HUE029275T2 - Phthalazinone ketone derivative, method of preparation and therapeutic use - Google Patents
Phthalazinone ketone derivative, method of preparation and therapeutic use Download PDFInfo
- Publication number
- HUE029275T2 HUE029275T2 HUE11815986A HUE11815986A HUE029275T2 HU E029275 T2 HUE029275 T2 HU E029275T2 HU E11815986 A HUE11815986 A HU E11815986A HU E11815986 A HUE11815986 A HU E11815986A HU E029275 T2 HUE029275 T2 HU E029275T2
- Authority
- HU
- Hungary
- Prior art keywords
- group
- pyrazine
- mmol
- formula
- trifluoromethyl
- Prior art date
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- -1 Phthalazinone ketone Chemical class 0.000 title claims description 75
- 238000002360 preparation method Methods 0.000 title claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 104
- 125000000217 alkyl group Chemical group 0.000 claims description 79
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 125000000623 heterocyclic group Chemical group 0.000 claims description 71
- 229910052757 nitrogen Inorganic materials 0.000 claims description 64
- 125000003118 aryl group Chemical group 0.000 claims description 57
- 125000001072 heteroaryl group Chemical group 0.000 claims description 57
- 229910052736 halogen Inorganic materials 0.000 claims description 53
- 150000002367 halogens Chemical class 0.000 claims description 52
- 150000003839 salts Chemical class 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 48
- 206010028980 Neoplasm Diseases 0.000 claims description 40
- 125000003545 alkoxy group Chemical group 0.000 claims description 37
- 201000011510 cancer Diseases 0.000 claims description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 25
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 24
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 14
- 206010006187 Breast cancer Diseases 0.000 claims description 13
- 208000026310 Breast neoplasm Diseases 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 206010009944 Colon cancer Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 239000002671 adjuvant Substances 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 206010033128 Ovarian cancer Diseases 0.000 claims description 7
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 7
- 206010060862 Prostate cancer Diseases 0.000 claims description 7
- 238000002512 chemotherapy Methods 0.000 claims description 7
- 208000029742 colonic neoplasm Diseases 0.000 claims description 7
- 125000005842 heteroatom Chemical group 0.000 claims description 7
- 230000005865 ionizing radiation Effects 0.000 claims description 7
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 6
- 208000000236 Prostatic Neoplasms 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
- 201000002528 pancreatic cancer Diseases 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 229940122308 MRP inhibitor Drugs 0.000 claims 1
- 150000001735 carboxylic acids Chemical class 0.000 claims 1
- 210000003238 esophagus Anatomy 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- 125000004438 haloalkoxy group Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 210000004303 peritoneum Anatomy 0.000 claims 1
- 230000001235 sensitizing effect Effects 0.000 claims 1
- HBMJWWWQQXIZIP-UHFFFAOYSA-N silicon carbide Chemical compound [Si+]#[C-] HBMJWWWQQXIZIP-UHFFFAOYSA-N 0.000 claims 1
- 229910010271 silicon carbide Inorganic materials 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 83
- 239000011541 reaction mixture Substances 0.000 description 81
- 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- 239000007787 solid Substances 0.000 description 48
- 239000000243 solution Substances 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 36
- 239000000706 filtrate Substances 0.000 description 33
- 238000004809 thin layer chromatography Methods 0.000 description 32
- 238000006243 chemical reaction Methods 0.000 description 31
- 238000010828 elution Methods 0.000 description 29
- 230000000694 effects Effects 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
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 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 20
- 229920000776 Poly(Adenosine diphosphate-ribose) polymerase Polymers 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 19
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- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 17
- 239000005711 Benzoic acid Substances 0.000 description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 16
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 16
- 235000010233 benzoic acid Nutrition 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 230000005764 inhibitory process Effects 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- 239000012661 PARP inhibitor Substances 0.000 description 12
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 12
- 238000003556 assay Methods 0.000 description 12
- 150000002431 hydrogen Chemical class 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 210000004881 tumor cell Anatomy 0.000 description 12
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 11
- 125000002619 bicyclic group Chemical group 0.000 description 11
- 125000003367 polycyclic group Chemical group 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 230000005778 DNA damage Effects 0.000 description 10
- 231100000277 DNA damage Toxicity 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000003342 alkenyl group Chemical group 0.000 description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 10
- 125000000304 alkynyl group Chemical group 0.000 description 10
- 229940079593 drug Drugs 0.000 description 10
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 9
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000006413 ring segment Chemical group 0.000 description 9
- 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 8
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- 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
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 8
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- 150000003573 thiols Chemical class 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
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- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 7
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- 125000004414 alkyl thio group Chemical group 0.000 description 7
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- 241001465754 Metazoa Species 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
- 230000002401 inhibitory effect Effects 0.000 description 6
- 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 6
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- 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 5
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- 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
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- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
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- 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
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- 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
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Landscapes
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- Nitrogen Condensed Heterocyclic Rings (AREA)
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Applications Claiming Priority (1)
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| 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 |
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| HUE029275T2 true HUE029275T2 (en) | 2017-02-28 |
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| HUE11815986A HUE029275T2 (en) | 2010-08-09 | 2011-07-26 | Phthalazinone ketone derivative, method of preparation and therapeutic use |
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| PL3325623T6 (pl) | 2015-07-23 | 2022-05-30 | Institut Curie | Zastosowanie skojarzenia cząsteczki dbait i inhibitorów parp do leczenia nowotworu |
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| WO2017101796A1 (zh) * | 2015-12-16 | 2017-06-22 | 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 |
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| CA3088288A1 (en) * | 2018-01-26 | 2019-08-01 | Recordati Industria Chimica E Farmaceutica S.P.A | Triazole, imidazole and pyrrole condensed piperazine derivatives and their use as modulators of mglu5 receptors |
| JP2021516229A (ja) * | 2018-02-28 | 2021-07-01 | ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア | 低親和性ポリ（ａｄ−リボース）ポリメラーゼ１依存性細胞毒性剤 |
| CN111819282A (zh) | 2018-03-13 | 2020-10-23 | 欧恩科斯欧公司 | 对抗癌症治疗中获得性耐药性的Dbait分子 |
| CN112165944B (zh) * | 2018-03-29 | 2024-04-09 | 德州大学系统董事会 | 转录激活蛋白的咪唑并哌嗪抑制剂 |
| ES2989438T3 (es) | 2018-09-19 | 2024-11-26 | Novo Nordisk Healthcare Ag | Activación de la piruvato cinasa R |
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| WO2020083187A1 (zh) * | 2018-10-22 | 2020-04-30 | 江苏恒瑞医药股份有限公司 | 一种ar拮抗剂联合parp抑制剂在制备治疗前列腺癌的药物中的用途 |
| CN115400087B (zh) * | 2018-11-16 | 2023-10-20 | 江苏恒瑞医药股份有限公司 | 一种包含parp抑制剂的药物组合物 |
| TW202110448A (zh) * | 2019-05-28 | 2021-03-16 | 大陸商江蘇恆瑞醫藥股份有限公司 | Ｐａｒｐ抑制劑聯合ｖｅｇｆｒ抑制劑用於治療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 |
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| 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 |
| MX2023013890A (es) * | 2021-05-24 | 2023-12-11 | Jiangsu Hengrui Pharmaceuticals Co Ltd | Compuesto heterociclico que contiene nitrogeno, metodo de preparacion del mismo y aplicacion del mismo en medicamentos. |
| US20240317762A1 (en) * | 2021-07-16 | 2024-09-26 | Oregon Health & Science University | Phthalazinone-based parp-1 inhibitors |
| TW202321224A (zh) * | 2021-07-29 | 2023-06-01 | 大陸商上海齊魯製藥研究中心有限公司 | 新型parp7抑制劑及其應用 |
| 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 |
| TW202502341A (zh) * | 2023-03-13 | 2025-01-16 | 大陸商江蘇豪森藥業集團有限公司 | 哌啶烯類化合物在製備治療癌症的藥物中的應用 |
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| MXPA03003218A (es) | 2000-10-30 | 2004-12-03 | Kudos Pharm Ltd | Derivados de ftalazinona. |
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| AR043443A1 (es) | 2003-03-07 | 2005-07-27 | Merck & Co Inc | Procedimiento de preparacion de tetrahidrotriazolopirazinas y productos intermedios |
| GB0305681D0 (en) | 2003-03-12 | 2003-04-16 | Kudos Pharm Ltd | Phthalazinone derivatives |
| HRP20050895B1 (hr) * | 2003-03-12 | 2014-06-06 | Kudos Pharmaceuticals Limited | Ftalazinon derivati |
| MX2007002318A (es) | 2004-08-26 | 2007-04-17 | Kudos Pharm Ltd | Derivados de ftalazinona substituidos con 4-heteroarilmetilo. |
| GB0610680D0 (en) * | 2006-05-31 | 2006-07-12 | Istituto Di Ricerche D Biolog | Therapeutic compounds |
| SI2120579T1 (sl) * | 2006-12-28 | 2014-03-31 | Abbvie Inc. | Inhibitorji poli (adp-riboze)polimeraze |
| US20090023727A1 (en) * | 2007-07-05 | 2009-01-22 | Muhammad Hashim Javaid | Phthalazinone derivatives |
| CA2696211C (en) | 2007-08-21 | 2015-05-26 | Merck Sharp & Dohme Corp. | 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 |
| EP2229394A1 (en) | 2008-01-17 | 2010-09-22 | Grünenthal GmbH | Substituted sulfonamide derivatives |
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| UA111161C2 (uk) | 2016-04-11 |
| US9566277B2 (en) | 2017-02-14 |
| EP2604610A4 (en) | 2013-12-25 |
| CN102686591A (zh) | 2012-09-19 |
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| AU2011288876A1 (en) | 2013-01-31 |
| CA2806324A1 (en) | 2012-02-16 |
| CN102686591B (zh) | 2014-03-19 |
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| PL2604610T3 (pl) | 2016-11-30 |
| PT2604610T (pt) | 2016-07-13 |
| BR112013002220B1 (pt) | 2021-09-21 |
| US9273052B2 (en) | 2016-03-01 |
| KR20130110149A (ko) | 2013-10-08 |
| EP2604610B1 (en) | 2016-05-11 |
| AU2011288876B2 (en) | 2014-08-21 |
| JP5808408B2 (ja) | 2015-11-10 |
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| CN102372716A (zh) | 2012-03-14 |
| RU2013106754A (ru) | 2014-09-20 |
| ES2582315T3 (es) | 2016-09-12 |
| WO2012019427A1 (zh) | 2012-02-16 |
| CA2806324C (en) | 2019-02-19 |
| WO2012019427A8 (zh) | 2012-05-10 |
| KR101829940B1 (ko) | 2018-02-19 |
| BR112013002220A2 (pt) | 2016-05-24 |
| HK1174030A1 (en) | 2013-05-31 |
| US20160151367A1 (en) | 2016-06-02 |
| EP2604610A1 (en) | 2013-06-19 |
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