AU728001B2 - Opioid antagonists and methods of their use - Google Patents
Opioid antagonists and methods of their use Download PDFInfo
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- AU728001B2 AU728001B2 AU67769/96A AU6776996A AU728001B2 AU 728001 B2 AU728001 B2 AU 728001B2 AU 67769/96 A AU67769/96 A AU 67769/96A AU 6776996 A AU6776996 A AU 6776996A AU 728001 B2 AU728001 B2 AU 728001B2
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- peptide
- opioid
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
-
- 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
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/36—Opioid-abuse
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Neurology (AREA)
- Neurosurgery (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Psychiatry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/514451 | 1995-08-11 | ||
| US08/514,451 US5837809A (en) | 1995-08-11 | 1995-08-11 | Mammalian opioid receptor ligand and uses |
| US08/553058 | 1995-11-03 | ||
| US08/553,058 US5821219A (en) | 1995-08-11 | 1995-11-03 | Opioid antagonists and methods of their use |
| PCT/US1996/013305 WO1997007212A1 (en) | 1995-08-11 | 1996-08-12 | Opioid antagonists and methods of their use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU6776996A AU6776996A (en) | 1997-03-12 |
| AU728001B2 true AU728001B2 (en) | 2001-01-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU67769/96A Ceased AU728001B2 (en) | 1995-08-11 | 1996-08-12 | Opioid antagonists and methods of their use |
Country Status (8)
| Country | Link |
|---|---|
| US (1) | US5821219A (https=) |
| EP (1) | EP0843726B1 (https=) |
| JP (1) | JP3868494B2 (https=) |
| AT (1) | ATE323160T1 (https=) |
| AU (1) | AU728001B2 (https=) |
| CA (1) | CA2229126A1 (https=) |
| DE (1) | DE69636037D1 (https=) |
| WO (1) | WO1997007212A1 (https=) |
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| EP0813065A3 (en) * | 1996-06-13 | 1998-07-22 | F. Hoffmann-La Roche Ag | Modulation of LC132 (opioid-like) receptor function |
| CA2206192A1 (en) | 1996-06-13 | 1997-12-13 | F. Hoffmann-La Roche Ag | Modulation of lc132 (opioid-like) receptor function |
| WO1999003880A1 (en) * | 1997-07-15 | 1999-01-28 | Novo Nordisk A/S | Nociceptin analogues |
| WO1999003491A1 (en) * | 1997-07-15 | 1999-01-28 | Novo Nordisk A/S | New use of nociceptin |
| US5929035A (en) * | 1998-04-14 | 1999-07-27 | Regents Of The University Of Michigan | Methods of treating intestinal disorders |
| GB9815618D0 (en) * | 1998-07-18 | 1998-09-16 | Univ Manchester | Treatment of dyskinesia |
| MA26659A1 (fr) | 1998-08-06 | 2004-12-20 | Pfizer | Dérivés de benzimidazole nouveaux, compositions pharmaceutiques les contenant et procédé pour leur préparation. |
| US6582457B2 (en) * | 2001-02-15 | 2003-06-24 | Radiant Medical, Inc. | Method of controlling body temperature while reducing shivering |
| US6849449B2 (en) * | 2001-03-01 | 2005-02-01 | Regents Of The University Of Michigan | Orphanin FQ receptor nucleic acids |
| EP1406629A1 (en) * | 2001-07-02 | 2004-04-14 | Omeros Corporation | Method for inducing analgesia comprising administration alternatively of an opioid receptor agonist and an opioid receptor like receptor 1 agonist for and an implantable infusion pump |
| US20030040479A1 (en) * | 2001-07-02 | 2003-02-27 | Omeros Corporation | Rotational intrathecal analgesia method and device |
| US7049287B2 (en) * | 2001-10-09 | 2006-05-23 | Synvax, Inc. | Nociceptin-based analgesics |
| EP1499888B1 (en) * | 2002-04-29 | 2010-07-07 | Euro-Celtique S.A. | Conformationally constrained peptides that bind the orl-1 receptor |
| WO2004013292A2 (en) * | 2002-08-02 | 2004-02-12 | Incyte Corporation | Extracellular messengers |
| NZ538307A (en) | 2002-09-09 | 2008-04-30 | Janssen Pharmaceutica Nv | Hydroxy alkyl substituted 1,3,8-triazaspiro[4.5]decan-4-one derivatives useful for the treatment of ORL-1 receptor mediated disorders |
| HRP20150037T4 (hr) | 2003-04-08 | 2022-09-02 | Progenics Pharmaceuticals, Inc. | Farmaceutske formulacije koje sadrže metilnaltrekson |
| US7173010B2 (en) * | 2003-05-19 | 2007-02-06 | Regents Of The University Of Michigan | Orphanin FQ receptor |
| US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| ES2714198T3 (es) | 2005-03-07 | 2019-05-27 | Univ Chicago | Uso de antagonistas opioideos para atenuar la proliferación y la migración de células endoteliales |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| AR057035A1 (es) | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SíNTESIS DE (R)-N-METILNALTREXONA, COMPOSICIONES FARMACÉUTICAS Y USOS |
| AR057325A1 (es) | 2005-05-25 | 2007-11-28 | Progenics Pharm Inc | Sintesis de (s)-n-metilnaltrexona, composiciones farmaceuticas y usos |
| US7655670B2 (en) | 2005-06-02 | 2010-02-02 | Janssen Pharmaceutica N.V. | 3-spirocyclic indolyl derivatives useful as ORL-1 receptor modulators |
| TWI489984B (zh) | 2006-08-04 | 2015-07-01 | Wyeth Corp | 用於非經腸道傳輸化合物之配方及其用途 |
| CN103202840B (zh) | 2006-11-28 | 2015-02-11 | 詹森药业有限公司 | 3-(3-氨基-2-(r)-羟基-丙基)-1-(4-氟-苯基)-8-(8-甲基-萘-1-基甲基)-1,3,8-三氮杂-螺[4.5]癸烷-4-酮的盐 |
| MX2009010550A (es) | 2007-03-29 | 2009-12-14 | Progenics Pharm Inc | Formas de cristal de bromuro de (r)-n-metilnaltrexona y uso de las mismas. |
| SI2565195T1 (sl) | 2007-03-29 | 2015-09-30 | Wyeth Llc | Periferalni opioidni receptorji in antagonisti in njih uporaba |
| CL2008000905A1 (es) | 2007-03-29 | 2008-08-22 | Progenics Pharm Inc | Compuestos derivados de morfina, antagonistas del receptor opioide periferico; metodo de preparacion; composicion farmaceutica; y uso para reducir los efectos de la actividad opioide endogena. |
| JP5490677B2 (ja) | 2007-04-09 | 2014-05-14 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 不安及び鬱病の処置のためのｏｒｌ−１受容体リガンドとしての１，３，８−三置換−１，３，８−トリアザ−スピロ［４．５］デカン−４−オン誘導体 |
| JP2010527980A (ja) | 2007-05-22 | 2010-08-19 | プロシディオン・リミテッド | 代謝障害を治療するための二環状アリールおよびヘテロアリール化合物 |
| WO2009030962A1 (en) | 2007-09-07 | 2009-03-12 | Prosidion Limited | Bicyclic aryl and heteroaryl receptor modulators |
| EP2240489A1 (en) | 2008-02-06 | 2010-10-20 | Progenics Pharmaceuticals, Inc. | Preparation and use of (r),(r)-2,2'-bis-methylnaltrexone |
| EP2278966B1 (en) | 2008-03-21 | 2019-10-09 | The University of Chicago | Treatment with opioid antagonists and mtor inhibitors |
| CA2676881C (en) | 2008-09-30 | 2017-04-25 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
| RU2492482C1 (ru) * | 2012-10-08 | 2013-09-10 | Игорь Петрович Папышев | Способ диагностики причины смерти от интоксикации наркотическими веществами группы опиатов |
Citations (1)
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|---|---|---|---|---|
| WO1995007983A1 (en) * | 1993-09-13 | 1995-03-23 | Indiana University Foundation | Human mu opioid receptor |
Family Cites Families (5)
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| US4582820A (en) * | 1982-12-23 | 1986-04-15 | Research Corporation | Orally administered biologically active peptides and proteins |
| US4683195A (en) * | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
| US4683202A (en) * | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
| US5017689A (en) * | 1989-07-06 | 1991-05-21 | Arizona Technology Development Corporation | Dynorphin analogs specific for kappa opioid receptors |
| US5512578A (en) * | 1992-09-21 | 1996-04-30 | Albert Einstein College Of Medicine Of Yeshiva University, A Division Of Yeshiva University | Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opiod agonists |
-
1995
- 1995-11-03 US US08/553,058 patent/US5821219A/en not_active Expired - Lifetime
-
1996
- 1996-08-12 CA CA002229126A patent/CA2229126A1/en not_active Abandoned
- 1996-08-12 AT AT96928209T patent/ATE323160T1/de not_active IP Right Cessation
- 1996-08-12 DE DE69636037T patent/DE69636037D1/de not_active Expired - Lifetime
- 1996-08-12 WO PCT/US1996/013305 patent/WO1997007212A1/en not_active Ceased
- 1996-08-12 AU AU67769/96A patent/AU728001B2/en not_active Ceased
- 1996-08-12 EP EP96928209A patent/EP0843726B1/en not_active Expired - Lifetime
- 1996-08-12 JP JP50950797A patent/JP3868494B2/ja not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995007983A1 (en) * | 1993-09-13 | 1995-03-23 | Indiana University Foundation | Human mu opioid receptor |
Also Published As
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|---|---|
| JP3868494B2 (ja) | 2007-01-17 |
| WO1997007212A1 (en) | 1997-02-27 |
| ATE323160T1 (de) | 2006-04-15 |
| AU6776996A (en) | 1997-03-12 |
| DE69636037D1 (de) | 2006-05-24 |
| EP0843726A1 (en) | 1998-05-27 |
| JP2001520634A (ja) | 2001-10-30 |
| US5821219A (en) | 1998-10-13 |
| EP0843726B1 (en) | 2006-04-12 |
| CA2229126A1 (en) | 1997-02-27 |
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