RU2564527C2 - Производное фталазинонкетона, способ его получения и его фармацевтическое применение - Google Patents
Производное фталазинонкетона, способ его получения и его фармацевтическое применение Download PDFInfo
- Publication number
- RU2564527C2 RU2564527C2 RU2013106754/04A RU2013106754A RU2564527C2 RU 2564527 C2 RU2564527 C2 RU 2564527C2 RU 2013106754/04 A RU2013106754/04 A RU 2013106754/04A RU 2013106754 A RU2013106754 A RU 2013106754A RU 2564527 C2 RU2564527 C2 RU 2564527C2
- Authority
- RU
- Russia
- Prior art keywords
- pyrazine
- trifluoromethyl
- mmol
- group
- methyl
- Prior art date
Links
- -1 Phthalazine ketone Chemical class 0.000 title abstract description 90
- 238000000034 method Methods 0.000 title abstract description 18
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 26
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 claims abstract description 23
- 102000012338 Poly(ADP-ribose) Polymerases Human genes 0.000 claims abstract description 22
- 108010061844 Poly(ADP-ribose) Polymerases Proteins 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 14
- 239000003112 inhibitor Substances 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 47
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- 150000003839 salts Chemical class 0.000 claims description 36
- 206010028980 Neoplasm Diseases 0.000 claims description 29
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 25
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 201000011510 cancer Diseases 0.000 claims description 20
- 125000004432 carbon atom Chemical group C* 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- 238000011282 treatment Methods 0.000 claims description 17
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 206010006187 Breast cancer Diseases 0.000 claims description 12
- 208000026310 Breast neoplasm Diseases 0.000 claims description 12
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 claims description 12
- 229960004964 temozolomide Drugs 0.000 claims description 12
- 210000004881 tumor cell Anatomy 0.000 claims description 12
- 206010009944 Colon cancer Diseases 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 206010033128 Ovarian cancer Diseases 0.000 claims description 6
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
- 238000002512 chemotherapy Methods 0.000 claims description 6
- 208000029742 colonic neoplasm Diseases 0.000 claims description 6
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- 239000002671 adjuvant Substances 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 230000005865 ionizing radiation Effects 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
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000002528 pancreatic cancer Diseases 0.000 claims description 5
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 230000035945 sensitivity Effects 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 239000000126 substance Substances 0.000 abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- 239000011541 reaction mixture Substances 0.000 description 79
- 230000002829 reductive effect Effects 0.000 description 78
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 54
- 238000003756 stirring Methods 0.000 description 54
- 238000004949 mass spectrometry Methods 0.000 description 53
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000007787 solid Substances 0.000 description 48
- 125000000753 cycloalkyl group Chemical group 0.000 description 46
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000706 filtrate Substances 0.000 description 34
- 239000000243 solution Substances 0.000 description 34
- 125000001072 heteroaryl group Chemical group 0.000 description 33
- 125000003118 aryl group Chemical group 0.000 description 32
- 238000004809 thin layer chromatography Methods 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 29
- 238000010828 elution Methods 0.000 description 29
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- PAXLJNGPFJEKQX-UHFFFAOYSA-N 2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoic acid Chemical compound C1=C(F)C(C(=O)O)=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=C1 PAXLJNGPFJEKQX-UHFFFAOYSA-N 0.000 description 22
- 210000004027 cell Anatomy 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 239000000047 product Substances 0.000 description 20
- 238000000746 purification Methods 0.000 description 19
- 238000012360 testing method Methods 0.000 description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 12
- 125000002619 bicyclic group Chemical group 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 230000005778 DNA damage Effects 0.000 description 11
- 231100000277 DNA damage Toxicity 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 11
- 230000005764 inhibitory process Effects 0.000 description 11
- 125000003367 polycyclic group Chemical group 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000012661 PARP inhibitor Substances 0.000 description 10
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 10
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 10
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 125000006413 ring segment Chemical group 0.000 description 10
- 239000000523 sample Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 8
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 125000005366 cycloalkylthio group Chemical group 0.000 description 8
- YARSFSWHQVBNGV-UHFFFAOYSA-N methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate Chemical compound C1CNCC2=C(C(=O)OC)N=C(C(F)(F)F)N21 YARSFSWHQVBNGV-UHFFFAOYSA-N 0.000 description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000012047 saturated solution Substances 0.000 description 8
- 150000003573 thiols Chemical class 0.000 description 8
- 0 *c1ccc(CC(C2C=CC=CC22)=NNC2=O)cc1C(N1Cc2ccc[n]2CC1)=O Chemical compound *c1ccc(CC(C2C=CC=CC22)=NNC2=O)cc1C(N1Cc2ccc[n]2CC1)=O 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 125000005842 heteroatom Chemical group 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 241000699670 Mus sp. Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 230000000259 anti-tumor effect Effects 0.000 description 6
- 229910052760 oxygen Inorganic materials 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 230000008439 repair process Effects 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OWUJPAWZSIXQKU-UHFFFAOYSA-N 4-[[4-fluoro-3-[1-(hydroxymethyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)CO)C(F)(F)F)=NNC(=O)C2=C1 OWUJPAWZSIXQKU-UHFFFAOYSA-N 0.000 description 5
- VWOYKROCGXYUOW-UHFFFAOYSA-N 7-[(2-methylpropan-2-yl)oxycarbonyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxylic acid Chemical compound C1N(C(=O)OC(C)(C)C)CCN2C(C(F)(F)F)=NC(C(O)=O)=C12 VWOYKROCGXYUOW-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 125000004122 cyclic group Chemical group 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 238000010253 intravenous injection Methods 0.000 description 5
- 230000007246 mechanism Effects 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 4
- IYQUOZXROLJXSS-UHFFFAOYSA-N 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1CNCC2=C(C(=O)N)N=C(C(F)(F)F)N21 IYQUOZXROLJXSS-UHFFFAOYSA-N 0.000 description 4
- JPYXQNYTOSHIAC-UHFFFAOYSA-N 4-[[3-(3,4-dihydro-1h-pyrrolo[1,2-a]pyrazine-2-carbonyl)-4-fluorophenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C=CC=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F JPYXQNYTOSHIAC-UHFFFAOYSA-N 0.000 description 4
- YEDUHTJDMOAIPF-UHFFFAOYSA-N 4-[[3-(6,8-dihydro-5h-imidazo[1,2-a]pyrazine-7-carbonyl)-4-fluorophenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C=CN=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F YEDUHTJDMOAIPF-UHFFFAOYSA-N 0.000 description 4
- HXCBYELCIGBFEZ-UHFFFAOYSA-N 4-[[3-[3-(difluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]-4-fluorophenyl]methyl]-2h-phthalazin-1-one Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CC4=NN=C(N4CC3)C(F)F)=NNC(=O)C2=C1 HXCBYELCIGBFEZ-UHFFFAOYSA-N 0.000 description 4
- HFYKJMSAJNKYCB-UHFFFAOYSA-N 4-[[4-fluoro-3-[1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(C1)CCN(C(=N2)C(F)(F)F)C1=C2C(=O)N1CCOCC1 HFYKJMSAJNKYCB-UHFFFAOYSA-N 0.000 description 4
- UETNQARZLQIKEB-UHFFFAOYSA-N 4-[[4-fluoro-3-[3-(2,2,2-trifluoroethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C(CC(F)(F)F)=NN=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F UETNQARZLQIKEB-UHFFFAOYSA-N 0.000 description 4
- QERWDUVWGUUQKN-UHFFFAOYSA-N 7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carbonitrile Chemical compound C1CN2C(C(F)(F)F)=NC(C#N)=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F QERWDUVWGUUQKN-UHFFFAOYSA-N 0.000 description 4
- DYWUYPWTHFULMZ-UHFFFAOYSA-N 7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)C(=O)N)C(F)(F)F)=NNC(=O)C2=C1 DYWUYPWTHFULMZ-UHFFFAOYSA-N 0.000 description 4
- XBIJJQIOLLAVSW-UHFFFAOYSA-N 7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-n,n-dimethyl-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)C(=O)N(C)C)C(F)(F)F)=NNC(=O)C2=C1 XBIJJQIOLLAVSW-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 230000033616 DNA repair Effects 0.000 description 4
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 229940009456 adriamycin Drugs 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 235000019270 ammonium chloride Nutrition 0.000 description 4
- 238000010171 animal model Methods 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 4
- 229960004316 cisplatin Drugs 0.000 description 4
- 229960003901 dacarbazine Drugs 0.000 description 4
- MUAHELSBFBMLBP-UHFFFAOYSA-N ethyl 7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-6,8-dihydro-5h-imidazo[1,2-a]pyrazine-3-carboxylate Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CC4=NC=C(N4CC3)C(=O)OCC)=NNC(=O)C2=C1 MUAHELSBFBMLBP-UHFFFAOYSA-N 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 4
- 229960005277 gemcitabine Drugs 0.000 description 4
- 150000002430 hydrocarbons Chemical group 0.000 description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 4
- HIIJWJUIQSSMSB-UHFFFAOYSA-N methyl 7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxylate Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)C(=O)OC)C(F)(F)F)=NNC(=O)C2=C1 HIIJWJUIQSSMSB-UHFFFAOYSA-N 0.000 description 4
- JUIGFLFFLLPDEZ-UHFFFAOYSA-N n-(cyclopropylmethyl)-7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxamide Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(C1)CCN(C(=N2)C(F)(F)F)C1=C2C(=O)NCC1CC1 JUIGFLFFLLPDEZ-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- NVODTGHCPPVEII-UHFFFAOYSA-N n-ethyl-7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)C(=O)NCC)C(F)(F)F)=NNC(=O)C2=C1 NVODTGHCPPVEII-UHFFFAOYSA-N 0.000 description 4
- JXHBMURNQNBDSX-UHFFFAOYSA-N n-methyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1CNCC2=C(C(=O)NC)N=C(C(F)(F)F)N21 JXHBMURNQNBDSX-UHFFFAOYSA-N 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 4
- 229960000303 topotecan Drugs 0.000 description 4
- YZBDXDPBLIQCJY-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2C=CC=C21 YZBDXDPBLIQCJY-UHFFFAOYSA-N 0.000 description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
- JAIBCSJOXCXCLR-UHFFFAOYSA-N 1-bromo-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine;hydrochloride Chemical compound Cl.C1NCCN2C(C(F)(F)F)=NC(Br)=C21 JAIBCSJOXCXCLR-UHFFFAOYSA-N 0.000 description 3
- RHYZIHOBSWRZDL-UHFFFAOYSA-N 2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine Chemical compound C1CNCC2=NC(C(F)(F)F)=CN21 RHYZIHOBSWRZDL-UHFFFAOYSA-N 0.000 description 3
- GZOZMIOBJGXNBA-UHFFFAOYSA-N 2-(trifluoromethyl)imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC(C(F)(F)F)=CN21 GZOZMIOBJGXNBA-UHFFFAOYSA-N 0.000 description 3
- HPDIRFBJYSOVKW-UHFFFAOYSA-N 2-pyrrol-1-ylethanamine Chemical compound NCCN1C=CC=C1 HPDIRFBJYSOVKW-UHFFFAOYSA-N 0.000 description 3
- UALWMRVSKAPXSF-UHFFFAOYSA-N 3-(2,2,2-trifluoroethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Chemical compound C1NCCN2C(CC(F)(F)F)=NN=C21 UALWMRVSKAPXSF-UHFFFAOYSA-N 0.000 description 3
- OPBRLKOINULLLT-UHFFFAOYSA-N 3-(difluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine Chemical compound C1NCCN2C(C(F)F)=NN=C21 OPBRLKOINULLLT-UHFFFAOYSA-N 0.000 description 3
- SGMCGPUNBVSXKH-UHFFFAOYSA-N 3-(difluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine Chemical compound C1=NC=CN2C(C(F)F)=NN=C21 SGMCGPUNBVSXKH-UHFFFAOYSA-N 0.000 description 3
- WLCFSLORIVPKES-UHFFFAOYSA-N 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carbonitrile Chemical compound C1NCCN2C(C(F)(F)F)=NC(C#N)=C21 WLCFSLORIVPKES-UHFFFAOYSA-N 0.000 description 3
- SRJDSKSFXULHFT-UHFFFAOYSA-N 4-[[3-(6,8-dihydro-5h-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl)-4-fluorophenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2N=CN=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F SRJDSKSFXULHFT-UHFFFAOYSA-N 0.000 description 3
- LPTZKVHRKLZWJU-UHFFFAOYSA-N 4-[[3-(6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl)-4-fluorophenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C=NN=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F LPTZKVHRKLZWJU-UHFFFAOYSA-N 0.000 description 3
- LFAUBKXFAKUSGT-UHFFFAOYSA-N 4-[[3-[1-(chloromethyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluorophenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C(C(F)(F)F)=NC(CCl)=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F LFAUBKXFAKUSGT-UHFFFAOYSA-N 0.000 description 3
- MUSBAKYPGTWEDT-UHFFFAOYSA-N 4-[[3-[1-bromo-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carbonyl]-4-fluorophenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C(C(F)(F)F)=NC(Br)=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F MUSBAKYPGTWEDT-UHFFFAOYSA-N 0.000 description 3
- QIEUOEGGPNFAIH-UHFFFAOYSA-N 4-[[4-fluoro-3-[1-(methylaminomethyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)CNC)C(F)(F)F)=NNC(=O)C2=C1 QIEUOEGGPNFAIH-UHFFFAOYSA-N 0.000 description 3
- RSZOOIGWDLRSKP-UHFFFAOYSA-N 4-[[4-fluoro-3-[1-(pyrrolidine-1-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound FC1=CC=C(CC=2C3=CC=CC=C3C(=O)NN=2)C=C1C(=O)N(C1)CCN(C(=N2)C(F)(F)F)C1=C2C(=O)N1CCCC1 RSZOOIGWDLRSKP-UHFFFAOYSA-N 0.000 description 3
- XJGXCBHXFWBOTN-UHFFFAOYSA-N 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2N=C(C(F)(F)F)N=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F XJGXCBHXFWBOTN-UHFFFAOYSA-N 0.000 description 3
- YKRHDVRJUDSJQC-UHFFFAOYSA-N 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C(C(F)(F)F)=NN=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F YKRHDVRJUDSJQC-UHFFFAOYSA-N 0.000 description 3
- SWBUHQQTIPEPMK-UHFFFAOYSA-N 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine Chemical compound C1NCCN2C=CN=C21 SWBUHQQTIPEPMK-UHFFFAOYSA-N 0.000 description 3
- SEDDDPUVBQPFIG-UHFFFAOYSA-N 7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxylic acid Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)C(=O)O)C(F)(F)F)=NNC(=O)C2=C1 SEDDDPUVBQPFIG-UHFFFAOYSA-N 0.000 description 3
- BNKWXZNVUFQNOW-UHFFFAOYSA-N 7-[2-fluoro-5-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-n-methyl-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1=CC=C2C(CC=3C=C(C(=CC=3)F)C(=O)N3CCN4C(=NC(=C4C3)C(=O)NC)C(F)(F)F)=NNC(=O)C2=C1 BNKWXZNVUFQNOW-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 108020004414 DNA Proteins 0.000 description 3
- 241000699660 Mus musculus Species 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- VUHSMYOXEILBCI-UHFFFAOYSA-N [3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanol Chemical compound C1CNCC2=C(CO)N=C(C(F)(F)F)N21 VUHSMYOXEILBCI-UHFFFAOYSA-N 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- PUSQIDJRNISKAT-UHFFFAOYSA-N ethyl 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-3-carboxylate Chemical compound C1NCCN2C(C(=O)OCC)=CN=C21 PUSQIDJRNISKAT-UHFFFAOYSA-N 0.000 description 3
- SQLWTMXBSLVISZ-UHFFFAOYSA-N ethyl imidazo[1,2-a]pyrazine-3-carboxylate Chemical compound C1=NC=CN2C(C(=O)OCC)=CN=C21 SQLWTMXBSLVISZ-UHFFFAOYSA-N 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- MBVAHHOKMIRXLP-UHFFFAOYSA-N imidazo[1,2-a]pyrazine Chemical compound C1=CN=CC2=NC=CN21 MBVAHHOKMIRXLP-UHFFFAOYSA-N 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
- 229960004768 irinotecan Drugs 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- BMXHOPPHYPKUCV-UHFFFAOYSA-N morpholin-4-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone Chemical compound C=12CNCCN2C(C(F)(F)F)=NC=1C(=O)N1CCOCC1 BMXHOPPHYPKUCV-UHFFFAOYSA-N 0.000 description 3
- AKAMFBZETDKAPC-UHFFFAOYSA-N morpholin-4-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone;hydrochloride Chemical compound Cl.C=12CNCCN2C(C(F)(F)F)=NC=1C(=O)N1CCOCC1 AKAMFBZETDKAPC-UHFFFAOYSA-N 0.000 description 3
- WIKCMQFSSCZDJO-UHFFFAOYSA-N n,n-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide;hydrochloride Chemical compound Cl.C1CNCC2=C(C(=O)N(C)C)N=C(C(F)(F)F)N21 WIKCMQFSSCZDJO-UHFFFAOYSA-N 0.000 description 3
- QFCAOTRAUOHDGB-UHFFFAOYSA-N n-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C=12CNCCN2C(C(F)(F)F)=NC=1C(=O)NCC1CC1 QFCAOTRAUOHDGB-UHFFFAOYSA-N 0.000 description 3
- NCFVNDCVTPXKDE-UHFFFAOYSA-N n-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide;hydrochloride Chemical compound Cl.C=12CNCCN2C(C(F)(F)F)=NC=1C(=O)NCC1CC1 NCFVNDCVTPXKDE-UHFFFAOYSA-N 0.000 description 3
- PREZIENXKGSPQL-UHFFFAOYSA-N n-ethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1CNCC2=C(C(=O)NCC)N=C(C(F)(F)F)N21 PREZIENXKGSPQL-UHFFFAOYSA-N 0.000 description 3
- RHNYHTDFCOMIFJ-UHFFFAOYSA-N n-methyl-7-[3-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoyl]-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1=CC=C2C(CC=3C=CC=C(C=3)C(=O)N3CCN4C(=NC(=C4C3)C(=O)NC)C(F)(F)F)=NNC(=O)C2=C1 RHNYHTDFCOMIFJ-UHFFFAOYSA-N 0.000 description 3
- 238000011580 nude mouse model Methods 0.000 description 3
- 230000005731 poly ADP ribosylation Effects 0.000 description 3
- SWLIEGXUSVCMJU-UHFFFAOYSA-N pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone Chemical compound C=12CNCCN2C(C(F)(F)F)=NC=1C(=O)N1CCCC1 SWLIEGXUSVCMJU-UHFFFAOYSA-N 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- LFIXLKYOYVUDIN-UHFFFAOYSA-N tert-butyl 1-(cyclopropylmethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN(C(=N2)C(F)(F)F)C1=C2C(=O)NCC1CC1 LFIXLKYOYVUDIN-UHFFFAOYSA-N 0.000 description 3
- WWQRPSYDTKPSNG-UHFFFAOYSA-N tert-butyl 1-(dimethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CC2=C(C(=O)N(C)C)N=C(C(F)(F)F)N21 WWQRPSYDTKPSNG-UHFFFAOYSA-N 0.000 description 3
- ZOCDJNKXSQBQFD-UHFFFAOYSA-N tert-butyl 1-(morpholine-4-carbonyl)-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN(C(=N2)C(F)(F)F)C1=C2C(=O)N1CCOCC1 ZOCDJNKXSQBQFD-UHFFFAOYSA-N 0.000 description 3
- SVHZDIVYRFEIBI-UHFFFAOYSA-N tert-butyl 1-bromo-3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN2C(C(F)(F)F)=NC(Br)=C12 SVHZDIVYRFEIBI-UHFFFAOYSA-N 0.000 description 3
- OQUGNDVVOSOMMQ-UHFFFAOYSA-N tert-butyl 3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCN2C(C(F)(F)F)=NC=C12 OQUGNDVVOSOMMQ-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- NNXKANOZYSUQHF-UHFFFAOYSA-N 2,2-difluoroacetic acid;2,2-difluoro-n'-pyrazin-2-ylacetohydrazide Chemical compound OC(=O)C(F)F.FC(F)C(=O)NNC1=CN=CC=N1 NNXKANOZYSUQHF-UHFFFAOYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- 125000005916 2-methylpentyl group Chemical group 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- AQCSCRYRCRORET-UHFFFAOYSA-N 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;hydrochloride Chemical compound Cl.C1NCCN2C(C(F)(F)F)=NN=C21 AQCSCRYRCRORET-UHFFFAOYSA-N 0.000 description 2
- FJZQOTCIQIQNPT-UHFFFAOYSA-N 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine;hydrochloride Chemical compound Cl.C1NCCN2C(C(F)(F)F)=NC=C21 FJZQOTCIQIQNPT-UHFFFAOYSA-N 0.000 description 2
- LOEQJTGFMWZFBM-UHFFFAOYSA-N 3-[(4-oxo-3h-phthalazin-1-yl)methyl]benzoic acid Chemical compound OC(=O)C1=CC=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=C1 LOEQJTGFMWZFBM-UHFFFAOYSA-N 0.000 description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000005917 3-methylpentyl group Chemical group 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 102000053602 DNA Human genes 0.000 description 2
- 230000005971 DNA damage repair Effects 0.000 description 2
- 230000008265 DNA repair mechanism Effects 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010028851 Necrosis Diseases 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 102100023652 Poly [ADP-ribose] polymerase 2 Human genes 0.000 description 2
- 101710144590 Poly [ADP-ribose] polymerase 2 Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- 238000003149 assay kit Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 229940044683 chemotherapy drug Drugs 0.000 description 2
- 231100000244 chromosomal damage Toxicity 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 230000037041 intracellular level Effects 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- BXYSTRSZVRSMEV-UHFFFAOYSA-N n,n-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxamide Chemical compound C1CNCC2=C(C(=O)N(C)C)N=C(C(F)(F)F)N21 BXYSTRSZVRSMEV-UHFFFAOYSA-N 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 230000017074 necrotic cell death Effects 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- XFTQRUTUGRCSGO-UHFFFAOYSA-N pyrazin-2-amine Chemical compound NC1=CN=CC=N1 XFTQRUTUGRCSGO-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 125000003003 spiro group Chemical group 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- IYXUFOCLMOXQSL-UHFFFAOYSA-N (2,2-difluoroacetyl) 2,2-difluoroacetate Chemical compound FC(F)C(=O)OC(=O)C(F)F IYXUFOCLMOXQSL-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004972 1-butynyl group Chemical group [H]C([H])([H])C([H])([H])C#C* 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 125000000530 1-propynyl group Chemical group [H]C([H])([H])C#C* 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003660 2,3-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003764 2,4-dimethylpentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- RJVZEPWRJJBXLH-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-1-yl)acetic acid Chemical compound C1=CC=C2C(CC(=O)O)CCC2=C1 RJVZEPWRJJBXLH-UHFFFAOYSA-N 0.000 description 1
- GYIDIDSTOZMTCM-UHFFFAOYSA-N 2-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine Chemical compound C1NCCN2N=C(C(F)(F)F)N=C21 GYIDIDSTOZMTCM-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 125000000069 2-butynyl group Chemical group [H]C([H])([H])C#CC([H])([H])* 0.000 description 1
- QSKPIOLLBIHNAC-UHFFFAOYSA-N 2-chloro-acetaldehyde Chemical compound ClCC=O QSKPIOLLBIHNAC-UHFFFAOYSA-N 0.000 description 1
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical compound [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- 125000003229 2-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- FEDHJRCOTOFVSG-UHFFFAOYSA-N 3-(2,2,2-trifluoroethyl)-[1,2,4]triazolo[4,3-a]pyrazine Chemical compound C1=NC=CN2C(CC(F)(F)F)=NN=C21 FEDHJRCOTOFVSG-UHFFFAOYSA-N 0.000 description 1
- ONZQYZKCUHFORE-UHFFFAOYSA-N 3-bromo-1,1,1-trifluoropropan-2-one Chemical compound FC(F)(F)C(=O)CBr ONZQYZKCUHFORE-UHFFFAOYSA-N 0.000 description 1
- JNETYVLEGPSOFY-UHFFFAOYSA-N 3-bromopyrrolidine-2,5-dione Chemical compound BrC1CC(=O)NC1=O JNETYVLEGPSOFY-UHFFFAOYSA-N 0.000 description 1
- PRRZDZJYSJLDBS-UHFFFAOYSA-M 3-bromopyruvate Chemical compound [O-]C(=O)C(=O)CBr PRRZDZJYSJLDBS-UHFFFAOYSA-M 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000000474 3-butynyl group Chemical group [H]C#CC([H])([H])C([H])([H])* 0.000 description 1
- 125000004337 3-ethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003469 3-methylhexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- GFQHOURETBJHTJ-UHFFFAOYSA-N 4-[[3-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1=CC=C2C(CC=3C=CC=C(C=3)C(=O)N3CC4=NN=C(N4CC3)C(F)(F)F)=NNC(=O)C2=C1 GFQHOURETBJHTJ-UHFFFAOYSA-N 0.000 description 1
- GUZPUVOLIXQXJC-UHFFFAOYSA-N 4-[[4-fluoro-3-[2-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,2-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C=C(C(F)(F)F)N=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F GUZPUVOLIXQXJC-UHFFFAOYSA-N 0.000 description 1
- ZLCNXYFKIHRDHF-UHFFFAOYSA-N 4-[[4-fluoro-3-[3-(trifluoromethyl)-6,8-dihydro-5h-imidazo[1,5-a]pyrazine-7-carbonyl]phenyl]methyl]-2h-phthalazin-1-one Chemical compound C1CN2C(C(F)(F)F)=NC=C2CN1C(=O)C1=CC(CC=2C3=CC=CC=C3C(=O)NN=2)=CC=C1F ZLCNXYFKIHRDHF-UHFFFAOYSA-N 0.000 description 1
- DXJKRLHHCGXHMB-UHFFFAOYSA-N 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrazine Chemical compound C1NCCN2N=CN=C21 DXJKRLHHCGXHMB-UHFFFAOYSA-N 0.000 description 1
- NKEHUOIDQUKFDV-UHFFFAOYSA-N 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine;hydrochloride Chemical compound Cl.C1NCCN2C=NN=C21 NKEHUOIDQUKFDV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 230000005730 ADP ribosylation Effects 0.000 description 1
- SRNWOUGRCWSEMX-KEOHHSTQSA-N ADP-beta-D-ribose Chemical group C([C@H]1O[C@H]([C@@H]([C@@H]1O)O)N1C=2N=CN=C(C=2N=C1)N)OP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](O)[C@H](O)[C@@H]1O SRNWOUGRCWSEMX-KEOHHSTQSA-N 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FGTCGDNHZXPFEQ-LFVJCYFKSA-N CCNC(/C(/C)=C(\CN(CC1)C(C2=CC(CC(c3ccccc33)=NNC3=O)CC=C2F)=O)/N1C(C(F)(F)F)=C)O Chemical compound CCNC(/C(/C)=C(\CN(CC1)C(C2=CC(CC(c3ccccc33)=NNC3=O)CC=C2F)=O)/N1C(C(F)(F)F)=C)O FGTCGDNHZXPFEQ-LFVJCYFKSA-N 0.000 description 1
- ATZWXDWXCISHBE-UHFFFAOYSA-N CN1CC(CCC2)N2CC1 Chemical compound CN1CC(CCC2)N2CC1 ATZWXDWXCISHBE-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 230000007035 DNA breakage Effects 0.000 description 1
- 239000012623 DNA damaging agent Substances 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 1
- 208000031448 Genomic Instability Diseases 0.000 description 1
- 101000801643 Homo sapiens Retinal-specific phospholipid-transporting ATPase ABCA4 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 1
- HNVTXLUINORUTN-UHFFFAOYSA-N O=C(c1cc(CC(C2C=CC=CC22)=NNC2=O)ccc1F)N1Cc2nc(C(F)(F)F)c[n]2CC1 Chemical compound O=C(c1cc(CC(C2C=CC=CC22)=NNC2=O)ccc1F)N1Cc2nc(C(F)(F)F)c[n]2CC1 HNVTXLUINORUTN-UHFFFAOYSA-N 0.000 description 1
- GYZALKAJGXTNBA-UHFFFAOYSA-N OC1NN=C(Cc(cc2C(N3Cc4cnc(C(F)(F)F)[n]4CC3)=O)ccc2F)c2c1cccc2 Chemical compound OC1NN=C(Cc(cc2C(N3Cc4cnc(C(F)(F)F)[n]4CC3)=O)ccc2F)c2c1cccc2 GYZALKAJGXTNBA-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108091026813 Poly(ADPribose) Proteins 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 102100033617 Retinal-specific phospholipid-transporting ATPase ABCA4 Human genes 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 108020004682 Single-Stranded DNA Proteins 0.000 description 1
- 235000002597 Solanum melongena Nutrition 0.000 description 1
- 244000061458 Solanum melongena Species 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical class [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 208000003721 Triple Negative Breast Neoplasms Diseases 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- ADRAATATUANKTQ-UHFFFAOYSA-O [BH+]c1c(CN(CC2)C(c3cc(CC(C4C=CC=CC44)=NNC4=O)ccc3F)=O)[n]2c(C(F)(F)F)n1 Chemical compound [BH+]c1c(CN(CC2)C(c3cc(CC(C4C=CC=CC44)=NNC4=O)ccc3F)=O)[n]2c(C(F)(F)F)n1 ADRAATATUANKTQ-UHFFFAOYSA-O 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 208000012998 acute renal failure Diseases 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 238000010609 cell counting kit-8 assay Methods 0.000 description 1
- 230000022131 cell cycle Effects 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- PBAYDYUZOSNJGU-UHFFFAOYSA-N chelidonic acid Natural products OC(=O)C1=CC(=O)C=C(C(O)=O)O1 PBAYDYUZOSNJGU-UHFFFAOYSA-N 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000002188 cycloheptatrienyl group Chemical group C1(=CC=CC=CC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- IGSKHXTUVXSOMB-UHFFFAOYSA-N cyclopropylmethanamine Chemical compound NCC1CC1 IGSKHXTUVXSOMB-UHFFFAOYSA-N 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 229920000137 polyphosphoric acid Polymers 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical class [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000006916 protein interaction Effects 0.000 description 1
- IVRLZJDPKUSDCF-UHFFFAOYSA-N pyrazin-2-ylhydrazine Chemical compound NNC1=CN=CC=N1 IVRLZJDPKUSDCF-UHFFFAOYSA-N 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 239000011535 reaction buffer Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000008263 repair mechanism Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
-
- 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
-
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010248307.5 | 2010-08-09 | ||
| CN2010102483075A CN102372716A (zh) | 2010-08-09 | 2010-08-09 | 酞嗪酮类衍生物、其制备方法及其在医药上的应用 |
| PCT/CN2011/001223 WO2012019427A1 (zh) | 2010-08-09 | 2011-07-26 | 酞嗪酮类衍生物、其制备方法及其在医药上的应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2013106754A RU2013106754A (ru) | 2014-09-20 |
| RU2564527C2 true RU2564527C2 (ru) | 2015-10-10 |
Family
ID=45567315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2013106754/04A RU2564527C2 (ru) | 2010-08-09 | 2011-07-26 | Производное фталазинонкетона, способ его получения и его фармацевтическое применение |
Country Status (15)
| Country | Link |
|---|---|
| US (2) | US9273052B2 (OSRAM) |
| EP (1) | EP2604610B1 (OSRAM) |
| JP (1) | JP5808408B2 (OSRAM) |
| KR (1) | KR101829940B1 (OSRAM) |
| CN (2) | CN102372716A (OSRAM) |
| AU (1) | AU2011288876B2 (OSRAM) |
| BR (1) | BR112013002220B1 (OSRAM) |
| CA (1) | CA2806324C (OSRAM) |
| ES (1) | ES2582315T3 (OSRAM) |
| HU (1) | HUE029275T2 (OSRAM) |
| PL (1) | PL2604610T3 (OSRAM) |
| PT (1) | PT2604610T (OSRAM) |
| RU (1) | RU2564527C2 (OSRAM) |
| UA (1) | UA111161C2 (OSRAM) |
| WO (1) | WO2012019427A1 (OSRAM) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2777519C2 (ru) * | 2017-12-06 | 2022-08-05 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Применение ингибитора parp в лечении резистентного к химиотерапии рака яичников или рака молочной железы |
Families Citing this family (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102898377B (zh) * | 2012-02-14 | 2016-01-20 | 南京圣和药业股份有限公司 | 一类酞嗪酮衍生物及其用途 |
| CN102702108A (zh) * | 2012-06-27 | 2012-10-03 | 上海大学 | 1,2-二氢酞嗪类化合物及其合成方法 |
| CN103570725B (zh) * | 2012-08-01 | 2017-03-22 | 中国科学院上海药物研究所 | 哌嗪并三唑类化合物及其制备方法和用途 |
| CN102863393A (zh) * | 2012-09-26 | 2013-01-09 | 上海大学 | 1,2-二氢酞嗪类化合物及其合成方法 |
| CA2890309A1 (en) * | 2012-12-31 | 2014-07-03 | Cadila Healthcare Limited | Substituted phthalazin-1 (2h)-one derivatives as selective inhibitors of poly (adp-ribose) polymerase-1 |
| KR101670126B1 (ko) | 2013-09-13 | 2016-10-27 | 일동제약(주) | 신규 프탈라지논 유도체 및 그 제조방법 |
| AR098414A1 (es) | 2013-11-14 | 2016-05-26 | Bristol Myers Squibb Co | PIPERAZINAS DE PIRAZOLO SUSTITUIDO COMO INHIBIDORES DE CASEÍNA QUINASA 1 d/e |
| EP3325623B3 (en) | 2015-07-23 | 2021-01-20 | Institut Curie | Use of a combination of dbait molecule and parp inhibitors to treat cancer |
| KR102708936B1 (ko) | 2015-11-20 | 2024-09-25 | 포르마 세라퓨틱스 인크. | 유비퀴틴-특이적 프로테아제 1 억제제로서의 퓨리논 |
| CN106749261A (zh) * | 2015-11-23 | 2017-05-31 | 中国科学院上海药物研究所 | 一类取代三唑并哌嗪类parp抑制剂及其制备方法和用途 |
| CN107207504B (zh) * | 2015-12-16 | 2020-03-10 | 四川科伦博泰生物医药股份有限公司 | 酞嗪酮衍生物、其制备方法及用途 |
| US10722484B2 (en) | 2016-03-09 | 2020-07-28 | K-Gen, Inc. | Methods of cancer treatment |
| EP3549608A4 (en) | 2016-12-01 | 2020-08-12 | Jiangsu Hengrui Medicine Co., Ltd. | USE OF A COMBINATION OF A VEGFR INHIBITOR AND PARP INHIBITOR IN THE MANUFACTURING OF A MEDICINAL PRODUCT FOR TREATMENT OF STOMACH CANCER |
| WO2018162439A1 (en) | 2017-03-08 | 2018-09-13 | Onxeo | New predictive biomarker for the sensitivity to a treatment of cancer with a dbait molecule |
| JP6594570B2 (ja) | 2017-03-20 | 2019-10-23 | フォーマ セラピューティクス，インコーポレイテッド | ピルビン酸キナーゼ（ｐｋｒ）活性化剤としてのピロロピロール組成物 |
| JP7161490B2 (ja) * | 2017-04-12 | 2022-10-26 | エフ．ホフマン－ラ ロシュ アーゲー | アルデヒドを含有する標的分子を標識する方法 |
| TWI765086B (zh) * | 2017-08-24 | 2022-05-21 | 大陸商江蘇恒瑞醫藥股份有限公司 | Parp-1抑制劑的晶型及其製備方法 |
| EP3721906A4 (en) * | 2017-12-06 | 2021-08-04 | Jiangsu Hengrui Medicine Co., Ltd. | USE OF PARP INHIBITOR TO TREAT CHEMOTHERAPY RESISTANT OVAR CANCER OR BREAST CANCER |
| AU2019207072A1 (en) | 2018-01-09 | 2020-07-16 | Jiangsu Hengrui Medicine Co., Ltd. | Method for preparing PARP inhibitor and intermediate thereof |
| BR112020015230A2 (pt) | 2018-01-26 | 2021-01-26 | Recordati Industria Chimica E Farmaceutica S.P.A | derivados de piperazina condensados a triazol, imidazol e pirrol e seu uso como moduladores de receptores mglu5 |
| US11542282B2 (en) | 2018-02-28 | 2023-01-03 | The Trustees Of The University Of Pennsylvania | Low affinity poly(AD-ribose) polymerase 1 dependent cytotoxic agents |
| WO2019175132A1 (en) | 2018-03-13 | 2019-09-19 | Onxeo | A dbait molecule against acquired resistance in the treatment of cancer |
| JP7387627B2 (ja) * | 2018-03-29 | 2023-11-28 | ボード オブ レジェンツ，ザ ユニバーシティ オブ テキサス システム | 転写活性化タンパク質のイミダゾピペラジン阻害剤 |
| WO2020061378A1 (en) | 2018-09-19 | 2020-03-26 | Forma Therapeutics, Inc. | Treating sickle cell disease with a pyruvate kinase r activating compound |
| WO2020061255A1 (en) | 2018-09-19 | 2020-03-26 | Forma Therapeutics, Inc. | Activating pyruvate kinase r |
| TW202029961A (zh) * | 2018-10-22 | 2020-08-16 | 大陸商江蘇恒瑞醫藥股份有限公司 | Ar拮抗劑聯合parp抑制劑在製備治療前列腺癌的藥物中的用途 |
| EP3881846A4 (en) | 2018-11-16 | 2022-08-17 | Jiangsu Hengrui Medicine Co., Ltd. | PHARMACEUTICAL COMPOSITION WITH PARP INHIBITORS |
| WO2020238932A1 (zh) * | 2019-05-28 | 2020-12-03 | 江苏恒瑞医药股份有限公司 | Parp抑制剂联合vegfr抑制剂用于治疗卵巢癌或乳腺癌的用途 |
| AU2020350763A1 (en) | 2019-09-19 | 2022-04-07 | Novo Nordisk Health Care Ag | Pyruvate kinase R (PKR) activating compositions |
| CN112870365A (zh) * | 2019-11-29 | 2021-06-01 | 江苏恒瑞医药股份有限公司 | Ezh2抑制剂和/或parp抑制剂与化疗药物联合在制备治疗肿瘤药物中的用途 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| BR112022021321A2 (pt) | 2020-04-21 | 2022-12-20 | Idience Co Ltd | Formas cristalinas do composto de ftalazinona. |
| US12060345B2 (en) | 2020-04-21 | 2024-08-13 | Idience Co., Ltd. | Process for preparing a phthalazinone derivative and intermediates thereof |
| CN111732594B (zh) * | 2020-08-18 | 2022-03-04 | 苏州富士莱医药股份有限公司 | 一种氟唑帕利的制备方法 |
| US12059419B2 (en) | 2020-10-16 | 2024-08-13 | Idience Co., Ltd. | Pharmaceutical composition comprising phthalazinone derivatives |
| US12128035B2 (en) | 2021-03-19 | 2024-10-29 | Novo Nordisk Health Care Ag | Activating pyruvate kinase R |
| BR112023022496A2 (pt) * | 2021-05-24 | 2024-01-16 | Jiangsu Hengrui Pharmaceuticals Co Ltd | Composto heterocíclico contendo nitrogênio, método de preparação do mesmo, e aplicação do mesmo em medicamentos |
| EP4370125A4 (en) * | 2021-07-16 | 2025-10-01 | Univ Oregon Health & Science | PHTHALAZINONE-BASED PARP-1 INHIBITORS |
| CA3226796A1 (en) * | 2021-07-29 | 2023-02-02 | Xiaoxia Yan | Novel parp7 inhibitor and use thereof |
| CN115650988B (zh) * | 2022-10-27 | 2024-09-13 | 江苏恒瑞医药股份有限公司 | 一种parp抑制剂的制备方法 |
| TW202421139A (zh) * | 2022-11-23 | 2024-06-01 | 大陸商江蘇恆瑞醫藥股份有限公司 | 一種含氮雜環類化合物的可藥用鹽、晶型及製備方法 |
| WO2024188265A1 (zh) * | 2023-03-13 | 2024-09-19 | 江苏豪森药业集团有限公司 | 哌啶烯类化合物在制备治疗癌症的药物中的应用 |
| WO2024261243A1 (en) | 2023-06-21 | 2024-12-26 | Hemispherian As | Combination comprising a deoxycytidine derivative and a parp inhibitor for use in a method of treating hr proficient cancer |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2292337C2 (ru) * | 2002-02-19 | 2007-01-27 | Оно Фармасьютикал Ко., Лтд. | Конденсированные производные пиридазина и лекарственные препараты, содержащие данные соединения в качестве активного ингредиента |
| EA200971100A1 (ru) * | 2007-07-05 | 2010-06-30 | Астразенека Аб | Производные фталазинона в качестве ингибиторов поли(адф-рибоза)полимеразы (parp-1) |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2384776C (en) | 2000-10-30 | 2006-02-03 | Kudos Pharm Ltd | Phthalazinone derivatives |
| AR043443A1 (es) | 2003-03-07 | 2005-07-27 | Merck & Co Inc | Procedimiento de preparacion de tetrahidrotriazolopirazinas y productos intermedios |
| KR101146806B1 (ko) * | 2003-03-12 | 2012-05-22 | 메이브릿지 리미티드 | 프탈라지논 유도체 |
| GB0305681D0 (en) | 2003-03-12 | 2003-04-16 | Kudos Pharm Ltd | Phthalazinone derivatives |
| NZ553979A (en) | 2004-08-26 | 2009-05-31 | Kudos Pharm Ltd | 4-heteroarylmethyl substituted phthalazinone derivatives |
| GB0610680D0 (en) | 2006-05-31 | 2006-07-12 | Istituto Di Ricerche D Biolog | Therapeutic compounds |
| SI2698062T1 (sl) * | 2006-12-28 | 2015-12-31 | Abbvie Inc. | Inhibitorji poli (ADP-riboza) polimeraze |
| WO2009025784A1 (en) | 2007-08-21 | 2009-02-26 | Merck & Co., Inc. | Heterocyclic compounds as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| CN101468988A (zh) | 2007-12-26 | 2009-07-01 | 上海恒瑞医药有限公司 | 哌嗪类衍生物,其制备方法及其在医药上的应用 |
| CA2712266A1 (en) | 2008-01-17 | 2009-07-23 | Gruenenthal Gmbh | Substituted sulfonamide derivatives |
-
2010
- 2010-08-09 CN CN2010102483075A patent/CN102372716A/zh active Pending
-
2011
- 2011-07-26 HU HUE11815986A patent/HUE029275T2/en unknown
- 2011-07-26 CN CN201180003990.9A patent/CN102686591B/zh active Active
- 2011-07-26 KR KR1020137003185A patent/KR101829940B1/ko active Active
- 2011-07-26 AU AU2011288876A patent/AU2011288876B2/en active Active
- 2011-07-26 PL PL11815986.2T patent/PL2604610T3/pl unknown
- 2011-07-26 CA CA2806324A patent/CA2806324C/en active Active
- 2011-07-26 JP JP2013523468A patent/JP5808408B2/ja active Active
- 2011-07-26 BR BR112013002220-5A patent/BR112013002220B1/pt active IP Right Grant
- 2011-07-26 ES ES11815986.2T patent/ES2582315T3/es active Active
- 2011-07-26 US US13/811,957 patent/US9273052B2/en active Active
- 2011-07-26 PT PT118159862T patent/PT2604610T/pt unknown
- 2011-07-26 RU RU2013106754/04A patent/RU2564527C2/ru active
- 2011-07-26 UA UAA201301524A patent/UA111161C2/uk unknown
- 2011-07-26 WO PCT/CN2011/001223 patent/WO2012019427A1/zh not_active Ceased
- 2011-07-26 EP EP11815986.2A patent/EP2604610B1/en active Active
-
2016
- 2016-02-05 US US15/016,986 patent/US9566277B2/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2292337C2 (ru) * | 2002-02-19 | 2007-01-27 | Оно Фармасьютикал Ко., Лтд. | Конденсированные производные пиридазина и лекарственные препараты, содержащие данные соединения в качестве активного ингредиента |
| EA200971100A1 (ru) * | 2007-07-05 | 2010-06-30 | Астразенека Аб | Производные фталазинона в качестве ингибиторов поли(адф-рибоза)полимеразы (parp-1) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2792620C2 (ru) * | 2017-08-24 | 2023-03-22 | Цзянсу Хэнжуй Медисин Ко., Лтд. | Кристаллическая форма ингибитора parp-1 и способ ее получения |
| RU2777519C2 (ru) * | 2017-12-06 | 2022-08-05 | Цзянсу Хэнжуй Медицин Ко., Лтд. | Применение ингибитора parp в лечении резистентного к химиотерапии рака яичников или рака молочной железы |
| RU2777597C2 (ru) * | 2018-01-09 | 2022-08-08 | Цзянсу Хэнжуй Медисин Ко., Лтд. | Способ получения ингибитора parp и его промежуточного соединения |
Also Published As
| Publication number | Publication date |
|---|---|
| UA111161C2 (uk) | 2016-04-11 |
| BR112013002220B1 (pt) | 2021-09-21 |
| US9273052B2 (en) | 2016-03-01 |
| AU2011288876A2 (en) | 2013-02-21 |
| CN102686591B (zh) | 2014-03-19 |
| US20130131068A1 (en) | 2013-05-23 |
| ES2582315T3 (es) | 2016-09-12 |
| EP2604610A4 (en) | 2013-12-25 |
| US20160151367A1 (en) | 2016-06-02 |
| KR20130110149A (ko) | 2013-10-08 |
| JP2013535491A (ja) | 2013-09-12 |
| HUE029275T2 (en) | 2017-02-28 |
| AU2011288876B2 (en) | 2014-08-21 |
| JP5808408B2 (ja) | 2015-11-10 |
| BR112013002220A2 (pt) | 2016-05-24 |
| WO2012019427A8 (zh) | 2012-05-10 |
| EP2604610B1 (en) | 2016-05-11 |
| CN102686591A (zh) | 2012-09-19 |
| AU2011288876A1 (en) | 2013-01-31 |
| US9566277B2 (en) | 2017-02-14 |
| CA2806324C (en) | 2019-02-19 |
| HK1174030A1 (en) | 2013-05-31 |
| PT2604610T (pt) | 2016-07-13 |
| RU2013106754A (ru) | 2014-09-20 |
| PL2604610T3 (pl) | 2016-11-30 |
| KR101829940B1 (ko) | 2018-02-19 |
| EP2604610A1 (en) | 2013-06-19 |
| WO2012019427A1 (zh) | 2012-02-16 |
| CA2806324A1 (en) | 2012-02-16 |
| CN102372716A (zh) | 2012-03-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2564527C2 (ru) | Производное фталазинонкетона, способ его получения и его фармацевтическое применение | |
| ES2590682T3 (es) | Derivados heterocíclicos, procesos de preparación y usos médicos de los mismos | |
| CN102762549B (zh) | 酞嗪酮类衍生物、其制备方法及其在医药上的应用 | |
| JP2019522055A (ja) | Ｆｇｆｒ阻害剤として使用される複素環式化合物 | |
| EA028175B1 (ru) | Производные пиразолопирролидин-4-она в качестве ингибиторов вет и их применение при лечении заболевания | |
| JP6670913B2 (ja) | 白血病を予防および治療するためのマレイミド誘導体の使用 | |
| CN116514846A (zh) | 杂环类衍生物、其制备方法及其医药上的用途 | |
| CN116162099A (zh) | 杂环类衍生物及其制备方法和用途 | |
| CN106187915A (zh) | 具有alk与egfr双重活性的抑制剂及其制备方法和应用 | |
| CN116157401B (zh) | 杂环类衍生物及其制备方法和用途 | |
| CN116157400B (zh) | 杂环类衍生物及其制备方法和用途 | |
| JP2023530768A (ja) | Ｆｇｆｒおよびその突然変異阻害剤、その製造方法と応用 | |
| CN113518779B (zh) | 噻吩并杂环类衍生物、其制备方法及其在医药上的应用 | |
| TWI548637B (zh) | 酞嗪酮類衍生物、其製備方法及其在醫藥上的應用 | |
| WO2014106763A1 (en) | Pyridopyrazines as anticancer agents | |
| KR102649886B1 (ko) | 신규한 피리미딘-4-온 화합물 및 이를 포함하는 항암제 조성물 | |
| HK1174030B (en) | Phthalazinone ketone derivative, preparation method thereof, and pharmaceutical use thereof | |
| CN105461733A (zh) | (2,4-二羟基-5-异丙基苯基)(4,6-二氢-5H-噻吩并[2,3-c]吡咯-5-基)甲酮类衍生物及其制备和应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PC41 | Official registration of the transfer of exclusive right |
Effective date: 20200521 |