CN115485262A - 低氧诱导因子-2(α)抑制剂及其在疾病治疗中的用途 - Google Patents
低氧诱导因子-2(α)抑制剂及其在疾病治疗中的用途 Download PDFInfo
- Publication number
- CN115485262A CN115485262A CN202180028716.0A CN202180028716A CN115485262A CN 115485262 A CN115485262 A CN 115485262A CN 202180028716 A CN202180028716 A CN 202180028716A CN 115485262 A CN115485262 A CN 115485262A
- Authority
- CN
- China
- Prior art keywords
- cancer
- hydroxy
- fluoro
- compound
- tetrahydro
- 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
- 108010018033 endothelial PAS domain-containing protein 1 Proteins 0.000 title claims abstract description 136
- 239000003112 inhibitor Substances 0.000 title claims abstract description 89
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 41
- 201000010099 disease Diseases 0.000 title claims abstract description 34
- 238000011282 treatment Methods 0.000 title description 26
- 238000000034 method Methods 0.000 claims abstract description 123
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 111
- 201000011510 cancer Diseases 0.000 claims abstract description 62
- 239000012661 PARP inhibitor Substances 0.000 claims abstract description 51
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 claims abstract description 51
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 13
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 319
- -1 methoxy, hydroxy Chemical group 0.000 claims description 307
- 150000001875 compounds Chemical class 0.000 claims description 281
- 150000003839 salts Chemical class 0.000 claims description 122
- 229910052739 hydrogen Inorganic materials 0.000 claims description 114
- 239000001257 hydrogen Substances 0.000 claims description 114
- 125000000217 alkyl group Chemical group 0.000 claims description 109
- 150000002431 hydrogen Chemical class 0.000 claims description 92
- 125000005843 halogen group Chemical group 0.000 claims description 87
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 76
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 66
- 229910052805 deuterium Inorganic materials 0.000 claims description 66
- 125000001188 haloalkyl group Chemical group 0.000 claims description 63
- 125000003545 alkoxy group Chemical group 0.000 claims description 53
- 125000001072 heteroaryl group Chemical group 0.000 claims description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 45
- 125000000623 heterocyclic group Chemical group 0.000 claims description 45
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 37
- 229910052799 carbon Inorganic materials 0.000 claims description 33
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 32
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 31
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 28
- 210000004027 cell Anatomy 0.000 claims description 26
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 25
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 23
- 239000011737 fluorine Substances 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 20
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 125000003107 substituted aryl group Chemical group 0.000 claims description 18
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 16
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 15
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 13
- 125000003342 alkenyl group Chemical group 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 13
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 13
- 206010038389 Renal cancer Diseases 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 208000005017 glioblastoma Diseases 0.000 claims description 12
- 201000010982 kidney cancer Diseases 0.000 claims description 12
- 206010039491 Sarcoma Diseases 0.000 claims description 11
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 206010006187 Breast cancer Diseases 0.000 claims description 10
- 208000026310 Breast neoplasm Diseases 0.000 claims description 10
- 229940127084 other anti-cancer agent Drugs 0.000 claims description 10
- 206010009944 Colon cancer Diseases 0.000 claims description 9
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 9
- 206010033128 Ovarian cancer Diseases 0.000 claims description 9
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 9
- 208000014018 liver neoplasm Diseases 0.000 claims description 9
- 208000002815 pulmonary hypertension Diseases 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 8
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 claims description 8
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 8
- 102000005157 Somatostatin Human genes 0.000 claims description 8
- 108010056088 Somatostatin Proteins 0.000 claims description 8
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 8
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 claims description 8
- JFDZBHWFFUWGJE-NHPOFCFZSA-N [2H]C1=C(C#N)C(=CC(=C1)[2H])[2H] Chemical compound [2H]C1=C(C#N)C(=CC(=C1)[2H])[2H] JFDZBHWFFUWGJE-NHPOFCFZSA-N 0.000 claims description 8
- 150000001721 carbon Chemical group 0.000 claims description 8
- 201000010881 cervical cancer Diseases 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 8
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical group FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 8
- 206010017758 gastric cancer Diseases 0.000 claims description 8
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 claims description 8
- 201000010536 head and neck cancer Diseases 0.000 claims description 8
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 8
- 201000007270 liver cancer Diseases 0.000 claims description 8
- 201000005202 lung cancer Diseases 0.000 claims description 8
- 208000020816 lung neoplasm Diseases 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- NHXLMOGPVYXJNR-ATOGVRKGSA-N somatostatin Chemical compound C([C@H]1C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CSSC[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)N1)[C@@H](C)O)NC(=O)CNC(=O)[C@H](C)N)C(O)=O)=O)[C@H](O)C)C1=CC=CC=C1 NHXLMOGPVYXJNR-ATOGVRKGSA-N 0.000 claims description 8
- 229960000553 somatostatin Drugs 0.000 claims description 8
- 201000011549 stomach cancer Diseases 0.000 claims description 8
- 238000006467 substitution reaction Methods 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 206010005003 Bladder cancer Diseases 0.000 claims description 7
- 206010014733 Endometrial cancer Diseases 0.000 claims description 7
- 206010014759 Endometrial neoplasm Diseases 0.000 claims description 7
- 206010029260 Neuroblastoma Diseases 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 7
- 229910005965 SO 2 Inorganic materials 0.000 claims description 7
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 7
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 201000001441 melanoma Diseases 0.000 claims description 7
- 201000011519 neuroendocrine tumor Diseases 0.000 claims description 7
- 208000007312 paraganglioma Diseases 0.000 claims description 7
- 208000028591 pheochromocytoma Diseases 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 7
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 6
- 208000018142 Leiomyosarcoma Diseases 0.000 claims description 6
- 206010025323 Lymphomas Diseases 0.000 claims description 6
- 206010027406 Mesothelioma Diseases 0.000 claims description 6
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 6
- 208000007913 Pituitary Neoplasms Diseases 0.000 claims description 6
- 208000008601 Polycythemia Diseases 0.000 claims description 6
- 239000002246 antineoplastic agent Substances 0.000 claims description 6
- 150000001602 bicycloalkyls Chemical group 0.000 claims description 6
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 6
- 201000004101 esophageal cancer Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims description 5
- 206010018338 Glioma Diseases 0.000 claims description 5
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims description 5
- 206010052399 Neuroendocrine tumour Diseases 0.000 claims description 5
- 206010061332 Paraganglion neoplasm Diseases 0.000 claims description 5
- 208000026149 Primary peritoneal carcinoma Diseases 0.000 claims description 5
- 125000005360 alkyl sulfoxide group Chemical group 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 201000010260 leiomyoma Diseases 0.000 claims description 5
- 208000016065 neuroendocrine neoplasm Diseases 0.000 claims description 5
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000004361 3,4,5-trifluorophenyl group Chemical group [H]C1=C(F)C(F)=C(F)C([H])=C1* 0.000 claims description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 4
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims description 4
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims description 4
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 4
- 201000001342 Fallopian tube cancer Diseases 0.000 claims description 4
- 208000013452 Fallopian tube neoplasm Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 208000033759 Prolymphocytic T-Cell Leukemia Diseases 0.000 claims description 4
- 208000016624 Retinal neoplasm Diseases 0.000 claims description 4
- 208000026651 T-cell prolymphocytic leukemia Diseases 0.000 claims description 4
- 206010046799 Uterine leiomyosarcoma Diseases 0.000 claims description 4
- 201000005969 Uveal melanoma Diseases 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 4
- 201000002222 hemangioblastoma Diseases 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 4
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 4
- QHNPYBLCZZRWBE-UHFFFAOYSA-N FC1(CC=2C=3C1(CC(C=3C=CC=2OC=1C=C(C#N)C=C(C=1)F)O)O)F Chemical compound FC1(CC=2C=3C1(CC(C=3C=CC=2OC=1C=C(C#N)C=C(C=1)F)O)O)F QHNPYBLCZZRWBE-UHFFFAOYSA-N 0.000 claims description 3
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 claims description 3
- 208000021712 Soft tissue sarcoma Diseases 0.000 claims description 3
- 201000009036 biliary tract cancer Diseases 0.000 claims description 3
- 208000020790 biliary tract neoplasm Diseases 0.000 claims description 3
- 208000019423 liver disease Diseases 0.000 claims description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 229960000572 olaparib Drugs 0.000 claims description 3
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical group FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 claims description 3
- 201000008968 osteosarcoma Diseases 0.000 claims description 3
- 208000010916 pituitary tumor Diseases 0.000 claims description 3
- 201000008933 retinal cancer Diseases 0.000 claims description 3
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 3
- ZWZKHJQCLZIUIT-UHFFFAOYSA-N 1h-indazole-7-carboxamide Chemical compound NC(=O)C1=CC=CC2=C1NN=C2 ZWZKHJQCLZIUIT-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 206010014714 Endocrine neoplasms Diseases 0.000 claims description 2
- 206010065973 Iron Overload Diseases 0.000 claims description 2
- 208000019693 Lung disease Diseases 0.000 claims description 2
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 claims description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 201000003115 germ cell cancer Diseases 0.000 claims description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
- 125000000336 imidazol-5-yl group Chemical group [H]N1C([H])=NC([H])=C1[*] 0.000 claims description 2
- JBXRLVPILRXPNH-UHFFFAOYSA-N indol-6-one Chemical compound O=C1C=CC2=CC=NC2=C1 JBXRLVPILRXPNH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 2
- 125000004304 oxazol-5-yl group Chemical group O1C=NC=C1* 0.000 claims description 2
- 125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 claims description 2
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 claims description 2
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 2
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- 239000011885 synergistic combination Substances 0.000 claims description 2
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 2
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 claims description 2
- 125000004496 thiazol-5-yl group Chemical group S1C=NC=C1* 0.000 claims description 2
- 150000004684 trihydrates Chemical class 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 abstract description 6
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 abstract description 6
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 abstract description 6
- 230000001404 mediated effect Effects 0.000 abstract description 6
- 102100036448 Endothelial PAS domain-containing protein 1 Human genes 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 151
- 239000000203 mixture Substances 0.000 description 125
- 235000019439 ethyl acetate Nutrition 0.000 description 72
- 239000011734 sodium Substances 0.000 description 58
- 239000000243 solution Substances 0.000 description 57
- 239000012044 organic layer Substances 0.000 description 49
- 239000000706 filtrate Substances 0.000 description 47
- 230000002829 reductive effect Effects 0.000 description 46
- 239000004698 Polyethylene Substances 0.000 description 43
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 42
- 238000001914 filtration Methods 0.000 description 41
- 238000001035 drying Methods 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
- 108090000623 proteins and genes Proteins 0.000 description 37
- 239000007787 solid Substances 0.000 description 36
- 239000012267 brine Substances 0.000 description 30
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
- 208000006265 Renal cell carcinoma Diseases 0.000 description 29
- 239000000460 chlorine Substances 0.000 description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 25
- 230000015572 biosynthetic process Effects 0.000 description 25
- 238000010898 silica gel chromatography Methods 0.000 description 25
- 239000012258 stirred mixture Substances 0.000 description 24
- 206010021143 Hypoxia Diseases 0.000 description 23
- 239000003921 oil Substances 0.000 description 23
- 235000019198 oils Nutrition 0.000 description 23
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 22
- 238000002953 preparative HPLC Methods 0.000 description 21
- 239000012299 nitrogen atmosphere Substances 0.000 description 20
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 19
- 125000004432 carbon atom Chemical group C* 0.000 description 19
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 18
- 201000011330 nonpapillary renal cell carcinoma Diseases 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- 230000014509 gene expression Effects 0.000 description 17
- 125000004043 oxo group Chemical group O=* 0.000 description 17
- 235000019000 fluorine Nutrition 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 230000000694 effects Effects 0.000 description 15
- 230000007954 hypoxia Effects 0.000 description 15
- 150000002430 hydrocarbons Chemical group 0.000 description 14
- 230000035772 mutation Effects 0.000 description 14
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 13
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 13
- 239000012298 atmosphere Substances 0.000 description 13
- 239000003795 chemical substances by application Substances 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- 125000006413 ring segment Chemical group 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 12
- 230000001965 increasing effect Effects 0.000 description 12
- 230000005764 inhibitory process Effects 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- 230000037361 pathway Effects 0.000 description 12
- 102000037982 Immune checkpoint proteins Human genes 0.000 description 11
- 108091008036 Immune checkpoint proteins Proteins 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 10
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 10
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 10
- 239000012043 crude product Substances 0.000 description 10
- 230000002950 deficient Effects 0.000 description 10
- SNWQUNCRDLUDEX-UHFFFAOYSA-N inden-1-one Chemical compound C1=CC=C2C(=O)C=CC2=C1 SNWQUNCRDLUDEX-UHFFFAOYSA-N 0.000 description 10
- 238000012552 review Methods 0.000 description 10
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 229940126546 immune checkpoint molecule Drugs 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 238000010791 quenching Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 230000001225 therapeutic effect Effects 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 230000006801 homologous recombination Effects 0.000 description 8
- 238000002744 homologous recombination Methods 0.000 description 8
- 230000001146 hypoxic effect Effects 0.000 description 8
- 229910052742 iron Inorganic materials 0.000 description 8
- 230000004083 survival effect Effects 0.000 description 8
- ATVNHLQIIAOSEM-UHFFFAOYSA-N 3-fluoro-5-hydroxybenzonitrile Chemical compound OC1=CC(F)=CC(C#N)=C1 ATVNHLQIIAOSEM-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 230000004913 activation Effects 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000007429 general method Methods 0.000 description 7
- 238000012746 preparative thin layer chromatography Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 235000018102 proteins Nutrition 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 239000000377 silicon dioxide Substances 0.000 description 7
- 210000000130 stem cell Anatomy 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- 230000002195 synergetic effect Effects 0.000 description 7
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 6
- 239000004215 Carbon black (E152) Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 108010050904 Interferons Proteins 0.000 description 6
- 102000014150 Interferons Human genes 0.000 description 6
- 125000002947 alkylene group Chemical group 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 229930195733 hydrocarbon Natural products 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 229940079322 interferon Drugs 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 208000024891 symptom Diseases 0.000 description 6
- UQNRTPFLTRZEIM-MRWUDIQNSA-N (2s)-2-amino-3-hydroxy-n-[2-methoxy-5-[(z)-2-(3,4,5-trimethoxyphenyl)ethenyl]phenyl]propanamide;hydrochloride Chemical compound Cl.C1=C(NC(=O)[C@@H](N)CO)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 UQNRTPFLTRZEIM-MRWUDIQNSA-N 0.000 description 5
- 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 5
- 229940045513 CTLA4 antagonist Drugs 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 241000872931 Myoporum sandwicense Species 0.000 description 5
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 5
- 125000004414 alkyl thio group Chemical group 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000006303 immediate early viral mRNA transcription Effects 0.000 description 5
- 238000010837 poor prognosis Methods 0.000 description 5
- 230000002685 pulmonary effect Effects 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- 229960001674 tegafur Drugs 0.000 description 5
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 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 4
- 206010067484 Adverse reaction Diseases 0.000 description 4
- 102000004452 Arginase Human genes 0.000 description 4
- 108700024123 Arginases Proteins 0.000 description 4
- 108010006654 Bleomycin Proteins 0.000 description 4
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 4
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 4
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 4
- RJURFGZVJUQBHK-UHFFFAOYSA-N actinomycin D Natural products CC1OC(=O)C(C(C)C)N(C)C(=O)CN(C)C(=O)C2CCCN2C(=O)C(C(C)C)NC(=O)C1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)NC4C(=O)NC(C(N5CCCC5C(=O)N(C)CC(=O)N(C)C(C(C)C)C(=O)OC4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-UHFFFAOYSA-N 0.000 description 4
- 230000006838 adverse reaction Effects 0.000 description 4
- 239000000556 agonist Substances 0.000 description 4
- 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 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 4
- 238000002648 combination therapy Methods 0.000 description 4
- 125000004966 cyanoalkyl group Chemical group 0.000 description 4
- 229960000684 cytarabine Drugs 0.000 description 4
- 210000004292 cytoskeleton Anatomy 0.000 description 4
- 230000003247 decreasing effect Effects 0.000 description 4
- 238000006731 degradation reaction Methods 0.000 description 4
- 230000005782 double-strand break Effects 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- XOPYFXBZMVTEJF-UHFFFAOYSA-N eleutherobin Natural products C1=CC2(OC)OC1(C)C(OC(=O)C=CC=1N=CN(C)C=1)CC(C(=CCC1C(C)C)C)C1C=C2COC1OCC(O)C(O)C1OC(C)=O XOPYFXBZMVTEJF-UHFFFAOYSA-N 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 229930013356 epothilone Natural products 0.000 description 4
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 description 4
- 150000003883 epothilone derivatives Chemical class 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 210000001035 gastrointestinal tract Anatomy 0.000 description 4
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 4
- 230000001939 inductive effect Effects 0.000 description 4
- 150000002576 ketones Chemical class 0.000 description 4
- GFIJNRVAKGFPGQ-LIJARHBVSA-N leuprolide Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CC=C(O)C=C1 GFIJNRVAKGFPGQ-LIJARHBVSA-N 0.000 description 4
- 229960004338 leuprorelin Drugs 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 102000004311 liver X receptors Human genes 0.000 description 4
- 108090000865 liver X receptors Proteins 0.000 description 4
- DQEUYIQDSMINEY-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].[CH2-]C=C DQEUYIQDSMINEY-UHFFFAOYSA-M 0.000 description 4
- 230000002503 metabolic effect Effects 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229960001156 mitoxantrone Drugs 0.000 description 4
- 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 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 description 4
- 230000002018 overexpression Effects 0.000 description 4
- 229960002621 pembrolizumab Drugs 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 229960002930 sirolimus Drugs 0.000 description 4
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 4
- DZMVCVHATYROOS-ZBFGKEHZSA-N soblidotin Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1=CC=CC=C1 DZMVCVHATYROOS-ZBFGKEHZSA-N 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- 230000005751 tumor progression Effects 0.000 description 4
- OOKIODJYZSVHDO-QMYFOHRPSA-N (2s)-n-tert-butyl-1-[(2s)-1-[(2s)-2-[[(2s)-2-[[(2s)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl]-methylamino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carboxamide;hydrochloride Chemical compound Cl.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)NC(C)(C)C)CCC1 OOKIODJYZSVHDO-QMYFOHRPSA-N 0.000 description 3
- 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 3
- GFMMXOIFOQCCGU-UHFFFAOYSA-N 2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C=1C=C(I)C=C(Cl)C=1NC1=C(F)C(F)=CC=C1C(=O)NOCC1CC1 GFMMXOIFOQCCGU-UHFFFAOYSA-N 0.000 description 3
- VOXBZHOHGGBLCQ-UHFFFAOYSA-N 2-amino-3,7-dihydropurine-6-thione;hydrate Chemical compound O.N1C(N)=NC(=S)C2=C1N=CN2.N1C(N)=NC(=S)C2=C1N=CN2 VOXBZHOHGGBLCQ-UHFFFAOYSA-N 0.000 description 3
- NNEAKBWZBQOQDH-UHFFFAOYSA-N 3-(1h-inden-2-yl)pyridine Chemical compound C=1C2=CC=CC=C2CC=1C1=CC=CN=C1 NNEAKBWZBQOQDH-UHFFFAOYSA-N 0.000 description 3
- QNKJFXARIMSDBR-UHFFFAOYSA-N 3-[2-[bis(2-chloroethyl)amino]ethyl]-1,3-diazaspiro[4.5]decane-2,4-dione Chemical compound O=C1N(CCN(CCCl)CCCl)C(=O)NC11CCCCC1 QNKJFXARIMSDBR-UHFFFAOYSA-N 0.000 description 3
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 3
- 108700020463 BRCA1 Proteins 0.000 description 3
- 102000036365 BRCA1 Human genes 0.000 description 3
- 101150072950 BRCA1 gene Proteins 0.000 description 3
- 108091007743 BRCA1/2 Proteins 0.000 description 3
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 3
- 108010021064 CTLA-4 Antigen Proteins 0.000 description 3
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 3
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 3
- 108010077544 Chromatin Proteins 0.000 description 3
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 3
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 description 3
- 108010092160 Dactinomycin Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 108010036781 Fumarate Hydratase Proteins 0.000 description 3
- 102100036160 Fumarate hydratase, mitochondrial Human genes 0.000 description 3
- 208000031448 Genomic Instability Diseases 0.000 description 3
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 3
- 101000831007 Homo sapiens T-cell immunoreceptor with Ig and ITIM domains Proteins 0.000 description 3
- 101000596234 Homo sapiens T-cell surface protein tactile Proteins 0.000 description 3
- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- 108010002350 Interleukin-2 Proteins 0.000 description 3
- 102000000588 Interleukin-2 Human genes 0.000 description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 3
- 102000017578 LAG3 Human genes 0.000 description 3
- 108010000817 Leuprolide Proteins 0.000 description 3
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 206010027476 Metastases Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 206010061309 Neoplasm progression Diseases 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 241000192656 Nostoc Species 0.000 description 3
- 108091034117 Oligonucleotide Proteins 0.000 description 3
- 229930012538 Paclitaxel Natural products 0.000 description 3
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 3
- 101710089372 Programmed cell death protein 1 Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 208000000453 Skin Neoplasms Diseases 0.000 description 3
- 102100024834 T-cell immunoreceptor with Ig and ITIM domains Human genes 0.000 description 3
- 102100035268 T-cell surface protein tactile Human genes 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 description 3
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 3
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 230000035508 accumulation Effects 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 125000003282 alkyl amino group Chemical group 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 229960000473 altretamine Drugs 0.000 description 3
- 230000000340 anti-metabolite Effects 0.000 description 3
- 229940100197 antimetabolite Drugs 0.000 description 3
- 239000002256 antimetabolite Substances 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 229960001561 bleomycin Drugs 0.000 description 3
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 3
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 3
- 229960005243 carmustine Drugs 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 3
- 229960004630 chlorambucil Drugs 0.000 description 3
- 210000003483 chromatin Anatomy 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 229960004397 cyclophosphamide Drugs 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 229960003603 decitabine Drugs 0.000 description 3
- 230000007812 deficiency Effects 0.000 description 3
- XOZIUKBZLSUILX-UHFFFAOYSA-N desoxyepothilone B Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC(C)=CCC1C(C)=CC1=CSC(C)=N1 XOZIUKBZLSUILX-UHFFFAOYSA-N 0.000 description 3
- 125000004663 dialkyl amino group Chemical group 0.000 description 3
- XOPYFXBZMVTEJF-PDACKIITSA-N eleutherobin Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](O)[C@@H]1OC(C)=O XOPYFXBZMVTEJF-PDACKIITSA-N 0.000 description 3
- 230000002124 endocrine Effects 0.000 description 3
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 3
- 229940011871 estrogen Drugs 0.000 description 3
- 239000000262 estrogen Substances 0.000 description 3
- 239000000328 estrogen antagonist Substances 0.000 description 3
- IRSJDVYTJUCXRV-UHFFFAOYSA-N ethyl 2-bromo-2,2-difluoroacetate Chemical compound CCOC(=O)C(F)(F)Br IRSJDVYTJUCXRV-UHFFFAOYSA-N 0.000 description 3
- 229960005420 etoposide Drugs 0.000 description 3
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 3
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 3
- 229960005277 gemcitabine Drugs 0.000 description 3
- 238000003197 gene knockdown Methods 0.000 description 3
- 210000004602 germ cell Anatomy 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 3
- 230000001506 immunosuppresive effect Effects 0.000 description 3
- 238000000099 in vitro assay Methods 0.000 description 3
- 230000002779 inactivation Effects 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 229960002247 lomustine Drugs 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 3
- 229960001428 mercaptopurine Drugs 0.000 description 3
- 230000009401 metastasis Effects 0.000 description 3
- 229960000485 methotrexate Drugs 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229950003600 ombrabulin Drugs 0.000 description 3
- 231100000590 oncogenic Toxicity 0.000 description 3
- 230000002246 oncogenic effect Effects 0.000 description 3
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 description 3
- 229960001592 paclitaxel Drugs 0.000 description 3
- 230000007170 pathology Effects 0.000 description 3
- 229960002340 pentostatin Drugs 0.000 description 3
- 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 3
- 239000006187 pill Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 230000008439 repair process Effects 0.000 description 3
- 201000002220 retinal hemangioblastoma Diseases 0.000 description 3
- 229930002330 retinoic acid Natural products 0.000 description 3
- 229960003440 semustine Drugs 0.000 description 3
- 230000003007 single stranded DNA break Effects 0.000 description 3
- 108010047846 soblidotin Proteins 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229950006050 spiromustine Drugs 0.000 description 3
- ICXJVZHDZFXYQC-UHFFFAOYSA-N spongistatin 1 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C ICXJVZHDZFXYQC-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000011580 syndromic disease Diseases 0.000 description 3
- 108010029464 tasidotin Proteins 0.000 description 3
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 3
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 3
- 229960001278 teniposide Drugs 0.000 description 3
- 229960003087 tioguanine Drugs 0.000 description 3
- 210000004981 tumor-associated macrophage Anatomy 0.000 description 3
- 230000003827 upregulation Effects 0.000 description 3
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 3
- 229960004982 vinblastine sulfate Drugs 0.000 description 3
- 229960004528 vincristine Drugs 0.000 description 3
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 3
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 3
- HZSBSRAVNBUZRA-RQDPQJJXSA-J (1r,2r)-cyclohexane-1,2-diamine;tetrachloroplatinum(2+) Chemical compound Cl[Pt+2](Cl)(Cl)Cl.N[C@@H]1CCCC[C@H]1N HZSBSRAVNBUZRA-RQDPQJJXSA-J 0.000 description 2
- BUSGWUFLNHIBPT-XYBORKQMSA-N (2e,4e,6e)-7-[(1r,5r,6s)-3-[[(2e,4e)-5-cyclohexylpenta-2,4-dienoyl]amino]-5-hydroxy-2-oxo-7-oxabicyclo[4.1.0]hept-3-en-5-yl]hepta-2,4,6-trienoic acid Chemical compound C([C@]([C@H]1O[C@H]1C1=O)(O)/C=C/C=C/C=C/C(=O)O)=C1NC(=O)\C=C\C=C\C1CCCCC1 BUSGWUFLNHIBPT-XYBORKQMSA-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
- SWXOGPJRIDTIRL-DOUNNPEJSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s)-1-amino-3-(1h-indol-3-yl)-1-oxopropan-2-yl]-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-pent Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 SWXOGPJRIDTIRL-DOUNNPEJSA-N 0.000 description 2
- LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 description 2
- CNTMOLDWXSVYKD-PSRNMDMQSA-N (e,4s)-4-[[(2s)-3,3-dimethyl-2-[[(2s)-3-methyl-2-(methylamino)-3-phenylbutanoyl]amino]butanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid Chemical compound OC(=O)C(/C)=C/[C@H](C(C)C)N(C)C(=O)[C@H](C(C)(C)C)NC(=O)[C@@H](NC)C(C)(C)C1=CC=CC=C1 CNTMOLDWXSVYKD-PSRNMDMQSA-N 0.000 description 2
- FONKWHRXTPJODV-DNQXCXABSA-N 1,3-bis[2-[(8s)-8-(chloromethyl)-4-hydroxy-1-methyl-7,8-dihydro-3h-pyrrolo[3,2-e]indole-6-carbonyl]-1h-indol-5-yl]urea Chemical compound C1([C@H](CCl)CN2C(=O)C=3NC4=CC=C(C=C4C=3)NC(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C4=CC(O)=C5NC=C(C5=C4[C@H](CCl)C3)C)=C2C=C(O)C2=C1C(C)=CN2 FONKWHRXTPJODV-DNQXCXABSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-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
- KGRVJHAUYBGFFP-UHFFFAOYSA-N 2,2'-Methylenebis(4-methyl-6-tert-butylphenol) Chemical compound CC(C)(C)C1=CC(C)=CC(CC=2C(=C(C=C(C)C=2)C(C)(C)C)O)=C1O KGRVJHAUYBGFFP-UHFFFAOYSA-N 0.000 description 2
- TXQPXJKRNHJWAX-UHFFFAOYSA-N 2-(3-aminopropylamino)ethylsulfanylphosphonic acid;trihydrate Chemical compound O.O.O.NCCCNCCSP(O)(O)=O TXQPXJKRNHJWAX-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- OPZDXMCOWFPQPE-UHFFFAOYSA-N 2-bromo-4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C(Br)=C1 OPZDXMCOWFPQPE-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 2
- UZFPOOOQHWICKY-UHFFFAOYSA-N 3-[13-[1-[1-[8,12-bis(2-carboxyethyl)-17-(1-hydroxyethyl)-3,7,13,18-tetramethyl-21,24-dihydroporphyrin-2-yl]ethoxy]ethyl]-18-(2-carboxyethyl)-8-(1-hydroxyethyl)-3,7,12,17-tetramethyl-22,23-dihydroporphyrin-2-yl]propanoic acid Chemical compound N1C(C=C2C(=C(CCC(O)=O)C(C=C3C(=C(C)C(C=C4N5)=N3)CCC(O)=O)=N2)C)=C(C)C(C(C)O)=C1C=C5C(C)=C4C(C)OC(C)C1=C(N2)C=C(N3)C(C)=C(C(O)C)C3=CC(C(C)=C3CCC(O)=O)=NC3=CC(C(CCC(O)=O)=C3C)=NC3=CC2=C1C UZFPOOOQHWICKY-UHFFFAOYSA-N 0.000 description 2
- FJHVWOFTAJCONF-UHFFFAOYSA-N 3-amino-5-fluorobenzonitrile Chemical compound NC1=CC(F)=CC(C#N)=C1 FJHVWOFTAJCONF-UHFFFAOYSA-N 0.000 description 2
- WELIVEBWRWAGOM-UHFFFAOYSA-N 3-amino-n-[2-[2-(3-aminopropanoylamino)ethyldisulfanyl]ethyl]propanamide Chemical compound NCCC(=O)NCCSSCCNC(=O)CCN WELIVEBWRWAGOM-UHFFFAOYSA-N 0.000 description 2
- LADBEVQAAMMPOM-UHFFFAOYSA-N 3-fluoro-5-sulfanylbenzonitrile Chemical compound Fc1cc(S)cc(c1)C#N LADBEVQAAMMPOM-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- AKJHMTWEGVYYSE-AIRMAKDCSA-N 4-HPR Chemical compound C=1C=C(O)C=CC=1NC(=O)/C=C(\C)/C=C/C=C(C)C=CC1=C(C)CCCC1(C)C AKJHMTWEGVYYSE-AIRMAKDCSA-N 0.000 description 2
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 2
- IUFLFKASIHPKNZ-UHFFFAOYSA-N 5-fluoropyridin-3-ol Chemical compound OC1=CN=CC(F)=C1 IUFLFKASIHPKNZ-UHFFFAOYSA-N 0.000 description 2
- 102100023990 60S ribosomal protein L17 Human genes 0.000 description 2
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 2
- GOJJWDOZNKBUSR-UHFFFAOYSA-N 7-sulfamoyloxyheptyl sulfamate Chemical compound NS(=O)(=O)OCCCCCCCOS(N)(=O)=O GOJJWDOZNKBUSR-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 102100030907 Aryl hydrocarbon receptor nuclear translocator Human genes 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
- 108010024976 Asparaginase Proteins 0.000 description 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 2
- 108010074708 B7-H1 Antigen Proteins 0.000 description 2
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 2
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 2
- LDZJNMJIPNOYGA-UHFFFAOYSA-N C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O Chemical compound C1=C(OC(C)=O)C(OC)=CC=C1C1=C2C3=CC(OC)=C(OC(C)=O)C=C3C=CN2C2=C1C(C=C(OC)C(OC(C)=O)=C1)=C1OC2=O LDZJNMJIPNOYGA-UHFFFAOYSA-N 0.000 description 2
- 102100027207 CD27 antigen Human genes 0.000 description 2
- 102100038078 CD276 antigen Human genes 0.000 description 2
- 101710185679 CD276 antigen Proteins 0.000 description 2
- 101150013553 CD40 gene Proteins 0.000 description 2
- 101000690445 Caenorhabditis elegans Aryl hydrocarbon receptor nuclear translocator homolog Proteins 0.000 description 2
- 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 2
- GAGWJHPBXLXJQN-UHFFFAOYSA-N Capecitabine Natural products C1=C(F)C(NC(=O)OCCCCC)=NC(=O)N1C1C(O)C(O)C(C)O1 GAGWJHPBXLXJQN-UHFFFAOYSA-N 0.000 description 2
- 208000005623 Carcinogenesis Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- JWBOIMRXGHLCPP-UHFFFAOYSA-N Chloditan Chemical compound C=1C=CC=C(Cl)C=1C(C(Cl)Cl)C1=CC=C(Cl)C=C1 JWBOIMRXGHLCPP-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 2
- 229920002786 Corilagin Polymers 0.000 description 2
- 235000018453 Curcuma amada Nutrition 0.000 description 2
- 241001512940 Curcuma amada Species 0.000 description 2
- 108010069514 Cyclic Peptides Proteins 0.000 description 2
- 102000001189 Cyclic Peptides Human genes 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 230000005778 DNA damage Effects 0.000 description 2
- 231100000277 DNA damage Toxicity 0.000 description 2
- 230000033616 DNA repair Effects 0.000 description 2
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 2
- ZQZFYGIXNQKOAV-OCEACIFDSA-N Droloxifene Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 ZQZFYGIXNQKOAV-OCEACIFDSA-N 0.000 description 2
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 description 2
- ATVNHLQIIAOSEM-CBYSEHNBSA-N FC1=C(C(C#N)=C(C(=C1[2H])O)[2H])[2H] Chemical compound FC1=C(C(C#N)=C(C(=C1[2H])O)[2H])[2H] ATVNHLQIIAOSEM-CBYSEHNBSA-N 0.000 description 2
- WJQHYKICWICOPI-UHFFFAOYSA-N Fc1cc(Oc2ccc(I)c3C(=O)CCc23)cc(c1)C#N Chemical compound Fc1cc(Oc2ccc(I)c3C(=O)CCc23)cc(c1)C#N WJQHYKICWICOPI-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 102100030708 GTPase KRas Human genes 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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000793115 Homo sapiens Aryl hydrocarbon receptor nuclear translocator Proteins 0.000 description 2
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 2
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 description 2
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 2
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 description 2
- 101000601770 Homo sapiens Protein polybromo-1 Proteins 0.000 description 2
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 2
- 101000851370 Homo sapiens Tumor necrosis factor receptor superfamily member 9 Proteins 0.000 description 2
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 2
- VSNHCAURESNICA-UHFFFAOYSA-N Hydroxyurea Chemical compound NC(=O)NO VSNHCAURESNICA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 2
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 2
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 2
- 102100040018 Interferon alpha-2 Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 2
- XNRVGTHNYCNCFF-UHFFFAOYSA-N Lapatinib ditosylate monohydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.CC1=CC=C(S(O)(=O)=O)C=C1.O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 XNRVGTHNYCNCFF-UHFFFAOYSA-N 0.000 description 2
- 229930126263 Maytansine Natural products 0.000 description 2
- 102000029749 Microtubule Human genes 0.000 description 2
- 108091022875 Microtubule Proteins 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- URCVCIZFVQDVPM-UHFFFAOYSA-N N-[2-(4-hydroxyanilino)-3-pyridinyl]-4-methoxybenzenesulfonamide Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=CN=C1NC1=CC=C(O)C=C1 URCVCIZFVQDVPM-UHFFFAOYSA-N 0.000 description 2
- LYPFDBRUNKHDGX-SOGSVHMOSA-N N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 Chemical compound N1C2=CC=C1\C(=C1\C=CC(=N1)\C(=C1\C=C/C(/N1)=C(/C1=N/C(/CC1)=C2/C1=CC(O)=CC=C1)C1=CC(O)=CC=C1)\C1=CC(O)=CC=C1)C1=CC(O)=CC=C1 LYPFDBRUNKHDGX-SOGSVHMOSA-N 0.000 description 2
- BUSGWUFLNHIBPT-UHFFFAOYSA-N Nisamycin Natural products O=C1C2OC2C(C=CC=CC=CC(=O)O)(O)C=C1NC(=O)C=CC=CC1CCCCC1 BUSGWUFLNHIBPT-UHFFFAOYSA-N 0.000 description 2
- 102000004473 OX40 Ligand Human genes 0.000 description 2
- 108010042215 OX40 Ligand Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102000038030 PI3Ks Human genes 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 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
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 description 2
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 description 2
- 102000004079 Prolyl Hydroxylases Human genes 0.000 description 2
- 108010043005 Prolyl Hydroxylases Proteins 0.000 description 2
- 229940079156 Proteasome inhibitor Drugs 0.000 description 2
- 102100037516 Protein polybromo-1 Human genes 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- 238000001069 Raman spectroscopy Methods 0.000 description 2
- 201000000582 Retinoblastoma Diseases 0.000 description 2
- 208000004337 Salivary Gland Neoplasms Diseases 0.000 description 2
- 206010061934 Salivary gland cancer Diseases 0.000 description 2
- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 2
- 108700012411 TNFSF10 Proteins 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
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 2
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 2
- 102000036693 Thrombopoietin Human genes 0.000 description 2
- 108010041111 Thrombopoietin Proteins 0.000 description 2
- 108010078233 Thymalfasin Proteins 0.000 description 2
- 108010050144 Triptorelin Pamoate Proteins 0.000 description 2
- 108010040002 Tumor Suppressor Proteins Proteins 0.000 description 2
- 102000001742 Tumor Suppressor Proteins Human genes 0.000 description 2
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 2
- 102100036856 Tumor necrosis factor receptor superfamily member 9 Human genes 0.000 description 2
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 2
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 2
- 108010079206 V-Set Domain-Containing T-Cell Activation Inhibitor 1 Proteins 0.000 description 2
- 102100038929 V-set domain-containing T-cell activation inhibitor 1 Human genes 0.000 description 2
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 2
- 208000032594 Vascular Remodeling Diseases 0.000 description 2
- QPWBZVAOCWJTFK-UHFFFAOYSA-L [2-(azanidylmethyl)-3-hydroxy-2-(hydroxymethyl)propyl]azanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC(C[NH-])(CO)CO.[O-]C(=O)C1(C([O-])=O)CCC1 QPWBZVAOCWJTFK-UHFFFAOYSA-L 0.000 description 2
- QDFKKJYEIFBEFC-NRUYWUNFSA-N [2H]C(C=C([2H])C(Br)=C1[2H])=C1F Chemical compound [2H]C(C=C([2H])C(Br)=C1[2H])=C1F QDFKKJYEIFBEFC-NRUYWUNFSA-N 0.000 description 2
- 230000001594 aberrant effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229960005339 acitretin Drugs 0.000 description 2
- QAWIHIJWNYOLBE-OKKQSCSOSA-N acivicin Chemical compound OC(=O)[C@@H](N)[C@@H]1CC(Cl)=NO1 QAWIHIJWNYOLBE-OKKQSCSOSA-N 0.000 description 2
- 229950008427 acivicin Drugs 0.000 description 2
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 2
- 229960004176 aclarubicin Drugs 0.000 description 2
- RJURFGZVJUQBHK-IIXSONLDSA-N actinomycin D Chemical compound C[C@H]1OC(=O)[C@H](C(C)C)N(C)C(=O)CN(C)C(=O)[C@@H]2CCCN2C(=O)[C@@H](C(C)C)NC(=O)[C@H]1NC(=O)C1=C(N)C(=O)C(C)=C2OC(C(C)=CC=C3C(=O)N[C@@H]4C(=O)N[C@@H](C(N5CCC[C@H]5C(=O)N(C)CC(=O)N(C)[C@@H](C(C)C)C(=O)O[C@@H]4C)=O)C(C)C)=C3N=C21 RJURFGZVJUQBHK-IIXSONLDSA-N 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 229960001686 afatinib Drugs 0.000 description 2
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 2
- 108700025316 aldesleukin Proteins 0.000 description 2
- 229960005310 aldesleukin Drugs 0.000 description 2
- 229940045714 alkyl sulfonate alkylating agent Drugs 0.000 description 2
- 150000008052 alkyl sulfonates Chemical class 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- IHUNBGSDBOWDMA-AQFIFDHZSA-N all-trans-acitretin Chemical compound COC1=CC(C)=C(\C=C\C(\C)=C\C=C\C(\C)=C\C(O)=O)C(C)=C1C IHUNBGSDBOWDMA-AQFIFDHZSA-N 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- 229960001097 amifostine Drugs 0.000 description 2
- 229960003437 aminoglutethimide Drugs 0.000 description 2
- ROBVIMPUHSLWNV-UHFFFAOYSA-N aminoglutethimide Chemical compound C=1C=C(N)C=CC=1C1(CC)CCC(=O)NC1=O ROBVIMPUHSLWNV-UHFFFAOYSA-N 0.000 description 2
- 229960001220 amsacrine Drugs 0.000 description 2
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 2
- 229960002932 anastrozole Drugs 0.000 description 2
- YBBLVLTVTVSKRW-UHFFFAOYSA-N anastrozole Chemical compound N#CC(C)(C)C1=CC(C(C)(C#N)C)=CC(CN2N=CN=C2)=C1 YBBLVLTVTVSKRW-UHFFFAOYSA-N 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000002280 anti-androgenic effect Effects 0.000 description 2
- 229940046836 anti-estrogen Drugs 0.000 description 2
- 230000001833 anti-estrogenic effect Effects 0.000 description 2
- 239000000051 antiandrogen Substances 0.000 description 2
- 229940030495 antiandrogen sex hormone and modulator of the genital system Drugs 0.000 description 2
- 229940045687 antimetabolites folic acid analogs Drugs 0.000 description 2
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 229960002756 azacitidine Drugs 0.000 description 2
- 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 2
- 230000004888 barrier function Effects 0.000 description 2
- XFILPEOLDIKJHX-QYZOEREBSA-N batimastat Chemical compound C([C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)[C@H](CSC=1SC=CC=1)C(=O)NO)C1=CC=CC=C1 XFILPEOLDIKJHX-QYZOEREBSA-N 0.000 description 2
- 229950001858 batimastat Drugs 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-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
- 229960000997 bicalutamide Drugs 0.000 description 2
- 229950006844 bizelesin Drugs 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- GXJABQQUPOEUTA-RDJZCZTQSA-N bortezomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)B(O)O)NC(=O)C=1N=CC=NC=1)C1=CC=CC=C1 GXJABQQUPOEUTA-RDJZCZTQSA-N 0.000 description 2
- 229960001467 bortezomib Drugs 0.000 description 2
- 229950003628 buparlisib Drugs 0.000 description 2
- 229960002092 busulfan Drugs 0.000 description 2
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 2
- 230000036952 cancer formation Effects 0.000 description 2
- 239000012830 cancer therapeutic Substances 0.000 description 2
- 229960004117 capecitabine Drugs 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 231100000504 carcinogenesis Toxicity 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 201000007988 cartilage cancer Diseases 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 108010046713 cemadotin Proteins 0.000 description 2
- BZXULYMZYPRZOG-UHFFFAOYSA-N centaureidin Chemical compound C1=C(O)C(OC)=CC=C1C1=C(OC)C(=O)C2=C(O)C(OC)=C(O)C=C2O1 BZXULYMZYPRZOG-UHFFFAOYSA-N 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- 229960002436 cladribine Drugs 0.000 description 2
- 238000011490 co-immunoprecipitation assay Methods 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- TUSDEZXZIZRFGC-XIGLUPEJSA-N corilagin Chemical compound O([C@H]1[C@H](O)[C@H]2OC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC[C@@H](O1)[C@H]2O)C(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-XIGLUPEJSA-N 0.000 description 2
- CPWYQGWOJMNXGJ-UHFFFAOYSA-N corilagin Natural products OC1C2COC(=O)c3c(O)c(O)c(O)c(O)c3c4c(O)c(O)c(O)c(O)c4C(=O)OC1C(O)C(OC(=O)c5cc(O)c(O)c(O)c5)O2 CPWYQGWOJMNXGJ-UHFFFAOYSA-N 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 229960005061 crizotinib Drugs 0.000 description 2
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- VEVZSMAEJFVWIL-UHFFFAOYSA-O cyanidin cation Chemical compound [O+]=1C2=CC(O)=CC(O)=C2C=C(O)C=1C1=CC=C(O)C(O)=C1 VEVZSMAEJFVWIL-UHFFFAOYSA-O 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229960000640 dactinomycin Drugs 0.000 description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- BEFZAMRWPCMWFJ-UHFFFAOYSA-N desoxyepothilone A Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC=CCC1C(C)=CC1=CSC(C)=N1 BEFZAMRWPCMWFJ-UHFFFAOYSA-N 0.000 description 2
- 238000006471 dimerization reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 description 2
- OFDNQWIFNXBECV-VFSYNPLYSA-N dolastatin 10 Chemical compound CC(C)[C@H](N(C)C)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H]([C@@H](C)CC)[C@H](OC)CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](C=1SC=CN=1)CC1=CC=CC=C1 OFDNQWIFNXBECV-VFSYNPLYSA-N 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 2
- 229950004203 droloxifene Drugs 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 229950009791 durvalumab Drugs 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- BEFZAMRWPCMWFJ-QJKGZULSSA-N epothilone C Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 BEFZAMRWPCMWFJ-QJKGZULSSA-N 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 2
- WCDWBPCFGJXFJZ-UHFFFAOYSA-N etanidazole Chemical compound OCCNC(=O)CN1C=CN=C1[N+]([O-])=O WCDWBPCFGJXFJZ-UHFFFAOYSA-N 0.000 description 2
- 229950006566 etanidazole Drugs 0.000 description 2
- VXNHPMZWODDHLQ-UHFFFAOYSA-N ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate Chemical compound CCOC(=O)C(F)(F)C(O)c1ccc(F)cc1Br VXNHPMZWODDHLQ-UHFFFAOYSA-N 0.000 description 2
- ZJBOQKWUYRGKLI-UHFFFAOYSA-N ethyl 3-(2-bromo-4-fluorophenyl)-2,2-difluoro-3-oxopropanoate Chemical compound CCOC(=O)C(F)(F)C(=O)c1ccc(F)cc1Br ZJBOQKWUYRGKLI-UHFFFAOYSA-N 0.000 description 2
- KLEPCGBEXOCIGS-XUZZJYLKSA-N ethyl N-[4-[[(2S,4S)-2-(imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl]methylsulfanyl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCC)=CC=C1SC[C@H]1O[C@](CN2C=NC=C2)(C=2C=CC(OC)=CC=2)OC1 KLEPCGBEXOCIGS-XUZZJYLKSA-N 0.000 description 2
- 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 2
- 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 2
- 229960000752 etoposide phosphate Drugs 0.000 description 2
- NMUSYJAQQFHJEW-ARQDHWQXSA-N fazarabine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-ARQDHWQXSA-N 0.000 description 2
- 229950005096 fazarabine Drugs 0.000 description 2
- 229950003662 fenretinide Drugs 0.000 description 2
- 229960000961 floxuridine Drugs 0.000 description 2
- 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 2
- 239000012025 fluorinating agent Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- IJJVMEJXYNJXOJ-UHFFFAOYSA-N fluquinconazole Chemical compound C=1C=C(Cl)C=C(Cl)C=1N1C(=O)C2=CC(F)=CC=C2N=C1N1C=NC=N1 IJJVMEJXYNJXOJ-UHFFFAOYSA-N 0.000 description 2
- 150000002224 folic acids Chemical class 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- CHPZKNULDCNCBW-UHFFFAOYSA-N gallium nitrate Chemical compound [Ga+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O CHPZKNULDCNCBW-UHFFFAOYSA-N 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- QBKSWRVVCFFDOT-UHFFFAOYSA-N gossypol Chemical compound CC(C)C1=C(O)C(O)=C(C=O)C2=C(O)C(C=3C(O)=C4C(C=O)=C(O)C(O)=C(C4=CC=3C)C(C)C)=C(C)C=C21 QBKSWRVVCFFDOT-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229960001330 hydroxycarbamide Drugs 0.000 description 2
- 238000005805 hydroxylation reaction Methods 0.000 description 2
- 229960003445 idelalisib Drugs 0.000 description 2
- IFSDAJWBUCMOAH-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 IFSDAJWBUCMOAH-HNNXBMFYSA-N 0.000 description 2
- 229940121569 ieramilimab Drugs 0.000 description 2
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 125000003114 inden-1-yl group Chemical group [H]C1=C([H])C([H])(*)C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 210000002490 intestinal epithelial cell Anatomy 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- DWOIXRLFJBZDSB-MLLHTCFKSA-N isoeleutherobin a Chemical compound C(/[C@H]1[C@H](C(=CC[C@@H]1C(C)C)C)C[C@@H]([C@@]1(C)O[C@@]2(C=C1)OC)OC(=O)\C=C\C=1N=CN(C)C=1)=C2\CO[C@@H]1OC[C@@H](O)[C@@H](OC(C)=O)[C@@H]1O DWOIXRLFJBZDSB-MLLHTCFKSA-N 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 108010021336 lanreotide Proteins 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 229960003881 letrozole Drugs 0.000 description 2
- HPJKCIUCZWXJDR-UHFFFAOYSA-N letrozole Chemical compound C1=CC(C#N)=CC=C1C(N1N=CN=C1)C1=CC=C(C#N)C=C1 HPJKCIUCZWXJDR-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 238000006138 lithiation reaction Methods 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- WKPWGQKGSOKKOO-RSFHAFMBSA-N maytansine Chemical compound CO[C@@H]([C@@]1(O)C[C@](OC(=O)N1)([C@H]([C@@H]1O[C@@]1(C)[C@@H](OC(=O)[C@H](C)N(C)C(C)=O)CC(=O)N1C)C)[H])\C=C\C=C(C)\CC2=CC(OC)=C(Cl)C1=C2 WKPWGQKGSOKKOO-RSFHAFMBSA-N 0.000 description 2
- 229960004296 megestrol acetate Drugs 0.000 description 2
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 description 2
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 2
- 229960001924 melphalan Drugs 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 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 2
- 210000004688 microtubule Anatomy 0.000 description 2
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 2
- 229960000350 mitotane Drugs 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- TXXHDPDFNKHHGW-UHFFFAOYSA-N muconic acid Chemical compound OC(=O)C=CC=CC(O)=O TXXHDPDFNKHHGW-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-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
- 229930014626 natural product Natural products 0.000 description 2
- 229950008835 neratinib Drugs 0.000 description 2
- JWNPDZNEKVCWMY-VQHVLOKHSA-N neratinib Chemical compound C=12C=C(NC(=O)\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 JWNPDZNEKVCWMY-VQHVLOKHSA-N 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 2
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 2
- 210000004940 nucleus Anatomy 0.000 description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229950008017 ormaplatin Drugs 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 2
- 229960005184 panobinostat Drugs 0.000 description 2
- FWZRWHZDXBDTFK-ZHACJKMWSA-N panobinostat Chemical compound CC1=NC2=CC=C[CH]C2=C1CCNCC1=CC=C(\C=C\C(=O)NO)C=C1 FWZRWHZDXBDTFK-ZHACJKMWSA-N 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- VOKSWYLNZZRQPF-GDIGMMSISA-N pentazocine Chemical compound C1C2=CC=C(O)C=C2[C@@]2(C)[C@@H](C)[C@@H]1N(CC=C(C)C)CC2 VOKSWYLNZZRQPF-GDIGMMSISA-N 0.000 description 2
- 229960005301 pentazocine Drugs 0.000 description 2
- NDTYTMIUWGWIMO-UHFFFAOYSA-N perillyl alcohol Chemical compound CC(=C)C1CCC(CO)=CC1 NDTYTMIUWGWIMO-UHFFFAOYSA-N 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 150000003058 platinum compounds Chemical class 0.000 description 2
- 229960004293 porfimer sodium 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
- 229960002965 pravastatin Drugs 0.000 description 2
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- LFILDSDQMSCNBV-LURJTMIESA-N propane-2-sulfinamide Chemical compound CC(C)[S@@](N)=O LFILDSDQMSCNBV-LURJTMIESA-N 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000003207 proteasome inhibitor Substances 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003212 purines Chemical class 0.000 description 2
- RXWNCPJZOCPEPQ-NVWDDTSBSA-N puromycin Chemical compound C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO RXWNCPJZOCPEPQ-NVWDDTSBSA-N 0.000 description 2
- FCFXLXGZHDHJLB-UHFFFAOYSA-N pyridine-2-sulfonyl fluoride Chemical compound FS(=O)(=O)C1=CC=CC=N1 FCFXLXGZHDHJLB-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000007634 remodeling Methods 0.000 description 2
- 230000008672 reprogramming Effects 0.000 description 2
- 230000008261 resistance mechanism Effects 0.000 description 2
- 229950003687 ribociclib Drugs 0.000 description 2
- CGFVUVWMYIHGHS-UHFFFAOYSA-N saintopin Chemical compound C1=C(O)C=C2C=C(C(=O)C=3C(=C(O)C=C(C=3)O)C3=O)C3=C(O)C2=C1O CGFVUVWMYIHGHS-UHFFFAOYSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 201000000849 skin cancer Diseases 0.000 description 2
- 229950004296 soblidotin Drugs 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- UWPXRVDIKGZQQW-UHFFFAOYSA-N sodium;(3-fluoro-4-methoxyphenyl)-(2,3,4,5,6-pentafluorophenyl)sulfonylazanide Chemical compound [Na+].C1=C(F)C(OC)=CC=C1[N-]S(=O)(=O)C1=C(F)C(F)=C(F)C(F)=C1F UWPXRVDIKGZQQW-UHFFFAOYSA-N 0.000 description 2
- 229960003787 sorafenib Drugs 0.000 description 2
- 229950007213 spartalizumab Drugs 0.000 description 2
- 238000004611 spectroscopical analysis Methods 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229960001052 streptozocin Drugs 0.000 description 2
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000008093 supporting effect Effects 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 229950007866 tanespimycin Drugs 0.000 description 2
- AYUNIORJHRXIBJ-TXHRRWQRSA-N tanespimycin Chemical compound N1C(=O)\C(C)=C\C=C/[C@H](OC)[C@@H](OC(N)=O)\C(C)=C\[C@H](C)[C@@H](O)[C@@H](OC)C[C@H](C)CC2=C(NCC=C)C(=O)C=C1C2=O AYUNIORJHRXIBJ-TXHRRWQRSA-N 0.000 description 2
- 238000002626 targeted therapy Methods 0.000 description 2
- URLYINUFLXOMHP-HTVVRFAVSA-N tcn-p Chemical compound C=12C3=NC=NC=1N(C)N=C(N)C2=CN3[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O URLYINUFLXOMHP-HTVVRFAVSA-N 0.000 description 2
- 229960002197 temoporfin Drugs 0.000 description 2
- 229960000235 temsirolimus Drugs 0.000 description 2
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229960001196 thiotepa Drugs 0.000 description 2
- NZVYCXVTEHPMHE-ZSUJOUNUSA-N thymalfasin Chemical compound CC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O NZVYCXVTEHPMHE-ZSUJOUNUSA-N 0.000 description 2
- 229960004231 thymalfasin Drugs 0.000 description 2
- 229950002376 tirapazamine Drugs 0.000 description 2
- QVMPZNRFXAKISM-UHFFFAOYSA-N tirapazamine Chemical compound C1=CC=C2[N+]([O-])=NC(=N)N(O)C2=C1 QVMPZNRFXAKISM-UHFFFAOYSA-N 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- 229960004066 trametinib Drugs 0.000 description 2
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- 150000004654 triazenes Chemical class 0.000 description 2
- 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 2
- 229960001099 trimetrexate Drugs 0.000 description 2
- VXKHXGOKWPXYNA-PGBVPBMZSA-N triptorelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 VXKHXGOKWPXYNA-PGBVPBMZSA-N 0.000 description 2
- 229960004824 triptorelin Drugs 0.000 description 2
- 108700029852 vapreotide Proteins 0.000 description 2
- 229960002730 vapreotide Drugs 0.000 description 2
- ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N verteporfin Chemical compound C=1C([C@@]2([C@H](C(=O)OC)C(=CC=C22)C(=O)OC)C)=NC2=CC(C(=C2C=C)C)=NC2=CC(C(=C2CCC(O)=O)C)=NC2=CC2=NC=1C(C)=C2CCC(=O)OC ZQFGRJWRSLZCSQ-ZSFNYQMMSA-N 0.000 description 2
- 229960003895 verteporfin Drugs 0.000 description 2
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 2
- 229960002110 vincristine sulfate Drugs 0.000 description 2
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 2
- 229960000237 vorinostat Drugs 0.000 description 2
- QDLHCMPXEPAAMD-QAIWCSMKSA-N wortmannin Chemical compound C1([C@]2(C)C3=C(C4=O)OC=C3C(=O)O[C@@H]2COC)=C4[C@@H]2CCC(=O)[C@@]2(C)C[C@H]1OC(C)=O QDLHCMPXEPAAMD-QAIWCSMKSA-N 0.000 description 2
- QDLHCMPXEPAAMD-UHFFFAOYSA-N wortmannin Natural products COCC1OC(=O)C2=COC(C3=O)=C2C1(C)C1=C3C2CCC(=O)C2(C)CC1OC(C)=O QDLHCMPXEPAAMD-UHFFFAOYSA-N 0.000 description 2
- 229950003017 zeniplatin Drugs 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- AADVCYNFEREWOS-UHFFFAOYSA-N (+)-DDM Natural products C=CC=CC(C)C(OC(N)=O)C(C)C(O)C(C)CC(C)=CC(C)C(O)C(C)C=CC(O)CC1OC(=O)C(C)C(O)C1C AADVCYNFEREWOS-UHFFFAOYSA-N 0.000 description 1
- OPFTUNCRGUEPRZ-UHFFFAOYSA-N (+)-beta-Elemen Natural products CC(=C)C1CCC(C)(C=C)C(C(C)=C)C1 OPFTUNCRGUEPRZ-UHFFFAOYSA-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
- WWUZIQQURGPMPG-UHFFFAOYSA-N (-)-D-erythro-Sphingosine Natural products CCCCCCCCCCCCCC=CC(O)C(N)CO WWUZIQQURGPMPG-UHFFFAOYSA-N 0.000 description 1
- FCCNKYGSMOSYPV-DEDISHTHSA-N (-)-Epothilone E Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(CO)sc2)/C)OC(=O)C[C@H](O)C1(C)C FCCNKYGSMOSYPV-DEDISHTHSA-N 0.000 description 1
- UKIMCRYGLFQEOE-RLHMMOOASA-N (-)-Epothilone F Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(CO)sc2)/C)OC(=O)C[C@H](O)C1(C)C UKIMCRYGLFQEOE-RLHMMOOASA-N 0.000 description 1
- OPFTUNCRGUEPRZ-QLFBSQMISA-N (-)-beta-elemene Chemical compound CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 1
- KQODQNJLJQHFQV-UHFFFAOYSA-N (-)-hemiasterlin Natural products C1=CC=C2C(C(C)(C)C(C(=O)NC(C(=O)N(C)C(C=C(C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-UHFFFAOYSA-N 0.000 description 1
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- XYLPKCDRAAYATL-OAHLLOKOSA-N (11S)-7-(3,5-dimethyl-1,2-oxazol-4-yl)-11-pyridin-2-yl-9-oxa-1,3-diazatricyclo[6.3.1.04,12]dodeca-4(12),5,7-trien-2-one Chemical compound CC1=NOC(C)=C1C1=CC=C2C3=C1OC[C@H](C=1N=CC=CC=1)N3C(=O)N2 XYLPKCDRAAYATL-OAHLLOKOSA-N 0.000 description 1
- FNEOHTTZLPHOSX-KZNAEPCWSA-N (1r)-1-[(2r,5r)-5-(hydroxymethyl)oxolan-2-yl]tridecan-1-ol Chemical compound CCCCCCCCCCCC[C@@H](O)[C@H]1CC[C@H](CO)O1 FNEOHTTZLPHOSX-KZNAEPCWSA-N 0.000 description 1
- XJYQGNNBDGDYCE-DXBBTUNJSA-N (1r)-1-[(2r,5r)-5-[(1s)-1-hydroxypent-4-enyl]oxolan-2-yl]tridecan-1-ol Chemical compound CCCCCCCCCCCC[C@@H](O)[C@H]1CC[C@H]([C@@H](O)CCC=C)O1 XJYQGNNBDGDYCE-DXBBTUNJSA-N 0.000 description 1
- GEJJWYZZKKKSEV-KGLIPLIRSA-N (1s,2r)-2-amino-1,2-diphenylethanol Chemical compound C1([C@H](O)[C@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-KGLIPLIRSA-N 0.000 description 1
- PFJFPBDHCFMQPN-RGJAOAFDSA-N (1s,3s,7s,10r,11s,12s,16r)-3-[(e)-1-[2-(aminomethyl)-1,3-thiazol-4-yl]prop-1-en-2-yl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CN)=N1 PFJFPBDHCFMQPN-RGJAOAFDSA-N 0.000 description 1
- WCWUXEGQKLTGDX-LLVKDONJSA-N (2R)-1-[[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-5-methyl-6-pyrrolo[2,1-f][1,2,4]triazinyl]oxy]-2-propanol Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=NC=NN3C=C(C(=C32)C)OC[C@H](O)C)=C1 WCWUXEGQKLTGDX-LLVKDONJSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- LTTQKYMNTNISSZ-MWTRTKDXSA-N (2S)-(-)-kurarinone Chemical compound C1([C@H]2OC=3C(C[C@@H](CC=C(C)C)C(C)=C)=C(O)C=C(C=3C(=O)C2)OC)=CC=C(O)C=C1O LTTQKYMNTNISSZ-MWTRTKDXSA-N 0.000 description 1
- ZWZOGTIRYWBHMQ-HNNXBMFYSA-N (2S)-2-[(3-tert-butyl-2-hydroxyphenyl)methylamino]-N,N,3-trimethylbutanamide Chemical compound CC(C)[C@H](NCc1cccc(c1O)C(C)(C)C)C(=O)N(C)C ZWZOGTIRYWBHMQ-HNNXBMFYSA-N 0.000 description 1
- MXABZXILAJGOTL-AUYMZICSSA-N (2S)-N-[(2S)-1-[(2S)-1-[(2S,3S)-1-[(2S)-1-[2-[(2S)-1,3-dihydroxy-1-[(E)-1-hydroxy-1-[(2S,3S)-1-hydroxy-3-methyl-1-[[(2Z,6S,9S,12R)-5,8,11-trihydroxy-9-(2-methylpropyl)-6-propan-2-yl-1-thia-4,7,10-triazacyclotrideca-2,4,7,10-tetraen-12-yl]imino]pentan-2-yl]iminobut-2-en-2-yl]iminopropan-2-yl]imino-2-hydroxyethyl]imino-1,5-dihydroxy-5-iminopentan-2-yl]imino-1-hydroxy-3-methylpentan-2-yl]imino-1-hydroxy-3-methylbutan-2-yl]imino-1-hydroxy-3-phenylpropan-2-yl]-2-[[(2S)-2-[[(2S)-2-[[(Z)-2-[[(2S)-2-[[(Z)-2-[[(2S)-2-[[[(2S)-1-[(Z)-2-[[(2S)-2-(dimethylamino)-1-hydroxypropylidene]amino]but-2-enoyl]pyrrolidin-2-yl]-hydroxymethylidene]amino]-1-hydroxypropylidene]amino]-1-hydroxybut-2-enylidene]amino]-1-hydroxy-3-phenylpropylidene]amino]-1-hydroxybut-2-enylidene]amino]-1-hydroxy-3-methylbutylidene]amino]-1-hydroxypropylidene]amino]pentanediimidic acid Chemical compound CC[C@H](C)[C@H](\N=C(/O)[C@@H](\N=C(/O)[C@H](Cc1ccccc1)\N=C(/O)[C@H](CCC(O)=N)\N=C(/O)[C@H](C)\N=C(/O)[C@@H](\N=C(/O)\C(=C\C)\N=C(/O)[C@H](Cc1ccccc1)\N=C(/O)\C(=C\C)\N=C(/O)[C@H](C)\N=C(/O)[C@@H]1CCCN1C(=O)\C(=C\C)\N=C(/O)[C@H](C)N(C)C)C(C)C)C(C)C)C(\O)=N\[C@@H](CCC(O)=N)C(\O)=N\C\C(O)=N\[C@@H](CO)C(\O)=N\C(=C\C)\C(\O)=N\[C@@H]([C@@H](C)CC)C(\O)=N\[C@H]1CS\C=C/N=C(O)\[C@@H](\N=C(O)/[C@H](CC(C)C)\N=C1\O)C(C)C MXABZXILAJGOTL-AUYMZICSSA-N 0.000 description 1
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 description 1
- DQJCDTNMLBYVAY-ZXXIYAEKSA-N (2S,5R,10R,13R)-16-{[(2R,3S,4R,5R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-5-(ethylamino)-6-hydroxy-2-(hydroxymethyl)oxan-4-yl]oxy}-5-(4-aminobutyl)-10-carbamoyl-2,13-dimethyl-4,7,12,15-tetraoxo-3,6,11,14-tetraazaheptadecan-1-oic acid Chemical compound NCCCC[C@H](C(=O)N[C@@H](C)C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@@H](C)NC(=O)C(C)O[C@@H]1[C@@H](NCC)C(O)O[C@H](CO)[C@H]1O[C@H]1[C@H](NC(C)=O)[C@@H](O)[C@H](O)[C@@H](CO)O1 DQJCDTNMLBYVAY-ZXXIYAEKSA-N 0.000 description 1
- FKHUGQZRBPETJR-RXSRXONKSA-N (2r)-2-[[(4r)-4-[[(2s)-2-[[(2r)-2-[(3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxypropanoyl]amino]propanoyl]amino]-5-amino-5-oxopentanoyl]amino]-6-(octadecanoylamino)hexanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCCCC[C@H](C(O)=O)NC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)OC(O)[C@@H]1NC(C)=O FKHUGQZRBPETJR-RXSRXONKSA-N 0.000 description 1
- SWTGJCNCBUCXSS-ISUZDFFFSA-N (2r)-3,4-dihydroxy-2-[(4s)-2-phenyl-1,3-dioxolan-4-yl]-2h-furan-5-one Chemical compound OC1=C(O)C(=O)O[C@@H]1[C@H]1OC(C=2C=CC=CC=2)OC1 SWTGJCNCBUCXSS-ISUZDFFFSA-N 0.000 description 1
- NOENHWMKHNSHGX-IZOOSHNJSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-(ca Chemical compound C([C@H](C(=O)N[C@H](CCCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCNC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 NOENHWMKHNSHGX-IZOOSHNJSA-N 0.000 description 1
- CUCSSYAUKKIDJV-FAXBSAIASA-N (2s)-2-[[(2r)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]amino]-3-(1h-indol-3-yl)propanoyl]-methylamino]-3-phenylpropanoyl]amino]-3-(1h-indol-3-yl)propanoyl]amino]-n-[(2s)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]-4-methylpent Chemical compound C([C@@H](C(=O)N[C@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)N(C)C(=O)[C@@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CUCSSYAUKKIDJV-FAXBSAIASA-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
- UWNLMCHWYYPYIQ-QMMMGPOBSA-N (2s)-2-azido-3-(4-hydroxyphenyl)propanoic acid Chemical compound [N-]=[N+]=N[C@H](C(=O)O)CC1=CC=C(O)C=C1 UWNLMCHWYYPYIQ-QMMMGPOBSA-N 0.000 description 1
- UGSLDMJXBQKDCT-WOPDTQHZSA-N (2s)-5-oxo-n-[(1s,2r)-2-phenylcyclopropyl]pyrrolidine-2-carboxamide Chemical compound C1([C@H]2C[C@@H]2NC(=O)[C@H]2NC(=O)CC2)=CC=CC=C1 UGSLDMJXBQKDCT-WOPDTQHZSA-N 0.000 description 1
- DLKUYSQUHXBYPB-NSSHGSRYSA-N (2s,4r)-4-[[2-[(1r,3r)-1-acetyloxy-4-methyl-3-[3-methylbutanoyloxymethyl-[(2s,3s)-3-methyl-2-[[(2r)-1-methylpiperidine-2-carbonyl]amino]pentanoyl]amino]pentyl]-1,3-thiazole-4-carbonyl]amino]-2-methyl-5-(4-methylphenyl)pentanoic acid Chemical compound N([C@@H]([C@@H](C)CC)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)C=1SC=C(N=1)C(=O)N[C@H](C[C@H](C)C(O)=O)CC=1C=CC(C)=CC=1)C(C)C)C(=O)[C@H]1CCCCN1C DLKUYSQUHXBYPB-NSSHGSRYSA-N 0.000 description 1
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 1
- RDIMTXDFGHNINN-UHFFFAOYSA-N (3R,9R,10R)-1-heptadecen-4,6-diyne-3,9,10-triol Natural products CCCCCCCC(O)C(O)CC#CC#CC(O)C=C RDIMTXDFGHNINN-UHFFFAOYSA-N 0.000 description 1
- UCJZOKGUEJUNIO-IINYFYTJSA-N (3S,4S)-8-[6-amino-5-(2-amino-3-chloropyridin-4-yl)sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine Chemical compound C[C@@H]1OCC2(CCN(CC2)C2=CN=C(SC3=C(Cl)C(N)=NC=C3)C(N)=N2)[C@@H]1N UCJZOKGUEJUNIO-IINYFYTJSA-N 0.000 description 1
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 1
- GWMHBVLPNWHWGW-CNYBTUBUSA-N (3s,6z)-3-benzyl-6-[[5-(2-methylbut-3-en-2-yl)-1h-imidazol-4-yl]methylidene]piperazine-2,5-dione Chemical compound N1C=NC(\C=C/2C(N[C@@H](CC=3C=CC=CC=3)C(=O)N\2)=O)=C1C(C)(C=C)C GWMHBVLPNWHWGW-CNYBTUBUSA-N 0.000 description 1
- GTEXXGIEZVKSLH-YPMHNXCESA-N (4as,12br)-8,10-dihydroxy-2,5,5,9-tetramethyl-3,4,4a,12b-tetrahydronaphtho[2,3-c]isochromene-7,12-dione Chemical compound O=C1C2=CC(O)=C(C)C(O)=C2C(=O)C2=C1[C@@H]1C=C(C)CC[C@@H]1C(C)(C)O2 GTEXXGIEZVKSLH-YPMHNXCESA-N 0.000 description 1
- DEQANNDTNATYII-OULOTJBUSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-19-[[(2r)-2-amino-3-phenylpropanoyl]amino]-16-benzyl-n-[(2r,3r)-1,3-dihydroxybutan-2-yl]-7-[(1r)-1-hydroxyethyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxa Chemical compound C([C@@H](N)C(=O)N[C@H]1CSSC[C@H](NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](CC=2C3=CC=CC=C3NC=2)NC(=O)[C@H](CC=2C=CC=CC=2)NC1=O)C(=O)N[C@H](CO)[C@H](O)C)C1=CC=CC=C1 DEQANNDTNATYII-OULOTJBUSA-N 0.000 description 1
- PUDHBTGHUJUUFI-SCTWWAJVSA-N (4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5,8,11,14,17-p Chemical compound C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 PUDHBTGHUJUUFI-SCTWWAJVSA-N 0.000 description 1
- MWWSFMDVAYGXBV-MYPASOLCSA-N (7r,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical compound Cl.O([C@@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-MYPASOLCSA-N 0.000 description 1
- MWWSFMDVAYGXBV-FGBSZODSSA-N (7s,9s)-7-[(2r,4s,5r,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydron;chloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-FGBSZODSSA-N 0.000 description 1
- GYPCWHHQAVLMKO-XXKQIVDLSA-N (7s,9s)-7-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-[(e)-n-[(1-hydroxy-2,2,6,6-tetramethylpiperidin-4-ylidene)amino]-c-methylcarbonimidoyl]-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione;hydrochloride Chemical group Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\N=C1CC(C)(C)N(O)C(C)(C)C1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 GYPCWHHQAVLMKO-XXKQIVDLSA-N 0.000 description 1
- IEXUMDBQLIVNHZ-YOUGDJEHSA-N (8s,11r,13r,14s,17s)-11-[4-(dimethylamino)phenyl]-17-hydroxy-17-(3-hydroxypropyl)-13-methyl-1,2,6,7,8,11,12,14,15,16-decahydrocyclopenta[a]phenanthren-3-one Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)CCCO)[C@@]2(C)C1 IEXUMDBQLIVNHZ-YOUGDJEHSA-N 0.000 description 1
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- DOEWDSDBFRHVAP-KRXBUXKQSA-N (E)-3-tosylacrylonitrile Chemical compound CC1=CC=C(S(=O)(=O)\C=C\C#N)C=C1 DOEWDSDBFRHVAP-KRXBUXKQSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- NSMXQKNUPPXBRG-SECBINFHSA-N (R)-lisofylline Chemical compound O=C1N(CCCC[C@H](O)C)C(=O)N(C)C2=C1N(C)C=N2 NSMXQKNUPPXBRG-SECBINFHSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- KQODQNJLJQHFQV-MKWZWQCGSA-N (e,4s)-4-[[(2s)-3,3-dimethyl-2-[[(2s)-3-methyl-2-(methylamino)-3-(1-methylindol-3-yl)butanoyl]amino]butanoyl]-methylamino]-2,5-dimethylhex-2-enoic acid Chemical compound C1=CC=C2C(C(C)(C)[C@@H](C(=O)N[C@H](C(=O)N(C)[C@H](\C=C(/C)C(O)=O)C(C)C)C(C)(C)C)NC)=CN(C)C2=C1 KQODQNJLJQHFQV-MKWZWQCGSA-N 0.000 description 1
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- POILWHVDKZOXJZ-ARJAWSKDSA-M (z)-4-oxopent-2-en-2-olate Chemical compound C\C([O-])=C\C(C)=O POILWHVDKZOXJZ-ARJAWSKDSA-M 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- DWZAEMINVBZMHQ-UHFFFAOYSA-N 1-[4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl]-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea Chemical compound C1CC(N(C)C)CCN1C(=O)C(C=C1)=CC=C1NC(=O)NC1=CC=C(C=2N=C(N=C(N=2)N2CCOCC2)N2CCOCC2)C=C1 DWZAEMINVBZMHQ-UHFFFAOYSA-N 0.000 description 1
- 102100025573 1-alkyl-2-acetylglycerophosphocholine esterase Human genes 0.000 description 1
- ZKFNOUUKULVDOB-UHFFFAOYSA-N 1-amino-1-phenylmethyl phosphonic acid Chemical compound OP(=O)(O)C(N)C1=CC=CC=C1 ZKFNOUUKULVDOB-UHFFFAOYSA-N 0.000 description 1
- AJXDZTRQWPEVQU-UHFFFAOYSA-N 1-benzyl-1-iodoguanidine Chemical compound NC(=N)N(I)CC1=CC=CC=C1 AJXDZTRQWPEVQU-UHFFFAOYSA-N 0.000 description 1
- RGJOJUGRHPQXGF-INIZCTEOSA-N 1-ethyl-3-[4-[4-[(3s)-3-methylmorpholin-4-yl]-7-(oxetan-3-yl)-6,8-dihydro-5h-pyrido[3,4-d]pyrimidin-2-yl]phenyl]urea Chemical compound C1=CC(NC(=O)NCC)=CC=C1C(N=C1N2[C@H](COCC2)C)=NC2=C1CCN(C1COC1)C2 RGJOJUGRHPQXGF-INIZCTEOSA-N 0.000 description 1
- CNQCTSLNJJVSAU-UHFFFAOYSA-N 132937-89-4 Chemical compound O.Cl.Cl.Cl.Cl.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO.OCCNCCN1N=C2C3=CC=CC(O)=C3C(=O)C3=C2C1=CC=C3NCCNCCO CNQCTSLNJJVSAU-UHFFFAOYSA-N 0.000 description 1
- BFPYWIDHMRZLRN-UHFFFAOYSA-N 17alpha-ethynyl estradiol Natural products OC1=CC=C2C3CCC(C)(C(CC4)(O)C#C)C4C3CCC2=C1 BFPYWIDHMRZLRN-UHFFFAOYSA-N 0.000 description 1
- NUXKIZBEPYVRKP-RWBWKAGLSA-N 1xa5 Chemical compound O([C@]12[C@@H]3N(C)C4=C([C@]53CCN3CC=C[C@@]([C@@H]53)(CC)C2)C=C(C(=C4)OC)[C@]2(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C2)C[C@@](C3)(O)CC)C(=O)N(CCCl)C1=O NUXKIZBEPYVRKP-RWBWKAGLSA-N 0.000 description 1
- LNELBQZKXVASLW-AWEZNQCLSA-N 2,2,2-trifluoro-n-[(7s)-1,2,3-trimethoxy-10-methylsulfanyl-9-oxo-6,7-dihydro-5h-benzo[a]heptalen-7-yl]acetamide Chemical compound C1([C@@H](NC(=O)C(F)(F)F)CC2)=CC(=O)C(SC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC LNELBQZKXVASLW-AWEZNQCLSA-N 0.000 description 1
- VKDGNNYJFSHYKD-UHFFFAOYSA-N 2,5-diamino-2-(difluoromethyl)pentanoic acid;hydron;chloride Chemical compound Cl.NCCCC(N)(C(F)F)C(O)=O VKDGNNYJFSHYKD-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- RWEVIPRMPFNTLO-UHFFFAOYSA-N 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-3-pyridinecarboxamide Chemical compound CN1C(=O)C(C)=CC(C(=O)NOCCO)=C1NC1=CC=C(I)C=C1F RWEVIPRMPFNTLO-UHFFFAOYSA-N 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- NJWBUDCAWGTQAS-UHFFFAOYSA-N 2-(chrysen-6-ylmethylamino)-2-methylpropane-1,3-diol;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1=CC=C2C(CNC(CO)(CO)C)=CC3=C(C=CC=C4)C4=CC=C3C2=C1 NJWBUDCAWGTQAS-UHFFFAOYSA-N 0.000 description 1
- LXMGXMQQJNULPR-NTISSMGPSA-N 2-[(4S)-6-(4-chlorophenyl)-1-methyl-4H-[1,2]oxazolo[5,4-d][2]benzazepin-4-yl]acetamide hydrate Chemical compound O.Cc1noc2[C@H](CC(N)=O)N=C(c3ccc(Cl)cc3)c3ccccc3-c12 LXMGXMQQJNULPR-NTISSMGPSA-N 0.000 description 1
- PXJJOGITBQXZEQ-JTHROIFXSA-M 2-[4-[(z)-1,2-diphenylbut-1-enyl]phenoxy]ethyl-trimethylazanium;iodide Chemical compound [I-].C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCC[N+](C)(C)C)=CC=1)/C1=CC=CC=C1 PXJJOGITBQXZEQ-JTHROIFXSA-M 0.000 description 1
- HYHJFNXFVPGMBI-UHFFFAOYSA-N 2-[[2-chloroethyl(nitroso)carbamoyl]-methylamino]acetamide Chemical compound NC(=O)CN(C)C(=O)N(CCCl)N=O HYHJFNXFVPGMBI-UHFFFAOYSA-N 0.000 description 1
- XDLYKKIQACFMJG-UHFFFAOYSA-N 2-amino-8-[4-(2-hydroxyethoxy)cyclohexyl]-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7-one Chemical compound C1=NC(OC)=CC=C1C(C1=O)=CC2=C(C)N=C(N)N=C2N1C1CCC(OCCO)CC1 XDLYKKIQACFMJG-UHFFFAOYSA-N 0.000 description 1
- VDCRFBBZFHHYGT-IOSLPCCCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-enyl-3h-purine-6,8-dione Chemical compound O=C1N(CC=C)C=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O VDCRFBBZFHHYGT-IOSLPCCCSA-N 0.000 description 1
- NIXVOFULDIFBLB-QVRNUERCSA-N 2-amino-9-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purine-6-sulfinamide Chemical compound C12=NC(N)=NC(S(N)=O)=C2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NIXVOFULDIFBLB-QVRNUERCSA-N 0.000 description 1
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- JPZXHKDZASGCLU-UHFFFAOYSA-N 2-azaniumyl-3-naphthalen-2-ylpropanoate Chemical compound C1=CC=CC2=CC(CC(N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-UHFFFAOYSA-N 0.000 description 1
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 1
- UPHOPMSGKZNELG-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=C(O)C=CC2=C1 UPHOPMSGKZNELG-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- XTKLTGBKIDQGQL-UHFFFAOYSA-N 2-methyl-1-[[2-methyl-3-(trifluoromethyl)phenyl]methyl]-6-morpholin-4-ylbenzimidazole-4-carboxylic acid Chemical compound CC1=NC2=C(C(O)=O)C=C(N3CCOCC3)C=C2N1CC1=CC=CC(C(F)(F)F)=C1C XTKLTGBKIDQGQL-UHFFFAOYSA-N 0.000 description 1
- OQHQOOLVQDEIGL-UHFFFAOYSA-N 2-methyl-2,7-diazaspiro[4.4]nonane Chemical compound C1N(C)CCC11CNCC1 OQHQOOLVQDEIGL-UHFFFAOYSA-N 0.000 description 1
- CESUXLKAADQNTB-SSDOTTSWSA-N 2-methylpropane-2-sulfinamide Chemical compound CC(C)(C)[S@](N)=O CESUXLKAADQNTB-SSDOTTSWSA-N 0.000 description 1
- CTRPRMNBTVRDFH-UHFFFAOYSA-N 2-n-methyl-1,3,5-triazine-2,4,6-triamine Chemical class CNC1=NC(N)=NC(N)=N1 CTRPRMNBTVRDFH-UHFFFAOYSA-N 0.000 description 1
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- MLMQPDHYNJCQAO-UHFFFAOYSA-N 3,3-dimethylbutyric acid Chemical compound CC(C)(C)CC(O)=O MLMQPDHYNJCQAO-UHFFFAOYSA-N 0.000 description 1
- NDMPLJNOPCLANR-UHFFFAOYSA-N 3,4-dihydroxy-15-(4-hydroxy-18-methoxycarbonyl-5,18-seco-ibogamin-18-yl)-16-methoxy-1-methyl-6,7-didehydro-aspidospermidine-3-carboxylic acid methyl ester Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 NDMPLJNOPCLANR-UHFFFAOYSA-N 0.000 description 1
- HJSSBIMVTMYKPD-UHFFFAOYSA-N 3,5-difluorophenol Chemical compound OC1=CC(F)=CC(F)=C1 HJSSBIMVTMYKPD-UHFFFAOYSA-N 0.000 description 1
- HDBQZGJWHMCXIL-UHFFFAOYSA-N 3,7-dihydropurine-2-thione Chemical compound SC1=NC=C2NC=NC2=N1 HDBQZGJWHMCXIL-UHFFFAOYSA-N 0.000 description 1
- XLZYKTYMLBOINK-UHFFFAOYSA-N 3-(4-hydroxybenzoyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C(=O)C=2C=CC(O)=CC=2)=C1 XLZYKTYMLBOINK-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-UHFFFAOYSA-N 3-Epi-Betulin-Saeure Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(=C)C)C5C4CCC3C21C QGJZLNKBHJESQX-UHFFFAOYSA-N 0.000 description 1
- GTJXPMSTODOYNP-BTKVJIOYSA-N 3-[(e)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-1-enyl]phenol;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(/CC)=C(C=1C=C(O)C=CC=1)\C1=CC=C(OCCN(C)C)C=C1 GTJXPMSTODOYNP-BTKVJIOYSA-N 0.000 description 1
- WUIABRMSWOKTOF-OYALTWQYSA-N 3-[[2-[2-[2-[[(2s,3r)-2-[[(2s,3s,4r)-4-[[(2s,3r)-2-[[6-amino-2-[(1s)-3-amino-1-[[(2s)-2,3-diamino-3-oxopropyl]amino]-3-oxopropyl]-5-methylpyrimidine-4-carbonyl]amino]-3-[(2r,3s,4s,5s,6s)-3-[(2r,3s,4s,5r,6r)-4-carbamoyloxy-3,5-dihydroxy-6-(hydroxymethyl)ox Chemical compound OS([O-])(=O)=O.N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1NC=NC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C WUIABRMSWOKTOF-OYALTWQYSA-N 0.000 description 1
- JRBVDAQXMNYPHC-UHFFFAOYSA-N 3-amino-5-chlorobenzonitrile Chemical compound NC1=CC(Cl)=CC(C#N)=C1 JRBVDAQXMNYPHC-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- JCPJGUPQZDEZQH-UHFFFAOYSA-N 3-bromo-5-fluorophenol Chemical compound OC1=CC(F)=CC(Br)=C1 JCPJGUPQZDEZQH-UHFFFAOYSA-N 0.000 description 1
- ZMFBYTAAMHWQHD-UHFFFAOYSA-N 3-chloro-5-fluorophenol Chemical compound OC1=CC(F)=CC(Cl)=C1 ZMFBYTAAMHWQHD-UHFFFAOYSA-N 0.000 description 1
- GHYUOOZZOMUNSY-UHFFFAOYSA-N 3-chloro-5-hydroxybenzonitrile Chemical compound OC1=CC(Cl)=CC(C#N)=C1 GHYUOOZZOMUNSY-UHFFFAOYSA-N 0.000 description 1
- SZCQFGBXBRVLOZ-UHFFFAOYSA-N 3-chloro-5-sulfanylbenzonitrile Chemical compound SC1=CC(Cl)=CC(C#N)=C1 SZCQFGBXBRVLOZ-UHFFFAOYSA-N 0.000 description 1
- ZRPLANDPDWYOMZ-UHFFFAOYSA-N 3-cyclopentylpropionic acid Chemical compound OC(=O)CCC1CCCC1 ZRPLANDPDWYOMZ-UHFFFAOYSA-N 0.000 description 1
- CNDYPZBYAOOPRP-UHFFFAOYSA-N 3-fluoro-5-[(1-oxo-2,3-dihydroinden-4-yl)oxy]benzonitrile Chemical compound C(#N)C=1C=C(OC=2C=CC=C3C(CCC=23)=O)C=C(C=1)F CNDYPZBYAOOPRP-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 1
- CLOUCVRNYSHRCF-UHFFFAOYSA-N 3beta-Hydroxy-20(29)-Lupen-3,27-oic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C(O)=O)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C CLOUCVRNYSHRCF-UHFFFAOYSA-N 0.000 description 1
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 1
- LIETVYHJBSLSSW-UHFFFAOYSA-N 4,6,9-trihydroxy-8-methyl-3,4-dihydro-2h-anthracen-1-one Chemical compound OC1CCC(=O)C2=C1C=C1C=C(O)C=C(C)C1=C2O LIETVYHJBSLSSW-UHFFFAOYSA-N 0.000 description 1
- CLPFFLWZZBQMAO-UHFFFAOYSA-N 4-(5,6,7,8-tetrahydroimidazo[1,5-a]pyridin-5-yl)benzonitrile Chemical compound C1=CC(C#N)=CC=C1C1N2C=NC=C2CCC1 CLPFFLWZZBQMAO-UHFFFAOYSA-N 0.000 description 1
- YTXSYWAKVMZICI-PVCZSOGJSA-N 4-(carboxymethyl)-2-[(1r)-1-[[2-[(2,5-dichlorobenzoyl)amino]acetyl]amino]-3-methylbutyl]-6-oxo-1,3,2-dioxaborinane-4-carboxylic acid Chemical compound N([C@@H](CC(C)C)B1OC(CC(O)=O)(CC(=O)O1)C(O)=O)C(=O)CNC(=O)C1=CC(Cl)=CC=C1Cl YTXSYWAKVMZICI-PVCZSOGJSA-N 0.000 description 1
- PBBGSZCBWVPOOL-HDICACEKSA-N 4-[(1r,2s)-1-ethyl-2-(4-hydroxyphenyl)butyl]phenol Chemical compound C1([C@H](CC)[C@H](CC)C=2C=CC(O)=CC=2)=CC=C(O)C=C1 PBBGSZCBWVPOOL-HDICACEKSA-N 0.000 description 1
- CTSNHMQGVWXIEG-UHFFFAOYSA-N 4-amino-n-(5-chloroquinoxalin-2-yl)benzenesulfonamide Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=CN=C(C(Cl)=CC=C2)C2=N1 CTSNHMQGVWXIEG-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- UZFMOKQJFYMBGY-UHFFFAOYSA-N 4-hydroxy-TEMPO Chemical compound CC1(C)CC(O)CC(C)(C)N1[O] UZFMOKQJFYMBGY-UHFFFAOYSA-N 0.000 description 1
- SXIFAEWFOJETOA-UHFFFAOYSA-N 4-hydroxy-butyl Chemical group [CH2]CCCO SXIFAEWFOJETOA-UHFFFAOYSA-N 0.000 description 1
- 102100022464 5'-nucleotidase Human genes 0.000 description 1
- LGZKGOGODCLQHG-CYBMUJFWSA-N 5-[(2r)-2-hydroxy-2-(3,4,5-trimethoxyphenyl)ethyl]-2-methoxyphenol Chemical compound C1=C(O)C(OC)=CC=C1C[C@@H](O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-CYBMUJFWSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- TUIDQYRZDZRHPQ-UHFFFAOYSA-N 5-chloropyridin-3-ol Chemical compound OC1=CN=CC(Cl)=C1 TUIDQYRZDZRHPQ-UHFFFAOYSA-N 0.000 description 1
- VGULLEUAAMBZTQ-UHFFFAOYSA-N 5-desacetylaltohyrtin A Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C VGULLEUAAMBZTQ-UHFFFAOYSA-N 0.000 description 1
- KAXIYYPIORYZLB-UHFFFAOYSA-N 5-hydroxypyridine-3-carbonitrile Chemical compound OC1=CN=CC(C#N)=C1 KAXIYYPIORYZLB-UHFFFAOYSA-N 0.000 description 1
- BSVYLJCOTFYPSN-UHFFFAOYSA-N 5h-furo[3,2-c]pyrazole Chemical compound N1=NC2=CCOC2=C1 BSVYLJCOTFYPSN-UHFFFAOYSA-N 0.000 description 1
- LRHPCRBOMKRVOA-UHFFFAOYSA-N 6-[2-(2-hydroxyethylamino)ethyl]indeno[1,2-c]isoquinoline-5,11-dione Chemical compound C12=CC=CC=C2C(=O)N(CCNCCO)C2=C1C(=O)C1=CC=CC=C12 LRHPCRBOMKRVOA-UHFFFAOYSA-N 0.000 description 1
- LJIRBXZDQGQUOO-KVTDHHQDSA-N 6-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,4-dihydro-1,3,5-triazin-2-one Chemical compound C1NC(N)=NC(=O)N1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 LJIRBXZDQGQUOO-KVTDHHQDSA-N 0.000 description 1
- GNMUEVRJHCWKTO-FQEVSTJZSA-N 6h-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine-6-acetamide, 4-(4-chlorophenyl)-n-(4-hydroxyphenyl)-2,3,9-trimethyl-, (6s)- Chemical compound C([C@@H]1N=C(C2=C(N3C(C)=NN=C31)SC(=C2C)C)C=1C=CC(Cl)=CC=1)C(=O)NC1=CC=C(O)C=C1 GNMUEVRJHCWKTO-FQEVSTJZSA-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
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 1
- LPDLEICKXUVJHW-QJILNLRNSA-N 78nz2pmp25 Chemical compound OS(O)(=O)=O.O([C@]12[C@H](OC(C)=O)[C@]3(CC)C=CCN4CC[C@@]5([C@H]34)[C@H]1N(C)C1=C5C=C(C(=C1)OC)[C@]1(C(=O)OC)C3=C(C4=CC=CC=C4N3)CCN3C[C@H](C1)C[C@@](C3)(O)CC)C(=O)N(CCCl)C2=O LPDLEICKXUVJHW-QJILNLRNSA-N 0.000 description 1
- ZGXJTSGNIOSYLO-UHFFFAOYSA-N 88755TAZ87 Chemical compound NCC(=O)CCC(O)=O ZGXJTSGNIOSYLO-UHFFFAOYSA-N 0.000 description 1
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 1
- UMBVAPCONCILTL-MRHIQRDNSA-N Ac-Asp-Glu-Val-Asp-H Chemical compound OC(=O)C[C@@H](C=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(O)=O)NC(C)=O UMBVAPCONCILTL-MRHIQRDNSA-N 0.000 description 1
- SMNNBONTPYNICF-UHFFFAOYSA-N Aclacinomycin B Natural products CCC1(O)CC(OC2CC(C(OC3CC(O)C(OC4CCC(=O)CO4)C(C)O3)C(C)O2)N(C)C)c5c(O)c6C(=O)c7ccccc7C(=O)c6cc5C1C(=O)OC SMNNBONTPYNICF-UHFFFAOYSA-N 0.000 description 1
- 108010085273 Adenosine A2B receptor Proteins 0.000 description 1
- SRNWOUGRCWSEMX-UHFFFAOYSA-N Adenosine diphosphate ribose Natural products C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COP(O)(=O)OP(O)(=O)OCC1OC(O)C(O)C1O SRNWOUGRCWSEMX-UHFFFAOYSA-N 0.000 description 1
- 101150051188 Adora2a gene Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- BOJKULTULYSRAS-OTESTREVSA-N Andrographolide Chemical compound C([C@H]1[C@]2(C)CC[C@@H](O)[C@]([C@H]2CCC1=C)(CO)C)\C=C1/[C@H](O)COC1=O BOJKULTULYSRAS-OTESTREVSA-N 0.000 description 1
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 1
- 102100034608 Angiopoietin-2 Human genes 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 241001440311 Armada Species 0.000 description 1
- BFYIZQONLCFLEV-DAELLWKTSA-N Aromasine Chemical compound O=C1C=C[C@]2(C)[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CC(=C)C2=C1 BFYIZQONLCFLEV-DAELLWKTSA-N 0.000 description 1
- 102000003916 Arrestin Human genes 0.000 description 1
- 108090000328 Arrestin Proteins 0.000 description 1
- 102000015790 Asparaginase Human genes 0.000 description 1
- 241000182988 Assa Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 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
- 229930187843 Atramycin Natural products 0.000 description 1
- 241001263178 Auriparus Species 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 239000012664 BCL-2-inhibitor Substances 0.000 description 1
- 229940125565 BMS-986016 Drugs 0.000 description 1
- 108700020462 BRCA2 Proteins 0.000 description 1
- 102000052609 BRCA2 Human genes 0.000 description 1
- 229940124291 BTK inhibitor Drugs 0.000 description 1
- 101000840545 Bacillus thuringiensis L-isoleucine-4-hydroxylase Proteins 0.000 description 1
- 229940123711 Bcl2 inhibitor Drugs 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- VGGGPCQERPFHOB-MCIONIFRSA-N Bestatin Chemical compound CC(C)C[C@H](C(O)=O)NC(=O)[C@@H](O)[C@H](N)CC1=CC=CC=C1 VGGGPCQERPFHOB-MCIONIFRSA-N 0.000 description 1
- 102000015735 Beta-catenin Human genes 0.000 description 1
- 108060000903 Beta-catenin Proteins 0.000 description 1
- DIZWSDNSTNAYHK-XGWVBXMLSA-N Betulinic acid Natural products CC(=C)[C@@H]1C[C@H]([C@H]2CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]34C)[C@@H]12)C(=O)O DIZWSDNSTNAYHK-XGWVBXMLSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 244000056139 Brassica cretica Species 0.000 description 1
- 235000003351 Brassica cretica Nutrition 0.000 description 1
- 235000003343 Brassica rupestris Nutrition 0.000 description 1
- 101150008921 Brca2 gene Proteins 0.000 description 1
- 241001260012 Bursa Species 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- KSFOVUSSGSKXFI-GAQDCDSVSA-N CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O Chemical compound CC1=C/2NC(\C=C3/N=C(/C=C4\N\C(=C/C5=N/C(=C\2)/C(C=C)=C5C)C(C=C)=C4C)C(C)=C3CCC(O)=O)=C1CCC(O)=O KSFOVUSSGSKXFI-GAQDCDSVSA-N 0.000 description 1
- 101000715943 Caenorhabditis elegans Cyclin-dependent kinase 4 homolog Proteins 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 101710167800 Capsid assembly scaffolding protein Proteins 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 102000005403 Casein Kinases Human genes 0.000 description 1
- 108010031425 Casein Kinases Proteins 0.000 description 1
- JDVVGAQPNNXQDW-WCMLQCRESA-N Castanospermine Natural products O[C@H]1[C@@H](O)[C@H]2[C@@H](O)CCN2C[C@H]1O JDVVGAQPNNXQDW-WCMLQCRESA-N 0.000 description 1
- JDVVGAQPNNXQDW-TVNFTVLESA-N Castinospermine Chemical compound C1[C@H](O)[C@@H](O)[C@H](O)[C@H]2[C@@H](O)CCN21 JDVVGAQPNNXQDW-TVNFTVLESA-N 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 238000003734 CellTiter-Glo Luminescent Cell Viability Assay Methods 0.000 description 1
- 201000005262 Chondroma Diseases 0.000 description 1
- 102000011022 Chorionic Gonadotropin Human genes 0.000 description 1
- 108010062540 Chorionic Gonadotropin Proteins 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- PPASFTRHCXASPY-UHFFFAOYSA-N Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 Chemical compound Cl.Cl.NCCCNc1ccc2c3c(nn2CCNCCO)c4c(O)ccc(O)c4C(=O)c13 PPASFTRHCXASPY-UHFFFAOYSA-N 0.000 description 1
- HVXBOLULGPECHP-WAYWQWQTSA-N Combretastatin A4 Chemical compound C1=C(O)C(OC)=CC=C1\C=C/C1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-WAYWQWQTSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- 102000008130 Cyclic AMP-Dependent Protein Kinases Human genes 0.000 description 1
- 102000016736 Cyclin Human genes 0.000 description 1
- 108050006400 Cyclin Proteins 0.000 description 1
- 108010058546 Cyclin D1 Proteins 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 108010025454 Cyclin-Dependent Kinase 5 Proteins 0.000 description 1
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 1
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 1
- 102100032857 Cyclin-dependent kinase 1 Human genes 0.000 description 1
- 101710106279 Cyclin-dependent kinase 1 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036329 Cyclin-dependent kinase 3 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 1
- 102100026810 Cyclin-dependent kinase 7 Human genes 0.000 description 1
- 102100024456 Cyclin-dependent kinase 8 Human genes 0.000 description 1
- 102100024457 Cyclin-dependent kinase 9 Human genes 0.000 description 1
- 102100024458 Cyclin-dependent kinase inhibitor 2A Human genes 0.000 description 1
- 102100026805 Cyclin-dependent-like kinase 5 Human genes 0.000 description 1
- 102100028183 Cytohesin-interacting protein Human genes 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
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-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
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 108010060248 DNA Ligase ATP Proteins 0.000 description 1
- 102000008158 DNA Ligase ATP Human genes 0.000 description 1
- 108010001132 DNA Polymerase beta Proteins 0.000 description 1
- 102000011724 DNA Repair Enzymes Human genes 0.000 description 1
- 108010076525 DNA Repair Enzymes Proteins 0.000 description 1
- 102100022302 DNA polymerase beta Human genes 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- GJKXGJCSJWBJEZ-XRSSZCMZSA-N Deslorelin Chemical compound CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)CC1=CNC2=CC=CC=C12 GJKXGJCSJWBJEZ-XRSSZCMZSA-N 0.000 description 1
- 102000001477 Deubiquitinating Enzymes Human genes 0.000 description 1
- 108010093668 Deubiquitinating Enzymes Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- OALVLUFFPXEHFO-UHFFFAOYSA-N Diazonamide A Natural products O1C=2C34C(O)OC5=C3C=CC=C5C(C3=5)=CC=CC=5NC(Cl)=C3C(=C(N=3)Cl)OC=3C=2N=C1C(C(C)C)NC(=O)C(NC(=O)C(N)C(C)C)CC1=CC=C(O)C4=C1 OALVLUFFPXEHFO-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- AADVCYNFEREWOS-OBRABYBLSA-N Discodermolide Chemical compound C=C\C=C/[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O)[C@@H](C)C\C(C)=C/[C@H](C)[C@@H](O)[C@@H](C)\C=C/[C@@H](O)C[C@@H]1OC(=O)[C@H](C)[C@@H](O)[C@H]1C AADVCYNFEREWOS-OBRABYBLSA-N 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000012286 ELISA Assay Methods 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 description 1
- 102100029722 Ectonucleoside triphosphate diphosphohydrolase 1 Human genes 0.000 description 1
- 102100037249 Egl nine homolog 1 Human genes 0.000 description 1
- 101710111663 Egl nine homolog 1 Proteins 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000001976 Endocrine Gland Neoplasms Diseases 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 102000050554 Eph Family Receptors Human genes 0.000 description 1
- 108091008815 Eph receptors Proteins 0.000 description 1
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 1
- BEFZAMRWPCMWFJ-JRBBLYSQSA-N Epothilone C Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C=C\C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C BEFZAMRWPCMWFJ-JRBBLYSQSA-N 0.000 description 1
- XOZIUKBZLSUILX-SDMHVBBESA-N Epothilone D Natural products O=C1[C@H](C)[C@@H](O)[C@@H](C)CCC/C(/C)=C/C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C XOZIUKBZLSUILX-SDMHVBBESA-N 0.000 description 1
- UKIMCRYGLFQEOE-UHFFFAOYSA-N Epothilone F Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC2(C)OC2CC1C(C)=CC1=CSC(CO)=N1 UKIMCRYGLFQEOE-UHFFFAOYSA-N 0.000 description 1
- VAPSMQAHNAZRKC-PQWRYPMOSA-N Epristeride Chemical compound C1C=C2C=C(C(O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)NC(C)(C)C)[C@@]1(C)CC2 VAPSMQAHNAZRKC-PQWRYPMOSA-N 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 description 1
- ITIONVBQFUNVJV-UHFFFAOYSA-N Etomidoline Chemical compound C12=CC=CC=C2C(=O)N(CC)C1NC(C=C1)=CC=C1OCCN1CCCCC1 ITIONVBQFUNVJV-UHFFFAOYSA-N 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- QHOUUAXSZZODMO-UHFFFAOYSA-N Fc1cc(Oc2ccc(I)c3C(=O)C(F)(F)Cc23)cc(c1)C#N Chemical compound Fc1cc(Oc2ccc(I)c3C(=O)C(F)(F)Cc23)cc(c1)C#N QHOUUAXSZZODMO-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 108010029961 Filgrastim Proteins 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
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 1
- 102000001267 GSK3 Human genes 0.000 description 1
- 108060006662 GSK3 Proteins 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229940121800 Gelatinase inhibitor Drugs 0.000 description 1
- JRZJKWGQFNTSRN-UHFFFAOYSA-N Geldanamycin Natural products C1C(C)CC(OC)C(O)C(C)C=C(C)C(OC(N)=O)C(OC)CCC=C(C)C(=O)NC2=CC(=O)C(OC)=C1C2=O JRZJKWGQFNTSRN-UHFFFAOYSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 244000060234 Gmelina philippensis Species 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 102400001066 Growth hormone-binding protein Human genes 0.000 description 1
- 108010072471 HTI-286 Proteins 0.000 description 1
- ZBLLGPUWGCOJNG-UHFFFAOYSA-N Halichondrin B Natural products CC1CC2(CC(C)C3OC4(CC5OC6C(CC5O4)OC7CC8OC9CCC%10OC(CC(C(C9)C8=C)C%11%12CC%13OC%14C(OC%15CCC(CC(=O)OC7C6C)OC%15C%14O%11)C%13O%12)CC%10=C)CC3O2)OC%16OC(CC1%16)C(O)CC(O)CO ZBLLGPUWGCOJNG-UHFFFAOYSA-N 0.000 description 1
- 102000001554 Hemoglobins Human genes 0.000 description 1
- 108010054147 Hemoglobins Proteins 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 108010036115 Histone Methyltransferases Proteins 0.000 description 1
- 102000011787 Histone Methyltransferases Human genes 0.000 description 1
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 1
- 101000678236 Homo sapiens 5'-nucleotidase Proteins 0.000 description 1
- 101000627872 Homo sapiens 72 kDa type IV collagenase Proteins 0.000 description 1
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 1
- 101000924533 Homo sapiens Angiopoietin-2 Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 101000715946 Homo sapiens Cyclin-dependent kinase 3 Proteins 0.000 description 1
- 101000911952 Homo sapiens Cyclin-dependent kinase 7 Proteins 0.000 description 1
- 101000980937 Homo sapiens Cyclin-dependent kinase 8 Proteins 0.000 description 1
- 101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 description 1
- 101000916686 Homo sapiens Cytohesin-interacting protein Proteins 0.000 description 1
- 101001095815 Homo sapiens E3 ubiquitin-protein ligase RING2 Proteins 0.000 description 1
- 101001012447 Homo sapiens Ectonucleoside triphosphate diphosphohydrolase 1 Proteins 0.000 description 1
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 description 1
- 101001055145 Homo sapiens Interleukin-2 receptor subunit beta Proteins 0.000 description 1
- 101000868279 Homo sapiens Leukocyte surface antigen CD47 Proteins 0.000 description 1
- 101001138062 Homo sapiens Leukocyte-associated immunoglobulin-like receptor 1 Proteins 0.000 description 1
- 101001088887 Homo sapiens Lysine-specific demethylase 5C Proteins 0.000 description 1
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 1
- 101001057193 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Proteins 0.000 description 1
- 101000615488 Homo sapiens Methyl-CpG-binding domain protein 2 Proteins 0.000 description 1
- 101001113483 Homo sapiens Poly [ADP-ribose] polymerase 1 Proteins 0.000 description 1
- 101000927796 Homo sapiens Rho guanine nucleotide exchange factor 7 Proteins 0.000 description 1
- 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 description 1
- 101000777277 Homo sapiens Serine/threonine-protein kinase Chk2 Proteins 0.000 description 1
- 101000987310 Homo sapiens Serine/threonine-protein kinase PAK 2 Proteins 0.000 description 1
- 101000987315 Homo sapiens Serine/threonine-protein kinase PAK 3 Proteins 0.000 description 1
- 101000987297 Homo sapiens Serine/threonine-protein kinase PAK 4 Proteins 0.000 description 1
- 101000864342 Homo sapiens Tyrosine-protein kinase BTK Proteins 0.000 description 1
- 101000740048 Homo sapiens Ubiquitin carboxyl-terminal hydrolase BAP1 Proteins 0.000 description 1
- 101000955962 Homo sapiens Vacuolar protein sorting-associated protein 51 homolog Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- MPBVHIBUJCELCL-UHFFFAOYSA-N Ibandronate Chemical compound CCCCCN(C)CCC(O)(P(O)(O)=O)P(O)(O)=O MPBVHIBUJCELCL-UHFFFAOYSA-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
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 description 1
- 101000668058 Infectious salmon anemia virus (isolate Atlantic salmon/Norway/810/9/99) RNA-directed RNA polymerase catalytic subunit Proteins 0.000 description 1
- 108700022013 Insecta cecropin B Proteins 0.000 description 1
- 102100039688 Insulin-like growth factor 1 receptor Human genes 0.000 description 1
- 101710184277 Insulin-like growth factor 1 receptor Proteins 0.000 description 1
- 108010078049 Interferon alpha-2 Proteins 0.000 description 1
- 108010079944 Interferon-alpha2b Proteins 0.000 description 1
- 102100026879 Interleukin-2 receptor subunit beta Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 208000016286 Iron metabolism disease Diseases 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 108091082332 JAK family Proteins 0.000 description 1
- 102000019145 JUN kinase activity proteins Human genes 0.000 description 1
- 102000002698 KIR Receptors Human genes 0.000 description 1
- 108010043610 KIR Receptors Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 108010043135 L-methionine gamma-lyase Proteins 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- 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 1
- 101000740049 Latilactobacillus curvatus Bioactive peptide 1 Proteins 0.000 description 1
- 208000001791 Leiomyomatosis Diseases 0.000 description 1
- 229920001491 Lentinan Polymers 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 102000004058 Leukemia inhibitory factor Human genes 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 102100032913 Leukocyte surface antigen CD47 Human genes 0.000 description 1
- 102100020943 Leukocyte-associated immunoglobulin-like receptor 1 Human genes 0.000 description 1
- HLFSDGLLUJUHTE-SNVBAGLBSA-N Levamisole Chemical compound C1([C@H]2CN3CCSC3=N2)=CC=CC=C1 HLFSDGLLUJUHTE-SNVBAGLBSA-N 0.000 description 1
- 241000234435 Lilium Species 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052765 Lutetium Inorganic materials 0.000 description 1
- 229940123628 Lysine (K)-specific demethylase 1A inhibitor Drugs 0.000 description 1
- 102100033249 Lysine-specific demethylase 5C Human genes 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 1
- 229930184337 Mannostatin Natural products 0.000 description 1
- 229940123394 Matriptase inhibitor Drugs 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 108700021154 Metallothionein 3 Proteins 0.000 description 1
- 102100028708 Metallothionein-3 Human genes 0.000 description 1
- 241000361919 Metaphire sieboldi Species 0.000 description 1
- 102100021299 Methyl-CpG-binding domain protein 2 Human genes 0.000 description 1
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 1
- 229930192392 Mitomycin Natural products 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
- TXXHDPDFNKHHGW-CCAGOZQPSA-N Muconic acid Natural products OC(=O)\C=C/C=C\C(O)=O TXXHDPDFNKHHGW-CCAGOZQPSA-N 0.000 description 1
- 206010048723 Multiple-drug resistance Diseases 0.000 description 1
- 101100189356 Mus musculus Papolb gene Proteins 0.000 description 1
- 101100407308 Mus musculus Pdcd1lg2 gene Proteins 0.000 description 1
- 101100533558 Mus musculus Sipa1 gene Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- WUKZPHOXUVCQOR-UHFFFAOYSA-N N-(1-azabicyclo[2.2.2]octan-3-yl)-6-chloro-4-methyl-3-oxo-1,4-benzoxazine-8-carboxamide Chemical compound C1N(CC2)CCC2C1NC(=O)C1=CC(Cl)=CC2=C1OCC(=O)N2C WUKZPHOXUVCQOR-UHFFFAOYSA-N 0.000 description 1
- QJMCKEPOKRERLN-UHFFFAOYSA-N N-3,4-tridhydroxybenzamide Chemical compound ONC(=O)C1=CC=C(O)C(O)=C1 QJMCKEPOKRERLN-UHFFFAOYSA-N 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- CXQHYVUVSFXTMY-UHFFFAOYSA-N N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 CXQHYVUVSFXTMY-UHFFFAOYSA-N 0.000 description 1
- 108010021717 Nafarelin Proteins 0.000 description 1
- GTEXXGIEZVKSLH-UHFFFAOYSA-N Naphterpin Natural products O=C1C2=CC(O)=C(C)C(O)=C2C(=O)C2=C1C1C=C(C)CCC1C(C)(C)O2 GTEXXGIEZVKSLH-UHFFFAOYSA-N 0.000 description 1
- 108090000028 Neprilysin Proteins 0.000 description 1
- 102000003729 Neprilysin Human genes 0.000 description 1
- 241000243827 Nereis Species 0.000 description 1
- 208000033383 Neuroendocrine tumor of pancreas Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- KYRVNWMVYQXFEU-UHFFFAOYSA-N Nocodazole Chemical compound C1=C2NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CS1 KYRVNWMVYQXFEU-UHFFFAOYSA-N 0.000 description 1
- 102000014736 Notch Human genes 0.000 description 1
- 108010070047 Notch Receptors Proteins 0.000 description 1
- WQLDJUQUFZDTSD-XXODBJNXSA-N O([C@@H]1[C@]2(O)C[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]31)OC(C)=O)C2(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)C(C)C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 Chemical compound O([C@@H]1[C@]2(O)C[C@@H](C(=C([C@@H](OC(C)=O)C(=O)[C@]3(C)[C@@H](O)C[C@H]4OC[C@]4([C@H]31)OC(C)=O)C2(C)C)C)OC(=O)[C@H](O)[C@@H](NC(=O)C(C)C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 WQLDJUQUFZDTSD-XXODBJNXSA-N 0.000 description 1
- 229960005524 O6-benzylguanine Drugs 0.000 description 1
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 1
- FOQXBQHXOQYZSM-UHFFFAOYSA-N OC1=NC2=CC=CC=C2C=C1.[P] Chemical compound OC1=NC2=CC=CC=C2C=C1.[P] FOQXBQHXOQYZSM-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 108010016076 Octreotide Proteins 0.000 description 1
- 241000123069 Ocyurus chrysurus Species 0.000 description 1
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 description 1
- VTAZRSXSBIHBMH-UHFFFAOYSA-N Ophiocordin Natural products OC1=CC(C(=O)O)=CC(O)=C1C(=O)C1=C(O)C=CC=C1C(=O)NC1C(OC(=O)C=2C=CC(O)=CC=2)CCCNC1 VTAZRSXSBIHBMH-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 101700056750 PAK1 Proteins 0.000 description 1
- 239000012828 PI3K inhibitor Substances 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYOQBYCIIJYKJA-UHFFFAOYSA-N Palauamine Natural products C1N2C(=O)C3=CC=CN3C3N=C(N)NC32C2C1C(CN)C(Cl)C12NC(N)=NC1O VYOQBYCIIJYKJA-UHFFFAOYSA-N 0.000 description 1
- 206010067517 Pancreatic neuroendocrine tumour Diseases 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229940083963 Peptide antagonist Drugs 0.000 description 1
- 229940122907 Phosphatase inhibitor Drugs 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 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
- 102000010752 Plasminogen Inactivators Human genes 0.000 description 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 description 1
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 1
- 102000015087 Poly (ADP-Ribose) Polymerase-1 Human genes 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 1
- 108091026813 Poly(ADPribose) Proteins 0.000 description 1
- 102100037935 Polyubiquitin-C Human genes 0.000 description 1
- 101710130420 Probable capsid assembly scaffolding protein Proteins 0.000 description 1
- 108700030875 Programmed Cell Death 1 Ligand 2 Proteins 0.000 description 1
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 102000004245 Proteasome Endopeptidase Complex Human genes 0.000 description 1
- 108090000708 Proteasome Endopeptidase Complex Proteins 0.000 description 1
- 102000003923 Protein Kinase C Human genes 0.000 description 1
- 108090000315 Protein Kinase C Proteins 0.000 description 1
- 229940123924 Protein kinase C inhibitor Drugs 0.000 description 1
- 108010090931 Proto-Oncogene Proteins c-bcl-2 Proteins 0.000 description 1
- 102000013535 Proto-Oncogene Proteins c-bcl-2 Human genes 0.000 description 1
- 239000005828 Pyrimethanil Substances 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108010068097 Rad51 Recombinase Proteins 0.000 description 1
- 102000002490 Rad51 Recombinase Human genes 0.000 description 1
- 208000037323 Rare tumor Diseases 0.000 description 1
- 102000003901 Ras GTPase-activating proteins Human genes 0.000 description 1
- 108090000231 Ras GTPase-activating proteins Proteins 0.000 description 1
- 229940078123 Ras inhibitor Drugs 0.000 description 1
- 108091027981 Response element Proteins 0.000 description 1
- 241000235527 Rhizopus Species 0.000 description 1
- FTALBRSUTCGOEG-UHFFFAOYSA-N Riluzole Chemical compound C1=C(OC(F)(F)F)C=C2SC(N)=NC2=C1 FTALBRSUTCGOEG-UHFFFAOYSA-N 0.000 description 1
- DREPOWITHQLFOD-UHFFFAOYSA-N S(=O)(=O)(O)NC(N(C1=CC=CC=C1)Cl)=O Chemical compound S(=O)(=O)(O)NC(N(C1=CC=CC=C1)Cl)=O DREPOWITHQLFOD-UHFFFAOYSA-N 0.000 description 1
- ZQUSFAUAYSEREK-WKILWMFISA-N SB-239063 Chemical compound COC1=NC=CC(C=2N(C=NC=2C=2C=CC(F)=CC=2)[C@@H]2CC[C@@H](O)CC2)=N1 ZQUSFAUAYSEREK-WKILWMFISA-N 0.000 description 1
- 102000001332 SRC Human genes 0.000 description 1
- 108060006706 SRC Proteins 0.000 description 1
- 101001037255 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Indoleamine 2,3-dioxygenase Proteins 0.000 description 1
- 101710204410 Scaffold protein Proteins 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 description 1
- 102100031075 Serine/threonine-protein kinase Chk2 Human genes 0.000 description 1
- 102100027910 Serine/threonine-protein kinase PAK 1 Human genes 0.000 description 1
- 102100027939 Serine/threonine-protein kinase PAK 2 Human genes 0.000 description 1
- 102100027911 Serine/threonine-protein kinase PAK 3 Human genes 0.000 description 1
- 102100027940 Serine/threonine-protein kinase PAK 4 Human genes 0.000 description 1
- 101150002444 Slc11a2 gene Proteins 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- HEMHJVSKTPXQMS-DYCDLGHISA-M Sodium hydroxide-d Chemical compound [Na+].[2H][O-] HEMHJVSKTPXQMS-DYCDLGHISA-M 0.000 description 1
- 208000032383 Soft tissue cancer Diseases 0.000 description 1
- 229920002334 Spandex Polymers 0.000 description 1
- PFNFFQXMRSDOHW-UHFFFAOYSA-N Spermine Natural products NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 description 1
- GCEUCUGYUPYUEC-UHFFFAOYSA-N Spongistatin 3 Natural products COC1CC2CC(=O)C(C)C(OC(=O)C)C(C)C(=C)CC3CC(C)(O)CC4(CCCC(CC(=O)OC5C(C)C(OC(CC(=C)CC(O)C=CC(=C)Cl)C5O)C(O)C6(O)CC(O)C(C)C(CCCC=C/C7CC(O)CC(C1)(O2)O7)O6)O4)O3 GCEUCUGYUPYUEC-UHFFFAOYSA-N 0.000 description 1
- JOEPUFOWFXWEDN-UHFFFAOYSA-N Spongistatin 5 Natural products C1C(=O)C(C)C(C2C)OCC2=CC(O2)CC(C)(O)CC2(O2)CC(O)CC2CC(=O)OC(C(C(CC(=C)CC(O)C=CC(Cl)=C)O2)O)C(C)C2C(O)C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC22CC(OC)CC1O2 JOEPUFOWFXWEDN-UHFFFAOYSA-N 0.000 description 1
- BTCJGYMVVGSTDN-UHFFFAOYSA-N Spongistatin 7 Natural products C1C(=O)C(C)C(C2C)OCC2=CC(O2)CC(C)(O)CC2(O2)CC(O)CC2CC(=O)OC(C(C(CC(=C)CC(O)C=CC=C)O2)O)C(C)C2C(O)C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC22CC(OC)CC1O2 BTCJGYMVVGSTDN-UHFFFAOYSA-N 0.000 description 1
- GLMCWICCTJHQKE-UHFFFAOYSA-N Spongistatin 9 Natural products C1C(=O)C(C)C(C2C)OCC2=CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC(C(C(CC(=C)CC(O)C=CC(Cl)=C)O2)O)C(C)C2C(O)C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC22CC(OC)CC1O2 GLMCWICCTJHQKE-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
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101710196623 Stimulator of interferon genes protein Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 108091005735 TGF-beta receptors Proteins 0.000 description 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 229940123582 Telomerase inhibitor Drugs 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
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testosterone Natural products O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 1
- PDMMFKSKQVNJMI-BLQWBTBKSA-N Testosterone propionate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CC)[C@@]1(C)CC2 PDMMFKSKQVNJMI-BLQWBTBKSA-N 0.000 description 1
- QHOPXUFELLHKAS-UHFFFAOYSA-N Thespesin Natural products CC(C)c1c(O)c(O)c2C(O)Oc3c(c(C)cc1c23)-c1c2OC(O)c3c(O)c(O)c(C(C)C)c(cc1C)c23 QHOPXUFELLHKAS-UHFFFAOYSA-N 0.000 description 1
- UPGGKUQISSWRJJ-XLTUSUNSSA-N Thiocoraline Chemical compound O=C([C@H]1CSSC[C@@H](N(C(=O)CNC2=O)C)C(=O)N(C)[C@@H](C(SC[C@@H](C(=O)NCC(=O)N1C)NC(=O)C=1C(=CC3=CC=CC=C3N=1)O)=O)CSC)N(C)[C@H](CSC)C(=O)SC[C@@H]2NC(=O)C1=NC2=CC=CC=C2C=C1O UPGGKUQISSWRJJ-XLTUSUNSSA-N 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 102000011923 Thyrotropin Human genes 0.000 description 1
- 108010061174 Thyrotropin Proteins 0.000 description 1
- 102000000591 Tight Junction Proteins Human genes 0.000 description 1
- 108010002321 Tight Junction Proteins Proteins 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-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
- IWEQQRMGNVVKQW-OQKDUQJOSA-N Toremifene citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 IWEQQRMGNVVKQW-OQKDUQJOSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000016715 Transforming Growth Factor beta Receptors Human genes 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 241000545405 Tripterygium Species 0.000 description 1
- 102100040653 Tryptophan 2,3-dioxygenase Human genes 0.000 description 1
- 101710136122 Tryptophan 2,3-dioxygenase Proteins 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 102100029823 Tyrosine-protein kinase BTK Human genes 0.000 description 1
- 101150049278 US20 gene Proteins 0.000 description 1
- 102100037587 Ubiquitin carboxyl-terminal hydrolase BAP1 Human genes 0.000 description 1
- 108010083111 Ubiquitin-Protein Ligases Proteins 0.000 description 1
- 102000006275 Ubiquitin-Protein Ligases Human genes 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 229930186114 Variolin Natural products 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 108010003205 Vasoactive Intestinal Peptide Proteins 0.000 description 1
- 102400000015 Vasoactive intestinal peptide Human genes 0.000 description 1
- MALFODICFSIXPO-UHFFFAOYSA-N Veratramin Natural products C=1C=C2C3CC=C4CC(O)CCC4(C)C3CC2=C(C)C=1C(C)C1NCC(C)CC1O MALFODICFSIXPO-UHFFFAOYSA-N 0.000 description 1
- 101150046474 Vhl gene Proteins 0.000 description 1
- 229940122803 Vinca alkaloid Drugs 0.000 description 1
- 229930003268 Vitamin C Natural products 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 101150042435 Xrcc1 gene Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 102100025093 Zinc fingers and homeoboxes protein 2 Human genes 0.000 description 1
- OGQICQVSFDPSEI-UHFFFAOYSA-N Zorac Chemical compound N1=CC(C(=O)OCC)=CC=C1C#CC1=CC=C(SCCC2(C)C)C2=C1 OGQICQVSFDPSEI-UHFFFAOYSA-N 0.000 description 1
- KMLCRELJHYKIIL-UHFFFAOYSA-N [1-(azanidylmethyl)cyclohexyl]methylazanide;platinum(2+);sulfuric acid Chemical compound [Pt+2].OS(O)(=O)=O.[NH-]CC1(C[NH-])CCCCC1 KMLCRELJHYKIIL-UHFFFAOYSA-N 0.000 description 1
- JJULHOZRTCDZOH-JGJFOBQESA-N [1-[[[(2r,3s,4s,5r)-5-(4-amino-2-oxopyrimidin-1-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-3-octadecylsulfanylpropan-2-yl] hexadecanoate Chemical compound O[C@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(CSCCCCCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)O[C@H]1N1C(=O)N=C(N)C=C1 JJULHOZRTCDZOH-JGJFOBQESA-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
- NAFFDQVVNWTDJD-UHFFFAOYSA-L [4-(azanidylmethyl)oxan-4-yl]methylazanide;cyclobutane-1,1-dicarboxylate;platinum(4+) Chemical compound [Pt+4].[NH-]CC1(C[NH-])CCOCC1.[O-]C(=O)C1(C([O-])=O)CCC1 NAFFDQVVNWTDJD-UHFFFAOYSA-L 0.000 description 1
- NIRCDTRHFKQIJU-UHFFFAOYSA-J [B+3].C([O-])([O-])=O.[Na+].C([O-])([O-])=O Chemical compound [B+3].C([O-])([O-])=O.[Na+].C([O-])([O-])=O NIRCDTRHFKQIJU-UHFFFAOYSA-J 0.000 description 1
- BBOPZLFBGQCZHF-UHFFFAOYSA-N [Br].C[Mg] Chemical compound [Br].C[Mg] BBOPZLFBGQCZHF-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 229950001573 abemaciclib 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
- 230000002159 abnormal effect Effects 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- RUGAHXUZHWYHNG-NLGNTGLNSA-N acetic acid;(4r,7s,10s,13r,16s,19r)-10-(4-aminobutyl)-n-[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]-19-[[(2r)-2-amino-3-naphthalen-2-ylpropanoyl]amino]-16-[(4-hydroxyphenyl)methyl]-13-(1h-indol-3-ylmethyl)-6,9,12,15,18-pentaoxo-7-propan-2-yl-1,2-dithia-5, Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1.C([C@H]1C(=O)N[C@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](N)CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)=O)C(C)C)C1=CC=C(O)C=C1 RUGAHXUZHWYHNG-NLGNTGLNSA-N 0.000 description 1
- 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 1
- 230000002378 acidificating effect Effects 0.000 description 1
- ZGAOCJJHFMRCEE-UHFFFAOYSA-N acridine 2,3-dihydro-1H-pyrazole Chemical class C1=CC=CC2=NC3=CC=CC=C3C=C12.N1NC=CC1 ZGAOCJJHFMRCEE-UHFFFAOYSA-N 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000008649 adaptation response Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 230000001919 adrenal effect Effects 0.000 description 1
- 208000024447 adrenal gland neoplasm Diseases 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 229960002833 aflibercept Drugs 0.000 description 1
- 108010081667 aflibercept Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 229910001413 alkali metal ion Inorganic materials 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 229950010482 alpelisib Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960002749 aminolevulinic acid Drugs 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 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
- 229960001694 anagrelide Drugs 0.000 description 1
- OTBXOEAOVRKTNQ-UHFFFAOYSA-N anagrelide Chemical compound N1=C2NC(=O)CN2CC2=C(Cl)C(Cl)=CC=C21 OTBXOEAOVRKTNQ-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003098 androgen Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- ASLUCFFROXVMFL-UHFFFAOYSA-N andrographolide Natural products CC1(CO)C(O)CCC2(C)C(CC=C3/C(O)OCC3=O)C(=C)CCC12 ASLUCFFROXVMFL-UHFFFAOYSA-N 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002870 angiogenesis inducing agent Substances 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- 108010070670 antarelix Proteins 0.000 description 1
- ACPOUJIDANTYHO-UHFFFAOYSA-N anthra[1,9-cd]pyrazol-6(2H)-one Chemical compound C1=CC(C(=O)C=2C3=CC=CC=2)=C2C3=NNC2=C1 ACPOUJIDANTYHO-UHFFFAOYSA-N 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical class C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 102000025171 antigen binding proteins Human genes 0.000 description 1
- 108091000831 antigen binding proteins Proteins 0.000 description 1
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 1
- 229940045713 antineoplastic alkylating drug ethylene imines Drugs 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000000074 antisense oligonucleotide Substances 0.000 description 1
- 238000012230 antisense oligonucleotides Methods 0.000 description 1
- NOFOAYPPHIUXJR-APNQCZIXSA-N aphidicolin Chemical compound C1[C@@]23[C@@]4(C)CC[C@@H](O)[C@@](C)(CO)[C@@H]4CC[C@H]3C[C@H]1[C@](CO)(O)CC2 NOFOAYPPHIUXJR-APNQCZIXSA-N 0.000 description 1
- SEKZNWAQALMJNH-YZUCACDQSA-N aphidicolin Natural products C[C@]1(CO)CC[C@]23C[C@H]1C[C@@H]2CC[C@H]4[C@](C)(CO)[C@H](O)CC[C@]34C SEKZNWAQALMJNH-YZUCACDQSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- XZNUGFQTQHRASN-XQENGBIVSA-N apramycin Chemical compound O([C@H]1O[C@@H]2[C@H](O)[C@@H]([C@H](O[C@H]2C[C@H]1N)O[C@@H]1[C@@H]([C@@H](O)[C@H](N)[C@@H](CO)O1)O)NC)[C@@H]1[C@@H](N)C[C@@H](N)[C@H](O)[C@H]1O XZNUGFQTQHRASN-XQENGBIVSA-N 0.000 description 1
- 229950006334 apramycin Drugs 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 108010055530 arginyl-tryptophyl-N-methylphenylalanyl-tryptophyl-leucyl-methioninamide Proteins 0.000 description 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- OPWOOOGFNULJAQ-UHFFFAOYSA-L azane;cyclopentanamine;2-hydroxybutanedioate;platinum(2+) Chemical compound N.[Pt+2].NC1CCCC1.[O-]C(=O)C(O)CC([O-])=O OPWOOOGFNULJAQ-UHFFFAOYSA-L 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- 229950005951 azasetron Drugs 0.000 description 1
- HRXVDDOKERXBEY-UHFFFAOYSA-N azatepa Chemical compound C1CN1P(=O)(N1CC1)N(CC)C1=NN=CS1 HRXVDDOKERXBEY-UHFFFAOYSA-N 0.000 description 1
- 229950002182 azatepa Drugs 0.000 description 1
- MIXLRUYCYZPSOQ-HXPMCKFVSA-N azatoxin Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=C(C4=CC=CC=C4N3)C[C@@H]3N2C(OC3)=O)=C1 MIXLRUYCYZPSOQ-HXPMCKFVSA-N 0.000 description 1
- 150000004200 baccatin III derivatives Chemical class 0.000 description 1
- XYUFCXJZFZPEJD-PGRDOPGGSA-N balanol Chemical compound OC(=O)C1=CC=CC(O)=C1C(=O)C1=C(O)C=C(C(=O)O[C@H]2[C@H](CNCCC2)NC(=O)C=2C=CC(O)=CC=2)C=C1O XYUFCXJZFZPEJD-PGRDOPGGSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- MMIMIFULGMZVPO-UHFFFAOYSA-N benzyl 3-bromo-2,6-dinitro-5-phenylmethoxybenzoate Chemical compound [O-][N+](=O)C1=C(C(=O)OCC=2C=CC=CC=2)C([N+](=O)[O-])=C(Br)C=C1OCC1=CC=CC=C1 MMIMIFULGMZVPO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 1
- QGJZLNKBHJESQX-FZFNOLFKSA-N betulinic acid Chemical compound C1C[C@H](O)C(C)(C)[C@@H]2CC[C@@]3(C)[C@]4(C)CC[C@@]5(C(O)=O)CC[C@@H](C(=C)C)[C@@H]5[C@H]4CC[C@@H]3[C@]21C QGJZLNKBHJESQX-FZFNOLFKSA-N 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000000090 biomarker Substances 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229950000080 birabresib Drugs 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical compound ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 229950008548 bisantrene Drugs 0.000 description 1
- 229960004395 bleomycin sulfate Drugs 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- IUEWAGVJRJORLA-HZPDHXFCSA-N bmn-673 Chemical compound CN1N=CN=C1[C@H]1C(NNC(=O)C2=CC(F)=C3)=C2C3=N[C@@H]1C1=CC=C(F)C=C1 IUEWAGVJRJORLA-HZPDHXFCSA-N 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- PZOHOALJQOFNTB-UHFFFAOYSA-M brequinar sodium Chemical compound [Na+].N1=C2C=CC(F)=CC2=C(C([O-])=O)C(C)=C1C(C=C1)=CC=C1C1=CC=CC=C1F PZOHOALJQOFNTB-UHFFFAOYSA-M 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 229960005520 bryostatin Drugs 0.000 description 1
- MJQUEDHRCUIRLF-TVIXENOKSA-N bryostatin 1 Chemical compound C([C@@H]1CC(/[C@@H]([C@@](C(C)(C)/C=C/2)(O)O1)OC(=O)/C=C/C=C/CCC)=C\C(=O)OC)[C@H]([C@@H](C)O)OC(=O)C[C@H](O)C[C@@H](O1)C[C@H](OC(C)=O)C(C)(C)[C@]1(O)C[C@@H]1C\C(=C\C(=O)OC)C[C@H]\2O1 MJQUEDHRCUIRLF-TVIXENOKSA-N 0.000 description 1
- MUIWQCKLQMOUAT-AKUNNTHJSA-N bryostatin 20 Natural products COC(=O)C=C1C[C@@]2(C)C[C@]3(O)O[C@](C)(C[C@@H](O)CC(=O)O[C@](C)(C[C@@]4(C)O[C@](O)(CC5=CC(=O)O[C@]45C)C(C)(C)C=C[C@@](C)(C1)O2)[C@@H](C)O)C[C@H](OC(=O)C(C)(C)C)C3(C)C MUIWQCKLQMOUAT-AKUNNTHJSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 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
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- 229960002882 calcipotriol Drugs 0.000 description 1
- LWQQLNNNIPYSNX-UROSTWAQSA-N calcipotriol Chemical compound C1([C@H](O)/C=C/[C@@H](C)[C@@H]2[C@]3(CCCC(/[C@@H]3CC2)=C\C=C\2C([C@@H](O)C[C@H](O)C/2)=C)C)CC1 LWQQLNNNIPYSNX-UROSTWAQSA-N 0.000 description 1
- 229960005084 calcitriol Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class 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
- 239000003560 cancer drug Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001722 carbon compounds Chemical class 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- WNRZHQBJSXRYJK-UHFFFAOYSA-N carboxyamidotriazole Chemical compound NC1=C(C(=O)N)N=NN1CC(C=C1Cl)=CC(Cl)=C1C(=O)C1=CC=C(Cl)C=C1 WNRZHQBJSXRYJK-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 108010021331 carfilzomib Proteins 0.000 description 1
- BLMPQMFVWMYDKT-NZTKNTHTSA-N carfilzomib Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)[C@]1(C)OC1)NC(=O)CN1CCOCC1)CC1=CC=CC=C1 BLMPQMFVWMYDKT-NZTKNTHTSA-N 0.000 description 1
- 229960002438 carfilzomib Drugs 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 230000018747 cellular response to hypoxia Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- CCWSQXBMKLEALQ-WMZOPIPTSA-N centaureidin Natural products CO[C@@H]1[C@@H](Oc2cc(O)c(OC)c(O)c2C1=O)c3ccc(OC)c(O)c3 CCWSQXBMKLEALQ-WMZOPIPTSA-N 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- GPUADMRJQVPIAS-QCVDVZFFSA-M cerivastatin sodium Chemical compound [Na+].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 GPUADMRJQVPIAS-QCVDVZFFSA-M 0.000 description 1
- SBNPWPIBESPSIF-MHWMIDJBSA-N cetrorelix Chemical compound C([C@@H](C(=O)N[C@H](CCCNC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 SBNPWPIBESPSIF-MHWMIDJBSA-N 0.000 description 1
- 108700008462 cetrorelix Proteins 0.000 description 1
- 229960003230 cetrorelix Drugs 0.000 description 1
- JOAASNKBYBFGDN-UHFFFAOYSA-N chembl1214554 Chemical compound ON=C(N)C1=CC=C(O)C(O)=C1 JOAASNKBYBFGDN-UHFFFAOYSA-N 0.000 description 1
- UKTAZPQNNNJVKR-KJGYPYNMSA-N chembl2368925 Chemical compound C1=CC=C2C(C(O[C@@H]3C[C@@H]4C[C@H]5C[C@@H](N4CC5=O)C3)=O)=CNC2=C1 UKTAZPQNNNJVKR-KJGYPYNMSA-N 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229930002875 chlorophyll Natural products 0.000 description 1
- 235000019804 chlorophyll Nutrition 0.000 description 1
- ATNHDLDRLWWWCB-AENOIHSZSA-M chlorophyll a Chemical compound C1([C@@H](C(=O)OC)C(=O)C2=C3C)=C2N2C3=CC(C(CC)=C3C)=[N+]4C3=CC3=C(C=C)C(C)=C5N3[Mg-2]42[N+]2=C1[C@@H](CCC(=O)OC\C=C(/C)CCC[C@H](C)CCC[C@H](C)CCCC(C)C)[C@H](C)C2=C5 ATNHDLDRLWWWCB-AENOIHSZSA-M 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- ARUGKOZUKWAXDS-SEWALLKFSA-N cicaprost Chemical compound C1\C(=C/COCC(O)=O)C[C@@H]2[C@@H](C#C[C@@H](O)[C@@H](C)CC#CCC)[C@H](O)C[C@@H]21 ARUGKOZUKWAXDS-SEWALLKFSA-N 0.000 description 1
- 229950000634 cicaprost Drugs 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical class C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 1
- 229960004022 clotrimazole Drugs 0.000 description 1
- 238000011260 co-administration Methods 0.000 description 1
- 229960002271 cobimetinib Drugs 0.000 description 1
- BSMCAPRUBJMWDF-KRWDZBQOSA-N cobimetinib Chemical compound C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-KRWDZBQOSA-N 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- LGZKGOGODCLQHG-UHFFFAOYSA-N combretastatin Natural products C1=C(O)C(OC)=CC=C1CC(O)C1=CC(OC)=C(OC)C(OC)=C1 LGZKGOGODCLQHG-UHFFFAOYSA-N 0.000 description 1
- 229960005537 combretastatin A-4 Drugs 0.000 description 1
- HVXBOLULGPECHP-UHFFFAOYSA-N combretastatin A4 Natural products C1=C(O)C(OC)=CC=C1C=CC1=CC(OC)=C(OC)C(OC)=C1 HVXBOLULGPECHP-UHFFFAOYSA-N 0.000 description 1
- 150000004814 combretastatins Chemical class 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 description 1
- 108010083340 cryptophycin 52 Proteins 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DMSZORWOGDLWGN-UHFFFAOYSA-N ctk1a3526 Chemical compound NP(N)(N)=O DMSZORWOGDLWGN-UHFFFAOYSA-N 0.000 description 1
- 235000007336 cyanidin Nutrition 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000004976 cyclobutylene group Chemical group 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- MKNXBRLZBFVUPV-UHFFFAOYSA-L cyclopenta-1,3-diene;dichlorotitanium Chemical compound Cl[Ti]Cl.C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 MKNXBRLZBFVUPV-UHFFFAOYSA-L 0.000 description 1
- YXQWGVLNDXNSJJ-UHFFFAOYSA-N cyclopenta-1,3-diene;vanadium(2+) Chemical compound [V+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 YXQWGVLNDXNSJJ-UHFFFAOYSA-N 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000004979 cyclopentylene group Chemical group 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000004980 cyclopropylene group Chemical group 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 108010041566 cypemycin Proteins 0.000 description 1
- 230000001461 cytolytic effect Effects 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- 229960002806 daclizumab Drugs 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 description 1
- 229960005484 daptomycin 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
- 229960000975 daunorubicin Drugs 0.000 description 1
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 1
- 229950001466 delanzomib Drugs 0.000 description 1
- SJFBTAPEPRWNKH-CCKFTAQKSA-N delanzomib Chemical compound CC(C)C[C@@H](B(O)O)NC(=O)[C@H]([C@@H](C)O)NC(=O)C1=CC=CC(C=2C=CC=CC=2)=N1 SJFBTAPEPRWNKH-CCKFTAQKSA-N 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000027832 depurination Effects 0.000 description 1
- 108700025485 deslorelin Proteins 0.000 description 1
- 229960005408 deslorelin Drugs 0.000 description 1
- WRPLJTYNAMMOEE-TXILBGFKSA-N desmethyleleutherobin Chemical compound O([C@H]1C[C@H]2C(C)=CC[C@@H]([C@H]2\C=C(CO[C@H]2[C@H]([C@H](O)[C@H](O)CO2)OC(C)=O)/[C@]2(O)O[C@@]1(C)C=C2)C(C)C)C(=O)\C=C\C1=CN(C)C=N1 WRPLJTYNAMMOEE-TXILBGFKSA-N 0.000 description 1
- WRPLJTYNAMMOEE-UHFFFAOYSA-N desmethyleleutherobin Natural products C1=CC2(C)OC1(O)C(COC1C(C(O)C(O)CO1)OC(C)=O)=CC1C(C(C)C)CC=C(C)C1CC2OC(=O)C=CC1=CN(C)C=N1 WRPLJTYNAMMOEE-UHFFFAOYSA-N 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- 229960000605 dexrazoxane Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- YKBUODYYSZSEIY-PLSHLZFXSA-N diazonamide a Chemical compound N([C@H]([C@]12C=3O4)O5)C6=C2C=CC=C6C(C2=6)=CC=CC=6NC(Cl)=C2C(=C(N=2)Cl)OC=2C=3N=C4[C@H](C(C)C)NC(=O)[C@@H](NC(=O)[C@@H](O)C(C)C)CC2=CC=C5C1=C2 YKBUODYYSZSEIY-PLSHLZFXSA-N 0.000 description 1
- KVBKAPANDHPRDG-UHFFFAOYSA-N dibromotetrafluoroethane Chemical compound FC(F)(Br)C(F)(F)Br KVBKAPANDHPRDG-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- CCAFPWNGIUBUSD-UHFFFAOYSA-N diethyl sulfoxide Chemical compound CCS(=O)CC CCAFPWNGIUBUSD-UHFFFAOYSA-N 0.000 description 1
- RGLYKWWBQGJZGM-ISLYRVAYSA-N diethylstilbestrol Chemical compound C=1C=C(O)C=CC=1C(/CC)=C(\CC)C1=CC=C(O)C=C1 RGLYKWWBQGJZGM-ISLYRVAYSA-N 0.000 description 1
- 229960000452 diethylstilbestrol Drugs 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- PZXJOHSZQAEJFE-UHFFFAOYSA-N dihydrobetulinic acid Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C(O)=O)CCC(C(C)C)C5C4CCC3C21C PZXJOHSZQAEJFE-UHFFFAOYSA-N 0.000 description 1
- MCWXGJITAZMZEV-UHFFFAOYSA-N dimethoate Chemical compound CNC(=O)CSP(=S)(OC)OC MCWXGJITAZMZEV-UHFFFAOYSA-N 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- LTYMSROWYAPPGB-UHFFFAOYSA-N diphenyl sulfide Chemical compound C=1C=CC=CC=1SC1=CC=CC=C1 LTYMSROWYAPPGB-UHFFFAOYSA-N 0.000 description 1
- CZLKTMHQYXYHOO-QTNFYWBSSA-L disodium;(2s)-2-[(2-phosphonatoacetyl)amino]butanedioic acid Chemical compound [Na+].[Na+].OC(=O)C[C@@H](C(O)=O)NC(=O)CP([O-])([O-])=O CZLKTMHQYXYHOO-QTNFYWBSSA-L 0.000 description 1
- SVJSWELRJWVPQD-KJWOGLQMSA-L disodium;(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]pentanedioate Chemical compound [Na+].[Na+].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 SVJSWELRJWVPQD-KJWOGLQMSA-L 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003968 dna methyltransferase inhibitor Substances 0.000 description 1
- 229960000735 docosanol Drugs 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229960003413 dolasetron Drugs 0.000 description 1
- 108010045524 dolastatin 10 Proteins 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000002222 downregulating effect Effects 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 229960004242 dronabinol Drugs 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 229950010033 ebselen Drugs 0.000 description 1
- VLCYCQAOQCDTCN-UHFFFAOYSA-N eflornithine Chemical compound NCCCC(N)(C(F)F)C(O)=O VLCYCQAOQCDTCN-UHFFFAOYSA-N 0.000 description 1
- 229960002759 eflornithine Drugs 0.000 description 1
- 229960002046 eflornithine hydrochloride Drugs 0.000 description 1
- 229940121647 egfr inhibitor Drugs 0.000 description 1
- MGQRRMONVLMKJL-KWJIQSIXSA-N elsamitrucin Chemical compound O1[C@H](C)[C@H](O)[C@H](OC)[C@@H](N)[C@H]1O[C@@H]1[C@](O)(C)[C@@H](O)[C@@H](C)O[C@H]1OC1=CC=CC2=C(O)C(C(O3)=O)=C4C5=C3C=CC(C)=C5C(=O)OC4=C12 MGQRRMONVLMKJL-KWJIQSIXSA-N 0.000 description 1
- 229950002339 elsamitrucin Drugs 0.000 description 1
- 201000011523 endocrine gland cancer Diseases 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- JOZGNYDSEBIJDH-UHFFFAOYSA-N eniluracil Chemical compound O=C1NC=C(C#C)C(=O)N1 JOZGNYDSEBIJDH-UHFFFAOYSA-N 0.000 description 1
- 229950010625 enloplatin Drugs 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000007247 enzymatic mechanism Effects 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 230000007608 epigenetic mechanism Effects 0.000 description 1
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 description 1
- 229960003449 epinastine Drugs 0.000 description 1
- 229960001904 epirubicin Drugs 0.000 description 1
- 229960003265 epirubicin hydrochloride Drugs 0.000 description 1
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 1
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 description 1
- FCCNKYGSMOSYPV-UHFFFAOYSA-N epothilone E Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC2OC2CC1C(C)=CC1=CSC(CO)=N1 FCCNKYGSMOSYPV-UHFFFAOYSA-N 0.000 description 1
- FCCNKYGSMOSYPV-OKOHHBBGSA-N epothilone e Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CO)=N1 FCCNKYGSMOSYPV-OKOHHBBGSA-N 0.000 description 1
- UKIMCRYGLFQEOE-RGJAOAFDSA-N epothilone f Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CO)=N1 UKIMCRYGLFQEOE-RGJAOAFDSA-N 0.000 description 1
- 229950009537 epristeride Drugs 0.000 description 1
- 229950001426 erbulozole Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 description 1
- 235000020774 essential nutrients Nutrition 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- IIUMCNJTGSMNRO-VVSKJQCTSA-L estramustine sodium phosphate Chemical compound [Na+].[Na+].ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)OP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 IIUMCNJTGSMNRO-VVSKJQCTSA-L 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229960002568 ethinylestradiol Drugs 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- IOLQWGVDEFWYNP-UHFFFAOYSA-N ethyl 2-bromo-2-methylpropanoate Chemical compound CCOC(=O)C(C)(C)Br IOLQWGVDEFWYNP-UHFFFAOYSA-N 0.000 description 1
- ARFLASKVLJTEJD-UHFFFAOYSA-N ethyl 2-bromopropanoate Chemical compound CCOC(=O)C(C)Br ARFLASKVLJTEJD-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- KLEPCGBEXOCIGS-UHFFFAOYSA-N ethyl n-[4-[[2-(imidazol-1-ylmethyl)-2-(4-methoxyphenyl)-1,3-dioxolan-4-yl]methylsulfanyl]phenyl]carbamate Chemical compound C1=CC(NC(=O)OCC)=CC=C1SCC1OC(CN2C=NC=C2)(C=2C=CC(OC)=CC=2)OC1 KLEPCGBEXOCIGS-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 1
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 1
- 229940009626 etidronate Drugs 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 229960000255 exemestane Drugs 0.000 description 1
- 229950011548 fadrozole Drugs 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- IKIBJHWXDSKRKV-UHFFFAOYSA-N fijianolide B Natural products CC1CC(=C)CC(O)C2OC2CC(OC(=O)C=C/CC3OC(C)(CC=C3)C1)C(O)C=CC4CC(=CCO4)C IKIBJHWXDSKRKV-UHFFFAOYSA-N 0.000 description 1
- 229960004177 filgrastim Drugs 0.000 description 1
- DBEPLOCGEIEOCV-WSBQPABSSA-N finasteride Chemical compound N([C@@H]1CC2)C(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)NC(C)(C)C)[C@@]2(C)CC1 DBEPLOCGEIEOCV-WSBQPABSSA-N 0.000 description 1
- 229960004039 finasteride Drugs 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- YLRFCQOZQXIBAB-RBZZARIASA-N fluoxymesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)C[C@@H]2O YLRFCQOZQXIBAB-RBZZARIASA-N 0.000 description 1
- 229960001751 fluoxymesterone Drugs 0.000 description 1
- 229960002074 flutamide 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
- 229950008692 foretinib Drugs 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 229960002258 fulvestrant Drugs 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 229940044658 gallium nitrate Drugs 0.000 description 1
- 229950004410 galocitabine Drugs 0.000 description 1
- 229950000456 galunisertib Drugs 0.000 description 1
- GJNXBNATEDXMAK-PFLSVRRQSA-N ganirelix Chemical compound C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 GJNXBNATEDXMAK-PFLSVRRQSA-N 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- 229960003794 ganirelix Drugs 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000002406 gelatinase inhibitor Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- QTQAWLPCGQOSGP-GBTDJJJQSA-N geldanamycin Chemical compound N1C(=O)\C(C)=C/C=C\[C@@H](OC)[C@H](OC(N)=O)\C(C)=C/[C@@H](C)[C@@H](O)[C@H](OC)C[C@@H](C)CC2=C(OC)C(=O)C=C1C2=O QTQAWLPCGQOSGP-GBTDJJJQSA-N 0.000 description 1
- 229960005144 gemcitabine hydrochloride Drugs 0.000 description 1
- 230000030279 gene silencing Effects 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 231100000118 genetic alteration Toxicity 0.000 description 1
- 230000004077 genetic alteration Effects 0.000 description 1
- 230000008303 genetic mechanism Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 125000005456 glyceride group Chemical group 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
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical class C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 1
- 229930000755 gossypol Natural products 0.000 description 1
- 229950005277 gossypol Drugs 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- FXNFULJVOQMBCW-VZBLNRDYSA-N halichondrin b Chemical compound O([C@@H]1[C@@H](C)[C@@H]2O[C@@H]3C[C@@]4(O[C@H]5[C@@H](C)C[C@@]6(C[C@@H]([C@@H]7O[C@@H](C[C@@H]7O6)[C@@H](O)C[C@@H](O)CO)C)O[C@H]5C4)O[C@@H]3C[C@@H]2O[C@H]1C[C@@H]1C(=C)[C@H](C)C[C@@H](O1)CC[C@H]1C(=C)C[C@@H](O1)CC1)C(=O)C[C@H](O2)CC[C@H]3[C@H]2[C@H](O2)[C@@H]4O[C@@H]5C[C@@]21O[C@@H]5[C@@H]4O3 FXNFULJVOQMBCW-VZBLNRDYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 108010057806 hemiasterlin Proteins 0.000 description 1
- 229930187626 hemiasterlin Natural products 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 238000005734 heterodimerization reaction Methods 0.000 description 1
- 229950001996 hexestrol Drugs 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229940084986 human chorionic gonadotropin Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- BNRNAKTVFSZAFA-UHFFFAOYSA-N hydrindane Chemical compound C1CCCC2CCCC21 BNRNAKTVFSZAFA-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 description 1
- MPGWGYQTRSNGDD-UHFFFAOYSA-N hypericin Chemical compound OC1=CC(O)=C(C2=O)C3=C1C1C(O)=CC(=O)C(C4=O)=C1C1=C3C3=C2C(O)=CC(C)=C3C2=C1C4=C(O)C=C2C MPGWGYQTRSNGDD-UHFFFAOYSA-N 0.000 description 1
- PHOKTTKFQUYZPI-UHFFFAOYSA-N hypericin Natural products Cc1cc(O)c2c3C(=O)C(=Cc4c(O)c5c(O)cc(O)c6c7C(=O)C(=Cc8c(C)c1c2c(c78)c(c34)c56)O)O PHOKTTKFQUYZPI-UHFFFAOYSA-N 0.000 description 1
- 229940005608 hypericin Drugs 0.000 description 1
- 230000006607 hypermethylation Effects 0.000 description 1
- 229960005236 ibandronic acid Drugs 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229960001176 idarubicin hydrochloride Drugs 0.000 description 1
- 229950002248 idoxifene Drugs 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- NITYDPDXAAFEIT-DYVFJYSZSA-N ilomastat Chemical compound C1=CC=C2C(C[C@@H](C(=O)NC)NC(=O)[C@H](CC(C)C)CC(=O)NO)=CNC2=C1 NITYDPDXAAFEIT-DYVFJYSZSA-N 0.000 description 1
- 229960003696 ilomastat Drugs 0.000 description 1
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 239000000367 immunologic factor Substances 0.000 description 1
- 239000002955 immunomodulating agent Substances 0.000 description 1
- 229940121354 immunomodulator Drugs 0.000 description 1
- 230000003308 immunostimulating effect Effects 0.000 description 1
- 238000009169 immunotherapy Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- VLQPTWRGZFDXMO-UHFFFAOYSA-N inden-4-one Chemical compound O=C1C=CC=C2C=CC=C12 VLQPTWRGZFDXMO-UHFFFAOYSA-N 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- VBUWHHLIZKOSMS-RIWXPGAOSA-N invicorp Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)C(C)C)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 VBUWHHLIZKOSMS-RIWXPGAOSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960005386 ipilimumab Drugs 0.000 description 1
- 229950010897 iproplatin Drugs 0.000 description 1
- 229960000779 irinotecan hydrochloride Drugs 0.000 description 1
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- RWXRJSRJIITQAK-ZSBIGDGJSA-N itasetron Chemical compound C12=CC=CC=C2NC(=O)N1C(=O)N[C@H](C1)C[C@H]2CC[C@@H]1N2C RWXRJSRJIITQAK-ZSBIGDGJSA-N 0.000 description 1
- 229950007654 itasetron Drugs 0.000 description 1
- FABUFPQFXZVHFB-PVYNADRNSA-N ixabepilone Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)N1)O)C)=C\C1=CSC(C)=N1 FABUFPQFXZVHFB-PVYNADRNSA-N 0.000 description 1
- 229960003648 ixazomib Drugs 0.000 description 1
- GQWYWHOHRVVHAP-DHKPLNAMSA-N jaspamide Chemical compound C1([C@@H]2NC(=O)[C@@H](CC=3C4=CC=CC=C4NC=3Br)N(C)C(=O)[C@H](C)NC(=O)[C@@H](C)C/C(C)=C/[C@H](C)C[C@@H](OC(=O)C2)C)=CC=C(O)C=C1 GQWYWHOHRVVHAP-DHKPLNAMSA-N 0.000 description 1
- 108010052440 jasplakinolide Proteins 0.000 description 1
- GQWYWHOHRVVHAP-UHFFFAOYSA-N jasplakinolide Natural products C1C(=O)OC(C)CC(C)C=C(C)CC(C)C(=O)NC(C)C(=O)N(C)C(CC=2C3=CC=CC=C3NC=2Br)C(=O)NC1C1=CC=C(O)C=C1 GQWYWHOHRVVHAP-UHFFFAOYSA-N 0.000 description 1
- 229930194861 kahalalide Natural products 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- XQVFLLMCNGKXSM-UHFFFAOYSA-N kurarinone Natural products COc1cc(O)c(C(CC=C(C)C)C(=C)C)c2OC(CC(=O)c12)c3ccc(O)cc3O XQVFLLMCNGKXSM-UHFFFAOYSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229930190794 lamellarin Natural products 0.000 description 1
- 229960002437 lanreotide Drugs 0.000 description 1
- 229960001739 lanreotide acetate Drugs 0.000 description 1
- MSBQEQDLFWWWMV-XZZGLLCESA-N laulimalide Chemical compound C(/[C@H](O)[C@H]1OC(=O)\C=C/C[C@@H]2C=CC[C@H](O2)C[C@H](CC(=C)C[C@H](O)[C@@H]2O[C@H]2C1)C)=C\[C@@H]1CC(C)=CCO1 MSBQEQDLFWWWMV-XZZGLLCESA-N 0.000 description 1
- 229940115286 lentinan Drugs 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 229960001614 levamisole Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 229950000909 lometrexol Drugs 0.000 description 1
- 229960003538 lonidamine Drugs 0.000 description 1
- 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 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 229960004844 lovastatin 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
- 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
- 229950005634 loxoribine Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000005265 lung cell Anatomy 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
- OHSVLFRHMCKCQY-UHFFFAOYSA-N lutetium atom Chemical compound [Lu] OHSVLFRHMCKCQY-UHFFFAOYSA-N 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 229940124302 mTOR inhibitor Drugs 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- BLOFGONIVNXZME-YDMGZANHSA-N mannostatin A Chemical compound CS[C@@H]1[C@@H](N)[C@@H](O)[C@@H](O)[C@H]1O BLOFGONIVNXZME-YDMGZANHSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229950008959 marimastat Drugs 0.000 description 1
- OCSMOTCMPXTDND-OUAUKWLOSA-N marimastat Chemical compound CNC(=O)[C@H](C(C)(C)C)NC(=O)[C@H](CC(C)C)[C@H](O)C(=O)NO OCSMOTCMPXTDND-OUAUKWLOSA-N 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 1
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 229960002985 medroxyprogesterone acetate Drugs 0.000 description 1
- PSGAAPLEWMOORI-PEINSRQWSA-N medroxyprogesterone acetate Chemical compound C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 PSGAAPLEWMOORI-PEINSRQWSA-N 0.000 description 1
- 229960003846 melengestrol acetate Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- BKBBTCORRZMASO-ZOWNYOTGSA-M methotrexate monosodium Chemical compound [Na+].C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C([O-])=O)C=C1 BKBBTCORRZMASO-ZOWNYOTGSA-M 0.000 description 1
- 229960003058 methotrexate sodium Drugs 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- BACHBFVBHLGWSL-UHFFFAOYSA-N methyl 2-[4-(2,4-dichlorophenoxy)phenoxy]propanoate Chemical compound C1=CC(OC(C)C(=O)OC)=CC=C1OC1=CC=C(Cl)C=C1Cl BACHBFVBHLGWSL-UHFFFAOYSA-N 0.000 description 1
- BDXPYXUQAYIUFG-UHFFFAOYSA-N methyl 3,5-diiodo-4-(4-methoxyphenoxy)benzoate Chemical compound IC1=CC(C(=O)OC)=CC(I)=C1OC1=CC=C(OC)C=C1 BDXPYXUQAYIUFG-UHFFFAOYSA-N 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 1
- 229960004503 metoclopramide Drugs 0.000 description 1
- HPNSFSBZBAHARI-UHFFFAOYSA-N micophenolic acid Natural products OC1=C(CC=C(C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-UHFFFAOYSA-N 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- VKHAHZOOUSRJNA-GCNJZUOMSA-N mifepristone Chemical compound C1([C@@H]2C3=C4CCC(=O)C=C4CC[C@H]3[C@@H]3CC[C@@]([C@]3(C2)C)(O)C#CC)=CC=C(N(C)C)C=C1 VKHAHZOOUSRJNA-GCNJZUOMSA-N 0.000 description 1
- 229960003248 mifepristone Drugs 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 229960003775 miltefosine Drugs 0.000 description 1
- PQLXHQMOHUQAKB-UHFFFAOYSA-N miltefosine Chemical compound CCCCCCCCCCCCCCCCOP([O-])(=O)OCC[N+](C)(C)C PQLXHQMOHUQAKB-UHFFFAOYSA-N 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
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 1
- 229960003539 mitoguazone Drugs 0.000 description 1
- MXWHMTNPTTVWDM-NXOFHUPFSA-N mitoguazone Chemical compound NC(N)=N\N=C(/C)\C=N\N=C(N)N MXWHMTNPTTVWDM-NXOFHUPFSA-N 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
- 229960004857 mitomycin Drugs 0.000 description 1
- ZAHQPTJLOCWVPG-UHFFFAOYSA-N mitoxantrone dihydrochloride Chemical compound Cl.Cl.O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO ZAHQPTJLOCWVPG-UHFFFAOYSA-N 0.000 description 1
- 229960004169 mitoxantrone hydrochloride Drugs 0.000 description 1
- VOWOEBADKMXUBU-UHFFFAOYSA-J molecular oxygen;tetrachlorite;hydrate Chemical compound O.O=O.[O-]Cl=O.[O-]Cl=O.[O-]Cl=O.[O-]Cl=O VOWOEBADKMXUBU-UHFFFAOYSA-J 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical class CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 230000001002 morphogenetic effect Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 235000010460 mustard Nutrition 0.000 description 1
- 229930192145 mycaperoxide Natural products 0.000 description 1
- 229960000951 mycophenolic acid Drugs 0.000 description 1
- HPNSFSBZBAHARI-RUDMXATFSA-N mycophenolic acid Chemical compound OC1=C(C\C=C(/C)CCC(O)=O)C(OC)=C(C)C2=C1C(=O)OC2 HPNSFSBZBAHARI-RUDMXATFSA-N 0.000 description 1
- 210000000066 myeloid cell Anatomy 0.000 description 1
- UFVHVURXVBHPDA-UHFFFAOYSA-N n-(dichloromethyl)-n-ethylethanamine Chemical compound CCN(CC)C(Cl)Cl UFVHVURXVBHPDA-UHFFFAOYSA-N 0.000 description 1
- NKFHKYQGZDAKMX-PPRKPIOESA-N n-[(e)-1-[(2s,4s)-4-[(2r,4s,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1h-tetracen-2-yl]ethylideneamino]benzamide;hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 NKFHKYQGZDAKMX-PPRKPIOESA-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
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 1
- JNGQUJZDVFZPEN-UHFFFAOYSA-N n-[[4-(5-bromopyrimidin-2-yl)oxy-3-methylphenyl]carbamoyl]-2-(dimethylamino)benzamide Chemical compound CN(C)C1=CC=CC=C1C(=O)NC(=O)NC(C=C1C)=CC=C1OC1=NC=C(Br)C=N1 JNGQUJZDVFZPEN-UHFFFAOYSA-N 0.000 description 1
- BRZOTEHEMOQUOY-UHFFFAOYSA-N n-[bis(aziridin-1-yl)phosphoryl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NP(=O)(N1CC1)N1CC1 BRZOTEHEMOQUOY-UHFFFAOYSA-N 0.000 description 1
- UMJJGDUYVQCBMC-UHFFFAOYSA-N n-ethyl-n'-[3-[3-(ethylamino)propylamino]propyl]propane-1,3-diamine Chemical compound CCNCCCNCCCNCCCNCC UMJJGDUYVQCBMC-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N n-hexanoic acid Natural products CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- RWHUEXWOYVBUCI-ITQXDASVSA-N nafarelin Chemical compound C([C@@H](C(=O)N[C@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 RWHUEXWOYVBUCI-ITQXDASVSA-N 0.000 description 1
- 229960002333 nafarelin Drugs 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- JZGDNMXSOCDEFQ-UHFFFAOYSA-N napavin Chemical compound C1C(CC)(O)CC(C2)CN1CCC(C1=CC=CC=C1N1)=C1C2(C(=O)OC)C(C(=C1)OC)=CC2=C1N(C)C1C2(C23)CCN3CC=CC2(CC)C(O)C1(O)C(=O)NCCNC1=CC=C(N=[N+]=[N-])C=C1[N+]([O-])=O JZGDNMXSOCDEFQ-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- CTMCWCONSULRHO-UHQPFXKFSA-N nemorubicin Chemical compound C1CO[C@H](OC)CN1[C@@H]1[C@H](O)[C@H](C)O[C@@H](O[C@@H]2C3=C(O)C=4C(=O)C5=C(OC)C=CC=C5C(=O)C=4C(O)=C3C[C@](O)(C2)C(=O)CO)C1 CTMCWCONSULRHO-UHQPFXKFSA-N 0.000 description 1
- 229950010159 nemorubicin Drugs 0.000 description 1
- KDADHLPROOOPIC-UHFFFAOYSA-N neokurarinol Natural products COc1cc(O)ccc1C1CC(=O)c2c(OC)cc(O)c(CC(CCC(C)(C)O)C(C)=C)c2O1 KDADHLPROOOPIC-UHFFFAOYSA-N 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- MQYXUWHLBZFQQO-UHFFFAOYSA-N nepehinol Natural products C1CC(O)C(C)(C)C2CCC3(C)C4(C)CCC5(C)CCC(C(=C)C)C5C4CCC3C21C MQYXUWHLBZFQQO-UHFFFAOYSA-N 0.000 description 1
- PUUSSSIBPPTKTP-UHFFFAOYSA-N neridronic acid Chemical compound NCCCCCC(O)(P(O)(O)=O)P(O)(O)=O PUUSSSIBPPTKTP-UHFFFAOYSA-N 0.000 description 1
- 229950010733 neridronic acid Drugs 0.000 description 1
- 210000005155 neural progenitor cell Anatomy 0.000 description 1
- 201000002120 neuroendocrine carcinoma Diseases 0.000 description 1
- XWXYUMMDTVBTOU-UHFFFAOYSA-N nilutamide Chemical compound O=C1C(C)(C)NC(=O)N1C1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 XWXYUMMDTVBTOU-UHFFFAOYSA-N 0.000 description 1
- 229960002653 nilutamide Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940125745 nitric oxide modulator Drugs 0.000 description 1
- 229950006344 nocodazole Drugs 0.000 description 1
- 229960004708 noscapine Drugs 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- UHGIMQLJWRAPLT-UHFFFAOYSA-N octadecyl dihydrogen phosphate Chemical compound CCCCCCCCCCCCCCCCCCOP(O)(O)=O UHGIMQLJWRAPLT-UHFFFAOYSA-N 0.000 description 1
- 229960002700 octreotide Drugs 0.000 description 1
- 229950011093 onapristone Drugs 0.000 description 1
- 230000004650 oncogenic pathway Effects 0.000 description 1
- 229960005343 ondansetron Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003256 osteocytic effect Effects 0.000 description 1
- ODHHTIYRUDURPW-UHFFFAOYSA-N ottelione A Natural products C1=C(O)C(OC)=CC=C1CC1C(C(=O)C=CC2=C)C2C(C=C)C1 ODHHTIYRUDURPW-UHFFFAOYSA-N 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000003101 oviduct Anatomy 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
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007248 oxidative elimination reaction Methods 0.000 description 1
- AFSVSXMRDKPOEW-UHFFFAOYSA-N oxidoiodine(.) Chemical compound I[O] AFSVSXMRDKPOEW-UHFFFAOYSA-N 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- VYOQBYCIIJYKJA-VORKOXQSSA-N palau'amine Chemical compound N([C@@]12[C@@H](Cl)[C@@H]([C@@H]3[C@@H]2[C@]24N=C(N)N[C@H]2N2C=CC=C2C(=O)N4C3)CN)C(N)=N[C@H]1O VYOQBYCIIJYKJA-VORKOXQSSA-N 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- WRUUGTRCQOWXEG-UHFFFAOYSA-N pamidronate Chemical compound NCCC(O)(P(O)(O)=O)P(O)(O)=O WRUUGTRCQOWXEG-UHFFFAOYSA-N 0.000 description 1
- 229960003978 pamidronic acid Drugs 0.000 description 1
- RDIMTXDFGHNINN-IKGGRYGDSA-N panaxytriol Chemical compound CCCCCCC[C@H](O)[C@@H](O)CC#CC#C[C@H](O)C=C RDIMTXDFGHNINN-IKGGRYGDSA-N 0.000 description 1
- ZCKMUKZQXWHXOF-UHFFFAOYSA-N panaxytriol Natural products CCC(C)C(C)C(C)C(C)C(C)C(O)C(O)CC#CC#CC(O)C=C ZCKMUKZQXWHXOF-UHFFFAOYSA-N 0.000 description 1
- 230000009996 pancreatic endocrine effect Effects 0.000 description 1
- 208000021010 pancreatic neuroendocrine tumor Diseases 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 229960005079 pemetrexed Drugs 0.000 description 1
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 1
- WUHLVXDDBHWHLQ-UHFFFAOYSA-N pentazole Chemical compound N=1N=NNN=1 WUHLVXDDBHWHLQ-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 208000000689 peptic esophagitis Diseases 0.000 description 1
- 125000001151 peptidyl group Chemical group 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- JGWRKYUXBBNENE-UHFFFAOYSA-N pexidartinib Chemical compound C1=NC(C(F)(F)F)=CC=C1CNC(N=C1)=CC=C1CC1=CNC2=NC=C(Cl)C=C12 JGWRKYUXBBNENE-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012660 pharmacological inhibitor Substances 0.000 description 1
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical class OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940043441 phosphoinositide 3-kinase inhibitor Drugs 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 1
- 229950010773 pidilizumab Drugs 0.000 description 1
- 229960002139 pilocarpine hydrochloride Drugs 0.000 description 1
- RNAICSBVACLLGM-GNAZCLTHSA-N pilocarpine hydrochloride Chemical compound Cl.C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C RNAICSBVACLLGM-GNAZCLTHSA-N 0.000 description 1
- 229960000952 pipobroman Drugs 0.000 description 1
- NJBFOOCLYDNZJN-UHFFFAOYSA-N pipobroman Chemical compound BrCCC(=O)N1CCN(C(=O)CCBr)CC1 NJBFOOCLYDNZJN-UHFFFAOYSA-N 0.000 description 1
- NUKCGLDCWQXYOQ-UHFFFAOYSA-N piposulfan Chemical compound CS(=O)(=O)OCCC(=O)N1CCN(C(=O)CCOS(C)(=O)=O)CC1 NUKCGLDCWQXYOQ-UHFFFAOYSA-N 0.000 description 1
- 229950001100 piposulfan Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 102000054765 polymorphisms of proteins Human genes 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 229920001021 polysulfide Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003089 pramipexole Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000007112 pro inflammatory response Effects 0.000 description 1
- 230000001023 pro-angiogenic effect Effects 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960001586 procarbazine hydrochloride Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229960003387 progesterone Drugs 0.000 description 1
- 239000000186 progesterone Substances 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- UQOQENZZLBSFKO-POPPZSFYSA-N prostaglandin J2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)C=CC1=O UQOQENZZLBSFKO-POPPZSFYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003528 protein farnesyltransferase inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitor Drugs 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 239000003881 protein kinase C inhibitor Substances 0.000 description 1
- 239000003806 protein tyrosine phosphatase inhibitor Substances 0.000 description 1
- 229950003776 protoporphyrin Drugs 0.000 description 1
- SSKVDVBQSWQEGJ-UHFFFAOYSA-N pseudohypericin Natural products C12=C(O)C=C(O)C(C(C=3C(O)=CC(O)=C4C=33)=O)=C2C3=C2C3=C4C(C)=CC(O)=C3C(=O)C3=C(O)C=C(O)C1=C32 SSKVDVBQSWQEGJ-UHFFFAOYSA-N 0.000 description 1
- 230000036593 pulmonary vascular resistance Effects 0.000 description 1
- 239000000784 purine nucleoside phosphorylase inhibitor Substances 0.000 description 1
- 229950010131 puromycin Drugs 0.000 description 1
- MKSVFGKWZLUTTO-FZFAUISWSA-N puromycin dihydrochloride Chemical compound Cl.Cl.C1=CC(OC)=CC=C1C[C@H](N)C(=O)N[C@H]1[C@@H](O)[C@H](N2C3=NC=NC(=C3N=C2)N(C)C)O[C@@H]1CO MKSVFGKWZLUTTO-FZFAUISWSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 1
- 229950001588 ramosetron Drugs 0.000 description 1
- 102000016914 ras Proteins Human genes 0.000 description 1
- 108010014186 ras Proteins Proteins 0.000 description 1
- 229940044601 receptor agonist Drugs 0.000 description 1
- 239000000018 receptor agonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 229940100552 retinamide Drugs 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- WUAPFZMCVAUBPE-UHFFFAOYSA-N rhenium atom Chemical compound [Re] WUAPFZMCVAUBPE-UHFFFAOYSA-N 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004181 riluzole Drugs 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 108700033545 romurtide Proteins 0.000 description 1
- 229950003733 romurtide Drugs 0.000 description 1
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 1
- 229950004707 rucaparib Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000012363 selectfluor Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 230000009758 senescence Effects 0.000 description 1
- VBSPHZOBAOWFCL-UHFFFAOYSA-N setastine Chemical compound C=1C=CC=CC=1C(C=1C=CC(Cl)=CC=1)(C)OCCN1CCCCCC1 VBSPHZOBAOWFCL-UHFFFAOYSA-N 0.000 description 1
- 229950003911 setastine Drugs 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- RQHZAASWYUEYCJ-JVWHUAOPSA-N siwenmycin Chemical compound O=C1C2=C(O)C=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O[C@@H]3O[C@@H](C)[C@@H](O[C@@H]4O[C@@H](C)[C@H]5O[C@@H]6O[C@H](C)C(=O)C[C@@H]6O[C@H]5C4)[C@H](C3)N(C)C)C[C@@](CC)(O)[C@H](C(=O)OC)C1=C2 RQHZAASWYUEYCJ-JVWHUAOPSA-N 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229940006198 sodium phenylacetate Drugs 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 108010033419 somatotropin-binding protein Proteins 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
- 239000004759 spandex Substances 0.000 description 1
- 229940063675 spermine Drugs 0.000 description 1
- WWUZIQQURGPMPG-KRWOKUGFSA-N sphingosine Chemical compound CCCCCCCCCCCCC\C=C\[C@@H](O)[C@@H](N)CO WWUZIQQURGPMPG-KRWOKUGFSA-N 0.000 description 1
- YBZRLMLGUBIIDN-NZSGCTDASA-N spicamycin Chemical compound O1[C@@H](C(O)CO)[C@H](NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)[C@@H](O)[C@@H](O)[C@H]1NC1=NC=NC2=C1N=CN2 YBZRLMLGUBIIDN-NZSGCTDASA-N 0.000 description 1
- YBZRLMLGUBIIDN-UHFFFAOYSA-N spicamycin Natural products O1C(C(O)CO)C(NC(=O)CNC(=O)CCCCCCCCCCCCC(C)C)C(O)C(O)C1NC1=NC=NC2=C1NC=N2 YBZRLMLGUBIIDN-UHFFFAOYSA-N 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical compound C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- IWDANOJGJIFBEL-UHFFFAOYSA-N spiro[3.4]octane Chemical compound C1CCC21CCCC2 IWDANOJGJIFBEL-UHFFFAOYSA-N 0.000 description 1
- VMWOETMUNAQFAX-UHFFFAOYSA-N spiro[3.5]nonane Chemical compound C1CCC21CCCCC2 VMWOETMUNAQFAX-UHFFFAOYSA-N 0.000 description 1
- PHICBFWUYUCFKS-UHFFFAOYSA-N spiro[4.4]nonane Chemical compound C1CCCC21CCCC2 PHICBFWUYUCFKS-UHFFFAOYSA-N 0.000 description 1
- DTFYGLNONOLGOT-UHFFFAOYSA-N spongistatin 2 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(OC(C)=O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC=C)OC1C2C DTFYGLNONOLGOT-UHFFFAOYSA-N 0.000 description 1
- VGULLEUAAMBZTQ-YGHPZBLNSA-N spongistatin 3 Chemical compound C([C@H](C[C@@]1(O2)C[C@H](O)C[C@H](O1)\C=C/CCC[C@H]1[C@@H](C)[C@H](O)C[C@@](O1)(O)[C@@H]1O)OC)C2CC(=O)[C@@H](C)[C@H](OC(C)=O)[C@@H](C)C(=C)C[C@@H](O2)C[C@@](C)(O)C[C@]2(O2)C[C@H](O)CC2CC(=O)O[C@H]2[C@H](O)[C@@H](CC(=C)C[C@@H](O)\C=C\C(Cl)=C)OC1[C@@H]2C VGULLEUAAMBZTQ-YGHPZBLNSA-N 0.000 description 1
- KRUKGDRIKMPUNX-JWFNSJLHSA-N spongistatin 4 Chemical compound C([C@H](C[C@@]1(O2)C[C@H](O)C[C@H](O1)\C=C/CCC[C@H]1[C@@H](C)[C@H](O)C[C@@](O1)(O)[C@@H]1O)OC)C2CC(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=C)C[C@@H](O2)C[C@@](C)(O)C[C@]2(O2)C[C@H](OC(C)=O)CC2CC(=O)O[C@H]2[C@H](O)[C@@H](CC(=C)C[C@@H](O)\C=C\C(Cl)=C)OC1[C@@H]2C KRUKGDRIKMPUNX-JWFNSJLHSA-N 0.000 description 1
- KRUKGDRIKMPUNX-UHFFFAOYSA-N spongistatin 4 Natural products OC1C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC2(O2)CC(OC)CC2CC(=O)C(C)C(O)C(C)C(=C)CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC2C(O)C(CC(=C)CC(O)C=CC(Cl)=C)OC1C2C KRUKGDRIKMPUNX-UHFFFAOYSA-N 0.000 description 1
- GQOOASKKXHUNEJ-PYATXCCJSA-N spongistatin 6 Chemical compound C([C@H](C[C@@]1(O2)C[C@H](O)C[C@H](O1)\C=C/CCC[C@H]1[C@@H](C)[C@H](O)C[C@@](O1)(O)[C@@H]1O)OC)C2CC(=O)[C@@H](C)[C@H](O)[C@@H](C)C(=C)C[C@@H](O2)C[C@@](C)(O)C[C@]2(O2)C[C@H](OC(C)=O)CC2CC(=O)O[C@H]2[C@H](O)[C@@H](CC(=C)C[C@@H](O)\C=C\C=C)OC1[C@@H]2C GQOOASKKXHUNEJ-PYATXCCJSA-N 0.000 description 1
- WYJXOZQMHBISBD-UHFFFAOYSA-N spongistatin 8 Natural products C1C(=O)C(C)C(C2C)OCC2=CC(O2)CC(C)(O)CC2(O2)CC(OC(C)=O)CC2CC(=O)OC(C(C(CC(=C)CC(O)C=CC=C)O2)O)C(C)C2C(O)C(O2)(O)CC(O)C(C)C2CCCC=CC(O2)CC(O)CC22CC(OC)CC1O2 WYJXOZQMHBISBD-UHFFFAOYSA-N 0.000 description 1
- HAOCRCFHEPRQOY-JKTUOYIXSA-N spongistatin-1 Chemical compound C([C@@H]1C[C@@H](C[C@@]2(C[C@@H](O)C[C@@H](C2)\C=C/CCC[C@@H]2[C@H](C)[C@@H](O)C[C@](O2)(O)[C@H]2O)O1)OC)C(=O)[C@@H](C)[C@@H](OC(C)=O)[C@H](C)C(=C)C[C@H](O1)C[C@](C)(O)C[C@@]1(O1)C[C@@H](OC(C)=O)C[C@@H]1CC(=O)O[C@H]1[C@H](O)[C@@H](CC(=C)C(C)[C@H](O)\C=C\C(Cl)=C)O[C@@H]2[C@@H]1C HAOCRCFHEPRQOY-JKTUOYIXSA-N 0.000 description 1
- RSHMLTSGIURLKH-SJMMKZBFSA-N spongistatin-2 Chemical compound C([C@@H]1C[C@@H](C[C@@]2(C[C@@H](O)C[C@@H](C2)\C=C/CCC[C@@H]2[C@H](C)[C@@H](O)C[C@](O2)(O)[C@H]2O)O1)OC)C(=O)[C@@H](C)[C@@H](OC(C)=O)[C@H](C)C(=C)C[C@H](O1)C[C@](C)(O)C[C@@]1(O1)C[C@@H](OC(C)=O)C[C@@H]1CC(=O)O[C@H]1[C@H](O)[C@@H](CC(=C)C(C)[C@H](O)\C=C\C=C)O[C@@H]2[C@@H]1C RSHMLTSGIURLKH-SJMMKZBFSA-N 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 229950001248 squalamine Drugs 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000024642 stem cell division Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 description 1
- 229960005314 suramin Drugs 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 229960005566 swainsonine Drugs 0.000 description 1
- FXUAIOOAOAVCGD-UHFFFAOYSA-N swainsonine Natural products C1CCC(O)C2C(O)C(O)CN21 FXUAIOOAOAVCGD-UHFFFAOYSA-N 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
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- VAZAPHZUAVEOMC-UHFFFAOYSA-N tacedinaline Chemical compound C1=CC(NC(=O)C)=CC=C1C(=O)NC1=CC=CC=C1N VAZAPHZUAVEOMC-UHFFFAOYSA-N 0.000 description 1
- 229950004550 talazoparib Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940126625 tavolimab Drugs 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- 229960000565 tazarotene Drugs 0.000 description 1
- 239000003277 telomerase inhibitor Substances 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 229960001712 testosterone propionate Drugs 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- ZCTJIMXXSXQXRI-UHFFFAOYSA-N thaliblastine Natural products CN1CCC2=CC(OC)=C(OC)C3=C2C1CC1=C3C=C(OC)C(OC2=C(CC3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-UHFFFAOYSA-N 0.000 description 1
- ZCTJIMXXSXQXRI-KYJUHHDHSA-N thalicarpine Chemical compound CN1CCC2=CC(OC)=C(OC)C3=C2[C@@H]1CC1=C3C=C(OC)C(OC2=C(C[C@H]3C4=CC(OC)=C(OC)C=C4CCN3C)C=C(C(=C2)OC)OC)=C1 ZCTJIMXXSXQXRI-KYJUHHDHSA-N 0.000 description 1
- 239000000892 thaumatin Substances 0.000 description 1
- 235000010436 thaumatin Nutrition 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 108010062880 thiocoraline Proteins 0.000 description 1
- UPGGKUQISSWRJJ-UHFFFAOYSA-N thiocoraline Natural products CN1C(=O)CNC(=O)C(NC(=O)C=2C(=CC3=CC=CC=C3N=2)O)CSC(=O)C(CSC)N(C)C(=O)C(N(C(=O)CNC2=O)C)CSSCC1C(=O)N(C)C(CSC)C(=O)SCC2NC(=O)C1=NC2=CC=CC=C2C=C1O UPGGKUQISSWRJJ-UHFFFAOYSA-N 0.000 description 1
- 150000003573 thiols Chemical group 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 108010013515 thymopoietin receptor Proteins 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960004167 toremifene citrate Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229950007217 tremelimumab Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- ILJSQTXMGCGYMG-UHFFFAOYSA-N triacetic acid Chemical compound CC(=O)CC(=O)CC(O)=O ILJSQTXMGCGYMG-UHFFFAOYSA-N 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229950003873 triciribine Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005533 tritiation Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- UIVFDCIXTSJXBB-ITGUQSILSA-N tropisetron Chemical compound C1=CC=C[C]2C(C(=O)O[C@H]3C[C@H]4CC[C@@H](C3)N4C)=CN=C21 UIVFDCIXTSJXBB-ITGUQSILSA-N 0.000 description 1
- 229960003688 tropisetron Drugs 0.000 description 1
- 229930184737 tubulysin Natural products 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229950009811 ubenimex Drugs 0.000 description 1
- 238000010798 ubiquitination Methods 0.000 description 1
- 230000034512 ubiquitination Effects 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- AUFUWRKPQLGTGF-FMKGYKFTSA-N uridine triacetate Chemical compound CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](COC(=O)C)O[C@H]1N1C(=O)NC(=O)C=C1 AUFUWRKPQLGTGF-FMKGYKFTSA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229950011257 veliparib Drugs 0.000 description 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 1
- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 description 1
- 229960001183 venetoclax Drugs 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- MALFODICFSIXPO-KFKQDBFTSA-N veratramine Chemical compound N([C@H]1[C@@H](C)C=2C(=C3C[C@@H]4[C@@]5(C)CC[C@H](O)CC5=CC[C@H]4C3=CC=2)C)C[C@@H](C)C[C@H]1O MALFODICFSIXPO-KFKQDBFTSA-N 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- 229960005212 vindesine sulfate Drugs 0.000 description 1
- BCXOZISMDZTYHW-IFQBWSDRSA-N vinepidine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@H](C2)CC)N2CCC2=C1NC1=CC=CC=C21 BCXOZISMDZTYHW-IFQBWSDRSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 235000019154 vitamin C Nutrition 0.000 description 1
- 239000011718 vitamin C Substances 0.000 description 1
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 1
- 229960004740 voriconazole Drugs 0.000 description 1
- 229960001771 vorozole Drugs 0.000 description 1
- XLMPPFTZALNBFS-INIZCTEOSA-N vorozole Chemical compound C1([C@@H](C2=CC=C3N=NN(C3=C2)C)N2N=CN=C2)=CC=C(Cl)C=C1 XLMPPFTZALNBFS-INIZCTEOSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- DVPVGSLIUJPOCJ-XXRQFBABSA-N x1j761618a Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(=O)CN(C)C)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 DVPVGSLIUJPOCJ-XXRQFBABSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/54—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本披露涉及某些低氧诱导因子2α(HIF‑2α)抑制剂以及其在治疗由HIF‑2α介导的疾病如癌症中的用途。还提供了HIF‑2α抑制剂与聚(ADP‑核糖)聚合酶(PARP)抑制剂组合的用途。特别地,本披露涉及使用HIF‑2α抑制剂与PARP抑制剂组合治疗癌症的方法以及包含所述抑制剂的药物组合物。
Description
相关申请的交叉引用
本申请要求于2020年4月16日提交的美国非临时申请号16/851,018和于2020年10月19日提交的美国临时申请号63/093,734的优先权和权益,将其各自的内容通过援引以其整体特此并入。
技术领域
本披露涉及某些低氧诱导因子2α(HIF-2α)抑制剂以及其在治疗由HIF-2α介导的疾病如癌症中的用途。还提供了HIF-2α抑制剂与聚(ADP-核糖)聚合酶(PARP)抑制剂组合的用途。特别地,本披露涉及使用HIF-2α抑制剂与PARP抑制剂组合治疗癌症的方法以及包含所述抑制剂的药物组合物。
背景技术
低氧是实体瘤的典型特征,并且癌细胞对低氧的适应有助于侵袭性表型的发展并与癌症患者的预后不良有关。对低氧的细胞应答主要由称为低氧诱导因子(HIF)(包括HIF-1α、HIF-2α和HIF-3α)的转录因子家族控制(参见Wang,G.L.,等人(1995),Proc Natl AcadSci U S A[美国国家科学院院刊],92(12),5510-5514;Tian,H.,等人(1997),Genes Dev[基因与发育],11(1),72-82;和Gu,Y.Z.,等人(1998),Gene Expr[基因表达],7(3),205-213)。在充分含氧的细胞中,HIFα亚基被脯氨酰基-4-羟化酶羟基化,然后被希佩尔-林道(Von Hippel Lindau)(VHL)E3泛素连接酶复合物多泛素化,随后是蛋白酶体介导的降解(参见Bishop,T.,等人(2014),Hypoxia[低氧](Auckl),2,197-213)。在低氧条件下,HIFα的羟基化被抑制,导致HIFα在细胞核中稳定和积累,在细胞核中它们与HIF-1β二聚化并调节大量靶基因的转录(参见Greer,S.N.,等人(2012),EMBO J[欧洲分子生物学学会杂志],31(11),2448-2460)。这允许对低氧的适应性应答必不可少的基因(包括对血管生成、代谢重编程、存活、增殖、和转移重要的基因)的协调激活。
通过HIF转录复合物对低氧的应答而增加的血管生成基因包括VEGF、FLT-1、ANG1、ANG2、TIE2、PDGF、MMP2、9和FLK1(参见Favaro,E.,等人(2011),Genome Med[基因组医学],3(8),55;和Semenza,G.L.(2014),Annu Rev Pathol[病理学年评],9,47-71)。VEGFR抑制剂和抗VEGF抗体两者在多种类型癌症(包括结直肠癌、胶质母细胞瘤、肝细胞癌、肾细胞癌、甲状腺癌、和神经内分泌癌)中的临床益处已经验证了肿瘤血管生成在驱动肿瘤进展中的重要性。尽管对抗VEGF途径治疗产生了初始应答,但许多患者产生了一种或多种抗性机制并变得难治。抗血管生成疗法的重要抗性机制包括HIF介导的替代性促血管生成因子的上调和代谢重编程(参见Bergers,G.,&Hanahan,D.(2008),Nat Rev Cancer[癌症自然评论],8(8),592-603;Welti,J.,等人(2013),J Clin Invest[临床研究杂志],123(8),3190-3200)。因此,靶向HIF代表一种直接靶向VEGF或VEGFR的替代性策略。
HIF-1α和HIF-2α是最具特征性的HIFα亚基,其中HIF-2α被认为是透明细胞肾细胞癌(ccRCC)的关键致癌驱动因子,并且由于VHL基因的基因失活或其启动子超甲基化而导致高频率的VHL功能缺陷(高达90%),该透明细胞肾细胞癌经常组成型地表达HIF-2α(参见Network,C.G.A.R.(2013),Nature[自然],499(7456),43-49;Sato,Y.,等人(2013),NatGenet[自然遗传学],45(8),860-867;Meléndez-Rodríguez,F.,等人(2018),Front Oncol[肿瘤学前沿],8,214;Rathmell,W.K.,&Chen,S.(2008),Expert Rev Anticancer Ther[抗癌疗法的专家评论],8(1),63-73)。临床前和临床数据已经证明,HIF-2α的药理学抑制剂可以有效对抗ccRCC的生长(参见Wallace,E.M.,等人(2016),Cancer Res[癌症研究],76(18),5491-5500;Courtney,K.D.,等人(2018),J Clin Oncol[临床肿瘤学杂志],36(9),867-874;和Choueiri,T.K.,等人(2020),ASCO)。
聚(ADP-核糖)聚合酶-1(PARP1)是在哺乳动物细胞的细胞核中高度表达的酶,并且其在修复受损DNA和维持基因组稳定性方面起重要作用。PARP的功能是检测和启动对代谢、化学或辐射诱导的单链DNA断裂(SSB)的细胞应答,这一功能通过合成聚合腺苷二磷酸核糖(聚(ADP-核糖)或PAR)链,随后发出复杂的酶促机制信号(包括DNA修复酶、DNA连接酶III(LigIII)、DNA聚合酶β(polβ)和支架蛋白,如X射线交叉互补基因1(XRCC1))以修复这些SSB来实现(参见Dulaney,C.,等人(2017),Semin Cell Dev Biol[细胞与发育生物学研讨会],63,144-153;和Morales,J.,等人(2014),Crit Rev Eukaryot Gene Expr[真核生物基因表达的关键评论],24(1),15-28)。当PARP活性受损时(例如当被PARP抑制剂抑制时),SSB将最终进展为可以对细胞具有高度毒性的双链断裂(DSB)(参见Dulaney,C.,等人(2017),Semin Cell Dev Biol[细胞与发育生物学研讨会],63,144-153)。可以通过同源重组(HR)机制修复DSB(参见Li,X.,&Heyer,W.D.(2008),Cell Res[细胞研究],18(1),99-113)。缺乏修复DSB能力的肿瘤,即具有BRCA1/2基因(HR途径的关键组分)的突变的那些肿瘤,对PARP抑制剂特别敏感(参见Slade,D.(2020),Genes Dev[基因与发育],34(5-6),360-394)。这种合成致死率已通过批准PARP抑制剂用于BRCA1/2缺陷型卵巢癌、输卵管癌或原发性腹膜癌和乳腺癌在临床前和临床上得到验证(参见Yi等人,等人(2019),Exp Hematol Oncol[实验血液学与肿瘤学],8,29;和Slade,D.(2020),Genes Dev[基因与发育],34(5-6),360-394)。另外,目前正在各种癌症环境(包括肾细胞癌(RCC))中的临床试验中对PARP抑制剂(如维利帕尼)进行测试。
RCC通常与HR途径的遗传改变(如BRCA1/2突变)无关,但表现出“BRCAness”表型(参见Warsow等人,等人(2018),Sci Rep[科学报告],8(1),7477)。“BRCAness”是一个专门创造的术语,用于描述在不存在BRCA1或BRCA2突变的情况下通过同源重组在DNA双链断裂修复方面存在缺陷的肿瘤(参见Turner,N.,等人(2004),Nat Rev Cancer[癌症自然评论],4(10),814-819)。最近,VHL-缺陷型RCC已被证明与“BRCAness”肿瘤具有一些共同特征(参见Scanlon,S.E.,等人(2018),Oncotarget[肿瘤靶标],9(4),4647-4660)。对VHL-缺陷型和VHL-WT肾肿瘤样品中DNA修复基因表达的癌症基因组图谱(TCGA)ccRCC数据库的分析鉴定了VHL失活与同源重组途径基因(包括ANCD2、BRCA1、RAD51)的表达减少之间存在相关性(参见Scanlon,S.E.,等人(2018),Oncotarget[肿瘤靶标],9(4),4647-4660)。因此,VHL缺陷型ccRCC可能表现出比正常组织对PARP抑制剂的敏感性更高的敏感性。
另外,已经发现,低氧可导致BRCA1表达的下调,从而导致对于介导对PARP抑制剂的敏感性很重要的同源重组活性的降低(参见Bindra,R.S.,等人(2005),Cancer Res[癌症研究],65(24),11597-11604)。由于HIF-2α抑制作用的关键机制之一是在肿瘤组织中创造低氧条件,将HIF-2α抑制剂与PARP抑制剂一起施用应导致HR途径中重要基因的减少,从而在抑制ccRCC肿瘤进展或诱导ccRCC肿瘤消退方面提供更大的治疗效果。
除VHL缺陷之外,其他ccRCC肿瘤在已知具有染色质重塑和DNA损伤应答功能的许多基因中表现出频繁的突变或缺失。无论处于哪个阶段,PBRM1(ccRCC中第二最常见的突变基因)都编码BRG1相关因子(BAF)180,它是起着调节染色质结构的作用的约2MDa聚溴BAF(PBAF)SWI/SNF复合物的限定性亚基(参见Hsieh等人,等人(2017),Eur Urol[欧洲泌尿学],71(3),405-414;和Varela等人,等人(2011),Nature[自然],469(7331),539-542)。ccRCC中其他频繁改变的基因(包括SETD2(组蛋白甲基转移酶)、KDM5C(去甲基化酶)和BAP1(去泛素化酶))也与染色质重塑和基因组稳定性有关(参见Mehdi,A.,&Riazalhosseini,Y.(2017),Int J Mol Sci[国际分子科学杂志],18(8))。这些缺陷还可用于使用PARP抑制剂通过诱导过度的基因组不稳定性和灾难性DNA损伤来进行治疗。例如,最近发现,具有PBRM1缺陷的ccRCC细胞对PARP抑制剂治疗更敏感(参见Chabanon,R.M.,等人(2020),AACR[美国癌症研究协会])。因此,通过靶向ccRCC中不同的关键致癌途径,HIF-2α抑制剂与PARP抑制剂的组合可以显著改善临床益处。
在多种肿瘤类型中也发现了HIF-2α过表达,这些肿瘤类型包括透明细胞亚型以外的肾细胞癌(RCC)(如乳头状RCC肿瘤模型)、乳腺癌、脑癌、膀胱癌、软骨癌、宫颈癌、结直肠癌、子宫内膜癌、头颈癌、肾癌、肝癌、肺癌、卵巢癌、胰腺癌、前列腺癌、唾液腺癌、皮肤癌、软组织癌和胃部癌症(参见Wong,S.C.,等人(2018),Mol Cancer Ther[分子癌症治疗学],17(1),140-149;Moreno Roig,E.,等人(2018),Front Oncol[肿瘤学前沿],8,224;和Luo,D.,等人(2019),Cancer Epidemiol Biomarkers Prev[癌症流行病学生物标志物和预防],28(5),857-866)。广泛接受的是,在肿瘤,特别是大且快速生长的肿瘤组织中,氧气需求超过了氧气供应。因此,在肿瘤组织内存在异质性低氧微环境,由于氧气扩散受到阻碍,低氧越来越严重,这与肿瘤细胞与现有脉管系统的距离有关。在几乎所有实体瘤类型中均已观察到这种现象,并且该现象驱动HIF-1α和/或HIF-2α的稳定和积累,从而促进新血管的发展,为肿瘤生长增加氧气和营养物质的供应。由于抑制HIF-2α会加重低氧状态,这种情况随后可能增加DNA损伤并降低DNA修复能力,从而产生了可通过用HIF-2α抑制剂与PARP抑制剂组合治疗这些癌症而导致的脆弱性。
尽管PARP抑制剂在临床上具有前景,但许多患者在初始应答后便没有应答或没有产生抗性。已知某些肿瘤细胞具有癌症干细胞(CSC)样特征,在许多肿瘤类型中介导对靶向疗法和传统化学疗法的抗性(参见Phi,L.T.H.,等人(2018),Stem Cells Int[国际干细胞],2018,5416923)。已经发现,HIF-2α调节多种肿瘤类型中的癌症干细胞特征,这些肿瘤类型包括胶质母细胞瘤、急性淋巴细胞白血病、急性髓性白血病、慢性髓性白血病、和乳腺癌(参见Peng,G.,&Liu,Y.(2015),Trends Pharmacol Sci[药理科学趋势],36(6),374-383)。实际上,胶质母细胞瘤中的HIF-2α沉默降低了自我更新、体外肿瘤细胞增殖和体内肿瘤启动能力(参见Nusblat,L.M.,等人(2020),Cancer Drug Resist[癌症抗药性],3(2),199-208)。因此,HIF-2α活性也可通过上调癌症干细胞样特性,在介导患者对PARP抑制剂的抗性方面发挥作用。HIF-2α抑制剂与PARP抑制剂的组合可能具有协同作用,并且可能代表治疗癌症类型的新范例,其中PARP抑制剂已得到批准或目前正在进行临床开发。
由于HIF-α蛋白在调节对含氧量变化的生理应答方面的作用,除癌症之外,它们还与许多与低氧相关的病理过程有因果关系。炎症性肠病(IBD)是慢性复发性肠道炎症性疾病。正常情况下,肠道维持细胞氧张力的动态急剧波动,其中上皮绒毛尖端缺氧,上皮绒毛底部含氧更好。上皮氧张力失调在IBD的肠道炎症和消退中起作用(参见Shah Y.M.,Molecular and Cellular Pediatrics[分子和细胞儿科学],2016年12月;3(1):1)。尽管HIF-1α和HIF-2α可以与相同的典型低氧应答元件(HRE)结合,但多项研究已经证明,HIF-1α和HIF-2α调节不同的基因子集,导致IBD症状的对比效应(contrasting effect)。肠道上皮细胞中的HIF-1α被广泛认为是IBD的主要保护因子(参见Karhausen J,等人J Clin Invest[临床研究杂志].2004;114(8):1098-1106;Furuta GT,等人J Exp Med[实验医学杂志].2001;193(9):1027-1034)。然而,HIF-2α激活通过多种机制促成IBD,包括直接调节多种促炎症性细胞因子(如肿瘤坏死因子-α)来驱动炎症,以及通过增加紧密连接蛋白(封闭蛋白)的周转来间接破坏肠道屏障完整性(参见Xue X,等人Gastroenterology[肠胃病学].2013;145(4):831-841;Glover LE,等人Proc Natl Acad Sci U S A[美国国家科学院院刊].2013;110(49):19820-19825)。因此,在IBD中,HIF-2α抑制剂有希望抑制HIF-2α的慢性激活以恢复促炎症性应答并增加肠道屏障完整性。
随着肥胖和代谢综合征的日益流行,NASH正在成为一种常见的慢性肝脏疾病,而可用的治疗选择有限。最近的研究表明,肠道HIF-2α信号传导与体质指数和肝脏毒性之间存在正相关关系,进一步的动物模型研究支持这种相关性的因果关系(参见Xie C,等人NatMed[自然医学].2017年11月;23(11):1298-1308.)。因此,靶向肠道HIF-2α代表了一种新的针对NASH的治疗策略。
PAH是一种危及生命的疾病,预后极差。以同心肺动脉壁增厚和闭塞性内膜病变为特征的进行性肺血管重塑是导致PAH患者的肺血管阻力(PVR)和肺动脉压(PAP)升高的主要原因之一(参见Aggarwal S,等人Compr Physiol[综合生理学].2013年7月;3(3):1011-34)。最近,发现HIF-2α有助于低氧肺血管重塑过程,降低血管床的可塑性,并最终使PAH虚弱(参见Andrew S.,等人Proc Natl Acad Sci U S A[美国国家科学院院刊].2016年8月2日;113(31):8801-8806,Tang H,等人Am J Physiol Lung Cell Mol Physiol.[美国生理学杂志-肺细胞与分子生理学]2018年2月1日;314(2):L256-L275.)。这些研究为肺内皮HIF-2α在调节肺血管对低氧的应答方面的作用提供了新的见解,并通过靶向HIF-2α提供了急需的干预治疗策略。
铁是氧气输送所需的必需营养素,并在许多关键的酶促反应和氧化还原反应中充当辅因子。HIF-2α调节有助于铁吸收的关键基因的表达,当这些基因被破坏时会导致铁负荷障碍。例如,一项针对肠道上皮细胞中缺乏HIF-2α的小鼠进行的优秀研究表明,HIF-2α敲除导致十二指肠中Dmt1、Dcytb和FPN mRNA的水平显著降低,这些都是铁运输和吸收的重要基因。更重要的是,HIF-1α并没有补偿这些影响(参见Mastrogiannaki M,等人J ClinInvest[临床研究杂志].2009;119(5):1159-1166)。因此,靶向HIF-2α的小分子具有改善患有铁障碍患者的铁稳态的潜力。
发明内容
在第一方面,提供了治疗患者的癌症的方法,该方法包括向该患者施用具有式(I)的HIF-2α抑制剂:
其中:
X1是CH或N;
R1是羟基、卤代、氨基、-OP(O)(OH)2、-OCH2OP(O)(OH)2、-OCOR10、-OCOOR11、
-OCONR12R13、-OCHR14OCOR15或-OCHR14OCOOR15a,其中R10、R11、和R15以及R15a独立地是烷基或被氨基、羧基或羟基取代的烷基,R12和R13独立地是氢,烷基,或被氨基、羧基或羟基取代的烷基,或R12和R13与它们所附接的氮原子一起形成任选地取代的杂环基,并且每个R14是氢、烷基、或卤代烷基;
R2是氢、氘、烷基、卤代、卤代烷基、烯基、或炔基;
R2a是氢、卤代、或氘;
R3和R4独立地是氢、氘、烷基、环烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基;或
R3和R4与它们所附接的碳一起形成氧代、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;
R5是氢、氘、烷基、卤代、卤代烷基、羟基、或烷氧基;
R6是氢、氘、烷基、环烷基、或卤代;或
R5和R6与它们所附接的碳一起形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;条件是R5和R6以及R3和R4与它们所附接的碳一起不同时形成氧代、环亚烷基或任选地取代的4元至6元杂亚环基;
R7是氢、氘、烷基、烷氧基、氰基、卤代、卤代烷基、或卤代烷氧基;
L是键、S、SO、SO2、O、CO、或NR16,其中R16是氢或烷基;
R8是烷基、卤代烷基、羟基烷基、烷氧基烷基、氨基烷基、环烷基、环烯基、二环环烷基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,或杂环基,本身或作为杂环基烷基的一部分,被Ra、Rb、Rc、Rg和Rh取代,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;
R9是氢、烷基、环烷基、羟基、烷氧基、氰基、卤代、卤代烷基、卤代烷氧基、烷基亚砜、烷基磺酰基、或杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代;或
当R9和R2附接至同一碳原子时,它们可以组合形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元杂亚环基;并且
R9a是氢、卤代、或氘;或
其药学上可接受的盐;
与PARP抑制剂或其药学上可接受的盐组合。
在第二方面,提供了组合,其包含如第一方面(和下文实施例1至52)所述的具有式(I)的Hif-2α抑制剂或其药学上可接受的盐、和PARP抑制剂或其药学上可接受的盐。在第二方面的实施例中,第二方面的组合用于在治疗患者的癌症中使用。
在第三方面,提供了组合的用途,该用途包括如第一方面(和下文实施例1至52)所述的具有式(I)的Hif-2α抑制剂或其药学上可接受的盐、和PARP抑制剂或其药学上可接受的盐用于治疗患者的癌症。
在第四方面,一种药物组合物,其包含如第一方面(和下文实施例1至52)所述的具有式(I)的HIF-2α抑制剂或其药学上可接受的盐、和PARP抑制剂(或下文披露的其实施例)或其药学上可接受的盐以及药学上可接受的赋形剂。在第四方面的实施例中,第四方面的药物组合用于治疗患者的癌症。
在第一、第二、第三和第四方面及其子实施例的第一子实施例中,HIF-2α抑制剂是3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(化合物5)。
在2020年4月16日提交的PCT申请号PCT/US20/28579中披露了包括化合物5及其一种或多种多晶型物的具有式(I)的化合物。
在第一、第二、第三和第四方面以及任一实施例和其中包含的子实施例的第四子实施例中,癌症选自肾脏癌、脑癌、软骨癌、肾癌、唾液腺癌、皮肤癌、胃部癌症、胶质母细胞瘤、神经母细胞瘤、副神经节瘤、嗜铬细胞瘤、生长抑素瘤、成血管细胞瘤、胃肠道间质瘤、垂体瘤、平滑肌瘤、平滑肌肉瘤、红细胞增多症、视网膜癌、肺癌、胰腺癌、肝癌、卵巢癌、乳腺癌、前列腺癌、结直肠癌、头颈癌、宫颈癌、子宫内膜癌、膀胱癌、胃癌、食管癌、淋巴瘤、黑素瘤、间皮瘤、肉瘤、神经内分泌瘤、葡萄膜黑素瘤、尿路上皮癌、输卵管癌、原发性腹膜癌、胆管癌、尤因肉瘤、子宫平滑肌肉瘤、慢性淋巴细胞白血病、急性淋巴细胞白血病、T细胞幼淋巴细胞白血病、多发性骨髓瘤、急性髓性白血病、慢性髓细胞性白血病、生殖细胞癌、骨肉瘤、胆道癌、软组织肉瘤、横纹肌肉瘤、套细胞淋巴瘤、和内分泌腺赘生物。
在第五方面,提供了具有式(IA)的化合物:
其中:
R2是氢或氘;
R9是氟;
R7是氢;
R7是被Ra、Rb、Rc、Rg和Rh取代的苯基,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;
R2a是氢、氘、或氟;并且
R9a是氟;或
其药学上可接受的盐。
具有式(IA)的化合物是具有式(I)的化合物的子集。
在第六方面,提供了在患者(优选需要这种治疗的患者)中治疗通过抑制HIF-2α可治疗的疾病的方法,该方法包括向该患者(优选需要这种治疗的患者)施用治疗有效量的具有式(IA)的化合物(或本文所述的其任一实施例)或其药学上可接受的盐。可以以药物组合物施用治疗有效量的化合物(IA),该药物组合物包含具有式(IA)的化合物或其药学上可接受的盐以及药学上可接受的赋形剂。
在第六方面的一个实施例中,疾病是癌症如肾脏癌、胶质母细胞瘤(参见PNAS2017,114,E6137-E6146)、肾细胞癌(特别是透明细胞肾细胞癌)、小细胞肺癌、胶质母细胞瘤、卵巢癌、肝癌、神经母细胞瘤、嗜铬细胞瘤和副神经节瘤(参见European Journal ofCancer[欧洲癌症杂志]2017,86,1-4)、生长抑素瘤、成血管细胞瘤、胃肠道间质瘤(GIST)、垂体瘤、平滑肌瘤、平滑肌肉瘤、红细胞增多症或视网膜瘤。在另一个实施例中,可受益于Hif-2α抑制的非癌症疾病包括VHL(希佩尔-林道)疾病(参见Oncotarget[肿瘤靶标],2015,6,23036-23037)、肺部疾病如PAH(肺动脉高压)(参见Mol.Cell.Biol[分子和细胞生物学].2016,36,1584-1594)、反流性食管炎(参见Current Opinion in Pharmacology[药理学当前观点]2017,37:93-99)、肝脂肪变性(参见Nature Medicine[自然医学]2017,23,1298-1308)、肝脏疾病如NASH、炎症性疾病如炎症性肠病(参见Nature Reviewsgastroenterology&Hepatology[自然评论,胃肠病学和肝病学]2017,14,596)、自身免疫性疾病如移植物抗宿主病(参见Blood[血液],2015,126,1865)、或铁超负荷。
在第七方面,本披露涉及药物组合物,其包含具有式(IA)的化合物(或本文所述的其任一实施例)或其药学上可接受的盐;以及药学上可接受的赋形剂。
在第八方面,提供了具有式(IA)的化合物(或本文所述的其任何实施例)或其药学上可接受的盐,用作药物。在一个实施例中,化合物式(IA)(和本文所述的其任何实施例)或药学上可接受的盐可用于治疗上述第六方面或第六方面的实施例中披露的疾病中的一种或多种。
在第九方面,提供了具有式(IA)的化合物或其药学上可接受的盐(和本文所披露的其任何实施例)在制造用于治疗患者的疾病的药物中的用途,其中HIF-2α的活性促成该疾病的病理学和/或症状。在一个实施例中,疾病是上述第六方面或第六方面的实施例中披露的疾病中的一种或多种。
在第十方面,提供了抑制HIF-2α的方法,该方法包括使HIF-2α与具有式(IA)的化合物(或本文所述的其任一实施例)或其药学上可接受的盐接触;或使HIF-2α与药物组合物接触,该药物组合物包含具有式(IA)的化合物(或本文所述的其任一实施例)或其药学上可接受的盐;以及药学上可接受的赋形剂。
附图说明
图1提供了共免疫沉淀测定的结果,该测定用于测量原代肺动脉平滑肌细胞(PASMC)和人肺动脉内皮细胞(HPAEC)中HIF-2α和ARNT二聚化的抑制。
具体实施方式
定义:
除非另外说明,在本说明书和权利要求书中使用的以下术语是出于本申请的目的定义的并且具有以下含义:
“烷基”是指具有一个至六个碳原子的直链饱和单价烃基或具有三个至六个碳原子的支链饱和单价烃基,例如,甲基、乙基、丙基、2-丙基、丁基、戊基等。本领域技术人员将认识到,术语“烷基”可包括“亚烷基”基团。
除非另作说明,“亚烷基”是指具有一个至六个碳原子的直链饱和二价烃基或具有三个至六个碳原子的支链饱和二价烃基,例如,亚甲基、亚乙基、亚丙基、1-甲基亚丙基、2-甲基亚丙基、亚丁基、亚戊基等。
“烯基”是指含有双键的具有两个至六个碳原子的直链单价烃基或具有三个至六个碳原子的支链单价烃基,例如,丙烯基、丁烯基等。
“烷基二烯基”是经由末端二价碳附接的如上所定义的烯基。例如,在以下的化合物中:
“卤代烷基二烯基”是被一个或两个卤代取代的烷基二烯基,每个基团如本文所定义。
“炔基”是指含有三键的具有两个至六个碳原子的直链单价烃基或具有三个至六个碳原子的支链单价烃基,例如,丙炔基、丁炔基等。
“烷硫基”是指-SR基(其中R是如上所定义的烷基),例如甲硫基、乙硫基等。
“烷基磺酰基”是指-SO2R基(其中R是如上所定义的烷基),例如甲基磺酰基、乙基磺酰基等。
“烷基亚砜”是指-SOR基(其中R是如上所定义的烷基),例如甲基亚砜、乙基亚砜等。
“氨基”是指-NH2。
“烷基氨基”是指-NHR基(其中R是如上所定义的烷基),例如甲基氨基、乙基氨基、丙基氨基、或2-丙基氨基等。
“氨基烷基”是指被-NR’R”取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基(其中R’和R”独立地是各自如本文所定义的氢、烷基、卤代烷基、羟基烷基、烷氧基烷基、或烷基羰基),例如氨基甲基、氨基乙基、甲基氨基甲基等。
“烷氧基”是指-OR基(其中R是如上所定义的烷基),例如甲氧基、乙氧基、丙氧基或2-丙氧基、正丁氧基、异丁氧基、或叔丁氧基等。
“烷氧基烷基”是指被至少一个如上所定义的烷氧基基团(例如一个或两个烷氧基基团)取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基,例如2-甲氧基乙基,1-、2-、或3-甲氧基丙基,2-乙氧基乙基等。
“烷氧基羰基”是指-C(O)OR基(其中R是如上所定义的烷基),例如甲氧基羰基、乙氧基羰基等。
“烷基羰基”是指-C(O)R基(其中R是如本文所定义的烷基),例如甲基羰基、乙基羰基等。
“芳基”是指具有6个至10个环原子的单价单环或二环芳香族烃基,例如苯基或萘基。
“芳烷基”是指-(亚烷基)-R基(其中R是如上所定义的芳基),例如苄基、苯乙基等。
“二环环烷基”是指任选地被独立地选自烷基、卤代、烷氧基、羟基、和氰基的一个或两个取代基取代的具有六个至十个碳原子的稠合二环饱和单价烃基。实例包括但不限于十氢化萘、八氢-1H-茚等。
“环烷基”是指任选地被独立地选自烷基、烷基二烯基、卤代、烷氧基、羟基、氰基、卤代烷基二烯基和氰基烷基的一个或两个取代基取代的具有三个至十个碳原子的单环饱和单价烃基。实例包括但不限于环丙基、环丁基、环戊基、环己基、1-氰基环丙-1-基、1-氰基甲基环丙-1-基、3-氟环己基等。环烷基可以包括如本文所定义的环亚烷基。
“环烷基烷基”是指-(亚烷基)-R基(其中R是如上所定义的环烷基),例如环丙基甲基、环己基甲基等。
除非另有说明,否则“环亚烷基”是指如上所定义的二价环烷基。
“环烯基”是指任选地被独立地选自烷基、卤代、烷氧基、羟基、氰基、和氰基烷基的一个或两个取代基取代的含有一个或两个双键的具有三个至十个碳原子的单环单价烃基。实例包括但不限于环丙烯基、环丁烯基、环戊烯基、或环己烯基等。
“氧代环烯基”是指含有一个或两个双键和氧代基团的具有三个至十个碳原子的单环单价烃基,并且任选地被独立地选自烷基、卤代、烷氧基、羟基、氰基、和氰基烷基的一个或两个取代基取代。实例包括但不限于3-氧代环己-1-烯基等。
“氰基烷基”是指被氰基取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基,例如氰基甲基、氰基乙基等。
“羧基”是指-COOH。
“二烷基氨基”是指-NRR’基(其中R和R’是如上所定义的烷基),例如二甲基氨基、甲基乙基氨基等。
“二取代的氨基”是指-NRR’基(其中R和R’独立地是各自如本文所定义的烷基、卤代烷基、羟基烷基、烷氧基烷基、或烷基羰基),例如二甲基氨基、乙基甲基氨基、双羟基乙基氨基、双甲氧基乙基氨基、二乙基氨基乙基氨基等。
“卤代”是指氟、氯、溴或碘,优选氟或氯。
“卤代烷基”是指被一个或多个卤素原子(例如一个至五个卤素原子(如氟或氯))取代的如上所定义的烷基,包括被不同卤素取代的那些,例如-CH2Cl、-CF3、-CHF2、-CH2CF3、-CF2CF3、-CF(CH3)2等。当烷基仅被氟取代时,在本申请中其可以被称作氟烷基。
“卤代烷氧基”是指-OR基(其中R是如上所定义的卤代烷基),例如-OCF3、
-OCHF2等。当R是卤代烷基(其中该烷基仅被氟取代)时,在本申请中其可被称作氟烷氧基。
“羟基烷基”是指被一个或两个羟基基团取代的具有一个至六个碳原子的直链单价烃基或具有三个至六个碳的支链单价烃基,条件是如果存在两个羟基基团,则它们两个不在同一碳原子上。代表性实例包括但不限于,羟基甲基、2-羟基-乙基、2-羟基丙基、3-羟基丙基、1-(羟基甲基)-2-甲基丙基、2-羟基丁基、3-羟基丁基、4-羟基丁基、2,3-二羟基丙基、1-(羟基甲基)-2-羟基乙基、2,3-二羟基丁基、3,4-二羟基丁基以及2-(羟基甲基)-3-羟基丙基,优选2-羟基乙基、2,3-二羟基丙基和1-(羟基甲基)-2-羟基乙基。
除非另有说明,否则“杂环基”是指具有4个至8个环原子的饱和或不饱和单价单环基团,其中一个或两个环原子是选自N、O或S(O)n(其中n是从0至2的整数)的杂原子,剩余的环原子是C。另外,在该杂环基环中的一个或两个环碳原子可以任选地被-CO-基团替代。更特别地,术语杂环基包括但不限于吡咯烷代、哌啶代、高哌啶代、2-氧代吡咯烷基、2-氧代哌啶基、吗啉代、哌嗪代、四氢-吡喃基、硫代吗啉代等。当该杂环基环不饱和时,其可以含有一个或两个环双键,条件是该环不是芳香族的。当该杂环基基团含有至少一个氮原子时,其在本文中也被称为杂环氨基并且其是杂环基基团的子集。
“杂环基烷基”或“杂环烷基”是指-(亚烷基)-R基(其中R是如上所定义的杂环基环),例如四氢呋喃基甲基、哌嗪基甲基、吗啉基乙基等。
除非另有说明,否则“杂亚环基”是指如上所定义的二价杂环基。当杂亚环(heterocyclene)含有4个、5个或6个环原子时,其在本文中也被称为4元至6元杂亚环基。
除非另有说明,否则“杂芳基”是指具有5个至10个环原子的单价单环或二环芳香族基,其中一个或多个(在一个实施例中,一个、两个或三个)环原子是选自N、O或S的杂原子,剩余的环原子是碳。代表性实例包括但不限于吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、异吲哚基、噁唑基、异噁唑基、苯并噻唑基、苯并噁唑基、喹啉基、异喹啉基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、四唑基等。如本文所定义,术语“杂芳基”和“芳基”是相互排斥的。当该杂芳基环含有5个或6个环原子时,其在本文中也可称为5元或6元杂芳基。
“杂亚芳基”是指如上所定义的二价杂芳基。
“杂芳烷基”是指-(亚烷基)-R基(其中R是如上所定义的杂芳基),例如吡啶基甲基等。当杂芳烷基中的杂芳基环含有5个或6个环原子时,其在本文中也被称为5元或6元杂芳烷基。
短语“R2和R9附接至环碳原子,该环碳原子位于附接至R1的环碳的间位”是指R2和R9的位置如下所示:
如本文单独或组合使用的,术语“氧代”是指=(O)。
当需要时,本文中的任何定义可以与任何其他定义组合使用以描述复合结构基团。按照惯例,任何这样的定义的后继元素是附接至亲本部分的元素。例如,复合基团烷氧基烷基是指烷氧基基团通过烷基基团附接至亲本分子。
本披露还包括具有式(I)的化合物的受保护的衍生物。例如,当具有式(I)的化合物含有基团(如羟基、羧基、硫醇或含有一个或多个氮原子的任何基团)时,这些基团可以被适合的保护基团保护。适合的保护基团的综合列表可以发现于T.W.Greene,ProtectiveGroups in Organic Synthesis[有机合成中的保护基团],第5版,John Wiley&Sons,Inc[约翰·威利父子出版公司].(2014)中,将该文献的披露内容通过援引以其整体并入本文。本披露的化合物的受保护的衍生物可以通过本领域熟知的方法制备。
本披露还包括具有式(I)的化合物或其药学上可接受的盐的多晶型形式。多晶型物是化合物的不同结晶形式,这些结晶形式在该化合物的分子在晶格中的排列方面不同。因此,单一化合物可产生多种多晶型形式。化合物的多晶型物通常具有不同的熔点、溶解度、密度和光学特性。化合物的多晶型形式可以通过几种技术来区分,例如X射线衍射法、IR或拉曼(Raman)光谱法。
术语“前药”是指在体内变得更具活性的化合物。具有式(I)的某些化合物还可以作为前药存在,如在Hydrolysis in Drug and Prodrug Metabolism:Chemistry,Biochemistry,and Enzymology[在药物和前药代谢中的水解:化学、生物化学、以及酶学](Testa,Bernard和Mayer,Joachim M.Wiley-VHCA,苏黎世,瑞士2003)中所描述。具有式(I)的化合物的前药是在生理条件下容易进行化学变化以提供活性化合物的化合物的结构修饰形式。因为在一些情况下前药比化合物或母体药物更容易施用,所以它们经常是有用的。例如,它们可以通过口服施用而具有可生物利用性,然而母体药物却不行。本领域已知多种前药衍生物,例如依赖前药的水解切割或氧化激活的那些。前药的实例(但不限于)是作为酯(该“前药”)施用的化合物,但是然后代谢水解为羧酸,活性实体。另外的实例包括具有式(I)的化合物的肽基衍生物。
化合物的“药学上可接受的盐”意指药学上可接受的并且具有母体化合物的所希望的药理学活性的盐。此类盐包括:
与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的酸加成盐;或与有机酸如甲酸、乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟基乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、葡萄庚酸、4,4’-亚甲基双-(3-羟基-2-烯-1-甲酸)、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡糖酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂酸、粘康酸等形成的酸加成盐;或
当母体化合物中存在的酸性质子被金属离子(例如碱金属离子、碱土离子或铝离子)替代而形成的盐;或与有机碱(如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺等)配位形成的盐。应理解,药学上可接受的盐是无毒的。关于适合的药学上可接受的盐的另外的信息可以发现于Remington’s Pharmaceutical Sciences[雷明顿药物科学],第17版,Mack Publishing Company[马克出版公司],伊斯顿,宾夕法尼亚州,1985中,将其通过援引以其整体并入本文。
具有式(I)的化合物可以具有不对称中心。包含不对称取代的原子的具有式(I)的化合物能以光学活性形式或外消旋形式被分离。化合物的单独的立体异构体可以通过从含有手性中心的可商购的起始材料合成制备,或通过制备对映异构体产物的混合物随后分离(例如转化成非对映体的混合物随后分离或重结晶、色谱技术、在手性色谱柱上直接分离对映异构体、或本领域已知的任何其他适当的方法)来制备。除非确切地指出特定的立体化学形式或异构体形式,所有的手性形式、非对映异构体形式、手性或非对映体形式的所有混合物、以及外消旋形式都在本披露的范围之内。
某些具有式(I)的化合物能以互变异构体和/或几何异构体存在。所有可能的互变异构体以及顺式和反式异构体(作为单独的形式及其混合物)都在本披露的范围之内。另外,如本文使用的,虽然仅列出了几个实例,但是术语烷基包括所述烷基基团的所有可能的异构体形式。此外,当这些环基团(例如芳基、杂芳基、杂环基)被取代时,虽然仅列出了几个实例,但是它们包括所有可能的异构体。此外,具有式(I)的化合物的所有水合物都在本披露的范围之内。
具有式(I)的化合物还可以在构成此类化合物的一个或多个原子上包含非天然量的同位素。非天然量的同位素可以定义为从自然中所发现的量至100%所考虑原子的量。不同之处仅在于存在一个或多个同位素富集的原子。可掺入具有式(I)的化合物(以及本文披露的其任何实施例,包括特定的化合物))中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟、氯和碘的同位素,分别为例如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、32P、33P、35S、18F、36Cl、123I和1251。同位素标记的化合物(例如,用3H和14C标记的化合物)可用于化合物或基质组织分布测定中。氚化的(即3H)和碳-14(即14C)同位素因其容易制备和可检测性而是有用的。此外,较重的同位素如氘(即2H)的取代可以赋予由更好的代谢稳定性引起的某些治疗优势(例如,增加的体内半衰期或降低的剂量需求)。在一些实施例中,在本文披露的化合物中,包括在下表1中,一个或多个氢原子被2H或3H替代,或者一个或多个碳原子被12C-或14C-富集的碳替代。正电子发射同位素(例如15O、13N、11C和15F)可用于正电子发射断层扫描(PET)研究,以检查基质受体的占有率。通过用同位素标记的试剂取代非同位素标记的试剂,通常可以通过以下程序来制备同位素标记的化合物,这些程序类似于本文方案或实例中披露的那些。
本文提供的某些结构被绘制为具有一个或多个浮动的取代基。除非另外提供或另外从上下文清楚可见,否则在化学上可行且化合价规则允许的情况下,一个或多个取代基可以存在于其所附接的环的任何原子上。例如,在结构:中,R7取代基可以替代三环的苯并部分上的任何氢,包括CH的氢(当X1是CH时)。
“任选地取代的芳基”是指任选地被一个、两个、或三个取代基取代的芳基,这些取代基独立地选自烷基、羟基、环烷基、羧基、烷氧基羰基、羟基、烷氧基、烷硫基、烷基磺酰基、氨基、烷基氨基、二烷基氨基、卤代、卤代烷基、卤代烷氧基、和氰基。
“任选地取代的杂芳基”是指任选地被一个、两个、或三个取代基取代的如上所定义的杂芳基,这些取代基独立地选自烷基、烷硫基、烷基磺酰基、羟基、环烷基、羧基、烷氧基羰基、羟基、烷氧基、卤代、卤代烷基、卤代烷氧基、氨基、烷基氨基、二烷基氨基、和氰基。
除非另有说明,否则“任选地取代的杂环基”是指任选地被一个、两个、或三个取代基取代的如上所定义的杂环基,这些取代基独立地选自烷基、烷硫基、烷基磺酰基、羟基、环烷基、羧基、烷氧基羰基、羟基、羟基烷基、烷氧基、烷氧基烷基、氨基烷基、卤代、卤代烷基、卤代烷氧基、和氰基。
“任选地取代的杂亚环基”是二价任选地取代的如上所定义的杂环基。
“药学上可接受的载剂或赋形剂”意指在制备药物组合物中有用的载剂或赋形剂,其通常是安全、无毒的并且不是生物学上或其他方面不希望的,并且包括对于兽用连同人类药用是可接受的载剂或赋形剂。如在本说明书和权利要求书中使用的“药学上可接受的载剂/赋形剂”包括一种和超过一种此类赋形剂两者。
“螺环烷基”是指具有6个至10个环碳原子的饱和二环,其中这些环仅通过一个原子连接,该连接原子也称为螺原子,最通常为季碳(“螺碳”)。螺环烷基环任选地被一个或两个取代基取代,这些取代基独立地选自烷基、卤代、烷氧基、羟基、和氰基。代表性实例包括但不限于螺[3.3]庚烷、螺[3.4]辛烷、螺[3.5]壬烷、螺[4.4]壬烷(1∶2∶1∶1)等。
“螺杂环基”是指具有6个至10个环原子的饱和二环,其中一个、两个或三个环原子是选自N、O或S(O)n(其中n是从0至2的整数)的杂原子,其余的环原子是C,并且这些环仅通过一个原子连接,该连接原子也称为螺原子,最通常为季碳(“螺碳”)。螺杂环基环任选地被一个、两个、或三个取代基取代,这些取代基独立地选自烷基、烷硫基、烷基磺酰基、羟基、环烷基、羧基、烷氧基羰基、羟基、羟基烷基、烷氧基、烷氧基烷基、氨基烷基、卤代、卤代烷基、卤代烷氧基、和氰基。代表性实例包括但不限于2,6-二氮杂螺[3.3]庚烷、2,6-二氮杂螺[3.4]辛烷、2-氮杂螺[3.4]辛烷、2-氮杂螺[3.5]壬烷、2,7-二氮杂螺[4.4]壬烷等。
如本文使用的,术语“约”旨在限定它所修饰的数值,表示这个值为在误差界限之内的变量。当没有列举出特定的误差范围(例如,数据图或表中给出的平均值的标准偏差)时,术语“约”应理解为表示涵盖±10%,优选为±5%的范围,包括所列举的值和范围。
在式(I)中R9的定义中,短语“杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代”(以及用于定义式(I)中其他基团的类似短语)旨在涵盖未被取代的杂芳基和被Rd、Re、和Rf中任一个取代的杂芳基。
如本文使用的,术语“疾病”旨在为一般同义的,并且可以与术语“障碍”、“综合征”和“病症”(在医学病症时)互换使用,其中所有这些都反映了人类或动物体的或者损害了其正常功能的部分之一的异常情况,典型表现为区别的体征和症状,并且使人或动物有减少的寿命期限或生活质量。
术语“组合疗法”或“与......组合施用”是指施用两种或更多种治疗剂来治疗本披露中描述的疾病或障碍。这种施用涵盖以同时的方式共同施用这些治疗剂,如以具有固定比率的活性成分的单个胶囊或片剂施用或以每种活性成分的多个分开的胶囊或片剂施用。此外,这种施用还涵盖以依次的方式使用每种类型的治疗剂。在任何一种情况下,治疗方案将在治疗本文所述的病症或障碍方面提供药物组合的有益作用。
术语“患者”通常与术语“受试者”同义,并且包括所有哺乳动物,包括人。患者的实例包括人、牲畜(例如牛、山羊、绵羊、猪和兔)和宠物(例如狗、猫、兔和马)。优选地,患者是人。
术语“协同”或“协同的”用于意指HIF-2α抑制剂或其药学上可接受的盐与PARP抑制剂或其药学上可接受的盐的组合的结果大于单独每种化合物的总和。这种对所治疗的疾病、病症或障碍的改善是“协同”效应。
“协同量”是产生协同效应(如本文所定义的“协同的”)的HIF-2α抑制剂或其药学上可接受的盐与PARP抑制剂或其药学上可接受的盐的组合的量。
“治疗(treating或treatment)”疾病包括:
(1)预防该疾病,即,使疾病的临床症状在可能暴露于或易患该疾病,但尚未经历或显示该疾病的症状的哺乳动物中不发展;
(2)抑制该疾病,即,阻滞或减少该疾病或其临床症状的发展;或
(3)缓解该疾病,即,使该疾病或其临床症状消退。
“治疗有效量”是指当向患者施用以用于治疗疾病时,足以影响该疾病的此类治疗的本披露化合物或其药学上可接受的盐的量。“治疗有效量”将根据化合物、疾病和它的严重性以及所要治疗的哺乳动物的年龄、体重等变化。
与HIF-2α相关的术语“抑制”和“降低”或这些术语的任何变体包括任何可测量的减少或完全抑制以达到所需的结果。例如,减少可以是与正常活性相比,HIF-2α活性降低约、至多约或至少约5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%、95%、99%或更多,或其中可衍生的任何范围。
以下化合物表I披露了具有式(I)的代表性HIF-2α抑制剂:
表I
实施例:
在以下另外的实施例1-52中,本披露包括:
1.在实施例1中,提供了治疗患者的癌症的方法,该方法包括向该患者施用具有式(I)的HIF-2α抑制剂:
其中:
X1是CH或N;
R1是羟基、卤代、氨基、-OP(O)(OH)2、-OCH2OP(O)(OH)2、-OCOR10、-OCOOR11、
-OCONR12R13、-OCHR14OCOR15或-OCHR14OCOOR15a,其中R10、R11、和R15以及R15a独立地是烷基或被氨基、羧基或羟基取代的烷基,R12和R13独立地是氢,烷基,或被氨基、羧基或羟基取代的烷基,或R12和R13与它们所附接的氮原子一起形成任选地取代的杂环基,并且每个R14是氢、烷基、或卤代烷基;
R2是氢、氘、烷基、卤代、卤代烷基、烯基、或炔基;
R2a是氢或氘;
R3和R4独立地是氢、氘、烷基、环烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基;或
R3和R4与它们所附接的碳一起形成氧代、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;
R5是氢、氘、烷基、卤代、卤代烷基、羟基、或烷氧基;
R6是氢、氘、烷基、环烷基、或卤代;或
R5和R6与它们所附接的碳一起形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;条件是R5和R6以及R3和R4与它们所附接的碳一起不同时形成氧代、环亚烷基或任选地取代的4元至6元杂亚环基;
R7是氢、氘、烷基、烷氧基、氰基、卤代、卤代烷基、或卤代烷氧基;
L是键、S、SO、SO2、O、CO、或NR16,其中R16是氢或烷基;
R8是烷基、卤代烷基、羟基烷基、烷氧基烷基、氨基烷基、环烷基、环烯基、二环环烷基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,或杂环基,本身或作为杂环基烷基的一部分,被Ra、Rb、Rc、Rg和/或Rh取代,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;并且
R9是氢、烷基、环烷基、羟基、烷氧基、氰基、卤代、卤代烷基、卤代烷氧基、烷基亚砜、烷基磺酰基、或杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代;或
当R9和R2附接至同一碳原子时,它们可以组合形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元杂亚环基;
R9w是氢或氘;
其药学上可接受的盐;
与PARP抑制剂或其药学上可接受的盐组合。
2.在实施例2中,提供了治疗患者的癌症的方法,该方法包括向该患者施用治疗有效量的具有式(I)的HIF-2α抑制剂:
其中:
X1是CH或N;
R1是羟基、卤代、氨基、-OP(O)(OH)2、-OCH2OP(O)(OH)2、-OCOR10、-OCOOR11、
-OCONR12R13、-OCHR14OCOR15或-OCHR14OCOOR15a,其中R10、R11、和R15以及R15a独立地是烷基或被氨基、羧基或羟基取代的烷基,R12和R13独立地是氢,烷基,或被氨基、羧基或羟基取代的烷基,或R12和R13与它们所附接的氮原子一起形成任选地取代的杂环基,并且每个R14是氢、烷基、或卤代烷基;
R2是氢、氘、烷基、卤代、卤代烷基、烯基、或炔基;
R2a是氢、卤代、或氘;
R3和R4独立地是氢、氘、烷基、环烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基;或
R3和R4与它们所附接的碳一起形成氧代、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;
R5是氢、氘、烷基、卤代、卤代烷基、羟基、或烷氧基;
R6是氢、氘、烷基、环烷基、或卤代;或
R5和R6与它们所附接的碳一起形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;条件是R5和R6以及R3和R4与它们所附接的碳一起不同时形成氧代、环亚烷基或任选地取代的4元至6元杂亚环基;
R7是氢、氘、烷基、烷氧基、氰基、卤代、卤代烷基、或卤代烷氧基;
L是键、S、SO、SO2、O、CO、或NR16,其中R16是氢或烷基;
R8是烷基、卤代烷基、羟基烷基、烷氧基烷基、氨基烷基、环烷基、环烯基、二环环烷基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,或杂环基,本身或作为杂环基烷基的一部分,被Ra、Rb、Rc、Rg和Rh取代,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;并且
R9是氢、烷基、环烷基、羟基、烷氧基、氰基、卤代、卤代烷基、卤代烷氧基、烷基亚砜、烷基磺酰基、或杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代;或
当R9和R2附接至同一碳原子时,它们可以组合形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元杂亚环基;
R9a是氢、卤代、或氘;或
其药学上可接受的盐;
与治疗有效量的PARP抑制剂或其药学上可接受的盐组合。
3.在实施例3中,如实施例1或2所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R3和R4独立地是卤代。
4.在实施例4中,如实施例1或2所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R3是卤代且R4是氢。
5.在实施例5中,如实施例1、2或3所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R1是羟基。
6.在实施例6中,如实施例1至3中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R1是氨基。
7.在实施例7中,如实施例1至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是卤代。
8.在实施例8中,如实施例1至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是烷基,优选地R6是甲基。
9.在实施例9中,如实施例1至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是氢。
10.在实施例10中,如实施例1至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R6是环烷基,优选地环丙基、环丁基、环戊基或环己基。
11.在实施例11中,如实施例1至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是卤代,优选氟。
12.在实施例12中,如实施例1至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是卤代烷基,优选地R5是二氟甲基或三氟甲基。
13.在实施例13中,如实施例1至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是烷基,优选地R5是甲基或乙基。
14.在实施例14中,如实施例1至10中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5是氢或烷氧基。
15.在实施例15中,如实施例1至6中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R5和R6与它们所附接的碳一起形成3元至6元环亚烷基,优选任选地被一个或两个氟取代的环亚丙基、环亚丁基或环亚戊基。
16.在实施例16中,如实施例1至15中任一项所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中X1是CR7。
17.在实施例17中,如实施例1所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIal)或(IIb1)的结构:
18.在实施例18中,如实施例1所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIa1’)或(IIb1’)的结构:
19.在实施例19中,如实施例1所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIa)或(IIb)的结构:
20.在实施例20中,如实施例1所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IIa’)或(IIb’)的结构:
21.在实施例21中,如实施例1所述的方法是其中具有式(I)的化合物或其药学上可接受的盐具有式(IVa)的结构:
其中R5和R6与它们所附接的碳一起形成3元至6元环亚烷基,优选任选地被一个或两个氟取代的环亚丙基、环亚丁基或环亚戊基。
22.在实施例22中,如实施例17至21中任一项所述的方法是其中具有式(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R3是氟。
23.在实施例23中,如实施例17至21中任一项所述的方法是其中具有式(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R3和R4是氟。
24.在实施例24中,如实施例1至23中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中L是O、S、SO、SO2、或NH。
25.在实施例25中,如实施例24所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物、其药学上可接受的盐是其中L是O。
26.在实施例26中,如实施例1至25中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物是其中R8是环烷基、环烯基、二环环烷基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,或杂环基,本身或作为杂环基烷基的一部分,被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基的Ra、Rb、和Rc取代。
27.在实施例27中,如实施例1至25中任一项和其中包含的子实施例所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R8是被Ra、Rb、Rc、Rg和Rh取代的苯基,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢和卤代。
28.在实施例28中,如实施例27和其中包含的子实施例所述的方法或其药学上可接受的盐是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物是其中R8是3-氯-5-氟苯基、3,5-二氟苯基、3-氟-5-甲氧基苯基、3-氰基-5-氟苯基、3-氯-5-氰基苯基、3-氰基-5-甲基苯基、3-氯-4-氟苯基、3-氯-5-氟苯基、3-氟-5-甲基苯基、3-氰基苯基、3一三氟甲基苯基、3,4-二氯苯基、3-氯-2-甲基苯基、3,5-二氯苯基、3,5-二甲基苯基、2-氯-6-甲基苯基、2,6-二氟苯基、3,4,5-三氟苯基、3,4-二氟苯基、4-氟-3-甲基苯基、3-氰基-4-氟苯基、3-氰基-5-二氟甲基苯基、或3-氰基-5-氟-2,4,6-三氘苯基。在实施例28的第一子实施例中,R10是3-氰基-5-氟苯基或3-氰基-5-氟-2,4,6-三氘苯基。
29.在实施例29中,如实施例1至25中任一项和其中包含的任何子实施例所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R8是各自任选地被独立地选自烷基、卤代、烷氧基、氰基、和羟基的一个或两个取代基取代的环烷基或环烷基烷基。
30.在实施例30中,如实施例1至25中任一项和其中包含的任何子实施例所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R8是被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基的Ra、Rb、和Rc取代的杂芳基。
31.在实施例31中,如实施例1至25中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R8是吡啶-3-基、吡啶-2-基、哒嗪-3-基、哒嗪-4-基、嘧啶-5-基、嘧啶-2-基、噻吩-2-基、呋喃-2-基、噻唑-5-基、噁唑-5-基、咪唑-5-基、呋喃-3-基、噻吩-3-基、噻唑-4-基、吡啶-4-基、噁唑-2-基、咪唑-2-基、吡啶-2-基、吡嗪-2-基、或噻唑-2-基,并且被Ra、Rb、和Rc取代,其中Ra和Rb独立地选自氢、甲基、甲氧基、羟基、氯、氟、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基,并且Rc选自氢、甲基、氰基、氯、氟、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基。
32.在实施例32中,如实施例1至31中任一项所述的方法,其中具有式(I)、(IIal)、(IIb1)、(IIal’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R7是氢、甲基、乙基、甲氧基、氟、三氟甲基、或三氟甲氧基,优选地R7是氢。
33.在实施例33中,如实施例1至32中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R2是氢、氟、甲基或乙基。
34.在实施例34中,如实施例1至33中任一项所述的方法是其中具有式(I)、(IIa1)、(IIbl)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIB’)和(IVa)的化合物或其药学上可接受的盐是其中R9是氢、烷基、卤代、羟基、或烷氧基。
35.在实施例35中,如实施例1至33中任一项所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)和(IVa)的化合物或其药学上可接受的盐是其中R9是氢、甲基、甲氧基、或氟。
36.在实施例36中,如实施例1至35中所述的方法是其中具有式(I)、(IIa1)、(IIb1)、(IIa1’)、(IIb1’)、(IIa)、(IIb)、(IIa’)、(IIb’)、和(IVa)的化合物或其药学上可接受的盐是其中R2和R9附接至环碳原子,该环碳原子位于附接至R1的环碳的间位。
37.在实施例37中,如实施例28或31中任一项所述的方法是其中该化合物是具有式(I)的化合物或其药学上可接受的盐,并且具有式(VIIIa1)或(VIIIb1)的结构:
优选具有式(VIIIb)的结构。
38.在实施例38中,如实施例37所述的方法是其中具有式(I)的化合物或其药学上可接受的盐是其中R2是氢或氘,R9是氢、氟、或甲基,并且R2a和R9a独立地是氢、氘或氟。
39.在实施例39中,如实施例1所述的方法是其中具有式(I)的化合物选自:
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aS)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
1,3,3,4,4-五氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢螺[环戊[cd]-茚-1,1’-环丙烷]-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-((2a-氨基-1,3,3,4,4-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈;
3-氟-5-((1,1,2a,3,3,4,4-七氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-((3,3-二氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-((3,3-二氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-((3,3-二氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-氟-5-((1,3,3-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈;
3-氟-5-((1,2,2,3,3,4,4-七氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]-茚-7-基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3;
(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
(S)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;以及
3-氟-5-(((1R,2R,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
40.在实施例40中,如实施例1所述的方法是其中具有式(I)的化合物选自:
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊-[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;及
其药学上可接受的盐。
41.在实施例41中,如实施例1所述的方法是其中具有式(I)的化合物是3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
42.在实施例42中,如实施例1所述的方法是其中具有式(I)的化合物是3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
46.在实施例46中,如实施例1至46中任一项所述的方法是其中PARP抑制剂是奥拉帕尼(olaparib)(4-[(3-[(4-环丙基羰基)哌嗪-1-基]羰基)-4-氟苯基]甲基(2H)-酞嗪-1-酮)、卢卡帕尼(rucaparib)(8-氟-2-{4-[(甲基氨基)-甲基]苯基}-1,3,4,5-四氢-6H-氮杂[5,4,3-cd]吲哚-6-酮)、尼拉帕尼(niraparib)(2-[4-[(3S)-3-哌啶基]苯基]吲唑-7-甲酰胺)、他拉唑帕尼(talazoparib)((8S,9R)-5-氟-8-(4-氟苯基)-9-(1-甲基-1H-1,2,4-三唑-5-基)-2,7,8,9-四氢-3H-吡啶并[4,3,2-de]酞嗪-3-酮)、或帕米帕利(pamiparib)((2R)-14-氟-2-甲基-6,9,10,19-四氮杂五环[14.2.1.02,6.08,18.012,17]十九-1(18),8,12(17),13,15-五烯-11-酮;三水合物)。
47.在实施例47中,如实施例1至46中任一项所述的方法是其中该癌症选自肾脏癌、胶质母细胞瘤、神经母细胞瘤、副神经节瘤、嗜铬细胞瘤、生长抑素瘤、成血管细胞瘤、胃肠道间质瘤、垂体瘤、平滑肌瘤、平滑肌肉瘤、红细胞增多症、视网膜癌、肺癌、胰腺癌、肝癌、卵巢癌、乳腺癌、前列腺癌、结直肠癌、头颈癌、宫颈癌、子宫内膜癌、膀胱癌、胃癌、食管癌、淋巴瘤、黑素瘤、间皮瘤、肉瘤和神经内分泌瘤。
48.在实施例48中,如实施例47所述的方法,其中该癌症是透明细胞肾脏癌。
49.在实施例49中,如实施例1至46中任一项所述的方法是其中该癌症选自卵巢癌、乳腺癌、前列腺癌、肾脏癌、结直肠癌、葡萄膜黑素瘤、胰腺癌、尿路上皮癌、子宫内膜癌、肺癌、淋巴瘤、头颈癌、输卵管癌、原发性腹膜癌、宫颈癌、黑素瘤、食管癌、胃癌、间皮瘤、胆管癌、胶质母细胞瘤、尤因肉瘤、子宫平滑肌肉瘤、慢性淋巴细胞白血病、T细胞幼淋巴细胞白血病、多发性骨髓瘤、急性髓性白血病、慢性髓细胞性白血病、生殖细胞癌、膀胱癌、神经内分泌瘤、骨肉瘤、胆道癌、软组织肉瘤、横纹肌肉瘤、套细胞淋巴瘤、和内分泌腺赘生物。
50.在实施例50中,如实施例1至49中任一项所述的方法是其中将具有式(I)的化合物和PARP抑制剂依次或同时施用。
51.在实施例51中,如实施例1至50中任一项所述的方法是其中该组合是协同组合。
52.在实施例52中,如实施例1至51中任一项所述的方法是其中该方法进一步包括施用一种或多种另外的抗癌剂。
实施例A:
A1.在实施例A1中,提供了如在本申请发明内容的第五方面提供的具有式(IA)的化合物或其药学上可接受的盐。
A2.在实施例A2中,具有(IA)的化合物或其药学上可接受的盐具有根据式(IA’)的结构:
A3.在实施例A3中,如实施例A1或A2所述的化合物或其药学上可接受的盐是其中Ra、Rb、和Rc独立地选自氢、氘、烷基、烷氧基、羟基、卤代、卤代烷基、卤代烷氧基、和氰基。
A4.在实施例A4中,如实施例A1或A2所述的化合物或其药学上可接受的盐是其中Ra、Rb、和Rc独立地选自氢、氘、甲基、甲氧基、羟基、氯、氟、氰基、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基,并且Rg和Rh独立地是氢或氘。
A5.在实施例A5中,如实施例A1或A2所述的化合物或其药学上可接受的盐是其中R8是3-氯-5-氟苯基、3,5-二氟苯基、3-氟-5-甲氧基苯基、3-氰基-5-氟苯基、3-氯-5-氰基苯基、3-氰基-5-甲基苯基、3-氯-4-氟苯基、3-氯-5-氟苯基、3-氟-5-甲基、3-氰基苯基、3-三氟甲基苯基、3,4-二氯苯基、3-氯-2-甲基苯基、3,5-二氯苯基、3,5-二甲基苯基、2-氯-6-甲基苯基、2,6-二氟苯基、3,4,5-三氟苯基、3,4-二氟苯基、4-氟-3-甲基苯基、3-氰基-4-氟苯基、3-氰基-5-二氟甲基苯基、或3-氰基-5-氟-2,4,6-三氘苯基。
A6.在实施例A6中,如实施例A1或A2所述的化合物或其药学上可接受的盐是其中R8是3-氰基-5-氟苯基或3-氰基-5-氟-2,4,6-三氘苯基。
A7.在实施例A7中,如实施例A1或A2所述的化合物选自:
3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;和
3-氟-5-(((1R,2R,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
通用合成方案
本披露的化合物可以通过在以下示出反应方案中描绘的方法制得。
用于制备这些化合物的起始材料和试剂可从商业供应商(如奥德里奇化学公司(Aldrich Chemical Co.)(密尔沃基,威斯康星州),巴亨公司(Bachem)(托伦斯,加利福尼亚州),或西格玛公司(Sigma)(圣路易斯,密苏里州)获得或通过本领域技术人员已知的方法遵循以下参考文献列出的程序制备,这些文献例如:Fieser and Fieser’s Reagentsfor Organic Synthesis[费塞尔和费塞尔氏有机合成试剂],1-17卷(约翰·威利父子出版公司,1991);Rodd’s Chemistry of Carbon Compounds[罗德氏碳化合物化学],1-5卷及增补(爱思唯尔科学出版社(Elsevier Science Publishers),1989);Organic Reactions[有机反应],第1-40卷(约翰·威利父子出版公司,1991);March’s Advanced OrganicChemistry[马驰氏高等有机化学](约翰·威利父子出版公司,第4版)以及Larock’sComprehensive Organic Transformations[拉罗克氏综合有机转化](VCH出版公司(VCHPublishers Inc.),1989)。这些方案仅仅是说明通过它可以合成本披露的化合物的一些方法,且可以对这些方案做出不同修改并且本领域普通技术人员阅读本披露时将得到启示。如果希望的话,这些起始材料和中间体以及反应的最终产物可以使用常规技术(包括但不局限于过滤、蒸馏、结晶、色谱等)进行分离与纯化。此类材料可以使用常规手段,包括物理常数以及光谱数据进行表征。
除非指出与此相反,否则本文所述的反应在大气压下,在从约-78℃至约150℃,例如从约0℃至约125℃的温度范围下,并且进一步例如在约室温(或环境温度),例如约20℃下发生。
可以如以下方案1中所说明和描述的那样制备具有式(I)的化合物,其中X1是CH,R1是羟基,R3、R4、R5、R6、R7、和R8如发明内容(或其任何实施例)所定义,并且R9与R2组合形成烷基二烯基。
方案1
具有式1-a的醛(其中R7是如在发明内容中所述的或其前体基团)与具有式1-b的化合物(其中X1是卤化物,并且R3是如所定义的,例如独立地是氢、氘、烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基)之间的由锌金属介导的瑞弗尔马斯基反应(Reformastkyreaction)提供了具有式1-c的化合物。具有式1-a和1-b的化合物是可商购的或它们可以通过本领域熟知的方法制备。例如,2-溴-4-氟苯甲醛、乙基2-溴-2,2-二氟乙酸酯、乙基2-溴-2-甲基丙酸酯、乙基2-溴丙酸酯、乙基2-溴乙酸酯是可商购的。可以在氧化条件(如2-碘酰基苯甲酸(IBX)或TPAP、NMO)下将1-c中的羟基基团氧化以给出具有式1-d的酮。通过本领域熟知的方法,可以将具有式1-d的化合物中的酮基团官能化以提供具有式1-e的化合物,其中R5和R6如发明内容中所述。例如,可以在本领域熟知的条件下,通过用氟化剂(如DAST或SF4)处理,从1-d中合成具有式1-e的化合物,其中R5和R6是氟。1-e的环化可以通过将其用烷基锂试剂(如n-BuLi)处理来实现以给出酮1-f。可以用还原剂(如NaBH4)将1-f中的羰基基团还原以提供醇1-g。
可以通过1-g的锂化,随后用CBr4处理锂中间体,将具有式1-g的化合物转化为具有式1-h的化合物。用氧化剂(如IBX)氧化1-h提供了具有式1-i的酮。将烯丙基金属试剂(如烯丙基溴化镁)添加至具有式1-i的化合物中,提供了具有式1-j的化合物。
可替代地,可通过将烯丙基金属试剂(如烯丙基溴化镁)添加至具有式1-f的化合物中,由1-f制备具有式1-j的化合物,如下所示:
用碱(如LDA)锂化1-g,随后用溴化试剂(如CBr4或1,2-二溴四氟乙烷)处理锂中间体,提供了具有式1-j的化合物。如果需要,可以在配体(如1-m)和有机溶剂(如MeOH、甲苯)中合适的碱(如tBuONa)的存在下,通过向具有式1-f的化合物中添加2-烯丙基-4,4,5,5-四甲基-1,3,2-二氧杂硼烷来实现具有式1-g的化合物的对映选择性合成,如下所示:
可以在Pd催化剂与合适的配体(如Pd(dppf)Cl2 CH2Cl2或Pd(PPh3)2Cl2)的存在下,对具有式1-j的化合物进行环化以提供具有式1-k的化合物。可以通过本领域熟知的方法,通过用具有式R8-LH的化合物(其中L是N、O、或S,并且R8如发明内容中所定义)处理化合物1-k,将具有式1-k的化合物中的氟基团转化为具有式-L-R8的基团(其中L和R8如发明内容中所述)。具有式R8-LH的化合物是可商购的或它们可以通过本领域熟知的方法制备。例如,3-氟-5-羟基苯甲腈、3,5-二氟苯酚、3-氯-5-氟苯酚、3-氯-5-羟基-苯甲腈、5-氟吡啶-3-醇、5-氯吡啶-3-醇、5-羟基烟腈、3-氟-5-巯基苯甲腈、3-氨基-5-氟苯甲腈、3,3-二氟环丁-1-醇、3-氨基-5-氟苯甲腈、3-氟-5-巯基苯甲腈、3-氯-5-巯基苯甲腈、3-氨基-5-氯苯甲腈是可商购的。
可以如以下方案2中所说明和描述的那样制备具有式(I)的化合物,其中R1是羟基,R3、R4、R5、R6、R7、和R8如发明内容(或其任何实施例)中所定义,并且R9与R2组合形成氧代。
方案2
可以在本领域熟知的条件下,通过用氧化切割试剂(如NaIO4和RuCl3水合物)处理具有式1-k的化合物,将其转化为具有式1-l的化合物。可以通过用具有式R8-LH的化合物处理化合物1-l,将具有式1-l的化合物中的氟基团转化为具有式-L-R8的基团(其中L和R8如发明内容中所述)。
可以通过本领域熟知的方法,将具有式(I)的化合物转化为其他具有式(I)的化合物。例如,可以如以下方法(i)和(ii)中所说明和描述的那样,通过进一步官能化羰基基团从具有式(I)的化合物(其中R9与R2组合形成氧代)中合成具有式(I)的化合物(其中R1是羟基,R2是氢,并且R9是羟基或氟)。
方法(i)
可以在本领域熟知的条件下,通过用还原剂(如硼氢化钠)处理具有式(I)的化合物(其中R1是羟基,R9与R2组合形成氧代),将其转化为具有式(I)的化合物(其中R1是羟基,R9是羟基)。
方法(ii)
可以在本领域熟知的条件下,通过用氟化试剂(如DAST)处理具有式(I)的化合物(其中R1是羟基,R9是羟基),将其转化为具有式(I)的化合物(其中R1是羟基,R9是氟)。
效用
HIF-2α在许多人类癌症的发生和进展中起着重要作用。许多广泛的研究已经证明了HIF-2α活性的增加在驱动透明细胞肾细胞癌(ccRCC)中的关键作用(参见Shen和Kaelin的综述,Seminars in Cancer Biology[癌症生物学研讨会]23:18-25,2013)。异常的HIF-2α活性主要是由于肿瘤抑制因子VHL的功能丧失所致。众所周知,百分之八十以上的ccRCC通过缺失、突变或受干扰的翻译后修饰而具有缺陷型VHL。无论含氧量如何,缺陷型VHL都会导致组成型活性的HIF-α蛋白。在小鼠模型中采用功能获得型和功能丧失型方法的各种研究已经证明,HIF-2α是VHL的关键致癌底物(参见Kondo等人Cancer Cell[癌细胞]1:237-246,2002;Kondo等人PLoS Biology[公共科学图书馆·生物学]1:439-444,2002;Maranchi等人Cancer Cell[癌细胞]1:247-255,2002;Zimmer等人Mol.Cancer Res[分子癌症研究]2:89-95,2004)。例如,在VHL无效的肿瘤中敲低HIF-2α抑制了肿瘤形成,而VHL的重新引入和HIF-2α的过表达克服了VHL的肿瘤抑制作用。此外,HIF-2α中的单核苷酸多态性与对PHD介导的降解的抗性相关,与患RCC的风险增加有关。除了作为ccRCC中典型的肿瘤起始事件之外,VHL-HIF-2α轴还通过其下游的CXCR4和CYTIP牵涉到ccRCC肿瘤转移(参见Vanharanta等人Nature Medicine[自然医学]19:50-59,2013;Peter Staller等人Nature[自然].2003年9月18日;425(6955):307-11)。总之,这些研究有力地支持了HIF-2α靶向药剂用于治疗ccRCC的潜在治疗效用。
缺陷型VHL不仅使患者易患肾癌(终生风险为70%),而且易患成血管细胞瘤、嗜铬细胞瘤、内淋巴囊肿瘤和胰腺神经内分泌瘤。来源于缺陷型VHL的肿瘤通常由组成型活性的下游HIF-α蛋白驱动,其中大多数依赖于HIF-2α活性(参见Maher等人Eur.J.Hum.Genet[欧洲人类遗传学期刊].19:617-623,2011)。遗传和表观遗传机制均可以导致VHL的功能丧失。在许多癌症中已发现了VHL表达的表观遗传失活以及由此的HIF-α蛋白的组成型激活,这些癌症包括RCC、多发性骨髓瘤、视网膜母细胞瘤、NSCLC、胰腺内分泌瘤、鳞状细胞癌、急性髓性白血病、骨髓增生异常综合征、和食管鳞状细胞癌(参见Nguyen等人的综述Arch.Phann.Res[药物研究文献]36:252-263,2013)。通过VHL的功能丧失和HIF-2α的激活突变两者,HIF-2α也与视网膜癌、肾上腺癌和胰腺癌有关。最近,在红细胞增多症和副神经节瘤伴红血球增多症中鉴定出了功能获得型HIF-2α突变(参见Zhuang等人NEJM[新英格兰医学杂志]367:922-930,2012;Percy等人NEJM[新英格兰医学杂志]358:162-168,2008;和Percy等人Am.J.Hematol[美国血液学杂志].87:439-442,2012)。值得注意的是,已经证明许多已知的HIF-2α靶基因产品(例如,VEGF、PDGF、和细胞周期蛋白Dl)在来源于肾脏、肝脏、结肠、肺和脑的癌症中起关键作用。因此,当由异常的HIF-2α途径激活下游的这些信号传导事件驱动时,HIF-2α靶向疗法可能对上述癌症有益。除了VHL的功能丧失和HIF-2α的激活突变之外,HIF-α蛋白在快速生长的肿瘤的瘤内环境中也经常上调,这是由于大肿瘤中血管化不良导致的低氧条件所致。进而,激活的HIF-α途径通过转录上调各种必需因子来进一步促进肿瘤细胞存活和增殖。
大量的研究已经证明,HIF-2α过表达与各种癌症(包括星形细胞瘤、乳腺癌、宫颈癌、结直肠癌、胶质母细胞瘤、神经胶质瘤、头颈癌、肝癌、非小细胞肺癌、黑素瘤、神经母细胞瘤、卵巢癌、和前列腺癌)的不良预后之间存在相关性,从而支持将HIF-2α作为治疗这些癌症的治疗靶标(参见Keith等人的综述Nature Rev.Cancer[癌症自然评论]12:9-22,2012)。HIF-2α已被证明可通过调节参与增殖、铁利用和炎症的基因来促进APC突变型结直肠癌的生长(参见Xue等人Cancer Res[癌症研究]72:2285-2293,2012;以及Xue和Shah,Carcinogenesis[致癌作用]32:163-169,2013)。在肝细胞癌(HCC)中,在临床前模型中敲低HIF-2α导致通过下调VEGF和细胞周期蛋白D1抑制体外细胞增殖和体内肿瘤生长(参见He等人Cancer Sci[癌症科学]103:528-534,2012)。在NSCLC中,大约50%的患者表现出HIF-2α蛋白的过表达,这与较高的VEGF表达密切相关,并且更重要的是,总体存活率降低。有趣的是,尽管HIF-1α表达也经常增加,但其与肺癌患者的总体存活率降低并不相关(参见Giatromanolaki等人Br.J.Cancer[英国癌症杂志]85:881-890,2001)。与仅具有突变型KRAS表达的小鼠相比,对用不可降解的HIF-2α和突变型KRAS肿瘤两者工程化的小鼠进行的广泛研究表明,肿瘤负荷增加且存活率下降(参见Kim,等人J.Clin.Invest[临床研究杂志].119:2160-2170,2009)。这些研究表明,HIF-2α促进肺癌的肿瘤生长和进展,并且也与临床预后呈负相关。
HIF-2α活性也被证明在中枢神经系统的癌症中很重要(参见Holmquist-Mengelbier,等人Cancer Cell[癌细胞]10:413-423,2006和Li,等人Cancer Cell[癌细胞]15:501-513,2009)。在神经母细胞瘤的临床前动物模型中,HIF-2α敲低减少了肿瘤生长,相反,HIF-2α的水平增加与晚期疾病、不良预后和较高的VEGF水平相关,这可能导致临床结果不佳。类似地,较高的HIF-2α表达与神经胶质瘤的存活率低相关。实验上,抑制神经胶质瘤干细胞中的HIF-2α减少了体外细胞增殖和存活以及体内肿瘤发生。虽然HIF-1α在神经祖细胞和脑肿瘤干细胞中均有表达,但HIF-2α仅在后者中发现。此外,神经胶质瘤患者的存活率与HIF-2α相关,而与HIF-1α水平无关。
生长抑素瘤是罕见的产生生长抑素的神经内分泌瘤,但往往是恶性的。已经发现,HIF-2α突变导致HIF-2α的脯氨酰基羟基化结构域(PHD)的破坏,从而消除了PHD的修饰,并随后减少了由VHL介导的HIF-2α降解(参见Yang,等人Blood[血液].121:2563-2566,2013)。然后,稳定的HIF-2α可以易位到细胞核,从而驱动低氧相关基因的表达增加,导致生长抑素瘤。因此,HIF-2α抑制剂将提供一种治疗生长抑素瘤的替代方法。
嗜铬细胞瘤和副神经节瘤(PPGL)是罕见的神经内分泌瘤,通常在易感基因突变的背景下发展,包括VHL或PHD2的功能丧失或HIF-2α的激活突变,所有这些都导致HIF-2α蛋白,随后是下游基因的高度表达以促进致癌进展(参见Dahia,Nat Rev Cancer[癌症自然评论].14:108-19,2014)。此外,已在患有遗传性嗜铬细胞瘤和副神经节瘤(PPGL)的患者中描述了编码琥珀酸脱氢酶(SDH)亚基和SDH复合物组装因子2蛋白(SDHAF2)的基因的种系杂合突变。这些突变可导致琥珀酸盐的积累,进而导致脯氨酰基-羟化酶的抑制,这对于介导VHL复合物对HIF蛋白的泛素化/降解至关重要。垂体腺瘤经常被发现与PPGL共存。因此,抑制HIF-2α应该可以用于治疗PPGL和垂体瘤两者。琥珀酸脱氢酶亚基突变也与胃肠道间质瘤(GIST)相关,因此支持探索HIF-2α抑制剂用于治疗GIST(参见Janeway,等人Proc.NatlAcad.Sci.USA[美国国家科学院院刊]108:314-318,2011)。
延胡索酸水合酶(FH)的功能丧失型突变使患者易患皮肤和子宫平滑肌瘤病的常染色体显性综合征。已经表明,HIF蛋白的激活通过激活低氧途径而促进FH相关的肿瘤发展。(参见O’Flaherty,等人Hum Mol Genet[人类分子遗传学].19:3844-3851,2010和Wei,等人J Med Genet[医学遗传学杂志].43:18-27,2006)。此外,在平滑肌肉瘤(一种平滑肌起源的罕见赘生物)中发现了HIF-2α的高表达(参见Mayer,等人Cancer Res[癌症研究].68:4719,2008)。因此,HIF-2α的抑制可能有益于治疗平滑肌瘤和平滑肌肉瘤两者。
视网膜毛细血管成血管细胞瘤可能是VHL疾病的眼部表现,它是由肿瘤抑制因子VHL的丧失引起的。已在视网膜成血管细胞瘤患者中检测到VHL丧失后HIF-2α的上调,并且这种上调表明促进视网膜成血管细胞瘤的侵袭性病程,从而导致对多种抗VEGF和放射疗法的抗性(参见Wang,等人Graefes Arch.Clin.Exp.Ophthalmol[格拉芙临床与实验眼科学文献].252:1319-1327,2014)。
除了在促进肿瘤细胞(例如ccRCC)的发生、进展和转移方面的直接作用之外,HIF-2α还通过增强肿瘤微环境内低氧的免疫抑制作用而间接促进肿瘤发生。已经在髓系细胞中检测到HIF-2α的表达(参见Talks KL,等人Am J Pathol[美国病理学杂志].2000;157(2):411-421)。例如,HIF-2α显示出有利于巨噬细胞向免疫抑制M2表型极化,并增强肿瘤相关巨噬细胞的迁移和侵袭(参见Imtiyaz HZ等人J Clin Invest[临床研究杂志].2010;120(8):2699-2714)。因此,肿瘤相关巨噬细胞(TAM)中HIF-2α的水平增加与高级别人肿瘤有关,并与不良预后相关。此外,HIF-2α可以通过调节关键信号传导调节因子(如腺苷A2B/A2A受体和精氨酸酶)的表达,间接促进其他免疫抑制途径(例如,腺苷和精氨酸酶等)。这些数据支持HIF-2α是用于治疗更广泛的炎症性障碍和癌症的潜在治疗靶标,无论是作为单一药剂还是与其他治疗药物(例如,免疫疗法)组合。
另外,HIF-2α化合物可用作单一药剂来治疗一种或多种软骨癌、一种或多种皮肤癌、唾液腺癌、胃癌、胃部癌症、肝癌、子宫内膜癌、膀胱癌、间皮瘤、肉瘤、食管癌、淋巴瘤、葡萄膜黑素瘤、尿路上皮癌、输卵管癌、原发性腹膜癌、胆管癌、尤因肉瘤、子宫平滑肌肉瘤、慢性淋巴细胞白血病、急性淋巴细胞白血病、T细胞幼淋巴细胞白血病、慢性髓细胞性白血病、生殖细胞癌、骨肉瘤、胆道癌、软组织肉瘤、横纹肌肉瘤、套细胞淋巴瘤、和内分泌腺赘生物。
另外,HIF-2α抑制剂(例如,本文披露的化合物24a或24b)可用于治疗非肿瘤适应症(如脉动脉高血压(PAH)、NASH、炎症性肠病(IBD)、或铁超负荷)。
测试
可以使用以下生物学实例1中描述的体外测定来测试本披露化合物的HIF-2α抑制活性。可以使用以下实例2中描述的体外测定来测试本披露的HIF-2α化合物抑制HIF-2α向HIF-1β(ARNT)的异源二聚化的能力。可以使用PCT申请公开号WO 2016145032的实例36和37中描述的低氧诱导的PAH体内模型来测定本披露的HIF-2α化合物预防或治疗PAH的能力。可以使用以下生物学实例3中描述的体外测定来评估HIF-2α抑制剂与PARP抑制剂组合在ccRCC癌症中的抗增殖作用。
药物组合物
通常,本披露的HIF-2α和PARP抑制剂将以治疗有效量,通过用于类似效用的药剂的任何接受的施用方式进行施用。作为单一药剂,本文披露的HIF-2α抑制剂的治疗有效量的范围可以为约5mg至约500mg/天,优选地10mg至200mg/天,其能以单剂量或多剂量施用。对于口服施用,组合物能以含有约5.0至约500毫克,优选地约5、10、20、50、75、100、150、200、250、300、400、或500毫克的HIF-2α抑制剂的片剂或胶囊形式提供。
对于组合疗法,HIF-2α抑制剂的治疗有效量的范围可以为约0.01至约100mg/kg患者体重/天,其能以单剂量或多剂量施用。HIF-2α抑制剂的适合的剂量水平可以是约0.1至约50mg/kg/天;约0.5至约15mg/kg/天。对于口服施用,组合物能以含有约20至约800毫克的HIF-2α抑制剂活性成分,特别是约50、75、100、150、200、250、300、400、500、600、750、800、900、和1000毫克的活性成分的片剂形式提供。用于在组合疗法中使用的PARP抑制剂的治疗有效量的范围可以为约0.001至约100mg/kg患者体重/天,其能以单剂量或多剂量施用。PARP抑制剂的适合的剂量水平可以是约0.001至约50mg/kg/天;0.003至约50mg/kg/天;约0.001至约20mg/kg/天;或约0.001至约15mg/kg/天。对于口服施用,组合物能以含有约0.25至约800毫克的PARP抑制剂活性成分,特别是约0.25、0.5、1、50、75、100、150、200、250、300、400、500、600、750、800、900、和1000毫克的PARP抑制剂活性成分的片剂形式提供。在一个实施例中,PARP抑制剂是帕米帕利,并且可以以20mg BID、40mg BID、或60mg BID、或以约0.5至约2mg/kg/天给药。在另一个实施例中,PARP抑制剂是卢卡帕尼,可以以600mg PO BID(如果有不良反应,则减少剂量)、或以约10至约20mg/kg/天给药。在另一个实施例中,PARP抑制剂是奥拉帕尼,并且可以以300mg PO BID(如果有不良反应,则减少剂量)、或以约2.5至约10mg/kg/天给药。在另一个实施例中,PARP抑制剂是尼拉帕尼,并且可以以300mg PO Q天(如果有不良反应,则减少剂量)、或以约1至约6mg/kg/天给药。在另一个实施例中,PARP抑制剂是他拉唑帕尼,并且可以以每天1mg PO(如果有不良反应,则减少剂量)、或以约0.003至约0.14mg/kg/天给药。
HIF-2α和/或PARP抑制剂的实际量(即活性成分)将取决于多种因素,例如待治疗的疾病的严重性、患者的年龄和相对健康状况、所利用的化合物的效价、施用的途径和形式、以及其他因素。
通常,本披露的HIF-2α和PARP抑制剂将通过以下途径中的任一种作为药物组合物施用:口服、全身(例如,经皮、鼻内或通过栓剂)、或肠胃外(例如,肌内、静脉内或皮下)施用。优选的施用方式是使用方便的日剂量方案口服,其可以根据患病程度进行调整。组合物可以采取片剂、丸剂、胶囊、半固体、粉末、缓释配制品、溶液、混悬液、酏剂、气溶胶或任何其他适当的组合物的形式。
配制品的选择取决于多种因素,如药物施用方式(例如,对于口服施用,优选呈片剂、丸剂或胶囊形式的配制品,包括肠溶包衣的或缓释的片剂、丸剂或胶囊)和药物物质的生物利用度。
通常,组合物由本披露的HIF-2α和/或PARP抑制剂与至少一种药学上可接受的赋形剂组合构成。可接受的赋形剂是无毒的,有助于施用,并且不会不利地影响HIF-2α和PARP抑制剂的治疗益处。此类赋形剂可以是任何固体、液体、半固体或在气溶胶组合物的情况下是本领域的普通技术人员通常可用的气体赋形剂。
固体药物赋形剂包括淀粉、纤维素、滑石、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、单硬脂酸甘油酯、氯化钠、脱脂乳粉等。液体和半固体赋形剂可以选自甘油、丙二醇、水、乙醇以及各种油,包括石油、动物、植物或合成来源的那些,例如,花生油、大豆油、矿物油、芝麻油等。优选的液体载剂(特别是对于可注射溶液)包括水、盐水、水性右旋糖和甘油。
化合物可配制为用于通过注射(例如,通过推注或连续输注)进行肠胃外施用。注射用配制品可以以单位剂型提供,例如,在添加有防腐剂的安瓿中或在多剂量容器中。组合物可以采取例如处于油性或水性媒介物中的混悬液、溶液或乳液的形式,并且可以含有配制剂(如混悬剂、稳定剂和/或分散剂)。配制品可存在于单位剂量或多剂量容器(例如,密封的安瓿和小瓶)中,并且可以以粉末形式储存或在冷冻干燥(冻干)条件下储存,只需要在使用前即时添加无菌液体载剂(例如,盐水或无菌的无热原水)。临时的注射溶液和混悬液可由前述种类的无菌粉末、颗粒和片剂制备。
用于肠胃外施用的配制品包括活性化合物的水性和非水性(油性)无菌注射溶液,其可包含抗氧化剂、缓冲液、抑菌剂和使配制品与预期接受体的血液等渗的溶质;以及水性和非水性无菌混悬液,其可包括混悬剂和增稠剂。合适的亲脂性溶剂或媒介物包括脂肪油(如芝麻油)、或合成的脂肪酸酯(如油酸乙酯或甘油三酯)、或脂质体。水性注射混悬液可包含增加混悬液的粘度的物质,如羧甲基纤维素钠、山梨醇、或葡聚糖。任选地,混悬液还可含有合适的稳定剂或增加化合物的溶解度的药剂,以允许制备高度浓缩的溶液。
除了前述配制品之外,化合物还可配制成贮库(depot)制剂。此类长效型配制品可通过植入(例如,皮下或肌内)或通过肌内注射进行施用。因此,例如,化合物可以用合适的聚合或疏水性材料配制(例如配制成可接受的油中的乳液)或用离子交换树脂配制,或配制成难溶性衍生物,例如配制成难溶性盐。
对于口腔含化或舌下施用,组合物可以采取以常规方式配制的片剂、锭剂、糖果锭剂、或凝胶的形式。此类组合物可以包含调味基质(如蔗糖和阿拉伯胶或黄芪胶)中的活性成分。
化合物还可被配制成直肠组合物(如栓剂或保留灌肠剂),例如包含常规的栓剂基质(如可可脂、聚乙二醇、或其他甘油酯)。
配制品中化合物的水平可以在本领域技术人员所使用的全范围内变化。典型地,基于总配制品,该配制品将含有以重量百分比(wt.%)计的约0.01-99.99wt.%的HIF-2α和/或一种或多种PARP抑制剂,其余的是一种或多种合适的药物赋形剂。例如,HIF-2α和/或一种或多种PARP抑制剂以约1-80wt.%的水平存在。
本文披露的HIF-2α抑制剂可以单独或与PARP抑制剂连同一种或多种其他抗癌药组合施用,这些抗癌药可用于治疗本披露的化合物对其具有效用的癌症。此类一种或多种其他药物可以通过一种途径以及其常用的量与HIF-2α抑制剂和/或一种或多种PARP抑制剂同时或依次施用。还预期,当与此类一种或多种其他活性成分组合使用时,HIF-2α抑制剂和/或PARP抑制剂以及其他活性成分能以比各自单独使用时更低的剂量使用。
因此,除了一种或多种HIF-2α抑制剂和/或一种或多种PARP抑制剂之外,本披露的药物组合物还包括含有一种或多种其他药物的那些。本披露的化合物与此类其他活性成分的重量比可以变化,并将取决于每种成分的有效剂量。通常,将使用各自的有效剂量。
此类其他抗癌剂的实例包括但不限于棉子酚、根纳三思、多酚E、氯融蛋白、全反式维甲酸(all trans-retinoic acid,ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2’-脱氧胞苷、全反式维甲酸、多柔比星、长春新碱、依托泊苷、吉西他滨、伊马替尼(GleevecTM)、格尔德霉素、17-N-烯丙基氨基-17-去甲氧基格尔德霉素(17-AAG)、夫拉平度、LY294002、硼替佐米、曲妥珠单抗、BAY 11-7082、PKC412、或PD184352、TaxolTM(也称为“紫杉醇”,其是熟知的通过增强和稳定微管形成而起作用的抗癌药)、以及TaxolTM的类似物(如TaxotereTM)。
其他抗癌剂包括与细胞增殖性障碍相关的激酶的抑制剂。这些激酶包括但不限于,Aurora-A、BTK、CDK1、CDK2、CDK3、CDK4、CDK6、CDK5、CDK7、CDK8、CDK9、肝配蛋白受体激酶、CHK1、CHK2、SRC、Yes、Fyn、Lck、Fer、Fes、Syk、Itk、Bmx、GSK3、JNK、MEK、PAK1、PAK2、PAK3、PAK4、PDK1、PKA、PKC、RAF、Rsk和SGK。特别地,CDK4/6的抑制剂(包括阿贝西尼(Verzenio)、帕博西尼(Ibrance)和瑞博西尼(Kisqali))具有与如下协同作用的潜力:HIF-2α抑制剂并逆转对HIF-2α抑制的抗性;丝裂原激活的蛋白激酶信号传导,例如,U0126、PD98059、PD184352、PD0325901、ARRY-142886、SB239063、SP600125、BAY 43-9006、渥曼青霉素(wortmannin)、或LY294002;Syk抑制剂;抗体(例如,利妥昔单抗);MET抑制剂(如福瑞替尼(foretinib)、卡博替尼(carbozantinib)、或克唑替尼(crizotinib));VEGFR抑制剂(如舒尼替尼(sunitinib)、索拉非尼(sorafenib)、瑞戈非尼(regorafinib)、乐伐替尼(lenvatinib)、凡德他尼(vandetanib)、卡博替尼、阿西替尼(axitinib));EGFR抑制剂(如阿法替尼(afatinib)、布立尼布(brivanib)、卡扎替尼(carbozatinib)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、来那替尼(neratinib)、拉帕替尼(lapatinib));PI3K抑制剂(如XL147、XL765、BKM120(布帕昔布(buparlisib))、GDC-0941、BYL719、IPIl45、BAY80-6946、BEX235(达托昔布(dactolisib))、CAL101(艾代拉里斯(idelalisib))、GSK2636771、TG100-115);MTOR抑制剂(如雷帕霉素(rapamycin)(西罗莫司(sirolimus))、坦罗莫司(temsirolimus)、依维莫司(everolimus)、XL388、XL765、AZD2013、PF04691502、PKI-587、BEZ235、GDC0349);MEK抑制剂(如AZD6244、曲美替尼(trametinib)、PD184352、皮马替尼(pimasertinib)、GDC-0973、AZD8330);CSFlR抑制剂(PLX3397、LY3022855等)和CSFlR抗体(IMC-054、RG7155等);TGFβ受体激酶抑制剂(如LY2157299);BTK抑制剂(如依鲁替尼)。
其他抗癌剂包括蛋白酶体抑制剂(如卡非佐米(carfilzomib)、MLN9708、德兰佐米(delanzomib)、或硼替佐米);BET抑制剂(如INCB054329、OTX015、CPI-0610);LSD1抑制剂(如GSK2979552、INCB059872);HDAC抑制剂(如帕比司他(panobinostat)、伏立诺他(vorinostat));DNA甲基转移酶抑制剂(如氮杂胞苷、地西他滨)和其他表观遗传调节剂;SHP-2抑制剂(如TNO155);Bcl2抑制剂ABT-199和其他Bcl-2家族蛋白抑制剂;HIF-2α抑制剂(如PT2977和PT2385);β连环蛋白途径抑制剂、notch途径抑制剂和hedgehog途径抑制剂。VEGF的抗体或其他治疗性蛋白包括贝伐单抗和阿柏西普。
可以与本发明的化合物组合使用的其他抗癌剂/药物包括但不限于,肝X受体(LXR)调节剂(包括LXR激动剂和LXRβ-选择性激动剂);芳烃受体(AhR)抑制剂。
可以与本披露的化合物组合使用的其他抗癌剂包括阿霉素(Adriamycin)、更生霉素(Dactinomycin)、博来霉素(Bleomycin)、长春碱(Vinblastine)、顺铂(cisplatin)、阿西维辛(acivicin);阿柔比星;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;安波霉素;醋酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;安曲霉素;天冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸比生群;二甲磺酸双奈法德;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素;卡普睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔比星;卡折来新;西地芬戈;苯丁酸氮芥;西罗霉素;克拉屈滨;甲磺酸克立那托(crisnatol mesylate);环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;甲磺酸地扎胍宁;地吖醌;多柔比星;盐酸多柔比星;屈洛昔芬;柠檬酸屈洛昔芬;丙酸屈他雄酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表柔比星;厄布洛唑;盐酸伊索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;氯苯乙嘧胺;盐酸法屈唑;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;白介素II(包括重组白介素II、或Ril2)、干扰素α-2a;干扰素α-2b;干扰素α-nl;干扰素α-n3;干扰素β-la;干扰素γ-lb;异丙铂;盐酸伊立替康;醋酸兰瑞肽;来曲唑;醋酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索罗酚;美坦辛;盐酸氮芥;醋酸甲地孕酮;醋酸美仑孕酮;美法仑;美诺立尔;巯基嘌呤;甲氨喋呤;甲氨蝶呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托克星;丝裂红素;米托洁林;米托马星;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;诺拉霉素;奥马铂;奥昔舒仑;培门冬酶;培利霉素;戊氮芥;硫酸培洛霉素;培磷酰胺;哌泊溴烷;哌泊舒凡;盐酸吡罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;甲基丝裂霉素;泼尼莫司汀;盐酸丙卡巴肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋林;利波腺苷;罗谷亚胺;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;司泊索非钠(sparfosate sodium);司帕霉素;盐酸锗螺胺;螺莫司汀;螺铂;链黑霉素;链脲菌素;磺氯苯脲;他利霉素;替可加兰钠;喃氟啶(tegafur);盐酸替洛蒽醌;替莫泊芬;替尼泊苷(teniposide);替罗昔隆;睾内酯;硫咪嘌呤;硫鸟嘌呤;噻替派;噻唑呋林;替拉扎明;柠檬酸托瑞米芬;醋酸曲托龙;磷酸曲西立滨;三甲曲沙;葡萄糖醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸长春罗辛;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春利定;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星。
可以与本披露的化合物组合使用的其他抗癌剂包括:20-表-1,25二羟基维生素D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;酰基富烯(acylfulvene);腺环戊醇;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;阿米多克斯(amidox);氨磷汀;氨基乙酰丙酸;氨柔比星;安吖啶;阿那格雷;阿那曲唑;穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯(antarelix);抗背部化形态发生蛋白-1;抗雄激素,前列腺癌;抗雌激素;抗瘤酮;反义寡核苷酸;甘氨酸阿非迪霉素;细胞凋亡基因调节剂;细胞凋亡调节剂;脱嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨酶;阿苏莱克林(asulacrine);阿他美坦;阿莫司汀;阿耐司汀(axinastatin)1;阿耐司汀2;阿耐司汀3;阿扎司琼;阿扎毒素;重氮酪氨酸;巴卡亭III衍生物;巴拉诺(balanol);巴马司他;BCR/ABL拮抗剂;苯并二氢卟酚;苯甲酰星状孢菌素(benzoylstaurosporine);β内酰胺衍生物;β-阿立辛(beta-alethine);亚阿克拉霉素B;桦木酸;Bfgf抑制剂;比卡鲁胺;比生群;双吖丙啶基精胺;双奈法德;双崔特(Bistratene)A;比折来新;布瑞弗莱特(breflate);溴匹立明;布度钛;丁胱亚磺酰亚胺;卡泊三醇;卡弗他丁C;喜树碱衍生物;金丝雀痘IL-2;卡培他滨(capecitabine);甲酰胺-氨基-三唑;羧基酰氨基三唑;卡思特(CaRest)M3;CARN 700;软骨衍生的抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);粟树精胺;天蚕素B;西曲瑞克;绿素类(chlorlns);氯喹喔啉磺酰胺;西卡前列素;顺卟啉;克拉屈滨;氯米芬类似物;克霉唑;柯林斯霉菌素(collismycin)A;柯林斯霉菌素B;康普瑞汀A4;康普瑞汀类似物;康那格林(conagenin);康伯西汀(crambescidin)816;克立那托;念珠藻环肽8;念珠藻环肽A衍生物;库拉素A;环戊蒽醌;赛克普拉特(cycloplatam);赛普米新(cypemycin);阿糖胞苷十八烷基磷酸酯;溶细胞因子;磷酸己烷雌酚;达昔单抗;地西他滨;脱氢膜海鞘素B;地洛瑞林;地塞米松;右异环磷酰胺;右雷佐生;右维拉帕米;地吖醌;膜海鞘素B;迪多克斯(didox);二乙基去甲精胺;二氢-5-氮杂胞苷;9-二氧杂霉菌素;联苯螺莫司汀;二十二醇;多拉司琼;脱氧氟尿苷;屈洛昔芬;屈大麻酚;多卡米新SA;依布硒;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表柔比星;依立雄胺;雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;磷酸依托泊苷;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;非那雄胺;夫拉平度;氟卓斯汀;弗拉斯特伦(fluasterone);氟达拉滨;盐酸氟柔红霉素(fluorodaunorunicin hydrochloride);福酚美克;福美斯坦;福司曲星;福莫司汀;钆替沙林;硝酸镓;加洛他滨;加尼瑞克;明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;海普撒凡(hepsulfam);调蛋白;六甲撑二乙酰胺;金丝桃素;伊班膦酸;伊达比星;艾多昔芬;伊决孟酮;伊莫福新;伊洛马司他;咪唑并吖啶酮;咪喹莫特;免疫刺激剂肽;胰岛素样生长因子-1受体抑制剂;干扰素激动剂;干扰素;白细胞介素;碘苄胍;碘多柔比星;甘薯苦醇(ipomeanol),4-;伊罗普拉(iroplact);伊索拉定;异本伽唑(isobengazole);异高软海绵素(isohomohalicondrin)B;伊他司琼;jasplakinolide;海蛞蝓提取物(kahalalide)F;三乙酸片螺素N(lamellarin-N triacetate);兰瑞肽;来那米新(leinamycin);来格司亭;硫酸香菇多糖;莱普妥斯新(leptolstatin);来曲唑;白血病抑制因子;白细胞α干扰素;亮丙瑞林+雌激素+孕酮;亮丙瑞林;左旋咪唑;利罗唑;线性多胺类似物;亲脂性二糖肽;亲脂性铂化合物;利沙克里那米得(lissoclinamide)7;洛铂;蚯蚓磷脂;洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;替沙林镥;利索茶碱;裂解肽;美坦新;制甘糖酶素(mannostatin)A;马立马司他;马索罗酚;乳腺丝抑蛋白;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;美巴龙;美替瑞林;甲硫氨酸酶;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;错配的双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;迈托毒素成纤维细胞生长因子-皂角素;米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体,人绒毛膜促性腺激素;莫哌达醇;多重抗药性基因抑制剂;基于多肿瘤抑制因子1的疗法;芥末抗癌剂;印度洋海绵(mycaperoxide)B;分枝杆菌细胞壁提取物;米利亚普隆(myriaporone);N-乙酰基地那林;N-取代的苯甲酰胺;那法瑞林;那瑞替喷;纳洛酮+喷他佐辛;纳帕因(napavin);纳福特平(naphterpin);那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性内肽酶;尼鲁米特;尼萨霉素(nisamycin);一氧化氮调节剂;氮氧化物抗氧化剂;尼图林(nitrullyn);O6-苄基鸟嘌呤;奥曲肽;奥琪森酮(okicenone);寡核苷酸;奥那司酮;昂丹司琼;奥罗新(oracin);口服细胞因子诱导剂;奥马铂;奥沙特隆;奥沙利铂;奥克萨霉素(oxaunomycin);帕劳霉素(palauamine);棕榈酰根霉菌素(palmitoylrhizoxin);帕米膦酸;人参炔三醇;帕诺米芬;副球菌素;帕折普汀;培门冬酶;培得星;木聚硫钠;喷司他丁;泮托唑(pentrozole);全氟溴烷;培磷酰胺;紫苏醇;苯连氮霉素;苯乙酸酯;磷酸酯酶抑制剂;沙培林;盐酸毛果芸香碱;吡柔比星;吡曲克辛;普拉斯汀(placetin)A;普拉斯汀B;纤溶酶原激活物抑制剂;铂复合物;铂化合物;铂-三胺复合物;卟吩姆钠;甲基丝裂霉素;强的松;丙基双-吖啶酮;前列腺素J2;蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂、微藻;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;羟基茜草素;吡唑啉吖啶;吡哆醛化血红蛋白聚氧乙烯结合物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法呢基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;去甲基化瑞替普汀;依替膦酸铼Re 186;根霉素;核酶;R.sub.11维甲酰胺;罗谷亚胺;罗希吐碱;罗莫肽;罗喹美克;鲁滨吉隆(rubiginone)B1;如波希尔(ruboxyl);沙芬戈;辛妥平(saintopin);SarCNU;肌肉叶绿醇A;沙格司亭;Sdi1模拟物;司莫司汀;衰老衍生的1;正义寡核苷酸;信号转导抑制剂;信号转导调节剂;单链抗原结合蛋白;西佐喃;索布佐生:硼卡钠;苯乙酸钠;索沃绕(solverol);生长介素结合蛋白;索纳明;膦门冬酸;穗霉素D;螺莫司汀;斯耐潘定;海绵素1;角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;斯蒂匹酰胺(stipiamide);基质分解素抑制剂;萨菲诺辛(sulfinosine);强效血管活性肠肽拮抗剂;苏拉蒂斯塔(suradista);苏拉明;苦马豆素;合成的糖胺聚糖;他莫司汀;他莫昔芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;喃氟啶;替鲁里姆(tellurapyrylium);端粒酶抑制剂;替莫泊芬;替莫唑胺;替尼泊苷;四氯十氧化物;四唑胺(tetrazomine);白蓬达亭(thaliblastine);噻可拉林;血小板生成素;血小板生成素模拟物;胸腺法新;胸腺生成素受体激动剂;胸腺曲南;促甲状腺激素;乙基初卟啉锡(tin ethyletiopurpurin);替拉扎明;二茂基二氯化钛;妥普森汀(topsentin);托瑞米芬;全能干细胞因子;翻译抑制剂;维甲酸;三乙酰尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂;UBC抑制剂;乌苯美司;泌尿生殖窦来源的生长抑制因子;尿激酶受体拮抗剂;伐普肽;维瑞尔林(variolin)B;载体系统,红细胞基因疗法;维拉雷琐;藜芦胺;维尔丁斯(verdins);维替泊芬;长春瑞滨;维撒丁(vinxaltine);维他星(vitaxin);伏氯唑;扎诺特隆;折尼铂;亚苄维C(zilascorb);和净司他丁斯酯。
可以与本披露的化合物组合使用的还其他抗癌剂包括烷化剂、抗代谢物、天然产物、或激素,例如,氮芥(例如,二氯甲基二乙胺(mechloroethamine)、环磷酰胺、苯丁酸氮芥等)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀、洛莫司汀等)、或三氮烯(鸨烯咪胺(decarbazine)等)。抗代谢物的实例包括但不限于叶酸类似物(例如,甲氨蝶呤)、或嘧啶类似物(例如,阿糖胞苷)、嘌呤类似物(例如,巯基嘌呤、硫鸟嘌呤、喷司他丁)。
可以与本披露的化合物组合使用的天然产物的实例包括但不限于长春花生物碱(例如,长春新碱)、表鬼臼毒素(例如,依托泊苷)、抗生素(例如,柔红霉素、多柔比星、博来霉素)、酶(例如,L-天冬酰胺酶)、或生物应答调节剂(biological response modifier)(例如,干扰素α)。
可以与本披露的化合物组合使用的烷化剂的实例包括但不限于氮芥(例如,二氯甲基二乙胺、环磷酰胺、苯丁酸氮芥、美法仑等)、乙烯亚胺和甲基三聚氰胺(例如,六甲基三聚氰胺、噻替派)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀、洛莫司汀、司莫司汀、链脲菌素等)、或三氮烯(鸨烯咪胺等)。抗代谢物的实例包括但不限于叶酸类似物(例如,甲氨蝶呤)、或嘧啶类似物(例如,氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤类似物(例如,巯基嘌呤,硫鸟嘌呤,喷司他丁)。
可以与本披露的化合物组合使用的激素和拮抗剂的实例包括但不限于肾上腺皮质类固醇(例如,强的松)、孕酮(例如,己酸羟孕酮、醋酸甲地孕酮和醋酸甲羟孕酮)、雌激素(例如,己烯雌酚、乙炔雌二醇)、抗雌激素(例如,他莫昔芬)、雄激素(例如,丙酸睾酮、氟甲睾酮)、抗雄激素(例如,氟他胺)、促性腺激素释放激素类似物(例如,亮丙瑞林)。可以用于本文描述的方法和组合物中的用于治疗或预防癌症的其他药剂包括铂配位复合物(例如,顺铂、卡铂)、蒽二酮(例如,米托蒽醌)、经取代的脲(例如,羟基脲)、甲基肼衍生物(例如,丙卡巴肼)、肾上腺皮质抑制药(例如,米托坦、氨鲁米特)。
可以与本披露的化合物组合使用的其他抗癌剂包括:由于稳定化的微管通过使细胞停留在G2-M期而起作用的抗癌剂包括厄布洛唑(也称为R-55104)、尾海兔素10(也称为DLS-10和NSC-376128)、羟乙磺酸米伏布林(Mivobulin isethionate)(也称为CI-980)、长春新碱、NSC-639829、圆皮海绵内酯(Discodermolide)(也称为NVP-XX-A-296)、ABT-751(雅培公司(Abbott),也称为E-7010)、阿托海汀(Altorhyrtin)(如阿托海汀A和阿托海汀C)、海绵毒素(Spongistatin)(如海绵毒素1、海绵毒素2、海绵毒素3、海绵毒素4、海绵毒素5、海绵毒素6、海绵毒素7、海绵毒素8、和海绵毒素9)、盐酸西马多丁(也称为LU-103793和NSC-D-669356)、埃博霉素(如埃博霉素A、埃博霉素B、埃博霉素C(也称为脱氧埃博霉素A或dEpoA)、埃博霉素D(也称为KOS-862、dEpoB、和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素BN-氧化物、埃博霉素AN-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(也称为BMS-310705)、21-羟基埃博霉素D(也称为脱氧埃博霉素F和dEpoF)、26-氟埃博霉素)、溴瑞他汀PE(也称为NSC-654663)、索利多亭(Soblidotin)(也称为TZT-1027)、LS-4559-P(法玛西亚公司(Pharmacia),也称为LS-4577)、LS-4578(法玛西亚公司,也称为LS-477-P)、LS-4477(法玛西亚公司)、LS-4559(法玛西亚公司)、RPR-112378(安内特公司(Aventis))、硫酸长春新碱、DZ-3358(第一实业公司(Daiichi))、FR-182877(藤泽公司(Fujisawa),也称为WS-9885B)、GS-164(武田制药公司(Takeda))、GS-198(武田制药公司)、KAR-2(匈牙利科学院(Hungarian Academy of Sciences))、BSF-223651(BASF公司,也称为ILX-651和LU-223651)、SAH-49960(礼来制药公司(Lilly)/诺华公司(Novartis))、SDZ-268970(礼来制药公司/诺华公司)、AM-97(阿曼达公司(Armad)/协和发酵工业株式会社(Kyowa Hakko))、AM-132(阿曼达公司)、AM-138(阿曼达公司/协和发酵工业株式会社)、IDN-5005(印第纳公司(Indena))、念珠藻素52(也称为LY-355703)、AC-7739(味之素公司(Ajinomoto),也称为AVE-8063A和CS-39.HCl)、AC-7700(味之素公司,也称为AVE-8062、AVE-8062A、CS-39-L-Ser.HCl、和RPR-258062A)、维提酰胺(Vitilevuamide)、微管蛋白抑制剂(Tubulysin)A、加纳单索(Canadensol)、矢车菊黄素(Centaureidin)(也称为NSC-106969)、T-138067(杜拉瑞克公司(Tularik),也称为T-67、TL-138067和TI-138067)、COBRA-1(帕克休斯研究院(Parker Hughes Institute),也称为DDE-261和WHI-261)、H10(堪萨斯州立大学(KansasState University))、H16(堪萨斯州立大学)、Oncocidin A1(也称为BTO-956和DIME)、DDE-313(帕克休斯研究院)、Fijianolide B.莱利霉素(Laulimalide)、SPA-2(帕克休斯研究院)、SPA-1(帕克休斯研究院,也称为SPIKET-P)、3-IAABU(细胞骨架公司(Cytoskeleton)/西奈山医学院(Mt.Sinai School of Medicine),也称为MF-569)、乐咳平(Narcosine)(也称为NSC-5366)、那卡平(Nascapine)、D-24851(爱斯达制药公司(Asta Medica))、A-105972(雅培公司)、哈米特林(Hemiasterlin)、3-BAABU(细胞骨架公司/西奈山医学院,也称为MF-191)、TMPN(亚利桑那州立大学(Arizona State University))、乙酰丙酮双钒(Vanadoceneacetylacetonate)、T-138026(杜拉瑞克公司(Tularik))、莫那撒尔(Monsatrol)、Inanocine(也称为NSC-698666)、3-1AABE(细胞骨架公司/西奈山医学院)、A-204197(雅培公司)、T-607(杜拉瑞克公司,也称为T-900607)、RPR-115781(安内特公司)、艾榴塞洛素(Eleutherobin)(如去甲基艾榴塞洛素(Desmethyleleutherobin)、去乙酰艾榴塞洛素(Desaetyleleutherobin)、异艾榴塞洛素A(Isoeleutherobin A)、和Z-艾榴塞洛素(Z-Eleutherobin))、卡利贝苷(Caribaeoside)、卡利贝林(Caribaeolin)、软海绵素B(Halichondrin B)、D-64131(爱斯达制药公司)、D-68144(爱斯达制药公司)、含氯环肽A(Diazonamide A)、A-293620(雅培公司)、NPI-2350(萊芮思公司(Nereus))、箭根薯酮内酯A(Taccalonolide A)、TUB-245(安内特公司)、A-259754(雅培公司)、地佐他汀(Diozostatin)、(-)-Phenylahistin(也称为NSCL-96F037)、D-68838(爱斯达制药公司)、D-68836(爱斯达制药公司)、肌基质蛋白B(Myoseverin B)、D-43411(Zentaris公司,也称为D-81862)、A-289099(雅培公司)、A-318315(雅培公司)、HTI-286(也称为SPA-110,三氟乙酸盐)(惠氏公司(Wyeth))、D-82317(Zentaris公司)、D-82318(Zentaris公司)、SC-12983(NCI)、力司弗拉司达汀(Resverastatin)磷酸钠、BPR-OY-007(国家卫生研究院(NationalHealth Research Institutes))、和SSR-250411(赛诺菲公司(Sanofi))。
一种或多种另外的免疫检查点抑制剂可与本披露的化合物组合使用。示例性免疫检查点抑制剂包括针对免疫检查点分子(如CD27、CD28、CD40、CD122、CD96、CD73、CD39、CD47、OX40、GITR、CSF1R、JAK、PI3Kδ、PI3Kγ、TAM、精氨酸酶、CD137(也称为4-1BB)、ICOS、A2AR、A2BR、SHP-2、B7-H3、B7-H4、BTLA、CTLA-4、LAG3、TIM3、VISTA、CD96、TIGIT、PD-1、PD-L1和PD-L2)的抑制剂(打击(smack)分子或生物制品)。在一些实施例中,免疫检查点分子是刺激性检查点分子,该刺激性检查点分子选自CD27、CD28、CD40、ICOS、OX40、GITR、CD137和STING。在一些实施例中,免疫检查点分子是抑制性检查点分子,该抑制性检查点分子选自B7-H3、B7-H4、BTLA、CTLA-4、IDO、TDO、精氨酸酶、KIR、LAG3、PD-1、TIM3、CD96、TIGIT和VISTA。在一些实施例中,本文提供的化合物可以与一种或多种药剂组合使用,这些药剂选自KIR抑制剂、TIGIT抑制剂、LAIR1抑制剂、CD160抑制剂、2B4抑制剂和TGFRβ抑制剂。
在一些实施例中,免疫检查点分子的抑制剂是PD-1的抑制剂,例如,抗PD-1单克隆抗体。在一些实施例中,抗PD-1单克隆抗体是纳武单抗、派姆单抗(也称为MK-3475)、佩蒂单抗(pidilizumab)、SHR-1210、PDR001、或AMP-224。在一些实施例中,抗PD-1单克隆抗体是纳武单抗、或派姆单抗或PDR001。在一些实施例中,抗PD1抗体是派姆单抗。
在一些实施例中,免疫检查点分子的抑制剂是PD-L1的抑制剂,例如,抗PD-L1单克隆抗体。在一些实施例中,抗PD-L1单克隆抗体是BMS-935559、MEDI4736、MPDL3280A(也称为RG7446)、或MSB0010718C。在一些实施例中,抗PD-L1单克隆抗体是MPDL3280A(阿特珠单抗)或MEDI4736(德瓦鲁单抗)。
在一些实施例中,免疫检查点分子的抑制剂是CTLA-4的抑制剂,例如,抗CTLA-4抗体。在一些实施例中,抗CTLA-4抗体是伊匹单抗或曲美木单抗。在一些实施例中,免疫检查点分子的抑制剂是LAG3的抑制剂,例如,抗LAG3抗体。在一些实施例中,抗LAG3抗体是BMS-986016或LAG525。在一些实施例中,免疫检查点分子的抑制剂是GITR的抑制剂,例如,抗GITR抗体。在一些实施例中,抗GITR抗体是TRX518、或MK-4166、INCAGN01876或MK-1248。在一些实施例中,免疫检查点分子的抑制剂是OX40的抑制剂,例如,抗OX40抗体或OX40L融合蛋白。在一些实施例中,抗OX40抗体是MEDI0562或INCAGN01949、GSK2831781、GSK-3174998、MOXR-0916、PF-04518600或LAG525。在一些实施例中,OX40L融合蛋白是MEDI6383。
此外,本文披露的组合疗法可以与放射一起施用。
实例
给出具有式(I)的化合物的以下制备,以使本领域技术人员能够更清楚地理解和实践本披露。不应该认为它们限制本披露的范围,而仅仅是作为其说明和代表。
实例1
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
步骤1:乙基3-(2-溴-4-氟苯基)-2,2-二氟-3-羟基丙酸酯
在室温下,在氮气氛下,向锌(6.97g,106.56mmol,1.03当量)、1,2-二溴乙烷(388.71mg,2.069mmol,0.02当量)和氯三甲基硅烷(1.12g,10.31mmol,0.10当量)在THF(200mL)中的搅拌混合物中逐滴添加乙基2-溴-2,2-二氟乙酸酯(21.0g,103.45mmol,1.0当量)和2-溴-4-氟苯甲醛(21.0g,103.45mmol,1.0当量)在THF(100mL)中的溶液。在75℃下,在氮气氛下,将所得混合物搅拌16h。将反应冷却并用冰/水淬灭。将有机溶剂在真空下除去,并且将所得混合物用EtOAc萃取。将合并的有机层用水洗涤,经无水Na2SO4干燥,并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(5∶1)洗脱,以得到呈黄色油状物的标题化合物(18g,53.2%)。
步骤2:乙基3-(2-溴-4-氟苯基)-2,2-二氟-3-氧代丙酸酯
在室温下,向乙基3-(2-溴-4-氟苯基)-2,2-二氟-3-羟基丙酸酯(16g,48.9mmol,1.0当量)在CH3CN(200mL)中的搅拌溶液中添加2-碘酰基苯甲酸(27.4g,97.83mmol,2.0当量),并且在80℃下,将所得混合物搅拌3h。然后将反应溶液冷却至室温,过滤,并且将滤饼用EtOAc洗涤。将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(10∶1)洗脱,以得到呈黄色油状物的标题化合物(10.3g,64.8%)。
步骤3:乙基3-(2-溴-4-氟苯基)-2,2,3,3-四氟丙酸酯
在室温下,向乙基3-(2-溴-4-氟苯基)-2,2-二氟-3-氧代丙酸酯(6.1g,18.8mmol,1.0当量)在CHCl3(6mL)中的搅拌溶液中逐滴添加DAST(30.25g,187.6mmol,10.0当量),并且在70℃下,在氮气氛下,将所得混合物搅拌16h。允许反应溶液冷却至室温,并且用冰/水淬灭。将混合物用DCM萃取。将有机层经无水Na2SO4干燥并浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(10∶1)洗脱,以得到呈黄色油状物的标题化合物(2.4g,36.8%)。
步骤4:2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-酮
在-78℃下,在氮气氛下,向乙基3-(2-溴-4-氟苯基)-2,2,3,3-四氟丙酸酯(4.20g,12.10mmol,1.0当量)在THF(50mL)中的搅拌溶液中逐滴添加n-BuLi(2.5M,7.26mL,18.15mmol,1.5当量),并且在-70℃与-80℃之间,在氮气氛下,将所得混合物搅拌2h。将反应用饱和NH4Cl(水溶液)淬灭,并用EtOAc萃取。将有机层经无水Na2SO4干燥并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(20∶1)洗脱,以得到标题化合物(2.25g,83.7%)。
步骤5:2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇
在0℃下,向2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-酮(300mg,1.35mmol,1.0当量)和三乙胺(273.35mg,2.70mmol,2.0当量)在DCM(3mL)中的搅拌溶液中逐滴添加甲酸(186.49mg,4.05mmol,3.0当量),随后添加RuCl(对伞花烃)[(S,S)-Ts-DPEN](8.59mg,0.014mmol,0.01当量)。将所得混合物在室温下在氮气氛下搅拌3h,然后用水洗涤。将有机层经无水Na2SO4干燥并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(5∶1)洗脱,以得到标题化合物(300mg,99.1%)。
步骤6:7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇
在-78℃下,在氮气氛下,向2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇(2500mg,11.154mmol,1.00当量)在四氢呋喃(60mL)中的搅拌溶液中逐滴添加LDA(2.0M,16.73mL,33.463mmol,3.00当量)。将所得混合物经30min升温至-30℃,并在-30℃下再搅拌30min。在-78℃下,向上述混合物中逐滴添加四溴化碳(3699.05mg,11.154mmol,1.00当量)在THF中的溶液。允许所得混合物经30min升温至-30℃,并在-30℃下再搅拌30min。将反应在-30℃下用饱和NH4Cl(水溶液)淬灭。将所得混合物用EtOAc萃取,并且将有机层用盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(10∶1)洗脱,以得到呈浅黄色油状物的标题化合物(2600mg,76.9%)。MS(ES,m/z):[M-H]-=300.9,302.9。
步骤7:7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-酮
在室温下,向7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇(2.63g,8.679mmol,1.00当量)在CH3CN(45mL)中的搅拌混合物中添加IBX(4.86g,17.356mmol,2.00当量)。在80℃下,将所得混合物搅拌3h,然后冷却并过滤。将滤饼用EtOAc洗涤。将合并的滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(10∶1)洗脱,以得到呈灰白色固体的标题化合物(1.8g,68.9%)。
步骤8:1-烯丙基-7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇
在-78℃下,在氮气氛下,向7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-酮(100mg,0.332mmol,1.00当量)在THF(3mL)中的搅拌溶液中逐滴添加烯丙基溴化镁(1.0M,0.50mL,0.50mmol,1.50当量)。在-78℃下,在氮气氛下,将所得混合物搅拌1h。将反应用饱和NH4Cl(水溶液)淬灭。将所得混合物用EtOAc萃取,并且将有机层经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(5∶1)洗脱,以得到呈黄色油状物的标题化合物(90mg,79.0%)。MS(ES,m/z):[M-H]-=340.9,342.9。
步骤9:3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇
在室温下,向1-烯丙基-7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇(1050mg,3.060mmol,1.00当量)在DMF(25mL)中的搅拌混合物中添加AcONa(753.17mg,9.181mmol,3.00当量)和Pd(dppf)Cl2·CH2Cl2(249.93mg,0.306mmol,0.10当量)。在100℃下,在氮气氛下,将所得混合物搅拌3h。将所得混合物用水稀释并用EtOAc萃取。将合并的有机层用水和盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(5∶1)洗脱,以得到呈浅黄色油状物的标题化合物(370mg,46.1%)。
步骤10:3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈
在室温下,向3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(40mg,0.15mmol,1.00当量)和3-氟-5-羟基苯甲腈(20.92mg,0.153mmol,1.00当量)在DMF(1mL)中的搅拌混合物中添加Cs2CO3(49.71mg,0.15mmol,1.00当量)。在100℃下,将所得混合物搅拌24h。将所得混合物过滤,并且将滤液通过制备型HPLC纯化以得到(16.77mg,29.0%)。MS(ES,m/z):[M-H]-=378.1。
实例2
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
步骤1:3,3,4,4,7-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮
在室温下,向3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(320mg,1.22mmol,1.00当量)在混合溶剂(DCM/CH3CN/H2O=3mL/3mL/4.50mL)中的搅拌混合物中添加NaIO4(1044.25mg,4.882mmol,4.00当量)和RuCl3·H2O(13.76mg,0.061mmol,0.05当量)。在室温下,将所得混合物搅拌6h。将所得混合物用水稀释并用DCM萃取。将合并的有机层用水和盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(3∶1)洗脱,以得到呈白色固体的标题化合物(250mg,77.5%)。MS(ES,m/z):[M-H]-=263.0。
步骤2:3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈
在室温下,向3,3,4,4,7-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮(200mg,0.757mmol,1.00当量)和3-氟-5-羟基苯甲腈(103.81mg,0.757mmol,1.0当量)在DMF(3mL)中的搅拌混合物中添加Cs2CO3(246.69mg,0.76mmol,1.0当量)。在室温下,将所得混合物搅拌16h。将所得混合物用水稀释并用EtOAc萃取。将合并的有机层用水和盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(3∶1)洗脱,以得到呈白色半固体的标题化合物(200mg,69.3%)。MS(ES,m/z):[M-H]-=380.0。
实例3
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
在室温下,向3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(40mg,0.105mmol,1.00当量)在MeOH(1mL)中的溶液中添加NaBH4(7.94mg,0.210mmol,2.0当量)。在室温下,将所得混合物搅拌3h。在室温下,将反应用HCl水溶液(2.0M)淬灭至pH=7。将所得混合物在真空下浓缩。将残余物用水稀释并用EtOAc萃取。将合并的有机层用水洗涤,经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过制备型TLC纯化,用PE/EtOAc(3∶1)洗脱,以得到呈无色油状物的标题化合物(40mg,99.5%)。MS(ES,m/z):[M-H]-=382.0。
实例4
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈[4]的合成
在-50℃下,向3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(20mg,0.05mmol,1.00当量)在DCM(0.5mL)中的搅拌溶液中逐滴添加DAST(6.73mg,0.04mmol,0.80当量)。在-50℃--40℃下,将所得混合物搅拌30min。将反应混合物用NaHCO3(水溶液)淬灭并用DCM萃取。将有机层经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过制备型HPLC纯化,以得到呈白色固体的标题化合物(4.3mg,21.3%)。MS(ES,m/z):[M-H]-=384.1。
实例5
1,3,3,4,4-五氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇的合成
步骤1:3,3,4,4-四氟-7-((5-氟吡啶-3-基)氧基)-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮
在室温下,在氮气氛下,向3,3,4,4,7-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮(95mg,0.36mmol,1.00当量)和5-氟吡啶-3-醇(41mg,0.36mmol,1.00当量)在DMF(2.00mL)中的搅拌混合物中添加Cs2CO3(128.90mg,0.40mmol,1.10当量)。在室温下搅拌4h后,将反应混合物在0℃下用水淬灭。将所得混合物用EtOAc萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过制备型TLC(PE/EtOAc=3/1)纯化,以得到呈白色固体的标题化合物(85mg,66%)。MS(ES,m/z):[M+1]+=358.1。
步骤2:3,3,4,4-四氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊-[cd]茚-1,2a-二醇
在室温下,向3,3,4,4-四氟-7-((5-氟吡啶-3-基)氧基)-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮(85mg,0.24mmol,1.00当量)在MeOH(1.50mL)中的搅拌溶液中添加NaBH4(18mg,0.48mmol,2.00当量)。在室温下搅拌1h后,将反应混合物在0℃下用饱和NH4Cl(水溶液)淬灭。将所得混合物用EtOAc萃取,并且将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(0-60%)洗脱,以得到呈浅黄色固体的标题化合物(80mg,93.7%)。MS(ES,m/z):[M+1]+=3601。
步骤3:1,3,3,4,4-五氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇
在-50℃下,在氮气氛下,向3,3,4,4-四氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊[cd]茚-1,2a-二醇(30mg,0.08mmol,1.00当量)在THF(1.00mL)中的搅拌溶液中添加DAST(20mg,0.12mmol,1.50当量)。在-50℃--30℃下搅拌2h后,将反应混合物在0℃下用饱和NaHCO3(水溶液)淬灭。将所得混合物用EtOAc萃取,并且将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将粗产物通过制备型HPLC纯化,以得到呈白色固体的标题化合物(3mg,10%)。MS(ES,m/z):[M+1]+=362.1。
实例6
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢螺[环戊[cd]茚-1,1’-环丙烷]-7-基)氧基)苯甲腈的合成
在0℃下,在氮气氛下,向二乙基锌(0.53mL,0.53mmol,1.0M在己烷中)在DCM(3mL)中的搅拌混合物中逐滴添加TFA(60mg,0.526mmol,4.00当量)。在0℃下,将所得混合物搅拌10min。在0℃下,向上述混合物中逐滴添加CH2I2(141mg,0.53mmol,4.0当量)。将所得混合物在0℃下再搅拌10min,随后添加3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(50mg,0.132mmol,1.00当量)。将反应混合物在0℃下搅拌10min,然后在室温下再搅拌1h。将反应混合物用水淬灭并用CH2Cl2萃取。将合并的有机层经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,并且将粗产物通过制备型HPLC纯化,以得到呈白色固体的标题化合物(5.6mg,10.8%)。MS(ES,m/z):[M-H]-=392.1。
实例7
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
在室温下,向3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(30mg,0.08mmol,1.00当量)和苯基硫醚(1.47mg,0.008mmol,0.10当量)在乙酸乙酯(3mL)和CH3OH(3mL)中的搅拌混合物中添加10%Pd/C(20mg)。将所得混合物在室温下在氢气氛下搅拌48h,然后过滤。将滤液在减压下浓缩,并且将粗产物通过制备型HPLC纯化,以得到呈白色固体的标题化合物(9mg,30%)。MS(ES,m/z):[M-H]-=380.1。
实例8
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
在-78℃下,在氮气氛下,向3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(20mg,0.05mmol,1.00当量)在THF(0.60mL)中的搅拌溶液中逐滴添加溴(甲基)镁(1.0M,0.16mL,0.16mmol,3.05当量)。将所得混合物在-78℃下在氮气氛下搅拌1h,然后在-78℃下用饱和NH4Cl(水溶液)(2mL)淬灭。将所得混合物用EtOAc萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过制备型HPLC纯化,以得到呈白色固体的标题化合物(10mg,48.0%)。MS(ES,m/z):[M-H]-=396.2。
实例9
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
在-50℃下,在氮气氛下,向3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(30mg,0.07mmol,1.00当量)在DCM(1.5mL)中的搅拌混合物中逐滴添加DAST(12mg,0.07mmol,1.00当量)。将所得混合物在-50℃--40℃下在氮气氛下搅拌1.5h,然后在0℃下用饱和NaHCO3(水溶液)淬灭。将所得混合物用DCM萃取,并且将合并的有机层用水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,并且将粗品通过制备型HPLC纯化,以得到呈白色固体的标题化合物(4.3mg,14.3%)。MS(ES,m/z):[M-H]-=398.1。
实例10
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
步骤1:O-(7-(3-氰基-5-氟苯氧基)-3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-基)1H-咪唑-1-硫代甲酸酯
在室温下,在氮气氛下,向3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(100mg,0.26mmol,1.00当量)和DMAP(6mg,0.05mmol,0.20当量)在DCE(2.0mL)中的搅拌溶液中添加二(1H-咪唑-1-基)甲烷硫酮(56mg,0.31mmol,1.20当量)。在室温下,将所得混合物搅拌3h。将反应混合物浓缩,并且将残余物通过制备型TLC(PE/EtOAc 2∶1)纯化以得到标题化合物(80mg,62%)。MS(ES,m/z):[M+H]+=494.1。
步骤2:3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈
在室温下,在氮气氛下,向O-(7-(3-氰基-5-氟苯氧基)-3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-基)1H-咪唑-1-硫代甲酸酯(65mg,0.13mmol,1.00当量)和Bu3SnH(115mg,0.40mmol,3.00当量)在甲苯(2.0mL)中的搅拌溶液中添加AIBN(65mg,0.40mmol,3.00当量)。将所得混合物在50℃下搅拌16h,冷却并用水稀释,并且用EtOAc萃取。将合并的有机层用水和盐水洗涤,经无水Na2SO4干燥并浓缩。将残余物通过制备型TLC(PE/EtOAc=2/1)和制备型HPLC纯化,以得到呈白色固体的标题化合物(12mg,25%)。MS(ES,m/z):[M-H]-=366.2。
实例11
3-((2a-氨基-1,3,3,4,4-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈的合成
步骤1:N-(7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-亚基)-2-甲基丙烷-2-亚磺酰胺
在室温下,向7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-酮(1.00g,3.32mmol,1.00当量)和2-甲基丙烷-2-亚磺酰胺(0.81g,6.64mmol,2.00当量)在THF(20.0mL)中的搅拌混合物中添加Ti(OEt)4(3.03g,13.29mmol,4.00当量)。在75℃下搅拌4h后,将反应混合物冷却并在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(0-60%)洗脱,以得到呈棕色油状物的标题化合物(900mg,67.0%)。MS(ES,m/z):[M+1]+=404.0。
步骤2:N-(1-烯丙基-7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-基)-2-甲基丙烷-2-亚磺酰胺
在0℃下,向N-(7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-亚基)-2-甲基丙烷-2-亚磺酰胺(900mg,2.23mmol,1.00当量)在THF(15.0mL)中的搅拌溶液中添加烯丙基溴化镁(2.0M,1.34mL,2.70mmol,1.20当量)。在0℃下搅拌1.5h后,将反应混合物在0℃下用饱和NH4Cl(水溶液)淬灭,然后用EtOAc萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(0-50%)洗脱,以得到呈浅黄色油状物的标题化合物(750mg,75.5%)。MS(ES,m/z):[M+1]+=446.1。
步骤3:2-甲基-N-(3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]-茚-2a-基)丙烷-2-亚磺酰胺
在室温下,在氮气氛下,向N-(1-烯丙基-7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-基)-2-甲基丙烷-2-亚磺酰胺(750mg,1.68mmol,1.00当量)和Pd(dppf)Cl2·CH2Cl2(137mg,0.17mmol,0.10当量)在DMF(15.0mL)中的搅拌混合物中添加NaOAc(414mg,5.05mmol,3.00当量)。在100℃下搅拌1.5h后,将反应混合物冷却至室温,用水淬灭并用EtOAc萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(10%-40%)洗脱,以得到呈浅黄色固体的标题化合物(450mg,73.3%)。MS(ES,m/z):[M+1]+=366.1。
步骤4:3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-胺
在室温下,向2-甲基-N-(3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-基)丙烷-2-亚磺酰胺(150mg,0.41mmol,1.00当量)在1,4-二噁烷(1.0mL)中的搅拌溶液中添加HCl在1,4-二噁烷(4.0M,1.00mL,4.0mmol,9.74当量)中的溶液。在室温下搅拌5h后,将反应混合物在室温下用NaHCO3(水溶液)淬灭并用EtOAc萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(0-60%)洗脱,以得到呈浅黄色油状物的标题化合物(85mg,79.3%)。MS(ES,m/z):[M+1]+=262.1。
步骤5:2a-氨基-3,3,4,4,7-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮
在室温下,向3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-胺(85mg,0.325mmol,1.00当量)和NaIO4(278mg,1.30mmol,4.00当量)在CH3CN(0.50mL)和DCM(0.50mL)中的搅拌混合物中添加水(0.75mL)和RuCl3·H2O(7.34mg,0.03mmol,0.10当量)。在室温下搅拌1h后,将所得混合物用DCM稀释。将有机层用盐水洗涤,并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,并且将残余物通过制备型TLC(PE/EtOAc=3/1)纯化,以得到呈浅黄色油状物的标题化合物(45mg,52.5%)。MS(ES,m/z):[M-1]-=261.9。
步骤6:3-((2a-氨基-3,3,4,4-四氟-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈
在室温下,向2a-氨基-3,3,4,4,7-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮(40mg,0.15mmol,1.00当量)和3-氟-5-羟基苯甲腈(21mg,0.15mmol,1.00当量)在DMF(1.00mL)中的搅拌混合物中添加Cs2CO3(50mg,0.15mmol,1.00当量)。在室温下搅拌1.5h后,将反应用水淬灭并用EtOAc萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过制备型TLC(PE/EtOAc=3/1)纯化,以得到呈白色固体的标题化合物(35mg,60.3%)。MS(ES,m/z):[M+1]+=381.1。
步骤7:3-((2a-氨基-3,3,4,4-四氟-1-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈
在室温下,向3-((2a-氨基-3,3,4,4-四氟-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈(35mg,0.09mmol,1.00当量)在MeOH(0.50mL)中的搅拌溶液中添加NaBH4(5mg,0.13mmol,1.4当量)。在室温下搅拌0.5h后,将反应混合物在0℃下用饱和NH4Cl(水溶液)淬灭并用EtOAc萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(0-60%)洗脱,以得到呈浅黄色油状物的标题化合物(30mg,85.3%)。MS(ES,m/z):[M+1]+=383.1。
步骤8:3-((2a-氨基-1,3,3,4,4-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈
在室温下,向3-((2a-氨基-3,3,4,4-四氟-1-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈(25mg,0.07mmol,1.00当量)在DCM(1.0mL)中的搅拌溶液中添加DAST(16mg,0.10mmol,1.5当量)。在室温下搅拌2h后,将反应混合物在0℃下用饱和NaHCO3(水溶液)淬灭并用DCM萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液浓缩并通过制备型HPLC纯化,以得到呈白色固体的标题化合物(6mg,24%)。MS(ES,m/z):[M+1]+=385.1。
实例12
3-氟-5-((1,1,2a,3,3,4,4-七氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈的合成
在室温下,向3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(30mg,0.08mmol,1.00当量)在DCM(1.0mL)中的搅拌混合物中添加4-叔丁基-2,6-二甲基苯基三氟化硫(59mg,0.24mmol,3.00当量)和氟化氢吡啶(0.05mL,65%-70%)。将所得混合物在室温下在氮气氛下搅拌24h,然后用水稀释并用DCM萃取。将合并的有机层用水洗涤并经无水Na2SO4干燥。过滤后,将滤液浓缩并通过制备型HPLC纯化,以得到呈白色固体的标题化合物(9.9mg,31.1%)。MS(ES,m/z):[M-H]-=404.1。
实例13
3-((3,3-二氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈的合成
步骤1:3-氟-5-((7-碘-1-氧代-2,3-二氢-1H-茚-4-基)氧基)苯甲腈
向2L圆底烧瓶中添加3-氟-5-((1-氧代-2,3-二氢-1H-茚-4-基)氧基)苯甲腈(28g,104.77mmol,1.00当量)、F-TEDA-BF4(33g,93.15mmol,0.89当量)和CH3CN(840mL)。在60℃下,向该搅拌溶液中逐滴添加I2(24g,94.56mmol,0.90当量)在CH3CN(560mL)中的溶液。在60℃下,将所得混合物搅拌3h。将混合物冷却至室温,然后在真空下浓缩。向残余物中添加乙酸乙酯(250mL),并且将所得混合物在80℃下搅拌1h。将混合物冷却至室温,并且将沉淀的固体通过过滤收集并用Et2O洗涤,以得到呈灰白色固体的标题化合物(16.8g,40.8%)。MS(ES,m/z):[M+H]+=394.0。
步骤2:3-((2,2-二氟-7-碘-1-氧代-2,3-二氢-1H-茚-4-基)氧基)-5-氟苯甲腈
在室温下,向3-氟-5-((7-碘-1-氧代-2,3-二氢-1H-茚-4-基)氧基)-苯甲腈(3.600g,9.15mmol,1.00当量)和丁-1-胺(6.7g,91.57mmol,10.00当量)在甲苯(90mL)中的搅拌混合物中逐滴添加TFA(209mg,1.83mmol,0.20当量)。将所得混合物在100℃下在氮气氛下搅拌16h,然后在真空下浓缩。将残余物溶于CH3CN(90mL)中,随后在室温下添加Na2SO4(5.2g,36.62mmol,4.00当量)和F-TEDA-BF4(6.5g,18.31mmol,2.00当量)。将所得混合物在80℃下搅拌2h,用水稀释,并用EtOAc萃取。将合并的有机层用水、盐水洗涤,并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(10∶1)洗脱,以得到呈黄色固体的标题化合物(1.60g,40.7%)。
步骤3:3-((1-烯丙基-2,2-二氟-1-羟基-7-碘-2,3-二氢-1H-茚-4-基)氧基)-5-氟苯甲腈
在室温下,向3-((2,2-二氟-7-碘-1-氧代-2,3-二氢-1H-茚-4-基)氧基)-5-氟苯甲腈(449mg,1.05mmol,1.00当量)和烯丙基溴(253.15mg,2.093mmol,2.00当量)在THF(10mL)中的搅拌混合物中添加吡啶(165.52mg,2.09mmol,2.00当量)和(1S,2R)-2-氨基-1,2-二苯基乙醇(446.30mg,2.09mmol,2.00当量)。然后将铟粉末(240.26mg,2.09mmol,2.00当量)添加至溶液中,并且将所得混合物在室温下在氮气氛下搅拌8h。将所得混合物过滤,并且将滤饼用EtOAc洗涤。将滤液浓缩,并通过硅胶柱色谱法纯化,用PE/EtOAc(9∶1)洗脱,以得到呈黄色油状物的标题化合物(430mg,87.2%)。MS(ES,m/z):[M-H]-=470.0。
步骤4:3-((3,3-二氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈
在室温下,在氮气氛下,向3-((1-烯丙基-2,2-二氟-1-羟基-7-碘-2,3-二氢-1H-茚-4-基)氧基)-5-氟苯甲腈(430mg,0.91mmol,1.00当量)和NaOAc(225mg,2.74mmol,3.00当量)在DMF(10mL)中的搅拌溶液中添加Pd(dppf)Cl2·CH2Cl2(75mg,0.09mmol,0.10当量)。将所得混合物在100℃下在氮气氛下搅拌3h,然后过滤。将滤饼用EtOAc洗涤,并且将滤液用H2O洗涤,经无水Na2SO4干燥并浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(5∶1)洗脱,以得到呈黄色油状物的标题化合物(223mg,71.2%)。
实例14
3-((3,3-二氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈的合成
在室温下,向25mL 2颈圆底烧瓶中添加3-((3,3-二氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈(210mg,0.61mmol,1.00当量)、DCM(2.0mL)、MeCN(2.0mL)和H2O(3.0mL)。然后将RuCl3·H2O(7mg,0.03mmol,0.05当量)添加至溶液中。在室温下,经2min向上述混合物中分批添加NaIO4(523mg,2.45mmol,4.00当量),并且将所得混合物在室温下搅拌3h。将所得混合物用DCM萃取,并且将合并的有机层用Na2S2O3(水溶液)、H2O和盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(5:1)洗脱,以得到呈黄色油状物的标题化合物(107mg,50.7%)。MS(ES,m/z):[2M-H]-=689.1。
实例15
3-((3,3-二氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈的合成
在室温下,向8mL密封管中添加3-((3,3-二氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈(100mg,0.29mmol,1.00当量)和MeOH(2.00mL)。在0℃下,向上述混合物中分批添加NaBH4(22mg,0.58mmol,2.0当量),并且将所得混合物在室温下搅拌1h。将反应在0℃下用水淬灭,并用HCl水溶液(1.0M)中和至pH=7。将所得混合物用DCM萃取,并且将合并的有机层经无水Na2SO4干燥。过滤后,将滤液浓缩并通过制备型TLC(PE/EtOAc=5/1)纯化,以得到呈白色固体的标题化合物(78mg,77.6%)。
实例16
3-氟-5-((1,3,3-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈的合成
在-50℃下,在氮气氛下,向3-((3,3-二氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈(20mg,0.06mmol,1.00当量)在THF(0.50mL)中的搅拌溶液中逐滴添加DAST(9.35mg,0.06mmol,1.00当量)在DCM(0.2mL)中的溶液。将所得混合物在-50℃下在氮气氛下搅拌1h,然后在-40℃下用水淬灭。将混合物用饱和NaHCO3(水溶液)中和至pH=7,然后用EtOAc萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液浓缩并通过制备型HPLC纯化,以得到呈白色固体的标题化合物(5.7mg,28.3%)。MS(ES,m/z):[2M-H]-=697.2。
实例17
3-氟-5-((1,1,2,2,3,3,4-七氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈的合成
步骤1:乙基2,2-二氟-2-(2,2,3,3,6-五氟-1-羟基-2,3-二氢-1H-茚-1-基)乙酸酯
在60℃下,在N2气氛下,将2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-酮(10.0g,45.02mmol,1.00当量)、In(7.7g,67.06mmol,1.5当量)和乙基2-溴-2,2-二氟乙酸酯(13.7g,67.5mmol,1.50当量)在THF(150mL)中的混合物搅拌16h。将反应在室温下用HCl水溶液(2.0M,50mL)淬灭,并且将所得混合物用乙酸乙酯萃取。将合并的有机层经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EA(5/1)洗脱,以得到呈浅黄色油状物的标题化合物(8.0g,51.3%)。MS(ES,m/z):[M-1]-=345.0
步骤2:1,1,2,2,3,3,5-七氟-2a-羟基-1,2,2a,3-四氢-4H-环戊[cd]茚-4-酮
在-78℃下,在N2气氛下,向乙基2,2-二氟-2-(2,2,3,3,6-五氟-1-羟基-2,3-二氢-1H-茚-1-基)乙酸酯(500mg,1.44mmol,1.00当量)在THF(10mL)中的搅拌溶液中逐滴添加LDA(2.2mL,4.40mmol,2.0M,3.06当量)。将所得混合物在-78℃下搅拌1h,然后在-78℃下用饱和NH4Cl水溶液(10mL)淬灭。将所得混合物用乙酸乙酯萃取,并且将合并的有机层经无水Na2SO4干燥。过滤后,将滤液浓缩,并通过硅胶柱色谱法纯化,用PE/EA(3/1)洗脱,以得到粗产物。将粗产物通过制备型HPLC纯化,以得到呈浅黄色油状物的标题产物(34mg,7.8%)。MS(ES,m/z):[M-1]-298.9
步骤3:3-氟-5-((1,1,2,2,3,3-六氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈
在-10℃下,在N2气氛下,将1,1,2,2,3,3,5-七氟-2a-羟基-1,2,2a,3-四氢-4H-环戊-[cd]茚-4-酮(100mg,0.33mmol,1.00当量)、Cs2CO3(217mg,0.67mmol,2.00当量)和3-氟-5-羟基苯甲腈(50mg,0.36mmol,1.10当量)在DMF(2mL)中的混合物搅拌1h。将粗反应混合物不经进一步纯化即直接用于下一步骤。MS(ES,m/z):[M-1]-=416.0。
步骤4:3-氟-5-((1,1,2,2,3,3-六氟-2a,4-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈
在-10℃下,在N2气氛下,向粗3-氟-5-((1,1,2,2,3,3-六氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈(0.33mmol,1.00当量)在MeOH(2mL)中的搅拌溶液中分批添加NaBH4(25mg,0.66mmol,2.00当量)。将所得混合物在-10℃下搅拌1h,然后用饱和NH4Cl水溶液淬灭。将所得混合物用乙酸乙酯萃取,并且将合并的有机层用盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EA(3/1)洗脱,以得到用于两个步骤的呈浅黄色油状物的标题化合物(90mg,63.6%)。MS(ES,m/z):[M-1]-=418.0。
步骤5:3-氟-5-((1,1,2,2,3,3,4-七氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈
在-20℃下,在N2气氛下,向3-氟-5-((1,1,2,2,3,3-六氟-2a,4-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈(50mg,0.12mmol,1.00当量)在DCM(1.0mL)中的搅拌溶液中逐滴添加DAST(38mg,0.24mmol,2.00当量)。将所得混合物在室温下搅拌2h,用饱和NaHCO3水溶液淬灭。将所得混合物用DCM萃取,并且将合并的有机层经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,并且将粗产物通过制备型HPLC纯化,以得到呈浅黄色固体的标题化合物(14mg,27.5%)。MS(ES,m/z):[M-1]-=420.0。
实例18
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈的合成
步骤1:(R)-1-烯丙基-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇
向t-BuONa(21.6mg,0.225mmol,0.10当量)在甲苯(3.0mL)中的搅拌溶液中添加(S)-2-((3-(叔丁基)-2-羟基苄基)氨基)-N,N,3-三甲基丁酰胺(275.8mg,0.90mmol,0.40当量)在甲苯(0.5mL)中的溶液,然后添加MeOH(90.2mg,2.8mmol,1.25当量)在甲苯(0.5mL)中的溶液,随后添加2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-酮(0.50g,2.25mmol,1.00当量)在甲苯(0.5mL)中的溶液。在室温下搅拌15min后,缓慢添加4,4,5,5-四甲基-2-(丙-2-烯-1-基)-1,3,2-二氧杂硼烷(416.1mg,2.48mmol,1.10当量)在甲苯(0.5mL)中的溶液。将所得混合物在60℃下搅拌6.5h,冷却并用乙酸乙酯稀释。分离后,将有机层用水和盐水洗涤,经Na2SO4干燥。过滤后,将滤液浓缩,并通过硅胶柱色谱法纯化,用DCM/PE(0-40%)洗脱,以得到呈浅黄色油状物的标题化合物(0.52g,87.4%)。MS(ES,m/z):[M-1]-=263.0。
步骤2:(1R)-7-溴-2,2,3,3,6-五氟-1-(丙-2-烯-1-基)茚-1-醇
在-40℃下,在氮气氛下,向(R)-1-烯丙基-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇(5.0g,18.93mmol,1.00当量)在四氢呋喃(60mL)中的搅拌溶液中逐滴添加2.0M LDA(28.4mL,56.8mmol,3.0当量)。在-40℃下搅拌1h后,在-40℃下逐滴添加四溴化碳(7.53g,22.71mmol,1.20当量)在THF中的溶液。将所得混合物在-40℃下再搅拌10min,然后在-40℃下用1.0M HCl(水溶液)(100mL)淬灭。将所得混合物用MTBE萃取。将有机层用水和盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液浓缩,并通过硅胶柱色谱法纯化,用EtOAc/PE(0-30%)洗脱,以得到呈浅黄色油状物的粗产物。将该粗产物通过反相C18硅胶柱(流动相,ACN在水中,梯度:在12min内50%至95%)进一步纯化,以得到呈浅黄色油状物的标题化合物(3.5g,53.9%)。MS(ES,m/z):[M-1]-=340.9。
步骤3:(R)-3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇
在室温下,在氮气氛下,向(R)-1-烯丙基-7-溴-2,2,3,3,6-五氟-2,3-二氢-1H-茚-1-醇(3.50g,10.20mmol,1.00当量)在DMF(5.0mL)中的搅拌混合物中添加AcONa(2.51g,30.60mmol,3.00当量)和Pd(dppf)Cl2·CH2Cl2(0.83g,1.02mmol,0.10当量)。将所得混合物在100℃下在氮气氛下搅拌3h,冷却并用水稀释,然后用乙酸乙酯萃取。将有机层用水和盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液浓缩,并通过硅胶柱色谱法纯化,用EtOAc/PE(0-40%)洗脱,以得到呈浅黄色固体的标题化合物(2.0g,74.8%)。MS(ES,m/z):[M-1]-=260.9。
步骤4:(R)-3,3,4,4,7-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮
在室温下,向(R)-3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(2.00g,7.63mmol,1.00当量)在混合溶剂(DCM/MeCN/H2O=1/1/1.5,70.0mL)中的搅拌混合物中添加RuCl3·H2O(86.0mg,0.38mmol,0.05当量)。在室温下,向所得混合物中分批添加NaIO4(6.53g,30.53mmol,4.0当量)。在室温下搅拌1h后,将反应混合物用水稀释,然后用DCM萃取。将有机层用饱和Na2S2O3(水溶液)、水和盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液浓缩以得到呈浅黄色固体的粗标题化合物(1.85g,91.8%),其未经进一步纯化即用于下一步骤。MS(ES,m/z):[M-1]-=262.9。
步骤5:(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈
在室温下,向(R)-3,3,4,4,7-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮(1.85g,7.0mmol,1.00当量)和3-氟-5-羟基苯甲腈(0.86g,6.30mmol,0.90当量)在DMF(20.0mL)中的搅拌溶液中添加Cs2CO3(2.28g,7.00mmol,1.00当量)。在室温下搅拌16h后,将反应混合物在0℃下用水淬灭,然后用EtOAc萃取。将有机层用水和盐水洗涤,经无水Na2SO4干燥。过滤后,将滤液浓缩,并通过硅胶柱色谱法纯化,用EtOAc/PE(0-40%)洗脱,以得到呈白色固体的标题化合物(1.95g,73.0%)。MS(ES,m/z):[M-1]-=380.1。
步骤6:(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-2,2-d2)氧基)苯甲腈
在室温下,向(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈(3.0g,7.87mmol,1.00当量)在THF(60mL)中的搅拌混合物中逐滴添加NaOD(645mg,15.737mmol,2.00当量)在D2O(24mL)中的溶液。将所得混合物在室温下搅拌4h,然后用D2O稀释并用MTBE萃取。将合并的有机层经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,并且将残余物通过硅胶柱色谱法纯化,用PE/EA(3∶1)洗脱,以得到呈白色固体的标题化合物(2.3g,76.3%)。MS(ES,m/z):[M-H]-=382.1。
步骤7:3-氟-5-(((1R,2aR)-3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈
在5℃下,向(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-2,2-d2)氧基)苯甲腈(1.5g,3.883mmol,1.00当量)在CD3OD(15mL)中的搅拌混合物中添加NaBD4(329mg,7.827mmol,2.00当量)。将所得混合物在室温下搅拌2h,然后在室温下用D2O淬灭。将所得混合物用MTBE萃取,并且将合并的有机层经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩,并且将残余物通过硅胶柱色谱法纯化,用PE/EA(3:1)洗脱,以得到呈浅黄色固体的标题化合物(1.5g,99.2%)。MS(ES,m/z):[M-H]-=385.1。
步骤8:3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈
在室温下,在氮气氛下,向3-氟-5-(((1R,2aR)-3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈(1.5g,3.88mmol,1.00当量)在THF(21mL)中的搅拌混合物中逐滴添加在THF(2mL)中的DBU(1.18g,7.77mmol,2.00当量)和吡啶-2-磺酰氟(814mg,5.05mmol,1.30当量)。将所得混合物在室温下在氮气氛下搅拌16h,然后在减压下浓缩。将残余物通过硅胶柱色谱法用PE/EA(4∶1)纯化。将所得产物通过手性制备型HPLC进一步纯化,以得到呈白色固体的光学纯的标题化合物(740mg,49.1%)。MS(ES,m/z):[M-H]-=387.1。
实例19
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3的合成
步骤1:3-溴-5-氟苯-2,4,6-d3-醇
在室温下在D2O下,向40mL密封管中添加3-溴-5-氟苯酚(5.00g,26.18mmol,1.00当量)和60%D2SO4(13.09g,78.53mmol,3.00当量)。将所得混合物在75℃下搅拌18h,然后缓慢倒入冰中。将所得混合物用EtOAc萃取,并且将合并的有机层用水、盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩以给出产物。在D2O下,将产物添加进60%D2SO4中,并且再将上述程序重复4次,以给出呈黄色油状物的标题化合物(4.20g,82.7%产率)。MS(ES,m/z):[M-H]-=191.9。
步骤2:3-氟-5-羟基苯甲腈-2,4,6-d3
在室温下,在氮气氛下,向3-溴-5-氟苯-2,4,6-d3-醇(100mg,0.515mmol,1.00当量)和Zn(CN)2(121mg,1.03mmol,2.0当量)在DMF(2.0mL)中的搅拌溶液中添加Pd(PPh3)4(60mg,0.05mmol,0.10当量)。将所得混合物在100℃下在氮气氛下搅拌3h,然后在室温下用水淬灭。将所得混合物用EtOAc萃取,并且将合并的有机层用水、盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用PE/EtOAc(1∶1)洗脱,以得到呈白色固体的标题化合物(37mg,51.2%)。MS(ES,m/z):[M-H]-=139.0。
步骤3:(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈-2,4,6-d3
在室温下,向(R)-3,3,4,4,7-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-1-酮(179mg,0.68mmol,1.00当量)和3-氟-5-羟基苯甲腈-2,4,6-d3(95mg,0.68mmol,1.00当量)在DMF(3.5mL)中的搅拌混合物中添加Cs2CO3(221mg,0.68mmol,1.00当量)。在室温下搅拌16h后,将反应混合物在0℃下用水淬灭。将所得混合物用EtOAc萃取,并且将合并的有机层用H2O、盐水洗涤并经无水Na2SO4干燥。过滤后,将滤液在减压下浓缩。将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(0-40%)洗脱,以得到呈白色固体的标题化合物(170mg,65.3%)。MS(ES,m/z):[M-H]-=383.0。
步骤4:3-氟-5-(((1R,2aR)-3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3
在室温下,向(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈-2,4,6-d3(170mg,0.442mmol,1.00当量)在CD3OD(3.5mL)中的搅拌混合物中分批添加NaBD4(37mg,0.885mmol,2.00当量)。将所得混合物在室温下搅拌3h,用D2O(3.0mL)稀释并用EtOAc萃取。将合并的有机层经无水Na2SO4干燥并过滤。将滤液浓缩,并且将残余物通过硅胶柱色谱法纯化,用EtOAc/PE(0-40%)洗脱,以得到呈白色固体的标题化合物(120mg,70.0%)。MS(ES,m/z):[2M-H]-=773.1。
步骤5:3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3
在室温下,在氮气氛下,向3-氟-5-(((1R,2aR)-3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3(125mg,0.32mmol,1.00当量)在THF(1.6mL)中的搅拌混合物中逐滴添加在THF(0.4mL)中的DBU(98mg,0.65mmol,2.00当量)和吡啶-2-磺酰氟(68mg,0.42mmol,1.30当量)。在室温下,在氮气氛下,将所得混合物搅拌16h。将反应溶液通过硅胶柱色谱法纯化,用PE/EtOAc(4∶1)洗脱,随后用制备型HPLC纯化,以得到呈白色固体的标题化合物(10mg,8.0%)。MS(ES,m/z):[M-H]-=388.1。
实例20
(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈[23a]和(S)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈[23b]的合成
在室温下,向(R)-3,3,4,4,7-五氟-1-亚甲基-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇(400mg,1.53mmol,1.0当量,约80%ee)和3-氟-5-羟基苯甲腈(209mg,1.53mmol,1.0当量)在DMF(10mL)中的搅拌混合物中添加Cs2CO3(497mg,1.53mmol,1.0当量),并且将所得混合物在100℃下搅拌24h。反应混合物冷却至室温后,将其过滤。将滤液通过制备型HPLC纯化,以得到131mg的呈对映异构体的混合物的产物。将对映异构体通过手性制备型HPLC[柱:CHIRALPAK OD-3,50*4.6mm,3um OD30CC-QE001,流速:1.0mL/min;烘箱温度:25℃;流动相A:正己烷;流动相B:乙醇;相B的浓度:10%)分离,以得到23a(65mg,11.2%)MS(ES,m/z):[M-H]-=378.0.tR:1.34min和23b(6mg,1.0%);MS(ES,m/z):[M-H]-=378.0.tR:1.77min。
实例21
3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈[24a]和3-氟-5-(((1R,2R,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈[24b]的合成
步骤1:(R)-3-((4-(丁基亚氨基)-1,1,2,2-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈
在100℃下,在N2气氛下,将(R)-3-氟-5-((1,1,2,2-四氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈(700mg,1.84mmol,1.0当量,约80%ee)、TFA(42mg,0.37mmol,0.2当量)和丁胺(1343mg,18.36mmol,10.0当量)在甲苯(15mL)中的溶液搅拌16h。将所得混合物在真空下浓缩,以得到呈浅棕色油状物的标题化合物(1.0g,粗品),将其直接用于下一步骤。MS(ES,m/z):[M+1]+=437.2。
步骤2:3-氟-5-(((2aS,3S)-1,1,2,2,3-五氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈和3-氟-5-(((2aS,3R)-1,1,2,2,3-五氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈
在60℃下,在N2气氛下,将(R)-3-((4-(丁基亚氨基)-1,1,2,2-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈(1.0g粗品,1.84mmol,1.0当量)、硫酸钠(651mg,4.58mmol,2.5当量)和Selectfluor(1.05g,2.96mmol,1.6当量)在MeCN(15mL)中的混合物搅拌4h。将粗产物通过制备型HPLC纯化,以得到150mg的3-氟-5-(((2aS,3S)-1,1,2,2,3-五氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈和300mg的3-氟-5-(((2aS,3R)-1,1,2,2,3-五氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈。MS(ES,m/z):[M-1]-=397.9。
步骤3:3-氟-5-(((2aS,3R,4S)-1,1,2,2,3-五氟-2a,4-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈
在0℃下,在N2气氛下,向3-氟-5-(((2aS,3S)-1,1,2,2,3-五氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈(100mg,0.25mmol,1.0当量)在MeOH(2mL)中的搅拌溶液中分批添加NaBH4(19mg,0.50mmol,2.0当量)。将所得混合物在室温下在N2气氛下搅拌1h,然后在室温下用饱和NH4Cl溶液(2mL)淬灭。将所得混合物用EtOAc萃取。将合并的有机层用盐水(2x2mL)洗涤,经无水Na2SO4干燥,并浓缩以得到标题化合物(90mg,90%)。MS(ES,m/z):[2M-1]-=801.2
步骤4:3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈[24a]
在-40℃下,在N2气氛下,向3-氟-5-(((2aS,3R,4S)-1,1,2,2,3-五氟-2a,4-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈(70mg,0.17mmol,1.0当量)在DCM(2mL)中的搅拌溶液中逐滴添加DAST(42mg,0.26mmol,1.5当量),并且将所得混合物在-40℃下在N2气氛下搅拌2h。将反应在室温下用饱和NH4Cl溶液(2mL)淬灭,并且将所得混合物用DCM萃取。将合并的有机层经无水Na2SO4干燥并浓缩。将残余物通过制备型HPLC纯化,以得到呈浅黄色固体的标题化合物(10mg,14%)。MS(ES,m/z):[M-1]-=402.0
步骤5:3-氟-5-(((2aS,3S,4S)-1,1,2,2,3-五氟-2a,4-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈
在0℃下,在N2气氛下,向3-氟-5-(((2aS,3R)-1,1,2,2,3-五氟-2a-羟基-4-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈(250mg粗品,0.63mmol,1.0当量)在MeOH(3mL)中的搅拌溶液中分批添加NaBH4(47mg,1.25mmol,2.0当量)。在室温下,在N2气氛下,将所得混合物搅拌1.0小时。将反应在室温下用饱和NH4Cl溶液(2mL)淬灭。将所得混合物用EtOAc萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并浓缩。将残余物通过制备型HPLC纯化以得到标题化合物(90mg)。MS(ES,m/z):[M-1]-=400.0
步骤6:3-氟-5-(((1R,2R,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈[24b]
在-40℃下,在N2气氛下,向3-氟-5-(((2aS,3S,4S)-1,1,2,2,3-五氟-2a,4-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈(70mg,0.17mmol,1.00当量)在DCM(2mL)中的搅拌溶液中逐滴添加DAST(42mg,0.26mmol,1.5当量)。在-40℃下,在N2气氛下,将所得混合物搅拌2h。将反应在室温下用饱和NH4Cl溶液(2mL)淬灭。将所得混合物用DCM萃取。将合并的有机层经无水Na2SO4干燥并浓缩。将残余物通过制备型HPLC纯化以给出标题化合物。MS(ES,m/z):[M-1]-=402.1
生物学实例
实例1
VEGF ELISA测定法
通过测定786-O细胞中的VEGF表达来测量所披露的化合物抑制HIF-2α的能力。将约7500个786-O细胞接种到含有200ul生长培养基的96孔白色透明底板(07-200-566,飞世尔科技公司(Fisher Scientific))的每个孔中。四小时后,通过Tecan D300e数字分配器将化合物分配到孔中,起始浓度为10uM并且将1/2对数稀释至1nM作为最终浓度。每个浓度的处理一式两份进行。约20小时后,除去培养基并添加新鲜培养基,随后如上所述处理化合物。24小时后,收集细胞培养基以按照制造商的说明使用ELISA试剂盒(R&D系统公司(R&Dsystems),目录号DVE00)测定VEGF浓度。
通过GraphPad Prism使用剂量-应答-抑制(四参数)方程式计算EC50。然后对含有细胞的板进行CellTiter-Glo发光细胞存活力测定(普洛麦格公司(Promega)),以确定上述处理后这些化合物对细胞数量的影响。
实例2
用于抑制HIF-2α二聚化的共免疫沉淀测定
细胞培养和化合物处理
将原代肺动脉平滑肌细胞(PASMC,ATCC#PCS-100-023)在补充有血管平滑肌细胞生长试剂盒(ATCC#PCS-100-042)的血管细胞基础培养基(ATCC#PCS-100-030)中培养。将原代肺动脉内皮细胞(HPAEC,ATCC#PCS-100-022)在补充有内皮细胞生长试剂盒-BBE(ATCC#PCS-100-040)的血管细胞基础培养基(ATCC#PCS-100-030)中培养。将0.5×106个细胞接种到含有2mL培养基的6孔细胞培养板(康宁公司(Coming)#3736)中,并且在37℃细胞培养箱中在大气水平的氧气和5%CO2下培养过夜。第二天,将细胞在常氧条件(大气水平的氧气和5%CO2)或低氧条件(1%O2和5%CO2)下培养,并用二甲亚砜(DMSO)或0.001、0.01、0.1和1μM的化合物24a处理24h。
HIF和ARNT的共免疫沉淀分析
处理后,将细胞用冰冷的PBS(含有如处理步骤中的化合物)洗涤。将PBS洗涤液完全除去,并且将1mL冰冷的含有蛋白酶抑制剂和磷酸酶抑制剂(#A32959,赛默科技公司(Thermo Scientific))的裂解缓冲液(#9803,细胞信号传导技术公司(Cell SignalingTech))添加至每个孔中。然后将细胞从孔上刮下,并转移到Eppendorf管中。将样品在冰上孵育10分钟,然后在4℃下以13,500rpm(Eppendorf#5417R)离心15分钟。将上清液(细胞裂解物)转移到新管中,并且通过BCA蛋白测定法测量蛋白质浓度。然后通过添加裂解缓冲液,将裂解物调节至相同浓度。对于共免疫沉淀,将40μL的抗人ARNT-蛋白A/G珠浆料(#sc-55526AC,圣克鲁兹生物技术公司(Santa Cruz Biotech))添加至1mL上清液中,随后在室温下旋转3hhr。将管以8,000g旋转5分钟,并除去上清液。然后将珠用冷的裂解缓冲液洗涤3次(在洗涤之间以8,000g旋转5分钟)。最后一次洗涤后,尽可能多地除去上清液。将30μL的上样缓冲液添加至洗涤珠中,然后将其在98℃下加热5分钟。将样品短暂旋转以收集管底部的所有液体。对上清液进行免疫印迹分析。
还通过免疫印迹(蛋白质印迹分析)分析细胞裂解物。对于每次免疫印迹,将等量的蛋白质样品上样到SDS-PAGE凝胶上,并在电泳后,将其转移到硝酸纤维素膜上。在室温下,将膜在25mL的封闭缓冲液(含有0.1%吐温-20和5%脱脂乳的tris缓冲盐水(TBS))中孵育1小时。然后将封闭的膜与一抗(1∶1000稀释,HIF-2α(D9E3兔mAb,#7098,细胞信号传导技术公司)、HIF1β/ARNT(D28F3兔mAb,#5537,细胞信号传导技术公司)和β-微管蛋白(D2N5G兔mAb,#15115,细胞信号传导技术公司))一起在10mL一抗稀释缓冲液(5%脱脂乳在1X TBST中)中伴随温和搅拌孵育过夜。与一抗一起孵育后,对膜进行三次5分钟的洗涤。每次洗涤使用15mL的1×TBST。然后将洗涤的膜与HRP连接的二抗(1∶2000稀释)一起在10mL二抗稀释缓冲液(5%脱脂乳在1X TBST中)中孵育1小时。与二抗一起孵育后,对膜进行三次5分钟的洗涤,每次洗涤使用15mL的1×TBST。在室温下,将洗涤的膜与2mL的SuperSignalWest Femto最高灵敏度底物(#PI34095,赛默科技公司)一起伴随温和搅拌孵育1分钟。将过量的显色底物排出,然后将膜用伯乐(Bio-Rad)ChemiDocMP成像系统成像。
HIF-2α和ARNT二聚化的破坏
如图1所示,在PASMC和HPAEC两者中,在常氧培养条件下,HIF-2α表达非常低,而在低氧培养条件下,其表达显著增强。化合物24a破坏HIF-2α/ARNT二聚化,并且与ARNT共沉淀的HIF-2α蛋白在用化合物24a处理的细胞的裂解物中以剂量依赖性方式减少。在低氧条件下,0.01μM的化合物24a能有效破坏PASMC/HPAEC中的HIF-2α/ARNT二聚化。
实例3
化合物5与尼拉帕尼在786-O ccRCC异种移植物肿瘤模型中的组合研究
将100μL PBS和基质胶(体积比为1∶1)中的786-O ccRCC细胞(5x106)皮下接种于处于6-8周龄的每只裸鼠(BALB/C)的右腹侧,进行肿瘤发育。当异种移植物肿瘤大小达到约100-150mm3时,将携带肿瘤的小鼠随机分为四组(n=8),并且开始用媒介物(BID)、化合物5(1mg/kg,BID)、尼拉帕尼(45mg/kg,QD)或化合物5(1mg/kg,BID)与尼拉帕尼(45mg/kg,QD)组合进行处理。在为期四周的研究期间,两周一次用卡尺在两个维度上测量肿瘤大小,并且使用公式V=0.5×A×B2计算体积(A和B分别为肿瘤的长径和短径)。同时两周一次测量这些小鼠的体重。将处理对肿瘤生长的影响作图,并显示为平均值和平均值标准误差(SEM)。
Claims (48)
3.如权利要求1或2所述的化合物,或其药学上可接受的盐,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、烷氧基、羟基、卤代、卤代烷基、卤代烷氧基、和氰基。
4.如权利要求1或2所述的化合物,或其药学上可接受的盐,是其中Ra、Rb、和Rc独立地选自氢、氘、甲基、甲氧基、羟基、氯、氟、氰基、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基,并且Rg和Rh独立地是氢或氘。
5.如权利要求1或2所述的化合物,或其药学上可接受的盐,其中R8是3-氯-5-氟苯基、3,5-二氟苯基、3-氟-5-甲氧基苯基、3-氰基-5-氟苯基、3-氯-5-氰基苯基、3-氰基-5-甲基苯基、3-氯-4-氟苯基、3-氯-5-氟苯基、3-氟-5-甲基、3-氰基苯基、3-三氟甲基苯基、3,4-二氯苯基、3-氯-2-甲基苯基、3,5-二氯苯基、3,5-二甲基苯基、2-氯-6-甲基苯基、2,6-二氟苯基、3,4,5-三氟苯基、3,4-二氟苯基、4-氟-3-甲基苯基、3-氰基-4-氟苯基、3-氰基-5-二氟甲基苯基、或3-氰基-5-氟-2,4,6-三氘苯基。
6.如权利要求1或2所述的化合物,或其药学上可接受的盐,其中R8是3-氰基-5-氟苯基或3-氰基-5-氟-2,4,6-三氘苯基。
7.如权利要求2所述的化合物,其中该化合物选自:
3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;和
3-氟-5-(((1R,2R,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
8.如权利要求7所述的化合物,其中该化合物是3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
9.如权利要求8所述的化合物,其中该化合物是3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈。
10.一种药物组合物,其包含如权利要求1至9中任一项所述的化合物或其药学上可接受的盐;以及药学上可接受的赋形剂。
11.如权利要求10所述的药物组合物,其中该化合物是3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈。
12.一种抑制HIF-2α的方法,该方法包括使HIF-2α与如权利要求1至9中任一项所述的化合物或其药学上可接受的盐接触。
13.一种治疗患者的癌症、炎症性疾病、肝脏疾病、铁超负荷、或肺部疾病的方法,该方法包括以药物组合物向有需要的患者施用治疗有效量的如权利要求1至9中任一项所述的化合物或其药学上可接受的盐,该药物组合物包含所述化合物或其药学上可接受的盐、以及药学上可接受的赋形剂。
14.如权利要求13所述的方法,其中该疾病是癌症,并且将如权利要求1至9所述的化合物或其药学上可接受的盐任选地与至少一种其他抗癌剂组合施用。
15.如权利要求13或14所述的方法,其中该疾病是选自以下的癌症:肾脏癌、乳腺癌、宫颈癌、结直肠癌、胶质母细胞瘤、神经胶质瘤、头颈癌、肝癌、非小细胞肺癌、黑素瘤、神经母细胞瘤、卵巢癌、和前列腺癌。
16.如权利要求13所述的方法,其中该疾病是肺动脉高压。
17.一种治疗患者的癌症的方法,该方法包括向该患者施用具有式(I)的HIF-2α抑制剂:
其中:
X1是CH或N;
R1是羟基、卤代、氨基、-OP(O)(OH)2、-OCH2OP(O)(OH)2、-OCOR10、-OCOOR11、
-OCONR12R13、-OCHR14OCOR15或-OCHR14OCOOR15a,其中R10、R11、和R15以及R15a独立地是烷基或被氨基、羧基或羟基取代的烷基,R12和R13独立地是氢,烷基,或被氨基、羧基或羟基取代的烷基,或R12和R13与它们所附接的氮原子一起形成任选地取代的杂环基,并且每个R14是氢、烷基、或卤代烷基;
R2是氢、氘、烷基、卤代、卤代烷基、烯基、或炔基;
R2a是氢、卤代、或氘;
R3和R4独立地是氢、氘、烷基、环烷基、卤代、卤代烷基、羟基烷基、或烷氧基烷基;或
R3和R4与它们所附接的碳一起形成氧代、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;
R5是氢、氘、烷基、卤代、卤代烷基、羟基、或烷氧基;
R6是氢、氘、烷基、环烷基、或卤代;或
R5和R6与它们所附接的碳一起形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元任选地取代的杂亚环基;条件是R5和R6以及R3和R4与它们所附接的碳一起不同时形成氧代、环亚烷基或任选地取代的4元至6元杂亚环基;
R7是氢、氘、烷基、烷氧基、氰基、卤代、卤代烷基、或卤代烷氧基;
L是键、S、SO、SO2、O、CO、或NR16,其中R16是氢或烷基;
R8是烷基、卤代烷基、羟基烷基、烷氧基烷基、氨基烷基、环烷基、环烯基、二环环烷基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,或杂环基,本身或作为杂环基烷基的一部分,被Ra、Rb、Rc、Rg和Rh取代,其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代;并且
R9是氢、烷基、环烷基、羟基、烷氧基、氰基、卤代、卤代烷基、卤代烷氧基、烷基亚砜、烷基磺酰基、或杂芳基,其中该杂芳基任选地被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、和氰基的Rd、Re、和Rf取代;或
当R9和R2附接至同一碳原子时,它们可以组合形成氧代、烷基二烯基、3元至6元环亚烷基、或4元至6元杂亚环基;
R9a是氢、卤代、或氘;或
其药学上可接受的盐;
与PARP抑制剂或其药学上可接受的盐组合。
18.如权利要求17所述的方法,其中该具有式(I)的化合物或其药学上可接受的盐是其中R1是羟基。
19.如权利要求17所述的方法,其中该具有式(I)的化合物或其药学上可接受的盐是其中R1是氨基。
20.如权利要求17至19中任一项所述的方法,其中该具有式(I)的化合物或其药学上可接受的盐是其中R6是卤代。
21.如权利要求17至20中任一项所述的方法,其中该具有式(I)的化合物或其药学上可接受的盐是其中R5是卤代。
22.如权利要求17至21中任一项所述的方法,其中该具有式(I)的化合物或其药学上可接受的盐是其中X1是CR7。
25.如权利要求17至24中任一项所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R3是氟。
26.如权利要求17至24中任一项所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R3和R4是氟。
27.如权利要求17至26中任一项所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中L是O、S、SO、SO2、或NH。
28.如权利要求27所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中L是O。
29.如权利要求17至28中任一项所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R8是环烷基、环烯基、二环环烷基、氧代环烯基、环烷基烷基、芳基、芳烷基、杂环基、螺环烷基、螺杂环基、杂环基烷基、杂芳基、或杂芳烷基,其中芳基或杂芳基,各自本身或作为芳烷基或杂芳烷基的一部分,或杂环基,本身或作为杂环基烷基的一部分,被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、烯基、炔基、烷叉基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基的Ra、Rb、和Rc取代。
30.如权利要求17至28中任一项所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R8是被Ra、Rb、Rc、Rg和Rh取代的苯基,并且其中Ra、Rb、和Rc独立地选自氢、氘、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基,并且Rg和Rh独立地选自氢、氘、和卤代。
31.如权利要求30所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R8是3-氯-5-氟苯基、3,5-二氟苯基、3-氟-5-甲氧基苯基、3-氰基-5-氟苯基、3-氯-5-氰基苯基、3-氰基-5-甲基苯基、3-氯-4-氟苯基、3-氯-5-氟苯基、3-氟-5-甲基苯基、3-氰基苯基、3-三氟甲基苯基、3,4-二氯苯基、3-氯-2-甲基苯基、3,5-二氯苯基、3,5-二甲基苯基、2-氯-6-甲基苯基、2,6-二氟苯基、3,4,5-三氟苯基、3,4-二氟苯基、4-氟-3-甲基苯基、3-氰基-4-氟苯基、3-氰基-5-二氟甲基苯基、或3-氰基-5-氟-2,4,6-三氘苯基。
32.如权利要求29所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R8是被独立地选自氢、烷基、卤代烷基、卤代烷氧基、烷氧基、羟基、卤代、氰基、羟基烷基、烷氧基烷基、氨基烷基、任选地取代的芳基、任选地取代的杂芳基、和任选地取代的杂环基的Ra、Rb、和Rc取代的杂芳基。
33.如权利要求29所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R8是吡啶-3-基、吡啶-2-基、哒嗪-3-基、哒嗪-4-基、嘧啶-5-基、嘧啶-2-基、噻吩-2-基、呋喃-2-基、噻唑-5-基、噁唑-5-基、咪唑-5-基、呋喃-3-基、噻吩-3-基、噻唑-4-基、吡啶-4-基、噁唑-2-基、咪唑-2-基、吡啶-2-基、吡嗪-2-基、或噻唑-2-基,并且前述环中的每一个被Ra、Rb、和Rc取代,其中Ra和Rb独立地选自氢、甲基、甲氧基、羟基、氯、氟、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基,并且Rc选自氢、甲基、氰基、氯、氟、二氟甲基、三氟甲基、二氟甲氧基、和三氟甲氧基。
34.如权利要求17至33中任一项所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R7是氢、甲基、乙基、甲氧基、氟、三氟甲基、或三氟甲氧基。
35.如权利要求17至34中任一项所述的方法,其中该具有式(I)、(IIa1)、(IIb1)、(IIa1’)或(IIb1’)的化合物或其药学上可接受的盐是其中R2是氢、氘、氟、甲基、或乙基,并且R9是氢、烷基、卤代、羟基、或烷氧基,并且R2和R9附接至环碳原子,该环碳原子位于附接至R1的环碳的间位。
37.如权利要求36所述的方法,其中该具有式(VIIIa)或(VIIIb)的化合物或其药学上可接受的盐是其中R2是氢或氘,R9是氢、氟、或甲基,并且R2a和R9a独立地是氢、氘或氟。
38.如权利要求17所述的方法,其中该具有式(I)的化合物选自:
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aS)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
1,3,3,4,4-五氟-7-((5-氟吡啶-3-基)氧基)-1,2,3,4-四氢-2aH-环戊[cd]茚-2a-醇;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢螺[环戊[cd]-茚-1,1’-环丙烷]-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-1,2a-二羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-1-甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-((3,3,4,4-四氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-((2a-氨基-1,3,3,4,4-五氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-5-氟苯甲腈;
3-氟-5-((1,1,2a,3,3,4,4-七氟-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-((3,3-二氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-((3,3-二氟-2a-羟基-1-氧代-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-((3,3-二氟-1,2a-二羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)-5-氟苯甲腈;
3-氟-5-((1,3,3-三氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-5-基)氧基)苯甲腈;
3-氟-5-((1,2,2,3,3,4,4-七氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚一7一基)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1,2,2-d3)氧基)苯甲腈;
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基-1-d)氧基)苯甲腈-2,4,6-d3;
(R)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
(S)-3-氟-5-((3,3,4,4-四氟-2a-羟基-1-亚甲基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;
3-氟-5-(((1R,2S,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;以及
3-氟-5-(((1R,2R,2aS)-1,2,3,3,4,4-六氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
39.如权利要求17所述的方法,其中该具有式(I)的化合物选自:
3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊-[cd]茚-7-基)氧基)苯甲腈;和
3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)苯甲腈;或
其药学上可接受的盐。
40.如权利要求17所述的方法,其中该具有式(I)的化合物是3-氟-5-(((1S,2aR)-1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
41.如权利要求17所述的方法,其中该具有式(I)的化合物是3-氟-5-((1,3,3,4,4-五氟-2a-羟基-2,2a,3,4-四氢-1H-环戊[cd]茚-7-基)氧基)-苯甲腈。
42.如权利要求17至41中任一项所述的方法,其中该PARP抑制剂是奥拉帕尼(4-[(3-[(4-环丙基羰基)哌嗪-1-基]羰基)-4-氟苯基]甲基(2H)酞嗪-1-酮)、卢卡帕尼(8-氟-2-{[(4-甲基氨基)-甲基]苯基}-1,3,4,5-四氢-6H-氮杂[5,4,3-cd]吲哚-6-酮)、尼拉帕尼(2-[4-[(3S)-3-哌啶基]苯基]吲唑-7-甲酰胺)、他拉唑帕尼((8S,9R)-5-氟-8-(4-氟苯基)-9-(1-甲基-1H-1,2,4-三唑-5-基)-2,7,8,9-四氢-3H-吡啶并[4,3,2-de]酞嗪-3-酮)、或帕米帕利((2R)-14-氟-2-甲基-6,9,10,19-四氮杂五环[14.2.1.02,6.08,18.012,17]十九-1(18),8,12(17),13,15-五烯-11-酮;三水合物)。
43.如权利要求17至42中任一项所述的方法,其中该癌症选自肾脏癌、胶质母细胞瘤、神经母细胞瘤、副神经节瘤、嗜铬细胞瘤、生长抑素瘤、成血管细胞瘤、胃肠道间质瘤、垂体瘤、平滑肌瘤、平滑肌肉瘤、红细胞增多症、视网膜癌、肺癌、胰腺癌、肝癌、卵巢癌、乳腺癌、前列腺癌、结直肠癌、头颈癌、宫颈癌、子宫内膜癌、膀胱癌、胃癌、食管癌、淋巴瘤、黑素瘤、间皮瘤、肉瘤和神经内分泌瘤。
44.如权利要求43所述的方法,其中该癌症是透明细胞肾脏癌。
45.如权利要求17至42中任一项所述的方法,其中该癌症选自卵巢癌、乳腺癌、前列腺癌、肾脏癌、结直肠癌、葡萄膜黑素瘤、胰腺癌、尿路上皮癌、子宫内膜癌、肺癌、淋巴瘤、头颈癌、输卵管癌、原发性腹膜癌、宫颈癌、黑素瘤、食管癌、胃癌、间皮瘤、胆管癌、胶质母细胞瘤、尤因肉瘤、子宫平滑肌肉瘤、慢性淋巴细胞白血病、T细胞幼淋巴细胞白血病、多发性骨髓瘤、急性髓性白血病、慢性髓细胞性白血病、生殖细胞癌、膀胱癌、神经内分泌瘤、骨肉瘤、胆道癌、软组织肉瘤、横纹肌肉瘤、套细胞淋巴瘤、和内分泌腺赘生物。
46.如权利要求17至45中任一项所述的方法,其中将具有式(I)的化合物和PARP抑制剂任选地彼此间隔1至30分钟依次施用、或同时施用。
47.如权利要求17至46中任一项所述的方法,其中该组合是协同组合。
48.如权利要求17至47中任一项所述的方法,其中该方法进一步包括施用一种或多种另外的抗癌剂。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/851018 | 2020-04-16 | ||
US16/851,018 US20200361855A1 (en) | 2019-04-18 | 2020-04-16 | Tetrahydro-1h-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors |
US202063093734P | 2020-10-19 | 2020-10-19 | |
US63/093734 | 2020-10-19 | ||
PCT/US2021/027811 WO2021212062A1 (en) | 2020-04-16 | 2021-04-16 | Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115485262A true CN115485262A (zh) | 2022-12-16 |
Family
ID=78085182
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180028716.0A Pending CN115485262A (zh) | 2020-04-16 | 2021-04-16 | 低氧诱导因子-2(α)抑制剂及其在疾病治疗中的用途 |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP4136069A1 (zh) |
CN (1) | CN115485262A (zh) |
AU (1) | AU2021256998A1 (zh) |
CA (1) | CA3179508A1 (zh) |
TW (1) | TW202204314A (zh) |
WO (1) | WO2021212062A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114315552A (zh) * | 2020-09-30 | 2022-04-12 | 江西济民可信集团有限公司 | 三并环类化合物及其制备方法和应用 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2022529166A (ja) | 2019-04-18 | 2022-06-17 | ニカン セラピューティクス,インコーポレイテッド | 低酸素誘導因子2(アルファ)阻害剤としてのテトラヒドロ-1H-シクロペンタ[cd]インデン誘導体 |
WO2022082337A1 (en) | 2020-10-19 | 2022-04-28 | Nikang Therapeutics, Inc. | Process of preparing 3-fluoro-5 ( ( (1r, 2ar) -3, 3, 4, 4-tetrafluoro-1, 2a-dihydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) benzonitrile |
WO2022082329A1 (en) * | 2020-10-19 | 2022-04-28 | Nikang Therapeutics, Inc. | Processes of preparing 3-fluoro-5- ( ( (1s, 2ar) -1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) -benzonitrile |
WO2022086882A1 (en) * | 2020-10-21 | 2022-04-28 | Nikang Therapeutics, Inc. | Diagnostic and therapeutic methods for treatment of cancer with a hif-2(alpha) inhibitor |
WO2023070483A1 (en) * | 2021-10-29 | 2023-05-04 | Nikang Therapeutics, Inc. | PROCESSES OF MAKING 3-FLUORO-5- ( ( (1R, 2S, 2aS) -1, 2, 3, 3, 4, 4-HEXAFLUORO-2A-HYDROXY-2, 2A, 3, 4-TETRAHYDRO-1H-CYCLOPENTA [CD] INDEN-7-YL) -OXY) -BENZONITRILE AND POLYMORPHS THEREOF |
EP4230682A1 (de) | 2022-02-18 | 2023-08-23 | Salamander SPS GmbH & Co. KG | Pflanzenfaser-verbundmaterial |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120316204A1 (en) * | 2011-06-06 | 2012-12-13 | Akebia Therapeutics Inc. | Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer |
WO2016144825A1 (en) * | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Aromatic compounds and uses thereof |
US20160362390A1 (en) * | 2015-06-12 | 2016-12-15 | Peloton Therapeutics, Inc. | Tricyclic inhibitors of hif-2-alpha and uses thereof |
WO2018031680A1 (en) * | 2016-08-10 | 2018-02-15 | Fronthera U.S. Pharmaceuticals Llc | Novel compounds, uses and methods for their preparation |
WO2019191227A1 (en) * | 2018-03-28 | 2019-10-03 | Peloton Therapeutics, Inc. | Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha |
WO2021016280A1 (en) * | 2019-07-22 | 2021-01-28 | Nikang Therapeutics, Inc. | Tricyclic derivatives as hypoxia inducible factor-2(alpha) inhibitors |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016145032A1 (en) | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Compositions for use in treating pulmonary arterial hypertension |
JP2022529166A (ja) * | 2019-04-18 | 2022-06-17 | ニカン セラピューティクス,インコーポレイテッド | 低酸素誘導因子2(アルファ)阻害剤としてのテトラヒドロ-1H-シクロペンタ[cd]インデン誘導体 |
-
2021
- 2021-04-16 AU AU2021256998A patent/AU2021256998A1/en active Pending
- 2021-04-16 EP EP21724110.8A patent/EP4136069A1/en active Pending
- 2021-04-16 CN CN202180028716.0A patent/CN115485262A/zh active Pending
- 2021-04-16 CA CA3179508A patent/CA3179508A1/en active Pending
- 2021-04-16 TW TW110113853A patent/TW202204314A/zh unknown
- 2021-04-16 WO PCT/US2021/027811 patent/WO2021212062A1/en unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120316204A1 (en) * | 2011-06-06 | 2012-12-13 | Akebia Therapeutics Inc. | Compounds and compositions for stabilizing hypoxia inducible factor-2 alpha as a method for treating cancer |
WO2016144825A1 (en) * | 2015-03-11 | 2016-09-15 | Peloton Therapeutics, Inc. | Aromatic compounds and uses thereof |
US20160362390A1 (en) * | 2015-06-12 | 2016-12-15 | Peloton Therapeutics, Inc. | Tricyclic inhibitors of hif-2-alpha and uses thereof |
WO2018031680A1 (en) * | 2016-08-10 | 2018-02-15 | Fronthera U.S. Pharmaceuticals Llc | Novel compounds, uses and methods for their preparation |
WO2019191227A1 (en) * | 2018-03-28 | 2019-10-03 | Peloton Therapeutics, Inc. | Methods of reducing inflammation of the digestive system with inhibitors of hif-2-alpha |
WO2021016280A1 (en) * | 2019-07-22 | 2021-01-28 | Nikang Therapeutics, Inc. | Tricyclic derivatives as hypoxia inducible factor-2(alpha) inhibitors |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114315552A (zh) * | 2020-09-30 | 2022-04-12 | 江西济民可信集团有限公司 | 三并环类化合物及其制备方法和应用 |
Also Published As
Publication number | Publication date |
---|---|
TW202204314A (zh) | 2022-02-01 |
CA3179508A1 (en) | 2021-10-21 |
WO2021212062A1 (en) | 2021-10-21 |
EP4136069A1 (en) | 2023-02-22 |
AU2021256998A1 (en) | 2022-10-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11753366B2 (en) | Tetrahydro-1H-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors | |
CN115485262A (zh) | 低氧诱导因子-2(α)抑制剂及其在疾病治疗中的用途 | |
US20220274914A1 (en) | Tricyclic derivatives as hypoxia inducible factor-2(alpha) inhibitors | |
EP3866927A1 (en) | Indane derivatives as hypoxia inducible factor-2(alpha) inhibitors | |
EP3849541A1 (en) | 2,3-dihydrobenzo[b]thiophene derivatives as hypoxia inducible factor-2(alpha) inhibitors | |
TW202233613A (zh) | 去氧胞苷激酶抑制劑之結晶型及其用途 | |
US11420936B2 (en) | Hypoxia inducible factor-2(alpha) inhibitors and their use in the treatment of diseases | |
WO2023060458A1 (en) | Processes of making 3-fluoro-5- ( ( (1s, 2ar) -1, 3, 3, 4, 4-pentafluoro-2a-hydroxy-2, 2a, 3, 4-tetrahydro-1h-cyclopenta [cd] inden-7-yl) oxy) -benzonitrile and polymorphs thereof | |
US20230115881A1 (en) | PROCESSES OF MAKING 3-FLUORO-5-(((1S,2aR)-1,3,3,4,4-PENTAFLUORO-2a-HYDROXY-2,2a,3,4-TETRAHYDRO-1H-CYCLOPENTA[CD]INDEN-7-YL)OXY)-BENZONITRILE AND POLYMORPHS THEREOF | |
WO2023070483A1 (en) | PROCESSES OF MAKING 3-FLUORO-5- ( ( (1R, 2S, 2aS) -1, 2, 3, 3, 4, 4-HEXAFLUORO-2A-HYDROXY-2, 2A, 3, 4-TETRAHYDRO-1H-CYCLOPENTA [CD] INDEN-7-YL) -OXY) -BENZONITRILE AND POLYMORPHS THEREOF | |
WO2022086882A1 (en) | Diagnostic and therapeutic methods for treatment of cancer with a hif-2(alpha) inhibitor | |
WO2023069372A1 (en) | Hypoxia inducible factor-2(alpha) inhibitors for the treatment of bladder cancer | |
US20210085786A1 (en) | Combination treatment of chemoresistant cancers |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |