ES2871327T3 - Inhibidores de la PDE1 para uso en el tratamiento y/o prevención de enfermedades o trastornos de SNC o SNP - Google Patents
Inhibidores de la PDE1 para uso en el tratamiento y/o prevención de enfermedades o trastornos de SNC o SNP Download PDFInfo
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- ES2871327T3 ES2871327T3 ES18205841T ES18205841T ES2871327T3 ES 2871327 T3 ES2871327 T3 ES 2871327T3 ES 18205841 T ES18205841 T ES 18205841T ES 18205841 T ES18205841 T ES 18205841T ES 2871327 T3 ES2871327 T3 ES 2871327T3
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- alkyl
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- pde1 inhibitor
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Family Cites Families (82)
| 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 |
| WO1982003626A1 (en) | 1981-04-22 | 1982-10-28 | Gauri Kailash Kumar | New derivatives of pyrazolo(3,4-d)pyrimidine,preparation method thereof and remedy containing them |
| US4469868A (en) | 1982-05-24 | 1984-09-04 | Warner-Lambert Company | Alkylimidazo[1,2-c]pyrazolo[3,4-e]pyrimidines |
| US4603203A (en) | 1983-12-14 | 1986-07-29 | Takeda Chemical Industries, Ltd. | 3-aminopyrazolo[3,4-d]pyrimidine derivatives and production thereof |
| 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 |
| NZ238609A (en) | 1990-06-21 | 1993-12-23 | Schering Corp | Polycyclic guanine derivatives; preparation, pharmaceutical compositions, |
| 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 |
| HUT72640A (en) | 1993-02-26 | 1996-05-28 | Schering Corp | 2-benzyl-polycyclic guanine derivatives, pharmaceutical compositions containing them 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 |
| EP0946523A1 (en) | 1996-12-23 | 1999-10-06 | Celltech Therapeutics Limited | Fused polycyclic 2-aminopyrimidine derivatives, their preparation and their use as protein tyrosine kinase inhibitors |
| 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 |
| AU3053999A (en) | 1998-03-31 | 1999-10-25 | Kyowa Hakko Kogyo Co. Ltd. | Nitrogenous heterocyclic compounds |
| US6133273A (en) | 1998-05-08 | 2000-10-17 | American Home Products Corporation | Pyrazolopyrimidine-2,4-dione sulfonamides |
| US6459908B1 (en) | 1998-12-31 | 2002-10-01 | Qwest Communications International Inc. | Method and system for supporting wireless features in a Generic C wireline architecture |
| GB9907658D0 (en) | 1999-04-06 | 1999-05-26 | Zeneca Ltd | Chemical compounds |
| AU5889100A (en) | 1999-06-30 | 2001-01-31 | Merck & Co., Inc. | Src kinase inhibitor compounds |
| CA2383546A1 (en) | 1999-06-30 | 2001-01-04 | William H. Parsons | Src kinase inhibitor compounds |
| DE19931206A1 (de) | 1999-07-07 | 2001-01-11 | Stief Christian | Arzneimittel zur Erhöhung des cAMP-Spiegels und deren Verwendung |
| ES2250186T3 (es) | 1999-09-10 | 2006-04-16 | MERCK & CO., INC. | Inhibidores de tirosina quinasa. |
| US6372743B1 (en) | 1999-09-30 | 2002-04-16 | Neurogen Corporation | Certain alkylene diamine-substituted pyrazlo (1,5-a)-1,5-pyrimidines and pyrazolo (1,5-a) 1,3,5-triazines |
| SK4562002A3 (en) | 1999-10-11 | 2003-04-01 | 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 |
| BR0208078A (pt) | 2001-03-16 | 2004-03-02 | Pfizer | Compostos pirazol[4,3-d]pirimidinona como inibidores de cgmp pde |
| 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 |
| MXPA04001891A (es) | 2001-08-28 | 2004-06-15 | Schering Corp | Inhibidores policiclicos de guanina fosfodiesterasa v. |
| US20030211040A1 (en) | 2001-08-31 | 2003-11-13 | Paul Greengard | Phosphodiesterase activity and regulation of phosphodiesterase 1B-mediated signaling in brain |
| CN1585771A (zh) | 2001-11-09 | 2005-02-23 | 先灵公司 | 多环鸟嘌呤衍生物磷酸二酯酶v抑制剂 |
| NZ535354A (en) | 2002-02-15 | 2008-01-31 | 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 |
| EP1604202A2 (en) * | 2003-03-11 | 2005-12-14 | Bayer HealthCare AG | Diagnostics and therapeutics for diseases associated with phosphodiesterase 1a (pde1a) |
| WO2004087906A1 (en) | 2003-03-31 | 2004-10-14 | Pfizer Products Inc. | Crystal structure of 3',5'-cyclic nucleotide phosphodiesterase 1b (pde1b) and uses thereof |
| KR20050115331A (ko) | 2003-04-01 | 2005-12-07 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | 불임증 포스포디에스터라제의 억제제 |
| AU2004270713A1 (en) | 2003-09-05 | 2005-03-17 | Aventis Pharmaceuticals Inc. | 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 |
| US7337005B2 (en) | 2004-09-08 | 2008-02-26 | Spinal Modulations, Inc. | Methods for stimulating a nerve root ganglion |
| ES2645371T3 (es) | 2005-06-06 | 2017-12-05 | Intra-Cellular Therapies, Inc. | Compuestos orgánicos |
| EP1919287A4 (en) | 2005-08-23 | 2010-04-28 | Intra Cellular Therapies Inc | ORGANIC COMPOUNDS FOR TREATING A REDUCED DOPAMINE RECEPTOR SIGNALING ACTIVITY |
| US9255099B2 (en) | 2006-06-06 | 2016-02-09 | Intra-Cellular Therapies, Inc. | Pyrazolo[3,4-D]pyrimidine-4,6(5H,7H)-diones as phosphodiesterase 1 inhibitors |
| US20070286890A1 (en) | 2006-06-07 | 2007-12-13 | John Garnett Walt | Eyelash applicator and method |
| US9198924B2 (en) | 2006-11-13 | 2015-12-01 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US9006258B2 (en) | 2006-12-05 | 2015-04-14 | Intra-Cellular Therapies, Inc. | Method of treating female sexual dysfunction with a PDE1 inhibitor |
| KR101227738B1 (ko) | 2007-12-06 | 2013-01-29 | 다케다 야쿠힌 고교 가부시키가이샤 | 유기 화합물 |
| AU2008331833A1 (en) | 2007-12-06 | 2009-06-11 | Intra-Cellular Therapies, Inc | Organic compounds |
| MX2011005935A (es) | 2008-12-06 | 2011-12-16 | Intra Cellular Therapies Inc | Compuestos organicos. |
| BRPI0922351A2 (pt) | 2008-12-06 | 2018-06-05 | Intracellular Therapies Inc | compostos orgânicos |
| JP5784501B2 (ja) | 2008-12-06 | 2015-09-24 | 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 |
| MA32940B1 (fr) | 2008-12-06 | 2012-01-02 | Intra Cellular Therapies Inc | Composes organiques |
| ES2638912T3 (es) | 2008-12-06 | 2017-10-24 | Intra-Cellular Therapies, Inc. | Compuestos orgánicos |
| AU2009322903A1 (en) | 2008-12-06 | 2010-06-10 | Intra-Cellular Therapies, Inc. | Organic compounds |
| US11464781B2 (en) * | 2009-02-25 | 2022-10-11 | Intra-Cellular Therapies, Inc. | PDE1 inhibitors for ophthalmic disorders |
| EP2434895A4 (en) | 2009-05-13 | 2013-08-07 | Intra Cellular Therapies Inc | ORGANIC CONNECTIONS |
| EP2485771A4 (en) | 2009-10-08 | 2014-11-12 | Intra Cellular Therapies Inc | TRACER AND METHODS TAGGED ON PHOSPHODIESTERASE 1 |
| JP5894574B2 (ja) | 2010-04-22 | 2016-03-30 | 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 |
| EP2575817A4 (en) | 2010-05-31 | 2014-01-08 | Intra Cellular Therapies Inc | ORGANIC CONNECTIONS |
| JP5894148B2 (ja) | 2010-05-31 | 2016-03-23 | 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 |
| TW201206937A (en) | 2010-05-31 | 2012-02-16 | Intra Cellular Therapies Inc | Organic compounds |
| US9763948B2 (en) | 2010-05-31 | 2017-09-19 | Intra-Cellular Therapies, Inc. | PDE1 inhibitory compounds and methods |
| WO2012171016A1 (en) * | 2011-06-10 | 2012-12-13 | 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 |
| 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 |
| RU2679142C2 (ru) | 2013-03-15 | 2019-02-06 | Интра-Селлулар Терапиз, Инк. | Органические соединения |
| ES2871327T3 (es) | 2013-03-15 | 2021-10-28 | Intra Cellular Therapies Inc | Inhibidores de la PDE1 para uso en el tratamiento y/o prevención de enfermedades o trastornos de SNC o SNP |
| EP3970719A1 (en) | 2016-09-12 | 2022-03-23 | Intra-Cellular Therapies, Inc. | Pde1 inhibitor for use in a method of treatment or prophylaxis of inflammation and/or an inflammatory disease or disorder |
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2014
- 2014-03-17 ES ES18205841T patent/ES2871327T3/es active Active
- 2014-03-17 US US14/777,448 patent/US9545406B2/en active Active
- 2014-03-17 ES ES14763482T patent/ES2717688T3/es active Active
- 2014-03-17 EP EP18205841.2A patent/EP3479825B1/en active Active
- 2014-03-17 EP EP14763482.8A patent/EP2968338B1/en active Active
- 2014-03-17 WO PCT/US2014/030412 patent/WO2014145617A2/en not_active Ceased
- 2014-03-17 JP JP2016503395A patent/JP2016518343A/ja not_active Withdrawn
-
2017
- 2017-01-13 US US15/406,346 patent/US10183023B2/en active Active
-
2018
- 2018-10-25 JP JP2018200930A patent/JP2019031544A/ja not_active Withdrawn
- 2018-12-13 US US16/219,589 patent/US10682355B2/en active Active
-
2020
- 2020-03-02 JP JP2020034938A patent/JP2020105186A/ja active Pending
- 2020-05-20 US US16/879,676 patent/US11504372B2/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| ES2717688T3 (es) | 2019-06-24 |
| US20170128453A1 (en) | 2017-05-11 |
| US20200375994A1 (en) | 2020-12-03 |
| JP2020105186A (ja) | 2020-07-09 |
| US10682355B2 (en) | 2020-06-16 |
| EP3479825B1 (en) | 2021-02-17 |
| US20190192519A1 (en) | 2019-06-27 |
| EP2968338A2 (en) | 2016-01-20 |
| US20160045507A1 (en) | 2016-02-18 |
| US10183023B2 (en) | 2019-01-22 |
| EP3479825A1 (en) | 2019-05-08 |
| JP2019031544A (ja) | 2019-02-28 |
| WO2014145617A3 (en) | 2015-01-29 |
| WO2014145617A2 (en) | 2014-09-18 |
| US9545406B2 (en) | 2017-01-17 |
| US11504372B2 (en) | 2022-11-22 |
| JP2016518343A (ja) | 2016-06-23 |
| EP2968338A4 (en) | 2016-12-21 |
| EP2968338B1 (en) | 2019-01-09 |
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