EA018931B1 - ДИЗАМЕЩЕННЫЕ ФТАЛАЗИНЫ-АНТАГОНИСТЫ СИГНАЛЬНОГО ПУТИ Hedgehog - Google Patents
ДИЗАМЕЩЕННЫЕ ФТАЛАЗИНЫ-АНТАГОНИСТЫ СИГНАЛЬНОГО ПУТИ Hedgehog Download PDFInfo
- Publication number
- EA018931B1 EA018931B1 EA201170640A EA201170640A EA018931B1 EA 018931 B1 EA018931 B1 EA 018931B1 EA 201170640 A EA201170640 A EA 201170640A EA 201170640 A EA201170640 A EA 201170640A EA 018931 B1 EA018931 B1 EA 018931B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- cancer
- compound
- fluorophenyl
- pharmaceutically acceptable
- fluorine
- Prior art date
Links
- 239000005557 antagonist Substances 0.000 title abstract description 9
- 230000037361 pathway Effects 0.000 title abstract description 3
- 241000289669 Erinaceus europaeus Species 0.000 title abstract 2
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical class C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 title description 8
- -1 1,4-disubstituted phthalazine Chemical class 0.000 claims abstract description 71
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 14
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims description 84
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 52
- 239000011737 fluorine Substances 0.000 claims description 52
- 229910052731 fluorine Inorganic materials 0.000 claims description 52
- 239000001257 hydrogen Substances 0.000 claims description 50
- 229910052739 hydrogen Inorganic materials 0.000 claims description 50
- 239000000460 chlorine Substances 0.000 claims description 39
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- 150000003839 salts Chemical class 0.000 claims description 29
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 6
- 206010060862 Prostate cancer Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 6
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 6
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 6
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 5
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 5
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 5
- 208000034578 Multiple myelomas Diseases 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 5
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 5
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 5
- 206010038389 Renal cancer Diseases 0.000 claims description 5
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 5
- 206010017758 gastric cancer Diseases 0.000 claims description 5
- 201000010982 kidney cancer Diseases 0.000 claims description 5
- 201000007270 liver cancer Diseases 0.000 claims description 5
- 208000014018 liver neoplasm Diseases 0.000 claims description 5
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 201000011549 stomach cancer Diseases 0.000 claims description 5
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 4
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 4
- 206010030155 Oesophageal carcinoma Diseases 0.000 claims description 4
- 201000004101 esophageal cancer Diseases 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 201000009036 biliary tract cancer Diseases 0.000 claims 1
- 208000020790 biliary tract neoplasm Diseases 0.000 claims 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 71
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 42
- 239000000203 mixture Substances 0.000 description 35
- 238000003786 synthesis reaction Methods 0.000 description 34
- 230000015572 biosynthetic process Effects 0.000 description 30
- 210000004027 cell Anatomy 0.000 description 28
- 238000000034 method Methods 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 239000007787 solid Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000010802 sludge Substances 0.000 description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 239000006260 foam Substances 0.000 description 15
- UVYKKFKLOUEFAR-UHFFFAOYSA-N hydron;piperazine-1-carboxamide;chloride Chemical compound Cl.NC(=O)N1CCNCC1 UVYKKFKLOUEFAR-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000003818 flash chromatography Methods 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- DZWBPVWZCQJMGW-UHFFFAOYSA-N 1-piperazin-1-ylphthalazine Chemical compound C1CNCCN1C1=NN=CC2=CC=CC=C12 DZWBPVWZCQJMGW-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 230000019491 signal transduction Effects 0.000 description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- ODCNAEMHGMYADO-UHFFFAOYSA-N 1,4-dichlorophthalazine Chemical compound C1=CC=C2C(Cl)=NN=C(Cl)C2=C1 ODCNAEMHGMYADO-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 7
- 239000003112 inhibitor Substances 0.000 description 7
- 239000012044 organic layer Substances 0.000 description 7
- DSVGFKBFFICWLZ-UHFFFAOYSA-N 1-fluoro-4-isocyanatobenzene Chemical compound FC1=CC=C(N=C=O)C=C1 DSVGFKBFFICWLZ-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 6
- LIFADULWFCVAQR-UHFFFAOYSA-N 1-chloro-4-(4-fluorophenyl)phthalazine Chemical compound C1=CC(F)=CC=C1C1=NN=C(Cl)C2=CC=CC=C12 LIFADULWFCVAQR-UHFFFAOYSA-N 0.000 description 5
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 5
- 150000004885 piperazines Chemical class 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 239000000523 sample Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- DWOZNANUEDYIOF-UHFFFAOYSA-L 4-ditert-butylphosphanyl-n,n-dimethylaniline;dichloropalladium Chemical compound Cl[Pd]Cl.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 DWOZNANUEDYIOF-UHFFFAOYSA-L 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 208000000172 Medulloblastoma Diseases 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 239000003636 conditioned culture medium Substances 0.000 description 4
- 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 4
- 230000014509 gene expression Effects 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 229960003793 midazolam Drugs 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- 239000002953 phosphate buffered saline Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- WJJDLSHYLZRFDD-UHFFFAOYSA-N 1-chloro-4-phenylphthalazine Chemical compound C12=CC=CC=C2C(Cl)=NN=C1C1=CC=CC=C1 WJJDLSHYLZRFDD-UHFFFAOYSA-N 0.000 description 3
- GCMUHGJHZLTCPV-UHFFFAOYSA-N 1-phenyl-4-piperazin-1-ylphthalazine Chemical compound C1CNCCN1C(C1=CC=CC=C11)=NN=C1C1=CC=CC=C1 GCMUHGJHZLTCPV-UHFFFAOYSA-N 0.000 description 3
- 206010004593 Bile duct cancer Diseases 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 208000026900 bile duct neoplasm Diseases 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 208000006990 cholangiocarcinoma Diseases 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- IFNWESYYDINUHV-OLQVQODUSA-N (2s,6r)-2,6-dimethylpiperazine Chemical compound C[C@H]1CNC[C@@H](C)N1 IFNWESYYDINUHV-OLQVQODUSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- QASFUMOKHFSJGL-LAFRSMQTSA-N Cyclopamine Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H](CC2=C3C)[C@@H]1[C@@H]2CC[C@@]13O[C@@H]2C[C@H](C)CN[C@H]2[C@H]1C QASFUMOKHFSJGL-LAFRSMQTSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Natural products CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- QASFUMOKHFSJGL-UHFFFAOYSA-N cyclopamine Natural products C1C=C2CC(O)CCC2(C)C(CC2=C3C)C1C2CCC13OC2CC(C)CNC2C1C QASFUMOKHFSJGL-UHFFFAOYSA-N 0.000 description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003623 enhancer Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- 210000002783 mesonephros Anatomy 0.000 description 2
- DDLIGBOFAVUZHB-UHFFFAOYSA-N midazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NC=C2CN=C1C1=CC=CC=C1F DDLIGBOFAVUZHB-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- SIRSTRHGFGFVME-UHFFFAOYSA-N piperazin-2-ylmethanol Chemical compound OCC1CNCCN1 SIRSTRHGFGFVME-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical compound [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- FMLPQHJYUZTHQS-UHFFFAOYSA-N tert-butyl 3-methylpiperazine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-UHFFFAOYSA-N 0.000 description 2
- CHHQTRKZJWJXAP-UHFFFAOYSA-N tert-butyl 4-[4-(4-fluorophenyl)phthalazin-1-yl]-3-methylpiperazine-1-carboxylate Chemical compound CC1CN(C(=O)OC(C)(C)C)CCN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 CHHQTRKZJWJXAP-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- OUCUOMVLTQBZCY-BYPYZUCNSA-N (2s)-1-azaniumylpyrrolidine-2-carboxylate Chemical compound NN1CCC[C@H]1C(O)=O OUCUOMVLTQBZCY-BYPYZUCNSA-N 0.000 description 1
- CEBAHYWORUOILU-UHFFFAOYSA-N (4-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=C(C#N)C=C1 CEBAHYWORUOILU-UHFFFAOYSA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- YUHBMKMFMJKUBT-UHFFFAOYSA-N 1-(3-methylpiperazin-1-yl)phthalazine Chemical compound C1CNC(C)CN1C1=NN=CC2=CC=CC=C12 YUHBMKMFMJKUBT-UHFFFAOYSA-N 0.000 description 1
- UTELQAPOBQFBPA-UHFFFAOYSA-N 1-(4-methoxyphenyl)phthalazine Chemical compound C1=CC(OC)=CC=C1C1=NN=CC2=CC=CC=C12 UTELQAPOBQFBPA-UHFFFAOYSA-N 0.000 description 1
- RQSQFGXQJQUZBS-KGLIPLIRSA-N 1-[(2s,5r)-2,5-dimethylpiperazin-1-yl]-4-(4-fluorophenyl)phthalazine Chemical compound C[C@H]1CN[C@H](C)CN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 RQSQFGXQJQUZBS-KGLIPLIRSA-N 0.000 description 1
- UCOVESIAFFGEOR-UHFFFAOYSA-N 1-chlorophthalazine Chemical compound C1=CC=C2C(Cl)=NN=CC2=C1 UCOVESIAFFGEOR-UHFFFAOYSA-N 0.000 description 1
- KHIILJVSYUGMSE-UHFFFAOYSA-N 1-phenylphthalazine Chemical compound C1=CC=CC=C1C1=NN=CC2=CC=CC=C12 KHIILJVSYUGMSE-UHFFFAOYSA-N 0.000 description 1
- NSMWYRLQHIXVAP-UHFFFAOYSA-N 2,5-dimethylpiperazine Chemical compound CC1CNC(C)CN1 NSMWYRLQHIXVAP-UHFFFAOYSA-N 0.000 description 1
- FGTYTUFKXYPTML-UHFFFAOYSA-N 2-benzoylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C(=O)C1=CC=CC=C1 FGTYTUFKXYPTML-UHFFFAOYSA-N 0.000 description 1
- IVRQEHRFUAUDFX-UHFFFAOYSA-N 2-fluoro-1-isocyanato-4-(trifluoromethyl)benzene Chemical compound FC1=CC(C(F)(F)F)=CC=C1N=C=O IVRQEHRFUAUDFX-UHFFFAOYSA-N 0.000 description 1
- IYZVZWLOBDAREX-UHFFFAOYSA-N 3-fluoro-4-isocyanatobenzonitrile Chemical compound FC1=CC(C#N)=CC=C1N=C=O IYZVZWLOBDAREX-UHFFFAOYSA-N 0.000 description 1
- RLMBRRQWBTWGMB-UHFFFAOYSA-N 4-amino-3-fluorobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1F RLMBRRQWBTWGMB-UHFFFAOYSA-N 0.000 description 1
- IQTHEAQKKVAXGV-UHFFFAOYSA-N 4-ditert-butylphosphanyl-n,n-dimethylaniline Chemical compound CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 IQTHEAQKKVAXGV-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- FOHYQHSLGCEHFQ-UHFFFAOYSA-N C1=CC(F)=CC=C1C1=NN=CC2=CC=CC=C12 Chemical compound C1=CC(F)=CC=C1C1=NN=CC2=CC=CC=C12 FOHYQHSLGCEHFQ-UHFFFAOYSA-N 0.000 description 1
- BHFLDRRWAYMUSL-UHFFFAOYSA-N Cl.CC1N(CCNC1)C(=O)N Chemical compound Cl.CC1N(CCNC1)C(=O)N BHFLDRRWAYMUSL-UHFFFAOYSA-N 0.000 description 1
- LNTOGILNHHJNAB-UHFFFAOYSA-N Cl.FC(F)(F)c1ccc(NC(=O)N2CCNCC2)cc1 Chemical compound Cl.FC(F)(F)c1ccc(NC(=O)N2CCNCC2)cc1 LNTOGILNHHJNAB-UHFFFAOYSA-N 0.000 description 1
- 241000207894 Convolvulus arvensis Species 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000402754 Erythranthe moschata Species 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241001460678 Napo <wasp> Species 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 101710185494 Zinc finger protein Proteins 0.000 description 1
- 102100023597 Zinc finger protein 816 Human genes 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004296 chiral HPLC Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N dmso dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 210000002257 embryonic structure Anatomy 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 239000003797 essential amino acid Substances 0.000 description 1
- 235000020776 essential amino acid Nutrition 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000006525 intracellular process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000001853 liver microsome Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N meoh methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- ZPJZSEHCMJYUPI-UHFFFAOYSA-N methyl piperazine-1-carboxylate Chemical compound COC(=O)N1CCNCC1 ZPJZSEHCMJYUPI-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000014500 neuronal tumor Diseases 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical class O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001120 potassium sulphate Substances 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920002477 rna polymer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 230000008410 smoothened signaling pathway Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229930003352 steroid alkaloid Natural products 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000012607 strong cation exchange resin Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- CTCGRXDGXGUOTE-UHFFFAOYSA-N tert-butyl 2-ethylpiperazine-1-carboxylate Chemical compound CCC1CNCCN1C(=O)OC(C)(C)C CTCGRXDGXGUOTE-UHFFFAOYSA-N 0.000 description 1
- DATRVIMZZZVHMP-UHFFFAOYSA-N tert-butyl 2-methylpiperazine-1-carboxylate Chemical compound CC1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11070308P | 2008-11-03 | 2008-11-03 | |
| PCT/US2009/061573 WO2010062507A1 (en) | 2008-11-03 | 2009-10-22 | Disubstituted phthalazine hedgehog pathway antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201170640A1 EA201170640A1 (ru) | 2011-12-30 |
| EA018931B1 true EA018931B1 (ru) | 2013-11-29 |
Family
ID=41566219
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201170640A EA018931B1 (ru) | 2008-11-03 | 2009-10-22 | ДИЗАМЕЩЕННЫЕ ФТАЛАЗИНЫ-АНТАГОНИСТЫ СИГНАЛЬНОГО ПУТИ Hedgehog |
Country Status (29)
| Country | Link |
|---|---|
| US (1) | US8404687B2 (OSRAM) |
| EP (1) | EP2364185B1 (OSRAM) |
| JP (1) | JP2012507535A (OSRAM) |
| KR (1) | KR101335746B1 (OSRAM) |
| CN (1) | CN102202737B (OSRAM) |
| AU (1) | AU2009320251C1 (OSRAM) |
| BR (1) | BRPI0921437A2 (OSRAM) |
| CA (1) | CA2742539C (OSRAM) |
| CL (1) | CL2011000979A1 (OSRAM) |
| CO (1) | CO6382123A2 (OSRAM) |
| CR (1) | CR20110202A (OSRAM) |
| CY (1) | CY1114023T1 (OSRAM) |
| DK (1) | DK2364185T3 (OSRAM) |
| EA (1) | EA018931B1 (OSRAM) |
| EC (1) | ECSP11011021A (OSRAM) |
| ES (1) | ES2418479T3 (OSRAM) |
| HR (1) | HRP20130527T1 (OSRAM) |
| IL (1) | IL211841A0 (OSRAM) |
| MA (1) | MA32726B1 (OSRAM) |
| MX (1) | MX2011004683A (OSRAM) |
| NZ (1) | NZ591945A (OSRAM) |
| PE (1) | PE20110433A1 (OSRAM) |
| PL (1) | PL2364185T3 (OSRAM) |
| PT (1) | PT2364185E (OSRAM) |
| SI (1) | SI2364185T1 (OSRAM) |
| TN (1) | TN2011000166A1 (OSRAM) |
| UA (1) | UA102115C2 (OSRAM) |
| WO (1) | WO2010062507A1 (OSRAM) |
| ZA (1) | ZA201102448B (OSRAM) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PE20090188A1 (es) * | 2007-03-15 | 2009-03-20 | Novartis Ag | Compuestos heterociclicos como moduladores de la senda de hedgehog |
| UA102250C2 (ru) | 2008-04-29 | 2013-06-25 | Эли Лилли Энд Компани | Двухзамещенные фталазины - антагонисты проводящего пути hedgehog |
| US20100041663A1 (en) | 2008-07-18 | 2010-02-18 | Novartis Ag | Organic Compounds as Smo Inhibitors |
| KR101335770B1 (ko) | 2008-11-17 | 2013-12-12 | 일라이 릴리 앤드 캄파니 | 사치환된 피리다진 헷지호그 경로 길항제 |
| EP2358698B1 (en) | 2008-11-17 | 2012-09-05 | Eli Lilly and Company | Tetrasubstituted pyridazine as hedgehog pathway antagonists |
| AR077014A1 (es) | 2009-06-19 | 2011-07-27 | Lilly Co Eli | Compuesto derivado de ftalazina 1,4-disustituida, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para el tratamiento de cancer |
| US9814703B2 (en) | 2013-11-14 | 2017-11-14 | The Board Of Trustees Of The Leland Stanford Junior University | Methods for treating cancer by activation of BMP signaling |
| CN105985320B (zh) * | 2015-02-11 | 2018-10-26 | 复旦大学 | 苄基酞嗪化合物及其制备方法和用途 |
| CN105985321B (zh) * | 2015-02-11 | 2018-10-26 | 复旦大学 | 吡唑酞嗪化合物及其制备方法和用途 |
| CN105985319B (zh) * | 2015-02-11 | 2019-02-26 | 复旦大学 | 芳基酞嗪化合物及其制备方法和用途 |
| CN116349204A (zh) | 2020-10-13 | 2023-06-27 | 奋进生物医药公司 | 治疗纤维化的方法 |
| WO2024064245A1 (en) * | 2022-09-23 | 2024-03-28 | Merck Sharp & Dohme Llc | Phthalazine derivatives useful as inhibitors of nod-like receptor protein 3 |
| US12447148B2 (en) | 2024-03-05 | 2025-10-21 | Endeavor Biomedicines, Inc. | Methods of improving lung function |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005033288A2 (en) * | 2003-09-29 | 2005-04-14 | The Johns Hopkins University | Hedgehog pathway antagonists |
| WO2006028958A2 (en) * | 2004-09-02 | 2006-03-16 | Genentech, Inc. | Pyridyl inhibitors of hedgehog signalling |
| WO2008110611A1 (en) * | 2007-03-15 | 2008-09-18 | Novartis Ag | Organic compounds and their uses |
| WO2009002469A1 (en) * | 2007-06-25 | 2008-12-31 | Amgen Inc. | Phthalazine compounds, compositions and methods of use |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1293565A (en) | 1969-05-03 | 1972-10-18 | Aspro Nicholas Ltd | Aminophthalazines and pharmaceutical compositions thereof |
| WO1998014431A1 (en) * | 1996-10-01 | 1998-04-09 | Kyowa Hakko Kogyo Co., Ltd. | Nitrogenous heterocyclic compounds |
| ES2162235T3 (es) | 1996-01-15 | 2001-12-16 | Janssen Pharmaceutica Nv | Piridazinaminas inhibidoras de la angiogenesis. |
| US6432970B2 (en) | 1998-04-09 | 2002-08-13 | Johns Hopkins University School Of Medicine | Inhibitors of hedgehog signaling pathways, compositions and uses related thereto |
| WO1999052534A1 (en) | 1998-04-09 | 1999-10-21 | Johns Hopkins University School Of Medicine | Use of steroidal alkaloid derivatives as inhibitors of hedgehog signaling pathways |
| AU780358B2 (en) | 1999-06-08 | 2005-03-17 | Lorantis Limited | Therapeutic use of an inhibitor of a hedgehog or a hedgehog-related signalling pathway |
| ATE404200T1 (de) | 2002-04-22 | 2008-08-15 | Univ Johns Hopkins Med | Modulatoren von hedgehog signalpfaden, zusammensetzungen und verwandte verwendungen |
| AU2003265853A1 (en) | 2002-08-29 | 2004-03-19 | Curis, Inc. | Hedgehog antagonists, methods and uses related thereto |
| TW200533356A (en) | 2004-02-24 | 2005-10-16 | Mitsubishi Pharma Corp | Fused pyridazine derivatives |
| CA2564996A1 (en) | 2004-05-08 | 2006-01-12 | Taeyoung Yoon | 3-aryl-5,6-disubstituted pyridazines |
| EP1900731A1 (de) | 2006-09-07 | 2008-03-19 | Bayer Schering Pharma Aktiengesellschaft | N-(1-Phthalazin-1-yl-piperidin-4-yl)-amide als EP2-Rezeptor Modulatoren |
| WO2009035568A1 (en) | 2007-09-07 | 2009-03-19 | Amgen Inc. | Annelated pyridazines for the treatment of tumors driven by inappropriate hedgehog signalling |
| UA102250C2 (ru) | 2008-04-29 | 2013-06-25 | Эли Лилли Энд Компани | Двухзамещенные фталазины - антагонисты проводящего пути hedgehog |
| US20100041663A1 (en) | 2008-07-18 | 2010-02-18 | Novartis Ag | Organic Compounds as Smo Inhibitors |
| EP2358698B1 (en) | 2008-11-17 | 2012-09-05 | Eli Lilly and Company | Tetrasubstituted pyridazine as hedgehog pathway antagonists |
| KR101335770B1 (ko) | 2008-11-17 | 2013-12-12 | 일라이 릴리 앤드 캄파니 | 사치환된 피리다진 헷지호그 경로 길항제 |
| AR077014A1 (es) | 2009-06-19 | 2011-07-27 | Lilly Co Eli | Compuesto derivado de ftalazina 1,4-disustituida, composicion farmaceutica que lo comprende y uso para preparar un medicamento util para el tratamiento de cancer |
-
2009
- 2009-10-22 CN CN200980143394.3A patent/CN102202737B/zh not_active Expired - Fee Related
- 2009-10-22 BR BRPI0921437A patent/BRPI0921437A2/pt not_active IP Right Cessation
- 2009-10-22 PL PL09740613T patent/PL2364185T3/pl unknown
- 2009-10-22 EP EP09740613.6A patent/EP2364185B1/en active Active
- 2009-10-22 CA CA2742539A patent/CA2742539C/en not_active Expired - Fee Related
- 2009-10-22 AU AU2009320251A patent/AU2009320251C1/en not_active Ceased
- 2009-10-22 JP JP2011534624A patent/JP2012507535A/ja active Pending
- 2009-10-22 ES ES09740613T patent/ES2418479T3/es active Active
- 2009-10-22 PE PE2011000937A patent/PE20110433A1/es not_active Application Discontinuation
- 2009-10-22 HR HRP20130527AT patent/HRP20130527T1/hr unknown
- 2009-10-22 UA UAA201105364A patent/UA102115C2/ru unknown
- 2009-10-22 MX MX2011004683A patent/MX2011004683A/es active IP Right Grant
- 2009-10-22 NZ NZ591945A patent/NZ591945A/xx not_active IP Right Cessation
- 2009-10-22 WO PCT/US2009/061573 patent/WO2010062507A1/en not_active Ceased
- 2009-10-22 SI SI200930625T patent/SI2364185T1/sl unknown
- 2009-10-22 PT PT97406136T patent/PT2364185E/pt unknown
- 2009-10-22 US US13/122,212 patent/US8404687B2/en not_active Expired - Fee Related
- 2009-10-22 DK DK09740613.6T patent/DK2364185T3/da active
- 2009-10-22 KR KR1020117010063A patent/KR101335746B1/ko not_active Expired - Fee Related
- 2009-10-22 EA EA201170640A patent/EA018931B1/ru not_active IP Right Cessation
-
2011
- 2011-03-21 IL IL211841A patent/IL211841A0/en unknown
- 2011-04-01 ZA ZA2011/02448A patent/ZA201102448B/en unknown
- 2011-04-07 TN TN2011000166A patent/TN2011000166A1/fr unknown
- 2011-04-15 CR CR20110202A patent/CR20110202A/es not_active Application Discontinuation
- 2011-04-22 MA MA33790A patent/MA32726B1/fr unknown
- 2011-05-02 EC EC2011011021A patent/ECSP11011021A/es unknown
- 2011-05-02 CL CL2011000979A patent/CL2011000979A1/es unknown
- 2011-05-11 CO CO11058054A patent/CO6382123A2/es active IP Right Grant
-
2013
- 2013-06-05 CY CY20131100447T patent/CY1114023T1/el unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005033288A2 (en) * | 2003-09-29 | 2005-04-14 | The Johns Hopkins University | Hedgehog pathway antagonists |
| WO2006028958A2 (en) * | 2004-09-02 | 2006-03-16 | Genentech, Inc. | Pyridyl inhibitors of hedgehog signalling |
| WO2008110611A1 (en) * | 2007-03-15 | 2008-09-18 | Novartis Ag | Organic compounds and their uses |
| WO2009002469A1 (en) * | 2007-06-25 | 2008-12-31 | Amgen Inc. | Phthalazine compounds, compositions and methods of use |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EA018931B1 (ru) | ДИЗАМЕЩЕННЫЕ ФТАЛАЗИНЫ-АНТАГОНИСТЫ СИГНАЛЬНОГО ПУТИ Hedgehog | |
| US9783499B2 (en) | Quinoline derivatives and their applications | |
| AU2009241561B2 (en) | Disubstituted phthalazine hedgehog pathway antagonists | |
| EP2358698B1 (en) | Tetrasubstituted pyridazine as hedgehog pathway antagonists | |
| WO2004039782A1 (ja) | Ｆｌｔ３自己リン酸化を阻害するキノリン誘導体およびキナゾリン誘導体並びにそれらを含有する医薬組成物 | |
| EA019059B1 (ru) | Дизамещенные фталазиновые антагонисты пути hedgehog | |
| EA018372B1 (ru) | Тетразамещенные пиридазины в качестве антагонистов пути hedgehog | |
| JP2010523530A (ja) | タンパク質キナーゼ阻害剤として有益な［２，６］ナフチリジン | |
| WO2022240966A1 (en) | Compounds and methods for yap/tead modulation and indications therefor | |
| US20250129028A1 (en) | Compounds and methods for yap/tead modulation and indications therefor | |
| US20240174659A1 (en) | Compounds and methods for yap/tead modulation and indications therefor | |
| HK1159010B (en) | Disubstituted phthalazine hedgehog pathway antagonists | |
| WO2025010279A9 (en) | Polo-like kinase 1 inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Lapse of a eurasian patent due to non-payment of renewal fees within the time limit in the following designated state(s) |
Designated state(s): AM AZ BY KZ KG MD TJ TM RU |