WO2007012650A1 - Isotopically substituted proton pump inhibitors - Google Patents

Isotopically substituted proton pump inhibitors Download PDF

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Publication number
WO2007012650A1
WO2007012650A1 PCT/EP2006/064666 EP2006064666W WO2007012650A1 WO 2007012650 A1 WO2007012650 A1 WO 2007012650A1 EP 2006064666 W EP2006064666 W EP 2006064666W WO 2007012650 A1 WO2007012650 A1 WO 2007012650A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
benzimidazole
trideuteriomethoxy
pyridinyl
compounds
Prior art date
Application number
PCT/EP2006/064666
Other languages
French (fr)
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
Priority to AU2006274036A priority Critical patent/AU2006274036B2/en
Priority to JP2008523354A priority patent/JP5448448B2/en
Priority to EA200800203A priority patent/EA016814B1/en
Priority to NZ565078A priority patent/NZ565078A/en
Priority to HK09102398.5A priority patent/HK1125098B/en
Priority to CN2006800345034A priority patent/CN101268051B/en
Priority to KR1020087003989A priority patent/KR101358509B1/en
Priority to BRPI0614039-4A priority patent/BRPI0614039A2/en
Priority to MX2008000901A priority patent/MX2008000901A/en
Application filed by Nycomed Gmbh filed Critical Nycomed Gmbh
Priority to EP06764258A priority patent/EP1910293A1/en
Priority to CA2615670A priority patent/CA2615670C/en
Publication of WO2007012650A1 publication Critical patent/WO2007012650A1/en
Priority to US12/000,376 priority patent/US7601737B2/en
Priority to ZA2008/00303A priority patent/ZA200800303B/en
Priority to IL188773A priority patent/IL188773A/en
Priority to NO20080839A priority patent/NO20080839L/en
Priority to US12/458,704 priority patent/US20100022779A1/en
Priority to US12/461,985 priority patent/US20100010047A1/en

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to isotopically substituted proton pump inhibitors and their (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- methyl
  • 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. Disclosure of the invention
  • the invention relates to compounds of the general formula 1
  • R1 is hydrogen or 1-4C-alkoxy
  • R2 is 1-4C-alkyl or 1-4C-alkoxy
  • R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy
  • R4 is hydrogen or 1-4C-alkyl
  • Z is C-H or N and pharmaceutical acceptable salts, solvates, preferably hydrates, and solvates, preferably hydrates of the salts thereof, wherein at least one hydrogen atom of R1 , R2, R3, R4 or any combination of R1 ,
  • R2, R3 and R4 is replaced by a deuterium atom.
  • 1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and, preferably, the methyl group.
  • 1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains one of the aforementioned 1-4C-alkyl groups or fluorinated 1-4C-alkyl groups.
  • 1-4C-alkyl groups which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and, preferably, the methoxy group.
  • fluorinated 1-4C-alkyl groups are 2,2,3,3,3- pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 1 -(trifluoromethyl)-2,2,2-trifluoroethyl, 2,2,3,3,4,4,4- heptafluorobutyl and, preferably, 2,2,2-trifluoroethyl and difluoromethyl.
  • 2-8C-Alkoxyalkoxy represents a group, which in addition to the oxygen atom contains an internal al- kylene which contains 1-4C alkylene groups and a terminal alkyl group which contains 1-4C alkyl groups and being connected by an oxygen atom to the internal alkylene group.
  • Examples are meth- oxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxypropoxy, ethoxyisopropoxy, isopropoxymethoxy, propoxymethoxy, methoxybutoxy, methoxyisobutoxy, propoxyethoxy, isopropoxyethoxy, propoxypro- poxy, isopropoxyisopropoxy, isopropoxypropoxy, propoxyisopropoxy, ethoxybutoxy, ethoxyisobutoxy, ethoxy-sec-butoxy, ethoxy-tert-butoxy and preferably methoxypropoxy.
  • 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 pharmaceutical compositions - 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.
  • deutero or “deuterio” should indicate a deuterium atom ([ 2 H]).
  • pre-terms bis” or “di” and “tri” or “tris”, respectively should indicate the occurrence of two or three, for example deuterio atoms in a specific group, i.e. 1 ,1-dideuterio-2,2,2-trifluoroethoxy or trideuteriomethoxy .
  • R3 is replaced by a deuterium atom and R3 is a 1-2C alkoxy group or a 2-5C- alkoxyalkoxy group.
  • R2 is a 1-4C alkyl group and R3 is a 2-8C-alkoxyalkoxy group, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom.
  • R1 is a 1-4C alkoxy group
  • R2 and R4 are a 1-4C alkyl group
  • R3 is a 1 -4C-alkoxy group, wherein at least one of the hydrogen atoms of R1 , R3, R4 or any combination of R1 , R3 and R4 is replaced by a deuterium atom.
  • R1 is hydrogen, methoxy or difluoromethoxy
  • R2 is methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy
  • R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.
  • R2 is methyl, R3 is methoxypropoxy and Z is C- H, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom.
  • R2 is a 1-4C alkyl group and R3 is a 2-8C- alkoxyalkoxy group, wherein all hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.
  • R1 is a 1 -4C alkoxy group
  • R2 and R4 are a 1 -4C alkyl group
  • R3 is a 1-4C-alkoxy group, wherein all hydrogen atoms of R1 , R3, R4 or any combination of R1 , R3 and R4 are replaced by deuterium atoms.
  • Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.
  • R2 is methyl
  • R3 is methoxypropoxy
  • Z is C-H, wherein all hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.
  • R1 is methoxy
  • R2 and R4 are methyl and R3 is methoxy
  • R1 is hydrogen, methoxy or difluoromethoxy
  • R2 is methyl or methoxy
  • R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy
  • R4 is hydrogen or methyl and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
  • R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
  • 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 .
  • 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.
  • Particularly preferred compounds with (S)-configuration within the scope of the invention are the compounds (S)-5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H- benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-methoxy-2-[(4-dideuteriomethoxy-3,5-dimethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-dideuteriomethoxy-3,5- dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-trideuteriomethoxy-2-[(
  • 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, (R)-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridylmethyl)sulphinyl]- 1 H-benzimidazole and the solvates, preferably hydrates of these compounds, the salts of these compounds and the solvates, preferably hydrates of the salts of these compounds.
  • 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 applications WO96/02535 or 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. In the most preferred embodiment, “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.
  • R1, R2, R3, R4 and Z have the meanings as given above and wherein at least one of the hydrogen atoms of R1 , R2, R3, R4 or any combination of R1 , R2, R3 and R4 is replaced by a deuterium atom, and their salts, such as the hydrochloride, the sulfate, the phosphate or other salts with acids, and their solvates.
  • These compounds can be used for the manufacture of compounds of general formula 1 , 1a or 1 b.
  • 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
  • R3 and R4 have the meanings as given above and wherein at least one of the hydrogen atoms of R2, R3 and/or R4 is replaced by a deuterium atom.
  • R2 is methyl or methoxy
  • R3 is methoxy, 2,2,2- trifluoroethoxy or methoxypropoxy
  • R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium atoms.
  • R2 is methyl, R3 is methoxy, R4 is methyl or R2 is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium atoms.
  • R2 is methyl, R3 is methoxy, R4 is methyl or R2 is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen and wherein at least two or all of the hydrogen atoms of R3 are replaced by deuterium atoms.
  • halogen is iodine, bromine, chlorine and fluorine.
  • X is chlorine.
  • An activated derivative of an alcohol is an alkylsulfonate group, for example mesylate or an aryl- sulfonate group, for example tosylate or besylate, or a perfluoroalkanesulfonate group, for example trifluormethanesulfonate.
  • X, R2 and R4 have the meanings as given above, R5 being chloro or nitro and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by a deuterium atom.
  • R5 being chloro or nitro and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by a deuterium atom.
  • Preferred are compounds of formula 3a wherein R2 is methyl or methoxy, R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by deuterium atoms.
  • R2 and R4 are methyl and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by deuterium atoms.
  • 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 and Z have the meaning as given above, thus providing compounds of formula 2 as described above.
  • the compounds of formula 3a can be used for the manufacture of compounds of formula 2a.
  • R1, R2, R5, R4 and Z have the meanings as given above and wherein at least one of the hydrogen atoms of R1 , R2, R4 or any combination of R1 , R2 and R4 is replaced by a deuterium atom.
  • the nitrogen atom of compound of formula 3a is first quatemised and then reacted with compounds of formula 4
  • R1 and Z have the meaning as given above, thus providing compounds of formula 2a as described above.
  • Compounds of formula 2a can be used for the manufacturing of compounds of formula 2 by substituting the residue R5 with a residue R3, both having the meanings as described above. Under the proviso that none of the hydrogens of R1 , R2 or R4 are replaced by a deuterium atom, at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.
  • Another aspect of the invention are compounds of formula 4.
  • R1 is 1-4C alkoxy
  • Z is C-H or N and wherein at least one of the hydrogen atoms of R1 is replaced by a deuterium atom.
  • R1 is methoxy.
  • R1 is methoxy and wherein all hydrogen atoms of R1 are replaced by deuterium atoms.
  • the deuterium homologes of the proton pump inhibitors and for example of R/S pantoprazole and S- pantoprazole are 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 pyridin group. Similar as described before an exchange of the halogen by dideute- riomethoxy or monodeuteriomethoxy will lead to the correspondingly deuterated compounds.
  • a halogen e.g. chloro, bromo or nitro
  • the thiocompounds are prepared either by exchange of halogen by mono-, di- or trideuteriomethoxy at the position of the final mono-, di- or trideuteriomethoxy-substituent or by coupling of 5- difluoromethoxy-2-mercaptobenzimidazole with the accordingly substituted 2-chloromethyl-3-methoxy- 4-trideuteriomethoxy-pyridinumchloride.
  • 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.
  • the mixture is stirred for another 12 hours during which the pH is monitored.
  • the beige crystals are filtered off and washed with 10 mL of water.
  • the title compound is obtained in a yield of about 1.6 g (75 % of theory) and an optical purity of > 98 %.
  • 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 filter cake was slurried at 60 0 C in isopropanol (200 mL) and water (300 mL) was added over 1 h. While maintaining the temperature between 50 and 60 0 C, 190 mL of solvents were distilled off. The resulting suspension was cooled to 10 0 C, filtered and washed with water (60 mL) to provide after drying at 30 0 C in vacuo 2-nitro-4-trideuteriomethoxy-aniline as a red solid (m. p. 120-122 0 C); yield 46.7 g (92%).
  • a solution of sodium trideuteriomethoxid was prepared by addition of methanol-d4 (1.70 mL, 41.5 mmol) at about 50 0 C over 30 min to a suspension of sodium hydride (60% in mineral oil, 1.70 g, 41.5 mmol) in NMP (12 mL). After heating to 60 0 C, a solution of 5-trideuteriomethoxy-2-[(4-chloro-3,5- dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (2.10 g, 5.92 mmol) in NMP (4 mL) was added. Stirring was continued, first at 70 0 C for 24 h, then at 85 0 C for 5 h.
  • zirconium (IV) n-propoxide (0.40 mL, 70 % in n-propanol, 0.90 mmol) was added and stirring at 40 0 C was continued for one more hour.
  • N-ethyldiisopropylamine (0.11 mL, 0.63 mmol) and cumene hydroperoxide (1.52 mL, ⁇ 80% strength, 8.55 mmol) were added.
  • the clear reaction mixture was diluted with methyl isobutyl ketone (8.5 mL) and quenched with sodium thiosulphate (0.11 g) in saturated sodium bicarbonate solution (15 mL).
  • the organic layer was washed twice with saturated sodium bicarbonate solution (7.5 mL each).
  • the organic layer was extracted twice more with water (7.5 mL) at pH 12.5-13 (through addition of prerequisite amount of 40% aqueous NaOH).
  • the combined organic phase was washed with dichloromethane (15 mL). Then, the pH was adjusted to about 10 with potassium dihydrogen phosphate and the aqueous solution was extracted with dichloromethane (once 40 mL and twice 10 mL).
  • 4-chloro-2-chloromethyl-3-methylpyridinium chloride could be reacted with 1 H- benzimidazole-2-thiol according to the procedure described under Example 7 to give 2-[(4-chloro-3- methyl-2-pyridinyl)methylthio]-1 /-/-benzimidazole.
  • 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride could be reacted with 5- methoxy-1/-/-imidazo[4,5-b]pyridine-2-thiol according to the procedure described under Example 33 to give 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 /-/-imidazo[4,5-b]pyridine.
  • 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 metabolisation 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 pharmaceutical compositions, GERD, Crohn's disease, IBD) which may be caused, for example, by microorganisms (for example Helicobacter pylori), bacterial toxins, pharmaceutical compositions (for example certain antiphlogistics and antirheumatic drugs), chemicals (for example ethanol), gastric acid or stress.
  • 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 pharmaceutical compositions, GERD, Crohn's disease, IBD
  • microorganisms for example Helicobacter pylori
  • bacterial toxins for example
  • 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 pharmacokinetic properties.
  • These improved pharmacokinetic 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 according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
  • the invention also embraces the use of the compounds according to 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 according to the invention.
  • the invention provides pharmaceutical compositions for oral use in solid form, containing the compounds of formulae 1 , 1 a or 1 b in the form of their salts, in particular in the form of a sodium or magnesium salt, and/or in the form of a hydrate of such salt.
  • the pharmaceutical 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 choice of auxiliaries and carriers, are tailored for the active compound and/or the desired onset of
  • 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 according to the invention can be administered orally, parenterally or percutaneously.
  • 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 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 one or more 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 one or more 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 one or more 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 one or more 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 one or more 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 one or more 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 pharmaceutical compositions.
  • pharmacologically active ingredients from other groups of pharmaceutical compositions.
  • 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 omeprazole, pantopra- zole and their deuterated analogues. All other cytochrome P450 isoenzymes (CYP1 A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any of the compounds investigated above the lower limit of assay resolution.
  • the 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1 H- benzimidazole (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. 5-hydroxy- omeprazole was quantified using LC-MS/MS.
  • Racemic, (R), and (S)-analogues (examples 19, 27and 28 deuterated in the 4-methoxy-pyridyl position exhibited formation rates that were at least 2.5-fold reduced compared to their non-deuterated counterparts ( Figure 2B).
  • the intrinsic clearances of racemic, (R), and (S)-analogues deuterated in the 4-methoxy-pyridyl position (examples 19, 27 and 28) were at least 4.7-fold reduced compared to their non-deuterated counterparts (Table 2).
  • the stereospecific differences in M2 formation rates observed for the [ 1 H] pantoprazole analogues were less pronounced for analogues deuterated in the 4-methoxy-pyridyl position ( Figure 2B).
  • Table 2 Intrinsic clearance (Cl ⁇ nt )) in pooled human hepatocytes obtained upon incubation with pantoprazole and compounds according to the invention.

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Abstract

The invention relates to benzimidazoles of Formula (1) and to pharmaceutical compositions comprising these compounds, further to intermediates of Formula (2 and 3).

Description

lsotopically Substituted Proton Pump Inhibitors
Subject matter of the invention
The present invention relates to isotopically substituted proton pump inhibitors and their (R)- and (S)- enantiomers. These compounds can be used in the pharmaceutical industry for preparing pharmaceutical compositions.
Background of the invention
Owing to their H+/K+-ATPase-inhibitory action, 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-2-yl]methylsulphinyl}-1 H-benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4- methoxy-3,5-dimethyl-2-pyridylmethyl)sulphinyl)-1 H-imidazo[4,5-b]pyridine (INN: tenatoprazole).
The above mentioned sulphinyl derivatives are, owing to their mechanism of action, also referred to as proton pump inhibitors or, abbreviated, as PPI.
Description of the related art
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 (60-800C) 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. Disclosure of the invention
It has now surprisingly been found that isotopically substituted compounds as disclosed in detail below influences significantly the inhibition of acid secretion.
The invention relates to compounds of the general formula 1
Figure imgf000004_0001
in which
R1 is hydrogen or 1-4C-alkoxy
R2 is 1-4C-alkyl or 1-4C-alkoxy
R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy
R4 is hydrogen or 1-4C-alkyl
Z is C-H or N and pharmaceutical acceptable salts, solvates, preferably hydrates, and solvates, preferably hydrates of the salts thereof, wherein at least one hydrogen atom of R1 , R2, R3, R4 or any combination of R1 ,
R2, R3 and R4 is replaced by a deuterium atom.
1-4C-Alkyl represents straight-chain or branched alkyl groups having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and, preferably, the methyl group.
1-4C-Alkoxy represents a group, which in addition to the oxygen atom contains one of the aforementioned 1-4C-alkyl groups or fluorinated 1-4C-alkyl groups. Examples for 1-4C-alkyl groups which may be mentioned are the butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy and, preferably, the methoxy group. Examples for fluorinated 1-4C-alkyl groups are 2,2,3,3,3- pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 1 -(trifluoromethyl)-2,2,2-trifluoroethyl, 2,2,3,3,4,4,4- heptafluorobutyl and, preferably, 2,2,2-trifluoroethyl and difluoromethyl.
2-8C-Alkoxyalkoxy represents a group, which in addition to the oxygen atom contains an internal al- kylene which contains 1-4C alkylene groups and a terminal alkyl group which contains 1-4C alkyl groups and being connected by an oxygen atom to the internal alkylene group. Examples are meth- oxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxypropoxy, ethoxyisopropoxy, isopropoxymethoxy, propoxymethoxy, methoxybutoxy, methoxyisobutoxy, propoxyethoxy, isopropoxyethoxy, propoxypro- poxy, isopropoxyisopropoxy, isopropoxypropoxy, propoxyisopropoxy, ethoxybutoxy, ethoxyisobutoxy, ethoxy-sec-butoxy, ethoxy-tert-butoxy and preferably methoxypropoxy.
According to the invention, within the meaning of salts all 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. Particularly preferred are the sodium and the magnesium salts.
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 pharmaceutical compositions - converted into the pharmacologically tolerable salts by processes known to the person skilled in the art.
It is known to the person skilled in the art that 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. Within the meaning of solvates all pharmaceutically acceptable solvents resulting in such solvates are included.
Concerning the nomenclature of the compounds according to the invention the terms "deutero" or "deuterio" should indicate a deuterium atom ([2H]). Similarly, the pre-terms "bis" or "di" and "tri" or "tris", respectively should indicate the occurrence of two or three, for example deuterio atoms in a specific group, i.e. 1 ,1-dideuterio-2,2,2-trifluoroethoxy or trideuteriomethoxy .
Preferred within the scope of the invention are compounds of formula 1 wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom and R3 is a 1-2C alkoxy group or a 2-5C- alkoxyalkoxy group.
Preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and R3 is a 2-8C-alkoxyalkoxy group, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom.
Preferred are compounds of formula 1 wherein R1 is a 1-4C alkoxy group, R2 and R4 are a 1-4C alkyl group and R3 is a 1 -4C-alkoxy group, wherein at least one of the hydrogen atoms of R1 , R3, R4 or any combination of R1 , R3 and R4 is replaced by a deuterium atom.
Preferred are also compounds of formula 1 wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom. Preferred are further compounds of formula 1 wherein R2 is methyl, R3 is methoxypropoxy and Z is C- H, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom.
Preferred are further compounds of formula 1 wherein R1 is methoxy, R2 and R4 are methyl and R3 is methoxy, wherein at least one of the hydrogen atoms of R1 , R3, R4 or any combination of R1 , R3 and R4 is replaced by a deuterium atom. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.
Preferred are also compounds of formula 1 wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.
Preferred are further also compounds of formula 1 wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and wherein at least two of the hydrogen atoms of R3 are replaced by a deuterium atom.
More preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and R3 is a 2-8C- alkoxyalkoxy group, wherein all hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.
More preferred are compounds of formula 1 wherein R1 is a 1 -4C alkoxy group, R2 and R4 are a 1 -4C alkyl group and R3 is a 1-4C-alkoxy group, wherein all hydrogen atoms of R1 , R3, R4 or any combination of R1 , R3 and R4 are replaced by deuterium atoms. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.
More preferred are compounds of formula 1 wherein all hydrogen atoms of R3 are replaced by deuterium atoms and wherein R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy.
More preferred are further compounds of formula 1 wherein R2 is methyl, R3 is methoxypropoxy and Z is C-H, wherein all hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.
More preferred are further compounds of formula 1 wherein R1 is methoxy, R2 and R4 are methyl and R3 is methoxy, wherein all hydrogen atoms of R1 , R3, R4 or any combination of R1 , R3 and R4 are replaced by deuterium atoms. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4. More preferred are also compounds of formula 1 wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
More preferred are also compounds of formula 1 wherein R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or wherein R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or wherein R is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
Most preferred are the compounds 5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-methoxy-2-[(4-dideuteriomethoxy-3,5-dimethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-trideuteriomethoxy-2-[(4-trideuteriomethoxy-3,5- dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-trideuteriomethoxy-2-[(4-dideuteriomethoxy- 3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-methoxy-2-[(3-methyl-4- trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5- trideuteriomethoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 2-[3-methyl-4-(1 ,1-dideuterio-2,2,2-trifluoroethoxy)-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-trideuteriomethoxy-4-methoxy-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-dideuteriomethoxy-4-methoxy-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3,4-bis(dideuteriomethoxy)-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, 2-{[4-(3-trideuteriomethoxyhexadeuteriopropoxy)-3- methylpyridin-2-yl]methylsulphinyl}-1 H-benzimidazole, 2-{[4-(3- trideuteriomethoxyhexadeuteriopropoxy)-3-trideuteriomethylpyridin-2-yl]methylsulphinyl}-1 H- benzimidazole, 5-methoxy-2-((4-trideuteriomethoxy-3,5-dimethyl-2-pyridylmethyl)sulphinyl)-1 H- imidazo[4,5-b]pyridine, 5-trideuteriomethoxy-2-((4-trideuteriomethoxy-3,5-dimethyl-2- pyridylmethyl)sulphinyl)-1H-imidazo[4,5-b]pyridine, 5-methoxy-2-((3-methyl-4-trideuteriomethoxy-5- trideuteriomethyl-2-pyridylmethyl)sulphinyl)-1 H-imidazo[4,5-b]pyridine or 5-trideuteriomethoxy-2-((3- methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridylmethyl)sulphinyl)-1 H-imidazo[4,5-b]pyridine.
According to the invention, 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. For example, if 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 -OCD3. The remaining part up to 100% includes -OCHD2, - OCH2D Or-OCH3. Preferred is a degree of deuteration of at least 90% for the specific hydrogen atom in the bulk material, meaning that at least 90% of the replaced hydrogen atoms should be deuterium atoms. More preferred is a degree of deuteration of at least 92% for the specific hydrogen atom in the bulk material. Even more preferred is a degree of deuteration of at least 94% for the specific hydrogen atom in the bulk material and most preferred is a degree of deuteration of at least 96% for the specific hydrogen atom in the bulk material.
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. In view of the fact that, from a medicinal point of view, it may be advantageous for certain chiral compounds to be administered in the form of the one or the other enantiomer, 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.
Accordingly, particularly preferred are on one hand the compounds with (S)-configuration of the general formula 1a
Figure imgf000008_0001
in which R1 , R2, R3, R4 and Z have the meanings given above.
Particularly preferred compounds with (S)-configuration within the scope of the invention are the compounds (S)-5-methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H- benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-methoxy-2-[(4-dideuteriomethoxy-3,5-dimethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-dideuteriomethoxy-3,5- dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-trideuteriomethoxy-2-[(4-methoxy-3,5- dimethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5-methoxy-2-[(3-methyl-4- trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole, (S)-5- trideuteriomethoxy-2-[(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2- pyridinyl)methylsulphinyl]-1 H-benzimidazole or (S)-5-difluoromethoxy-2-[(3-methoxy-4- trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole, (S)-5-difluoromethoxy-2-[(3-methoxy- 4-dideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole and the solvates, preferably hydrates of these compounds, the salts of these compounds and the solvates, preferably hydrates of the salts of these compounds. Particularly preferred are on the other hand the compounds with (R)-configuration of the general formula 1b
Figure imgf000009_0001
in which R1 , R2, R3, R4 and Z 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, (R)-5-difluoromethoxy-2-[(3-methoxy-4-dideuteromethoxy-2-pyridylmethyl)sulphinyl]- 1 H-benzimidazole and the solvates, preferably hydrates of these compounds, the salts of these compounds and the solvates, preferably hydrates of the salts of these compounds.
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. Alternatively, the compounds of formulae 1a and 1b can be obtained by chiral oxidation of the sulphides as described in international patent applications WO96/02535 or 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. As an example, 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).
According to the invention, "compounds with (S)-configuration" is understood to include "compounds with (S)-configuration being substantially free of compounds with (R)-configuration".
"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. Preferably, "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. More preferably, "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.
According to the invention, "compounds with (R)-configuration" is understood to include "compounds with (R)-configuration being substantially free of compounds with (S)-configuration".
"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. Preferably, "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. More preferably, "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. In the most preferred embodiment, "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.
Additional subject matter of the invention are compounds of formula 2
Figure imgf000010_0001
in which R1, R2, R3, R4 and Z have the meanings as given above and wherein at least one of the hydrogen atoms of R1 , R2, R3, R4 or any combination of R1 , R2, R3 and R4 is replaced by a deuterium atom, and their salts, such as the hydrochloride, the sulfate, the phosphate or other salts with acids, and their solvates. These compounds can be used for the manufacture of compounds of general formula 1 , 1a or 1 b. 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
Figure imgf000011_0001
in which X is a halogen or an activated derivative of an alcohol and R2, R3 and R4 have the meanings as given above and wherein at least one of the hydrogen atoms of R2, R3 and/or R4 is replaced by a deuterium atom.
Preferred are compounds of formula 3 wherein R2 is methyl or methoxy, R3 is methoxy, 2,2,2- trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium atoms.
More preferred are compounds of formula 3 wherein R2 is methyl, R3 is methoxy, R4 is methyl or R2 is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium atoms.
Also more preferred are compounds of formula 3 wherein R2 is methyl, R3 is methoxy, R4 is methyl or R2 is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen and wherein at least two or all of the hydrogen atoms of R3 are replaced by deuterium atoms.
For the purpose of the invention, halogen is iodine, bromine, chlorine and fluorine. Preferably X is chlorine. An activated derivative of an alcohol is an alkylsulfonate group, for example mesylate or an aryl- sulfonate group, for example tosylate or besylate, or a perfluoroalkanesulfonate group, for example trifluormethanesulfonate.
Related to a compound of formula 3 and thus an aspect of the invention is a compound of formula 3a
Figure imgf000011_0002
in which X, R2 and R4 have the meanings as given above, R5 being chloro or nitro and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by a deuterium atom. Preferred are compounds of formula 3a wherein R2 is methyl or methoxy, R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by deuterium atoms.
More preferred are compounds of formula 3a wherein R2 and R4 are methyl and wherein at least one of the hydrogen atoms of R2 and/or R4 is replaced by deuterium atoms.
The compounds of formula 3 can be used for the manufacture of compounds of formula 1 , 1 a or 1 b. Preferably the nitrogen atom of compound of formula 3 is first quatemised and then reacted with compounds of formula 4
Figure imgf000012_0001
in which R1 and Z have the meaning as given above, thus providing compounds of formula 2 as described above.
The compounds of formula 3a can be used for the manufacture of compounds of formula 2a.
Figure imgf000012_0002
in which R1, R2, R5, R4 and Z have the meanings as given above and wherein at least one of the hydrogen atoms of R1 , R2, R4 or any combination of R1 , R2 and R4 is replaced by a deuterium atom. Preferably the nitrogen atom of compound of formula 3a is first quatemised and then reacted with compounds of formula 4
Figure imgf000012_0003
in which R1 and Z have the meaning as given above, thus providing compounds of formula 2a as described above.
Compounds of formula 2a can be used for the manufacturing of compounds of formula 2 by substituting the residue R5 with a residue R3, both having the meanings as described above. Under the proviso that none of the hydrogens of R1 , R2 or R4 are replaced by a deuterium atom, at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.
Another aspect of the invention are compounds of formula 4
Figure imgf000013_0001
wherein R1 is 1-4C alkoxy, Z is C-H or N and wherein at least one of the hydrogen atoms of R1 is replaced by a deuterium atom. Preferably R1 is methoxy. These compounds may be used for the manufacture of compounds of formula 1 or 2.
More preferred are compounds wherein R1 is methoxy and wherein all hydrogen atoms of R1 are replaced by deuterium atoms.
The deuterium homologes of the proton pump inhibitors and for example of R/S pantoprazole and S- pantoprazole are 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 pyridin group. Similar as described before an exchange of the halogen by dideute- riomethoxy or monodeuteriomethoxy will lead to the correspondingly deuterated compounds.
In analogy the thiocompounds are prepared either by exchange of halogen by mono-, di- or trideuteriomethoxy at the position of the final mono-, di- or trideuteriomethoxy-substituent or by coupling of 5- difluoromethoxy-2-mercaptobenzimidazole with the accordingly substituted 2-chloromethyl-3-methoxy- 4-trideuteriomethoxy-pyridinumchloride.
The compound of formula 1 can be prepared according to the following reaction scheme:
Figure imgf000013_0002
Figure imgf000014_0001
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.
Alternatively 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.
The following examples serve to illustrate the invention in greater detail without restricting it to the described examples. The other above mentioned compounds can be obtain by using the described methods.
Examples
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.
Example 1
5-Difluoromethoxy (R/S) 2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole
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 0C 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.
The reaction mixture is concentrated in vacuo (30 - 40 0C) to about one third of the original volume and water (about 70 mL) is added.
After extraction of the water phase with dichloromethane (2 x 10 mL each) again dichloromethane (50 mL) is added and the pH is adjusted to 7 - 8 by addition of aqueous potassium dihydrogenphosphate while stirring. Phase separation, one further extraction of the water phase with dichloromethane (20 mL), washing of the combined organic phases with water (20 mL) drying with magnesium sulfate and filtration of the drying agent gives a solution of the crude title compound.
Addition of petroleum ether (50/70; 150 mL) and concentration in a rotary evaporator in vacuo at 30 - 40 0C to about 30 mL volume followed by filtration of the precipitated solid, rinse with petroleum ether 50/70 (20 mL) and drying in vacuo (35 0C, 5 hours) yields the title compound 5-difluoromethoxy (R/S) 2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl]-1 H-benzimidazole as an off white solid of m. p. 135 - 136 0C (decomp.); yield 1.0 g (95 % of theoretical).
1H-NMR (400 MHz, DMSO d-6): d = 3,78 (s, 3 H, OMe), 4,68 (d, 1 H, J(CHa1CHb) = 13 Hz, S-CH2-Py), 4,73 (d, 1 H, J(CHb1CHa) = 13 Hz, S-CH2-Py), 7,10 (d, 1 H, J(H5',H6') = 5 Hz, H5') 7,18 (bd, 1H, H6), 7,24 (t, 1 H, J(H1F) = 74 Hz, OCHF2), 7,4 (bs, 1 H, H4), 7,70 (bs, 1 H, H7), 8,15 (d, 1H, J(H6',H5') = 5 Hz, H6'), 13,7 (s, 1 H, NH). Example 2
S(-)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole
At room temperature, 2.0 g of 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylthio]-1 H-benzimidazole are suspended in 20 ml. of methyl isobutyl ketone together with (+)-L-tartaric acid bis-(N-pyrrolidinamide) (2.3 g) and zirconium (IV) n-propoxide (1.0 g, 70 % in propanol). The mixture is heated at 40 0C for one hour, resulting in the formation of a solution which is almost clear. After cooling to room temperature, 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. 15 mL of water are added to the methyl isobutyl ketone phase, and the pH is adjusted to pH = 13 using a 40 % by weight strenghth solution of sodium hydroxide. After phase separation, the methyl isobutyl ketone phase is extracted with another 5 mL of water at pH 13. The aqueous phases are combined and, at 40 0C, subjected to incipient distillation under reduced pressure. Hyflo Super Cell as filtration aid (0.05 g) is added and after stirring for one hour at 20 - 25 0C filtered off. At 40 - 45 0C, the crude title compound is precipitated by addition of 10 % strength acetic acid to the filtrate to pH = 9.0. The mixture is stirred for another 12 hours during which the pH is monitored. The beige crystals are filtered off and washed with 10 mL of water. The title compound is obtained in a yield of about 1.6 g (75 % of theory) and an optical purity of > 98 %.
To increase the purity, (-) trideuteriopantoprazole is dissolved in water/aqueous sodium hydroxide solution at pH = 13 and re-precipitated with acetic acid (10 %) at pH = 9.0.
Recrystallisation from dichloromethane/tert-butylmethylether gives the title compound S(-)-5- difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimidazole as an offwhite solid of m. p. 146-148 0C (decomp.); yield 1.6 g.
Example 3
Synthesis of starting material 2-chloromethyl-3-methoxy-4-trideuteriomethoxy pyridiniumchloride
Preparation of 3-methoxy-2-methyl-4-trideuteriomethoxypyridine N-oxide
4-chloro-3methoxy-2-methylpyridine N-oxide (10 g) and sodium trideuteriomethanolate (6.2 g) in deu- teromethanol D4 (20 mL) were heated at reflux. After 15 hours the solvent was evaporated in vacuo, the residue was extracted with hot toluene (50 mL) and the insolubles were filtered off. Addition of diisopropylether to the filtrate precipitated a solid, which after drying in vacuo yielded 8.1 g of 3- methoxy-2-methyl-4-trideuteriomethoxypyridine N-oxide as a light brown powder. It was subsequently used in the following step.
Preparation of 2-hydroxymethyl-3-methoxy-4-trideuteriomethoxypyridine
The product (8.1 g) from the previous step was dissolved in acetic anhydride (50 mL) and was heated at 90 0C for 2 hours. After evaporation in vacuo, the dark oily residue was agitated with 2N NaOH (20 mL) for 2 hours at 80 0C. After cooling the product was extracted into dichloromethane, dried (K2CO3), and concentrated in vacuo to low volume. Addition of petroleum ether (50/70) afforded, after filtration and drying in vacuo 2-hydroxy-3-methoxy-4-trideuteriomethoxypyridine as light brown solid (5.5 g) which was used in the following step.
Preparation of 2-chloromethyl-3-methoxy-4-trideuteriomethoxy pyridinium chloride
The product form the previous step (5.5 g) was dissolved in dry dichloromethane (40 mL) and thionyl- chloride (3 mL) was added dropwise at 5 - 10 0C while stirring. The mixture was allowed to warm up to 20 0C and after 3 hours evaporated to dryness in vacuo.
Addition of toluene (20 mL) yielded 6.6 g of the title compound 2-chloromethyl-3-methoxy-4- trideuteriomethoxypyridinium chloride as light brown solid.
Material synthesized in this manner contained some difficult-to-remove impurities, which showed a propensity to get carried through the next steps leading to compounds of general formula (2) and, ultimately, general formula (1). For the preparation of compounds of general formula (1) with exceptionally high purity, it is therefore frequently preferable to resort to the deuterioalkoxylation method featured in Examples 9 and 35.
Example 4
4-Chloro-2-chloromethyl-3-methoxypyridinium chloride
At 85-95 0C, a solution of 4-chloro-3-methoxy-2-methylpyridine-Λ/-oxide (19.2 kg, 111 mol) in toluene (148 L), was added over 5-7 h to acetic anhydride (71 L). Under vacuum at about 60 0C, the reaction mixture was concentrated until about 170 L had been distilled off. Toluene (160 L) was added and, again, solvents were distilled off (160 L). This last operation was repeated once more. Then, toluene (14 L) and 40% aqueous NaOH (14.6 L) were added at 35-45 0C and the reaction mixture was kept at this temperature for 2-3 h. If at this point pH was below 13, more NaOH was added and heating continued for 2 more h. The resulting biphasic reaction mixture was diluted with toluene (26 L) and saturated aqueous sodium bicarbonate (26 L), the phases were separated and the aqueous layer was extracted thrice more with toluene (26 L and 2 x 13 L). Finally, the combined organic phase was washed with saturated aqueous sodium bicarbonate (13 L) and concentrated under vacuum at 50-65 0C until about 115 L had been distilled off. After dilution with toluene (100 L), another 100 L of solvents were distilled off.
The resulting solution of 4-chloro-2-hydroxymethyl-3-methoxypyridine (-30% strength) was diluted with CH2CI2 (48 L). DMF (65.5 g, 0.896 mol) was added in one portion and, then, thionyl chloride (11.1 kg, 93.2 mol) over 3-5 h at 15-30 0C. After stirring for additional 1.5 h, about 45 L of solvents were distilled off. Toluene (20 L) was added and, again, 20 L of solvents were removed by distillation. Then, ethanol (1.5 L) was added to the resulting thick slurry. The solids were filtered off at 10-15 0C, washed with toluene (17 L) and dried in vacuo at 30 0C to give 4-chloro-2-chloromethyl-3-methoxypyridinium chloride as an off-white solid (m. p. 132 0C); yield 15.0 kg (59%).
1H-NMR (200 MHz, CDCI3): δ= 4.19 (s, 3H), 5.14 (s, 2H), 7.92 (d, 6.0 Hz, 1 H), 8.59 (d, 6.0 Hz, 1 H), 11.64 (br s, 1 H); LC-MS: MH+ = 192/194/196.
Example 5
4-Chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride
Starting material, 4-chloro-2-methyl-3-trideuteriomethoxypyridine-Λ/-oxide was prepared according to method D for the non-deuterated analogue in J. Med. Chem. 1992, 35, 1049-1057: Starting from 3-hydroxy-2-methyl-4-pyrone, conversion with trideuterio-iodomethane in the presence of potassium carbonate in DMF yielded 2-methyl-3-trideuteriomethoxy-4-pyrone (yield: 83-96%), which upon heating with ammonia at 150 0C in ethanol gave, after crystallization from acetone/isopropanol 4:1 ; 4-hydroxy-2-methyl-trideuteriomethoxypyridine (yield: 52-60%). Treatment of this material with phosphorus oxychloride led to formation of 4-chloro-2-methyl-trideuteriomethoxypyridine (yield: 64- 81 %). Subsequent oxidation with hydrogen peroxide in acetic acid gave 4-chloro-2-methyl-3- trideuteriomethoxypyridine-Λ/-oxide as a slightly yellow solid (yield: 87-89%).
The final transformations via 4-chloro-2-hydroxymethyl-3-trideuteriomethoxypyridine were carried out as described under Example 4 to give 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride as a colorless crystalline solid (m. p. 129-130 0C); yield 19.6 g (42%).
Example 6
2-Chloromethyl-3,4-bis(trideuteriomethoxy)pyridinium chloride
According to the procedure described under Example 3, 4-chloro-2-methyl-3- trideuteriomethoxypyridine-Λ/-oxide (25.3 g, 144 mmol; for preparation see Example 5) was converted into 2-methyl-3,4-bis(trideuteriomethoxy)pyridine-Λ/-oxide (yield: 23.5 g, 96%), which, in turn, gave 2- hydroxymethyl-3,4-bis(trideuteriomethoxy)pyridine (yield: 13.0 g, 56%) and, ultimately, 2-chloromethyl- 3,4-bis(trideuteriomethoxy)pyridinium chloride (yield: 15.4 g, 89%) as an off-white crystalline solid. Example 7
5-Difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1 /-/-benzimidazole
At 55-65 0C, a solution of 4-chloro-2-chloromethyl-3-methoxypyridinium chloride (10.0 kg, 43.8 mol) in water (20 L) was added over 2-3 h to a mixture of 5-trideuteriomethoxy-1 H-benzimidazole-2-thiol (8.84 kg, 40.9 mol), toluene (43 L), water (21 L) and 40% aqueous NaOH (10.3 kg, 103 mol). Stirring at 60 0C was continued for 2-3 h before the reaction mixture was cooled to 10-15 0C. The precipitate was centrifuged off, washed with toluene (16 L) and re-pulped in water (122 L). Centrifugation followed by an aqueous rinse (32 L) and drying at 35 0C in vacuo gave 5-difluoromethoxy-2-[(4-chloro-3-methoxy- 2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (KF = 4.6%) as an off-white solid (m. p. 95-99 0C); yield 14.2 kg (92%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.55 (br s, NH + H2O), 3.92 (s, 3H), 4.79 (s, 2H), 6.97 (dd, 8.6 Hz, 2.3 Hz, 1 H), 7.16 (t, 74.8 Hz, 1 H), 7.28 (d, 2.2 Hz, 1 H), 7.47 (d, 8.7 Hz, 1 H), 7.55 (d, 5.3 Hz, 1 H), 8.25 (d, 5.2 Hz, 1 H); LC-MS: MH+ = 372/374.
Example 8
5-Difluoromethoxy-2-[(4-chloro-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole
Starting from 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride (5.00 g, 21.6 mmol) and following the procedure described under Example 7, 5-difluoromethoxy-2-[(4-chloro-3- trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (KF = 4.7%) was obtained as an off-white solid (m. p. 94-99 0C); yield 7.24 g (85%).
1H-NMR (200 MHz, DMSO-d6): δ= 4.79 (s, 2H), 6.98 (dd, 8.7 Hz, 2.3 Hz, 1 H), 7.16 (t, 74.8 Hz, 1 H), 7.28 (d, 2.0 Hz, 1H), 7.47 (d, 8.6 Hz, 1 H), 7.55 (d, 5.2 Hz, 1 H), 8.25 (d, 5.2 Hz, 1H), 12.75 (br s, 1 H); LC-MS: MH+ = 375/377.
Example 9
5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole
At 15-30 0C, methanol-d4 (2.26 kg, 62.7 mol) was added over 30-60 min to a mixture of sodium tert- butoxide (6.00 kg, 62.4 mol) in DMAc (27 L). After heating to 57-65 0C, a solution of 5-difluoromethoxy- 2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (6.08 kg, 15.6 mol) in DMAc (10 L) was added over 30-60 min. Stirring at 57-65 0C was continued for about 10 h. The reaction mixture was cooled to 20-30 0C 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 0C for 1.5 h before being chilled to 10-15 0C. 5- difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 /-/-benzimidazole was obtained as a water-wet brownish solid by centrifugation including an aqueous rinse (58 L), re-pulping in water (78 L) and, again; centrifugation including another aqueous rinse (58 L); yield 10.4 kg, KF = 49.7% (91%).
Drying of a sample of water-wet product (16.2 g, KF = 49.7 %) at 25 0C in vacuo gave an amorphous solid, which upon crystallization from toluene (30 mL) yielded water-free 5-difluoromethoxy-2-[(3- methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole as an off-white solid (5.80 g, 71% recovery, m. p. = 115-116 0C).
1H-NMR (200 MHz, DMSO-d6): δ= 3.82 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.1 Hz, 1 H), 7.08 (d, 5.6 Hz, 1 H), 7.16 (t, 74.8 Hz, 1 H), 7.28 (br s, 1 H), 7.47 (br d, -8.3 Hz, 1H), 8.16 (d, 5.6 Hz, 1 H), 12.75 (br s, 1 H); LC-MS: MH+ = 371.
[Example 10
5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylthio]-1H-benzimidazole
Starting from 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (28.6 g, 73.4 mmol) and methanol-d2 (10.0 g, 294 mmol), the procedure described under Example 9 was followed to give 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2- pyridinyl)methylthio]-1 H-benzimidazole as a water-wet brownish solid; yield 46.4 g, KF = 51.6% (82%).
1H-NMR (400 MHz, DMSO-d6): δ= 3.81 (s, 3H), 3.86 (s, 1 H), 4.67 (s, 2H), 6.97 (dd, 8.4 Hz, 2.0 Hz, 1 H), 7.08 (d, 5.5 Hz, 1 H), 7.16 (t, 74.7 Hz, 1H), 7.21-7.53 (br m, 2H), 8.16 (d, 5.5 Hz, 1 H), 12.78 (br s, 1 H); LC-MS: MH+ = 370.
[Example 11
5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole
Starting from 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (29.5 g, 75.6 mmol) and methanol-d1 (10.0 g, 303 mmol), the procedure described under Example 9 was followed to give 5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2- pyridinyl)methylthio]-1 H-benzimidazole as a water-wet brownish solid; yield 50.3 g, KF = 50.8% (89%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.82 (s, 3H), 3.88 (s, 2H), 4.67 (s, 2H), 6.98 (dd, 8.6 Hz, 2.2 Hz, 1 H), 7.08 (d, 5.6 Hz, 1 H), 7.15 (t, 74.8 Hz, 1H), 7.22-7.53 (br m, 2H), 8.16 (d, 5.6 Hz, 1 H), 12.79 (br s, 1 H); LC-MS: MH+ = 369. Example 12
5-Difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole
Starting from 5-difluoromethoxy-2-[(4-chloro-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H- benzimidazole mono hydrate (6.97 g, 17.7 mmol) and methanol (2.28 g, 71.2 mmol), the procedure described under Example 9 was followed to give 5-difluoromethoxy-2-[(4-methoxy-3- trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole as a water-wet brownish solid; yield 7.01 g, KF = 19.1% (87%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.89 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.0 Hz, 1 H), 7.08 (d, 5.5 Hz, 1 H), 7.16 (t, 74.7 Hz, 1 H), 7.18-7.47 (br m, 2H), 8.16 (d, 5.6 Hz, 1 H), 12.76 (br s, 1 H); LC-MS: MH+ = 371.
Example 13
5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylthio]-1 H-benzimidazole
At 50-55 0C, a 2-chloromethyl-3,4-bis(trideuteriomethoxy)pyridinium chloride (15.4 g, 66.8 mmol) was added portionwise over 30 min to a mixture of 5-difluoromethoxy-1 H-benzimidazole-2-thiol (14.5 g, 66.8 mmol), ethanol (133 mL), and 2M aqueous NaOH (73.5 mL, 147 mmol). Stirring at 50-55 0C was continued for 1-2 h before ethanol was removed by distillation under vacuum at 40 0C. The remaining aqueous emulsion was diluted with water (50 mL) and extracted three times with dichloromethane (165 mL portions). The combined organic phase was washed with 0.1 M aqueous NaOH (165 mL), dried over Na2SO4, and evaporated to dryness to give 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2- pyridinyl)methylthio]-1 /-/-benzimidazole as a brown oil; yield 23.8 g (95%).
Example 14
rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole - large scale procedure
At 25-35 0C, aqueous sodium hypochlorite (10.5 kg at 10% strength, 14.2 mol) was added over 3-4 h to a solution of 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H- benzimidazole (10.4 kg, KF = 49.7%, 14.2 mol) and 40% aqueous NaOH (2.84 kg) in a mixture of water (49 L) and isopropanol (49 L). Stirring at 25-35 0C was continued for 0.5-1 h before the reaction was quenched by addition of 1% aqueous Na2S2O3 (4.3 L). Then, about 65 L of solvents were distilled off at 30-45 0C under vacuum. After dilution with water (55 L), another portion of solvents (8-10 L) was removed by distillation. While keeping the reaction mixture at 40-45 0C, 10% aqueous acetic acid (~13 L) was added over 1.5 h until pH 8.5-9.5 was reached. Once crystallization had set in, the pH was slowly adjusted to 6.8-7.2 by addition of more 10% aqueous acetic acid (~0.6 L). After cooling to 20-25 0C, crude product was filtered off and washed with water (7.5 L) and re-dissolved in a mixture of water (80 L), 40% aqueous NaOH (1.6 L) and Na2S2O3 (60 g). 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 0C. Once product started to crystallize, further 10% acetic acid was added so as to continuously maintain a pH of 9.0-9.5. Finally, centrifugation at 20-25 0C including an aqueous rinse (7.5 L) and drying in vacuo at about 50 0C gave rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole as an off-white solid (m. p. = 134-135 0C, decomp.); yield 3.59 kg (65%).
1H-NMR (400 MHz, DMSO-d6): δ= 3.78 (s, 3H), 4.67 (d, 13.1 Hz, 1 H), 4.73 (d, 13.1 Hz, 1 H), 7.10 (d, 5.5 Hz, 1 H), 7.18 (br d, 8.7 Hz, 1 H), 7.24 (t, 74.4 Hz, 1 H), 7.44 (br s, 1 H), 7.70 (br s, 1 H), 8.15 (d, 5.5 Hz, 1 H), 13.73 (br s, 1 H); LC-MS: MH+ = 387.
Example 15
rao5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/- benzimidazole
Starting from wet 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylthio]-1 H- benzimidazole (32.7 g, KF = 51.6%, 42.8 mmol) and following the procedure described under Example 14, rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H- benzimidazole was obtained as an off-white solid (m. p. = 133-135 0C, decomp.); yield 10.8 g (65%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.32 (br s, NH + H2O), 3.77 (s, 3H), 3.86 (s, 1 H), 4.65 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1 H), 7.10 (d, 5.5 Hz, 1 H), 7.15 (dd, 8.8 Hz, 2.4 Hz, 1 H), 7.23 (t, 74.4 Hz, 1 H), 7.44 (d, 2.2 Hz, 1 H), 7.69 (d, 8.8 Hz, 1 H), 8.15 (d, 5.5 Hz, 1 H); LC-MS: MH+ = 386.
Example 16
rac-5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole
Starting from wet 5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylthio]-1 H- benzimidazole (34.8 g, KF = 50.8%, 46.5 mmol) and following the procedure described under Example 14, rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole was obtained as an off-white solid (m. p. = 134-135 0C, decomp.); yield 14.0 g (78%). 1H-NMR (200 MHz, DMSO-d6): δ= 3.78 (s, 3H), 3.88 (s, 2H), 4.66 (d, 13.2 Hz, 1 H), 4.73 (d, 13.1 Hz, 1 H), 7.10 (d, 5.6 Hz, 1 H), 7.16 (dd, 8.8 Hz, 2.4 Hz, 1 H), 7.24 (t, 74.4 Hz, 1 H), 7.45 (d, 2.2 Hz, 1 H), 7.69 (d, 8.8 Hz, 1 H), 8.15 (d, 5.5 Hz, 1H), 13.77 (br s, 1 H); LC-MS: MH+ = 385.
Example 17
rac-5-Difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/- benzimidazole
Starting from wet 5-difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H- benzimidazole (3.00 g, KF = 19.1%, 6.55 mmol) and following the procedure described under Example 38, rao5-difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/- benzimidazole was obtained, after crystallization from TBME (10 ml_); as an off-white solid (m. p. = 133-134 0C, decomp.); yield 1.83 g (72%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.90 (s, 3H), 4.66 (d, 13.1 Hz, 1 H), 4.73 (d, 13.1 Hz, 1 H), 7.10 (d, 5.6 Hz, 1 H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1 H), 7.24 (t, 74.4 Hz, 1 H), 7.45 (d, 2.1 Hz, 1 H), 7.69 (d, 8.8 Hz, 1 H), 8.15 (d, 5.5 Hz, 1H), 13.77 (br s, 1 H); LC-MS: MH+ = 387.
Example 18
rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole
Starting from 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylthio]-1 H- benzimidazole (23.8 g, 63.7 mmol) and following the procedure described under Example 38, rao5- difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole was obtained, after crystallization from diisopropyl ether (700 mL), as an off-white solid; yield 20.9 g (84%).
Example 19
rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt mono hydrate
At 15-30 0C, 40 % aqueous NaOH (0.85 kg, 8.50 mol) was added over 10-30 min to a solution of rao5- difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole (3.29 kg, 8.51 mol) in acetone (18 L). The resulting suspension was heated at 50-55 0C until a clear solution was obtained. Crystallization of product was achieved by slow cooling to 10-15 0C over about 12 h. The solids were filtered off and washed with acetone (1.7 L) before being re-crystallized from acetone/water 32:1 (19 L). Finally, drying at 50 0C in vacuo gave rac-5-difluoromethoxy-2-[(3-methoxy-4- trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt mono hydrate as an off- white solid (m. p. = 151-152 0C (decomp.), KF = 4.3 %); yield 2.93 kg (81%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.78 (s, 3H), 4.34 (d, 12.9 Hz, 1 H), 4.68 (d, 12.9 Hz, 1 H), 6.72 (dd, 8.6 Hz, 2.4 Hz, 1 H), 7.02 (t, 75.8 Hz, 1 H), 7.07 (d, 5.6 Hz, 1 H), 7.24 (d, 2.2 Hz, 1 H), 7.44 (d, 8.6 Hz, 1H), 8.22 (d, 5.5 Hz, 1H); LC-MS: MNa+ = 409, MH+ = 387.
Example 20
rac-5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt mono hydrate
Starting from rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole (8.10 g, 21.0 mmol), the procedure described under Example 19 gave rac-5- difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt mono hydrate as an off-white solid (m. p. = 150-152 0C (decomp.), KF = 4.8 %); yield 6.05 g (68%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.77 (s, 3H), 3.85 (s, 1 H), 4.36 (d, 12.9 Hz, 1 H), 4.66 (d, 12.9 Hz, 1 H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1 H), 7.02 (t, 75.8 Hz, 1 H), 7.07 (d, 5.6 Hz, 1 H), 7.25 (d, 2.3 Hz, 1 H), 7.45 (d, 8.6 Hz, 1 H), 8.22 (d, 5.5 Hz, 1 H); LC-MS: MNa+ = 408, MH+ = 386.
Example 21
rao5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/- benzimidazole sodium salt mono hydrate
Starting from rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylsulfinyl]- 1 H-benzimidazole (10.2 g, 26.5 mmol), the procedure described under Example 19 gave rac-5- difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt mono hydrate as an off-white solid (m. p. = 151-152 0C (decomp.), KF = 4.1%); yield 8.95 g (79%).
1H-NMR (200 MHz, DMSO-d6): δ= 3.78 (s, 3H), 3.88 (s, 2H), 4.34 (d, 12.9 Hz, 1 H), 4.68 (d, 12.9 Hz, 1 H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1 H), 7.03 (t, 75.8 Hz, 1 H), 7.08 (d, 5.5 Hz, 1 H), 7.24 (d, 2.2 Hz, 1 H), 7.44 (d, 8.6 Hz, 1 H), 8.22 (d, 5.5 Hz, 1 H); LC-MS: MNa+ = 407, MH+ = 385.
Example 22 rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 /-/-benzimidazole sodium salt mono hydrate
At 15-25 0C, 6M aqueous NaOH (8.92 mL, 53.5 mmol) was added over about 15 min to a solution of rac-5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 /-/-benzimidazole (21.0 g, 53.9 mmol) in a 6:1 mixture of ethanol/dichloromethane (725 mL). After stirring for another 10 min at room temperature, most of the solvents were distilled off. The resulting concentrate (115 g) was diluted with diisopropyl ether (1.7 L). Some dark waxy residue remained undissolved, and the supernatant clear yellow solution was decanted off. To this solution, another portion of diisopropyl ether (3.4 L) was added to effect precipitation of product. The suspension was cooled to 0 0C, and the solids were filtered off, washed with diisopropyl ether (100 mL) and dried at 40 °c in vacuo to give rao5- Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt mono hydrate as an off-white solid (KF = 4.0 %); yield 18.9 g (82%).
1H-NMR (400 MHz, DMSO-d6): δ= 4.32 (d, 12.9 Hz, 1 H), 4.70 (d, 12.9 Hz, 1 H), 6.72 (dd, 8.6 Hz, 2.4 Hz, 1 H), 7.04 (t, 75.8 Hz, 1H), 7.08 (d, 5.5 Hz, 1 H), 7.23 (d, 2.4 Hz, 1 H), 7.44 (d, 8.6 Hz, 1 H), 8.22 (d, 5.5 Hz, 1 H); LC-MS: MNa+ = 412, MH+ = 390.
Example 23
rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt sesqui hydrate
At 48-55 0C, rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt mono hydrate (2.93 kg, 6.87 mol) was dissolved in a mixture of isopropanol (12 L) and water (0.50 L). After treatment with Hyflo Super CeI (56 g) and cooling to 18-25 0C, crystallization was accomplished by seeding with an authentic sample of product followed by stirring for 40 h at 18-25 °c and another 5 h at 10-15 0C. Centrifugation and drying at 45 0C in vacuo gave rao5- difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole so- dium salt sesqui hydrate as a white solid (m. p. = 140-142 0C (decomp.), KF = 6.6%); yield 2.28 kg (78%).
Example 24
Bis-[rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole] magnesium salt di hydrate
At 40 0C, a solution of rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt (500 mg, KF = 4.3 %, 1.17 mmol) in water (10.0 mL) was subjected to a clean filtration. After cooling to room temperature, a solution of anhydrous magnesium chloride (61.4 mg, 0.644 mmol) in 1.0 ml. of water was added. The resulting suspension was stirred at room temperature for an additional 18 h before being cooled to 0 0C and filtered. The filter cake was re-pulped in water (7.5 mL), filtered, rinsed with water (5.0 mL) and dried at 40 0C in vacuo to give bis-[rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]- 1 H-benzimidazole] magnesium salt di hydrate as a white solid (m. p. 180-182 0C (decomp.); KF = 4.7%; HPLC: 99.5% a/a); yield 369 mg (76 %).
Example 25
(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole - large scale procedure for undried starting material
At room temperature, 382 g of wet 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylthio]-1 H-benzimidazole (KF = 47.6%, 0.540 mol) were suspended in 2.44 L of methyl isobutyl ketone together with (+)-L-tartaric acid bis-(N-pyrrolidinamide) (55.0 g). The mixture was heated to 40 0C and about 1.25 L of solvent were evaporated under vacuum to remove water. Then, zirconium (IV) n-propoxide (24.0 mL, 70 % in n-propanol) was added and stirring at 40 0C was continued for one more hour. After cooling to 30 0C, N-ethyldiisopropylamine (6.5 mL) and cumene hydroperoxide (103 mL, ~80% strength) were added. After stirring for about 18 h at 30 0C, TLC indicated no further conversion of starting material. The clear reaction mixture was diluted with 500 mL of methyl isobutyl ketone and quenched with 7.0 g of sodium thiosulphate in 800 mL of saturated sodium bicarbonate solution. After phase separation, the organic layer was washed twice with 400 mL of saturated sodium bicarbonate solution. To the organic phase, 1.5 L of water were added, and the pH was adjusted to pH = 13 using 40 % aqueous sodium hydroxide. 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 0C. 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).
To further increase the purity, crude product was dissolved in dichloromethane (2.0 L) and washed with water (400 mL). Crystallization was achieved by a solvent chase with TBME (final volume about 1.1 L). The crystals were filtered off at about 0 0C, washed with TBME (400 mL), and dried at 30 0C in vacuo to give (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole as an off-white solid (m. p. 146-148 0C (decomp.); KF = 0.8%); yield 135 g (64 %).
Chiral HPLC: > 98.0% ee; optical rotation: [α|D = -98° (MeOH, c = 0.50).
1H-NMR (200 MHz, DMSO-d6): δ= 3.41 (br s, NH + H2O), 3.77 (s, 3H), 4.65 (d, 13.0 Hz, 1 H), 4.73 (d, 13.1 Hz, 1 H), 7.09 (d, 5.6 Hz, 1 H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1 H), 7.23 (t, 74.4 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.68 (d, 8.9 Hz, 1 H), 8.14 (d, 5.5 Hz, 1 H); LC-MS: MH+ = 387. Example 26
(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole
Starting from 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H- benzimidazole (70.7 g, KF = 47.6%, 100 mmol) and using (-)-D-tartaric acid bis-(N-pyrrolidinamide) (10.3 g, 40.0 mmol) as chiral ligand, the procedure described under Example 25 gave, after recrystallizatiion from TBME, (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylsulfinyl]-1H-benzimidazole as an off-white solid (m. p. 140-142 0C (decomp.); KF = 0.8%); yield 22.2 g (57 %).
Chiral HPLC: > 98.0% ee; optical rotation: [α|D = +97° (MeOH, c = 0.50).
1H-NMR (200 MHz, DMSO-d6): δ= 3.77 (s, 3H), 4.65 (d, 13.2 Hz, 1 H), 4.73 (d, 13.1 Hz, 1 H), 7.09 (d, 5.5 Hz, 1 H), 7.16 (br d, -10.3 Hz, 1 H), 7.23 (t, 74.4 Hz, 1 H), 7.44 (br s, 1 H), 7.68 (br s, 1 H), 8.14 (d, 5.5 Hz, 1 H), 13.73 (br s, 1 H); LC-MS: MH+ = 387.
Example 27
(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt
At room temperature, to a suspension of (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylsulfinyl]-1 H-benzimidazole (100 g, 0.259 mol) in a mixture of methyl isobutyl ketone (750 mL), isopropanol (75 mL), and water (5.0 mL) was added 40% aqueous NaOH (18.1 mL, 259 mmol). After heating to 50 °c a clear solution was obtained, which was subjected to treatment with Hyflo Super CeI (10.0 g). Crystallization of product set in upon cooling to room temperature and was driven to completion by further cooling to 0 0C. Finally, the crystals were filtered off, washed with methyl isobutyl ketone (3 portions, 40 mL each) and dried at 35 0C in vacuo to give (S)-5- difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole sodium salt as a white hygroscopic solid (m. p. 105-106 0C (decomp.); KF = 10.3%); yield 105 g (89 %).
Chiral HPLC: > 99.0% ee; optical rotation: [α|D = -94° (MeOH, c = 0.50).
Example 28 (R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt
Starting from (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole (15.5 g, 40.1 mmol) and following the procedure described under Example 27, (R)-5- difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole so- dium salt was obtained as a white hygroscopic solid (m. p. 98-103 0C (decomp.); KF = 11.3%); yield 17.4 g (94 %).
Chiral HPLC: > 98.0% ee; optical rotation: [α|D = +91° (MeOH, c = 0.50).
[Example 29
Bis-[(S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole] magnesium salt tri hydrate
Starting from (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt (500 mg, KF = 10.3 %, 1.10 mmol) and following the procedure described under Example 24, bis-[(S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylsulfinyl]-1 H-benzimidazole] magnesium salt tri hydrate was obtained as a white solid (m. p. 169-175 0C (decomp.); KF = 6.4%); yield 350 mg (75 %).
Chiral HPLC: > 99.0% ee; optical rotation: [α|D = -122° (MeOH, c = 0.50).
Example 30
Bis-[(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole] magnesium salt tri hydrate
Starting from (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H- benzimidazole sodium salt (2.30 g, KF = 11.3 %, 5.00 mmol) and following the procedure described under Example 24, bis-[(R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- pyridinyl)methylsulfinyl]-1 H-benzimidazole] magnesium salt tri hydrate was obtained as a white solid (m. p. 141-145 0C (decomp.); KF = 6.9%); yield 1.23 g (58 %).
Chiral HPLC: > 99.0% ee; optical rotation: [α|D = +120° (MeOH, c = 0.50).
Example 31
Synthesis of starting material 5-trideuteriomethoxy-1 H-benzimidazole-2-thiol Preparation of 4-trideuteriomethoxy-nitrobenzene
To a solution of sodium hydroxide (15.6 g, 390 mmol) in a mixture of methanol-d4 (47.4 ml_, 1.17 mol) and THF (50 ml.) was added a solution of 1 -fluoro-4-nitrobenzene (50.0 g, 354 mmol) in THF (200 ml.) over 2 h at 15-25 0C. The resulting suspension was stirred for 3 more h at room temperature before 10% aqueous HCI (100 ml.) and toluene (150 ml.) were added. The organic phase was separated and evaporated to dryness to give 4-trideuteriomethoxy-nitrobenzene as a brown oil, which crystallized upon standing (m. p. 48-51 0C); yield 56.6 g (quantitative).
1H-NMR (200 MHz, DMSO-d6): δ= 7.15 (m, 2H), 8.22 (m, 2H); GC-MS: M+ = 156.
Preparation of 4-trideuteriomethoxy-acetanilide
An autoclave was charged with 10% Pd/C (3.6 g, water wet), 4-trideuteriomethoxy-nitrobenzene (72.5 g, 464 mmol) and isopropanol (508 ml_). After thorough purging with nitrogen (4 times), the resulting mixture was stirred under hydrogen pressure (3-4 bar) at 50-60 0C until the uptake of hydrogen stopped (about 2.5 h). The reaction mixture was cooled to room temperature and acetic anhydride (62.5 mL, 580 mmol) was added. Stirring was continued for 4 more h before the catalyst was filtered off and washed with hot 2-propanol (270 mL, about 60 0C). The combined filtrates were concentrated under vacuum to about 150 mL, methylcyclohexane (350 mL) was added, and the resulting slurry was cooled to 10 0C. Filtration and drying at 45 0C in vacuo gave 4-trideuteriomethoxy-acetanilide as a grayish solid (m. p. 125-127 0C); yield 67.0 g (86 %).
1H-NMR (200 MHz, DMSO-d6): δ= 2.00 (s, 3H), 6.85 (m, 2H), 7.47 (m, 2H), 9.74 (br s, 1 H); LC-MS: MH+ = 169.
Preparation of 2-nitro-4-trideuteriomethoxy-aniline
At 10-150C, 50% aqueous nitric acid (63.0 mL, 654 mmol) was added over 1 ,5 h to a solution of 4- trideuteriomethoxy-acetanilide (50.0 g, 297 mmol) in acetic acid (175 mL). Stirring was continued for 18 h at room temperature. Then, 20% aqueous NaOH (671 mL) was added over about 1 h at 15-20 0C. The resulting brown suspension was heated at 50 0C for 20 h before the pH was adjusted to about 8 by addition of 20% aqueous HCI (49 mL). Crude product was obtained by cooling to 10 0C and filtration. After an aqueous rinse, the filter cake was slurried at 60 0C in isopropanol (200 mL) and water (300 mL) was added over 1 h. While maintaining the temperature between 50 and 60 0C, 190 mL of solvents were distilled off. The resulting suspension was cooled to 10 0C, filtered and washed with water (60 mL) to provide after drying at 30 0C in vacuo 2-nitro-4-trideuteriomethoxy-aniline as a red solid (m. p. 120-122 0C); yield 46.7 g (92%). 1H-NMR (200 MHz, DMSO-d6): δ= 7.00 (d, 9.3 Hz, 1 H), 7.16 (dd, 9.3 Hz, 2.9 Hz, 1 H), 7.24 (br s, 2H), 7.37 (d, 2.9 Hz, 1 H); GC-MS: M+ = 171.
Preparation of 5-trideuteriomethoxy-1 /-/-benzimidazole-2-thiol
An autoclave was charged with 10% Pd/C (2.23 g, water wet), 2-nitro-4-trideuteriomethoxy-acetanilide (45.6 g, 267 mmol) and isopropanol (460 mL). After thorough purging with nitrogen (4 times), the resulting mixture was stirred under hydrogen pressure (3-4 bar) at 40-50 0C until the uptake of hydrogen stopped (about 6 h). Then, O-ethylxanthic acid potassium salt (51.2 g, 319 mmol) was added and the reaction mixture was heated at reflux for 23 h. Water (340 mL) was added and the pH was adjusted to 12.5 with 20 % aqueous NaOH (10 mL) before roughly the amount of isopropanol (460 mL) was distilled off. The resulting dark suspension was treated with charcoal (10 g), cleared by filtration and washed with toluene (350 mL). Product was precipitated by addition of 20% aqueous HCI (53 mL) and isolated by filtration at 0 0C. Rinsing with water (100 mL) and drying at 35 °c in vacuo finally gave 5- trideuteriomethoxy-1 /-/-benzimidazole-2-thiol as an off-white solid (m. p. 247-250 0C); yield 45.5 g (93 %).
1H-NMR (400 MHz, DMSO-d6): δ= 6.67 (d, 2.3 Hz, 1 H), 6.72 (dd, 8.7 Hz, 2.4 Hz, 1 H), 7.03 (d, 8.6 Hz, 1 H), 12.36 (br s, 1 H), 12.40 (br s, 1 H); LC-MS: MH+ = 184.
Example 32
Synthesis of starting material 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride
Preparation of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine
At 90-95 0C, a solution of 4-chloro-2,3,5-trimethylpyridine-Λ/-oxide (60.0 g, 350 mmol) in toluene (920 mL), which was kept at about 60 0C, was added over 7 h to acetic anhydride (232 mL). Under vacuum at about 60 0C, the reaction mixture was concentrated until 820 mL had been distilled off. Toluene (840 mL) was added and, again, solvents were distilled off (940 mL). Then, toluene (180 mL) and 40% aqueous NaOH (80 mL) were added before the reaction mixture was heated at 50 0C for about 15 h. After addition of saturated aqueous sodium bicarbonate (120 mL), the phases were separated and the aqueous layer was extracted once more with toluene (80 mL). Finally, the combined organic phase was washed with saturated aqueous sodium bicarbonate (120 mL) and evaporated to dryness to give 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine as a brownish oil which solidified upon standing; yield 61.8 g (quantitative).
1H-NMR (200 MHz, DMSO-d6): δ= 2.30 (s, 3H), 2.36 (s, 3H), 4.58 (br s, 2H), 5.11 (br s, 1H), 8.27 (s, 1 H); LC-MS: MH+ = 172/174. Preparation of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride
To a solution of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine (60.7 g, 354 mmol) and DMF (0.25 ml_, 3.54 mmol) in toluene (200 mL) was added thionyl chloride (26.9 mL, 371 mmol) over 2 h at 15-30 0C. After stirring for 2 more h at ambient temperature, ethanol (6 mL) was added to the thick slurry. The solids were filtered off at about 10 0C, washed with toluene (80 mL) and dried at 40 0C in vacuo to give 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride as an off-white solid (m. p. 195-196 0C); yield 66.5 g (84%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.36 (s, 3H), 2.46 (s, 3H), 4.93 (s, 2H), 8.44 (s, 1 H), 8.79 (br s, 1 H); LC-MS: MH+ = 190/192/194.
Example 33
5-Trideuteriomethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole
At 55-65 0C, a solution of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride (12.6 g, 55.6 mmol) in water (21 mL) was added over 2 h to a mixture of 5-trideuteriomethoxy-1 H-benzimidazole-2-thiol (9.50 g, 51.8 mmol), toluene (47 mL), water (23 mL) and 40% aqueous NaOH (14 mL). Stirring at 60 0C was continued for 16 h before the reaction mixture was cooled to about 10 0C. The precipitate was filtered off, washed with toluene (17 mL) and re-pulped in water (132 mL). Filtration followed by an aqueous rinse (70 mL) and drying at 35 0C in vacuo gave 5-trideuteriomethoxy-2-[(4-chloro-3,5- dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (KF = 5.0%) as an off-white solid (m. p. 99-102 0C); yield 15.1 g (82%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76 (dd, 8.7 Hz, 2.5 Hz, 1 H), 6.97 (br s, 1 H), 7.35 (d, 8.7 Hz, 1 H), 8.28 (s, 1 H), 12.47 (br s, 1 H); LC-MS: MH+ = 337/339.
Example 34
5-Methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole
Starting from 5-methoxy-1 H-benzimidazole-2-thiol (24.0 g, 111 mmol) and following the procedure described under Example 33, 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 H- benzimidazole mono hydrate (KF = 5.2%) was obtained as an off-white solid (m. p. 100-102 0C); yield 34.8 g (89%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76 (dd, 8.7 Hz, 2.5 Hz, 1 H), 6.98 (br s, 1 H), 7.35 (d, 8.7 Hz, 1 H), 8.28 (s, 1 H), 12.41 (br s, 1 H); LC-MS: MH+ = 334/336. Example 35
5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole
At 60-65 0C, to a solution of 5-trideuteriomethoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 /-/- benzimidazole mono hydrate (5.20 g, 14.7 mmol) in NMP (30 mL) was added over 1.5 h solid sodium methoxide (5.80 g, 104 mmol) in about 10 equal portions. Stirring at 60 0C was continued for 16 h, then the reaction mixture was heated at 70 0C for 24 h and, finally, at 80 0C for 4 h. After dilution with water (200 mL) and addition of 10% aqueous HCI (10 mL), the resulting dark brown solution was extracted twice with toluene (100 + 40 mL). The combined organic phase was washed successively with 5% aqueous NaOH (2 x 200 mL) and water (100 mL) before being evaporated to dryness. The residue was taken up in hot toluene (50 mL), subjected to a clear filtration and, again, evaporated to dryness. Finally, crystallization from TBME/toluene 10:1 (33 mL) yielded 5-trideuteriomethoxy-2-[(4-methoxy- 3,5-dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole as a white solid (m. p. 120-121 0C); yield 2.27 g (46%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.20 (s, 3H), 2.27 (s, 3H), 3.73 (s, 3H), 4.65 (s, 2H), 6.75 (dd, 8.7 Hz, 2.5 Hz, 1 H), 6.97 (br s, 1 H), 7.35 (d, 8.7 Hz, 1 H), 8.17 (s, 1 H), 12.44 (br s, 1 H); LC-MS: MH+ = 333.
Example 36
5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole
A solution of sodium trideuteriomethoxid was prepared by addition of methanol-d4 (1.70 mL, 41.5 mmol) at about 50 0C over 30 min to a suspension of sodium hydride (60% in mineral oil, 1.70 g, 41.5 mmol) in NMP (12 mL). After heating to 60 0C, a solution of 5-trideuteriomethoxy-2-[(4-chloro-3,5- dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole mono hydrate (2.10 g, 5.92 mmol) in NMP (4 mL) was added. Stirring was continued, first at 70 0C for 24 h, then at 85 0C for 5 h. Following the work-up procedure described under Example 35, 5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2- pyridinyl)methylthio]-1 /-/-benzimidazole was obtained as a white solid (m. p. 120-121 0C); yield 0.55 g (28%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.20 (s, 3H), 2.27 (s, 3H), 4.64 (s, 2H), 6.75 (dd, 8.7 Hz, 2.4 Hz, 1 H), 6.89-7.38 (br m, 2H), 8.17 (s, 1 H), 12.42 (br s, 1 H); LC-MS: MH+ = 336.
Example 37
5-Methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole Starting from 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1/-/-benzimidazole mono hydrate (24.0 g, 68.2 mmol) and following the procedure described under Example 36, 5-methoxy-2- [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole was obtained as a white solid (m. p. 119-121 0C); yield 8.72 g (38%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.20 (s, 3H), 2.27 (s, 3H), 3.77 (s, 3H), 4.64 (s, 2H), 6.75 (dd, 8.7 Hz, 2.5 Hz, 1 H), 6.98 (br s, 1 H), 7.35 (br d, 8.6 Hz, 1 H), 8.17 (s, 1 H), 12.43 (br s, 1 H); LC-MS: MH+ = 333.
Example 38
rao5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1 /-/-benzimidazole
5-Trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylthio]-1 H-benzimidazole (1.50 g, 4.51 mmol) was dissolved in CH2CI2 (15 ml.) and cooled to -55 to -40 0C. At this temperature, a solution of 3-chloroperoxybenzoic acid (wet, 77% strength, 1.12 g, 5.00 mmol) in CH2CI2 (8 mL) was slowly added over 1.5 h. After one more h at -55 to -40 0C, triethylamine (0.87 mL, 6.28 mmol) and a 1 :1 mixture of 6% aqueous Na2CO3 and 2% aqueous Na2S2O3 (10 mL) were successively added while allowing the mixture to warm to about 0 0C. Stirring was continued for 1 h at ambient temperature. The phases were separated, and the organic layer was washed twice with a 1 :1 mixture of 6% aqueous Na2CO3 and 2% aqueous Na2S2O3 and once with water (10 mL each) before being evaporated to dryness. The resulting residue was crystallized from ethyl acetate (6.0 mL) to give rac-5- trideuteriomethoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole as a white solid (m. p. 150-152 0C, decomp.); yield 1.27 g (81%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.17 (s, 3H), 2.20 (s, 3H), 3.69 (s, 3H), 4.67 (d, 13.6 Hz, 1 H), 4.77 (d, 13.5 Hz, 1 H), 6.92 (dd, 8.9 Hz, 2.4 Hz, 1 H), 7.09 (br s, 1H), 7,54 (br d, 8.9 Hz, 1H), 8.18 (s, 1 H), 13.39 (br s, 1 H); LC-MS: MH+ = 349.
Example 39
rac-5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/- benzimidazole
Starting from 5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 /-/- benzimidazole (1.20 g, 3.57 mmol) and following the procedure described under Example 38, rac-5- trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/-benzimidazole was obtained as a white solid (m. p. 147-148 0C, decomp.); yield 0.90 g (72%). 1H-NMR (200 MHz, DMSO-d6): δ= 2.16 (s, 3H), 2.20 (s, 3H), 4.67 (d, 13.5 Hz, 1 H), 4.77 (d, 13.5 Hz, 1 H), 6.90-7.55 (br m, 3H), 8.18 (s, 1 H), 13.39 (br s, 1 H); LC-MS: MH+ = 352.
Example 40
rac-5-Methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole
Starting from 5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H- benzimidazole (1.00 g, 3.01 mmol) and following the procedure described under Example 38, rac-5- methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole was obtained as a white solid (m. p. 143-144 0C, decomp.); yield 0.86 g (82%).
1H-NMR (200 MHz, DMSO-d6): δ= 2.17 (s, 3H), 2.20 (s, 3H), 3.81 (s, 3H), 4.67 (d, 13.6 Hz, 1 H), 4.77 (d, 13.5 Hz, 1 H), 6.90-7.55 (br m, 3H), 8.18 (s, 1 H), 13.40 (br s, 1 H); LC-MS: MH+ = 349.
Example 41
(S)-5-Trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/- benzimidazole sodium salt
At room temperature, 5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2- pyridinyl)methylthio]-1 H-benzimidazole (3.02 g, 9.00 mmol) and (+)-L-tartaric acid bis-(N- pyrrolidinamide) (0.92 g, 3.60 mmol) were suspended in 35 mL of methyl isobutyl ketone. The mixture was heated to 40 0C and about 8 mL of solvent were evaporated under vacuum to remove water. Then, zirconium (IV) n-propoxide (0.40 mL, 70 % in n-propanol, 0.90 mmol) was added and stirring at 40 0C was continued for one more hour. After cooling to 30 0C, N-ethyldiisopropylamine (0.11 mL, 0.63 mmol) and cumene hydroperoxide (1.52 mL, ~80% strength, 8.55 mmol) were added. After stirring for about 20 h at 30 0C, the clear reaction mixture was diluted with methyl isobutyl ketone (8.5 mL) and quenched with sodium thiosulphate (0.11 g) in saturated sodium bicarbonate solution (15 mL). After phase separation, the organic layer was washed twice with saturated sodium bicarbonate solution (7.5 mL each). To the organic phase, water was added (25 mL), and the pH was adjusted to pH = 12.5-13 using 40 % aqueous NaOH (0.71 mL). The organic layer was extracted twice more with water (7.5 mL) at pH 12.5-13 (through addition of prerequisite amount of 40% aqueous NaOH). The combined organic phase was washed with dichloromethane (15 mL). Then, the pH was adjusted to about 10 with potassium dihydrogen phosphate and the aqueous solution was extracted with dichloromethane (once 40 mL and twice 10 mL). Evaporation of the organic phase to dryness gave (S)-5-trideuteriomethoxy-2- [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole as a brownish oil, which was further purified by formation of the corresponding sodium salt.
To this end, the crude product was taken up in methyl isobutyl ketone (15 mL) and isopropanol (1.5 mL). Then, 40% aqueous NaOH (0.63 mL) was added and the resulting suspension wsa cooled to 0 0C. The solids were filtered off, washed with methyl isobutyl ketone (twice 2.0 mL) and dried at 45 °C in vacuo to give (S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]- 1 /-/-benzimidazole sodium salt as an off-white solid (m. p. 224-225 0C (decomp.), KF = 1.5%); yield 2.05 g (61%).
Chiral HPLC: > 97.0% ee; optical rotation: [α|D = -44° (MeOH, c = 0.53), [a]D = +39° (H2O, c = 0.39).
1H-NMR (200 MHz, DMSO-d6): δ= 2.18 (s, 3H), 2.21 (s, 3H), 4.39 (d, 12.9 Hz, 1 H), 4.63 (d, 12.9 Hz, 1 H), 6.54 (dd, 8.7 Hz, 2.5 Hz, 1 H), 6.98 (d, 2.5 Hz, 1 H), 7,32 (br d, 8.6 Hz, 1 H), 8.23 (s, 1 H).
Example 42
Bis-[(S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/- benzimidazole] magnesium salt
Starting from (S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]- 1 /-/-benzimidazole sodium salt (200 mg, KF = 1.5 %, 0.528 mmol) and following the procedure described under Example 24, bis-[(S)-5-trideuteriomethoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2- pyridinyl)methylsulfinyl]-1 /-/-benzimidazole] magnesium salt was obtained as a white solid (m. p. 161- 162 0C (decomp.); KF = 1.5%); yield 132 mg (68 %).
Chiral HPLC: > 97.0% ee; optical rotation: [α|D = -120° (MeOH, c = 0.50).
By proper combination of the procedures described above, further compounds of general formula (1) are also accessible:
For example, 4-chloro-2-chloromethyl-3-methylpyridinium chloride could be reacted with 1 H- benzimidazole-2-thiol according to the procedure described under Example 7 to give 2-[(4-chloro-3- methyl-2-pyridinyl)methylthio]-1 /-/-benzimidazole. Conversion of this product with, for instance, 1 ,1- dideuterio-3-methoxy-1-propanol or 1 ,1-dideuterio-2,2,2-trifluoroethanol following the protocol described under Example 9 would then give rise to formation of 2-[(4-(1,1-dideuterio-3-methoxyprop-1- oxy)-3-methyl-2-pyridinyl)methylthio]-1 /-/-benzimidazole and 2-[(4-(1 ,1-dideuterio-2,2,2-trifluoroethoxy)- 3-methyl-2-pyridinyl)methylthio]-1 /-/-benzimidazole, respectively. Finally, oxidation of these compounds according to the procedure used in Example 38 would provide rao2-[(4-(1,1-dideuterio-3- methoxypropan-1-oxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1 /-/-benzimidazole and rac-2-[(4-(1 ,1- dideuterio-2,2,2-trifluoroethoxy)-3-methyl-2-pyridinyl)methylsulfinyl]-1 /-/-benzimidazole, respectively, both of which represent compounds of formula (1).
As a further example, 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride could be reacted with 5- methoxy-1/-/-imidazo[4,5-b]pyridine-2-thiol according to the procedure described under Example 33 to give 5-methoxy-2-[(4-chloro-3,5-dimethyl-2-pyridinyl)methylthio]-1 /-/-imidazo[4,5-b]pyridine. Conversion of this product with methanol-d4 following the protocol described under Example 36 would then give rise to formation of 5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H- imidazo[4,5-ϋ]pyridine, which, in turn, could be oxidized according to the procedure used in Example 38 to rac-5-methoxy-2-[(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 /-/-imidazo[4,5- b]pyridine, that is, another compound of formula (1).
Commercial utility
The compounds of the general formula 1 and their salts and solvates, preferably hydrates, and the solvates, preferably hydrates of the salts (hereinafter "compounds of the invention") 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. Here, the compounds according to the invention are distinguished by a highly selective action, an advantageous duration of action, a particularly high bioavailability, a metabolisation profile that is uniform among different individuals, the lack of significant side-effects and a wide therapeutic spectrum.
In this context, "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 pharmaceutical compositions, GERD, Crohn's disease, IBD) which may be caused, for example, by microorganisms (for example Helicobacter pylori), bacterial toxins, pharmaceutical compositions (for example certain antiphlogistics and antirheumatic drugs), chemicals (for example ethanol), gastric acid or stress.
With their excellent properties, 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 pharmacokinetic properties. These improved pharmacokinetic 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. Related with these properties are advantages concerning patient safety or economical aspects, e.g. like drug costs etc.. Owing to these properties, 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.
Accordingly, the invention furthermore provides the use of the compounds according to the invention for the treatment and/or prophylaxis of the abovementioned diseases.
The invention also embraces the use of the compounds according to 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 according to the invention. In particular, the invention provides pharmaceutical compositions for oral use in solid form, containing the compounds of formulae 1 , 1 a or 1 b in the form of their salts, in particular in the form of a sodium or magnesium salt, and/or in the form of a hydrate of such salt. The pharmaceutical compositions are prepared by processes known per se which are familiar to the person skilled in the art. As pharmaceutical compositions, 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.
The auxiliaries or carriers suitable for the desired pharmaceutical formulations are known to the person skilled in the art. In addition to solvents, gel formers, suppository bases, tabletting auxiliaries and other carriers for active compounds, it is possible to use, 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 according to the invention can be administered orally, parenterally or percutaneously.
In human medicine, it has generally been found to be advantageous to administer the compounds according to the invention, when given orally, in a daily dose of from about 0.01 to about 1, preferably about 0.02 to about 0.5 and in particular about 0.04 to about 0.3, mg/kg of body weight [calculated on the basis of the compounds according to the invention in free form, i. e. not in salt form (= "free compound"], if appropriate in the form of a plurality of, preferably 1 to 4, individual doses, to obtain the desired result. For parenteral treatment, it is possible to use similar or (in particular when the active compounds are administered intravenously) generally lower dosages. The optimum dosage and the type of administration of the active compounds required in each case can easily be determined by the person skilled in the art.
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 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 one or more 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 one or more 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 one or more 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 one or more 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 one or more 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 one or more 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.
If the compounds according to the invention are to be used for treating the abovementioned diseases, the pharmaceutical preparations may also comprise one or more pharmacologically active ingredients from other groups of pharmaceutical compositions. 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.
In this context, particular emphasis is given to the combination of the compounds according to the invention with other pharmaceuticals which buffer or neutralize gastric acid or which inhibit the secretion of acid, such as, for example, antacids (such as, for example, magaldrate) or H2 blockers (e.g., ci- metidine, ranitidine), and with gastrin antagonists with the aim to enhance the main action in an additive or superadditive sense and/or to eliminate or reduce side-effects or to obtain a more rapid onset of action. Mention may also be made of the fixed or free combination with NSAIDs (such as, for example, etofenamate, diclofenac, indometacin, ibuprofen or piroxicam) for preventing the gastrointestinal damage caused by the NSAIDs, or with compounds, which modify gastrointestinal motility, or with compounds, which reduce the incidence of transient lower esophageal sphincter relaxation (TLOSR), or with antibacterial substances (such as, for example, cephalosporins, tetracyclins, penicillins, mac- rolides, nitroimidazoles or else bismuth salt) for controlling Helicobacter pylori. 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).
In practicing the present invention, 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.
The term "combination" according to this invention 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. One example of 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.
A "kit-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. One example of 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. Pharmacology
Metabolisation in liver microsomes
Materials and methods
Pantoprazole or examples 1 or 2 (10 μM 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 NADPH2). Reaction was terminated after 90 minutes by liquid nitrogen, the parent compound was detected by HPLC (10 mM KH2PO4, pH 7.4, acetonitril gradient 20-44 %).
Tablei:
Metabolism of H-pantoprazole versus deutero-compounds (example 1, 2) with microsomes after 90 minutes incubation time (species dependent).
Figure imgf000042_0001
Metabolic clearance
In order to evaluate the properties of the compounds according to the invention the compounds' intrinsic clearances in recombinant human cytochrome P450 (CYP) isoenzymes CYP1 A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were determined.
Materials and methods
Compounds as described in examples 17, 19, 20, 21 , 27, 28, 38, 39, 40 and 41 and the non- deuterated racemic omeprazole, its (S)-enantiomer and non-deuterated pantoprazole and its enanti- omers were incubated in a buffer containing 1 nmol/mL recombinant P450 (Cypex, Dundee, UK), 4 mg/mL microsomal protein, 100 mMol/L Tris-HCI (pH 7.4) and 1 mMol/L NADPH for 0, 3, 6, 12, and 15 or 30 minutes at 37° C. Incubations were carried out in triplicate. For incubations with CYP2C19 the P450 concentration was lowered to 0.5 nmol/mL and the incubation interval changed to 0, 1 , 2, 3, 4, and 5 min. The intrinsic clearance was determined based on the rate of disappearance of parent com- pound. Omeprazole and the deuterated analogues were determined by HPLC-UV. The lower limit of assay resolution based on experimental variability was 17.6 μl/min/nmol P450.
Results
CYP2C19 and CYP3A4 were found to contribute to the oxidative metabolism of omeprazole, pantopra- zole and their deuterated analogues. All other cytochrome P450 isoenzymes (CYP1 A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any of the compounds investigated above the lower limit of assay resolution.
Formation kinetics of omeprazole 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-rr(3- methoxy-4-sulfate-2-pyridyl)-methyllsulfinyll-1H-benzimidazole
Following the evaluation of the metabolic clearance of the compounds according to the invention via P450 enzymes, the formation kinetics of the main metabolite identified in humans, i.e. 5-hydroxy- omeprazole (5-methoxy-2[[(4-methoxy-3-methyl-5-hydroxymethyl-2-pyridinyl)-methyl]sulfinyl]-1 H- benzimidazole) for omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)- methyl]sulfinyl]-1 H-benzimidazole for pantoprazole was determined. The generation of 5-hydroxy- omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1 H- benzimidazole is predominantly carried out by CYP2C19. We chose pooled human cryopreserved hepatocytes as the more advanced in vitro system compared to human liver microsomes, because all major drug metabolizing enzymes (phase I, phase II, hydrolases) are functional in this in vitro system.
Materials and methods
Compounds as described in examples 17, 19, 20, 21 , 27, 28, 38, 39, 40 and 41 and the non- deuterated racemic omeprazole, its (S)-enantiomer and non-deuterated pantoprazole and its enanti- omers were incubated in Krebs Henseleit Puffer (KHB), containing 84 μg/mL amikacin, 1 mMol/L calcium chloride, 20 mMol/L Hepes, 4.2 μMol/L hepatonic acid, 28.5 mMol/L sodium bicarbonate, and human cryopreserved hepatocytes (10 donor pool, InVitro Technologies, Baltimore, MD USA) at a concentration of 106 cells/mL. 5-hydroxy-omeprazole and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate- 2-pyridyl)-methyl]sulfinyl]-1 H-benzimidazole (M2) formation rates under these conditions were linear up to 60 min. The 5-hydroxy-omeprazole formation rate was determined at ten different compound concentrations (0, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, 100, 200 and 2500 μMol/L) incubated in duplicate for 60 min at 37° C. The 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1 H- benzimidazole (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 μMol/L) incubated in duplicate for 60 min at 37° C. 5-hydroxy- omeprazole was quantified using LC-MS/MS. 5-hydroxy-omeprazole obtained from Ramidius AB, Lund, Sweden and 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1H- benzimidazole (M2) isolated from human urine were used as an external standard. The concentration to reach the half-maximal formation rate (KM-value) and the maximal formation rate (Vmax) were obtai- ned by non-linear regression analysis using the Michaelis-Menten equation. The intrinsic clearance (Clint) was obtained dividing Vmax over KM.
Results
-Examples 39 and 40, both deuterated in the 4-methoxy-pyridinyl position exhibited formation rates that were about 1.5-fold reduced compared to non-deuterated omeprazole. There was no difference between the KM-values of racemic [1H], [2H3], and [2H6] omeprazole analogues that exceeded experimental variability (Figure 1). Reduction in the 5-hydroxy-omeprazole formation rate was observed for example 40, but was surprisingly not found for example 38 (Figure 1). Moreover, there was no difference in the formation rate between [2H3]omeprazole deuterated in the 4-methoxy-pyridinyl position (example 40) and [2H6]omeprazole additionally deuterated in the 5-methoxy-benzimidazole position (example 41 , Figure 3).The formation of 5-hydroxy-omeprazole from rac. [1H]omeprazole and its (S)-enantiomer exhibited stereospecific differences, since the difference between the KM and Vmax values of racemic and (S)-omeprazole exceeded experimental variability. The substitution of six [1H] atoms by [2H] atoms in the 4-methoxy-pyridinyl and 5-methoxy-benzimidazole position of (S)-omeprazole (example 41), did not alter the intrinsic clearance (Clιnt) of 5-hydroxy-omeprazole (Figure 3).
The formation of 5-(difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1 H- benzimidazole (M2) from pantoprazole, its enantiomers and from compounds as described in examples 17, 19, 20, 21 , 27 and 28 appeared to be inhibited by substrate concentrations above 100 μM. Therefore, the data for incubations with 100 and 250 μM substrate concentrations were excluded from the calculation of Km and Vmax. The formation of M2 from racemic [1H]pantoprazole and enantiomers exhibited stereospecific differences (Figure 2A). Racemic, (R), and (S)-analogues (examples 19, 27and 28 deuterated in the 4-methoxy-pyridyl position exhibited formation rates that were at least 2.5-fold reduced compared to their non-deuterated counterparts (Figure 2B). The intrinsic clearances of racemic, (R), and (S)-analogues deuterated in the 4-methoxy-pyridyl position (examples 19, 27 and 28) were at least 4.7-fold reduced compared to their non-deuterated counterparts (Table 2). The stereospecific differences in M2 formation rates observed for the [1H] pantoprazole analogues were less pronounced for analogues deuterated in the 4-methoxy-pyridyl position (Figure 2B). Surprisingly, the reduction in M2 formation rate as compared to the non-deuterated compounds seems to dependent on the position of the trideuteriomethoxy-group in the pyridyl moiety of the molecule (Figure 4). Increasing the number of [1H] atoms substituted by [2H] atoms in the 4-methoxy-pyridyl position of the molecule ([1H], [2H1] example 21 , [2H2] example 20, and [2H3] example 19) decreased M2 formation rates.
Table 2: Intrinsic clearance (Clιnt)) in pooled human hepatocytes obtained upon incubation with pantoprazole and compounds according to the invention.
Figure imgf000045_0001

Claims

Claims
1. Compounds of the general formula 1
Figure imgf000046_0001
in which
R1 is hydrogen or 1-4C-alkoxy
R2 is 1-4C-alkyl or 1-4C-alkoxy
R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy
R4 is hydrogen or 1-4C-alkyl
Z is C-H or N and pharmaceutical acceptable salts, solvates and solvates of the salts thereof, wherein at least one hydrogen atom of R1 , R2, R3, R4 or any combination of R1 , R2, R3 and R4 is replaced by a deuterium atom.
2. Compounds of formula 2
Figure imgf000046_0002
in which
R1 is hydrogen or 1-4C-alkoxy
R2 is 1-4C-alkyl or 1-4C-alkoxy
R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy
R4 is hydrogen or 1-4C-alkyl
Z is C-H or N thereof, wherein at least one hydrogen atom of R1 , R2, R3, R4 or any combination of R1 , R2,
R3 and R4 is replaced by a deuterium atom.
3. Compounds according to claim 1 or 2 wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom and R3 is a 1-2C alkoxy group or a 2-5C-alkoxyalkoxy group.
4. Compounds according to claim 1 or 2 wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium atoms.
5. Compounds according to claim 1 or 2 wherein R3 is methoxy, 2,2,2-trifluoroethoxy or meth- oxypropoxy and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
6. Compounds according to claim 1 or 2 wherein R1 is hydrogen, methoxy or difluoromethoxy, R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
7. (R/S)-5-Methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1H- benzimidazole and pharmaceutical acceptable salts, solvates and solvates of the salts thereof.
8. (R/S)-2-[3-Methyl-4-(1 ,1-dideuterio-2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1H- benzimidazole and pharmaceutical acceptable salts, solvates and solvates of the salts thereof.
9. (R/S)- 5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1 H- benzimidazole and pharmaceutical acceptable salts, solvates and solvates of the salts thereof.
10. (R/S)-2-{[4-(3-Trideuteriomethoxyhexadeuteriopropoxy)-3-methylpyridin-2-yl]methylsulphinyl}- 1 H-benzimidazole.
11. (R/S)-5-Methoxy-2-((4-trideuteriomethoxy-3,5-dimethyl-2-pyridylmethyl)sulphinyl)-1 H- imidazo[4,5-b]pyridine.
12. S(-)-5-Methoxy-2-[(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl)methylsulphinyl]-1 H- benzimidazole and pharmaceutical acceptable salts, solvates and solvates of the salts thereof.
13. Pharmaceutical composition comprising one or more compound according to any of claims 1 or 3 to 12 together with one or more pharmaceutically acceptable excipient.
14. Pharmaceutical composition comprising one or more compound according to any of claims 1 or 3 to 12 together with one or more pharmaceutically acceptable excipient wherein the single dose comprises from about 2 to 60 mg of the compound of general formula 1.
15. Use of a compound according to any of claims 1 or 3 to 12 for treating and/or prophylaxis gastrointestinal disorders.
16. Use of a compound according to any of claims 2 to 6 for manufacture of a compound of formula 1 as defined in any of claims 1 or 3 to 6.
17. Compounds of formula 3
Figure imgf000048_0001
in which
X is a halogen or an activated derivative of an alcohol
R2 is 1-4C-alkyl or 1-4C-alkoxy
R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy
R4 is hydrogen or 1-4C-alkyl thereof, wherein at least one hydrogen atom of R2, R3, R4 or any combination of R2, R3 and R4 is replaced by a deuterium atom.
18. Compounds according to claim 17, wherein X is a halogen selected from iodine, bromine, fluorine or chlorine.
19. Compound according to claim 17, wherein X is an activated derivate of an alcohol selected from an alkylsulfonate group, an arylsulfonate group or a perfluoroalkanesulfonate group.
20. Compound according to one of claims 17 to 19 wherein R2 is methyl or methoxy, R3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, R4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium atoms.
21. Compound according to claim 20 wherein all hydrogen atoms of R3 are replaced by deuterium atoms.
22. Use of a compound according to any of claims 17 to 21 for manufacture of a compound of formula 1 or 2 as defined in any of claims 1 to 12.
23. Use of a compound according to any of claims 1 or 3 to 12 for the manufacture of a medicament for treating and/or prophylaxis of gastrointestinal disorders.
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CN104530003A (en) * 2014-06-10 2015-04-22 广东东阳光药业有限公司 Preparation method of salt of pyridylmethylsulfinyl-1H-benzimidazole compound

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