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WO2007073301A1 - Derives du benzoimidazole en tant que promedicaments d'inhibiteurs de la pompe a protons - Google Patents

Derives du benzoimidazole en tant que promedicaments d'inhibiteurs de la pompe a protons Download PDF

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Publication number
WO2007073301A1
WO2007073301A1 PCT/SE2006/001465 SE2006001465W WO2007073301A1 WO 2007073301 A1 WO2007073301 A1 WO 2007073301A1 SE 2006001465 W SE2006001465 W SE 2006001465W WO 2007073301 A1 WO2007073301 A1 WO 2007073301A1
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WIPO (PCT)
Prior art keywords
methoxy
methyl
och
compound according
compound
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.)
Ceased
Application number
PCT/SE2006/001465
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English (en)
Inventor
Rolf Bergman
Per Lindberg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
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AstraZeneca AB
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Filing date
Publication date
Application filed by AstraZeneca AB filed Critical AstraZeneca AB
Publication of WO2007073301A1 publication Critical patent/WO2007073301A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • Benzoimidazole derivatives as prodrugs of proton pump inhibitors .
  • the present invention relates to new compounds, which are prodrugs of proton pump inhibitors and to pharmaceutical formulations and the use thereof.
  • the present application is also related to a process for preparing said prodrugs.
  • Benzimidazole derivatives intended for inhibiting gastric acid secretion are for instance disclosed in U.S. Pat. Nos. 4,045, 563; 4,255,431; 4,628,098; 4,686,230; 4,758,579;
  • PPI proton pump inhibitors
  • benzimidazole compounds capable of inhibiting the gastric H 5 K- ATPase enzyme have found substantial use as drugs in human medicine and are known under such names as lansoprazole (U.S. Pat. No. 4,628,098), omeprazole (U.S. Pat. Nos. 4,255,431), esomeprazole (U.S. Pat No. 6,369,085, US 5,714,504, US 6,875,872) pantoprazole (U.S. Pat. No. 4,758,579), and rabeprazole (U.S. Pat. No. 5,045,552).
  • Some of the diseases treated by proton pump inhibitors and specifically by the five above-mentioned drugs include peptic ulcer, heartburn, reflex esophagitis, erosive esophagitis, non- ulcer dyspepsia, infection by Helicobacter pylori, laryngitis and asthma.
  • the present invention relates to new compounds, which are prodrugs of proton pump inhibitor and to pharmaceutical formulations and the use thereof.
  • the present application is also related to a process for preparing said prodrugs.
  • the prodrugs of the present invention are prodrugs of esomeprazole.
  • the term "prodrug” as used herein is intended to include a derivate of the esomeprazole, which after administration undergo conversion to esomeprazole. The conversion may be spontaneous, or enzyme catalyzed.
  • the present invention relates to a compound of formula (I)
  • R 1 is selected from COOH, (CH 2 ) 2 COOH, OCH 2 COOH, OCH 2 COOCH 3 or
  • R 2 is selected from H, OCH 3 , CH 3 , CH(CH 3 ) 2; COOH, or
  • R 3 is selected from H, OCH 3 , CH 3 , or CH(CH 3 ) 2 ; or isomers thereof or mixtures of such isomers or pharmaceutically acceptable salts of such compounds, isomers or mixtures of such isomers, or esters of such compounds or isomers or mixtures of such isomers.
  • a pharmaceutically acceptable salt is any salt that retains the activity of the parent compound and does not impart any deleterious or unwanted effect on the subject to which it is administered and in the context in which is it administered.
  • the pharmaceutically acceptable salt may be derived from organic or inorganic basis.
  • the inorganic salt may be a mono or polyvalent ion such as an alkali metal ion (such as sodium, potassium, or lithium), or an alkali earth metal ion (such as calcium or magnesium), or a metal ion (such as zinc).
  • the organic salt may be selected from ammonium salt such as primary, secondary, tertiary or quaternary ammonium salts, such as triethyl ammonium salt, tert-butyl ammonium salt.
  • ammonium salt such as primary, secondary, tertiary or quaternary ammonium salts, such as triethyl ammonium salt, tert-butyl ammonium salt.
  • Other examples are mono-, di- or trialkyl amines or ethanolamine.
  • pharmaceutically acceptable salts of the compounds of the present invention may be obtained using standard procedures well known in the art.
  • esters are methyl esters.
  • Ri is in the 3-position of the phenyl ring.
  • R 1 is in the 4- position of the phenyl ring.
  • Rj is in the 5-position of the phenyl ring
  • R 1 is OCH 2 COOCH 3 .
  • Rj is OCH 2 COOH or an ammonium salt thereof According to a further embodiment of the present invention the ammonium salt is triethyl ammonium salt.
  • One embodiment of the present invention relates to compounds selected from: Methyl ⁇ 4-[(5-methoxy-2- ⁇ (S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfrnyl ⁇ - 1 H-benzimidazolr 1 -yl)sulfonyl]phenoxy ⁇ acetate or
  • Another embodiment of the present invention relates to compounds selected from 4-[(5- methoxy-2- ⁇ (S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl ⁇ -lH-benzimidazol- l-yl)sulfonyl]phenoxyacetic acid, triethylammonium salt or 4-[(6-methoxy-2- ⁇ (S)-[(4- methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfmyl ⁇ - lH-benzimidazol- 1 - yl)sulfonyl]phenoxyacetic acid, triethylammonium salt or mixtures thereof.
  • the present invention also relates to a pharmaceutical formulation comprising a s pharmaceutically acceptable excipient and one of the compounds disclosed above.
  • Another aspect of the present invention relates to an oral dosage form comprising a compound as disclosed above.
  • oral dosage form as used herein is intended to include any form of solid or o liquid to be administered orally to a person.
  • the optically pure compound may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivates, gelatine or another suitable carrier, stabilizing substances such as alkaline compounds e.g. carbonates, hydroxides and oxides s of sodium, potassium, calcium, magnesium and the like as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes.
  • the mixture is then processed into granules or compressed into tablets.
  • 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 0 stomach.
  • the compounds of the invention are admixed with pharmaceutically acceptable excipients, which per se are well known in the art.
  • the oral dosage form may be designed as a powder, pill or a tablet. S
  • the oral dosage form may also be a capsule.
  • the compounds of the present invention are included in the oral dosage form according to methods familiar to the man skilled in the art.
  • liquid preparation for oral 0 administration may be prepared in the form of syrups or suspensions. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents. These 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 compounds of the present invention can also be used in intravenous solution.
  • Solutions for parenteral administrations may be prepared as solutions of the optically pure compounds of the invention in pharmaceutically acceptable solvents, preferably in a concentration from 0.1 to 10% by weight (% compound per total solution). These solutions may also contain stabilizing agents and/or buffering agents and may be manufactured in different unit dose ampoules or vials. Solutions for parenteral administration may also be prepared as dry preparations to be reconstituted with a suitable solvent extemporaneously before use.
  • the amount of active compound is between 0.1 —95 wt% of the preparation and between 1-50% by weight in preparations for oral administration.
  • 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.
  • Another embodiment of the present invention relates to that the compounds of the present invention can be combined with certain amounts of known proton pump inhibitor, e.g. omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole, thus providing a drug-prodrug combination.
  • known proton pump inhibitor e.g. omeprazole, esomeprazole, lansoprazole, pantoprazole or rabeprazole
  • the present invention relates to the use of a compound as disclosed above for the reduction and/or prevention of gastrointestinal complications and/or gastric acid secretion.
  • gastrointestinal complications as used herein is intended to include ulcer in the stomach or duodenum, some complications to said ulcers, such as bleeding, perforation and/or obstruction, and dyspeptic symptoms such as epigastric pain and/or discomfort.
  • prevention as used herein, also includes the inhibition of "gastrointestinal complications”.
  • reduction as used herein is intended to also include the "risk reduction” of "gastrointestinal complications”.
  • Another aspect of the present invention relates to a method for the reduction and/or prevention of gastrointestinal complications and/or acid gastric secretion by administering to a man or mammal in need thereof a pharmaceutical formulation as disclosed above or an oral dosage form as disclosed above.
  • Yet another aspect of the present invention relates to a method for the reduction and/or prevention of gastrointestinal complications and/or acid gastric secretion by administering to a man or mammal in need thereof a therapeutically effective dose of the compounds of the present invention.
  • Yet another aspect of the present invention relates to a process for preparing the compounds disclosed above comprising the steps of:
  • Step (i) and step (ii) are performed in room temperature.
  • the solvent used for step (i) may be ethanol, methanol, methylene chloride, a mixture of tetrahydrofuran and water or a mixture of dimethoxyethane and water.
  • the solvent used for step (ii) may be tetrahydrofuran or dimethoxyethane.
  • the base used in step (ii) may be sodium hydroxide or triethyl amine.
  • the obtained compounds are separated from the solvent by conventional methods, such as chromatography.
  • solvent and bases which can be used for the claimed process without departing from the spirit and scope of the present invention.
  • the mono or polyvalent cation (X) may be selected from cation such as Li + , Na + , K + Mg 2+ Ca 2+ , Zn 2+ or Et 3 NH + .
  • NaHCO 3 can be used in step (i) for protection of the composition of esomeprazole.
  • the compounds obtained from step (i) may be purified before step (ii).
  • the purification methods used are conventional methods, such as chromatography.
  • Y + is selected from H* " , Na + or K + .
  • the reaction can be performed with little or no racemization.
  • the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position.
  • Another embodiment of the present invention related to a process of preparing a compound of formula (V-A) wherein R 1 is OCH 2 COOCH 3 and R 2 is H and R 3 is H comprising the steps of
  • step (ii) performing selective base catalyzed hydrolysis, in a solvent, on the compound of formula (FV-A) whereby a compound of formula (V-A) is obtained.
  • the reaction performed in step (ii) is a selective base catalyzed hydrolysis of phenoxyacetic acid esters coupled as the sulfonamide of esomeprazole.
  • the process is shown in the reaction scheme 2.
  • Y 1" is selected from H + , Na + or K + and
  • X 1" is a monovalent or polyvalent cation such as Li + , Na + , K + , Mg 2+ , Ca 2+ Zn 2+ or Et 3 NH + .
  • the methoxygroup (*) on the benzimidazole moiety is situated either in 5- or 6- position.
  • Example 1 Methyl ⁇ 4-[(5-methoxy-2- ⁇ (S)-[(4-methoxy-3,5-dimethylpyridin-2- yl) methyl] sulfinyl ⁇ -lH-benzimidazol-1 -yl)sulfonyl]phenoxy ⁇ acetate and Methyl ⁇ 4-[(6- methoxy-2- ⁇ (S)-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl ⁇ -lH-benzimidazol-l- yl)sulfonyl]phenoxy ⁇ acetate.
  • Example 2 4-[(5-methoxy-2- ⁇ (S)-[(4-methoxy-3, 5-dimethylpyridin-2-yl)methyl]sulfinyl ⁇ - lH-henzimidazol-l-yl)sulfonyl]phenoxyacetic acid, triethylammonium salt and 4-[(6- methoxy-2- ⁇ (S)-[(4-methoxy-3,5-dimethylpyridm-2-yl)methyl]sulflnyl ⁇ -lH-benz ⁇ nidazol-l- yl)sulfonyl]phenoxy acetic acid, triethylammonium salt

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (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)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés nouveaux qui sont des promédicaments d'inhibiteurs de la pompe à protons, ainsi que leurs formulations pharmaceutiques et leur utilisation. L'invention concerne également un procédé de préparation desdits promédicaments.
PCT/SE2006/001465 2005-12-23 2006-12-21 Derives du benzoimidazole en tant que promedicaments d'inhibiteurs de la pompe a protons Ceased WO2007073301A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US75400205P 2005-12-23 2005-12-23
US60/754,002 2005-12-23

Publications (1)

Publication Number Publication Date
WO2007073301A1 true WO2007073301A1 (fr) 2007-06-28

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PCT/SE2006/001465 Ceased WO2007073301A1 (fr) 2005-12-23 2006-12-21 Derives du benzoimidazole en tant que promedicaments d'inhibiteurs de la pompe a protons

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6559167B1 (en) * 1998-08-10 2003-05-06 Regents Of The University Of California Prodrugs of proton pump inhibitors
US20050038076A1 (en) * 2003-07-15 2005-02-17 Garst Michael E. Process for preparing isomerically pure prodrugs of proton pump inhibitors
US20050182101A1 (en) * 2002-07-19 2005-08-18 Michael Garst Prodrugs of proton pump inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6559167B1 (en) * 1998-08-10 2003-05-06 Regents Of The University Of California Prodrugs of proton pump inhibitors
US20050182101A1 (en) * 2002-07-19 2005-08-18 Michael Garst Prodrugs of proton pump inhibitors
US20050038076A1 (en) * 2003-07-15 2005-02-17 Garst Michael E. Process for preparing isomerically pure prodrugs of proton pump inhibitors

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