JP5484568B2 - プロテインキナーゼおよびヒストンデアセチラーゼの阻害剤としてのナフタレンカルボキサミド誘導体、その製造方法および用途 - Google Patents
プロテインキナーゼおよびヒストンデアセチラーゼの阻害剤としてのナフタレンカルボキサミド誘導体、その製造方法および用途 Download PDFInfo
- Publication number
- JP5484568B2 JP5484568B2 JP2012513451A JP2012513451A JP5484568B2 JP 5484568 B2 JP5484568 B2 JP 5484568B2 JP 2012513451 A JP2012513451 A JP 2012513451A JP 2012513451 A JP2012513451 A JP 2012513451A JP 5484568 B2 JP5484568 B2 JP 5484568B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- mmol
- hydrogen
- group
- alkoxy
- 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.)
- Active
Links
- 102000003964 Histone deacetylase Human genes 0.000 title claims description 35
- 108090000353 Histone deacetylase Proteins 0.000 title claims description 35
- 102000001253 Protein Kinase Human genes 0.000 title claims description 15
- 108060006633 protein kinase Proteins 0.000 title claims description 15
- 238000004519 manufacturing process Methods 0.000 title claims description 9
- 239000003112 inhibitor Substances 0.000 title description 9
- RMHJJUOPOWPRBP-UHFFFAOYSA-N naphthalene-1-carboxamide Chemical class C1=CC=C2C(C(=O)N)=CC=CC2=C1 RMHJJUOPOWPRBP-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 95
- 206010028980 Neoplasm Diseases 0.000 claims description 80
- 238000002360 preparation method Methods 0.000 claims description 42
- 229910052739 hydrogen Inorganic materials 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 21
- 239000001257 hydrogen Substances 0.000 claims description 21
- 230000000694 effects Effects 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 150000002431 hydrogen Chemical class 0.000 claims description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 14
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 12
- 230000002159 abnormal effect Effects 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 230000004770 neurodegeneration Effects 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 208000030159 metabolic disease Diseases 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 208000023275 Autoimmune disease Diseases 0.000 claims description 3
- 206010020751 Hypersensitivity Diseases 0.000 claims description 3
- 230000007815 allergy Effects 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229940088597 hormone Drugs 0.000 claims description 3
- 239000005556 hormone Substances 0.000 claims description 3
- 208000027866 inflammatory disease Diseases 0.000 claims description 3
- 210000000653 nervous system Anatomy 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002674 ointment Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 150000003839 salts Chemical group 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000006188 syrup Substances 0.000 claims description 2
- 235000020357 syrup Nutrition 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 8
- 239000003960 organic solvent Substances 0.000 claims 2
- 239000007787 solid Substances 0.000 description 48
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 44
- 241000699670 Mus sp. Species 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 30
- 230000005764 inhibitory process Effects 0.000 description 22
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 20
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 20
- 229940125877 compound 31 Drugs 0.000 description 20
- 230000014509 gene expression Effects 0.000 description 17
- 229940079593 drug Drugs 0.000 description 16
- 206010009944 Colon cancer Diseases 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 102000001301 EGF receptor Human genes 0.000 description 15
- 208000029742 colonic neoplasm Diseases 0.000 description 15
- 239000003981 vehicle Substances 0.000 description 15
- XWWMBEVYYTUBAX-UHFFFAOYSA-N 6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=CC(OC=3N=CN=C4C=C(C(=CC4=3)OC)OC)=CC=C21 XWWMBEVYYTUBAX-UHFFFAOYSA-N 0.000 description 14
- 108060006698 EGF receptor Proteins 0.000 description 14
- LBWFXVZLPYTWQI-IPOVEDGCSA-N n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-2-oxo-1h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C LBWFXVZLPYTWQI-IPOVEDGCSA-N 0.000 description 14
- 108090000623 proteins and genes Proteins 0.000 description 14
- 229940034785 sutent Drugs 0.000 description 14
- 229940126639 Compound 33 Drugs 0.000 description 13
- PNUZDKCDAWUEGK-CYZMBNFOSA-N Sitafloxacin Chemical compound C([C@H]1N)N(C=2C(=C3C(C(C(C(O)=O)=CN3[C@H]3[C@H](C3)F)=O)=CC=2F)Cl)CC11CC1 PNUZDKCDAWUEGK-CYZMBNFOSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000037396 body weight Effects 0.000 description 12
- 230000004663 cell proliferation Effects 0.000 description 12
- 238000011580 nude mouse model Methods 0.000 description 12
- 238000011282 treatment Methods 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 description 9
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 9
- 230000000259 anti-tumor effect Effects 0.000 description 9
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 8
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 8
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 8
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 8
- 229940125807 compound 37 Drugs 0.000 description 8
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 8
- -1 pyrrole-substituted 2-indolinone compounds Chemical class 0.000 description 8
- JCJUKCIXTRWAQY-UHFFFAOYSA-N 6-hydroxynaphthalene-1-carboxylic acid Chemical compound OC1=CC=C2C(C(=O)O)=CC=CC2=C1 JCJUKCIXTRWAQY-UHFFFAOYSA-N 0.000 description 7
- 102100039996 Histone deacetylase 1 Human genes 0.000 description 7
- 102100039999 Histone deacetylase 2 Human genes 0.000 description 7
- 102100022537 Histone deacetylase 6 Human genes 0.000 description 7
- 101001035024 Homo sapiens Histone deacetylase 1 Proteins 0.000 description 7
- 101001035011 Homo sapiens Histone deacetylase 2 Proteins 0.000 description 7
- 101000899330 Homo sapiens Histone deacetylase 6 Proteins 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 102000004169 proteins and genes Human genes 0.000 description 7
- 230000004614 tumor growth Effects 0.000 description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 6
- WWGBHDIHIVGYLZ-UHFFFAOYSA-N N-[4-[3-[[[7-(hydroxyamino)-7-oxoheptyl]amino]-oxomethyl]-5-isoxazolyl]phenyl]carbamic acid tert-butyl ester Chemical compound C1=CC(NC(=O)OC(C)(C)C)=CC=C1C1=CC(C(=O)NCCCCCCC(=O)NO)=NO1 WWGBHDIHIVGYLZ-UHFFFAOYSA-N 0.000 description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 210000001099 axilla Anatomy 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 6
- 239000008108 microcrystalline cellulose Substances 0.000 description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 229910052708 sodium Inorganic materials 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- 239000008107 starch Substances 0.000 description 6
- 229960001796 sunitinib Drugs 0.000 description 6
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 6
- 230000003442 weekly effect Effects 0.000 description 6
- KWEWNOOZQVJONF-UHFFFAOYSA-N 4-fluorobenzene-1,2-diamine Chemical compound NC1=CC=C(F)C=C1N KWEWNOOZQVJONF-UHFFFAOYSA-N 0.000 description 5
- DPSDOEJRMFSIIF-UHFFFAOYSA-N 6-(6,7-dimethoxyquinolin-4-yl)oxynaphthalene-1-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=CC(OC=3C=CN=C4C=C(C(=CC4=3)OC)OC)=CC=C21 DPSDOEJRMFSIIF-UHFFFAOYSA-N 0.000 description 5
- SYPNKNPSBVMPNR-UHFFFAOYSA-N 6-(7-methoxyquinolin-4-yl)oxynaphthalene-1-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=CC(OC=3C4=CC=C(C=C4N=CC=3)OC)=CC=C21 SYPNKNPSBVMPNR-UHFFFAOYSA-N 0.000 description 5
- 102100021455 Histone deacetylase 3 Human genes 0.000 description 5
- 101000899282 Homo sapiens Histone deacetylase 3 Proteins 0.000 description 5
- 101000891649 Homo sapiens Transcription elongation factor A protein-like 1 Proteins 0.000 description 5
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 201000002740 oral squamous cell carcinoma Diseases 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 230000001105 regulatory effect Effects 0.000 description 5
- 230000019491 signal transduction Effects 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- AJAOIHOZBOYYOE-UHFFFAOYSA-N 4-(aminomethyl)-n-(2-aminophenyl)benzamide Chemical compound C1=CC(CN)=CC=C1C(=O)NC1=CC=CC=C1N AJAOIHOZBOYYOE-UHFFFAOYSA-N 0.000 description 4
- ADCUEPOHPCPMCE-UHFFFAOYSA-N 4-cyanobenzoic acid Chemical compound OC(=O)C1=CC=C(C#N)C=C1 ADCUEPOHPCPMCE-UHFFFAOYSA-N 0.000 description 4
- QSCKPKYAGQLLNG-UHFFFAOYSA-N 6-(7-chloroquinolin-4-yl)oxynaphthalene-1-carboxylic acid Chemical compound ClC1=CC=C2C(OC=3C=C4C=CC=C(C4=CC=3)C(=O)O)=CC=NC2=C1 QSCKPKYAGQLLNG-UHFFFAOYSA-N 0.000 description 4
- UUMZJTULRYRUQS-UHFFFAOYSA-N 6-(aminomethyl)-n-(2-aminophenyl)pyridine-3-carboxamide Chemical compound C1=NC(CN)=CC=C1C(=O)NC1=CC=CC=C1N UUMZJTULRYRUQS-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 4
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 4
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 230000030279 gene silencing Effects 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 235000021590 normal diet Nutrition 0.000 description 4
- 230000002018 overexpression Effects 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- 239000003909 protein kinase inhibitor Substances 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 4
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 4
- 239000012679 serum free medium Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 description 3
- BVWMNYRLWUJAQJ-UHFFFAOYSA-N 6-[8-(trifluoromethyl)quinolin-4-yl]oxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(OC=3C=C4C=CC=C(C4=CC=3)C(=O)O)=CC=NC2=C1C(F)(F)F BVWMNYRLWUJAQJ-UHFFFAOYSA-N 0.000 description 3
- 108090000461 Aurora Kinase A Proteins 0.000 description 3
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 3
- 208000026310 Breast neoplasm Diseases 0.000 description 3
- 102000003903 Cyclin-dependent kinases Human genes 0.000 description 3
- 108090000266 Cyclin-dependent kinases Proteins 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 206010020880 Hypertrophy Diseases 0.000 description 3
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 3
- 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 3
- 108700008625 Reporter Genes Proteins 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 108091023040 Transcription factor Proteins 0.000 description 3
- 102000040945 Transcription factor Human genes 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000033115 angiogenesis Effects 0.000 description 3
- 230000035578 autophosphorylation Effects 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 229940121372 histone deacetylase inhibitor Drugs 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- 235000005152 nicotinamide Nutrition 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 230000002829 reductive effect Effects 0.000 description 3
- 229960003787 sorafenib Drugs 0.000 description 3
- 238000002626 targeted therapy Methods 0.000 description 3
- 238000001890 transfection Methods 0.000 description 3
- 229960000237 vorinostat Drugs 0.000 description 3
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 2
- VIEYKBRRZWORHT-UHFFFAOYSA-N 3-(aminomethyl)-n-(2-aminophenyl)benzamide Chemical compound NCC1=CC=CC(C(=O)NC=2C(=CC=CC=2)N)=C1 VIEYKBRRZWORHT-UHFFFAOYSA-N 0.000 description 2
- BMMGUSWBXGBSII-UHFFFAOYSA-N 4-(aminomethyl)-n-(2-amino-4-methylphenyl)benzamide Chemical compound NC1=CC(C)=CC=C1NC(=O)C1=CC=C(CN)C=C1 BMMGUSWBXGBSII-UHFFFAOYSA-N 0.000 description 2
- VANKDQBQDYRKFA-UHFFFAOYSA-N 4-(aminomethyl)-n-[2-amino-4-(trifluoromethyl)phenyl]benzamide Chemical compound C1=CC(CN)=CC=C1C(=O)NC1=CC=C(C(F)(F)F)C=C1N VANKDQBQDYRKFA-UHFFFAOYSA-N 0.000 description 2
- RQWJHUJJBYMJMN-UHFFFAOYSA-N 4-(trifluoromethyl)benzene-1,2-diamine Chemical compound NC1=CC=C(C(F)(F)F)C=C1N RQWJHUJJBYMJMN-UHFFFAOYSA-N 0.000 description 2
- AGAHETWGCFCMDK-UHFFFAOYSA-N 4-methoxybenzene-1,2-diamine Chemical compound COC1=CC=C(N)C(N)=C1 AGAHETWGCFCMDK-UHFFFAOYSA-N 0.000 description 2
- DGRGLKZMKWPMOH-UHFFFAOYSA-N 4-methylbenzene-1,2-diamine Chemical compound CC1=CC=C(N)C(N)=C1 DGRGLKZMKWPMOH-UHFFFAOYSA-N 0.000 description 2
- RVICVSKJUKLCDO-UHFFFAOYSA-N 6-(8-methylquinolin-4-yl)oxynaphthalene-1-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=CC(OC3=C4C=CC=C(C4=NC=C3)C)=CC=C21 RVICVSKJUKLCDO-UHFFFAOYSA-N 0.000 description 2
- WMHSQCDPPJRWIL-UHFFFAOYSA-N 6-cyanopyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=C(C#N)N=C1 WMHSQCDPPJRWIL-UHFFFAOYSA-N 0.000 description 2
- JXLKDCBUKGRAPA-UHFFFAOYSA-N 6-quinolin-4-yloxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(OC=3C=C4C=CC=C(C4=CC=3)C(=O)O)=CC=NC2=C1 JXLKDCBUKGRAPA-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 102100032311 Aurora kinase A Human genes 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 108091008794 FGF receptors Proteins 0.000 description 2
- 102000044168 Fibroblast Growth Factor Receptor Human genes 0.000 description 2
- 102000009465 Growth Factor Receptors Human genes 0.000 description 2
- 108010009202 Growth Factor Receptors Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- 108060001084 Luciferase Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 108010029485 Protein Isoforms Proteins 0.000 description 2
- 102000001708 Protein Isoforms Human genes 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 108050002485 Sirtuin Proteins 0.000 description 2
- 102000011990 Sirtuin Human genes 0.000 description 2
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 2
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000001028 anti-proliverative effect Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 230000022131 cell cycle Effects 0.000 description 2
- 230000011748 cell maturation Effects 0.000 description 2
- 230000009087 cell motility Effects 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 210000000805 cytoplasm Anatomy 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 210000002889 endothelial cell Anatomy 0.000 description 2
- 230000001973 epigenetic effect Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000001605 fetal effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007421 fluorometric assay Methods 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000006698 induction Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- BFKPTWWXZLZNHX-UHFFFAOYSA-N n-(2-amino-4-bromophenyl)-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=C(Br)C=C1N BFKPTWWXZLZNHX-UHFFFAOYSA-N 0.000 description 2
- LYUYXMCADSOWLJ-UHFFFAOYSA-N n-(2-amino-4-fluorophenyl)-4-(aminomethyl)benzamide Chemical compound C1=CC(CN)=CC=C1C(=O)NC1=CC=C(F)C=C1N LYUYXMCADSOWLJ-UHFFFAOYSA-N 0.000 description 2
- UCDJWWZUSWKWTG-UHFFFAOYSA-N n-(2-amino-4-fluorophenyl)-6-(aminomethyl)pyridine-3-carboxamide Chemical compound C1=NC(CN)=CC=C1C(=O)NC1=CC=C(F)C=C1N UCDJWWZUSWKWTG-UHFFFAOYSA-N 0.000 description 2
- ABOCFGUXUZBENZ-UHFFFAOYSA-N n-(2-amino-4-methoxyphenyl)-4-(aminomethyl)benzamide Chemical compound NC1=CC(OC)=CC=C1NC(=O)C1=CC=C(CN)C=C1 ABOCFGUXUZBENZ-UHFFFAOYSA-N 0.000 description 2
- XYJRCZUSPNSHHQ-UHFFFAOYSA-N n-(2-aminophenyl)-4-cyanobenzamide Chemical compound NC1=CC=CC=C1NC(=O)C1=CC=C(C#N)C=C1 XYJRCZUSPNSHHQ-UHFFFAOYSA-N 0.000 description 2
- MQZGBMVEIHPCNR-UHFFFAOYSA-N n-(2-aminophenyl)-6-(7-chloroquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound NC1=CC=CC=C1NC(=O)C1=CC=CC2=CC(OC=3C4=CC=C(Cl)C=C4N=CC=3)=CC=C12 MQZGBMVEIHPCNR-UHFFFAOYSA-N 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 125000004430 oxygen atom Chemical group O* 0.000 description 2
- 238000009521 phase II clinical trial Methods 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 238000006366 phosphorylation reaction Methods 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- SMUQFGGVLNAIOZ-UHFFFAOYSA-N quinaldine Chemical compound C1=CC=CC2=NC(C)=CC=C21 SMUQFGGVLNAIOZ-UHFFFAOYSA-N 0.000 description 2
- 108010077182 raf Kinases Proteins 0.000 description 2
- 102000009929 raf Kinases Human genes 0.000 description 2
- 230000022983 regulation of cell cycle Effects 0.000 description 2
- 230000008672 reprogramming Effects 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-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 1
- JWOGUUIOCYMBPV-GMFLJSBRSA-N (3S,6S,9S,12R)-3-[(2S)-Butan-2-yl]-6-[(1-methoxyindol-3-yl)methyl]-9-(6-oxooctyl)-1,4,7,10-tetrazabicyclo[10.4.0]hexadecane-2,5,8,11-tetrone Chemical group N1C(=O)[C@H](CCCCCC(=O)CC)NC(=O)[C@H]2CCCCN2C(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]1CC1=CN(OC)C2=CC=CC=C12 JWOGUUIOCYMBPV-GMFLJSBRSA-N 0.000 description 1
- GNYCTMYOHGBSBI-SVZOTFJBSA-N (3s,6r,9s,12r)-6,9-dimethyl-3-[6-[(2s)-oxiran-2-yl]-6-oxohexyl]-1,4,7,10-tetrazabicyclo[10.3.0]pentadecane-2,5,8,11-tetrone Chemical compound C([C@H]1C(=O)N2CCC[C@@H]2C(=O)N[C@H](C(N[C@H](C)C(=O)N1)=O)C)CCCCC(=O)[C@@H]1CO1 GNYCTMYOHGBSBI-SVZOTFJBSA-N 0.000 description 1
- AOYBLZGEIIBUTE-UHFFFAOYSA-N 1,2,5-oxadiazol-3-amine Chemical class NC=1C=NON=1 AOYBLZGEIIBUTE-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical group NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 1
- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- ZTQNUTNKGQGWCM-UHFFFAOYSA-N 2-methoxyquinoline Chemical compound C1=CC=CC2=NC(OC)=CC=C21 ZTQNUTNKGQGWCM-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- 102000003737 3-Phosphoinositide-Dependent Protein Kinases Human genes 0.000 description 1
- 108010082078 3-Phosphoinositide-Dependent Protein Kinases Proteins 0.000 description 1
- GYLKKXHEIIFTJH-UHFFFAOYSA-N 3-cyanobenzoic acid Chemical compound OC(=O)C1=CC=CC(C#N)=C1 GYLKKXHEIIFTJH-UHFFFAOYSA-N 0.000 description 1
- BXIXXXYDDJVHDL-UHFFFAOYSA-N 4-Chloro-ortho-phenylenediamine Chemical compound NC1=CC=C(Cl)C=C1N BXIXXXYDDJVHDL-UHFFFAOYSA-N 0.000 description 1
- APRZHQXAAWPYHS-UHFFFAOYSA-N 4-[5-[3-(carboxymethoxy)phenyl]-3-(4,5-dimethyl-1,3-thiazol-2-yl)tetrazol-3-ium-2-yl]benzenesulfonate Chemical compound S1C(C)=C(C)N=C1[N+]1=NC(C=2C=C(OCC(O)=O)C=CC=2)=NN1C1=CC=C(S([O-])(=O)=O)C=C1 APRZHQXAAWPYHS-UHFFFAOYSA-N 0.000 description 1
- WIHHVKUARKTSBU-UHFFFAOYSA-N 4-bromobenzene-1,2-diamine Chemical compound NC1=CC=C(Br)C=C1N WIHHVKUARKTSBU-UHFFFAOYSA-N 0.000 description 1
- LLLHRNQLGUOJHP-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 LLLHRNQLGUOJHP-UHFFFAOYSA-N 0.000 description 1
- KNDOFJFSHZCKGT-UHFFFAOYSA-N 4-chloroquinoline Chemical compound C1=CC=C2C(Cl)=CC=NC2=C1 KNDOFJFSHZCKGT-UHFFFAOYSA-N 0.000 description 1
- 150000005653 4-chloroquinolines Chemical class 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 1
- 102000004000 Aurora Kinase A Human genes 0.000 description 1
- 108010081589 Becaplermin Proteins 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZFEFHTOOGZVUQZ-UHFFFAOYSA-N C1(=CC=CC2=CC=CC=C12)C(=O)N.C1(=CC=CC2=CC=CC=C12)C(=O)N Chemical class C1(=CC=CC2=CC=CC=C12)C(=O)N.C1(=CC=CC2=CC=CC=C12)C(=O)N ZFEFHTOOGZVUQZ-UHFFFAOYSA-N 0.000 description 1
- LMHGVQPPWCKOOB-UHFFFAOYSA-N COC1=C(C=C2C(=C1)C(=NC=N2)OC3=CC4=C(C=C3)C(=C(C=C4)CC5=CC=CC=C5)C(=O)N)OC Chemical compound COC1=C(C=C2C(=C1)C(=NC=N2)OC3=CC4=C(C=C3)C(=C(C=C4)CC5=CC=CC=C5)C(=O)N)OC LMHGVQPPWCKOOB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 1
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 1
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 1
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 208000001914 Fragile X syndrome Diseases 0.000 description 1
- 208000024412 Friedreich ataxia Diseases 0.000 description 1
- 108010051975 Glycogen Synthase Kinase 3 beta Proteins 0.000 description 1
- 102100038104 Glycogen synthase kinase-3 beta Human genes 0.000 description 1
- 108010051041 HC toxin Proteins 0.000 description 1
- 101150041489 HDAC3 gene Proteins 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- 102000006947 Histones Human genes 0.000 description 1
- 108010033040 Histones Proteins 0.000 description 1
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 1
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 description 1
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 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
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 1
- 239000005089 Luciferase Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 230000027311 M phase Effects 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 102000008934 Muscle Proteins Human genes 0.000 description 1
- 108010074084 Muscle Proteins Proteins 0.000 description 1
- VEYYWZRYIYDQJM-ZETCQYMHSA-N N(2)-acetyl-L-lysine Chemical group CC(=O)N[C@H](C([O-])=O)CCCC[NH3+] VEYYWZRYIYDQJM-ZETCQYMHSA-N 0.000 description 1
- 208000008636 Neoplastic Processes Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 102000011931 Nucleoproteins Human genes 0.000 description 1
- 108010061100 Nucleoproteins Proteins 0.000 description 1
- 108010047956 Nucleosomes Proteins 0.000 description 1
- JWOGUUIOCYMBPV-UHFFFAOYSA-N OT-Key 11219 Natural products N1C(=O)C(CCCCCC(=O)CC)NC(=O)C2CCCCN2C(=O)C(C(C)CC)NC(=O)C1CC1=CN(OC)C2=CC=CC=C12 JWOGUUIOCYMBPV-UHFFFAOYSA-N 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 208000037273 Pathologic Processes Diseases 0.000 description 1
- 101150029101 Pdk1 gene Proteins 0.000 description 1
- 101150036454 Pdpk1 gene Proteins 0.000 description 1
- 102100032287 Phosphatidylinositide phosphatase SAC2 Human genes 0.000 description 1
- 101710149053 Phosphatidylinositide phosphatase SAC2 Proteins 0.000 description 1
- 102100035194 Placenta growth factor Human genes 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 238000011529 RT qPCR Methods 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
- 108091027981 Response element Proteins 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 102100021947 Survival motor neuron protein Human genes 0.000 description 1
- 208000031673 T-Cell Cutaneous Lymphoma Diseases 0.000 description 1
- 229930189037 Trapoxin Natural products 0.000 description 1
- RTKIYFITIVXBLE-UHFFFAOYSA-N Trichostatin A Natural products ONC(=O)C=CC(C)=CC(C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-UHFFFAOYSA-N 0.000 description 1
- 102000004243 Tubulin Human genes 0.000 description 1
- 108090000704 Tubulin Proteins 0.000 description 1
- 102000009524 Vascular Endothelial Growth Factor A Human genes 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000037842 advanced-stage tumor Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000001772 anti-angiogenic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 108010082820 apicidin Proteins 0.000 description 1
- 229930186608 apicidin Natural products 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 210000004413 cardiac myocyte Anatomy 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000025084 cell cycle arrest Effects 0.000 description 1
- 230000006369 cell cycle progression Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000004709 cell invasion Effects 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 238000001516 cell proliferation assay Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 210000001100 crypt cell Anatomy 0.000 description 1
- 201000007241 cutaneous T cell lymphoma Diseases 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 210000004292 cytoskeleton Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 230000002074 deregulated effect Effects 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 230000007783 downstream signaling Effects 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 230000000431 effect on proliferation Effects 0.000 description 1
- 239000012636 effector Substances 0.000 description 1
- 230000010595 endothelial cell migration Effects 0.000 description 1
- 210000003989 endothelium vascular Anatomy 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005562 fading Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 238000012226 gene silencing method Methods 0.000 description 1
- 108091006104 gene-regulatory proteins Proteins 0.000 description 1
- 102000034356 gene-regulatory proteins Human genes 0.000 description 1
- GNYCTMYOHGBSBI-UHFFFAOYSA-N helminthsporium carbonum toxin Natural products N1C(=O)C(C)NC(=O)C(C)NC(=O)C2CCCN2C(=O)C1CCCCCC(=O)C1CO1 GNYCTMYOHGBSBI-UHFFFAOYSA-N 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 230000006197 histone deacetylation Effects 0.000 description 1
- 102000058223 human VEGFA Human genes 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 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 1
- 230000008102 immune modulation Effects 0.000 description 1
- 230000008073 immune recognition Effects 0.000 description 1
- 238000010185 immunofluorescence analysis Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000031146 intracellular signal transduction Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002510 keratinocyte Anatomy 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 108020001756 ligand binding domains Proteins 0.000 description 1
- 238000003670 luciferase enzyme activity assay Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 230000035168 lymphangiogenesis Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000004088 microvessel Anatomy 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- LUZBLBQBLFRGAR-UHFFFAOYSA-N n-(2-amino-4-chlorophenyl)-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=C(Cl)C=C1N LUZBLBQBLFRGAR-UHFFFAOYSA-N 0.000 description 1
- BKFXANGDVYSOTA-UHFFFAOYSA-N n-(2-amino-4-fluorophenyl)-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=C(F)C=C1N BKFXANGDVYSOTA-UHFFFAOYSA-N 0.000 description 1
- ARTWRTPHTULDTI-UHFFFAOYSA-N n-(2-amino-4-fluorophenyl)-6-(6,7-dimethoxyquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=C(F)C=C1N ARTWRTPHTULDTI-UHFFFAOYSA-N 0.000 description 1
- RCVNVSYHEYKUKL-UHFFFAOYSA-N n-(2-amino-4-fluorophenyl)-6-(7-methoxyquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=1C=NC2=CC(OC)=CC=C2C=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=C(F)C=C1N RCVNVSYHEYKUKL-UHFFFAOYSA-N 0.000 description 1
- ADTNTNBIMKCULS-UHFFFAOYSA-N n-(2-amino-4-methoxyphenyl)-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound NC1=CC(OC)=CC=C1NC(=O)C1=CC=CC2=CC(OC=3C4=CC(OC)=C(OC)C=C4N=CN=3)=CC=C12 ADTNTNBIMKCULS-UHFFFAOYSA-N 0.000 description 1
- QDKUAOJVJBYHGX-UHFFFAOYSA-N n-(2-amino-4-methylphenyl)-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=C(C)C=C1N QDKUAOJVJBYHGX-UHFFFAOYSA-N 0.000 description 1
- LORODOHKOJIIOA-UHFFFAOYSA-N n-(2-aminophenyl)-6-(6,7-dimethoxyquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=CC=C1N LORODOHKOJIIOA-UHFFFAOYSA-N 0.000 description 1
- BRKWREZNORONDU-UHFFFAOYSA-N n-(2-aminophenyl)-6-(7-methoxyquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=1C=NC2=CC(OC)=CC=C2C=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=CC=C1N BRKWREZNORONDU-UHFFFAOYSA-N 0.000 description 1
- MJTHSQAKWDERDV-UHFFFAOYSA-N n-(2-aminophenyl)-6-(8-methylquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C1=CN=C2C(C)=CC=CC2=C1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=CC=C1N MJTHSQAKWDERDV-UHFFFAOYSA-N 0.000 description 1
- RMCYPRKPHZCQKX-UHFFFAOYSA-N n-(2-aminophenyl)-6-[8-(trifluoromethyl)quinolin-4-yl]oxynaphthalene-1-carboxamide Chemical compound NC1=CC=CC=C1NC(=O)C1=CC=CC2=CC(OC=3C4=CC=CC(=C4N=CC=3)C(F)(F)F)=CC=C12 RMCYPRKPHZCQKX-UHFFFAOYSA-N 0.000 description 1
- QIERONPTKNIVLI-UHFFFAOYSA-N n-(2-aminophenyl)-6-quinolin-4-yloxynaphthalene-1-carboxamide Chemical compound NC1=CC=CC=C1NC(=O)C1=CC=CC2=CC(OC=3C4=CC=CC=C4N=CC=3)=CC=C12 QIERONPTKNIVLI-UHFFFAOYSA-N 0.000 description 1
- HQJPEUGYACZENI-UHFFFAOYSA-N n-[2-amino-4-(trifluoromethyl)phenyl]-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NC1=CC=C(C(F)(F)F)C=C1N HQJPEUGYACZENI-UHFFFAOYSA-N 0.000 description 1
- JUYGUJTWYYITCD-UHFFFAOYSA-N n-[[3-[(2-aminophenyl)carbamoyl]phenyl]methyl]-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NCC(C=1)=CC=CC=1C(=O)NC1=CC=CC=C1N JUYGUJTWYYITCD-UHFFFAOYSA-N 0.000 description 1
- ACCAOQJCUYSISU-UHFFFAOYSA-N n-[[4-[(2-amino-4-fluorophenyl)carbamoyl]phenyl]methyl]-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NCC(C=C1)=CC=C1C(=O)NC1=CC=C(F)C=C1N ACCAOQJCUYSISU-UHFFFAOYSA-N 0.000 description 1
- VNBKYXBXKYAHTI-UHFFFAOYSA-N n-[[4-[(2-amino-4-methoxyphenyl)carbamoyl]phenyl]methyl]-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound NC1=CC(OC)=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)C1=CC=CC2=CC(OC=3C4=CC(OC)=C(OC)C=C4N=CN=3)=CC=C12 VNBKYXBXKYAHTI-UHFFFAOYSA-N 0.000 description 1
- OYUPJLQHWJHION-UHFFFAOYSA-N n-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NCC(C=C1)=CC=C1C(=O)NC1=CC=CC=C1N OYUPJLQHWJHION-UHFFFAOYSA-N 0.000 description 1
- FKQNEYXPEQOUDK-UHFFFAOYSA-N n-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]-6-(6,7-dimethoxyquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NCC(C=C1)=CC=C1C(=O)NC1=CC=CC=C1N FKQNEYXPEQOUDK-UHFFFAOYSA-N 0.000 description 1
- TZBOHWZKGMPTKV-UHFFFAOYSA-N n-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]-6-(7-chloroquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)C1=CC=CC2=CC(OC=3C4=CC=C(Cl)C=C4N=CC=3)=CC=C12 TZBOHWZKGMPTKV-UHFFFAOYSA-N 0.000 description 1
- IEQXGKZFXRAMPP-UHFFFAOYSA-N n-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]-6-(7-methoxyquinolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=1C=NC2=CC(OC)=CC=C2C=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NCC(C=C1)=CC=C1C(=O)NC1=CC=CC=C1N IEQXGKZFXRAMPP-UHFFFAOYSA-N 0.000 description 1
- ZEEVHXHIGOMBHA-UHFFFAOYSA-N n-[[4-[(2-aminophenyl)carbamoyl]phenyl]methyl]-6-[8-(trifluoromethyl)quinolin-4-yl]oxynaphthalene-1-carboxamide Chemical compound NC1=CC=CC=C1NC(=O)C(C=C1)=CC=C1CNC(=O)C1=CC=CC2=CC(OC=3C4=CC=CC(=C4N=CC=3)C(F)(F)F)=CC=C12 ZEEVHXHIGOMBHA-UHFFFAOYSA-N 0.000 description 1
- JZQCYQFYAXNLLI-UHFFFAOYSA-N n-[[4-[[2-amino-4-(trifluoromethyl)phenyl]carbamoyl]phenyl]methyl]-6-(6,7-dimethoxyquinazolin-4-yl)oxynaphthalene-1-carboxamide Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC(C=C1C=CC=2)=CC=C1C=2C(=O)NCC(C=C1)=CC=C1C(=O)NC1=CC=C(C(F)(F)F)C=C1N JZQCYQFYAXNLLI-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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([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
- 230000006654 negative regulation of apoptotic process Effects 0.000 description 1
- 230000018791 negative regulation of catalytic activity Effects 0.000 description 1
- 230000019569 negative regulation of cell differentiation Effects 0.000 description 1
- 230000035407 negative regulation of cell proliferation Effects 0.000 description 1
- 230000017066 negative regulation of growth Effects 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 class 0.000 description 1
- 210000001623 nucleosome Anatomy 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 230000009054 pathological process Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 208000025638 primary cutaneous T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011092 protein amplification Methods 0.000 description 1
- 230000009822 protein phosphorylation Effects 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000020874 response to hypoxia Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000010079 rubber tapping Methods 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000021391 short chain fatty acids Nutrition 0.000 description 1
- 150000004666 short chain fatty acids Chemical class 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 208000002320 spinal muscular atrophy Diseases 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 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
- 208000008732 thymoma Diseases 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000012096 transfection reagent Substances 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 108010060597 trapoxin A Proteins 0.000 description 1
- 230000001960 triggered effect Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000004222 uncontrolled growth Effects 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 230000006444 vascular growth Effects 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
- C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- 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
-
- 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
-
- 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
- A61P37/08—Antiallergic agents
-
- 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
- A61P5/00—Drugs for disorders of the endocrine system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/24—Oxygen atoms attached in position 8
- C07D215/26—Alcohols; Ethers thereof
- C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Description
ZはCHまたはNであり、
R1、R2およびR3は、それぞれ水素、ハロ、アルキル、アルコキシまたはトリフルオロメチルであり、
R4は
Xはベンゼン環またはピリジン環であり、
R5は、水素、ハロ、アルキル、アルコキシおよびトリフルオロメチルからなる群より選択される1つ以上の置換基である]
の化合物(その遊離型、塩型、立体異性体、エナンチオマー、ジアステレオマー、または水和物を含む)を提供する。
ZがCHであり、
R1、R2およびR3が、それぞれ水素、ハロ、アルキル、アルコキシまたはトリフルオロメチルであり、
R4が
Xがベンゼン環またはピリジン環であり、
R5が、水素、ハロ、アルキル、アルコキシおよびトリフルオロメチルからなる群より選択される1つ以上の置換基である。
ZがCHであり、
R1、R2およびR3が、それぞれ水素またはアルコキシであり、
R4が
Xがベンゼン環またはピリジン環であり、
R5が、水素、ハロ、アルキル、アルコキシおよびトリフルオロメチルからなる群より選択される1つ以上の置換基である。
ZがCHであり、
R1およびR2が、それぞれ水素またはメトキシであり、
R3がHであり、
R4が
Xがベンゼン環またはピリジン環であり、
R5が、水素、ハロ、アルキル、アルコキシおよびトリフルオロメチルからなる群より選択される1つ以上の置換基である。
ZがCHであり、
R1およびR2が、それぞれ水素またはメトキシであり、
R3がHであり、
R4が
Xがベンゼン環またはピリジン環であり、
R5がHまたはFである。
処方(1000錠):
化合物31 5g
微結晶セルロース 90g
ナトリウムカルボキシメチルデンプン 5g
4%ポリビドン(K30)無水エタノール溶液 50g
タルク末 0.5g
化合物31を100メッシュふるいで篩分した。微結晶セルロース、ナトリウムカルボキシメチルデンプンおよびタルク末を、それぞれ80メッシュふるいで篩分した。処方量の微結晶セルロースおよびナトリウムカルボキシメチルデンプンを計量し、少しずつ、化合物31と均一に混和した。適切な量の4%ポリビドン(K30)無水エタノール溶液を加えて湿顆粒を作った。その顆粒を乾燥し、処方量のタルク末を加えた。次に打錠を行って錠剤を得た。
処方(1000カプセル):
化合物31 5g
微結晶セルロース 55g
ラクトース 35g
ナトリウムカルボキシメチルデンプン 5g
ステアリン酸マグネシウム 0.5g
化合物31を100メッシュふるいで篩分した。微結晶セルロース、ラクトース、ナトリウムカルボキシメチルデンプンおよびステアリン酸マグネシウムを、それぞれ80メッシュふるいで篩分した。処方量の微結晶セルロース、ラクトースおよびナトリウムカルボキシメチルデンプンを計量し、少しずつ、化合物31と均一に混和した。次に、処方量のステアリン酸マグネシウムを加え、均一に混合した。次に、カプセル充填を行ってカプセル剤を得た。
処方:
化合物31 1.00mg
DMSO 0.10ml
エタノール 1.00ml
化合物31をDMSOに溶解し、次にエタノールを加えて注射剤を得た。
受容体リガンド依存的細胞増殖に対するインビボ阻害の測定
1.PDGF依存的細胞増殖:
ヒトPDGFRβを安定に発現するように操作されたNIH−3T3マウス線維芽細胞株を構築し、それを使って、PDGF依存的細胞増殖を評価した。PDGFRβ NIH−3T3細胞を1ウェルあたり5,000個の割合で96ウェルプレートにプレーティングし、24時間後に無血清培地で終夜インキュベートした。被験化合物およびPDGF BB(50ng/ml)を加え、無血清培地中で72時間インキュベートした。増殖に対する効果を、MTS法(Promega)により、その説明書に従って決定した。インキュベーションを、CO2培養器中、37℃で2時間行い、ELISAプレートリーダーを使って490nmにおける吸光度を測定した。
HUVEC細胞を1ウェルあたり6,000個の割合で96ウェルプレートにプレーティングし、24時間後に、無血清培地で2時間インキュベートした。被験化合物およびVEGF165(50ng/ml)を加え、無血清培地中で72時間インキュベートした。細胞増殖に対する効果を、MTS法(Promega)により、その説明書に従って決定した。インキュベーションを、CO2培養器中、37℃で2時間行い、ELISAプレートリーダーを使って490nmにおける吸光度を決定した。
インビトロ総HDAC酵素活性のアッセイ:
インビトロ総HDAC酵素活性を、HDAC Fluorimetric Assay/Drug Dsicovery Kit(HDAC蛍光測定アッセイ/創薬キット)(BIOMOL)により、製造者の説明書に従って決定した。実験の原理は次のとおりである。ヒストンデアセチラーゼ(この実験では、さまざまなサブタイプのHDACに富むHeLa細胞核抽出物を使用した)の作用で、特殊な基質Fluor de Lysからアセチル基が除去されて、遊離のアミノ基が露出する。顕色剤を加えると、基質は蛍光を発することになる。この蛍光の場合、励起波長は360nmであり、蛍光波長は460nmである。基質の脱アセチル化が完全に近いほど、高い蛍光が誘導される。阻害剤の非存在下での蛍光値を対照とする。阻害剤が存在する場合は、誘導される蛍光値が低下することになり、酵素が存在しない場合(酵素活性の完全な阻害に相当する)の蛍光値がブランクである。一般に、抑制後の蛍光値は、対照とブランクの間になるだろう。分析を行う際は、ブランクを0として使用し、対照を1として使用する。小さい値ほど高い阻害活性を意味する。
異なるHDACサブタイプは異なる転写因子と結合することができ、さまざまな遺伝子の発現調節に関与する。HDACサブタイプに対する阻害剤の選択的阻害を評価するために使用することができるレポーター遺伝子を構築する目的で、転写因子の適切な調節要素を選択する。簡単に述べると、トランスフェクション時に50〜80%コンフルエントになるように、トランスフェクションの前日に、HeLa細胞を96ウェルプレートに播種した。ルシフェラーゼ遺伝子構築物の上流にp21プロモーター配列または応答要素を含有するレポーター遺伝子プラスミドの一つを、FuGene6トランスフェクション試薬を使い、製造者の説明書(Roche)に従って、細胞にトランスフェクトした。トランスフェクション効率を規格化するために、GFP発現プラスミドを同時トランスフェクトした。24時間後に、化合物または媒体対照(DMSO)を加えた。24時間後に細胞を収集し、溶解し、ルシフェラーゼアッセイキット(Promega)を使い、製造者の説明書に従って、ルシフェラーゼの量を評価した。
腫瘍細胞をトリプシン処理し、1ウェルあたり3,000個の割合で96ウェルプレートにプレーティングし、10%FBSを含む完全培地中で24時間インキュベートした。被験化合物および媒体対照を加えた。化合物の最終濃度は100nmol/L〜100μmol/Lの範囲にある。化合物を完全培地中で72時間インキュベートした。MTS試薬(Promega)を説明書に従って加え、CO2培養器中、37℃で2時間インキュベートした。次に、ELISAプレートリーダーを使って490nmにおける吸光度を読み取る。
14〜16gの雌nu/nuマウスに通常飼料を3日間与えた。次に、培養A549ヒト肺がん細胞を50匹のマウスの腋窩に移植した。腫瘍が直径6mmを上回る大きさに達したら、マウスを6つの群にランダムに分割した。各群は8匹のマウスを含んだ。1群を媒体で処置した。1群を陽性対照薬スーテントで処置した。他の4群は用量が5、10、20および40mg/kg体重の化合物31で処置した。各群に24日間にわたって1日1回経口投与した。腫瘍体積を体重と共に毎週2回記録した。24回投与した翌日に、マウスを屠殺し、腫瘍重量を測定した。次の式を使って各群の腫瘍成長阻害を計算した。
{[(対照群の平均腫瘍重量)−(試験群の平均腫瘍重量)]/(対照群の平均腫瘍重量)}×100%。
18〜20gの雌nu/nuマウスに通常飼料を3日間与えた。次に、培養ヒトHCT−8結腸がん細胞を50匹のマウスの腋窩に移植した。腫瘍が少なくとも100mm3を上回る大きさに達したら、マウスを6つの群にランダムに分割した。各群は8匹のマウスを含んだ。1群を媒体で処置した。1群を陽性対照薬スーテントで処置した。他の4群は用量が2.5、5、10および20mg/kg体重の化合物31で処置した。各群に24日間にわたって1日1回経口投与した。腫瘍体積を体重と共に毎週2回記録した。20回投与した翌日に、マウスを屠殺し、腫瘍重量を測定した。次の式を使って各群の腫瘍成長阻害を計算した。
{[(対照群の平均腫瘍重量)−(試験群の平均腫瘍重量)]/(対照群の平均腫瘍重量)}×100%。
18〜20gの雌nu/nuマウスに通常飼料を3日間与えた。次に、培養ヒトSSMC7721結腸がん細胞を50匹のマウスの腋窩に移植した。腫瘍が少なくとも100mm3を上回る大きさに達したら、マウスを6つの群にランダムに分割した。各群は8匹のマウスを含んだ。1群を媒体で処置した。1群を陽性対照薬スーテントで処置した。他の4群は用量が2.5、5、10および20mg/kg体重の化合物31で処置した。各群に24日間にわたって1日1回経口投与した。腫瘍体積を体重と共に毎週2回記録した。24回投与した翌日に、マウスを屠殺し、腫瘍重量を測定した。次の式を使って各群の腫瘍成長阻害を計算した。
{[(対照群の平均腫瘍重量)−(試験群の平均腫瘍重量)]/(対照群の平均腫瘍重量)}×100%。
18〜20gの雌nu/nuマウスに通常飼料を3日間与えた。次に、培養ヒトHCT−8結腸がん細胞を50匹のマウスの腋窩に移植した。腫瘍が少なくとも100mm3を上回る大きさに達したら、マウスを6つの群にランダムに分割した。各群は8匹のマウスを含んだ。1群を媒体で処置した。1群を陽性対照薬スーテントで処置した。1群を異なる濃度の化合物33で処置した。他の2群は異なる濃度の化合物34で処置した。各群に20日間にわたって1日1回経口投与した。腫瘍体積を体重と共に毎週2回記録した。20回投与した翌日に、マウスを屠殺し、腫瘍重量を測定した。次の式を使って各群の腫瘍成長阻害を計算した。
{[(対照群の平均腫瘍重量)−(試験群の平均腫瘍重量)]/(対照群の平均腫瘍重量)}×100%。
18〜20gの雌nu/nuマウスに通常飼料を3日間与えた。次に、培養ヒトHCT−8結腸がん細胞を50匹のマウスの腋窩に移植した。腫瘍が少なくとも100mm3を上回る大きさに達したら、マウスを6つの群にランダムに分割した。各群は8匹のマウスを含んだ。1群を媒体で処置した。1群を陽性対照薬スーテントで処置した。2群を異なる濃度の化合物33で処置した。他の2群は異なる濃度の化合物37で処置した。化合物33は6時間毎の間隔で1日2回投与した。他の群では、投与は1日に1回行われた。各群に20日間にわたって1日1回経口投与した。腫瘍体積を体重と共に毎週2回記録した。20回投与した翌日に、マウスを屠殺し、腫瘍重量を測定した。次の式を使って各群の腫瘍成長阻害を計算した。
{[(対照群の平均腫瘍重量)−(試験群の平均腫瘍重量)]/(対照群の平均腫瘍重量)}×100%。
18〜20gの雌nu/nuマウスに通常飼料を3日間与えた。次に、培養ヒトSSMC7721肝がん細胞を50匹のマウスの腋窩に移植した。腫瘍が少なくとも100mm3を上回る大きさに達したら、マウスを6つの群にランダムに分割した。各群は8匹のマウスを含んだ。1群を媒体で処置した。1群を陽性対照薬スーテントで処置した。2群を異なる濃度の化合物33で処置した。他の2群は異なる濃度の化合物37で処置した。各群に30日間にわたって1日1回経口投与した。腫瘍体積を体重と共に毎週2回記録した。30回投与した翌日に、マウスを屠殺し、腫瘍重量を測定した。次の式を使って各群の腫瘍成長阻害を計算した。
{[(対照群の平均腫瘍重量)−(試験群の平均腫瘍重量)]/(対照群の平均腫瘍重量)}×100%。
Claims (13)
- 前記ペプチド縮合剤が、1−エチル−3−(3−ジメチル−アミノプロピル)カルボジイミド(EDC)、N,N’−ジシクロヘキシルカルボジイミド(DCC)およびN,N’−カルボニルジイミダゾール(CDI)からなる群より選択される、請求項6の方法。
- 前記有機溶媒が、ベンゼン、トルエン、テトラヒドロフラン、1,4−ジオキサン、ジクロロメタン、クロロホルムおよびN,N−ジメチルホルムアミドからなる群より選択される、請求項6の方法。
- 請求項1に記載の式(I)の化合物と医薬上許容される担体、賦形剤、または希釈剤とを含む、異常なプロテインキナーゼ活性または異常なヒストンデアセチラーゼ活性に関連する疾患を処置するための医薬調製物。
- 錠剤、カプセル剤、散剤、シロップ剤、溶液剤、懸濁剤、注射剤または軟膏の形態である、請求項9に記載の医薬調製物。
- 炎症性疾患、自己免疫疾患、がん、神経系疾患および神経変性疾患、アレルギー、喘息、心血管疾患および代謝性疾患、またはホルモン関連疾患を処置するための医薬品の製造における、請求項1の化合物の使用。
- 炎症性疾患、自己免疫疾患、がん、神経系疾患および神経変性疾患、アレルギー、喘息、心血管疾患および代謝性疾患、またはホルモン関連疾患を処置するための医薬品の製造における、請求項9の医薬調製物の使用。
- 0.001〜200mgの範囲内の量の前記式(I)の化合物を含む、請求項9の医薬調製物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200910143978 | 2009-06-04 | ||
CN200910143978.2 | 2009-06-04 | ||
PCT/CN2010/000272 WO2010139180A1 (zh) | 2009-06-04 | 2010-03-05 | 作为蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘酰胺衍生物、其制备方法及应用 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2012528800A JP2012528800A (ja) | 2012-11-15 |
JP5484568B2 true JP5484568B2 (ja) | 2014-05-07 |
Family
ID=43261686
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012513451A Active JP5484568B2 (ja) | 2009-06-04 | 2010-03-05 | プロテインキナーゼおよびヒストンデアセチラーゼの阻害剤としてのナフタレンカルボキサミド誘導体、その製造方法および用途 |
Country Status (18)
Country | Link |
---|---|
EP (1) | EP2439195B1 (ja) |
JP (1) | JP5484568B2 (ja) |
KR (2) | KR101421786B1 (ja) |
CN (1) | CN101906076B (ja) |
AU (1) | AU2010256246B9 (ja) |
BR (1) | BRPI1011994B8 (ja) |
CA (1) | CA2763822C (ja) |
DK (1) | DK2439195T3 (ja) |
ES (1) | ES2509615T3 (ja) |
HR (1) | HRP20140717T1 (ja) |
MX (1) | MX2011012752A (ja) |
PL (1) | PL2439195T3 (ja) |
PT (1) | PT2439195E (ja) |
RU (1) | RU2497809C2 (ja) |
SI (1) | SI2439195T1 (ja) |
UA (1) | UA103092C2 (ja) |
WO (1) | WO2010139180A1 (ja) |
ZA (1) | ZA201109030B (ja) |
Families Citing this family (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2011057661A (ja) * | 2009-08-14 | 2011-03-24 | Bayer Cropscience Ag | 殺虫性カルボキサミド類 |
CN102260210B (zh) * | 2011-05-30 | 2012-06-27 | 王立强 | 蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘酰胺衍生物的制备方法 |
CN102603627B (zh) * | 2011-05-31 | 2013-02-06 | 王立强 | 作为蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘酰胺衍生物及其制备方法 |
CN102850236B (zh) * | 2011-06-27 | 2016-05-18 | 国药一心制药有限公司 | 新型苯甲酰胺类组蛋白去乙酰化酶抑制剂及其应用 |
CN103420923B (zh) * | 2012-05-18 | 2015-08-19 | 国药一心制药有限公司 | 4-氨基喹唑啉异羟肟酸类化合物及作为抗肿瘤药物应用 |
CN103288728A (zh) * | 2013-05-17 | 2013-09-11 | 华侨大学 | 一种萘甲酰胺衍生物、其制备方法以及应用 |
CN103351336A (zh) * | 2013-06-28 | 2013-10-16 | 华侨大学 | 作为蛋白激酶抑制剂和组蛋白去乙酰化酶抑制剂的萘甲酰胺衍生物及其制备方法 |
CN103432077A (zh) * | 2013-08-21 | 2013-12-11 | 北京淦航医药科技有限公司 | 西达苯胺固体分散制剂 |
CN104418867B (zh) * | 2013-08-26 | 2016-12-28 | 上海汇伦生命科技有限公司 | 作为PI3K/mTOR抑制剂的化合物,其制备方法和用途 |
CN103724260A (zh) * | 2013-12-18 | 2014-04-16 | 华侨大学 | 一种苯甲酰胺衍生物及其制备方法和应用 |
CN104860885B (zh) | 2014-02-24 | 2017-11-17 | 中国科学院上海药物研究所 | 萘酰胺类化合物、其制备方法和用途 |
CN103896836A (zh) * | 2014-03-20 | 2014-07-02 | 华侨大学 | N-苯基-6-[(7-氯喹啉-4-氧基)酚醚]-2-萘甲酰胺及其制备方法 |
CN103923004A (zh) * | 2014-04-04 | 2014-07-16 | 华侨大学 | 一种萘甲酰胺衍生物及其制备和应用 |
CN104030980A (zh) * | 2014-06-10 | 2014-09-10 | 华侨大学 | N-(3-甲氧基-4-氯苯基)-4-[(7-氯-4-喹啉)氨基]苯甲酰胺及其制备和应用 |
CN105399685B (zh) * | 2014-09-16 | 2018-05-22 | 深圳微芯生物科技有限责任公司 | 作为选择性jak3和/或jak1激酶抑制剂的芳杂环化合物的制备方法及其应用 |
CN104447534A (zh) * | 2014-12-04 | 2015-03-25 | 厦门大学 | 6-[(7-氯喹啉-4-氧基)酚醚]-2-萘甲酰胺类衍生物及其制备方法和用途 |
CN107868044B (zh) * | 2016-09-27 | 2020-10-16 | 深圳微芯生物科技股份有限公司 | 一种非溶剂化晶体及其制备方法与应用 |
CN109803645B (zh) * | 2017-04-10 | 2022-03-25 | 师健友 | 一种用于治疗肿瘤疾病以及具有抗菌、抗病毒和抗炎作用的药物 |
CN109985039A (zh) * | 2017-12-29 | 2019-07-09 | 深圳微芯生物科技股份有限公司 | 用于治疗白血病的联合用药物及其在制备用于治疗急性髓性白血病的药物中的用途 |
CN110833544B (zh) * | 2018-08-17 | 2022-08-09 | 深圳微芯生物科技股份有限公司 | 组蛋白去乙酰化酶抑制剂与蛋白激酶抑制剂之组合及其制药用途 |
CN109908143B (zh) * | 2018-12-18 | 2021-11-19 | 厦门大学附属第一医院 | 西奥罗尼在制备治疗急性髓系白血病药物的新用途 |
TWI797426B (zh) * | 2019-03-25 | 2023-04-01 | 大陸商深圳微芯生物科技股份有限公司 | 西奧羅尼用於小細胞肺癌的治療 |
CN113440615A (zh) * | 2020-03-24 | 2021-09-28 | 深圳微芯生物科技股份有限公司 | 包含蛋白激酶抑制剂和化疗药物的药物组合物及其用途 |
KR20230074533A (ko) * | 2020-09-23 | 2023-05-30 | 상하이 인스티튜트 오브 마테리아 메디카 차이니즈 아카데미 오브 싸이언시즈 | Csf1r 키나아제 억제제 및 이의 용도 |
WO2022247844A1 (zh) * | 2021-05-26 | 2022-12-01 | 深圳微芯生物科技股份有限公司 | 包含蛋白激酶抑制剂的药物组合物及其医药用途 |
Family Cites Families (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6174905B1 (en) | 1996-09-30 | 2001-01-16 | Mitsui Chemicals, Inc. | Cell differentiation inducer |
US6316429B1 (en) | 1997-05-07 | 2001-11-13 | Sugen, Inc. | Bicyclic protein kinase inhibitors |
JP4405602B2 (ja) * | 1998-04-16 | 2010-01-27 | バイエル・シエーリング・ファーマ アクチエンゲゼルシャフト | ヒストン脱アセチル化酵素阻害剤 |
YU22402A (sh) | 1999-09-08 | 2006-01-16 | Sloan-Kettering Institute For Cancer Research | Nova klasa agenasa za citodiferencijaciju i inhibitora histon deacetilaze, i postupci za njihovu upotrebu |
ATE369359T1 (de) | 2000-02-15 | 2007-08-15 | Sugen Inc | Pyrrol substituierte indolin-2-on protein kinase inhibitoren |
EP1280764B1 (en) | 2000-03-24 | 2010-11-24 | Methylgene, Inc. | Inhibitors of histone deacetylase |
MXPA02010759A (es) | 2000-05-02 | 2004-07-30 | Sugen Inc | Derivados del acido (2-oxindol-3-ilidenil) acetico y su uso como inhibidores de la proteina quinasa. |
PE20020506A1 (es) | 2000-08-22 | 2002-07-09 | Glaxo Group Ltd | Derivados de pirazol fusionados como inhibidores de la proteina cinasa |
AU2001292670A1 (en) | 2000-09-15 | 2002-03-26 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
WO2002026696A1 (en) | 2000-09-29 | 2002-04-04 | Prolifix Limited | Carbamic acid compounds comprising an amide linkage as hdac inhibitors |
US20020103192A1 (en) | 2000-10-26 | 2002-08-01 | Curtin Michael L. | Inhibitors of histone deacetylase |
AR042586A1 (es) | 2001-02-15 | 2005-06-29 | Sugen Inc | 3-(4-amidopirrol-2-ilmetiliden)-2-indolinona como inhibidores de la protein quinasa; sus composiciones farmaceuticas; un metodo para la modulacion de la actividad catalitica de la proteinquinasa; un metodo para tratar o prevenir una afeccion relacionada con la proteinquinasa |
CN1578663B (zh) * | 2001-09-14 | 2011-05-25 | 梅特希尔基因公司 | 组蛋白脱乙酰化酶抑制剂 |
TW200306819A (en) | 2002-01-25 | 2003-12-01 | Vertex Pharma | Indazole compounds useful as protein kinase inhibitors |
TWI319387B (en) * | 2002-04-05 | 2010-01-11 | Astrazeneca Ab | Benzamide derivatives |
AU2004203977B2 (en) | 2003-01-09 | 2010-06-17 | Pfizer Inc. | Diazepinoindole derivatives as kinase inhibitors |
WO2004078682A2 (en) | 2003-03-05 | 2004-09-16 | Irm Llc | Cyclic compounds and compositions as protein kinase inhibitors |
AU2004267094A1 (en) | 2003-08-20 | 2005-03-03 | Vertex Pharmaceuticals Incorporated | (4 -amino -1,2, 5-oxadiazol-4-yl) -hetxiroaromatic compounds useful as protein kinase inhibitors |
BRPI0414011A (pt) * | 2003-08-29 | 2006-10-24 | Pfizer | naftalencarboxamidas e seus derivados úteis como novos agentes antiangiogênicos |
JP4932495B2 (ja) * | 2004-01-23 | 2012-05-16 | アムゲン インコーポレイテッド | 化合物及び使用方法 |
EP2060565A1 (en) * | 2007-11-16 | 2009-05-20 | 4Sc Ag | Novel bifunctional compounds which inhibit protein kinases and histone deacetylases |
-
2009
- 2009-11-24 CN CN2009102238615A patent/CN101906076B/zh active Active
-
2010
- 2010-03-05 SI SI201030695T patent/SI2439195T1/sl unknown
- 2010-03-05 KR KR1020117030659A patent/KR101421786B1/ko active IP Right Grant
- 2010-03-05 CA CA2763822A patent/CA2763822C/en active Active
- 2010-03-05 KR KR1020147000095A patent/KR20140014313A/ko not_active Application Discontinuation
- 2010-03-05 EP EP10782884.0A patent/EP2439195B1/en active Active
- 2010-03-05 ES ES10782884.0T patent/ES2509615T3/es active Active
- 2010-03-05 JP JP2012513451A patent/JP5484568B2/ja active Active
- 2010-03-05 PT PT107828840T patent/PT2439195E/pt unknown
- 2010-03-05 BR BRPI1011994A patent/BRPI1011994B8/pt active IP Right Grant
- 2010-03-05 AU AU2010256246A patent/AU2010256246B9/en active Active
- 2010-03-05 MX MX2011012752A patent/MX2011012752A/es active IP Right Grant
- 2010-03-05 WO PCT/CN2010/000272 patent/WO2010139180A1/zh active Application Filing
- 2010-03-05 RU RU2011152113/04A patent/RU2497809C2/ru active
- 2010-03-05 DK DK10782884.0T patent/DK2439195T3/da active
- 2010-03-05 PL PL10782884T patent/PL2439195T3/pl unknown
- 2010-03-05 UA UAA201115118A patent/UA103092C2/ru unknown
-
2011
- 2011-12-08 ZA ZA2011/09030A patent/ZA201109030B/en unknown
-
2014
- 2014-07-25 HR HRP20140717AT patent/HRP20140717T1/hr unknown
Also Published As
Publication number | Publication date |
---|---|
BRPI1011994B1 (pt) | 2020-04-07 |
KR101421786B1 (ko) | 2014-07-22 |
SI2439195T1 (sl) | 2014-12-31 |
JP2012528800A (ja) | 2012-11-15 |
AU2010256246B9 (en) | 2014-01-30 |
ZA201109030B (en) | 2013-02-27 |
DK2439195T3 (da) | 2014-09-22 |
AU2010256246B2 (en) | 2013-04-11 |
MX2011012752A (es) | 2012-03-07 |
UA103092C2 (ru) | 2013-09-10 |
KR20120016659A (ko) | 2012-02-24 |
PL2439195T3 (pl) | 2015-02-27 |
AU2010256246A1 (en) | 2012-01-12 |
EP2439195A4 (en) | 2012-10-31 |
PT2439195E (pt) | 2014-09-10 |
KR20140014313A (ko) | 2014-02-05 |
WO2010139180A8 (zh) | 2012-01-05 |
WO2010139180A1 (zh) | 2010-12-09 |
CN101906076B (zh) | 2013-03-13 |
RU2497809C2 (ru) | 2013-11-10 |
CA2763822A1 (en) | 2010-12-09 |
EP2439195A1 (en) | 2012-04-11 |
CN101906076A (zh) | 2010-12-08 |
EP2439195B1 (en) | 2014-07-16 |
BRPI1011994A2 (pt) | 2016-05-10 |
ES2509615T3 (es) | 2014-10-17 |
CA2763822C (en) | 2014-12-09 |
BRPI1011994B8 (pt) | 2021-05-25 |
HRP20140717T1 (hr) | 2014-11-21 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5484568B2 (ja) | プロテインキナーゼおよびヒストンデアセチラーゼの阻害剤としてのナフタレンカルボキサミド誘導体、その製造方法および用途 | |
US8211901B2 (en) | Naphthamide derivatives as multi-target protein kinase inhibitors and histone deacetylase inhibitors | |
CA2825367C (en) | Diarylacetylene hydrazide containing tyrosine kinase inhibitors | |
JP6126233B2 (ja) | 新たなキノリン類の化合物及びその使用 | |
WO2017101803A1 (zh) | 一种新型egfr和alk激酶的双重抑制剂 | |
AU2011285247A1 (en) | Bicyclic azaheterocyclic carboxamides as inhibitors of the kinase p70S6K | |
JPWO2006104161A1 (ja) | c−Met自己リン酸化阻害作用を有するチエノピリジン誘導体、キノリン誘導体、およびキナゾリン誘導体 | |
CN112480078B (zh) | 一种喹唑啉异羟肟酸衍生物及其制备方法与应用 | |
WO2020221006A1 (zh) | 一种bet蛋白抑制剂、其制备方法及用途 | |
CN110835334B (zh) | 吲哚取代唑类化合物及其用途 | |
CN108794398B (zh) | 具有荧光的选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用 | |
US11207296B2 (en) | XPA inhibitor compounds and their use | |
WO2009014941A1 (en) | 3-(4-amidopyrrol-2-ylmethlidene)-2-indolinone derivatives as multi-target protein kinase inhibitors and histone deacetylase inhibitors | |
WO2013159698A1 (zh) | 稠环喹唑啉羟肟酸类化合物及其作为抗肿瘤药物的应用 | |
CN114539162B (zh) | 含取代芳基脲亚胺基二芳基嘧啶类衍生物及其制备方法和用途 | |
US8158656B2 (en) | 2-indolinone derivatives as multi-target protein kinase inhibitors and histone deacetylase inhibitors | |
Hou et al. | Design, synthesis and antitumor activity of novel 6, 7-dimethoxyquinazoline derivatives containing diaryl urea moiety | |
WO2023055580A1 (en) | Benzylthiophene derivatives | |
JP2011520891A (ja) | 強力かつ選択的なヒストン脱アセチル化酵素阻害剤としての6−アミノニコチンアミド誘導体 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20131001 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20131003 |
|
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: 20140122 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20140218 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5484568 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |