CA2650999A1 - Substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases - Google Patents
Substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases Download PDFInfo
- Publication number
- CA2650999A1 CA2650999A1 CA002650999A CA2650999A CA2650999A1 CA 2650999 A1 CA2650999 A1 CA 2650999A1 CA 002650999 A CA002650999 A CA 002650999A CA 2650999 A CA2650999 A CA 2650999A CA 2650999 A1 CA2650999 A1 CA 2650999A1
- Authority
- CA
- Canada
- Prior art keywords
- substituted
- compound
- cancer
- alkyl
- amino
- 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.)
- Abandoned
Links
- 206010028980 Neoplasm Diseases 0.000 title claims abstract description 74
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 38
- 201000011510 cancer Diseases 0.000 title claims description 17
- 201000010099 disease Diseases 0.000 title abstract description 20
- 238000011282 treatment Methods 0.000 title description 34
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 5
- 239000003909 protein kinase inhibitor Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 124
- 238000000034 method Methods 0.000 claims abstract description 29
- 230000005764 inhibitory process Effects 0.000 claims abstract description 26
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 18
- 208000035475 disorder Diseases 0.000 claims abstract description 18
- 108060006633 protein kinase Proteins 0.000 claims abstract description 18
- 208000032839 leukemia Diseases 0.000 claims abstract description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
- 208000024770 Thyroid neoplasm Diseases 0.000 claims abstract description 5
- 201000002510 thyroid cancer Diseases 0.000 claims abstract description 5
- -1 nitro, hydroxyl Chemical group 0.000 claims description 139
- 125000005431 alkyl carboxamide group Chemical group 0.000 claims description 29
- 125000005432 dialkylcarboxamide group Chemical group 0.000 claims description 26
- 108091000080 Phosphotransferase Proteins 0.000 claims description 25
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 claims description 25
- 102000020233 phosphotransferase Human genes 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 125000002252 acyl group Chemical group 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 15
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 14
- 125000004423 acyloxy group Chemical group 0.000 claims description 13
- 125000004001 thioalkyl group Chemical group 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000001188 haloalkyl group Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 10
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 8
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 8
- 125000004421 aryl sulphonamide group Chemical group 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- 229940002612 prodrug Drugs 0.000 claims description 7
- 125000004422 alkyl sulphonamide group Chemical group 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 239000002207 metabolite Substances 0.000 claims description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 108091008598 receptor tyrosine kinases Proteins 0.000 claims description 5
- 102000027426 receptor tyrosine kinases Human genes 0.000 claims description 5
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 206010006187 Breast cancer Diseases 0.000 claims description 3
- 208000026310 Breast neoplasm Diseases 0.000 claims description 3
- 206010060862 Prostate cancer Diseases 0.000 claims description 3
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 3
- UOCJDOLVGGIYIQ-PBFPGSCMSA-N cefatrizine Chemical group S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)[C@H](N)C=2C=CC(O)=CC=2)CC=1CSC=1C=NNN=1 UOCJDOLVGGIYIQ-PBFPGSCMSA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 208000020816 lung neoplasm Diseases 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 206010005003 Bladder cancer Diseases 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 2
- 206010033128 Ovarian cancer Diseases 0.000 claims description 2
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 claims description 2
- 206010038389 Renal cancer Diseases 0.000 claims description 2
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims description 2
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 2
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 201000010536 head and neck cancer Diseases 0.000 claims description 2
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 2
- 201000010982 kidney cancer Diseases 0.000 claims description 2
- 201000001441 melanoma Diseases 0.000 claims description 2
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 2
- 201000005112 urinary bladder cancer Diseases 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 3
- FSPQCTGGIANIJZ-UHFFFAOYSA-N 2-[[(3,4-dimethoxyphenyl)-oxomethyl]amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NC1=C(C(N)=O)C(CCCC2)=C2S1 FSPQCTGGIANIJZ-UHFFFAOYSA-N 0.000 claims 2
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 claims 2
- 206010003571 Astrocytoma Diseases 0.000 claims 1
- 208000023275 Autoimmune disease Diseases 0.000 claims 1
- 208000024172 Cardiovascular disease Diseases 0.000 claims 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 206010016654 Fibrosis Diseases 0.000 claims 1
- 208000032612 Glial tumor Diseases 0.000 claims 1
- 206010018338 Glioma Diseases 0.000 claims 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 claims 1
- 208000007766 Kaposi sarcoma Diseases 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 1
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 claims 1
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 claims 1
- 201000004681 Psoriasis Diseases 0.000 claims 1
- 208000008385 Urogenital Neoplasms Diseases 0.000 claims 1
- 230000033115 angiogenesis Effects 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 claims 1
- 230000004761 fibrosis Effects 0.000 claims 1
- 208000026278 immune system disease Diseases 0.000 claims 1
- 201000005202 lung cancer Diseases 0.000 claims 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 claims 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 claims 1
- 201000008482 osteoarthritis Diseases 0.000 claims 1
- 208000037803 restenosis Diseases 0.000 claims 1
- 206010039073 rheumatoid arthritis Diseases 0.000 claims 1
- 206010041823 squamous cell carcinoma Diseases 0.000 claims 1
- 208000006542 von Hippel-Lindau disease Diseases 0.000 claims 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 abstract description 24
- 230000000694 effects Effects 0.000 abstract description 22
- 230000004663 cell proliferation Effects 0.000 abstract description 9
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical class C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 abstract description 5
- 201000001320 Atherosclerosis Diseases 0.000 abstract description 3
- 208000031852 Gastrointestinal stromal cancer Diseases 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 abstract description 2
- 230000002159 abnormal effect Effects 0.000 abstract description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 230000004054 inflammatory process Effects 0.000 abstract description 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 abstract 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 abstract 1
- 230000001594 aberrant effect Effects 0.000 abstract 1
- 208000037765 diseases and disorders Diseases 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 210000004027 cell Anatomy 0.000 description 48
- 239000000203 mixture Substances 0.000 description 40
- 229940125782 compound 2 Drugs 0.000 description 33
- 229940125898 compound 5 Drugs 0.000 description 30
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 22
- 108010003374 fms-Like Tyrosine Kinase 3 Proteins 0.000 description 21
- 229910001868 water Inorganic materials 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 17
- 239000004480 active ingredient Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000000543 intermediate Substances 0.000 description 14
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 238000001727 in vivo Methods 0.000 description 12
- 230000035772 mutation Effects 0.000 description 12
- 238000011580 nude mouse model Methods 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 239000012267 brine Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical group OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 10
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 9
- 239000003480 eluent Substances 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000000902 placebo Substances 0.000 description 9
- 229940068196 placebo Drugs 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910052786 argon Inorganic materials 0.000 description 8
- 125000000753 cycloalkyl group Chemical group 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 229940043355 kinase inhibitor Drugs 0.000 description 8
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 241000699660 Mus musculus Species 0.000 description 7
- 230000001093 anti-cancer Effects 0.000 description 7
- 238000011717 athymic nude mouse Methods 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 7
- 230000035755 proliferation Effects 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 6
- 230000022534 cell killing Effects 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 230000008878 coupling Effects 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 229940080856 gleevec Drugs 0.000 description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000007920 subcutaneous administration Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- 108091008606 PDGF receptors Proteins 0.000 description 5
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 150000005347 biaryls Chemical group 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 230000003389 potentiating effect Effects 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 150000001502 aryl halides Chemical class 0.000 description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 238000001802 infusion Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 230000003068 static effect Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 4
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 4
- SPQSQDAXIWSWKS-UHFFFAOYSA-N (4-bromo-2-propan-2-yloxyphenoxy)-tert-butyl-dimethylsilane Chemical compound CC(C)OC1=CC(Br)=CC=C1O[Si](C)(C)C(C)(C)C SPQSQDAXIWSWKS-UHFFFAOYSA-N 0.000 description 3
- WYOMQCWDDSHKNE-UHFFFAOYSA-N 4-[5-(1,3-dioxolan-2-yl)pyridin-2-yl]-2-nitro-6-propan-2-yloxyphenol Chemical compound CC(C)Oc1cc(cc(c1O)[N+]([O-])=O)-c1ccc(cn1)C1OCCO1 WYOMQCWDDSHKNE-UHFFFAOYSA-N 0.000 description 3
- FNTADVRAOKUXAT-UHFFFAOYSA-N 5-[5-(diethoxymethyl)pyridin-2-yl]-7-propan-2-yloxy-1,3-benzoxazol-2-amine Chemical compound N1=CC(C(OCC)OCC)=CC=C1C1=CC(OC(C)C)=C(OC(N)=N2)C2=C1 FNTADVRAOKUXAT-UHFFFAOYSA-N 0.000 description 3
- HAHQULAEMZWNLT-UHFFFAOYSA-N 6-(2-amino-7-propan-2-yloxy-1,3-benzoxazol-5-yl)pyridine-3-carbaldehyde Chemical compound C=1C=2N=C(N)OC=2C(OC(C)C)=CC=1C1=CC=C(C=O)C=N1 HAHQULAEMZWNLT-UHFFFAOYSA-N 0.000 description 3
- LBRROPGZZIPADT-UHFFFAOYSA-N 6-(4-hydroxy-3-nitro-5-propan-2-yloxyphenyl)pyridine-3-carbaldehyde Chemical compound CC(C)Oc1cc(cc(c1O)[N+]([O-])=O)-c1ccc(C=O)cn1 LBRROPGZZIPADT-UHFFFAOYSA-N 0.000 description 3
- HPSIGWDAEJELJW-UHFFFAOYSA-N 6-(4-hydroxy-3-propan-2-yloxyphenyl)pyridine-3-carbaldehyde Chemical compound CC(C)Oc1cc(ccc1O)-c1ccc(C=O)cn1 HPSIGWDAEJELJW-UHFFFAOYSA-N 0.000 description 3
- IASJPACKYGNUKC-UHFFFAOYSA-N 6-[4-[tert-butyl(dimethyl)silyl]oxy-3-propan-2-yloxyphenyl]pyridine-3-carbaldehyde Chemical compound C1=C(O[Si](C)(C)C(C)(C)C)C(OC(C)C)=CC(C=2N=CC(C=O)=CC=2)=C1 IASJPACKYGNUKC-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 241000282412 Homo Species 0.000 description 3
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 3
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 3
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- JAAMEIDQDVOEBA-UHFFFAOYSA-N [4-[tert-butyl(dimethyl)silyl]oxy-3-propan-2-yloxyphenyl]boronic acid Chemical compound CC(C)OC1=CC(B(O)O)=CC=C1O[Si](C)(C)C(C)(C)C JAAMEIDQDVOEBA-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 238000001516 cell proliferation assay Methods 0.000 description 3
- 239000013626 chemical specie Substances 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 238000002648 combination therapy Methods 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000000499 gel Substances 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 230000000977 initiatory effect Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 125000002346 iodo group Chemical group I* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 230000026731 phosphorylation Effects 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 229920000728 polyester Polymers 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 210000002307 prostate Anatomy 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000003107 substituted aryl group Chemical group 0.000 description 3
- 239000000375 suspending agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 3
- ITVHNCCEKHVTTP-UHFFFAOYSA-N 2-amino-4-[5-(1,3-dioxolan-2-yl)pyridin-2-yl]-6-propan-2-yloxyphenol Chemical compound CC(C)Oc1cc(cc(N)c1O)-c1ccc(cn1)C1OCCO1 ITVHNCCEKHVTTP-UHFFFAOYSA-N 0.000 description 2
- BXOYQPKNGGAODC-UHFFFAOYSA-N 4-bromo-2-propan-2-yloxyphenol Chemical compound CC(C)OC1=CC(Br)=CC=C1O BXOYQPKNGGAODC-UHFFFAOYSA-N 0.000 description 2
- DXYNOCDYTSTJOU-UHFFFAOYSA-N 6-[2-(ethylamino)-7-propan-2-yloxy-1,3-benzoxazol-5-yl]pyridine-3-carbaldehyde Chemical compound C=1C(OC(C)C)=C2OC(NCC)=NC2=CC=1C1=CC=C(C=O)C=N1 DXYNOCDYTSTJOU-UHFFFAOYSA-N 0.000 description 2
- 241000220479 Acacia Species 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- XYWDPYKBIRQXQS-UHFFFAOYSA-N Diisopropyl sulfide Chemical compound CC(C)SC(C)C XYWDPYKBIRQXQS-UHFFFAOYSA-N 0.000 description 2
- 102000001301 EGF receptor Human genes 0.000 description 2
- 108060006698 EGF receptor Proteins 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 2
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 2
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 2
- 229930182816 L-glutamine Natural products 0.000 description 2
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- 206010061309 Neoplasm progression Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 239000012979 RPMI medium Substances 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 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
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 2
- 108091008605 VEGF receptors Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 150000001491 aromatic compounds Chemical class 0.000 description 2
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000008512 biological response Effects 0.000 description 2
- 230000036765 blood level Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 108010082117 matrigel Proteins 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical class CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical class 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
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000003381 stabilizer 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
- 239000005720 sucrose Substances 0.000 description 2
- 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 2
- 238000002626 targeted therapy Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000000844 transformation Methods 0.000 description 2
- 230000005751 tumor progression Effects 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 238000013414 tumor xenograft model Methods 0.000 description 2
- FIARMZDBEGVMLV-UHFFFAOYSA-N 1,1,2,2,2-pentafluoroethanolate Chemical group [O-]C(F)(F)C(F)(F)F FIARMZDBEGVMLV-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- ZNCUUYCDKVNVJH-UHFFFAOYSA-N 2-isopropoxyphenol Chemical compound CC(C)OC1=CC=CC=C1O ZNCUUYCDKVNVJH-UHFFFAOYSA-N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- RYCSNJCJOVQGBC-UHFFFAOYSA-N 3-(1-cyclopropyl-2h-pyridin-4-yl)-1h-quinolin-2-one Chemical class O=C1NC2=CC=CC=C2C=C1C(C=C1)=CCN1C1CC1 RYCSNJCJOVQGBC-UHFFFAOYSA-N 0.000 description 1
- NHFDRBXTEDBWCZ-ZROIWOOFSA-N 3-[2,4-dimethyl-5-[(z)-(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]propanoic acid Chemical compound OC(=O)CCC1=C(C)NC(\C=C/2C3=CC=CC=C3NC\2=O)=C1C NHFDRBXTEDBWCZ-ZROIWOOFSA-N 0.000 description 1
- MZSAMHOCTRNOIZ-UHFFFAOYSA-N 3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxy-N-phenylaniline Chemical compound NCC1=CC(=NC(=C1)C(F)(F)F)OC=1C=C(NC2=CC=CC=C2)C=CC=1 MZSAMHOCTRNOIZ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- PZQKYDURTHGZLR-UHFFFAOYSA-N 5-[5-(diethoxymethyl)pyridin-2-yl]-n-ethyl-7-propan-2-yloxy-1,3-benzoxazol-2-amine Chemical compound C=1C(OC(C)C)=C2OC(NCC)=NC2=CC=1C1=CC=C(C(OCC)OCC)C=N1 PZQKYDURTHGZLR-UHFFFAOYSA-N 0.000 description 1
- PJFPIFJUQAGUSM-UHFFFAOYSA-N 5-[[6-(2-amino-7-propan-2-yloxy-1,3-benzoxazol-5-yl)pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C=2N=C(N)OC=2C(OC(C)C)=CC=1C(N=C1)=CC=C1C=C1SC(=O)NC1=O PJFPIFJUQAGUSM-UHFFFAOYSA-N 0.000 description 1
- SPCLJXSYSDKCOJ-UHFFFAOYSA-N 5-[[6-[2-(diethylamino)-7-propan-2-yloxy-1,3-benzoxazol-5-yl]pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C(OC(C)C)=C2OC(N(CC)CC)=NC2=CC=1C(N=C1)=CC=C1C=C1SC(=O)NC1=O SPCLJXSYSDKCOJ-UHFFFAOYSA-N 0.000 description 1
- DGMLIPMUSNBQAC-UHFFFAOYSA-N 5-[[6-[2-(ethylamino)-7-propan-2-yloxy-1,3-benzothiazol-5-yl]pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C(OC(C)C)=C2SC(NCC)=NC2=CC=1C(N=C1)=CC=C1C=C1SC(=O)NC1=O DGMLIPMUSNBQAC-UHFFFAOYSA-N 0.000 description 1
- VZTTZCCCGXWGGQ-UHFFFAOYSA-N 5-[[6-[2-(ethylamino)-7-propan-2-yloxy-1,3-benzoxazol-5-yl]pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C(OC(C)C)=C2OC(NCC)=NC2=CC=1C(N=C1)=CC=C1C=C1SC(=O)NC1=O VZTTZCCCGXWGGQ-UHFFFAOYSA-N 0.000 description 1
- PNCCBXXSAPGQQZ-UHFFFAOYSA-N 5-[[6-[2-(ethylamino)-7-propan-2-yloxy-3h-benzimidazol-5-yl]pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C2NC(NCC)=NC2=C(OC(C)C)C=C1C(N=C1)=CC=C1C=C1SC(=O)NC1=O PNCCBXXSAPGQQZ-UHFFFAOYSA-N 0.000 description 1
- BTVJIZYCTLWBJH-UHFFFAOYSA-N 5-[[6-[2-(propan-2-ylamino)-7-propan-2-yloxy-1,3-benzothiazol-5-yl]pyridin-3-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound C=1C(OC(C)C)=C2SC(NC(C)C)=NC2=CC=1C(N=C1)=CC=C1CC1SC(=O)NC1=O BTVJIZYCTLWBJH-UHFFFAOYSA-N 0.000 description 1
- VVLLQBASNFKGGS-UHFFFAOYSA-N 5-[[6-[2-(propan-2-ylamino)-7-propan-2-yloxy-1,3-benzothiazol-5-yl]pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C(OC(C)C)=C2SC(NC(C)C)=NC2=CC=1C(N=C1)=CC=C1C=C1SC(=O)NC1=O VVLLQBASNFKGGS-UHFFFAOYSA-N 0.000 description 1
- YHHLHIIIYSDGNI-UHFFFAOYSA-N 5-[[6-[2-(propan-2-ylamino)-7-propan-2-yloxy-3h-benzimidazol-5-yl]pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C1=C2NC(NC(C)C)=NC2=C(OC(C)C)C=C1C(N=C1)=CC=C1C=C1SC(=O)NC1=O YHHLHIIIYSDGNI-UHFFFAOYSA-N 0.000 description 1
- GNGHITDKFOJNKR-UHFFFAOYSA-N 5-[[6-[7-propan-2-yloxy-2-(propylamino)-1,3-benzoxazol-5-yl]pyridin-3-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound C=1C(OC(C)C)=C2OC(NCCC)=NC2=CC=1C(N=C1)=CC=C1CC1SC(=O)NC1=O GNGHITDKFOJNKR-UHFFFAOYSA-N 0.000 description 1
- CHGITEHCAISDJK-UHFFFAOYSA-N 5-[[6-[7-propan-2-yloxy-2-(propylamino)-1,3-benzoxazol-5-yl]pyridin-3-yl]methylidene]-1,3-thiazolidine-2,4-dione Chemical compound C=1C(OC(C)C)=C2OC(NCCC)=NC2=CC=1C(N=C1)=CC=C1C=C1SC(=O)NC1=O CHGITEHCAISDJK-UHFFFAOYSA-N 0.000 description 1
- PVUKGNBRJFTFNJ-UHFFFAOYSA-N 6-bromopyridine-3-carbaldehyde Chemical compound BrC1=CC=C(C=O)C=N1 PVUKGNBRJFTFNJ-UHFFFAOYSA-N 0.000 description 1
- 101150095401 AURKA gene Proteins 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 241001249193 Artemisia campestris Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 102000004000 Aurora Kinase A Human genes 0.000 description 1
- 108090000461 Aurora Kinase A Proteins 0.000 description 1
- 208000032800 BCR-ABL1 positive blast phase chronic myelogenous leukemia Diseases 0.000 description 1
- 101150049556 Bcr gene Proteins 0.000 description 1
- OGBVRMYSNSKIEF-UHFFFAOYSA-N Benzylphosphonic acid Chemical class OP(O)(=O)CC1=CC=CC=C1 OGBVRMYSNSKIEF-UHFFFAOYSA-N 0.000 description 1
- 208000004860 Blast Crisis Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- RNBORMFFVRAVQU-UHFFFAOYSA-N C(C)(C)OC1=CC(=CC2=C1NC(=N2)NC(C)C)C2=CC=C(C=N2)CC2C(NC(S2)=O)=O Chemical compound C(C)(C)OC1=CC(=CC2=C1NC(=N2)NC(C)C)C2=CC=C(C=N2)CC2C(NC(S2)=O)=O RNBORMFFVRAVQU-UHFFFAOYSA-N 0.000 description 1
- JGLMVXWAHNTPRF-CMDGGOBGSA-N CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O Chemical compound CCN1N=C(C)C=C1C(=O)NC1=NC2=CC(=CC(OC)=C2N1C\C=C\CN1C(NC(=O)C2=CC(C)=NN2CC)=NC2=CC(=CC(OCCCN3CCOCC3)=C12)C(N)=O)C(N)=O JGLMVXWAHNTPRF-CMDGGOBGSA-N 0.000 description 1
- DKAUHFJQCZNEND-UHFFFAOYSA-N CCNc1nc2cc(cc(OC(C)C)c2s1)-c1ccc(CC2SC(=O)NC2=O)cn1 Chemical compound CCNc1nc2cc(cc(OC(C)C)c2s1)-c1ccc(CC2SC(=O)NC2=O)cn1 DKAUHFJQCZNEND-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 241000282465 Canis Species 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282324 Felis Species 0.000 description 1
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000034951 Genetic Translocation Diseases 0.000 description 1
- 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 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 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 1
- 102000016844 Immunoglobulin-like domains Human genes 0.000 description 1
- 108050006430 Immunoglobulin-like domains Proteins 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102000019149 MAP kinase activity proteins Human genes 0.000 description 1
- 108040008097 MAP kinase activity proteins Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101100293737 Mus musculus Nde1 gene Proteins 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 101710164680 Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102000001712 STAT5 Transcription Factor Human genes 0.000 description 1
- 108010029477 STAT5 Transcription Factor Proteins 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical group C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 101100111052 Xenopus laevis aurka-a gene Proteins 0.000 description 1
- 101100111053 Xenopus laevis aurka-b gene Proteins 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000008135 aqueous vehicle Substances 0.000 description 1
- 150000001543 aryl boronic acids Chemical class 0.000 description 1
- 150000001556 benzimidazoles Chemical class 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000009287 biochemical signal transduction Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000019065 cervical carcinoma Diseases 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000298 cyclopropenyl group Chemical group [H]C1=C([H])C1([H])* 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 125000001664 diethylamino group Chemical group [H]C([H])([H])C([H])([H])N(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000013213 extrapolation Methods 0.000 description 1
- 102000052178 fibroblast growth factor receptor activity proteins Human genes 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 108700014844 flt3 ligand Proteins 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 108010042209 insulin receptor tyrosine kinase Proteins 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- ACVHDOLKAPAIGB-UHFFFAOYSA-N n-benzyl-n-methylformamide Chemical compound O=CN(C)CC1=CC=CC=C1 ACVHDOLKAPAIGB-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KERBAAIBDHEFDD-UHFFFAOYSA-N n-ethylformamide Chemical compound CCNC=O KERBAAIBDHEFDD-UHFFFAOYSA-N 0.000 description 1
- KVTGAKFJRLBHLU-UHFFFAOYSA-N n-propan-2-ylformamide Chemical compound CC(C)NC=O KVTGAKFJRLBHLU-UHFFFAOYSA-N 0.000 description 1
- 210000003739 neck Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000010603 pastilles Nutrition 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000004323 potassium nitrate Substances 0.000 description 1
- 235000010333 potassium nitrate Nutrition 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 102220058910 rs786201402 Human genes 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000002805 secondary assay Methods 0.000 description 1
- 150000003346 selenoethers Chemical class 0.000 description 1
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 102000034285 signal transducing proteins Human genes 0.000 description 1
- 108091006024 signal transducing proteins Proteins 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000005504 styryl group Chemical group 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 150000005671 trienes Chemical class 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 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
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Physical Education & Sports Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Transplantation (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Biomedical Technology (AREA)
- Hematology (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68606205P | 2005-05-31 | 2005-05-31 | |
| US60/686,062 | 2005-05-31 | ||
| PCT/US2006/020986 WO2006130613A2 (en) | 2005-05-31 | 2006-05-30 | Substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2650999A1 true CA2650999A1 (en) | 2006-12-07 |
Family
ID=37482228
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002650999A Abandoned CA2650999A1 (en) | 2005-05-31 | 2006-05-30 | Substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1896462A2 (https=) |
| JP (1) | JP2008542382A (https=) |
| CN (1) | CN101233129A (https=) |
| AU (1) | AU2006252629A1 (https=) |
| CA (1) | CA2650999A1 (https=) |
| WO (1) | WO2006130613A2 (https=) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ604708A (en) | 2010-05-20 | 2015-05-29 | Array Biopharma Inc | Macrocyclic compounds as trk kinase inhibitors |
| ES2541054T3 (es) * | 2010-10-20 | 2015-07-15 | Université De Bordeaux | Firmas del resultado clínico en tumores estromales gastrointestinales y método de tratamiento de tumores estromales gastrointestinales |
| BR112018000808A2 (pt) | 2015-07-16 | 2018-09-04 | Array Biopharma Inc | compostos de pirazolo[1,5-a]piridina substituída como inibidores de ret cinase |
| TWI704148B (zh) | 2016-10-10 | 2020-09-11 | 美商亞雷生物製藥股份有限公司 | 作為ｒｅｔ激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物 |
| TWI752098B (zh) | 2016-10-10 | 2022-01-11 | 美商亞雷生物製藥股份有限公司 | 作為ret激酶抑制劑之經取代吡唑并[1,5-a]吡啶化合物 |
| US11168090B2 (en) | 2017-01-18 | 2021-11-09 | Array Biopharma Inc. | Substituted pyrazolo[1,5-a]pyrazines as RET kinase inhibitors |
| WO2018136663A1 (en) | 2017-01-18 | 2018-07-26 | Array Biopharma, Inc. | Ret inhibitors |
| JOP20190213A1 (ar) | 2017-03-16 | 2019-09-16 | Array Biopharma Inc | مركبات حلقية ضخمة كمثبطات لكيناز ros1 |
| TWI791053B (zh) | 2017-10-10 | 2023-02-01 | 美商亞雷生物製藥股份有限公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之結晶形式及其醫藥組合物 |
| TWI812649B (zh) | 2017-10-10 | 2023-08-21 | 美商絡速藥業公司 | 6-(2-羥基-2-甲基丙氧基)-4-(6-(6-((6-甲氧基吡啶-3-基)甲基)-3,6-二氮雜雙環[3.1.1]庚-3-基)吡啶-3-基)吡唑并[1,5-a]吡啶-3-甲腈之調配物 |
| CN111615514B (zh) | 2018-01-18 | 2022-10-11 | 奥瑞生物药品公司 | 作为ret激酶抑制剂的取代的吡唑并[4,3-c]吡啶化合物 |
| EP3740491A1 (en) | 2018-01-18 | 2020-11-25 | Array Biopharma, Inc. | Substituted pyrrolo[2,3-d]pyrimidines compounds as ret kinase inhibitors |
| WO2019143991A1 (en) | 2018-01-18 | 2019-07-25 | Array Biopharma Inc. | SUBSTITUTED PYRAZOLO[3,4-d]PYRIMIDINE COMPOUNDS AS RET KINASE INHIBITORS |
| EP3849986B1 (en) | 2018-09-10 | 2022-06-08 | Array Biopharma, Inc. | Fused heterocyclic compounds as ret kinase inhibitors |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU778723B2 (en) * | 1999-08-23 | 2004-12-16 | Kyorin Pharmaceutical Co. Ltd. | Substituted benzylthiazolidine-2,4-dione derivatives |
-
2006
- 2006-05-30 WO PCT/US2006/020986 patent/WO2006130613A2/en not_active Ceased
- 2006-05-30 EP EP06771644A patent/EP1896462A2/en not_active Withdrawn
- 2006-05-30 CA CA002650999A patent/CA2650999A1/en not_active Abandoned
- 2006-05-30 JP JP2008514781A patent/JP2008542382A/ja not_active Withdrawn
- 2006-05-30 AU AU2006252629A patent/AU2006252629A1/en not_active Abandoned
- 2006-05-30 CN CNA2006800281850A patent/CN101233129A/zh active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1896462A2 (en) | 2008-03-12 |
| WO2006130613A2 (en) | 2006-12-07 |
| CN101233129A (zh) | 2008-07-30 |
| JP2008542382A (ja) | 2008-11-27 |
| WO2006130613A3 (en) | 2007-02-08 |
| AU2006252629A1 (en) | 2006-12-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5261575B2 (ja) | 化学化合物 | |
| CN101379060B (zh) | 作为Aurora激酶抑制剂的苯并唑系衍生物、组合物和使用方法 | |
| WO2013016720A2 (en) | Novel substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases | |
| KR101433629B1 (ko) | 아연 결합 부분을 함유한 티로신 키나아제 억제제 | |
| EP1605946B1 (en) | Thiazoles useful as inhibitors of protein kinases | |
| US20040097566A1 (en) | 2-Substituted thiazolidinone and oxazolidinone derivatives for the inhibition of phosphatases and the treatment of cancer | |
| AU2013283318B2 (en) | Bifluorodioxalane-amino-benzimidazole kinase inhibitors for the treatment of cancer, autoimmuneinflammation and CNS disorders | |
| CA2650999A1 (en) | Substituted biarylheterocycle derivatives as protein kinase inhibitors for the treatment of cancer and other diseases | |
| TW202003505A (zh) | 甲基修飾酵素之調節劑、其組成物及用途 | |
| JP5463592B2 (ja) | アデノシンａ１レセプターアンタゴニストとしての新規化合物 | |
| SK4772002A3 (en) | Tyrosine kinase inhibitors, pharmaceutical composition containing the same and their use | |
| US20090186905A1 (en) | Anaplastic lymphoma kinase modulators and methods of use | |
| JP2019523237A (ja) | 乳酸脱水素酵素の阻害剤としての１ｈ−ピラゾール−１−イル−チアゾールおよびそれらの使用方法 | |
| AU2016214283B2 (en) | Compounds with anti-tumoral activity | |
| US7897602B2 (en) | Indolinone compounds as kinase inhibitors | |
| CN101987848A (zh) | 新的二氢吲哚酮化合物、它们的制备方法以及包含它们的药物组合物 | |
| US20030216432A1 (en) | Heterocyclic amide derivatives for the treatment of diabetes and other diseases | |
| RU2391342C2 (ru) | Новые азаиндолтиазолиноны в качестве противораковых агентов | |
| US20050014767A1 (en) | Benzoxazole, benzothiazole, and benzimidazole derivatives for the treatment of cancer and other diseases | |
| JP2008504324A (ja) | チアゾリノン非置換型キノリン | |
| CN101039939B (zh) | 作为cdk1抑制剂的喹唑啉基亚甲基噻唑啉酮类 | |
| WO2006106721A1 (ja) | チロシンキナーゼ阻害作用を有するピリミジン誘導体 | |
| RU2395509C2 (ru) | Тиазолинон-2-замещенные хинолины | |
| EP2395001A1 (en) | Novel pyrimidine derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |