CA2402092C - 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases - Google Patents
1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases Download PDFInfo
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- CA2402092C CA2402092C CA2402092A CA2402092A CA2402092C CA 2402092 C CA2402092 C CA 2402092C CA 2402092 A CA2402092 A CA 2402092A CA 2402092 A CA2402092 A CA 2402092A CA 2402092 C CA2402092 C CA 2402092C
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- Prior art keywords
- alkyl
- cr10r20
- optionally substituted
- dihydro
- methylphenyl
- Prior art date
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- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 title claims abstract description 42
- -1 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds Chemical class 0.000 title claims description 108
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 59
- 201000010099 disease Diseases 0.000 title claims description 54
- 230000001404 mediated effect Effects 0.000 title claims description 20
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 title claims 4
- 102100023482 Mitogen-activated protein kinase 14 Human genes 0.000 claims abstract description 74
- 108010084680 Heterogeneous-Nuclear Ribonucleoprotein K Proteins 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 307
- 150000001875 compounds Chemical class 0.000 claims description 233
- 125000000623 heterocyclic group Chemical group 0.000 claims description 142
- 125000003118 aryl group Chemical group 0.000 claims description 141
- 229910052739 hydrogen Inorganic materials 0.000 claims description 137
- 239000001257 hydrogen Substances 0.000 claims description 129
- 125000001072 heteroaryl group Chemical group 0.000 claims description 128
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 124
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 106
- 238000000034 method Methods 0.000 claims description 103
- 150000002431 hydrogen Chemical group 0.000 claims description 101
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 94
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 88
- 229910052736 halogen Inorganic materials 0.000 claims description 75
- 150000002367 halogens Chemical class 0.000 claims description 73
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 67
- 238000011282 treatment Methods 0.000 claims description 57
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical class C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 53
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 49
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- 125000003107 substituted aryl group Chemical group 0.000 claims description 45
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 37
- 239000001301 oxygen Substances 0.000 claims description 37
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 35
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 35
- 229910052717 sulfur Inorganic materials 0.000 claims description 33
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 30
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 28
- 125000006650 (C2-C4) alkynyl group Chemical class 0.000 claims description 27
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- 125000000753 cycloalkyl group Chemical group 0.000 claims description 27
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
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- 229910052757 nitrogen Inorganic materials 0.000 claims description 25
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 24
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 23
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- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000001153 fluoro group Chemical group F* 0.000 claims description 20
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims description 19
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000004093 cyano group Chemical class *C#N 0.000 claims description 8
- 125000000449 nitro group Chemical class [O-][N+](*)=O 0.000 claims description 8
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- 239000003638 chemical reducing agent Substances 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
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- 150000004678 hydrides Chemical group 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 5
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 5
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- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 5
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- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
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- 206010012601 diabetes mellitus Diseases 0.000 claims description 4
- 235000011007 phosphoric acid Nutrition 0.000 claims description 4
- 125000004105 2-pyridyl group Chemical class N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- ALFUUHHEXQAFKA-UHFFFAOYSA-N 3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one Chemical compound N1=CN=C2NC(=O)NCC2=C1 ALFUUHHEXQAFKA-UHFFFAOYSA-N 0.000 claims description 3
- 125000003349 3-pyridyl group Chemical class N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000000339 4-pyridyl group Chemical class N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
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- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
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- 229910052708 sodium Inorganic materials 0.000 claims description 3
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- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 2
- 208000018652 Closed Head injury Diseases 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 206010019280 Heart failures Diseases 0.000 claims description 2
- 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 claims description 2
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- UAWABSHMGXMCRK-UHFFFAOYSA-L samarium(ii) iodide Chemical group I[Sm]I UAWABSHMGXMCRK-UHFFFAOYSA-L 0.000 claims description 2
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- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 5
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims 4
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 4
- 125000001188 haloalkyl group Chemical group 0.000 claims 3
- XFIVQPQXMLYMEL-UHFFFAOYSA-N 8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-2-(2-pyridin-3-ylethylamino)-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound CC1=CC(F)=CC=C1C1=NC(NCCC=2C=NC=CC=2)=NC2=C1CNC(=O)N2C1=C(F)C=CC=C1F XFIVQPQXMLYMEL-UHFFFAOYSA-N 0.000 claims 2
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- GFPULOWPXJKUAA-UHFFFAOYSA-N 1-[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7-oxo-5,6-dihydropyrimido[4,5-d]pyrimidin-2-yl]piperidine-4-carboxylic acid Chemical compound CC1=CC(F)=CC=C1C1=NC(N2CCC(CC2)C(O)=O)=NC2=C1CNC(=O)N2C1=C(F)C=CC=C1F GFPULOWPXJKUAA-UHFFFAOYSA-N 0.000 claims 1
- ITCXGNOGLOWIDP-UHFFFAOYSA-N 2-[2-(diethylamino)ethylamino]-8-(2,6-difluorophenyl)-4-(2-methylphenyl)-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound N=1C(NCCN(CC)CC)=NC=2N(C=3C(=CC=CC=3F)F)C(=O)NCC=2C=1C1=CC=CC=C1C ITCXGNOGLOWIDP-UHFFFAOYSA-N 0.000 claims 1
- INHFBBAQFRVOHD-UHFFFAOYSA-N 2-[2-(diethylamino)ethylamino]-8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound N=1C(NCCN(CC)CC)=NC=2N(C=3C(=CC=CC=3F)F)C(=O)NCC=2C=1C1=CC=C(F)C=C1C INHFBBAQFRVOHD-UHFFFAOYSA-N 0.000 claims 1
- ZMIKRTDSJYSRIQ-UHFFFAOYSA-N 2-[2-[bis(2-hydroxyethyl)amino]ethoxy]-8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound CC1=CC(F)=CC=C1C1=NC(OCCN(CCO)CCO)=NC2=C1CNC(=O)N2C1=C(F)C=CC=C1F ZMIKRTDSJYSRIQ-UHFFFAOYSA-N 0.000 claims 1
- NHWQNBZGHWTZTF-UHFFFAOYSA-N 2-methoxy-4,8-diphenyl-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound N=1C(OC)=NC=2N(C=3C=CC=CC=3)C(=O)NCC=2C=1C1=CC=CC=C1 NHWQNBZGHWTZTF-UHFFFAOYSA-N 0.000 claims 1
- CWCJLZDWHSYWBJ-IBGZPJMESA-N 4-(4-fluoro-2-methylphenyl)-2-[3-(2-oxopyrrolidin-1-yl)propylamino]-8-[(1s)-1-phenylethyl]-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound N1([C@@H](C)C=2C=CC=CC=2)C(=O)NCC(C(=N2)C=3C(=CC(F)=CC=3)C)=C1N=C2NCCCN1CCCC1=O CWCJLZDWHSYWBJ-IBGZPJMESA-N 0.000 claims 1
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- POIUUYBLAPDZRL-AWEZNQCLSA-N 4-(4-fluoro-2-methylphenyl)-2-methylsulfanyl-8-[(1s)-1-phenylethyl]-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound C1([C@H](C)N2C=3N=C(N=C(C=3CNC2=O)C=2C(=CC(F)=CC=2)C)SC)=CC=CC=C1 POIUUYBLAPDZRL-AWEZNQCLSA-N 0.000 claims 1
- UCAQHFUBHMNONM-UHFFFAOYSA-N 4-(4-fluoro-2-methylphenyl)-8-(2-methylphenyl)-2-[3-(2-oxopyrrolidin-1-yl)propylamino]-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound CC1=CC=CC=C1N1C(N=C(NCCCN2C(CCC2)=O)N=C2C=3C(=CC(F)=CC=3)C)=C2CNC1=O UCAQHFUBHMNONM-UHFFFAOYSA-N 0.000 claims 1
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- UXTBSKJWTIWZJC-UHFFFAOYSA-N 8-(2,6-difluorophenyl)-2-(2,3-dihydroxypropylamino)-4-(4-fluoro-2-methylphenyl)-5,6-dihydropyrimido[4,5-d]pyrimidin-7-one Chemical compound CC1=CC(F)=CC=C1C1=NC(NCC(O)CO)=NC2=C1CNC(=O)N2C1=C(F)C=CC=C1F UXTBSKJWTIWZJC-UHFFFAOYSA-N 0.000 claims 1
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Landscapes
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| US18641900P | 2000-03-02 | 2000-03-02 | |
| US60/186,419 | 2000-03-02 | ||
| PCT/US2001/006688 WO2001064679A1 (en) | 2000-03-02 | 2001-03-02 | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
Publications (2)
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| CA2402092A1 CA2402092A1 (en) | 2001-09-07 |
| CA2402092C true CA2402092C (en) | 2012-01-24 |
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Family Applications (1)
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| ZA (1) | ZA200207017B (enExample) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US6858617B2 (en) | 1998-05-26 | 2005-02-22 | Smithkline Beecham Corporation | Substituted imidazole compounds |
| TR200003429T2 (tr) | 1998-05-26 | 2001-07-23 | Warner-Lambert Company | Hücresel çoğalma inhibitörleri olarak bisiklik pirimidinler ve bisiklik 3,4-dihidropirimidinler. |
| EP1233950B1 (en) | 1999-11-23 | 2005-10-05 | Smithkline Beecham Corporation | 3,4-DIHYDRO-(1H)QUINAZOLIN-2-ONE COMPOUNDS AS CSBP/P39 kINASE INHIBITORS |
| ATE281439T1 (de) | 1999-11-23 | 2004-11-15 | Smithkline Beecham Corp | 3,4-dihydro-(1h)chinazolin-2-on-verbindungen als csbp/p38-kinase-inhibitoren |
| JP2003514900A (ja) | 1999-11-23 | 2003-04-22 | スミスクライン・ビーチャム・コーポレイション | ＣＳＢＰ／ｐ３８キナーゼ阻害剤としての３，４−ジヒドロ−（１Ｈ）−キナゾリン−２−オン化合物 |
| US7235551B2 (en) | 2000-03-02 | 2007-06-26 | Smithkline Beecham Corporation | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
| CN100525768C (zh) * | 2000-10-23 | 2009-08-12 | 史密丝克莱恩比彻姆公司 | 新化合物 |
| JP2004521892A (ja) * | 2000-12-20 | 2004-07-22 | メルク エンド カムパニー インコーポレーテッド | （ハロ−ベンゾカルボニル）複素環縮合フェニル系ｐ３８キナーゼ阻害剤 |
| GB0124848D0 (en) | 2001-10-16 | 2001-12-05 | Celltech R&D Ltd | Chemical compounds |
| ATE375980T1 (de) | 2002-02-12 | 2007-11-15 | Smithkline Beecham Corp | Nicotinamide und deren verwendung als p38 inhibitoren |
| JP4359146B2 (ja) * | 2002-02-13 | 2009-11-04 | エフ．ホフマン−ラ ロシュ アーゲー | 新規なピリジン−およびピリミジン−誘導体 |
| KR20040103972A (ko) * | 2002-04-19 | 2004-12-09 | 스미스클라인 비참 코포레이션 | 신규 화합물 |
| GB0214268D0 (en) * | 2002-06-20 | 2002-07-31 | Celltech R&D Ltd | Chemical compounds |
| US7196090B2 (en) | 2002-07-25 | 2007-03-27 | Warner-Lambert Company | Kinase inhibitors |
| GB0218800D0 (en) * | 2002-08-13 | 2002-09-18 | Celltech R&D Ltd | Chemical compounds |
| US7084270B2 (en) * | 2002-08-14 | 2006-08-01 | Hoffman-La Roche Inc. | Pyrimido compounds having antiproliferative activity |
| WO2004019873A2 (en) | 2002-08-29 | 2004-03-11 | Scios Inc. | Methods of promoting osteogenesis |
| US7112676B2 (en) | 2002-11-04 | 2006-09-26 | Hoffmann-La Roche Inc. | Pyrimido compounds having antiproliferative activity |
| WO2004043367A2 (en) | 2002-11-06 | 2004-05-27 | Bristol-Myers Squibb Company | Fused heterocyclic compounds and use thereof |
| US7098332B2 (en) | 2002-12-20 | 2006-08-29 | Hoffmann-La Roche Inc. | 5,8-Dihydro-6H-pyrido[2,3-d]pyrimidin-7-ones |
| WO2004089955A1 (en) | 2003-04-10 | 2004-10-21 | F.Hoffmann-La Roche Ag | Pyrimido compounds |
| WO2005030091A2 (en) | 2003-09-25 | 2005-04-07 | Scios Inc. | Stents and intra-luminal prostheses containing map kinase inhibitors |
| AU2004309420B2 (en) * | 2003-12-23 | 2008-10-30 | Novartis Ag | Bicyclic heterocyclic p-38 kinase inhibitors |
| US7767687B2 (en) | 2004-12-13 | 2010-08-03 | Biogen Idec Ma Inc. | Pyrido pyrimidinones, dihydro pyrimido pyrimidinones and pteridinones useful as RAF kinase inhibitors |
| EP1676574A3 (en) | 2004-12-30 | 2006-07-26 | Johnson & Johnson Vision Care, Inc. | Methods for promoting survival of transplanted tissues and cells |
| JP5201817B2 (ja) * | 2005-10-28 | 2013-06-05 | 大塚製薬株式会社 | 医薬組成物 |
| EP2031965A4 (en) * | 2006-06-16 | 2010-06-30 | Glaxo Group Ltd | NEW COMPOUNDS |
| US20090318424A1 (en) * | 2006-06-16 | 2009-12-24 | Mauro Corsi | Novel compounds |
| KR101040394B1 (ko) * | 2010-05-18 | 2011-06-09 | (주)이성산업 | 역화 방지 기능을 갖는 야외용 가스 히터 |
| CN102816162B (zh) * | 2011-06-10 | 2016-04-27 | 中国科学院广州生物医药与健康研究院 | 嘧啶并嘧啶酮类化合物及其药用组合物和应用 |
| EP3943087A1 (en) | 2013-03-15 | 2022-01-26 | Celgene CAR LLC | Heteroaryl compounds and uses thereof |
| CN105307657B (zh) | 2013-03-15 | 2020-07-10 | 西建卡尔有限责任公司 | 杂芳基化合物和其用途 |
| US9321786B2 (en) | 2013-03-15 | 2016-04-26 | Celgene Avilomics Research, Inc. | Heteroaryl compounds and uses thereof |
| CN104557872B (zh) | 2013-10-16 | 2017-05-24 | 上海璎黎药业有限公司 | 稠合杂环化合物、其制备方法、药物组合物和用途 |
| US20190060286A1 (en) | 2016-02-29 | 2019-02-28 | University Of Florida Research Foundation, Incorpo | Chemotherapeutic Methods |
| US10342786B2 (en) | 2017-10-05 | 2019-07-09 | Fulcrum Therapeutics, Inc. | P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD |
| BR112020006677A2 (pt) | 2017-10-05 | 2020-10-06 | Fulcrum Therapeutics, Inc. | uso de inibidores p38 para reduzir a expressão de dux4 |
| AR127404A1 (es) | 2021-10-20 | 2024-01-17 | Insilico Medicine Ip Ltd | Inhibidores de la metionina adenosiltransferasa 2a (mat2a) y usos de los mismos |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60226882A (ja) * | 1984-04-24 | 1985-11-12 | Nippon Zoki Pharmaceut Co Ltd | 新規ピリミドピリミジン誘導体 |
| BR9710808A (pt) * | 1996-08-06 | 1999-08-17 | Pfizer | Derivados biciclicos 6,6 ou 6,7 contendo pirito ou pirimido substitu¡dos |
| TR200003429T2 (tr) * | 1998-05-26 | 2001-07-23 | Warner-Lambert Company | Hücresel çoğalma inhibitörleri olarak bisiklik pirimidinler ve bisiklik 3,4-dihidropirimidinler. |
| JP2002517486A (ja) * | 1998-06-12 | 2002-06-18 | バーテックス ファーマシューティカルズ インコーポレイテッド | ｐ３８のインヒビター |
| HK1041483B (zh) * | 1998-10-23 | 2004-12-24 | 霍夫曼-拉罗奇有限公司 | 雙環氮雜環 |
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- 2001-03-02 AU AU3999201A patent/AU3999201A/xx active Pending
- 2001-03-02 NZ NZ520914A patent/NZ520914A/en not_active IP Right Cessation
- 2001-03-02 TW TW090104783A patent/TWI290926B/zh not_active IP Right Cessation
- 2001-03-02 HU HU0204431A patent/HUP0204431A3/hu unknown
- 2001-03-02 EP EP01914625A patent/EP1265900B1/en not_active Expired - Lifetime
- 2001-03-02 AT AT01914625T patent/ATE362473T1/de active
- 2001-03-02 DK DK01914625T patent/DK1265900T3/da active
- 2001-03-02 PL PL01358280A patent/PL358280A1/xx not_active Application Discontinuation
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2002
- 2002-08-22 IL IL151426A patent/IL151426A/en not_active IP Right Cessation
- 2002-08-30 NO NO20024134A patent/NO326409B1/no not_active IP Right Cessation
- 2002-09-02 ZA ZA200207017A patent/ZA200207017B/en unknown
-
2003
- 2003-05-07 AR ARP030101602A patent/AR040075A2/es unknown
-
2007
- 2007-08-13 CY CY20071101080T patent/CY1106816T1/el unknown
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2008
- 2008-02-28 IL IL189865A patent/IL189865A0/en unknown
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