WO1995032957A1 - Nouveaux derives ethoxycarbonyloxymethyles de benzinidazoles substituees - Google Patents

Nouveaux derives ethoxycarbonyloxymethyles de benzinidazoles substituees Download PDF

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Publication number
WO1995032957A1
WO1995032957A1 PCT/SE1994/000512 SE9400512W WO9532957A1 WO 1995032957 A1 WO1995032957 A1 WO 1995032957A1 SE 9400512 W SE9400512 W SE 9400512W WO 9532957 A1 WO9532957 A1 WO 9532957A1
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WIPO (PCT)
Prior art keywords
methoxy
benzimidazole
dimethyl
methyl
ethyl carbonate
Prior art date
Application number
PCT/SE1994/000512
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English (en)
Inventor
Sverker Von Unge
Original Assignee
Astra Aktiebolag
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
Application filed by Astra Aktiebolag filed Critical Astra Aktiebolag
Priority to PCT/SE1994/000512 priority Critical patent/WO1995032957A1/fr
Publication of WO1995032957A1 publication Critical patent/WO1995032957A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to new compounds with high optical purity, their use in medicine, a process for their preparation and their use in the manufacture of pharmaceutical preparation.
  • omeprazole The compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]- sulfinyl]-lH-benzimidazole, having the generic name omeprazole is described in EP 5129.
  • Omeprazole is an effective gastric acid secretion inhibitor, and is useful as an antiulcer agent.
  • a number of alkoxycarbonyloxymethyl derivatives of omeprazole are disclosed in EP 0233284.
  • the compounds, omeprazole as well as its N-substituted derivatives, being sulfoxides, have an asymmetric center in the sulfur atom, i.e. exist as two optical isomers (enantiomers). It is desirable to obtain compounds with improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as lower degree of interindividual variation.
  • the present invention provides such compounds, which are novel single enantiomers of ethoxy- carbonyloxymethyl derivatives of omeprazole.
  • the present invention refers to the new single enantiomers of 5-methoxy-2-[[(4- methoxy-3 ,5-dimethyl-2-pyridinyl)rnethyl] sulfinyl] - 1 H-benzimidazole- 1 -ylmethyl ethyl carbonate according to compounds la and lb
  • the invention also refers to the new single enantiomers of the regioisomeric mixture
  • optically pure compound of the invention is meant the (+)- enantiomer of said compound (or compounds) essentially free of the corresponding (-)-enantiomer and the (-)-enantiomer essentially free of the corresponding (+)- enantiomer, respectively.
  • the compounds according to the invention may be used for inhibiting gastric acid secretion in mammals and man.
  • the single enantiomeric compounds of the invention may be used for the treatment of gastric acid-related diseases and gastrointestinal inflammatory diseases in mammals and man, such as gastric ulcer, duodenal ulcer, reflux esophagitis, and gastritis.
  • the compounds may be used for treatment of other gastrointestinal disorders where gastric antisecretory effect is desirable e.g. in patients on NSAID therapy, in patients with gastrinomas, and in patients with accute upper gastrointestinal bleeding. They may also be used in patients in intensive care situations, and pre- and postoperatively to prevent acid aspiration and stress ulceration.
  • the compound of the invention may also be used for treatment or prophylaxis of inflammatory conditions in mammals, including man, especially those involving lysozymal enzymes. Conditions that may be specifically mentioned are rheumatoid arthritis and goat.
  • the compounds of the invention may also be useful in the treatment of psoriasis as well as in the treatment of Helicobacter infections.
  • optically pure compounds of the invention i.e. the single enantiomers may be prepared according to one of the following methods a), b) or c) described below.
  • methoxy substituent in the benzimidazole moiety is in position 5 or 6 and wherein Z is either a metal cation such as Na + , K + , Li + or Ag + or a quaternary ammonium ion, such as tetrabutylammonium, with chloromethyl ethyl carbonate.
  • Z is either a metal cation such as Na + , K + , Li + or Ag + or a quaternary ammonium ion, such as tetrabutylammonium, with chloromethyl ethyl carbonate.
  • X is Cl or imidazole or p-nitrophenoxy or a functionally equivalent group, in the presence of a suitable base such as trietylamine.
  • This oxidation may be carried out by using a chiral inducing oxidizing agent or by using an oxidizing agent with a chiral catalyst or any other chiral enviroment such as e.g. chiral solvents.
  • the oxidation may also be carried out enzymatically by using an oxidizing enzyme or
  • the reactions according to methods a) and b) above are suitably carried out under protective gas in the absence of water.
  • Suitable solvents are acetonitrile, l-methyl-2- pyrrolidinone, acetone or dimethyl formamide or hydrocarbons such as toluene or benzene or halogenated hydrocarbons such as methylene chloride or chloroform.
  • the reactions may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture.
  • the starting compounds IVa) and IVb), respectively, being salt of the single enantiomers of omeprazole, can be prepared by separating the two stereoisomers of a diastereomeric mixture of the following type 5- or 6-methoxy-2-[[(4-methoxy-3,5- dimethyl-2-pyridinyl)methyl]sulf ⁇ nyl]-l-[acyloxymethyl]-lH-benzimidazole, formula VII
  • the Acyl moiety in the diastereomeric ester may be a chiral acyl group such as mandeloyl, and the asymmetric center in the chiral acyl group can have either R or S configuration.
  • the diastereomeric esters can be separated either by chromatography or fractional
  • the solvolysis usually takes place together with a base in a protic solvent such as alcohols or water, but the acyl group may also be hydrolysed off by a base in an aprotic solvent such as dimethylsulfoxide or dimethylformamide.
  • Th reacting base may be OH" or R ⁇ O" where R ⁇ can be any alkyl or aryl group.
  • the resulting compound is treated with a base, such as NaOH, in an aqueous or nonaqueous medium, or with NaOR ⁇ where R ⁇ is an alkyl group containing 1-4 carbon atoms, or with NaNH2-
  • a base such as NaOH
  • NaOR ⁇ where R ⁇ is an alkyl group containing 1-4 carbon atoms
  • NaNH2- NaNH2-
  • addition of NaOH in a non-aqueous medium such as a mixture of 2-butanone and toluene, is preferred.
  • a pure regioisomer of a single enantiomer of the invention can be isolated by means of crystallization or chromatography.
  • the single enantiomers can be separated according to known methods, e.g. by crystallisation from different solvents.
  • the starting materials utilized in the methods a)-c) are unknown. These unknown starting materials may be obtained from known compounds by utilizing processes known per se.
  • Chloromethyl ethyl carbonate may be obtained from ethanol by treatment with chloromethyl chloroformate in the presence of pyridine.
  • Starting materials of the formula V may be obtained by known methods, e.g. from ethanol by treatment with phosgene or l,l'-carbonyl diimidazole or p-nitrophenyl chloroformate.
  • the single enantiomers, i.e. the optically pure compounds, of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other modes of administrations.
  • the pharmaceutical formulations contain the single enantiomers of the invention normally in combination with a pharmaceutically acceptable carrier.
  • the carrier may be in form of a solid, semi-solid or liquid diluent, or capsule.
  • These pharmaceutical preparations are a further object of the invention.
  • the amount of active compound is between 0.1-95% by weight of the preparation, and between 1-50% by weight in preparations for oral administration.
  • the optically pure compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivates, gelatin or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylenglycol waxes.
  • a solid, powdered carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivates, gelatin or another suitable carrier
  • stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides of sodium, potassium, calcium, magnesium and the like as well as with lubricating agents such as magnesium stearate, calcium stea
  • Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalysed degradation as long as the dosage form remains in the stomach.
  • the enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers and the like, if preferred in combination with a suitable plasticizer.
  • enteric-coating materials e.g. beeswax, shellac or anionic film-forming polymers and the like, if preferred in combination with a suitable plasticizer.
  • To the coating various dyes may be added in order to distinguish among tablets or granules with different amounts of the active compound present.
  • Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Soft gelatine capsules may also be enteric -coated as described above.
  • Hard gelatine capsules may contain granules or enteric-coated granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivates or gelatin. The capsules may be enteric -coated as described above.
  • Dosage units for rectal administration may be prepared in the form of suppositories
  • SUBSTITUTE SHEET which contain the active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
  • Liquid preparation for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.
  • Liquid preparations for oral administration may also be prepared in the form of dry powder to be reconstituted with a suitable solvent prior to use.
  • the typical daily dose of the active compound will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 5 to 500 mg per day of active substance.
  • Example 1 Preparation of (-)-5-methoxy-2-rr(4-methoxy-3.5-dimethyl-2- pyridinyPmethvHsulfinyll-lH-benzimidazole-l-ylmethyl ethyl carbonate and (-)-6- methoxy-2-rr(4-methoxy-3.5-dimethyl-2-pyridinyl methyllsulf ⁇ nvn-lH- benzimidazole-l-ylmethyl ethyl carbonate
  • (+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-py ⁇ idinyl)methyl]sulfinyl]-lll- benzimidazole sodium salt 3.0 g (8.2 mmol) was dissolved in water (200 ml). The solution was neutralized with an aqueous solution of ammonium chloride and thereafter extracted with methylene chloride. The organic phase was dried over Na2SO4, filtered and then removed by film evaporation.
  • CDCI3 1.3 (m, 3H), 2.2-2.3 (m, 6H), 3.71 (s, 3H), 3.86 and 3.90 300 MHz (two singlets, 3H), 4.18-4.27 (m, 2H), 4.88 (d, 1H), 4.98 (d, lH),6.37-6.42 (m, 1H), 6.51-6.58 (m, 1H), 6.96-7.26 (m, 2H),
  • CDCI3 1.3 (m, 3H), 2.2-2.3 (m, 6H), 3.70 (s, 3H), 3.84 and 3.89 300 MHz (two singlets, 3H), 4.17-4.26 (m, 2H), 4.87 (d, 1H), 4.97 (d, 1H), 6.36-6.42 (m, 1H), 6.50-6.57 (m, 1H), 6.95-7.26 (m, 2H),
  • CDCI3 1.28 (s, 3H), 2.20 (s, 3H), 2.24 (s, 3H), 3.69 (s, 3H),
  • Example 8 Separation of the more hydrophilic diastereomer of 6-methoxy-2-riY4- methoxy-3.5-dimethyl-2-pyridinyl)methvfl-(R/S)-sulfinv ⁇ - 1 - ⁇ (R)- mandeloyloxymethy ⁇ - 1 H-benzimidazole
  • the product was obtained from 8.1 g (202 mmol) sodium hydroxide in 100 ml water,
  • Example 10 Separation of the more hydrophilic diastereomer of 6-methoxy-2-rF(4- methoxy-3.5-dimethyl-2-pyridlnyl methvn-(R S -sulf ⁇ nyll-l-r(S - mandeloyloxymethyll - 1 H-benzimidazole
  • Example 9 The diastereomers of the title compound in Example 9 were separated using reversed phase chromatography (HPLC) in the same way as In Example 8, but using the diasteromeric mixture of 6-methoxy-2-[[(4-methoxy-3,5-dlmethyl-2-pyridlnyl)methyl]- (I S)-sulf_nyl]-l-[(S)-mandeloyloxyme ⁇ yl]-lH-ber__imidazole instead of the (R)- mandelic ester used in Example 8. Using 2.1 g of the diastereomeric mixture, the more hydrophilic isomer, 760 mg, was obtained in a pure state as a colourless syrup.
  • CDCI3 2.19 (s, 3H), 2.20 (s, 3H), 2.36 (s, 3H), 2.39 (s, 3H), 3.77 500 MHz (s, 3H), 3.78 (s, 3H), 3.83 (s, 3H), 3.87 (s, 3H), 4.80 (d, IH), 4.88 (d, IH), 5.0 (m, 2H), 5.34 (s, 2H), 6.43 (d, IH), 6.54 (d,
  • CDCI3 2.18, (s, 3H), 2.22 (s, 3H), 3.68 (s, 3H), 3.83 (s, 3H),
  • a syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
  • a tablet containing 50 mg of active compound was prepared from the following
  • Capsules containing 30 mg of active compound were prepared from the following ingredients:
  • the active compound was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate.
  • the wet mass was forced through an extruder and spheronized and dried in a fluidlzed bed dryer.
  • the final coated pellets were filled into capsules.
  • Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
  • the active compound was homogenously mixed with Witepsol H- 15 at a temperature of 41° C.
  • the molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed.
  • Each suppository contained 40 mg of active compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur de nouveaux composés optiquement purs, c'est-à-dire sur les composés énantiomères individuels (-)-5-méthoxy-2-[[(4-méthoxy-3,5-diméthyl-2-pyridinyl)méthyl]sulfinyl]-1H-benzimidazole-1-ylméthyl éthyl carbonate, (-)-6-méthoxy-2-[[(4-méthoxy-3,5-diméthyl-2-pyridinyl)méthyl]sulfinyl]-1H-benzimidazole-1-ylméthyl éthyl carbonate, (+)-5-méthoxy-2-[[(4-méthoxy-3,5-diméthyl-2-pyridinyl)méthyl]sulfinyl]-1H-benzimidazole-1-ylméthyl éthyl carbonate, et (+)-6-méthoxy-2-[[(4-méthoxy-3,5-diméthyl-2-pyridinyl)méthyl]sulfinyl]-1H-benzimidazole-1-ylméthyl éthyl carbonate; et sur leurs procédés d'obtention, sur des préparations pharmaceutiques les utilisant comme principes actifs, sur l'utilisation desdits composés dans des préparations pharmaceutiques, et sur leurs intermédiaires de préparation.
PCT/SE1994/000512 1994-05-27 1994-05-27 Nouveaux derives ethoxycarbonyloxymethyles de benzinidazoles substituees WO1995032957A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001014367A1 (fr) * 1999-08-26 2001-03-01 Applied Analytical Industries, Inc. Composes benzimidazole substitues par un alcoxy, preparations pharmaceutiques contenant ces derniers, et procedes d'utilisation
US6316020B1 (en) * 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
EP1186602A2 (fr) * 1997-06-26 2002-03-13 AstraZeneca AB Sel de sodium de l'oméprazole et son utilisation comme agent anti-ulcères
US6617338B2 (en) 2000-02-24 2003-09-09 Kopran Research Laboratories Limited Orally administrable acid stable antiulcer benzimidazole derivatives
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
EP1595879A2 (fr) * 1999-08-26 2005-11-16 aaiPharma Inc. Composés benzimidazole substitués par un alcoxy, préparations pharmaceutiques contenant des derniers, et procédés d'utilisation
WO2007140608A1 (fr) * 2006-06-09 2007-12-13 Apotex Pharmachem Inc. Procédé de préparation de l'ésoméprazole et de ses sels
JP2008503574A (ja) * 2004-06-24 2008-02-07 アストラゼネカ・アクチエボラーグ エソメプラゾールのナトリウム塩の製造に使用するための結晶の改変型の作成方法
CN100384859C (zh) * 1996-07-26 2008-04-30 吉里德科学公司 核苷酸类似物
US8592397B2 (en) 2003-01-14 2013-11-26 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8598185B2 (en) 2005-06-13 2013-12-03 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8869204B2 (en) 1996-05-03 2014-10-21 Starsight Telecast, Inc. Method and system for displaying advertisements in an electronic program guide
US8871271B2 (en) 2005-06-13 2014-10-28 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US9113107B2 (en) 2005-11-08 2015-08-18 Rovi Guides, Inc. Interactive advertising and program promotion in an interactive television system
US9215504B2 (en) 2006-10-06 2015-12-15 Rovi Guides, Inc. Systems and methods for acquiring, categorizing and delivering media in interactive media guidance applications

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5021433A (en) * 1985-10-29 1991-06-04 Aktiebolaget Hassle Novel pharmacological compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5021433A (en) * 1985-10-29 1991-06-04 Aktiebolaget Hassle Novel pharmacological compounds

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8869204B2 (en) 1996-05-03 2014-10-21 Starsight Telecast, Inc. Method and system for displaying advertisements in an electronic program guide
CN100384859C (zh) * 1996-07-26 2008-04-30 吉里德科学公司 核苷酸类似物
EP1186602A2 (fr) * 1997-06-26 2002-03-13 AstraZeneca AB Sel de sodium de l'oméprazole et son utilisation comme agent anti-ulcères
EP1186602A3 (fr) * 1997-06-26 2002-03-27 AstraZeneca AB Sel de sodium de l'oméprazole et son utilisation comme agent anti-ulcères
KR100580987B1 (ko) * 1997-06-27 2006-05-17 아스트라제네카 악티에볼라그 오메프라졸 나트륨염
WO2001014367A1 (fr) * 1999-08-26 2001-03-01 Applied Analytical Industries, Inc. Composes benzimidazole substitues par un alcoxy, preparations pharmaceutiques contenant ces derniers, et procedes d'utilisation
US6316020B1 (en) * 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
EP1595879A2 (fr) * 1999-08-26 2005-11-16 aaiPharma Inc. Composés benzimidazole substitués par un alcoxy, préparations pharmaceutiques contenant des derniers, et procédés d'utilisation
EP1595879A3 (fr) * 1999-08-26 2010-01-27 aaiPharma Inc. Composés de benzimidazole substitués par un alkoxy, préparations pharmaceutiques contenant ces derniers, et procédés d'utilisation
US6617338B2 (en) 2000-02-24 2003-09-09 Kopran Research Laboratories Limited Orally administrable acid stable antiulcer benzimidazole derivatives
US8592397B2 (en) 2003-01-14 2013-11-26 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US9744181B2 (en) 2003-01-14 2017-08-29 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US9457036B2 (en) 2003-01-14 2016-10-04 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8716264B2 (en) 2003-01-14 2014-05-06 Gilead Sciences, Inc. Compositions and methods for combination antiviral therapy
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
JP2008503574A (ja) * 2004-06-24 2008-02-07 アストラゼネカ・アクチエボラーグ エソメプラゾールのナトリウム塩の製造に使用するための結晶の改変型の作成方法
US8871271B2 (en) 2005-06-13 2014-10-28 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US9018192B2 (en) 2005-06-13 2015-04-28 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US8598185B2 (en) 2005-06-13 2013-12-03 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US9545414B2 (en) 2005-06-13 2017-01-17 Bristol-Myers Squibb & Gilead Sciences, Llc Unitary pharmaceutical dosage form
US9113107B2 (en) 2005-11-08 2015-08-18 Rovi Guides, Inc. Interactive advertising and program promotion in an interactive television system
US8563733B2 (en) 2006-06-09 2013-10-22 Apotex Pharmachem Inc Process for the preparation of esomeprazole and salts thereof
WO2007140608A1 (fr) * 2006-06-09 2007-12-13 Apotex Pharmachem Inc. Procédé de préparation de l'ésoméprazole et de ses sels
US7786309B2 (en) 2006-06-09 2010-08-31 Apotex Pharmachem Inc. Process for the preparation of esomeprazole and salts thereof
US9215504B2 (en) 2006-10-06 2015-12-15 Rovi Guides, Inc. Systems and methods for acquiring, categorizing and delivering media in interactive media guidance applications

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