- 229940120655 eloxatin Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 1
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 1
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229960005309 estradiol Drugs 0.000 description 1
- 229930182833 estradiol Natural products 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 229960003399 estrone Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- LBKPGNUOUPTQKA-UHFFFAOYSA-N ethyl n-phenylcarbamate Chemical compound CCOC(=O)NC1=CC=CC=C1 LBKPGNUOUPTQKA-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
- LIQODXNTTZAGID-OCBXBXKTSA-N etoposide phosphate Chemical compound COC1=C(OP(O)(O)=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 LIQODXNTTZAGID-OCBXBXKTSA-N 0.000 description 1
- 229960000752 etoposide phosphate Drugs 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 229940085363 evista Drugs 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 229940087861 faslodex Drugs 0.000 description 1
- 229940087476 femara Drugs 0.000 description 1
- 229940126864 fibroblast growth factor Drugs 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 235000008191 folinic acid Nutrition 0.000 description 1
- 239000011672 folinic acid Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 229940001490 fosamax Drugs 0.000 description 1
- YRTCKZIKGWZNCU-UHFFFAOYSA-N furo[3,2-b]pyridine Chemical compound C1=CC=C2OC=CC2=N1 YRTCKZIKGWZNCU-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 235000010382 gamma-tocopherol Nutrition 0.000 description 1
- 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 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 229940020967 gemzar Drugs 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 229940084910 gliadel Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002972 glutethimide Drugs 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 229960003690 goserelin acetate Drugs 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- VNSFGLSIVSOPEC-UHFFFAOYSA-N guanidine;urea Chemical compound NC(N)=N.NC(N)=O VNSFGLSIVSOPEC-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 108091008039 hormone receptors Proteins 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- 230000000148 hypercalcaemia Effects 0.000 description 1
- 208000030915 hypercalcemia disease Diseases 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 229950006905 ilmofosine Drugs 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 229960001691 leucovorin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229950008745 losoxantrone Drugs 0.000 description 1
- YROQEQPFUCPDCP-UHFFFAOYSA-N losoxantrone Chemical compound OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO YROQEQPFUCPDCP-UHFFFAOYSA-N 0.000 description 1
- 229960000994 lumiracoxib Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000026037 malignant tumor of neck Diseases 0.000 description 1
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical class N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 1
- 229950008959 marimastat 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
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 230000010358 mechanical oscillation Effects 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 201000001441 melanoma Diseases 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
- 229960001924 melphalan Drugs 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- ROXQOUUAPQUMLN-UHFFFAOYSA-N methyl 2,3-dibromopropanoate Chemical class COC(=O)C(Br)CBr ROXQOUUAPQUMLN-UHFFFAOYSA-N 0.000 description 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 230000009456 molecular mechanism Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- VYGYNVZNSSTDLJ-HKCOAVLJSA-N monorden Natural products CC1CC2OC2C=C/C=C/C(=O)CC3C(C(=CC(=C3Cl)O)O)C(=O)O1 VYGYNVZNSSTDLJ-HKCOAVLJSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 229940087004 mustargen Drugs 0.000 description 1
- HEZFNHCADLDVKN-UHFFFAOYSA-N n'-methylprop-2-enimidamide Chemical compound CN=C(N)C=C HEZFNHCADLDVKN-UHFFFAOYSA-N 0.000 description 1
- BLCLNMBMMGCOAS-UHFFFAOYSA-N n-[1-[[1-[[1-[[1-[[1-[[1-[[1-[2-[(carbamoylamino)carbamoyl]pyrrolidin-1-yl]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amin Chemical compound C1CCC(C(=O)NNC(N)=O)N1C(=O)C(CCCN=C(N)N)NC(=O)C(CC(C)C)NC(=O)C(COC(C)(C)C)NC(=O)C(NC(=O)C(CO)NC(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C(CC=1NC=NC=1)NC(=O)C1NC(=O)CC1)CC1=CC=C(O)C=C1 BLCLNMBMMGCOAS-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 230000012106 negative regulation of microtubule depolymerization Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 229940085033 nolvadex Drugs 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- XYEOALKITRFCJJ-UHFFFAOYSA-N o-benzylhydroxylamine Chemical compound NOCC1=CC=CC=C1 XYEOALKITRFCJJ-UHFFFAOYSA-N 0.000 description 1
- QNDVLZJODHBUFM-WFXQOWMNSA-N okadaic acid Chemical compound C([C@H](O1)[C@H](C)/C=C/[C@H]2CC[C@@]3(CC[C@H]4O[C@@H](C([C@@H](O)[C@@H]4O3)=C)[C@@H](O)C[C@H](C)[C@@H]3[C@@H](CC[C@@]4(OCCCC4)O3)C)O2)C(C)=C[C@]21O[C@H](C[C@@](C)(O)C(O)=O)CC[C@H]2O QNDVLZJODHBUFM-WFXQOWMNSA-N 0.000 description 1
- VEFJHAYOIAAXEU-UHFFFAOYSA-N okadaic acid Natural products CC(CC(O)C1OC2CCC3(CCC(O3)C=CC(C)C4CC(=CC5(OC(CC(C)(O)C(=O)O)CCC5O)O4)C)OC2C(O)C1C)C6OC7(CCCCO7)CCC6C VEFJHAYOIAAXEU-UHFFFAOYSA-N 0.000 description 1
- 208000023983 oral cavity neoplasm Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000011860 particles by size Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- WVUNYSQLFKLYNI-AATRIKPKSA-N pelitinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC1=CC=C(F)C(Cl)=C1 WVUNYSQLFKLYNI-AATRIKPKSA-N 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- SZFPYBIJACMNJV-UHFFFAOYSA-N perifosine Chemical compound CCCCCCCCCCCCCCCCCCOP([O-])(=O)OC1CC[N+](C)(C)CC1 SZFPYBIJACMNJV-UHFFFAOYSA-N 0.000 description 1
- 229950010632 perifosine Drugs 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- PARWUHTVGZSQPD-UHFFFAOYSA-N phenylsilane Chemical compound [SiH3]C1=CC=CC=C1 PARWUHTVGZSQPD-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229960005141 piperazine Drugs 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 208000010626 plasma cell neoplasm Diseases 0.000 description 1
- YJGVMLPVUAXIQN-XVVDYKMHSA-N podophyllotoxin Chemical compound COC1=C(OC)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@H](O)[C@@H]3[C@@H]2C(OC3)=O)=C1 YJGVMLPVUAXIQN-XVVDYKMHSA-N 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 229950003608 prinomastat Drugs 0.000 description 1
- YKPYIPVDTNNYCN-INIZCTEOSA-N prinomastat Chemical compound ONC(=O)[C@H]1C(C)(C)SCCN1S(=O)(=O)C(C=C1)=CC=C1OC1=CC=NC=C1 YKPYIPVDTNNYCN-INIZCTEOSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- YEYHFKBVNARCNE-UHFFFAOYSA-N pyrido[2,3-b]pyrazine Chemical compound N1=CC=NC2=CC=CN=C21 YEYHFKBVNARCNE-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002534 radiation-sensitizing agent Substances 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- AECPBJMOGBFQDN-YMYQVXQQSA-N radicicol Chemical compound C1CCCC(=O)C[C@H]2[C@H](Cl)C(=O)CC(=O)[C@H]2C(=O)O[C@H](C)C[C@H]2O[C@@H]21 AECPBJMOGBFQDN-YMYQVXQQSA-N 0.000 description 1
- 229930192524 radicicol Natural products 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000012508 resin bead Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 229930002330 retinoic acid Natural products 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- 229950005230 rogletimide Drugs 0.000 description 1
- QXKJWHWUDVQATH-UHFFFAOYSA-N rogletimide Chemical compound C=1C=NC=CC=1C1(CC)CCC(=O)NC1=O QXKJWHWUDVQATH-UHFFFAOYSA-N 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- IYLGZMTXKJYONK-UHFFFAOYSA-N ruwenine Natural products O1C(=O)C(CC)(O)CC(C)C(C)(OC(C)=O)C(=O)OCC2=CCN3C2C1CC3 IYLGZMTXKJYONK-UHFFFAOYSA-N 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 229940112726 skelid Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical class C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 description 1
- 229940075620 somatostatin analogue Drugs 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 125000004646 sulfenyl group Chemical group S(*)* 0.000 description 1
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 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
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- UXXQOJXBIDBUAC-UHFFFAOYSA-N tandutinib Chemical compound COC1=CC2=C(N3CCN(CC3)C(=O)NC=3C=CC(OC(C)C)=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 UXXQOJXBIDBUAC-UHFFFAOYSA-N 0.000 description 1
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 1
- 229950007866 tanespimycin Drugs 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- YVSQVYZBDXIXCC-INIZCTEOSA-N telomestatin Chemical compound N=1C2=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(N=1)=COC=1C(=C(O1)C)N=C1C(=C(O1)C)N=C1[C@@]1([H])N=C2SC1 YVSQVYZBDXIXCC-INIZCTEOSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- GJJYYMXBCYYXPQ-UHFFFAOYSA-N tert-butyl 2-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1=O GJJYYMXBCYYXPQ-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- 229960005353 testolactone Drugs 0.000 description 1
- BPEWUONYVDABNZ-DZBHQSCQSA-N testolactone Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(OC(=O)CC4)[C@@H]4[C@@H]3CCC2=C1 BPEWUONYVDABNZ-DZBHQSCQSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-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
- 229940034915 thalomid Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- KVJXBPDAXMEYOA-CXANFOAXSA-N trilostane Chemical compound OC1=C(C#N)C[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CC[C@@]32O[C@@H]31 KVJXBPDAXMEYOA-CXANFOAXSA-N 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- TUCIOBMMDDOEMM-RIYZIHGNSA-N tyrphostin B42 Chemical compound C1=C(O)C(O)=CC=C1\C=C(/C#N)C(=O)NCC1=CC=CC=C1 TUCIOBMMDDOEMM-RIYZIHGNSA-N 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 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 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- JXLYSJRDGCGARV-CFWMRBGOSA-N vinblastine 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-CFWMRBGOSA-N 0.000 description 1
- 229960004528 vincristine 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
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 229940053867 xeloda Drugs 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 229940033942 zoladex Drugs 0.000 description 1
- 229940002005 zometa Drugs 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 235000019145 α-tocotrienol Nutrition 0.000 description 1
- 150000003773 α-tocotrienols Chemical class 0.000 description 1
- 239000002478 γ-tocopherol Substances 0.000 description 1
- QUEDXNHFTDJVIY-DQCZWYHMSA-N γ-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-DQCZWYHMSA-N 0.000 description 1
- 235000019150 γ-tocotrienol Nutrition 0.000 description 1
- 150000003786 γ-tocotrienols Chemical class 0.000 description 1
- 239000002446 δ-tocopherol Substances 0.000 description 1
- 235000019144 δ-tocotrienol Nutrition 0.000 description 1
- 150000003790 δ-tocotrienols Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/26—Androgens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/06—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
可抑制Smac蛋白与细胞凋亡蛋白抑制剂(IAP)结合的式(I)的新化合物。
Description
本发明涉及可抑制Smac蛋白与细胞凋亡蛋白抑制剂(IAP)结合的新化合物。本发明包括新化合物、新组合物、它们的使用方法及其生产方法,其中所述的化合物通常是在药物学上用作治疗剂,它的作用机理取决于对Smac/IAP相互作用的抑制,特别是用作用于治疗增殖性疾病、包括癌症的治疗剂。
发明背景
程序性细胞死亡在调节细胞数量以及从正常组织中消除受刺激或受损的细胞中起着重要的作用。事实上,大部分细胞类型中所固有的细胞凋亡信号传导机制网络为阻止人类癌症的形成和发展提供了一个重要的屏障。由于最常用的放射和化学疗法均依赖于激活细胞凋亡途径以杀死癌症细胞,因此能够逃避程序性细胞死亡的肿瘤细胞通常会对治疗产生抗药性。
细胞凋亡信号传导网络分为内在的(由死亡受体-配体相互作用所介导)和外在的(由细胞应激和线粒体通透化所介导)。两种途径最终在半胱天冬酶(Caspases)处会合。一旦被激活,半胱天冬酶就会裂解大量与细胞死亡相关的底物,造成细胞的破坏。
肿瘤细胞遗承了大量的策略以规避细胞凋亡。一种最近报道的分子机制涉及IAP(细胞凋亡抑制剂)蛋白家族成员的过度表达。IAP通过直接与半胱天冬酶相互作用并中和半胱天冬酶来阻止细胞凋亡。原型IAP-XIAP和cIAP-具有三种功能结构域,分别为称为BIR1、2和3结构域。BIR3结构域直接与半胱天冬酶9相互作用并抑制其结合和裂解其天然底物半胱天冬酶-3酶原的能力。
有报道指出,促凋亡线粒体蛋白Smac(也称为DIABLO)能够通过与BIR3表面上的蛋白结合袋(Smac结合位点)相结合来中和XIAP和/或cIAP,从而阻止XIAP和/或cIAP与半胱天冬酶9之间的相互作用。本发明涉及可与Smac结合袋相结合从而促进迅速分化的细胞发生细胞凋亡的治疗性分子。所述治疗性分子可用于治疗增殖性疾病,包括癌症。换句话说,Smac类似物可与IAP的BIR3结构域相结合并消除IAP对活化的半胱天冬酶9的抑制作用,从而使半胱天冬酶9可以诱导细胞凋亡。
发明概述
本发明涉及可抑制Smac蛋白与细胞凋亡蛋白抑制剂(IAP)结合的新化合物。本发明包括新化合物、新组合物、它们的使用方法及其生产方法,其中所述的化合物通常是在药物学上用作治疗剂,它的作用机理取决于对Smac/IAP相互作用的抑制,特别是用作用于治疗增殖性疾病、包括癌症的治疗剂。
发明详述
本发明涉及式(I)化合物或其可药用盐:
其中
R1是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或C3-C10环烷基,它们是未取代的或取代的;
R2是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或C3-C10环烷基,它们是未取代的或取代的;
R3是H;-CF3;-C2F5;C1-C4烷基;C1-C4链烯基;C1-C4炔基;-CH2-Z或R2和R3与氮一起形成het环;
Z是H;-OH;F;Cl;-CH3;-CF3;-CH2Cl;-CH2F或-CH2OH;
R4是C1-C16直链或支链烷基;C1-C16链烯基;C1-C16炔基;或-C3-C10环烷基;-(CH2)1-6-Z1;-(CH2)0-6-芳基;和-(CH2)0-6-het;其中烷基、环烷基和苯基是未取代的或取代的;
Z1是-N(R8)-C(O)-C1-C10烷基;-N(R8)-C(O)-(CH2)1-6-C3-C7环烷基;-N(R8)-C(O)-(CH2)0-6-苯基;-N(R8)-C(O)-(CH2)1-6-het;-C(O)-N(R9)(R10);-C(O)-O-C1-C10烷基;-C(O)-O-(CH2)1-6-C3-C7环烷基;-C(O)-O-(CH2)0-6-苯基;-C(O)-O-(CH2)1-6-het;-O-C(O)-C1-C10烷基;-O-C(O)-(CH2)1-6-C3-C7环烷基;-O-C(O)-(CH2)0-6-苯基;-O-C(O)-(CH2)1-6-het;其中烷基、环烷基和苯基是未取代的或取代的;
het是含有1-4个选自N、O和S的杂原子的5-7元的杂环或包括至少一个含有1、2或3个选自N、O和S的杂原子的5-7元的杂环的8-12元的稠环系,所述的杂环或稠环系是未取代的或者在碳或氮原子上被取代;R8是H;-CH3;-CF3;-CH2OH或-CH2Cl;
R9和R10彼此独立地是H;C1-C4烷基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;-(CH2)0-6-苯基;其中烷基、环烷基和苯基是未取代的或取代的,或R9和R10与氮一起形成het;
R5是H;C1-C10-烷基;芳基;苯基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;
-C1-C10烷基-芳基;-(CH2)0-6-C3-C7环烷基-(CH2)0-6-苯基;
-(CH2)0-4CH-((CH2)1-4-苯基)2;-(CH2)0-6-CH(苯基)2;-茚满基;-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7-环烷基;-C(O)-(CH2)0-6-苯基;-(CH2)0-6-C(O)-苯基;-(CH2)0-6-het;-C(O)-(CH2)1-6-het;或R5是氨基酸的残基,其中烷基、环烷基、苯基和芳基取代基是未取代的或取代的;
U如结构式II所示:
其中
n=0-5;
X是-CH或N;
Ra和Rb独立地是O、S或N原子或C0-8烷基,其中烷基链中的一个或多个碳原子可被选自O、S或N的杂原子所代替,并且其中烷基是未取代的或取代的;
Rd选自:
(a)-Re-Q-(Rf)p(Rg)q;或
(b)Ar1-D-Ar2;
Rc是H或Rc和Rd可一起形成环烷基或het;其中如果Rd和Rc形成环烷基或het,则R5在C或N原子处连接到所形成的环上;
p和q独立地是0或1;
Re是C1-8烷基或亚烷基,并且Re是未取代的或取代的;
Q是N、O、S、S(O)或S(O)2;
Ar1和Ar2是取代或未取代的芳基或het;
Rf和Rg彼此独立地是H;-C1-C10烷基;C1-C10烷基芳基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;芳基;苯基-苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;-S(O)2-NR11R12;-NR11-S(O)2-R12;S-C1-C10烷基;芳基-C1-C4烷基;het-C1-C4-烷基,其中烷基、环烷基、het和芳基是未取代的或取代的;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4烷基;或Rg和Rf形成选自het或芳基的环;
D是-CO-;-C(O)-C1-7亚烷基或亚芳基;-CF2-;-O-;-S(O)r,其中r是0-2;1,3-二氧杂环戊烷;或C1-7烷基-OH;其中烷基、亚烷基或亚芳基是未取代的或者被一个或多个卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3所取代,或者D是-N(Rh),其中Rh是H;C1-7烷基(未取代的或取代的);芳基;-O(C1-7环烷基)(未取代的或取代的);C(O)-C1-C10烷基;C(O)-C0-C10烷基-芳基;C-O-C1-C10烷基;C-O-C0-C10烷基-芳基或SO2-C1-C10-烷基;SO2-(C0-C10-烷基芳基);
R6、R7、R’6和R’7彼此独立地是H;-C1-C10烷基;-C1-C10烷氧基;芳基
-C1-C10烷氧基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;
-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;
-S(O)2-NR11R12;-NR11-S(O)2-R12;其中烷基、环烷基和芳基是未取代的或取代的;并且R6、R7、R’6和R’7可连接形成环系;
R11和R12独立地是H;C1-C10烷基;-(CH2)0-6-C3-C7环烷基;
-(CH2)0-6-(CH)0-1(芳基)1-2;-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7环烷基;
-C(O)-O-(CH2)0-6-芳基;-C(O)-(CH2)0-6-O-芴基;-C(O)-NH-(CH2)0-6-芳基;
-C(O)-(CH2)0-6-芳基;-C(O)-(CH2)1-6-het;-C(S)-C1-C10烷基;
-C(S)-(CH2)1-6-C3-C7环烷基;-C(S)-O-(CH2)0-6-芳基;-C(S)-(CH2)0-6-O-芴基;-C(S)-NH-(CH2)0-6-芳基;-C(S)-(CH2)0-6-芳基;-C(S)-(CH2)1-6-het;其中烷基、环烷基和芳基是未取代的或取代的;或R11和R12是有利于分子跨过细胞膜转运的取代基;或R11和R12与氮原子一起形成het;
其中R11和R12的烷基取代基可以是未取代的或者被一个或多个选自下列的取代基所取代:C1-C10烷基、卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3;
R11和R12的取代的环烷基取代基被一个或多个选自下列的取代基所取代:
C1-C10链烯烃;C1-C6烷基;卤素;OH;-O-C1-C6烷基;-S-C1-C6烷基或-CF3;并且
R11和R12的取代的苯基或芳基被一个或多个选自下列的取代基所取代:卤素;羟基;C1-C4烷基;C1-C4烷氧基;硝基;-CN;-O-C(O)-C1-C4烷基和-C(O)-O-C1-C4-芳基。
本发明还涉及式I化合物在治疗增殖性疾病、尤其是依赖于Smac蛋白与细胞凋亡蛋白抑制剂(IAP)的结合的那些疾病中的用途,或其在生产用于治疗所述疾病的药物中的用途、使用式(I)化合物治疗所述疾病的方法、包含式(I)化合物的用于治疗所述疾病的药物制剂、用于治疗所述疾病的式(I)化合物。
上下文中所用的一般术语在本文中具有以下含义,除非另有说明:
“芳基”是含有6-14个碳原子的芳香族基团,其可以是稠合的或非稠合的,并且可以是未取代的或者被一个或多个、优选1或2个取代基所取代,其中取代基如以下所定义。优选的“芳基”是苯基、萘基或茚满基。
“Het”是指杂芳基和杂环以及含有芳香族和非芳香族杂环的稠环。“Het”是含有1-4个选自N、O和S的杂原子的5-7元的杂环或包括至少一个含有1、2或3个选自N、O和S的杂原子的5-7元的杂环的8-12元的稠环系。适当的het取代基包括未取代的和取代的吡咯烷基、四氢呋喃基、四氢硫代呋喃基、哌啶基、哌嗪基、四氢吡喃基、吗啉代、1,3-二氮杂环庚烷、1,4-二氮杂环庚烷、1,4-氧氮杂环庚烷、1,4-氧硫杂环庚烷、呋喃基、噻吩基、吡咯、吡唑、三唑、1,2,3-三唑、四唑基、噁二唑、噻吩,咪唑、吡咯烷、吡咯烷酮、噻唑、噁唑、吡啶、嘧啶、异噁唑基、吡嗪、喹啉、异喹啉、吡啶并吡嗪、吡咯并吡啶、呋喃并吡啶、吲哚、苯并呋喃、苯并硫代呋喃、苯并吲哚、苯并噁唑、吡咯并喹啉等。het取代基是未取代的或者在碳原子上被卤素、尤其是氟或氯、羟基、C1-C4烷基、诸如甲基和乙基、C1-C4烷氧基、尤其是甲氧基和乙氧基、硝基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4烷基所取代或者在氮原子上被C1-C4烷基、尤其是甲基或乙基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4烷基、诸如甲氧羰基或乙氧羰基所取代。
当两个取代基与共同连接的氮一起是het时,可以理解成所形成的杂环是含氮环,诸如氮杂环丙烷、氮杂环丁烷、吡咯、哌啶、哌嗪、吗啉、吡咯,吡唑、噻唑、噁唑、吡啶、嘧啶,异噁唑基等。
卤素是氟、氯、溴或碘,尤其是氟和氯。
除非另有说明,“烷基”包括直链或支链烷基,诸如甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、正戊基和支链戊基、正己基和支链己基等。
“环烷基”是指含有3-8个环碳原子的C3-C10环烷基,其可以是例如环丙基、环丁基、环戊基、环己基、环庚基或环辛基。优选的环烷基是环庚基。环烷基可以是未取代的或者被以下所定义的任何一个取代基所取代,优选卤素、羟基或C1-C4烷基诸如甲基。
氨基酸残基包括标准氨基酸诸如丙氨酸、精氨酸、天冬酰胺、天冬氨酸、半胱氨酸、谷酰胺、谷氨酸、甘氨酸、组氨酸、异亮氨酸、亮氨酸、赖氨酸、蛋氨酸、苯丙氨酸、脯氨酸、丝氨酸、苏氨酸、色氨酸、酪氨酸和缬氨酸的残基。氨基酸残基还包括不常见的和修饰的氨基酸的侧链。不常见的和修饰的氨基酸对于本领域技术人员来说是已知的(参见例如G.B.Fields,Z.Tiam和G Barany;Synthetic Peptides A Users Guide,Universityof Wisconsin Biochemistry Center,第3章,(1992)),并且包括氨基酸诸如4-羟基脯氨酸、5-羟基赖氨酸、锁链素、β-丙氨酸、α、γ-和β-氨基丁酸、高半胱氨酸、高丝氨酸、瓜氨酸、鸟氨酸、2-或3-氨基己二酸、6-氨基己酸、2-或3-氨基异丁酸、2,3-二氨基丙酸、二苯基丙氨酸、羟基脯氨酸等。如果氨基酸残基的侧链含有可衍生化的基团诸如COOH、-OH或氨基,则侧链可通过与该可衍生化的基团反应的取代基来衍生化。例如,酸性氨基酸例如天冬氨酸和谷氨酸或羟基取代的侧链例如丝氨酸或苏氨酸的侧链可衍生化以形成酯,或者氨基侧链可形成酰胺或烷基氨基衍生物。尤其是所述的衍生物可以是有利于跨过细胞膜转运的取代基。另外,氨基酸残基中的任何羧酸基团例如α羧酸基团可按照以上所述的方法衍生化以形成酯或酰胺。
有利于分子跨过细胞膜转运的取代基对于药物化学领域的技术人员来说是已知的(参见例如Gangewar S.,Pauletti G.M.,Wang B.,Siahaan T.J.,Stella V.J.,Borchardt R.T.,Drug Discovery Today,vol.2.p148-155(1997)和Bundgaard H.和Moss J.,Pharmaceutical Research、vol.7,p 885(1990))。通常,所述的取代基是亲脂性取代基。所述的亲脂性取代基包括C6-C30烷基(其是饱和的、单不饱和的、多不饱和的,包括亚甲基中断的多烯)、苯基、被1或2个C1-C8烷基取代的苯基、C5-C9环烷基、被1或2个C1-C8烷基取代的C5-C9环烷基、-X1-苯基、在苯环中被1或2个C1-C8烷基取代的-X1-苯基、X1-C5-C9环烷基或被1或2个C1-C8烷基取代的X1-C5-C9环烷基;其中X1是C1-C24烷基,它是饱和的、单不饱和的或多不饱和的并且是直链或支链的。
未取代的是指氢是唯一的取代基。
以上所定义的芳基、het、烷基、环烷基或杂环基团中的任何一个都可以是未取代的或者独立地被最多四个、优选一、二或三个选自下列的取代基所取代:卤素(诸如Cl或Br);羟基;低级烷基(诸如C1-C3低级烷基);可被本文所定义的取代基中的任何一个所取代的低级烷基;低级链烯基;低级炔基;低级烷酰基;烷氧基(诸如甲氧基);芳基(诸如苯基或苄基);取代的芳基(诸如氟苯基或甲氧基苯基);氨基;单-或二取代的氨基;氨基低级烷基(诸如二甲基氨基);乙酰基氨基;氨基低级烷氧基(诸如乙氧基胺);硝基;氰基;氰基低级烷基;羧基;酯化的羧基(诸如低级烷氧基羰基,例如甲氧基羰基);正丙氧基羰基或异丙氧基羰基;烷酰基;苯甲酰基;氨基甲酰基;N-单-或N,N-二取代的氨基甲酰基;氨基甲酸酯;烷基氨基甲酸酯;脒基;胍;脲;脲基;巯基;磺基;低级烷硫基;磺氨基;磺酰胺;苯磺酰胺;磺酸酯;硫基低级烷基(诸如甲硫基);磺氨基;取代或未取代的磺酰胺(诸如苯磺酰胺);取代或未取代的磺酸酯(诸如氯-苯基磺酸酯);低级烷基亚磺酰基;苯基亚磺酰基;苯基-低级烷基亚磺酰基;烷基苯基亚磺酰基;低级烷烃磺酰基;苯基磺酰基;苯基-低级烷基磺酰基;烷基苯基磺酰基;卤代-低级烷基巯基;卤素-低级烷基磺酰基;诸如尤其是三氟甲磺酰基;膦酰基(-P(=O)(OH)2);羟基-低级烷氧基磷酰基或二-低级烷氧基磷酰基;取代的脲(诸如3-三氟-甲基-苯基脲);烷基氨基甲酸酯或氨基甲酸酯(诸如乙基-N-苯基-氨基甲酸酯)或-NR4R5,其中R4和R5可以相同或不同,并且独立地是H;低级烷基(例如甲基、乙基或丙基);或R4和R5与N原子一起形成含有1-4个氮、氧或硫原子的3-至8-元的杂环(例如哌嗪基、吡嗪基、低级烷基-哌嗪基、吡啶基、吲哚基、噻吩基、噻唑基、N-甲基哌嗪基、苯并噻吩基、吡咯烷基、哌啶-1-基或咪唑啉基),其中所述的杂环可以被本文所定义的任何取代基所取代。
优选以上所述的烷基、环烷基、芳基或het基团可以被卤素、羰基、硫醇、S(O)、S(O2)、-OH、-SH、-OCH3、-SCH3、-CN、-SCN或硝基所取代。
在将复数形式用于化合物、盐、药物制剂、疾病等的情况下,它也指单一的化合物、盐等。
对于本领域技术人员来说显而易见的是,本发明化合物可以以盐的形式、尤其是以酸加成盐或碱加成盐的形式存在。当化合物以盐的形式存在时,所述盐的形式也包括在本发明的范围内。尽管任何盐的形式都可用于化学加工处理、诸如纯化过程,但仅有可药用盐能够用于制药产品。
在适当的情况下,可药用盐包括可药用碱加成盐和酸加成盐,例如金属盐诸如碱金属和碱土金属盐、铵盐、有机胺加成盐、氨基酸加成盐和磺酸盐。酸加成盐包括无机酸加成盐诸如盐酸盐、硫酸盐和磷酸盐以及有机酸加成盐诸如烷基磺酸盐、芳基磺酸盐、乙酸盐、马来酸盐、富马酸盐、酒石酸盐、柠檬酸盐和乳酸盐。金属盐的例子是碱金属盐、诸如锂盐、钠盐和钾盐、碱土金属盐诸如镁盐和钙盐、铝盐和锌盐。铵盐的例子是铵盐和四甲基铵盐。有机胺加成盐的例子是与吗啉和哌啶所形成的盐。氨基酸加成盐的例子是与甘氨酸、苯丙氨酸、谷氨酸和赖氨酸所形成的盐。磺酸盐包括甲磺酸盐、甲苯磺酸盐和苯磺酸盐。
鉴于游离形式的化合物与它们的盐(包括可用作例如化合物的纯化或鉴别中的中间体的那些盐)、互变体或互变体混合物及其盐之间的密切关系,所以,若无另外说明,在适当且有利的情况下,上下文所提到的任何化合物、尤其是式I化合物均应还理解成是指这些化合物、尤其是式I化合物的相应的互变体、这些化合物、尤其是式I化合物的互变体混合物或这些化合物中任何一种的盐。
任何不对称的碳原子都可以(R)-、(S)-或(R,S)-构型存在,优选以(R)-或(S)-构型存在。如果可能的话,在环上具有饱和键的原子上的取代基以顺式-(=Z-)或反式(=E-)形式存在。因此该化合物可以以异构体混合物或优选以纯异构体、优选以对映体纯的非对映体或纯对映体的形式存在。
本发明的优选实施方案:
在以下优选的实施方案中,一般表述可以被上下文提供的相应的更具体的定义所代替,由此得到本发明的特别优选的实施方案。
优选的是式I化合物或其可药用盐的用途,其中待治疗的疾病是依赖于Smac蛋白与细胞凋亡蛋白抑制剂(IAP)相结合的增殖性疾病。
本发明的一种实施方案涉及式(I)化合物或其可药用盐:
其中
R1是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或环烷基,它们是未取代的或者被一个或多个选自下列的取代基所取代:卤素、-OH、-SH、-OCH3、-SCH3、-CN、-SCN和硝基;
R2是H;C1-C4烷基;C1-C4链烯基;C1-C4炔基或环烷基,它们是未取代的或者被一个或多个选自下列的取代基所取代:卤素、-OH、-SH、-OCH3、-SCH3、-CN、-SCN和硝基;
R3是H;-CF3;-C2F5;C1-C4烷基;C1-C4链烯基;C1-C4炔基;-CH2-Z或R2和R3与氮一起形成het;
Z是H;-OH;F;Cl;-CH3;-CF3;-CH2Cl;-CH2F或-CH2OH;
R4是C1-C16直链或支链烷基;C1-C16链烯基;C1-C16炔基;或-C3-C16环烷基;-(CH2)1-6-Z1;-(CH2)0-6-苯基;和-(CH2)0-6-het,其中烷基、环烷基和苯基是未取代的或取代的;
Z1是-N(R8)-C(O)-C1-C10烷基;-N(R8)-C(O)-(CH2)1-6-C3-C7环烷基;
-N(R8)-C(O)-(CH2)0-6-苯基;-N(R8)-C(O)-(CH2)1-6-het;-C(O)-N(R9)(R10);
-C(O)-O-C 1-C10烷基;-C(O)-O-(CH2)1-6-C3-C7环烷基;-C(O)-O-(CH2)0-6-苯基;-C(O)-O-(CH2)1-6-het;-O-C(O)-C1-C10烷基;-O-C(O)-(CH2)1-6-C3-C7环烷基;-O-C(O)-(CH2)0-6-苯基;-O-C(O)-(CH2)1-6-het,其中烷基、环烷基和苯基是未取代的或取代的;
het是含有1-4个选自N、O和S的杂原子的5-7元的杂环或包括至少一个含有1、2或3个选自N、O和S的杂原子的5-7元的杂环的8-12元的稠环系,所述的杂环或稠环系是未取代的或者在碳原子上被卤素、羟基、C1-C4烷基、C1-C4烷氧基、硝基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4-烷基所取代或者在氮原子上被C1-C4烷基、-O-C(O)-C1-C4烷基或-C(O)-O-C1-C4烷基所取代;
R8是H、-CH3、-CF3、-CH2OH或-CH2Cl;
R9和R10彼此独立地是H;C1-C4烷基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;-(CH2)0-6-苯基;其中烷基、环烷基和苯基是未取代的或取代的,或R9和R10与氮一起形成het;
R5是H;C1-C10-烷基;C3-C7环烷基;-(CH2)1-6-C3-C7环烷基;-C1-C10烷基-芳基;-(CH2)0-6-C3-C7环烷基-(CH2)0-6-苯基;-(CH2)0-4CH-((CH2)1-4-苯基)2;-(CH2)0-6-CH(苯基)2;-(CH2)0-6-C(O)苯基-茚满基;芳基-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7环烷基;-C(O)-(CH2)0-6-苯基;-(CH2)0-6-het;-C(O)-(CH2)1-6-het;或R5是氨基酸的残基,其中烷基、环烷基、苯基和芳基是未取代的或取代的;
U如结构式II所示:
其中
n=0-5;
X是-CH或N;
Ra和Rb独立地是O、S或N原子或C0-8烷基,其中烷基链中的一个或多个碳原子被选自O、S或N的杂原子所代替,并且其中烷基是未取代的或取代的;
Rd选自:
(a)-Re-Q-(Rf)p(Rg)q;或
(b)Ar1-D-Ar2;
Rc是H或Rd和Rc一起形成环烷基或het;其中如果Rd和Rc形成环烷基或杂环,则R5在C或N原子处连接到所形成的环上;
p和q独立地是0或1;
Re是C1-8烷基或亚烷基,优选亚甲基,Re是未取代的或取代的;
Q是N、O、S、S(O)或S(O)2;
Ar1和Ar2是取代或未取代的芳基或het;
Rf和Rg彼此独立地是H;-C1-C10烷基;C1-C10烷基芳基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;芳基;苯基-苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;-S(O)2-NR11R12;-NR11-S(O)2-R12;S-C1-C1-烷基;芳基-C1-C4烷基;het-C1-C4烷基,其中烷基、环烷基、het和芳基是未取代的或取代的;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4烷基;或Rg和Rf形成选自het或芳基的环;
D是-CO-;-C(O)-C1-7亚烷基或亚芳基;-CF2-;-O-;-S(O)r,其中r是0-2;
1,3-二氧杂环戊烷;或C1-7烷基-OH;其中烷基、亚烷基或亚芳基是未取代的或者被一个或多个卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3所取代;或者D是-N(Rh),其中Rh是H;C1-7烷基(未取代的或取代的);芳基;-O(C1-7环烷基)(未取代的或取代的);C(O)-C1-C10烷基;C(O)-C0-C10烷基-芳基;C-O-C1-C10烷基;C-O-C0-C10烷基-芳基或SO2-C1-C10-烷基;SO2-(C0-C10-烷基芳基);
R6、R7、R’6和R’7彼此独立地是H;-C1-C10烷基;-C1-C10烷氧基;芳基-C1-C10烷氧基;-OH;-O-C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-O-(CH2)0-6-芳基;苯基;-(CH2)1-6-het;-O-(CH2)1-6-het;-OR11;-C(O)-R11;-C(O)-N(R11)(R12);-N(R11)(R12);-S-R11;-S(O)-R11;-S(O)2-R11;-S(O)2-NR11R12;-NR11-S(O)2-R12;其中烷基、环烷基和芳基是未取代的或取代的;并且R6、R7、R’6和R’7可连接形成环系;
R11和R12独立地是H;C1-C10烷基;-(CH2)0-6-C3-C7环烷基;-(CH2)0-6-(CH)0-1(芳基)1-2;-C(O)-C1-C10烷基;-C(O)-(CH2)1-6-C3-C7环烷基;-C(O)-O-(CH2)0-6-芳基;-C(O)-(CH2)0-6-O-芴基;-C(O)-NH-(CH2)0-6-芳基;-C(O)-(CH2)0-6-芳基;-C(O)-(CH2)1-6-het;-C(S)-C1-C10烷基;-C(S)-(CH2)1-6-C3-C7环烷基;-C(S)-O-(CH2)0-6-芳基;-C(S)-(CH2)0-6-O-芴基;-C(S)-NH-(CH2)0-6-芳基;-C(S)-(CH2)0-6-芳基;-C(S)-(CH2)1-6-het;其中烷基、环烷基和芳基是未取代的或取代的;或R11和R12是有利于分子跨过细胞膜转运的取代基;或R11和R12与氮一起是het;R11和R12的芳基可以是苯基、萘基或茚满基,它是未取代的或取代的;
R11和R12的烷基是未取代的或者被一个或多个选自下列的取代基所取代:C1-C10链烯烃、卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基和-CF3;
R11和R12的环烷基是未取代的或者被一个或多个选自下列的取代基所取代:C1-C10链烯烃、一个或多个卤素、C1-C6烷基、卤素、OH、-O-C1-C6烷基、-S-C1-C6烷基或-CF3;并且
R11和R12的苯基或芳基是未取代的或者被一个或多个选自下列的取代基所取代:卤素、羟基、C1-C4烷基、C1-C4烷氧基、硝基、-CN、-O-C(O)-C1-C4烷基和-C(O)-O-C1-C4-芳基。
本发明的另一种实施方案涉及式(I)化合物在治疗增殖性疾病、尤其是依赖于Smac蛋白与细胞凋亡蛋白抑制剂(IAP)的结合的那些疾病中的用途,或者在生产用于治疗所述疾病的药物中的用途、使用式(I)化合物治疗所述疾病的方法、包含式(I)化合物的用于治疗所述疾病的药物制剂、用于治疗所述疾病的式(I)化合物。
本发明的一种实施方案涉及式(I)化合物及其可药用盐:
其中
R1和R2独立地是H或取代或未取代的C1-C4烷基;
R4是C1-C16直链或支链烷基或C3-C10环烷基,其中烷基或环烷基是未取代的或取代的;
R5是H;C1-C10烷基;C1-C10烷基-芳基;-C(O)-(CH2)0-6-苯基;-(CH2)0-6-C(O)-苯基;芳基;茚满基;萘基,或R5是氨基酸的残基,其中烷基或芳基取代基是未取代的或取代的;
U如结构式II所示:
其中
n=0-5;
X是-CH或N;
Ra和Rb独立地是O、S或N原子或C0-8烷基,其中烷基链中的一个或多个碳原子被选自O、S或N的杂原子所代替,并且其中烷基是未取代的或取代的;
Rd选自
(a)-Re-Q-(Rf)p(Rg)q;或
(b)Ar1-D-Ar2;
Rc是H或Rc和Rd一起形成环烷基或het;其中如果Rd和Rc形成环烷基或杂环,则R5在C或N原子处连接到所形成的环上;
p和q独立地是0或1;
Re是C1-8烷基或亚甲基,它是未取代的或取代的;
Q是N、O、S、S(O)或S(O)2;
Ar1和Ar2是取代或未取代的芳基或het;
Rf和Rg彼此独立地是H或取代或未取代的C0-C10烷基;C1-C10烷基芳基;芳基-C1-C10烷基;het-C1-C10烷基;-C(O)-C1-C4-烷基-苯基;-C(O)-C1-C4-烷基;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4-烷基;
D是-C(O)-;C1-7亚烷基或亚芳基;-O-或-S(O)r,其中r是0-2;其中烷基、亚烷基或亚芳基是未取代的或者被一个或多个卤素;-OH;-O-C1-C6烷基;-S-C1-C6烷基或-CF3所取代;或者D是NRh,其中Rh是H;C1-7烷基(未取代的或取代的);芳基;-OC1-7环烷基(未取代的或取代的);-CO-C0-10烷基或芳基或SO2-C0-10-烷基或芳基;并且R6、R7、R’6和R’7彼此独立地是H、-C1-C10烷基或-OH、烷氧基或芳基氧基。
在另一种实施方案中,U是完全由碳骨架构成的或者含有一个或多个杂原子诸如O、N、S的二环饱和或不饱和环系,但优选如结构式III所示:
其中
任何的环碳原子均是未取代的或者被以上关于R6、R7、R6’和R7’所定义的取代基中的任何一个所取代;
X是CH或N;
V是O、F2、Cl2、Br2、I2、S、YH、H2、NH或C1-C4烷基;
W是-CH或-N;
n是0-3;并且
m是0-3。
在优选的实施方案中,环原子可以被独立地选自卤素、H、OH、低级烷基或低级烷氧基的取代基所取代,其中烷基或烷氧基是未取代的或者被卤素、OH、低级烷基或低级烷氧基取代。
在另一种实施方案中,式II或III的U与R5一起形成稠环系。
特别优选的是如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H;甲基;乙基;氯甲基;二氯甲基或三氟甲基;
R4是-C1-C4烷基;-C3-C7环烷基;-(CH2)1-6环烷基或-(CH2)0-6芳基。R4尤其是乙基;丙基;异丙基;叔丁基;环戊基或环己基;-CH2-环戊基;-CH2-环己基或-CH2-苯基。
R5是-C1-C4烷基-苯基;-C(O)-C1-C4烷基-苯基;-C1-C4烷基-C(O)-苯基或芳基;R5尤其是苯基甲基、苯基乙基和苯基丙基;茚满基、萘基;-C(O)-CH2-苯基或-CH2-C(O)-苯基;
R6和R7是H或甲基;
U具有式III的结构:
其中
任何的环碳原子均是未取代的或者被以上关于R6、R7、R6’和R7’所定义的取代基中的任何一个所取代;
X是N;
V是O或H2;
W是-N;
n是1;并且
m是1或2。
特别优选的是如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2是H;
R4是C1-C4烷基;C3-C7环烷基;C1-C7环烷基-C1-C7烷基;苯基-C1-C7烷基或芳基。R4尤其是甲基;乙基;丁基;异丙基;叔丁基或环己基;-CH2-环戊基;-CH2-环己基;-CH2-环丙基;苯基或-CH2-苯基;
R5是-C1-C4烷基-苯基;-C(O)-C1-C4烷基-苯基;-C1-C4烷基-C(O)-苯基或芳基。R5尤其是苯基乙基;茚满基、萘基;-C(O)-CH2-苯基;-CH2-C(O)-苯基或(CF3O)苯基乙基;
R6、R’6、R7和R’7是H;
U具有式III的结构,其中
任何的环碳原子均是未取代的或者被以上关于R6、R7、R6’和R7’所定义的取代基中的任何一个所取代;
X是N;
V是O或H2;
W是-N;
n是1;并且
m是1或2。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H;
U具有式II的结构,其中
X是N;
R6、R’6、R7和R’7是H;
n是0;
Rc是H;
Ar1和Ar2是取代或未取代的苯基或het,尤其是四唑基、1,2,3-三唑、吡唑、噁唑、吡咯基、三嗪、嘧啶、咪唑、噁二唑;并且
D是任选地被卤素、尤其是F取代的C1烷基。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基;C3-C7环烷基;C1-C7环烷基-C1-C7烷基;苯基-C1-C7烷基或芳基。R4尤其是甲基、乙基、丁基、异丙基、叔丁基或环己基;-CH2-环戊基;-CH2-环己基;-CH2-环丙基;苯基或-CH2-苯基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R’6、R7和R’7是H;或R6是-C(O)-C1-C4烷基.苯基且R’6、R7和R’7是H;
n是0:
Rc是H:
Ar1和Ar2是取代或未取代的苯基或het,尤其是三嗪、嘧啶、吡啶、噁唑、2,4-二氟苯基-Cl-苯基或氟苯基;并且
D是N(Rh),其中Rh是H、Me、-CHO、-SO2、-C(O)、-CHOH、-CF3或-SO2CH3。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基;C3-C7环烷基;C1-C7环烷基-C1-C7烷基;苯基-C1-C7烷基或芳基。R4尤其是甲基、乙基、丁基、异丙基、叔丁基或环己基;-CH2-环戊基;-CH2-环己基;-CH2-环丙基;苯基或-CH2-苯基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R’6、R7和R’7是H;
n是0:
Rc是H;
Ar1和Ar2是取代或未取代的苯基或het,尤其是嘧啶、吡啶、噁唑、2-甲基噁唑;并且
D是-O-。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R’6、R7和R’7是H;
n是0;
Rc是H:
Ar1和Ar2是取代或未取代的苯基或het;并且
D是S、S(O)或S(O)2。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H;
U具有式II的结构,其中
X是N:
R6、R,6、R7和R’7是H;
n是0:
Rc是H;
Ar1和Ar2是取代或未取代的苯基或het,尤其是噁唑、噻唑和噁二唑;
并且D是C(O)或1,3-二氧戊环。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H或苯基C1-C10烷基,诸如苯基乙基;
U具有式II的结构,其中
X是N;
R6、R’6、R7和R’7是H;
n是0;
Rc和Rd是杂环,尤其是吡咯烷;吡咯烷-2-酮或吡咯烷-3-酮。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H、茚满基或苯基;
U具有式II的结构,其中
X是N;
Q是O;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;并且
p和q是0。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H、茚满基或苯基;
U具有式II的结构,其中
X是N;
Q是N;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;并且
Rg是H、C1-C8烷基、甲基、乙基、己基、庚基、辛基或CH2CF3或芳基-C1-C4烷基,尤其是苯基乙基、呋喃基乙基;C3-C7环烷基,尤其是环己基;乙基苯基;-C(O)-C1-C4烷基-苯基;-C(O)-C1-C4烷基;-C1-C4烷基-芳基,尤其是-CH2-苯基;-CH2-噻吩、-CH2-呋喃、-CH2-吡咯烷基、-CH2-咪唑、-CH2-三唑、-CH2-咪唑;
并且Rf是C1-C2烷基;C1-C2烷基苯基;-SO2-C1-C2烷基;-SO2-C1-C2烷基苯基;-O-C1-C4烷基,尤其是O-乙基;苯基-苯基、1,2,3,4-四氢萘和茚满基。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是H、茚满基或苯基;
U具有式II的结构,其中
X是N;
Q是N;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;并且
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基:
R5是苯基;
U具有式II的结构,其中
X是N:
Q是O、S、S(O)或S(O)2;
R6、R’6、R7和R’7是H;
n是0;
Re是C1烷基;
q是0;
Rc是H:
并且Rf是C2烷基。
另一种实施方案涉及如下式(I)化合物,其中
R1和R3优选是甲基或乙基;
R2特别是H、甲基、乙基、氯甲基、二氯甲基或三氟甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是苯基;
U具有式II的结构,其中
X是N:
Q是N;
R6、R’6、R7和R’7是H;
n是0;
Re是CH;
q是0;
Rc是H;
并且Rf是OC1烷基。
在本发明的一个尤其重要的实施方案中,R3和R4具有式IV所示的立体化学结构,以上所述的可变取代基的定义和优选情况也适用于具有式IV所示的立体化学结构的化合物。
特别优选的是具有式(IV)的立体化学结构的化合物,其中
R1和R3优选是甲基或乙基;
R2是H、甲基、乙基或取代的甲基,尤其是氯甲基、二氯甲基和三氟甲基;优选R2是H或未取代的甲基;
R4是C1-C4烷基或C3-C7环烷基,尤其是异丙基、叔丁基、环戊基或环己基;
R5是-C1-C4-烷基-苯基,尤其是苯基甲基、苯基乙基和苯基丙基、茚满基、萘基;并且
R6和R7是H或甲基。
优选的U的立体化学结构如式V所示:
在本发明的一个具体实施方案中,R6、R7、R6’和R7’中的一个或两个是H。如果R6、R7、R6’和R7’中的一个不是H,则它尤其是羟基或苯氧基。
合成方法
缩写词:
CH2Cl2 二氯甲烷
CH3CN 乙腈
DIBAL 二异丁基氢化铝
DIPEA 二异丙基乙基胺
DME 乙二醇二甲醚
DMF N,N二甲基甲酰胺
DTBB 4,4’-二叔丁基联苯
EtOAc 乙酸乙酯
HBTU O-苄基三唑-1-基-N,N,N’,N’-四甲基脲六氟磷酸盐
HOBt 1-羟基苯并三唑
HPLC 高压液相色谱
KOTMS 三甲基硅烷醇钾(potassium trimethysilanoate)
MeOH 甲醇
MgO4 硫酸镁
MnO2 二氧化锰
Na2CO3 碳酸钠
NaHCO3 碳酸氢钠
NaOH 氢氧化钠
Tetrakis (三苯基膦)钯(0)
TFA 三氟乙酸
THF 四氢呋喃
式(I)化合物可按照以下方案1所述的方法制得(用于化合物#9-25、29-31):
用于其中W=N且X和X’独立地选自以上关于R6所定义的取代基的式1化合物的一般合成方案:
KOTMS指三甲基硅烷醇钾。
步骤A
步骤B
步骤C
步骤D
分离非对映体
步骤E
步骤F
步骤G
步骤H
方案1
步骤A:该步骤包括通过标准的碱介导的条件形成氮杂环丙烷环。
步骤B:该步骤包括通过烷基溴与过量胺在碱的存在下反应以形成仲胺。
步骤C:该步骤包括仲胺与氮杂环丙烷甲酯的活性衍生物的偶联以形成酰胺取代的氮杂环丙烷。
步骤D:该步骤包括氮杂环丙烷与悬挂的链烯烃经由热生成的甲亚胺叶立德中间体进行的分子内环加成。
步骤E:该步骤包括通过标准的还原条件用DIBAL-H将酰胺还原成胺。
步骤F:该步骤包括利用标准的钯条件在氢气氛下除去苄基型保护基。
步骤G:该步骤包括利用标准的肽偶联条件将基本骨架与t-Boc保护的天然或非天然氨基酸相偶联,然后用TFA除去t-Boc基团。
步骤H:该步骤包括利用标准的肽偶联条件将前一步骤产生的胺与t-Boc保护的或叔型天然或非天然氨基酸相偶联,然后用TFA除去t-Boc基团,
如果合适的话。然后将产物通过高效液相色谱(HPLC)纯化。
式(I)化合物可按照以下方案2所述的方法制得(用于化合物#26-28):
方案2
式(I)化合物可按照以下方案3所述的方法制得(用于化合物#32-33):
方案3
式(I)化合物可按照以下方案4所述的方法制得(用于化合物#34-35):
方案4
化合物36-38可按照方案4按照类似于制备化合物34-35的方法来制得。
如上所述,本发明化合物可用于治疗增殖性疾病。因此,本发明进一步涉及治疗增殖性疾病的方法,该方法包括向需要所述治疗的哺乳动物、优选人施用治疗有效量的本发明化合物。
增殖性疾病主要是肿瘤疾病(或癌症)(和/或任何转移瘤)。本发明化合物尤其可用于治疗的肿瘤是乳腺癌、泌尿生殖系统癌症、肺癌、胃肠癌、表皮样癌、黑瘤、卵巢癌、胰腺癌、成神经细胞瘤、头和/或颈部癌症或膀胱癌,或者广义上的肾、脑或胃癌;尤其是(i)乳腺肿瘤;表皮样肿瘤,例如表皮样头和/或颈部肿瘤或口腔肿瘤;肺肿瘤,例如小细胞或非小细胞肺肿瘤;胃肠肿瘤,例如结肠直肠肿瘤;或泌尿生殖系统肿瘤,例如前列腺肿瘤(尤其是激素难治性前列腺肿瘤);或(ii)用其它化疗剂难以治疗的增殖性疾病;或(iii)由于多重抗药性而用其它化疗剂难以治疗的肿瘤。
从本发明的广义上说,增殖性疾病还可以是过度增殖性状况,诸如白血病、增生、纤维化(尤其是肺纤维化,但也可以是其它类型的纤维化诸如肾的纤维化)、血管生成、牛皮癣、动脉粥样硬化和血管内的平滑肌增生诸如血管成形术后的狭窄或再狭窄。
当提到肿瘤、肿瘤疾病、癌或癌症时,还另外或额外地暗指在原器官或组织和/或任何其它部位的转移瘤,无论肿瘤和/或转移瘤的部位如何。
本发明化合物具有选择性的毒性,或者对快速增殖的细胞比对正常细胞具有更大的毒性,尤其是在人类癌细胞例如癌性肿瘤中,该化合物具有显著的抗增殖效果并能促进分化,例如促进细胞周期停滞和细胞凋亡。
本发明化合物可单独给药或者与其它抗癌剂联合给药,诸如可抑制肿瘤血管生成的化合物,例如蛋白酶抑制剂、表皮生长因子受体激酶抑制剂、血管内皮生长因子受体激酶抑制剂等;细胞毒性药物,诸如抗代谢物、例如嘌呤和嘧啶模拟抗代谢物;抗有丝分裂剂如微管稳定化药物和抗有丝分裂的生物碱;铂配位的络合物;抗肿瘤的抗生素;烷基化剂诸如氮芥和亚硝基脲;内分泌药物诸如肾上腺皮质类固醇、雄激素、抗雄激素、雌激素、抗雌激素、芳香酶抑制剂、促性腺激素释放激素激动剂和生长抑素类似物以及靶向于在肿瘤细胞中被上调的特定代谢途径中过度表达和/或涉及的酶或受体的化合物,例如ATP和GTP磷酸二酯酶抑制剂、组蛋白脱乙酰酶抑制剂、蛋白激酶抑制剂诸如丝氨酸、苏氨酸和酪氨酸激酶抑制剂,例如Abelson蛋白酪氨酸激酶和各种生长因子、它们的受体和激酶抑制剂,诸如表皮生长因子受体激酶抑制剂、血管内皮生长因子受体激酶抑制剂、成纤维细胞生长因子抑制剂、类胰岛素生长因子受体抑制剂和源自血小板的生长因子受体激酶抑制剂等;蛋氨酸氨基肽酶抑制剂、蛋白酶体抑制剂和环加氧酶抑制剂,例如,环加氧酶-1或-2抑制剂。
本发明进一步涉及促进快速增殖的细胞发生细胞凋亡的方法,该方法包括将快速增殖的细胞与促进细胞凋亡有效量的可与XIAP和/或cIAP蛋白的Smac结合位点相结合的非天然存在的化合物接触。优选非天然存在的化合物是本发明的式I或IV化合物。
本发明进一步涉及治疗或抑制骨髓瘤、尤其是多发性骨髓瘤的方法。本文所用的术语“骨髓瘤”涉及由在正常情况下存在于骨髓中的细胞类型所组成的肿瘤。本文所用的术语“多发性骨髓瘤”是指弥散的恶性浆细胞肿瘤,其特征在于多发的骨髓肿瘤病灶以及M成分(一种单克隆免疫球蛋白片断)的分泌,伴有广泛的溶骨性损伤,可导致骨痛、病理性骨折、高钙血症和正常血色素贫血。多发性骨髓瘤无法用常规和高剂量的化疗剂治愈。本发明涉及治疗骨髓瘤、特别是对常规化学疗法具有抗药性的骨髓瘤的方法。
药物组合物
本发明还涉及包含式I化合物的药物组合物、它们在治疗性(从本发明的广义上说也是预防性的)处置或治疗激酶依赖性疾病、尤其是以上所述的优选疾病中的应用、用于所述应用的化合物以及尤其是用于所述应用的药物制剂及其生产。
本发明还涉及在体内可转化成式I化合物本身的式I化合物的前药。因此,所提到的任何式I化合物都应理解成也是指相应的式I化合物的前药,如果合适且有利的话。
本发明的可药用化合物可以以例如药物组合物的形式存在或用于制备药物组合物,所述的药物组合物包含作为活性成分的有效量的式I化合物或其可药用盐或其与一种或多种无机或有机、固体或液体的可药用载体(载体物质)的混合物。
本发明还涉及适于给药于温血动物、尤其是人(或者给药于温血动物、尤其是人的细胞或细胞系,例如淋巴细胞)用于治疗(从本发明的广义上说,也包括预防)对抑制蛋白激酶活性有响应的疾病的药物组合物,所述的药物组合物包含一定量的、优选对于所述抑制有效量的式I化合物或其可药用盐,以及至少一种可药用载体。
本发明的药物组合物是可用于肠道诸如鼻、直肠或口服或非肠道诸如肌内或静脉内给药于温血动物(尤其是人)的药物组合物,所述的组合物包含有效剂量的药物活性成分本身或者还包含显著量的可药用载体。活性成分的剂量取决于温血动物的种类、体重、年龄和个体状况、个体的药动学数据、待治疗的疾病和给药方式。
本发明还涉及治疗对抑制蛋白激酶有响应的疾病和/或增殖性疾病的方法,该方法包括向因上述疾病之一而需要所述治疗的温血动物、例如人施用(针对所述疾病的)预防或尤其是治疗有效量的本发明的式I化合物或其互变体或其可药用盐。
给药于温血动物例如约70kg体重的人的式I化合物或其可药用盐的剂量优选是约3mg-约10g,更优选约10mg-约1.5g,最优选约100mg-约1000mg/人/天,优选分成1-3个例如可以是相同大小的单一剂量。小孩的用量是成人剂量的一半。
药物组合物包含约1%-约95%、优选约20%-约90%的活性成分。本发明的药物组合物可以是例如单位剂量形式,诸如安瓿、小瓶、栓剂、糖衣丸、片剂或胶囊的形式。
本发明的药物组合物按照本领域已知的方式例如通过常规的溶解、冷冻干燥、混合、造粒或成型过程来制得。
联合形式
式I化合物还可有利地与其它抗增殖剂联合施用。所述的抗增殖剂包括但不限于芳香酶抑制剂;抗雌激素;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管活化剂;烷化剂;组蛋白脱酰酶抑制剂;诱导细胞分化过程的化合物;环加氧酶抑制剂;MMP抑制剂;mTOR抑制剂;抗肿瘤抗代谢剂;铂化合物;靶向于/降低蛋白质或脂类激酶活性的化合物和其它抗血管生成化合物;靶向于、降低或抑制蛋白质或脂类磷酸酯酶活性的化合物;戈那瑞林激动剂;抗雄激素;蛋氨酸氨基肽酶抑制剂;二膦酸类;生物响应调节剂;抗增殖抗体;乙酰肝素酶抑制剂;Ras致癌同工型抑制剂;端粒酶抑制剂;蛋白酶体抑制剂;用于治疗血液恶性肿瘤的试剂;靶向于、降低或抑制Flt-3活性的化合物;Hsp90抑制剂;替莫唑胺;和亚叶酸钙(leucovorin)。
本文所用的术语“芳香酶抑制剂”涉及能抑制雌激素生成(即将雄甾烯二酮和睾酮底物分别转化为雌酮和雌二醇)的化合物。该术语包括但不局限于甾类,尤其是阿他美坦、依西美坦和福美坦,和特别是非甾类,尤其是氨鲁米特、罗谷亚胺、吡啶基苯乙哌啶酮、曲洛司坦、睾内酯、酮康唑、伏氯唑、法倔唑、阿那曲唑和来曲唑。依西美坦可以如市售形式如商标为AROMASIN的形式给药。福美坦可以如市售形式如商标为LENTARON的形式给药。法倔唑可以如市售形式如商标为AFEMA的形式给药。阿那曲唑可以如市售形式如商标为ARIMIDEX的形式给药。来曲唑可以如市售形式如商标为FEMARA或FEMAR的形式给药。氨鲁米特可以如市售形式如商标为ORIMETEN的形式给药。本发明中含芳香酶抑制剂化疗剂的联合给药对治疗激素受体阳性肿瘤如乳腺肿瘤特别有效。
本文所用的术语“抗雌激素药”涉及能在雌激素受体水平拮抗雌激素效应的化合物。该术语包括但不局限于他莫昔芬、氟维司群、雷洛昔芬和盐酸雷洛昔芬。他莫昔芬可以如市售形式如商标NOLVADEX的形式给药。盐酸雷洛昔芬可以如市售形式如商标为EVISTA的形式给药。氟维司群可按US4,659,516中公开的内容制得或以如市售形式如商标为FASLODEX的形式给药。本发明中含有抗雌激素药化疗剂的联合给药对治疗雌激素受体阳性肿瘤如乳腺肿瘤特别有效。
本文所用的术语“抗雄激素药”涉及能抑制雄性激素的生物学效应的任何物质,包括但不局限于比卡鲁胺(CASODEX),其可按照US4,636,505中公开的内容配制。
本文所用的术语“戈那瑞林激动剂”包括但不局限于阿巴瑞克、戈舍瑞林和醋酸戈舍瑞林。戈舍瑞林在US4,100,274中公开,可以如市售形式如商标为ZOLADEX的形式给药。阿巴瑞克可按照US5,843,901中公开的内容配制。
本文所用的术语“拓扑异构酶I抑制剂”包括但不局限于托泊替康、伊立替康、9-硝基喜树碱和大分子喜树碱轭合物PNU-166148(WO99/17804中的化合物A1)。伊立替康可以例如市售形式如商标为CAMPTOSAR的形式给药。托泊替康可以如市售形式如商标为HYCAMTIN的形式给药。
本文所用的术语“拓扑异构酶II抑制剂”包括但不局限于蒽环霉素类如阿霉素(包括脂质体剂型,例如CAELYX)、柔红霉素、表柔比星、伊达比星和奈莫柔比星(nemorubicin)、蒽醌米托蒽醌和洛索蒽醌,和鬼臼脂素(podophyllotoxines)依托泊苷和替尼泊苷。依托泊苷可以例如市售形式如商标为ETOPOPHOS的形式给药。替尼泊苷以如市售形式如商标为VM26-BRISTOL的形式给药。阿霉素以如市售形式如商标为ADRIBLASTIN的形式给药。表柔比星以如市售形式如商标为FARMORUBICIN的形式给药。伊达比星以如市售形式如商标为ZAVEDOS的形式给药。米托蒽醌以如市售形式如商标为NOVANTRON的形式给药。
本文所用的术语“微管活化药”涉及微管稳定药、微管去稳定药以及微管蛋白聚合抑制剂,包括但不局限于紫杉烷类如紫杉醇和多西他赛,长春生物碱如长春花碱,特别是硫酸长春花碱、长春新碱,特别是硫酸长春新碱和长春瑞滨、海绵内酯(discodermolide)、秋水仙素(cochicine)和埃博霉素及其衍生物,如埃博霉素B或D或其衍生物。紫杉醇以如市售形式如商标为TAXOL的形式给药。多西他赛以如市售形式如商标为TAXOTERE的形式给药。硫酸长春花碱以例如市售形式如商标为VINBLASTIN R.P.的形式给药。硫酸长春新碱以例如市售形式如商标为FARMISTIN的形式给药。海绵内酯可如US5,010,099中公开的内容得到。还包括公开于WO98/10121、US6,194,181、WO98/25929、WO98/08849、WO99/43653、WO98/22461和WO00/31247中的埃博霉素及其衍生物。特别优选的是埃博霉素A和/或B。
本文所用的术语“烷化剂”包括但不局限于环磷酰胺、异环磷酰胺、苯丙氨酸氮芥或亚硝基脲(BCNU或Gliadel)。环磷酰胺以例如市售形式如商标为CYCLOSTIN的形式给药。异环磷酰胺以例如市售形式如商标为HOLOXAN的形式给药。
术语“组蛋白脱酰酶抑制剂”或“HDAC抑制剂”涉及可抑制组蛋白脱酰酶并且具有抗增殖活性的化合物。它包括公开于WO02/22577中的化合物,尤其是N-羟基-3-[4-[[(2-羟基乙基)[2-(1H-吲哚-3-基)乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺、N-羟基-3-[4-[[[2-(2-甲基-1H-吲哚-3-基)-乙基]-氨基]甲基]苯基]-2E-2-丙烯酰胺及其可药用盐。它进一步尤其包括辛二酰苯胺异羟肟酸(SAHA)。
术语“抗肿瘤抗代谢药剂”包括但不局限于5-氟尿嘧啶或5-FU、卡培他滨、吉西他滨、DNA脱甲基化试剂诸如5-氮杂胞苷和地西他滨(decitabine)、甲氨蝶呤和依达曲沙,以及叶酸拮抗剂诸如培美曲塞(pemetrexed)。卡培他滨以例如市售形式如商标为XELODA的形式给药。吉西他滨以例如市售形式如商标为GEMZAR的形式给药。还包括单克隆抗体曲妥珠单抗(trastuzumab),其可以以例如市售形式如商标为HERCEPTIN的形式给药。
本文所用的术语“铂化合物”包括但不局限于卡铂、顺铂、cisplatinum和奥沙利铂。卡铂以例如市售形式如商标为CARBOPLAT的形式给药。奥沙利铂以例如市售形式如商标为ELOXATIN的形式给药。
本文所用的术语“靶向于/降低蛋白或脂类激酶的活性的化合物以及其它抗血管生成化合物”包括但不限于:蛋白酪氨酸激酶和/或丝氨酸和/或苏氨酸激酶抑制剂或脂类激酶抑制剂,例如:
a)靶向于、降低或抑制成纤维细胞生长因子受体(FGF-Rs)活性的化合物;
b)靶向于、降低或抑制类胰岛素生长因子受体I(IGF-IR)活性的化合物,诸如靶向于、降低或抑制IGF-IR活性的化合物,尤其是可抑制IGF-IR受体的化合物,诸如公开于WO02/092599的那些化合物;
c)靶向于、降低或抑制Trk受体酪氨酸激酶家族的活性的化合物;
d)靶向于、降低或抑制Axl受体酪氨酸激酶家族的活性的化合物;
e)靶向于、降低或抑制c-Met受体的活性的化合物;
f)靶向于、降低或抑制蛋白激酶C(PKC)和丝氨酸/苏氨酸激酶的Raf家族的成员、MEK、SRC、JAK、FAK、PDK的成员和Ras/MAPK家族成员或PI(3)激酶家族或PI(3)-激酶相关性激酶家族和/或细胞周期蛋白依赖性激酶家族(CDK)的成员的活性的化合物,尤其是公开于US5,093,330中的星形孢菌素衍生物,例如米哚妥林(midostaurin);其它化合物的例子包括例如UCN-01、沙芬戈(safingol)、BAY 43-9006、Bryostatin 1、哌立福新(Perifosine);伊莫福新(Ilmofosine);RO318220和RO320432;GO6976;Isis3521;LY333531/LY379196;异喹啉化合物诸如公开于WO00/09495的那些化合物;FTIs;PD184352或QAN697(P13K抑制剂);
g)靶向于、降低或抑制蛋白-酪氨酸激酶的活性的化合物,诸如甲磺酸伊马替尼(GLIVEC/GLEEVEC)或tyrphostin。Tyrphostin优选是低分子量(Mr<1500)的化合物或其可药用盐,尤其是选自苄亚基丙二腈类或S-芳基苯丙二腈类或二取代的喹啉类的化合物,更优选选自下列的任何化合物:Tyrphostin A23/RG-50810;AG 99;Tyrphostin AG 213;Tyrphostin AG1748;Tyrphostin AG 490;Tyrphostin B44;Tyrphostin B44(+)对映体;Tyrphostin AG 555;AG 494;Tyrphostin AG 556、AG957和adaphostin(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷基酯;NSC680410、adaphostin);和
h)靶向于、降低或抑制受体酪氨酸激酶的表皮生长因子家族(EGF-R、ErbB2、ErbB3、ErbB4,为均或杂二聚体形式)的活性的化合物,诸如靶向于、降低或抑制表皮生长因子受体家族的活性的化合物,尤其是可抑制EGF受体酪氨酸激酶家族的成员例如EGF受体、ErbB2、ErbB3和ErbB4或与EGF或EGF相关性配体结合的化合物、蛋白质或抗体,尤其是概括性地和具体地公开于以下文献的那些化合物、蛋白质或单克隆抗体:WO97/02266,例如实施例39的化合物;或EP 0 564 409、WO99/03854、EP0520722、EP 0 566 226、EP 0 787 722、EP 0 837 063、US5,747,498、WO98/10767、WO97/30034、WO97/49688、WO97/38983和尤其是WO96/30347(例如称作CP358774的化合物)、WO96/33980(例如化合物ZD1839)和WO95/03283(例如化合物ZM105180);例如公开于WO03/013541的曲妥珠单抗(HERCEPTIN)、西妥昔单抗(cetuximab)、Iressa、Tarceva、CI-1033、EKB-569、GW-2016、E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3或E7.6.3和7H-吡咯并-[2,3-d]嘧啶衍生物。
其它抗血管生成化合物包括具有另外的活性机制,例如与蛋白或脂类激酶抑制作用无关的化合物,例如萨力多胺(THALOMID)和TNP-470。
靶向于、降低或抑制蛋白或脂类磷酸酯酶活性的化合物是例如磷酸酯酶1、磷酸酯酶2A、PTEN或CDC25的抑制剂,例如冈田酸或其衍生物。
可诱导细胞分化过程的化合物是例如视黄酸、α-、γ-或δ-生育酚或α-、γ-或δ-生育三烯酚。
本文所用的术语“环加氧酶抑制剂”包括但不限于例如Cox-2抑制剂、5-烷基取代的2-芳基氨基苯基乙酸和衍生物,诸如塞来考昔(CELEBREX)、罗非考昔(VIOXX)、依托考昔(etoricoxib)、伐地考昔或5-烷基-2-芳基氨基苯基乙酸例如5-甲基-2-(2’-氯-6’-氟苯氨基)苯基乙酸、lumiracoxib。
术语“mTOR抑制剂”涉及可抑制哺乳动物的雷帕霉素靶点(mTOR)并且具有抗增殖活性的化合物,诸如西罗莫司(sirolimus)、依维莫司(everolimus)(CerticanTM)、CCI-779和ABT578。
本文所用的术语“二膦酸类”包括但不限于依替膦酸、氯膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、依班膦酸、利塞膦酸和唑来膦酸。“依替膦酸”可以以市售的形式例如以商标DIDRONEL市售的形式给药。“氯膦酸”可以以市售的形式例如以商标BONEFOS市售的形式给药。“替鲁膦酸”可以以市售的形式例如以商标SKELID市售的形式给药。“帕米膦酸”可以以市售的形式例如以商标AREDIATM市售的形式给药。“阿仑膦酸”可以以市售的形式例如以商标FOSAMAX市售的形式给药。“依班膦酸”可以以市售的形式例如以商标BONDRANAT市售的形式给药。“利塞膦酸”可以以市售的形式例如以商标ACTONEL市售的形式给药。“唑来膦酸”可以以市售的形式例如以商标ZOMETA市售的形式给药。
本文所用的术语“乙酰肝素酶抑制剂”是指靶向于、降低或抑制硫酸肝素降解的化合物。该术语包括但不限于PI-88。
本文所用的术语“生物学响应修饰剂”是指淋巴因子或干扰素,例如干扰素γ。
本文所用的术语“Ras致癌同工型”,例如H-Ras、K-Ras或N-Ras是指靶向于、降低或抑制Ras的致癌活性的化合物,例如“法尼基转移酶抑制剂”,例如L-744832、DK8G557或R115777(Zarnestra)。
本文所用的术语“端粒酶抑制剂”是指靶向于、降低或抑制端粒酶的活性的化合物。靶向于、降低或抑制端粒酶的活性的化合物尤其是可抑制端粒酶受体的化合物、例如telomestatin。
本文所用的术语“蛋氨酸氨基肽酶抑制剂”是指靶向于、降低或抑制蛋氨酸氨基肽酶的活性的化合物。靶向于、降低或抑制蛋氨酸氨基肽酶的活性的化合物是例如bengamide或其衍生物。
本文所用的术语“蛋白酶体抑制剂”是指靶向于、降低或抑制蛋白酶体的活性的化合物。靶向于、降低或抑制蛋白酶体的活性的化合物包括例如PS-341和MLN341。
本文所用的术语“基质金属蛋白酶抑制剂”或(“MMP抑制剂”)包括但不限于胶原模拟肽和非模拟肽抑制剂、四环素衍生物例如异羟肟酸模拟肽抑制剂巴马司他及其口服生物可利用的类似物马立马司他(BB-2516)、普啉司他(AG3340)、metastat(NSC 683551)BMS-279251、BAY 12-9566、TAA211、MMI270B或AAJ996。
本文所用的术语“用于治疗血液恶性肿瘤的试剂”包括但不限于类FMS-酪氨酸激酶抑制剂,例如靶向于、降低或抑制Flt-3的活性的化合物;干扰素、1-b-D-阿拉伯呋喃糖基胞嘧啶(ara-c)和bisulfan;和ALK抑制剂,例如靶向于、降低或抑制间变性淋巴瘤激酶的化合物。
术语“靶向于、降低或抑制Flt-3的活性的化合物”特别是可抑制Flt-3的化合物、蛋白质或抗体,例如PKC412、米哚妥林、星形孢菌素衍生物、SU11248和MLN518。
本文所用的术语“HSP90抑制剂”包括但不限于靶向于、降低或抑制HSP90的固有ATP酶活性的化合物;通过遍在蛋白酶体途径降解、靶向于、降低或抑制HSP90的客户(client)蛋白的化合物。靶向于、降低或抑制HSP90的固有ATP酶活性的化合物尤其是可抑制HSP90的ATP酶活性的化合物、蛋白质或抗体,例如17-烯丙基氨基,17-脱甲氧基格尔德霉素(17AAG)、格尔德霉素衍生物;其它格尔德霉素相关化合物;radicicol和HDAC抑制剂。
本文所用的术语“抗增殖性抗体”包括但不限于曲妥珠单抗(HerceptinTM)、曲妥珠单抗-DM1、埃罗替尼(erlotinib)(TarcevaTM)、贝伐单抗(bevacizumab)(AvastinTM)、利妥昔单抗、PRO64553(抗-CD40)和2C4抗体。抗体是指例如完整的单克隆抗体、多克隆抗体、由至少两个完整的抗体形成的多特异性抗体以及抗体片断,只要它们能够显示所需的生物学活性即可。
对于急性骨髓性白血病(AML)的治疗而言,可将式I化合物与标准的白血病治疗联合使用,尤其是与用于治疗AML的治疗联合使用。更确切地说,式I化合物可以与例如法尼基转移酶抑制剂和/或其它用于治疗AML的药物诸如柔红霉素、阿霉素、Ara-C、VP-16、替尼泊苷、米托蒽醌、伊达比星、卡铂和PKC412联合给药。
用代码、类名或商标名确定的活性剂的结构可以得自标准纲要“默克索引(The Merck Index)”的现行版本或得自数据库,例如PatentsInternational(例如,IMS World Publications)。
可以与式I化合物联合使用的上述化合物可按照本领域已知的诸如以上所引用的文献所述的方法进行制备和给药。
式I化合物还可有利地与已知的治疗方法组合使用,例如激素疗法或尤其是放射疗法。
式I化合物尤其可用作放射致敏剂,特别是用于治疗对放射疗法表现出不良敏感性的肿瘤。
“联合形式”是指在一个剂量单位形式中的固定的组合,或用于联合给药的成套的药盒,其中式I化合物和联合伴侣可以独立地在相同的时间给药或在一定时间间隔内、尤其是可以使联合伴侣产生合作的,例如协同的效果的时间间隔内分别给药,或它们的各种组合。
实施例
以下实施例是用于解释说明、而不是进一步限制本发明。
实施例1
N-[1-环己基-2-氧代-2-(6-苯乙基-八氢-吡咯并[2,3-c]吡啶-1-基)-乙基]-2-甲基氨基-丙酰胺(9);
式I的化合物9按照方案5所述的方法制得。
方案5
1-(1-萘-1-基-乙基)-氮杂环丙烷-2-甲酸甲酯(1)
向(S)-(-)-1-(1-萘基)乙基胺(20.8g,120mmol)的乙腈(HPLC级,600mL)溶液中加入K2CO3(52.7g,360mmol)和2,3-二溴丙酸甲酯(30g,120mmol)。将该溶液在室温下搅拌过夜。将溶液蒸发至干,然后加入H2O/EtOAc(1∶1)(600mL),将混合物用EtOAc萃取(4×100mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶2)得到24g(78%)标题化合物,为等分子比率的两种非对映体的混合物。M+H+=256.10。
丁-3-烯基-苯乙基-胺(2)
向2-苯基乙基胺(72mL,570mmol)的溶液中加入K2CO3(82g,570mmol)和4-溴-1-丁烯(25g,185mmol)。将该溶液在室温下搅拌过夜。将溶液蒸发至干并加入H2O/EtOAc(1∶1)(600mL)。将混合物用EtOAc萃取(4×150mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc1∶8)得到20g(62%)标题化合物。M+H+=176.10。1-(1-萘-1-基-乙基)-氮杂环丙烷-2-甲酸丁-3-烯基-苯乙基-酰胺(3)
向1(12.6g,49.75mmol)的THF(200mL)溶液中加入KOTMS(6.38g,49.75mmol)。将混合物在室温下搅拌过夜。将混合物浓缩,将残余物溶于二氯甲烷(200mL)并冷却至0℃。缓慢加入三甲基乙酰氯(5.94g,49.25mmol),将混合物在2小时升温至室温。将混合物冷却至-78℃,加入2(8.63g,49.25mmol),然后在-78℃下继续搅拌1.5小时。加入饱和碳酸氢钠(100mL)并将混合物升温至室温。将混合物用EtOAc萃取(4×100mL),将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶8)得到15g(76%)标题化合物,为等分子比率的两种非对映体的混合物。M+H+=399.37。
1-(1-萘-1-基-乙基)-6-苯乙基-八氢-吡咯并[2,3-c]吡啶-7-酮(4)
将3(15g,58.7mmol)的邻二氯苯(100mL)溶液在250℃下在微波反应器中加热1200秒。将混合物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶1;第二个点)得到5g(33%)标题化合物,为对映体纯的化合物。M+H+399.32。
1-(1-萘-1-基-乙基)-6-苯乙基-八氢-吡咯并[2,3-c]吡啶(5)
向4(4.8g,12mmol)的THF(100mL)溶液中于-78℃下缓慢加入1MDIBAL的甲苯溶液(50mL,50mmol)。将混合物在室温下搅拌1小时,然后用20mL水终止反应。蒸发溶剂,将残余物用100mL 1∶1饱和Rochells盐/15%NaOH稀释并用EtOAc萃取(4×50mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶9)得到2.3g(48%)标题化合物。M+H+=385.26。
6-苯乙基-八氢-吡咯并[2,3-c]吡啶(6)
向5(2.3g,6mmol)的MeOH/CH2Cl2(1∶1;200mL)溶液中加入Pd(OH)2(300mg)。将混合物在50psi.氢气氛下搅拌10小时。将混合物通过硅藻土垫过滤,将滤液浓缩,残余物不经进一步纯化即可直接用于下一步骤。M+H+=231.17。
化合物(7)
向6的二氯甲烷(25mL)溶液中依次加入二异丙基乙基胺(4.17mL,24mmol)、t-Boc-L-环己基甘氨酸(1.54g,6mmol)和0.45 M HOBt/HBTU的DMF溶液(16mL,7.19mmol)。将混合物在室温下搅拌过夜,然后用EtOAc(200mL)稀释,依次用1M柠檬酸水溶液(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水洗涤(2×50mL)。将有机层干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 1∶9)得到黄色油。将该黄色油溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩得到1.75g(79%两步骤)标题化合物,其不经进一步纯化或表征即可用于下一步骤。
化合物(9)
向7(1.75g,4.74mmol)的二氯甲烷(25mL)溶液中依次加入二异丙基乙基胺(3.30mL,19mmol)、t-Boc-N-甲基-L-丙氨酸(0.97g,4.74mmol)和0.45MHOBt/HBTU的DMF溶液(13mL,5.691mmol)。将混合物在室温下搅拌过夜。将混合物用EtOAc(200mL)稀释,依次用1M柠檬酸(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水洗涤(2×50mL)。将有机层干燥并真空浓缩。将残余物溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过HPLC纯化(C-18硅胶,20%CH3CN/H2O的0.5%TFA溶液)得到1g(36%,两步)标题化合物,为TFA盐。M+H+=455.39。
实施例2
(S)-N-((S)-1-环己基-2-{(2S,3R)-2-[(乙基-苯乙基-氨基)-甲基]-3-甲基-吡咯烷-1-基}-2-氧代-乙基)-2-甲基氨基-丙酰胺(23)
丁-3-烯基-((S)-1-苯基-乙基)-胺(A)
向S-(-)-1-苯基乙基胺(15.75g,130mmol)的150mL DMF溶液中于0℃下分成小份加入K2CO3(53.9g,390mmol)。在0℃下搅拌10分钟后,滴加4-溴丁烯(13.5g,100mmol),然后分成小份加入NaI(58.5g,390mmol)。将反应混合物(白色悬浮液)加热至95℃并搅拌过夜/16小时。将溶液冷却至室温,用200mL乙醚稀释,用3×100ml水洗涤。将有机层用Na2SO4干燥并浓缩。将粗产物通过蒸馏纯化(65~70℃,在高真空下)得到无色液体(13.5g,76.7%)。(经NMR和MS数据证实,U-4117-28-23)。
[丁-3-烯基-((S)-1-苯基-乙基)-氨基]-乙酸乙酯(B)
向丁-3-烯基-((S)-1-苯基-乙基)-胺(6.37g,36.4mmol)的150mL DMF溶液中于0℃下分成小份加入K2CO3(10.0g,72.8mmol)。在0℃下搅拌10分钟后,缓慢加入溴乙酸乙酯(8.35g,54.6mmol)。将反应混合物(白色悬浮液)在室温下搅拌过夜/16小时。将溶液用200mL乙醚稀释,用3×100ml水洗涤。将粗产物通过色谱纯化(己烷/CH2Cl2:50/50)得到浅色液体(8.5g,94.5%)。(经NMR和MS数据证实,U-4117-58)。
(2S,3R)-3-丁-3-烯基-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(C)
向二异丙基胺(3.6g,35.7mmol)的THF(80mL)溶液中于-40℃下缓慢加入BuLi(14.28mL,35.7mmol,2.5M的己烷溶液)。将溶液温热至0℃并搅拌30分钟以形成LDA溶液。将该LDA溶液冷却至-70℃并将其于-70℃下缓慢加入到[丁-3-烯基-((S)-1-苯基-乙基)-氨基]-乙酸乙酯(7.8g,29.8mmol)的THF(80mL)溶液中。将浅黄色反应溶液在-20℃下搅拌30分钟,变成深黄色溶液,然后冷却至-70℃。向该溶液中于-70℃下滴加**ZnBr2 **(16.76g,74.5mmol)的乙醚(50mL)溶液。在室温下搅拌1.5小时后,将反应溶液冷却至0℃并缓慢加入CuCN(3.47g,38.74mmol)和LiCl(3.29g,77.48mmol)的THF(80mL)溶液。在0℃下搅拌10分钟后,将烯丙基溴(7.26g,60mmol)滴加到该反应溶液中,然后非常缓慢地升温至室温。在室温下搅拌过夜后,通过加入60mL饱和NH4Cl终止反应,然后用3X150mL乙醚萃取。将合并的有机层浓缩。将粗产物通过色谱纯化(己烷/EtOAc:85/15)得到无色液体(7.4g,82.6%)。(经NMR和MS数据证实,U-4117-40-19,U-4117-34-35)。将**ZnBr2 **于使用前在150℃及高真空下干燥1小时**。
(2S,3R)-1-((2E,4Z)-(S)-1,2-二甲基-己-2,4-二烯基)-3-(3-氧代-丙基)吡咯烷-2-甲酸乙酯(D)
将(2S,3R)-3-丁-3-烯基-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(1.0g,3.32mmol)溶于EtOH(10mL)和HCl(0.5mL,37%),然后冷却至-70℃。将臭氧气体通过溶液鼓泡约10分钟,或者直至溶液变成非常浅的蓝色。将氮气通过该溶液鼓泡15分钟以除去溶液中过量的臭氧。向冷却的溶液中加入Zn粉(0.43g.6.6mmol)和HCl(0.5mL,37%)并在室温下搅拌20分钟。过滤后,将溶液用50mL CH2Cl2稀释,用饱和NaHCO3(10mL)和2×20ml水洗涤。干燥并浓缩后,得到无色液体(1.0g),其不经进一步纯化即可用于下一步骤的反应。(经NMR和MS数据证实,U-4117-51-30)。
(2S,3R)-3-(3-苯乙基氨基-丙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(E)
向(2S,3R)-1-((2E,4Z)-(S)-1,2-二甲基-己-2,4-二烯基)-3-(3-氧代-丙基)吡咯烷-2-甲酸乙酯(1.g,粗品)的EtOH(10mL)溶液中于室温下加入苯乙基胺(0.44g,3.65mmol)。在室温下搅拌30分钟后,一次性加入NaBH3CN(0.3g,4.87mmol)。在室温下搅拌1.5小时后,将反应溶液用50mL乙醚稀释,用20mL盐水洗涤。将乙醚层浓缩,将粗产物通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色液体(405mg,30.0%)。(经NMR和MS数据证实,U-4117-52-20)。
(3aS,7aS)-6-苯乙基-1-((S)-1-苯基-乙基)-八氢-吡咯并[2,3-c]吡啶-7-酮(F):
将(2S,3R)-3-(3-苯乙基氨基-丙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸乙酯(340mg,0.83mmol)溶于20mL MeOH/KOH/H2O(10mL/5g/5mL)。在80℃下搅拌2小时后,将溶液冷却至0℃,通过加入HCl(37%)中和至pH=5。浓缩后,将粗产物溶于1mL CH2Cl2并通过短硅胶柱过滤,用CH2Cl2/MeOH(93/7)洗脱得到酸形式的浅色玻璃状固体(250mg,78.9%)。(经NMR和MS数据证实,U-4117-60-22)。
向(0.05~0.1M)酸(1当量)的DMF溶液中于室温下加入二异丙基乙基胺(5当量)。在室温下搅拌20分钟后,将(0.05~0.1M)HOBT(1.2当量)和HBTU(1.2当量)的DMF溶液加入到反应混合物中并继续搅拌1.5小时(或者通过TLC监测)。将反应溶液用乙醚稀释(溶液体积的1X5~10倍),用水洗涤(两次,每次为3倍溶液体积)。将合并的有机溶液浓缩。将粗产物用CH2Cl2稀释,用Na2SO4干燥,通过色谱纯化(CH2Cl2/MeOH:97/3)得到纯产物(70~95%的收率)。(经NMR和MS数据证实,U-4117-102)。
合成化合物F的方法:
将(2S,3R)-3-(2-苯乙基氨基-乙基)-1-((S)-1-苯基-乙基)-吡咯烷-2-甲酸甲酯(400mg,1.05mmol)和2-羟基吡啶(100mg,1.05mmol)的THF(10mL)溶液在40℃下搅拌24小时。将反应液用50mL乙醚稀释,用2×120mL水洗涤。干燥并浓缩后得到浅色液体(350mg,LC/MS表明仅有纯净的产物),其不经进一步纯化即可用于下一步骤的反应。
(3aR,8aS)-7-苯乙基-1-((S)-1-苯基-乙基)-十氢-吡咯并[2,3-c]氮杂(G)
向(0.02M)内酰胺(1当量)的THF溶液中于-20℃下缓慢加入LiAlH4(2当量)的THF溶液(0.02M)。在室温下搅拌1.5小时后,将溶液用乙醚稀释(溶液体积的1×5倍),用水洗涤(两次,每次为溶液体积的2倍),干燥并浓缩。将粗产物通过色谱纯化(CH2Cl2/MeOH:97/3)得到产物(收率:70~90%)。(经NMR和MS数据证实,U-4117-104)。
(3aR,8aS)-7-苯乙基-十氢-吡咯并[2,3-c]氮杂(H)
将1000ml圆底烧瓶中的反应物(<1g)和10%Pd碳(20重量%)的MeOH(10mL,含有2滴乙酸)溶液/悬浮液在室温及气囊产生的氢气(在大气压下)下剧烈搅拌4~8小时。通过室内真空脱气10分钟后,将反应混合物过滤除去催化剂并浓缩。将粗产物用CH2Cl2/H2O(8/2,适量)稀释,用10%NH4OH中和至pH=7~8。干燥并浓缩后得到产物(80%~定量收率),其不经进一步纯化即可用于下一步骤的反应。(经NMR和MS数据证实,U-4117-105)。
(S)-N-((S)-1-环己基-2-{(2S,3R)-2-[(乙基-苯乙基-氨基)-甲基]-3-甲基-吡咯烷-1-基}-2-氧代-乙基)-2-甲基氨基-丙酰胺(化合物23):从化合物H按照方案5所述的方法制得。
实施例3
方案6
二苯乙基胺(D)
向苯乙醛(6.0g,50mmol)和2-苯基乙基胺的THF(200mL)溶液中滴加三乙酰氧基-硼氢化钠。将溶液在氮气下于室温下搅拌过夜。将溶液用饱和碳酸氢钠水溶液(200mL)终止反应并用EtOAc(4×100mL)萃取。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;EtOAc/MeOH 9∶1)得到1.25g(11%)化合物D,为澄清的油。M+H+=226.10。二苯乙基-(S)-1-吡咯烷-2-基甲基-胺(E)
向(S)-2-甲酰基-吡咯烷-1-甲酸叔丁酯(1.0g,5.0mmol)和D(1.125g,5.0mmol)的THF(40mL)溶液中滴加三乙酰氧基硼氢化钠。将溶液在氮气下于室温下搅拌过夜。将溶液用饱和碳酸氢钠水溶液(40mL)终止反应。将混合物用EtOAc萃取(4×50mL)。将有机萃取液合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc4∶1)得到黄色油。将该黄色油溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩得到1.04g(68%,两步)标题化合物E,其不经进一步纯化或表征即可用于下一步骤。
化合物(F)
向t-Boc-L-环己基甘氨酸(0.868g,3.38mmol)的DMF(20mL)溶液中加入二异丙基乙基胺(1.83mL,16.9mmol)。将混合物在室温下搅拌20分钟。然后加入E、HOBt(516mg,3.82mmol)和HBTU(1.448g,3.82mmol)的DMF(30mL)溶液。将混合物在室温下搅拌过夜,然后用乙醚(200mL)稀释并依次用1M柠檬酸水溶液(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水(2×50mL)洗涤。将有机萃取液干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;己烷/EtOAc 2∶3)得到黄色油。将该黄色油溶于二氯甲烷(20mL),加入TFA(10mL)并将混合物在室温下搅拌3小时。将混合物浓缩,将残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩得到780mg(52%,两步)标题化合物F,其不经进一步纯化或表征即可用于下一步骤。
化合物26
向t-Boc-N-甲基-L-丙氨酸(354mg,1.75mmol)的DMF(20mL)溶液中加入二异丙基乙基胺(0.938mL,8.75mmol)。将混合物在室温下搅拌20分钟。然后加入F、HOBt(267mg,1.98mmol)和HBTU(751mg,1.98mmol)的DMF(30mL)溶液。将混合物在室温下搅拌3小时,然后用乙醚(200mL)稀释并依次用1M柠檬酸(50mL)、水(50mL)、饱和NaHCO3水溶液(50mL)和盐水(2×50mL)洗涤。将有机萃取液干燥并真空浓缩。将残余物溶于二氯甲烷(20mL)并加入TFA(10mL)。将混合物在室温下搅拌3小时并浓缩。将得到的残余物溶于二氯甲烷(100mL)并用饱和碳酸氢钠中和。将溶液用二氯甲烷萃取(3×50mL)。将有机萃取液合并,干燥并真空浓缩。将部分残余物通过HPLC纯化(C-18硅胶,30%CH3CN/H2O的0.5%TFA溶液)得到120mg化合物26,为TFA盐。M+H+=533.47。
实施例4
化合物32按照以下方法制得:
方案7
化合物I
将化合物G(122mg,1mmol)和H(226mg,1mmol)溶于5mL DME。向该混合物中加入1mL 2N Na2CO3水溶液和50mg Tetrakis。将形成的混合物脱气5分钟,在90℃下搅拌6小时,冷却至室温并浓缩。将残余物通过快速色谱纯化(乙酸乙酯/己烷)得到琥珀色油状的I(204mg,90%)。该粗产物不经进一步纯化或表征即可直接用于下一步反应。
化合物J
将LAH(38mg)于0℃下加入到I(226mg,1mmol)的5mL THF溶液中。将该混合物的温度升温至室温并继续搅拌过夜。通过Fisher方法终止反应,过滤并浓缩得到无色油状的J(183mg,92%),其不经进一步纯化或表征即可直接用于下一步反应。
化合物K
将化合物J(198mg,1mmol)和MnO2(870mg,10mmol)的15mL氯仿悬浮液搅拌过夜。过滤并浓缩得到无色油状的产物K(192mg,98%)。1H NMR(CDCl3)δ9.96(s,1H),7.72(s,2H),7.47(s,2H),7.15-7.35(m,5H),4.07(s,2H)。
化合物L
将3-氯丙基胺盐酸盐(140mg,1.1mmol)、醛K(196mg,1.0mmol)和碳酸钠(212mg,2mmol)在水(10mL)中的混合物于室温下搅拌过夜。将形成的溶液用乙酸乙酯萃取(3×20mL),分离,用Na2SO4干燥,真空(15Torr)蒸发得到基本上纯净的油状残余物(270mg),其不经进一步纯化即可用于下一步反应。(M+H+272,计算值:272)。
化合物M
将亚胺L(271mg,1mmol)于-78℃下加入到锂粉末(75mg,10mmol)和催化量的DTBB(30mg,0.10mmol;5%mol)在THF(5mL)中的蓝色悬浮液中。将形成的混合物在相同的温度下搅拌2小时。用水(20mL)终止反应,将温度升至20℃。将形成的溶液依次通过用2 M盐酸(3×15mL)和4 M氢氧化钠(3×20mL)酸-碱萃取而进行纯化。将最终的溶液用乙酸乙酯萃取(3×20mL),分离,用Na2SO4干燥,蒸发得到纯化合物M(214mg,90%);(M+H+238,计算值:238)。
化合物O
将化合物M(237mg,1mmol)、化合物N(257mg,1mmol)、HBTU(460mg,1.2mmol)、HOBT(170mg,1.1mmol)、DIPEA(512mg,3mmol)和5mL DMF的混合物搅拌过夜。将混合物用乙醚(25mL)稀释,用水、盐水洗涤,用MgO4干燥,过滤并浓缩。将得到的残余物用2mL CH2Cl2/TFA(1/1)处理,搅拌2小时,浓缩得到浅黄色固体状产物O(320mg,85%);(M+H+377,计算值:377)。
化合物32
将化合物O(376mg,1mmol)、t-Boc-N-甲基丙氨酸P(203mg,1mmol)、HBTU(460mg,1.2mmol)、HOBT(170mg,1.1mmol)、DIPEA(512mg,3mmol)和5mL DMF的混合物搅拌过夜。将混合物用乙醚(25mL)稀释,用水、盐水洗涤,用MgO4干燥,过滤并浓缩。将得到的残余物用2mL CH2Cl2/TFA(1/1)处理,搅拌2小时并真空浓缩。通过柱色谱纯化得到浅黄色固体状化合物32(397mg,86%)。(M+H+462,计算值:462)。
实施例5
(S)-N-{(S)-1-环己基-2-[(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-基]-2-氧代-乙基}-2-甲基氨基-丙酰胺(34)
(S)-2-甲磺酰基氧基甲基-吡咯烷-1-甲酸叔丁酯,(P)
将火焰干燥的装有(S)-2-羟基甲基-吡咯烷-1-甲酸叔丁酯(1g,5mmol)、二氯甲烷(DCM)(20mL)和三乙基胺(0.70mL,5.2mmol)的烧瓶在N2下冷却至0℃,然后在10分钟内向其中滴加甲磺酰氯(0.38mL,5mmol)的DCM(5mL)溶液。将反应液搅拌1小时。加入DCM(100mL)后,将反应混合物用盐水洗涤,干燥并真空浓缩。将残余物通过SiO2色谱纯化(5%EtOAc/己烷)得到1.38g甲磺酸酯(P),为澄清的无色油:LCMS(ES)280.10(MH+)。(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-甲酸叔丁酯,(Q)
将氢化钠(60%)(0.6g,14.4mmol)加入到火焰干燥的装有茚满-2-醇(0.965g,7.2mmol)和N,N’-二甲基甲酰胺(DMF)(20mL)的烧瓶中,在N2下冷却至0℃并搅拌30分钟。将(S)-2-甲磺酰基氧基甲基-吡咯烷-1-甲酸叔丁酯(P)(1g,3.6mmol)的DMF(5mL)溶液以使反应混合物的温度保持在0℃的方式滴加到反应混合物中。将反应液在60℃下搅拌1小时,冷却至0℃,用盐水终止反应,用EtOAc稀释,用盐水反复洗涤(6X),干燥并真空浓缩。将残余物通过SiO2色谱纯化(5%EtOAc/己烷)得到0.20g茚满基醚(Q),为澄清的无色油:LCMS(ES)340.17(MNa+)。
(S)-N-{(S)-1-环己基-2-[(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-基]-2-氧代-乙基}-2-甲基氨基-丙酰胺,(34)
将((S)-1-{(S)-1-环己基-2-[(S)-2-(茚满-2-基氧基甲基)-吡咯烷-1-基]-2-氧代-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(Q)(0.54g,1mmol)溶于DCM(8mL)并用三氟乙酸(4mL)处理45分钟。将反应混合物真空浓缩,通过制备型反相hplc纯化得到澄清树胶状的0.096g甲基胺(34):LCMS(ES)442.26(MH+)。
实施例6
1-溴-3-苯氧基-苯(A)
将二溴苯(3g,12.75mmol)、苯酚(1g,10.6mmol)、氧化亚铜(I)(152mg,1mmol)和碳酸铯(3.46g,10.6mmol)在8mL NMP中的混合物在微波中于195℃下加热20分钟。将该多相混合物通过硅藻土床过滤,将残余物用EtOAc洗涤(1×20mL)。将滤液用1N NaOH(200mL)稀释并用EtOAc萃取(3×100mL)。将有机液合并,用Na2SO4干燥,过滤并减压浓缩得到黄色油状粗产物,将其通过柱色谱纯化(100%己烷)得到无色油状的1-溴-3-苯氧基-苯(1.4g,53%)。LCMS m/z 250(M+1)。
5-(3-苯氧基-苯基)-3,4-二氢-2H-吡咯(B):
向1-溴-3-苯氧基-苯(10.13g,40.6mmol)在无水THF(100mL)中的冷却的溶液(-78℃)中于氮气下加入n-BuLi(1.6M,44.7mmol,27mL)。将混合物搅拌30分钟,然后在氮气下通过套管将其加入到冷的(-780℃)1-(叔丁氧基羰基)-2-吡咯烷酮的无水THF(50mL)溶液中。将形成的混合物升温至室温过夜,然后用水(200mL)终止反应并用EtOAc萃取(3×100mL)。收集有机液,用Na2SO4干燥,过滤并减压浓缩。将残余物溶于CH2Cl2(20mL)并在搅拌下加入TFA(10mL)。将混合物搅拌30分钟,用冰冷的饱和NaHCO3终止反应,用CH2Cl2萃取(3×100mL),将有机液合并,用Na2SO4干燥,过滤并减压浓缩。将残余物通过硅胶柱色谱纯化(20%EtOAc/己烷)得到浅黄色油状的5-(3-苯氧基-苯基)-3,4-二氢-2H-吡咯(6.1g,63%)。LCMS m/z238(M+1)。
(S)-2-(3-苯氧基-苯基)-吡咯烷(C):
向烘箱干燥的圆底烧瓶中加入S,S-EBTHITiF2(100mg,0.3mmol)并用THF(5mL)稀释。将烧瓶密封并用氩气净化。向该黄色溶液中加入苯基硅烷(4.6mL,37.5mmol)、吡咯烷(100μL,1.1mmol)和无水甲醇(100μL,1.1mmol)。将形成的黄色混合物搅拌45分钟,直至持续是绿色。将5-(3-苯氧基-苯基)-3,4-二氢-2H-吡咯(1.2g,5.05mmol)的THF(2mL)溶液加入到催化剂中并将混合物搅拌8小时。用10%HCl(100mL)小心地终止反应,直至停止气体溢出并且pH~2。将混合物用EtOAc(100mL)稀释,除去水层,用3M NaOH(50mL)中和至碱性,然后用EtOAc萃取(3×100mL)。将有机液合并,用Na2SO4干燥,过滤并减压浓缩。将固体残余物通过硅胶柱色谱纯化(100%EtOAc)得到黄色固体状的(S)-2-(3-苯氧基-苯基)-吡咯烷(580mg,48%)。LCMS m/z 240.1(M+1)。
{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-氨基甲酸叔丁酯(D):
将(S)-2-(3-苯氧基-苯基)-吡咯烷(1.2g,5.02mmol)加入到Boc-L-α-环己基甘氨酸(1.42g,5.2mmol)、HOBt(1.0g,7.53mmol)和HBTU(2.86g,7.53mmol)的10mL DMF溶液中。加入Hunig碱(3.6ml,20mmol)并将混合物搅拌30分钟。将混合物用盐水(20mL)稀释并用EtOAc萃取(3×10mL)。将有机液合并,用Na2SO4干燥,过滤,减压浓缩,然后通过硅胶柱色谱纯化(20%EtOAc/己烷)得到白色粉末状的{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-氨基甲酸叔丁酯(1.65g,66%)。LCMS m/z 479.2(M+1)。
(S)-2-氨基-2-环己基-1-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙酮(E):
向{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-氨基甲酸叔丁酯的CH2Cl2(20mL)溶液中加入TFA(10mL)并将混合物搅拌30分钟。将混合物减压浓缩,以定量收率得到(S)-2-氨基-2-环己基-1-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙酮的TFA盐(1.65g)。LCMS m/z379(M+1)。
((S)-1-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(F):
向Boc-N-甲基-L-丙氨酸(771mg,3.79mmol)、HOBt(700mg,5.17mmol)和HBTU(2.0g,5.17mmol)的DMF(10mL)溶液中加入(S)-2-氨基-2-环己基-1-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙酮和DIPEA(3mL,17.25mmol)。将混合物搅拌30分钟,用盐水(20mL)稀释并用EtOAc萃取(3×10mL)。将有机液合并,用Na2SO4干燥,过滤,减压浓缩,然后通过硅胶柱色谱纯化(50%EtOAc/己烷)得到白色粉末状产物((S)-1-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(1.3g,84%)。LCMS m/z 564(M+1)。
(S)-N-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基}-2-甲基氨基-丙酰胺(45):
向((S)-1-{(S)-1-环己基-2-氧代-2-[(S)-2-(3-苯氧基-苯基)-吡咯烷-1-基]-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(450mg,0.79mmol)的CH2Cl2(20mL)溶液中加入TFA(10mL)并搅拌30分钟。将混合物减压浓缩,然后通过反相柱色谱纯化得到TFA盐形式的产物(370mg,82%)。LCMS m/z 464.1(M+1)。
实施例7
(S)-2-(1H-四唑-5-基)-吡咯烷-1-甲酸叔丁酯(A)
向(S)-2-氰基-吡咯烷-1-甲酸叔丁酯(500mg,2.55mmol)的N,N-二甲基-甲酰胺(20mL)溶液中加入叠氮化钠(174mg,2.68mmol)和氯化铵(150mg,2.81mmol)。将溶液在93℃下搅拌过夜。将溶液倒入5%柠檬酸溶液和冰中,然后将混合物用EtOAc萃取。将有机萃取液用盐水洗涤,干燥并真空浓缩。将粗品油不经进一步纯化直接用于下一步骤。M+H+240。
(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-甲酸叔丁酯(B)
向粗品化合物A的N,N-二甲基-甲酰胺(5mL)溶液中加入K2CO3(1.16g,8.4mmol)和苄基溴(665μL,5.6mmol)。将溶液在室温下搅拌1小时。将混合物用EtOAc稀释并用盐水洗涤。将有机层干燥并真空浓缩。将残余物通过快速柱色谱纯化(己烷/EtOAc)得到404mg标题化合物M+H+=330和401mg另一种区域异构体(S)-2-(1-苄基-1H-四唑-5-基)-吡咯烷-1-甲酸叔丁酯(C)。M+H+=330。该两步的合并收率是87%。
2-苄基-5-(S)-吡咯烷-2-基-2H-四唑(D)
向化合物B的DCM(5mL)溶液中加入三乙基硅烷(479μL,3.0mmol)和TFA(5mL)。将溶液在室温下搅拌1小时并真空干燥。将粗品油不经进一步纯化直接用于下一步骤。M+H+=230。
{2-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-氨基甲酸叔丁酯(E)
向(S)-叔丁氧基羰基氨基-环己基-乙酸(123.8mg,0.48mmol)的DMA(5mL)溶液中加入HBTU(248.8mg,0.656mmol)、HOBt(88.6mg,0.656mmol)和二异丙基乙基胺(305μL,1.75mmol)。将混合物在室温下搅拌5分钟。将化合物D的DCM(5mL)溶液于0℃下加入到上述混合物中。将反应混合物在室温下搅拌1小时并真空浓缩。将残余物用EtOAc稀释。将有机液用盐水、柠檬酸(5%)、盐水、NaHCO3(饱和)和盐水洗涤。然后将有机层干燥并真空浓缩。将残余物通过快速柱色谱纯化(己烷/EtOAc)得到标题化合物190mg(92%)。M+H+=369。
2-氨基-1-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-2-环己基-乙酮;与三氟乙酸所形成的化合物(F)
向化合物E的DCM(4mL)溶液中于0℃下加入TFA(4mL)。将溶液在室温下搅拌1小时并真空干燥。将粗品油不经进一步纯化直接用于下一步骤。M+H+=369。
((S)-1-{2-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基氨基甲酰基}-丙基)-甲基-氨基甲酸叔丁酯(G)
向(S)-2-(叔丁氧基羰基-甲基-氨基)-丁酸(53.0mg,0.24mmol)的DMA(2mL)溶液中加入HBTU(125.0mg,0.33mmol)、HOBt(44.6mg,0.33mmol)和二异丙基乙基胺(192μL,1.1mmol)。将混合物在室温下搅拌5分钟。将化合物F的DCM(2mL)溶液于0℃下加入到上述混合物中。将反应混合物在室温下搅拌1小时并真空浓缩。将残余物用EtOAc稀释。将有机液用盐水、柠檬酸(5%)、盐水、NaHCO3(饱和)和盐水洗涤。然后将有机层干燥并真空浓缩。将粗品油不经进一步纯化直接用于下一步骤。M+H+=554。
(S)-N-{2-[(S)-2-(2-苄基-2H-四唑-5-基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-2-甲基氨基-丁酰胺;与三氟乙酸所形成的化合物(50)
向化合物G的DCM(2mL)溶液中于0℃下加入TFA(2mL)。将溶液在室温下搅拌1小时并真空干燥。将粗品油通过HPLC纯化得到标题化合物。M+H+=467。
实施例8
2-(苄氧基亚氨基-甲基)-吡咯烷-1-甲酸叔丁酯(A)
向苄基羟基胺(2.64g,16.56mmol)的干燥吡啶(20ml)溶液中加入2-甲酰基-吡咯烷-1-甲酸叔丁酯(3.30g,16.56mmol)。将溶液在室温下搅拌3小时。将反应溶液用水终止反应并用二氯甲烷萃取。将有机层合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;50%至50%乙酸乙酯的己烷溶液)得到4.9g(98%)标题化合物。M+H+-Boc=205.1。
吡咯烷-2-甲醛-O-苄基-肟(B)
将2-(苄氧基亚氨基-甲基)-吡咯烷-1-甲酸叔丁酯(1.50g,4.92mmol)和TFA(10ml)的二氯甲烷(10ml)溶液在室温下搅拌2小时。除去溶剂。粗产物不经进一步纯化即可用于下一步骤。M+H+=205.1。
{(S)-2-[苄氧基亚氨基-甲基-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-氨基甲酸叔丁酯(C)
将boc-L-α-环己基甘氨酸(1.27g,4.92mmol)、1-羟基苯并三唑(0.99g,7.38mmol)、二异丙基乙基胺(2.54g,19.68mmol)和O-苯并三唑-N,N,N,N-四甲基-脲六氟磷酸盐(2.80g,7.38mmol)的二氯甲烷(30ml)溶液在室温下搅拌15分钟。加入吡咯烷-2-甲醛-O-苄基-肟(~1.00g,0.49mmol)的二氯甲烷溶液。将反应溶液在室温下搅拌3小时,然后用饱和NaHCO3水溶液终止反应,用二氯甲烷萃取。将有机层合并,干燥并真空浓缩。将残余物通过快速色谱纯化(硅胶;20%至70%乙酸乙酯的己烷溶液)得到1.81g(83%,2步)标题化合物。M+H+=444.2。
1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-甲醛-O-苄基-肟(D)
将{(S)-2-[苄氧基亚氨基-甲基-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-氨基甲酸叔丁酯(1.76g,3.97mmol)和TFA(10ml)的二氯甲烷(20ml)溶液搅拌1小时。真空除去溶剂。残余物不经进一步纯化即可用于下一步骤。M+H+=344.2。
((S)-1-{(S)-2-[2-(苄氧基亚氨基-甲基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(E)
将Boc-L-α-环己基甘氨酸(0.81g,3.87mmol)、1-羟基苯并三唑(0.81g,5.95mmol)、二异丙基乙基胺(2.05g,15.88mmol)和O-苯并三唑-N,N,N,N-四甲基-脲六氟磷酸盐(2.35g,5.95mmol)的二氯甲烷溶液在室温下搅拌15分钟。加入1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-甲醛-O-苄基-肟(~1.40g,3.97mmol)的二氯甲烷溶液。将反应溶液在室温下搅拌3小时,然后用饱和NaHCO3水溶液终止反应并用二氯甲烷萃取。将有机层合并,干燥并真空浓缩。残余物不经进一步纯化即可用于下一步骤。M+H+=529.4。
(S)-N-{2-[2-(苄氧基亚氨基-甲基-吡咯烷-1-基]-1-环己基-2-氧代-乙基}-2-甲基氨基-丙酰胺(8)
将((S)-1-{(S)-2-[2-(苄氧基亚氨基-甲基)-吡咯烷-1-基]-1-环己基-2-氧代-乙基氨基甲酰基}-乙基)-甲基-氨基甲酸叔丁酯(~2.10g,3.97mmol)和TFA(20ml)的二氯甲烷(40ml)溶液搅拌1小时。真空除去溶剂。得到1.36g粗产物。将粗产物(0.66g)通过HPLC纯化(C18硅胶,10%至70%CH3CN/H2O的0.1%TFA溶液)得到0.058g标题化合物,为异构体混合物的TFA盐。M+H+=429.4。
实施例9-78
以下化合物通过与本文所述的相类似的方法利用类似的原料制得:
式I范围内的另外的化合物包括:
实施例195
(S)-N-[(S)-1-环己基-2-((R)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基]-2-甲基氨基-丙酰胺(78)
4,4,N-三甲氧基-N-甲基-丁酰胺(1)
向4,4-二甲氧基-丁酸甲酯(4.99g,30.8mmol)和N,O-二甲基羟基胺HCl(4.65g,47.68mmol)的60mL THF溶液中于-20℃下加入异丙基氯化镁(46mL,92.28mmol,2.0M的THF溶液),将温度保持在-20℃以下。在-10℃下搅拌30分钟后,将反应混合物用50mL水终止反应并用3×80mL EtOAc萃取。将合并的有机层用Na2SO4干燥并通过短硅胶柱过滤。将溶液浓缩得到浅色液体状的4,4,N-三甲氧基-N-甲基-丁酰胺(5.9g,99%)。M/Z=191.0。N-[1-乙-(Z)-亚基-5,5-二甲氧基-2-氧代-戊基]-丙烯酰亚胺酰基(acrylimidoyl)溴(2)
向2,6-二溴吡啶(8.1g,34.03mmol)的80mL乙醚悬浮液中于-70℃下一次性加入BuLi(12.3mL,26.17mmol,2.5 M的己烷溶液)。在-70℃下搅拌5分钟后,将4,4,N-三甲氧基-N-甲基-丁酰胺(5.0g,26.17mmol)加入到该溶液中。在-70℃下搅拌1.5小时后,将反应混合物用120mL水终止反应并用3×130mL EtOAc萃取。将合并的有机层浓缩,通过色谱纯化(己烷/EtOAc:70/30)得到浅黄色液体状的N-[1-乙-(Z)-亚基-5,5-二甲氧基-2-氧代-戊基]-丙烯酰亚胺酰基溴(5.96g,60.5%)。M/Z=288.0。
N-[1-乙-(Z)-亚基-2,5-二氧代-戊基]-丙烯酰亚胺酰基溴(3)
向N-[1-乙-(Z)-亚基-5,5-二甲氧基-2-氧代-戊基]丙烯酰亚胺酰基溴(7.0g,28.9mmol)在丙酮(30mL)和水(1.5mL)中的溶液中于室温下加入Amberlyse-15(20g)。在室温下机械振荡3小时后,将反应混合物过滤。将树脂珠粒用丙酮(含有10%Et3N)洗涤。将合并的有机层浓缩,通过色谱纯化(己烷/EtOAc:70/30)得到浅黄色液体状的N-[1-乙-(Z)-亚基-2,5-二氧代-戊基]-丙烯酰亚胺酰基溴(5.18g,88.1%)。M/Z=421,243.9[M+1]。
2-溴-6-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-吡啶(4)
向N-[1-乙-(Z)-亚基-2,5-二氧代-戊基]-丙烯酰亚胺酰基溴(1.0g,4.1mmol)和R(+)-α-甲基苄基胺(0.5g,4.1mmol)的17mL CH2Cl2溶液中于-70℃下加入乙酸(0.6mL)和三乙酰氧基硼氢化钠(1.74g,8.2mmol)。在-70℃下搅拌40分钟后,除去干冰浴,将反应溶液升温至室温。在室温下搅拌过夜后,将反应混合物用20mL水终止反应并用3×30mL CH2Cl2.萃取。将合并的有机层浓缩,通过色谱纯化(己烷/EtOAc:70/30)得到浅黄色液体状的2-溴-6-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-吡啶(0.86g,62.9%)。M/Z=332.7[M+1]。
(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(5)
向2-溴-6-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-吡啶(86.5mg,2.57mmol)、2-氟-甲基苯胺(64.7mg,5.14mmol)和2-(二-环己基膦)-联苯(38.5mg,0.13mmol)的20mL甲苯溶液中于室温下加入Pd2(dba)3(117.6mg,0.13mmol)。将反应混合物在80℃下搅拌2小时,然后冷却至室温。将反应混合物通过硅藻土过滤,将滤液用50mL EtOAc稀释并用2×50mL水洗涤。将合并的有机层浓缩,通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色固体状的(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(870mg,90.3%)。M/Z=376.0[M+1]。(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(6)
在含有300mg Pd/C的500mL圆底烧瓶中,将(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(500mg,1.33mmol)溶于10mL MeOH。将反应混合物在气囊产生的H2气(1atm)下搅拌24小时。真空脱气后,将反应混合物过滤以除去催化剂。将粗产物通过反相HPLC纯化得到黄色油状的(Z)-N-(2-氟-苯基)-N-甲基-N′-[1-[(S)-1-((R)-1-苯基-乙基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-丙烯脒(200mg,55.4%)。M/Z=272.07[M+1]。
[(S)-1-环己基-2-((S)-2-{1-[(E)-(Z)-N-(2-氟-苯基)-N-甲基-1-imioxo-丙烯基亚氨基]-烯丙基}-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁酯(7)
向Boc-L-a-环己基甘氨酸(204mg,0.79mmol)的5mL DMF溶液中于室温下缓慢加入二异丙基乙基胺(0.58mL,3.3mmol)。在室温下搅拌20分钟后,将HOBT(116mg,0.86mmol)和HBTU(325mg,0.86mmol)的DMF(5mL)溶液加入到反应混合物中,然后将溶液转移到另一个含有(Z)-N-(2-氟-苯基)-N-甲基-N′-[(S)-1-吡咯烷-2-基-丙-2-烯-(E)-亚基]-丙烯脒(180mg,0.66mmol)的烧瓶中。搅拌1小时后,将反应溶液用EtOAc(50mL)稀释并用水洗涤(3×20mL)。将合并的有机层浓缩。将粗产物用CH2Cl2(10mL)稀释并用Na2SO4干燥,通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色树胶状的[(S)-1-环己基-2-((S)-2-{1-[(E)-(Z)-N-(2-氟-苯基)-N-甲基-1-imioxo-丙烯基亚氨基]-烯丙基}-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁酯(320mg,94.5%)。N/Z=511.14[M+1]。
(Z)-N′-[1-[(S)-1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-N-(2-氟-苯基)-N-甲基-丙烯脒(8)
向[(S)-1-环己基-2-((S)-2-{1-[(E)-(Z)-N-(2-氟-苯基)-N-甲基-1-imioxo-丙烯基亚氨基]-烯丙基}-吡咯烷-1-基)-2-氧代-乙基]-氨基甲酸叔丁酯(320mg,0.63mmol)的CH2Cl2(3mL)溶液中于-20℃下缓慢加入TFA(5mL,预冷却至-20℃)。在0℃下搅拌30分钟后,将反应混合物浓缩以除去大部分的TFA。将残余物溶于20mL CH2Cl2,用10%NH4OH中和至pH=8。将溶液用Na2SO4干燥,浓缩得到浅色树胶状(Z)-N′-[1-[(S)-1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-N-(2-氟-苯基)-N-甲基-丙烯脒(260mg,定量),其不经进一步纯化即可用于下一步骤的反应。
M/Z=411.2[M+1]。
{(S)-1-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基氨基甲酰基]-乙基}-甲基-氨基甲酸叔丁酯(9)
向Boc-N-甲基-L-a-丙氨酸(155mg,0.76mmol)的5mL DMF溶液中于室温下缓慢加入二异丙基乙基胺(0.58mL,3.3mmol)。在室温下搅拌20分钟后,将HOBT(111mg,0.82mmol)和HBTU(311mg,0.82mmol)的DMF(5mL)溶液加入到反应混合物中,然后将该溶液转移到另一个含有(Z)-N′-[1-[(S)-1-((S)-2-氨基-2-环己基-乙酰基)-吡咯烷-2-基]-丙-2-烯-(E)-亚基]-N-(2-氟-苯基)-N-甲基-丙烯脒(260mg,0.63mmol)的烧瓶中。搅拌1小时后,将反应溶液用EtOAc(50mL)稀释,用水洗涤(3×20mL)。将合并的有机层浓缩。将粗产物用CH2Cl2(10mL)稀释并用Na2SO4干燥,然后通过色谱纯化(CH2Cl2/MeOH:97/3)得到浅色树胶状的{(S)-1-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基氨基甲酰基]-乙基}-甲基-氨基甲酸叔丁酯(300mg,79.5%)。M/Z=596.2[M+1]。
(S)-N-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基]-2-甲基氨基-丙酰胺(78)
向{(S)-1-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基氨基甲酰基]-乙基}-甲基-氨基甲酸叔丁酯(300mg,0.50mmol)的CH2Cl2(1mL)溶液中于-20℃下缓慢加入TFA(5mL,预冷却至-20℃)。在0℃下搅拌30分钟后,将反应混合物浓缩,通过制备型HPLC纯化(柱:Waters Sunfire prep C18 30×100mm;流动相:恒溶剂条件,CH3CN 28%/H2O 72%,含0.1%TFA;流速:45mL/min)得到(S)-N-[(S)-1-环己基-2-((S)-2-{6-[(2-氟-苯基)-甲基-氨基]-吡啶-2-基}-吡咯烷-1-基)-2-氧代-乙基]-2-甲基氨基-丙酰胺(206mg,67.0%),为白色固体状的TFA盐。(HRMass M/Z=496.3069[M+1])。
为了测定本发明化合物与BIR3肽结合袋结合的能力,采用ELISA和基于细胞的试验。
Elisa
将化合物与GST-BIR3融合蛋白和生物素化的SMAC肽(AVPFAQK)一起在涂覆有链霉抗生物素的96孔板中培养。对于XIAP BIR3 Smac Elisa,采用含有来自XIAP的氨基酸248-358的GST-BIR3融合蛋白。对于CIAP1BIR3 Smac Elisa,采用含有来自CIAP1的氨基酸259-364的GST-BIR3融合蛋白。培养30分钟后,将各孔充分洗涤。通过ELISA试验检测剩余的GST-BIR3融合蛋白,该试验包括,首先与山羊抗-GST抗体一起培养,然后进行洗涤并与同碱性磷酸酶结合的抗-山羊抗体一起培养。将信号用Attophos(Promega)放大并用Cytoflour Ex 450nm/40和Em 580nm读取信号。IC50相当于置换一半GST-BIR3信号的化合物浓度。对于非生物素结合的Smac的IC50是400nM。在所述的ELISA试验中,表1所列的化合物的IC50值为0.005-10μM。
细胞增殖试验
化合物在体外抑制肿瘤细胞生长的能力用AQueousNon-Radioactive Cell Proliferation Assay(Promega)进行测定。该试验由新的四唑鎓化合物[3-(4,5-二甲基噻唑-2-基)-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H-四唑鎓,内盐;MTS]和电子偶合试剂(吩嗪硫酸甲酯)PMS组成。MTS被细胞生物还原成甲产物,在490nm测定其吸光度。MTS向水溶性田产物的转化由具有代谢活性的细胞内的脱氢酶来完成。由490nm的吸光度所测得的甲产物的量与培养物内活细胞的数量成正比。在所述的细胞试验中,表1所列的化合物的IC50值为0.005-50μM。
实施例196
包含式(I)化合物的片剂1
利用常规方法制得具有下列组成的片剂,所述的片剂包含作为活性成分的50mg前述实施例9-194所述的式(I)化合物中的任一种化合物:
组成: | |
活性成分 | 50mg |
小麦淀粉 | 60mg |
乳糖 | 50mg |
胶态二氧化硅 | 5mg |
滑石 | 9mg |
硬脂酸镁 | 1mg |
总量 | 175mg |
生产:将活性成分与一部分小麦淀粉、乳糖和胶态二氧化硅相混合,然后将混合物过筛。将另一部分小麦淀粉与5.倍量的水在水浴中混合以形成糊剂,然后将首先制得的混合物与该糊剂捏合,直至形成弱可塑性物质。
将干燥颗粒通过筛孔尺寸为3mm的筛网,与剩余的玉米淀粉、硬脂酸镁和滑石的预先过筛的混合物(1mm筛网)相混合并压片以形成略微双凸的片剂。
实施例197
包含式(I)化合物的片剂2
按照标准方法制得具有下列组成的片剂,所述的片剂包含作为活性成分的100mg实施例9-194的式(I)化合物中的任一种化合物:
组成: | |
活性成分 | 100mg |
结晶乳糖 | 240mg |
微晶纤维素(Avicel) | 80mg |
PVPPXL | 20mg |
气相法二氧化硅(Aerosil) | 2mg |
硬脂酸镁 | 5mg |
总量 | 447mg |
生产:将活性成分与载体物质相混合,然后通过压片机(Korsch EKO,Stempeldurchmesser 10mm)压片。
实施例198
胶囊
按照标准方法制得具有下列组成的胶囊,所述的胶囊包含作为活性成分的100mg实施例9-194给出的式(I)化合物中的任一种化合物:
组成: | |
活性成分 | 100mg |
微晶纤维素(Avicel) | 200mg |
PVPPXL | 15mg |
气相法二氧化硅(Aerosil) | 2mg |
硬脂酸镁 | 1.5mg |
总量 | 318.5mg |
生产通过混合各成分、然后将其填充到1号硬明胶胶囊中来完成。
Claims (4)
1.式IVa化合物或其可药用盐:
其中
R1是H或C1-C4烷基;
R2是H或C1-C4烷基;
R3是C1-C4烷基;
R4是环己基、环戊基或C1-C4烷基;
R5是H;
U如结构式V所示:
其中
n=0;
X是N;
Rc是H;
Rd是Ar1-D-Ar2,其中D是-CH2-、-CF2-、-O-、-C(O)-、-S-、-S(O)-、-S(O)2-、1,3-二氧杂环戊烷或N(Rh)-,其中Rh是H、任选地被OH取代的C1-C7烷基、CF3、-C(O)H或-SO2CH3,并且Ar1和Ar2是取代或未取代的芳基或het,其中所述het可被甲基取代并且选自吡啶基、嘧啶基、四唑基、三唑基、吡唑基、唑基、噻唑基、二唑基、吡咯基或三嗪基,并且所述的芳基是可被一个或两个卤素取代的苯基;
R6、R7、R′6和R′7均是H。
2.权利要求1所述的化合物或其可药用盐,其中Ar1是吡啶基或噻唑基;Ar2是可被一个或两个卤素取代的苯基。
3.权利要求1或2所述的化合物或其可药用盐,其中D是-CH2-、-CF2-、-O-或-C(O)-。
4.权利要求1所述的化合物,其选自
N-[(1S)-1-环己基-2-[(2S)-2-[6-[(2-氟苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[2-(苯基甲基)-2H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丁酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-咪唑-4-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[6-(苯基甲基)吡嗪基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[4-(苯基甲基)-1,3,5-三嗪-2-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-[(4-氟苯基)甲基氨基]-4-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-吡咯-3-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-(4-苯甲酰基-2-噻唑基)-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[4-(苯基甲基)-2-唑基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-(4-苯甲酰基-5-甲基-2-唑基)-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-吡唑-4-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-1,2,3-三唑-4-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-氟-5-(甲基-2-吡啶基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲基-2-嘧啶基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲基-2-吡啶基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-(甲基-2-吡啶基氨基)-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-[(2,4-二氟苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-[6-[(3-氯苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-[(4-氟苯基)甲基氨基]-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[6-(甲基苯基氨基)-2-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-[(2-氟苯基)甲基氨基]-4-吡啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[2-[(2-氟苯基)甲基氨基]-4-嘧啶基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-[苯基(三氟甲基)氨基]苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-[(2-羟基乙基)苯基氨基]苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲酰基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-[(甲基磺酰基)苯基氨基]苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环戊基-2-[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2,2-二甲基-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丙基]-2-(甲基氨基)-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-3-甲基-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丁基]-(2S)-丙酰胺,
2-(甲基氨基)-N-[(1S)-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丙基]-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-1-甲基-2-[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基氨基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(3-吡啶基氧基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(2-苯氧基-4-嘧啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(2-苯氧基-4-吡啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(5-苯氧基-3-吡啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(6-苯氧基-2-吡啶基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2,2-二甲基-1-[[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]羰基]丙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环戊基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-3-甲基-1-[[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]羰基]丁基]-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-1-甲基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-2-甲基-1-[[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]羰基]丙基]-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(2-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(4-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(2-苯基-1,3-二氧杂环戊烷-2-基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-2-[(2S)-2-(3-苯甲酰基苯基)-1-吡咯烷基]-1-环己基-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(二氟苯基甲基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基亚磺酰基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基磺酰基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丁酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[1-(苯基甲基)-1H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[2-(苯基甲基)-2H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丁酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[2-(苯基甲基)-2H-四唑-5-基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯硫基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-(3-苯氧基苯基)-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
N-[(1S)-1-环己基-2-[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]-2-氧代乙基]-2-(甲基氨基)-(2S)-丙酰胺;
2-(甲基氨基)-N-[(1S)-2-甲基-1-[[(2S)-2-[3-(甲基苯基氨基)苯基]-1-吡咯烷基]羰基]丙基]-(2S)-丙酰胺;和
N-[(1S)-1-环己基-2-氧代-2-[(2S)-2-[3-(苯基甲基)苯基]-1-吡咯烷基]乙基]-2-(甲基氨基)-(2S)-丙酰胺;
或其可药用盐。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US56018604P | 2004-04-07 | 2004-04-07 | |
US60/560,186 | 2004-04-07 | ||
PCT/EP2005/003619 WO2005097791A1 (en) | 2004-04-07 | 2005-04-06 | Inhibitors of iap |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1964970A CN1964970A (zh) | 2007-05-16 |
CN1964970B true CN1964970B (zh) | 2011-08-03 |
Family
ID=34962601
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2005800186137A Expired - Fee Related CN1964970B (zh) | 2004-04-07 | 2005-04-06 | Iap的抑制剂 |
Country Status (32)
Country | Link |
---|---|
US (4) | US20080242658A1 (zh) |
EP (3) | EP2253614B1 (zh) |
JP (3) | JP4691549B2 (zh) |
KR (2) | KR20080083220A (zh) |
CN (1) | CN1964970B (zh) |
AR (1) | AR048927A1 (zh) |
AU (1) | AU2005231956B2 (zh) |
BR (1) | BRPI0509721A (zh) |
CA (1) | CA2560162C (zh) |
CY (1) | CY1113511T1 (zh) |
DK (1) | DK2253614T3 (zh) |
EC (1) | ECSP066893A (zh) |
ES (2) | ES2394441T3 (zh) |
HK (1) | HK1100930A1 (zh) |
HR (1) | HRP20121023T1 (zh) |
IL (1) | IL178104A (zh) |
MA (1) | MA28630B1 (zh) |
ME (1) | ME02125B (zh) |
MY (1) | MY165401A (zh) |
NO (1) | NO20065114L (zh) |
NZ (1) | NZ549925A (zh) |
PE (2) | PE20110102A1 (zh) |
PL (1) | PL2253614T3 (zh) |
PT (1) | PT2253614E (zh) |
RS (1) | RS52545B (zh) |
RU (1) | RU2425838C2 (zh) |
SG (1) | SG152225A1 (zh) |
SI (1) | SI2253614T1 (zh) |
TN (1) | TNSN06323A1 (zh) |
TW (1) | TWI417092B (zh) |
WO (1) | WO2005097791A1 (zh) |
ZA (1) | ZA200607696B (zh) |
Families Citing this family (140)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP5122275B2 (ja) | 2004-03-23 | 2013-01-16 | ジェネンテック, インコーポレイテッド | Iapのアザビシクロ−オクタンインヒビター |
KR20080083220A (ko) * | 2004-04-07 | 2008-09-16 | 노파르티스 아게 | Iap 억제제 |
WO2006014361A1 (en) | 2004-07-02 | 2006-02-09 | Genentech, Inc. | Inhibitors of iap |
EP1773766B1 (en) | 2004-07-15 | 2014-04-02 | Tetralogic Pharmaceuticals Corporation | Iap binding compounds |
ES2349110T5 (es) * | 2004-12-20 | 2013-11-27 | Genentech, Inc. | Inhibidores de IAP derivados de pirrolidina |
EP1879574A2 (en) * | 2005-02-23 | 2008-01-23 | Prexa Pharmaceuticals, Inc. | Multimediator 5-ht6 receptor antagonists, and uses related thereto |
US7517906B2 (en) | 2005-02-25 | 2009-04-14 | Tetralogic Pharmaceuticals Corporation | Dimeric IAP inhibitors |
WO2006107964A2 (en) * | 2005-04-06 | 2006-10-12 | Novartis Ag | Processes to prepare 6-phenethyl-octahydro-pyrrolo [2 , 3-c] pyridine and related compounds |
CA2607940C (en) | 2005-05-18 | 2009-12-15 | Aegera Therapeutics Inc. | Bir domain binding compounds |
AU2006279929A1 (en) * | 2005-08-09 | 2007-02-22 | Tetralogic Pharmaceuticals Corporation | Treatment of proliferative disorders |
US20100256046A1 (en) * | 2009-04-03 | 2010-10-07 | Tetralogic Pharmaceuticals Corporation | Treatment of proliferative disorders |
KR20080067357A (ko) | 2005-10-25 | 2008-07-18 | 에게라 쎄라퓨틱스 인코포레이티드 | Iap bir 도메인 결합 화합물 |
CN101374829A (zh) | 2005-12-19 | 2009-02-25 | 健泰科生物技术公司 | Iap的抑制剂 |
ES2684120T3 (es) | 2005-12-20 | 2018-10-01 | Novartis Ag | Combinación de un inhibidor de IAP y un taxano |
TWI543988B (zh) * | 2006-03-16 | 2016-08-01 | 科學製藥股份有限公司 | 結合於細胞凋亡抑制蛋白(iap)之桿狀病毒iap重複序列(bir)區域之化合物 |
KR20080109068A (ko) * | 2006-04-05 | 2008-12-16 | 노파르티스 아게 | 암을 치료하기 위한 bcr-abl/c-kit/pdgf-r tk 억제제를 포함하는 조합물 |
MX2008012716A (es) * | 2006-04-05 | 2008-10-14 | Novartis Ag | Combinaciones de agentes terapeuticos para el tratamiento de cancer. |
US8168383B2 (en) | 2006-04-14 | 2012-05-01 | Cell Signaling Technology, Inc. | Gene defects and mutant ALK kinase in human solid tumors |
ES2637592T3 (es) | 2006-04-14 | 2017-10-13 | Cell Signaling Technology, Inc. | Defectos de genes y quinasa ALK mutante en tumores sólidos humanos |
MX2008014502A (es) * | 2006-05-16 | 2008-11-27 | Aegera Therapeutics Inc | Compuestos de union a dominio de repeticion de proteinas inhibidoras de apoptosis baculovirales de las proteinas inhibidoras de apoptosis. |
US8163792B2 (en) * | 2006-05-16 | 2012-04-24 | Pharmascience Inc. | IAP BIR domain binding compounds |
WO2008014240A2 (en) * | 2006-07-24 | 2008-01-31 | Tetralogic Pharmaceuticals Corporation | Dimeric iap inhibitors |
KR20090041391A (ko) * | 2006-07-24 | 2009-04-28 | 테트랄로직 파마슈티칼스 | 이량체성 iap 길항제 |
JP5452223B2 (ja) | 2006-07-24 | 2014-03-26 | テトラロジック ファーマシューティカルズ コーポレーション | Iap阻害剤 |
US20100144650A1 (en) * | 2006-07-24 | 2010-06-10 | Tetralogic Pharmaceuticals Corporation | Dimeric iap inhibitors |
WO2008014236A1 (en) * | 2006-07-24 | 2008-01-31 | Tetralogic Pharmaceuticals Corporation | Dimeric iap inhibitors |
PE20110217A1 (es) | 2006-08-02 | 2011-04-01 | Novartis Ag | DERIVADOS DE 2-OXO-ETIL-AMINO-PROPIONAMIDA-PIRROLIDIN-2-IL-SUSTITUIDOS COMO INHIBIDORES DEL ENLACE DE LA PROTEINA Smac AL INHIBIDOR DE LA PROTEINA DE APOPTOSIS |
KR20090065548A (ko) * | 2006-10-12 | 2009-06-22 | 노파르티스 아게 | Iap 억제제로서의 피롤리딘 유도체 |
US20100316573A1 (en) * | 2006-10-19 | 2010-12-16 | Larry Alexander Gaither | Organic Compounds |
PT2089024E (pt) * | 2006-11-28 | 2011-08-31 | Novartis Ag | Combinação de inibidores de iap e inibidores de flt3 |
US20100076013A1 (en) * | 2006-11-28 | 2010-03-25 | Novartis Ag | Methods of Treatment |
KR20090094461A (ko) * | 2006-12-19 | 2009-09-07 | 제넨테크, 인크. | Iap의 이미다조피리딘 억제제 |
WO2008109057A1 (en) * | 2007-03-02 | 2008-09-12 | Dana-Farber Cancer Institute, Inc. | Organic compounds and their uses |
MX2009010667A (es) | 2007-04-12 | 2010-02-24 | Joyant Pharmaceuticals Inc | Dimeros y trimeros mimeticos de smac utiles como agentes anti-cancer. |
TWI432212B (zh) * | 2007-04-30 | 2014-04-01 | Genentech Inc | Iap抑制劑 |
CA2686638A1 (en) * | 2007-05-07 | 2008-11-13 | Tetralogic Pharmaceuticals Corp. | Tnf.alpha. gene expression as a biomarker of sensitivity to antagonists of inhibitor of apoptosis proteins |
US20100203012A1 (en) * | 2007-05-30 | 2010-08-12 | Aegera Therapeutics, Inc. | Iap bir domain binding compounds |
SI2240506T1 (sl) * | 2008-01-11 | 2013-04-30 | Genentech, Inc. | Inhibitorji IAP |
EP2242362A4 (en) * | 2008-01-24 | 2012-04-11 | Tetralogic Pharm Corp | INHIBITORS OF APOPTOSIS PROTEINS |
WO2009136290A1 (en) * | 2008-05-05 | 2009-11-12 | Aegera Therapeutics, Inc. | Functionalized pyrrolidines and use thereof as iap inhibitors |
BRPI0912692A2 (pt) * | 2008-05-16 | 2017-03-21 | Dana Farber Cancer Inst Inc | imunomodulação através de inibidores de iap |
CA2728933A1 (en) * | 2008-06-27 | 2009-12-30 | Aegera Therapeutics Inc. | Bridged secondary amines and use thereof as iap bir domain binding compounds |
EP2318395A4 (en) | 2008-08-02 | 2011-10-26 | Genentech Inc | IPA INHIBITORS |
NZ590500A (en) * | 2008-08-16 | 2012-06-29 | Genentech Inc | Azaindole inhibitors of iap |
WO2010033531A1 (en) * | 2008-09-17 | 2010-03-25 | Tetralogic Pharmaceuticals Corp. | Iap inhibitors |
US8841067B2 (en) | 2009-01-09 | 2014-09-23 | Dana-Farber Cancer Institute, Inc. | NOL3 is a predictor of patient outcome |
WO2010138496A1 (en) * | 2009-05-28 | 2010-12-02 | Tetralogic Pharmaceuticals Corp. | Iap inhibitors |
US8415486B2 (en) | 2009-05-28 | 2013-04-09 | Tetralogic Pharmaceuticals Corp. | IAP inhibitors |
CN101928326B (zh) * | 2009-06-24 | 2015-07-08 | 中国人民解放军军事医学科学院毒物药物研究所 | 取代的氨酰基五元杂环烷类化合物及其用途 |
US8283372B2 (en) | 2009-07-02 | 2012-10-09 | Tetralogic Pharmaceuticals Corp. | 2-(1H-indol-3-ylmethyl)-pyrrolidine dimer as a SMAC mimetic |
UY32826A (es) | 2009-08-04 | 2011-02-28 | Takeda Pharmaceutical | Compuestos heterocíclicos |
BR112012003118A2 (pt) | 2009-08-12 | 2016-02-23 | Novartis Ag | formulações orais sólidas e formas cristalinas de um inibidor de proteína apoptose |
JP2013505446A (ja) | 2009-09-18 | 2013-02-14 | ノバルティス アーゲー | Iap阻害剤化合物のためのバイオマーカー |
US8551955B2 (en) | 2009-10-28 | 2013-10-08 | Joyant Pharmaceuticals, Inc. | Dimeric Smac mimetics |
SG10201501095WA (en) | 2010-02-12 | 2015-04-29 | Pharmascience Inc | Iap bir domain binding compounds |
UY33227A (es) | 2010-02-19 | 2011-09-30 | Novartis Ag | Compuestos de pirrolopirimidina como inhibidores de la cdk4/6 |
CA2800260C (en) * | 2010-04-19 | 2013-07-09 | Sri International | Compositions and method for the treatment of multiple myeloma |
WO2012052758A1 (en) | 2010-10-22 | 2012-04-26 | Astrazeneca Ab | Response biomarkers for iap antagonists in human cancers |
GB201106817D0 (en) | 2011-04-21 | 2011-06-01 | Astex Therapeutics Ltd | New compound |
EP2760446A1 (en) | 2011-09-30 | 2014-08-06 | Tetralogic Pharmaceuticals Corporation | Smac mimetic (birinapant) for use in the treatment of proliferative diseases (cancer) |
GB201121122D0 (en) | 2011-12-08 | 2012-01-18 | Dow Corning | Hydrolysable silanes and elastomer compositions containing them |
GB201121124D0 (en) | 2011-12-08 | 2012-01-18 | Dow Corning | Hydrolysable silanes |
GB201121133D0 (en) * | 2011-12-08 | 2012-01-18 | Dow Corning | Hydrolysable silanes |
GB201121128D0 (en) | 2011-12-08 | 2012-01-18 | Dow Corning | Treatment of filler with silane |
GB201121132D0 (en) * | 2011-12-08 | 2012-01-18 | Dow Corning | Modifying polymeric materials by amines |
US20130196927A1 (en) * | 2012-01-27 | 2013-08-01 | Christopher BENETATOS | Smac Mimetic Therapy |
KR20150011822A (ko) | 2012-05-04 | 2015-02-02 | 노파르티스 아게 | Iap 억제제 요법을 위한 바이오마커 |
KR20140011773A (ko) * | 2012-07-19 | 2014-01-29 | 한미약품 주식회사 | 이중 저해 활성을 갖는 헤테로고리 유도체 |
US9498532B2 (en) | 2013-03-13 | 2016-11-22 | Novartis Ag | Antibody drug conjugates |
NZ710929A (en) | 2013-03-15 | 2018-02-23 | Novartis Ag | Antibody drug conjugates |
US20140303090A1 (en) * | 2013-04-08 | 2014-10-09 | Tetralogic Pharmaceuticals Corporation | Smac Mimetic Therapy |
NZ714347A (en) | 2013-06-25 | 2020-01-31 | Walter & Eliza Hall Inst Medical Res | Method of treating intracellular infection |
GB201311888D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compounds |
GB201311891D0 (en) | 2013-07-03 | 2013-08-14 | Glaxosmithkline Ip Dev Ltd | Novel compound |
US9278978B2 (en) * | 2013-08-23 | 2016-03-08 | Boehringer Ingelheim International Gmbh | 6-Alkynyl Pyridine |
US9249151B2 (en) * | 2013-08-23 | 2016-02-02 | Boehringer Ingelheim International Gmbh | Bis-amido pyridines |
RS62301B1 (sr) | 2013-12-20 | 2021-09-30 | Astex Therapeutics Ltd | Biciklična heterociklična jedinjenja i njihove upotrebe u terapiji |
CA2974651A1 (en) | 2014-01-24 | 2015-07-30 | Children's Hospital Of Eastern Ontario Research Institute Inc. | Smc combination therapy for the treatment of cancer |
JP6768522B2 (ja) | 2014-06-04 | 2020-10-14 | サンフォード−バーンハム メディカル リサーチ インスティテュート | Hiv治療におけるアポトーシスタンパク質阻害剤(iap)のアンタゴニストの使用 |
US10786578B2 (en) | 2014-08-05 | 2020-09-29 | Novartis Ag | CKIT antibody drug conjugates |
CN106659790A (zh) | 2014-08-12 | 2017-05-10 | 诺华股份有限公司 | 抗cdh6抗体药物缀合物 |
WO2016079527A1 (en) | 2014-11-19 | 2016-05-26 | Tetralogic Birinapant Uk Ltd | Combination therapy |
WO2016097773A1 (en) | 2014-12-19 | 2016-06-23 | Children's Cancer Institute | Therapeutic iap antagonists for treating proliferative disorders |
BR112017015497A2 (pt) | 2015-01-20 | 2018-01-30 | Arvinas, Inc. | composto, e, composição |
US20170327469A1 (en) | 2015-01-20 | 2017-11-16 | Arvinas, Inc. | Compounds and methods for the targeted degradation of androgen receptor |
CN104592214A (zh) * | 2015-02-13 | 2015-05-06 | 佛山市赛维斯医药科技有限公司 | 含葡萄糖酰胺吡啶和烷氧吡嗪结构的化合物及用途 |
EP3302482A4 (en) | 2015-06-05 | 2018-12-19 | Arvinas, Inc. | Tank-binding kinase-1 protacs and associated methods of use |
EP3310813A1 (en) | 2015-06-17 | 2018-04-25 | Novartis AG | Antibody drug conjugates |
EP3322986A4 (en) * | 2015-07-13 | 2018-09-05 | Arvinas, Inc. | Alanine-based modulators of proteolysis and associated methods of use |
US10772962B2 (en) | 2015-08-19 | 2020-09-15 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of bromodomain-containing proteins |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
CN105566447B (zh) * | 2016-01-20 | 2019-09-20 | 广东工业大学 | 一种凋亡抑制蛋白的类肽拮抗剂及其合成方法与应用 |
CN105585583B (zh) * | 2016-01-20 | 2018-04-13 | 广东工业大学 | 一种非肽类凋亡抑制蛋白拮抗剂及其合成方法与应用 |
CN106188098B (zh) * | 2016-07-06 | 2017-11-03 | 广东工业大学 | 一种杂化抗癌药物及其制备方法与应用 |
CN109715620B (zh) * | 2016-08-29 | 2022-05-06 | 密歇根大学董事会 | 作为alk抑制剂的氨基嘧啶 |
JP6899993B2 (ja) * | 2016-10-04 | 2021-07-07 | 国立医薬品食品衛生研究所長 | 複素環化合物 |
US11458123B2 (en) | 2016-11-01 | 2022-10-04 | Arvinas Operations, Inc. | Tau-protein targeting PROTACs and associated methods of use |
EP3689868B1 (en) | 2016-12-01 | 2023-09-27 | Arvinas Operations, Inc. | Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders |
CA3047784A1 (en) | 2016-12-23 | 2018-06-28 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of rapidly accelerated fibrosarcoma polypeptides |
BR112019012682A2 (pt) | 2016-12-23 | 2019-12-17 | Arvinas Operations Inc | moléculas quiméricas visando a proteólise de egfr e métodos associados de uso |
US11173211B2 (en) | 2016-12-23 | 2021-11-16 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of rapidly accelerated Fibrosarcoma polypeptides |
EP3559006A4 (en) | 2016-12-23 | 2021-03-03 | Arvinas Operations, Inc. | COMPOUNDS AND METHODS FOR TARGETED DEGRADATION OF FETAL LIVER KINASE POLYPEPTIDES |
US11191741B2 (en) | 2016-12-24 | 2021-12-07 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of enhancer of zeste homolog 2 polypeptide |
KR20230140606A (ko) | 2017-01-26 | 2023-10-06 | 아비나스 오퍼레이션스, 인코포레이티드 | 에스트로겐 수용체 단백질 분해 조절제 및 관련 사용 방법 |
JOP20190187A1 (ar) | 2017-02-03 | 2019-08-01 | Novartis Ag | مترافقات عقار جسم مضاد لـ ccr7 |
WO2018163051A1 (en) | 2017-03-06 | 2018-09-13 | Novartis Ag | Methods of treatment of cancer with reduced ubb expression |
WO2018185618A1 (en) | 2017-04-03 | 2018-10-11 | Novartis Ag | Anti-cdh6 antibody drug conjugates and anti-gitr antibody combinations and methods of treatment |
AR111651A1 (es) | 2017-04-28 | 2019-08-07 | Novartis Ag | Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación |
EP3630162A1 (en) | 2017-05-24 | 2020-04-08 | Novartis AG | Antibody-cytokine engrafted proteins and methods of use |
WO2018215937A1 (en) | 2017-05-24 | 2018-11-29 | Novartis Ag | Interleukin-7 antibody cytokine engrafted proteins and methods of use in the treatment of cancer |
AU2018274216A1 (en) | 2017-05-24 | 2019-12-12 | Novartis Ag | Antibody-cytokine engrafted proteins and methods of use in the treatment of cancer |
CN114685602A (zh) * | 2017-11-13 | 2022-07-01 | 正大天晴药业集团股份有限公司 | 用作iap抑制剂的smac模拟物及其用途 |
US11065231B2 (en) | 2017-11-17 | 2021-07-20 | Arvinas Operations, Inc. | Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides |
US11028088B2 (en) | 2018-03-10 | 2021-06-08 | Yale University | Modulators of BTK proteolysis and methods of use |
CN112218859A (zh) | 2018-04-04 | 2021-01-12 | 阿尔维纳斯运营股份有限公司 | 蛋白水解调节剂及相关使用方法 |
AR116109A1 (es) | 2018-07-10 | 2021-03-31 | Novartis Ag | Derivados de 3-(5-amino-1-oxoisoindolin-2-il)piperidina-2,6-diona y usos de los mismos |
JOP20210001A1 (ar) | 2018-07-10 | 2021-01-05 | Novartis Ag | مشتقات 3-(5- هيدروكسي -1- أوكسو أيزو إندولين -2- يل) بيبريدين -2، 6- دايون واستخدامها لمعالجة أمراض مرتبطة ببروتين ذات أصبع الزنك من عائلة (ikaros 2 (ikzf2 |
WO2020023851A1 (en) | 2018-07-26 | 2020-01-30 | Yale University | Bifunctional substitued pyrimidines as modulators of fak proteolyse |
WO2020041331A1 (en) | 2018-08-20 | 2020-02-27 | Arvinas Operations, Inc. | Proteolysis targeting chimeric (protac) compound with e3 ubiquitin ligase binding activity and targeting alpha-synuclein protein for treating neurodegenerative diseases |
KR102642203B1 (ko) | 2018-09-07 | 2024-03-04 | 아비나스 오퍼레이션스, 인코포레이티드 | 급속 진행형 섬유육종 폴리펩티드의 표적화 분해를 위한 다중 고리 화합물 및 방법 |
EP3873532A1 (en) | 2018-10-31 | 2021-09-08 | Novartis AG | Dc-sign antibody drug conjugates |
KR20210106437A (ko) | 2018-12-20 | 2021-08-30 | 노파르티스 아게 | 3-(1-옥소이소인돌린-2-일)피페리딘-2,6-디온 유도체를 포함하는 투약 요법 및 약학적 조합물 |
CN113195541B (zh) | 2018-12-21 | 2024-08-30 | 诺华股份有限公司 | 针对pmel17的抗体及其缀合物 |
EP3924055B1 (en) | 2019-02-15 | 2024-04-03 | Novartis AG | Substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
CN113490528A (zh) | 2019-02-15 | 2021-10-08 | 诺华股份有限公司 | 3-(1-氧代-5-(哌啶-4-基)异吲哚啉-2-基)哌啶-2,6-二酮衍生物及其用途 |
EP3999182A1 (en) | 2019-07-17 | 2022-05-25 | Arvinas Operations, Inc. | Tau-protein targeting compounds and associated methods of use |
CN114514032A (zh) | 2019-08-02 | 2022-05-17 | 兰提欧派普有限公司 | 用于治疗癌症的血管紧张素2型(at2)受体激动剂 |
MX2022007759A (es) | 2019-12-20 | 2022-07-19 | Novartis Ag | Combinacion del anticuerpo anti tim-3 mbg453 y anticuerpo anti tgf-beta nis793, con o sin decitabina o el anticuerpo anti pd-1 spartalizumab, para el tratamiento de mielofibrosis y sindrome mielodisplasico. |
KR20220130190A (ko) | 2020-01-20 | 2022-09-26 | 아스트라제네카 아베 | 암 치료를 위한 표피성장인자 수용체 티로신 키나제 억제제 |
WO2021220178A1 (en) | 2020-04-29 | 2021-11-04 | Cominnex Zrt. | Iap antagonists and their therapeutic applications |
US20230181756A1 (en) | 2020-04-30 | 2023-06-15 | Novartis Ag | Ccr7 antibody drug conjugates for treating cancer |
AU2021288224A1 (en) | 2020-06-11 | 2023-01-05 | Novartis Ag | ZBTB32 inhibitors and uses thereof |
CN115916199A (zh) | 2020-06-23 | 2023-04-04 | 诺华股份有限公司 | 包含3-(1-氧代异吲哚啉-2-基)哌啶-2,6-二酮衍生物的给药方案 |
EP4188549A1 (en) | 2020-08-03 | 2023-06-07 | Novartis AG | Heteroaryl substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione derivatives and uses thereof |
TW202304979A (zh) | 2021-04-07 | 2023-02-01 | 瑞士商諾華公司 | 抗TGFβ抗體及其他治療劑用於治療增殖性疾病之用途 |
WO2022221720A1 (en) | 2021-04-16 | 2022-10-20 | Novartis Ag | Antibody drug conjugates and methods for making thereof |
AR125874A1 (es) | 2021-05-18 | 2023-08-23 | Novartis Ag | Terapias de combinación |
WO2023214325A1 (en) | 2022-05-05 | 2023-11-09 | Novartis Ag | Pyrazolopyrimidine derivatives and uses thereof as tet2 inhibitors |
WO2024023666A1 (en) | 2022-07-26 | 2024-02-01 | Novartis Ag | Crystalline forms of an akr1c3 dependent kars inhibitor |
WO2024054591A1 (en) | 2022-09-07 | 2024-03-14 | Arvinas Operations, Inc. | Rapidly accelerated fibrosarcoma (raf) degrading compounds and associated methods of use |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004005248A1 (en) * | 2002-07-02 | 2004-01-15 | Novartis Ag | Peptide inhibitors of smac protein binding to inhibitor of apoptosis proteins (iap) |
Family Cites Families (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1524747A (en) | 1976-05-11 | 1978-09-13 | Ici Ltd | Polypeptide |
DE2714880A1 (de) * | 1977-04-02 | 1978-10-26 | Hoechst Ag | Cephemderivate und verfahren zu ihrer herstellung |
ATE28864T1 (de) | 1982-07-23 | 1987-08-15 | Ici Plc | Amide-derivate. |
JPS59141547A (ja) | 1983-02-01 | 1984-08-14 | Eisai Co Ltd | 鎮痛作用を有する新規ペプタイドおよび製法 |
GB8327256D0 (en) | 1983-10-12 | 1983-11-16 | Ici Plc | Steroid derivatives |
FR2575753B1 (fr) * | 1985-01-07 | 1987-02-20 | Adir | Nouveaux derives peptidiques a structure polycyclique azotee, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US5093330A (en) | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
US5010099A (en) | 1989-08-11 | 1991-04-23 | Harbor Branch Oceanographic Institution, Inc. | Discodermolide compounds, compositions containing same and method of preparation and use |
DK167813B1 (da) * | 1989-12-07 | 1993-12-20 | Carlbiotech Ltd As | Pentapeptidderivat, farmaceutisk acceptable salte heraf, fremgangsmaade til fremstilling deraf og farmaceutisk praeparat indeholdende et saadant derivat |
NZ243082A (en) | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
AU661533B2 (en) | 1992-01-20 | 1995-07-27 | Astrazeneca Ab | Quinazoline derivatives |
TW225528B (zh) | 1992-04-03 | 1994-06-21 | Ciba Geigy Ag | |
US5559209A (en) * | 1993-02-18 | 1996-09-24 | The General Hospital Corporation | Regulator regions of G proteins |
GB9314893D0 (en) | 1993-07-19 | 1993-09-01 | Zeneca Ltd | Quinazoline derivatives |
EP3103799B1 (en) | 1995-03-30 | 2018-06-06 | OSI Pharmaceuticals, LLC | Quinazoline derivatives |
GB9508538D0 (en) | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
US5843901A (en) | 1995-06-07 | 1998-12-01 | Advanced Research & Technology Institute | LHRH antagonist peptides |
CA2224435C (en) | 1995-07-06 | 2008-08-05 | Novartis Ag | Pyrrolopyrimidines and processes for the preparation thereof |
US5760041A (en) | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
IL126351A0 (en) | 1996-04-12 | 1999-05-09 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
JP2000512990A (ja) | 1996-06-24 | 2000-10-03 | ファイザー・インク | 過増殖性疾患を処置するためのフェニルアミノ置換三環式誘導体 |
NZ334821A (en) | 1996-08-30 | 2000-12-22 | Novartis Ag | Method for producing epothilones |
DE69724269T2 (de) | 1996-09-06 | 2004-06-09 | Obducat Ab | Verfahren für das anisotrope ätzen von strukturen in leitende materialien |
CA2265630A1 (en) | 1996-09-13 | 1998-03-19 | Gerald Mcmahon | Use of quinazoline derivatives for the manufacture of a medicament in the treatment of hyperproliferative skin disorders |
EP0837063A1 (en) | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
DK1367057T3 (da) | 1996-11-18 | 2009-01-19 | Biotechnolog Forschung Gmbh | Epothiloner E og F |
US6441186B1 (en) | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
CO4940418A1 (es) | 1997-07-18 | 2000-07-24 | Novartis Ag | Modificacion de cristal de un derivado de n-fenil-2- pirimidinamina, procesos para su fabricacion y su uso |
GB9721069D0 (en) | 1997-10-03 | 1997-12-03 | Pharmacia & Upjohn Spa | Polymeric derivatives of camptothecin |
US6194181B1 (en) | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
CA2322157C (en) | 1998-02-25 | 2012-05-29 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US6472172B1 (en) * | 1998-07-31 | 2002-10-29 | Schering Aktiengesellschaft | DNA encoding a novel human inhibitor-of-apoptosis protein |
BR9912938B1 (pt) | 1998-08-11 | 2011-06-28 | derivados de isoquinolina, composição que os compreende, processo para preparação e uso dos mesmos. | |
EP1135470A2 (en) | 1998-11-20 | 2001-09-26 | Kosan Biosciences, Inc. | Recombinant methods and materials for producing epothilone and epothilone derivatives |
MXPA02000823A (es) * | 2000-05-23 | 2002-07-30 | Vertex Pharma | Inhibidores de caspasa y uso de los mismos. |
US6608026B1 (en) * | 2000-08-23 | 2003-08-19 | Board Of Regents, The University Of Texas System | Apoptotic compounds |
PE20020354A1 (es) | 2000-09-01 | 2002-06-12 | Novartis Ag | Compuestos de hidroxamato como inhibidores de histona-desacetilasa (hda) |
US20020160975A1 (en) * | 2001-02-08 | 2002-10-31 | Thomas Jefferson University | Conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO for mediating apoptosis |
AR035885A1 (es) | 2001-05-14 | 2004-07-21 | Novartis Ag | Derivados de 4-amino-5-fenil-7-ciclobutilpirrolo (2,3-d)pirimidina, un proceso para su preparacion, una composicion farmaceutica y el uso de dichos derivados para la preparacion de una composicion farmaceutica |
GB0119249D0 (en) | 2001-08-07 | 2001-10-03 | Novartis Ag | Organic compounds |
WO2003040172A2 (en) * | 2001-11-09 | 2003-05-15 | Aegera Therapeutics, Inc. | Methods and reagents for peptide-bir interaction screens |
ES2318167T3 (es) * | 2002-07-15 | 2009-05-01 | The Trustees Of Princeton University | Compuestos de union a iap. |
US20040171554A1 (en) * | 2003-02-07 | 2004-09-02 | Genentech, Inc. | Compositions and methods for enhancing apoptosis |
CA2543897A1 (en) * | 2003-11-13 | 2005-06-02 | Genentech, Inc. | Compositions and methods for screening pro-apoptotic compounds |
US20100093645A1 (en) | 2004-01-16 | 2010-04-15 | Shaomeng Wang | SMAC Peptidomimetics and the Uses Thereof |
JP4674231B2 (ja) * | 2004-03-01 | 2011-04-20 | 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 | 2量体小分子アポトーシス増強剤 |
KR20080083220A (ko) * | 2004-04-07 | 2008-09-16 | 노파르티스 아게 | Iap 억제제 |
WO2006014361A1 (en) | 2004-07-02 | 2006-02-09 | Genentech, Inc. | Inhibitors of iap |
ES2349110T5 (es) | 2004-12-20 | 2013-11-27 | Genentech, Inc. | Inhibidores de IAP derivados de pirrolidina |
PE20110217A1 (es) | 2006-08-02 | 2011-04-01 | Novartis Ag | DERIVADOS DE 2-OXO-ETIL-AMINO-PROPIONAMIDA-PIRROLIDIN-2-IL-SUSTITUIDOS COMO INHIBIDORES DEL ENLACE DE LA PROTEINA Smac AL INHIBIDOR DE LA PROTEINA DE APOPTOSIS |
-
2005
- 2005-04-06 KR KR1020087021449A patent/KR20080083220A/ko not_active Application Discontinuation
- 2005-04-06 US US10/594,413 patent/US20080242658A1/en not_active Abandoned
- 2005-04-06 PE PE2009001297A patent/PE20110102A1/es active IP Right Grant
- 2005-04-06 CN CN2005800186137A patent/CN1964970B/zh not_active Expired - Fee Related
- 2005-04-06 RU RU2006139010/04A patent/RU2425838C2/ru active
- 2005-04-06 PL PL10172398T patent/PL2253614T3/pl unknown
- 2005-04-06 AR ARP050101365A patent/AR048927A1/es not_active Application Discontinuation
- 2005-04-06 WO PCT/EP2005/003619 patent/WO2005097791A1/en active Application Filing
- 2005-04-06 BR BRPI0509721-5A patent/BRPI0509721A/pt not_active Application Discontinuation
- 2005-04-06 US US11/099,941 patent/US7419975B2/en active Active
- 2005-04-06 ES ES05716547T patent/ES2394441T3/es active Active
- 2005-04-06 RS RS20120557A patent/RS52545B/en unknown
- 2005-04-06 SI SI200531639T patent/SI2253614T1/sl unknown
- 2005-04-06 ME MEP-2012-557A patent/ME02125B/me unknown
- 2005-04-06 AU AU2005231956A patent/AU2005231956B2/en not_active Ceased
- 2005-04-06 SG SG200902372-2A patent/SG152225A1/en unknown
- 2005-04-06 JP JP2007506718A patent/JP4691549B2/ja not_active Expired - Fee Related
- 2005-04-06 PE PE2005000384A patent/PE20060166A1/es active IP Right Grant
- 2005-04-06 CA CA2560162A patent/CA2560162C/en active Active
- 2005-04-06 EP EP10172398A patent/EP2253614B1/en active Active
- 2005-04-06 NZ NZ549925A patent/NZ549925A/en not_active IP Right Cessation
- 2005-04-06 MY MYPI20051543A patent/MY165401A/en unknown
- 2005-04-06 DK DK10172398.9T patent/DK2253614T3/da active
- 2005-04-06 EP EP09153639A patent/EP2065368A1/en not_active Withdrawn
- 2005-04-06 PT PT101723989T patent/PT2253614E/pt unknown
- 2005-04-06 EP EP05716547A patent/EP1735307B1/en active Active
- 2005-04-06 ES ES10172398T patent/ES2396195T3/es active Active
- 2005-04-06 KR KR1020067023240A patent/KR100892185B1/ko active IP Right Grant
- 2005-04-06 TW TW094110874A patent/TWI417092B/zh not_active IP Right Cessation
-
2006
- 2006-09-14 IL IL178104A patent/IL178104A/en active IP Right Grant
- 2006-09-14 ZA ZA200607696A patent/ZA200607696B/en unknown
- 2006-09-29 EC EC2006006893A patent/ECSP066893A/es unknown
- 2006-10-06 TN TNP2006000323A patent/TNSN06323A1/en unknown
- 2006-10-30 MA MA29422A patent/MA28630B1/fr unknown
- 2006-11-06 NO NO20065114A patent/NO20065114L/no not_active Application Discontinuation
-
2007
- 2007-06-06 HK HK07106025.9A patent/HK1100930A1/xx not_active IP Right Cessation
-
2010
- 2010-04-27 JP JP2010102494A patent/JP2010215635A/ja not_active Withdrawn
-
2011
- 2011-07-08 US US13/178,946 patent/US8207183B2/en not_active Expired - Fee Related
-
2012
- 2012-04-26 US US13/456,274 patent/US8338440B2/en active Active
- 2012-12-12 HR HRP20121023TT patent/HRP20121023T1/hr unknown
- 2012-12-13 JP JP2012272668A patent/JP2013049733A/ja active Pending
- 2012-12-19 CY CY20121101238T patent/CY1113511T1/el unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004005248A1 (en) * | 2002-07-02 | 2004-01-15 | Novartis Ag | Peptide inhibitors of smac protein binding to inhibitor of apoptosis proteins (iap) |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1964970B (zh) | Iap的抑制剂 | |
CN103717589B (zh) | 用于治疗或预防呼吸道合胞病毒疾病的化合物 | |
CN102971317B (zh) | 四氢-吡啶并-嘧啶衍生物 | |
CN107849013A (zh) | 作为dub抑制剂用于治疗癌症的氰基吡咯烷类 | |
CN102827073A (zh) | 治疗活性组合物和它们的使用方法 | |
CN104203952A (zh) | 咪唑并吡咯烷酮化合物 | |
CN107922392A (zh) | 1‑(杂)芳基磺酰基‑(吡咯烷或哌啶)‑2‑甲酰胺衍生物及其作为trpa1拮抗剂的用途 | |
CN106573906A (zh) | 哌啶‑二酮衍生物 | |
CN105777756A (zh) | 杂芳化合物及其在药物中的应用 | |
AU2006319401A1 (en) | 3-(substituted amino)-pyrazolo[3,4-d]pyrimidines as EphB and VEGFR2 kinase inhibitors | |
AU2006322187A1 (en) | Pyrazolo[1,5-a]pyridine-3-carboxylic acids as EphB and VEGFR2 kinase inhibitors | |
CN1984908A (zh) | 病毒聚合酶抑制剂 | |
US20170342051A1 (en) | Indole and pyrrole compounds, a process for their preparation and pharmaceutical compositions containing them | |
CN101959865A (zh) | 作为法尼基焦磷酸合酶抑制剂的喹啉类化合物 | |
CN102485743A (zh) | 抗肿瘤化合物 | |
CN104995183B (zh) | 新的磷酸二酯酶10a型的抑制剂化合物 | |
CN103459396A (zh) | 作为c-Met酪氨酸激酶抑制剂的[1,2,4]三唑并[4,3-b]哒嗪化合物 | |
MXPA06011583A (en) | Inhibitors of iap |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C56 | Change in the name or address of the patentee |
Owner name: NOVARTIS CO., LTD. Free format text: FORMER NAME: NOVARTIS AG |
|
CP01 | Change in the name or title of a patent holder |
Address after: Basel, Switzerland Patentee after: NOVARTIS AG Address before: Basel, Switzerland Patentee before: Novartis AG |
|
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20110803 |
|
CF01 | Termination of patent right due to non-payment of annual fee |