NO324324B1 - Laktamforbindelse samt farmasoytisk sammensetning inneholdende denne - Google Patents
Laktamforbindelse samt farmasoytisk sammensetning inneholdende denne Download PDFInfo
- Publication number
- NO324324B1 NO324324B1 NO20032236A NO20032236A NO324324B1 NO 324324 B1 NO324324 B1 NO 324324B1 NO 20032236 A NO20032236 A NO 20032236A NO 20032236 A NO20032236 A NO 20032236A NO 324324 B1 NO324324 B1 NO 324324B1
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- tetrahydro
- benzazepin
- amino
- compound
- Prior art date
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- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- 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
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US24955200P | 2000-11-17 | 2000-11-17 | |
| PCT/US2001/027799 WO2002047671A2 (en) | 2000-11-17 | 2001-11-05 | Lactam compound to inhibit beta-amyloid peptide release or synthesis |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20032236D0 NO20032236D0 (no) | 2003-05-16 |
| NO20032236L NO20032236L (no) | 2003-07-10 |
| NO324324B1 true NO324324B1 (no) | 2007-09-24 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20032236A NO324324B1 (no) | 2000-11-17 | 2003-05-16 | Laktamforbindelse samt farmasoytisk sammensetning inneholdende denne |
Country Status (33)
| Country | Link |
|---|---|
| US (1) | US20050261495A1 (cs) |
| EP (1) | EP1341531B1 (cs) |
| JP (1) | JP4116437B2 (cs) |
| KR (1) | KR100819679B1 (cs) |
| CN (1) | CN1486184A (cs) |
| AR (1) | AR035927A1 (cs) |
| AU (2) | AU4319202A (cs) |
| BR (1) | BR0115427A (cs) |
| CA (1) | CA2427227C (cs) |
| CY (1) | CY1106366T1 (cs) |
| CZ (1) | CZ20031351A3 (cs) |
| DE (1) | DE60126132T2 (cs) |
| DK (1) | DK1341531T3 (cs) |
| DZ (1) | DZ3453A1 (cs) |
| EA (1) | EA005954B1 (cs) |
| EC (1) | ECSP034600A (cs) |
| ES (1) | ES2278804T3 (cs) |
| HR (1) | HRP20030383B1 (cs) |
| HU (1) | HU228117B1 (cs) |
| IL (2) | IL155960A0 (cs) |
| MX (1) | MXPA03004292A (cs) |
| MY (1) | MY134559A (cs) |
| NO (1) | NO324324B1 (cs) |
| NZ (1) | NZ525854A (cs) |
| PE (1) | PE20020802A1 (cs) |
| PL (1) | PL212199B1 (cs) |
| PT (1) | PT1341531E (cs) |
| SI (1) | SI1341531T1 (cs) |
| SK (1) | SK288065B6 (cs) |
| TW (1) | TWI305204B (cs) |
| UA (1) | UA74849C2 (cs) |
| WO (1) | WO2002047671A2 (cs) |
| ZA (1) | ZA200303789B (cs) |
Families Citing this family (49)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7468365B2 (en) | 2000-11-17 | 2008-12-23 | Eli Lilly And Company | Lactam compound |
| UA74849C2 (en) * | 2000-11-17 | 2006-02-15 | Lilly Co Eli | Lactam |
| NZ561961A (en) | 2005-04-08 | 2010-06-25 | Daiichi Sankyo Co Ltd | Pyridylmethylsulfone derivative |
| EP1888050B1 (en) | 2005-05-17 | 2012-03-21 | Merck Sharp & Dohme Ltd. | cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexanepropanoic acid for the treatment of cancer |
| US8258302B2 (en) | 2006-01-31 | 2012-09-04 | Api Corporation | Method for producing benzazepinone |
| JP2010518064A (ja) | 2007-02-12 | 2010-05-27 | メルク・シャープ・エンド・ドーム・コーポレイション | Ａｄおよび関連状態の治療のためのピペラジン誘導体 |
| PA8789701A1 (es) * | 2007-07-16 | 2009-04-23 | Wyeth Corp | Inhibidores de producción de beta amiloide |
| CN101778826B (zh) | 2007-08-14 | 2012-10-31 | 伊莱利利公司 | 作为γ分泌酶抑制剂的氮杂*衍生物 |
| TW200920362A (en) | 2007-09-11 | 2009-05-16 | Daiichi Sankyo Co Ltd | Alkylsulfone derivatives |
| CN101945853B (zh) | 2007-12-21 | 2014-08-20 | 配体药物公司 | 选择性雄激素受体调节剂(sarm)及其应用 |
| WO2009128057A2 (en) | 2008-04-18 | 2009-10-22 | UNIVERSITY COLLEGE DUBLIN, NATIONAL UNIVERSITY OF IRELAND, DUBLIN et al | Psycho-pharmaceuticals |
| WO2010114780A1 (en) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibitors of akt activity |
| EA023838B1 (ru) | 2009-10-14 | 2016-07-29 | Мерк Шарп Энд Домэ Корп. | ЗАМЕЩЕННЫЕ ПИПЕРИДИНЫ, КОТОРЫЕ ПОВЫШАЮТ АКТИВНОСТЬ p53, И ИХ ПРИМЕНЕНИЕ |
| WO2011163330A1 (en) | 2010-06-24 | 2011-12-29 | Merck Sharp & Dohme Corp. | Novel heterocyclic compounds as erk inhibitors |
| US8518907B2 (en) | 2010-08-02 | 2013-08-27 | Merck Sharp & Dohme Corp. | RNA interference mediated inhibition of catenin (cadherin-associated protein), beta 1 (CTNNB1) gene expression using short interfering nucleic acid (siNA) |
| RU2745848C2 (ru) | 2010-08-17 | 2021-04-01 | Сирна Терапьютикс, Инк. | ОПОСРЕДУЕМОЕ РНК-ИНТЕРФЕРЕНЦИЕЙ ИНГИБИРОВАНИЕ ЭКСПРЕССИИ ГЕНОВ ВИРУСА ГЕПАТИТА B (HBV) С ПРИМЕНЕНИЕМ МАЛОЙ ИНТЕРФЕРИРУЮЩЕЙ НУКЛЕИНОВОЙ КИСЛОТЫ (миНК) |
| EP2613782B1 (en) | 2010-09-01 | 2016-11-02 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as erk inhibitors |
| US9242981B2 (en) | 2010-09-16 | 2016-01-26 | Merck Sharp & Dohme Corp. | Fused pyrazole derivatives as novel ERK inhibitors |
| WO2012040444A2 (en) * | 2010-09-24 | 2012-03-29 | Bristol-Myers Squibb Company | Treatment of patients with incipient alzheimer's disease |
| US9260471B2 (en) | 2010-10-29 | 2016-02-16 | Sirna Therapeutics, Inc. | RNA interference mediated inhibition of gene expression using short interfering nucleic acids (siNA) |
| US9351965B2 (en) | 2010-12-21 | 2016-05-31 | Merck Sharp & Dohme Corp. | Indazole derivatives useful as ERK inhibitors |
| WO2013063214A1 (en) | 2011-10-27 | 2013-05-02 | Merck Sharp & Dohme Corp. | Novel compounds that are erk inhibitors |
| CN102690231B (zh) * | 2012-04-11 | 2014-07-09 | 南京友杰医药科技有限公司 | 治疗阿尔茨海默病潜在药物司马西特的合成方法 |
| EP3358013B1 (en) | 2012-05-02 | 2020-06-24 | Sirna Therapeutics, Inc. | Short interfering nucleic acid (sina) compositions |
| WO2014039908A1 (en) | 2012-09-07 | 2014-03-13 | Massachusetts Eye And Ear Infirmary | Methods and compositions for regenerating hair cells and/or supporting cells |
| HK1211875A1 (en) | 2012-09-07 | 2016-06-03 | Massachusetts Eye & Ear Infirmary | Treating hearing loss |
| JP6280554B2 (ja) | 2012-09-28 | 2018-02-14 | メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． | Ｅｒｋ阻害剤である新規化合物 |
| PT2925888T (pt) | 2012-11-28 | 2017-12-13 | Merck Sharp & Dohme | Composições e métodos para tratamento do cancro |
| EP2935263B1 (en) | 2012-12-20 | 2018-12-05 | Merck Sharp & Dohme Corp. | Substituted imidazopyridines as hdm2 inhibitors |
| WO2014120748A1 (en) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | 2,6,7,8 substituted purines as hdm2 inhibitors |
| US20160067306A1 (en) | 2013-04-19 | 2016-03-10 | National University Corporation Hokkaido University | Treatment agent for cognitive impairment induced by amyloid beta-protein, therapeutic agent for alzheimer's disease, and treatment method and pathological analysis method related to these |
| WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
| EP3094323A4 (en) | 2014-01-17 | 2017-10-11 | Ligand Pharmaceuticals Incorporated | Methods and compositions for modulating hormone levels |
| WO2016069906A1 (en) | 2014-10-29 | 2016-05-06 | Massachusetts Eye And Ear Infirmary | Efficient delivery of therapeutic molecules to cells of the inner ear |
| CA3024424A1 (en) | 2016-05-16 | 2017-11-23 | The General Hospital Corporation | Human airway stem cells in lung epithelial engineering |
| US10975084B2 (en) | 2016-10-12 | 2021-04-13 | Merck Sharp & Dohme Corp. | KDM5 inhibitors |
| US11098059B2 (en) | 2017-11-08 | 2021-08-24 | Merck Sharp & Dohme Corp. | PRMT5 inhibitors |
| WO2019094311A1 (en) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| WO2019148067A1 (en) | 2018-01-26 | 2019-08-01 | Massachusetts Eye And Ear Infirmary | Treatment of hearing loss |
| US11993602B2 (en) | 2018-08-07 | 2024-05-28 | Merck Sharp & Dohme Llc | PRMT5 inhibitors |
| CA3108388A1 (en) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| EP3833667B1 (en) | 2018-08-07 | 2024-03-13 | Merck Sharp & Dohme LLC | Prmt5 inhibitors |
| US12319651B2 (en) | 2019-04-19 | 2025-06-03 | Ligand Pharmaceuticals Incorporated | Crystalline forms and methods of producing crystalline forms of a compound |
| US20230108452A1 (en) | 2019-12-17 | 2023-04-06 | Merck Sharp & Dohme Llc | Prmt5 inhibitors |
| US20230108114A1 (en) | 2019-12-17 | 2023-04-06 | Merck Sharp & Dohme Llc | Prmt5 inhibitors |
| WO2021126729A1 (en) | 2019-12-17 | 2021-06-24 | Merck Sharp & Dohme Corp. | Prmt5 inhibitors |
| IL319241A (en) | 2022-09-02 | 2025-04-01 | Merck Sharp & Dohme Llc | Pharmaceutical preparations of topoisomerase-1 inhibitors of extacan derivatives, and their uses |
| TW202432099A (zh) | 2022-10-25 | 2024-08-16 | 美商默沙東有限責任公司 | 源自依克沙替康(exatecan)之adc連接子-載藥(payload)、醫藥組合物及其用途 |
| JP2025522671A (ja) | 2022-12-14 | 2025-07-17 | メルク・シャープ・アンド・ドーム・エルエルシー | アウリスタチンリンカー－ペイロード、医薬組成物及びその使用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2319239T3 (es) * | 1996-12-23 | 2009-05-05 | Elan Pharmaceuticals, Inc. | Cicloalquilo, lactama, lactona y compuestos relacionados, composiciones farmaceuticas que comprenden los mismos y procedimientos para inhibir la liberacion del peptido beta-amiloide y/o sintesis mediante el uso de tales compuestos. |
| EP1089977A1 (en) * | 1998-06-22 | 2001-04-11 | Elan Pharmaceuticals, Inc. | Compounds for inhibiting beta-amyloid peptide release and/or its synthesis |
| CA2390376A1 (en) * | 1999-11-09 | 2001-05-17 | William Leonard Scott | .beta.-aminoacid compounds useful for inhibiting .beta.-amyloid peptide release and/or its synthesis |
| UA74849C2 (en) * | 2000-11-17 | 2006-02-15 | Lilly Co Eli | Lactam |
| UA77165C2 (en) * | 2000-11-17 | 2006-11-15 | Lilly Co Eli | (n)-((s)-2-hydroxy-3-methyl-butyryl)-1-(l-alaninyl)-(s)-1-amino-3-methyl-4,5,6,7-tetrahydro-2h-3-benzazepin-2-one dihydrate, processes for manufacturing and pharmaceutical composition |
| ES2311561T3 (es) * | 2000-11-17 | 2009-02-16 | Eli Lilly And Company | Dipeptido de lactama y su uso en la inhibicion de la liberacion del peptido beta amiloide. |
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