JP5274842B2 - 免疫疾患、炎症疾患および増殖疾患の処置のためのセリン−スレオニンキナーゼモジュレーター(p70S6K、Akt−1およびAkt−2)としての[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジンまたは[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジン化合物 - Google Patents
免疫疾患、炎症疾患および増殖疾患の処置のためのセリン−スレオニンキナーゼモジュレーター(p70S6K、Akt−1およびAkt−2)としての[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジンまたは[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジン化合物 Download PDFInfo
- Publication number
- JP5274842B2 JP5274842B2 JP2007549530A JP2007549530A JP5274842B2 JP 5274842 B2 JP5274842 B2 JP 5274842B2 JP 2007549530 A JP2007549530 A JP 2007549530A JP 2007549530 A JP2007549530 A JP 2007549530A JP 5274842 B2 JP5274842 B2 JP 5274842B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- aryl
- compound according
- substituents
- kinase
- 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.)
- Expired - Fee Related
Links
- 101100322915 Caenorhabditis elegans akt-1 gene Proteins 0.000 title claims abstract description 12
- 101100162366 Caenorhabditis elegans akt-2 gene Proteins 0.000 title claims abstract description 12
- 230000002062 proliferating effect Effects 0.000 title description 5
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 title description 3
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 title description 3
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 title description 3
- 230000002757 inflammatory effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 217
- 230000000694 effects Effects 0.000 claims abstract description 72
- 108091000080 Phosphotransferase Proteins 0.000 claims abstract description 60
- 102000020233 phosphotransferase Human genes 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 50
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 23
- 108060006633 protein kinase Proteins 0.000 claims abstract description 21
- 230000035755 proliferation Effects 0.000 claims abstract description 12
- 230000005764 inhibitory process Effects 0.000 claims abstract description 10
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 121
- 125000000217 alkyl group Chemical group 0.000 claims description 77
- -1 independently Chemical group 0.000 claims description 76
- 125000003118 aryl group Chemical group 0.000 claims description 64
- 125000001424 substituent group Chemical group 0.000 claims description 57
- 125000005843 halogen group Chemical group 0.000 claims description 44
- 125000004122 cyclic group Chemical group 0.000 claims description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 30
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- 125000000623 heterocyclic group Chemical group 0.000 claims description 26
- 229920006395 saturated elastomer Polymers 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 15
- 125000004429 atom Chemical group 0.000 claims description 13
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 238000012216 screening Methods 0.000 claims description 10
- 125000002619 bicyclic group Chemical group 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- 239000003937 drug carrier Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 238000001727 in vivo Methods 0.000 claims description 7
- 125000006413 ring segment Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 abstract description 69
- 108010013238 70-kDa Ribosomal Protein S6 Kinases Proteins 0.000 abstract description 48
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 37
- 201000010099 disease Diseases 0.000 abstract description 36
- 230000004060 metabolic process Effects 0.000 abstract description 9
- 230000001413 cellular effect Effects 0.000 abstract description 8
- 230000005012 migration Effects 0.000 abstract description 6
- 238000013508 migration Methods 0.000 abstract description 6
- 230000001419 dependent effect Effects 0.000 abstract description 5
- 230000004069 differentiation Effects 0.000 abstract description 4
- 230000019491 signal transduction Effects 0.000 abstract description 4
- 238000003782 apoptosis assay Methods 0.000 abstract description 3
- 230000002255 enzymatic effect Effects 0.000 abstract description 3
- 230000005522 programmed cell death Effects 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 235000019439 ethyl acetate Nutrition 0.000 description 43
- 230000027455 binding Effects 0.000 description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 28
- 239000011734 sodium Substances 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 26
- 239000012267 brine Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- 210000004027 cell Anatomy 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 206010028980 Neoplasm Diseases 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- 238000003556 assay Methods 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- 239000012043 crude product Substances 0.000 description 20
- 239000001257 hydrogen Substances 0.000 description 20
- 102000004169 proteins and genes Human genes 0.000 description 19
- 150000003254 radicals Chemical class 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 108090000623 proteins and genes Proteins 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 17
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 17
- 235000018102 proteins Nutrition 0.000 description 17
- 102000004190 Enzymes Human genes 0.000 description 15
- 108090000790 Enzymes Proteins 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 238000003756 stirring Methods 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 13
- 239000003446 ligand Substances 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 11
- 108020001756 ligand binding domains Proteins 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 10
- 208000009956 adenocarcinoma Diseases 0.000 description 10
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- 235000019198 oils Nutrition 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 102000038030 PI3Ks Human genes 0.000 description 8
- 108091007960 PI3Ks Proteins 0.000 description 8
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000005094 computer simulation Methods 0.000 description 8
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000000546 pharmaceutical excipient Substances 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 229910052720 vanadium Inorganic materials 0.000 description 8
- 201000009030 Carcinoma Diseases 0.000 description 7
- 206010025323 Lymphomas Diseases 0.000 description 7
- 108091008611 Protein Kinase B Proteins 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 229920004890 Triton X-100 Polymers 0.000 description 7
- 239000013504 Triton X-100 Substances 0.000 description 7
- 230000002159 abnormal effect Effects 0.000 description 7
- 125000001118 alkylidene group Chemical group 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 7
- 125000003710 aryl alkyl group Chemical group 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 125000004093 cyano group Chemical group *C#N 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 238000000021 kinase assay Methods 0.000 description 7
- 208000030159 metabolic disease Diseases 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 238000011084 recovery Methods 0.000 description 7
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
- 108060001084 Luciferase Proteins 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000004590 computer program Methods 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 238000011534 incubation Methods 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 230000002503 metabolic effect Effects 0.000 description 6
- 239000002207 metabolite Substances 0.000 description 6
- 229940002612 prodrug Drugs 0.000 description 6
- 239000000651 prodrug Substances 0.000 description 6
- 125000005415 substituted alkoxy group Chemical group 0.000 description 6
- 230000004614 tumor growth Effects 0.000 description 6
- MLHXQODYFJDYAV-UHFFFAOYSA-N 2-[4-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)-2-oxopiperazin-1-yl]-2-(4-chlorophenyl)-n-[2-(dimethylamino)ethyl]acetamide Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CC(=O)N1C(C(=O)NCCN(C)C)C1=CC=C(Cl)C=C1 MLHXQODYFJDYAV-UHFFFAOYSA-N 0.000 description 5
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 5
- 101000798015 Homo sapiens RAC-beta serine/threonine-protein kinase Proteins 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 201000004681 Psoriasis Diseases 0.000 description 5
- 102100032315 RAC-beta serine/threonine-protein kinase Human genes 0.000 description 5
- 206010039491 Sarcoma Diseases 0.000 description 5
- 125000002252 acyl group Chemical group 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 230000004663 cell proliferation Effects 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 150000002367 halogens Chemical class 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- 125000004043 oxo group Chemical group O=* 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 108090000765 processed proteins & peptides Proteins 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 206010041823 squamous cell carcinoma Diseases 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000003107 substituted aryl group Chemical group 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- DTBKKESEAXYGMM-UHFFFAOYSA-N 3-bromo-2h-pyrazolo[4,3-d]pyrimidine Chemical compound N1=CN=C2C(Br)=NNC2=C1 DTBKKESEAXYGMM-UHFFFAOYSA-N 0.000 description 4
- MDFHFCAMBZNSLV-UHFFFAOYSA-N 3-bromo-4-chloro-2h-pyrazolo[3,4-d]pyrimidine Chemical compound ClC1=NC=NC2=NNC(Br)=C12 MDFHFCAMBZNSLV-UHFFFAOYSA-N 0.000 description 4
- 101150107888 AKT2 gene Proteins 0.000 description 4
- 229910000906 Bronze Inorganic materials 0.000 description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 206010024612 Lipoma Diseases 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 101150045355 akt1 gene Proteins 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 235000008206 alpha-amino acids Nutrition 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 230000006907 apoptotic process Effects 0.000 description 4
- 230000036983 biotransformation Effects 0.000 description 4
- 239000010974 bronze Substances 0.000 description 4
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 4
- KUNSUQLRTQLHQQ-UHFFFAOYSA-N copper tin Chemical compound [Cu].[Sn] KUNSUQLRTQLHQQ-UHFFFAOYSA-N 0.000 description 4
- 206010012601 diabetes mellitus Diseases 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- 239000006185 dispersion Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003995 emulsifying agent Substances 0.000 description 4
- 206010016629 fibroma Diseases 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 235000006408 oxalic acid Nutrition 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- 239000003656 tris buffered saline Substances 0.000 description 4
- KISWVXRQTGLFGD-UHFFFAOYSA-N 2-[[2-[[6-amino-2-[[2-[[2-[[5-amino-2-[[2-[[1-[2-[[6-amino-2-[(2,5-diamino-5-oxopentanoyl)amino]hexanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-(diaminomethylideneamino)p Chemical compound C1CCN(C(=O)C(CCCN=C(N)N)NC(=O)C(CCCCN)NC(=O)C(N)CCC(N)=O)C1C(=O)NC(CO)C(=O)NC(CCC(N)=O)C(=O)NC(CCCN=C(N)N)C(=O)NC(CO)C(=O)NC(CCCCN)C(=O)NC(C(=O)NC(CC(C)C)C(O)=O)CC1=CC=C(O)C=C1 KISWVXRQTGLFGD-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 3
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 3
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 3
- 201000008808 Fibrosarcoma Diseases 0.000 description 3
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000008589 Obesity Diseases 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 3
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 3
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 3
- 206010043276 Teratoma Diseases 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 3
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 3
- 150000001408 amides Chemical group 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 229940024606 amino acid Drugs 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 238000010256 biochemical assay Methods 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 150000001721 carbon Chemical class 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 230000019522 cellular metabolic process Effects 0.000 description 3
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 3
- 239000005516 coenzyme A Substances 0.000 description 3
- 229940093530 coenzyme a Drugs 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 239000013058 crude material Substances 0.000 description 3
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 229940000406 drug candidate Drugs 0.000 description 3
- 238000009510 drug design Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 201000011066 hemangioma Diseases 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 3
- 230000009545 invasion Effects 0.000 description 3
- 230000003211 malignant effect Effects 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- LWQLLIVTGSMSCT-UHFFFAOYSA-N methyl 2-bromo-2-(4-chlorophenyl)acetate Chemical compound COC(=O)C(Br)C1=CC=C(Cl)C=C1 LWQLLIVTGSMSCT-UHFFFAOYSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- DILRJUIACXKSQE-UHFFFAOYSA-N n',n'-dimethylethane-1,2-diamine Chemical compound CN(C)CCN DILRJUIACXKSQE-UHFFFAOYSA-N 0.000 description 3
- YCTMEBNARXMODJ-UHFFFAOYSA-N n-[[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-chlorophenyl)methyl]-n',n'-diethylethane-1,2-diamine Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1C(NCCN(CC)CC)C1=CC=C(Cl)C=C1 YCTMEBNARXMODJ-UHFFFAOYSA-N 0.000 description 3
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 3
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 3
- 235000020824 obesity Nutrition 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000001301 oxygen Chemical group 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 229940032147 starch Drugs 0.000 description 3
- 125000000547 substituted alkyl group Chemical group 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- 230000014616 translation Effects 0.000 description 3
- 241000701447 unidentified baculovirus Species 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 2
- HHXLCKJLVWXLBY-UHFFFAOYSA-N 1-[[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-chlorophenyl)methyl]-3-[2-(dimethylamino)ethyl]urea Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1C(NC(=O)NCCN(C)C)C1=CC=C(Cl)C=C1 HHXLCKJLVWXLBY-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- XEMIIPOLFGIISJ-UHFFFAOYSA-N 2-(dimethylamino)ethyl n-[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-n-(4-chlorophenyl)carbamate Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1N(C(=O)OCCN(C)C)C1=CC=C(Cl)C=C1 XEMIIPOLFGIISJ-UHFFFAOYSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 2
- URQJLEHTWPIESE-UHFFFAOYSA-N 3-chloro-2h-pyrazolo[4,3-d]pyrimidine Chemical compound N1=CN=C2C(Cl)=NNC2=C1 URQJLEHTWPIESE-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 201000003076 Angiosarcoma Diseases 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- WGVYCXYGPNNUQA-UHFFFAOYSA-N Cc1ccccc1CBr Chemical compound Cc1ccccc1CBr WGVYCXYGPNNUQA-UHFFFAOYSA-N 0.000 description 2
- 201000009047 Chordoma Diseases 0.000 description 2
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 2
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 208000007569 Giant Cell Tumors Diseases 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 208000002927 Hamartoma Diseases 0.000 description 2
- 208000001258 Hemangiosarcoma Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 206010022489 Insulin Resistance Diseases 0.000 description 2
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 2
- 208000007766 Kaposi sarcoma Diseases 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 2
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 2
- 208000018142 Leiomyosarcoma Diseases 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 208000034578 Multiple myelomas Diseases 0.000 description 2
- 102000047918 Myelin Basic Human genes 0.000 description 2
- 101710107068 Myelin basic protein Proteins 0.000 description 2
- 201000004404 Neurofibroma Diseases 0.000 description 2
- 102000008052 Nitric Oxide Synthase Type III Human genes 0.000 description 2
- 108010075520 Nitric Oxide Synthase Type III Proteins 0.000 description 2
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 2
- 208000000035 Osteochondroma Diseases 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 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
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 2
- 102400001320 Transforming growth factor alpha Human genes 0.000 description 2
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 2
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- 125000004104 aryloxy group Chemical group 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 229960001948 caffeine Drugs 0.000 description 2
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 238000004422 calculation algorithm Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 230000012292 cell migration Effects 0.000 description 2
- 208000019065 cervical carcinoma Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 2
- 229960001231 choline Drugs 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000000295 complement effect Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 230000003436 cytoskeletal effect Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 229960005156 digoxin Drugs 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 239000002532 enzyme inhibitor Substances 0.000 description 2
- 229940125532 enzyme inhibitor Drugs 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 238000007667 floating Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 229940080856 gleevec Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 229960002885 histidine Drugs 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- PQNFLJBBNBOBRQ-UHFFFAOYSA-N indane Chemical compound C1=CC=C2CCCC2=C1 PQNFLJBBNBOBRQ-UHFFFAOYSA-N 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 201000010260 leiomyoma Diseases 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000018977 lysine Nutrition 0.000 description 2
- 208000002780 macular degeneration Diseases 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 201000001441 melanoma Diseases 0.000 description 2
- 206010027191 meningioma Diseases 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 208000015122 neurodegenerative disease Diseases 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 230000000771 oncological effect Effects 0.000 description 2
- 201000008968 osteosarcoma Diseases 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 2
- 239000011574 phosphorus Substances 0.000 description 2
- OHEDMAIVEXQCOZ-UHFFFAOYSA-N piperidine;dihydrochloride Chemical compound Cl.Cl.C1CCNCC1 OHEDMAIVEXQCOZ-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000005551 pyridylene group Chemical group 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 238000007423 screening assay Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- 238000005556 structure-activity relationship Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 2
- 125000004434 sulfur atom Chemical group 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- UGKNVKLWKSPWPH-UHFFFAOYSA-N tert-butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1C(=O)C1=CC=C(Cl)C=C1 UGKNVKLWKSPWPH-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- ICLYJLBTOGPLMC-KVVVOXFISA-N (z)-octadec-9-enoate;tris(2-hydroxyethyl)azanium Chemical compound OCCN(CCO)CCO.CCCCCCCC\C=C/CCCCCCCC(O)=O ICLYJLBTOGPLMC-KVVVOXFISA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- XLOVPKCQAPHUKK-UHFFFAOYSA-N 1,2,3,4,4a,5,8,8a-octahydronaphthalene Chemical compound C1C=CCC2CCCCC21 XLOVPKCQAPHUKK-UHFFFAOYSA-N 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- SUYQOVLUPLPLGV-UHFFFAOYSA-N 1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)-4-(4-chlorophenyl)-n-[3-(diethylamino)propyl]piperidine-4-carboxamide Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1(C(=O)NCCCN(CC)CC)C1=CC=C(Cl)C=C1 SUYQOVLUPLPLGV-UHFFFAOYSA-N 0.000 description 1
- CKUXKQZDPSNTSV-UHFFFAOYSA-N 1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)-4-[(4-chlorophenyl)methyl]-n-[3-(diethylamino)propyl]piperidine-4-carboxamide Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1(C(=O)NCCCN(CC)CC)CC1=CC=C(Cl)C=C1 CKUXKQZDPSNTSV-UHFFFAOYSA-N 0.000 description 1
- CDCMLAUCQJCJOQ-UHFFFAOYSA-N 1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)-n-(4-chlorophenyl)piperidin-4-amine Chemical compound C1=CC(Cl)=CC=C1NC1CCN(C=2C=3C(Br)=NNC=3N=CN=2)CC1 CDCMLAUCQJCJOQ-UHFFFAOYSA-N 0.000 description 1
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical group CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 1
- BCMYXYHEMGPZJN-UHFFFAOYSA-N 1-chloro-2-isocyanatoethane Chemical compound ClCCN=C=O BCMYXYHEMGPZJN-UHFFFAOYSA-N 0.000 description 1
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 description 1
- PTZNCCIULVXFIJ-UHFFFAOYSA-N 1-o-tert-butyl 4-o-methyl piperidine-1,4-dicarboxylate Chemical compound COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1 PTZNCCIULVXFIJ-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 1
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical compound C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 1
- UZURTQHPMXADGG-UHFFFAOYSA-N 2,3,3a,4,7,7a-hexahydro-1h-indene Chemical compound C1C=CCC2CCCC21 UZURTQHPMXADGG-UHFFFAOYSA-N 0.000 description 1
- PHXGAJLBHUUAKB-UHFFFAOYSA-N 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan Chemical compound O1CCC2OCCC21 PHXGAJLBHUUAKB-UHFFFAOYSA-N 0.000 description 1
- FWUJIDULGWIBPD-UHFFFAOYSA-N 2-(1-phenylhex-5-en-1-yn-3-yl)naphthalene Chemical compound C=1C=C2C=CC=CC2=CC=1C(CC=C)C#CC1=CC=CC=C1 FWUJIDULGWIBPD-UHFFFAOYSA-N 0.000 description 1
- GTEXIOINCJRBIO-UHFFFAOYSA-N 2-[2-(dimethylamino)ethoxy]-n,n-dimethylethanamine Chemical compound CN(C)CCOCCN(C)C GTEXIOINCJRBIO-UHFFFAOYSA-N 0.000 description 1
- QUFXMTKDHLGQAE-UHFFFAOYSA-N 2-[2-(dimethylamino)ethoxy]-n,n-dimethylethanamine;dihydrochloride Chemical compound Cl.Cl.CN(C)CCOCCN(C)C QUFXMTKDHLGQAE-UHFFFAOYSA-N 0.000 description 1
- UFNIERATEHAXDW-UHFFFAOYSA-N 2-[[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-fluorophenyl)methoxy]-n,n-dimethylethanamine Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1C(OCCN(C)C)C1=CC=C(F)C=C1 UFNIERATEHAXDW-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- LQLJZSJKRYTKTP-UHFFFAOYSA-N 2-dimethylaminoethyl chloride hydrochloride Chemical compound Cl.CN(C)CCCl LQLJZSJKRYTKTP-UHFFFAOYSA-N 0.000 description 1
- WRFPVMFCRNYQNR-UHFFFAOYSA-N 2-hydroxyphenylalanine Chemical compound OC(=O)C(N)CC1=CC=CC=C1O WRFPVMFCRNYQNR-UHFFFAOYSA-N 0.000 description 1
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical group CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 1
- WNLWBCIUNCAMPH-UHFFFAOYSA-N 2-n,2-n-dimethylpropane-1,2-diamine Chemical compound NCC(C)N(C)C WNLWBCIUNCAMPH-UHFFFAOYSA-N 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- URKNKOFMKSTDIG-UHFFFAOYSA-N 3-[[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-chlorophenyl)methoxy]-n,n-dimethylpropan-1-amine Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1C(OCCCN(C)C)C1=CC=C(Cl)C=C1 URKNKOFMKSTDIG-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- FXIUWVNFYZNXCK-UHFFFAOYSA-N 3-bromo-4-[4-(1-phenylethyl)piperazin-1-yl]-2h-pyrazolo[3,4-d]pyrimidine Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCN1C(C)C1=CC=CC=C1 FXIUWVNFYZNXCK-UHFFFAOYSA-N 0.000 description 1
- AVFPOWPKUSYREA-UHFFFAOYSA-N 3-bromo-4-[4-[(4-chlorophenyl)methyl]-3-methylpiperazin-1-yl]-2h-pyrazolo[3,4-d]pyrimidine Chemical compound CC1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCN1CC1=CC=C(Cl)C=C1 AVFPOWPKUSYREA-UHFFFAOYSA-N 0.000 description 1
- AEMXXZPJJCZOLU-UHFFFAOYSA-N 3-bromo-4-[4-[(4-chlorophenyl)methyl]piperazin-1-yl]-2h-pyrazolo[3,4-d]pyrimidine Chemical compound C1=CC(Cl)=CC=C1CN1CCN(C=2C=3C(Br)=NNC=3N=CN=2)CC1 AEMXXZPJJCZOLU-UHFFFAOYSA-N 0.000 description 1
- WVUULNDRFBHTFG-UHFFFAOYSA-N 3-chloro-n,n-diethylpropan-1-amine Chemical compound CCN(CC)CCCCl WVUULNDRFBHTFG-UHFFFAOYSA-N 0.000 description 1
- 102100037263 3-phosphoinositide-dependent protein kinase 1 Human genes 0.000 description 1
- JXJSQQWPUMCYGJ-UHFFFAOYSA-N 4-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-chlorophenyl)methyl]piperazin-2-one Chemical compound C1=CC(Cl)=CC=C1CN1C(=O)CN(C=2C=3C(Br)=NNC=3N=CN=2)CC1 JXJSQQWPUMCYGJ-UHFFFAOYSA-N 0.000 description 1
- QRKLUICYAXZGJB-UHFFFAOYSA-N 4-[4-(2-fluorophenyl)piperazin-1-yl]-1h-pyrazolo[3,4-d]pyrimidine Chemical compound FC1=CC=CC=C1N1CCN(C=2C=3C=NNC=3N=CN=2)CC1 QRKLUICYAXZGJB-UHFFFAOYSA-N 0.000 description 1
- LCGMENDABLGZBC-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)piperazin-1-yl]-1h-pyrazolo[3,4-d]pyrimidine Chemical compound ClC1=CC=CC(N2CCN(CC2)C=2C=3C=NNC=3N=CN=2)=C1 LCGMENDABLGZBC-UHFFFAOYSA-N 0.000 description 1
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- SNZSSCZJMVIOCR-UHFFFAOYSA-N 7-azabicyclo[2.2.1]heptane Chemical compound C1CC2CCC1N2 SNZSSCZJMVIOCR-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 description 1
- 241000321096 Adenoides Species 0.000 description 1
- 206010001233 Adenoma benign Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 102000007299 Amphiregulin Human genes 0.000 description 1
- 108010033760 Amphiregulin Proteins 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 206010004146 Basal cell carcinoma Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 description 1
- 0 C*(*(C(C)C1C)C(*)C(*)N1c1c(c(*)n[n]2)c2nc(*)n1)IC Chemical compound C*(*(C(C)C1C)C(*)C(*)N1c1c(c(*)n[n]2)c2nc(*)n1)IC 0.000 description 1
- NLTYMRXEVHKXQJ-UHFFFAOYSA-N C1=NN(C2=C1C(=NC=N2)Cl)Br Chemical compound C1=NN(C2=C1C(=NC=N2)Cl)Br NLTYMRXEVHKXQJ-UHFFFAOYSA-N 0.000 description 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 1
- 102000038625 CMGCs Human genes 0.000 description 1
- 108091007913 CMGCs Proteins 0.000 description 1
- 101100381481 Caenorhabditis elegans baz-2 gene Proteins 0.000 description 1
- 102100022789 Calcium/calmodulin-dependent protein kinase type IV Human genes 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 229920002157 Cellulin Polymers 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 208000010126 Chondromatosis Diseases 0.000 description 1
- 208000019591 Chondromyxoid fibroma Diseases 0.000 description 1
- 208000005243 Chondrosarcoma Diseases 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 description 1
- 206010048832 Colon adenoma Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 206010011732 Cyst Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- LTMHDMANZUZIPE-AMTYYWEZSA-N Digoxin Natural products O([C@H]1[C@H](C)O[C@H](O[C@@H]2C[C@@H]3[C@@](C)([C@@H]4[C@H]([C@]5(O)[C@](C)([C@H](O)C4)[C@H](C4=CC(=O)OC4)CC5)CC3)CC2)C[C@@H]1O)[C@H]1O[C@H](C)[C@@H](O[C@H]2O[C@@H](C)[C@H](O)[C@@H](O)C2)[C@@H](O)C1 LTMHDMANZUZIPE-AMTYYWEZSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 101100291385 Drosophila melanogaster p38a gene Proteins 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 208000000471 Dysplastic Nevus Syndrome Diseases 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 206010014967 Ependymoma Diseases 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- 208000006168 Ewing Sarcoma Diseases 0.000 description 1
- 208000007659 Fibroadenoma Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108091007911 GSKs Proteins 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 208000021309 Germ cell tumor Diseases 0.000 description 1
- 208000000527 Germinoma Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 201000005409 Gliomatosis cerebri Diseases 0.000 description 1
- 206010018404 Glucagonoma Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000019058 Glycogen Synthase Kinase 3 beta Human genes 0.000 description 1
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 1
- 102000004103 Glycogen Synthase Kinases Human genes 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 101800001649 Heparin-binding EGF-like growth factor Proteins 0.000 description 1
- 102400001369 Heparin-binding EGF-like growth factor Human genes 0.000 description 1
- 206010019629 Hepatic adenoma Diseases 0.000 description 1
- 102100021866 Hepatocyte growth factor Human genes 0.000 description 1
- 208000017604 Hodgkin disease Diseases 0.000 description 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 1
- 101000600756 Homo sapiens 3-phosphoinositide-dependent protein kinase 1 Proteins 0.000 description 1
- 101100287682 Homo sapiens CAMK2G gene Proteins 0.000 description 1
- 101100126883 Homo sapiens CAMK4 gene Proteins 0.000 description 1
- 101000898034 Homo sapiens Hepatocyte growth factor Proteins 0.000 description 1
- 101001076408 Homo sapiens Interleukin-6 Proteins 0.000 description 1
- 101000798007 Homo sapiens RAC-gamma serine/threonine-protein kinase Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000868152 Homo sapiens Son of sevenless homolog 1 Proteins 0.000 description 1
- 101001117146 Homo sapiens [Pyruvate dehydrogenase (acetyl-transferring)] kinase isozyme 1, mitochondrial Proteins 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 206010023330 Keloid scar Diseases 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 1
- JZKXXXDKRQWDET-QMMMGPOBSA-N L-m-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(O)=C1 JZKXXXDKRQWDET-QMMMGPOBSA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 1
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000002404 Liver Cell Adenoma Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000000172 Medulloblastoma Diseases 0.000 description 1
- 206010027406 Mesothelioma Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101100268066 Mus musculus Zap70 gene Proteins 0.000 description 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- 241000872931 Myoporum sandwicense Species 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 125000000815 N-oxide group Chemical group 0.000 description 1
- 208000034176 Neoplasms, Germ Cell and Embryonal Diseases 0.000 description 1
- 102400000058 Neuregulin-1 Human genes 0.000 description 1
- 108090000556 Neuregulin-1 Proteins 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 108091005461 Nucleic proteins Chemical group 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000034038 Pathologic Neovascularization Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 206010050487 Pinealoblastoma Diseases 0.000 description 1
- 208000007641 Pinealoma Diseases 0.000 description 1
- 102000001393 Platelet-Derived Growth Factor alpha Receptor Human genes 0.000 description 1
- 108010068588 Platelet-Derived Growth Factor alpha Receptor Proteins 0.000 description 1
- 102000018967 Platelet-Derived Growth Factor beta Receptor Human genes 0.000 description 1
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 1
- 101710098940 Pro-epidermal growth factor Proteins 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 1
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100032314 RAC-gamma serine/threonine-protein kinase Human genes 0.000 description 1
- 101100372762 Rattus norvegicus Flt1 gene Proteins 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 201000000582 Retinoblastoma Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 208000005678 Rhabdomyoma Diseases 0.000 description 1
- 102000002278 Ribosomal Proteins Human genes 0.000 description 1
- 108010000605 Ribosomal Proteins Proteins 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 201000010208 Seminoma Diseases 0.000 description 1
- 208000000097 Sertoli-Leydig cell tumor Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 206010048215 Xanthomatosis Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- LTAZYRJFJBDOBO-UHFFFAOYSA-N [1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-chlorophenyl)methanol Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1C(O)C1=CC=C(Cl)C=C1 LTAZYRJFJBDOBO-UHFFFAOYSA-N 0.000 description 1
- IXRXEXNQINCIRZ-UHFFFAOYSA-N [1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-chlorophenyl)methanone Chemical compound C1=CC(Cl)=CC=C1C(=O)C1CCN(C=2C=3C(Br)=NNC=3N=CN=2)CC1 IXRXEXNQINCIRZ-UHFFFAOYSA-N 0.000 description 1
- SUMHHCMWZBLBCC-UHFFFAOYSA-N [1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-fluorophenyl)methanol Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1C(O)C1=CC=C(F)C=C1 SUMHHCMWZBLBCC-UHFFFAOYSA-N 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- BSMOPWRSRTXLSN-UHFFFAOYSA-N [4-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)-1-[(4-chlorophenyl)methyl]piperazin-2-yl]methanol Chemical compound OCC1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCN1CC1=CC=C(Cl)C=C1 BSMOPWRSRTXLSN-UHFFFAOYSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000012042 active reagent Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 210000002534 adenoid Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 238000011122 anti-angiogenic therapy Methods 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000009949 anti-apoptotic pathway Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008365 aqueous carrier Substances 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical group 0.000 description 1
- 125000000732 arylene group Chemical group 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 238000010170 biological method Methods 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000003149 breast fibroadenoma Diseases 0.000 description 1
- 210000003123 bronchiole Anatomy 0.000 description 1
- 208000003362 bronchogenic carcinoma Diseases 0.000 description 1
- 201000002143 bronchus adenoma Diseases 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 239000004067 bulking agent Substances 0.000 description 1
- LSOBPYSQSPIQJF-UHFFFAOYSA-N but-2-yne Chemical compound [CH2]C#CC LSOBPYSQSPIQJF-UHFFFAOYSA-N 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 1
- 229940095259 butylated hydroxytoluene Drugs 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000005518 carboxamido group Chemical group 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012069 chiral reagent Substances 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 201000005217 chondroblastoma Diseases 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 208000009060 clear cell adenocarcinoma Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000009137 competitive binding Effects 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 208000031513 cyst Diseases 0.000 description 1
- 208000002445 cystadenocarcinoma Diseases 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 230000002380 cytological effect Effects 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 125000005507 decahydroisoquinolyl group Chemical group 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000000032 diagnostic agent Substances 0.000 description 1
- 229940039227 diagnostic agent Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- LTMHDMANZUZIPE-PUGKRICDSA-N digoxin Chemical compound C1[C@H](O)[C@H](O)[C@@H](C)O[C@H]1O[C@@H]1[C@@H](C)O[C@@H](O[C@@H]2[C@H](O[C@@H](O[C@@H]3C[C@@H]4[C@]([C@@H]5[C@H]([C@]6(CC[C@@H]([C@@]6(C)[C@H](O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)C[C@@H]2O)C)C[C@@H]1O LTMHDMANZUZIPE-PUGKRICDSA-N 0.000 description 1
- LTMHDMANZUZIPE-UHFFFAOYSA-N digoxine Natural products C1C(O)C(O)C(C)OC1OC1C(C)OC(OC2C(OC(OC3CC4C(C5C(C6(CCC(C6(C)C(O)C5)C=5COC(=O)C=5)O)CC4)(C)CC3)CC2O)C)CC1O LTMHDMANZUZIPE-UHFFFAOYSA-N 0.000 description 1
- 125000004982 dihaloalkyl group Chemical group 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- XNMQEEKYCVKGBD-UHFFFAOYSA-N dimethylacetylene Natural products CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 1
- 125000005879 dioxolanyl group Chemical group 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 239000013013 elastic material Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 229940012017 ethylenediamine Drugs 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 108091071773 flk family Proteins 0.000 description 1
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000002825 functional assay Methods 0.000 description 1
- 239000000054 fungal extract Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 238000001030 gas--liquid chromatography Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 description 1
- 201000000052 gastrinoma Diseases 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 201000003115 germ cell cancer Diseases 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 229960002743 glutamine Drugs 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000003106 haloaryl group Chemical group 0.000 description 1
- 201000002735 hepatocellular adenoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005549 heteroarylene group Chemical group 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000013537 high throughput screening Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 229960003685 imatinib mesylate Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000010324 immunological assay Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000012750 in vivo screening Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000004001 inositols Chemical class 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 208000028774 intestinal disease Diseases 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000010985 invasive ductal carcinoma Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000003965 isoxazolidinyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000001117 keloid Anatomy 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 206010024627 liposarcoma Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000006249 magnetic particle Substances 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 201000000289 malignant teratoma Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000002418 meninge Anatomy 0.000 description 1
- JZKXXXDKRQWDET-UHFFFAOYSA-N meta-tyrosine Natural products OC(=O)C(N)CC1=CC=CC(O)=C1 JZKXXXDKRQWDET-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- WWIYGBWRUXQDND-UHFFFAOYSA-N methyl 2-(4-chlorophenyl)acetate Chemical compound COC(=O)CC1=CC=C(Cl)C=C1 WWIYGBWRUXQDND-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 208000025113 myeloid leukemia Diseases 0.000 description 1
- 208000009091 myxoma Diseases 0.000 description 1
- QUMIGAREEPSVLG-UHFFFAOYSA-N n',n'-diethyl-n-phenylethane-1,2-diamine Chemical compound CCN(CC)CCNC1=CC=CC=C1 QUMIGAREEPSVLG-UHFFFAOYSA-N 0.000 description 1
- BAVMTSYATQUKTC-UHFFFAOYSA-N n',n'-diethyl-n-phenylethane-1,2-diamine;dihydrochloride Chemical compound Cl.Cl.CCN(CC)CCNC1=CC=CC=C1 BAVMTSYATQUKTC-UHFFFAOYSA-N 0.000 description 1
- UDGSVBYJWHOHNN-UHFFFAOYSA-N n',n'-diethylethane-1,2-diamine Chemical compound CCN(CC)CCN UDGSVBYJWHOHNN-UHFFFAOYSA-N 0.000 description 1
- KMAZZGRJPAIUCG-UHFFFAOYSA-N n'-[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-n'-(4-chlorophenyl)-n-[2-(dimethylamino)ethyl]oxamide Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1N(C(=O)C(=O)NCCN(C)C)C1=CC=C(Cl)C=C1 KMAZZGRJPAIUCG-UHFFFAOYSA-N 0.000 description 1
- JEBHZGWMOAXSJV-UHFFFAOYSA-N n-[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-n-(4-chlorophenyl)-3-(diethylamino)propanamide Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1N(C(=O)CCN(CC)CC)C1=CC=C(Cl)C=C1 JEBHZGWMOAXSJV-UHFFFAOYSA-N 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- XLLDZUYDQDQUTP-UHFFFAOYSA-N n-[[1-(3-bromo-2h-pyrazolo[3,4-d]pyrimidin-4-yl)piperidin-4-yl]-(4-chlorophenyl)methyl]-3-(diethylamino)propanamide Chemical compound C1CN(C=2C=3C(Br)=NNC=3N=CN=2)CCC1C(NC(=O)CCN(CC)CC)C1=CC=C(Cl)C=C1 XLLDZUYDQDQUTP-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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000009826 neoplastic cell growth Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000007538 neurilemmoma Diseases 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 208000004649 neutrophil actin dysfunction Diseases 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N o-biphenylenemethane Natural products C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- 125000005060 octahydroindolyl group Chemical group N1(CCC2CCCCC12)* 0.000 description 1
- 125000005061 octahydroisoindolyl group Chemical group C1(NCC2CCCCC12)* 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 208000003388 osteoid osteoma Diseases 0.000 description 1
- 208000008798 osteoma Diseases 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 210000003101 oviduct Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000005968 oxazolinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003906 phosphoinositides Chemical class 0.000 description 1
- 238000003566 phosphorylation assay Methods 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 201000003113 pineoblastoma Diseases 0.000 description 1
- IYPZRUYMFDWKSS-UHFFFAOYSA-N piperazin-1-amine Chemical class NN1CCNCC1 IYPZRUYMFDWKSS-UHFFFAOYSA-N 0.000 description 1
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- FLKRMXAWABTWSH-UHFFFAOYSA-N piperidine-1-sulfonamide Chemical compound NS(=O)(=O)N1CCCCC1 FLKRMXAWABTWSH-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 108091033319 polynucleotide Proteins 0.000 description 1
- 102000040430 polynucleotide Human genes 0.000 description 1
- 239000002157 polynucleotide Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 230000004647 pro-inflammatory pathway Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- IAHIMVFWYADCJJ-UHFFFAOYSA-N prop-1-enylcyclohexane Chemical group CC=CC1CCCCC1 IAHIMVFWYADCJJ-UHFFFAOYSA-N 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 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 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 201000006845 reticulosarcoma Diseases 0.000 description 1
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 206010039667 schwannoma Diseases 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000009211 stress pathway Effects 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- FCMLWBBLOASUSO-UHFFFAOYSA-N tert-butyl 3-oxopiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(=O)C1 FCMLWBBLOASUSO-UHFFFAOYSA-N 0.000 description 1
- VYRKXOIQPVOACW-UHFFFAOYSA-N tert-butyl 4-[(4-chlorophenyl)methyl]-3-(hydroxymethyl)piperazine-1-carboxylate Chemical compound OCC1CN(C(=O)OC(C)(C)C)CCN1CC1=CC=C(Cl)C=C1 VYRKXOIQPVOACW-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- SCMFJWWKJBCJDC-UHFFFAOYSA-N tert-butyl n-[4-(4-chlorophenyl)piperidine-4-carbonyl]carbamate Chemical compound C=1C=C(Cl)C=CC=1C1(C(=O)NC(=O)OC(C)(C)C)CCNCC1 SCMFJWWKJBCJDC-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 238000011200 topical administration Methods 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
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 206010044412 transitional cell carcinoma Diseases 0.000 description 1
- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940117013 triethanolamine oleate Drugs 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004799 tryptophan Drugs 0.000 description 1
- 208000022271 tubular adenoma Diseases 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 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
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 208000009540 villous adenoma Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P3/04—Anorexiants; Antiobesity agents
-
- 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
- A61P3/06—Antihyperlipidemics
-
- 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
-
- 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
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Transplantation (AREA)
- Vascular Medicine (AREA)
- Neurosurgery (AREA)
- Ophthalmology & Optometry (AREA)
- Child & Adolescent Psychology (AREA)
- Dermatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本発明は、増殖、分化、プログラム細胞死、移動(migration)、化学的侵襲(chemoinvasion)および代謝のような細胞活性を調節するためのプロテインキナーゼ酵素活性を調節するための化合物に関連する。より具体的には、本発明は、上記のような細胞活性における変化に関連したキナーゼレセプターシグナル伝達経路を阻害、制御および/または調節する化合物、これらの化合物を含有する組成物、およびそれらを使用してキナーゼ依存性の疾患および状態を処置する方法に関する。
癌を処置するために使用される薬剤の特異性についての改良は、これらの薬剤の投与に関係する副作用が減少されるか否かが確認されるという治療的利益に起因して、相当に興味深い。伝統的に、癌の処置における劇的な改良は、新規の機構を通じて作用する治療因子の同定に関連する。
Manningら、Science,(2002),298,1912 Plowmanら、DN&P(1994)7(6):334−339 Bolen,Oncogene(1993)8:2025−2031 Matter A.Drug Disc Technol(2001)6,1005−1024 Peneら、Oncogene(2002)21,6587 Miyakawaら、Endocrin J.(2003)50,77,83 Leら、Oncogene(2003)22,484 Peralbaら、Clinical Cancer Research(2003)9,2887 Umら、Nature(2004)431,200−205 Pendeら、Nature(2000)408,994−997 Hajduch,Eら、FEBS Lett.(2001)492:199−203 Vanhaesebroeck,B.およびAlessi,D.R.Biochem.J.(2000)346:561−576 Dudek H.ら、Science(1997)275:661−663 Kauffmann−Zeh A,ら、Nature(1997)385:544−548 Songyang Z.ら、Proc Natl Acad Sci U S A(1997)94:11345−11350 Liang J.ら、Nature Med.(2002)8:1153−1160 Vasco Vら、J.Med.Genet.(2004)41:161−170 Dickson LMおよびRhodes CJ、Am J Physiol Endocrinol Metab.(2004)287:E192−8 George Sら、Science(2004)304:1325−1328 Cheng,J.Q.ら、Proc.Nat.Acad.Sci.(1992)89:9267−9271 Cheng,J.Q.ら、Proc.Nat.Acad.Sci.(1996)93:3636−3641
1局面では、本発明は、キナーゼ(好ましくは、p70S6、Akt−1またはAkt−2キナーゼ)の活性を調節する化合物、これらの化合物およびそれらの医薬組成物を使用してキナーゼ(好ましくは、p70S6、Akt−1またはAkt−2キナーゼ)の活性により媒介される疾患を治療する方法を提供する。p70S6活性、Akt−1活性および/またはAkt−2キナーゼ活性により媒介される疾患には、侵襲性細胞増殖および代謝に関連した移動、侵入、増殖および他の生物活性で一部特徴付けられる疾患が挙げられるが、これらに限定されない。
本発明の組成物は、異常な細胞活性、および、または、制御されていない細胞活性に関連した疾患を処置するために、使用される。本明細書中で提供される方法および組成物によって処置され得る疾患状態としては、癌(以下でさらに議論される)、免疫学的障害(例えば、慢性関節リウマチ、移植片−宿主疾患、多発性硬化症、乾癬);心臓血管疾患(例えば、動脈硬化症(artheroscrosis)、心筋梗塞(myocardioinfarction)、虚血、発作および.再狭窄);代謝障害および疾患(例えば、糖尿病、肥満および高コレステロール血症);ならびに他の炎症性疾患および変性疾患(例えば、腸間疾患(interbowel diseases)、変形性関節症(osteoarthritus)、黄斑変性、糖尿病性網膜症)が挙げられるが、これらに限定されない。
R2は、H、NH2、SH、OH、またはC1〜C2アルキルである;
R3、R4、R5およびR6は、それぞれ別個に、H、オキソ、CO2R10、CONR10R11、C1〜4アルキル、C1〜C6アルコキシ、またはC1〜C6アルコキシ−C1〜C4アルキルであり、ここで、各基内の該C1〜C4アルキル、C1〜C6アルコキシおよびC1〜C6アルコキシ−C1〜C4アルキルは、別個に、必要に応じて、1個または2個の置換基で置換されており、該置換基は、別個に、CO2R10、CONR10R11、OR10、およびNR10R11から選択されるか、あるいは、
R3およびR5は、それらが結合する炭素と一緒になって、C3〜C7炭素環を形成し、ここで、該環は、必要に応じて、H、ハロ、シアノ、ニトロ、またはアミノで置換されているか、
R4およびR6は、それらが結合する炭素と一緒になって、C3〜C7炭素環を形成し、ここで、該環は、必要に応じて、H、ハロ、シアノ、ニトロ、またはアミノで置換されているか、R3およびR6は、それらが結合する炭素と一緒になって、架橋されたC5〜C7炭素環を形成し、ここで、該環は、必要に応じて、H、ハロ、シアノ、ニトロ、またはアミノで置換されているか、あるいは
R4およびR5は、それらが結合する炭素と一緒になって、架橋されたC5〜C7炭素環を形成し、ここで、該環は、必要に応じて、H、ハロ、シアノ、ニトロ、またはアミノで置換されている;
Lは、C0〜4アルキル、C2〜C6アルケニル、−N(R12)−、−C(O)N(R12)−、−N(R12)C(O)−、−C(O)−、−O−(CH2)n−、または−(CH2)n−O−であり、ここで、nは、1〜4である;
Q1は、NまたはCR13であり、ここで、R13は、HまたはC(O)NR12(CH2)nNR10R11である;
Q2は、結合、CR14、OまたはNであり、ここで、R14は、H、OH、C1〜4アルキル、C1〜4アルコキシ、NR15R15であり、ここで、R15は、HまたはC1〜4アルキルであるか、あるいはQ2およびVは、一緒になって、C(=O)を形成する;
Q2が結合であるとき、Vは、存在せず、そしてR13は、Hではない;
Q1がCR13であり、そしてQ2がCHであるとき、
Vは、H、OH、NH2、C1〜C6アルコキシ、NR10R11、O(CH2)nNR10R11、4員〜7員ヘテロシクリルのCまたはNに結合されたO(CH2)n、NR12(CH2)nNR10R11、NR12C(O)NR12(CH2)nNR10R11、NR12C(O)(CH2)nNR10R11、(CH2)mO(CH2)nNR10R11、(CH2)mNR12(CH2)nNR10R11、(CH2)mCHR12(CH2)nNR10R11、C1〜4アルキルであって、該C1〜4アルキルは、必要に応じて、OHまたはNR10R11で置換されているか、あるいは、
Vは、4員〜7員不飽和環であり、該不飽和環は、OまたはNの1個〜3個の原子を含有するか、あるいは
Vは、二環式可溶化基である;
Q1がNであり、そしてQ2がCHであるとき、あるいはQ1がCR13であり、そしてQ2がOまたはNであるとき、
Vは、H、(CH2)mO(CH2)nNR10R11、(CH2)mNR12(CH2)nNR10R11、(CH2)mCHR12(CH2)nNR10R11、C(O)NR12(CH2)nNR10R11、C(O)(CH2)nNR10R11、C(O)O(CH2)nNR10R11、C(O)C(O)NR12(CH2)nNR10R11、SO2(CH2)nNR10R11、C(O)−C2〜C6アルケニル、またはC1〜4アルキルであり、該C1〜4アルキルは、必要に応じて、OHまたNR10R11で置換されているか、あるいは
Vは、4員〜7員飽和または不飽和環または複素環であり、該不飽和環または複素環は、OまたはNの1個〜3個の原子を含有し、必要に応じて、1個または2個のC1〜C3アルコキシ基で置換されているか、あるいは
Vは、「二環式可溶化基」である;
mは、1〜3であり、
nは、1〜4であり、
Wは、C1〜C6アルキル、NR10R11であるか、あるいはWは、
アリール、C3〜C7シクロアルキル、ヘテロシクリル、ヘテロアリール、あるいは5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系であり、該環系は、N、OおよびSから選択される、0個〜4個の環原子を含有し、ここで、各アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、および縮合二環式または三環式環系は、必要に応じて、1個、2個または3個の置換基で置換されており、該置換基は、別個に、ハロ、CN、NO2、CF3、OH、NR10R11、C1〜C6アルコキシ、C1〜C6アルキル、NO2、C(O)OC1〜C6アルキル、C(O)NR12−C1〜C6アルコキシ、C(O)NR12−ヘテロシクリル、アリール、O−アリール、O−CH2−アリール、N−アリールから選択され、ここで、各アリール置換基は、必要に応じて、ハロでさらに置換されているか、あるいは
V、Q2、LおよびWは、一緒になって、アリール環、ヘテロアリール環、C3〜C7シクロアルキル環、ヘテロシクリル環、あるいは5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環系を形成し、該環系は、N、OおよびSから選択される、0個〜4個の環原子を含有し、ここで、各環または環系は、必要に応じて、1個、2個または3個の基で置換されており、該基は、別個に、ハロ、CN、NO2、CF3、OH、NR10R11、C1〜C6アルコキシ、C1〜C6アルキル、NO2、C(O)OC1〜C6アルキル、C(O)NR12−C1〜C6アルコキシ、C(O)NR12−ヘテロシクリル、アリール、O−アリール、NH−アリールから選択され、ここで、各アリール置換基は、必要に応じて、ハロでさらに置換されている;そして
R10、R11およびR12は、それぞれ別個に、HまたはC1〜6アルキルであり、該C1〜6アルキルは、必要に応じて、アリールまたはヘテロアリールで置換されている。
4−(4−(2−フルオロフェニル)ピペラジン−1−イル)−1H−ピラゾロ[3,4−d]ピリミジン;
4−(4−(3−クロロフェニル)ピペラジン−1−イル)−1H−ピラゾロ[3,4−d]ピリミジン;
4−(1H−ピラゾロ[3,4−d]ピリミジン−4−イル)ピペラジン−1−カルボン酸エチル;
4−(1H−ピラゾロ[3,4−d]ピリミジン−4−イル)ピペラジン−1−カルボン酸第三級ブチル;そして
N−(4−フェノキシフェニル)−4−(1H−ピラゾロ[3,4−d]ピリミジン−4−イル)ピペラジン−1−カルボキサミド。
(表1)
本明細書中で使用する以下の用語および語句は、一般に、それらが使用される文脈がそれ以外の意味を指示しているか異なる何かを意味すると明白に定義されている場合を除いて、以下で述べる意味を有すると解釈される。
純粋形態かまたは適切な薬学的組成物での、本発明の化合物またはそれらの薬学的に受容可能な塩の投与は、任意の容認された投与の様式、または同様の有用性を与える薬剤を介して行われ得る。したがって、投与は、例えば、経口的、経鼻的、非経口的(静脈内、筋内、または皮下)、局所的、経皮的、膣内、膀胱内、槽内、または直腸内への、固体投薬形態、半固体投薬形態、凍結乾燥粉末投薬形態、または液体投薬形態の形状(例えば、錠剤、坐剤、丸剤、柔らかな弾性材料および硬いゼラチンのカプセル剤、粉剤、液剤、懸濁液、またはエーロゾル剤など)であり得、好ましくは、正確な投薬量の単回投与のために適切な単位投薬形態である。
例えば、p70S6Kレセプターキナーゼに結合する候補因子に関するスクリーニングの方法において本発明の化合物を使用するために、タンパク質は支持体に結合され、そして本発明の化合物がアッセイのために添加される。代替的に、本発明の化合物は上記支持体に結合され、そしてタンパク質が添加される。探求され得る新規の結合因子の中で候補因子の分類は、特異的抗体、化学的ライブラリーのスクリーニングにおいて同定された非天然結合因子、ペプチドアナログなどが挙げられる。特に関心があるものは、ヒト細胞に対して低い毒性を有する候補因子に関するスクリーニングアッセイである。広範な種々のアッセイは、この目的のために使用され得る。このアッセイとしては、標識化インビトロタンパク質−タンパク質結合アッセイ、電気泳動移動度変化アッセイ、タンパク質結合に関する免疫学的アッセイ、機能的アッセイ(リン酸化アッセイなど)などが挙げられる。
以下の略語および用語は、本明細書全体を通じて、以下で指定した意味を有する:
スキーム1は、式Iに従った本発明の代表的な化合物の一般的な合成経路を描写しているが、これに限定されるとは解釈されない。特定の例は、この一般的な合成経路に引き続いて、記述されている。これらの一般的な経路および後の特定の実施例の記述に関して、当業者は、発明の詳細な説明および請求項で記述されているように、本発明の化合物を製造できる。
N−Boc−4−(4−クロロベンゾイル)ピペリジン(300mg、0.92mmol)および2−(ジエチルアミノ)エチルアミン(215mg、1.85mmol)の混合物に、室温で、Ti(OiPr)4(1.05g、3.70mmol)を加えた。撹拌を12時間継続した。次いで、MeOH(3mL)およびAcOH(1mL)を加えた。続いて、NaBH4(70mg、1.85mmol)を少しずつ慎重に加えた。次いで、その反応混合物をさらに1時間撹拌し、そしてセライトで濾過した。セライトパッドをEtOAcで洗浄した。そのEtOAc溶液を、5%NaOH、ブラインで洗浄し、そしてNa2SO4で乾燥した。溶媒を除去すると、粗生成物(200mg、50%)を得、これを、次の工程で使用した。
1H NMR(400 MHz,DMSO−d6)δ 14.07(br s,1H),10.81(br s,1H), 10.05 (br s, 1 H), 8.30 (s, 1 H), 7.69 (d, J = 8.6 Hz, 2 H), 7.56 (d, J = 8.6 Hz, 2 H), 4.54−4.37 (m, 2 H), 3.60−3.40 (m, 5 H), 3.20−2.90
LC−MS(M+1):536.5(100%)、534.5(80%)。
1H NMR (400 MHz, DMSO−d6) δ 8.27 (s, 1 H), 7.41 (d, J = 8.3 Hz, 2 H), 7.25 (d, J = 8.3 Hz, 2 H), 4.50 (d, J = 13.2 Hz, 1 H), 4.34 (d, J = 12.8 Hz, 1 H), 3.36 (d, J = 10.4 Hz, 1 H), 3.20−3.00 (m, 2 H), 2.50−2.40 (m, 2 H), 2.45 (q, J = 7.1 Hz, 4 H), 2.40−2.30 (m, 2 H), 2.25−2.20 (m, 1 H), 2.18−2.10 (m, 1 H), 2.05 (s, 3 H), 1.40−1.28 (m, 2 H), 1.18−1.08 (m, 1 H), 0.92 (t, J = 7.2 Hz, 6 H).
LC−MS(M+1):550.4(100%)、548.4(80%).
1H NMR (400 MHz, DMSO−d6) δ 8.52 (d, J = 9.0 Hz, 1 H), 8.28 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.5 Hz, 2 H), 4.70 (t, J = 8.6 Hz, 1 H), 4.48 (d, J = 12.7 Hz, 1 H), 4.39 (d, J = 12.7 Hz, 1 H), 3.10−2.90 (m, 2 H), 2.70−2.50 (m, 2 H), 2.45−2.38 (m, 4 H), 2.30−2.10 (m, 2 H), 2.00−1.80 (m, 2 H), 1.40−1.30 (m, 3 H), 0.89 (t, J = 7.3 Hz, 6 H).
観察されたM+、臭素同位体:549.1、551.1(1:1)
1HNMR (d6−DMSO): 9.40 (br s, 1H), 8.90 (br t, 1H), 8.28 (s, 1H), 7.47 (d, 2H), 7.28 (d, 2h), 4.95 (m, 1H), 4.50 (d, 2H), 3.21 (m, 4H), 2.86 (d, 2H), 2.71 (d, 6H), 1.94 (d, 2H), 1.5 (m, 2H) ppm.
EtOH(25mL)およびH2O(5mL)中のN−Boc−4−(4−クロロベンゾイル)ピペリジン(1.0g、3.08mmol)の混合物に、ヒドロキシルアミン塩酸塩(536mg、7.72mmol)およびNaOAc(633mg、7.72mmol)を加えた。その反応混合物を、還流下にて、3時間撹拌した。EtOHを除去した。残渣をEtOAcに溶解し、ブラインで洗浄し、そしてNa2SO4で乾燥した。EtOAcを除去すると、所望のオキシムの混合物(1.0g、96%)が得られた。
1H NMR (400 MHz, DMSO−d6) δ 8.25 (s, 1 H), 7.36 (d, J = 8.6 Hz, 2 H), 7.24 (d, J = 8.5 Hz, 2 H), 6.75 (d, J = 8.7 Hz, 1 H), 5.83 (t, J = 5.3 Hz, 1 H), 4.55−4.47 (m, 3 H), 3.20−2.80 (m, 5 H), 2.20 (t, J = 6.1 Hz, 2 H), 2.09 (s, 6 H), 1.80−1.70 (m, 1 H), 1.48−1.30 (m, 3 H).
CCl4中の(4−クロロフェニル)−酢酸メチルエステル(2.5g、13.5mmol)およびNBS(2.52g、14.1mmol)から、2−ブロモ−(p−クロロフェニル)−酢酸メチルエステルを調製した。
1H NMR (400 MHz, DMSO−d6) δ 8.31 (s, 1 H), 8.17 (t, J = 5.7 Hz, 1 H), 7.45−7.40 (m, 4 H), 3.95 (s, 1 H), 3.81 (br s, 4 H), 3.16 (q, J = 5.9 Hz, 2 H), 2.60−2.52 (m, 2 H), 2.50−2.44 (m, 2 H), 2.28 (t, J = 6.6 Hz, 2 H), 2.14 (s, 6 H).
LC−MS(M+1):423.3(100%)、421.3(80%).
1H NMR (400 MHz, CDCl3) δ 13.20 (br s, 1 H), 8.45 (s, 1 H), 7.32 (d, J = 8.6 Hz, 2 H), 7.24 (d, J = 8.4 Hz, 2 H), 4.66 (s, 2 H), 4.63 (s, 2 H), 4.17 (t, J = 5.5 Hz, 2 H), 3.50 (t, J = 5.4 Hz, 2 H).
観察されたM+、臭素同位体:406.9、408.9(1:1)
1HNMR (d6−DMSO): 10.00 (br s, 1H), 8.42 (s, 1H), 7.54 (q, 4H), 4.40 (m, 4H), 4.41 (s, 2H), 3.46−3.20 (m, 4H) ppm.
4−Bocピペラジノン(240mg、1.2mmol)のDMF(3mL)溶液に、NaH(58mg、1.44mmol、鉱油中で60%)を加えた。得られた溶液を、室温で、30分間撹拌した。次いで、2−ブロモ−(p−クロロフェニル)−酢酸メチルエステル(315mg、1.2mmol)を加えた。その反応混合物を、室温で、さらに3時間撹拌した。それをEtOAcで希釈し、そしてブラインで洗浄し、Na2SO4で乾燥した。EtOAcを除去すると、所望生成物が得られ、次いで、これを、3時間にわたって、MeOH(2mL)およびH2O(1mL)中のNaOH(102mg、2.56mmol)で処理した。減圧下にてMeOHを除去した。残渣をH2O(5mL)に溶解し、そしてエーテルで洗浄した。水相を1N HClで酸性化した。固形物を濾過し、H2Oで洗浄し、そして真空乾燥した。粗カルボン酸(165mg、0.44mmol)を、DCM(2mL)中の2−(ジメチルアミノ)エチルアミン(157mg、1.79mmol)、HATU(680mg、1.79mmol)およびDIEA(231mg、1.79mmol)と混合した。この撹拌を2時間継続した。その混合物を濃縮し、そして残渣をEtOAcに溶解した。有機相を飽和NaHCO3およびブラインで洗浄した。溶媒を除去すると、粗カップリング生成物が得られた。
1H NMR (400 MHz, DMSO−d6) δ 8.33−8.31 (m, 2 H), 7.45 (d, J = 8.4 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H), 6.21 (s, 1 H), 4.55−4.42 (m, 2 H), 4.05−4.00 (m, 3 H), 3.74−3.68 (m, 1 H), 3.32−3.22 (m, 1 H), 3.20−3.10 (m, 1 H), 3.08−3.00 (m, 1 H), 2.28 (t, J = 6.5 Hz, 2 H), 2.13 (s, 6 H).
1−N−Boc−4−ピペリジンカルボン酸メチルエステル(2.0g、8.22mmol)の−78℃THF(30mL)溶液に、LiHMDS(THF中で1.0M、12ml、12.3mmol)を滴下した。この撹拌を45分間継続した。次いで、THF(3mL)の溶液として、塩化4−クロロベンジル(1.59g、9.86)を加えた。その混合物を、室温までゆっくりと温めつつ、5時間撹拌した。H2Oを加えて、この反応をクエンチした。次いで、それをEtOAcで抽出した。有機相をブラインで洗浄し、そしてNa2SO4で乾燥した。EtOAcを除去すると、粗生成物が得られた。
LC−MS(M+1):564.4(100%)、562.4(80%)。
1H NMR (400 MHz, DMSO−d6) δ 14.17 (br s, 1 H), 10.34 (br s, 1 H), 8.33 (s, 1 H), 8.11 (br s, 1 H), 7.34 (d, J = 7.9 Hz, 2 H), 7.10 (d, J = 7.7 Hz, 2 H), 4.27 (br d, J = 13.4 Hz, 2 H), 3.28−3.27 (m, 2 H), 3.20−3.10 (m, 2 H), 3.10−3.00 (m, 4 H), 3.00−2.90 (m, 2 H), 2.85 (s, 2 H), 2.17 (br d, J = 13.0 Hz, 2 H), 1.82 (br s, 2 H), 1.64 (br s, 2 H), 1.21−1.18 (m, 6 H).
N−Boc−4−(p−クロロフェニル)−ピペリジン−4−カルバミド(135mg、0.40mmol)のDMF(4mL)溶液に、NaH(鉱油中で60%、20mg、0.5mmol)を加えた。この撹拌を30分間継続した。次いで、塩化3−(ジエチルアミノ)プロピル(90mg、0.60)を加えた。次いで、その混合物を90℃まで温めた。この撹拌をさらに3時間継続した。冷却した混合物に、H2Oを加えた。次いで、それをEtOAcで抽出した。有機相をブラインで洗浄し、そしてNa2SO4で乾燥した。EtOAcを除去すると、粗生成物が得られた。
1H NMR (400 MHz, DMSO−d6) δ 8.31 (s, 1 H), 7.83 (t, J = 5.5 Hz, 1 H), 7.41 (s, 4 H), 4.25 (br d, J = 13.4 Hz, 2 H), 3.37 (br t, J = 11.9 Hz, 2 H), 3.08 (q, J = 6.4 Hz, 2 H), 2.63 (br d, J = 13.7 Hz, 2 H), 2.34 (q, J = 7.2 Hz, 4 H), 2.23−2.19 (m, 2 H), 1.99−1.92 (m, 2 H), 1.49−1.41 (m, 2 H), 0.85 (t, J = 7.2 Hz, 6 H).
NMR, DMSO−d6, HCl salt : δ 10.40 (s, 1H), 8.30 (s, 1H), 7.49 (d, 2H), 7.26 (d, 2H), 4.88 (s, 1H), 4.59 (m, 2H), 4.50 (obs m, 2H), 3.34−3.23 (m, 4H), 3.07−3.03 (m, 2H), 2.73 (s, 6H), 1.94 (d, 2H), 1.38−1.34 (m, 2H) ppm.
観察されたMS 408.9(M+H),
(DMSO−d6) δ 8.32 (s, 1H), 7.12 (d, 2H), 6.71 (d, 2H), 4.40 (d, 2H), 3.62 (s, 1H), 3.35 (t, 2H), 2.08 (d, 2H), 1.55 (m, 2H) ppm.
観察されたMS 536.1(M+H),
(DMSO−d6) δ 9.59 (br. s, 1H), 8.28 (s, 1H), 7.58 (d, 2H), 7.37 (d, 2H), 4.80 (m, 1H), 4.50 (d, 2H), 3.21 (m, 4H), 3.0 (m, 4H), 2.34 (m, 2H), 1.92 (d, 2H), 1.39 (m, 2H), 1.17 (t, 6H) ppm.
観察されたMS 522.1(M+H),
(CD3OD) δ 8.27 (s, 1H), 7.18 (d, 2H), 6.90 (d, 2H), 4.90 (m, 2H), 4.71 (d, 2H), 3.91 (m, 1H), 3.28 (m, 4H), 2.62 (m, 4H), 1.93 (m, 4H), 1.70 (m, 2H), 1.08 (t, 6H) ppm.
観察されたM+H:524.1
NMR, DMSO−d6, HCl salt: δ 10.66 (br s, 1H), 8.29 (s, 1H), 7.46 (d, 2H), 7.29 (d, 2H), 4.51−4.48 (m, 3H), 4.34 (m, 2H), 3.29−3.23 (m, 4H), 2.67−2.45 (obs s, 6H), 2.01 (d, 2H), 1.47−1.41 (m, 2H) ppm.
NMR, DMSO−d6, HCl salt: δ 10.51 (br s, 1H), 8.89 (s, 1H), 7.52 (d, 2H), 7.39 (d, 2H), 4.78−4.75 (m, 2H), 4.50 (d, 2H), 4.33 (m, 1H), 3.86 (m, 2H), 3.41 (m, 2H), 3.26−3.18 (m, 6H), 2.12 (d, 2H), 1.42 (m, 2H), 1.24−1.14 (m, 6H) ppm.
観察されたMS 387.0(M+H),
(DMSO−d6) δ 10.18 (br. s, 1H), 8.43 (s, 1H), 7.52 (m, 5H), 4.60 (m, 2H), 4.49 (m, 1H), 3.90 (m, 2H), 3.20, (m, 2H), 3.05 (m, 2H), 2.70 (d, 3H) ppm.
NMR, DMSO−d6, HCl salt: δ 8.30 (s, 1H), 7.50 (d, 2H), 7.39 (d, 2H), 4.45 (m, 2H), 4.20 (d, 1H), 3.71 (m, 2H), 3.43 (m, 1H), 3.23 (m, 2H), 3.03 (m, 2H), 2.80 (d, 3H), 2.75 (d, 3H), 2.13−1.90 (m, 2H), 1.51−1.23 (m, 2H) ppm.
観察されたMS 509.0 (M+H),
(DMSO−d6) δ 8.30 (s, 1H), 7.46 (d, 2H), 7.32 (d, 2H), 4.41 (dd, 2H), 4.11 (d, 1H), 3.22 (m, 2H), 3.06 (m, 4H), 2.72 (s, 6H), 2.08 (d, 1H), 1.88 (m, 2H), 1.51−1.32 (m, 4H) ppm.
観察されたM+H、臭素同位体:406.1、408.1(1:1)
1HNMR (d6−DMSO): δ 8.21 (s, 1H), 7.42 (d, 2H), 7.20 (d, 2H), 4.45 (m, 3H), 2.98 (q, 2H), 1.90 (d, 1H), 1.80 (br s, 1H), 1.40 (m, 4H) ppm.
観察されたM+H、臭素同位体:477.1、479.1(1:1)
1HNMR (d6−DMSO): δ10.25 (br s, 1H), 8.25 (s, 1H), 7.42 (t, 2H), 7.20 (t, 2H), 4.80 (m, 1H), 4.20 (d, 1H), 3.45 (m, 2H), 3.20 (m, 4H), 2.70 (d, 6H), 2.10 (d, 1H), 2.00 (m, 1H), 1.40 (m, 4H) ppm.
観察されたM+、臭素同位体:421.9、423.9(1:1)
1HNMR (d6−DMSO): δ 8.27 (s, 1H), 7.36 (m, 4H), 5.40 (d, 1H), 4.45 (m, 1H), 4.33(t,1H), 2.99 (m, 2H), 1.87 (m, 2H), 1.41 (m, 4H) ppm.
観察されたM+、臭素同位体:420.4、422.4(1:1)
1HNMR (d6−DMSO): δ 8.30 (s, 1H), 8.04 (d, 2H), 7.61 (d, 2H), 4.46 (d, 2H), 3.82 (m, 1H), 3.32 (m,2H), 1.95 (d, 2H), 1.73 (dq, 2H) ppm.
NMR, DMSO−d6, HCl salt: δ 10.43 (br. s, 1H), 8.30 (s, 1H), 7.22 (d, 2H), 7.03 (d, 2H), 4.60 (d, 2H), 4.01 (m, 1H), 3.63 (m, 2H), 3.29 (m, 2H), 3.14 (m, 4H), 3.02 (m, 2H), 1.84 (m, 4H), 1.19 (t, 6H) ppm.
観察されたM+H:524.1
NMR, DMSO−d6, HCl salt: δ 10.66 (br s, 1H), 8.29 (s, 1H), 7.46 (d, 2H), 7.29 (d, 2H), 4.51−4.48 (m, 3H), 4.34 (m, 2H), 3.29−3.23 (m, 4H), 2.67−2.45 (obs s, 6H), 2.01 (d, 2H), 1.47−1.41 (m, 2H) ppm.
1HNMR (d6−DMSO): 7.35 (dd, 4H), 4.0 (d, 1H), 3.98 (dd, 1H), 3.60 (m, 2H), 3.4 (d, 4H), 3.8 (m, 4H), 2.15 (m, 1H), 1.6 (s, 9H) ppm.
[4−(3−ブロモ−1H−ピラゾロ[3,4−d]ピリミジン−4−イル)−1−(4−クロロ−ベンジル)−ピペラジン−2−イル]−メタノール(10)。丸底フラスコに、8(100mg、0.29mmol、1.0当量)、MeOH(1.0mL)、およびジオキサン中の4N HCl(1.0mL)を加えた。その反応物を、室温で、1時間撹拌し、ロータリーエバポレーターで濃縮し、そして1時間にわたって高真空に置いた。得られた脱boc化(de−boc’ed)残渣をTHF(5mL)およびEt3N(0.1mL)に溶解した後、3−ブロモ−4−クロロ−1H−ピラゾロ[3,4−d]ピリミジン(52mg、0.25mmol、0.9当量)を加えた。その混合物を、30分間にわたって、65℃まで加熱し、ロータリーエバポレーションで濃縮し、DMSO(4mL)に溶解し、そして分取HPLC(これは、20:80%の勾配、11分間の実行時間、40mL/分を使用する)で精製した。凍結乾燥後、固形物として、60mgの8を回収した。
1HNMR (d6−DMSO): δ 10.0 (br s, 1H), 8.41 (s, 1H), 7.58 (m, 4H), 4.8 (br d, 1H), 4.70 (d, 2H), 4.50 (br d, 2H), 4.20 (m, 2H), 3.20 (m, 4H) ppm.
観察されたM+H:422.9
NMR, DMSO−d6, TFA salt: δ 10.26 (br s, 1H), 8.44 (s, 1H), 7.59−7.57 (m, 4H), 4.81 (m, 1H), 4.56−4.45 (m, 3H), 4.18 (m, 1H), 3.58 (m, 1H), 3.39−3.33 (m, 2H), 3.19 (s, 2H), 1.53 (s, 3H) ppm.
(実施例2)
キナーゼアッセイを、固定化されたミエリン塩基性タンパク質(MBP)へのγ−33P ATPの取り込みを測定することにより行った。高結合ホワイト384ウェルプレート(Greiner)を、ウェルあたりTris緩衝生理食塩水(TBS;50mM Tris pH8.0、138mM NaCl、2.7mM KCl)中、20μg/mL MBP(Sigma カタログ番号M−1891)を、4℃で24時間インキュベーションすることによりMBPでコートした。プレートを3回、100μl TBSで洗浄した。キナーゼ反応を、全量34μlのキナーゼ緩衝液(5mM Hepes pH7.6、15mM NaCl、0.01%ウシγグロブリン(Sigma カタログ番号I−5506)、10mM MgCl2、1mM DTT、0.02% TritonX−100)中で行った。化合物の希釈をDMSOで行い、1%の最終DMSO濃度でアッセイウェルに添加した。各データポイントは、二連で測定し、それぞれ個々の化合物の測定について少なくとも2回の二連アッセイを行った。酵素を、例えば最終濃度10nMまたは20nMで添加した。非標識ATPとγ−33P ATPとの混合物を、反応を開始するために添加した(代表的には、1ウェルあたり2×106cpmのγ−33P ATP(3000Ci/mmole)および10μMまたは30μMいずれかの非標識ATP)。この反応を振盪しながら室温で1時間行った。プレートをTBSで7回洗浄し、続いて50μl/ウェルのシンチレーション溶液(Wallac)を添加した。放射活性をWallac Triluxカウンターを使用して測定した。これはそのようなアッセイのほんの1つの形式であり、当業者に公知であるように、様々な他の形式が可能である。
キナーゼ活性および化合物の阻害を、下記の3つのアッセイ形式のうちの1つ以上を使用して調べる。各々のアッセイのATP濃度を、それぞれ個々のキナーゼについてミカエリス−メンテン定数(KM)に近くなるように選択する。用量反応実験を、384−ウェルプレート形式中、10個の異なるインヒビター濃度で行う。このデータを、下の4つのパラメーターの式(2)にあてはめる;ここでYは観測されたシグナル、Xはインヒビター濃度、Minは酵素非存在でのシグナルのバックグラウンド(0%酵素活性)、Maxはインヒビター非存在でのシグナル(100%酵素活性)、IC50は50%酵素阻害でのインヒビター濃度、Hは協調性を測定するための経験的なヒル係数を示す。代表的にHは1に近い。
p70S6キナーゼの生化学活性をルシフェラーゼ共役(coupled)化学発光キナーゼアッセイ(LCCA)形式を使用して測定した。キナーゼ活性を、キナーゼ反応後に残存しているATPの割合として評価した。残存しているATPを、ルシフェラーゼ−ルシフェリン結合化学発光により検出した。具体的には、この反応を、20μLのアッセイ緩衝液(20mM Tris−HCl pH7.5、10mM MgCl2、0.02% Triton X−100、100mM DTT、2mM MnCl2)中、試験化合物、5μM ATP、5μM RRRLSSLRAペプチドおよび12nM p70S6K(バキュロウイルスで発現させたT412E変異を含むヒトp70S6キナーゼドメイン残基1−421)を混合することにより開始した。この混合物を、20μLのルシフェラーゼ−ルシフェリン混合物を加えた後、2時間周囲温度でインキュベーションし、化学発光シグナルをWallac Victor2リーダーを使用して読み取る。このルシフェラーゼ−ルシフェリン混合物は、50mM HEPES、pH7.8、8.5μg/mLシュウ酸(pH7.8)、5(または50)mM DTT、0.4% Triton X−100、0.25mg/mL コエンザイムA、63μM AMP、28μg/mLルシフェリンおよび40,000ユニット/mLルシフェラーゼからなる。
Akt1キナーゼの生化学アッセイを、ルシフェラーゼ結合化学発光キナーゼアッセイ(LCCA)形式を使用して評価した。キナーゼ活性を、キナーゼ反応後に残存しているATPの割合として評価した。残存しているATPを、ルシフェラーゼ−ルシフェリン結合化学発光により検出した。具体的には、この反応を、20μLのアッセイ緩衝液中(20mM Tris−HCL pH7.5、10mM MgCl2、0.01% Triton X−100、1mM DTT、3mM MnCl2)、試験化合物、1μM ATP、5μMクロスチド(crosstide)ペプチドおよび1.3nM Akt1(バキュロウイルスで発現させたPDK1で活性化されるヒトAkt1キナーゼドメイン残基R144−A480)の混合により開始した。この混合物を、20μLのルシフェラーゼ−ルシフェリン混合物を加えた後、2時間周囲温度でインキュベーションし、化学発光シグナルをWallac Victor2リーダーを使用して読み取る。このルシフェラーゼ−ルシフェリン混合物は、50mM HEPES、pH7.8、8.5μg/mLシュウ酸(pH7.8)、5(または50)mM DTT、0.4% Triton X−100、0.25mg/mL コエンザイムA、63μM AMP、28μg/mLルシフェリンおよび40,000ユニット/mLルシフェラーゼからなる。
Akt2の生化学アッセイを、ルシフェラーゼ結合化学発光キナーゼアッセイ(LCCA)形式を使用して評価した。キナーゼ活性を、キナーゼ反応後に残存しているATPの割合として評価した。残存しているATPを、ルシフェラーゼ−ルシフェリン結合化学発光により検出した。具体的には、この反応を、20μLのアッセイ緩衝液中(20mM Tris−HCl pH7.5、10mM MgCl2、0.03% Triton X−100、1mM DTT、3mM MnCl2)、試験化合物、2μM ATP、5μMクロスチドペプチドおよび10nM Akt2(ヒトAkt2キナーゼドメイン残基K146−R480を発現させたバキュロウイルス)の混合により開始した。この混合物を、20μLのルシフェラーゼ−ルシフェリン混合物を加えた後、2時間周囲温度でインキュベーションし、化学発光シグナルをWallac Victor2リーダーを使用して読み取る。このルシフェラーゼ−ルシフェリン混合物は、50mM HEPES、pH7.8、8.5μg/mLシュウ酸(pH7.8)、5(または50)mM DTT、0.4% Triton X−100、0.25mg/mL コエンザイムA、63μM AMP、28μg/mLルシフェリンおよび40,000ユニット/mLルシフェラーゼからなる。
表2は、選択された本発明の化合物についての構造活性相関のデータを示す。阻害を、以下の略語を用いてIC50として示す:A=50nM未満のIC50、B=50nMより大きいが500nM未満のIC50、C=500nMより大きいが2000nM未満のIC50、およびD=2000nMに等しいかまたは2000nMより大きいIC50。
Claims (27)
- 式Iに従った化合物、
R1は、ハロであり;
R2は、Hであり;
R3、R4、R5およびR6は、それぞれ別個に、H、オキソ、CO2R10、CONR10R11、C1〜4アルキル、C1〜C6アルコキシ、またはC1〜C6アルコキシ−C1〜C4アルキルであり、ここで、各基内の該C1〜C4アルキル、C1〜C6アルコキシおよびC1〜C6アルコキシ−C1〜C4アルキルは、別個に、必要に応じて、1個または2個の置換基で置換されており、該置換基は、別個に、CO2R10、CONR10R11、OR10、およびNR10R11から選択され;
Lは、結合、C1〜C4アルキル、C2〜C6アルケニル、−N(R12)−、−C(O)N(R12)−、−N(R12)C(O)−、−C(O)−、−O−(CH2)n−、または−(CH2)n−O−であり、ここで、nは、1〜4である;
Q 1 はCHまたはNであり、Q 2 はCHまたはNであり、ただし、Q 1 およびQ 2 が同時にNであることはなく、
Q 1 がCHであり、かつQ 2 がCHであるとき、
Vは、H、OH、NH2、C1〜C6アルコキシ、NR10R11、O(CH2)nNR10R11、4員〜7員ヘテロシクリルのCまたはNに結合されたO(CH2)n、NR12(CH2)nNR10R11、NR12C(O)NR12(CH2)nNR10R11、NR12C(O)(CH2)nNR10R11、(CH2)mO(CH2)nNR10R11、(CH2)mNR12(CH2)nNR10R11、(CH2)mCHR12(CH2)nNR10R11、C1〜4アルキルであって、該C1〜4アルキルは、必要に応じて、OHまたはNR10R11で置換されているか、あるいは、
Vは、4員〜7員不飽和環であり、該不飽和環は、OまたはNの1個〜3個の原子を含有する;
Q1がNであり、かつQ2がCHであるとき、
Vは、H、(CH2)mO(CH2)nNR10R11、(CH2)mNR12(CH2)nNR10R11、(CH2)mCHR12(CH2)nNR10R11、C(O)NR12(CH2)nNR10R11、C(O)(CH2)nNR10R11、C(O)O(CH2)nNR10R11、C(O)C(O)NR12(CH2)nNR10R11、SO2(CH2)nNR10R11、C(O)−C2〜C6アルケニル、またはC1〜4アルキルであり、該C1〜4アルキルは、必要に応じて、OHまたNR10R11で置換されているか、あるいは
Vは、4員〜7員飽和または不飽和環または複素環であり、該不飽和環または複素環は、OまたはNの1個〜3個の原子を含有し、必要に応じて、1個または2個のC1〜C3アルコキシ基で置換されているか、あるいは
Q1がCHであり、かつQ2がNであるとき、
Vは、H、(CH2)mO(CH2)nNR10R11、(CH2)mNR12(CH2)nNR10R11、(CH2)mCHR12(CH2)nNR10R11、C(O)NR12(CH2)nNR10R11、C(O)(CH2)nNR10R11、C(O)O(CH2)nNR10R11、C(O)C(O)NR12(CH2)nNR10R11、SO2(CH2)nNR10R11、C(O)−C2−C6アルケニル、またはC1-4アルキルであり、該C1〜4アルキルは、必要に応じて、OHまたNR10R11で置換されているか、あるいは
Vは、4員〜7員飽和または不飽和環または複素環であり、該不飽和環または複素環は、OまたはNの1個〜3個の原子を含有し、必要に応じて、1個または2個のC1〜C3アルコキシ基で置換されている;
mは、1〜3であり;
nは、1〜4であり;
Wは、C1〜C6アルキル、NR10R11であるか、あるいはWは、
アリール、C3〜C7シクロアルキル、ヘテロシクリル、ヘテロアリール、あるいは5員〜12員縮合二環式または三環式飽和、部分飽和または不飽和環であり、該環は、N、OおよびSから選択される、0個〜4個の環原子を含有し、ここで、各アリール、シクロアルキル、ヘテロシクリル、ヘテロアリール、および縮合二環式または三環式環は、必要に応じて、1個、2個または3個の置換基で置換されており、該置換基は、別個に、ハロ、CN、NO2、CF3、OH、NR10R11、C1〜C6アルコキシ、C1〜C6アルキル、NO2、C(O)OC1〜C6アルキル、C(O)NR12−C1〜C6アルコキシ、C(O)NR12−ヘテロシクリル、アリール、O−アリール、O−CH2−アリール、NH−アリールから選択され、ここで、各アリール置換基は、必要に応じて、ハロでさらに置換されている;そして
R10、R11およびR12は、それぞれ別個に、HまたはC1〜6アルキルであり、該C1〜6アルキルは、必要に応じて、アリールまたはヘテロアリールで置換されている、
化合物。 - R1が、ブロモである、請求項1に記載の化合物。
- R3、R4、R5およびR6が、それぞれ、Hである、請求項1または2に記載の化合物。
- Q1が、CHであり、そしてQ2が、CHである請求項1〜3のいずれかに記載の化合物。
- Lが、結合である、請求項1〜4のいずれかに記載の化合物。
- Wが、アリールであり、該アリールが、必要に応じて、1個、2個または3個の置換基で置換されており、該置換基が、別個に、ハロ、CN、NO2、CF3、OH、NR10R11、C1〜C6アルコキシ、C1〜C6アルキル、NO2、C(O)OC1〜C6アルキル、C(O)NR12−C1〜C6アルコキシ、C(O)NR12−ヘテロシクリル、アリール、O−アリール、O−CH2−アリール、NH−アリールから選択され、ここで、各アリール置換基が、必要に応じて、ハロでさらに置換されている、請求項1〜5のいずれかに記載の化合物。
- Wが、フェニルであり、該フェニルが、必要に応じて、1個、2個または3個の置換基で置換されており、該置換基が、別個に、ハロ、CN、NO2、CF3、OH、NR10R11、C1〜C6アルコキシ、C1〜C6アルキル、NO2、C(O)OC1〜C6アルキル、C(O)NR12−C1〜C6アルコキシ、C(O)NR12−ヘテロシクリル、アリール、O−アリール、O−CH2−アリール、NH−アリールから選択され、ここで、各アリール置換基が、必要に応じて、ハロでさらに置換されている、請求項6に記載の化合物。
- Wが、フェニルであり、該フェニルが、必要に応じて、1個または2個の置換基で置換されており、該置換基が、別個に、ハロ、CF3、C1〜4アルキル、およびC1〜C4アルコキシから選択される、請求項7に記載の化合物。
- Wが、フェニルであり、該フェニルが、必要に応じて、1個または2個の置換基で置換されており、該置換基が、別個に、F、ClおよびBrから選択される、請求項8に記載の化合物。
- Vが、H、OH、O(CH2)nNR10R11、NR12(CH2)nNR10R11、NR12C(O)NR12(CH2)nNR10R11、またはNR12C(O)(CH2)nNR10R11である、請求項1〜9のいずれかに記載の化合物。
- Vが、H、OH、O(CH2)nNR10R11、NR12(CH2)nNR10R11、NR12C(O)NR12(CH2)nNR10R11、またはNR12C(O)(CH2)nNR10R11であり、そしてR10およびR11が、それぞれ、CH3である、請求項1〜10のいずれかに記載の化合物。
- Q1が、Nであり、そしてQ2が、CHである請求項1〜3のいずれか記載の化合物。
- Lが、結合であり、Wが、フェニルであり、該フェニルが、必要に応じて、1個または2個の置換基で置換されており、該置換基が、別個に、F、ClおよびBrから選択され、Vが、H、C(O)NR12(CH2)nNR10R11、またはC1〜4アルキルである、請求項12に記載の化合物。
- Vが、H、C(O)NR12(CH2)nNR10R11、またはC1〜4アルキルであり、そしてR10およびR11が、それぞれ、CH3である、請求項12または13に記載の化合物。
- Vが、Hである、請求項14に記載の化合物。
- Q1がCHであり、そしてQ2がNである請求項1〜3のいずれかに記載の化合物。
- Lが、結合であり、Wが、フェニルであり、該フェニルが、必要に応じて、1個または2個の置換基で置換されており、該置換基が、別個に、F、ClおよびBrから選択され、Vが、H、C(O)NR12(CH2)nNR10R11、C(O)(CH2)nNR10R11、C(O)O(CH2)nNR10R11、C(O)C(O)NR12(CH2)nNR10R11、SO2(CH2)nNR10R11、C(O)−C2〜C6アルケニル、またはC1〜4アルキルであり、該C1〜4アルキルが、必要に応じて、NR10R11で置換されている、請求項16に記載の化合物。
- Vが、H、C(O)NR12(CH2)nNR10R11、C(O)(CH2)nNR10R11、C(O)O(CH2)nNR10R11、C(O)C(O)NR12(CH2)nNR10R11、SO2(CH2)nNR10R11、C(O)−C2〜C6アルケニル、またはC1〜4アルキルであり、該C1〜4アルキルが、必要に応じて、NR10R11で置換されており、そしてR10およびR11が、それぞれ、CH3である、請求項16または17に記載の化合物。
- キナーゼのインビボ活性を調節するための薬学的組成物であって、治療有効量の請求項1〜19のいずれかに記載の化合物の少なくとも1種と、必要に応じて、薬学的に受容可能なキャリアとを含有する薬学的組成物。
- 前記キナーゼが、p70S6Kである、請求項20に記載の薬学的組成物。
- p70S6Kのインビボ活性の調節が、該p70S6Kの阻害を包含する、請求項21に記載の薬学的組成物。
- p70S6、Akt−1およびAkt−2キナーゼの少なくとも1種のモジュレーターをスクリーニングする方法であって、請求項1〜19のいずれか1項に記載の化合物、および少なくとも1種の候補薬剤のいずれかを混ぜ合わせる工程、および該キナーゼの活性に対する該候補薬剤の効果を決定する工程を包含する、方法。
- 細胞内における増殖活性を阻害するための薬学的組成物であって、治療有効量の請求項1〜19のいずれかに記載の化合物の少なくとも1種と薬学的に受容可能なキャリアとを含有する薬学的組成物。
- キナーゼのインビボ活性調節用医薬の製造のための、請求項1〜19のいずれかに記載の化合物の使用。
- 前記キナーゼが、p70S6Kである、請求項25に記載の使用。
- 細胞内における増殖活性阻害用医薬の製造のための、請求項1〜19のいずれかに記載の化合物の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US64020004P | 2004-12-28 | 2004-12-28 | |
US60/640,200 | 2004-12-28 | ||
PCT/US2005/046938 WO2006071819A1 (en) | 2004-12-28 | 2005-12-27 | [1h-pyrazolo[3, 4-d]pyrimidin-4-yl]-piperidine or -piperazine compounds as serine-theoronine kinase modulators (p70s6k, atk1 and atk2) for the treatment of immunological, inflammatory and proliferative diseases |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2008525526A JP2008525526A (ja) | 2008-07-17 |
JP2008525526A5 JP2008525526A5 (ja) | 2009-03-05 |
JP5274842B2 true JP5274842B2 (ja) | 2013-08-28 |
Family
ID=36121369
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2007549530A Expired - Fee Related JP5274842B2 (ja) | 2004-12-28 | 2005-12-27 | 免疫疾患、炎症疾患および増殖疾患の処置のためのセリン−スレオニンキナーゼモジュレーター(p70S6K、Akt−1およびAkt−2)としての[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジンまたは[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジン化合物 |
Country Status (7)
Country | Link |
---|---|
US (1) | US7994172B2 (ja) |
EP (1) | EP1848719B1 (ja) |
JP (1) | JP5274842B2 (ja) |
AT (1) | ATE543821T1 (ja) |
AU (1) | AU2005322085B2 (ja) |
CA (1) | CA2590961C (ja) |
WO (1) | WO2006071819A1 (ja) |
Families Citing this family (93)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL1706385T3 (pl) | 2003-12-23 | 2011-03-31 | Astex Therapeutics Ltd | Pochodne pirazolu jako modulatory kinazy białkowej |
CA2563699C (en) * | 2004-04-23 | 2014-03-25 | Exelixis, Inc. | Kinase modulators and method of use |
MY179032A (en) | 2004-10-25 | 2020-10-26 | Cancer Research Tech Ltd | Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors |
JP2008546751A (ja) | 2005-06-22 | 2008-12-25 | アステックス・セラピューティクス・リミテッド | 医薬組成物 |
JP5345842B2 (ja) | 2005-06-23 | 2013-11-20 | アステックス・セラピューティクス・リミテッド | プロテインキナーゼモジュレーターとしてのピラゾール誘導体を含む医薬組み合わせ |
EP2043655A2 (en) | 2006-04-25 | 2009-04-08 | Astex Therapeutics Limited | Purine and deazapurine derivatives as pharmaceutical compounds |
WO2007125325A1 (en) * | 2006-04-25 | 2007-11-08 | Astex Therapeutics Limited | Pharmaceutical compounds |
US8063050B2 (en) | 2006-07-06 | 2011-11-22 | Array Biopharma Inc. | Hydroxylated and methoxylated pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
WO2008006025A1 (en) | 2006-07-06 | 2008-01-10 | Array Biopharma Inc. | Dihydrofuro pyrimidines as akt protein kinase inhibitors |
JP5231411B2 (ja) | 2006-07-06 | 2013-07-10 | アレイ バイオファーマ、インコーポレイテッド | Aktプロテインキナーゼ阻害剤としてのジヒドロチエノピリミジン |
EP2049500B1 (en) | 2006-07-06 | 2011-09-07 | Array Biopharma, Inc. | Cyclopenta [d] pyrimidines as akt protein kinase inhibitors |
WO2008061108A2 (en) | 2006-11-15 | 2008-05-22 | Forest Laboratories Holdings Limited | Phthalazine derivatives |
AR064415A1 (es) * | 2006-12-21 | 2009-04-01 | Cancer Rec Tech Ltd | Derivados de pirrolo-piperidinas y purinas,composiciones farmaceuticas que los contienen y usos en trastornos y/o enfermedades mediadas por pka y pkb. |
EP2125750B1 (en) * | 2007-02-26 | 2014-05-21 | Vitae Pharmaceuticals, Inc. | Cyclic urea and carbamate inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
GB0704932D0 (en) | 2007-03-14 | 2007-04-25 | Astex Therapeutics Ltd | Pharmaceutical compounds |
UA99284C2 (ru) | 2007-05-11 | 2012-08-10 | Елі Ліллі Енд Компані | ИНГИБИТОРЫ р70 S6-КИНАЗЫ |
RU2486181C2 (ru) | 2007-07-05 | 2013-06-27 | Эррэй Биофарма Инк. | Пиримидилциклопентаны как ингибиторы акт-протеинкиназ |
US9409886B2 (en) | 2007-07-05 | 2016-08-09 | Array Biopharma Inc. | Pyrimidyl cyclopentanes as AKT protein kinase inhibitors |
US8846683B2 (en) | 2007-07-05 | 2014-09-30 | Array Biopharma, Inc. | Pyrimidyl cyclopentanes as Akt protein kinase inhibitors |
SI2173723T1 (sl) | 2007-07-05 | 2011-12-30 | Array Biopharma Inc | Pirimidil ciklopentani kot inhibitorji AKT-protein-kinaze |
CL2008002199A1 (es) * | 2007-07-26 | 2009-10-23 | Vitae Pharmaceuticals Inc | Compuestos derivados de 1,3-oxazin-2-ona; composicion farmaceutica que comprende a dichos compuestos; y uso para tratar una enfermedad asociada con la actividad de la 11beta-hidroxiesteroide deshidrogenasa tipo 1 (11beta-hsd1) tales como dislipidemia, hiperlipidemia, hipertension, obesidad y enfermedad cardiovascular, entre otras. |
EP2050748A1 (en) * | 2007-10-18 | 2009-04-22 | Bayer Schering Pharma Aktiengesellschaft | Novel fused pyrimidines |
EP2188291B1 (en) * | 2007-08-14 | 2012-09-19 | Bayer Pharma Aktiengesellschaft | Fused bicyclic pyrimidines |
PL2201012T3 (pl) | 2007-10-11 | 2014-11-28 | Astrazeneca Ab | Pochodne pirolo[2,3-d]pirymidyny jako inhibitory kinazy białkowej b |
AR069207A1 (es) * | 2007-11-07 | 2010-01-06 | Vitae Pharmaceuticals Inc | Ureas ciclicas como inhibidores de la 11 beta - hidroxi-esteroide deshidrogenasa 1 |
JP5490014B2 (ja) | 2007-12-11 | 2014-05-14 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | 11β−ヒドロキシステロイドデヒドロゲナーゼ1型の環状尿素阻害剤 |
TW200934490A (en) * | 2008-01-07 | 2009-08-16 | Vitae Pharmaceuticals Inc | Lactam inhibitors of 11 &abgr;-hydroxysteroid dehydrogenase 1 |
CN101959887B (zh) | 2008-01-08 | 2013-07-31 | 阵列生物制药公司 | 作为激酶抑制剂的吡咯并吡啶 |
US8329709B2 (en) * | 2008-01-09 | 2012-12-11 | Genentech, Inc. | 5H-cyclopenta[D]pyrimidines as AKT protein kinase inhibitors |
ES2392014T3 (es) | 2008-01-09 | 2012-12-03 | Array Biopharma, Inc. | Pirazolopiridinas como inhibidores de la cinasa |
KR101624753B1 (ko) | 2008-01-09 | 2016-05-26 | 어레이 바이오파마 인크. | Akt 단백질 키나제 저해물질로서의 수산화된 피리미딜 시클로펜탄 |
ES2401685T3 (es) | 2008-01-09 | 2013-04-23 | Array Biopharma, Inc. | Pirimidil ciclopentano hidroxilado como inhibidor de la proteína quinasa AKT |
EP2252601B1 (en) | 2008-01-24 | 2012-12-19 | Vitae Pharmaceuticals, Inc. | Cyclic carbazate and semicarbazide inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
CN101981037B (zh) * | 2008-01-30 | 2013-09-04 | 吉宁特有限公司 | 吡唑并嘧啶pi3k抑制剂化合物及使用方法 |
CA2714532A1 (en) * | 2008-02-11 | 2009-08-20 | Vitae Pharmaceuticals, Inc. | 1,3-oxazepan-2-one and 1,3-diazepan-2-one inhibitors of 11.beta.-hydroxysteroid dehydrogenase 1 |
EP2254872A2 (en) * | 2008-02-15 | 2010-12-01 | Vitae Pharmaceuticals, Inc. | Cycloalkyl lactame derivatives as inhibitors of 11-beta-hydroxysteroid dehydrogenase 1 |
JP5538356B2 (ja) * | 2008-03-18 | 2014-07-02 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | 11β−ヒドロキシステロイドデヒドロゲナーゼ1型の阻害剤 |
BRPI0911764A2 (pt) * | 2008-05-01 | 2015-10-06 | Boehringer Ingelheim Int | inibidores cíclicos de 11beta-hidroxiesteroide desigrogenase 1 |
CL2009001058A1 (es) | 2008-05-01 | 2010-09-10 | Vitae Pharmaceuticals Inc | Compuestos derivados de oxazinas sustituidas, inhibidores de la 11b-hidroxiesteroide deshidrogenasa de tipo-1; composicion farmaceutica; y uso del compuesto para inhibir la actividad de 11b-hsd1, como en el tratamiento de la diabetes, dislipidemia, hipertension, obesidad, cancer, glaucoma, entre otras. |
CA2723034A1 (en) | 2008-05-01 | 2009-11-05 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
JP5451752B2 (ja) * | 2008-05-01 | 2014-03-26 | ヴァイティー ファーマシューティカルズ,インコーポレイテッド | 11β−ヒドロキシステロイドデヒドロゲナーゼ1の環状インヒビター |
TW201016691A (en) | 2008-07-25 | 2010-05-01 | Boehringer Ingelheim Int | Inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
US8114868B2 (en) | 2008-07-25 | 2012-02-14 | Boehringer Ingelheim International Gmbh | Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 |
JP2012508239A (ja) * | 2008-11-11 | 2012-04-05 | イーライ リリー アンド カンパニー | P70s6キナーゼ阻害剤およびmtor阻害剤の併用療法 |
AR074072A1 (es) | 2008-11-11 | 2010-12-22 | Lilly Co Eli | Compuesto de imidazol -piperidin -pirrol-pirimidin-6-ona, composicion farmaceutica que lo comprende y su uso para preparar un medicamento util para tratar el glioblastoma multiforme |
JP2012508240A (ja) * | 2008-11-11 | 2012-04-05 | イーライ リリー アンド カンパニー | P70s6キナーゼ阻害剤およびegfr阻害剤の併用療法 |
ES2392488T3 (es) | 2008-11-20 | 2012-12-11 | Genentech, Inc. | Compuestos inhibidores de PI3K de tipo pirazolopiridina y sus procedimientos de uso |
WO2010089303A1 (en) | 2009-02-04 | 2010-08-12 | Boehringer Ingelheim International Gmbh | CYCLIC INHIBITORS OF 11 β-HYDROXYSTEROID DEHYDROGENASE 1 |
EA020731B1 (ru) | 2009-02-11 | 2015-01-30 | Мерк Патент Гмбх | Аминоазагетероциклические карбоксамиды |
TW201039034A (en) * | 2009-04-27 | 2010-11-01 | Chunghwa Picture Tubes Ltd | Pixel structure and the method of forming the same |
MA33216B1 (fr) | 2009-04-30 | 2012-04-02 | Boehringer Ingelheim Int | Inhibiteurs cycliques de la 11béta-hydroxysteroïde déshydrogénase 1 |
KR20120061771A (ko) * | 2009-04-30 | 2012-06-13 | 비타이 파마슈티컬즈, 인코포레이티드 | 11베타-하이드록시스테로이드 탈수소효소 1의 고리형 억제제 |
US8927539B2 (en) | 2009-06-11 | 2015-01-06 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11β-hydroxysteroid dehydrogenase 1 based on the 1,3-oxazinan-2-one structure |
WO2011002910A1 (en) | 2009-07-01 | 2011-01-06 | Vitae Pharmaceuticals, Inc. | Cyclic inhibitors of 11beta-hydroxysteroid dehydrogenase 1 |
CN102471338B (zh) | 2009-08-07 | 2014-07-02 | 默克专利有限公司 | 氮杂杂环化合物 |
PL2473049T3 (pl) | 2009-09-04 | 2019-07-31 | Biogen Ma Inc. | Inhibitory kinazy tyrozynowej brutona |
EP2491032B1 (en) * | 2009-10-23 | 2014-04-16 | Eli Lilly and Company | Akt inhibitors |
EP2582698B1 (en) | 2010-06-16 | 2016-09-14 | Vitae Pharmaceuticals, Inc. | Substituted 5-,6- and 7-membered heterocycles, medicaments containing such compounds, and their use |
EP2585444B1 (en) | 2010-06-25 | 2014-10-22 | Boehringer Ingelheim International GmbH | Azaspirohexanones as inhibitors of 11-beta-hsd1 for the treatment of metabolic disorders |
UA110113C2 (xx) | 2010-07-29 | 2015-11-25 | Біциклічні азагетероциклічні карбоксаміди | |
CN103140484B (zh) | 2010-07-29 | 2015-04-22 | 默克专利有限公司 | 环状胺氮杂杂环甲酰胺 |
BR112013010021A2 (pt) | 2010-11-02 | 2019-09-24 | Boehringer Ingelheim Int | combinações farmacêuticas para o tratamento de distúrbios metabólicos. |
KR101894116B1 (ko) | 2010-11-24 | 2018-08-31 | 메르크 파텐트 게엠베하 | 퀴나졸린 카르복사미드 아제티딘 |
MX2013011333A (es) | 2011-04-01 | 2014-04-16 | Genentech Inc | Combinaciones de compuestos inhibidores de akt y mek, y metodos de uso. |
ES2761311T3 (es) | 2011-04-01 | 2020-05-19 | Astrazeneca Ab | Tratamiento terapéutico |
ES2620644T3 (es) | 2011-04-01 | 2017-06-29 | Genentech, Inc. | Combinaciones de compuestos inhibidores de AKT y agentes quimioterapéuticos, y métodos de uso |
MX346095B (es) | 2011-09-12 | 2017-03-07 | Merck Patent Gmbh | Nuevas imidazol-aminas como moduladores de la actividad de cinasas. |
SI2755958T1 (sl) * | 2011-09-12 | 2017-12-29 | Merck Patent Gmbh | Aminopirimidinski derivati za uporabo kot modulatorji kinazne aktivnosti |
MY175800A (en) | 2011-11-30 | 2020-07-09 | Astrazeneca Ab | Combination treatment of cancer |
US9139568B2 (en) | 2011-12-22 | 2015-09-22 | Merck Patent Gmbh | Heterocyclic carboxamides as modulators of kinase activity |
AU2013204533B2 (en) | 2012-04-17 | 2017-02-02 | Astrazeneca Ab | Crystalline forms |
AR091273A1 (es) | 2012-06-08 | 2015-01-21 | Biogen Idec Inc | Inhibidores de pirimidinil tirosina quinasa |
JP6318156B2 (ja) * | 2012-09-06 | 2018-04-25 | プレキシコン インコーポレーテッドPlexxikon Inc. | キナーゼをモジュレートするための化合物および方法、ならびにその指標 |
US9562047B2 (en) | 2012-10-17 | 2017-02-07 | The University Of North Carolina At Chapel Hill | Pyrazolopyrimidine compounds for the treatment of cancer |
AU2013344552B2 (en) | 2012-11-16 | 2018-03-15 | Xiaoling Chen | Novel heterocyclic derivatives as modulators of kinase activity |
CN105102435A (zh) | 2012-11-16 | 2015-11-25 | 默克专利有限公司 | 用作激酶活性调节剂的新颖的咪唑-哌啶基衍生物 |
WO2014085225A1 (en) | 2012-11-27 | 2014-06-05 | The University Of North Carolina At Chapel Hill | Pyrimidine compounds for the treatment of cancer |
BR112015011974A8 (pt) | 2012-11-29 | 2019-10-08 | Merck Patent Gmbh | derivados de azaquinazolina carboxamida, seus usos e processo para sua produção, medicamento e composição farmacêutica |
USRE48622E1 (en) | 2012-12-20 | 2021-07-06 | UCB Biopharma SRL | Therapeutically active pyrazolo-pyrimidine derivatives |
WO2014096423A1 (en) * | 2012-12-20 | 2014-06-26 | Ucb Pharma S.A. | Therapeutically active pyrazolo-pyrimidine derivatives |
KR20150124957A (ko) | 2013-03-11 | 2015-11-06 | 메르크 파텐트 게엠베하 | 키나아제 활성의 조절인자로서 (6-[4-1h-이미다졸-2-일)피페리딘-1-일]피리미딘-4-아민 유도체 |
NZ725361A (en) | 2014-04-03 | 2022-09-30 | Merck Patent Gmbh | Combinations of cancer therapeutics |
US9603850B2 (en) | 2014-04-11 | 2017-03-28 | The University Of North Carolina At Chapel Hill | MerTK-specific pyrazolopyrimidine compounds |
US10709708B2 (en) | 2016-03-17 | 2020-07-14 | The University Of North Carolina At Chapel Hill | Method of treating cancer with a combination of MER tyrosine kinase inhibitor and an epidermal growth factor receptor (EGFR) inhibitor |
WO2018017153A1 (en) | 2016-07-21 | 2018-01-25 | Biogen Ma Inc. | Succinate forms and compositions of bruton's tyrosine kinase inhibitors |
US11472799B2 (en) * | 2018-03-06 | 2022-10-18 | Icahn School Of Medicine At Mount Sinai | Serine threonine kinase (AKT) degradation / disruption compounds and methods of use |
CN110396067B (zh) * | 2018-04-25 | 2022-07-08 | 复旦大学 | 1,4-二取代-2-哌嗪酮类化合物及其药物用途 |
GB201918815D0 (en) * | 2019-12-19 | 2020-02-05 | Imperial College Innovations Ltd | Treatment of cancer |
BR112022017856A2 (pt) * | 2020-03-17 | 2022-11-01 | Jiangsu Hengrui Pharmaceuticals Co Ltd | Derivado bicíclico fundido, método de preparação do mesmo e uso farmacêutico do mesmo |
CN113444110B (zh) * | 2020-03-25 | 2023-05-12 | 江苏恒瑞医药股份有限公司 | 四氢吡咯并吡唑类衍生物、其制备方法及其在医药上的应用 |
JP2023522965A (ja) * | 2020-04-21 | 2023-06-01 | ユニバーシティ オブ マサチューセッツ | 加齢性黄斑変性を処置するための方法および組成物 |
AU2021376892A1 (en) | 2020-11-16 | 2023-06-29 | Merck Patent Gmbh | Kinase inhibitor combinations for cancer treatment |
CA3231865A1 (en) | 2021-09-17 | 2023-03-23 | Tingting SHANG | Fused bicyclic derivative, pharmaceutically acceptable salt, crystal form thereof and preparation method therefor |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6423716B1 (en) * | 1998-03-31 | 2002-07-23 | Kyowa Hakko Kogyo Co., Ltd. | Nitrogenous heterocyclic compounds |
JP2003252871A (ja) * | 2001-03-29 | 2003-09-10 | Tanabe Seiyaku Co Ltd | スピロイソキノリン誘導体、その製法およびその合成中間体 |
JP2004115450A (ja) * | 2002-09-27 | 2004-04-15 | Tanabe Seiyaku Co Ltd | 医薬組成物 |
US7589086B2 (en) * | 2003-05-28 | 2009-09-15 | Universita Degli Studi Di Siena | Substituted pyrazolo[3,4-D]pyrimidines as anti-tumor agents |
KR101223914B1 (ko) | 2003-11-21 | 2013-01-18 | 어레이 바이오파마 인크. | Akt 단백질 키나제 억제제 |
CA2557575A1 (en) | 2004-02-27 | 2005-09-15 | F. Hoffmann-La Roche Ag | Fused derivatives of pyrazole |
CA2563699C (en) * | 2004-04-23 | 2014-03-25 | Exelixis, Inc. | Kinase modulators and method of use |
-
2005
- 2005-12-27 JP JP2007549530A patent/JP5274842B2/ja not_active Expired - Fee Related
- 2005-12-27 CA CA2590961A patent/CA2590961C/en not_active Expired - Fee Related
- 2005-12-27 WO PCT/US2005/046938 patent/WO2006071819A1/en active Application Filing
- 2005-12-27 AU AU2005322085A patent/AU2005322085B2/en not_active Ceased
- 2005-12-27 EP EP05855490A patent/EP1848719B1/en active Active
- 2005-12-27 US US11/722,291 patent/US7994172B2/en not_active Expired - Fee Related
- 2005-12-27 AT AT05855490T patent/ATE543821T1/de active
Also Published As
Publication number | Publication date |
---|---|
ATE543821T1 (de) | 2012-02-15 |
CA2590961A1 (en) | 2006-07-06 |
AU2005322085A1 (en) | 2006-07-06 |
US7994172B2 (en) | 2011-08-09 |
EP1848719A1 (en) | 2007-10-31 |
WO2006071819A1 (en) | 2006-07-06 |
CA2590961C (en) | 2013-11-26 |
EP1848719B1 (en) | 2012-02-01 |
AU2005322085B2 (en) | 2012-07-19 |
US20080188482A1 (en) | 2008-08-07 |
JP2008525526A (ja) | 2008-07-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5274842B2 (ja) | 免疫疾患、炎症疾患および増殖疾患の処置のためのセリン−スレオニンキナーゼモジュレーター(p70S6K、Akt−1およびAkt−2)としての[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジンまたは[1H−ピペラゾ[3,4−d]ピリミジン−4−イル]−ピペラジン化合物 | |
JP4800216B2 (ja) | p70S6キナーゼモジュレーターおよび使用方法 | |
JP5010917B2 (ja) | c−Kit調節因子および使用方法 | |
JP5208516B2 (ja) | キナーゼモジュレーターとしてのピリミジン誘導体および使用方法 | |
JP5063351B2 (ja) | ピラゾールキナーゼモジュレーターおよび使用方法 | |
JP5213229B2 (ja) | キナーゼ調節因子および使用方法 | |
JP2007527413A5 (ja) | ||
JP4703183B2 (ja) | 受容体型キナーゼモジュレーターおよびその使用方法 | |
JP2007527412A (ja) | Taoキナーゼモジュレーターおよび使用方法 | |
JP2008502595A (ja) | 未分化リンパ腫キナーゼモジュレータおよびその使用方法 | |
JP4960085B2 (ja) | Tie−2モジュレータと使用方法 | |
US7626031B2 (en) | Substituted 3-(diarylmethylene)indolin-2-ones and methods of their use |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20081226 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090108 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120424 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120719 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120726 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120823 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120830 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20120920 |
|
A602 | Written permission of extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A602 Effective date: 20120927 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20121023 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20121211 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130306 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130416 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130515 |
|
R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |