CA2899091A1 - Compounds - Google Patents
Compounds Download PDFInfo
- Publication number
- CA2899091A1 CA2899091A1 CA2899091A CA2899091A CA2899091A1 CA 2899091 A1 CA2899091 A1 CA 2899091A1 CA 2899091 A CA2899091 A CA 2899091A CA 2899091 A CA2899091 A CA 2899091A CA 2899091 A1 CA2899091 A1 CA 2899091A1
- Authority
- CA
- Canada
- Prior art keywords
- pyrimidin
- dihydroimidazo
- esi
- mmol
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 412
- 238000000034 method Methods 0.000 claims abstract description 269
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 87
- 201000010099 disease Diseases 0.000 claims abstract description 84
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 27
- 238000011282 treatment Methods 0.000 claims abstract description 22
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims description 102
- 229910052739 hydrogen Inorganic materials 0.000 claims description 57
- 229910052731 fluorine Inorganic materials 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 31
- 125000001424 substituent group Chemical group 0.000 claims description 29
- -1 R c is H Chemical group 0.000 claims description 26
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 25
- 230000004770 neurodegeneration Effects 0.000 claims description 23
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- 125000004076 pyridyl group Chemical group 0.000 claims description 19
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 15
- 239000003814 drug Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 238000002560 therapeutic procedure Methods 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- WCYWZMWISLQXQU-FIBGUPNXSA-N trideuteriomethane Chemical compound [2H][C]([2H])[2H] WCYWZMWISLQXQU-FIBGUPNXSA-N 0.000 claims description 7
- 239000012458 free base Substances 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 125000001475 halogen functional group Chemical group 0.000 claims 7
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 108010024976 Asparaginase Proteins 0.000 abstract description 82
- 102000016752 1-Alkyl-2-acetylglycerophosphocholine Esterase Human genes 0.000 abstract description 78
- 239000000203 mixture Substances 0.000 abstract description 39
- 230000000694 effects Effects 0.000 abstract description 27
- 230000008569 process Effects 0.000 abstract description 19
- 238000002360 preparation method Methods 0.000 abstract description 9
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 236
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 87
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 87
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 86
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 84
- 239000011541 reaction mixture Substances 0.000 description 82
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 79
- 239000000243 solution Substances 0.000 description 76
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 71
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 52
- 238000000746 purification Methods 0.000 description 47
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 46
- 239000007787 solid Substances 0.000 description 46
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 43
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 39
- 238000003556 assay Methods 0.000 description 37
- 239000000047 product Substances 0.000 description 33
- YHPVIBUEXBEHPV-UHFFFAOYSA-N 2,6-dihydro-1h-pyrimidin-5-one Chemical compound O=C1CNCN=C1 YHPVIBUEXBEHPV-UHFFFAOYSA-N 0.000 description 32
- 229940093499 ethyl acetate Drugs 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 32
- 229910052938 sodium sulfate Inorganic materials 0.000 description 32
- 235000011152 sodium sulphate Nutrition 0.000 description 32
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 239000003112 inhibitor Substances 0.000 description 28
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 26
- 239000007832 Na2SO4 Substances 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 230000008499 blood brain barrier function Effects 0.000 description 20
- 210000001218 blood-brain barrier Anatomy 0.000 description 20
- 125000005843 halogen group Chemical group 0.000 description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 19
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 18
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 18
- 201000004810 Vascular dementia Diseases 0.000 description 17
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 239000012267 brine Substances 0.000 description 15
- 239000012043 crude product Substances 0.000 description 14
- 208000001344 Macular Edema Diseases 0.000 description 13
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000460 chlorine Substances 0.000 description 13
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 239000012453 solvate Substances 0.000 description 13
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 12
- 206010025415 Macular oedema Diseases 0.000 description 12
- 208000029725 Metabolic bone disease Diseases 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 12
- 206010012601 diabetes mellitus Diseases 0.000 description 12
- 210000002540 macrophage Anatomy 0.000 description 12
- 201000010230 macular retinal edema Diseases 0.000 description 12
- 229910000104 sodium hydride Inorganic materials 0.000 description 12
- 208000022873 Ocular disease Diseases 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 11
- 239000000741 silica gel Substances 0.000 description 11
- 229910002027 silica gel Inorganic materials 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- DPVIABCMTHHTGB-UHFFFAOYSA-N 2,4,6-trichloropyrimidine Chemical compound ClC1=CC(Cl)=NC(Cl)=N1 DPVIABCMTHHTGB-UHFFFAOYSA-N 0.000 description 10
- 108091006629 SLC13A2 Proteins 0.000 description 10
- 201000006417 multiple sclerosis Diseases 0.000 description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 10
- 229910052702 rhenium Inorganic materials 0.000 description 10
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 9
- UMCMPZBLKLEWAF-BCTGSCMUSA-N 3-[(3-cholamidopropyl)dimethylammonio]propane-1-sulfonate Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(=O)NCCC[N+](C)(C)CCCS([O-])(=O)=O)C)[C@@]2(C)[C@@H](O)C1 UMCMPZBLKLEWAF-BCTGSCMUSA-N 0.000 description 9
- 239000007995 HEPES buffer Substances 0.000 description 9
- 239000012131 assay buffer Substances 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 230000003247 decreasing effect Effects 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 9
- 239000003208 petroleum Substances 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- 229910052701 rubidium Inorganic materials 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- DZOMRYLZWBYFLF-UHFFFAOYSA-N (2-acetyloxy-3-octadecylsulfanylpropyl) 2-(trimethylazaniumyl)ethyl phosphate Chemical compound CCCCCCCCCCCCCCCCCCSCC(OC(C)=O)COP([O-])(=O)OCC[N+](C)(C)C DZOMRYLZWBYFLF-UHFFFAOYSA-N 0.000 description 8
- GNQLTCVBSGVGHC-UHFFFAOYSA-N (3,4-difluorophenyl)methanol Chemical compound OCC1=CC=C(F)C(F)=C1 GNQLTCVBSGVGHC-UHFFFAOYSA-N 0.000 description 8
- RYCNUMLMNKHWPZ-SNVBAGLBSA-N 1-acetyl-sn-glycero-3-phosphocholine Chemical compound CC(=O)OC[C@@H](O)COP([O-])(=O)OCC[N+](C)(C)C RYCNUMLMNKHWPZ-SNVBAGLBSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 101150041968 CDC13 gene Proteins 0.000 description 8
- 101001097889 Homo sapiens Platelet-activating factor acetylhydrolase Proteins 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 201000002491 encephalomyelitis Diseases 0.000 description 8
- 102000047182 human PLA2G7 Human genes 0.000 description 8
- 230000010287 polarization Effects 0.000 description 8
- 239000000758 substrate Substances 0.000 description 8
- JSFGDUIJQWWBGY-UHFFFAOYSA-N 2,3-difluorobenzyl alcohol Chemical compound OCC1=CC=CC(F)=C1F JSFGDUIJQWWBGY-UHFFFAOYSA-N 0.000 description 7
- 108700003842 2-acetyl-S-octadecyl-1-thioglycero-3-phosphocholine Proteins 0.000 description 7
- NLAVHUUABUFSIG-UHFFFAOYSA-N 3,4,5-trifluorobenzaldehyde Chemical compound FC1=CC(C=O)=CC(F)=C1F NLAVHUUABUFSIG-UHFFFAOYSA-N 0.000 description 7
- PCOFIIVWHXIDGT-UHFFFAOYSA-N 3-(hydroxymethyl)benzonitrile Chemical compound OCC1=CC=CC(C#N)=C1 PCOFIIVWHXIDGT-UHFFFAOYSA-N 0.000 description 7
- 208000002691 Choroiditis Diseases 0.000 description 7
- 208000001132 Osteoporosis Diseases 0.000 description 7
- 101710096328 Phospholipase A2 Proteins 0.000 description 7
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
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- LOGIHEKXJKHXEC-UHFFFAOYSA-N (3,5-difluorophenyl)methanol Chemical compound OCC1=CC(F)=CC(F)=C1 LOGIHEKXJKHXEC-UHFFFAOYSA-N 0.000 description 6
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- 238000004458 analytical method Methods 0.000 description 6
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- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 6
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- 230000002265 prevention Effects 0.000 description 6
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
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- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Epidemiology (AREA)
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| CN2013070976 | 2013-01-25 | ||
| CNPCT/CN2013/070976 | 2013-01-25 | ||
| CNPCT/CN2013/001556 | 2013-12-12 | ||
| CN2013001556 | 2013-12-12 | ||
| PCT/EP2014/051286 WO2014114694A1 (en) | 2013-01-25 | 2014-01-23 | 2,3-dihydroimidazol[1,2-c]pyrimidin-5(1h)-one based lipoprotein-associated phospholipase a2 (lp-pla2) inhibitors |
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| WO2016012917A1 (en) * | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
| WO2016012916A1 (en) * | 2014-07-22 | 2016-01-28 | Glaxosmithkline Intellectual Property Development Limited | 1,2,3,5-tetrahydroimidazo[1,2-c]pyrimidine derivatives useful in the treatment of diseases and disorders mediated by lp-pla2 |
| JP6625604B2 (ja) * | 2014-07-22 | 2019-12-25 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ | 化合物 |
| CN104892459A (zh) * | 2015-06-16 | 2015-09-09 | 苏州明锐医药科技有限公司 | 利奥西呱中间体及其制备方法 |
| CN112574221B (zh) * | 2019-09-30 | 2022-03-04 | 上海纽思克生物科技有限公司 | 四环嘧啶酮类化合物、其制备方法、其组合物和用途 |
| IL292668A (en) * | 2019-11-09 | 2022-07-01 | Shanghai Simr Biotechnology Co Ltd | A tricyclic derivative of dihydroimidazopyrimidone, its preparation method, pharmaceutical preparation and its use |
| CN111533699B (zh) * | 2020-05-27 | 2023-12-01 | 龙曦宁（上海）医药科技有限公司 | 一种2-（三氟甲基）嘧啶-5-醇的合成方法 |
| CN113861220B (zh) * | 2020-06-30 | 2023-06-16 | 上海纽思克生物科技有限公司 | 三环嘧啶酮类化合物、其制备方法、其组合物和用途 |
| CN113912622B (zh) * | 2020-07-10 | 2023-12-01 | 上海纽思克生物科技有限公司 | 三环嘧啶酮类化合物、其制备方法、其组合物和用途 |
| CN115304620A (zh) | 2021-05-07 | 2022-11-08 | 上海赛默罗生物科技有限公司 | 嘧啶酮衍生物、其制备方法、药物组合物和用途 |
| CN114057740B (zh) * | 2021-12-15 | 2024-04-02 | 上海赛默罗生物科技有限公司 | 螺环嘧啶酮衍生物、其制备方法、药物组合物和用途 |
| EP4565587A1 (en) * | 2022-08-04 | 2025-06-11 | 4B Technologies (Beijing) Co., Limited | Dihydroimidazo-pyrimidinone compounds as lp-pla2 inhibitors and use thereof |
| CN116925023B (zh) * | 2023-07-18 | 2025-11-21 | 江苏桐孚高新材料有限公司 | 2-全氟烷基-4h-吡喃-4-酮衍生物的改进合成方法 |
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| CH690264A5 (fr) | 1995-06-30 | 2000-06-30 | Symphar Sa | Dérivés aminophosphonates substitués, leur procédé de préparation et leur utilisation pour la préparation de compositions pharmaceutiques. |
| CZ422197A3 (cs) | 1995-07-01 | 1998-06-17 | Smithkline Beecham Plc | Azetidinonové deriváty, způsob jejich přípravy, meziprodukty tohoto postupu, farmaceutický prostředek obsahující tyto sloučeniny a použití těchto sloučenin jako léčiv |
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| JP3757703B2 (ja) | 1999-09-22 | 2006-03-22 | 凸版印刷株式会社 | 再封可能な開口維持部材付パウチ |
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| WO2005003118A1 (de) | 2003-07-02 | 2005-01-13 | Bayer Healthcare Ag | Amid-substituierte 1,2,4-triazin-5 (2h)-one zur behandlung von chronisch inflammatorischen krankheiten |
| DE102004061009A1 (de) | 2004-12-18 | 2006-06-22 | Bayer Healthcare Ag | Substituierte 1,2,4-Triazin-5(2H)-one |
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| EP2619203A4 (en) * | 2010-09-20 | 2014-04-16 | Glaxo Group Ltd | TRICYCLIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND APPLICATIONS THEREOF |
| EP2649050A4 (en) * | 2010-12-06 | 2014-04-23 | Glaxo Group Ltd | LINKS |
| EP2651403B1 (en) | 2010-12-17 | 2020-12-02 | Glaxo Group Limited | Use of lp-pla2 inhibitors in the treatment and prevention of eye diseases |
| JP2014521611A (ja) * | 2011-07-27 | 2014-08-28 | グラクソ グループ リミテッド | Ｌｐ−ＰＬＡ２阻害剤としての２，３−ジヒドロイミダゾ［１，２−ｃ］ピリミジン−５（１Ｈ）−オン化合物の使用 |
| CN103827116B (zh) | 2011-07-27 | 2016-08-31 | 葛兰素集团有限公司 | 用作LP-PLA2抑制剂的2,3-二氢咪唑并[1,2-c]嘧啶-5(1H)-酮化合物 |
| TW201443054A (zh) | 2013-01-25 | 2014-11-16 | Glaxosmithkline Ip Dev Ltd | 化合物 |
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2014
- 2014-01-23 TW TW103102388A patent/TW201443054A/zh unknown
- 2014-01-23 AU AU2014209949A patent/AU2014209949B2/en not_active Ceased
- 2014-01-23 ES ES14701355.1T patent/ES2642762T3/es active Active
- 2014-01-23 UY UY0001035276A patent/UY35276A/es not_active Application Discontinuation
- 2014-01-23 US US14/761,636 patent/US9708330B2/en not_active Expired - Fee Related
- 2014-01-23 HK HK16104389.3A patent/HK1216425A1/zh unknown
- 2014-01-23 EP EP14701355.1A patent/EP2948452B1/en active Active
- 2014-01-23 BR BR112015017759-0A patent/BR112015017759B1/pt not_active IP Right Cessation
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- 2014-01-23 KR KR1020157022396A patent/KR20150108897A/ko not_active Ceased
- 2014-01-23 EA EA201591379A patent/EA025885B1/ru not_active IP Right Cessation
- 2014-01-23 WO PCT/EP2014/051286 patent/WO2014114694A1/en not_active Ceased
- 2014-01-23 CN CN201480013675.8A patent/CN105008368B/zh not_active Expired - Fee Related
- 2014-01-23 SG SG11201505520WA patent/SG11201505520WA/en unknown
- 2014-01-23 MA MA38284A patent/MA38284B1/fr unknown
- 2014-01-23 MX MX2015009633A patent/MX2015009633A/es unknown
- 2014-01-23 PE PE2015001537A patent/PE20151251A1/es not_active Application Discontinuation
- 2014-01-23 CA CA2899091A patent/CA2899091A1/en not_active Abandoned
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2015
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- 2015-07-20 IL IL240046A patent/IL240046A0/en unknown
- 2015-07-20 PH PH12015501586A patent/PH12015501586A1/en unknown
- 2015-07-23 CL CL2015002060A patent/CL2015002060A1/es unknown
- 2015-07-24 CR CR20150390A patent/CR20150390A/es unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP2948452A1 (en) | 2015-12-02 |
| PH12015501586A1 (en) | 2015-10-05 |
| CN105008368B (zh) | 2017-02-01 |
| EP2948452B1 (en) | 2017-08-09 |
| US9708330B2 (en) | 2017-07-18 |
| JP2016505058A (ja) | 2016-02-18 |
| US20150361082A1 (en) | 2015-12-17 |
| AU2014209949B2 (en) | 2016-09-08 |
| HK1216425A1 (zh) | 2016-11-11 |
| KR20150108897A (ko) | 2015-09-30 |
| CN105008368A (zh) | 2015-10-28 |
| TW201443054A (zh) | 2014-11-16 |
| JP6306053B2 (ja) | 2018-04-04 |
| ES2642762T3 (es) | 2017-11-20 |
| UY35276A (es) | 2014-08-29 |
| MX2015009633A (es) | 2015-11-30 |
| EA201591379A1 (ru) | 2016-01-29 |
| BR112015017759B1 (pt) | 2022-05-24 |
| SG11201505520WA (en) | 2015-08-28 |
| IL240046A0 (en) | 2015-08-31 |
| CL2015002060A1 (es) | 2015-11-27 |
| MA38284A1 (fr) | 2017-12-29 |
| PE20151251A1 (es) | 2015-09-10 |
| CR20150390A (es) | 2015-10-19 |
| MA38284B1 (fr) | 2018-05-31 |
| EA025885B1 (ru) | 2017-02-28 |
| ZA201505025B (en) | 2017-08-30 |
| AU2014209949A1 (en) | 2015-07-30 |
| WO2014114694A1 (en) | 2014-07-31 |
| BR112015017759A2 (pt) | 2017-07-11 |
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| EEER | Examination request |
Effective date: 20190121 |
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| FZDE | Discontinued |
Effective date: 20220209 |