ES2906107T3 - Usos novedosos - Google Patents
Usos novedosos Download PDFInfo
- Publication number
- ES2906107T3 ES2906107T3 ES17849790T ES17849790T ES2906107T3 ES 2906107 T3 ES2906107 T3 ES 2906107T3 ES 17849790 T ES17849790 T ES 17849790T ES 17849790 T ES17849790 T ES 17849790T ES 2906107 T3 ES2906107 T3 ES 2906107T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- pde1
- pde1 inhibitor
- phenyl
- aryl
- 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.)
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- 150000001875 compounds Chemical class 0.000 claims abstract description 129
- 229940121836 Phosphodiesterase 1 inhibitor Drugs 0.000 claims abstract description 116
- -1 tetrahydro-2H-pyran-4-yl Chemical group 0.000 claims abstract description 55
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims abstract description 37
- 230000003959 neuroinflammation Effects 0.000 claims abstract description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 36
- 125000003118 aryl group Chemical group 0.000 claims abstract description 32
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 31
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 27
- 201000010099 disease Diseases 0.000 claims abstract description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 24
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 125000005843 halogen group Chemical group 0.000 claims abstract description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 20
- 230000002025 microglial effect Effects 0.000 claims abstract description 20
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 19
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- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 15
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- 208000035475 disorder Diseases 0.000 claims abstract description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 12
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 12
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- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 10
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims abstract description 9
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- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 6
- 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 claims abstract description 4
- 125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims abstract description 3
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims abstract description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 3
- 125000004512 1,2,3-thiadiazol-4-yl group Chemical group S1N=NC(=C1)* 0.000 claims abstract description 3
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims abstract description 3
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- LVZWSLJZHVFIQJ-UHFFFAOYSA-N Cyclopropane Chemical compound C1CC1 LVZWSLJZHVFIQJ-UHFFFAOYSA-N 0.000 claims abstract description 3
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- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 3
- 125000001769 aryl amino group Chemical group 0.000 claims abstract description 3
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 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 abstract description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 3
- 125000002720 diazolyl group Chemical group 0.000 claims abstract description 3
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- 125000004446 heteroarylalkyl group Chemical group 0.000 claims abstract description 3
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- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 3
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims abstract description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims abstract description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 3
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| EP3436083A4 (en) * | 2016-03-28 | 2019-11-27 | Intra-Cellular Therapies, Inc. | NOVEL COMPOSITIONS AND METHOD |
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| JP2022502501A (ja) * | 2018-09-25 | 2022-01-11 | イントラ−セルラー・セラピーズ・インコーポレイテッドIntra−Cellular Therapies, Inc. | 新規使用 |
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Family Cites Families (90)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6032638B2 (ja) | 1976-09-01 | 1985-07-29 | 武田薬品工業株式会社 | ３−アミノピラゾロ〔３，４−ｄ〕ピリミジン誘導体 |
| EP0077372A1 (de) | 1981-04-22 | 1983-04-27 | Byk Gulden Lomberg Chemische Fabrik GmbH | NEUE PYRAZOLO(3,4-d)PYRIMIDINE, VERFAHREN ZU DEREN HERSTELLUNG UND SIE ENTHALTENDE ARZNEIMITTEL |
| US4469868A (en) | 1982-05-24 | 1984-09-04 | Warner-Lambert Company | Alkylimidazo[1,2-c]pyrazolo[3,4-e]pyrimidines |
| US4690935A (en) | 1983-03-31 | 1987-09-01 | Wayne State University | Inhibition of tumor growth and metastasis with calcium channel blocker compounds |
| US4666908A (en) | 1985-04-05 | 1987-05-19 | Warner-Lambert Company | 5-Substituted pyrazolo[4,3-d]pyrimidine-7-ones and methods of use |
| KR920004437B1 (ko) | 1989-09-12 | 1992-06-05 | 삼성전자 주식회사 | 금전등록기의 거래선 관리방법 |
| ZA914727B (en) | 1990-06-21 | 1992-03-25 | Schering Corp | Polycyclic guanine derivatives |
| US5202328A (en) | 1991-03-06 | 1993-04-13 | Merck & Co., Inc. | Substituted fused pyrimidinones |
| US5294612A (en) | 1992-03-30 | 1994-03-15 | Sterling Winthrop Inc. | 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof |
| WO1994019351A1 (en) | 1993-02-26 | 1994-09-01 | Schering Corporation | 2-benzyl-polycyclic guanine derivatives and process for preparing them |
| GB9304919D0 (en) | 1993-03-10 | 1993-04-28 | Celltech Ltd | Chemical compounds |
| GB9315017D0 (en) | 1993-07-20 | 1993-09-01 | Glaxo Lab Sa | Chemical compounds |
| GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| US5824683A (en) | 1995-11-28 | 1998-10-20 | Schering Corporation | 2'- 4'-halo- 1,1'-biphenyl!-4-yl!methyl!-5'-methyl-spiro cyclopentane-1,7' (8'H)- 3H! imidazo 2,1-b!purin!-4' (5'H)-ones |
| GB9526245D0 (en) | 1995-12-21 | 1996-02-21 | Celltech Therapeutics Ltd | Chemical compounds |
| GB9622363D0 (en) | 1996-10-28 | 1997-01-08 | Celltech Therapeutics Ltd | Chemical compounds |
| US6057329A (en) | 1996-12-23 | 2000-05-02 | Celltech Therapeutics Limited | Fused polycyclic 2-aminopyrimidine derivatives |
| SE9701398D0 (sv) | 1997-04-15 | 1997-04-15 | Astra Pharma Prod | Novel compounds |
| IT1291372B1 (it) | 1997-05-21 | 1999-01-07 | Schering Plough S P A | Uso di analoghi eterociclici di 1,2,4-triazolo (1,5-c) pirimidine per la preparazione di medicamenti utili per il trattamento delle malattie |
| US6013621A (en) | 1997-10-17 | 2000-01-11 | The Rockfeller University | Method of treating psychosis and/or hyperactivity |
| GB9722520D0 (en) | 1997-10-24 | 1997-12-24 | Pfizer Ltd | Compounds |
| DE69943144D1 (de) | 1998-03-31 | 2011-03-03 | Kyowa Hakko Kirin Co Ltd | Stickstoffenthaltende heterocyclische verbindungen |
| US6133273A (en) | 1998-05-08 | 2000-10-17 | American Home Products Corporation | Pyrazolopyrimidine-2,4-dione sulfonamides |
| GB9907658D0 (en) | 1999-04-06 | 1999-05-26 | Zeneca Ltd | Chemical compounds |
| WO2001000214A1 (en) | 1999-06-30 | 2001-01-04 | Merck & Co., Inc. | Src kinase inhibitor compounds |
| AU5636900A (en) | 1999-06-30 | 2001-01-31 | Merck & Co., Inc. | Src kinase inhibitor compounds |
| DE19931206A1 (de) | 1999-07-07 | 2001-01-11 | Stief Christian | Arzneimittel zur Erhöhung des cAMP-Spiegels und deren Verwendung |
| DE60023926T2 (de) | 1999-09-10 | 2006-07-20 | Merck & Co., Inc. | Tyrosin kinase inhibitoren |
| JP2003510325A (ja) | 1999-09-30 | 2003-03-18 | ニューロジェン・コーポレーション | ある種のアルキレンジアミン−置換ピラゾロ［１，５−ａ］−１，５−ピリミジン及びピラゾロ［１，５−ａ］−１，３，５−トリアジン |
| AP2002002455A0 (en) | 1999-10-11 | 2002-06-30 | Pfizer | 5-(2-substituted-5-heterocyclylsulphonylpyrid-3-yl)-dIhydropyrazolo[4,3-D] pyrimidin-7-ones as phosphodiesterase inhibitors. |
| TWI265925B (en) | 1999-10-11 | 2006-11-11 | Pfizer | Pyrazolo[4,3-d]pyrimidin-7-ones useful in inhibiting type 5 cyclic guanosine 3',5'-monophosphate phosphodiesterases(cGMP PDE5), process and intermediates for their preparation, their uses and composition comprising them |
| IL139073A0 (en) | 1999-10-21 | 2001-11-25 | Pfizer | Treatment of neuropathy |
| MY125533A (en) | 1999-12-06 | 2006-08-30 | Bristol Myers Squibb Co | Heterocyclic dihydropyrimidine compounds |
| GB0004890D0 (en) | 2000-03-01 | 2000-04-19 | Astrazeneca Uk Ltd | Chemical compounds |
| JP2004500425A (ja) | 2000-04-19 | 2004-01-08 | リリー アイコス リミテッド ライアビリティ カンパニー | パーキンソン病の処置に対する環状ｇｍｐ特異的ホスホジエステラーゼインヒビターの使用 |
| US6693099B2 (en) | 2000-10-17 | 2004-02-17 | The Procter & Gamble Company | Substituted piperazine compounds optionally containing a quinolyl moiety for treating multidrug resistance |
| EP1372656B1 (en) | 2001-03-16 | 2005-06-22 | Pfizer Limited | Pyrazolo[4,3-d]pyrimidinone compounds as cgmp pde inhibitors |
| WO2002088079A2 (en) | 2001-05-01 | 2002-11-07 | Bristol-Myers Squibb Company | Dual inhibitors of pde 7 and pde 4 |
| SE0102315D0 (sv) | 2001-06-28 | 2001-06-28 | Astrazeneca Ab | Compounds |
| WO2003020724A1 (en) | 2001-08-28 | 2003-03-13 | Schering Corporation | Polycyclic guanine phosphodiesterase v inhibitors |
| EP1575916B1 (en) | 2001-08-31 | 2013-05-22 | The Rockefeller University | Phosphodiesterase activity and regulation of phosphodiesterase 1-b-mediated signaling in brain |
| CA2465893A1 (en) | 2001-11-09 | 2003-05-22 | Schering Corporation | Polycyclic guanine derivative phosphodiesterase v inhibitors |
| AU2003219770B2 (en) | 2002-02-15 | 2008-10-09 | Merckle Gmbh | Conjugates of biologically active compounds, methods for their preparation and use, formulation and pharmaceutical applications thereof |
| IL163575A0 (en) | 2002-02-21 | 2005-12-18 | Univ Rockefeller | Compositions and method for regulation of calcium-dependent signalling in brain |
| GB0230045D0 (en) | 2002-12-23 | 2003-01-29 | Glaxo Group Ltd | Compounds |
| AU2003272728A1 (en) | 2002-09-27 | 2004-04-19 | Children's Medical Center Corporation | Methods and compositions for treatment of neurological disorder |
| WO2004031375A2 (en) | 2002-10-01 | 2004-04-15 | Bayer Healthcare Ag | Regulation of human 3’, 5’ cyclic nucleotide phosphodiesterase pde1c |
| US20070155662A1 (en) | 2003-03-11 | 2007-07-05 | Stefan Golz | Diagnostics and therapeutics for diseases associated with phosphodiesterase 1a (pde1a) |
| EP1613747A1 (en) | 2003-03-31 | 2006-01-11 | Pfizer Products Inc. | Crystal structure of 3 ,5 -cyclic nucleotide phosphodiesterase 1b (pde1b) and uses thereof |
| MXPA05010373A (es) | 2003-04-01 | 2005-12-05 | Applied Research Systems | Inhibidores de fosfodiesterasas en infertilidad. |
| US20050113379A1 (en) | 2003-09-05 | 2005-05-26 | Ping Ge | Heteroaryl fused pyridines, pyrazines and pyrimidines as CRF1 receptor ligands |
| US20050287665A1 (en) | 2004-06-23 | 2005-12-29 | Henrich Cheng | Method for inducing neural differentiation |
| AU2005282379B8 (en) | 2004-09-08 | 2012-04-05 | Spinal Modulation Inc. | Neurostimulation methods and systems |
| US8273750B2 (en) | 2005-06-06 | 2012-09-25 | Takeda Pharmaceutical Company Limited | Organic compounds |
| EP1919287A4 (en) | 2005-08-23 | 2010-04-28 | Intra Cellular Therapies Inc | ORGANIC COMPOUNDS FOR TREATING A REDUCED DOPAMINE RECEPTOR SIGNALING ACTIVITY |
| JP5453086B2 (ja) | 2006-06-06 | 2014-03-26 | イントラ−セルラー・セラピーズ・インコーポレイテッド | 有機化合物 |
| US20070286890A1 (en) | 2006-06-07 | 2007-12-13 | John Garnett Walt | Eyelash applicator and method |
| JP2010509399A (ja) | 2006-11-13 | 2010-03-25 | イントラ−セルラー・セラピーズ・インコーポレイテッド | 有機化合物 |
| US9006258B2 (en) | 2006-12-05 | 2015-04-14 | Intra-Cellular Therapies, Inc. | Method of treating female sexual dysfunction with a PDE1 inhibitor |
| JP5498392B2 (ja) | 2007-11-30 | 2014-05-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | １，５−ジヒドロ−ピラゾロ［３，４−ｄ］ピリミジン−４−オン誘導体及びｃｎｓ障害の治療のためのｐｄｅ９ａモジュレーターとしてのそれらの使用 |
| ES2588238T3 (es) | 2007-12-06 | 2016-10-31 | Intra-Cellular Therapies, Inc. | Derivados de pirazolopirimidin-4,6-diona y su uso como producto farmacéutico |
| AU2008335811B2 (en) | 2007-12-06 | 2012-05-17 | Intra-Cellular Therapies, Inc. | Organic compounds |
| KR20110098732A (ko) | 2008-12-06 | 2011-09-01 | 인트라-셀룰라 써래피스, 인코퍼레이티드. | 유기 화합물 |
| CN102231953A (zh) | 2008-12-06 | 2011-11-02 | 细胞内治疗公司 | 有机化合物 |
| JP5989993B2 (ja) | 2008-12-06 | 2016-09-07 | イントラ−セルラー・セラピーズ・インコーポレイテッドＩｎｔｒａ−Ｃｅｌｌｕｌａｒ Ｔｈｅｒａｐｉｅｓ， Ｉｎｃ． | 有機化合物 |
| AU2009322904A1 (en) | 2008-12-06 | 2010-06-10 | Intra-Cellular Therapies, Inc. | Organic compounds |
| MX2011005936A (es) | 2008-12-06 | 2011-12-16 | Intra Cellular Therapies Inc | Compuestos organicos. |
| WO2010065147A1 (en) | 2008-12-06 | 2010-06-10 | Intra-Cellular Therapies, Inc. | Organic compounds |
| JP2012518685A (ja) | 2009-02-25 | 2012-08-16 | イントラ−セルラー・セラピーズ・インコーポレイテッド | 眼障害のためのｐｄｅ１阻害剤 |
| US9468637B2 (en) | 2009-05-13 | 2016-10-18 | Intra-Cellular Therapies, Inc. | Organic compounds |
| JP2013507360A (ja) | 2009-10-08 | 2013-03-04 | イントラ−セルラー・セラピーズ・インコーポレイテッド | ホスホジエステラーゼ１−標的トレーサーおよび方法 |
| TW201206937A (en) | 2010-05-31 | 2012-02-16 | Intra Cellular Therapies Inc | Organic compounds |
| WO2011153135A1 (en) | 2010-05-31 | 2011-12-08 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US9763948B2 (en) | 2010-05-31 | 2017-09-19 | Intra-Cellular Therapies, Inc. | PDE1 inhibitory compounds and methods |
| US9434730B2 (en) | 2010-05-31 | 2016-09-06 | Intra-Cellular Therapies, Inc. | PDE1 inhibitor compounds |
| EP2717877B1 (en) | 2011-06-10 | 2017-11-08 | Intra-Cellular Therapies, Inc. | Organic compounds |
| CA2845039A1 (en) | 2011-08-18 | 2013-02-21 | Shire Ag | Combinations of a 5-ht4 receptor agonist and a pde4 inhibitor for use in therapy |
| JP6224597B2 (ja) | 2011-09-27 | 2017-11-01 | バイオメッド バレー ディスカバリーズ，インコーポレイティド | グリオーマを処置するための組成物及び方法 |
| AR091507A1 (es) | 2012-06-21 | 2015-02-11 | Intra Cellular Therapies Inc | SALES DE (6aR,9aS)-5,6a,7,8,9,9a-HEXAHIDRO-5-METIL-3-(FENILAMINO)-2-((4-(6-FLUOROPIRIDIN-2-IL)FENIL)METIL)-CICLOPENT[4,5]IMIDAZO[1,2-a]PIRAZOLO[4,3-e]PIRIMIDIN-4(2H)-ONA |
| US9801882B2 (en) * | 2013-02-17 | 2017-10-31 | Intra-Cellular Therapies, Inc. | Phosphodiesterase-1 inhibitors and their use in treatment of cardiovascular diseases |
| CA2906640C (en) | 2013-03-15 | 2021-07-20 | Intra-Cellular Therapies, Inc. | Substituted imidazo-[1,2-a]pyrazolo[4.3-e]pyrimidin-4[5h]-one compounds and pharmaceutical compositions and use therof as pde1 inhibitors |
| US9545406B2 (en) | 2013-03-15 | 2017-01-17 | Intra-Cellular Therapies, Inc. | Method of treating a CNS injury with a PDE1 inhibitor |
| EP3091983B1 (en) | 2014-01-08 | 2019-10-02 | Intra-Cellular Therapies, Inc. | Pharmaceutical compositions comprising a pde-1 inhibitor and a pde-2 inhibitor |
| WO2015196186A1 (en) | 2014-06-20 | 2015-12-23 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US10300064B2 (en) | 2014-12-06 | 2019-05-28 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US20160362489A1 (en) | 2015-04-28 | 2016-12-15 | Bristol-Myers Squibb Company | Treatment of PD-L1-Positive Melanoma Using an Anti-PD-1 Antibody |
| WO2018049417A1 (en) | 2016-09-12 | 2018-03-15 | Intra-Cellular Therapies, Inc. | Novel uses |
| US20190292246A1 (en) | 2016-11-03 | 2019-09-26 | Juno Therapeutics, Inc. | Combination therapy of a cell based therapy and a microglia imhibitor |
| MX2020002183A (es) | 2017-08-31 | 2020-10-05 | Abbvie Inc | Inhibidores de la ectonucleótido pirofosfatasa-fosfodiesterasa 1 (enpp-1) y usos de los mismos. |
| US12396992B2 (en) | 2019-01-07 | 2025-08-26 | Intra-Cellular Therapies, Inc. | Organic compounds |
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| US20210213018A1 (en) | 2021-07-15 |
| JP2019531285A (ja) | 2019-10-31 |
| JP2022137064A (ja) | 2022-09-21 |
| EP3509589B1 (en) | 2021-11-17 |
| JP7506711B2 (ja) | 2024-06-26 |
| EP3970719A1 (en) | 2022-03-23 |
| WO2018049417A1 (en) | 2018-03-15 |
| EP3509589A4 (en) | 2020-03-18 |
| EP3509589A1 (en) | 2019-07-17 |
| JP7134168B6 (ja) | 2024-02-02 |
| JP7134168B2 (ja) | 2022-09-09 |
| US11291666B2 (en) | 2022-04-05 |
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