TWI541244B - 咪唑三酮化合物 - Google Patents
咪唑三酮化合物 Download PDFInfo
- Publication number
- TWI541244B TWI541244B TW100133825A TW100133825A TWI541244B TW I541244 B TWI541244 B TW I541244B TW 100133825 A TW100133825 A TW 100133825A TW 100133825 A TW100133825 A TW 100133825A TW I541244 B TWI541244 B TW I541244B
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- Taiwan
- Prior art keywords
- alkyl
- group
- mmol
- etoac
- imidazo
- Prior art date
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- IJYHVZICHKCLMQ-UHFFFAOYSA-N imidazo[4,5-d]triazin-4-one Chemical class O=C1N=NN=C2N=CN=C12 IJYHVZICHKCLMQ-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 163
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 71
- 201000010099 disease Diseases 0.000 claims description 69
- 101100407341 Drosophila melanogaster Pde9 gene Proteins 0.000 claims description 42
- 150000003839 salts Chemical class 0.000 claims description 40
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 239000003814 drug Substances 0.000 claims description 24
- 208000024827 Alzheimer disease Diseases 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 16
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 298
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 287
- -1 ketone compound Chemical class 0.000 description 205
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 196
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 188
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 170
- 235000019439 ethyl acetate Nutrition 0.000 description 152
- 239000000243 solution Substances 0.000 description 142
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 140
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 135
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 128
- 239000011541 reaction mixture Substances 0.000 description 124
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 117
- 239000000460 chlorine Substances 0.000 description 112
- 238000004809 thin layer chromatography Methods 0.000 description 86
- 238000005481 NMR spectroscopy Methods 0.000 description 85
- 239000000203 mixture Substances 0.000 description 78
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 77
- 230000015572 biosynthetic process Effects 0.000 description 75
- 238000005160 1H NMR spectroscopy Methods 0.000 description 74
- 238000003786 synthesis reaction Methods 0.000 description 74
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 74
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 71
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 71
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 71
- 238000003756 stirring Methods 0.000 description 63
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 61
- 238000004128 high performance liquid chromatography Methods 0.000 description 57
- 230000003287 optical effect Effects 0.000 description 57
- 239000012071 phase Substances 0.000 description 57
- 229910052736 halogen Inorganic materials 0.000 description 55
- 150000002367 halogens Chemical class 0.000 description 55
- 239000012044 organic layer Substances 0.000 description 54
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 52
- 239000012298 atmosphere Substances 0.000 description 49
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
- 239000013058 crude material Substances 0.000 description 48
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 46
- 125000001424 substituent group Chemical group 0.000 description 46
- 238000000034 method Methods 0.000 description 45
- 125000000217 alkyl group Chemical group 0.000 description 44
- 230000002829 reductive effect Effects 0.000 description 44
- 239000007864 aqueous solution Substances 0.000 description 43
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 43
- 125000001072 heteroaryl group Chemical group 0.000 description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 41
- 235000002639 sodium chloride Nutrition 0.000 description 40
- 239000007787 solid Substances 0.000 description 38
- 125000000000 cycloalkoxy group Chemical group 0.000 description 37
- OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 36
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 34
- 229910052938 sodium sulfate Inorganic materials 0.000 description 34
- 235000011152 sodium sulphate Nutrition 0.000 description 34
- 239000000725 suspension Substances 0.000 description 30
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 28
- 239000002904 solvent Substances 0.000 description 28
- PGJLOGNVZGRMGX-UHFFFAOYSA-L iron(2+);trifluoromethanesulfonate Chemical compound [Fe+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F PGJLOGNVZGRMGX-UHFFFAOYSA-L 0.000 description 27
- 229920006395 saturated elastomer Polymers 0.000 description 27
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 26
- 229910052731 fluorine Inorganic materials 0.000 description 26
- 239000007858 starting material Substances 0.000 description 26
- 125000000753 cycloalkyl group Chemical group 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 24
- 229910052799 carbon Inorganic materials 0.000 description 23
- 125000003118 aryl group Chemical group 0.000 description 22
- 229910052801 chlorine Inorganic materials 0.000 description 22
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 22
- 239000003039 volatile agent Substances 0.000 description 22
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 21
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- 238000003818 flash chromatography Methods 0.000 description 20
- 238000009472 formulation Methods 0.000 description 20
- 239000000651 prodrug Substances 0.000 description 20
- 229940002612 prodrug Drugs 0.000 description 20
- 238000000746 purification Methods 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 19
- 239000013078 crystal Substances 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 19
- 238000006467 substitution reaction Methods 0.000 description 19
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- 125000006413 ring segment Chemical group 0.000 description 17
- 239000011734 sodium Substances 0.000 description 17
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 16
- 125000005842 heteroatom Chemical group 0.000 description 16
- 125000002950 monocyclic group Chemical group 0.000 description 16
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 15
- 229910052757 nitrogen Inorganic materials 0.000 description 15
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 15
- 125000003226 pyrazolyl group Chemical group 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- 229910052708 sodium Inorganic materials 0.000 description 14
- 208000024891 symptom Diseases 0.000 description 14
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 13
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 13
- 125000004076 pyridyl group Chemical group 0.000 description 13
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 12
- 239000012267 brine Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 12
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- 239000000463 material Substances 0.000 description 11
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- 125000003386 piperidinyl group Chemical group 0.000 description 11
- 230000008569 process Effects 0.000 description 11
- 230000000946 synaptic effect Effects 0.000 description 11
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 10
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 10
- 239000005909 Kieselgur Substances 0.000 description 10
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 10
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- 125000003282 alkyl amino group Chemical group 0.000 description 9
- 125000005605 benzo group Chemical group 0.000 description 9
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- MSFVEEFXECBJPG-UHFFFAOYSA-N 2-(chloromethyl)pyrimidine Chemical compound ClCC1=NC=CC=N1 MSFVEEFXECBJPG-UHFFFAOYSA-N 0.000 description 8
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
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- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 6
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- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
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Classifications
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
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| Publication number | Priority date | Publication date | Assignee | Title |
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| AU2011305568B2 (en) | 2010-09-20 | 2015-12-10 | Ironwood Pharmaceuticals, Inc. | Imidazotriazinone compounds |
| CN106905324B (zh) * | 2011-10-10 | 2018-09-25 | H.隆德贝克有限公司 | 具有咪唑并吡嗪酮骨架的pde9抑制剂 |
| CN104093720B (zh) * | 2012-01-26 | 2017-04-12 | H.隆德贝克有限公司 | 具有咪唑并三嗪酮骨架的pde9抑制剂 |
| HK1206726A1 (en) | 2012-03-19 | 2016-01-15 | Ironwood Pharmaceuticals, Inc. | Imidazotriazinone compounds |
| WO2014024125A1 (en) | 2012-08-08 | 2014-02-13 | Celon Pharma S.A. | Pyrazolo[4,3-d]pyrimidin-7(6h)-one derivatives as pde9 inhibitors |
| CN102786525B (zh) | 2012-08-08 | 2014-12-17 | 中山大学 | N-取代吡唑并[3,4-d]嘧啶酮类化合物、其制备方法及其应用 |
| CN104884449A (zh) | 2012-10-31 | 2015-09-02 | 拜尔农作物科学股份公司 | 作为害虫防治剂的新的杂环化合物 |
| TW201629064A (zh) | 2014-10-10 | 2016-08-16 | Ｈ 朗德貝克公司 | 作爲ｐｄｅ１抑制劑之三唑並吡酮 |
| US20180044343A1 (en) * | 2015-03-16 | 2018-02-15 | Sumitomo Dainippon Pharma Co., Ltd. | Bicyclic imidazolo derivative |
| US20160311831A1 (en) * | 2015-04-22 | 2016-10-27 | H. Lundbeck A/S | Imidazotriazinones as PDE1 Inhibitors |
| JO3627B1 (ar) | 2015-04-30 | 2020-08-27 | H Lundbeck As | إيميدازو بيرازينونات على هيئة مثبطات pde1 |
| BR112018000254A2 (pt) | 2015-07-07 | 2018-09-04 | H Lundbeck As | inibidores de pde9 com cadeia principal de imidazotriazinona e cadeia principal de imidazopirazinona para o tratamento de doenças periféricas |
| WO2017070293A1 (en) * | 2015-10-20 | 2017-04-27 | Ironwood Pharmaceuticals, Inc. | Phosphodiesterase 9 inhibitor and levodopa therapy |
| CN105669680B (zh) * | 2016-03-24 | 2018-02-23 | 南京药捷安康生物科技有限公司 | 吡咯并[2,1‑f][1,2,4]三嗪‑4(1H)‑酮衍生物类PDE9A抑制剂 |
| TWI729109B (zh) | 2016-04-12 | 2021-06-01 | 丹麥商Ｈ 朗德貝克公司 | 作爲PDE1抑制劑的1,5-二氫-4H-吡唑并[3,4-d]嘧啶-4-酮和1,5-二氫-4H-吡唑并[4,3-c]吡啶-4-酮 |
| AU2017292650A1 (en) | 2016-07-06 | 2018-12-13 | H. Lundbeck A/S | PDE9 inhibitors for treatment of peripheral diseases |
| EP3529250B1 (en) | 2016-10-18 | 2023-12-06 | H. Lundbeck A/S | Imidazopyrazinones, pyrazolopyrimidinones and pyrazolopyridinones as pde1 inhibitors |
| SG11201903770UA (en) | 2016-10-28 | 2019-05-30 | H Lundbeck As | Combination treatments comprising imidazopyrazinones for the treatment of psychiatric and/or cognitive disorders |
| BR112018013084A2 (pt) | 2016-10-28 | 2018-12-11 | H Lundbeck As | tratamentos de combinação compreendendo a administração de imidazopirazinonas |
| SI3630772T1 (sl) | 2017-05-26 | 2024-05-31 | Cardurion Pharmaceuticals, Inc., | Postopki izdelave in uporabe zaviralcev pde9 |
| EP3801526B1 (en) | 2018-05-25 | 2023-12-27 | Imara Inc. | Monohydrate and crystalline forms of 6-[(3s,4s)-4-methyl-1- (pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-3-tetrahydropyran-4-yl- 7h-imid azo [1,5- a] pyrazin-8-one |
| CN112996512B (zh) | 2018-08-31 | 2025-01-03 | 卡都瑞恩医药公司 | 用于治疗镰状细胞病的pde9抑制剂 |
| US20220041667A1 (en) * | 2018-11-14 | 2022-02-10 | The Board Of Trustees Of The Leland Stanford Junior University | Targeting of makap-pde4d3 complexes in neurodegenerative disease |
| KR102712818B1 (ko) * | 2018-12-06 | 2024-09-30 | 한국화학연구원 | Pde9a 저해 활성을 가지는 화합물 및 이들의 의약 용도 |
| EP4049661A4 (en) * | 2019-10-21 | 2023-11-08 | SK Biopharmaceuticals Co., Ltd. | USE OF AN IMIDAZOPYRIMIDINE OR IMIDAZOTRIAZINE COMPOUND TO PREVENT, RELIEF OR TREAT DEVELOPMENTAL DISABILITIES |
| CN112724079A (zh) * | 2021-02-04 | 2021-04-30 | 康化（上海）新药研发有限公司 | 一种6-甲氧基吡啶甲酸甲酯的合成方法 |
| GB2632307A (en) * | 2023-08-02 | 2025-02-05 | Duke Street Bio Ltd | PARP1 inhibitor compounds |
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| PT72878B (en) | 1980-04-24 | 1983-03-29 | Merck & Co Inc | Process for preparing mannich-base hydroxamic acid pro-drugs for the improved delivery of non-steroidal anti-inflammatory agents |
| TR200001338T2 (tr) | 1997-11-12 | 2000-08-21 | Bayer Aktiengesellschaft | 2-Fenil-ikameli imidazotriazinonlar |
| DE19750085A1 (de) * | 1997-11-12 | 1999-05-20 | Bayer Ag | 2-Phenyl-substituierte Imidazotriazinone |
| GB0113343D0 (en) * | 2001-06-01 | 2001-07-25 | Bayer Ag | Novel Heterocycles 2 |
| US7087605B2 (en) | 2001-06-01 | 2006-08-08 | Bayer Aktiengesellschaft | 5-Ethyl-imidazotriazinones |
| JP2005508978A (ja) * | 2001-11-02 | 2005-04-07 | ファイザー・プロダクツ・インク | Ｐｄｅ９阻害薬によるインスリン抵抗性症候群及び２型糖尿病の治療 |
| DE10229778A1 (de) * | 2002-07-03 | 2004-01-29 | Bayer Ag | Neue Verwendung von Imidazotriazinonen |
| CA2514733A1 (en) | 2003-02-28 | 2004-09-16 | Transform Pharmaceuticals, Inc. | Pharmaceutical co-crystal compositions of drugs such as carbamazepine, celecoxib, olanzapine, itraconazole, topiramate, modafinil, 5-fluorouracil, hydrochlorothiazide, acetaminophen, aspirin, flurbiprofen, phenytoin and ibuprofen |
| US20040220186A1 (en) | 2003-04-30 | 2004-11-04 | Pfizer Inc. | PDE9 inhibitors for treating type 2 diabetes,metabolic syndrome, and cardiovascular disease |
| WO2006127368A2 (en) | 2005-05-20 | 2006-11-30 | Lexicon Genetics Incorporated | Methods for synthesizing imidazotriazinones |
| EP1896476A2 (en) | 2005-06-28 | 2008-03-12 | Orchid Research Laboratories Limited | Novel pyrazolopyrimidinone derivatives |
| MX2009011830A (es) * | 2007-05-11 | 2009-11-13 | Pfizer | Compuestos amino-heterociclicos. |
| BRPI0914772A2 (pt) | 2008-06-25 | 2015-10-20 | Envivo Pharmaceuticals Inc | compostos heterocíclicos 1,2-dissubstituídos |
| AU2011305568B2 (en) | 2010-09-20 | 2015-12-10 | Ironwood Pharmaceuticals, Inc. | Imidazotriazinone compounds |
| CN104093720B (zh) | 2012-01-26 | 2017-04-12 | H.隆德贝克有限公司 | 具有咪唑并三嗪酮骨架的pde9抑制剂 |
| HK1206726A1 (en) | 2012-03-19 | 2016-01-15 | Ironwood Pharmaceuticals, Inc. | Imidazotriazinone compounds |
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| AR083058A1 (es) | 2013-01-30 |
| EP3181566A1 (en) | 2017-06-21 |
| RU2603140C2 (ru) | 2016-11-20 |
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| UY33616A (es) | 2012-04-30 |
| CN103313988A (zh) | 2013-09-18 |
| US20140330014A1 (en) | 2014-11-06 |
| EP2619208B1 (en) | 2016-11-09 |
| CN103313988B (zh) | 2016-06-08 |
| AU2011305568A1 (en) | 2013-04-04 |
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| TW201217381A (en) | 2012-05-01 |
| CA2811714A1 (en) | 2012-03-29 |
| BR112013008140A8 (pt) | 2018-04-03 |
| PL2619208T3 (pl) | 2017-03-31 |
| EP2619208A1 (en) | 2013-07-31 |
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| CA2811714C (en) | 2017-11-21 |
| AU2016200970A1 (en) | 2016-03-03 |
| US20170152265A1 (en) | 2017-06-01 |
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| JP2013540755A (ja) | 2013-11-07 |
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| HK1187908A1 (en) | 2014-04-17 |
| ES2610360T3 (es) | 2017-04-27 |
| AU2011305568B2 (en) | 2015-12-10 |
| MX2013003093A (es) | 2013-10-28 |
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