EA018378B1 - ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 3-ИЗОБУТИЛ-9,10-ДИМЕТОКСИ-1,3,4,6,7,11b-ГЕКСАГИДРО-2Н-ПИРИДО[2,1-a]ИЗОХИНОЛИН-2-ОЛА И СВЯЗАННЫЕ С НИМИ СПОСОБЫ - Google Patents
ЗАМЕЩЕННЫЕ ПРОИЗВОДНЫЕ 3-ИЗОБУТИЛ-9,10-ДИМЕТОКСИ-1,3,4,6,7,11b-ГЕКСАГИДРО-2Н-ПИРИДО[2,1-a]ИЗОХИНОЛИН-2-ОЛА И СВЯЗАННЫЕ С НИМИ СПОСОБЫ Download PDFInfo
- Publication number
- EA018378B1 EA018378B1 EA200970461A EA200970461A EA018378B1 EA 018378 B1 EA018378 B1 EA 018378B1 EA 200970461 A EA200970461 A EA 200970461A EA 200970461 A EA200970461 A EA 200970461A EA 018378 B1 EA018378 B1 EA 018378B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- isobutyl
- pyrido
- hexahydro
- compounds
- compound
- Prior art date
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
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| US86494406P | 2006-11-08 | 2006-11-08 | |
| PCT/US2007/084176 WO2008058261A1 (en) | 2006-11-08 | 2007-11-08 | Substituted 3-isobutyl-9, 10-dimethoxy-1,3,4,6,7,11b-hexahydro-2h-pyrido[2,1-a] isoquinolin-2-ol compounds and methods relating thereto |
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| EA200970461A1 EA200970461A1 (ru) | 2009-12-30 |
| EA018378B1 true EA018378B1 (ru) | 2013-07-30 |
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| CA (1) | CA2668689C (enExample) |
| DK (1) | DK2081929T3 (enExample) |
| EA (1) | EA018378B1 (enExample) |
| ES (1) | ES2402220T3 (enExample) |
| IL (1) | IL198250A0 (enExample) |
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| PT (1) | PT2081929E (enExample) |
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| US11654142B2 (en) | 2017-10-10 | 2023-05-23 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
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| WO2025038959A1 (en) | 2023-08-17 | 2025-02-20 | Neurocrine Biosciences, Inc. | Methods for the administration of certain vmat2 inhibitors |
| TW202521119A (zh) | 2023-08-17 | 2025-06-01 | 美商紐羅克里生物科學有限公司 | 用於投與特定vmat2抑制劑之方法 |
| WO2025096823A1 (en) | 2023-11-01 | 2025-05-08 | Neurocrine Biosciences, Inc. | Improvement, maintenance or reduction of decline of motor function associated with huntington disease using valbenazine |
| WO2025188830A1 (en) | 2024-03-06 | 2025-09-12 | Neurocrine Biosciences, Inc. | Methods for the administration of certain vmat2 inhibitors |
| WO2025199234A1 (en) | 2024-03-20 | 2025-09-25 | Neurocrine Biosciences, Inc. | Vmat2 inhibitors and methods of use |
| WO2026050236A1 (en) | 2024-08-27 | 2026-03-05 | Neurocrine Biosciences, Inc. | Muscarinic receptor agonist in combination with a vesicular monoamine transporter 2 inhibitor, for use in the treatment of a neurological or psychiatric disorder |
| WO2026126112A1 (en) | 2024-12-10 | 2026-06-18 | Lupin Limited | Liquid compositions of valbenazine for oral administration |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2843591A (en) * | 1958-07-15 | Method for preparing same | ||
| US3209005A (en) * | 1965-09-28 | Hexahydro-llbh-benzo[a] quinolizines and processes therefor | ||
| US2852518A (en) * | 1957-05-23 | 1958-09-16 | Parke Davis & Co | Di-substituted quinoline compounds |
| AU7872491A (en) | 1990-05-07 | 1991-11-27 | Vical, Inc. | Lipid prodrugs of salicylate and nonsteroidal anti-inflammatory drugs |
| US6610841B1 (en) | 1997-12-18 | 2003-08-26 | Gilead Sciences, Inc. | Nucleotide-based prodrugs |
| US7045543B2 (en) * | 2001-11-05 | 2006-05-16 | Enzrel Inc. | Covalent conjugates of biologically-active compounds with amino acids and amino acid derivatives for targeting to physiologically-protected sites |
| GB2410947B (en) * | 2004-02-11 | 2008-09-17 | Cambridge Lab Ltd | Pharmaceutical compounds |
| WO2006053067A2 (en) | 2004-11-09 | 2006-05-18 | Prestwick Pharmaceuticals, Inc. | Combination of amantadine and a tetrabenazine compound for treating hyperkinetic disorders |
| CA2623794A1 (en) | 2005-06-29 | 2007-01-11 | The Trustees Of Columbia University In The City Of New York | Use of dtbz for imaging endocrine pancreas and beta cell mass in type 1 diabetes |
| GB0514501D0 (en) | 2005-07-14 | 2005-08-24 | Cambridge Lab Ireland Ltd | Pharmaceutical compounds |
| GB0516168D0 (en) | 2005-08-05 | 2005-09-14 | Cambridge Lab Ireland Ltd | Pharmaceutical compounds |
| ES2318771T3 (es) | 2005-08-06 | 2009-05-01 | Cambridge Laboratories (Ireland) Limited | 3,11b-cis-dihidrotetrabenazinas para el tratamiento de la esquizofrenia y otras psicosis. |
| DK2081929T3 (da) | 2006-11-08 | 2013-04-15 | Neurocrine Biosciences Inc | Substituerede 3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11B-hexahydro-2H-pyrido[2,1-A]isoquinolin-2-ol-forbindelser og fremgangsmåder angående disse |
-
2007
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-
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Non-Patent Citations (3)
| Title |
|---|
| ARANDA ET AL.: "Synthesis and biological activity of iodinated and photosensitive derivatives or tetrabenazine" EUREOPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 25, 1990, pages 369-374, XP002471185 compound 6 on page 372 * |
| BROSSI A. ET AL.: "SYNTHESEVERSUCHE IN DER EMETIN-REIHE 3. MITTEILUNG 2-HYDROXY-HYDROBENZOÄAÜCHINOLIZINE" HELVETICA CHIMICA ACTA, VERLAG HELVETICA CHIMICA ACTA. BASEL, CH, vol. 41, no. 4, 1958, pages 1793-1806, XP008047475 ISSN: 0018-019X acetate ester on page 1798 isobutyl ester in table 4, 9th compound * |
| KILBOURN M.R. ET AL.: "Absolute Configuration of (+)-alpha-Dihydrotetrabenazine, an Active Metabolite of Tetrabenazine" CHIRALITY, WILEY-LISS, NEW YORK, US, vol. 9, no. 1, 1997, pages 59-62, XP002329921 ISSN: 0899-0042 cited in the application acetate ester on page 60 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2753740C2 (ru) * | 2014-05-06 | 2021-08-23 | Ньюрокрайн Байосайенсиз, Инк. | Лечение гиперкинетических двигательных расстройств |
| US11439629B2 (en) | 2017-01-27 | 2022-09-13 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
| US11311532B2 (en) | 2017-09-21 | 2022-04-26 | Neurocrine Biosciences, Inc. | High dosage valbenazine formulation and compositions, methods, and kits related thereto |
| US11654142B2 (en) | 2017-10-10 | 2023-05-23 | Neurocrine Biosciences, Inc. | Methods for the administration of certain VMAT2 inhibitors |
Also Published As
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| IL198250A0 (en) | 2009-12-24 |
| MX2009004910A (es) | 2009-07-24 |
| AU2007317242B2 (en) | 2013-08-01 |
| ES2402220T8 (es) | 2021-12-23 |
| KR101500766B9 (ko) | 2024-09-25 |
| JP2010509366A (ja) | 2010-03-25 |
| DK2081929T3 (da) | 2013-04-15 |
| CN101553487A (zh) | 2009-10-07 |
| EA200970461A1 (ru) | 2009-12-30 |
| PT2081929E (pt) | 2013-04-15 |
| CA2668689A1 (en) | 2008-05-15 |
| BRPI0718247A2 (pt) | 2014-01-07 |
| CA2668689C (en) | 2015-12-29 |
| US8357697B2 (en) | 2013-01-22 |
| US8039627B2 (en) | 2011-10-18 |
| EP2081929B1 (en) | 2013-01-09 |
| PL2081929T3 (pl) | 2013-06-28 |
| US20080167337A1 (en) | 2008-07-10 |
| ES2402220T3 (es) | 2013-04-29 |
| KR101500766B1 (ko) | 2015-03-16 |
| WO2008058261A1 (en) | 2008-05-15 |
| EP2081929A1 (en) | 2009-07-29 |
| US20120077839A1 (en) | 2012-03-29 |
| KR20090079257A (ko) | 2009-07-21 |
| JP5290185B2 (ja) | 2013-09-18 |
| BRPI0718247B1 (pt) | 2021-09-21 |
| AU2007317242A1 (en) | 2008-05-15 |
| CN101553487B (zh) | 2012-06-13 |
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