CA2508764A1 - Pyrrolo [2,1-c] [1,4] benzodiazepines as vasopressin agonists - Google Patents
Pyrrolo [2,1-c] [1,4] benzodiazepines as vasopressin agonists Download PDFInfo
- Publication number
- CA2508764A1 CA2508764A1 CA002508764A CA2508764A CA2508764A1 CA 2508764 A1 CA2508764 A1 CA 2508764A1 CA 002508764 A CA002508764 A CA 002508764A CA 2508764 A CA2508764 A CA 2508764A CA 2508764 A1 CA2508764 A1 CA 2508764A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- group
- alkylene
- alkyl
- vasopressin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 229940083335 Vasopressin agonist Drugs 0.000 title description 7
- MSNVESLISHTIRS-UHFFFAOYSA-N 9h-pyrrolo[2,1-c][1,4]benzodiazepine Chemical class N1=C2C=CC=CC2=CN2CC=CC2=C1 MSNVESLISHTIRS-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
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- 125000000217 alkyl group Chemical group 0.000 claims description 43
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
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Classifications
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- 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
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- 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
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (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)
- Public Health (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10/320,761 | 2002-12-16 | ||
| US10/320,761 US7138393B2 (en) | 1998-07-24 | 2002-12-16 | Biologically active vasopressin agonist metabolites |
| PCT/US2003/039897 WO2004060894A1 (en) | 2002-12-16 | 2003-12-16 | Pyrrolo`2,1-c!`1,4! benzodiazepines as vasopressin agonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2508764A1 true CA2508764A1 (en) | 2004-07-22 |
Family
ID=32710746
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002508764A Abandoned CA2508764A1 (en) | 2002-12-16 | 2003-12-16 | Pyrrolo [2,1-c] [1,4] benzodiazepines as vasopressin agonists |
Country Status (15)
| Country | Link |
|---|---|
| US (1) | US7138393B2 (https=) |
| EP (1) | EP1572694B1 (https=) |
| JP (1) | JP2006514956A (https=) |
| CN (1) | CN1745083A (https=) |
| AR (1) | AR042467A1 (https=) |
| AT (1) | ATE410428T1 (https=) |
| AU (1) | AU2003297127A1 (https=) |
| BR (1) | BR0317383A (https=) |
| CA (1) | CA2508764A1 (https=) |
| DE (1) | DE60324018D1 (https=) |
| DK (1) | DK1572694T3 (https=) |
| ES (1) | ES2312859T3 (https=) |
| MX (1) | MXPA05006241A (https=) |
| TW (1) | TW200413355A (https=) |
| WO (1) | WO2004060894A1 (https=) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0210397D0 (en) * | 2002-05-07 | 2002-06-12 | Ferring Bv | Pharmaceutical formulations |
| JP5451613B2 (ja) | 2007-08-06 | 2014-03-26 | アラーガン、インコーポレイテッド | デスモプレシン薬物送達のための方法及びデバイス |
| US20100286045A1 (en) | 2008-05-21 | 2010-11-11 | Bjarke Mirner Klein | Methods comprising desmopressin |
| US11963995B2 (en) | 2008-05-21 | 2024-04-23 | Ferring B.V. | Methods comprising desmopressin |
| NO3085381T3 (https=) * | 2008-05-21 | 2018-09-15 | ||
| KR101385433B1 (ko) | 2008-11-18 | 2014-04-14 | 에프. 호프만-라 로슈 아게 | 다이하이드로테트라아자벤조아줄렌의 알킬사이클로헥실에터 |
| US9532959B2 (en) | 2010-07-08 | 2017-01-03 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for reducing frequency of urination and method of use thereof |
| US10010514B2 (en) | 2010-07-08 | 2018-07-03 | Wellesley Pharmaceuticals, Llc | Pharmaceutical formulation for reducing frequency of urination and method of use thereof |
| MX2014008283A (es) * | 2012-01-04 | 2015-03-03 | Wellesley Pharmaceutical Llc | Formulacion de liberacion prolongada para reducir la frecuencia de orinar y metodos de uso de esta. |
| BR112014016550A8 (pt) * | 2012-01-04 | 2017-07-04 | Wellesley Pharmaceuticals Llc | formulação de liberação retardada para reduzir a frequência de urinação e método de uso da mesma |
| US10278925B2 (en) | 2012-01-04 | 2019-05-07 | Wellesley Pharmaceuticals, Llc | Delayed-release formulations, methods of making and use thereof |
| US10105330B2 (en) | 2012-01-04 | 2018-10-23 | Wellesley Pharmaceuticals, Llc | Extended, delayed and immediate release formulation method of manufacturing and use thereof |
| US10105328B2 (en) | 2014-06-06 | 2018-10-23 | Wellesley Pharmaceuticals, Llc | Composition for reducing frequency of urination, method of making and use thereof |
Family Cites Families (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1251767B (de) * | 1964-02-28 | 1968-04-18 | Dr Karl Thomae Gesellschaft mit beschrankter Haftung Biberach/Riß | Verfahren zur Herstellung von neuen m 6 Stellung substituierten 5 6 Dihydro-5oxo HH pyrido[2,3-b] [l,5]benzodiazepinen |
| US4680298A (en) | 1983-05-31 | 1987-07-14 | Schering Corporation | Tricyclic anti-allergy and use as anti-inflammatory agents |
| US4766108A (en) * | 1986-12-04 | 1988-08-23 | Smith Kline Beckman Corporation | Tyr-Arg-vasopressin antagonists |
| US5055448A (en) * | 1987-06-25 | 1991-10-08 | Medical College Of Ohio | Linear derivatives of arginine vasopressin antagonists |
| US4839355A (en) | 1987-09-09 | 1989-06-13 | Sterling Drug Inc. | Tricyclic-pyridinylquinoline compounds, their preparation and use |
| US5070187A (en) * | 1989-11-03 | 1991-12-03 | Trustees Of Boston University | Pharmacologically effective antagonists of arginine-vasopressin |
| CA2048003A1 (en) | 1990-08-21 | 1992-02-22 | Serge Burner | Tricyclic pyridone derivatives |
| US5516774A (en) | 1993-07-29 | 1996-05-14 | American Cyanamid Company | Tricyclic diazepine vasopressin antagonists and oxytocin antagonists |
| US5512563A (en) * | 1993-07-29 | 1996-04-30 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
| US5420270A (en) * | 1993-10-07 | 1995-05-30 | G. D. Searle & Co. | Aryl substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use |
| ES2199251T3 (es) | 1994-06-15 | 2004-02-16 | Otsuka Pharmaceutical Company, Limited | Derivados benzoheterociclicos utilizables como moduladores de vasopresina o de oxitocina. |
| JPH0881460A (ja) | 1994-09-08 | 1996-03-26 | Yamanouchi Pharmaceut Co Ltd | 新規なテトラヒドロベンゾジアゼピン誘導体又はその塩 |
| US5536718A (en) * | 1995-01-17 | 1996-07-16 | American Cyanamid Company | Tricyclic benzazepine vasopressin antagonists |
| US5521173A (en) * | 1995-01-17 | 1996-05-28 | American Home Products Corporation | Tricyclic benzazepine vasopressin antagonists |
| AR002459A1 (es) | 1995-01-17 | 1998-03-25 | American Cyanamid Co | Antagonistas de vasopresina de benzacepina triciclicos, una composicion farmaceutica que los contiene, un metodo para tratar enfermedades y unprocedimiento para su preparacion. |
| TW359669B (en) | 1995-12-15 | 1999-06-01 | Otsuka Pharma Co Ltd | Benzazepine derivatives |
| US5880122A (en) * | 1996-11-01 | 1999-03-09 | American Home Products Corporation | 3-Carboxamide derivatives of 5H-pyrrolo 2,1-c! 1,4!-benzodiazepines |
| AU727654B2 (en) | 1997-06-13 | 2000-12-21 | Yamanouchi Pharmaceutical Co., Ltd. | Tricyclic pyrazole derivative |
| DE69826487T2 (de) | 1997-07-30 | 2005-12-01 | Wyeth | Trizyclische vasopressin-agonisten |
| US6194407B1 (en) * | 1997-07-30 | 2001-02-27 | American Home Products Corporation | Tricyclic pyrido vasopressin agonists |
| US6297234B1 (en) | 1999-02-04 | 2001-10-02 | American Home Products Corporation | Arylthiophene vasopressin agonists |
| WO2000046228A2 (en) | 1999-02-04 | 2000-08-10 | American Home Products Corporation | Pyrrolobenzodiazepine carboxyamide vasopressin agonists |
| CN1391476A (zh) | 1999-09-27 | 2003-01-15 | 美国氰胺公司 | 血管升压素激动剂制剂和方法 |
| CN1399542A (zh) | 1999-09-27 | 2003-02-26 | 美国氰胺公司 | 药用载体制剂 |
| GB0000079D0 (en) | 2000-01-05 | 2000-02-23 | Ferring Bv | Novel antidiuretic agents |
| GB0015601D0 (en) | 2000-06-26 | 2000-08-16 | Ferring Bv | Novel antidiuretic agents |
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2002
- 2002-12-16 US US10/320,761 patent/US7138393B2/en not_active Expired - Fee Related
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2003
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- 2003-12-15 AR ARP030104629A patent/AR042467A1/es not_active Application Discontinuation
- 2003-12-16 AT AT03814820T patent/ATE410428T1/de not_active IP Right Cessation
- 2003-12-16 CA CA002508764A patent/CA2508764A1/en not_active Abandoned
- 2003-12-16 DE DE60324018T patent/DE60324018D1/de not_active Expired - Lifetime
- 2003-12-16 DK DK03814820T patent/DK1572694T3/da active
- 2003-12-16 EP EP03814820A patent/EP1572694B1/en not_active Expired - Lifetime
- 2003-12-16 CN CNA2003801095935A patent/CN1745083A/zh active Pending
- 2003-12-16 JP JP2004565510A patent/JP2006514956A/ja active Pending
- 2003-12-16 WO PCT/US2003/039897 patent/WO2004060894A1/en not_active Ceased
- 2003-12-16 BR BR0317383-6A patent/BR0317383A/pt not_active IP Right Cessation
- 2003-12-16 AU AU2003297127A patent/AU2003297127A1/en not_active Withdrawn
- 2003-12-16 ES ES03814820T patent/ES2312859T3/es not_active Expired - Lifetime
- 2003-12-16 MX MXPA05006241A patent/MXPA05006241A/es active IP Right Grant
Also Published As
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|---|---|
| CN1745083A (zh) | 2006-03-08 |
| JP2006514956A (ja) | 2006-05-18 |
| EP1572694B1 (en) | 2008-10-08 |
| WO2004060894A1 (en) | 2004-07-22 |
| DK1572694T3 (da) | 2009-02-02 |
| US7138393B2 (en) | 2006-11-21 |
| DE60324018D1 (de) | 2008-11-20 |
| AR042467A1 (es) | 2005-06-22 |
| AU2003297127A1 (en) | 2004-07-29 |
| ATE410428T1 (de) | 2008-10-15 |
| MXPA05006241A (es) | 2005-08-19 |
| US20030134845A1 (en) | 2003-07-17 |
| ES2312859T3 (es) | 2009-03-01 |
| TW200413355A (en) | 2004-08-01 |
| BR0317383A (pt) | 2005-11-16 |
| EP1572694A1 (en) | 2005-09-14 |
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| Date | Code | Title | Description |
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| EEER | Examination request | ||
| FZDE | Discontinued |