CA2780759A1 - Protein kinase c inhibitors and uses thereof - Google Patents
Protein kinase c inhibitors and uses thereof Download PDFInfo
- Publication number
- CA2780759A1 CA2780759A1 CA2780759A CA2780759A CA2780759A1 CA 2780759 A1 CA2780759 A1 CA 2780759A1 CA 2780759 A CA2780759 A CA 2780759A CA 2780759 A CA2780759 A CA 2780759A CA 2780759 A1 CA2780759 A1 CA 2780759A1
- Authority
- CA
- Canada
- Prior art keywords
- fluoro
- ylamino
- methyl
- tetrazol
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229940123924 Protein kinase C inhibitor Drugs 0.000 title description 2
- 239000003881 protein kinase C inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 294
- 108090000315 Protein Kinase C Proteins 0.000 claims abstract description 145
- 102000003923 Protein Kinase C Human genes 0.000 claims abstract description 145
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 108
- 238000000034 method Methods 0.000 claims abstract description 80
- 230000000694 effects Effects 0.000 claims abstract description 50
- 230000001404 mediated effect Effects 0.000 claims abstract description 31
- 238000011282 treatment Methods 0.000 claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 25
- 230000002459 sustained effect Effects 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 268
- -1 amino, substituted amino, carboxyl Chemical group 0.000 claims description 218
- 229910052739 hydrogen Inorganic materials 0.000 claims description 205
- 239000001257 hydrogen Substances 0.000 claims description 204
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 172
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 158
- 125000000623 heterocyclic group Chemical group 0.000 claims description 157
- 125000001072 heteroaryl group Chemical group 0.000 claims description 142
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 122
- 229910052736 halogen Inorganic materials 0.000 claims description 98
- 125000002252 acyl group Chemical group 0.000 claims description 94
- 125000003118 aryl group Chemical group 0.000 claims description 85
- 150000002367 halogens Chemical group 0.000 claims description 85
- 125000003545 alkoxy group Chemical group 0.000 claims description 77
- 125000005415 substituted alkoxy group Chemical group 0.000 claims description 74
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 72
- 150000003839 salts Chemical class 0.000 claims description 66
- 201000010099 disease Diseases 0.000 claims description 61
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 57
- 125000000304 alkynyl group Chemical group 0.000 claims description 51
- 125000003342 alkenyl group Chemical group 0.000 claims description 50
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 47
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 47
- 208000035475 disorder Diseases 0.000 claims description 46
- 125000003107 substituted aryl group Chemical group 0.000 claims description 42
- 238000003556 assay Methods 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 38
- 125000002947 alkylene group Chemical group 0.000 claims description 38
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 37
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 32
- 125000001153 fluoro group Chemical group F* 0.000 claims description 32
- 125000004442 acylamino group Chemical group 0.000 claims description 31
- 239000012453 solvate Substances 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 230000002757 inflammatory effect Effects 0.000 claims description 22
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 20
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 18
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 208000022873 Ocular disease Diseases 0.000 claims description 16
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 16
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 15
- 230000005764 inhibitory process Effects 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 208000023275 Autoimmune disease Diseases 0.000 claims description 12
- 239000012472 biological sample Substances 0.000 claims description 12
- 229940002612 prodrug Drugs 0.000 claims description 11
- 239000000651 prodrug Substances 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 208000028867 ischemia Diseases 0.000 claims description 8
- 201000006417 multiple sclerosis Diseases 0.000 claims description 8
- JRXJIGCQQDRUIV-UHFFFAOYSA-N 1-[2-cyclopropyl-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1C1CC1 JRXJIGCQQDRUIV-UHFFFAOYSA-N 0.000 claims description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical class OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 7
- 230000004913 activation Effects 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- 239000000523 sample Substances 0.000 claims description 7
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 159000000021 acetate salts Chemical class 0.000 claims description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical class [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- SQDWRAPQUQMHEY-UHFFFAOYSA-N 1-[2-cyclopropyl-3-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(F)=C1C1CC1 SQDWRAPQUQMHEY-UHFFFAOYSA-N 0.000 claims description 5
- CGWRSWPWEOFYGO-UHFFFAOYSA-N 1-[2-cyclopropyl-4-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C(F)C=C1C1CC1 CGWRSWPWEOFYGO-UHFFFAOYSA-N 0.000 claims description 5
- OCIZSTIHTDBDFL-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-(oxetan-3-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1OC1COC1 OCIZSTIHTDBDFL-UHFFFAOYSA-N 0.000 claims description 5
- RZWDZBKHCHFJLR-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-propan-2-yloxy-3-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound C1=C(C(F)(F)F)C(OC(C)C)=C(N2C(N(C)N=N2)=O)C=C1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 RZWDZBKHCHFJLR-UHFFFAOYSA-N 0.000 claims description 5
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 5
- 206010019280 Heart failures Diseases 0.000 claims description 5
- 206010020751 Hypersensitivity Diseases 0.000 claims description 5
- 201000004681 Psoriasis Diseases 0.000 claims description 5
- 230000007815 allergy Effects 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 5
- 150000001558 benzoic acid derivatives Chemical class 0.000 claims description 5
- 201000011510 cancer Diseases 0.000 claims description 5
- 208000037976 chronic inflammation Diseases 0.000 claims description 5
- 150000001860 citric acid derivatives Chemical class 0.000 claims description 5
- 150000004675 formic acid derivatives Chemical class 0.000 claims description 5
- 208000024908 graft versus host disease Diseases 0.000 claims description 5
- 150000002688 maleic acid derivatives Chemical class 0.000 claims description 5
- 208000010125 myocardial infarction Diseases 0.000 claims description 5
- PUUCFGYZKZDLEA-UHFFFAOYSA-N 1-[2,6-difluoro-3-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C(=C(C(F)=CC=2)N2C(N(C)N=N2)=O)F)=NC=C1F PUUCFGYZKZDLEA-UHFFFAOYSA-N 0.000 claims description 4
- LOGYTIMVAIIDDY-UHFFFAOYSA-N 1-[2,6-difluoro-3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=C(F)C=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C1F LOGYTIMVAIIDDY-UHFFFAOYSA-N 0.000 claims description 4
- DLQSAOIIZIFBSL-UHFFFAOYSA-N 1-[2-chloro-4-fluoro-5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C(=CC(Cl)=C(C=2)N2C(N(C)N=N2)=O)F)=NC=C1F DLQSAOIIZIFBSL-UHFFFAOYSA-N 0.000 claims description 4
- ACOKGWBSHZSKIA-UHFFFAOYSA-N 1-[2-chloro-4-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C(F)C=C1Cl ACOKGWBSHZSKIA-UHFFFAOYSA-N 0.000 claims description 4
- DRKMNTMQJWMKCQ-UHFFFAOYSA-N 1-[2-chloro-5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(Cl)=CC=2)N2C(N(C)N=N2)=O)=NC=C1F DRKMNTMQJWMKCQ-UHFFFAOYSA-N 0.000 claims description 4
- RYANWIJWDHPLGF-UHFFFAOYSA-N 1-[2-chloro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C(F)(F)F)=C1Cl RYANWIJWDHPLGF-UHFFFAOYSA-N 0.000 claims description 4
- SQIXWDJIPSMYTO-UHFFFAOYSA-N 1-[2-chloro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1Cl SQIXWDJIPSMYTO-UHFFFAOYSA-N 0.000 claims description 4
- CGWRSWPWEOFYGO-VPYROQPTSA-N 1-[2-cyclopropyl-4-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-(trideuteriomethyl)tetrazol-5-one Chemical compound O=C1N(C([2H])([2H])[2H])N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C(F)C=C1C1CC1 CGWRSWPWEOFYGO-VPYROQPTSA-N 0.000 claims description 4
- CIORCHOFGHDWCX-UHFFFAOYSA-N 1-[2-cyclopropyl-5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(C3CC3)=C(C=2)N2C(N(C)N=N2)=O)C(F)(F)F)=NC=C1F CIORCHOFGHDWCX-UHFFFAOYSA-N 0.000 claims description 4
- HWGSCFJJCINYLP-UHFFFAOYSA-N 1-[2-cyclopropyl-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-3-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C(F)(F)F)=C1C1CC1 HWGSCFJJCINYLP-UHFFFAOYSA-N 0.000 claims description 4
- HLYVGISNDNHMRA-UHFFFAOYSA-N 1-[3-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(oxetan-3-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(OC3COC3)C=2)N2C(N(C)N=N2)=O)=NC=C1F HLYVGISNDNHMRA-UHFFFAOYSA-N 0.000 claims description 4
- KNEKNESDJHXFEK-UHFFFAOYSA-N 1-[3-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(C=2)N2C(N(C)N=N2)=O)C(F)(F)F)=NC=C1F KNEKNESDJHXFEK-UHFFFAOYSA-N 0.000 claims description 4
- AUYAEELPWLXUTR-UHFFFAOYSA-N 1-[3-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-methoxyphenyl]-4-methyltetrazol-5-one Chemical compound C=1C(N2C(N(C)N=N2)=O)=CC(OC)=CC=1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)N(C)C(C)(C)C1 AUYAEELPWLXUTR-UHFFFAOYSA-N 0.000 claims description 4
- AETZGBGKMCNDSF-UHFFFAOYSA-N 1-[3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(oxetan-3-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(OC2COC2)=C1 AETZGBGKMCNDSF-UHFFFAOYSA-N 0.000 claims description 4
- WXGOHMWDDPBVDZ-UHFFFAOYSA-N 1-[3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C(F)(F)F)=C1 WXGOHMWDDPBVDZ-UHFFFAOYSA-N 0.000 claims description 4
- ZGKRWXRFAKVAPT-UHFFFAOYSA-N 1-[3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-methoxyphenyl]-4-methyltetrazol-5-one Chemical compound C=1C(N2C(N(C)N=N2)=O)=CC(OC)=CC=1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 ZGKRWXRFAKVAPT-UHFFFAOYSA-N 0.000 claims description 4
- JBFLPWZXBJDGIR-UHFFFAOYSA-N 1-[3-chloro-5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methylphenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(C)=C(Cl)C=2)N2C(N(C)N=N2)=O)=NC=C1F JBFLPWZXBJDGIR-UHFFFAOYSA-N 0.000 claims description 4
- FYCINSPFXIGRPL-UHFFFAOYSA-N 1-[3-chloro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methylphenyl]-4-methyltetrazol-5-one Chemical compound C1=C(N2C(N(C)N=N2)=O)C(C)=C(Cl)C=C1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 FYCINSPFXIGRPL-UHFFFAOYSA-N 0.000 claims description 4
- ROQGVJRDHXKHEP-UHFFFAOYSA-N 1-[3-chloro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(Cl)=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C1 ROQGVJRDHXKHEP-UHFFFAOYSA-N 0.000 claims description 4
- FEXKZLUVFQESSZ-UHFFFAOYSA-N 1-[3-cyclopropyl-2-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C2CC2)=C1F FEXKZLUVFQESSZ-UHFFFAOYSA-N 0.000 claims description 4
- JULQRINCWYXZHC-UHFFFAOYSA-N 1-[3-cyclopropyl-5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(C=2)C2CC2)N2C(N(C)N=N2)=O)=NC=C1F JULQRINCWYXZHC-UHFFFAOYSA-N 0.000 claims description 4
- UPMRZHACVQMULL-UHFFFAOYSA-N 1-[3-cyclopropyl-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C2CC2)=C1 UPMRZHACVQMULL-UHFFFAOYSA-N 0.000 claims description 4
- XSVGHNSPSGZWJL-UHFFFAOYSA-N 1-[3-fluoro-5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(F)C=2)N2C(N(C)N=N2)=O)=NC=C1F XSVGHNSPSGZWJL-UHFFFAOYSA-N 0.000 claims description 4
- NPOURDHLPUTPKN-UHFFFAOYSA-N 1-[3-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(F)=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C1 NPOURDHLPUTPKN-UHFFFAOYSA-N 0.000 claims description 4
- NIXPJPGANXTIFX-UHFFFAOYSA-N 1-[4-fluoro-3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC=C(F)C(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C1 NIXPJPGANXTIFX-UHFFFAOYSA-N 0.000 claims description 4
- NAARYWGPIGVOCV-HIFRSBDPSA-N 1-[4-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-[(1s,2s)-2-(trifluoromethyl)cyclopropyl]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C(F)C=C1[C@@H]1[C@@H](C(F)(F)F)C1 NAARYWGPIGVOCV-HIFRSBDPSA-N 0.000 claims description 4
- XVXNDEPKECAPTD-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2,3-dimethylphenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(C)=C(C)C=2)N2C(N(C)N=N2)=O)=NC=C1F XVXNDEPKECAPTD-UHFFFAOYSA-N 0.000 claims description 4
- BFIBCXLPSFGLAF-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-(1,1,1-trifluoro-2-methylpropan-2-yl)oxyphenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(OC(C)(C)C(F)(F)F)=CC=2)N2C(N(C)N=N2)=O)=NC=C1F BFIBCXLPSFGLAF-UHFFFAOYSA-N 0.000 claims description 4
- LEUAPHBHGUFLAP-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-(oxan-4-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(OC3CCOCC3)=CC=2)N2C(N(C)N=N2)=O)=NC=C1F LEUAPHBHGUFLAP-UHFFFAOYSA-N 0.000 claims description 4
- XBEXCZLWOWTTAU-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-(oxetan-3-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(OC3COC3)=CC=2)N2C(N(C)N=N2)=O)=NC=C1F XBEXCZLWOWTTAU-UHFFFAOYSA-N 0.000 claims description 4
- CMXHCHOUHWIZEW-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methyl-3-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(C)=C(C=2)N2C(N(C)N=N2)=O)C(F)(F)F)=NC=C1F CMXHCHOUHWIZEW-UHFFFAOYSA-N 0.000 claims description 4
- WUFZZSSAKYWINZ-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-propan-2-yloxy-3-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound C1=C(C(F)(F)F)C(OC(C)C)=C(N2C(N(C)N=N2)=O)C=C1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)N(C)C(C)(C)C1 WUFZZSSAKYWINZ-UHFFFAOYSA-N 0.000 claims description 4
- SGYJJVFPSFIHQQ-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2,3-dimethylphenyl]-4-methyltetrazol-5-one Chemical compound C=1C(N2C(N(C)N=N2)=O)=C(C)C(C)=CC=1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 SGYJJVFPSFIHQQ-UHFFFAOYSA-N 0.000 claims description 4
- SYDHZOULYFQDQZ-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-(1,1,1-trifluoro-2-methylpropan-2-yl)oxyphenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1OC(C)(C)C(F)(F)F SYDHZOULYFQDQZ-UHFFFAOYSA-N 0.000 claims description 4
- RJPLZPMCGCGUDR-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-(oxan-4-yloxy)phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1OC1CCOCC1 RJPLZPMCGCGUDR-UHFFFAOYSA-N 0.000 claims description 4
- MMRVAXALLLOUNL-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-[(3-methyloxetan-3-yl)methoxy]phenyl]-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1OCC1(C)COC1 MMRVAXALLLOUNL-UHFFFAOYSA-N 0.000 claims description 4
- LFOIWZXERCSMCT-UHFFFAOYSA-N 1-[5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methyl-3-(trifluoromethyl)phenyl]-4-methyltetrazol-5-one Chemical compound C1=C(C(F)(F)F)C(C)=C(N2C(N(C)N=N2)=O)C=C1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 LFOIWZXERCSMCT-UHFFFAOYSA-N 0.000 claims description 4
- YYZXGLSWGPYECZ-UHFFFAOYSA-N 1-[6-fluoro-3-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methoxyphenyl]-4-methyltetrazol-5-one Chemical compound C1=CC(F)=C(N2C(N(C)N=N2)=O)C(OC)=C1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)N(C)C(C)(C)C1 YYZXGLSWGPYECZ-UHFFFAOYSA-N 0.000 claims description 4
- QYUOKBLGDCWBAS-UHFFFAOYSA-N 1-[6-fluoro-3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methoxyphenyl]-4-methyltetrazol-5-one Chemical compound C1=CC(F)=C(N2C(N(C)N=N2)=O)C(OC)=C1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 QYUOKBLGDCWBAS-UHFFFAOYSA-N 0.000 claims description 4
- FYHLVUVJUSAMCY-UHFFFAOYSA-N 2-[3-cyclopropyl-4-fluoro-5-(4-methyl-5-oxotetrazol-1-yl)anilino]-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(C#N)=CN=2)=CC(C2CC2)=C1F FYHLVUVJUSAMCY-UHFFFAOYSA-N 0.000 claims description 4
- QPTDKHVNGWZMFB-UHFFFAOYSA-N 2-[4-cyclopropyl-2-fluoro-5-(4-methyl-5-oxotetrazol-1-yl)anilino]-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C(=CC(=C(C=2)N2C(N(C)N=N2)=O)C2CC2)F)=NC=C1C#N QPTDKHVNGWZMFB-UHFFFAOYSA-N 0.000 claims description 4
- HTFFZYWUFAOFBC-UHFFFAOYSA-N 2-[4-cyclopropyl-2-fluoro-5-(4-methyl-5-oxotetrazol-1-yl)anilino]-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(C#N)=CN=2)=C(F)C=C1C1CC1 HTFFZYWUFAOFBC-UHFFFAOYSA-N 0.000 claims description 4
- MINUKFGQHQKOPN-UHFFFAOYSA-N 2-[4-cyclopropyl-3-(4-methyl-5-oxotetrazol-1-yl)-5-(trifluoromethyl)anilino]-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(C#N)=CN=2)=CC(C(F)(F)F)=C1C1CC1 MINUKFGQHQKOPN-UHFFFAOYSA-N 0.000 claims description 4
- FFBXKPTUXUWNDX-UHFFFAOYSA-N 2-[4-cyclopropyl-3-fluoro-5-(4-methyl-5-oxotetrazol-1-yl)anilino]-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(C#N)=CN=2)=CC(F)=C1C1CC1 FFBXKPTUXUWNDX-UHFFFAOYSA-N 0.000 claims description 4
- FNOZOAANUAVIBR-UHFFFAOYSA-N 2-[4-cyclopropyl-3-fluoro-5-(4-methyl-5-oxotetrazol-1-yl)anilino]-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidine-5-carboxamide Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(C(N)=O)=CN=2)=CC(F)=C1C1CC1 FNOZOAANUAVIBR-UHFFFAOYSA-N 0.000 claims description 4
- MUZMDCWXIKHEMB-UHFFFAOYSA-N 3-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(4-methyl-5-oxotetrazol-1-yl)benzonitrile Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C=C(C=2)C#N)N2C(N(C)N=N2)=O)=NC=C1F MUZMDCWXIKHEMB-UHFFFAOYSA-N 0.000 claims description 4
- AAADLSUGXLKUOY-UHFFFAOYSA-N 3-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-5-(4-methyl-5-oxotetrazol-1-yl)benzonitrile Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC(C#N)=C1 AAADLSUGXLKUOY-UHFFFAOYSA-N 0.000 claims description 4
- GEBXEVCDUIJQCI-UHFFFAOYSA-N 4-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-(4-methyl-5-oxotetrazol-1-yl)benzonitrile Chemical compound O=C1N(C)N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=CC=C1C#N GEBXEVCDUIJQCI-UHFFFAOYSA-N 0.000 claims description 4
- IZJPJPQQYMCOOD-UHFFFAOYSA-N 5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methyl-3-(4-methyl-5-oxotetrazol-1-yl)benzoic acid Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(C)=C(C(O)=O)C=2)N2C(N(C)N=N2)=O)=NC=C1F IZJPJPQQYMCOOD-UHFFFAOYSA-N 0.000 claims description 4
- SNKYOBXFYQSUKL-UHFFFAOYSA-N 5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-n,2-dimethyl-3-(4-methyl-5-oxotetrazol-1-yl)benzamide Chemical compound C=1C(N2C(N(C)N=N2)=O)=C(C)C(C(=O)NC)=CC=1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)N(C)C(C)(C)C1 SNKYOBXFYQSUKL-UHFFFAOYSA-N 0.000 claims description 4
- PGUYSYIGCUINJJ-UHFFFAOYSA-N 5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methyl-3-(4-methyl-5-oxotetrazol-1-yl)benzoic acid Chemical compound C1=C(N2C(N(C)N=N2)=O)C(C)=C(C(O)=O)C=C1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 PGUYSYIGCUINJJ-UHFFFAOYSA-N 0.000 claims description 4
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 206010012442 Dermatitis contact Diseases 0.000 claims description 4
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 4
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 4
- 206010052779 Transplant rejections Diseases 0.000 claims description 4
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 4
- 206010046851 Uveitis Diseases 0.000 claims description 4
- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 230000003463 hyperproliferative effect Effects 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 206010023332 keratitis Diseases 0.000 claims description 4
- 201000010666 keratoconjunctivitis Diseases 0.000 claims description 4
- HVZYQYSQBVXEHI-UHFFFAOYSA-N methyl 5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methyl-3-(4-methyl-5-oxotetrazol-1-yl)benzoate Chemical compound C=1C(N2C(N(C)N=N2)=O)=C(C)C(C(=O)OC)=CC=1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)N(C)C(C)(C)C1 HVZYQYSQBVXEHI-UHFFFAOYSA-N 0.000 claims description 4
- JFXGIOBPRWVFCC-UHFFFAOYSA-N methyl 5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]-2-methyl-3-(4-methyl-5-oxotetrazol-1-yl)benzoate Chemical compound C=1C(N2C(N(C)N=N2)=O)=C(C)C(C(=O)OC)=CC=1NC(N=1)=NC=C(F)C=1NC1CC(C)(C)NC(C)(C)C1 JFXGIOBPRWVFCC-UHFFFAOYSA-N 0.000 claims description 4
- 208000011580 syndromic disease Diseases 0.000 claims description 4
- CDLMDUOFJHDRNY-UHFFFAOYSA-N 2-[4-cyclopropyl-3-(4-methyl-5-oxotetrazol-1-yl)-5-(trifluoromethyl)anilino]-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C=C(C(C3CC3)=C(C=2)N2C(N(C)N=N2)=O)C(F)(F)F)=NC=C1C#N CDLMDUOFJHDRNY-UHFFFAOYSA-N 0.000 claims description 3
- 208000030507 AIDS Diseases 0.000 claims description 3
- 208000030090 Acute Disease Diseases 0.000 claims description 3
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
- 208000024827 Alzheimer disease Diseases 0.000 claims description 3
- 201000001320 Atherosclerosis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 208000035473 Communicable disease Diseases 0.000 claims description 3
- 201000004624 Dermatitis Diseases 0.000 claims description 3
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 3
- 208000002705 Glucose Intolerance Diseases 0.000 claims description 3
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 3
- 206010020772 Hypertension Diseases 0.000 claims description 3
- 206010067125 Liver injury Diseases 0.000 claims description 3
- 208000004852 Lung Injury Diseases 0.000 claims description 3
- 208000013901 Nephropathies and tubular disease Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 208000001647 Renal Insufficiency Diseases 0.000 claims description 3
- 206010063837 Reperfusion injury Diseases 0.000 claims description 3
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 claims description 3
- 206010040070 Septic Shock Diseases 0.000 claims description 3
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- 206010069363 Traumatic lung injury Diseases 0.000 claims description 3
- 206010044541 Traumatic shock Diseases 0.000 claims description 3
- 208000024248 Vascular System injury Diseases 0.000 claims description 3
- 208000012339 Vascular injury Diseases 0.000 claims description 3
- 206010053648 Vascular occlusion Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 3
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
- 208000002029 allergic contact dermatitis Diseases 0.000 claims description 3
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 3
- 238000002399 angioplasty Methods 0.000 claims description 3
- 201000008937 atopic dermatitis Diseases 0.000 claims description 3
- 208000010668 atopic eczema Diseases 0.000 claims description 3
- 208000015114 central nervous system disease Diseases 0.000 claims description 3
- 208000037893 chronic inflammatory disorder Diseases 0.000 claims description 3
- 208000030533 eye disease Diseases 0.000 claims description 3
- 231100000753 hepatic injury Toxicity 0.000 claims description 3
- 208000001875 irritant dermatitis Diseases 0.000 claims description 3
- 201000006370 kidney failure Diseases 0.000 claims description 3
- 231100000515 lung injury Toxicity 0.000 claims description 3
- 206010028417 myasthenia gravis Diseases 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 201000010065 polycystic ovary syndrome Diseases 0.000 claims description 3
- 201000009104 prediabetes syndrome Diseases 0.000 claims description 3
- 208000023504 respiratory system disease Diseases 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 208000008742 seborrheic dermatitis Diseases 0.000 claims description 3
- 230000036303 septic shock Effects 0.000 claims description 3
- 230000035939 shock Effects 0.000 claims description 3
- 208000017520 skin disease Diseases 0.000 claims description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 3
- 230000009529 traumatic brain injury Effects 0.000 claims description 3
- 208000021331 vascular occlusion disease Diseases 0.000 claims description 3
- 208000020925 Bipolar disease Diseases 0.000 claims description 2
- 208000032843 Hemorrhage Diseases 0.000 claims description 2
- 208000006011 Stroke Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 17
- 125000005490 tosylate group Chemical class 0.000 claims 2
- 239000003112 inhibitor Substances 0.000 abstract description 16
- 230000008569 process Effects 0.000 abstract description 14
- 239000000543 intermediate Substances 0.000 abstract description 11
- 208000037765 diseases and disorders Diseases 0.000 abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 120
- 239000000203 mixture Substances 0.000 description 111
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 67
- 210000004027 cell Anatomy 0.000 description 60
- 125000000392 cycloalkenyl group Chemical group 0.000 description 52
- 235000019439 ethyl acetate Nutrition 0.000 description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 45
- 125000001424 substituent group Chemical group 0.000 description 43
- 229910001868 water Inorganic materials 0.000 description 42
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 38
- 238000012360 testing method Methods 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 30
- 230000015572 biosynthetic process Effects 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- 229910052701 rubidium Inorganic materials 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 24
- 125000005843 halogen group Chemical group 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- 108010029485 Protein Isoforms Proteins 0.000 description 21
- 102000001708 Protein Isoforms Human genes 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 239000007832 Na2SO4 Substances 0.000 description 20
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 229910052938 sodium sulfate Inorganic materials 0.000 description 20
- 235000011152 sodium sulphate Nutrition 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 19
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 19
- 241001465754 Metazoa Species 0.000 description 18
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 18
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 18
- 125000005309 thioalkoxy group Chemical group 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 241000282414 Homo sapiens Species 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 17
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 15
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 15
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 14
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 13
- 239000005977 Ethylene Substances 0.000 description 13
- 238000009472 formulation Methods 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 238000004809 thin layer chromatography Methods 0.000 description 13
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 12
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 150000002500 ions Chemical class 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- 238000011160 research Methods 0.000 description 12
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 12
- 239000003981 vehicle Substances 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 10
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 10
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 10
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 10
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 10
- 125000004181 carboxyalkyl group Chemical group 0.000 description 10
- 230000003053 immunization Effects 0.000 description 10
- 238000002649 immunization Methods 0.000 description 10
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 230000002062 proliferating effect Effects 0.000 description 10
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- PNWZZCRDHBFKJE-UHFFFAOYSA-N 1-(2-cyclopropyl-4-fluoro-5-nitrophenyl)-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC([N+]([O-])=O)=C(F)C=C1C1CC1 PNWZZCRDHBFKJE-UHFFFAOYSA-N 0.000 description 9
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 9
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 9
- 108010044467 Isoenzymes Proteins 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000004423 acyloxy group Chemical group 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 125000004104 aryloxy group Chemical group 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 description 9
- 238000011534 incubation Methods 0.000 description 9
- 238000006467 substitution reaction Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- 125000005296 thioaryloxy group Chemical group 0.000 description 9
- 125000005404 thioheteroaryloxy group Chemical group 0.000 description 9
- 150000003573 thiols Chemical class 0.000 description 9
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 8
- 208000012526 B-cell neoplasm Diseases 0.000 description 8
- 208000017604 Hodgkin disease Diseases 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 201000003793 Myelodysplastic syndrome Diseases 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 8
- 125000004470 heterocyclooxy group Chemical group 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 150000003230 pyrimidines Chemical class 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 238000010561 standard procedure Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 7
- 208000025317 T-cell and NK-cell neoplasm Diseases 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 125000000033 alkoxyamino group Chemical group 0.000 description 7
- 125000003277 amino group Chemical group 0.000 description 7
- 125000004429 atom Chemical group 0.000 description 7
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 7
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- 201000002491 encephalomyelitis Diseases 0.000 description 7
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 7
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- 229910017604 nitric acid Inorganic materials 0.000 description 7
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 7
- PHEDXBVPIONUQT-RGYGYFBISA-N phorbol 13-acetate 12-myristate Chemical compound C([C@]1(O)C(=O)C(C)=C[C@H]1[C@@]1(O)[C@H](C)[C@H]2OC(=O)CCCCCCCCCCCCC)C(CO)=C[C@H]1[C@H]1[C@]2(OC(C)=O)C1(C)C PHEDXBVPIONUQT-RGYGYFBISA-N 0.000 description 7
- 239000002953 phosphate buffered saline Substances 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- 108090000765 processed proteins & peptides Proteins 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 210000000130 stem cell Anatomy 0.000 description 7
- 150000003536 tetrazoles Chemical class 0.000 description 7
- 125000005323 thioketone group Chemical group 0.000 description 7
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 7
- GAMFOCVSHQFYPF-UHFFFAOYSA-N 1-(2-bromo-4-fluoro-5-nitrophenyl)-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC([N+]([O-])=O)=C(F)C=C1Br GAMFOCVSHQFYPF-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 102000001253 Protein Kinase Human genes 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 125000002541 furyl group Chemical group 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 150000007522 mineralic acids Chemical class 0.000 description 6
- 238000007799 mixed lymphocyte reaction assay Methods 0.000 description 6
- 150000007524 organic acids Chemical class 0.000 description 6
- 125000004043 oxo group Chemical group O=* 0.000 description 6
- 125000005255 oxyaminoacyl group Chemical group 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 108060006633 protein kinase Proteins 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 6
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 description 6
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 6
- 125000005988 1,1-dioxo-thiomorpholinyl group Chemical group 0.000 description 5
- OGYGFUAIIOPWQD-UHFFFAOYSA-N 1,3-thiazolidine Chemical compound C1CSCN1 OGYGFUAIIOPWQD-UHFFFAOYSA-N 0.000 description 5
- 238000004293 19F NMR spectroscopy Methods 0.000 description 5
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 5
- VEPOHXYIFQMVHW-XOZOLZJESA-N 2,3-dihydroxybutanedioic acid (2S,3S)-3,4-dimethyl-2-phenylmorpholine Chemical compound OC(C(O)C(O)=O)C(O)=O.C[C@H]1[C@@H](OCCN1C)c1ccccc1 VEPOHXYIFQMVHW-XOZOLZJESA-N 0.000 description 5
- VLRSADZEDXVUPG-UHFFFAOYSA-N 2-naphthalen-1-ylpyridine Chemical compound N1=CC=CC=C1C1=CC=CC2=CC=CC=C12 VLRSADZEDXVUPG-UHFFFAOYSA-N 0.000 description 5
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 5
- GDRVFDDBLLKWRI-UHFFFAOYSA-N 4H-quinolizine Chemical compound C1=CC=CN2CC=CC=C21 GDRVFDDBLLKWRI-UHFFFAOYSA-N 0.000 description 5
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 5
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 5
- 206010061187 Haematopoietic neoplasm Diseases 0.000 description 5
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 5
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 5
- 108010002350 Interleukin-2 Proteins 0.000 description 5
- 102000000588 Interleukin-2 Human genes 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 5
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 5
- 239000012979 RPMI medium Substances 0.000 description 5
- 239000012980 RPMI-1640 medium Substances 0.000 description 5
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 5
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 230000001594 aberrant effect Effects 0.000 description 5
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 229910052805 deuterium Inorganic materials 0.000 description 5
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000012894 fetal calf serum Substances 0.000 description 5
- 230000014509 gene expression Effects 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 150000004820 halides Chemical class 0.000 description 5
- 201000005787 hematologic cancer Diseases 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 150000002391 heterocyclic compounds Chemical class 0.000 description 5
- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 5
- LPAGFVYQRIESJQ-UHFFFAOYSA-N indoline Chemical compound C1=CC=C2NCCC2=C1 LPAGFVYQRIESJQ-UHFFFAOYSA-N 0.000 description 5
- HOBCFUWDNJPFHB-UHFFFAOYSA-N indolizine Chemical compound C1=CC=CN2C=CC=C21 HOBCFUWDNJPFHB-UHFFFAOYSA-N 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- PGHMRUGBZOYCAA-ADZNBVRBSA-N ionomycin Chemical compound O1[C@H](C[C@H](O)[C@H](C)[C@H](O)[C@H](C)/C=C/C[C@@H](C)C[C@@H](C)C(/O)=C/C(=O)[C@@H](C)C[C@@H](C)C[C@@H](CCC(O)=O)C)CC[C@@]1(C)[C@@H]1O[C@](C)([C@@H](C)O)CC1 PGHMRUGBZOYCAA-ADZNBVRBSA-N 0.000 description 5
- PGHMRUGBZOYCAA-UHFFFAOYSA-N ionomycin Natural products O1C(CC(O)C(C)C(O)C(C)C=CCC(C)CC(C)C(O)=CC(=O)C(C)CC(C)CC(CCC(O)=O)C)CCC1(C)C1OC(C)(C(C)O)CC1 PGHMRUGBZOYCAA-UHFFFAOYSA-N 0.000 description 5
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 5
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 5
- 210000001165 lymph node Anatomy 0.000 description 5
- 208000003747 lymphoid leukemia Diseases 0.000 description 5
- 208000019420 lymphoid neoplasm Diseases 0.000 description 5
- 201000000050 myeloid neoplasm Diseases 0.000 description 5
- 230000002093 peripheral effect Effects 0.000 description 5
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 5
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 5
- 125000003386 piperidinyl group Chemical group 0.000 description 5
- 235000015320 potassium carbonate Nutrition 0.000 description 5
- 210000004986 primary T-cell Anatomy 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 5
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000000829 suppository Substances 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 229930192474 thiophene Natural products 0.000 description 5
- 238000002054 transplantation Methods 0.000 description 5
- 150000003852 triazoles Chemical class 0.000 description 5
- 125000004953 trihalomethyl group Chemical group 0.000 description 5
- 229940035893 uracil Drugs 0.000 description 5
- OFWRVKYSHHIRRQ-UHFFFAOYSA-N 1-(2-bromo-4-fluorophenyl)-2h-tetrazol-5-one Chemical compound BrC1=CC(F)=CC=C1N1C(=O)NN=N1 OFWRVKYSHHIRRQ-UHFFFAOYSA-N 0.000 description 4
- WHPFEQUEHBULBW-UHFFFAOYSA-N 2,4-dichloro-5-fluoropyrimidine Chemical compound FC1=CN=C(Cl)N=C1Cl WHPFEQUEHBULBW-UHFFFAOYSA-N 0.000 description 4
- DCIBUUVLQYMJPQ-UHFFFAOYSA-N 2-chloro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound C1C(C)(C)NC(C)(C)CC1NC1=NC(Cl)=NC=C1C#N DCIBUUVLQYMJPQ-UHFFFAOYSA-N 0.000 description 4
- HNMNCBZJXFIURI-UHFFFAOYSA-N 2-cyclopropyl-4-fluoro-5-nitroaniline Chemical compound NC1=CC([N+]([O-])=O)=C(F)C=C1C1CC1 HNMNCBZJXFIURI-UHFFFAOYSA-N 0.000 description 4
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 description 4
- 208000011691 Burkitt lymphomas Diseases 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- 238000002965 ELISA Methods 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 208000010747 Hodgkins lymphoma Diseases 0.000 description 4
- 206010061218 Inflammation Diseases 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
- 229930182816 L-glutamine Natural products 0.000 description 4
- 108060001084 Luciferase Proteins 0.000 description 4
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 4
- 102000006386 Myelin Proteins Human genes 0.000 description 4
- 108010083674 Myelin Proteins Proteins 0.000 description 4
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 4
- WYNCHZVNFNFDNH-UHFFFAOYSA-N Oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 4
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 description 4
- 101150077555 Ret gene Proteins 0.000 description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 4
- 230000006044 T cell activation Effects 0.000 description 4
- 108091008874 T cell receptors Proteins 0.000 description 4
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 4
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 4
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 4
- 101710112791 Tyrosine-protein kinase JAK2 Proteins 0.000 description 4
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 125000003725 azepanyl group Chemical group 0.000 description 4
- 125000002393 azetidinyl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 229940098773 bovine serum albumin Drugs 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 239000008120 corn starch Substances 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 229940088598 enzyme Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 201000009277 hairy cell leukemia Diseases 0.000 description 4
- 230000004054 inflammatory process Effects 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
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 4
- 238000003305 oral gavage Methods 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 229910052717 sulfur Chemical group 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 208000024891 symptom Diseases 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 4
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- CGXOAAMIQPDTPE-UHFFFAOYSA-N 1,2,2,6,6-pentamethylpiperidin-4-amine Chemical compound CN1C(C)(C)CC(N)CC1(C)C CGXOAAMIQPDTPE-UHFFFAOYSA-N 0.000 description 3
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 3
- KKHQQDMOLRKWJA-UHFFFAOYSA-N 1-(2-bromo-4-fluorophenyl)-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC=C(F)C=C1Br KKHQQDMOLRKWJA-UHFFFAOYSA-N 0.000 description 3
- VEQFGOGMGJAANN-UHFFFAOYSA-N 1-(2-cyclopropyl-4-fluoro-5-nitrophenyl)-2h-tetrazol-5-one Chemical compound C1=C(F)C([N+](=O)[O-])=CC(N2C(NN=N2)=O)=C1C1CC1 VEQFGOGMGJAANN-UHFFFAOYSA-N 0.000 description 3
- HRGUNZREDKDSPB-UHFFFAOYSA-N 1-(5-amino-2-cyclopropyl-4-fluorophenyl)-4-methyltetrazol-5-one Chemical compound O=C1N(C)N=NN1C1=CC(N)=C(F)C=C1C1CC1 HRGUNZREDKDSPB-UHFFFAOYSA-N 0.000 description 3
- FBVOIJABNHHFIF-UHFFFAOYSA-N 2-bromo-4-fluoro-5-nitroaniline Chemical compound NC1=CC([N+]([O-])=O)=C(F)C=C1Br FBVOIJABNHHFIF-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 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 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 208000031404 Chromosome Aberrations Diseases 0.000 description 3
- 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 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 3
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 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
- 239000005089 Luciferase Substances 0.000 description 3
- 208000001344 Macular Edema Diseases 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- 208000033833 Myelomonocytic Chronic Leukemia Diseases 0.000 description 3
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 3
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 3
- 208000017442 Retinal disease Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 208000036142 Viral infection Diseases 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 125000002877 alkyl aryl group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 210000000709 aorta Anatomy 0.000 description 3
- 238000004166 bioassay Methods 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 230000010261 cell growth Effects 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 201000010902 chronic myelomonocytic leukemia Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003636 conditioned culture medium Substances 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 3
- 210000002950 fibroblast Anatomy 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000002875 fluorescence polarization Methods 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 230000002140 halogenating effect Effects 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 208000032839 leukemia Diseases 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 206010025135 lupus erythematosus Diseases 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 210000005012 myelin Anatomy 0.000 description 3
- 239000012038 nucleophile Substances 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 3
- 229940049954 penicillin Drugs 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229920001592 potato starch Polymers 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000003755 preservative agent Substances 0.000 description 3
- 125000002577 pseudohalo group Chemical group 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 125000006413 ring segment Chemical group 0.000 description 3
- 229960005322 streptomycin Drugs 0.000 description 3
- 239000011593 sulfur Chemical group 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 230000005945 translocation Effects 0.000 description 3
- 238000001665 trituration Methods 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DDVILBOMZPOEAF-UHFFFAOYSA-N 1-(2-bromo-4-fluoro-5-nitrophenyl)-2h-tetrazol-5-one Chemical compound C1=C(F)C([N+](=O)[O-])=CC(N2C(NN=N2)=O)=C1Br DDVILBOMZPOEAF-UHFFFAOYSA-N 0.000 description 2
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 2
- NADZMUZERVWRKC-UHFFFAOYSA-N 1-methyl-4-[4-nitro-2-(trifluoromethyl)phenyl]piperazine Chemical compound C1CN(C)CCN1C1=CC=C([N+]([O-])=O)C=C1C(F)(F)F NADZMUZERVWRKC-UHFFFAOYSA-N 0.000 description 2
- FTVFPPFZRRKJIH-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidin-4-amine Chemical compound CC1(C)CC(N)CC(C)(C)N1 FTVFPPFZRRKJIH-UHFFFAOYSA-N 0.000 description 2
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 2
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- PCPPHQICRFLBPM-UHFFFAOYSA-N 2-chloro-5-fluoro-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidin-4-amine Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(Cl)=NC=C1F PCPPHQICRFLBPM-UHFFFAOYSA-N 0.000 description 2
- LOXQPDUWKQVKSN-UHFFFAOYSA-N 2-chloro-5-fluoro-n-(1,2,2,6,6-pentamethylpiperidin-4-yl)pyrimidin-4-amine;hydrochloride Chemical compound Cl.C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(Cl)=NC=C1F LOXQPDUWKQVKSN-UHFFFAOYSA-N 0.000 description 2
- JWQXDHKFVICOAN-UHFFFAOYSA-N 2-chloro-5-fluoro-n-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidin-4-amine Chemical compound C1C(C)(C)NC(C)(C)CC1NC1=NC(Cl)=NC=C1F JWQXDHKFVICOAN-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- PCJSQXQRMJJBBS-UHFFFAOYSA-N 4-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-5-phenylpyrimidine-2,4-diamine Chemical compound C1(=CC=CC=C1)C=1C(=NC(=NC=1)N)NC1CC(N(C(C1)(C)C)C)(C)C PCJSQXQRMJJBBS-UHFFFAOYSA-N 0.000 description 2
- LMNPKIOZMGYQIU-UHFFFAOYSA-N 5-(trifluoromethyl)-1h-pyrimidine-2,4-dione Chemical compound FC(F)(F)C1=CNC(=O)NC1=O LMNPKIOZMGYQIU-UHFFFAOYSA-N 0.000 description 2
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 2
- KSNXJLQDQOIRIP-UHFFFAOYSA-N 5-iodouracil Chemical compound IC1=CNC(=O)NC1=O KSNXJLQDQOIRIP-UHFFFAOYSA-N 0.000 description 2
- TUARVSWVPPVUGS-UHFFFAOYSA-N 5-nitrouracil Chemical compound [O-][N+](=O)C1=CNC(=O)NC1=O TUARVSWVPPVUGS-UHFFFAOYSA-N 0.000 description 2
- YCBKWEWWGGPBAM-UHFFFAOYSA-N 5-phenyl-4-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyrimidine-2,4-diamine Chemical compound C1(=CC=CC=C1)C=1C(=NC(=NC=1)N)NC1CC(NC(C1)(C)C)(C)C YCBKWEWWGGPBAM-UHFFFAOYSA-N 0.000 description 2
- GMMWNTHAIOJBSD-UHFFFAOYSA-N 6-chloro-4-n-(2,3-dimethylphenyl)-2-n,2-n-dimethylpyrimidine-2,4-diamine Chemical compound CN(C)C1=NC(Cl)=CC(NC=2C(=C(C)C=CC=2)C)=N1 GMMWNTHAIOJBSD-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 208000033496 Acute myeloid leukaemia with myelodysplasia-related features Diseases 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 206010073478 Anaplastic large-cell lymphoma Diseases 0.000 description 2
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 2
- 241000208199 Buxus sempervirens Species 0.000 description 2
- 238000011749 CBA mouse Methods 0.000 description 2
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 2
- 208000006029 Cardiomegaly Diseases 0.000 description 2
- 102000000503 Collagen Type II Human genes 0.000 description 2
- 108010041390 Collagen Type II Proteins 0.000 description 2
- 206010058202 Cystoid macular oedema Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- 102000015212 Fas Ligand Protein Human genes 0.000 description 2
- 108010039471 Fas Ligand Protein Proteins 0.000 description 2
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 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
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 208000021519 Hodgkin lymphoma Diseases 0.000 description 2
- 101001002657 Homo sapiens Interleukin-2 Proteins 0.000 description 2
- 208000008839 Kidney Neoplasms Diseases 0.000 description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 2
- 208000032004 Large-Cell Anaplastic Lymphoma Diseases 0.000 description 2
- 241001139947 Mida Species 0.000 description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- SEQKRHFRPICQDD-UHFFFAOYSA-N N-tris(hydroxymethyl)methylglycine Chemical compound OCC(CO)(CO)[NH2+]CC([O-])=O SEQKRHFRPICQDD-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 208000003435 Optic Neuritis Diseases 0.000 description 2
- 206010033799 Paralysis Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-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
- 208000009527 Refractory anemia Diseases 0.000 description 2
- 206010072684 Refractory cytopenia with unilineage dysplasia Diseases 0.000 description 2
- 206010038389 Renal cancer Diseases 0.000 description 2
- 108700008625 Reporter Genes Proteins 0.000 description 2
- 208000007014 Retinitis pigmentosa Diseases 0.000 description 2
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 2
- 239000006146 Roswell Park Memorial Institute medium Substances 0.000 description 2
- 229940124639 Selective inhibitor Drugs 0.000 description 2
- 229920002472 Starch Polymers 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
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 230000003187 abdominal effect Effects 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 208000038016 acute inflammation Diseases 0.000 description 2
- 230000006022 acute inflammation Effects 0.000 description 2
- 208000016544 acute myeloid leukemia with multilineage dysplasia Diseases 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000000443 aerosol Substances 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000005133 alkynyloxy group Chemical group 0.000 description 2
- 230000000735 allogeneic effect Effects 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 210000000612 antigen-presenting cell Anatomy 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-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
- 230000033228 biological regulation Effects 0.000 description 2
- 238000005415 bioluminescence Methods 0.000 description 2
- 230000029918 bioluminescence Effects 0.000 description 2
- 210000003969 blast cell Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000002168 brachiocephalic trunk Anatomy 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000002771 cell marker Substances 0.000 description 2
- 230000010307 cell transformation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 231100000005 chromosome aberration Toxicity 0.000 description 2
- 230000006020 chronic inflammation Effects 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 125000006165 cyclic alkyl group Chemical group 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- WLVKDFJTYKELLQ-UHFFFAOYSA-N cyclopropylboronic acid Chemical compound OB(O)C1CC1 WLVKDFJTYKELLQ-UHFFFAOYSA-N 0.000 description 2
- 201000010206 cystoid macular edema Diseases 0.000 description 2
- 230000002559 cytogenic effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 150000001982 diacylglycerols Chemical class 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
- 231100000676 disease causative agent Toxicity 0.000 description 2
- 239000003596 drug target Substances 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 208000012997 experimental autoimmune encephalomyelitis Diseases 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000003818 flash chromatography Methods 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000000524 functional group Chemical group 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
- 102000054766 genetic haplotypes Human genes 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 230000003394 haemopoietic effect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 208000026278 immune system disease Diseases 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 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 2
- 201000010982 kidney cancer Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000007726 management method Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 208000017869 myelodysplastic/myeloproliferative disease Diseases 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 210000004287 null lymphocyte Anatomy 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 230000036961 partial effect Effects 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- RDOWQLZANAYVLL-UHFFFAOYSA-N phenanthridine Chemical compound C1=CC=C2C3=CC=CC=C3C=NC2=C1 RDOWQLZANAYVLL-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 150000004633 phorbol derivatives Chemical class 0.000 description 2
- 239000002644 phorbol ester Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 210000001147 pulmonary artery Anatomy 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 210000002027 skeletal muscle Anatomy 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 210000004989 spleen cell Anatomy 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 2
- 230000003442 weekly effect Effects 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
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-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
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- MJAXMBPQWZSTMK-UHFFFAOYSA-N 1-[2-cyclopropyl-4-fluoro-5-[[5-fluoro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-methyltetrazol-5-one Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(NC=2C(=CC(=C(C=2)N2C(N(C)N=N2)=O)C2CC2)F)=NC=C1F MJAXMBPQWZSTMK-UHFFFAOYSA-N 0.000 description 1
- CGWRSWPWEOFYGO-UICOGKGYSA-N 1-[2-cyclopropyl-4-fluoro-5-[[5-fluoro-4-[(2,2,6,6-tetramethylpiperidin-4-yl)amino]pyrimidin-2-yl]amino]phenyl]-4-(deuteriomethyl)tetrazol-5-one Chemical compound O=C1N(C[2H])N=NN1C1=CC(NC=2N=C(NC3CC(C)(C)NC(C)(C)C3)C(F)=CN=2)=C(F)C=C1C1CC1 CGWRSWPWEOFYGO-UICOGKGYSA-N 0.000 description 1
- DNTHMWUMRGOJRY-UHFFFAOYSA-N 1-fluoro-4-nitro-2-(trifluoromethyl)benzene Chemical compound [O-][N+](=O)C1=CC=C(F)C(C(F)(F)F)=C1 DNTHMWUMRGOJRY-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Substances C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- DZTIFMWYYHCREC-UHFFFAOYSA-N 2,4-dichloropyrimidine-5-carbonyl chloride Chemical compound ClC(=O)C1=CN=C(Cl)N=C1Cl DZTIFMWYYHCREC-UHFFFAOYSA-N 0.000 description 1
- OACCNUGECQQVLB-UHFFFAOYSA-N 2,4-dichloropyrimidine-5-carboxamide Chemical compound NC(=O)C1=CN=C(Cl)N=C1Cl OACCNUGECQQVLB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- POVYZTLPZBUFBB-UHFFFAOYSA-N 2-bromo-4-fluoro-1-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C(Br)=C1 POVYZTLPZBUFBB-UHFFFAOYSA-N 0.000 description 1
- YLMFXCIATJJKQL-UHFFFAOYSA-N 2-bromo-4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1Br YLMFXCIATJJKQL-UHFFFAOYSA-N 0.000 description 1
- AXZRUTPBQMAWLP-UHFFFAOYSA-N 2-bromo-4-fluorobenzoyl chloride Chemical compound FC1=CC=C(C(Cl)=O)C(Br)=C1 AXZRUTPBQMAWLP-UHFFFAOYSA-N 0.000 description 1
- MVJPGVRRYVHIKK-UHFFFAOYSA-N 2-chloro-4-[(1,2,2,6,6-pentamethylpiperidin-4-yl)amino]pyrimidine-5-carbonitrile Chemical compound C1C(C)(C)N(C)C(C)(C)CC1NC1=NC(Cl)=NC=C1C#N MVJPGVRRYVHIKK-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 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
- CBKDCOKSXCTDAA-UHFFFAOYSA-N 4,5,6,7-tetrahydro-1-benzothiophene Chemical compound C1CCCC2=C1C=CS2 CBKDCOKSXCTDAA-UHFFFAOYSA-N 0.000 description 1
- 206010068532 5q minus syndrome Diseases 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000016557 Acute basophilic leukemia Diseases 0.000 description 1
- 206010000871 Acute monocytic leukaemia Diseases 0.000 description 1
- 206010000890 Acute myelomonocytic leukaemia Diseases 0.000 description 1
- 208000016585 Acute panmyelosis with myelofibrosis Diseases 0.000 description 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 description 1
- 206010001413 Adult T-cell lymphoma/leukaemia Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102100034613 Annexin A2 Human genes 0.000 description 1
- 108090000668 Annexin A2 Proteins 0.000 description 1
- 101000719121 Arabidopsis thaliana Protein MEI2-like 1 Proteins 0.000 description 1
- 241001553178 Arachis glabrata Species 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000025324 B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000032568 B-cell prolymphocytic leukaemia Diseases 0.000 description 1
- 206010003908 B-cell small lymphocytic lymphoma Diseases 0.000 description 1
- 238000011725 BALB/c mouse Methods 0.000 description 1
- 208000033775 Basophilic Acute Leukemia Diseases 0.000 description 1
- 102000051485 Bcl-2 family Human genes 0.000 description 1
- 108700038897 Bcl-2 family Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 206010048396 Bone marrow transplant rejection Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- LEQNPQWTSJNGPE-UHFFFAOYSA-N C(N)(=O)C=1C=NC=NC1.NC1=CC(=NC=N1)N Chemical class C(N)(=O)C=1C=NC=NC1.NC1=CC(=NC=N1)N LEQNPQWTSJNGPE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 206010008805 Chromosomal abnormalities 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
- 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 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 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
- 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 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-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
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108700020911 DNA-Binding Proteins Proteins 0.000 description 1
- 102000052510 DNA-Binding Proteins Human genes 0.000 description 1
- 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 1
- 208000016192 Demyelinating disease Diseases 0.000 description 1
- 206010012305 Demyelination Diseases 0.000 description 1
- 239000004338 Dichlorodifluoromethane Substances 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 206010058314 Dysplasia Diseases 0.000 description 1
- 238000008157 ELISA kit Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000002460 Enteropathy-Associated T-Cell Lymphoma Diseases 0.000 description 1
- 208000036566 Erythroleukaemia Diseases 0.000 description 1
- 208000032027 Essential Thrombocythemia Diseases 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000009386 Experimental Arthritis Diseases 0.000 description 1
- 206010015719 Exsanguination Diseases 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 208000033371 Extranodal NK/T-cell lymphoma, nasal type Diseases 0.000 description 1
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 1
- 208000032087 Hereditary Leber Optic Atrophy Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100456320 Homo sapiens NR3C2 gene Proteins 0.000 description 1
- 101000944909 Homo sapiens Ribosomal protein S6 kinase alpha-1 Proteins 0.000 description 1
- 101000857677 Homo sapiens Runt-related transcription factor 1 Proteins 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010062016 Immunosuppression Diseases 0.000 description 1
- 102100023915 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 108090000862 Ion Channels Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 208000010038 Ischemic Optic Neuropathy Diseases 0.000 description 1
- 206010023203 Joint destruction Diseases 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 208000031671 Large B-Cell Diffuse Lymphoma Diseases 0.000 description 1
- 208000006404 Large Granular Lymphocytic Leukemia Diseases 0.000 description 1
- 201000003533 Leber congenital amaurosis Diseases 0.000 description 1
- 201000000639 Leber hereditary optic neuropathy Diseases 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 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 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 201000003791 MALT lymphoma Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 208000025205 Mantle-Cell Lymphoma Diseases 0.000 description 1
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000035489 Monocytic Acute Leukemia Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 101100351501 Mus musculus Cbfb gene Proteins 0.000 description 1
- 208000033835 Myelomonocytic Acute Leukemia Diseases 0.000 description 1
- 208000037538 Myelomonocytic Juvenile Leukemia Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 208000033755 Neutrophilic Chronic Leukemia Diseases 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- 206010029461 Nodal marginal zone B-cell lymphomas Diseases 0.000 description 1
- 208000019569 Nodular lymphocyte predominant Hodgkin lymphoma Diseases 0.000 description 1
- 102000007999 Nuclear Proteins Human genes 0.000 description 1
- 108010089610 Nuclear Proteins Proteins 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 206010030924 Optic ischaemic neuropathy Diseases 0.000 description 1
- 206010061323 Optic neuropathy Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 108091082203 PKC family Proteins 0.000 description 1
- 102000042846 PKC family Human genes 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 206010033661 Pancytopenia Diseases 0.000 description 1
- 241001111421 Pannus Species 0.000 description 1
- 241000935974 Paralichthys dentatus Species 0.000 description 1
- 206010073286 Pathologic myopia Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000027190 Peripheral T-cell lymphomas Diseases 0.000 description 1
- 241000577979 Peromyscus spicilegus Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 208000007452 Plasmacytoma Diseases 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 206010036030 Polyarthritis Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000017414 Precursor T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 208000032758 Precursor T-lymphoblastic lymphoma/leukaemia Diseases 0.000 description 1
- 206010065857 Primary Effusion Lymphoma Diseases 0.000 description 1
- 206010036711 Primary mediastinal large B-cell lymphomas Diseases 0.000 description 1
- 208000035416 Prolymphocytic B-Cell Leukemia Diseases 0.000 description 1
- 208000033759 Prolymphocytic T-Cell Leukemia Diseases 0.000 description 1
- 208000033826 Promyelocytic Acute Leukemia Diseases 0.000 description 1
- 102000001892 Protein Kinase C-theta Human genes 0.000 description 1
- 108010015499 Protein Kinase C-theta Proteins 0.000 description 1
- 108010010974 Proteolipids Proteins 0.000 description 1
- 102000016202 Proteolipids 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
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 206010038460 Renal haemorrhage Diseases 0.000 description 1
- 201000007737 Retinal degeneration Diseases 0.000 description 1
- 206010038848 Retinal detachment Diseases 0.000 description 1
- 102100023606 Retinoic acid receptor alpha Human genes 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 102100033536 Ribosomal protein S6 kinase alpha-1 Human genes 0.000 description 1
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 208000022758 Sorsby fundus dystrophy Diseases 0.000 description 1
- 208000035286 Spontaneous Remission Diseases 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 208000010502 Subcutaneous panniculitis-like T-cell lymphoma Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010042618 Surgical procedure repeated Diseases 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- UZMAPBJVXOGOFT-UHFFFAOYSA-N Syringetin Natural products COC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UZMAPBJVXOGOFT-UHFFFAOYSA-N 0.000 description 1
- 230000033540 T cell apoptotic process Effects 0.000 description 1
- 208000031672 T-Cell Peripheral Lymphoma Diseases 0.000 description 1
- 208000029052 T-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 206010042971 T-cell lymphoma Diseases 0.000 description 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 208000026651 T-cell prolymphocytic leukemia Diseases 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
- 229920001615 Tragacanth Polymers 0.000 description 1
- 239000007997 Tricine buffer Substances 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 108700005077 Viral Genes Proteins 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- 210000003815 abdominal wall Anatomy 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 208000021841 acute erythroid leukemia Diseases 0.000 description 1
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 description 1
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 1
- 208000026784 acute myeloblastic leukemia with maturation Diseases 0.000 description 1
- 208000010816 acute myeloblastic leukemia without maturation Diseases 0.000 description 1
- 208000011912 acute myelomonocytic leukemia M4 Diseases 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 208000015230 aggressive NK-cell leukemia Diseases 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 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
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 125000005055 alkyl alkoxy group Chemical group 0.000 description 1
- 125000000278 alkyl amino alkyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000005275 alkylenearyl group Chemical class 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003872 anastomosis Effects 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 206010002449 angioimmunoblastic T-cell lymphoma Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 201000007058 anterior ischemic optic neuropathy Diseases 0.000 description 1
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 description 1
- 230000003367 anti-collagen effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 239000012911 assay medium Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 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
- 230000027455 binding Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000023549 cell-cell signaling Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 201000010903 chronic neutrophilic leukemia Diseases 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- WCZVZNOTHYJIEI-UHFFFAOYSA-N cinnoline Chemical compound N1=NC=CC2=CC=CC=C21 WCZVZNOTHYJIEI-UHFFFAOYSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 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 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 108010010201 core binding factor alpha Proteins 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 230000004940 costimulation Effects 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
- 239000010779 crude oil Substances 0.000 description 1
- 125000004465 cycloalkenyloxy group Chemical group 0.000 description 1
- 125000000000 cycloalkoxy group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 208000024389 cytopenia Diseases 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 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 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 150000001975 deuterium Chemical group 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- KCFYHBSOLOXZIF-UHFFFAOYSA-N dihydrochrysin Natural products COC1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 KCFYHBSOLOXZIF-UHFFFAOYSA-N 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- 230000002327 eosinophilic effect Effects 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 230000000925 erythroid effect Effects 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 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
- 125000005290 ethynyloxy group Chemical group C(#C)O* 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 235000013355 food flavoring agent Nutrition 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
- 230000004927 fusion Effects 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000004475 gamma-delta t lymphocyte Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229950006191 gluconic acid Drugs 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000006377 glucose transport Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 210000003714 granulocyte Anatomy 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000009033 hematopoietic malignancy Effects 0.000 description 1
- 210000000777 hematopoietic system Anatomy 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000004446 heteroarylalkyl group Chemical group 0.000 description 1
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 description 1
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 1
- 125000004468 heterocyclylthio group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 102000055277 human IL2 Human genes 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 230000007954 hypoxia Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 125000006301 indolyl methyl group Chemical group 0.000 description 1
- 208000017532 inherited retinal dystrophy Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 150000002484 inorganic compounds Chemical class 0.000 description 1
- 229910010272 inorganic material Inorganic materials 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 239000002555 ionophore Substances 0.000 description 1
- 230000000236 ionophoric effect Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000000302 ischemic effect Effects 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
- 238000002955 isolation Methods 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 208000018937 joint inflammation Diseases 0.000 description 1
- 201000005992 juvenile myelomonocytic leukemia Diseases 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000037652 lymphocytic-histiocytic predominance Hodgkin lymphoma Diseases 0.000 description 1
- 210000003563 lymphoid tissue Anatomy 0.000 description 1
- 201000007919 lymphoplasmacytic lymphoma Diseases 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 235000014380 magnesium carbonate Nutrition 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Inorganic materials [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 208000020968 mature T-cell and NK-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 238000012961 medicinal therapy Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- 238000007069 methylation reaction Methods 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 208000037524 mixed cellularity Hodgkin lymphoma Diseases 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 210000005087 mononuclear cell Anatomy 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000005962 mycosis fungoides Diseases 0.000 description 1
- 108010064578 myelin proteolipid protein (139-151) Proteins 0.000 description 1
- 210000003643 myeloid progenitor cell Anatomy 0.000 description 1
- 230000002107 myocardial effect Effects 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
- 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
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000000822 natural killer cell Anatomy 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 208000025275 nodular sclerosis classical Hodgkin lymphoma Diseases 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 230000000683 nonmetastatic effect Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 210000004248 oligodendroglia Anatomy 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 208000020911 optic nerve disease Diseases 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 230000037324 pain perception Effects 0.000 description 1
- 238000002559 palpation Methods 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000001769 paralizing effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 210000004214 philadelphia chromosome Anatomy 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 101150031651 pkc-3 gene Proteins 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 210000001778 pluripotent stem cell Anatomy 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 208000017426 precursor B-cell acute lymphoblastic leukemia Diseases 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 208000003476 primary myelofibrosis Diseases 0.000 description 1
- 210000001948 pro-b lymphocyte Anatomy 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- TURAMGVWNUTQKH-UHFFFAOYSA-N propa-1,2-dien-1-one Chemical group C=C=C=O TURAMGVWNUTQKH-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- CSNFMBGHUOSBFU-UHFFFAOYSA-N pyrimidine-2,4,5-triamine Chemical compound NC1=NC=C(N)C(N)=N1 CSNFMBGHUOSBFU-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000004451 qualitative analysis Methods 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 238000010791 quenching Methods 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
- 239000000700 radioactive tracer Substances 0.000 description 1
- 238000003653 radioligand binding assay Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 230000004258 retinal degeneration Effects 0.000 description 1
- 230000004264 retinal detachment Effects 0.000 description 1
- 108091008726 retinoic acid receptors α Proteins 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 102220084927 rs778740017 Human genes 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical compound I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000020341 sensory perception of pain Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 206010062113 splenic marginal zone lymphoma Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
- 125000006296 sulfonyl amino group Chemical group [H]N(*)S(*)(=O)=O 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 210000005222 synovial tissue Anatomy 0.000 description 1
- 201000004595 synovitis Diseases 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 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
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- OUOJIFQQBPKAMU-UHFFFAOYSA-N tetrazol-5-one Chemical compound O=C1N=NN=N1 OUOJIFQQBPKAMU-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 150000008648 triflates Chemical class 0.000 description 1
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- JLEXUIVKURIPFI-UHFFFAOYSA-N tris phosphate Chemical compound OP(O)(O)=O.OCC(N)(CO)CO JLEXUIVKURIPFI-UHFFFAOYSA-N 0.000 description 1
- 231100000588 tumorigenic Toxicity 0.000 description 1
- 230000000381 tumorigenic effect Effects 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000001631 vena cava inferior Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
-
- 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
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- 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
-
- 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
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
- A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
-
- 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
- A61P25/24—Antidepressants
-
- 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
- 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
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
- A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- 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
- C07D401/14—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 three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Hematology (AREA)
- Heart & Thoracic Surgery (AREA)
- Neurosurgery (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Biomedical Technology (AREA)
- Physical Education & Sports Medicine (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
- Virology (AREA)
- Reproductive Health (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Emergency Medicine (AREA)
- Psychiatry (AREA)
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26564809P | 2009-12-01 | 2009-12-01 | |
| US61/265,648 | 2009-12-01 | ||
| US36646910P | 2010-07-21 | 2010-07-21 | |
| US61/366,469 | 2010-07-21 | ||
| US40596810P | 2010-10-22 | 2010-10-22 | |
| US61/405,968 | 2010-10-22 | ||
| PCT/US2010/058597 WO2011068898A1 (en) | 2009-12-01 | 2010-12-01 | Protein kinase c inhibitors and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2780759A1 true CA2780759A1 (en) | 2011-06-09 |
Family
ID=43902714
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2780759A Abandoned CA2780759A1 (en) | 2009-12-01 | 2010-12-01 | Protein kinase c inhibitors and uses thereof |
Country Status (5)
| Country | Link |
|---|---|
| US (2) | US20110130415A1 (cg-RX-API-DMAC10.html) |
| EP (1) | EP2507227B1 (cg-RX-API-DMAC10.html) |
| JP (1) | JP5802677B2 (cg-RX-API-DMAC10.html) |
| CA (1) | CA2780759A1 (cg-RX-API-DMAC10.html) |
| WO (1) | WO2011068898A1 (cg-RX-API-DMAC10.html) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK1663242T3 (da) * | 2003-08-07 | 2011-08-01 | Rigel Pharmaceuticals Inc | 2,4-Pyrimidindiamin-forbindelser og anvendelse som antiproliferative midler |
| CA2801781C (en) | 2010-07-21 | 2018-02-27 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
| WO2012075316A2 (en) | 2010-12-01 | 2012-06-07 | Rigel Pharmaceuticals, Inc. | Cyclopropyl mida boronate |
| TWI548621B (zh) | 2011-04-22 | 2016-09-11 | 標誌製藥公司 | 經取代之二胺基甲醯胺及二胺基甲腈嘧啶、其組合物、及以該等治療之方法 |
| WO2012174412A2 (en) * | 2011-06-16 | 2012-12-20 | La Jolla Institute For Allergy And Immunology | Compositions targeting pkc-theta and uses and methods of treating pkc-theta pathologies, adverse immune responses and diseases |
| GB201200555D0 (en) * | 2012-01-13 | 2012-02-29 | Univ Birmingham | Peptide |
| US9839671B2 (en) | 2012-01-13 | 2017-12-12 | The University Of Birmingham | Peptide and uses therefor |
| US9321763B2 (en) | 2012-04-04 | 2016-04-26 | Rigel Pharmaceuticals, Inc. | Protein kinase C inhibitors and uses thereof |
| US8754251B2 (en) | 2012-06-06 | 2014-06-17 | Rigel Pharmaceuticals, Inc. | Cyclopropyl PIDA boronate |
| EP2928891B1 (en) | 2012-12-04 | 2019-02-20 | Rigel Pharmaceuticals, Inc. | Protein kinase c inhibitors and uses thereof |
| US9169249B2 (en) | 2013-03-14 | 2015-10-27 | Rigel Pharmaceuticals, Inc. | Protein kinase C inhibitors and uses thereof |
| EP3010893B1 (de) | 2013-06-20 | 2019-10-02 | Bayer CropScience Aktiengesellschaft | Arylsulfid- und arylsulfoxid-derivate als akarizide und insektizide |
| EP3064492B1 (en) * | 2013-10-28 | 2018-12-26 | Sumitomo Chemical Company, Limited | Tetrazolinone compound and application for same |
| NZ715903A (en) | 2014-01-30 | 2017-06-30 | Signal Pharm Llc | Solid forms of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide, compositions thereof and methods of their use |
| WO2015146552A1 (ja) * | 2014-03-28 | 2015-10-01 | 住友化学株式会社 | テトラゾリノン化合物の製造方法 |
| US9399637B2 (en) | 2014-03-28 | 2016-07-26 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| JO3589B1 (ar) * | 2014-08-06 | 2020-07-05 | Novartis Ag | مثبطات كيناز البروتين c وطرق استخداماتها |
| US10059689B2 (en) | 2014-10-14 | 2018-08-28 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
| US9513297B2 (en) | 2014-12-16 | 2016-12-06 | Signal Pharmaceuticals, Llc | Methods for measurement of inhibition of c-Jun N-terminal kinase in skin |
| EP3712134B1 (en) | 2014-12-16 | 2023-11-29 | Signal Pharmaceuticals, LLC | Salts of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methycyclohexylamino)-pyrimidine-5-carboxamide |
| US9439888B2 (en) | 2015-01-26 | 2016-09-13 | Rigel Pharmaceuticals, Inc. | Tetrazolones as a carboxylic acid bioisosteres |
| EP3250557B1 (en) | 2015-01-29 | 2024-11-20 | Signal Pharmaceuticals, LLC | Isotopologues of 2-(tert-butylamino)-4-((1r,3r,4r)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide |
| EP3325432B1 (en) | 2015-07-24 | 2020-09-02 | Celgene Corporation | Methods of synthesis of (1r,2r,5r)-5-amino-2-methylcyclohexanol hydrochloride and intermediates useful therein |
| EP3347097B1 (en) | 2015-09-11 | 2021-02-24 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine derivatives as modulators of the kinases jak, flt3 and aurora |
| EP3383396B1 (en) | 2015-12-04 | 2023-07-12 | Alexion Pharmaceuticals, Inc. | Cerdulatinib and venetoclax for treating non-hodgkin's lymphoma |
| CN106316864A (zh) * | 2016-08-22 | 2017-01-11 | 苏州天马精细化学品股份有限公司 | 4‑甲基‑3‑三氟甲基苯胺的制备方法 |
| EP3544973B1 (en) * | 2016-11-28 | 2021-07-28 | Sumitomo Chemical Company, Limited | Tetrazolinone compounds and its use as pest control agents |
| WO2019099311A1 (en) | 2017-11-19 | 2019-05-23 | Sunshine Lake Pharma Co., Ltd. | Substituted heteroaryl compounds and methods of use |
| EP3560913B1 (en) | 2018-04-25 | 2026-07-29 | Dynamit Nobel GmbH Explosivstoff- und Systemtechnik | Process for the production of tetrazolinones |
| US10851087B2 (en) | 2018-05-04 | 2020-12-01 | Portola Pharmaceuticals, Inc. | Synthesis of cerdulatinib |
| WO2019213606A2 (en) | 2018-05-04 | 2019-11-07 | Portola Pharmaceuticals, Inc. | Solid forms of cerdulatinib |
| EP3616724A1 (en) | 2018-08-27 | 2020-03-04 | SmartDyeLivery GmbH | Pkc inhibitors for the treatment of septic cholestasis with ctm targeting |
| EP3616725A1 (en) | 2018-08-27 | 2020-03-04 | SmartDyeLivery GmbH | Pkc inhibitors for the treatment of septic cholestasis with polymethine dye targeting |
| WO2025097025A1 (en) * | 2023-11-03 | 2025-05-08 | Evommune, Inc. | Protein kinase c (pkc) theta inhibitor compounds |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5136868A (en) * | 1983-11-04 | 1992-08-11 | Fmc Corporation | Herbicidal 1-aryl-4-substituted-1,4-dihydro-5h-tetrazol-5-ones and sulfur analogs thereof |
| JPH0782258A (ja) | 1993-09-14 | 1995-03-28 | Nippon Bayeragrochem Kk | １−置換−テトラゾール−５−オン類の製造方法 |
| GB9523675D0 (en) * | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| JP2002534515A (ja) | 1999-01-13 | 2002-10-15 | ワーナー−ランバート・カンパニー | １−複素環置換されたジアリールアミン |
| JP4460292B2 (ja) * | 2001-10-17 | 2010-05-12 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | ピリミジン誘導体、これらの化合物を含む医薬組成物、その使用及びその調製方法 |
| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| IL166241A0 (en) * | 2002-07-29 | 2006-01-15 | Rigel Pharmaceuticals Inc | Method of treating or preventing autoimmune diseases with 2,4-pyrimidinedinediamine compounds |
| WO2004043386A2 (en) | 2002-11-08 | 2004-05-27 | Tolerrx, Inc. | Molecules preferentially associated with effector t cells and methods of their use |
| ES2421139T3 (es) | 2003-07-30 | 2013-08-29 | Rigel Pharmaceuticals, Inc. | Compuestos de 2,4-pirimidindiamina para su uso en el tratamiento o la prevención de enfermedades autoinmunitarias |
| DK1663242T3 (da) * | 2003-08-07 | 2011-08-01 | Rigel Pharmaceuticals Inc | 2,4-Pyrimidindiamin-forbindelser og anvendelse som antiproliferative midler |
| WO2005020921A2 (en) | 2003-08-29 | 2005-03-10 | Exelixis, Inc. | C-kit modulators and methods of use |
| KR20060127415A (ko) | 2003-12-24 | 2006-12-12 | 와이어쓰 | 천식의 치료방법 |
| JP2008540436A (ja) * | 2005-05-03 | 2008-11-20 | ライジェル ファーマシューティカルズ， インコーポレイテッド | Ｊａｋキナーゼインヒビターおよびそれらの使用 |
| AU2007257650A1 (en) * | 2006-06-15 | 2007-12-21 | Boehringer Ingelheim International Gmbh | 2-anilino-4-(heterocyclic)amino-pyrimidines as inhibitors of protein kinase C-alpha |
| CN101903357A (zh) | 2007-07-17 | 2010-12-01 | 里格尔药品股份有限公司 | 作为pkc抑制剂的环状胺取代的嘧啶二胺 |
| AU2009262068C1 (en) * | 2008-06-27 | 2015-07-02 | Celgene Car Llc | Heteroaryl compounds and uses thereof |
| WO2010090875A1 (en) * | 2009-01-21 | 2010-08-12 | Rigel Pharmaceuticals, Inc. | Derivatives of n2-(3-pyridil or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases |
-
2010
- 2010-12-01 US US12/958,284 patent/US20110130415A1/en not_active Abandoned
- 2010-12-01 WO PCT/US2010/058597 patent/WO2011068898A1/en not_active Ceased
- 2010-12-01 JP JP2012542165A patent/JP5802677B2/ja not_active Expired - Fee Related
- 2010-12-01 CA CA2780759A patent/CA2780759A1/en not_active Abandoned
- 2010-12-01 EP EP10796518.8A patent/EP2507227B1/en not_active Not-in-force
-
2016
- 2016-09-09 US US15/261,294 patent/US9732070B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US20170152246A1 (en) | 2017-06-01 |
| EP2507227A1 (en) | 2012-10-10 |
| JP2013512281A (ja) | 2013-04-11 |
| US9732070B2 (en) | 2017-08-15 |
| US20110130415A1 (en) | 2011-06-02 |
| WO2011068898A1 (en) | 2011-06-09 |
| JP5802677B2 (ja) | 2015-10-28 |
| EP2507227B1 (en) | 2014-10-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2507227B1 (en) | Tetrazolones as protein kinase c inhibitors and uses thereof | |
| CA2801781C (en) | Protein kinase c inhibitors and uses thereof | |
| EP2389373B1 (en) | Derivatives of n2-(3-pyridyl or phenyl)-n4-(4-piperidyl)-2,4-pyrimidinediamine useful in the treatment of inflammatory, autoimmune or proliferative diseases | |
| CA2867760C (en) | Indolizinyl derivatives as protein kinase c inhibitors and uses thereof | |
| JP6421170B2 (ja) | プロテインキナーゼｃ阻害剤およびその使用 | |
| EP2928891B1 (en) | Protein kinase c inhibitors and uses thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |
Effective date: 20151201 |