CN103080093A - 吲唑化合物及其应用 - Google Patents
吲唑化合物及其应用 Download PDFInfo
- Publication number
- CN103080093A CN103080093A CN2011800243883A CN201180024388A CN103080093A CN 103080093 A CN103080093 A CN 103080093A CN 2011800243883 A CN2011800243883 A CN 2011800243883A CN 201180024388 A CN201180024388 A CN 201180024388A CN 103080093 A CN103080093 A CN 103080093A
- Authority
- CN
- China
- Prior art keywords
- alkyl
- compound
- cancer
- heterocyclic radical
- kinases
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 125000003453 indazolyl group Chemical class N1N=C(C2=C1C=CC=C2)* 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 74
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 71
- 238000011282 treatment Methods 0.000 claims abstract description 65
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 47
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 47
- 230000000694 effects Effects 0.000 claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims description 209
- -1 heterocyclic radical Chemical class 0.000 claims description 119
- 238000000034 method Methods 0.000 claims description 93
- 229910052799 carbon Inorganic materials 0.000 claims description 69
- 229910052739 hydrogen Inorganic materials 0.000 claims description 61
- 201000011510 cancer Diseases 0.000 claims description 58
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 102000001253 Protein Kinase Human genes 0.000 claims description 45
- 239000003795 chemical substances by application Substances 0.000 claims description 45
- 108060006633 protein kinase Proteins 0.000 claims description 45
- 238000002360 preparation method Methods 0.000 claims description 43
- 201000010099 disease Diseases 0.000 claims description 42
- 239000003814 drug Substances 0.000 claims description 41
- 150000003839 salts Chemical class 0.000 claims description 38
- 230000008859 change Effects 0.000 claims description 33
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 claims description 32
- 125000001188 haloalkyl group Chemical group 0.000 claims description 24
- 230000002496 gastric effect Effects 0.000 claims description 23
- 208000004197 mesenchymoma Diseases 0.000 claims description 23
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 claims description 22
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 21
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 21
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 claims description 21
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 21
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 21
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 21
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 claims description 20
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 claims description 19
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 claims description 19
- 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 229960002411 imatinib Drugs 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 16
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 206010025323 Lymphomas Diseases 0.000 claims description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- TXIOGJHPPVXTOY-UHFFFAOYSA-N 1-ethyl-4-methylpiperazine Chemical compound CCN1CCN(C)CC1 TXIOGJHPPVXTOY-UHFFFAOYSA-N 0.000 claims description 10
- 230000004048 modification Effects 0.000 claims description 10
- 238000012986 modification Methods 0.000 claims description 10
- 208000032839 leukemia Diseases 0.000 claims description 9
- 239000005536 L01XE08 - Nilotinib Substances 0.000 claims description 8
- 208000014951 hematologic disease Diseases 0.000 claims description 8
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 claims description 8
- 229960001346 nilotinib Drugs 0.000 claims description 8
- 230000003327 cancerostatic effect Effects 0.000 claims description 7
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 5
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 5
- 201000010989 colorectal carcinoma Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- 210000002751 lymph Anatomy 0.000 claims description 5
- 201000008261 skin carcinoma Diseases 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 208000030507 AIDS Diseases 0.000 claims description 4
- 206010000830 Acute leukaemia Diseases 0.000 claims description 4
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 4
- 208000019838 Blood disease Diseases 0.000 claims description 4
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 4
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 208000024207 chronic leukemia Diseases 0.000 claims description 4
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 4
- 210000004698 lymphocyte Anatomy 0.000 claims description 4
- 230000003211 malignant effect Effects 0.000 claims description 4
- 230000001613 neoplastic effect Effects 0.000 claims description 4
- 210000004180 plasmocyte Anatomy 0.000 claims description 4
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 claims description 3
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
- 101000950669 Homo sapiens Mitogen-activated protein kinase 9 Proteins 0.000 claims description 3
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 claims description 3
- 102100037809 Mitogen-activated protein kinase 9 Human genes 0.000 claims description 3
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 claims description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 3
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 claims description 3
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 claims description 3
- 201000010881 cervical cancer Diseases 0.000 claims description 3
- 210000004907 gland Anatomy 0.000 claims 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 claims description 3
- 108010087686 src-Family Kinases Proteins 0.000 claims description 3
- 102000009076 src-Family Kinases Human genes 0.000 claims description 3
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 claims description 2
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 claims description 2
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 claims description 2
- 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 claims description 2
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 claims description 2
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 claims description 2
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 claims description 2
- 102100036109 Dual specificity protein kinase TTK Human genes 0.000 claims description 2
- 102100037813 Focal adhesion kinase 1 Human genes 0.000 claims description 2
- 102100022603 Homeodomain-interacting protein kinase 4 Human genes 0.000 claims description 2
- 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 claims description 2
- 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 claims description 2
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 claims description 2
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 claims description 2
- 101000659223 Homo sapiens Dual specificity protein kinase TTK Proteins 0.000 claims description 2
- 101000878536 Homo sapiens Focal adhesion kinase 1 Proteins 0.000 claims description 2
- 101001045363 Homo sapiens Homeodomain-interacting protein kinase 4 Proteins 0.000 claims description 2
- 101000663003 Homo sapiens Non-receptor tyrosine-protein kinase TNK1 Proteins 0.000 claims description 2
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 claims description 2
- 101000984551 Homo sapiens Tyrosine-protein kinase Blk Proteins 0.000 claims description 2
- 101001022129 Homo sapiens Tyrosine-protein kinase Fyn Proteins 0.000 claims description 2
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 claims description 2
- 101000753253 Homo sapiens Tyrosine-protein kinase receptor Tie-1 Proteins 0.000 claims description 2
- 102100037669 Non-receptor tyrosine-protein kinase TNK1 Human genes 0.000 claims description 2
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 claims description 2
- 102100030571 STE20-like serine/threonine-protein kinase Human genes 0.000 claims description 2
- 102100027053 Tyrosine-protein kinase Blk Human genes 0.000 claims description 2
- 102100024537 Tyrosine-protein kinase Fer Human genes 0.000 claims description 2
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 claims description 2
- 102100022007 Tyrosine-protein kinase receptor Tie-1 Human genes 0.000 claims description 2
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 claims description 2
- 229960003685 imatinib mesylate Drugs 0.000 claims description 2
- 108010067366 proto-oncogene protein c-fes-fps Proteins 0.000 claims description 2
- 208000012991 uterine carcinoma Diseases 0.000 claims description 2
- 101710168331 ALK tyrosine kinase receptor Proteins 0.000 claims 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical class C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 77
- 239000002585 base Substances 0.000 description 38
- 210000004027 cell Anatomy 0.000 description 33
- 239000000243 solution Substances 0.000 description 33
- 208000035475 disorder Diseases 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- 239000000463 material Substances 0.000 description 23
- 150000001721 carbon Chemical group 0.000 description 21
- 239000002775 capsule Substances 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 20
- 235000018102 proteins Nutrition 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 20
- 108090000623 proteins and genes Proteins 0.000 description 20
- 239000003826 tablet Substances 0.000 description 20
- 239000002253 acid Substances 0.000 description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 101150001535 SRC gene Proteins 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000000126 substance Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 239000003153 chemical reaction reagent Substances 0.000 description 13
- 150000002148 esters Chemical class 0.000 description 13
- 229910052757 nitrogen Inorganic materials 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 230000008569 process Effects 0.000 description 13
- 239000007787 solid Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- 239000003981 vehicle Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 125000000304 alkynyl group Chemical group 0.000 description 12
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 10
- 238000013016 damping Methods 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 235000019439 ethyl acetate Nutrition 0.000 description 10
- 239000012530 fluid Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 239000000460 chlorine Substances 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000001257 hydrogen Substances 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000004659 sterilization and disinfection Methods 0.000 description 9
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 125000003545 alkoxy group Chemical group 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 238000003119 immunoblot Methods 0.000 description 8
- 239000002674 ointment Substances 0.000 description 8
- 239000001301 oxygen Substances 0.000 description 8
- 230000001954 sterilising effect Effects 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 7
- 239000003937 drug carrier Substances 0.000 description 7
- 238000003818 flash chromatography Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 6
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000002354 daily effect Effects 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 229920000159 gelatin Polymers 0.000 description 6
- 235000019322 gelatine Nutrition 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 6
- 230000000670 limiting effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 229910052938 sodium sulfate Inorganic materials 0.000 description 6
- 235000011152 sodium sulphate Nutrition 0.000 description 6
- 125000002769 thiazolinyl group Chemical group 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 102000003916 Arrestin Human genes 0.000 description 5
- 108090000328 Arrestin Proteins 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 5
- 108010010803 Gelatin Proteins 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 5
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 5
- 239000004141 Sodium laurylsulphate Substances 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- 102000004357 Transferases Human genes 0.000 description 5
- 108090000992 Transferases Proteins 0.000 description 5
- 230000002159 abnormal effect Effects 0.000 description 5
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 5
- 125000003368 amide group Chemical group 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 230000003078 antioxidant effect Effects 0.000 description 5
- 235000006708 antioxidants Nutrition 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 125000000392 cycloalkenyl group Chemical group 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 229960002448 dasatinib Drugs 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000008273 gelatin Substances 0.000 description 5
- 235000011852 gelatine desserts Nutrition 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 150000002430 hydrocarbons Chemical class 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 238000012545 processing Methods 0.000 description 5
- XJMOSONTPMZWPB-UHFFFAOYSA-M propidium iodide Chemical compound [I-].[I-].C12=CC(N)=CC=C2C2=CC=C(N)C=C2[N+](CCC[N+](C)(CC)CC)=C1C1=CC=CC=C1 XJMOSONTPMZWPB-UHFFFAOYSA-M 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 5
- 229960004793 sucrose Drugs 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 230000009385 viral infection Effects 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 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 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 241000124008 Mammalia Species 0.000 description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229920001615 Tragacanth Polymers 0.000 description 4
- 229940123468 Transferase inhibitor Drugs 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 description 4
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 239000000305 astragalus gummifer gum Substances 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 230000002860 competitive effect Effects 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- AIMMVWOEOZMVMS-UHFFFAOYSA-N cyclopropanecarboxamide Chemical compound NC(=O)C1CC1 AIMMVWOEOZMVMS-UHFFFAOYSA-N 0.000 description 4
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 4
- 238000004520 electroporation Methods 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 230000036541 health Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 description 4
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000011159 matrix material Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 210000000214 mouth Anatomy 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 239000006187 pill Substances 0.000 description 4
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 210000000664 rectum Anatomy 0.000 description 4
- 210000000582 semen Anatomy 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- 239000003558 transferase inhibitor Substances 0.000 description 4
- 210000001215 vagina Anatomy 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 3
- 244000215068 Acacia senegal Species 0.000 description 3
- 235000006491 Acacia senegal Nutrition 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- 102100032187 Androgen receptor Human genes 0.000 description 3
- 208000023275 Autoimmune disease Diseases 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 3
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 3
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 3
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 3
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229920002684 Sepharose Polymers 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 239000006180 TBST buffer Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 3
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 3
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 125000000539 amino acid group Chemical group 0.000 description 3
- 150000001413 amino acids Chemical group 0.000 description 3
- 108010080146 androgen receptors Proteins 0.000 description 3
- 230000008485 antagonism Effects 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 3
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 208000037976 chronic inflammation Diseases 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 235000009508 confectionery Nutrition 0.000 description 3
- 229940127089 cytotoxic agent Drugs 0.000 description 3
- 239000002254 cytotoxic agent Substances 0.000 description 3
- 231100000599 cytotoxic agent Toxicity 0.000 description 3
- WHBIGIKBNXZKFE-UHFFFAOYSA-N delavirdine Chemical compound CC(C)NC1=CC=CN=C1N1CCN(C(=O)C=2NC3=CC=C(NS(C)(=O)=O)C=C3C=2)CC1 WHBIGIKBNXZKFE-UHFFFAOYSA-N 0.000 description 3
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011888 foil Substances 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 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 3
- 238000001114 immunoprecipitation Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 239000003607 modifier Substances 0.000 description 3
- 230000002969 morbid Effects 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 3
- 150000002894 organic compounds Chemical class 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 3
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920001451 polypropylene glycol Polymers 0.000 description 3
- 229940100552 retinamide Drugs 0.000 description 3
- 102000027483 retinoid hormone receptors Human genes 0.000 description 3
- 108091008679 retinoid hormone receptors Proteins 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 208000012201 sexual and gender identity disease Diseases 0.000 description 3
- 208000015891 sexual disease Diseases 0.000 description 3
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 3
- 235000012239 silicon dioxide Nutrition 0.000 description 3
- 210000003491 skin Anatomy 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- MEIRRNXMZYDVDW-MQQKCMAXSA-N (2E,4E)-2,4-hexadien-1-ol Chemical compound C\C=C\C=C\CO MEIRRNXMZYDVDW-MQQKCMAXSA-N 0.000 description 2
- XSAKVDNHFRWJKS-IIZANFQQSA-N (2s)-n-benzyl-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC=2C=CC=CC=2)CCC1 XSAKVDNHFRWJKS-IIZANFQQSA-N 0.000 description 2
- REHVCPNQQBDOJJ-UHFFFAOYSA-N (3-ethoxycarbonylphenyl)boronic acid Chemical compound CCOC(=O)C1=CC=CC(B(O)O)=C1 REHVCPNQQBDOJJ-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- QUNOQBDEVTWCTA-UHFFFAOYSA-N 2-[2-[3-[2-(1,3-dioxobenzo[de]isoquinolin-2-yl)ethylamino]propylamino]ethyl]benzo[de]isoquinoline-1,3-dione Chemical compound C1=CC(C(=O)N(CCNCCCNCCN2C(C=3C=CC=C4C=CC=C(C=34)C2=O)=O)C2=O)=C3C2=CC=CC3=C1 QUNOQBDEVTWCTA-UHFFFAOYSA-N 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- AXGPLXKWYRKBHB-UHFFFAOYSA-N 4-(3-chlorophenyl)-1-methylquinolin-2-one Chemical compound C=1C(=O)N(C)C2=CC=CC=C2C=1C1=CC=CC(Cl)=C1 AXGPLXKWYRKBHB-UHFFFAOYSA-N 0.000 description 2
- GAMYYCRTACQSBR-UHFFFAOYSA-N 4-azabenzimidazole Chemical compound C1=CC=C2NC=NC2=N1 GAMYYCRTACQSBR-UHFFFAOYSA-N 0.000 description 2
- GBOQUHPYCRYKGV-UHFFFAOYSA-N 5-nitro-2-(2-pyrrolidin-1-ylethyl)benzo[de]isoquinoline-1,3-dione Chemical compound O=C1C(C=23)=CC=CC3=CC([N+](=O)[O-])=CC=2C(=O)N1CCN1CCCC1 GBOQUHPYCRYKGV-UHFFFAOYSA-N 0.000 description 2
- 101710153593 Albumin A Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 2
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 2
- 206010057248 Cell death Diseases 0.000 description 2
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 2
- 229930188224 Cryptophycin Natural products 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- LQKSHSFQQRCAFW-UHFFFAOYSA-N Dolastatin 15 Natural products COC1=CC(=O)N(C(=O)C(OC(=O)C2N(CCC2)C(=O)C2N(CCC2)C(=O)C(C(C)C)N(C)C(=O)C(NC(=O)C(C(C)C)N(C)C)C(C)C)C(C)C)C1CC1=CC=CC=C1 LQKSHSFQQRCAFW-UHFFFAOYSA-N 0.000 description 2
- 239000004278 EU approved seasoning Substances 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 241000233866 Fungi Species 0.000 description 2
- 241000206672 Gelidium Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 229940122440 HIV protease inhibitor Drugs 0.000 description 2
- 101001126417 Homo sapiens Platelet-derived growth factor receptor alpha Proteins 0.000 description 2
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 2
- 101000823316 Homo sapiens Tyrosine-protein kinase ABL1 Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 206010048643 Hypereosinophilic syndrome Diseases 0.000 description 2
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 206010023347 Keratoacanthoma Diseases 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 108010043135 L-methionine gamma-lyase Proteins 0.000 description 2
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 2
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 2
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 2
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 208000015634 Rectal Neoplasms Diseases 0.000 description 2
- 102000001332 SRC Human genes 0.000 description 2
- 108060006706 SRC Proteins 0.000 description 2
- 206010039491 Sarcoma Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 102000013275 Somatomedins Human genes 0.000 description 2
- 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 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 240000006474 Theobroma bicolor Species 0.000 description 2
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 2
- 239000004473 Threonine Substances 0.000 description 2
- 208000033781 Thyroid carcinoma Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 101710183280 Topoisomerase Proteins 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 102100040247 Tumor necrosis factor Human genes 0.000 description 2
- 102100022596 Tyrosine-protein kinase ABL1 Human genes 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 230000003213 activating effect Effects 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- 230000003044 adaptive effect Effects 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 125000004947 alkyl aryl amino group Chemical group 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 125000005128 aryl amino alkyl group Chemical group 0.000 description 2
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 2
- 125000001769 aryl amino group Chemical group 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 2
- 229950008548 bisantrene Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 2
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000011111 cardboard Substances 0.000 description 2
- 229960003261 carmofur Drugs 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 239000013592 cell lysate Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 108010046713 cemadotin Proteins 0.000 description 2
- 229950009017 cemadotin Drugs 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229960005537 combretastatin A-4 Drugs 0.000 description 2
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000000875 corresponding effect Effects 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
- 239000012043 crude product Substances 0.000 description 2
- 108010006226 cryptophycin Proteins 0.000 description 2
- PSNOPSMXOBPNNV-VVCTWANISA-N cryptophycin 1 Chemical compound C1=C(Cl)C(OC)=CC=C1C[C@@H]1C(=O)NC[C@@H](C)C(=O)O[C@@H](CC(C)C)C(=O)O[C@H]([C@H](C)[C@@H]2[C@H](O2)C=2C=CC=CC=2)C/C=C/C(=O)N1 PSNOPSMXOBPNNV-VVCTWANISA-N 0.000 description 2
- PSNOPSMXOBPNNV-UHFFFAOYSA-N cryptophycin-327 Natural products C1=C(Cl)C(OC)=CC=C1CC1C(=O)NCC(C)C(=O)OC(CC(C)C)C(=O)OC(C(C)C2C(O2)C=2C=CC=CC=2)CC=CC(=O)N1 PSNOPSMXOBPNNV-UHFFFAOYSA-N 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 229950009278 dimesna Drugs 0.000 description 2
- KQYGMURBTJPBPQ-UHFFFAOYSA-L disodium;2-(2-sulfonatoethyldisulfanyl)ethanesulfonate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)CCSSCCS([O-])(=O)=O KQYGMURBTJPBPQ-UHFFFAOYSA-L 0.000 description 2
- 229960003668 docetaxel Drugs 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000009977 dual effect Effects 0.000 description 2
- 229950004438 elinafide Drugs 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 235000011194 food seasoning agent Nutrition 0.000 description 2
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 125000002350 geranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229940015043 glyoxal Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 210000000777 hematopoietic system Anatomy 0.000 description 2
- 230000011132 hemopoiesis Effects 0.000 description 2
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 2
- 239000004030 hiv protease inhibitor Substances 0.000 description 2
- 150000002431 hydrogen Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- CCBYKULDFQDEAC-UHFFFAOYSA-N indazol-2-amine Chemical compound C1=CC=CC2=NN(N)C=C21 CCBYKULDFQDEAC-UHFFFAOYSA-N 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- QWTDNUCVQCZILF-UHFFFAOYSA-N isopentane Chemical compound CCC(C)C QWTDNUCVQCZILF-UHFFFAOYSA-N 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229960003538 lonidamine Drugs 0.000 description 2
- WDRYRZXSPDWGEB-UHFFFAOYSA-N lonidamine Chemical compound C12=CC=CC=C2C(C(=O)O)=NN1CC1=CC=C(Cl)C=C1Cl WDRYRZXSPDWGEB-UHFFFAOYSA-N 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- VGLXPHXEBCVQOQ-UHFFFAOYSA-N n-(6-bromo-1h-indazol-3-yl)cyclopropanecarboxamide Chemical compound N=1NC2=CC(Br)=CC=C2C=1NC(=O)C1CC1 VGLXPHXEBCVQOQ-UHFFFAOYSA-N 0.000 description 2
- NJSMWLQOCQIOPE-OCHFTUDZSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine Chemical compound N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 NJSMWLQOCQIOPE-OCHFTUDZSA-N 0.000 description 2
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- NQDJXKOVJZTUJA-UHFFFAOYSA-N nevirapine Chemical compound C12=NC=CC=C2C(=O)NC=2C(C)=CC=NC=2N1C1CC1 NQDJXKOVJZTUJA-UHFFFAOYSA-N 0.000 description 2
- IYDNQWWOZQLMRH-UHFFFAOYSA-N octadec-1-yne Chemical compound CCCCCCCCCCCCCCCCC#C IYDNQWWOZQLMRH-UHFFFAOYSA-N 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 description 2
- 239000000123 paper Substances 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 150000003016 phosphoric acids Chemical class 0.000 description 2
- 229910052698 phosphorus Inorganic materials 0.000 description 2
- 229950004317 pinafide Drugs 0.000 description 2
- 229950008499 plitidepsin Drugs 0.000 description 2
- UUSZLLQJYRSZIS-LXNNNBEUSA-N plitidepsin Chemical compound CN([C@H](CC(C)C)C(=O)N[C@@H]1C(=O)N[C@@H]([C@H](CC(=O)O[C@H](C(=O)[C@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N2CCC[C@H]2C(=O)N(C)[C@@H](CC=2C=CC(OC)=CC=2)C(=O)O[C@@H]1C)C(C)C)O)[C@@H](C)CC)C(=O)[C@@H]1CCCN1C(=O)C(C)=O UUSZLLQJYRSZIS-LXNNNBEUSA-N 0.000 description 2
- 108010049948 plitidepsin Proteins 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 239000001294 propane Substances 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 206010038038 rectal cancer Diseases 0.000 description 2
- 201000001275 rectum cancer Diseases 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 208000037803 restenosis Diseases 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 2
- 229960001860 salicylate Drugs 0.000 description 2
- 238000007789 sealing Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000001509 sodium citrate Substances 0.000 description 2
- 159000000000 sodium salts Chemical group 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 235000010199 sorbic acid Nutrition 0.000 description 2
- 239000004334 sorbic acid Substances 0.000 description 2
- 229940075582 sorbic acid Drugs 0.000 description 2
- 238000003153 stable transfection Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 2
- 229960003723 tiazofurine Drugs 0.000 description 2
- FVRDYQYEVDDKCR-DBRKOABJSA-N tiazofurine Chemical compound NC(=O)C1=CSC([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=N1 FVRDYQYEVDDKCR-DBRKOABJSA-N 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 229940038773 trisodium citrate Drugs 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 241001430294 unidentified retrovirus Species 0.000 description 2
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 2
- 230000004862 vasculogenesis Effects 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 229910052727 yttrium Inorganic materials 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- DTGKSKDOIYIVQL-WEDXCCLWSA-N (+)-borneol Chemical group C1C[C@@]2(C)[C@@H](O)C[C@@H]1C2(C)C DTGKSKDOIYIVQL-WEDXCCLWSA-N 0.000 description 1
- BMKDZUISNHGIBY-ZETCQYMHSA-N (+)-dexrazoxane Chemical compound C([C@H](C)N1CC(=O)NC(=O)C1)N1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-ZETCQYMHSA-N 0.000 description 1
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 description 1
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 1
- JKFZMIQMKFWJAY-RQJQXFIZSA-N (1r,3s,5z)-5-[(2e)-2-[(3as,7as)-1-[(2r)-6-hydroxy-6-methylhept-4-yn-2-yl]-7a-methyl-3a,5,6,7-tetrahydro-3h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C1(/[C@@H]2CC=C([C@]2(CCC1)C)[C@@H](CC#CC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C JKFZMIQMKFWJAY-RQJQXFIZSA-N 0.000 description 1
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 1
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- ZUQBAQVRAURMCL-DOMZBBRYSA-N (2s)-2-[[4-[2-[(6r)-2-amino-4-oxo-5,6,7,8-tetrahydro-1h-pyrido[2,3-d]pyrimidin-6-yl]ethyl]benzoyl]amino]pentanedioic acid Chemical compound C([C@@H]1CC=2C(=O)N=C(NC=2NC1)N)CC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZUQBAQVRAURMCL-DOMZBBRYSA-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
- PSVUJBVBCOISSP-SPFKKGSWSA-N (2s,3r,4s,5s,6r)-2-bis(2-chloroethylamino)phosphoryloxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical compound OC[C@H]1O[C@@H](OP(=O)(NCCCl)NCCCl)[C@H](O)[C@@H](O)[C@@H]1O PSVUJBVBCOISSP-SPFKKGSWSA-N 0.000 description 1
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
- CUFQBQOBLVLKRF-RZDMPUFOSA-N (4r)-3-[(2s,3s)-2-hydroxy-3-[(3-hydroxy-2-methylbenzoyl)amino]-4-phenylbutanoyl]-5,5-dimethyl-n-[(2-methylphenyl)methyl]-1,3-thiazolidine-4-carboxamide Chemical compound CC1=CC=CC=C1CNC(=O)[C@@H]1C(C)(C)SCN1C(=O)[C@@H](O)[C@@H](NC(=O)C=1C(=C(O)C=CC=1)C)CC1=CC=CC=C1 CUFQBQOBLVLKRF-RZDMPUFOSA-N 0.000 description 1
- HINZVVDZPLARRP-YSVIXOAZSA-N (4r,5s,6s,7r)-1,3-bis[(3-aminophenyl)methyl]-4,7-dibenzyl-5,6-dihydroxy-1,3-diazepan-2-one;methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.NC1=CC=CC(CN2C(N(CC=3C=C(N)C=CC=3)[C@H](CC=3C=CC=CC=3)[C@H](O)[C@@H](O)[C@H]2CC=2C=CC=CC=2)=O)=C1 HINZVVDZPLARRP-YSVIXOAZSA-N 0.000 description 1
- WTSKMKRYHATLLL-UHFFFAOYSA-N (6-benzoyloxy-3-cyanopyridin-2-yl) 3-[3-(ethoxymethyl)-5-fluoro-2,6-dioxopyrimidine-1-carbonyl]benzoate Chemical compound O=C1N(COCC)C=C(F)C(=O)N1C(=O)C1=CC=CC(C(=O)OC=2C(=CC=C(OC(=O)C=3C=CC=CC=3)N=2)C#N)=C1 WTSKMKRYHATLLL-UHFFFAOYSA-N 0.000 description 1
- BSRQHWFOFMAZRL-BODGVHBXSA-N (7s,9s)-7-[(2r,4s,5s,6s)-5-[(2s,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-4-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@H]1[C@@H](O)C[C@H](O[C@@H]2C3=C(O)C=4C(=O)C5=CC=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)O[C@H]1C BSRQHWFOFMAZRL-BODGVHBXSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- 125000006730 (C2-C5) alkynyl group Chemical group 0.000 description 1
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 1
- NQBWNECTZUOWID-UHFFFAOYSA-N (E)-cinnamyl (E)-cinnamate Natural products C=1C=CC=CC=1C=CC(=O)OCC=CC1=CC=CC=C1 NQBWNECTZUOWID-UHFFFAOYSA-N 0.000 description 1
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 1
- 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 1
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 1
- ZGNLFUXWZJGETL-YUSKDDKASA-N (Z)-[(2S)-2-amino-2-carboxyethyl]-hydroxyimino-oxidoazanium Chemical compound N[C@@H](C\[N+]([O-])=N\O)C(O)=O ZGNLFUXWZJGETL-YUSKDDKASA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- KPZGRMZPZLOPBS-UHFFFAOYSA-N 1,3-dichloro-2,2-bis(chloromethyl)propane Chemical compound ClCC(CCl)(CCl)CCl KPZGRMZPZLOPBS-UHFFFAOYSA-N 0.000 description 1
- MZNMZWZGUGFQJP-UHFFFAOYSA-N 1-[11-(dodecylamino)-10-hydroxyundecyl]-3,7-dimethylpurine-2,6-dione Chemical compound O=C1N(CCCCCCCCCC(O)CNCCCCCCCCCCCC)C(=O)N(C)C2=C1N(C)C=N2 MZNMZWZGUGFQJP-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-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
- GKKYIFVZOUAVAT-UHFFFAOYSA-N 2-(9h-acridin-10-yl)-n,n-dimethylethanamine Chemical compound C1=CC=C2N(CCN(C)C)C3=CC=CC=C3CC2=C1 GKKYIFVZOUAVAT-UHFFFAOYSA-N 0.000 description 1
- XWNJMSJGJFSGRY-UHFFFAOYSA-N 2-(benzylamino)-3,7-dihydropurin-6-one Chemical compound N1C=2N=CNC=2C(=O)N=C1NCC1=CC=CC=C1 XWNJMSJGJFSGRY-UHFFFAOYSA-N 0.000 description 1
- BMGMINKVTPDDRZ-UHFFFAOYSA-N 2-acetamido-n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methylpentanamide;n-[1-[[5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]-4-methyl-2-(propanoylamino)pentanamide Chemical compound CC(C)CC(NC(C)=O)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N.CCC(=O)NC(CC(C)C)C(=O)NC(CC(C)C)C(=O)NC(C=O)CCCN=C(N)N BMGMINKVTPDDRZ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- MIDXCONKKJTLDX-UHFFFAOYSA-N 3,5-dimethylcyclopentane-1,2-dione Chemical compound CC1CC(C)C(=O)C1=O MIDXCONKKJTLDX-UHFFFAOYSA-N 0.000 description 1
- BRMWTNUJHUMWMS-UHFFFAOYSA-N 3-Methylhistidine Natural products CN1C=NC(CC(N)C(O)=O)=C1 BRMWTNUJHUMWMS-UHFFFAOYSA-N 0.000 description 1
- FQWNGSKQHPNIQG-UHFFFAOYSA-N 3-[[bis(2-chloroethyl)amino-(2-chloroethoxy)phosphoryl]amino]propan-1-ol Chemical compound OCCCNP(=O)(OCCCl)N(CCCl)CCCl FQWNGSKQHPNIQG-UHFFFAOYSA-N 0.000 description 1
- CURYRIVJTBNEGU-UHFFFAOYSA-L 3-bromo-1-[12-(3-bromopropanoyl)-3,12-diaza-6,9-diazoniadispiro[5.2.5^{9}.2^{6}]hexadecan-3-yl]propan-1-one;dichloride Chemical compound [Cl-].[Cl-].C1CN(C(=O)CCBr)CC[N+]21CC[N+]1(CCN(CC1)C(=O)CCBr)CC2 CURYRIVJTBNEGU-UHFFFAOYSA-L 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UCFZVQHKTRSZMM-UHFFFAOYSA-N 4-(4-methylpiperazin-1-yl)benzoic acid Chemical compound C1CN(C)CCN1C1=CC=C(C(O)=O)C=C1 UCFZVQHKTRSZMM-UHFFFAOYSA-N 0.000 description 1
- NDCQPJCNZBQYAO-UHFFFAOYSA-N 4-[[3-[3-benzoyl-8-(trifluoromethyl)quinolin-4-yl]phenoxy]methyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1COC1=CC=CC(C=2C3=CC=CC(=C3N=CC=2C(=O)C=2C=CC=CC=2)C(F)(F)F)=C1 NDCQPJCNZBQYAO-UHFFFAOYSA-N 0.000 description 1
- GLRNUORBOPEUCX-UHFFFAOYSA-N 4-aminobenzenesulfonamide;benzene Chemical compound C1=CC=CC=C1.NC1=CC=C(S(N)(=O)=O)C=C1 GLRNUORBOPEUCX-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- HGXWRDPQFZKOLZ-UHFFFAOYSA-N 4-bromo-2-fluorobenzonitrile Chemical compound FC1=CC(Br)=CC=C1C#N HGXWRDPQFZKOLZ-UHFFFAOYSA-N 0.000 description 1
- 229940113178 5 Alpha reductase inhibitor Drugs 0.000 description 1
- 239000002677 5-alpha reductase inhibitor Substances 0.000 description 1
- XAUDJQYHKZQPEU-KVQBGUIXSA-N 5-aza-2'-deoxycytidine Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 XAUDJQYHKZQPEU-KVQBGUIXSA-N 0.000 description 1
- QRXMUCSWCMTJGU-UHFFFAOYSA-N 5-bromo-4-chloro-3-indolyl phosphate Chemical compound C1=C(Br)C(Cl)=C2C(OP(O)(=O)O)=CNC2=C1 QRXMUCSWCMTJGU-UHFFFAOYSA-N 0.000 description 1
- WLDHNAMVDBASAW-UHFFFAOYSA-N 6-bromo-1h-indazol-3-amine Chemical compound BrC1=CC=C2C(N)=NNC2=C1 WLDHNAMVDBASAW-UHFFFAOYSA-N 0.000 description 1
- WMKDUJVLNZANRN-UHFFFAOYSA-N 6-bromo-1h-indazole Chemical compound BrC1=CC=C2C=NNC2=C1 WMKDUJVLNZANRN-UHFFFAOYSA-N 0.000 description 1
- KAEVHZSIYLATMK-UHFFFAOYSA-N 6-n-[bis(aziridin-1-yl)phosphoryl]-2-n,2-n,7-trimethylpurine-2,6-diamine Chemical compound C=12N(C)C=NC2=NC(N(C)C)=NC=1NP(=O)(N1CC1)N1CC1 KAEVHZSIYLATMK-UHFFFAOYSA-N 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- RGVRUQHYQSORBY-UHFFFAOYSA-N 7-(4-amino-5-hydroxy-6-methyloxan-2-yl)oxy-6,9,11-trihydroxy-9-(2-hydroxyethyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(CCO)CC1OC1CC(N)C(O)C(C)O1 RGVRUQHYQSORBY-UHFFFAOYSA-N 0.000 description 1
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 1
- KABRXLINDSPGDF-UHFFFAOYSA-N 7-bromoisoquinoline Chemical compound C1=CN=CC2=CC(Br)=CC=C21 KABRXLINDSPGDF-UHFFFAOYSA-N 0.000 description 1
- 102100038079 AP2-associated protein kinase 1 Human genes 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 208000003200 Adenoma Diseases 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
- 102400000068 Angiostatin Human genes 0.000 description 1
- 108010079709 Angiostatins Proteins 0.000 description 1
- 229940123413 Angiotensin II antagonist Drugs 0.000 description 1
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 description 1
- 241001225321 Aspergillus fumigatus Species 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- 102100035080 BDNF/NT-3 growth factors receptor Human genes 0.000 description 1
- 206010004593 Bile duct cancer Diseases 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- SWEBIMCKBWFCKI-UHFFFAOYSA-N C(=O)=Cl.C1CC1 Chemical compound C(=O)=Cl.C1CC1 SWEBIMCKBWFCKI-UHFFFAOYSA-N 0.000 description 1
- CDBUICWZJWAFKI-UHFFFAOYSA-N C/C(/[N]#C)=C/NCC=S Chemical compound C/C(/[N]#C)=C/NCC=S CDBUICWZJWAFKI-UHFFFAOYSA-N 0.000 description 1
- 101100498819 Caenorhabditis elegans ddr-1 gene Proteins 0.000 description 1
- 101100314454 Caenorhabditis elegans tra-1 gene Proteins 0.000 description 1
- 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 1
- 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 1
- 241000283707 Capra Species 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 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
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229940093444 Cyclooxygenase 2 inhibitor Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 101100503636 Danio rerio fyna gene Proteins 0.000 description 1
- 101100314281 Danio rerio trappc11 gene Proteins 0.000 description 1
- WEAHRLBPCANXCN-UHFFFAOYSA-N Daunomycin Natural products CCC1(O)CC(OC2CC(N)C(O)C(C)O2)c3cc4C(=O)c5c(OC)cccc5C(=O)c4c(O)c3C1 WEAHRLBPCANXCN-UHFFFAOYSA-N 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- 101100066566 Drosophila melanogaster FER gene Proteins 0.000 description 1
- 102100023274 Dual specificity mitogen-activated protein kinase kinase 4 Human genes 0.000 description 1
- 102100023332 Dual specificity mitogen-activated protein kinase kinase 7 Human genes 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- XPOQHMRABVBWPR-UHFFFAOYSA-N Efavirenz Natural products O1C(=O)NC2=CC=C(Cl)C=C2C1(C(F)(F)F)C#CC1CC1 XPOQHMRABVBWPR-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 201000009273 Endometriosis Diseases 0.000 description 1
- SAMRUMKYXPVKPA-VFKOLLTISA-N Enocitabine Chemical compound O=C1N=C(NC(=O)CCCCCCCCCCCCCCCCCCCCC)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 SAMRUMKYXPVKPA-VFKOLLTISA-N 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 1
- 101150036586 FES gene Proteins 0.000 description 1
- 101150017750 FGFRL1 gene Proteins 0.000 description 1
- 101150106356 FPS gene Proteins 0.000 description 1
- 101150018370 FRK gene Proteins 0.000 description 1
- 101150018272 FYN gene Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 101150040897 Fgr gene Proteins 0.000 description 1
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100027844 Fibroblast growth factor receptor 4 Human genes 0.000 description 1
- 102100026149 Fibroblast growth factor receptor-like 1 Human genes 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 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 1
- CEVCTNCUIVEQOY-UHFFFAOYSA-N Fumagillol Natural products O1C(CC=C(C)C)C1(C)C1C(OC)C(O)CCC21CO2 CEVCTNCUIVEQOY-UHFFFAOYSA-N 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- 102000038624 GSKs Human genes 0.000 description 1
- 108091007911 GSKs Proteins 0.000 description 1
- 201000003741 Gastrointestinal carcinoma Diseases 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 201000010915 Glioblastoma multiforme Diseases 0.000 description 1
- 206010018364 Glomerulonephritis Diseases 0.000 description 1
- 229920004449 Halon® Polymers 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 102100032822 Homeodomain-interacting protein kinase 1 Human genes 0.000 description 1
- 102100032827 Homeodomain-interacting protein kinase 2 Human genes 0.000 description 1
- 101000742699 Homo sapiens AP2-associated protein kinase 1 Proteins 0.000 description 1
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 1
- 101000596896 Homo sapiens BDNF/NT-3 growth factors receptor Proteins 0.000 description 1
- 101001115395 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 4 Proteins 0.000 description 1
- 101000624594 Homo sapiens Dual specificity mitogen-activated protein kinase kinase 7 Proteins 0.000 description 1
- 101000917134 Homo sapiens Fibroblast growth factor receptor 4 Proteins 0.000 description 1
- 101001066404 Homo sapiens Homeodomain-interacting protein kinase 1 Proteins 0.000 description 1
- 101001066401 Homo sapiens Homeodomain-interacting protein kinase 2 Proteins 0.000 description 1
- 101000872458 Homo sapiens Huntingtin-interacting protein 1-related protein Proteins 0.000 description 1
- 101000852483 Homo sapiens Interleukin-1 receptor-associated kinase 1 Proteins 0.000 description 1
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 description 1
- 101000628949 Homo sapiens Mitogen-activated protein kinase 10 Proteins 0.000 description 1
- 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 description 1
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 1
- 101000846284 Homo sapiens Pre-mRNA 3'-end-processing factor FIP1 Proteins 0.000 description 1
- 101000878540 Homo sapiens Protein-tyrosine kinase 2-beta Proteins 0.000 description 1
- 101000652133 Homo sapiens STE20-like serine/threonine-protein kinase Proteins 0.000 description 1
- 101000648174 Homo sapiens Serine/threonine-protein kinase 10 Proteins 0.000 description 1
- 101000880439 Homo sapiens Serine/threonine-protein kinase 3 Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 101001026870 Homo sapiens Serine/threonine-protein kinase D1 Proteins 0.000 description 1
- 101000601441 Homo sapiens Serine/threonine-protein kinase Nek2 Proteins 0.000 description 1
- 241000701806 Human papillomavirus Species 0.000 description 1
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- JJKOTMDDZAJTGQ-DQSJHHFOSA-N Idoxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN2CCCC2)=CC=1)/C1=CC=C(I)C=C1 JJKOTMDDZAJTGQ-DQSJHHFOSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061217 Infestation Diseases 0.000 description 1
- 102100036342 Interleukin-1 receptor-associated kinase 1 Human genes 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- SHGAZHPCJJPHSC-NUEINMDLSA-N Isotretinoin Chemical compound OC(=O)C=C(C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C SHGAZHPCJJPHSC-NUEINMDLSA-N 0.000 description 1
- KJHKTHWMRKYKJE-SUGCFTRWSA-N Kaletra Chemical compound N1([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=2C=CC=CC=2)NC(=O)COC=2C(=CC=CC=2C)C)CC=2C=CC=CC=2)CCCNC1=O KJHKTHWMRKYKJE-SUGCFTRWSA-N 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-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
- MLFKVJCWGUZWNV-UHFFFAOYSA-N L-alanosine Natural products OC(=O)C(N)CN(O)N=O MLFKVJCWGUZWNV-UHFFFAOYSA-N 0.000 description 1
- QAQJMLQRFWZOBN-LAUBAEHRSA-N L-ascorbyl-6-palmitate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](O)[C@H]1OC(=O)C(O)=C1O QAQJMLQRFWZOBN-LAUBAEHRSA-N 0.000 description 1
- 235000000072 L-ascorbyl-6-palmitate Nutrition 0.000 description 1
- 239000011786 L-ascorbyl-6-palmitate Substances 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
- 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
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- 101150028321 Lck gene Proteins 0.000 description 1
- 108010011078 Leupeptins Proteins 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 206010062038 Lip neoplasm Diseases 0.000 description 1
- 108010058398 Macrophage Colony-Stimulating Factor Receptor Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 238000003820 Medium-pressure liquid chromatography Methods 0.000 description 1
- NPPQSCRMBWNHMW-UHFFFAOYSA-N Meprobamate Chemical compound NC(=O)OCC(C)(CCC)COC(N)=O NPPQSCRMBWNHMW-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 102100026931 Mitogen-activated protein kinase 10 Human genes 0.000 description 1
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 1
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 1
- 208000003445 Mouth Neoplasms Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- JDHILDINMRGULE-LURJTMIESA-N N(pros)-methyl-L-histidine Chemical compound CN1C=NC=C1C[C@H](N)C(O)=O JDHILDINMRGULE-LURJTMIESA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- OAOKXFHGWGPRNV-UHFFFAOYSA-N NCCNC1=NC=CC2=CC3=C(C=C12)C=CC=C3 Chemical compound NCCNC1=NC=CC2=CC3=C(C=C12)C=CC=C3 OAOKXFHGWGPRNV-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 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
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000000020 Nitrocellulose Substances 0.000 description 1
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 1
- 108091034117 Oligonucleotide Proteins 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
- 241000906034 Orthops Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101100381429 Oryza sativa subsp. japonica BADH2 gene Proteins 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- 101150054473 PTK2 gene Proteins 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 102100021061 Palmitoyltransferase ZDHHC17 Human genes 0.000 description 1
- 101150034459 Parpbp gene Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000009565 Pharyngeal Neoplasms Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000254064 Photinus pyralis Species 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)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]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 241000223960 Plasmodium falciparum Species 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 102100031755 Pre-mRNA 3'-end-processing factor FIP1 Human genes 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 1
- 101710109947 Protein kinase C alpha type Proteins 0.000 description 1
- 102100037787 Protein-tyrosine kinase 2-beta Human genes 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 101000852966 Rattus norvegicus Interleukin-1 receptor-like 1 Proteins 0.000 description 1
- 108010079933 Receptor-Interacting Protein Serine-Threonine Kinase 2 Proteins 0.000 description 1
- 102100022502 Receptor-interacting serine/threonine-protein kinase 2 Human genes 0.000 description 1
- OWPCHSCAPHNHAV-UHFFFAOYSA-N Rhizoxin Natural products C1C(O)C2(C)OC2C=CC(C)C(OC(=O)C2)CC2CC2OC2C(=O)OC1C(C)C(OC)C(C)=CC=CC(C)=CC1=COC(C)=N1 OWPCHSCAPHNHAV-UHFFFAOYSA-N 0.000 description 1
- 102100039314 Rho-associated protein kinase 2 Human genes 0.000 description 1
- 101710088493 Rho-associated protein kinase 2 Proteins 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 206010039361 Sacroiliitis Diseases 0.000 description 1
- 190014017285 Satraplatin Chemical compound 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102100037628 Serine/threonine-protein kinase 3 Human genes 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 102100037310 Serine/threonine-protein kinase D1 Human genes 0.000 description 1
- 102100037703 Serine/threonine-protein kinase Nek2 Human genes 0.000 description 1
- 241000580858 Simian-Human immunodeficiency virus Species 0.000 description 1
- 241000700584 Simplexvirus Species 0.000 description 1
- 206010054184 Small intestine carcinoma Diseases 0.000 description 1
- OCOKWVBYZHBHLU-UHFFFAOYSA-N Sobuzoxane Chemical compound C1C(=O)N(COC(=O)OCC(C)C)C(=O)CN1CCN1CC(=O)N(COC(=O)OCC(C)C)C(=O)C1 OCOKWVBYZHBHLU-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- PFNFFQXMRSDOHW-UHFFFAOYSA-N Spermine Natural products NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 1
- UIRKNQLZZXALBI-MSVGPLKSSA-N Squalamine Chemical compound C([C@@H]1C[C@H]2O)[C@@H](NCCCNCCCCN)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@H](C(C)C)OS(O)(=O)=O)[C@@]2(C)CC1 UIRKNQLZZXALBI-MSVGPLKSSA-N 0.000 description 1
- UIRKNQLZZXALBI-UHFFFAOYSA-N Squalamine Natural products OC1CC2CC(NCCCNCCCCN)CCC2(C)C2C1C1CCC(C(C)CCC(C(C)C)OS(O)(=O)=O)C1(C)CC2 UIRKNQLZZXALBI-UHFFFAOYSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- NAVMQTYZDKMPEU-UHFFFAOYSA-N Targretin Chemical compound CC1=CC(C(CCC2(C)C)(C)C)=C2C=C1C(=C)C1=CC=C(C(O)=O)C=C1 NAVMQTYZDKMPEU-UHFFFAOYSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- SUJUHGSWHZTSEU-UHFFFAOYSA-N Tipranavir Natural products C1C(O)=C(C(CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)C(=O)OC1(CCC)CCC1=CC=CC=C1 SUJUHGSWHZTSEU-UHFFFAOYSA-N 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 206010062129 Tongue neoplasm Diseases 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 229940122618 Trypsin inhibitor Drugs 0.000 description 1
- 101710162629 Trypsin inhibitor Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000018594 Tumour necrosis factor Human genes 0.000 description 1
- 108050007852 Tumour necrosis factor Proteins 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 description 1
- 102000016663 Vascular Endothelial Growth Factor Receptor-3 Human genes 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 206010048218 Xeroderma Diseases 0.000 description 1
- NRUFLTXGIPFVSH-KBVRNWHJSA-N [(8r,9s,13s,14s,17s)-3-[bis(2-chloroethyl)carbamoyloxy]-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] (2s)-2-aminopropanoate Chemical compound C1CC2=CC(OC(=O)N(CCCl)CCCl)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)[C@@H](N)C)[C@@]1(C)CC2 NRUFLTXGIPFVSH-KBVRNWHJSA-N 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- CKXIPXAIFMTQCS-LRDUUELOSA-N [2-[(2s,4s)-4-[(2r,3r,4r,5s,6s)-3-fluoro-4,5-dihydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]-2-oxoethyl] 3-aminopropanoate 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)COC(=O)CCN)[C@@H]1O[C@@H](C)[C@@H](O)[C@@H](O)[C@H]1F CKXIPXAIFMTQCS-LRDUUELOSA-N 0.000 description 1
- YKNZTUQUXUXTLE-UHFFFAOYSA-N [3-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=CC=CC(C(F)(F)F)=C1 YKNZTUQUXUXTLE-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- QCLRUNIZLOTOPA-UHFFFAOYSA-N [Pt].CC1=NC=CC(Cl)=C1Cl Chemical compound [Pt].CC1=NC=CC(Cl)=C1Cl QCLRUNIZLOTOPA-UHFFFAOYSA-N 0.000 description 1
- IKWTVSLWAPBBKU-UHFFFAOYSA-N a1010_sial Chemical compound O=[As]O[As]=O IKWTVSLWAPBBKU-UHFFFAOYSA-N 0.000 description 1
- MCGSCOLBFJQGHM-SCZZXKLOSA-N abacavir Chemical compound C=12N=CN([C@H]3C=C[C@@H](CO)C3)C2=NC(N)=NC=1NC1CC1 MCGSCOLBFJQGHM-SCZZXKLOSA-N 0.000 description 1
- 229960004748 abacavir Drugs 0.000 description 1
- GZOSMCIZMLWJML-VJLLXTKPSA-N abiraterone Chemical compound C([C@H]1[C@H]2[C@@H]([C@]3(CC[C@H](O)CC3=CC2)C)CC[C@@]11C)C=C1C1=CC=CN=C1 GZOSMCIZMLWJML-VJLLXTKPSA-N 0.000 description 1
- 229960000853 abiraterone Drugs 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229940091179 aconitate Drugs 0.000 description 1
- GTZCVFVGUGFEME-UHFFFAOYSA-N aconitic acid Chemical compound OC(=O)CC(C(O)=O)=CC(O)=O GTZCVFVGUGFEME-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000012382 advanced drug delivery Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 229950005033 alanosine Drugs 0.000 description 1
- 229950009009 alestramustine Drugs 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000005089 alkenylaminocarbonyl group Chemical group 0.000 description 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 125000005088 alkynylcarbonylamino 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
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000005001 aminoaryl group Chemical group 0.000 description 1
- 125000006598 aminocarbonylamino group Chemical group 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- LNTHITQWFMADLM-UHFFFAOYSA-N anhydrous gallic acid Natural products OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 1
- CIDNKDMVSINJCG-GKXONYSUSA-N annamycin Chemical compound I[C@@H]1[C@H](O)[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(=O)CO)C1 CIDNKDMVSINJCG-GKXONYSUSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- RHJPBGWFGOAEID-UHFFFAOYSA-N aplysiatoxin Natural products O1C2(OC(O)(CC(=O)OC(CC(=O)O3)C(C)O)C(C)CC2(C)C)CC3C(C)C1C(C)CCC(OC)C1=CC(O)=CC=C1Br RHJPBGWFGOAEID-UHFFFAOYSA-N 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 210000000576 arachnoid Anatomy 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 229960002594 arsenic trioxide Drugs 0.000 description 1
- GOLCXWYRSKYTSP-UHFFFAOYSA-N arsenic trioxide Inorganic materials O1[As]2O[As]1O2 GOLCXWYRSKYTSP-UHFFFAOYSA-N 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000005129 aryl carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- MCGDSOGUHLTADD-UHFFFAOYSA-N arzoxifene Chemical compound C1=CC(OC)=CC=C1C1=C(OC=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 MCGDSOGUHLTADD-UHFFFAOYSA-N 0.000 description 1
- 125000003289 ascorbyl group Chemical class [H]O[C@@]([H])(C([H])([H])O*)[C@@]1([H])OC(=O)C(O*)=C1O* 0.000 description 1
- FZCSTZYAHCUGEM-UHFFFAOYSA-N aspergillomarasmine B Natural products OC(=O)CNC(C(O)=O)CNC(C(O)=O)CC(O)=O FZCSTZYAHCUGEM-UHFFFAOYSA-N 0.000 description 1
- 229940091771 aspergillus fumigatus Drugs 0.000 description 1
- TWHSQQYCDVSBRK-UHFFFAOYSA-N asulacrine Chemical compound C12=CC=CC(C)=C2N=C2C(C(=O)NC)=CC=CC2=C1NC1=CC=C(NS(C)(=O)=O)C=C1OC TWHSQQYCDVSBRK-UHFFFAOYSA-N 0.000 description 1
- 229950011088 asulacrine Drugs 0.000 description 1
- AXRYRYVKAWYZBR-GASGPIRDSA-N atazanavir Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)[C@@H](O)CN(CC=1C=CC(=CC=1)C=1N=CC=CC=1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)C1=CC=CC=C1 AXRYRYVKAWYZBR-GASGPIRDSA-N 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 108010044540 auristatin Proteins 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
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 description 1
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 1
- 239000012964 benzotriazole Substances 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- 229940000635 beta-alanine Drugs 0.000 description 1
- 229960002938 bexarotene Drugs 0.000 description 1
- 229960000997 bicalutamide Drugs 0.000 description 1
- 208000026900 bile duct neoplasm Diseases 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- UBJAHGAUPNGZFF-XOVTVWCYSA-N bms-184476 Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3C[C@@H]([C@]2(C(=O)[C@H](OC(C)=O)C2=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)C=3C=CC=CC=3)C=3C=CC=CC=3)C[C@]1(O)C2(C)C)C)OCSC)C(=O)C1=CC=CC=C1 UBJAHGAUPNGZFF-XOVTVWCYSA-N 0.000 description 1
- GMJWGJSDPOAZTP-MIDYMNAOSA-N bms-188797 Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](OC(C)=O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)C=4C=CC=CC=4)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)OC)C(=O)C1=CC=CC=C1 GMJWGJSDPOAZTP-MIDYMNAOSA-N 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229960004117 capecitabine Drugs 0.000 description 1
- 235000013736 caramel Nutrition 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 229960004562 carboplatin Drugs 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 229920003064 carboxyethyl cellulose Polymers 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- XREUEWVEMYWFFA-UHFFFAOYSA-N carminomycin I Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=C(O)C=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XREUEWVEMYWFFA-UHFFFAOYSA-N 0.000 description 1
- 229950001725 carubicin Drugs 0.000 description 1
- SVURIXNDRWRAFU-OGMFBOKVSA-N cedrol Chemical compound C1[C@]23[C@H](C)CC[C@H]3C(C)(C)[C@@H]1[C@@](O)(C)CC2 SVURIXNDRWRAFU-OGMFBOKVSA-N 0.000 description 1
- 229940026455 cedrol Drugs 0.000 description 1
- PCROEXHGMUJCDB-UHFFFAOYSA-N cedrol Natural products CC1CCC2C(C)(C)C3CC(C)(O)CC12C3 PCROEXHGMUJCDB-UHFFFAOYSA-N 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 201000007455 central nervous system cancer Diseases 0.000 description 1
- 229960005110 cerivastatin Drugs 0.000 description 1
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- RHJPBGWFGOAEID-BEDNPZBZSA-N chembl1256416 Chemical compound C1([C@H](CC[C@H](C)[C@@H]2[C@H]([C@@H]3C[C@@]4(O[C@@](O)(CC(=O)O[C@H](CC(=O)O3)[C@@H](C)O)[C@H](C)CC4(C)C)O2)C)OC)=CC(O)=CC=C1Br RHJPBGWFGOAEID-BEDNPZBZSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 208000037893 chronic inflammatory disorder Diseases 0.000 description 1
- 229940114081 cinnamate Drugs 0.000 description 1
- NQBWNECTZUOWID-QSYVVUFSSA-N cinnamyl cinnamate Chemical compound C=1C=CC=CC=1\C=C/C(=O)OC\C=C\C1=CC=CC=C1 NQBWNECTZUOWID-QSYVVUFSSA-N 0.000 description 1
- 125000000259 cinnolinyl group Chemical class N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- GTZCVFVGUGFEME-IWQZZHSRSA-N cis-aconitic acid Chemical compound OC(=O)C\C(C(O)=O)=C\C(O)=O GTZCVFVGUGFEME-IWQZZHSRSA-N 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 230000003750 conditioning effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- POADTFBBIXOWFJ-VWLOTQADSA-N cositecan Chemical compound C1=CC=C2C(CC[Si](C)(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 POADTFBBIXOWFJ-VWLOTQADSA-N 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 229960001305 cysteine hydrochloride Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- 229960003603 decitabine Drugs 0.000 description 1
- 125000005070 decynyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C#C* 0.000 description 1
- 229950004239 defosfamide Drugs 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 229920006237 degradable polymer Polymers 0.000 description 1
- 229960005319 delavirdine Drugs 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000002781 deodorant agent Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 229950007457 dibrospidium chloride Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- LFQCJSBXBZRMTN-OAQYLSRUSA-N diflomotecan Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC(F)=C(F)C=C3N=C21 LFQCJSBXBZRMTN-OAQYLSRUSA-N 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 125000005594 diketone group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N dimethyl butane Natural products CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- MMXKVMNBHPAILY-UHFFFAOYSA-N dodecanoic acid ethyl ester Natural products CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 1
- AMRJKAQTDDKMCE-UHFFFAOYSA-N dolastatin Chemical compound CC(C)C(N(C)C)C(=O)NC(C(C)C)C(=O)N(C)C(C(C)C)C(OC)CC(=O)N1CCCC1C(OC)C(C)C(=O)NC(C=1SC=CN=1)CC1=CC=CC=C1 AMRJKAQTDDKMCE-UHFFFAOYSA-N 0.000 description 1
- 229930188854 dolastatin Natural products 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- ZWAOHEXOSAUJHY-ZIYNGMLESA-N doxifluridine Chemical compound O[C@@H]1[C@H](O)[C@@H](C)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ZWAOHEXOSAUJHY-ZIYNGMLESA-N 0.000 description 1
- 229950005454 doxifluridine Drugs 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 238000013399 early diagnosis Methods 0.000 description 1
- XPOQHMRABVBWPR-ZDUSSCGKSA-N efavirenz Chemical compound C([C@]1(C2=CC(Cl)=CC=C2NC(=O)O1)C(F)(F)F)#CC1CC1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
- 229960003804 efavirenz Drugs 0.000 description 1
- 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 229950005450 emitefur Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229950011487 enocitabine Drugs 0.000 description 1
- NJCUSQKMYNTYOW-MWUYRYRWSA-N enramicina Chemical compound O.N1C(=O)NC(=O)C(C=2C=C(Cl)C(O)=C(Cl)C=2)NC(=O)C(CO)NC(=O)C(C=2C=CC(O)=CC=2)NC(=O)C(CC2N=C(N)NC2)NC(=O)C(CCCNC(N)=O)NC(=O)C(C(C)O)NC(=O)C(C=2C=CC(O)=CC=2)NC(=O)C(C=2C=CC(O)=CC=2)NC(=O)C(C(C)O)NC(=O)N(CCCCN)C(=O)C(C=2C=CC(O)=CC=2)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)/C=C/C=C/CCCCC(C)CC)C(C)OC(=O)C(C=2C=CC(O)=CC=2)NC(=O)C(C)NC(=O)C1CC1CNC(N)=N1 NJCUSQKMYNTYOW-MWUYRYRWSA-N 0.000 description 1
- 108700041171 enramycin Proteins 0.000 description 1
- 229950003984 enramycin Drugs 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 238000007046 ethoxylation reaction Methods 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- XXBDOTXPQDVHIP-JTQLQIEISA-N ethyl n-[(2s)-5-amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamate Chemical compound C=1([C@H](C)NC=2C=C(N=C(N)C=2N=1)NC(=O)OCC)C1=CC=CC=C1 XXBDOTXPQDVHIP-JTQLQIEISA-N 0.000 description 1
- JEFPWOBULVSOTM-PPHPATTJSA-N ethyl n-[(2s)-5-amino-2-methyl-3-phenyl-1,2-dihydropyrido[3,4-b]pyrazin-7-yl]carbamate;2-hydroxyethanesulfonic acid Chemical compound OCCS(O)(=O)=O.C=1([C@H](C)NC=2C=C(N=C(N)C=2N=1)NC(=O)OCC)C1=CC=CC=C1 JEFPWOBULVSOTM-PPHPATTJSA-N 0.000 description 1
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229960005420 etoposide Drugs 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
- 238000000605 extraction Methods 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 230000004992 fission Effects 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- MKXKFYHWDHIYRV-UHFFFAOYSA-N flutamide Chemical compound CC(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 MKXKFYHWDHIYRV-UHFFFAOYSA-N 0.000 description 1
- 229960002074 flutamide Drugs 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- CEVCTNCUIVEQOY-STXHBLNNSA-N fumagillol Chemical compound C([C@@H](O)[C@H](C1[C@]2(C)[C@H](O2)CC=C(C)C)OC)C[C@@]21CO2 CEVCTNCUIVEQOY-STXHBLNNSA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229940089256 fungistat Drugs 0.000 description 1
- 229950011325 galarubicin Drugs 0.000 description 1
- 229940074391 gallic acid Drugs 0.000 description 1
- 235000004515 gallic acid Nutrition 0.000 description 1
- 229950004410 galocitabine Drugs 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 229940014259 gelatin Drugs 0.000 description 1
- 235000003869 genetically modified organism Nutrition 0.000 description 1
- 125000002686 geranylgeranyl group Chemical group [H]C([*])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])/C([H])=C(C([H])([H])[H])/C([H])([H])C([H])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229950011595 glufosfamide Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-M glutaminate Chemical compound [O-]C(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-M 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000003163 gonadal steroid hormone Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 210000002768 hair cell Anatomy 0.000 description 1
- 230000012447 hatching Effects 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- YVXHZKKCZYLQOP-UHFFFAOYSA-N hept-1-yne Chemical compound CCCCCC#C YVXHZKKCZYLQOP-UHFFFAOYSA-N 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical compound CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229940088013 hycamtin Drugs 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000001261 hydroxy acids Chemical group 0.000 description 1
- SKOWZLGOFVSKLB-UHFFFAOYSA-N hypodiboric acid Chemical compound OB(O)B(O)O SKOWZLGOFVSKLB-UHFFFAOYSA-N 0.000 description 1
- 229960001680 ibuprofen Drugs 0.000 description 1
- 206010021198 ichthyosis Diseases 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 208000024364 idiopathic hypereosinophilic syndrome Diseases 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- DBIGHPPNXATHOF-UHFFFAOYSA-N improsulfan Chemical compound CS(=O)(=O)OCCCNCCCOS(C)(=O)=O DBIGHPPNXATHOF-UHFFFAOYSA-N 0.000 description 1
- 229950008097 improsulfan Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000007373 indentation Methods 0.000 description 1
- CBVCZFGXHXORBI-PXQQMZJSSA-N indinavir Chemical compound C([C@H](N(CC1)C[C@@H](O)C[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H]2C3=CC=CC=C3C[C@H]2O)C(=O)NC(C)(C)C)N1CC1=CC=CN=C1 CBVCZFGXHXORBI-PXQQMZJSSA-N 0.000 description 1
- 229960001936 indinavir Drugs 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000976 ink Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 239000000138 intercalating agent Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 201000002313 intestinal cancer Diseases 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- RGXCTRIQQODGIZ-UHFFFAOYSA-O isodesmosine Chemical compound OC(=O)C(N)CCCC[N+]1=CC(CCC(N)C(O)=O)=CC(CCC(N)C(O)=O)=C1CCCC(N)C(O)=O RGXCTRIQQODGIZ-UHFFFAOYSA-O 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
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 229960005280 isotretinoin Drugs 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- SVURIXNDRWRAFU-UHFFFAOYSA-N juniperanol Natural products C1C23C(C)CCC3C(C)(C)C1C(O)(C)CC2 SVURIXNDRWRAFU-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
- 208000003849 large cell carcinoma Diseases 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 201000006721 lip cancer Diseases 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229950000909 lometrexol Drugs 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- HWYHZTIRURJOHG-UHFFFAOYSA-N luminol Chemical compound O=C1NNC(=O)C2=C1C(N)=CC=C2 HWYHZTIRURJOHG-UHFFFAOYSA-N 0.000 description 1
- RVFGKBWWUQOIOU-NDEPHWFRSA-N lurtotecan Chemical compound O=C([C@]1(O)CC)OCC(C(N2CC3=4)=O)=C1C=C2C3=NC1=CC=2OCCOC=2C=C1C=4CN1CCN(C)CC1 RVFGKBWWUQOIOU-NDEPHWFRSA-N 0.000 description 1
- 229950002654 lurtotecan Drugs 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 150000002689 maleic acids Chemical class 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- GRWIABMEEKERFV-UHFFFAOYSA-N methanol;oxolane Chemical compound OC.C1CCOC1 GRWIABMEEKERFV-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- VFKZTMPDYBFSTM-GUCUJZIJSA-N mitolactol Chemical compound BrC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-GUCUJZIJSA-N 0.000 description 1
- 229950010913 mitolactol Drugs 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 229960001156 mitoxantrone Drugs 0.000 description 1
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 1
- 229950011535 mivobulin Drugs 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical group CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- TVYPSLDUBVTDIS-FUOMVGGVSA-N n-[1-[(2r,3r,4s,5r)-3,4-dihydroxy-5-methyloxolan-2-yl]-5-fluoro-2-oxopyrimidin-4-yl]-3,4,5-trimethoxybenzamide Chemical compound COC1=C(OC)C(OC)=CC(C(=O)NC=2C(=CN(C(=O)N=2)[C@H]2[C@@H]([C@H](O)[C@@H](C)O2)O)F)=C1 TVYPSLDUBVTDIS-FUOMVGGVSA-N 0.000 description 1
- NFVJNJQRWPQVOA-UHFFFAOYSA-N n-[2-chloro-5-(trifluoromethyl)phenyl]-2-[3-(4-ethyl-5-ethylsulfanyl-1,2,4-triazol-3-yl)piperidin-1-yl]acetamide Chemical compound CCN1C(SCC)=NN=C1C1CN(CC(=O)NC=2C(=CC=C(C=2)C(F)(F)F)Cl)CCC1 NFVJNJQRWPQVOA-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 229940086322 navelbine Drugs 0.000 description 1
- 229960000801 nelarabine Drugs 0.000 description 1
- IXOXBSCIXZEQEQ-UHTZMRCNSA-N nelarabine Chemical compound C1=NC=2C(OC)=NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1O IXOXBSCIXZEQEQ-UHTZMRCNSA-N 0.000 description 1
- NQHXCOAXSHGTIA-SKXNDZRYSA-N nelfinavir mesylate Chemical compound CS(O)(=O)=O.CC1=C(O)C=CC=C1C(=O)N[C@H]([C@H](O)CN1[C@@H](C[C@@H]2CCCC[C@@H]2C1)C(=O)NC(C)(C)C)CSC1=CC=CC=C1 NQHXCOAXSHGTIA-SKXNDZRYSA-N 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 206010061311 nervous system neoplasm Diseases 0.000 description 1
- 229960000689 nevirapine Drugs 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229920001220 nitrocellulos Polymers 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- OSSQSXOTMIGBCF-UHFFFAOYSA-N non-1-yne Chemical group CCCCCCCC#C OSSQSXOTMIGBCF-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000003287 optical effect Effects 0.000 description 1
- 201000005443 oral cavity cancer Diseases 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 239000011087 paperboard Substances 0.000 description 1
- 201000010198 papillary carcinoma Diseases 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 201000008006 pharynx cancer Diseases 0.000 description 1
- 125000005561 phenanthryl group Chemical group 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
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical compound O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 description 1
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000004437 phosphorous atom Chemical group 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N phthalic anhydride Chemical compound C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical class CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
- 239000002745 poly(ortho ester) Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000007639 printing Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002599 prostaglandin synthase inhibitor Substances 0.000 description 1
- 238000002731 protein assay Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000001185 psoriatic effect Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 229950007401 pumitepa Drugs 0.000 description 1
- 125000004309 pyranyl group Chemical class O1C(C=CC=C1)* 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 150000004492 retinoid derivatives Chemical class 0.000 description 1
- OWPCHSCAPHNHAV-LMONGJCWSA-N rhizoxin Chemical compound C/C([C@H](OC)[C@@H](C)[C@@H]1C[C@H](O)[C@]2(C)O[C@@H]2/C=C/[C@@H](C)[C@]2([H])OC(=O)C[C@@](C2)(C[C@@H]2O[C@H]2C(=O)O1)[H])=C\C=C\C(\C)=C\C1=COC(C)=N1 OWPCHSCAPHNHAV-LMONGJCWSA-N 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 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
- 229960000371 rofecoxib Drugs 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
- 239000012266 salt solution Substances 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229950010372 sobuzoxane Drugs 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 1
- NSFFYSQTVOCNLX-JKIHJDPOSA-M sodium;[(2r,3s,4s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl octadecyl phosphate;hydrate Chemical compound O.[Na+].O[C@H]1[C@H](O)[C@@H](COP([O-])(=O)OCCCCCCCCCCCCCCCCCC)O[C@H]1N1C(=O)N=C(N)C=C1 NSFFYSQTVOCNLX-JKIHJDPOSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229940075554 sorbate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 210000001562 sternum Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-FKSUSPILSA-N swainsonine Chemical compound C1CC[C@H](O)[C@H]2[C@H](O)[C@H](O)CN21 FXUAIOOAOAVCGD-FKSUSPILSA-N 0.000 description 1
- FXUAIOOAOAVCGD-UHFFFAOYSA-N swainsonine Natural products C1CCC(O)C2C(O)C(O)CN21 FXUAIOOAOAVCGD-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 229960003102 tasonermin Drugs 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- BEUUJDAEPJZWHM-COROXYKFSA-N tert-butyl n-[(2s,3s,5r)-3-hydroxy-6-[[(2s)-1-(2-methoxyethylamino)-3-methyl-1-oxobutan-2-yl]amino]-6-oxo-1-phenyl-5-[(2,3,4-trimethoxyphenyl)methyl]hexan-2-yl]carbamate Chemical compound C([C@@H]([C@@H](O)C[C@H](C(=O)N[C@H](C(=O)NCCOC)C(C)C)CC=1C(=C(OC)C(OC)=CC=1)OC)NC(=O)OC(C)(C)C)C1=CC=CC=C1 BEUUJDAEPJZWHM-COROXYKFSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010496 thistle oil Substances 0.000 description 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 201000006134 tongue cancer Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 description 1
- 229960000977 trabectedin Drugs 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- PQDJYEQOELDLCP-UHFFFAOYSA-N trimethylsilane Chemical compound C[SiH](C)C PQDJYEQOELDLCP-UHFFFAOYSA-N 0.000 description 1
- 229940094989 trimethylsilane Drugs 0.000 description 1
- NOYPYLRCIDNJJB-UHFFFAOYSA-N trimetrexate Chemical compound COC1=C(OC)C(OC)=CC(NCC=2C(=C3C(N)=NC(N)=NC3=CC=2)C)=C1 NOYPYLRCIDNJJB-UHFFFAOYSA-N 0.000 description 1
- 229960001099 trimetrexate Drugs 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- 229950010147 troxacitabine Drugs 0.000 description 1
- RXRGZNYSEHTMHC-BQBZGAKWSA-N troxacitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)OC1 RXRGZNYSEHTMHC-BQBZGAKWSA-N 0.000 description 1
- 239000002753 trypsin inhibitor Substances 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000010576 undifferentiated carcinoma Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- NMDYYWFGPIMTKO-HBVLKOHWSA-N vinflunine Chemical compound C([C@@](C1=C(C2=CC=CC=C2N1)C1)(C2=C(OC)C=C3N(C)[C@@H]4[C@@]5(C3=C2)CCN2CC=C[C@]([C@@H]52)([C@H]([C@]4(O)C(=O)OC)OC(C)=O)CC)C(=O)OC)[C@H]2C[C@@H](C(C)(F)F)CN1C2 NMDYYWFGPIMTKO-HBVLKOHWSA-N 0.000 description 1
- 229960000922 vinflunine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940023080 viracept Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 239000010497 wheat germ oil Substances 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 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 1
- 229960000641 zorubicin Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Virology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Endocrinology (AREA)
- AIDS & HIV (AREA)
- Communicable Diseases (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Physical Education & Sports Medicine (AREA)
- Molecular Biology (AREA)
- Reproductive Health (AREA)
- Pulmonology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
本申请涉及在癌症和相关搅拌的治疗中用作激酶-活性调节剂的取代的1H-吲唑化合物。
Description
相关的申请
本申请要求2010年3月10日提交的USSN 61/314,402的优先权利。该申请的内容通过参考结合于本文。
政府支持
本发明在国家自然科学基金会授予的拨款号# 074441-3和国立卫生研究院授予的R01拨款的政府支持下作出的。美国政府对本发明具有某些权利。
发明背景
依据由美国癌症协会收集的数据,2008年美国有超过143万人被诊断为癌症。虽然较早期诊断和改善的治疗已经使得五年生存率适度地提高,但自1950年来每100,000人总体死亡率仅下降5个百分点,原因是在相同期间的多种类型的癌症患病率增加(SEER Cancer Statistics Review
1975-2004, NCI "55-Year Trends in U.S. Cancer Death Rates")。
针对癌症细胞增殖和生存的机制的研究已经暗示蛋白激酶的失控。因此,包括使用小分子量药物调节或抑制激酶活性的方法,代表肿瘤药物开发有前途的方向。
从而,对抑制一个或多个蛋白激酶(kinases, kinses)活性的化合物仍存在着需求,因为可期望它们在癌症的治疗中是有用的。
发明简述
本发明提供化合物、包含这样的化合物的药用组合物和使用这样的化合物治疗或预防与异常的或失调的激酶活性相关的疾病或紊乱,特别是涉及Abl、BCR-Abl、EML4-ALK、TEL-ALK、Src或PDGFR激酶的异常激活的疾病或紊乱的方法。这样的疾病包括,例如癌症,如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病。
从而,在一个方面,本文提供式I化合物。在一个实施方案中,式I代表如式II。
在另一方面,本文提供治疗癌症的方法,该方法包括给予有需要的受试者式I化合物。所述癌症可选自腺癌、多发性骨髓瘤、慢性骨髓性白血病、胰腺癌、非小细胞肺癌、肺癌、乳腺癌、结肠癌、卵巢癌、前列腺癌、宫颈癌、子宫癌、恶性黑色素瘤、非黑色素瘤皮肤癌、胃肠型间质瘤、血液肿瘤、恶性血液病、儿童白血病、儿童淋巴瘤、何杰金氏病、淋巴细胞来源的淋巴瘤、源于皮肤的淋巴瘤、急性白血病、慢性白血病、急性成淋巴细胞白血病、急性髓细胞性白血病、慢性髓细胞性白血病、浆细胞性肿瘤、淋巴肿瘤和与AIDS相关的癌症。在另一个实施方案中,癌症是胰腺癌或非小细胞肺癌。在还一个实施方案中,癌症是胃肠型间质瘤或慢性骨髓性白血病。癌症可对用格列卫(Gleevec)或伊马替尼治疗产生抵抗,其中治疗抵抗可由于Abl激酶、BCR-Abl激酶域、c-kit激酶、EML4-ALK激酶、TEL-ALK激酶、Src激酶或PDGFR激酶中的一个或多个点-突变所致。
在另一个方面,本文提供式I化合物制备在受试者中治疗癌症的药物中的用途。
还在另一个方面,本文提供包括利用式I化合物的抑制激酶的活性的方法。在一个实施方案中,激酶选自Abl、Abl (T315I)、BCR-Abl、ALK、BLK、CDK5、CDK2、CDK3、CDK7、CDK8、CSFIR、EML4-ALK、FAK、FER、FLT1、FLT3、FLT4、HIPK4、JNK2、KDR、kit、LCK、p38、RET、RIPK1、SLK、TEL-ALK、TIE1、TNK1、TTK或Src,包括利用式I化合物。
在另一个方面,本文提供包括利用式I化合物抑制Abl激酶、BCR-Abl激酶、c-kit激酶、EML4-ALK激酶、TEL-ALK激酶、PDGFRA或PDGFRB激酶或Src激酶的活性的方法。在又一个实施方案中,本文提供在患者中治疗疾病的方法,其包括给予受试者式I化合物,其中疾病的病因学或进程至少部分由Abl激酶、BCR-Abl激酶、c-kit激酶、Src激酶、EML4-ALK激酶、TEL-ALK激酶或PDGFR激酶的活性介导。在又一个实施方案中,本文提供治疗癌症的方法,其包括联合药学上有效量的另外的抗癌剂给予有需要的受试者式I化合物。其他的抗癌剂可为伊马替尼或尼罗替尼。
发明详述
本发明的化合物
本发明涉及化合物、附随的中间体及其衍生物,以及含该化合物的、用于治疗蛋白激酶-相关的紊乱的药用组合物。本发明的化合物或其组合物被用作激酶c-Abl、c-kit、BCR-Abl、PDGFR、EML4-ALK、TEL-ALK、Src及其组合的抑制剂。此外,本发明的化合物或其组合物可被用于治疗癌症,如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病。本发明也涉及抑制细胞中蛋白激酶活性的方法或联合另外的抗癌剂使用本发明的化合物或药用组合物治疗、预防或缓解癌症的一个或多个症状的方法。
在一个方面,本发明提供式I化合物:
及其药学上可接受的盐、对映体、立体异构体、旋转异构体、互变异构体、非对映异构体或外消旋体,其中
X是NR、O、S或键;
其中R选自H和C1-6烷基;
R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基,
其中C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基可被杂环基或杂环基-C1-6烷基独立地取代一次或多次;
RA选自H、C1-6烷基、C1-6烷氧基和QR5,前提条件是RA的至少一个实例是QR5;
其中Q选自-C(O)-、-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-;
R5选自C1-6烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷基氧基、杂环基或苯基环;
其中C1-6烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷基氧基、杂环基或苯基环任选被下列基团独立地取代一次或多次:C1-6烷基、C2-6烯基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基;和
n选自1-5。
在式I的一个实施方案中,
X是NR、O、S或键;
其中R选自H和C1-6烷基;
R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基,
其中C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基可被杂环基或杂环基-C1-6烷基独立地取代一次或多次;
RA选自H、C1-6烷基、C1-6烷氧基和QR5,前提条件是RA的至少一个实例是QR5;
其中Q选自-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-;
R5是任选被下列基团独立地取代一次或多次的苯基环:C1-6烷基、C2-6烯基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基;和
n选自1-5。
在一个实施方案中,式I如式II代表的那样:
及其药学上可接受的盐、对映体、立体异构体、旋转异构体、互变异构体、非对映异构体或外消旋体,其中:
X是NR、O、S或键,
其中R选自H和C1-6烷基;
R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基;
其中苯基可被杂环基或杂环基-C1-6烷基独立地取代一次或多次;
R2选自H和C1-6烷基;和
R3和R4任选独立地选自H和QR5,前提条件是R3和R4的至少一个是QR5;
其中Q选自-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-;
R5是任选被下列基团独立地取代一次或多次的苯基环:H、C1-6烷基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基;
其中杂环基部分可被取代或未被取代。
在式I或II的另一个实施方案中,R1a是C(O)-苯基且该苯基未被取代。
在式II的一个实施方案中,R2选自H或C1-6烷基;R3和R4任选独立地选自H和QR5,前提条件是R3和R4的至少一个是QR5;其中Q选自-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-,而其中R5是任选被下列基团独立地取代一次或多次的苯基环:H、C1-6烷基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基,其中杂环基部分可被取代或未被取代。
在式II的另一个实施方案中,R5是:
;
其中R6、R7、R8和R9各自独立为H、C1-6烷基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基。
在式II的另一个实施方案中,R2是H或C1-6烷基。
在式II的另一个实施方案中,R3是H或QR5。
在式II的另一个实施方案中,R4是H或QR5。
在式II的另一个实施方案中,R6是H。
在式II的另一个实施方案中,R7是H、C1-6卤代烷基或杂芳基-C1-6烷基。
在式II的另一个实施方案中,R8是H或C1-6烷基-杂环基-C1-6烷基。
在式II的另一个实施方案中,R9是H、C1-6卤代烷基或杂芳基-C1-6烷基。
在式II的另一个实施方案中,X是NR、O、S或键,其中R选自H和C1-6烷基;R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基、C(O)-苯基和C(O)-苯基-哌嗪基-C1-6烷基;R2是H或C1-6烷基;R3是H或QR5;R4是H或QR5;其中R5是:
其中R6是H;R7选自H、C1-6三卤代烷基和杂环基-C1-6烷基;R8选自H和C1-6烷基-杂环基-C1-6烷基;而R9选自H、C1-6三卤代烷基和杂环基-C1-6烷基。
在式II的另一个实施方案中,X是NR、O、S或键;R是H;R1a是H、CH3、C(O)-环丙基、C(O)Ph或C(O)Ph-哌嗪基-CH3;R1b是H;R2是H或CH3;R3是H或C(O)N(H)-R5;R4是H或QR5;其中R5是:
其中R6是H;R7选自H、CF3和咪唑基-CH3;R8选自H、-CH2-哌嗪基-CH3和-CH2-哌嗪基-CH2CH3;而R9选自H、CF3和咪唑基-CH3。
在式II的另一个实施方案中,R8和R9各自独立为H、CF3、1-乙基-4-甲基哌嗪基或4-甲基-1H-咪唑基,即分别为
。
在式II的另一个实施方案中,X是NR。
在式II的另一个实施方案中,X是O。
在式II的另一个实施方案中,X是S。
在式II的另一个实施方案中,X是键。
在式II的另一个实施方案中,R1a选自H和C(O)-环丙基;R1b是H;R2选自H和C1-6烷基;R3和R4各自独立为H或QR5;前提条件是R3和R4的至少一个是H而另一个是QR5,其中R5是:
其中R6是H;R7是CF3;R8选自H和1-乙基-4-甲基哌嗪基;R9选自H和4-甲基-1H-咪唑基。
在式II的另一个实施方案中,R1a是C(O)-环丙基;R1b是H;R2是H;R3和R4各自独立为H或QR5,前提条件是R3和R4之一是H而另一个是QR5;其中R5是:
其中R6是H;R7是CF3;R8是H或1-乙基-4-甲基哌嗪基;R9是H或4-甲基-1H-咪唑基。
在式II的另一个实施方案中,R4是C(O)N(H)-R5;其中R5是
其中R8是1-乙基-4-甲基哌嗪基而R9是H;或R4是C(O)N(H)-R5;其中R5是:
其中R8是H而R9是4-甲基-1H-咪唑基;或R4是N(H)C(O)-R5;其中R5是:
其中R8是1-乙基-4-甲基哌嗪基而R9是H。
在另一个实施方案,式I或II化合物选自列于表A中的化合物。
优选的式I的实施方案(包括其药学上可接受的盐,以及其对映体、立体异构体、旋转异构体、互变异构体、非对映异构体、阻转异构体或外消旋体)示于下表A中并且也被认为是“本发明的化合物”。本发明的化合物在本文也被称作“蛋白激酶抑制剂”。
表A
治疗方法
本发明的化合物在治疗蛋白激酶-相关的紊乱中是有用的。
如在本文中使用的,术语“蛋白激酶-相关的紊乱”包括与蛋白激酶的活性相关的紊乱和状态(如,疾病状态)。蛋白激酶-相关的紊乱的非限制性实例包括异常细胞增殖,包括蛋白激酶-相关的癌症、病毒感染、真菌感染、自身免疫性疾病和神经退行性紊乱。
蛋白-激酶相关的紊乱的非限制性实例包括增殖性疾病,诸如病毒感染、自身免疫疾病、真菌疾病、癌症、银屑病、与动脉粥样硬化相关的血管平滑肌细胞增殖、肺纤维化、关节炎、肾小球肾炎、慢性炎症、神经退行性紊乱,诸如阿尔茨海默氏(Alzheimer's)病和手术后狭窄和再狭窄。蛋白激酶-相关的紊乱也包括与细胞异常增殖相关的疾病,所述疾病包括,但不限于头和颈癌、乳腺癌、卵巢癌、子宫颈癌、前列腺癌、睾丸癌、食道癌、胃癌、皮肤癌、肺癌、骨癌、结肠癌、胰腺癌、甲状腺癌、胆道癌、口腔和咽癌(口腔)、喉癌、唇癌、舌癌、口癌、小肠癌、结肠-直肠癌、大肠癌、直肠癌、前列腺癌、脑癌和中枢神经系统癌、胶质母细胞瘤、神经母细胞瘤、角化棘皮瘤、表皮样癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化癌、乳头状癌、精原细胞瘤、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、髓系紊乱、淋巴紊乱、何杰金氏氏(Hodgkin's)病、毛细胞癌和白血病。
蛋白激酶-相关的紊乱也包括与细胞凋亡相关的疾病,包括,但不限于癌症、病毒感染、自身免疫疾病和神经退行性紊乱。
蛋白激酶-相关的癌症的实例包括癌症、淋巴系的造血系统肿瘤、髓系的造血系统肿瘤、间叶细胞来源的肿瘤、中枢和外周神经系统肿瘤、黑色素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病、角化棘皮瘤、滤泡状甲状腺癌和卡波济氏(Kaposi's)肉瘤。
另外,蛋白-激酶相关的紊乱的非限制性实例包括肿瘤血管新生和转移。蛋白-激酶相关的紊乱的非限制性实例也包括与动脉粥样硬化相关的血管平滑肌细胞增殖、手术后血管狭窄和再狭窄和子宫内膜异位症。
蛋白-激酶相关的紊乱的非限制性实例包括在需要的患者中的病毒感染,其中病毒的感染包括,但不限于HIV、人类乳头瘤病毒、疱疹病毒、痘病毒(poxyirus)、爱泼斯坦-巴尔病毒(Epstein-Barr virus)、辛德毕斯病毒和腺病毒。
蛋白-激酶相关的紊乱的更多的非限制性实例包括那些与感染源相关的紊乱,所述感染源包括酵母、真菌、原生动物寄生虫,诸如恶性疟原虫(Plasitiodium
falciparum)和DNA和RNA病毒。
本发明的化合物对癌症的治疗是有用的,其中癌症选自多发性骨髓瘤、慢性骨髓性白血病、胰腺癌、非小细胞肺癌、肺癌、乳腺癌、结肠癌、卵巢癌、前列腺癌、恶性黑色素瘤、非黑色素瘤皮肤癌、胃肠型间质瘤、血液肿瘤、恶性血液病、儿童白血病、儿童淋巴瘤、多发性骨髓瘤、何杰金氏病、淋巴细胞来源的淋巴瘤、源于皮肤的淋巴瘤、急性白血病、慢性白血病、急性成淋巴细胞白血病、急性髓细胞性白血病、慢性髓细胞性白血病、浆细胞性肿瘤、淋巴肿瘤和与AIDS相关的癌症。
在另一个实施方案,本发明的化合物对蛋白激酶活性的调节是有用的,所述蛋白激酶包括,但不限于,选自以下的蛋白激酶:Abl、ATK、BCR-Abl、Blk、Brk、Btk、BRAF、c-fms、e-kit、c-met、c-src、CDK、cRafl、CSFIR、CSK、EGFR、EML4-ALK、ErbB2、ErbB3、ErbB4、ERK、DDR-1、Fak、fes、FGFRI、FGFR2、FGFR3、FGFR4、FGFR5、Fgr、FLK-4、fit-1、flt-3、flt-4、Fps、Frk、Fyn、GSK、Gst-Flkl、Hck、Her-2、Her-4、HIPK-1、IGF-1R、INS-R、Jak、JNK、KDR、Lck、LOK、Lyn、MEK、p38、panHER、PDGFR、PLK、PKC、PYK2、Raf、Rho、ros、SRC、TEL-ALK、TRK、TYK2、UL97、VEGFR、Yes、Zap70、Aurora-A、GSK3-α、HIPK1、HIPK2、HIP3、IRAK1、JNK1、JNK2、JNK3、TRKB、CAMKII、CK1、CK2、RAF、GSK3β、MAPK1、MKK4、MKK7、MST2、NEK2、AAK1、PKCα、PKD、RET、RIPK2、ROCK-II和TIE2。
如在本文中使用的,术语“调制”或“调节”指的是改变蛋白激酶的催化活性。具体地,调节指的是激活蛋白激酶的催化活性,优选激活或抑制蛋白激酶的催化活性,这取决于暴露于蛋白激酶的化合物或盐的浓度,或者更优选地,抑制蛋白激酶的催化活性。如在本文使用的,术语“催化活性”指的是在蛋白激酶的直接或间接的影响下,络氨酸、丝氨酸或苏氨酸的磷酸化率。
激酶活性的药理学上的抑制剂被分类成的三个主要类型,它们是(1) I型或“DFG-in”ATP竞争性抑制剂,其在ATP结合位点(即双重Src (dual Src)与ATP直接竞争,ABL抑制剂达沙替尼,(2) II型或“DFG-out”ATP竞争性抑制剂,其除了结合ATP结合位点外,还接合至当该激酶处于不被激活构型时仅易接近的邻近的疏水结合位点(即激活环路导向将阻断底物结合的构象) (即伊马替尼、尼罗替尼)和(3) 在影响激酶(即GNF-2)的活性的ATP结合位点外的位点结合的非-ATP竞争性抑制剂。
第二代Abl抑制剂,诸如达沙替尼和尼罗替尼具有对抗耐伊马替尼的白血病的高度活性。两种药物均比伊马替尼显著更有效地对抗Bcr-Abl,并且有效对抗许多耐伊马替尼的Bcr-Abl突变体。然而,两个药物任一种均不可能克服伊马替尼抵抗,原因是在苏氨酸至异亮氨酸的残基315
(T315I,“看门者(gatekeeper)”位置)的突变。此非常普遍发生的和高度耐伊马替尼突变集中位于Abl的核苷结合槽(binding cleft)。达沙替尼和尼罗替尼两者均对T315的侧链羟基产生氢键相互作用,该作用对这些化合物抵抗,原因是异丁基侧链的直接空间位阻干扰(steric
intrusion)和氢键相互作用的ATP-槽(cleft)的中部丢失。
除了BCR-Abl T315I之外,在耐伊马替尼疾病中起完整作用的其他看门者残基包括c-kit-T6701,其与耐伊马替尼的胃肠型间质瘤相关联,该肿瘤以早期转移和更短进展-无存活为特征;该突变实质上修饰c-Kit的结合袋(binding pocket)和仅在伊马替尼疗法、PDGFRA-T674
M/I和PDGFRB-T681 M/I的选择性的压力出现,PDGFRA-T674M/I在FIP1
LI-PDGFRA激酶域发现和在特发性嗜酸粒细胞增多综合征(HES)中引起伊马替尼抵抗。
本发明的化合物是II型类别激酶抑制剂,以适应多种尺寸的氨基酸侧链的方式横贯(traverse)看门者位置。
以上所列的蛋白激酶可展示出一个或多个点突变,包括,但不限于铰链区突变、P-环路突变和A-环路突变。
在优选的实施方案中,蛋白激酶选自突变或非-突变的Abl、突变或非-突变的c-kit、突变或非-突变的BCR-Abl、突变或非-突变的PDGFR、突变或非-突变的Src及其任何组合。在特别优选的实施方案中,蛋白激酶选自突变或非-突变的c-kit、突变或非-突变的BCR-Abl、突变或非-突变的PDGFR、突变或非-突变的Src、突变或非-突变的TEL-ALK和突变或非-突变的EML4-ALK。
在一个实施方案中,本发明的化合物的特征为蛋白激酶,如,BCR-Abl和/或c-kit和/或PDGFR的组合的抑制剂。
在某些实施方案中,本发明的化合物用于蛋白激酶-相关疾病和/或用作任何一个或多个蛋白激酶的抑制剂。可以预见,应用可包括抑制蛋白激酶的一个或多个同工型(isoforms)。
治疗用激酶抑制剂,诸如伊马替尼、达沙替尼和尼罗替尼的功效典型地与它们的对一个或多个激酶靶标的亲和力相关,所述激酶靶标与特定的疾病状态相关联。可在自然或化学疗法的选择性压力下发生的点-突变,可降低化学疗法对其激酶靶标的亲和力,因此赋予对这些疗法的抵抗。
本发明的化合物也是激酶Abl、BCR-Abl、c-kit、PDGFR、EML4-ALK、TEL-ALK或Src的突变或非-突变形式的抑制剂,所述酶暗示涉及癌症,如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病的某些疾病状态。BCR-Abl激活许多细胞周期控制蛋白和酶,加速细胞分裂和抑制DNA修复,因而导致基因组不稳定性和潜在地在CML中爆炸危机。在大多数胃肠型间质瘤中观察到c-kit的异常激活,而PDGFR的效应包括细胞增殖和血管生成。
不受理论的束缚,相信激酶Abl、BCR-Abl、c-kit、PDGFR、EML4-ALK、TEL-ALK和Src的抑制将促进细胞凋亡,抑制癌症细胞增殖和抑制肿瘤生长。
本发明也包括治疗癌症的一个或多个症状,所述癌症为例如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病,以及蛋白激酶-相关的紊乱,诸如那些在以上描述的癌症,但是本发明并不意欲受限于化合物实施其治疗疾病的计划功能的方式。本发明包括以使产生治疗的任何方式治疗本文描述的疾病。
在某些实施方案中,本发明的化合物单独或联合其他治疗剂,如伊马替尼、尼罗替尼或达沙替尼应用。
在另一个实施方案中,本发明提供任何的本发明的化合物的药用组合物。在相关的实施方案中,本发明提供任何的本发明的化合物和药学上可接受的载体或赋形剂的药用组合物。在某些实施方案中,本发明包括作为新的化合物实体的化合物。
在其他实施方案中,本发明提供抑制蛋白激酶的活性的方法。该方法包括使细胞与任何的本发明的化合物接触。在相关的实施方案中,该方法进一步提供的是,本化合物以有效选择性地抑制蛋白激酶的活性的量存在。
再者,本发明的方法包括给予受试者有效量的调节蛋白激酶的本发明的化合物,如,调节蛋白激酶的式I化合物,以及表A中的化合物(包括其药学上可接受的盐,以及其对映体、立体异构体、旋转异构体、互变异构体、非对映异构体、阻转异构体或外消旋体)。
在其他实施方案中,本发明提供任何的本发明的化合物对制备治疗癌症的药物中的应用。
在其他实施方案中,本发明提供制备药物的方法,该方法包括为治疗受试者配制任何的本发明的化合物。
本文提供的一个实施方案是治疗胰腺癌的方法,该方法包括给予有需要的受试者化合物6,以便治疗胰腺癌。
本文提供的另一个实施方案是治疗非小细胞肺癌的方法,该方法包括给予有需要的受试者化合物6,以便治疗非小细胞肺癌。
本文提供的再一个实施方案是治疗胃肠型间质瘤的方法,该方法包括给予有需要的受试者化合物6,这样治疗胃肠型间质瘤。
本文提供的又一个实施方案是治疗慢性骨髓性白血病的方法,该方法包括给予有需要的受试者化合物6,这样治疗慢性骨髓性白血病。
本文提供的一个其他的实施方案是治疗胰腺癌的方法,该方法包括给予有需要的受试者化合物19,这样治疗胰腺癌。
本文提供的另一个实施方案是是治疗非小细胞肺癌的方法,该方法包括给予有需要的受试者化合物19,这样治疗非小细胞肺癌。
本文提供的再一个实施方案是治疗胃肠型间质瘤的方法,该方法包括给予有需要的受试者化合物19,这样治疗胃肠型间质瘤。
在还一个实施方案中,本文提供的实施方案是治疗慢性骨髓性白血病的方法,该方法包括给予有需要的受试者化合物19,这样治疗慢性骨髓性白血病。
本文提供的一个实施方案是化合物6在制备用于在需要的受试者中治疗胰腺癌的药物中的应用。
在另一个实施方案中,本文提供化合物6在制备用于在需要的受试者中治疗非小细胞肺癌的药物中的应用。
在又一个实施方案中,本文提供化合物6对于制备用于在需要的受试者中治疗胃肠型间质瘤的药剂的应用。
在再一个实施方案中,本文提供化合物6对于制备用于在需要的受试者中治疗慢性骨髓性白血病的药剂的应用。
本文提供的一个其他的实施方案是化合物19对于制备用于在需要的受试者中治疗胰腺癌的药剂的应用。
在另一个实施方案中,本文提供化合物19对于制备用于在需要的受试者中治疗非小细胞肺癌的药剂的应用。
在又一个实施方案中,本文提供化合物19对于制备用于在需要的受试者中治疗胃肠型间质瘤的药剂的应用。
在还一个实施方案中,本文提供化合物19对于制备用于在需要的受试者中治疗慢性骨髓性白血病的药剂的应用。
定义
术语“治疗”、“被治疗的”、“治疗中的”或“处理”包括减少或缓解与被治疗的状态、紊乱或疾病相关的或由它们引起的至少一个症状。在某些实施方案中,治疗包括在本发明的化合物的激活之后的蛋白激酶-相关的紊乱的减少,其转而减少或缓解与被治疗的蛋白激酶-相关的紊乱相关的或由它们引起的至少一个症状。例如,治疗可为一个活数个紊乱的症状的减少或紊乱的完全消除。
如果没有另行说明,适当和适宜的是,术语“应用”分别包括以下的本发明的实施方案中的任何一个或多个:在蛋白激酶-相关的紊乱的治疗中的应用;用于在这些疾病的治疗中的药用组合物的制备,如,在药剂的制备中的应用;本发明的化合物在这些疾病的治疗中的使用方法;具有本发明的化合物的、用于这些疾病的治疗的药用制剂;和用于这些疾病的治疗的本发明的化合物。特别是,需要治疗并因而优选使用本发明的化合物的疾病选自癌症,如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病或炎症、心肌肥大和HIV感染,以及那些依赖于蛋白激酶活性的疾病。术语“应用”还包括本文的组合物的实施方案,将它们充分结合至蛋白激酶以用作示踪物或标记物,这样,当偶联至荧光或标签或被制成放射性时,可用作研究试剂或作为诊断或成像剂。
术语“受试者”意欲包括有机物,如,原核生物和真核生物,它们可能罹患或患有与蛋白激酶的活性相关的疾病、紊乱或病症或遭受其侵害。所述受试者的实例包括哺乳动物,如,人类、犬、牛、马、猪、绵羊、山羊、猫、小鼠、兔、大鼠和转基因非-人动物。在某些实施方案中,受试者是人,如,罹患癌症、处于罹患癌症风险或潜在地可能罹患癌症的人,所述癌症为例如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病或炎症、心肌肥大和HIV感染和本文描述的其他疾病或病症(如蛋白激酶-相关的紊乱)。在另一个实施方案中,受试者是细胞。
语言“调节蛋白激酶的化合物”、“蛋白激酶的调节剂”或“蛋白激酶的抑制剂”指的是调节,如抑制或以其他方式改变蛋白激酶的活性的化合物。调节蛋白激酶的化合物的实例包括本发明的化合物,即,式I,以及表A的化合物(包括其药学上可接受的盐,及其对映体、立体异构体、旋转异构体、互变异构体、非对映异构体、阻转异构体或外消旋体)。
如在本文中使用的,术语“烷基”指的是完全饱和的支链或非支链烃部分。优选烷基包括1-20个碳原子,更优选1-16个碳原子、1-10个碳原子、1-7个碳原子或1-4个碳原子。烷基的代表性实例包括,但不限于甲基、乙基、正-丙基、异-丙基、正-丁基、仲-丁基、异-丁基、叔-丁基、正-戊基、异戊基、新戊基、正-己基、3-甲基己基、2,2-二甲基戊基、2,3-二甲基戊基、正-庚基、正-辛基、正-壬基、正-癸基等。此外,表达“Cx-Cy-烷基”,其中x是1-5和y是2-10,指特定范围的碳的具体的烷基(直链或支链)。例如,表达C1-C4-烷基包括,但不限于甲基、乙基、丙基、丁基、异丙基、叔-丁基和异丁基。
术语“烯基”,单独或组合,指的是由至少一个烯键和指定数量的碳原子组成的直链、环状或支链烃残基。优选的烯基具有最多至8个,优选最多至6个,特别优选最多至4个碳原子。烯基的实例为乙烯基、1-丙烯基、2-丙烯基、异丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、异丁烯基、1-环己烯基、1-环戊烯基。
术语“炔基”包括在长度上类似于以上描述的烷基但含有至少一个叁键的不饱和的脂族基团。
例如,术语“炔基”包括直链炔基(如,乙炔基、丙炔基、丁炔基、戊炔基、己炔基、庚炔基、辛炔基、壬炔基、癸炔基等)、支链炔基和环烷基或环烯基取代的炔基。术语炔基还包括包含置换烃骨架中的一个或多个碳的氧、氮、硫或磷原子的炔基。在某些实施方案中,直链或支链炔基在其骨架中具有6个或更少的碳原子(如对于直链C2-C6,对于支链C3-C6)。术语C2-C6包括含2-6个碳原子的炔基。
如在本文中使用的,术语“环烷基”指的是3-12个碳原子,优选3-9或3-7个碳原子的、饱和或不饱和的单环、双环或三环烃基。作为例证的单环烃基包括,但不限于环丙基、环丁基、环戊基、环戊烯基、环己基和环己烯基等。作为例证的双环烃基包括冰片基、吲哚基(indyl)、六氢吲哚基(hexahydroindyl)、四氢萘基、十氢萘基、双环[2.1.1]己基、双环[2.2.1]庚基、双环[2.2.1]庚烯基、6,6-二甲基双环[3.1.1]庚基、2,6,6-三甲基双环[3.1.1]庚基、双环[2.2.2]辛基等。作为例证的三环烃基包括金刚烷基等。
术语“环烯基”指的是含1-3个环且每个环有4-8个碳的、部分不饱和的环状烃基。作为例证的基团包括环丁烯基、环戊烯基和环己烯基。术语“环烯基”也包括双环和三环基团,其中至少一个环是部分不饱和的含碳环,而第二个和第三个环可为碳环或杂环,前提条件是连接点是环烯基。
“烷氧基”指的是那些经由氧原子连接至分子的其余部分的、具有1-10个碳原子的烷基。优选具有1-8个碳原子的烷氧基。烷氧基的烷基部分可为线性的、环状的或支链的,或其组合。烷氧基的实例包括甲氧基、乙氧基、异丙氧基、丁氧基、环戊基氧基等。烷氧基也可由下式代表:-ORi,这里Ri是烷氧基的“烷基部分”。
术语“杂烷基”,就其自身或联合另一个术语,除非另行说明,意指由指定数量的碳原子和选自O、N、Si和S的1-5杂原子,更优选1-3个杂原子组成的稳定的直链或支链,或其组合,其中氮和硫原子可任选被氧化和氮杂原子可任选被季化。杂烷基通过碳原子或杂原子连接至分子的其余部分。
术语“烷基羰基”指的是具有式-C(O)-Rii的基团,其中Rii是如上定义的烷基,且其中碳原子的总数量指的是合并的烷基和羰基部分。“烷基羰基”基团可经由烷基连接至分子的其余部分(即,-烷基-C(O)-Rii)。
术语“烷氧基羰基”指的是具有式-C(O)O-Riii的基团,其中Riii是如上定义的烷基,且其中碳原子的总数量指的是合并的烷基和羰基部分。“烷基氧羰基”基团可经由烷基连接至分子的其余部分(即,-烷基-C(O)O-Riii)。
术语“杂烷基羰基”指的是具有式-C(O)Riv的基团,其中Riv是如上定义的杂烷基,且其中碳原子的总数量指的是合并的烷基和羰基部分。“杂烷基羰基”基团可经由烷基或杂烷基连接至分子的其余部分(即,-烷基-C(O)O-Riv或-杂烷基-C(O)O-Riv)。
术语“芳基”包括仅由氢和碳且含从六至十九个碳原子或六至十个碳原子组成的芳族单环或多环,如,三环、双环、烃环系统,此处的环系统可为部分饱和的。芳基包括,但不限于基团诸如苯基、甲苯基、二甲苯基、蒽基、萘基和菲基。芳基也可与脂环或杂环稠合或桥接,所述脂环烃环或杂环不是芳族的,这样形成多环(polycycle)
(如,四氢萘)。
如在本文使用的,术语“杂芳基”代表各环最多至7个原子的、稳定的单环或双环,其中至少一个环是芳族的且含1-4个选自O、N和S的杂原子。纳入本定义的杂芳基包括,但不限于:吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。如按以下的杂环的定义,“杂芳基”也被理解包括任何含氮杂芳基的N-氧化物衍生物。在杂芳基取代基是双环且一个环是非-芳族的或不含杂原子的情况下,应该理解的是分别经由芳环或经由含杂原子的环连接。
术语“杂环”或“杂环基”指的是含至少一个杂原子,诸如O、S或N的五元至十元完全饱和的或部分不饱和的非芳族杂环基团。最频繁的实例是哌啶基、吗啉基、哌嗪基、吡咯烷基或吡嗪基。杂环基取代基的连接可经由碳原子或经由杂原子发生。
此外,以上描述的烷基、烯基、环烷基、环烯基、烷氧基、芳基、杂芳基和杂环基可“未被取代”或“被取代”。术语“被取代”意欲描述具有替换分子的一个或多个原子,如C、O或N上的氢的取代基的部分。这样的取代基可独立包括,例如以下的一个或多个:直链或支链烷基(优选C1-C5)、环烷基(优选C3-C8)、烷氧基(优选C1-C6)、硫代烷基(优选C1-C6)、烯基(优选C2-C6)、炔基(优选C2-C6)、杂环基、碳环基、芳基(如,苯基)、芳基氧基(如,苯氧基)、芳烷基(如,苄基)、芳基氧基烷基(如,苯基氧基烷基)、芳基乙酰胺基、烷基芳基、杂芳烷基、烷基羰基和芳基羰基或其他这样的酰基、杂芳基羰基或杂芳基、(CR'R")0-3NR'R"
(如,-NH2)、(CR'R")0-3CN (如,-CN)、-NO2、卤素(如,-F、-Cl、-Br或-I)、(CR'R")0-3CH(卤素)3 (如,-CF3)、(CR'R")0-3C(卤素)2、(CR'R")0-3CH2(卤素)、(CR'R")0-3CONR'R"、(CR'R")0-3(CNH)NR'R"、(CR'R")0-3S(O)1-2NR'R"、(CR'R")0-3CHO、
(CR'R")0-3O(CR'R")0-3H、(CR'R")0-3S(O)0-3R' (如,-SO3H、-OSO3H)、
(CR'R")0-3O(CR'R")0-3H (如,-CH2OCH3和-OCH3)、(CR'R")0-3S(CR'R")0-3H
(如-SH和-SCH3)、(CR'R")0-3OH (如,-OH)、(CR'R")0-3COR'、(CR'R")0-3(取代的或未取代的苯基)、(CR'R")0-3 (C3-C8环烷基)、(CR'R")0-3CO2R'
(如,-CO2H)或(CR'R")0-3OR'基团或任何天然存在的氨基酸的侧链;其中R'和R"各自独立为氢、C1-C5烷基、C2-C5烯基、C2-C5炔基或芳基。
术语“胺”或“氨基”应该被理解为被广泛应用于分子或部分或官能团两者,如本领域一般理解的那样,并且可为伯、仲或叔胺或伯、仲或叔氨基。术语“胺”或“氨基”包括其中的氮原子共价结合至至少一个碳、氢或杂原子的化合物。该术语包括,例如但不限于“烷基氨基”、“芳基氨基”、“二芳基氨基”、“烷基芳基氨基”、“烷基氨基芳基”、“芳基氨基烷基”、“烷基氨基烷基”、“酰胺”、“酰胺基”和“氨基羰基”。术语“烷基氨基”包括其中氮结合至至少一个额外的烷基的基团和化合物。术语“二烷基氨基”包括其中氮原子结合至至少两个额外的烷基的基团。术语“芳基氨基”和“二芳基氨基”包括其中氮分别结合至至少一个或两个芳基的基团。术语“烷基芳基氨基”、“烷基氨基芳基”或“芳基氨基烷基”指的是结合至至少一个烷基和至少一个芳基的氨基。术语“烷基氨基烷基”指的是结合至氮原子的烷基、烯基或炔基,所述氮原子也结合至烷基。
术语“酰胺”、“酰氨基”或“氨基羰基”包括含结合至羰基或硫代羰基的碳的氮原子的化合物或部分。该术语包括“烷基氨基羰基”或“烷基氨基羰基”,它们包括结合至氨基的烷基、烯基、芳基或炔基,所述氨基结合至羰基。其包括包含结合至氨基的芳基或杂芳基部分的芳基氨基羰基和芳基羰基氨基,所述氨基结合至羰基或硫代羰基的碳。术语“烷基氨基羰基”、“烯基氨基羰基”、“炔基氨基羰基”、“芳基氨基羰基”、“烷基羰基氨基”、“烯基羰基氨基”、“炔基羰基氨基”和“芳基羰基氨基”包括在术语“酰胺”中。
酰胺也包括尿素基团(氨基羰基氨基)和氨基甲酸酯基团(氧基羰基氨基)。
在本发明特别的实施方案中,术语“胺”或“氨基”指的是式N(R8)R9、CH2N(R8)R9和CH(CH3)N(R8)R9的取代基,其中R8和R9各自独立地选自H和(C1-C4-烷基)0-1G,其中G选自COOH、H、PO3H、SO3H、Br、Cl、F、O-C1-4-烷基、S-C1-4-烷基、芳基、C(O)OC1-C6-烷基、C(O)C1-C4-烷基-COOH、C(O)C1-C4-烷基和C(O)-芳基。
本文公开的描述应该被解释为与化学结合的规律和原理相协调一致。例如,可为必需的是去除氢原子以在任何给定的位置容纳取代基。此外,应该理解的是,变量(即,“R基团”)的定义,以及本发明通式(如式I或II)的键定位,将与本领域已知的化学键合的规律相协调一致。也应该理解的是,以上描述的所有本发明的化合物应还包括相邻原子之间的键和/或氢以在需要时满足各原子的化合价。即,加入键和/或氢原子以提供对以下各原子类型的以下的总键数:碳:四个键;氮:三个键;氧:两个键;和硫:两个至六个键。
本发明的化合物可包括不对称的碳原子。因此应该理解的是,产生于这样的不对称性异构体(如,所有的对映体、立体异构体、旋转异构体、互变异构体、非对映异构体或外消旋体)被纳入本发明范畴内。可通过化学分离技术和通过立体化学控制的合成,获得基本上纯形式的这样的异构体。此外,在本申请中公开的结构和其他化合物和部分也包括其所有互变异构体。可通过本领域认可的合成策略获得本文描述的化合物。
也将要指出的是,一些本发明的化合物的取代基包括异构体性环状结构。因此应该理解的是,除非另行指明,具体取代基的结构性异构体被纳入本发明范畴内。例如,术语“四唑”包括四唑、2H-四唑、3H-四唑、4H-四唑和5H-四唑。
同位素
本发明包括所有药学上可接受的同位素标记的本发明的化合物,即,式(I)和(II)化合物,其中一个或多个原子被具有相同原子数但原子质量或质量数不同于通常在自然界发现的原子质量或质量数的原子所置换。
适宜纳入本发明的化合物中的同位素的实例包括氢的同位素,诸如2H和3H、碳的同位素,诸如11C、13C和14C、氯的同位素,诸如36Cl、氟的同位素,诸如18F、碘的同位素,诸如123I和125I、氮的同位素,诸如13N和15N、氧的同位素,诸如15O、17O和18O、磷的同位素,诸如32P和硫的同位素,诸如35S。
某些同位素-标记的式(I)和(II)化合物,例如那些整合了放射性同位素的化合物,在药物和/或底物组织分布研究中是有用的。放射性同位素氚、即3H和碳-14,即14C,就易于整合它们和现成的探测方式而言,对于该目的是特别有用的。
用较重的同位素,诸如氘,即2H取代,可获得某些治疗优势,因为更大的代谢稳定性,例如在体内增加半衰期或降低剂量需求,并且因此在一些环境中可为优选的。
用正电子发射同位素,诸如11C、18F、15O和13N取代,在用于检查底物受体占位的正电子发射断层成像(PET)研究中可为有用的。
一般可通过本领域技术人员已知的常规技术或者类似于在伴随的实施例和制备中描述的方法,采用适当的同位素标记的试剂代替之前所用的非-标记的试剂,制备同位素标记的式(I)和(II)化合物。
组合
本发明的化合物也用于联合已知的抗癌剂。这样的已知的抗癌剂包括如下:雌激素受体调节剂、雄激素受体调节剂、类维生素A受体调节剂、细胞毒性剂、抗增殖剂、异戊二烯基-蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂和其他血管生成抑制剂。
“雌激素受体调节剂”指的是不论什么机制干扰或抑制雌激素与受体的结合的化合物。雌激素受体调节剂的实例包括,但不限于他莫昔芬、雷洛昔芬、艾多昔芬、LY353381、LY117081、托瑞米芬、氟维司群、4-[7-(2,2二甲基-1-氧代丙氧基-4-甲基-2-[4-[2-(1-哌啶基)乙氧基]苯基]-2H-1-苯并吡喃-3-基]-苯基-2,2-二甲基丙酸酯、4,4'-二羟基二苯甲酮-2,4-二硝基苯基-腙和SH646。
“雄激素受体调节剂”指的是不论什么机制干扰或抑制雄激素与受体的结合的化合物。雄激素受体调节剂的实例包括非那雄胺和其他5α-还原酶抑制剂、尼鲁米特、氟他胺、比卡鲁胺、利罗唑和乙酸阿比特龙。
“类维生素A受体调节剂”指的是不论什么机制干扰或抑制类维生素A与受体的结合的化合物。这样的类维生素A受体调节剂的实例包括贝沙罗汀、维A酸、13-顺式-维甲酸、9-顺式-维甲酸、α.-二氟代甲基鸟氨酸、ILX23-7553、反式-N-(4'-羟基苯基)异维A酰胺和N-4-羧基苯基异维A酰胺(retinamide)。
“细胞毒性剂”指的是主要通过直接干扰细胞功能或抑制或干扰细胞有丝分裂(myosis),引起的细胞死亡的化合物,包括烷化剂、肿瘤坏死因子、嵌入剂(intercalators)、微管蛋白抑制剂和拓扑异构酶抑制剂。
细胞毒性剂的实例包括,但不限于普拉扎明(tirapazimine)、sertenef、恶液质素(cachectin)、异环磷酰胺、他索纳明、氯尼达明(lonidamine)、卡铂、多柔比星、六甲蜜胺、泼尼莫司汀、二溴卫矛醇、雷莫司汀、福莫司汀、奈达铂、奥沙利铂、替莫唑胺(temozolomnide)、依铂(heptaplatin)、阿雌莫司汀、甲苯磺酸英丙舒凡、曲洛磷胺(trofosfainide)、尼莫司汀、二溴螺氯铵、嘌嘧替派、洛铂、沙铂、泊非霉素(profiromycin)、顺铂、伊洛福芬、地磷酰胺(dexifosfamide)、顺式-胺二氯代(2-甲基-吡啶)铂、苄基鸟嘌呤、葡膦酰胺、GPX100、(反式、反式、反式)-双-mu-(己烷-1,6-二胺)-μ-[二胺-铂(II)]双[二胺(-氯代)铂(II)]四氯化物、二吖丙啶基精胺(diarizidinylspermine)、三氧化二砷、1-(11-十二烷基氨基-10-羟基十一烷基)-3,7-二甲基黄嘌呤、佐柔比星、伊达比星、道诺霉素、比生群(bisantrene)、米托蒽醌、吡柔比星、吡萘非特(pinafide)、戊柔比星、氨柔比星、抗瘤酮(antineoplaston)、3'-脱氨基-3'-吗啉代-13-脱氧代-10-羟基卡柔比星、恩拉霉素(annamycin)、加柔比星、依利萘法德(elinafide)、MEN 10755和4-去甲氧基-3-去氨基-3-吖丙啶基-4-甲基磺酰基-道诺霉素(参见WO 00/50032)。
微管蛋白抑制剂的实例包括紫杉醇、硫酸长春地辛、3',4'-二脱氢-4'-脱氧-8'-去甲长春碱(norvincaleukoblastine)、多西他赛(docetaxol)、力索新(rhizoxin)、海兔毒素(dolastatin)、羟乙基磺酸米伏布林(mivobulin
isethionate)、auristatin、西马多丁(cemadotin)、RPR109881、BMS184476、长春氟宁、自念珠藻环肽(cryptophycin)、2,3,4,5,6-五氟-N-(3-氟代4-甲氧基苯基)苯磺胺、脱水长春碱、N,N-二甲基-L-缬氨酰基-L-缬氨酰基-N-甲基-L-缬氨酰基-L-脯氨酰基-L-脯氨酸-叔-丁基酰胺、TDX258和BMS188797。
拓扑异构酶抑制剂的一些实例为托泊替康、hycaptamine、伊立替康、卢比替康、6-乙氧基丙酰基-3',4'-O-外型-亚苄基-教酒菌素、9-甲氧基-N,N-二甲基-5-硝基吡唑并[3,4,5-kl]吖啶-2-(6H)丙胺、1-氨基-9-乙基-5-氟代-2,3-二氢-9-羟基4-甲基-1H,12H-苯并[de]吡喃并[3',4':b,7]中氮茚并[1,2b]喹啉-10,13(9H,5H)二酮、勒托替康、7-[2-(N-异丙基氨基)乙基]-(20S)喜树碱、BNP1350、BNPI1100、BN80915、BN80942、磷酸依托泊苷、替尼泊苷、索布佐生、2'-二甲基氨基-2'-脱氧-依托泊苷、GL331、N-[2-(二甲基氨基)乙基]-9-羟基-5,6-二甲基-6H-吡啶并[4,3-b]咔唑-1-甲酰胺、asulacrine、(5a,5aB,8aa,9b)-9-[2-[N-[2-(二甲基氨基)乙基]-N-甲基氨基]乙基]-5-[4-羟基-3,5-二甲氧基苯基]-5,5a,6,8,8a,9-六氢呋喃并(3',4':6,7)萘并(2,3-d-)-1,3-二氧杂环戊烯-6-酮(dioxol-6-one)、2,3-(亚甲基二氧基)-5-甲基-7-羟基-8-甲氧基苯并[c]-菲啶鎓盐、6,9-双[(2-氨基乙基)氨基]苯并[g]异喹啉-5,10-二酮、5-(3-氨基丙基氨基)-7,10-二羟基-2-(2-羟基乙基氨基甲基)-6H-吡唑并[4,5,1-de]吖啶-6-酮、N-[1-[2(二乙基氨基)乙基氨基]-7-甲氧基-9-氧代-9H-噻吨4-基甲基-]甲酰胺、N-(2-(二甲基氨基)乙基)吖啶4-甲酰胺、6-[[2-(二甲基氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-c]喹啉-7-酮和地美司钠(dimesna)。
“抗增殖剂”包括反义RNA和DNA寡核苷酸,诸如G3139、ODN698、RVASKRAS、GEM231和INX3001,和抗代谢剂,诸如依诺他滨、卡莫氟(carmofur)、替加氟、喷司他丁、去氧氟尿苷、三甲曲沙、氟达拉滨、卡培他滨、加洛他滨、阿糖胞苷十八烷基磷酸盐(ocfosfate)、fosteabine 钠水合物、雷替曲塞、paltitrexid、依米替氟(emitefur)、噻唑呋林(tiazofurin)、地西他滨、诺拉曲特、培美曲塞、奈拉滨、2'-脱氧-2'-次甲基胞苷、2'-氟代亚甲基-2'-脱氧胞苷、N-[ 5-(2,3-二氢-苯并呋喃基)磺酰基]-N'-(3,4-二氯代苯基)脲、N6-[4-脱氧-4-[N2-[2(E),4(E)-十四碳二烯酰基]甘氨酰氨基]-L-丙三醇-B-L-甘露-吡喃庚糖基]腺嘌呤、脱氢膜海鞘素B (aplidine)、海鞘素、曲沙他滨、4-[2-氨基4-氧代4,6,7,8-四氢-3H-嘧啶并[5,4-b] [1,4]噻嗪-6-基-(-S)-乙基]-2,5-噻吩酰基-L-谷氨酸、氨基喋呤、5-氟尿嘧啶、阿拉诺新、11-乙酰基-8-(氨基甲酰基氧基甲基)4-甲酸基-6-甲氧基-14-氧杂-1,11-二氮杂四-环(7.4.1.0.0)-十四-2,4,6-三烯-9-基乙酸酯、苦马豆碱(swainsonine)、洛美曲索、右雷佐生、蛋氨酸酶(methioninase)、2'-氰基-2'-脱氧-N4-棕榈酰-1-B-D-阿拉伯呋喃糖基胞嘧啶和3-氨基吡啶-2-甲醛缩氨基硫脲。
“抗增殖剂”也包括针对生长因子的单克隆抗体,而不是那些列于“血管生成抑制剂”的药物,诸如曲司珠单抗和肿瘤抑制基因,诸如p53,其可经由重组病毒介导的基因转移传递(参见例如,美国专利号6,069,134)。
“HMG-CoA还原酶抑制剂”指的是3-羟基-3-甲基戊二酰基-CoA还原酶的抑制剂。可采用本领域熟知的分析法,例如,参见在美国专利号4,231,938,于col. 6和WO 84/02131于30-33页中描述或引用的分析法,容易地鉴别对HMG-CoA还原酶具有抑制活性的化合物。当在本文中使用时,术语“HMG-CoA还原酶抑制剂”和“HMG-CoA还原酶的抑制剂”具有相同含义。
可使用的HMG-CoA还原酶抑制剂的实例包括,但不限于洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀和西立伐他汀。可被用于本文方法的这些和额外的HMG-CoA还原酶抑制剂的结构式在M. Yalpani, "降胆固醇药(Cholesterol
Lowering Drugs)"、Chemistry &
Industry,85-89页(1996年2月5日)的第87页和美国专利号4,782,084和4,885,314中有描述。如在本文使用的,术语HMG-CoA还原酶抑制剂包括所有药学上可接受的内酯和开环-酸形式(即,其中内酯环打开以形成游离酸)以及具有HMG-CoA还原酶抑制活性的化合物的盐和酯形式,并因此,这样的盐、酯、开环-酸和内酯形式的应用纳入本发明的范畴之内。
“异戊二烯基-蛋白转移酶抑制剂”指的是抑制异戊二烯基-蛋白转移酶中的任何一种或任何组合的化合物,包括法呢基-蛋白转移酶(FPTase)、香叶基香叶基(geranyl)-I型蛋白转移酶(GGPTase-I)和香叶基香叶基-II型蛋白转移酶(GGPTase-II,也被称为Rab GGPTase)。抑制异戊二烯基-蛋白转移酶的化合物的实例包括(+/-)-6-[氨基(4-氯代苯基)(1-甲基-1H-咪唑-5-基)甲基]-4-(3-氯代苯基)-1-甲基-2(1H)-喹啉酮、(-)-6-[氨基(4-氯代苯基)(1-甲基-1H-咪唑-5-基)甲基]4-(3-氯代-苯基)-1-甲基-2(1H)-喹啉酮、(+)-6-氨基(4-氯代苯基)(1-甲基-1H-咪唑-5-基)甲基]4-(3-氯代苯基)-1-甲基-2(1H)-喹啉酮、5(S)-正-丁基-1-(2,3-二甲基苯基)4-[1-(4-氰基苄基)-5-咪唑基甲基]-2-哌嗪酮、(S)-1-(3-氯代苯基)4-[1-(4-氰基苄基)-5-咪唑基甲基]-5-[2-(乙烷磺酰基)甲基)-2-哌嗪酮、5(S)-正-丁基-1-(2-甲基苯基)4-[1-(4-氰基苄基)-5-咪唑基甲基]-2-哌嗪酮、1-(3-氯代苯基)-4-[1-(4-氰基苄基)-2-甲基-5-咪唑基甲基]-2-哌嗪酮、1-(2,2-二苯基乙基)-3-[N-(1-(4-氰基苄基)-1H-咪唑-5-基乙基)氨基甲酰基]哌啶、4-{5-[4-羟基甲基4-(4-氯代吡啶-2-基甲基)-哌啶-1-基甲基-]-2-甲基咪唑-1-基甲基}苯甲腈、4-{5-[4-羟基甲基-4-(3-氯代苄基)-哌啶-1-基甲基]-2-甲基咪唑-1-基甲基}苯甲腈、4-{3-[4-(2-氧代-2H-吡啶-1-基)苄基]-3H-咪唑4-基甲基}苯甲腈-、4-{3-[4-(5-氯代-2-氧代-2H-[1,2']二吡啶-5'-基甲基]-3H-咪唑4-基甲基}苯甲腈、4-{3-[4-(2-氧代-2H-[1,2']二吡啶-5'-基甲基]-3H-咪唑4-基甲基}苯甲腈、4-[3-(2-氧代-1-苯基-1,2-二氢吡啶4-基甲基)-3H-咪唑4-基甲基}苯甲腈、18,19-二氢-19-氧代-5H,17H-6,10:12,16-二甲烯桥基(dimetheno)-1H-咪唑[4,3-c][1,11,4]二氧杂氮杂环-十九炔(nonadecine)-9-甲腈、(+/-)-19,20-二氢-19-氧代-5H-18,21-桥亚乙基-12,14-亚乙烯基-6,10-二甲烯桥基-22H-苯并[d]咪唑并[4,3-k][1,6,9,12]氧杂三氮杂-环十八炔(octadecine)-9-甲腈、19,20-二氢-19-氧代-5H,17H-18,21-桥亚乙基-6,10:12,16-二甲烯桥基-22H-咪唑并-[3,4-h][1,8,1l,14]氧杂三氮杂环二十炔(eicosine)-9-甲腈,和(+/-)-19,20-二氢-3-甲基-19-氧代-5H-18,21-乙醇-12,14-亚乙烯基-6,10-甲烯桥基-22H-苯并[d]咪唑并[4,3-k][1,6,9,12]氧杂-三氮杂环十八炔(octadecine)-9-甲腈。
可在以下出版物和专利中发现异戊二烯基-蛋白转移酶抑制剂其他的实例:WO
96/30343、WO 97/18813、WO 97/21701、WO
97/23478、WO 97/38665、WO 98/28980、WO
98/29119、WO 95/32987、美国专利号5,420,245、5,523,430、5,532,359、5,510,510、5,589,485、5,602,098、欧洲专利公布号0 618 221、欧洲专利公布号0 675 112、欧洲专利公布号0 604 181、欧洲专利公布号0 696 593、WO 94/19357、WO
95/08542、WO 95/11917、WO 95/12612、WO
95/12572、WO 95/10514、美国专利号5,661,152、WO 95/10515、WO 95/10516、WO
95/24612、WO 95/34535、WO 95/25086、WO
96/05529、WO 96/06138、WO 96/06193、WO
96/16443、WO 96/21701、WO 96/21456、WO
96/22278、WO 96/24611、WO 96/24612、WO
96/05168、WO 96/05169、WO 96/00736、美国专利号5,571,792、WO 96/17861、WO
96/33159、WO 96/34850、WO 96/34851、WO
96/30017、WO 96/30018、WO 96/30362、WO
96/30363、WO 96/31111、WO 96/31477、WO
96/31478、WO 96/31501、WO 97/00252、WO
97/03047、WO 97/03050、WO 97/04785、WO
97/02920、WO 97/17070、WO 97/23478、WO
97/26246、WO 97/30053、WO 97/44350、WO
98/02436和美国专利号5,532,359。异戊二烯基-蛋白转移酶抑制剂对血管生成的作用的实例,参见European J. of Cancer,Vol 35, No. 9, pp. 1394-1401 (1999)。
HIV蛋白酶抑制剂的实例包括氨普那韦、阿巴卡韦、CGP-73547、CGP-61755、DMP-450、茚地那韦、奈非那韦、替拉那韦、利托那韦、沙奎那韦、ABT-378、AG1776和BMS-232,632。逆转录酶抑制剂的实例包括地拉韦啶(delaviridine)、依法韦仑、GS-840、HB Y097、拉米夫定、奈韦拉平、AZT、3TC、ddC和ddI。
“血管生成抑制剂”指的是不论何种机制抑制新生血管形成的化合物。血管生成抑制剂的实例包括,但不限于络氨酸激酶抑制剂,诸如络氨酸激酶受体Flt-1
(VEGFR1)和Flk-1/KDR (VEGFR20)的抑制剂、源于表皮的、源于成纤维细胞或源于血小板的生长因子的抑制剂、MMP (基质金属蛋白酶)抑制剂、整联蛋白阻断剂、干扰素-α.、白介素-12、戌聚糖多硫酸盐(polysulfate)、环加氧酶抑制剂,包括非甾体抗炎药(NSAIDs),如阿司匹林和布洛芬以及选择性环加氧酶-2抑制剂,如塞来考昔和罗非考昔(PNAS,
Vol. 89, p. 7384 (1992);JNCI, Vol. 69,
p. 475 (1982);Arch. Opthalmol., Vol. 108, p.573 (1990);Anat. Rec, Vol. 238, p. 68 (1994);FEBS Letters, Vol. 372, p. 83 (1995);Clin, Orthop. Vol. 313, p. 76 (1995);J. Mol. Endocrinol., Vol. 16, p.107 (1996);Jpn. J. Pharmacol., Vol. 75, p. 105 (1997);Cancer Res., Vol. 57, p. 1625 (1997);Cell, Vol. 93, p. 705 (1998);Intl. J. Mol. Med., Vol. 2, p. 715 (1998);J. Biol. Chem., Vol. 274, p. 9116 (1999))、羧基酰胺基三唑、康普瑞汀A-4 (combretastatin A-4)、角鲨胺(squalamnine)、6-O-氯代乙酰基-羰基)-烟曲霉醇(fumagillol)、沙利度胺、血管抑素、肌钙蛋白-1、血管紧张素II拮抗剂(参见Fernandez等,J. Lab. Clin.
Med. 105: 141-145 (1985))和VEGF的抗体。(参见Nature Biotechnology,
Vol. 17, pp.963-968 (1999年10月);Kim等,Nature, 362, 841-844 (1993);WO
00/44777;和WO 00/61186)。
试验
可采用许多本领域可利用的试验,例如,在下节实施例中描述的这样的试验,检测本发明的化合物对蛋白激酶活性的抑制。
药用组合物
本发明的化合物适宜作为药用组合物中的活性剂,所述组合物对治疗蛋白激酶-相关的紊乱和癌症,如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病特别有效。在多个实施方案中的药用组合物具有药学上有效量的本文的活性剂连同其他药学上可接受的赋形剂、载体、填充剂、稀释剂等。
语言化合物的“药学上的有效量”是需要或足以治疗或预防蛋白激酶-相关的紊乱的量,如预防本文描述的蛋白激酶-相关的紊乱和/或疾病或病症的多种形态学和肉体症状。在一个实例中,本发明的化合物的有效量是在受试者中足以治疗蛋白激酶-相关的紊乱的量。有效量可依据如受试者的大小和重量、疾病的类型或本发明的具体化合物这样的因素不同而异。例如,本发明的化合物的选择可影响“有效量”的制定。本领域普通技术人员应该能研究本文包含的诸因素并确定本发明的化合物的有效量而不需要过多的实验。
给药方案可影响有效量的制定。可或者在蛋白激酶-相关的紊乱发病之前或者在其之后给予受试者本发明的化合物。再有,可每天或序贯地给予多个分开的剂量以及错开的剂量,或可连续地输注给药或可大剂量推注给药。此外,在治疗或预防紧急情形下,可按比例地增加或减少本发明的化合物的剂量。
词组本发明的化合物的“药学上可接受的量”指的是将引起受试者产生生物学或医学反应,例如减少或抑制酶或蛋白活性或缓解症状、减轻病情、减缓或延迟疾病进程或预防疾病等的本发明的化合物的量。在一个非-限制性实施方案中,词组“药学上可接受的量”指的是本发明的化合物的量,即在给予受试者时,有效(1) 至少部分减轻、抑制、预防和/或缓解(i) 由激酶c-Abl、BCR-Abl、c-kit、Src、EML4-ALK、TEL-ALK和/或PDGFR介导的,或(ii) 与激酶c-Abl、BCR-Abl、c-kit、Src、EML4-ALK、TEL-ALK和/或PDGFR活性相关的,或(iii) 以激酶c-Abl、BCR-Abl、c-kit、Src、EML4-ALK、TEL-ALK和/或PDGFR的异常活性为特征的病症或紊乱或疾病;或(2) 降低或抑制激酶c-Abl、BCR-Abl、c-kit、Src、EML4-ALK、TEL-ALK和/或PDGFR的活性;或(3) 减少或抑制激酶c-Abl、BCR-Abl、c-kit、Src、EML4-ALK、TEL-ALK和/或PDGFR的表达。在另一个非-限制性实施方案中,词组“药学上可接受的量”指的是本发明的化合物的量,即在给予受试者时,有效至少部分减轻、抑制、预防和/或缓解癌症,如胰腺癌、非小细胞肺癌、胃肠型间质瘤或慢性骨髓性白血病。在还一个非-限制性实施方案中,术语“药学上可接受的量”指的是本发明的化合物的量,即在给予细胞或组织或非-细胞生物材料或介质时,有效至少部分降低或抑制激酶c-Abl、BCR-Abl、c-kit、Src、EML4-ALK、TEL-ALK和/或PDGFR的活性;或至少部分减少或抑制激酶c-Abl、BCR-Abl、c-kit、Src、EML4-ALK、TEL-ALK和/或PDGFR的表达。
可接受的量可依据如受试者的大小和重量、疾病的类型或具体的有机化合物这样的因素不同而异。例如,有机化合物的选择可影响“可接受的量”的制定。本领域普通技术人员应该能研究下述诸因素并确定有机化合物的可接受的量而不需要过多的实验。
本发明的化合物可被用于治疗如本文描述的状态、紊乱或疾病或用于制备供治疗这些疾病的药用组合物。在这些疾病的治疗中使用本发明的化合物的方法,或用于治疗这些疾病的、具有本发明的化合物的药用制剂。
语言“药用组合物”包括适宜给予哺乳动物,如,人类的制剂。本发明的化合物当作为药品给予哺乳动物,如人类时,可给予本发明的化合物本身或作为含例如联合药学上可接受的载体的0.1-99.5%
(更优选0.5-90%)的活性成分的药用组合物给予。
词组“药学上可接受的载体”是本领域公认的并且包括适宜给予哺乳动物本发明的化合物的药学上可接受的材料、组合物或媒介物。载体包括液体或固体填充剂、稀释剂、赋形剂、溶剂或包囊材料,涉及将主药从身体的一个器官或部分携带或转运至身体的另一个器官或部分。各载体在与制剂的其他成分适配的意义上必须是“可接受的”并且对患者无害。可用作药学上可接受的载体的材料的一些实例包括:糖,诸如乳糖、葡萄糖和蔗糖;淀粉,诸如玉米淀粉和马铃薯淀粉;纤维素,及其衍生物,诸如羧基甲基纤维素钠、乙基纤维素和乙酸纤维素;粉末黄蓍胶;麦芽;明胶;滑石粉;赋形剂,诸如可可油和栓剂蜡;油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,诸如聚丙二醇;多元醇,诸如丙三醇、山梨醇、甘露醇和聚乙二醇;酯,诸如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,诸如氢氧化镁和氢氧化铝;褐藻酸;无热源水;等张盐水;林格氏溶液;乙醇;磷酸盐缓冲溶液;和在药用制剂中使用的其他无-毒性的可适配的物质。
润湿剂、乳化剂和滑润剂,诸如十二烷基硫酸钠和硬脂酸镁,以及着色剂、释放剂、包衣剂、甜味剂、调味剂和调香剂,防腐剂和抗氧化剂也可存在于组合物中。
药学上可接受的抗氧化剂的实例包括:水溶性抗氧化剂,诸如抗坏血酸、盐酸半胱氨酸、硫酸氢钠、偏亚硫酸氢钠、亚硫酸氢钠等;油-溶性抗氧化剂,诸如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙基酯、α-生育酚等;和金属螯合剂,诸如柠檬酸、四乙酸二乙胺(EDTA)、山梨醇、酒石酸、磷酸等。
本发明的制剂包括那些适宜于口服、经鼻、局部、口颊、舌下、直肠、阴道和/或胃肠外给药的制剂。制剂可便利地以单位剂型呈现并且可通过药学领域熟知的任何方法制备。可与载体材料合并以产生单一剂型的活性成分的量,将一般为产生治疗效应的化合物的量。一般地,多于百分之一,该量将在从约1 %至约99 %的活性成分,优选从约5 %至约70 %,最优选从约10 %至约30 %的范围内。
制备这些制剂或组合物的方法包括将本发明的化合物与载体,并且任选与一个或多个附加成分混合的步骤。一般地,通过将本发明的化合物与液体载体或细微分散的固体载体或两者均一和密切地结合,然后,如果需要,成形为产品,制备该制剂。
适宜口服给药的本发明的制剂可呈现为以下形式:胶囊剂、囊片剂、丸剂、片剂、糖锭剂(采用香味基质,通常是蔗糖和阿拉伯树胶或黄蓍胶)、散剂、颗粒剂或作为水性或非-水性液体的溶液剂或混悬剂形式,或作为水包油或油包水液体乳剂或作为酏剂或糖浆剂或锭剂(采用惰性基质,诸如明胶和丙三醇或蔗糖和阿拉伯树胶)和/或作为口腔洗漱剂等,每一种含预定量的作为活性成分的本发明的化合物。本发明的化合物也可作为大丸药剂、药糖剂或糊剂给予。
在本发明的口服给药的固体剂型(胶囊剂、片剂、丸剂、糖衣丸剂、散剂、颗粒剂等)中,活性成分与一个或多个药学上可接受的载体,诸如柠檬酸钠或磷酸氢二钙和/或以下任何材料混合:填充剂或增量剂,诸如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;粘合剂,例如羧基甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯树胶;保湿剂,诸如丙三醇;崩解剂,诸如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、褐藻酸、某些硅酸盐和碳酸钠;溶液迟延剂,诸如石蜡;吸收加速剂,诸如季铵化合物;润湿剂,例如十六醇和丙三醇单硬脂酸酯;吸收剂,诸如高岭土和膨润土;滑润剂,诸如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠及其混合物;和着色剂。在胶囊剂、片剂和丸剂的情况下,药用组合物也可包含缓冲剂。相似类型的固体组合物也可在软或硬的填充的明胶胶囊剂中被用作填充剂,所述填充剂采用如乳糖或牛奶糖,以及高分子量聚乙二醇等这样的赋形剂。
可通过任选压制或模制一个或多个附加成分,制备片剂。可使用粘合剂(例如,明胶或羟基丙基甲基纤维素)、滑润剂、惰性稀释剂、防腐剂、崩解剂(例如,淀粉乙醇酸钠或交联羧基甲基纤维素钠)、表面活性或分散剂制备压制片剂。可通过在适宜机器中,压模经惰性液体稀释剂湿润的、粉末化的化合物的混合物,制备模制片剂。
可任选对本发明药用组合物的片剂和其他固体剂型,诸如糖衣丸剂、胶囊剂、丸剂和颗粒剂刻痕或用包衣料或壳,诸如肠溶衣料和制药领域熟知的其他衣料制备。也可采用,例如不同比例的羟基丙基甲基纤维素,以提供所需的释放特性,其他的聚合物基质、脂质体和/或微球配制它们,以使它们提供活性成分的缓慢或控制释放。可通过,例如经除菌滤器过滤对它们进行灭菌消毒,或通过在灭菌固体组合物形式中掺入杀菌消毒剂进行灭菌消毒,所述固体组合物形式可在即将使用前溶解于灭菌用水或一些其他的灭菌可注射媒介中。这些组合物也可任选含遮光剂并且可仅或优选在胃肠道的一定部分释放,任选以延时的方式释放。可使用的包埋组合物的实例包括聚合物质和蜡类。如果适当的话,也可用以上描述的一个或多个赋形剂以微囊包埋的形式包埋活性成分。
本发明的化合物的口服给药的液体剂型包括药学上可接受的乳剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性成分之外,液体剂型可含本领域普通使用的惰性稀释剂,例如水或其他溶剂、助溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、聚丙二醇、1,3-丁二醇、油(特别是棉籽油、落花生油、玉米油、麦胚油(germ
oil)、橄榄油、蓖麻油和芝麻油)、丙三醇、四氢呋喃醇、聚乙二醇类和山梨聚糖的脂肪酸酯,及其混合物。
除了惰性稀释剂外,口服组合物还可包括辅助剂,诸如润湿剂、乳化剂和助悬剂、甜味剂、调味剂、着色剂、增香剂和防腐剂。
混悬剂,除了活性化合物之外,可含助悬剂,如,例如乙氧基化的异十八醇、聚氧乙烯山梨醇和山梨聚糖酯类、微晶纤维素、偏氢氧化铝、膨润土、琼脂-琼脂和黄蓍胶及其混合物。
可将本发明药用组合物的直肠或阴道给药制剂制备为栓剂,其可通过使一个或多个本发明的化合物与一种或多种适宜的无刺激的赋形剂或载体混合制备,所述赋形剂或载体包括,例如可可油、聚乙二醇、栓剂蜡或水杨酸酯,且其在室温下为固体,而在体温下为液体,因此,将在直肠或阴道腔融化并释放活性化合物。
适宜阴道给药的本发明的制剂也包括含有如本领域已知的适当的此类载体的阴道栓剂、阴道棉条、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾剂制剂。
本发明的化合物的局部或透皮给药剂型包括散剂、喷雾剂、油膏剂、糊剂、乳膏剂、洗剂、凝胶剂、溶液剂、贴片剂和吸入剂。可将活性化合物在无菌条件下与药学上可接受的载体以及与任何可为必需的防腐剂、缓冲剂或抛射剂混合。
除了本发明的活性化合物之外,油膏剂、糊剂、乳膏剂和凝胶剂还可含赋形剂,诸如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌,或其混合物。
除了本发明的化合物之外,散剂和喷雾剂还可含赋形剂,诸如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末或这些物质的混合物。喷雾剂可额外地含惯例的抛射剂,诸如氯代氟代烃和挥发性未取代的烃,诸如丁烷和丙烷。
透皮贴片剂具有更多的优点,其提供对本发明的化合物的向身体的控制释放。可通过将所述化合物溶解或分散于适当的介质中制备这样的剂型。吸收促进剂也可用于增加化合物经皮的流量。可通过或者提供速率控制膜或者将活性化合物分散在聚合物基质或凝胶中,控制这样的流量的速率。
眼用制剂,眼膏剂、粉末剂、溶液剂等也预期纳入本发明的范畴之内。
适宜胃肠外给药的本发明药用组合物包括一个或多个本发明的化合物,联合一个或多个药学上可接受的灭菌等张水性或非水性溶液剂、分散剂、混悬剂或乳剂,或可在即将使用前重新配制成灭菌可注射溶液剂或分散剂的灭菌粉末剂,其可含抗氧化剂、缓冲剂、抑菌剂、使制剂与计划的接受者的血液等张的溶质或助悬剂或增稠剂。
可用于本发明药用组合物的适宜的水性和非水性载体的实例包括水、乙醇、多元醇(诸如丙三醇、聚丙二醇、聚乙二醇等)和其适宜的混合物,植物油,诸如橄榄油和可注射的有机酯,诸如油酸乙基酯。可例如,通过采用包衣材料,诸如卵磷脂,通过维持分散剂情况下的必需的粒径以及通过使用表面活性剂,维持适当的流动性。
这些组合物也可含辅助剂,诸如防腐剂、润湿剂、乳化剂和分散剂。可通过纳入各种抗细菌剂和抗真菌剂,例如尼泊金、氯代丁醇、苯酚山梨酸等,确保预防微生物的作用。也为可值得的是在组合物中包括等张剂,诸如糖、氯化钠等。另外,可通过纳入延长吸收的试剂,诸如单硬脂酸铝和明胶,实现可注射的药用形式的延长吸收。
在一些情况下,为了延长药物的效应,值得的是从皮下或肌肉注射减慢药物的吸收。此可通过使用具有差的水溶性的结晶或无定性材料的液体混悬剂完成。药物的吸收速率则依赖于其溶解速率,其转而可依赖于晶体大小和晶型。或者,通过将药物溶解或悬浮于油性媒介中,实现胃肠外给药的药物形式的延缓吸收。
可通过在生物可降解的聚合物,诸如聚丙交酯-聚乙交酯中形成本化合物的微包囊基质,制备可注射的贮库形式。依据药物对聚合物的比率和所用的具体聚合物的性质,可控制药物释放的速率。其他生物可降解的聚合物的实例包括聚(原酸酯)和聚(酐)。也通过将药物包埋在可与身体组织相容的脂质体或微乳剂中,制备可注射的贮库制剂。
本发明的制剂可口服、胃肠外、局部或直肠给药。当然是通过适宜的各种给药途径给予它们。例如,以片剂或胶囊剂形式给予它们,经注射、输注或吸入通过注射剂、吸入剂、眼用洗剂、软膏剂、栓剂等给予它们;通过洗剂或软膏剂局部给药;和通过栓剂直肠给药。口服和/或IV给药是优选的。
如在本文使用的,词组“胃肠外给予”和“经胃肠外给药”意指不是经肠道和局部给予的给药模式,通常经注射给药,并且包括,但不限于静脉、肌肉、动脉内、鞘内、囊内、眶内、心脏内、皮内、腹膜内、经气管、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。
如在本文使用的,词组“全身给药”、“全身给予”“外周给药”和“外周给予”意指不是直接给予中枢神经系统以化合物、药物或其他物质,这样其进入患者的系统,从而,经历代谢和其他类似的过程,例如皮下给药。
可为了疗法通过任何适宜的给药途径给予人类和其他动物这些化合物,所述途径包括口服、如通过,例如喷雾剂经鼻给药、经直肠、阴道内、胃肠外、脑池内(intracistenally)和局部给予,如通过散剂、油膏剂或滴剂,包括经口颊和舌下。
不管选择的给药途径如何,可通过本领域技术人员已知的常规方法,将以适宜的水合形式使用的本发明的化合物和/或本发明的药用组合物配制成药学上可接受的剂型。
活性成分在本发明药用组合物中的实际剂量水平可有变化,以对于具体的患者、组合物和给药模式而言,获得有效达到所需的治疗反应的活性成分的量,而对患者无毒害。
所选择的剂量水平将取决于多种因素,包括所用的具体的本发明的化合物或其酯、盐或酰胺的活性、给药途径、给药次数、所用的具体化合物的排泄速率、疗程、与所用的具体化合物联合应用的其他药物、化合物和/或材料、被治疗的患者的年龄、性别、体重、病症、一般健康状况和之前的病史以及医学领域熟知的类似的因素。
具有本领域普通技术的内科医生或兽医可易于确定和开具需要的药用组合物的有效量的处方。例如,内科医生或兽医可以在低于必需的水平的药用组合物中所用的本发明的化合物的剂量起始,以达到所需的治疗效应并逐渐增加剂量直至达到所需的效应。
一般地,适宜的本发明化合物的日剂量将是有效产生治疗效应的最低剂量的化合物的量。这样的有效剂量将一般取决于以上描述的因素。
一般地,对患者而言,当用于指定的止痛效应时,本发明的化合物的静脉和皮下剂量,将在每天每公斤体重从约0.0001至约100 mg范围内,更优选每天每kg从约0.01至约50 mg,且还更优选的是每天每kg从约1.0至约100 mg。有效量是治疗蛋白激酶-相关的紊乱的量。
如果希望,可在一天中以适当的间隔,分开给予两个、三个、四个、五个、六个或更多个亚剂量,任选以单位剂型给予活性化合物的有效日剂量。
在本发明的化合物可能单独给予时,优选作为药用组合物给予化合物。
合成方法
从通常可获得的化合物使用本领域技术人员已知的方法,包括任何一个或多个以下非限制的条件,制备本发明的化合物:
最适宜从药学上可接受的酸形成本发明的化合物的酸加成盐,包括例如,那些从无机酸,如盐酸、氢溴酸、硫酸或磷酸和有机酸,如丁二酸、顺丁烯二酸、乙酸或反丁烯二酸形成的酸加成盐。其他非-药学上可接受的盐,如草酸盐可用于,例如,本发明的化合物的分离,用于实验室应用或用于后续的转化为药学上可接受的酸加成盐。也包括在本发明范畴内的是本发明溶剂化物和水合物。
通过应用标准技术,其中用碱溶液,如碳酸钠或氢氧化钾处理给定盐的水溶液,以释放游离碱,然后萃取入适当的溶剂,诸如醚中,实现给定化合物盐至所需化合物盐的转化。然后从水性部分分离游离碱,干燥和用必要的酸处理以得到所需的盐。
可通过在碱的存在下,在惰性溶剂,诸如二氯甲烷或氯仿中,用所需的酯的酰氯处理那些具有游离羟基或氨基官能团的化合物,形成某些本发明的化合物的体内可水解的酯类或酰胺。适宜的碱包括三乙胺或吡啶。相反,可采用标准条件,使具有游离羧基的本发明的化合物酯化,其可包括激活后通过在适宜的碱的存在下用所需的醇处理。
药学上可接受的加成盐的实例包括,但不限于非-毒性无机和有机酸加成盐,诸如衍生于盐酸的盐酸盐、衍生于氢溴酸的氢溴酸盐、衍生于硝酸的硝酸盐、衍生于高氯酸的高氯酸盐、衍生于磷酸的磷酸盐、衍生于硫酸的硫酸盐、衍生于甲酸的甲酸盐、衍生于乙酸的乙酸盐、衍生于乌头酸的乌头酸盐、衍生于抗坏血酸的抗坏血酸盐、衍生于苯磺酸的苯磺酸盐、衍生于苯甲酸的苯甲酸盐、衍生于肉桂酸的肉桂酸盐、衍生于柠檬酸的柠檬酸盐、衍生于双羟萘酸的双羟萘酸盐、衍生于庚酸的庚酸盐、衍生于反丁烯二酸的反丁烯二酸盐、衍生于谷氨酸的谷氨酸盐、衍生于乙醇酸的乙醇酸盐、衍生于乳酸的乳酸盐、衍生于顺丁烯二酸的顺丁烯二酸盐、衍生于丙二酸的丙二酸盐、衍生于扁桃酸的扁桃酸盐、衍生于甲烷磺酸的甲烷磺酸盐、衍生于萘-2-磺酸的萘-2-磺酸盐、衍生于酞酸的酞酸盐、衍生于水杨酸的水杨酸盐、衍生于山梨酸的山梨酸盐、衍生于硬脂酸的硬脂酸盐、衍生于丁二酸的丁二酸盐、衍生于酒石酸的酒石酸盐、衍生于对-甲苯磺酸的甲苯-对-磺酸盐等。特别优选的盐是本发明的化合物的钠盐、赖氨酸盐和精氨酸盐。可通过本领域熟悉和描述的方法形成这样的盐。
其他酸,诸如草酸,其可不被认为是药学上可接受的,可用于被用作在获得本发明的化合物及其药学上可接受的酸加成盐中的中间体的盐的制备中。
本发明的化合物的金属盐包括碱金属盐,诸如含羧基的本发明的化合物的钠盐。
可采用本身已知的方式将依据本发明可得到的异构体的混合物分离成单个的异构体;可例如通过在多相溶剂混合物之间分配、再结晶和/或色谱法分离,例如,经硅胶或通过,如在反相柱上经中压液相色谱法分离非对映异构体,和可例如通过与光学纯的成盐试剂形成盐,并例如,通过分步结晶手段或通过在光学活性柱材料上经色谱法,分离如此得到的非对映异构体的混合物,分离外消旋体。
可对中间体和终产物进行后处理,和/或依据标准方法,如采用色谱法、分制剂法、(再-)结晶等纯化。
在反应的所有阶段,可将形成的异构体的混合物分离成单个的异构体,例如,非对映异构体或对映体,或分离成任何所需的异构体的混合物,例如,外消旋体或非对映异构体的混合物,例如,类似于合成的科学:分子转换的Houben-Weyl方法(Science of Synthesis: Houben-Weyl Methods of Molecular
Transformation). Georg Thieme Verlag, Stuttgart, Germany, 2005中描述的方法。
可从适宜于任何独特的反应的那些溶剂中选择的溶剂包括特别提到的那些,或者,例如水、酯,诸如低级烷基-低级链烷酸酯,例如,乙酸乙酯;醚,诸如脂族醚,例如,乙醚或环醚,例如,四氢呋喃或二氧杂环己烷;液体芳烃,诸如苯或甲苯;醇,诸如甲醇、乙醇或1-或2-丙醇;腈,诸如乙腈;卤化烃,诸如二氯甲烷或氯仿;酸酰胺,诸如二甲基甲酰胺或二甲基乙酰胺;碱,诸如杂环氮碱,例如,吡啶或N-甲基吡咯烷-2-酮;羧酸酐,诸如低级烷酸酐,例如,乙酸酐;环状、线性或支链烃,诸如环己烷、己烷或异戊烷,或那些溶剂的混合物,例如,水性溶液,除非在本方法的描述中另有所指。这样的溶剂混合物也可被用于后处理,例如,通过色谱法或分配法。
也可获得以水合物形式呈现的本化合物,包括它们的盐,或它们的结晶可例如包括用于结晶的溶剂。可存在不同的晶形。
本发明也涉及那些方法的形式,其中可在方法的任何阶段得到的作为中间体的化合物,被用作起始原料并实施所剩下的方法步骤,或其中在反应条件下形成起始原料,或起始原料被以衍生物的形式,例如,以保护的形式或以盐的形式使用,或者可通过依据本发明得到的化合物,在加工条件下产生并且就地再加工。
前药
本发明也包括含本发明化合物的药学上可接受的前药化合物的药用组合物和通过给予本发明化合物的药学上可接受的的前药化合物治疗蛋白激酶-相关的紊乱的方法。例如,具有游离氨基、酰胺基、羟基或羧基的本发明的化合物可转化为前药。前药包括化合物,其中氨基酸残基或两个或更多个(如,两个、三个或四个)氨基酸残基的多肽链经酰胺或酯键共价连接至本发明化合物的游离氨基、羟基或羧酸基团。氨基酸残基包括,但不限于20个天然存在的氨基酸,通常由三个字母符号指定,并且也包括4-羟基脯氨酸、羟基赖氨酸、锁链赖氨素(demosine)、异锁链赖氨素、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高半胱氨酸、高丝氨酸、鸟氨酸和蛋氨酸砜。也包括额外类型的前药。例如,游离羧基可衍生为酰胺或烷基酯。可采用基团,包括但不限于半琥珀酸酯、磷酸酯、二甲基氨基乙酸酯和磷酰基氧基甲基氧基羰基,使游离羟基衍生,如在Advanced
Drug Delivery Reviews, 1996, 19, 115中概述的。也包括羟基和氨基的氨基甲酸盐(酯)前药,作为羟基的碳酸盐(酯)前药、磺酸酯和硫酸酯。羟基衍生为(酰氧基)甲基和(酰氧基)乙基醚,其中酰基可为烷基酯,任选被包括但不限于醚、胺和羧酸官能团的基团取代,或其中的酰基是如上描述的氨基酸酯,也包括在内。该类型的前药在J.
Med. Chem. 1996, 39, 10中描述。游离胺也可衍生为酰胺、磺胺或磷酰胺。可使所有这些前药部分掺入基团,包括但不限于醚、胺和羧酸官能团。
因此,在适当和方便时,本发明的化合物的任何参考资料被理解为也涉及本发明的化合物相应的前药。
药剂盒
便利地,本发明也提供药盒供消费者治疗疾病使用。该药盒包括a) 包含抗体和药学上可接受的载体、媒介物或稀释剂的药用组合物;和,任选地,b) 描述使用所述药用组合物治疗特定疾病的方法的说明书。该说明书也可指示,该药盒是为了治疗疾病,同时在实质上是减少与抗体给予相关的不良效应伴随的倾向。
如本申请中所用的“药剂盒”包括装分离的单位剂型,诸如分开的瓶子或分开的铝箔包装的容器。所述容器可呈现任何方便的形状或形式,如本领域已知的,其由药学上可接受的材料制成,例如,纸或纸板盒、玻璃或塑料瓶或罐、可再封口的袋(例如,为了保存“补充”的片剂装进不同的容器)或具有依据治疗方案压出包装的单一剂量的罩泡眼包装。所用的容器可取决于所涉及的实际剂型,例如,方便的纸板盒将一般不用于盛液体混悬剂。切实可行的是可在单一包装中一起使用多于一个容器以销售单一剂型。例如,可将片剂装入瓶子中再将瓶子装进盒子中。
这样的药剂盒的一个实例是所谓的罩泡眼包装。罩泡眼包装为包装行业所熟悉并广泛应用于药用单位剂型(片剂、胶囊剂等)的包装。罩泡眼包装一般由覆盖优选透明塑料材料的箔的相对硬直的材料薄片组成。在包装加工过程中,在塑料箔中形成凹陷。凹陷处具有将要包装的单个片剂或胶囊剂的大小和形状或可具有容纳将要包装的多个片剂和/或胶囊剂的大小和形状。接下来,将片剂或胶囊剂相应地装入凹陷处和将相对硬直的材料的薄片封盖在塑料箔上,箔的表面背朝形成凹陷的方向。作为结果,如果需要,将片剂或胶囊剂单独密封或集合密封在塑料箔与薄片之间的凹陷中。优选薄片的强度是这样的,可用手在凹陷上施压,由此将片剂或胶囊剂从在凹陷位置处的薄片上形成的开口的罩泡眼包装中取出。然后可将片剂或胶囊剂经由所述开口取出。
可为值得的是提供书写的记忆辅助物,这里书写的记忆辅助物具有包含针对内科医生、药剂师或患者的信息和/或使用说明书的的印刷品,如,与应该摄取的如此指定的片剂或胶囊剂给药方案的相应天数几乎相同(next to)的片剂或胶囊剂的数目的表格,或含相同类型信息的卡片。这样的记忆辅助物的另一个实例是印刷在卡片上的日历,如,如下:“第一周,星期一、星期二”…等…“第二周,星期一、星期二…”等。记忆辅助物其他变体将是易于显而易见的。“日剂量”可为在指定日将服用的单一片剂或胶囊剂或多个片剂或胶囊剂。
药剂盒的另一个特定实施方案是设计每次分发一个日剂量的分药器。优选该分药器配备记忆辅助物,以至进一步方便给药的依从性。这样的记忆辅助物的实例是机械计数器,其指示已经分发的日剂量的数目。这样的记忆辅助物的另一个实例是电池为动力的微-芯片存储器,配备液晶读出器或声音提示信号,例如读出已经取用的最后日剂量的数据和/或提醒下一个要取用的剂量。
本发明的例证
通过以下的实施例进一步阐述本发明,所述实施例应该不被解释为进一步的限制。除非另有指明,本发明的实践将使用细胞生物学、细胞培养、分子生物学、转基因生物学、微生物和免疫学的常规技术,这些均在本领域技术人员的范围内。
一般的合成方法
流程1
流程2
总的合成方法
在流程1和流程2中描述了非-限制性的通用合成方法。如示于流程1中的,步骤I涉及在使用本领域熟知的条件(如,使用溶剂,诸如正-丁醇,在温度诸如130 ℃)下,使氟代腈化合物与肼的缩合,得到2-氨基吲唑产物。步骤II和III涉及使用本领域熟知的条件(如,使用溶剂诸如吡啶,在温度诸如0 ℃)下,用包括R、R1a和R1b基团的反应物使指定的氮原子任选烷基化或酰基化。步骤IV涉及使分别带有Y和W基团的反应物偶联,其中Y和W是本领域技术人员已知的官能团,在本领域熟知的条件(如,使用金属催化剂诸如Pd(dppf)Cl2、碱诸如Na2CO3和溶剂,诸如二氧杂环己烷/水,在温度,诸如100 ℃)下,经历这样的反应。
如流程2所示,步骤1涉及在使用本领域熟知的条件(如,使用溶剂,诸如正-丁醇,在温度诸如130 ℃)下,使氟代腈化合物与肼的缩合,以得到2-氨基吲唑产物。步骤II和III涉及使用本领域熟知的条件(如,使用溶剂,诸如吡啶,在温度,诸如0 ℃)下,用包括R、R1a和R1b基团的反应物使指定的氮原子任选烷基化或酰基化。步骤IV涉及使分别带有Y和Z基团的反应物偶联,其中Y和Z是本领域技术人员已知的官能团,在本领域熟知的条件(如,使用金属催化剂,诸如Pd2(dba)3、配体,诸如X-Phos、碱,诸如K2CO3和溶剂,诸如叔-丁醇)下,经历这样的反应。
用于合成本发明的化合物的所有起始原料、结构单位、反应物、酸、碱、脱水剂、溶剂和催化剂,或者为商业上可获得的,或者可通过本领域普通技术人员已知的有机合成方法(Houben-Weyl
4th Ed. 1952, Methors of Organic Synthesis, Thieme, 第21卷)生产。再有,本发明的化合物可通过本领域普通技术人员已知的、如示于以下实施例的有机合成方法产生。
提到以下的实施例,采用本文描述的方法或本领域已知的其他方法合成优选的实施方案的化合物。
合成实施例
流程
3
6-溴代 -1H- 吲唑 -3- 胺
将4-溴代-2-氟代苄腈(10 g, 50 mmol)、肼水合物(7.85
ml, 250 mmol)在正-丁醇(60
mL)中的反应混合物于130 ℃加热过夜。冷却至室温后,滤掉沉淀的结晶固体并用乙酸乙酯洗涤三次(每次15 mL)。真空中干燥产物(10.3 g)。
1H NMR
600 MHz (DMSO-d6) δ 11.48 (s, 1H);7.62 (d, 8.4 Hz, 1H), 7.40 (d, 1.2 Hz, 1H), 6.99 (dd,
8.4, 1.2 Hz, 1H), 5.43 (s, 2H)。MS m/z:211.97 (M + 1)。
N-(6-溴代 -1H- 吲唑 -3- 基 ) 环丙烷甲酰胺
于0 ℃,向吡啶(100
mL)中的6-溴-1H-吲唑-3-胺(4.24 g, 20
mmol)溶液中,逐滴加入环丙烷羰基氯(1.83 mL, 20 mmol)。于该温度下搅拌反应混合物4小时。一旦反应完成,真空中去除溶剂。将残余物溶解于DMF中并逐滴加入水。滤掉沉淀的固体并用己烷(每次15
ml)洗涤三次。真空中干燥产物和不经进一步纯化即使用(4.3 g)。
1H NMR
600 MHz (DMSO-d6) δ 12.71 (s, 1H),
10.72 (s, 1H), 7.74 (d, 8.4 Hz, 1H), 7.62 (d, 1.2 Hz, 1H), 7.14 (dd, 8.4, 1.2
Hz, 1H), 1.90 (m, 1H), 0.82 (m, 4H)。MS
m/z:280.0 (M + 1)。
3-(3-(环丙烷甲酰胺基 )-1H- 吲唑 -6- 基 ) 苯甲酸乙酯
向于二氧杂环己烷(20 mL)和1 N碳酸钠溶液(8 mL)中的N-(6-溴代-1H-吲唑-3-基)环丙烷甲酰胺(560 mg, 2.0
mmol)溶液中,加入3-(乙氧基羰基)苯基硼酸(388 mg, 2.0 mmol)和Pd(dppf)Cl2
(103 mg, 0.2 mmol)。将反应物于100 ℃搅拌4小时和冷却至室温后,经硅藻土过滤混合物和用乙酸乙酯洗涤。用盐水洗涤合并的有机溶液,经硫酸钠干燥和真空中浓缩。粗残余物经快速色谱法用20∶1 (v/v)二氯甲烷-甲醇纯化,得到标题产物(560 mg)。
1H NMR
600 MHz (DMSO-d6) δ 12.70 (s, 1H),
10.69 (s, 1H), 8.21 (s, 1H), 7.99 (d, 7.8 Hz, 1H), 7.96 (d, 7.8 Hz, 1H), 7.88
(d, 8.4 Hz, 1H), 7.63 (m, 2H), 7.34 (d, 8.4 Hz, 1H), 4.35 (q, 7.2 Hz, 2H), 1.94
(m, 1H), 1.34 (t, 7.2 Hz, 3H), 0.8-0.9 (m, 4H)。MS
m/z:350.14 (M + l )。
3-(3-(环丙烷甲酰胺基 )-1H- 吲唑 -6- 基 )-N-(3-( 三氟代甲基 ) 苯基苯甲酰胺
向于THF MeOH/H2O中的3-(3-(环丙烷甲酰胺基)-1H-吲唑-6-基)苯甲酸乙酯(42 mg, 0.12 mmol)溶液中,加入氢氧化锂单水合物(50
mg, 1.2 mmol)。于室温搅拌反应混合物过夜。一旦反应完成,去除反应溶剂至三分之一和调节pH至约6。过滤形成的沉淀物,真空中干燥且不经进一步纯化即使用。向于DMSO中的以上的酸溶液中,加入3-(三氟代甲基)苄胺(25 μL, 0.20 mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟代磷酸盐(HATU)
(57 mg, 0.15 mmol)和DIEA (52 μL, 0.30 mmol)。于室温搅拌反应混合物过夜和经HPLC纯化,得到标题产物(10 mg)。
1H NMR
600 MHz (CD3OD) δ 8.28 (s, 1H),
8.19 (s, 1H), 7.97 (t, 7.8 Hz, 2H), 7.93 (d, 8.4 Hz, 1H), 7.88 (d, 8.4 Hz, 1H),
7.73 (s, 1H), 7.63 (t, 7.8 Hz, 1H), 7.56 (t, 7.8 Hz, 1H), 7.48 (d, 8.4 Hz, 1H),
7.44 (d, 7.8 Hz, 1H), 1.95 (m, 1H), 1.04 (s, 2H), 0.94 (m, 2H)。MS m/z:465.15 (M + 1)。
流程
4
氨基甲酸苯基
-6-
溴代
-1H-
吲唑
-3-
基酯
于0 ℃,向于吡啶(24
mL)中的6-溴代-1H-吲唑-3-胺(1.27 g, 6.0
mmol)溶液中,逐滴加入氯甲酸苯酯(0.83 mL, 6.6 mmol)。于该温度下搅拌4小时后,用水猝灭反应。去除溶剂后,将残余物溶解于乙酸乙酯中并用1 N
HCl和盐水洗涤。有机层经硫酸钠干燥和真空中浓缩。粗残余物经快速色谱法用30∶70 (v/v)乙酸乙酯-正己烷纯化,得到标题产物(0.80 g)。
1H NMR
600 MHz (DMSO-d6) δ 12.82 (s, 1H),
10.53 (br, 1H), 7.77 (d, 8.4 Hz, 1H), 7.68 (d, 1.2 Hz, 1H), 7.40 (m, 2H), 7.23
(m, 3H), 7.20 (dd, 8.4, 1.2 Hz, 1H)。MS
m/z:332.0 (M + 1)。
6-溴代 -N- 甲基 -1H- 吲唑 -3- 胺
于室温,向于1,4-二氧杂环己烷(40
mL)中的6-溴代-1H-吲唑-3-基氨基甲酸苯酯(0.80 g, 2.42
mmol)溶液中,逐滴加入氢化铝锂(于THF中的2 M溶液,2.42 mL, 2.42
mmol)。于100 ℃搅拌4小时后,用0.2 mL水猝灭反应,随后加入0.2 mL 15% NaOH和0.6 mL水。然后过滤反应混合物,并用乙酸乙酯洗涤固体物。合并的有机层经用盐水洗涤,经硫酸钠干燥和真空中浓缩。粗残余物经快速色谱法用50∶50 (v/v)乙酸乙酯-正己烷纯化,得到标题产物(0.29 g)。
1H NMR
600 MHz (DMSO-d6) δ 11.50 (s, 1H),
7.58 (d, 8.4 Hz, 1H), 7.41 (d, 1.2 Hz, 1H), 7.00 (dd, 8.4, 1.2 Hz, 1H), 6.02
(q, 4.8 Hz, 1H), 2.82 (d, 4.8 Hz, 3H)。MS
m/z:226.0 (M + 1)。
N-甲基 -6-(4,4,5,5- 四甲基 -1,3,2- 二氧杂硼杂环戊烷 -2- 基 )-1H- 吲唑 -3- 胺
向于DMF (20 mL)中的6-溴代-N-甲基-1H-吲唑-3-胺(158 mg, 0.7 mmol)溶液中,加入二硼酸二频哪醇酯(196
mg, 0.77 mmol)、KOAc (206 mg, 2.1 mmol)、dppf (39 mg, 0.07 mmol)和Pd(dppf)Cl2
(57 mg, 0.07 mmol)。于100 ℃搅拌反应4小时并冷却至室温,混合物经硅藻土过滤和用乙酸乙酯洗涤。合并的有机溶液用碳酸氢钠溶液和盐水洗涤,经硫酸钠干燥和真空中浓缩。粗残余物经快速色谱法用50∶50 (v/v)乙酸乙酯-己烷纯化,得到标题产物(175 mg)。
1H NMR
600 MHz (DMSO-d6) 5 11.41 (s, 1H), 7.62 (d, 7.8 Hz, 1H), 7.55 (s, 1H), 7.14 (d,
7.8 Hz, 1H), 5.91 (q, 4.8 Hz, 1H), 2.83 (d, 4.8 Hz, 3H), 1.29 (s, 12H)。MS m/z:274.16 (M + 1)。
N-(4-((4-乙基哌嗪 -1- 基 ) 甲基 )-3-( 三氟代甲基 ) 苯基 )-3-(3-( 甲基氨基 )-1H- 吲唑 -6- 基 ) 苯甲酰胺
向于二氧杂环己烷(1.25 mL)和1 N碳酸钠溶液(0.25 mL)中的N-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1H-吲唑-3-胺(14 mg, 0.05 mmol)溶液中,加入N-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟代甲基)苯基)-3-碘代苯甲酰胺(26 mg, 0.05 mmol)和Pd(dppf)Cl2
(4 mg, 5 μmol)。于100 ℃搅拌反应物4小时和冷却至室温后,混合物经硅藻土过滤和用乙酸乙酯洗涤。合并的有机溶液用盐水洗涤,经硫酸钠干燥和真空中浓缩。粗残余物经HPLC纯化,得到标题产物(4.9 mg)。
1H NMR
600 MHz (DMSO-d6) δ 11.52 (s, 1H),
10.59 (s, 1H), 8.26 (s, 1H), 8.21 (d, 1.8 Hz, 1H), 8.05 (dd, 8.4, 1.8 Hz, 1H),
7.92 (m, 2H), 7.76 (d, 8.4 Hz, 1H), 7.71 (d, 8.4 Hz, 1H), 7.61 (m, 1H), 7.54
(s, 1H), 7.28 (dd, 8.4, 1.8 Hz, 1H), 5.98 (q, 4.8 Hz, 1H), 3.55 (s, 2H), 2.86
(d, 4.8 Hz, 3H), 2.3-2.5 (m, 10H), 0.97 (t, 7.2 Hz, 3H)。MS m/z:537.25 (M+ 1)。
流程
5
3-(3-氨基 -1H- 吲唑 -6- 基 ) 苯甲酸乙酯
向于二氧杂环己烷(100 mL)和碳酸钠(1 N,
40 mL)中的6-溴代-1H-吲唑-3-胺(2.1 g, 10.0
mmol)溶液中,加入3-(乙氧基羰基)苯基硼酸(1.94 g, 10.0 mmol)和Pd(dppf)Cl2
(816 mg, 1.0 mmol)。于100 ℃搅拌反应物4小时和冷却至室温后,混合物经硅藻土过滤和用乙酸乙酯洗涤。合并的有机溶液将盐水洗涤,经硫酸钠干燥和真空中浓缩。粗残余物经快速色谱法用50∶1 (v/v)二氯甲烷-甲醇纯化,得到标题产物(1.46 g),MS
m/z:282.11 (M + 1)。
3-(3-(4-(4-甲基哌嗪 -1- 基 ) 苯甲酰胺基 )-1H- 吲唑 -6- 基 ) 苯甲酸乙酯
于0 ℃,向搅拌的、于5 mL的二氯甲烷和20 μL的DMF中的4-(4-甲基哌嗪-1-基)苯甲酸(220.27 mg, 1.0 mmol)混悬液中,加入草酰氯(87 μL, 1.0 mmol)。于室温搅拌2小时后,用旋转蒸发器浓缩反应物。真空泵下干燥残余物,且粗品无需进一步纯化即用于下一步骤。
于0 ℃,向搅拌的、于5 mL的吡啶中的3-(3-氨基-1H-吲唑-6-基)苯甲酸乙酯(160 mg)溶液中,加入于4 mL的DMF中的以上的酰氯的混悬液。然后,将反应逐渐温热至室温和搅拌过夜。经反相分析用液相-色谱电喷雾质谱(LC-MS)监测反应完成后,加入100 mL的二氯甲烷和用盐水洗涤得到的混合物。有机层经无水硫酸钠干燥和浓缩。残余物经硅胶色谱法用二氯甲烷∶3.5 N氨甲醇溶液(50∶1 v/v)纯化,得到标题化合物(126 mg),MS
m/z:484.22 (M + 1)。
3-(3-(4-(4-甲基哌嗪 -1- 基 ) 苯甲酰胺基 )-1H- 吲唑 -6- 基 )-N-(3-( 三氟代甲基 ) 苯基 ) 苯甲酰胺
向THF/MeOH (2.0 mL/2.0 mL)中的3-(3-(环丙烷甲酰胺基)-1H-吲唑-6-基)苯甲酸乙酯(121 mg, 0.25 mmol)溶液中,加入2.0
mL的1.0 N氢氧化锂水溶液。于室温搅拌反应混合物。由LC-MS监测完全反应后,去除溶剂至三分之一和用1 N HCl溶液调节pH至约6。得到的沉淀物经过滤、真空中干燥和不经进一步纯化即使用。
向1.0 mL的DMSO中的以上的酸(23 mg, 0.05 mmol)溶液中,加入3-(三氟甲基)苄胺(25 μL, 0.20 mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟代磷酸盐(HATU) (38 mg, 0.10 mmol)和DIEA (52 μL, 0.30 mmol)。于室温搅拌反应混合物过夜,并经反相制备型HPLC用水(0.05%
TFA)/乙腈(0.05% TFA)梯度纯化,得到作为TFA盐的标题化合物(8 mg),MS m/z:599.23(M + 1)。
流程
6
N-(6-溴代 -1-((2-( 三甲基甲硅烷基 ) 乙氧基 ) 甲基 )-1H- 吲唑 -3- 基 ) 环丙烷 - 甲酰胺
于0 ℃,向于DMF
(20 mL)中的6-溴代-1H-吲唑-3-胺(560 mg, 2.0
mmol)溶液中,加入氢化钠(160 mg, 60%于矿物油中)。30 mins后,逐滴加入(2-(氯代甲氧基)乙基)三甲基硅烷(0.39 mL, 2.2
mmol)。于0 ℃搅拌反应物直至其经LC-MS监测反应完全。将得到的混合物倾倒入冰水中并用乙酸乙酯提取。有机层经用盐水洗涤,经无水硫酸钠干燥和真空中浓缩。粗残余物经快速色谱法用1∶5 (v/v)乙酸乙酯-己烷纯化,得到标题产物(548 mg, 67%),MS
(ESI) m/z 411 (M+H)+。
3-(3-( 环丙烷甲酰胺基 )-1-((2-( 三甲基甲硅烷基 ) 乙氧基 ) 甲基 )-1H- 吲唑 -6- 基氨基 )-4- 甲基 -N-(3-( 三氟代甲基 ) 苯基 ) 苯甲酰胺
向于t-BuOH (1.5 mL)中的N-(6-溴代-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-3-基)环-丙烷甲酰胺(41 mg, 0.1 mmol)溶液中,加入3-氨基-4-甲基-N-(3-(三氟代甲基)-苯基)苯甲酰胺(29 mg, 0.1 mmol)和K2CO3
(42 mg, 0.3 mmol)。将反应混合物除气10分钟。向混合物中加入Pd2(dba)3 (6.0 mg)和t-Bu-X-phos (4 mg)。于100 ℃加热反应混合物直至其经LC-MS监测反应完全。然后,经硅藻土垫过滤得到的混合物,并用二氯甲烷稀释。经旋转蒸发器去除溶剂,和粗残余物经快速色谱法用二氯甲烷-甲醇纯化,得到标题产物(25 mg, 40%),MS
(ESI) m/z 624 (M+H)+。
3-(3-( 环丙烷甲酰胺基 )-1H- 吲唑 -6- 基氨基 )-4- 甲基 -N-(3-( 三氟 - 甲基 ) 苯基 ) 苯甲酰胺
于室温,向于CH2Cl2 (1 mL)中的3-(3-(环丙烷甲酰胺基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-吲唑-6-基氨基)-4-甲基-N-(3-(三氟代甲基)苯基)苯甲酰胺(25 mg)溶液中,加入TFA (0.25 mL)。搅拌反应混合物2个小时和减压下浓缩有机溶剂。向得到的混合物于THF
(0.5 mL)和MeOH (0.5 mL)中的溶液中,加入LiOH水性溶液(1.0 M, 1.0 mL)。再于室温搅拌得到的混合物另外2小时。减压下去除有机溶剂,和用乙酸乙酯提取水层。有机提取物经用盐水洗涤,经MgSO4干燥和减压下浓缩。粗产物经制备型HPLC纯化和减压下去除乙腈。残余的水经冷冻干燥,以得到标题化合物TFA盐(16 mg, 66 %),MS
(ESI) m/z 494 (M+H)+。
化合物和生物反应试剂
最初将所有化合物溶解于DMSO中制成10 mM储备溶液,然后系列稀释以得到体外实验用的终浓度。
细胞系和细胞培养
通过用含p210BCR-ABL (B2A2) cDNA的pGD载体转染IL-3-依赖的海洋生物造血Ba/F3细胞系,获得Ba/F3 p210细胞(Daley和Baltimore, 1988;Sattler等,1996;Okuda等,1996)。用逆转录病毒转导海洋生物造血32D细胞,以表达p210 BCR-ABL
(32D.p210细胞) (Matulonis等,1993);通过电穿孔用聚藏(harboring)点突变T315I (Weisberg等,2005)的伊马替尼抵抗的BCR-ABL构件(pCI-neo哺乳动物表达载体;Promega (#E1841)转染32D-T315I细胞系。通过电穿孔用聚藏点突变T315I、F317L、F486S和M351T的伊马替尼抵抗的BCR-ABL构件(pCI-neo哺乳动物表达载体;Promega (#E1841)稳定转染Ba/F3细胞;选择转染剂用于新霉素抵抗和IL-3-依赖的生长(Weisberg等,2005)。通过电穿孔用BCR-ABL点突变稳定转染Ba/F3细胞,所述BCR-ABL点突变由在赋予抵抗尼罗替尼的BCR-ABL点突变异种:Q252H、E292K、Y253C、Y253H、E255K和V289L (Ray等,2007)的随机突变筛查中鉴别。如由Golub等,1994和Carroll等,1996描述的,制备Ba/F3细胞以表达Tel-PDGFRβ。通过电穿孔将克隆进pcDNA3.1的D842V-PDGFRα和V561D-PDGFRα cDNA的构件稳定转染进Ba/F3细胞,并如Weisberg等,2006描述的,选择对于新霉素抵抗和IL3-依赖的生长的细胞。
于37 ℃,在含有10%胎牛血清(FCS)并补充1 % L-谷氨酰胺的RPMI (Mediatech, Inc., Herndon, VA)中用5% CO2培养所有细胞系。类似地用作为IL-3源的15% WEHI-调理的培养基培养亲代Ba/F3细胞。在补充l mg/ml G418的培养基中培养转染的细胞系。
抗体和免疫印迹和免疫沉淀
在免疫印迹中使用1∶1000的抗-p-Tyr (克隆4G10, Upstate
Biotechnology, NY)。在免疫印迹中使用1∶1000 的ABL抗体(克隆24-21,
Calbiochem, San Diego, CA)。在免疫印迹中使用1∶1000的KIT抗体(C-19, Santa Cruz Biotechnology, CA)。在免疫印迹中使用1∶1000的磷酸化-KIT抗体(Tyr7 19, Cell
Signaling, Danvers, MA )。在免疫印迹中使用1∶200的PDGFRA抗体(C-20, Santa Cruz Biotechnology, CA)。使用1∶2000稀释液的单克隆抗-β-肌动蛋白抗体(克隆AC-15) (Sigma-Aldrich,
St. Louis, MO)。细胞在细胞溶解缓冲液(0.02 M Tris [pH 8.0]、0.15 M NaCl、10%丙三醇、1 % NP-40 (wt/vol)、0.1 M
NaF、1 mM苯基甲基磺酰氟、1 mM原钒酸钠、40 μg/ml亮抑酶肽和20 μg/ml抑肽酶)中溶解。在冰上孵育蛋白溶解产物25 min,间隔5 min漩涡式振荡(vortexing),然后于12,000 x g离心1 5
min。保留上清液和用Bio-Rad蛋白试验法(Bio-Rad
Protein Assay)测定蛋白收率(Bio-Rad Laboratories, Hercules, CA)。随后将等价量的蛋白直接加载于凝胶上进行免疫印迹实验。对于免疫沉淀,于4 ℃不停摇动中,用FLT3/Flk-2 (C-20)抗体和蛋白A琼脂糖凝胶(Sepharose)孵育细胞溶解产物过夜。作为对照,也单用蛋白A琼脂糖凝胶磁珠孵育细胞溶解产物。孵育后,用细胞溶解缓冲液洗涤免疫复合物2x,用1x PBS洗涤2x,并经煮沸5 min将其溶解于Laemmeli' s样品缓冲液中。对于免疫印迹和免疫沉淀,将全部细胞溶解产物和免疫复合物分别溶解于十二烷基硫酸钠(SDS)-7.5%聚丙烯酰胺凝胶。随后,将蛋白经电泳转移到Protran硝酸纤维素转移和固定膜(Schleicher
and Schuell, Dassel, Germany)。然后于4 ℃用在1 x TBS (10 mM Tris-HCl [pH 8.0]、150 mM NaCl)中的5%脱脂奶粉封闭该膜过夜,然后于25 ℃用pTYR、抗体经探针探测2 hr,或于4 ℃用于l x TBST缓冲液(10 mM Tris-HCl
[pH 8.0]、150 mM NaCl、0.05% Tween20)中的FLT3/Flk-2
(C-20)抗体探测过夜。用l x TBST洗涤3次后,于25 ℃用抗-小鼠免疫球蛋白(来自绵羊的辣根过氧化酶-交联的全抗体)或抗-兔免疫球蛋白(来自驴的辣根过氧化酶交联的全抗体)
(Amersham Life Science, Inc., Arlington Heights, IL)孵育膜1 hr。在各次变换缓冲液之间间隔5 min,在1 x TBST缓冲液中洗涤膜5x,并按制造商(NEN Life Science Products, Boston, MA)的详细说明,用增强的鲁米诺和氧化剂探测结合的抗体。于50 ℃,用脱膜缓冲液(2%
SDS、0.0625 mol/L Tris [pH 6.8]和0.7% 2-巯基乙醇)去除结合的抗体30 min。然后,用额外的抗体经探针探测滤器。
细胞周期分析
采用约500,000个细胞进行细胞周期分析,所述细胞于1500
rpm离心5 min,在PBS中洗涤和将细胞团粒再悬浮于500 μl的碘化丙啶(propidium iodide)溶液(50 μg/ml碘化丙啶、0.1 % NP-40、0.1 %柠檬酸钠)中。将混合物在暗处存储于4 ℃最少15 min,然后经流式细胞仪分析。采用Annexin-V-Fluos染色试剂盒(Annexin-V-Fluos
Staining Kit) (Boehringer Mannheim, Indianapolis)检测药物-处理的细胞的细胞凋亡。
细胞凋亡试验
将在药物中或没有药物中培养的细胞用磷酸盐-缓冲盐水(PBS)洗涤l x,并于1500 rpm离心5 min。将洗涤的细胞团粒再悬浮于100 μl的于HEPES缓冲液中的20% Annexin-V-荧光素标记的试剂和20%碘化丙啶(PI)中。于室温孵育细胞15 min,随后用0.8 ml的HEPES缓冲液稀释。然后,经流式细胞仪分析样品。作为对照,单用PI、单用Annexin-V-荧光素标记的试剂或HEPES缓冲液孵育细胞15 min,然后用HEPES缓冲液稀释和用流式细胞仪分析。
药物组合研究
对于药物组合研究,以固定比率同时将化合物加入细胞中,并通过台盼蓝拒染(trypan
blue exclusion)测定细胞生存能力,并表达为影响生长的(FA)药物-处理相比于对照细胞的功能。通过Calcusyn软件(Biosoft, Ferguson, MO and Cambridge, UK),采用Chou-Talalay法(Chou和Talalay, 1984)评估协同作用。合用指数(combination
index) = [D]1 [Dx]1 + [D]2/[Dx]2,此处[D]1和[D]2为各药物在组合中达到如单用各药物浓度[Dx]1和[Dx]2时相同效应的必需的浓度。小于1的值表示协同作用,而大于1的值表示拮抗作用。
活体成像技术
用逆转录病毒编码的萤火虫荧光素酶(SCV-Luc)转导细胞,和用2 μg/ml嘌呤霉素挑选细胞以产生32D.p210-luc+细胞,如由Weisberg等,2005描述的那样。按照如由Weisberg等,2005描述的相同方案,用MSCV-luc-neo载体转导Ba/F3-KIT-T670I细胞。
激酶筛查
利用KINOMEscan™ (Ambit Biosciences, San Diego, CA),一种高产量的筛查对抗大批的(a large panel of)人类激酶的小分子试剂的方法。该技术是竞争结合试验,检测出化合物对抗350个激酶的选择性,所述激酶各自融合至专有的标记物。在存在及不存在化合物下,检测各激酶结合至固定不动的、活性位点导向的配体的量。
表和数字
表
I.
表 I. 化合物抑制激酶靶标的IC50值(以微摩尔的单位计)。
等价物
本领域技术人员将会认识到或仅采用常规实验能够确定本文描述的特定实施方案和方法的许多等价物。以下的权力要求书的范畴意欲包括这样的等价物。
通过参考结合
本文引用的所有专利、出版的专利申请和其他参考文献的全部内容,通过全文参考特别地结合于本文。
Claims (40)
1.一种式I化合物:
及其药学上可接受的盐、对映体、立体异构体、旋转异构体、互变异构体、非对映异构体或外消旋体,其中:
X是NR、O、S或键;
其中R选自H和C1-6烷基;
R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基;
其中C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基可被杂环基或杂环基-C1-6烷基独立地取代一次或多次;
RA选自H、C1-6烷基、C1-6烷氧基和QR5,前提条件是RA的至少一个实例是QR5;
其中Q选自-C(O)-、-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-;和
R5选自C1-6烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷基氧基、杂环基或苯基环;
其中C1-6烷基、C3-6环烷基、C3-6杂环烷基、C1-6烷基氧基、杂环基或苯基环任选被下列基团独立地取代一次或多次:C1-6烷基、C2-6烯基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基;和
n选自1-5。
2.一种式I化合物:
及其药学上可接受的盐、对映体、立体异构体、旋转异构体、互变异构体、非对映异构体或外消旋体,其中:
X是NR、O、S或键;
其中R选自H和C1-6烷基;
R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基;
其中C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基可被杂环基或杂环基-C1-6烷基独立地取代一次或多次;
RA选自H、C1-6烷基、C1-6烷氧基和QR5,前提条件是RA的至少一个实例是QR5;
其中Q选自-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-;
R5是任选被下列基团独立地取代一次或多次的苯基环:C1-6烷基、C2-6烯基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基;和
n选自1-5。
3.一种式II的依据权利要求1的化合物:
及其药学上可接受的盐、对映体、立体异构体、旋转异构体、互变异构体、非对映异构体或外消旋体,其中:
X是NR、O、S或键;
其中R选自H和C1-6烷基;
R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基和C(O)-苯基;
其中苯基可被H、杂环基或杂环基-C1-6烷基独立地取代一次或多次;
R2选自H和C1-6烷基;和
R3和R4任选独立地选自H和QR5,前提条件是R3和R4的任一个是H而另一个是QR3;
其中Q选自-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-;
R5是任选被下列基团独立地取代一次或多次的苯基环:H、C1-6烷基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基;
其中杂环基部分可被取代或未被取代。
4.以上权利要求的任一项的化合物,其中R1a是C(O)-苯基和苯基未被取代。
5.权利要求3-4的任一项的化合物,其中:
R2选自H或C1-6烷基;
R3和R4任选独立地选自H和QR5,前提条件是R3和R4的任一个是H而另一个是QR5;
其中Q选自-C(O)N(H)-、-NHC(O)-和-N(H)C(O)N(H)-;
R5是任选被下列基团独立地取代一次或多次的苯基环:H、C1-6烷基、C1-6杂烷基、C1-6单卤代烷基、C1-6二卤代烷基、C1-6三卤代烷基、杂环基、杂芳基、杂芳基-C1-6烷基或C1-6烷基-杂环基-C1-6烷基;
其中杂环基部分可被取代或未被取代。
7.权利要求3-6的任一项的化合物,其中R2是H或C1-6烷基。
8.权利要求3-7的任一项的化合物,其中R3是H或QR5。
9.权利要求3-8的任一项的化合物,其中R4是H或QR5。
10.权利要求6-9的任一项的化合物,其中R6是H。
11.权利要求6-10的任一项的化合物,其中R7是H、C1-6卤代烷基或杂芳基-C1-6烷基。
12.权利要求6-11的任一项的化合物,其中R8是H或C1-6烷基-杂环基-C1-6烷基。
13.权利要求6-12的任一项的化合物,其中R9是H、C1-6卤代烷基、杂芳基-C1-6烷基。
14.权利要求6-13的任一项的化合物,其中:
X是NR、O、S或键;
其中R选自H和C1-6烷基;
R1a和R1b任选独立地选自H、C1-6烷基、C(O)-C3-6环烷基、C(O)-苯基和C(O)-苯基-哌嗪基-C1-6烷基;
R2是H或C1-6烷基;
R3是H或QR5;
R4是H或QR5;
其中R5是:
其中R6是H;
R7选自H、C1-6三卤代烷基和杂环基-C1-6烷基;
R8选自H和C1-6烷基-杂环基-C1-6烷基;
R9选自H、C1-6三卤代烷基和杂环基-C1-6烷基。
17.以上权利要求任一项的化合物,其中X是NR。
18.以上权利要求任一项的化合物,其中X是O。
19.以上权利要求任一项的化合物,其中X是S。
20.以上权利要求任一项的化合物,其中X是键。
22.权利要求6-21的任一项的化合物,其中:
R1a是C(O)-环丙基;
R1b是H;
R2是H;
R3和R4各自独立为H或QR5,前提条件是R3和R4之一是H而另一个是QR5;
其中R5是:
其中R6是H;
R7是CF3;
R8是H或1-乙基-4-甲基哌嗪基;
R9是H或4-甲基-1H-咪唑基。
24.以上权利要求的任一项的化合物,其中式I化合物选自列于表A的化合物。
25.一种治疗癌症的方法,该方法包括给予需要的受试者权利要求1-24的任一项的化合物。
26.权利要求25的方法,其中的癌症选自腺癌、多发性骨髓瘤、慢性骨髓性白血病、胰腺癌、非小细胞肺癌、肺癌、乳腺癌、结肠癌、卵巢癌、宫颈癌、子宫癌、前列腺癌、恶性黑色素瘤、非黑色素瘤皮肤癌、胃肠型间质瘤、血液肿瘤、恶性血液病、儿童白血病、儿童淋巴瘤、多发性骨髓瘤、何杰金氏病、淋巴细胞来源的淋巴瘤、源于皮肤的淋巴瘤、急性白血病、慢性白血病、急性成淋巴细胞白血病、急性髓细胞性白血病、慢性髓细胞性白血病、浆细胞性肿瘤、淋巴肿瘤和与AIDS相关的癌症。
27.权利要求25-26的任一项的方法,其中的癌症是胰腺癌或非小细胞肺癌。
28.权利要求25-27的任一项的方法,其中的癌症是胃肠型间质瘤或慢性骨髓性白血病。
29.权利要求25-28的任一项的方法,其中的癌症对用格列卫或伊马替尼的治疗有抵抗。
30.权利要求29的方法,其中治疗抵抗是由于Abl激酶、BCR-Abl激酶域、c-kit激酶、EML4-ALK激酶、TEL-ALK激酶、Src激酶或PDGFR激酶中的一点或多点-突变。
31.权利要求1-24的任一项的化合物在制备治疗受试者的癌症的药物中的应用。
32.权利要求31的应用,其中癌症选自多发性骨髓瘤、慢性骨髓性白血病、胰腺癌、非小细胞肺癌、肺癌、乳腺癌、结肠癌、卵巢癌、前列腺癌、恶性黑色素瘤、非黑色素瘤皮肤癌、胃肠型间质瘤、血液肿瘤、恶性血液病、儿童白血病、儿童淋巴瘤、何杰金氏病、淋巴细胞来源的淋巴瘤、源于皮肤的淋巴瘤、急性白血病、慢性白血病、急性成淋巴细胞白血病、急性髓细胞性白血病、慢性髓细胞性白血病、浆细胞性肿瘤、淋巴肿瘤和与AIDS相关的癌症。
33.权利要求31-32的任一项的应用,其中的癌症是胰腺癌或非小细胞肺癌。
34.权利要求31-33的任一项的应用,其中的癌症是胃肠型间质瘤或慢性骨髓性白血病。
35.一种抑制激酶活性的方法,该方法包括利用权利要求1-24的任一项的化合物。
36.一种抑制激酶活性的方法,其中激酶选自Abl、Abl
(T315I)、BCR-Abl、ALK、BLK、CDK5、CDK2、CDK3、CDK7、CDK8、CSFIR、EML4-ALK、FAK、FER、FLT1、FLT3、FLT4、HIPK4、JNK2、KDR、kit、LCK、p38、RET、RIPK1、SLK、TEL-ALK、TIE1、TNK1、TTK,该方法包括利用权利要求1-24的任一项的化合物。
37.一种抑制Abl激酶、BCR-Abl激酶和c-kit激酶的活性的方法,该方法包括利用权利要求1-24的任一项的化合物。
38.一种在受试者中治疗疾病的方法,其中疾病的病因学或进展至少部分由Abl激酶、BCR-Abl激酶域、c-kit激酶、EML4-ALK激酶、TEL-ALK激酶、NPM-ALK、Src激酶或PDGFR激酶的活性介导,该方法包括给予受试者权利要求1-24的任一项的化合物。
39.一种治疗癌症的方法,该方法包括联合药学上有效量的另外的抗癌剂,给予有需要的受试者权利要求1-21的任一项的化合物。
40.权利要求39的方法,其中其他的抗癌剂是伊马替尼或尼罗替尼。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US31440210P | 2010-03-16 | 2010-03-16 | |
US61/314,402 | 2010-03-16 | ||
PCT/US2011/025423 WO2011115725A2 (en) | 2010-03-16 | 2011-02-18 | Indazole compounds and their uses |
Publications (1)
Publication Number | Publication Date |
---|---|
CN103080093A true CN103080093A (zh) | 2013-05-01 |
Family
ID=43971357
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN2011800243883A Pending CN103080093A (zh) | 2010-03-16 | 2011-02-18 | 吲唑化合物及其应用 |
Country Status (11)
Country | Link |
---|---|
US (1) | US8987275B2 (zh) |
EP (1) | EP2547661A2 (zh) |
JP (1) | JP2013522292A (zh) |
KR (1) | KR20130006664A (zh) |
CN (1) | CN103080093A (zh) |
AU (1) | AU2011227643A1 (zh) |
BR (1) | BR112012023021A2 (zh) |
CA (1) | CA2791613A1 (zh) |
EA (1) | EA201290919A1 (zh) |
MX (1) | MX2012010617A (zh) |
WO (1) | WO2011115725A2 (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020087565A1 (zh) * | 2018-11-02 | 2020-05-07 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类激酶抑制剂及其用途 |
CN115087651A (zh) * | 2019-10-03 | 2022-09-20 | 百时美施贵宝公司 | 作为激酶抑制剂的吲唑甲酰胺 |
Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102482277B (zh) | 2009-05-05 | 2017-09-19 | 达纳-法伯癌症研究所有限公司 | 表皮生长因子受体抑制剂及治疗障碍的方法 |
AU2010343102B2 (en) | 2009-12-29 | 2016-03-24 | Dana-Farber Cancer Institute, Inc. | Type II Raf kinase inhibitors |
WO2012088266A2 (en) | 2010-12-22 | 2012-06-28 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of fgfr3 |
WO2012127030A1 (en) * | 2011-03-23 | 2012-09-27 | Proteosys Ag | Arylpiperazines as neuroprotective agents |
JP6106685B2 (ja) | 2011-11-17 | 2017-04-05 | ダナ−ファーバー キャンサー インスティテュート, インコーポレイテッド | C−jun−n−末端キナーゼ(jnk)の阻害剤 |
KR102406771B1 (ko) | 2012-06-13 | 2022-06-13 | 인사이트 홀딩스 코포레이션 | Fgfr 억제제로서 치환된 트리사이클릭 화합물 |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
WO2014063068A1 (en) | 2012-10-18 | 2014-04-24 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
US9758522B2 (en) | 2012-10-19 | 2017-09-12 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged small molecules as inducers of protein degradation |
US10000483B2 (en) | 2012-10-19 | 2018-06-19 | Dana-Farber Cancer Institute, Inc. | Bone marrow on X chromosome kinase (BMX) inhibitors and uses thereof |
EP2914266B1 (en) * | 2012-11-01 | 2019-06-19 | University of South Carolina | Cdk8/cdk19 selective inhibitors for use in a method for treating prostate cancer |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
EP3318564B1 (en) | 2013-04-19 | 2021-07-28 | Incyte Holdings Corporation | Bicyclic heterocycles as fgfr inhibitors |
AU2014337044A1 (en) | 2013-10-18 | 2016-05-05 | Dana-Farber Cancer Institute, Inc. | Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7) |
US20160264551A1 (en) | 2013-10-18 | 2016-09-15 | Syros Pharmaceuticals, Inc. | Heteroaromatic compounds useful for the treatment of prolferative diseases |
US10017477B2 (en) | 2014-04-23 | 2018-07-10 | Dana-Farber Cancer Institute, Inc. | Janus kinase inhibitors and uses thereof |
WO2015164604A1 (en) | 2014-04-23 | 2015-10-29 | Dana-Farber Cancer Institute, Inc. | Hydrophobically tagged janus kinase inhibitors and uses thereof |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
AU2015360291A1 (en) | 2014-12-11 | 2017-07-13 | President And Fellows Of Harvard College | Inhibitors of cellular necrosis and related methods |
US10336707B2 (en) | 2014-12-16 | 2019-07-02 | Eudendron S.R.L. | Heterocyclic derivatives modulating activity of certain protein kinases |
CA2972239A1 (en) | 2014-12-23 | 2016-06-30 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinase 7 (cdk7) |
ES2751669T3 (es) | 2015-02-20 | 2020-04-01 | Incyte Corp | Heterociclos bicíclicos como inhibidores FGFR |
WO2016134294A1 (en) | 2015-02-20 | 2016-08-25 | Incyte Corporation | Bicyclic heterocycles as fgfr4 inhibitors |
MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
CA2978518C (en) | 2015-03-27 | 2023-11-21 | Nathanael S. Gray | Inhibitors of cyclin-dependent kinases |
AU2016276963C1 (en) | 2015-06-12 | 2021-08-05 | Dana-Farber Cancer Institute, Inc. | Combination therapy of transcription inhibitors and kinase inhibitors |
CA2996978A1 (en) | 2015-09-09 | 2017-03-16 | Dana-Farber Cancer Institute, Inc. | Inhibitors of cyclin-dependent kinases |
KR20170085619A (ko) * | 2016-01-14 | 2017-07-25 | 연세대학교 산학협력단 | Alk 저해제에 대한 내성을 획득한 eml4-alk 양성 비소세포폐암의 치료를 위한 스타틴계 약물의 용도 |
EP3512837B1 (en) * | 2016-09-15 | 2020-07-22 | Boehringer Ingelheim International GmbH | Pyridine and pyrazine compounds as inhibitors of ripk2 |
AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
DK3788047T3 (da) | 2018-05-04 | 2024-09-16 | Incyte Corp | Faste former af en FGFR-inhibitor og fremgangsmåder til fremstilling deraf |
MA52493A (fr) | 2018-05-04 | 2021-03-10 | Incyte Corp | Sels d'un inhibiteur de fgfr |
WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
WO2021007269A1 (en) | 2019-07-09 | 2021-01-14 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
WO2021046515A1 (en) | 2019-09-06 | 2021-03-11 | Board Of Regents, The University Of Texas System | Inhibitors of receptor interacting protein kinase i for the treatment of disease |
BR112022005627A2 (pt) | 2019-09-27 | 2022-07-12 | Univ Texas | Composto de fórmula estrutural i ou um sal do mesmo, composição farmacêutica e uso de um composto |
WO2021076602A1 (en) | 2019-10-14 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
WO2021076728A1 (en) | 2019-10-16 | 2021-04-22 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
CA3162605A1 (en) | 2019-11-26 | 2021-06-03 | Board Of Regents, The University Of Texas System | Inhibitors of receptor interacting protein kinase i for the treatment of disease |
CA3163875A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
CN115151539A (zh) | 2019-12-04 | 2022-10-04 | 因赛特公司 | Fgfr抑制剂的衍生物 |
US12012409B2 (en) | 2020-01-15 | 2024-06-18 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
JP2024513575A (ja) | 2021-04-12 | 2024-03-26 | インサイト・コーポレイション | Fgfr阻害剤及びネクチン-4標的化剤を含む併用療法 |
CA3220274A1 (en) | 2021-06-09 | 2022-12-15 | Incyte Corporation | Tricyclic heterocycles as fgfr inhibitors |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040235892A1 (en) * | 2003-05-22 | 2004-11-25 | Yujia Dai | Indazole and benzisoxazole kinase inhibitors |
WO2004113303A1 (en) * | 2003-06-26 | 2004-12-29 | Astrazeneca Ab | INDAZOLE/PYRZOLO[4,3-c]PYRIDIN DERIVATIVES AS JNK INHIBITORS, COMPOSITIONS AND METHODS RELATED THERETO AS WELL AS INTERMEDIATE THEREOF |
WO2007024680A1 (en) * | 2005-08-22 | 2007-03-01 | Amgen Inc. | Pyrazolopyridine and pyrazolopyrimidine compounds useful as kinase enzymes modulators |
WO2009028655A1 (ja) * | 2007-08-30 | 2009-03-05 | Takeda Pharmaceutical Company Limited | 複素環化合物およびその用途 |
Family Cites Families (84)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4231938A (en) | 1979-06-15 | 1980-11-04 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
HU204253B (en) | 1982-11-22 | 1991-12-30 | Sandoz Ag | Process for producing mevalonolactone analogues and derivatives and pharmaceutical compositions containing them |
US4782084A (en) | 1987-06-29 | 1988-11-01 | Merck & Co., Inc. | HMG-COA reductase inhibitors |
US4885314A (en) | 1987-06-29 | 1989-12-05 | Merck & Co., Inc. | Novel HMG-CoA reductase inhibitors |
US5420245A (en) | 1990-04-18 | 1995-05-30 | Board Of Regents, The University Of Texas | Tetrapeptide-based inhibitors of farnesyl transferase |
US5747469A (en) | 1991-03-06 | 1998-05-05 | Board Of Regents, The University Of Texas System | Methods and compositions comprising DNA damaging agents and p53 |
CA2111902A1 (en) | 1992-12-21 | 1994-06-22 | Jack Beuford Campbell | Antitumor compositions and methods of treatment |
WO1994019357A1 (en) | 1993-02-23 | 1994-09-01 | Merrell Dow Pharmaceuticals Inc. | Farnesyl:protein transferase inhibitors as anticancer agents |
CA2118985A1 (en) | 1993-04-02 | 1994-10-03 | Dinesh V. Patel | Heterocyclic inhibitors of farnesyl protein transferase |
JPH09500615A (ja) | 1993-05-14 | 1997-01-21 | ジェネンテク,インコーポレイテッド | Ras−ファルネシル転移酵素阻害剤 |
US5602098A (en) | 1993-05-18 | 1997-02-11 | University Of Pittsburgh | Inhibition of farnesyltransferase |
US5728830A (en) | 1993-09-22 | 1998-03-17 | Kyowa Hakko Kogyo Co., Ltd. | Farnesyltransferase inhibitor |
ES2164717T3 (es) | 1993-10-15 | 2002-03-01 | Schering Corp | Compuestos triciclicos de sulfonamida utiles para inhibir la funcion de la proteina-g y para el tratamiento de enfermedades proliferativas. |
US5661152A (en) | 1993-10-15 | 1997-08-26 | Schering Corporation | Tricyclic sulfonamide compounds useful for inhibition of G-protein function and for treatment of proliferative diseases |
US5719148A (en) | 1993-10-15 | 1998-02-17 | Schering Corporation | Tricyclic amide and urea compounds useful for inhibition of g-protein function and for treatment of proliferative diseases |
US5721236A (en) | 1993-10-15 | 1998-02-24 | Schering Corporation | Tricyclic carbamate compounds useful for inhibition of G-protein function and for treatment of proliferative diseases |
CA2174105C (en) | 1993-10-15 | 2002-02-12 | W. Robert Bishop | Tricyclic carbamate compounds useful for inhibition of g-protein function and for treatment of proliferative diseases |
IL111235A (en) | 1993-10-15 | 2001-03-19 | Schering Plough Corp | Medicinal preparations for inhibiting protein G activity and for the treatment of malignant diseases, containing tricyclic compounds, some such new compounds and a process for the preparation of some of them |
ATE200677T1 (de) | 1993-10-25 | 2001-05-15 | Parke Davis & Co | Substituierte tetra- und pentapeptid hemmstoffe der farnesyl protein transferase |
JPH08505646A (ja) | 1993-11-04 | 1996-06-18 | アボツト・ラボラトリーズ | スクアレンシンテターゼ及びプロテインファルネシルトランスフェラーゼのインヒビターとしてのシクロブタン誘導体 |
US5783593A (en) | 1993-11-04 | 1998-07-21 | Abbott Laboratories | Inhibitors of squalene synthetase and protein farnesyltransferase |
HUT75308A (en) | 1993-11-05 | 1997-05-28 | Warner Lambert Co | Substituted di- and tripeptide inhibitors of protein:farnesyl transferase |
US5484799A (en) | 1993-12-09 | 1996-01-16 | Abbott Laboratories | Antifungal dorrigocin derivatives |
WO1995024612A1 (de) | 1994-03-07 | 1995-09-14 | International Business Machines Corporation | Verfahren und vorrichtung zur schnellen interpolation von zwischenwerten aus periodischen phasenverschobenen signalen und zur erkennung von defekten in einem drehkörper |
JP3969737B2 (ja) | 1994-03-15 | 2007-09-05 | エーザイ株式会社 | イソプレニルトランスフェラーゼ阻害剤 |
US6312699B1 (en) | 1994-03-28 | 2001-11-06 | Uab Research Foundation | Ligands added to adenovirus fiber |
HUT72440A (en) | 1994-03-31 | 1996-04-29 | Bristol Myers Squibb Co | Imidazole-containing inhibitors of farnesyl protein transferase and pharmaceutical compositions containing them |
US5523430A (en) | 1994-04-14 | 1996-06-04 | Bristol-Myers Squibb Company | Protein farnesyl transferase inhibitors |
US5510510A (en) | 1994-05-10 | 1996-04-23 | Bristol-Meyers Squibb Company | Inhibitors of farnesyl protein transferase |
US5563255A (en) | 1994-05-31 | 1996-10-08 | Isis Pharmaceuticals, Inc. | Antisense oligonucleotide modulation of raf gene expression |
EP0764149B1 (fr) | 1994-06-10 | 1999-01-20 | Aventis Pharma S.A. | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
US5571792A (en) | 1994-06-30 | 1996-11-05 | Warner-Lambert Company | Histidine and homohistidine derivatives as inhibitors of protein farnesyltransferase |
WO1996005529A1 (en) | 1994-08-09 | 1996-02-22 | Micron Optics, Inc. | Temperature compensated fiber fabry-perot filters |
CA2155448A1 (en) | 1994-08-11 | 1996-02-12 | Katerina Leftheris | Inhibitors of farnesyl protein transferase |
DE69514367T2 (de) | 1994-08-11 | 2000-07-27 | Banyu Pharmaceutical Co., Ltd. | Substituierte amidderivate |
EP0805154A1 (en) | 1994-08-12 | 1997-11-05 | Banyu Pharmaceutical Co., Ltd. | N,n-disubstituted amic acid derivative |
DE4429506B4 (de) | 1994-08-19 | 2007-09-13 | Degussa Gmbh | Verfahren zur Extraktion natürlicher Carotinoid-Farbstoffe |
DE4429653C2 (de) | 1994-08-20 | 1997-04-03 | Anton Dr More | Konverter und Verfahren zum Frischen von Metallschmelzen insbesondere von Roheisen zu Stahl |
KR100389754B1 (ko) | 1994-11-22 | 2003-10-17 | 코닌클리즈케 필립스 일렉트로닉스 엔.브이. | 반도체장치 |
AU3971295A (en) | 1994-12-09 | 1996-06-26 | Warner-Lambert Company | Substituted tetra- and pentapeptide inhibitors of protein:farnesyl transferase |
EA000164B1 (ru) | 1995-01-09 | 1998-10-29 | Магла Интернэшнл Лтд. | Состав для печати изображения на поверхности изделия из каучукового латекса, способ печати изображения и изделия из каучукового латекса |
AU4915796A (en) | 1995-01-12 | 1996-07-31 | University Of Pittsburgh | Inhibitors of prenyl transferases |
FR2729390A1 (fr) | 1995-01-18 | 1996-07-19 | Rhone Poulenc Rorer Sa | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
FR2730492B1 (fr) | 1995-02-09 | 1997-03-14 | Rhone Poulenc Rorer Sa | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
FR2730491B1 (fr) | 1995-02-09 | 1997-03-14 | Rhone Poulenc Rorer Sa | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
US5700806A (en) | 1995-03-24 | 1997-12-23 | Schering Corporation | Tricyclic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases |
US5684013A (en) | 1995-03-24 | 1997-11-04 | Schering Corporation | Tricyclic compounds useful for inhibition of g-protein function and for treatment of proliferative diseases |
IL117580A0 (en) | 1995-03-29 | 1996-07-23 | Merck & Co Inc | Inhibitors of farnesyl-protein transferase and pharmaceutical compositions containing them |
IL117798A (en) | 1995-04-07 | 2001-11-25 | Schering Plough Corp | Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them |
US5712280A (en) | 1995-04-07 | 1998-01-27 | Schering Corporation | Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases |
WO1996031501A1 (en) | 1995-04-07 | 1996-10-10 | Schering Corporation | Carbonyl-piperazinyl and piperidinil compounds which inhibit farnesyl protein transferase |
US5891872A (en) | 1995-04-07 | 1999-04-06 | Schering Corporation | Tricyclic compounds |
US5831115A (en) | 1995-04-21 | 1998-11-03 | Abbott Laboratories | Inhibitors of squalene synthase and protein farnesyltransferase |
IL118101A0 (en) | 1995-05-03 | 1996-09-12 | Abbott Lab | Inhibitors of farnesyltransferase |
AU6034296A (en) | 1995-06-16 | 1997-01-15 | Warner-Lambert Company | Tricyclic inhibitors of protein farnesyltransferase |
FR2736641B1 (fr) | 1995-07-10 | 1997-08-22 | Rhone Poulenc Rorer Sa | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
AT402617B (de) | 1995-07-11 | 1997-07-25 | Datacon Schweitzer & Zeindl Gm | Anlage zum automatisierten, hermetischen anlage zum automatisierten, hermetischen verschliessen von gehäusen verschliessen von gehäusen |
FR2736638B1 (fr) | 1995-07-12 | 1997-08-22 | Rhone Poulenc Rorer Sa | Nouveaux inhibiteurs de farnesyl transferase, leur preparation et les compositions pharmaceutiques qui les contiennent |
CH690163A5 (fr) | 1995-07-28 | 2000-05-31 | Symphar Sa | Dérivés gem-diphosphonates substitués utiles en tant qu'agents anti-cancers. |
WO1997017070A1 (en) | 1995-11-06 | 1997-05-15 | University Of Pittsburgh | Inhibitors of protein isoprenyl transferases |
EP0862435A4 (en) | 1995-11-22 | 1999-02-03 | Merck & Co Inc | INHIBITORS OF FARNESYL PROTEIN TRANSFERASE |
EP1162201B1 (en) | 1995-12-08 | 2006-03-29 | Janssen Pharmaceutica N.V. | Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivatives |
NZ326035A (en) | 1995-12-22 | 2000-01-28 | Schering Corp | Tricyclic amides useful for inhibition of g-protein function and for treatment of proliferative diseases |
WO1997026246A1 (en) | 1996-01-16 | 1997-07-24 | Warner-Lambert Company | Substituted histidine inhibitors of protein farnesyltransferase |
US6673927B2 (en) | 1996-02-16 | 2004-01-06 | Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. | Farnesyl transferase inhibitors |
JP2001519766A (ja) | 1996-04-03 | 2001-10-23 | メルク エンド カンパニー インコーポレーテッド | ファルネシルタンパク質トランスフェラーゼの阻害剤 |
NZ332712A (en) | 1996-05-22 | 2000-07-28 | Warner Lambert Co | Polypeptide inhibitors of protein farnesyl transferase |
AU709409B2 (en) | 1996-07-15 | 1999-08-26 | Bristol-Myers Squibb Company | Thiadioxobenzodiazepine inhibitors of farnesyl protein transferase |
EP0951285A1 (en) | 1996-12-30 | 1999-10-27 | Merck & Co., Inc. | Inhibitors of farnesyl-protein transferase |
JP2002511054A (ja) | 1996-12-30 | 2002-04-09 | メルク エンド カンパニー インコーポレーテッド | ファルネシル蛋白トランスフェラーゼ阻害薬 |
JP2002536968A (ja) | 1999-01-29 | 2002-11-05 | イムクローン システムズ インコーポレイティド | Kdrに特異的な抗体およびその使用 |
GB9904387D0 (en) | 1999-02-25 | 1999-04-21 | Pharmacia & Upjohn Spa | Antitumour synergistic composition |
WO2000061186A1 (en) | 1999-04-08 | 2000-10-19 | Arch Development Corporation | Use of anti-vegf antibody to enhance radiation in cancer therapy |
PE20010306A1 (es) * | 1999-07-02 | 2001-03-29 | Agouron Pharma | Compuestos de indazol y composiciones farmaceuticas que los contienen utiles para la inhibicion de proteina kinasa |
WO2003051847A1 (en) * | 2001-12-19 | 2003-06-26 | Smithkline Beecham P.L.C. | (1-h-indazol-3-yl) -amide derivatives as gsk-3 inhibitors |
FR2836915B1 (fr) * | 2002-03-11 | 2008-01-11 | Aventis Pharma Sa | Derives d'aminoindazoles, procede de preparation et intermediaires de ce procede a titre de medicaments et compositions pharmaceutiques les renfermant |
CA2486101C (en) | 2002-05-17 | 2009-07-07 | Pharmacia Italia S.P.A. | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
GB0217757D0 (en) * | 2002-07-31 | 2002-09-11 | Glaxo Group Ltd | Novel compounds |
ES2398074T3 (es) * | 2003-05-22 | 2013-03-13 | Abbott Laboratories | Inhibidores de quinasa de tipo indazol, bencisoxazol y bencisotiazol |
FR2871158A1 (fr) * | 2004-06-04 | 2005-12-09 | Aventis Pharma Sa | Indazoles substitues, compositions les contenant, procede de fabrication et utilisation |
DE102004028862A1 (de) * | 2004-06-15 | 2005-12-29 | Merck Patent Gmbh | 3-Aminoindazole |
US7632854B2 (en) * | 2004-11-17 | 2009-12-15 | Pfizer Italia S.R.L. | Aminoindazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
AU2007336335B8 (en) * | 2006-12-20 | 2014-07-24 | Nerviano Medical Sciences S.R.L. | Indazole derivatives as kinase inhibitors for the treatment of cancer |
US20100197688A1 (en) * | 2008-05-29 | 2010-08-05 | Nantermet Philippe G | Epha4 rtk inhibitors for treatment of neurological and neurodegenerative disorders and cancer |
-
2011
- 2011-02-18 AU AU2011227643A patent/AU2011227643A1/en not_active Abandoned
- 2011-02-18 US US13/583,974 patent/US8987275B2/en not_active Expired - Fee Related
- 2011-02-18 EA EA201290919A patent/EA201290919A1/ru unknown
- 2011-02-18 JP JP2013500056A patent/JP2013522292A/ja active Pending
- 2011-02-18 EP EP11713102A patent/EP2547661A2/en not_active Ceased
- 2011-02-18 CA CA2791613A patent/CA2791613A1/en not_active Abandoned
- 2011-02-18 CN CN2011800243883A patent/CN103080093A/zh active Pending
- 2011-02-18 KR KR1020127027019A patent/KR20130006664A/ko not_active Application Discontinuation
- 2011-02-18 WO PCT/US2011/025423 patent/WO2011115725A2/en active Application Filing
- 2011-02-18 BR BR112012023021A patent/BR112012023021A2/pt not_active IP Right Cessation
- 2011-02-18 MX MX2012010617A patent/MX2012010617A/es not_active Application Discontinuation
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040235892A1 (en) * | 2003-05-22 | 2004-11-25 | Yujia Dai | Indazole and benzisoxazole kinase inhibitors |
WO2004113303A1 (en) * | 2003-06-26 | 2004-12-29 | Astrazeneca Ab | INDAZOLE/PYRZOLO[4,3-c]PYRIDIN DERIVATIVES AS JNK INHIBITORS, COMPOSITIONS AND METHODS RELATED THERETO AS WELL AS INTERMEDIATE THEREOF |
WO2007024680A1 (en) * | 2005-08-22 | 2007-03-01 | Amgen Inc. | Pyrazolopyridine and pyrazolopyrimidine compounds useful as kinase enzymes modulators |
WO2009028655A1 (ja) * | 2007-08-30 | 2009-03-05 | Takeda Pharmaceutical Company Limited | 複素環化合物およびその用途 |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2020087565A1 (zh) * | 2018-11-02 | 2020-05-07 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类激酶抑制剂及其用途 |
CN111138426A (zh) * | 2018-11-02 | 2020-05-12 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类激酶抑制剂及其用途 |
CN111138426B (zh) * | 2018-11-02 | 2023-03-10 | 安徽中科拓苒药物科学研究有限公司 | 吲唑类激酶抑制剂及其用途 |
CN115087651A (zh) * | 2019-10-03 | 2022-09-20 | 百时美施贵宝公司 | 作为激酶抑制剂的吲唑甲酰胺 |
Also Published As
Publication number | Publication date |
---|---|
WO2011115725A3 (en) | 2012-12-27 |
EA201290919A1 (ru) | 2013-03-29 |
MX2012010617A (es) | 2012-10-05 |
US8987275B2 (en) | 2015-03-24 |
WO2011115725A2 (en) | 2011-09-22 |
AU2011227643A1 (en) | 2012-09-20 |
CA2791613A1 (en) | 2011-09-22 |
JP2013522292A (ja) | 2013-06-13 |
EP2547661A2 (en) | 2013-01-23 |
BR112012023021A2 (pt) | 2016-05-31 |
US20130184287A1 (en) | 2013-07-18 |
KR20130006664A (ko) | 2013-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN103080093A (zh) | 吲唑化合物及其应用 | |
CN102480966B (zh) | 融合的杂环化合物及其用途 | |
CN107108637B (zh) | 三唑并嘧啶化合物及其用途 | |
JP5629752B2 (ja) | キナーゼインヒビターおよびこれを用いた癌の治療方法 | |
TWI239957B (en) | Tyrosine kinase inhibitors | |
CN104093722B (zh) | 作为TBK1和IKK抑制剂的呋喃并[3,2-b]-和噻吩并[3,2-b]吡啶衍生物 | |
JP5442906B2 (ja) | キナーゼインヒビターおよびこれを用いた癌の治療方法 | |
CN107922431A (zh) | Hpk1抑制剂及其使用方法 | |
CN102574842B (zh) | 用于抑制pi3激酶的吡啶基咪唑酮衍生物 | |
CN101754965A (zh) | Csf-1r抑制剂、组合物及使用方法 | |
CN101568529A (zh) | 作为cdk抑制剂、用于治疗癌症、炎症和病毒感染的杂芳基-杂芳基化合物 | |
US11759450B2 (en) | Substituted benzothiophene analogs as selective estrogen receptor degraders | |
TW200938202A (en) | Heterocyclic compounds | |
CN110461853A (zh) | 苯并噻吩雌激素受体调节剂 | |
CN110831926B (zh) | 新型四氢萘基脲衍生物 | |
CN109906224A (zh) | 三唑吡啶化合物及其应用 | |
CN103596938A (zh) | 噻唑衍生物 | |
CN103402995B (zh) | 吲哚、吲唑衍生物或其盐 | |
US10266535B2 (en) | Inhibitor of FLT3 kinase and use thereof | |
KR20220132538A (ko) | 디하이드로오로테이트 데하이드로게나제를 억제하는 방법 및 조성물 | |
CN103764651B (zh) | 适合治疗癌症疾病的7-氮杂吲哚衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20130501 |