KR102531693B1 - 6,7―디히드로피라졸로[1,5―a]피라진―4(5H)―온 화합물 및 MGLUR2 수용체의 음성 알로스테릭 조절제로서의 그 용도 - Google Patents
6,7―디히드로피라졸로[1,5―a]피라진―4(5H)―온 화합물 및 MGLUR2 수용체의 음성 알로스테릭 조절제로서의 그 용도 Download PDFInfo
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- KR102531693B1 KR102531693B1 KR1020177005638A KR20177005638A KR102531693B1 KR 102531693 B1 KR102531693 B1 KR 102531693B1 KR 1020177005638 A KR1020177005638 A KR 1020177005638A KR 20177005638 A KR20177005638 A KR 20177005638A KR 102531693 B1 KR102531693 B1 KR 102531693B1
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Classifications
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- C—CHEMISTRY; METALLURGY
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- 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
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP14179599 | 2014-08-01 | ||
| EP14179599.7 | 2014-08-01 | ||
| PCT/EP2015/067533 WO2016016381A1 (en) | 2014-08-01 | 2015-07-30 | 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5h)-one compounds and their use as negative allosteric modulators of mglur2 receptors |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20170032464A KR20170032464A (ko) | 2017-03-22 |
| KR102531693B1 true KR102531693B1 (ko) | 2023-05-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020177005638A Active KR102531693B1 (ko) | 2014-08-01 | 2015-07-30 | 6,7―디히드로피라졸로[1,5―a]피라진―4(5H)―온 화합물 및 MGLUR2 수용체의 음성 알로스테릭 조절제로서의 그 용도 |
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| Country | Link |
|---|---|
| US (1) | US10112949B2 (enExample) |
| EP (1) | EP3174880B1 (enExample) |
| JP (1) | JP6615864B2 (enExample) |
| KR (1) | KR102531693B1 (enExample) |
| CN (1) | CN106573935B (enExample) |
| AR (1) | AR101393A1 (enExample) |
| AU (1) | AU2015295299B2 (enExample) |
| BR (1) | BR112017001998A2 (enExample) |
| CA (1) | CA2954218C (enExample) |
| EA (1) | EA031038B1 (enExample) |
| ES (1) | ES2702192T3 (enExample) |
| JO (1) | JO3601B1 (enExample) |
| MX (1) | MX2017001453A (enExample) |
| TW (1) | TWI696625B (enExample) |
| WO (1) | WO2016016381A1 (enExample) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JOP20150179B1 (ar) | 2014-08-01 | 2021-08-17 | Janssen Pharmaceutica Nv | مركبات 6 ، 7 ثاني هيدرو بيرازولو [ 1، 5 الفا ] بيرازين – 4 (5 يد) – اون واستخدامها كمنظمات الوسترية سلبية لمستقبلات ملجور 2 |
| JOP20150177B1 (ar) | 2014-08-01 | 2021-08-17 | Janssen Pharmaceutica Nv | مركبات 6 ، 7 ثاني هيدرو بيرازولو [ 1، 5 الفا ] بيرازين – 4 (5 يد) – اون واستخدامها كمنظمات الوسترية سلبية لمستقبلات ملجور 2 |
| US10967078B2 (en) | 2014-12-03 | 2021-04-06 | Janssen Pharmaceutica Nv | Radiolabelled mGluR2 PET ligands |
| AU2015357167B2 (en) | 2014-12-03 | 2020-06-25 | Janssen Pharmaceutica Nv | 6,7-dihydropyrazolo(1,5-alpha)pyrazin-4(5H)-one compounds and their use as negative allosteric modulators of mGluR2 receptors |
| RS60981B1 (sr) * | 2015-12-18 | 2020-11-30 | Janssen Pharmaceutica Nv | Radiooznačeni mglur2/3 pet ligandi |
| ES2820823T3 (es) | 2015-12-18 | 2021-04-22 | Janssen Pharmaceutica Nv | Ligandos PET mGluR2/3 radiomarcados |
| EP3719023B1 (en) | 2017-11-24 | 2024-10-16 | Sumitomo Pharma Co., Ltd. | 6,7-DIHYDROPYRAZOLO[1,5-a]PYRAZINONE DERIVATIVE AND MEDICAL USE THEREOF |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012083224A1 (en) | 2010-12-17 | 2012-06-21 | Vanderbilt University | Bicyclic triazole and pyrazole lactams as allosteric modulators of mglur5 receptors |
| WO2013192350A1 (en) | 2012-06-20 | 2013-12-27 | Vanderbilt University | Substituted bicyclic aralkyl pyrazole lactam analogs as allosteric modulators of mglur5 receptors |
| WO2013192343A1 (en) | 2012-06-20 | 2013-12-27 | Vanderbilt University | Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors |
| WO2013192347A1 (en) | 2012-06-20 | 2013-12-27 | Vanderbilt University | Substituted bicyclic cycloalkyl pyrazole lactam analogs as allosteric modulators of mglur5 receptors |
Family Cites Families (8)
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| DE102004054665A1 (de) * | 2004-11-12 | 2006-05-18 | Bayer Cropscience Gmbh | Substituierte bi- und tricyclische Pyrazol-Derivate Verfahren zur Herstellung und Verwendung als Herbizide und Pflanzenwachstumsregulatoren |
| DK1863818T3 (da) * | 2005-03-23 | 2010-05-10 | Hoffmann La Roche | Acetylenyl-pyrazolo-pyrimidinderivater som mglur2-antagonister |
| ES2440001T3 (es) | 2009-05-12 | 2014-01-27 | Janssen Pharmaceuticals, Inc. | Derivados de 1,2,4-triazolo[4,3-A]piridina y su uso para el tratamiento o prevención de trastornos neurológicos y psiquiátricos |
| WO2012172093A1 (en) * | 2011-06-17 | 2012-12-20 | Merz Pharma Gmbh & Co. Kgaa | Dihydroindolizine derivate as metabotropic glutamate receptor modulators |
| CA2853923A1 (en) | 2011-11-03 | 2013-05-10 | Merck Sharp & Dohme Corp. | Quinoline carboxamide and quinoline carbonitrile derivatives as mglur2-negative allosteric modulators, compositions, and their use |
| EP2666775A1 (en) | 2012-05-21 | 2013-11-27 | Domain Therapeutics | Substituted pyrazoloquinazolinones and pyrroloquinazolinones as allosteric modulators of group II metabotropic glutamate receptors |
| RU2015116749A (ru) * | 2012-10-23 | 2016-12-20 | Ф. Хоффманн-Ля Рош Аг | Антагонисты mglu2/3 для лечения аутических расстройств |
| EP3174882B1 (en) * | 2014-08-01 | 2018-11-07 | Janssen Pharmaceutica NV | 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5h)-one compounds and their use as negative allosteric modulators of mglu2 receptors |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012083224A1 (en) | 2010-12-17 | 2012-06-21 | Vanderbilt University | Bicyclic triazole and pyrazole lactams as allosteric modulators of mglur5 receptors |
| WO2013192350A1 (en) | 2012-06-20 | 2013-12-27 | Vanderbilt University | Substituted bicyclic aralkyl pyrazole lactam analogs as allosteric modulators of mglur5 receptors |
| WO2013192343A1 (en) | 2012-06-20 | 2013-12-27 | Vanderbilt University | Substituted bicyclic alkoxy pyrazole analogs as allosteric modulators of mglur5 receptors |
| WO2013192347A1 (en) | 2012-06-20 | 2013-12-27 | Vanderbilt University | Substituted bicyclic cycloalkyl pyrazole lactam analogs as allosteric modulators of mglur5 receptors |
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| BR112017001998A2 (pt) | 2017-12-12 |
| US20180222908A1 (en) | 2018-08-09 |
| WO2016016381A1 (en) | 2016-02-04 |
| EA201692496A1 (ru) | 2017-06-30 |
| AU2015295299B2 (en) | 2019-05-02 |
| AU2015295299A1 (en) | 2017-01-19 |
| CN106573935B (zh) | 2020-01-17 |
| CA2954218A1 (en) | 2016-02-04 |
| ES2702192T3 (es) | 2019-02-27 |
| CA2954218C (en) | 2022-11-29 |
| TWI696625B (zh) | 2020-06-21 |
| EP3174880B1 (en) | 2018-09-26 |
| EP3174880A1 (en) | 2017-06-07 |
| AR101393A1 (es) | 2016-12-14 |
| MX2017001453A (es) | 2017-05-11 |
| KR20170032464A (ko) | 2017-03-22 |
| US10112949B2 (en) | 2018-10-30 |
| EA031038B1 (ru) | 2018-11-30 |
| JO3601B1 (ar) | 2020-07-05 |
| JP6615864B2 (ja) | 2019-12-04 |
| JP2017523201A (ja) | 2017-08-17 |
| CN106573935A (zh) | 2017-04-19 |
| TW201609742A (zh) | 2016-03-16 |
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