AU2008343524B2 - 6H-dibenzo [B, E] oxepine derived nonsteroidal mineralocorticoid receptor antagonists - Google Patents
6H-dibenzo [B, E] oxepine derived nonsteroidal mineralocorticoid receptor antagonists Download PDFInfo
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- AU2008343524B2 AU2008343524B2 AU2008343524A AU2008343524A AU2008343524B2 AU 2008343524 B2 AU2008343524 B2 AU 2008343524B2 AU 2008343524 A AU2008343524 A AU 2008343524A AU 2008343524 A AU2008343524 A AU 2008343524A AU 2008343524 B2 AU2008343524 B2 AU 2008343524B2
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- TYVPMGGBXKDZAF-SFYZADRCSA-N tert-butyl (2S,4R)-4-azido-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](C[C@H]1CO)N=[N+]=[N-] TYVPMGGBXKDZAF-SFYZADRCSA-N 0.000 description 1
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- OCLZOKUGIXLYJZ-JGVFFNPUSA-N tert-butyl (2r,4s)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@@H](N)C[C@@H]1CO OCLZOKUGIXLYJZ-JGVFFNPUSA-N 0.000 description 1
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- ZDIVZXZUIPLHNP-HUUCEWRRSA-N tert-butyl (3r,4r)-4-(benzylamino)-3-hydroxypiperidine-1-carboxylate Chemical compound O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1NCC1=CC=CC=C1 ZDIVZXZUIPLHNP-HUUCEWRRSA-N 0.000 description 1
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- MOZOQDNRVPHFOO-BQBZGAKWSA-N tert-butyl (3s,4s)-3-amino-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C[C@H](N)[C@@H](O)C1 MOZOQDNRVPHFOO-BQBZGAKWSA-N 0.000 description 1
- ITPHGVPTTDIMDB-JKSUJKDBSA-N tert-butyl (3s,4s)-3-hydroxy-4-(2-phenylethyl)piperidine-1-carboxylate Chemical compound O[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1CCC1=CC=CC=C1 ITPHGVPTTDIMDB-JKSUJKDBSA-N 0.000 description 1
- OLMYDBBHYVEIME-DHLKQENFSA-N tert-butyl (3s,4s)-4-(benzylamino)-3-hydroxy-4-(2-phenylethyl)piperidine-1-carboxylate Chemical compound O[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@]1(NCC=1C=CC=CC=1)CCC1=CC=CC=C1 OLMYDBBHYVEIME-DHLKQENFSA-N 0.000 description 1
- SHHHRQFHCPINIB-UHFFFAOYSA-N tert-butyl 3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=CC1 SHHHRQFHCPINIB-UHFFFAOYSA-N 0.000 description 1
- WPGLRFGDZJSQGI-UHFFFAOYSA-N tert-butyl 3-aminoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(N)C1 WPGLRFGDZJSQGI-UHFFFAOYSA-N 0.000 description 1
- ZDIVZXZUIPLHNP-UHFFFAOYSA-N tert-butyl 4-(benzylamino)-3-hydroxypiperidine-1-carboxylate Chemical compound OC1CN(C(=O)OC(C)(C)C)CCC1NCC1=CC=CC=C1 ZDIVZXZUIPLHNP-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- GPTXCAZYUMDUMN-UHFFFAOYSA-N tert-butyl n-(2-hydroxyethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCO GPTXCAZYUMDUMN-UHFFFAOYSA-N 0.000 description 1
- PDAFIZPRSXHMCO-ZCFIWIBFSA-N tert-butyl n-[(2r)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-ZCFIWIBFSA-N 0.000 description 1
- PDAFIZPRSXHMCO-LURJTMIESA-N tert-butyl n-[(2s)-1-hydroxypropan-2-yl]carbamate Chemical compound OC[C@H](C)NC(=O)OC(C)(C)C PDAFIZPRSXHMCO-LURJTMIESA-N 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/42—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of mineralocorticosteroids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Endocrinology (AREA)
- Heart & Thoracic Surgery (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Steroid Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1477607P | 2007-12-19 | 2007-12-19 | |
| US61/014,776 | 2007-12-19 | ||
| PCT/US2008/085997 WO2009085584A1 (en) | 2007-12-19 | 2008-12-09 | 6h-dibenz0 [b, e] oxepine derived nonsteroidal mineralocorticoid receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU2008343524A1 AU2008343524A1 (en) | 2009-07-09 |
| AU2008343524B2 true AU2008343524B2 (en) | 2012-03-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2008343524A Ceased AU2008343524B2 (en) | 2007-12-19 | 2008-12-09 | 6H-dibenzo [B, E] oxepine derived nonsteroidal mineralocorticoid receptor antagonists |
Country Status (33)
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| US (1) | US7994164B2 (https=) |
| EP (2) | EP2235007B1 (https=) |
| JP (1) | JP5562866B2 (https=) |
| KR (1) | KR101254382B1 (https=) |
| CN (1) | CN101903377B (https=) |
| AR (1) | AR069554A1 (https=) |
| AU (1) | AU2008343524B2 (https=) |
| BR (1) | BRPI0820805A2 (https=) |
| CA (1) | CA2710409C (https=) |
| CL (1) | CL2008003600A1 (https=) |
| CO (1) | CO6300953A2 (https=) |
| DK (1) | DK2235007T3 (https=) |
| DO (1) | DOP2010000185A (https=) |
| EA (1) | EA017668B1 (https=) |
| EC (2) | ECSP10010266A (https=) |
| ES (2) | ES2459318T3 (https=) |
| GT (1) | GT201000179A (https=) |
| HR (1) | HRP20120916T1 (https=) |
| IL (1) | IL206353A (https=) |
| MA (1) | MA31910B1 (https=) |
| MX (1) | MX2010006911A (https=) |
| MY (1) | MY150474A (https=) |
| NZ (1) | NZ586300A (https=) |
| PE (1) | PE20091057A1 (https=) |
| PL (1) | PL2235007T3 (https=) |
| PT (1) | PT2235007E (https=) |
| RS (1) | RS52594B (https=) |
| SI (1) | SI2235007T1 (https=) |
| TN (1) | TN2010000292A1 (https=) |
| TW (1) | TWI431010B (https=) |
| UA (1) | UA100131C2 (https=) |
| WO (1) | WO2009085584A1 (https=) |
| ZA (1) | ZA201004257B (https=) |
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| US8242140B2 (en) | 2007-08-03 | 2012-08-14 | Boehringer Ingelheim International Gmbh | Viral polymerase inhibitors |
| EP2234977A4 (en) | 2007-12-19 | 2011-04-13 | Boehringer Ingelheim Int | VIRAL POLYMERASE INHIBITORS |
| AU2010222902B2 (en) * | 2009-03-12 | 2013-04-18 | Eli Lilly And Company | Mineralocorticoid receptor antagonist and methods of use |
| EP2977084B1 (en) | 2010-05-10 | 2017-07-05 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods and compositions for the treatment of fluid accumulation in and/ or under the retina |
| JP6180930B2 (ja) | 2010-06-16 | 2017-08-16 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 創傷治癒過程における再上皮化を刺激するための方法及び組成物 |
| CN102060670A (zh) * | 2011-01-04 | 2011-05-18 | 常州大学 | 一种2-溴-6-氟苯甲醇的制备方法 |
| AU2014261070A1 (en) | 2013-05-02 | 2015-10-29 | Pfizer Inc. | Imidazo-triazine derivatives as PDE10 inhibitors |
| AR099416A1 (es) | 2014-02-28 | 2016-07-20 | Lilly Co Eli | Terapia combinada para la hipertensión resistente |
| MX367404B (es) | 2014-06-30 | 2019-08-20 | Astrazeneca Ab | Amidas de benzoxazinona como moduladores del receptor de mineralocorticoides. |
| US20170246166A1 (en) * | 2014-11-21 | 2017-08-31 | Eli Lilly And Company | 1,2-benzothiazole compounds for the treatment of kidney disorders |
| JP6835836B2 (ja) | 2015-10-13 | 2021-02-24 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 脈絡膜血管新生の処置のための方法及び医薬組成物 |
| EP3490606B8 (en) | 2016-07-26 | 2024-04-10 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Antagonist of mineralocorticoid receptor for the treatment of osteoarthritis |
| RU2725153C1 (ru) * | 2016-09-24 | 2020-06-30 | Кбп Биосаенсес Ко., Лтд | Фармацевтическая композиция, содержащая антагонист минералокортикоидных рецепторов, и ее применение |
| JP7697961B2 (ja) | 2020-03-11 | 2025-06-24 | アンスティチュ ナショナル ドゥ ラ サンテ エ ドゥ ラ ルシェルシュ メディカル | 対象が中心性漿液性脈絡網膜症を有するか、または有する危険性があるかどうかを決定する方法。 |
| US20240366632A1 (en) | 2021-08-31 | 2024-11-07 | Institut National de la Santé et de la Recherche Médicale | Methods for the treatment of ocular rosacea |
Family Cites Families (21)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4072756A (en) * | 1973-05-17 | 1978-02-07 | Sandoz Ltd. | Tricyclo piperidino ketones and soporific compositions thereof |
| SE426341C (sv) * | 1980-02-14 | 1985-09-23 | Fagersta Ab | Sett att forhindra korrosion i en forbrenningsanleggnings kylare och skorsten vid kylning av rokgaser |
| DE3730258A1 (de) * | 1986-09-10 | 1988-04-07 | Canon Kk | Elektrophotographisches lichtempfindliches aufzeichnungsmaterial, 5h-dibenzo(a,d)cycloheptanylidenderivat, 5h-dibenzo(a,d)cycloheptenylidenderivat und verfahren zu ihrer herstellung |
| CA1338625C (en) * | 1988-06-09 | 1996-10-01 | Kyowa Hakko Kogyo Co., Ltd. | Tricyclic compounds |
| GB8914061D0 (en) * | 1989-06-19 | 1989-08-09 | Wellcome Found | Agents for potentiating the effects of antitumour agents and combating multiple drug resistance |
| US5378701A (en) * | 1991-12-27 | 1995-01-03 | Kyowa Hakko Kogyo | Tricyclic compounds |
| AR014195A1 (es) | 1997-12-29 | 2001-02-07 | Ortho Mcneil Pharm Inc | Compuestos de trifenilpropanamida utiles para el tratamiento de procesos inflamatorios, composiciones anti-inflamatorias que los comprenden, ymetodos para prepararlos |
| US7056911B1 (en) | 1999-01-26 | 2006-06-06 | Dana-Farber Cancer Institute | Dibenz[B,F]azepine compounds, pharmaceutical compositions comprising same and methods of use thereof |
| NZ596484A (en) * | 2001-11-21 | 2013-05-31 | Millennium Pharm Inc | Chemokine receptor antagonists and methods of use thereof |
| TW200400816A (en) * | 2002-06-26 | 2004-01-16 | Lilly Co Eli | Tricyclic steroid hormone nuclear receptor modulators |
| US7482344B2 (en) * | 2003-12-19 | 2009-01-27 | Eli Lilly And Company | Tricyclic steroid hormone nuclear receptor modulators |
| CN1918151A (zh) * | 2003-12-19 | 2007-02-21 | 伊莱利利公司 | 三环甾类激素核受体调节剂 |
| TWI350168B (en) | 2004-05-07 | 2011-10-11 | Incyte Corp | Amido compounds and their use as pharmaceuticals |
| RU2007107177A (ru) | 2004-07-28 | 2008-09-10 | Айрм Ллк (Bm) | Соединения и композиции, как модуляторы ядерных рецепторов стероидных гормонов |
| CA2585797C (en) | 2004-11-10 | 2015-01-06 | Incyte Corporation | Lactam compounds and their use as pharmaceuticals |
| SI2089367T1 (sl) | 2006-10-31 | 2012-02-29 | Pfizer Prod Inc | Spojine pirazolina kot antagonisti mineralokortikoidnih receptorjev |
| JP2010522732A (ja) | 2007-03-29 | 2010-07-08 | ナームローゼ・フエンノートチヤツプ・オルガノン | 鉱質コルチコイド受容体アンタゴニスト |
| GB0725102D0 (en) | 2007-12-21 | 2008-01-30 | Glaxo Group Ltd | Compounds |
| PE20091339A1 (es) | 2007-12-21 | 2009-09-26 | Glaxo Group Ltd | Derivados de oxadiazol con actividad sobre receptores s1p1 |
| AU2009206733A1 (en) | 2008-01-25 | 2009-07-30 | Arena Pharmaceuticals, Inc. | Dihydro- 1H- pyrrolo [1,2-a] indol-1-yl carboxylic derivatives which act as S1P1 agonists |
| AU2010222902B2 (en) | 2009-03-12 | 2013-04-18 | Eli Lilly And Company | Mineralocorticoid receptor antagonist and methods of use |
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