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WO2007012651A1 - Pantoprazole substitue d'un point de vue isotopique - Google Patents

Pantoprazole substitue d'un point de vue isotopique Download PDF

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Publication number
WO2007012651A1
WO2007012651A1 PCT/EP2006/064669 EP2006064669W WO2007012651A1 WO 2007012651 A1 WO2007012651 A1 WO 2007012651A1 EP 2006064669 W EP2006064669 W EP 2006064669W WO 2007012651 A1 WO2007012651 A1 WO 2007012651A1
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WO
WIPO (PCT)
Prior art keywords
compound
difluoromethoxy
methoxy
compounds
trideuteriomethoxy
Prior art date
Application number
PCT/EP2006/064669
Other languages
English (en)
Inventor
Bernhard Kohl
Bernd Müller
Dieter Haag
Wolfgang-Alexander Simon
Karl Zech
Michael David
Oliver Von Richter
Felix Huth
Original Assignee
Nycomed Gmbh
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 Nycomed Gmbh filed Critical Nycomed Gmbh
Priority to EP06777980A priority Critical patent/EP1912947A1/fr
Priority to CN2006800344239A priority patent/CN101268050B/zh
Priority to JP2008523355A priority patent/JP5289951B2/ja
Priority to CA2615678A priority patent/CA2615678C/fr
Priority to AU2006274037A priority patent/AU2006274037B2/en
Publication of WO2007012651A1 publication Critical patent/WO2007012651A1/fr
Priority to US12/000,376 priority patent/US7601737B2/en
Priority to US12/458,704 priority patent/US20100022779A1/en
Priority to US12/461,985 priority patent/US20100010047A1/en

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/69—Two or more oxygen atoms

Definitions

  • the present invention relates to isotopically substituted pantoprazole and its (R)- and (S)-enantiomers. These compounds can be used in the pharmaceutical industry for preparing pharmaceutical compositions.
  • pyridin-2-ylmethylsulphinyl-1 H-benzimidazoles such as those known, for example, from EP-A-0005129, EP-A-0166287, EP-A-0174726, EP-A-0254588 and EP-A-0268956 are of considerable importance in the therapy of disorders associated with an increased secretion of gastric acid.
  • Examples of active compounds from this group which are commercially available or in clinical development are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: omeprazole), (S)-5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole (INN: lansoprazole), 2- ⁇ [4-(3-methoxypropoxy)-3-methylpyridin
  • PPI proton pump inhibitors
  • US Patent 6,818,200 discloses dihydropyridine compounds and antibiotics wherein at least one hydrogen atom is replaced by a deuterium atom.
  • the deuterated compounds are obtained by reacting the H- form with mixtures of deuterium oxide and a suitable catalyst in sealed vessels at drastic reaction conditions, i.e. at elevated temperatures (60-80 0 C) and for prolonged reaction times (up to 190 hours). It further discloses some influence on the pharmacological properties of these compounds due to the H/D exchange.
  • the invention relates to compounds of the general formula 1
  • R1 is difluormethoxy
  • R2 is methoxy
  • R3 is methoxy and salts, solvates, preferably hydrates and solvates of the salts, preferably hydrates of the salts thereof, wherein at least one of the hydrogen atoms of R1 , R2, R3 or any combination of R1 , R2 and R3 is replaced by a deuterium atom.
  • Possible combinations are R1 and R2, R1 and R3, R2 and R3 or R1 and R2 and R3.
  • salts with inorganic and organic bases are included, in particular the salts with alkali metals, such as the lithium, sodium and potassium salts, or the salts with alkaline earth metals, such as the magnesium and calcium salts, but also other pharmacologically compatible salts, such as, for example, the aluminium or the zinc salts.
  • alkali metals such as the lithium, sodium and potassium salts
  • alkaline earth metals such as the magnesium and calcium salts
  • other pharmacologically compatible salts such as, for example, the aluminium or the zinc salts.
  • the sodium and the magnesium salts are particularly preferred.
  • Pharmacologically incompatible salts which can initially be obtained, for example, as process products in the production of the compounds according to the invention on the industrial scale, which are also within the scope of the invention, are - for the production of medicaments - converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.
  • the compounds according to the invention and their salts if, for example, they are isolated in crystalline form, can contain various amounts of solvents.
  • the invention therefore also comprises all solvates and in particular all hydrates of the compounds of the formula 1 , and also all solvates and in particular all hydrates of the salts of the compounds of the formula 1.
  • solvates all pharmaceutically acceptable solvents resulting in such solvates are included.
  • the term "at least one" refers to 1 to 3 hydrogen atoms of R2 or R3, which can be replaced by deuterium atoms. - -
  • deutero or “deuterio” should indicate a deuterium atom ([ 2 H]).
  • tri or “tris” should indicate the occurrence of three, for example deuterio atoms in a specific group, i.e. trideuteriomethoxy.
  • R1 is deuteriodifluoromethoxy.
  • examples of such compounds may be 5-difluoromethoxy-2-[(3-methoxy-4- monodeuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy- 4-dideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[3- monodeuteriomethoxy-4-methoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2- [(3-dideuteriomethoxy-4-methoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2- [(3-dideuteriomethoxy-4-meth
  • R2, R3 or R2 and R3 is trideuteriomethoxy. More preferred is a compound wherein R3 is trideuteriomethoxy.
  • examples of such compounds may be 5- difluoromethoxy-2-[(3-trideuteriomethoxy-4-methoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5- difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole or 5- difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole.
  • R1 is difluoromethoxy
  • R2 is methoxy
  • R3 is dideute- riomethoxy or trideuteriomethoxy.
  • the sodium or magnesium salt of a compound of formula 1 is a monohydrate salt and, even more preferred, a sesquihydrate salt.
  • the magnesium salt is a trihydrate salt and, even more preferred, a dihydrate salt.
  • the compounds according to the invention show significant improved properties with respect to the known compounds concerning the influences on secretion of gastric acid.
  • the compounds according to the invention are chiral compounds.
  • the invention thus relates to the racemates as well as to the enantiomers and mixtures thereof in any desired ratio.
  • a preferred subject matter of the inventions are the enantiomers of the compounds of formula 1 , preferably the enantiomers being substantially free of the respective other enantiomer with opposite configuration.
  • R1, R2 and R3 have the meanings given above.
  • a particularly preferred compound with (S)-configuration within the scope of the invention is the compound (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H- benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound.
  • Another particularly preferred compound with (S)-configuration within the scope of the invention is the compound (S)-5-difluoromethoxy- 2-[(3-methoxy-4-dideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound.
  • the sodium or magnesium salt of a compound of formula 1 a is a trihydrate.
  • R1, R2 and R3 have the meanings given above.
  • a particularly preferred compound with (R)-configuration within the scope of the invention is the compound (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H- benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound.
  • Another particularly preferred compound with (R)-configuration within the scope of the invention is the compound (R)-5-difluoromethoxy- 2-[(3-methoxy-4-dideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound.
  • the separation of the compounds of formula 1 into the enantiomers can be accomplished according to various processes, for example as described in international patent application WO92/08716 or by column chromatography.
  • the compounds of formulae 1a and 1b can be obtained by chiral oxidation of the sulphides as described in international patent application WO 2004/052881.
  • the salts of the compounds of formulae 1 , 1a and 1 b are prepared by processes known per se by reacting the compounds of formulae 1 , 1a, and 1 b, which can be regarded as weak acids, with suitable bases, for example with alkali metal hydroxides or alkoxides, such as sodium hydroxide or sodium methoxide, or with alkaline earth metal alkoxides, such as magnesium methoxide.
  • suitable bases for example with alkali metal hydroxides or alkoxides, such as sodium hydroxide or sodium methoxide, or with alkaline earth metal alkoxides, such as magnesium methoxide.
  • the magnesium salts of the compounds of formulae 1 , 1a and 1 b which are - besides the sodium salts - the preferred salts, are prepared in a manner known per se by reacting compounds of formulae 1 , 1a and 1 b with a magnesium base, for example a magnesium alkoxide, or from a readily soluble salt of a compound of formulae 1 , 1a and 1 b (for example of a sodium salt) using a magnesium salt in water or in mixtures of water with polar organic solvents (for example alcohols, preferably methanol, ethanol or isopropanol, or ketones, preferably acetone).
  • a magnesium base for example a magnesium alkoxide
  • a readily soluble salt of a compound of formulae 1 , 1a and 1 b for example of a sodium salt
  • polar organic solvents for example alcohols, preferably methanol, ethanol or isopropanol, or ketones, preferably acetone.
  • substantially free in the context of the invention means that the compounds with (S)-configuration and/or their salts, solvates or solvates of salts contain less than 10 % by weight of compounds with (R)-configuration and/or their salts, solvates or solvates of salts.
  • substantially free means that compounds with (S)-configuration and/or their salts, solvates or solvates of salts contain less than 5 % by weight of compounds with (R)-configuration and/or their salts, solvates or solvates of salts.
  • substantially free means that compounds with (S)-configuration and/or their salts, solvates or solvates of salts contain less than 2 % by weight of compounds with (R)-configuration and/or their salts, solvates or solvates of salts. In the most preferred embodiment, “substantially free” means that compounds with (S)-configuration and/or their salts, solvates or solvates of salts contain less than 1 % by weight of compounds with (R)-configuration and/or their salts, solvates or solvates of salts.
  • substantially free in the context of the invention means that the compounds with (R)-configuration and/or their salts, solvates or solvates of salts contain less than 10 % by weight of compounds with (S)-configuration and/or their salts, solvates or solvates of salts.
  • substantially free means that compounds with (R)-configuration and/or their salts, solvates or solvates of salts contain less than 5 % by weight of compounds with (S)-configuration and/or their salts, solvates or solvates of salts.
  • substantially free means that compounds with (R)-configuration and/or their salts, solvates or solvates of salts contain less than 2 % by weight of compounds with (S)-configuration and/or their salts, solvates or solvates of salts.
  • substantially free means that compounds with (R)-configuration and/or their salts, solvates or solvates of salts contain - - less than 1 % by weight of compounds with (S)-configuration and/or their salts, solvates or solvates of salts.
  • the term "hydrogen atom replaced by a deuterium atom” has to be understood as defining a degree of deuteration of at least 80 % for the bulk material, where all these correspondingly mentioned hydrogen atoms are replaced by deuterium atoms.
  • the substitu- ent R2 or R3 refers to a methoxy group having all three "hydrogen atoms replaced by a deuterium atoms” it is to be understood according to the above definition that at least 80% of all the R2 or R3 methoxy groups in the bulk material are -OCD 3 .
  • the remaining part up to 100% includes -OCHD 2 , - OCH 2 D Or-OCH 3 .
  • R1 , R2 and R3 have the meanings as given above and wherein at least one of the hydrogen atoms of R1 , R2, R3 or any combination of R1 , R2 and R3 is replaced by a deuterium atom.
  • Possible combinations are R1 and R2, R1 and R3, R2 and R3 or R1 and R2 and R3.
  • the compounds of formula 2 include further their salts with acid, preferably the hydrochloride, the sulphate or the phosphate salts, and/or solvates. These compounds can be used for the manufacture of compounds of general formula 1, 1a or 1b.
  • the compounds of formula 2 are suitable especially as starting material for an oxidation reaction resulting in compounds according formulae 1 , 1 a or 1 b.
  • Another aspect of the invention are compounds of formula 3
  • X is a halogen or an activated derivative of an alcohol and R2 and R3 have the meanings as given above and wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom.
  • halogen is iodine, bromine, chlorine and fluorine.
  • X is chlorine.
  • an activated derivate of an alcohol is an alkylsulfonate group, for example mesylate or an arylsulfonate group, for example tosylate or besylate, or a perfluoroalkanesul- fonate group, for example trifluoromethanesulfonate.
  • the compounds of formula 3 can be used for the manufacture of compounds of formula 1 , 1 a or 1 b.
  • the nitrogen atom of compound of formula 3 is first quatemised and then reacted with compounds of formula 4
  • R1 has the meaning as given above, thus providing compounds of formula 2 as described above.
  • the deuterium homologes of R/S pantoprazole and S-pantoprazole can be prepared by oxidation of the corresponding thio-compounds according to methods known from literature, e.g. Kohl et al. J. Med. Chem. 1992, 35, 1049 ff. or WO 2004/052881 or by exchange of halogen for trideuteriomethoxy from the corresponding sulfoxides with a halogen (e.g. chloro, bromo or nitro) substituent at the position of the final trideuteriomethoxy group, in particular in 4-position of the pyridine group.
  • a halogen e.g. chloro, bromo or nitro
  • the thiocompounds are prepared either by exchange of halogen by trideuteriomethoxy at the position of the final trideuteriomethoxy-substituent or by coupling of 5-difluoromethoxy-2- mercaptobenzimidazole with the accordingly substituted 2-chloromethyl-3-methoxy-4- trideuteriomethoxy-pyridinumchloride.
  • the disclosed preparation routes can also be used to substitute the halogen by dideuteriomethoxy or monodeuteriomethoxy instead of trideuteriomethoxy as described above. These syntheses will lead to the correspondingly deuterated compounds.
  • the compound of formula 1 can be prepared according to the following reaction scheme: - -
  • Salts of the sulfoxides with anorganic bases are prepared according to methods known from literature by reaction of the sulfoxides with the corresponding hydroxides or alkoxides in organic solvents or mixtures of organic solvents with water.
  • salts are prepared by reaction of sulfoxides with alkali hydroxides to give the corresponding alkali salt (Na, K, Li) and further reaction with e.g. magnesium, calcium, aluminum, zinc salts.
  • methanol-d4 As trideuteriomethoxylation agent, methanol-d4 with >99.8 atom% D was used. Isomeric purity of the trideuteriomethoxy substituent(s) in all resulting products was >98.0% as determined by NMR and MS. As further deuteration agents, methanol-d2 with >98.0 atom% D, and methanol-d1 with >98.0 atom% D were used. Isomeric purity of the dideuteriomethoxy and monodeuteriomethoxy substituents in the resulting products was >96.0% as determined by NMR and MS.
  • a solution of sodium hypochlorite (10 % strength) (3.3 mmol) is added over one to two hours to a slurry of 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio]-1 H-benzimidazole (1.0 g, 2.7 mmol) in water (20 ml_), 2-propanol (10 ml.) and sodium hydroxide (0.5 ml.40 % strength solution, 7.1 mmol) at 30-35 0 C with stirring. After 30-60 minutes at the stated temperature sodium thiosulfate (0.3 g dissolved in 5 ml. of water) is added and stirring is continued for a further 15-30 minutes.
  • reaction mixture is concentrated in vacuo (30-40 0 C) to about one third of the original volume and water (about 70 mL) is added.
  • N-ethyldiisopropylamine (0.07 mL) and cumene hydroperoxide (1.05 mL) are added.
  • the mixture is stirred at room temperature until the oxidation has ended (10-24 hours, monitored by TLC).
  • the clear solution is diluted with 10 mL of methyl isobutyl ketone and quenched with 0.08 g of sodium thiosulphate in 14 mL of saturated sodium bicarbonate solution and stirred for a further 2 hours. After phase separation the mixture is washed twice with 5 mL of saturated sodium bicarbonate solution.
  • reaction mixture After four hours at the stated temperature the reaction mixture is cooled to 20 - 25 0 C and water (500 ml.) is added over 1 - 2 hours while stirring. After adjustment to pH 7 with 2N aqueous hydrochloric acid the mixture is stirred for a further hour at 20-25 0 C.
  • the precipitate is filtered off over a suction filter, rinsed with water (200 mL) in several portions and dried (35 0 C, 20 mbar, 20 hours).
  • the dried crude product (22 g) is dissolved in toluene (250 mL) at 80-85 0 C and aluminium oxide (Merck, 90 active basic; 10 g) is added. After stirring for 30 minutes at the stated temperature the mixture is filtered and the clear filtrate is concentrated in vacuo (40-50 0 C) to a volume of 50 mL.
  • the resulting suspension is stirred at an internal temperature of ⁇ 20 0 C for 18 h.
  • the suspension is then filtered, and the crystals are washed with 5 ml of acetone. Drying is carried out in a vacuum drying cabinet at ⁇ 50 mbar and 40 0 C.
  • the title compound is achieved as white to off white crystalline solid; yield 8.8 g, 88 % of theory;
  • the water content is 5,2 %, by Karl Fischer titration, corresponding to a monohydrate; m.p.: 155 - 158°C (decomposition), purity > 99.3 % by HPLC.
  • reaction mixture was cooled to 20-30 0 C and diluted with water (21 L) before the pH was adjusted to 7-8 with 20% aqueous HCI ( ⁇ 7.5 L). Precipitation of product was achieved by addition of water (75 h) over about 4 h. The resulting slurry was heated to 35-45 0 C for 1.5 h before being chilled to 10-15 0 C.
  • the resulting slightly turbid aqueous solution was washed twice with MIBK (12 L each) and cleared by Hyflo treatment (0.40 kg), before the pH was adjusted to 9.0-9.5 by addition of 10% aqueous acetic acid (-8 L) at 40-45 0 C. Once product started to crystallize, further 10% acetic acid was added so as to continuously maintain a pH of 9.0-9.5.
  • the organic layer was extracted with another 400 mL of water at pH 13. After treatment with Hyflo Super CeI (5.0 g), the pH of the combined aqueous phase is adjusted to about 9 by addition of 10% aqueous acetic acid at 40 - 45 0 C. Once precipitation of product had set in, the mixture was stirred for another 12 h with eventual readjustment of the pH. Crude product (160 g, 75% yield) with an optical purity of > 98 % was obtained by filtration including an aqueous rinse (200 mL).
  • the compounds of the general formula 1 and their salts and solvates, preferably hydrates, and the solvates, preferably hydrates of the salts have useful pharmacological properties, rendering them commercially utilizable. In particular, they have a pronounced inhibitory effect on the secretion of gastric acid and excellent gastrointestinal protective action in warmblooded animals, in particular man.
  • the compounds according to the invention are distinguished by a highly selective action, an advantageous duration of action, a particularly high bioavailability, a metabolization profile that is uniform among different individuals, the lack of significant side-effects and a wide therapeutic spectrum.
  • gastrointestinal protection is to be understood as the prevention and treatment of gastrointestinal disorders, in particular gastrointestinal inflammatory disorders and lesions (such as, for example, Ulcus ventriculi, Ulcus duodeni, gastritis, irritable bowel owing to an increased production of acid or as a result of medicaments, GERD, Crohn's disease, IBD) which may be caused, for example, by microorganisms (for example Helicobacter pylori), bacterial toxins, medicaments (for example certain antiphlogistics and antirheumatic drugs), chemicals (for example ethanol), gastric acid or stress.
  • microorganisms for example Helicobacter pylori
  • medicaments for example certain antiphlogistics and antirheumatic drugs
  • chemicals for example ethanol
  • the compounds according to the invention in various models for the determination of antiulcerogenic and antisecretory properties, surprisingly prove to be clearly superior to the prior art compounds, in particular with respect to their metabolization properties.
  • These improved metabolization properties allow for example a reduction of the amount of a compound according to the invention, which is needed for treatment or prophylaxis. Or by using the same amount of the compound according to the invention as done for the prior art compounds a longer duration of action may be achieved.
  • advantages concerning patient safety or economical aspects e.g. like drug costs etc..
  • the compounds according to the invention are highly suitable for use in human and veterinary medicine, where they are used, in particular, for the treatment and/or prophylaxis of gastrointestinal disorders.
  • the invention furthermore provides the use of the compounds of the invention for the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention also embraces the use of the compounds of the invention for preparing pharmaceutical compositions used for the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention also provides pharmaceutical compositions comprising the compounds of the invention.
  • the invention provides pharmaceutical compositions containing the compounds of formulae 1 , 1 a or 1 b in the form of their pharmaceutically acceptable salts, in particular in the form of a sodium or magnesium salt, and/or in the form of a hydrate of such salt.
  • compositions are prepared by processes known per se which are familiar to the person skilled in the art.
  • the compounds according to the invention are employed either as such or, preferably, in combination with suitable pharmaceutical auxiliaries or carriers in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions, where the content of active compound is advantageously from about 0.1 to about 95% and where it is possible to produce pharmaceutical dosage forms (for example flow-release forms or enteric forms) which, by the appropriate choice of auxiliaries and carriers, are tailored for the active compound and/or the desired onset of action and/or the duration of action.
  • suitable pharmaceutical auxiliaries or carriers in the form of tablets, coated tablets, capsules, suppositories, plasters (for example as TTS), emulsions, suspensions or solutions, where the content of active compound is advantageously from about 0.1 to about 95% and where it is possible to produce pharmaceutical dosage forms (for example flow-release forms or enteric forms) which, by the appropriate
  • auxiliaries or carriers suitable for the desired pharmaceutical formulations are known to the person skilled in the art.
  • solvents for example, antioxidants, dispersants, emulsifiers, antifoams, flavour-masking agents, preservatives, solubilizers, colorants or, in particular, permeation promoters and complex formers (for example cyclodextrins).
  • the compounds of the invention can be administered orally, parenterally or percutaneously. Preferably, the compounds of the invention are administered orally.
  • a further aspect of the invention is thus a pharmaceutical composition, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of the free compound.
  • a further aspect of the invention is a pharmaceutical composition, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of the free compound.
  • a further aspect of the invention is the use of the compounds according to the invention for treating gastrointestinal disorders.
  • a further aspect of the invention is the use of the compounds according to the invention for the manufacture of pharmaceutical composition for the treatment or prophylaxis of gastrointestinal disorders. - -
  • a further aspect of the invention is a method of treating gastrointestinal disorders by administering a pharmaceutical composition comprising one or more compounds according to the invention.
  • a further aspect of the invention is the use of the compounds according to the invention for treating gastrointestinal disorders in patients who are slow metabolizers.
  • a further aspect of the invention is the use of the compounds according to the invention hereof for treating gastrointestinal disorders in patients who have a risk of drug interactions.
  • a further aspect of the invention is the use of the compounds according to the invention for treating gastrointestinal disorders in patients who need an inhibition of acid secretion for an extended period of time.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk of drug interactions, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk of drug interactions, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising in an oral solid application form a pharmaceutically salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk for drug interactions, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk for drug interactions, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound.
  • a further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound.
  • the pharmaceutical preparations may also comprise one or more pharmacologically active ingredients from other groups of medicaments.
  • pharmacologically active ingredients from other groups of medicaments.
  • examples that may be mentioned include tranquilizers (for example from the group of the benzodiazepines, e. g., diazepam), spasmolytic drugs (e. g., bietamiverine or camylofine), anticholinergic drugs (e. g., oxyphencyclimine or phencarbamide), local anesthetics (e. g., tetracaine or procaine), and optionally also enzymes, vitamins or amino acids.
  • tranquilizers for example from the group of the benzodiazepines, e. g., diazepam
  • spasmolytic drugs e. g., bietamiverine or camylofine
  • anticholinergic drugs e. g., oxyphencyclimine or phencarbamide
  • NSAIDs such as, for example, etofenamate, diclofenac, indometacin, ibuprofen or piroxicam
  • TLOSR transient lower esophageal sphincter relaxation
  • antibacterial substances such as, for example, cephalosporins, tetracyclins, penicillins, mac- rolides, nitroimidazoles or else bismuth salt
  • Antibacterial combination partners that may be mentioned include, for example, mezlocillin, ampicillin, amoxicillin, cefalothin, cefoxitin, cefotaxim, imipenem, gentamycin, amicacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and combinations thereof (e.g., clarithromycin + metronidazole or amoxicillin + clarithromycin).
  • the compounds according to this invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically staggered (such as e.g. as combined unit dosage forms, as separate unit dosage forms, as adjacent discrete unit dosage forms, as fixed or non-fixed combinations, as kit-of-parts or as admixtures) with one or more standard therapeutics as those mentioned above.
  • combination may be present as a fixed combination, a non-fixed combination or a kit-of-parts.
  • a “fixed combination” is defined as a combination wherein a first active ingredient and a second active ingredient are present together in one unit dosage or in a single entity.
  • a “fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in admixture of simultaneous administration, such as in a formulation.
  • Another example of a "fixed combination” is a pharmaceutical composition wherein the said first active ingredient and the said second active ingredient are present in one unit without being in admixture.
  • kits-of-parts is defined as a combination wherein the said first active ingredient and the said second active ingredient are present in more than one unit.
  • a “kit-of-parts” is a combination - - the said first active ingredient and the said second active ingredient are present separately.
  • the components of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologically staggered.
  • Pantoprazole or examples 1 or 2 (10 ⁇ M each) were incubated with liver microsomes (source: all from GenTest except Mini Pig from TEBU ),incubation in 1 mg/ml protein, 100 mM Tris-HCI, pH 7.4, 1 mM NADPH 2 ). Reaction was terminated after 90 minutes by liquid nitrogen, the parent compound was detected by HPLC (10 mM KH 2 PO 4 , pH 7.4, acetonitril gradient 20-44 %).
  • CYP cytochrome P450
  • CYP2C19 and CYP3A4 were found to contribute to the oxidative metabolism of pantoprazole and its deuterated analogues. All other cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any of the compounds investigated above the lower limit of assay resolution.
  • pantoprazole M2 (5-(difluorornethoxy)-2-IT(3-nriethoxy-4-sulfate-2-pyridvO- methyllsulfinvIl-IH-benzimidazole)
  • M2 (difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1 H-benzimidazole) was determined.
  • M2 involves the oxidation of the 4-methoxy-pyridyl group by CYP2C19 and subsequent conjugation with 3'-phosphoadenosine-5'-phosphosulfate (PAPS) by an unidentified sulphotransferase
  • PAPS 3'-phosphoadenosine-5'-phosphosulfate
  • the M2 formation rate was determined at nine different compound concentrations (0, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0 and 100 ⁇ Mol/L) incubated in duplicate for 60 min at 37° C. M2 was quantified using LC-MS/MS. M2 isolated from human urine was used as an external standard. The concentration to reach the half-maximal formation rate (K M -value) and the maximal formation rate (V max ) were obtained by non-linear regression analysis using the Michaelis- Menten equation. The intrinsic clearance (Cl ⁇ nt ) was obtained dividing V max over K M .
  • Intrinsic clearance (Cl ⁇ nt )) in pooled human hepatocytes obtained upon incubation with pantoprazole and compounds according to the invention.

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Abstract

L'invention concerne des composés représentés par la formule 1, des médicaments comprenant ces composés, et des intermédiaires représentés par les formules 2 et 3.
PCT/EP2006/064669 2005-07-26 2006-07-26 Pantoprazole substitue d'un point de vue isotopique WO2007012651A1 (fr)

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EP06777980A EP1912947A1 (fr) 2005-07-26 2006-07-26 Pantoprazole substitue d'un point de vue isotopique
CN2006800344239A CN101268050B (zh) 2005-07-26 2006-07-26 同位素取代的泮托拉唑
JP2008523355A JP5289951B2 (ja) 2005-07-26 2006-07-26 同位体置換されたパントプラゾール
CA2615678A CA2615678C (fr) 2005-07-26 2006-07-26 Pantoprazole substitue d'un point de vue isotopique
AU2006274037A AU2006274037B2 (en) 2005-07-26 2006-07-26 Isotopically substituted pantoprazole
US12/000,376 US7601737B2 (en) 2005-07-26 2007-12-12 Isotopically substituted proton pump inhibitors
US12/458,704 US20100022779A1 (en) 2005-07-26 2009-07-21 Isotopically substituted proton pump inhibitors
US12/461,985 US20100010047A1 (en) 2005-07-26 2009-08-31 Isotopically substituted proton pump inhibitors

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EP05106874.0 2005-07-26

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JP2010507576A (ja) * 2006-10-23 2010-03-11 コンサート ファーマシューティカルズ インコーポレイテッド オキサゾリジノン誘導体および使用方法
JP2010520291A (ja) * 2007-03-07 2010-06-10 コンサート ファーマシューティカルズ インコーポレイテッド 抗狭心症化合物としての重水素化ピペラジン誘導体
JP2010529994A (ja) * 2007-06-13 2010-09-02 オースペックス・ファーマシューティカルズ・インコーポレイテッド 置換ピペラジン
JP2011510079A (ja) * 2008-01-22 2011-03-31 コンサート ファーマシューティカルズ インコーポレイテッド ゲフィチニブ誘導体
JP2018115199A (ja) * 2007-05-01 2018-07-26 コンサート ファーマシューティカルズ インコーポレイテッド モルフィナン化合物
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JP5770997B2 (ja) * 2009-12-09 2015-08-26 大塚製薬株式会社 Ｃｙｐ３ａ４の代謝機能測定方法
CN103349655B (zh) * 2013-07-22 2015-04-29 南通广泰生化制品有限公司 枸橼酸他莫昔芬肠溶胶囊
JP2017527614A (ja) * 2014-09-02 2017-09-21 ブピンダー シン 重水素化又は非重水素化分子及び医薬製剤

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JP2009511481A (ja) * 2005-10-06 2009-03-19 オースペックス・ファーマシューティカルズ・インコーポレイテッド 増強された治療特性を持つ、胃Ｈ＋，Ｋ＋−ＡＴＰａｓｅの重水素化阻害剤
US7598273B2 (en) 2005-10-06 2009-10-06 Auspex Pharmaceuticals, Inc Inhibitors of the gastric H+, K+-ATPase with enhanced therapeutic properties
JP2010507576A (ja) * 2006-10-23 2010-03-11 コンサート ファーマシューティカルズ インコーポレイテッド オキサゾリジノン誘導体および使用方法
JP2010520291A (ja) * 2007-03-07 2010-06-10 コンサート ファーマシューティカルズ インコーポレイテッド 抗狭心症化合物としての重水素化ピペラジン誘導体
JP2018115199A (ja) * 2007-05-01 2018-07-26 コンサート ファーマシューティカルズ インコーポレイテッド モルフィナン化合物
JP2020073522A (ja) * 2007-05-01 2020-05-14 コンサート ファーマシューティカルズ インコーポレイテッド モルフィナン化合物
US11473123B2 (en) 2007-05-01 2022-10-18 Concert Pharmaceuticals, Inc. Morphinan compounds
JP2010529994A (ja) * 2007-06-13 2010-09-02 オースペックス・ファーマシューティカルズ・インコーポレイテッド 置換ピペラジン
JP2011510079A (ja) * 2008-01-22 2011-03-31 コンサート ファーマシューティカルズ インコーポレイテッド ゲフィチニブ誘導体
GB2560750A (en) * 2017-03-24 2018-09-26 Taher Darreh Shori Biological methods
WO2018172557A1 (fr) * 2017-03-24 2018-09-27 Darreh Shori Taher Méthodes biologiques

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AU2006274037A1 (en) 2007-02-01
AU2006274037B2 (en) 2012-04-26
TW200745039A (en) 2007-12-16
CA2615678A1 (fr) 2007-02-01
CN101268050A (zh) 2008-09-17
JP5289951B2 (ja) 2013-09-11
CA2615678C (fr) 2015-01-20
EP1912947A1 (fr) 2008-04-23
TWI410409B (zh) 2013-10-01

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