JP2016512835A5 - - Google Patents

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Publication number

JP2016512835A5

JP2016512835A5 JP2016501741A JP2016501741A JP2016512835A5 JP 2016512835 A5 JP2016512835 A5 JP 2016512835A5 JP 2016501741 A JP2016501741 A JP 2016501741A JP 2016501741 A JP2016501741 A JP 2016501741A JP 2016512835 A5 JP2016512835 A5 JP 2016512835A5

Authority

JP

Japan

Prior art keywords

inhibitor

kinase

item

day

combination

Prior art date

2014-03-12

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.)

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• 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims description 81
• 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims description 81
• 229940124302 mTOR inhibitor Drugs 0.000 claims description 53
• 239000003628 mammalian target of rapamycin inhibitor Substances 0.000 claims description 53
• 229940098445 PI3 kinase alpha inhibitor Drugs 0.000 claims description 44
• 239000003112 inhibitor Substances 0.000 claims description 14
• 230000001613 neoplastic effect Effects 0.000 claims description 8
• 150000003839 salts Chemical class 0.000 claims description 5
• 238000009472 formulation Methods 0.000 claims description 4
• 239000000203 mixture Substances 0.000 claims description 4
• 206010006187 Breast cancer Diseases 0.000 claims description 3
• 208000026310 Breast neoplasm Diseases 0.000 claims description 3
• 206010014733 Endometrial cancer Diseases 0.000 claims description 3
• 206010014759 Endometrial neoplasm Diseases 0.000 claims description 3
• 208000006265 Renal cell carcinoma Diseases 0.000 claims description 3
• 206010033128 Ovarian cancer Diseases 0.000 claims description 2
• 206010061535 Ovarian neoplasm Diseases 0.000 claims description 2
• 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
• 206010060862 Prostate cancer Diseases 0.000 claims description 2
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 2
• 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims description 2
• 210000000481 breast Anatomy 0.000 claims description 2
• 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims description 2
• 239000002502 liposome Substances 0.000 claims description 2
• 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
• 201000002120 neuroendocrine carcinoma Diseases 0.000 claims description 2
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
• 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
• 238000001361 intraarterial administration Methods 0.000 claims 1
• 238000007918 intramuscular administration Methods 0.000 claims 1
• 238000007912 intraperitoneal administration Methods 0.000 claims 1
• 238000001990 intravenous administration Methods 0.000 claims 1
• 210000000496 pancreas Anatomy 0.000 claims 1
• 125000000217 alkyl group Chemical group 0.000 description 69
• 238000000034 method Methods 0.000 description 65
• RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 description 58
• 108091007960 PI3Ks Proteins 0.000 description 37
• 125000000304 alkynyl group Chemical group 0.000 description 36
• 125000003118 aryl group Chemical group 0.000 description 28
• 229910052757 nitrogen Inorganic materials 0.000 description 25
• 125000005843 halogen group Chemical group 0.000 description 21
• 125000001072 heteroaryl group Chemical group 0.000 description 20
• 125000004404 heteroalkyl group Chemical group 0.000 description 17
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
• -1 heterocycloalkyloxy Chemical class 0.000 description 14
• 229910052739 hydrogen Inorganic materials 0.000 description 13
• 125000003342 alkenyl group Chemical group 0.000 description 12
• 125000000753 cycloalkyl group Chemical group 0.000 description 12
• 239000001257 hydrogen Substances 0.000 description 12
• 125000004122 cyclic group Chemical group 0.000 description 11
• 150000002431 hydrogen Chemical class 0.000 description 11
• 125000004093 cyano group Chemical group *C#N 0.000 description 10
• 238000000338 in vitro Methods 0.000 description 10
• 239000013543 active substance Substances 0.000 description 9
• 125000003545 alkoxy group Chemical group 0.000 description 9
• 125000003710 aryl alkyl group Chemical group 0.000 description 9
• 125000004446 heteroarylalkyl group Chemical group 0.000 description 9
• 125000000623 heterocyclic group Chemical group 0.000 description 9
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 9
• 238000000021 kinase assay Methods 0.000 description 9
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 9
• 230000001225 therapeutic effect Effects 0.000 description 8
• 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 7
• BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 7
• 102000008135 Mechanistic Target of Rapamycin Complex 1 Human genes 0.000 description 7
• 108010035196 Mechanistic Target of Rapamycin Complex 1 Proteins 0.000 description 7
• 229910019142 PO4 Inorganic materials 0.000 description 7
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 7
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 7
• XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 7
• 125000002252 acyl group Chemical group 0.000 description 7
• 125000004423 acyloxy group Chemical group 0.000 description 7
• 125000004453 alkoxycarbonyl group Chemical group 0.000 description 7
• 150000001408 amides Chemical class 0.000 description 7
• 239000004202 carbamide Substances 0.000 description 7
• 229910052799 carbon Inorganic materials 0.000 description 7
• 230000007170 pathology Effects 0.000 description 7
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 7
• 239000010452 phosphate Substances 0.000 description 7
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
• 125000002877 alkyl aryl group Chemical group 0.000 description 6
• 238000004806 packaging method and process Methods 0.000 description 6
• 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 6
• 102000009308 Mechanistic Target of Rapamycin Complex 2 Human genes 0.000 description 5
• 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 description 5
• 206010028980 Neoplasm Diseases 0.000 description 4
• 229910052736 halogen Inorganic materials 0.000 description 4
• 150000002367 halogens Chemical class 0.000 description 4
• 230000005764 inhibitory process Effects 0.000 description 4
• 125000004433 nitrogen atom Chemical group N* 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
• 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
• 229960002930 sirolimus Drugs 0.000 description 4
• BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=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 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 3
• 230000007012 clinical effect Effects 0.000 description 3
• 125000002950 monocyclic group Chemical group 0.000 description 3
• 229960001302 ridaforolimus Drugs 0.000 description 3
• 229910052717 sulfur Inorganic materials 0.000 description 3
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 description 2
• 108091000080 Phosphotransferase Proteins 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
• 125000005024 alkenyl aryl group Chemical group 0.000 description 2
• 125000005025 alkynylaryl group Chemical group 0.000 description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
• 125000000392 cycloalkenyl group Chemical group 0.000 description 2
• 230000000694 effects Effects 0.000 description 2
• 229910052760 oxygen Inorganic materials 0.000 description 2
• 102000020233 phosphotransferase Human genes 0.000 description 2
• 229920006395 saturated elastomer Polymers 0.000 description 2
• 230000002459 sustained effect Effects 0.000 description 2
• 229960000235 temsirolimus Drugs 0.000 description 2
• YYSFXUWWPNHNAZ-PKJQJFMNSA-N umirolimus Chemical compound C1[C@@H](OC)[C@H](OCCOCC)CC[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 YYSFXUWWPNHNAZ-PKJQJFMNSA-N 0.000 description 2
• 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
• 208000023275 Autoimmune disease Diseases 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
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
• 125000002619 bicyclic group Chemical group 0.000 description 1
• 150000001875 compounds Chemical class 0.000 description 1
• 201000010099 disease Diseases 0.000 description 1
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
• 230000003828 downregulation Effects 0.000 description 1
• 230000001747 exhibiting effect Effects 0.000 description 1
• 230000003176 fibrotic effect Effects 0.000 description 1
• 125000005842 heteroatom Chemical group 0.000 description 1
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
• 238000010348 incorporation Methods 0.000 description 1
• 208000027866 inflammatory disease Diseases 0.000 description 1
• 208000017169 kidney disease Diseases 0.000 description 1
• 230000001404 mediated effect Effects 0.000 description 1
• 230000035772 mutation Effects 0.000 description 1
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
• 239000002773 nucleotide Substances 0.000 description 1
• 125000003729 nucleotide group Chemical group 0.000 description 1
• 125000004043 oxo group Chemical group O=* 0.000 description 1
• 201000002528 pancreatic cancer Diseases 0.000 description 1
• 230000004952 protein activity Effects 0.000 description 1
• 230000025915 regulation of apoptotic process Effects 0.000 description 1
• 229940124530 sulfonamide Drugs 0.000 description 1
• 150000003456 sulfonamides Chemical class 0.000 description 1
• 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 1
• 229950007775 umirolimus Drugs 0.000 description 1
• CGTADGCBEXYWNE-GTTQIJKGSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](\C(C)=C\C=C\C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-GTTQIJKGSA-N 0.000 description 1