JP2011527692A5 - - Google Patents

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Publication number

JP2011527692A5

JP2011527692A5 JP2011517583A JP2011517583A JP2011527692A5 JP 2011527692 A5 JP2011527692 A5 JP 2011527692A5 JP 2011517583 A JP2011517583 A JP 2011517583A JP 2011517583 A JP2011517583 A JP 2011517583A JP 2011527692 A5 JP2011527692 A5 JP 2011527692A5

Authority

JP

Japan

Prior art keywords

cycloalkyl

alkyl

heterocycloalkyl

heteroalkyl

compound

Prior art date

2009-07-08

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.)

Granted

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• 125000000217 alkyl group Chemical group 0.000 claims description 50
• 150000001875 compounds Chemical class 0.000 claims description 48
• 229910052739 hydrogen Inorganic materials 0.000 claims description 45
• 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 claims description 40
• 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 claims description 40
• 108091007960 PI3Ks Proteins 0.000 claims description 38
• 125000000304 alkynyl group Chemical group 0.000 claims description 36
• 239000001257 hydrogen Substances 0.000 claims description 35
• 125000003118 aryl group Chemical group 0.000 claims description 32
• 125000001072 heteroaryl group Chemical group 0.000 claims description 32
• 238000000034 method Methods 0.000 claims description 30
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 29
• 125000003545 alkoxy group Chemical group 0.000 claims description 28
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 28
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 27
• -1 —C 3-8 cycloalkyl Chemical group 0.000 claims description 27
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 17
• 229910052757 nitrogen Inorganic materials 0.000 claims description 17
• 230000000694 effects Effects 0.000 claims description 13
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• 125000001424 substituent group Chemical group 0.000 claims description 11
• 102000009308 Mechanistic Target of Rapamycin Complex 2 Human genes 0.000 claims description 10
• 108010034057 Mechanistic Target of Rapamycin Complex 2 Proteins 0.000 claims description 10
• 201000010099 disease Diseases 0.000 claims description 9
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 8
• 239000002246 antineoplastic agent Substances 0.000 claims description 8
• 229910052799 carbon Inorganic materials 0.000 claims description 8
• 238000000338 in vitro Methods 0.000 claims description 8
• 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 claims description 8
• 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 claims description 8
• 229960002930 sirolimus Drugs 0.000 claims description 8
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
• 210000004027 cell Anatomy 0.000 claims description 7
• 125000005215 cycloalkylheteroaryl group Chemical group 0.000 claims description 6
• KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 claims description 6
• 238000003556 assay Methods 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 230000026731 phosphorylation Effects 0.000 claims description 5
• 238000006366 phosphorylation reaction Methods 0.000 claims description 5
• 125000006413 ring segment Chemical group 0.000 claims description 5
• 229940124597 therapeutic agent Drugs 0.000 claims description 5
• 239000005517 L01XE01 - Imatinib Substances 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 201000011510 cancer Diseases 0.000 claims description 4
• 229940080856 gleevec Drugs 0.000 claims description 4
• 230000001613 neoplastic effect Effects 0.000 claims description 4
• 230000004913 activation Effects 0.000 claims description 3
• 229910052760 oxygen Inorganic materials 0.000 claims description 3
• 230000002195 synergetic effect Effects 0.000 claims description 3
• 208000023275 Autoimmune disease Diseases 0.000 claims description 2
• 208000003950 B-cell lymphoma Diseases 0.000 claims description 2
• 208000020084 Bone disease Diseases 0.000 claims description 2
• 208000012902 Nervous system disease Diseases 0.000 claims description 2
• 108091000080 Phosphotransferase Proteins 0.000 claims description 2
• 206010042971 T-cell lymphoma Diseases 0.000 claims description 2
• 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims description 2
• 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 claims description 2
• 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 claims description 2
• 208000016097 disease of metabolism Diseases 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 208000019622 heart disease Diseases 0.000 claims description 2
• 208000026278 immune system disease Diseases 0.000 claims description 2
• 208000027866 inflammatory disease Diseases 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 230000001404 mediated effect Effects 0.000 claims description 2
• 208000030159 metabolic disease Diseases 0.000 claims description 2
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
• 239000008194 pharmaceutical composition Substances 0.000 claims description 2
• 102000020233 phosphotransferase Human genes 0.000 claims description 2
• 208000023504 respiratory system disease Diseases 0.000 claims description 2
• 150000003839 salts Chemical class 0.000 claims description 2
• 239000000203 mixture Substances 0.000 claims 12
• 125000005843 halogen group Chemical group 0.000 claims 9
• 150000002431 hydrogen Chemical class 0.000 description 16
• 125000001475 halogen functional group Chemical group 0.000 description 15
• 238000000021 kinase assay Methods 0.000 description 6
• 230000005764 inhibitory process Effects 0.000 description 3
• 101150097381 Mtor gene Proteins 0.000 description 2
• 230000002401 inhibitory effect Effects 0.000 description 2
• 229910052717 sulfur Inorganic materials 0.000 description 2
• 0 C*C(*C([*-])=C1*=*)[N+]1[O-] Chemical compound C*C(*C([*-])=C1*=*)[N+]1[O-] 0.000 description 1
• PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 1
• 230000006907 apoptotic process Effects 0.000 description 1
• 238000000423 cell based assay Methods 0.000 description 1
• 230000022131 cell cycle Effects 0.000 description 1
• 230000032823 cell division Effects 0.000 description 1
• 230000004663 cell proliferation Effects 0.000 description 1
• 238000001516 cell proliferation assay Methods 0.000 description 1
• 238000010293 colony formation assay Methods 0.000 description 1
• 230000001747 exhibiting effect Effects 0.000 description 1
• 238000000684 flow cytometry Methods 0.000 description 1
• 238000003119 immunoblot Methods 0.000 description 1
• 239000002502 liposome Substances 0.000 description 1
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
• 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
• 210000005170 neoplastic cell Anatomy 0.000 description 1
• 208000037803 restenosis Diseases 0.000 description 1
• 210000001519 tissue Anatomy 0.000 description 1