IN1998KO01500A - - Google Patents

Info

Publication number
IN1998KO01500A
IN1998KO01500A IN1500KO1998A IN1998KO01500A IN 1998KO01500 A IN1998KO01500 A IN 1998KO01500A IN 1500KO1998 A IN1500KO1998 A IN 1500KO1998A IN 1998KO01500 A IN1998KO01500 A IN 1998KO01500A
Authority
IN
India
Application number
Other languages
English (en)
Inventor
Bao-Shan Huang
Aris Christodoulou
Yansong Lu
Ben-Yi Ji
Original Assignee
Penick Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=25401603&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=IN1998KO01500(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Penick Corp filed Critical Penick Corp
Publication of IN1998KO01500A publication Critical patent/IN1998KO01500A/en

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D489/00Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/06Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
    • C07D489/08Oxygen atom
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/04Centrally acting analgesics, e.g. opioids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D489/00Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
IN1500KO1998 1997-07-11 1998-08-21 IN1998KO01500A (enrdf_load_html_response)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US08/893,464 US5869669A (en) 1996-07-26 1997-07-11 Preparation of 14-hydroxynormorphinones from normorphinone dienol acylates

Publications (1)

Publication Number Publication Date
IN1998KO01500A true IN1998KO01500A (enrdf_load_html_response) 2005-03-11

Family

ID=25401603

Family Applications (1)

Application Number Title Priority Date Filing Date
IN1500KO1998 IN1998KO01500A (enrdf_load_html_response) 1997-07-11 1998-08-21

Country Status (19)

Country Link
US (7) US5869669A (enrdf_load_html_response)
EP (1) EP1000065B1 (enrdf_load_html_response)
JP (1) JP2001518444A (enrdf_load_html_response)
KR (1) KR100363486B1 (enrdf_load_html_response)
CN (1) CN1152880C (enrdf_load_html_response)
AT (1) ATE291023T1 (enrdf_load_html_response)
AU (1) AU740822B2 (enrdf_load_html_response)
CA (1) CA2296035C (enrdf_load_html_response)
DE (1) DE69829379D1 (enrdf_load_html_response)
HU (1) HUP0003918A3 (enrdf_load_html_response)
IL (1) IL133792A0 (enrdf_load_html_response)
IN (1) IN1998KO01500A (enrdf_load_html_response)
NO (1) NO20000111L (enrdf_load_html_response)
RU (1) RU2183636C2 (enrdf_load_html_response)
SK (1) SK102000A3 (enrdf_load_html_response)
TR (1) TR200000033T2 (enrdf_load_html_response)
TW (1) TW505648B (enrdf_load_html_response)
WO (1) WO1999002529A1 (enrdf_load_html_response)
ZA (1) ZA986144B (enrdf_load_html_response)

Families Citing this family (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5912347A (en) * 1996-09-30 1999-06-15 Mallinckrodt Inc. Process for preparing a morphinan derivative
WO2000066588A1 (en) * 1999-05-05 2000-11-09 The Government Of The United States Of America, Represented By The Secretary, Departmentof Health A Nd Human Services Direct c-14 oxidation of opioids
US6177567B1 (en) 1999-10-15 2001-01-23 Boehringer Ingelheim Chemicals, Inc. Method for preparing oxycodone
WO2003018588A2 (en) * 2001-08-23 2003-03-06 Akzo Nobel N.V. Process for the preparation of a 14-hydroxynormorphinone derivative
JP3961796B2 (ja) * 2001-08-27 2007-08-22 ソニー株式会社 情報提供システム、情報処理装置および方法、情報提供装置および方法、記録媒体、並びにプログラム
DE10161963A1 (de) * 2001-12-17 2003-07-03 Johannes Schuetz 6-Aminomorphinanderivate, Herstellungsverfahren dafür und deren Verwendung
US20040001889A1 (en) 2002-06-25 2004-01-01 Guohua Chen Short duration depot formulations
US20040058946A1 (en) * 2002-07-05 2004-03-25 Buchwald Stephen L. Abuse-resistant prodrugs of oxycodone and other pharmaceuticals
RU2236412C2 (ru) * 2002-07-18 2004-09-20 Власов Михаил Иванович Способ получения производных морфинона, способ получения производных 14-гидроксиморфинона, и способ получения производных оксиморфона
RU2215741C1 (ru) * 2002-11-05 2003-11-10 Открытое Акционерное Общество "Международная Научно-Технологическая Корпорация" Сложные эфиры n-замещенных 14-гидроксиморфинанов и способ их получения
RU2215742C1 (ru) * 2002-11-05 2003-11-10 Открытое Акционерное Общество "Международная Научно-Технологическая Корпорация" Способ получения сложных эфиров n-замещенных 14-гидроксиморфинанов
DE60329520D1 (de) * 2002-11-08 2009-11-12 Mallinckrodt Inc Verfahren zur herstellung von quaternäre n-alkyl morphinan alkaloid salzen
SI1575569T1 (sl) 2002-12-13 2010-12-31 Durect Corp Oralni sistem dostave zdravila, ki obsega visokoviskozne tekoče nosilne materiale
US6864370B1 (en) 2003-06-05 2005-03-08 Zhaiwei Lin Process for manufacturing oxycodone
US6790959B1 (en) 2003-06-05 2004-09-14 Halsey Drug Company, Inc. Process for manufacturing thebaine
US7875718B2 (en) * 2003-09-22 2011-01-25 Johnson Matthey Public Limited Company Process for the synthesis of morphinane compounds and intermediates thereof
ES2627995T3 (es) 2003-09-22 2017-08-01 Glaxosmithkline Australia Pty Ltd Procedimiento para la síntesis de compuestos de morfinano y productos intermedios de los mismos
ES2313299T3 (es) * 2004-02-06 2009-03-01 Euro-Celtique S.A. Procedimientos para producir morfinonas 3 o protegidas y carboxilatos de morfinona dienol 3 o protegidos.
TWI483944B (zh) 2004-03-30 2015-05-11 Euro Celtique Sa 含有小於25ppm14-羥可待因酮之羥可酮鹽酸鹽組成物、醫藥劑型、延遲釋出口服劑型及醫藥上可以接受的包裝
SK286047B6 (sk) * 2004-04-13 2008-01-07 Zentiva, A. S. Spôsob prípravy derivátov 4,5alfa-epoxy-6-oxomorfínanu
US6946556B1 (en) * 2004-05-21 2005-09-20 Acura Pharmaceuticals, Inc. Preparation of opioid analgesics by a one-pot process
CN1964976A (zh) * 2004-06-08 2007-05-16 马林克罗特公司 从鸦片中提取生物碱
LT1765292T (lt) 2004-06-12 2018-01-10 Collegium Pharmaceutical, Inc. Nuo piktnaudžiavimo apsaugotos vaistų formos
LT2767292T (lt) 2004-09-17 2016-12-12 Durect Corporation Palaikomosios vietinės anestezijos mišinys su saib
GB0421149D0 (en) * 2004-09-23 2004-10-27 Johnson Matthey Plc Preparation of oxycodone
GB0421687D0 (en) * 2004-09-30 2004-11-03 Johnson Matthey Plc Preparation of opiate analgesics
WO2006084389A1 (de) * 2005-02-11 2006-08-17 Cilag Ltd. Verfahren zur reinigung von noroxymorphon-verbindungen
CN101133062B (zh) * 2005-03-04 2014-08-06 欧洲凯尔特公司 减少阿片样物质组合物中α,β-不饱和酮的方法
ES2568475T3 (es) * 2005-04-06 2016-04-29 Toray Industries, Inc. Cristales de derivado de morfinano y procedimiento para producir los mismos
US8071768B2 (en) * 2005-06-10 2011-12-06 Janssen Pharmaceutica, N.V. Alkylquinoline and alkylquinazoline kinase modulators
CN101198612A (zh) * 2005-06-16 2008-06-11 马林克罗特公司 通过1-卤代-蒂巴因或类似物制备14-羟基阿片类的合成路线
US20070027105A1 (en) 2005-07-26 2007-02-01 Alza Corporation Peroxide removal from drug delivery vehicle
US20070117826A1 (en) * 2005-11-23 2007-05-24 Forest Laboratories, Inc. Pharmaceutical formulations comprising ibuprofen, oxycodone, and 14-hydroxycodeinone
US8871779B2 (en) 2006-03-02 2014-10-28 Mallinckrodt Llc Process for preparing morphinan-6-one products with low levels of α,β-unsaturated ketone compounds
SA07280459B1 (ar) 2006-08-25 2011-07-20 بيورديو فارما إل. بي. أشكال جرعة صيدلانية للتناول عن طريق الفم مقاومة للعبث تشتمل على مسكن شبه أفيوني
CA2663909A1 (en) * 2006-09-20 2008-03-27 Mallinckrodt Inc. Preparation of substituted morphinan-6-ones and salts and intermediates thereof
US20080125592A1 (en) * 2006-10-17 2008-05-29 Penick Corporation Process for preparing oxymorphone, naltrexone, and buprenorphine
AU2012216358B2 (en) * 2006-10-17 2014-11-20 Penick Corporation Process For Preparing Oxymorphone, Naltrexone and Buprenorphine
US8134002B2 (en) 2006-10-17 2012-03-13 Penick Corporation Process for preparing oxymorphone
CA2674915C (en) * 2006-10-17 2015-06-30 Penick Corporation Process for preparing oxymorphone
PT2117521E (pt) 2006-11-03 2012-09-10 Durect Corp Sistemas de administração transdérmica que compreendem bupivacaína
JP2010511725A (ja) * 2006-12-04 2010-04-15 ノランコ・インコーポレーテツド オキシコドン塩基中の不純物を減少させる方法
ES2393221T3 (es) * 2006-12-04 2012-12-19 Noramco, Inc. Procedimiento de preparación de oxicodona con niveles reducidos de 14-hidroxicodeinona
GB0624880D0 (en) * 2006-12-14 2007-01-24 Johnson Matthey Plc Improved method for making analgesics
US9040726B2 (en) * 2007-03-06 2015-05-26 Mallinckrodt Llc Process for the preparation of quaternary N-alkyl morphinan alkaloid salts
NZ579469A (en) * 2007-03-06 2011-02-25 Mallinckrodt Inc Process for the preparation of quaternary n-alkyl morphinan alkaloid salts
AU2008231127B2 (en) * 2007-03-23 2013-05-02 SpecGx LLC Improved preparation of oxymorphone from oripavine
CA2684458A1 (en) * 2007-04-16 2008-10-30 Mallinckrodt Inc. Novel opiate reduction utilizing catalytic hydrogen transfer reaction
US20090018154A1 (en) * 2007-05-17 2009-01-15 Endo Pharmaceuticals, Inc., A Corporation Of Delaware Opioid and methods of making and using the same
US8415401B2 (en) 2007-12-06 2013-04-09 Durect Corporation Oral pharmaceutical dosage forms
AU2008338970B2 (en) * 2007-12-17 2013-08-22 SpecGx LLC Sinomenine derivatives and processes for their synthesis
US8067596B2 (en) 2007-12-17 2011-11-29 Mallinckrodt Llc Processes for the production of (+)- “Nal” morphinan compounds
ATE519765T1 (de) 2008-02-29 2011-08-15 Mallinckrodt Inc Verfahren zur herstellung von 3-hydroxymorphinan- derivaten
CN102066381A (zh) * 2008-04-24 2011-05-18 詹森药业有限公司 纳美芬前药
ES2549904T3 (es) * 2008-05-27 2015-11-03 Mallinckrodt Llc Procesos y compuestos para la preparación de normorfinanos
WO2010028004A2 (en) 2008-09-03 2010-03-11 Mallinckrodt Inc. Substituted berbines and processes for their synthesis
ES2566559T3 (es) * 2008-09-30 2016-04-13 Mallinckrodt Llc Procesos para la alquilación de grupos amino secundarios de derivados de morfinano
US20100260844A1 (en) 2008-11-03 2010-10-14 Scicinski Jan J Oral pharmaceutical dosage forms
UA102916C2 (uk) 2009-07-02 2013-08-27 Кемфарм, Інк. Композиція на основі кон'югату гідрокодону з бензойною кислотою, похідними бензойної кислоти або гетероарилкарбоновою кислотою, проліки, спосіб лікування від зловживань
US10668060B2 (en) 2009-12-10 2020-06-02 Collegium Pharmaceutical, Inc. Tamper-resistant pharmaceutical compositions of opioids and other drugs
WO2011154826A1 (en) 2010-06-11 2011-12-15 Rhodes Technologies Process for n-dealkylation of tertiary amines
EP2580201B1 (en) 2010-06-11 2017-08-02 Rhodes Technologies Transition metal-catalyzed processes for the preparation of n-allyl compounds and use thereof
GB2495062A (en) 2010-07-02 2013-03-27 Johnson Matthey Plc Process for the synthesis and purification of oxycodone
RU2448709C1 (ru) * 2011-02-01 2012-04-27 Учреждение Российской академии наук Институт проблем химико-энергетических технологий Сибирского отделения РАН (ИПХЭТ СО РАН) Способ получения налтрексона
TWI560170B (en) * 2011-12-06 2016-12-01 Lundbeck & Co As H Process for recovery of nalmefene hydrochloride
US9315514B2 (en) 2012-08-27 2016-04-19 Rhodes Technologies 1,3-dioxanomorphides and 1,3-dioxanocodides
CA2894971C (en) 2012-12-14 2018-06-26 Purdue Pharma L.P. Nitrogen containing morphinan derivatives and the use thereof
ES2631197T3 (es) 2012-12-14 2017-08-29 Purdue Pharma Lp Análogos de piridonamorfinano y actividad biológica sobre los receptores opiodes
US8987287B2 (en) 2012-12-14 2015-03-24 Purdue Pharma L.P. Spirocyclic morphinans and their use
ES2653265T3 (es) 2012-12-28 2018-02-06 Purdue Pharma Lp Morfinanos sustituidos y el uso de éstos
JP6159416B2 (ja) 2012-12-28 2017-07-05 パーデュー、ファーマ、リミテッド、パートナーシップ 7,8−環式モルフィナン類似体
WO2014102591A1 (en) 2012-12-31 2014-07-03 Rhodes Technologies PROCESS FOR PREPARING 7β-SUBSTITUTED 6α,14α -ETHENOMORPHINANS AND 7β-SUBSTITUTED 6α,14α-ETHANOMORPHINANS
US9555113B2 (en) 2013-03-15 2017-01-31 Durect Corporation Compositions with a rheological modifier to reduce dissolution variability
EP2829541A1 (en) * 2013-07-26 2015-01-28 Siegfried AG Novel synthesis of noroxymorphone from morphine
WO2015015146A1 (en) 2013-08-02 2015-02-05 Johnson Matthey Public Limited Company Process for the preparation of oxymorphone
WO2015097546A1 (en) 2013-12-26 2015-07-02 Purdue Pharma L.P. Propellane-based compounds and their use as opioid receptor modulators
WO2015097545A1 (en) 2013-12-26 2015-07-02 Purdue Pharma L.P. Opioid receptor modulating oxabicyclo[2.2.2]octane morphinans
EP3087078B1 (en) 2013-12-26 2019-05-15 Purdue Pharma LP 7-beta-alkyl analogs of orvinols
US9994571B2 (en) 2013-12-26 2018-06-12 Purdue Pharma L.P. 10-substituted morphinan hydantoins
WO2015102682A1 (en) 2013-12-30 2015-07-09 Purdue Pharma L.P. Pyridone-sulfone morphinan analogs as opioid receptor ligands
WO2016086113A1 (en) 2014-11-25 2016-06-02 Kempharm, Inc. Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of oxycodone
ES2701855T3 (es) 2016-05-31 2019-02-26 Alcaliber Investig Desarrollo E Innovacion Slu Proceso para la obtención de 3,14-diacetiloximorfona a partir de oripavina
US9737530B1 (en) 2016-06-23 2017-08-22 Collegium Pharmaceutical, Inc. Process of making stable abuse-deterrent oral formulations
CA3028450A1 (en) 2016-07-06 2018-01-11 Durect Corporation Oral dosage form with drug composition, barrier layer and drug layer
LT3559010T (lt) 2016-12-23 2022-10-10 Minoryx Therapeutics S.L. 5-[[4-[2-[5-(1-hidroksietil)-2-piridinil]etoksi]fenil]metil]-2,4-tiazolidindiono ir jo druskų gavimo būdas
SK592017A3 (sk) 2017-07-04 2019-01-08 Saneca Pharmaceuticals A. S. Spôsob prípravy morfínanových zlúčenín
US11845759B2 (en) 2018-02-23 2023-12-19 Rhodes Technologies Opioid compounds and uses thereof
CN110054656B (zh) * 2019-05-28 2021-02-02 宜昌人福药业有限责任公司 一种10-羰基/羟基吗啡-6-葡萄糖苷酸的合成方法
US11613547B2 (en) 2019-07-08 2023-03-28 University Of Health Sciences & Pharmacy In St. Louis G-protein biased opioid receptor agonist/analgesics with reduced arrestin recruitment
CN115666621A (zh) 2020-01-13 2023-01-31 度勒科特公司 具有减少的杂质的持续释放药物递送系统及相关方法
CN114621239A (zh) * 2020-12-10 2022-06-14 鲁南制药集团股份有限公司 一种纳曲酮的制备方法
CA3200832A1 (en) * 2020-12-28 2022-07-07 Navin Saxena Research & Technology Pvt. Ltd. Novel process for the synthesis of noroxymorphone from morphine
JP2024503402A (ja) 2021-01-12 2024-01-25 デュレクト コーポレーション 徐放性薬物送達システム及び関連の方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3819636A (en) * 1970-09-15 1974-06-25 American Home Prod 4a,10-(methaniminomethano)phenanthrene derivatives
US4795813A (en) * 1981-08-17 1989-01-03 The Florida Board Of Regents On Behalf Of The Florida State University Synthesis of derivatives of codeine and other 3-O-alkylmorphines
DE3581423D1 (de) * 1984-03-27 1991-02-28 Mallinckrodt Inc Herstellung von noroxymorphon aus morphin.
US4639520A (en) * 1984-03-27 1987-01-27 Mallinckrodt, Inc. Preparation of 14-hydroxy-N-ethoxy-carbonyl-norcodeinone
US5112975A (en) * 1984-03-27 1992-05-12 Mallinckrodt Specialty Chemicals Company Preparation of noroxymorphone from morphine
US4668685A (en) * 1984-07-05 1987-05-26 E.I. Du Pont De Nemours And Company Substituted benzoate ester prodrug derivatives of 3-hydroxymorphinans, which are analgesics or narcotic antagonists
US4912114A (en) * 1988-03-18 1990-03-27 Sandoz Ltd. Morphinan derivatives

Also Published As

Publication number Publication date
RU2183636C2 (ru) 2002-06-20
EP1000065A4 (en) 2001-09-12
CA2296035C (en) 2004-04-13
US6013796A (en) 2000-01-11
CA2296035A1 (en) 1999-01-21
ZA986144B (en) 1999-05-19
US6008355A (en) 1999-12-28
HUP0003918A3 (en) 2003-04-28
US5952495A (en) 1999-09-14
KR100363486B1 (ko) 2002-12-16
AU740822B2 (en) 2001-11-15
US5922876A (en) 1999-07-13
NO20000111L (no) 2000-02-25
DE69829379D1 (de) 2005-04-21
US5948788A (en) 1999-09-07
CN1272845A (zh) 2000-11-08
ATE291023T1 (de) 2005-04-15
WO1999002529A1 (en) 1999-01-21
US5869669A (en) 1999-02-09
TR200000033T2 (tr) 2000-12-21
CN1152880C (zh) 2004-06-09
EP1000065A1 (en) 2000-05-17
NO20000111D0 (no) 2000-01-10
SK102000A3 (en) 2000-07-11
JP2001518444A (ja) 2001-10-16
KR20010021693A (ko) 2001-03-15
HUP0003918A2 (hu) 2001-07-30
TW505648B (en) 2002-10-11
EP1000065B1 (en) 2005-03-16
IL133792A0 (en) 2001-04-30
US6008354A (en) 1999-12-28
HK1028025A1 (en) 2001-02-02
AU8379198A (en) 1999-02-08

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