CA2742539C - Disubstituted phthalazine hedgehog pathway antagonists - Google Patents
Disubstituted phthalazine hedgehog pathway antagonists Download PDFInfo
- Publication number
- CA2742539C CA2742539C CA2742539A CA2742539A CA2742539C CA 2742539 C CA2742539 C CA 2742539C CA 2742539 A CA2742539 A CA 2742539A CA 2742539 A CA2742539 A CA 2742539A CA 2742539 C CA2742539 C CA 2742539C
- Authority
- CA
- Canada
- Prior art keywords
- cancer
- fluorophenyl
- fluoro
- phthalazin
- pharmaceutically acceptable
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 239000005557 antagonist Substances 0.000 title abstract description 10
- 230000037361 pathway Effects 0.000 title abstract description 8
- 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 17
- -1 1,4-disubstituted phthalazine Chemical class 0.000 claims abstract description 102
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000001153 fluoro group Chemical group F* 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 51
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 30
- 150000003839 salts Chemical class 0.000 claims description 30
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 15
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 7
- 206010041067 Small cell lung cancer Diseases 0.000 claims description 7
- 208000000587 small cell lung carcinoma Diseases 0.000 claims description 7
- 208000003950 B-cell lymphoma Diseases 0.000 claims description 6
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 6
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 6
- 208000008839 Kidney Neoplasms Diseases 0.000 claims description 6
- 208000034578 Multiple myelomas Diseases 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 6
- 206010038389 Renal cancer Diseases 0.000 claims description 6
- 208000005718 Stomach Neoplasms Diseases 0.000 claims description 6
- 206010017758 gastric cancer Diseases 0.000 claims description 6
- 201000010982 kidney cancer Diseases 0.000 claims description 6
- 201000007270 liver cancer Diseases 0.000 claims description 6
- 208000014018 liver neoplasm Diseases 0.000 claims description 6
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 6
- 201000001441 melanoma Diseases 0.000 claims description 6
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 6
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 6
- 201000011549 stomach cancer Diseases 0.000 claims description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 6
- 208000000461 Esophageal Neoplasms Diseases 0.000 claims description 5
- 201000009036 biliary tract cancer Diseases 0.000 claims description 5
- 208000020790 biliary tract neoplasm Diseases 0.000 claims description 5
- 201000004101 esophageal cancer Diseases 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 3
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 3
- ZXHWXYWBYLYAKF-LMOVPXPDSA-N (2s)-n-(4-fluorophenyl)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-2-methylpiperazine-1-carboxamide;hydrochloride Chemical compound Cl.C([C@@H]1C)N(C=2C3=CC=CC=C3C(C=3C=CC(F)=CC=3)=NN=2)CCN1C(=O)NC1=CC=C(F)C=C1 ZXHWXYWBYLYAKF-LMOVPXPDSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 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
- HNUNJRNFMAFWKV-KRWDZBQOSA-N (2s)-n-(4-fluorophenyl)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-2-methylpiperazine-1-carboxamide Chemical compound C([C@@H]1C)N(C=2C3=CC=CC=C3C(C=3C=CC(F)=CC=3)=NN=2)CCN1C(=O)NC1=CC=C(F)C=C1 HNUNJRNFMAFWKV-KRWDZBQOSA-N 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 69
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 41
- 125000001207 fluorophenyl group Chemical group 0.000 description 39
- 239000000203 mixture Substances 0.000 description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 32
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 29
- 210000004027 cell Anatomy 0.000 description 27
- 239000012141 concentrate Substances 0.000 description 26
- 238000000034 method Methods 0.000 description 26
- 238000002360 preparation method Methods 0.000 description 25
- 239000007787 solid Substances 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000006260 foam Substances 0.000 description 15
- 125000004802 cyanophenyl group Chemical group 0.000 description 14
- 244000060234 Gmelina philippensis Species 0.000 description 13
- 150000003857 carboxamides Chemical class 0.000 description 13
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 13
- 239000011541 reaction mixture Substances 0.000 description 13
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 230000002829 reductive effect Effects 0.000 description 12
- IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical compound NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- DZWBPVWZCQJMGW-UHFFFAOYSA-N 1-piperazin-1-ylphthalazine Chemical compound C1CNCCN1C1=NN=CC2=CC=CC=C12 DZWBPVWZCQJMGW-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- ODCNAEMHGMYADO-UHFFFAOYSA-N 1,4-dichlorophthalazine Chemical compound C1=CC=C2C(Cl)=NN=C(Cl)C2=C1 ODCNAEMHGMYADO-UHFFFAOYSA-N 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
- 239000003112 inhibitor Substances 0.000 description 6
- 239000002002 slurry Substances 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
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- 239000007832 Na2SO4 Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 150000007942 carboxylates Chemical class 0.000 description 5
- 239000003636 conditioned culture medium Substances 0.000 description 5
- 230000005764 inhibitory process Effects 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 4
- 238000002825 functional assay Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- UVYKKFKLOUEFAR-UHFFFAOYSA-N hydron;piperazine-1-carboxamide;chloride Chemical compound Cl.NC(=O)N1CCNCC1 UVYKKFKLOUEFAR-UHFFFAOYSA-N 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
- 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000011664 signaling Effects 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XCPBBXSUIFMNMJ-ZDUSSCGKSA-N 1-(4-fluorophenyl)-4-[(3s)-3-methylpiperazin-1-yl]phthalazine Chemical compound C1CN[C@@H](C)CN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 XCPBBXSUIFMNMJ-ZDUSSCGKSA-N 0.000 description 3
- 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
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 208000000172 Medulloblastoma Diseases 0.000 description 3
- ACFIXJIJDZMPPO-NNYOXOHSSA-N NADPH Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](OP(O)(O)=O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 ACFIXJIJDZMPPO-NNYOXOHSSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 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 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- 125000004193 piperazinyl group Chemical group 0.000 description 3
- 230000003389 potentiating effect Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 238000012799 strong cation exchange Methods 0.000 description 3
- DATRVIMZZZVHMP-QMMMGPOBSA-N tert-butyl (2s)-2-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CNCCN1C(=O)OC(C)(C)C DATRVIMZZZVHMP-QMMMGPOBSA-N 0.000 description 3
- BEKLNCGIRLORTK-INIZCTEOSA-N tert-butyl (2s)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-2-methylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 BEKLNCGIRLORTK-INIZCTEOSA-N 0.000 description 3
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 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
- XFYXLHXTAHZORU-ZDUSSCGKSA-N 1-(4-fluorophenyl)-4-[(2s)-2-methylpiperazin-1-yl]phthalazine Chemical compound C[C@H]1CNCCN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 XFYXLHXTAHZORU-ZDUSSCGKSA-N 0.000 description 2
- KHIILJVSYUGMSE-UHFFFAOYSA-N 1-phenylphthalazine Chemical compound C1=CC=CC=C1C1=NN=CC2=CC=CC=C12 KHIILJVSYUGMSE-UHFFFAOYSA-N 0.000 description 2
- RSSGKNIPDNJYDI-UHFFFAOYSA-N 2-phenyl-1h-phthalazine Chemical compound N1=CC2=CC=CC=C2CN1C1=CC=CC=C1 RSSGKNIPDNJYDI-UHFFFAOYSA-N 0.000 description 2
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 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
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BHFLDRRWAYMUSL-UHFFFAOYSA-N Cl.CC1N(CCNC1)C(=O)N Chemical compound Cl.CC1N(CCNC1)C(=O)N BHFLDRRWAYMUSL-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
- 108020004414 DNA Proteins 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
- 239000004606 Fillers/Extenders Substances 0.000 description 2
- 108090000031 Hedgehog Proteins Proteins 0.000 description 2
- 102000003693 Hedgehog Proteins Human genes 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
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 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
- NUGCDLCAYZIBTE-OAHLLOKOSA-N [(2r)-4-[4-(4-fluorophenyl)phthalazin-1-yl]piperazin-2-yl]methanol Chemical compound C1CN[C@@H](CO)CN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 NUGCDLCAYZIBTE-OAHLLOKOSA-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
- 239000002253 acid Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 235000013877 carbamide Nutrition 0.000 description 2
- 235000011089 carbon dioxide Nutrition 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 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
- 238000001514 detection method Methods 0.000 description 2
- 125000004212 difluorophenyl group Chemical group 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 238000004020 luminiscence type Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 239000012452 mother liquor Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 229920002477 rna polymer Polymers 0.000 description 2
- 238000002098 selective ion monitoring Methods 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 230000008410 smoothened signaling pathway Effects 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 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
- OCJUKXWFPOGFHV-LBPRGKRZSA-N tert-butyl (2s)-4-(4-chlorophthalazin-1-yl)-2-methylpiperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1C1=NN=C(Cl)C2=CC=CC=C12 OCJUKXWFPOGFHV-LBPRGKRZSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- VGVMZZXUJBGLCX-ZMBIFBSDSA-N (2r)-n-(4-fluorophenyl)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-2-(hydroxymethyl)piperazine-1-carboxamide;hydrochloride Chemical compound Cl.C([C@@H]1CO)N(C=2C3=CC=CC=C3C(C=3C=CC(F)=CC=3)=NN=2)CCN1C(=O)NC1=CC=C(F)C=C1 VGVMZZXUJBGLCX-ZMBIFBSDSA-N 0.000 description 1
- OUCUOMVLTQBZCY-BYPYZUCNSA-N (2s)-1-azaniumylpyrrolidine-2-carboxylate Chemical compound NN1CCC[C@H]1C(O)=O OUCUOMVLTQBZCY-BYPYZUCNSA-N 0.000 description 1
- RCXMIZDFLJCWKB-MSOLQXFVSA-N (2s,5r)-n-(4-fluorophenyl)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-2,5-dimethylpiperazine-1-carboxamide Chemical class C([C@@H](C)N(C[C@@H]1C)C=2C3=CC=CC=C3C(C=3C=CC(F)=CC=3)=NN=2)N1C(=O)NC1=CC=C(F)C=C1 RCXMIZDFLJCWKB-MSOLQXFVSA-N 0.000 description 1
- BPOQPMSRUDFRCM-URBRKQAFSA-N (2s,5r)-n-(4-fluorophenyl)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-2,5-dimethylpiperazine-1-carboxamide;hydrochloride Chemical compound Cl.C([C@@H](C)N(C[C@@H]1C)C=2C3=CC=CC=C3C(C=3C=CC(F)=CC=3)=NN=2)N1C(=O)NC1=CC=C(F)C=C1 BPOQPMSRUDFRCM-URBRKQAFSA-N 0.000 description 1
- BPOQPMSRUDFRCM-APTPAJQOSA-N (2s,5s)-n-(4-fluorophenyl)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-2,5-dimethylpiperazine-1-carboxamide;hydrochloride Chemical compound Cl.C([C@H](C)N(C[C@@H]1C)C=2C3=CC=CC=C3C(C=3C=CC(F)=CC=3)=NN=2)N1C(=O)NC1=CC=C(F)C=C1 BPOQPMSRUDFRCM-APTPAJQOSA-N 0.000 description 1
- QGKVUAJBSIJCSL-LMOVPXPDSA-N (3s)-n-(4-fluorophenyl)-4-[4-(4-fluorophenyl)phthalazin-1-yl]-3-methylpiperazine-1-carboxamide;hydrochloride Chemical compound Cl.C([C@@H]1C)N(C(=O)NC=2C=CC(F)=CC=2)CCN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 QGKVUAJBSIJCSL-LMOVPXPDSA-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
- IDFPQEHZYBXIFO-GFCCVEGCSA-N (R)-(4-fluoro-2-propylphenyl)-(1H-imidazol-2-yl)methanol Chemical compound CCCc1cc(F)ccc1[C@@H](O)c1ncc[nH]1 IDFPQEHZYBXIFO-GFCCVEGCSA-N 0.000 description 1
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 description 1
- ARHYWWAJZDAYDJ-UHFFFAOYSA-N 1,2-dimethylpiperazine Chemical compound CC1CNCCN1C ARHYWWAJZDAYDJ-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-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
- 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
- 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
- XCJLBNVENUPHEA-UHFFFAOYSA-N 4-phenyl-2h-phthalazin-1-one Chemical compound C12=CC=CC=C2C(=O)NN=C1C1=CC=CC=C1 XCJLBNVENUPHEA-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
- WUCXRFAXMQOBIC-UHFFFAOYSA-N Cl.CC1CN(CCN1)C(N)=O Chemical compound Cl.CC1CN(CCN1)C(N)=O WUCXRFAXMQOBIC-UHFFFAOYSA-N 0.000 description 1
- 102000004328 Cytochrome P-450 CYP3A Human genes 0.000 description 1
- 108010081668 Cytochrome P-450 CYP3A Proteins 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
- 206010017993 Gastrointestinal neoplasms Diseases 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
- 241000051107 Paraechinus aethiopicus 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
- 102100028651 Tenascin-N Human genes 0.000 description 1
- 101710087911 Tenascin-N Proteins 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 241000489524 Veratrum californicum Species 0.000 description 1
- 101710185494 Zinc finger protein Proteins 0.000 description 1
- 102100023597 Zinc finger protein 816 Human genes 0.000 description 1
- SIRSTRHGFGFVME-RXMQYKEDSA-N [(2r)-piperazin-2-yl]methanol Chemical compound OC[C@H]1CNCCN1 SIRSTRHGFGFVME-RXMQYKEDSA-N 0.000 description 1
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 238000004458 analytical method Methods 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
- 239000012298 atmosphere Substances 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 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
- 239000004202 carbamide Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000004296 chiral HPLC Methods 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
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 239000003596 drug target Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000029600 embryonic pattern specification Effects 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
- 239000000706 filtrate Substances 0.000 description 1
- PUPFATUGTIQBQA-UZQPLGKSSA-N fluorophen Chemical compound C([C@@]1(C)C2=CC(O)=CC=C2C[C@H]2[C@@H]1C)CN2CCC1=CC=C(F)C=C1 PUPFATUGTIQBQA-UZQPLGKSSA-N 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 208000005017 glioblastoma Diseases 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000003228 microsomal effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000007758 minimum essential medium Substances 0.000 description 1
- WPHXYKUPFJRJDK-AHWVRZQESA-N n-[(3s,5s)-1-(1,3-benzodioxol-5-ylmethyl)-5-(piperazine-1-carbonyl)pyrrolidin-3-yl]-n-[(3-methoxyphenyl)methyl]-3,3-dimethylbutanamide Chemical compound COC1=CC=CC(CN([C@@H]2CN(CC=3C=C4OCOC4=CC=3)[C@@H](C2)C(=O)N2CCNCC2)C(=O)CC(C)(C)C)=C1 WPHXYKUPFJRJDK-AHWVRZQESA-N 0.000 description 1
- LAHSIPAAIPQMCT-UHFFFAOYSA-N n-[3-(1h-benzimidazol-2-yl)-4-chlorophenyl]-3,5-dimethoxybenzamide Chemical compound COC1=CC(OC)=CC(C(=O)NC=2C=C(C(Cl)=CC=2)C=2NC3=CC=CC=C3N=2)=C1 LAHSIPAAIPQMCT-UHFFFAOYSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000014500 neuronal tumor Diseases 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 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
- 229910052763 palladium Inorganic materials 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
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- SIRSTRHGFGFVME-UHFFFAOYSA-N piperazin-2-ylmethanol Chemical compound OCC1CNCCN1 SIRSTRHGFGFVME-UHFFFAOYSA-N 0.000 description 1
- 230000004481 post-translational protein modification Effects 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 229940054269 sodium pyruvate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007921 spray Substances 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
- 239000007858 starting material Substances 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- ZKNVKHREIQBPOE-IBGZPJMESA-N tert-butyl (2s)-2-ethyl-4-[4-(4-fluorophenyl)phthalazin-1-yl]piperazine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)[C@@H](CC)CN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(F)C=C1 ZKNVKHREIQBPOE-IBGZPJMESA-N 0.000 description 1
- DYACKSBXVUWLHA-KRWDZBQOSA-N tert-butyl (2s)-4-[4-(4-methoxyphenyl)phthalazin-1-yl]-2-methylpiperazine-1-carboxylate Chemical compound C1=CC(OC)=CC=C1C(C1=CC=CC=C11)=NN=C1N1C[C@H](C)N(C(=O)OC(C)(C)C)CC1 DYACKSBXVUWLHA-KRWDZBQOSA-N 0.000 description 1
- FMLPQHJYUZTHQS-QMMMGPOBSA-N tert-butyl (3s)-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1 FMLPQHJYUZTHQS-QMMMGPOBSA-N 0.000 description 1
- FCBOLKCHKKSBFG-LBPRGKRZSA-N tert-butyl (3s)-4-(4-chlorophthalazin-1-yl)-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C1=NN=C(Cl)C2=CC=CC=C12 FCBOLKCHKKSBFG-LBPRGKRZSA-N 0.000 description 1
- HRMYIQGSKJINMW-KRWDZBQOSA-N tert-butyl (3s)-4-[4-(4-cyanophenyl)phthalazin-1-yl]-3-methylpiperazine-1-carboxylate Chemical compound C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(C1=CC=CC=C11)=NN=C1C1=CC=C(C#N)C=C1 HRMYIQGSKJINMW-KRWDZBQOSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical group 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000030968 tissue homeostasis 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
- 239000003643 water by type Substances 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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11070308P | 2008-11-03 | 2008-11-03 | |
| US61/110,703 | 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 |
|---|---|
| CA2742539A1 CA2742539A1 (en) | 2010-06-03 |
| CA2742539C true CA2742539C (en) | 2014-05-06 |
Family
ID=41566219
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2742539A Expired - Fee Related CA2742539C (en) | 2008-11-03 | 2009-10-22 | Disubstituted phthalazine hedgehog pathway antagonists |
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 |
|---|---|---|---|---|
| AR065718A1 (es) * | 2007-03-15 | 2009-06-24 | Novartis Ag | Compuestos heterociclicos nitrogenados,utiles en el diagnostico y tratamiento de trastornos hiperproliferativos. |
| MX2010011948A (es) | 2008-04-29 | 2010-12-14 | Lilly Co Eli | Antagonistas de la trayectoria hedgehog de ftalazina disustituida. |
| US20100041663A1 (en) * | 2008-07-18 | 2010-02-18 | Novartis Ag | Organic Compounds as Smo Inhibitors |
| ES2392759T3 (es) | 2008-11-17 | 2012-12-13 | Eli Lilly And Company | Piridazina tetrasustituida como antagonistas de la vía Hedgehog. |
| ES2446307T3 (es) | 2008-11-17 | 2014-03-07 | Eli Lilly And Company | Piridazinas tetrasustituidas antagonistas de la ruta de Hedgehog |
| 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 |
| 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 |
| 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 |
| 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 |
| KR20230107568A (ko) | 2020-10-13 | 2023-07-17 | 엔데버 바이오메디신스, 인크. | 섬유증 치료 방법 |
| PE20251293A1 (es) * | 2022-09-23 | 2025-05-14 | Merck Sharp And Dohme Llc | Derivados de ftalazina utiles como inhibidores de la proteina receptora 3 similar a nod |
| US12447148B2 (en) | 2024-03-05 | 2025-10-21 | Endeavor Biomedicines, Inc. | Methods of improving lung function |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1293565A (en) * | 1969-05-03 | 1972-10-18 | Aspro Nicholas Ltd | Aminophthalazines and pharmaceutical compositions thereof |
| ZA97288B (en) | 1996-01-15 | 1998-07-14 | Janssen Pharmaceutica Nv | Angiogenesis inhibiting pyridazinamines |
| DK0882717T3 (da) * | 1996-10-01 | 2010-12-13 | Kyowa Hakko Kirin Co Ltd | Nitrogenholdige heterocykliske forbindelser |
| US6432970B2 (en) * | 1998-04-09 | 2002-08-13 | Johns Hopkins University School Of Medicine | Inhibitors of hedgehog signaling pathways, compositions and uses related thereto |
| IL138645A0 (en) | 1998-04-09 | 2001-10-31 | Univ Johns Hopkins Med | Use of steroidal alkaloid derivatives as inhibitors of hedghog signalling pathways |
| ES2233383T3 (es) | 1999-06-08 | 2005-06-16 | Lorantis Limited | Utilizacion terapeutica de un ihibidor de la via de señalizacion hedgehog. |
| US7655674B2 (en) | 2002-04-22 | 2010-02-02 | The Johns Hopkins University | Modulators of hedgehog signaling pathways, compositions and uses related thereto |
| AU2003265853A1 (en) | 2002-08-29 | 2004-03-19 | Curis, Inc. | Hedgehog antagonists, methods and uses related thereto |
| WO2005033288A2 (en) | 2003-09-29 | 2005-04-14 | The Johns Hopkins University | Hedgehog pathway antagonists |
| WO2005080378A1 (ja) | 2004-02-24 | 2005-09-01 | Mitsubishi Pharma Corporation | 縮合ピリダジン誘導体 |
| CA2564996A1 (en) | 2004-05-08 | 2006-01-12 | Taeyoung Yoon | 3-aryl-5,6-disubstituted pyridazines |
| CN102964294A (zh) | 2004-09-02 | 2013-03-13 | 遗传技术研究公司 | Hedgehog信号转导的吡啶基抑制剂 |
| 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 |
| AR065718A1 (es) | 2007-03-15 | 2009-06-24 | Novartis Ag | Compuestos heterociclicos nitrogenados,utiles en el diagnostico y tratamiento de trastornos hiperproliferativos. |
| WO2009002469A1 (en) * | 2007-06-25 | 2008-12-31 | Amgen Inc. | Phthalazine compounds, compositions and methods of use |
| ES2392157T3 (es) | 2007-09-07 | 2012-12-05 | Amgen Inc. | Piridazinas anilladas para el tratamiento de tumores dirigidos por señalización Hedgehog inapropiada |
| MX2010011948A (es) * | 2008-04-29 | 2010-12-14 | Lilly Co Eli | Antagonistas de la trayectoria hedgehog de ftalazina disustituida. |
| US20100041663A1 (en) | 2008-07-18 | 2010-02-18 | Novartis Ag | Organic Compounds as Smo Inhibitors |
| ES2392759T3 (es) | 2008-11-17 | 2012-12-13 | Eli Lilly And Company | Piridazina tetrasustituida como antagonistas de la vía Hedgehog. |
| ES2446307T3 (es) | 2008-11-17 | 2014-03-07 | Eli Lilly And Company | Piridazinas tetrasustituidas antagonistas de la ruta de Hedgehog |
| 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 US US13/122,212 patent/US8404687B2/en not_active Expired - Fee Related
- 2009-10-22 EA EA201170640A patent/EA018931B1/ru not_active IP Right Cessation
- 2009-10-22 DK DK09740613.6T patent/DK2364185T3/da active
- 2009-10-22 CA CA2742539A patent/CA2742539C/en not_active Expired - Fee Related
- 2009-10-22 MX MX2011004683A patent/MX2011004683A/es active IP Right Grant
- 2009-10-22 AU AU2009320251A patent/AU2009320251C1/en not_active Ceased
- 2009-10-22 HR HRP20130527AT patent/HRP20130527T1/hr unknown
- 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 JP JP2011534624A patent/JP2012507535A/ja active Pending
- 2009-10-22 PE PE2011000937A patent/PE20110433A1/es not_active Application Discontinuation
- 2009-10-22 SI SI200930625T patent/SI2364185T1/sl unknown
- 2009-10-22 BR BRPI0921437A patent/BRPI0921437A2/pt not_active IP Right Cessation
- 2009-10-22 CN CN200980143394.3A patent/CN102202737B/zh not_active Expired - Fee Related
- 2009-10-22 EP EP09740613.6A patent/EP2364185B1/en active Active
- 2009-10-22 UA UAA201105364A patent/UA102115C2/ru unknown
- 2009-10-22 KR KR1020117010063A patent/KR101335746B1/ko not_active Expired - Fee Related
- 2009-10-22 PL PL09740613T patent/PL2364185T3/pl unknown
- 2009-10-22 PT PT97406136T patent/PT2364185E/pt unknown
- 2009-10-22 ES ES09740613T patent/ES2418479T3/es active Active
-
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
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2742539C (en) | Disubstituted phthalazine hedgehog pathway antagonists | |
| EP2443104B1 (en) | Disubstituted phthalazine hedgehog pathway antagonists | |
| EP2358698B1 (en) | Tetrasubstituted pyridazine as hedgehog pathway antagonists | |
| EP2358703B1 (en) | Tetrasubstituted pyridazines hedgehog pathway antagonists | |
| HK1159010B (en) | Disubstituted phthalazine hedgehog pathway antagonists | |
| HK1164872B (en) | Disubstituted phthalazine hedgehog pathway antagonists |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20151022 |