JP5241709B2 - デオキシノジリマイシンおよびｄ−アラビニトールのアナログおよび使用方法 - Google Patents
デオキシノジリマイシンおよびｄ−アラビニトールのアナログおよび使用方法 Download PDFInfo
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- JP5241709B2 JP5241709B2 JP2009512260A JP2009512260A JP5241709B2 JP 5241709 B2 JP5241709 B2 JP 5241709B2 JP 2009512260 A JP2009512260 A JP 2009512260A JP 2009512260 A JP2009512260 A JP 2009512260A JP 5241709 B2 JP5241709 B2 JP 5241709B2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/48—Oxygen atoms attached in position 4 having an acyclic carbon atom attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Virology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US80277606P | 2006-05-24 | 2006-05-24 | |
| US60/802,776 | 2006-05-24 | ||
| PCT/US2007/069448 WO2007140184A2 (en) | 2006-05-24 | 2007-05-22 | Deoxynojirimycin and d-arabinitol analogs and methods of using |
Related Child Applications (1)
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| US20080138351A1 (en) * | 2006-08-02 | 2008-06-12 | United Therapeutics Corporation | Liposome treatment of viral infections |
| US20090252785A1 (en) * | 2008-03-26 | 2009-10-08 | University Of Oxford | Endoplasmic reticulum targeting liposomes |
| JP5600329B2 (ja) * | 2009-02-23 | 2014-10-01 | ユナイテッド セラピューティクス コーポレーション | イミノ糖およびウイルス性疾患を治療する方法 |
| KR101787434B1 (ko) | 2009-02-24 | 2017-11-15 | 유나이티드 세러퓨틱스 코오포레이션 | 이미노슈가 및 아레나바이러스성 감염을 치료하는 방법 |
| CN102427804A (zh) * | 2009-03-27 | 2012-04-25 | 牛津大学之校长及学者 | 降低胆固醇水平的脂质体 |
| WO2010111711A2 (en) * | 2009-03-27 | 2010-09-30 | Zacharon Pharmaceuticals, Inc. | Ganglioside biosynthesis modulators |
| JP5634510B2 (ja) * | 2009-06-12 | 2014-12-03 | ユナイテッド セラピューティクス コーポレイション | イミノ糖ならびにブニヤウイルスおよびトガウイルス疾患を治療する方法 |
| KR101497194B1 (ko) * | 2009-09-04 | 2015-02-27 | 유나이티드 세러퓨틱스 코오포레이션 | 오르토믹소바이러스 감염의 치료 방법 |
| JP5752689B2 (ja) * | 2009-09-04 | 2015-07-22 | ユナイテッド セラピューティクス コーポレイション | フィロウイルス疾患を治療するイミノ糖および方法 |
| KR101459530B1 (ko) * | 2009-09-04 | 2014-11-07 | 유나이티드 세러퓨틱스 코오포레이션 | 폭스바이러스 감염의 치료 방법 |
| CN104703597A (zh) | 2012-06-06 | 2015-06-10 | 尤尼特尔滤过性微生物学有限责任公司 | 新型亚氨基糖及它们的应用 |
| CN105246478A (zh) | 2013-03-15 | 2016-01-13 | 优尼特尔病毒学公司 | 抗菌化合物 |
| HK1221871A1 (zh) * | 2013-05-02 | 2017-06-16 | The Chancellor, Masters And Scholars Of The University Of Oxford | 使用亚氨基糖进行的糖脂抑制 |
| MX2016003323A (es) | 2013-09-16 | 2016-08-12 | Emergent Virology Llc | Derivados de dosoxinojirimicina y sus metodos de uso. |
| CA2966893C (en) | 2014-11-05 | 2023-10-24 | Emergent Virology Llc | Iminosugars |
| EP3318277A1 (en) | 2016-11-04 | 2018-05-09 | Institut du Cerveau et de la Moelle Epiniere-ICM | Inhibitors of glucosylceramide synthase for the treatment of motor neuron diseases |
Family Cites Families (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO154918C (no) | 1977-08-27 | 1987-01-14 | Bayer Ag | Analogifremgangsmaate til fremstilling av terapeutisk aktive derivater av 3,4,5-trihydroksypiperidin. |
| JPS54106477A (en) | 1978-02-03 | 1979-08-21 | Nippon Shinyaku Co Ltd | Moranoline derivative |
| JPS5943947B2 (ja) * | 1978-05-03 | 1984-10-25 | 日本新薬株式会社 | Ｎ−置換モラノリン誘導体 |
| JPS5943949B2 (ja) | 1978-09-29 | 1984-10-25 | 日本新薬株式会社 | モラノリンのｎ−置換誘導体 |
| JPS5943948B2 (ja) * | 1978-07-06 | 1984-10-25 | 日本新薬株式会社 | 置換モラノリン誘導体 |
| GB2020278B (en) | 1978-05-03 | 1983-02-23 | Nippon Shinyaku Co Ltd | Moranoline dervitives |
| DE3007078A1 (de) | 1980-02-26 | 1981-09-10 | Bayer Ag, 5090 Leverkusen | Neue derivate von 3,4,5-trihydroxypiperidin, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel sowie in der tierernaehrung |
| DE3024901A1 (de) | 1980-07-01 | 1982-01-28 | Bayer Ag, 5090 Leverkusen | Herbizide mittel auf basis von piperidin-derivaten |
| JPS62155291A (ja) | 1985-12-20 | 1987-07-10 | バイエル・アクチエンゲゼルシヤフト | ３−アミノ−４，５−ジヒドロキシピペリジン類、それらの製造方法及びそれらの使用 |
| DE3620645A1 (de) | 1985-12-20 | 1987-07-02 | Bayer Ag | 3-amino-4,5-dihydroxypiperidine, verfahren zu ihrer herstellung und ihre verwendung |
| DE3737523A1 (de) | 1987-11-05 | 1989-05-18 | Bayer Ag | Verwendung von substituierten hydroxypiperidinen als antivirale mittel |
| JPH0643306B2 (ja) * | 1988-02-12 | 1994-06-08 | 明治製菓株式会社 | 癌細胞転移抑制剤 |
| US4985445A (en) | 1988-02-12 | 1991-01-15 | Meiji Seika Kaisha, Ltd. | Cancer cell metastasis inhibitors and novel compounds |
| EP0350012A3 (en) | 1988-07-08 | 1990-09-05 | Meiji Seika Kaisha Ltd. | Antiviral composition |
| EP0367747B1 (en) * | 1988-11-03 | 1996-03-13 | G.D. Searle & Co. | Dideoxy-L-arabinitol derivatives as antiviral compounds |
| JPH0675510B2 (ja) | 1989-02-13 | 1994-09-28 | 日本新薬株式会社 | モラノリン誘導体の製法 |
| US5256788A (en) | 1989-02-13 | 1993-10-26 | Nippon Shinyaku Co. Ltd. | Moranoline derivatives and their production and the use of moranoline and its derivatives as a stabilizing agent for enzymes |
| US5051401A (en) * | 1989-04-07 | 1991-09-24 | University Of South Alabama | Inhibition of mineral deposition by phosphorylated and related polyanionic peptides |
| DE4009561A1 (de) | 1990-03-24 | 1991-09-26 | Bayer Ag | Neue desoxynojirimycinderivate, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln |
| CA2086413A1 (en) | 1990-06-29 | 1991-12-30 | Yohji Ezure | Piperidine derivatives |
| US5290948A (en) | 1990-09-17 | 1994-03-01 | Mcneilab, Inc. | Process for producing polyhydroxylated piperidines and pyrrolidines and compounds thereof |
| DE69421828T2 (de) | 1994-01-13 | 2000-04-20 | G.D. Searle & Co. | Verwendung von 1,5-dideoxy-1,5-imino-d-glucitol n-alkylderivaten zur behandlung von hepatitis b infektionen |
| WO1995022975A1 (en) | 1994-02-25 | 1995-08-31 | G.D. Searle & Co. | Use of 1-deoxynojirimycin and its derivatives for treating mammals infected with respiratory syncytial virus |
| DK1030839T3 (da) | 1997-11-10 | 2004-05-03 | Searle & Co | Anvendelse af alkylerede iminosukkere til behandling af multidrugresistens |
| US6809083B1 (en) * | 1998-02-12 | 2004-10-26 | Richard A. Mueller | Use of N-substituted-1, 5-dideoxy-1, 5-imino-D-glucitol compounds for treating hepatitis virus infections |
| GB0100889D0 (en) * | 2001-01-12 | 2001-02-21 | Oxford Glycosciences Uk Ltd | Compounds |
| EP1261339A1 (en) | 2000-02-14 | 2002-12-04 | Pharmacia Corporation | Use of n-substituted-1,5-dideoxy-1,5-imino-d-glucitol compounds for treating hepatitis virus infections |
| ES2271548T3 (es) * | 2002-03-13 | 2007-04-16 | Unither Pharmaceuticals, Inc. | Enfoque no hormonal de anticoncepcion masculina. |
| AU2003248960B2 (en) * | 2002-07-17 | 2009-06-25 | Idorsia Pharmaceuticals Ltd | Piperidinetriol derivatives as inhibitors of glycosylceramidsynthase |
| AU2006247065B8 (en) | 2005-05-17 | 2012-07-12 | Amicus Therapeutics, Inc. | A method for the treatment of Pompe disease using 1-deoxynojirimycin derivatives |
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2007
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- 2007-05-22 CN CN201510202505.0A patent/CN104876855A/zh active Pending
- 2007-05-22 EP EP07797651.2A patent/EP2023927B1/en not_active Not-in-force
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2016
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Also Published As
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| WO2007140184A2 (en) | 2007-12-06 |
| WO2007140184A3 (en) | 2008-11-27 |
| EP2023927A4 (en) | 2013-04-10 |
| US8975280B2 (en) | 2015-03-10 |
| US20070275998A1 (en) | 2007-11-29 |
| CN104876855A (zh) | 2015-09-02 |
| HK1214261A1 (zh) | 2016-07-22 |
| EP2023927B1 (en) | 2015-02-25 |
| ES2537572T3 (es) | 2015-06-09 |
| EP2023927A2 (en) | 2009-02-18 |
| CA2652958A1 (en) | 2007-12-06 |
| JP2013129662A (ja) | 2013-07-04 |
| CN101489554A (zh) | 2009-07-22 |
| JP2009538336A (ja) | 2009-11-05 |
| CA2652958C (en) | 2015-11-17 |
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