TWI729109B - 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 - Google Patents
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 Download PDFInfo
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- TWI729109B TWI729109B TW106111366A TW106111366A TWI729109B TW I729109 B TWI729109 B TW I729109B TW 106111366 A TW106111366 A TW 106111366A TW 106111366 A TW106111366 A TW 106111366A TW I729109 B TWI729109 B TW I729109B
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- Prior art keywords
- methyl
- pyrazolo
- group
- pyridin
- tetrahydropiperan
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- 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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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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| 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 |
| JO3627B1 (ar) | 2015-04-30 | 2020-08-27 | H Lundbeck As | إيميدازو بيرازينونات على هيئة مثبطات pde1 |
| 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 |
| EP3529250B1 (en) | 2016-10-18 | 2023-12-06 | H. Lundbeck A/S | Imidazopyrazinones, pyrazolopyrimidinones and pyrazolopyridinones as pde1 inhibitors |
| BR112018013084A2 (pt) | 2016-10-28 | 2018-12-11 | H Lundbeck As | tratamentos de combinação compreendendo a administração de imidazopirazinonas |
| SG11201903770UA (en) | 2016-10-28 | 2019-05-30 | H Lundbeck As | Combination treatments comprising imidazopyrazinones for the treatment of psychiatric and/or cognitive disorders |
| KR102590848B1 (ko) | 2016-12-28 | 2023-10-19 | 다트 뉴로사이언스, 엘엘씨 | Pde2 억제제로서 치환된 피라졸로피리미디논 화합물 |
| ES2902365T3 (es) * | 2017-11-27 | 2022-03-28 | Dart Neuroscience Llc | Compuestos de furanopirimidina sustituidos como inhibidores de PDE1 |
| KR20210013214A (ko) | 2018-05-25 | 2021-02-03 | 인트라-셀룰라 써래피스, 인코퍼레이티드. | 유기 화합물 |
| WO2020210614A1 (en) | 2019-04-12 | 2020-10-15 | Intra-Cellular Therapies, Inc. | Organic compounds |
| CN115304607B (zh) * | 2022-07-06 | 2023-06-27 | 华南农业大学 | 吡唑并嘧啶衍生物的制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004018474A1 (de) * | 2002-08-23 | 2004-03-04 | Bayer Healthcare Ag | Phenyl-substituierte pyrazolopyrimidine |
| WO2004026876A1 (de) * | 2002-08-23 | 2004-04-01 | Bayer Healthcare Ag | Alkyl-substituierte pyrazolopyrimidine |
Family Cites Families (40)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB973361A (en) * | 1960-05-11 | 1964-10-28 | Ciba Ltd | Pyrazolo-pyrimidines and process for their manufacture |
| DE19709877A1 (de) | 1997-03-11 | 1998-09-17 | Bayer Ag | 1,5-Dihydro-pyrazolo[3,4-d]-pyrimidinon-derivate |
| DE10238722A1 (de) * | 2002-08-23 | 2004-03-11 | Bayer Ag | Selektive Phosphodiesterase 9A-Inhibitoren als Arzneimittel zur Verbesserung kognitiver Prozesse |
| EP1626971B1 (de) * | 2003-05-09 | 2011-08-10 | Boehringer Ingelheim International Gmbh | 6-cyclylmethyl- und 6-alkylmethyl-substituierte pyrazolopyrimidine |
| EP1828192B1 (en) | 2004-12-21 | 2014-12-03 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
| US20080194592A1 (en) | 2005-08-23 | 2008-08-14 | Intra-Cellular Therapies, Inc. | Organic Compounds |
| US8012936B2 (en) | 2006-03-29 | 2011-09-06 | New York University | Tau fragments for immunotherapy |
| EP2089034A4 (en) | 2006-12-05 | 2010-07-28 | Intra Cellular Therapies Inc | NEW USES |
| MX2009011830A (es) | 2007-05-11 | 2009-11-13 | Pfizer | Compuestos amino-heterociclicos. |
| WO2009068320A1 (en) | 2007-11-30 | 2009-06-04 | Elbion Gmbh | Aryl and heteroaryl fused imidazo (1,5-a) pyrazines as inhibitors of phosphodiesterase 10 |
| UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
| CN102143965A (zh) | 2008-09-08 | 2011-08-03 | 贝林格尔.英格海姆国际有限公司 | 吡唑并嘧啶酮及其在治疗中枢神经系统疾病中的用途 |
| EA201170772A1 (ru) | 2008-12-06 | 2012-03-30 | Интра-Селлулар Терапиз, Инк. | Органические соединения |
| TWI404721B (zh) | 2009-01-26 | 2013-08-11 | Pfizer | 胺基－雜環化合物 |
| US9434730B2 (en) * | 2010-05-31 | 2016-09-06 | Intra-Cellular Therapies, Inc. | PDE1 inhibitor compounds |
| AU2011305568B2 (en) | 2010-09-20 | 2015-12-10 | Ironwood Pharmaceuticals, Inc. | Imidazotriazinone compounds |
| WO2012040048A2 (en) | 2010-09-21 | 2012-03-29 | Schering Corporation | Triazolopyrazinones as p2x7 receptor antagonists |
| JO3089B1 (ar) | 2010-11-19 | 2017-03-15 | H Lundbeck As | مشتقات ايميدازول كمثبطات لانزيمات pde10a |
| US9499610B2 (en) | 2011-04-08 | 2016-11-22 | H. Lundbeck A/S | Antibodies specific to pyroglutamated Aβ |
| WO2012171016A1 (en) | 2011-06-10 | 2012-12-13 | Intra-Cellular Therapies, Inc. | Organic 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 |
| CA2877146C (en) | 2012-06-18 | 2020-10-20 | Dart Neuroscience (Cayman) Ltd | Substituted thiophene- and furan-fused azolopyrimidine-5-(6h)-one compounds |
| US9598426B2 (en) | 2013-03-15 | 2017-03-21 | Intra-Cellular Therapies, Inc. | Organic compounds |
| JP5783297B2 (ja) | 2013-08-06 | 2015-09-24 | 株式会社デンソー | 力学量センサ |
| TW201609713A (zh) * | 2013-12-19 | 2016-03-16 | Ｈ 朗德貝克公司 | 作爲ｐｄｅ１抑制劑之喹唑啉－ｔｈｆ－胺 |
| JP5797815B1 (ja) | 2014-06-27 | 2015-10-21 | 細田建設株式会社 | 後施工アンカー及びその施工方法 |
| US20160083391A1 (en) | 2014-09-18 | 2016-03-24 | Sunovion Pharmaceuticals Inc. | Tricyclic piperazine derivative |
| WO2016042775A1 (en) | 2014-09-18 | 2016-03-24 | Sunovion Pharmaceuticals Inc. | Tricyclic derivative |
| US20160083400A1 (en) | 2014-09-18 | 2016-03-24 | Sunovion Pharmaceuticals Inc. | Tricyclic guanidine derivative |
| 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 |
| AR107456A1 (es) | 2016-02-12 | 2018-05-02 | Lilly Co Eli | Inhibidor de pde1 |
| 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 |
| JP2018076285A (ja) | 2016-09-14 | 2018-05-17 | 大日本住友製薬株式会社 | 二環性イミダゾロ誘導体を含む医薬 |
| 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 |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004018474A1 (de) * | 2002-08-23 | 2004-03-04 | Bayer Healthcare Ag | Phenyl-substituierte pyrazolopyrimidine |
| WO2004026876A1 (de) * | 2002-08-23 | 2004-04-01 | Bayer Healthcare Ag | Alkyl-substituierte pyrazolopyrimidine |
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