AU2006274037A1

AU2006274037A1 - Isotopically substituted pantoprazole

Info

Publication number: AU2006274037A1
Application number: AU2006274037A
Authority: AU
Inventors: Michael David; Dieter Haag; Felix Huth; Bernhard Kohl; Bernd Mueller; Wolfgang-Alexander Simon; Oliver Von Richter; Karl Zech
Original assignee: Nycomed GmbH
Current assignee: Takeda GmbH
Priority date: 2005-07-26
Filing date: 2006-07-26
Publication date: 2007-02-01
Anticipated expiration: 2026-07-26
Also published as: CN101268050B; EP1912947A1; CA2615678C; JP5289951B2; WO2007012651A1; CN101268050A; CA2615678A1; TW200745039A; JP2009502872A; AU2006274037B2; TWI410409B; AR054583A1

Description

WO 2007/012651 PCT/EP2006/064669 Isotopically Substituted Pantoprazole Subject master of the invention The present invention relates to isotopically substituted pantoprazole and its (R)- and (S)-enantiomers. These compounds can be used in the pharmaceutical industry for preparing pharmaceutical composi tions. 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 develop ment 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]-1H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulphinyl]-1 H-benzimida zole (INN: pantoprazole), 2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulphinyl]-1 H-benzimi dazole (INN: lansoprazole), 2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulphinyl}-1 H-benz imidazole (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 hydro gen 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 con ditions, i.e. at elevated temperatures (60-80*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.

WO 2007/012651 PCT/EP2006/064669 -2 Disclosure of the invention It has now surprisingly been found that isotopically substituted compounds as disclosed in detail below influences significantly the properties of these compounds with respect to the inhibition of acid secre tion. The invention relates to compounds of the general formula 1 R2 R3 H ,C N ( ) RI N R1 N O in which R1 is difluormethoxy, R2 is methoxy, R3 is methoxy and salts, solvates, preferably hydrates and solvates of the salts, preferably hydrates of the salts thereof, wherein at least one of the hydrogen atoms of R1, R2, R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom. Possible combinations are R1 and R2, R1 and R3, R2 and R3 or R1 and R2 and R3. 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 pharma cologically compatible salts, such as, for example, the aluminium or the zinc salts. Particularly pre ferred 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 medicaments - converted into the pharma cologically 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 for mula 1. Within the meaning of solvates all pharmaceutically acceptable solvents resulting in such sol vates are included. According to the invention the term "at least one" refers to 1 to 3 hydrogen atoms of R2 or R3, which can be replaced by deuterium atoms.

WO 2007/012651 PCT/EP2006/064669 -3 Concerning the nomenclature of the compounds according to the invention the terms "deutero" or "deuterio" should indicate a deuterium atom ([ 2 H]). Similarly, the pre-terms "tri" or "tris" should indicate the occurrence of three, for example deuterio atoms in a specific group, i.e. trideuteriomethoxy. Preferred within the scope of the invention are compounds wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom. Also preferred are compounds wherein R1 is deuteriodifluoromethoxy. Examples of such compounds may be 5-difluoromethoxy-2-[(3-methoxy-4 monodeuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[(3-methoxy 4-dideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2-[3 monodeuteriomethoxy-4-methoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2 [(3-dideuteriomethoxy-4-methoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5-difluoromethoxy-2 [(3,4-bis(monodeuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole or 5-difluoromethoxy-2 [(3,4-bis(dideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole. Preferred are further compounds wherein R2, R3 or R2 and R3 is trideuteriomethoxy. More preferred is a compound wherein R3 is trideuteriomethoxy. Examples of such compounds may be 5 difluoromethoxy-2-[(3-trideuteriomethoxy-4-methoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole, 5 difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole or 5 difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole. Most preferred is a compound wherein R1 is difluoromethoxy, R2 is methoxy and R3 is dideute riomethoxy or trideuteriomethoxy. Preferred is the sodium or magnesium salt of a compound of formula 1. Preferably, the sodium salt is a monohydrate salt and, even more preferred, a sesquihydrate salt. Preferably, the magnesium salt is a trihydrate salt and, even more preferred, a dihydrate salt. The compounds according to the invention show significant improved properties with respect to the known compounds concerning the influences on secretion of gastric acid. The compounds according to the invention are chiral compounds. The invention thus relates to the racemates as well as to the enantiomers and mixtures thereof in any desired ratio. In view of the fact that, from a medicinal point of view, it may be advantageous for certain chiral compounds to be admin istered 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 gen eral formula 1a WO 2007/012651 PCT/EP2006/064669 -4 R2 R3 H S-. ".a) R1 N N in which R1, R2 and R3 have the meanings given above. A particularly preferred compound with (S)-configuration within the scope of the invention is the com pound (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound. Another particularly preferred com pound with (S)-configuration within the scope of the invention is the compound (S)-5-difluoromethoxy 2-[(3-methoxy-4-dideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound. Preferred is the sodium or magnesium salt of a compound of formula 1 a. Preferably, the sodium salt or the magnesium salt of the S-enantiomer is a trihydrate. Particularly preferred are on the other hand the compounds with (R)-configuration of the general for mula 1b R2 R3 H \ C / (1Ib) R 1 S N in which R1, R2 and R3 have the meanings given above. A particularly preferred compound with (R)-configuration within the scope of the invention is the com pound (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound. Another particularly preferred com pound with (R)-configuration within the scope of the invention is the compound (R)-5-difluoromethoxy 2-[(3-methoxy-4-dideuteriomethoxy-2-pyridylmethyl)sulphinyl]-1 H-benzimidazole and the solvates, preferably hydrates of this compound, the salts of this compound and the solvates, preferably hydrates of the salts of this compound. The separation of the compounds of formula 1 into the enantiomers can be accomplished according to various processes, for example as described in international patent application W092/08716 or by WO 2007/012651 PCT/EP2006/064669 -5 column chromatography. Alternatively, the compounds of formulae 1a and 1b can be obtained by chiral oxidation of the sulphides as described in international patent application WO 2004/052881. The salts of the compounds of formulae 1, 1a and 1b are prepared by processes known per se by re acting 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, 1 a 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, 1 a and 1b with a magnesium base, for example a magnesium alkoxide, or from a readily soluble salt of a compound of formulae 1, 1a and 1b (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 WO 2007/012651 PCT/EP2006/064669 -6 less than 1 % by weight of compounds with (S)-configuration and/or their salts, solvates or solvates of salts. According to the invention, the term "hydrogen atom replaced by a deuterium atom" has to be under stood as defining a degree of deuteration of at least 80 % for the bulk material, where all these corre spondingly 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 -OCD 3 .The remaining part up to 100% includes -OCHD 2 , OCH 2 D or -OCH 3 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. Additional subject matter of the invention are compounds of formula 2 R2 R3 H NI > S (2) RI N R1 SN in which R1, R2 and R3 have the meanings as given above and wherein at least one of the hydrogen atoms of R1, R2, R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom. Possible combinations are R1 and R2, R1 and R3, R2 and R3 or R1 and R2 and R3. The compounds of formula 2 include further their salts with acid, preferably the hydrochloride, the sulphate or the phosphate salts, and/or solvates. These compounds can be used for the manufacture of compounds of general formula 1, 1 a or 1b. The compounds of formula 2 are suitable especially as starting material for an oxidation reaction resulting in compounds according formulae 1, 1 a or 1b. Another aspect of the invention are compounds of formula 3 R2 R3 N(3) X N WO 2007/012651 PCT/EP2006/064669 -7 in which X is a halogen or an activated derivative of an alcohol and R2 and R3 have the meanings as given above and wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom. For the purpose of the invention, halogen is iodine, bromine, chlorine and fluorine. Preferably X is chlo rine. For the purpose of the invention, an activated derivate of an alcohol is an alkylsulfonate group, for example mesylate or an arylsulfonate group, for example tosylate or besylate, or a perfluoroalkanesul fonate group, for example trifluoromethanesulfonate. The compounds of formula 3 can be used for the manufacture of compounds of formula 1, 1a or 1b. Preferably the nitrogen atom of compound of formula 3 is first quaternised and then reacted with com pounds of formula 4 H N (4) R/1 SH in which R1 has the meaning as given above, thus providing compounds of formula 2 as described above. The deuterium homologes of R/S pantoprazole and S-pantoprazole can be prepared by oxidation of the corresponding thio-compounds according to methods known from literature, e.g. Kohl et al. J. Med. Chem. 1992, 35, 1049 ff. or WO 2004/052881 or by exchange of halogen for trideuteriomethoxy from the corresponding sulfoxides with a halogen (e.g. chloro, bromo or nitro) substituent at the position of the final trideuteriomethoxy group, in particular in 4-position of the pyridine group. In analogy the thiocompounds are prepared either by exchange of halogen by trideuteriomethoxy at the position of the final trideuteriomethoxy-substituent or by coupling of 5-difluoromethoxy-2 mercaptobenzimidazole with the accordingly substituted 2-chloromethyl-3-methoxy-4 trideuteriomethoxy-pyridinumchloride. The disclosed preparation routes can also be used to substitute the halogen by dideuteriomethoxy or monodeuteriomethoxy instead of trideuteriomethoxy as described above. These syntheses will lead to the correspondingly deuterated compounds. The compound of formula 1 can be prepared according to the following reaction scheme: WO 2007/012651 PCT/EP2006/064669 -8 R3 R3 R2 R2 X X : N~N+ 3H CI R3 R2 X * R2 R3 H N N HCI H I />-SH ~- N R1 N 1.KOH/EtOH R1 N>S N (8000) RIN> 4 2 R2 R3 R2 R3 H Oxidation H _N /-0/ 0N R1 N SR1 N S N 2 1 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 correspond ing 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. The novel compounds named expressly as examples, and any salts, solvates, preferably hydrates or solvates of salts, preferably hydrates of salts of these compounds, are preferred subject matter of the invention.

WO 2007/012651 PCT/EP2006/064669 -9 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 I (R/S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridiny)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 *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 min utes. The reaction mixture is concentrated in vacuo (30-40 *C) 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 *C 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 *C, 5 hours) yields the title compound (R/S)-5-difluoromethoxy 2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl]-1 H-benzimidazole as an offwhite solid of m. p. 135-136 *C (decomp.); yield 1.0 g (95 % of theoretical). 1 H-NMR (400 MHz, DMSO d-6): d = 3,78 (s, 3 H, OMe), 4,68 (d, 1H, J(CHa,CHb) = 13 Hz, S-CH2-Py), 4,73 (d, 1H, J(CHb,CHa) = 13 Hz, S-CH2-Py), 7,10 (d, 1H, J(H5',H6') = 5 Hz, H5') 7,18 (bd, 1H, H6), 7,24 (t, 1H, J(H,F) = 74 Hz, OCHF2), 7,4 (bs, 1H, H4), 7,70 (bs, 1H, H7), 8,15 (d, 1H, J(H6',H5')=5 Hz) H6'), 13,7 (s, 1H, NH).

WO 2007/012651 PCT/EP2006/064669 - 10 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 propa nol). The mixture is heated at 40 *C for one hour, resulting in the formation of a solution which is al most clear. After cooling to room temperature, N-ethyldiisopropylamine (0.07 mL) and cumene hydrop eroxide (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 satu rated 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 strength 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 *C, 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 *C filtered off. At 40-45 *C, 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 moni tored. The beige crystals are filtered off and washed with 10 mL of water. The title compound is ob tained in a yield of about 1.6 g (75 % of theory) and an optical purity of > 98 %. To increase the purity, (-) pantoprazole 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 *C (decomp.); yield 1.6 g. Example 3 5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole 2-[(4-chloro-3-methoxy-2-pyridinyl)-methylthio]-5-difluoromethoxy-1 H-benzimidazole (20 g) is added in four portions over 30 - 60 minutes at 50 - 60 *C to a solution of sodium trideuteriomethanolate (pre pared from deuteromethanol D4 (7.8 g) and sodium hydride (8.6 g, 60 % strength in paraffin) in N methyl-pyrrolidin-2-one (150 mL).

WO 2007/012651 PCT/EP2006/064669 After four hours at the stated temperature the reaction mixture is cooled to 20 - 25 *C and water (500 mL) is added over 1 - 2 hours while stirring. After adjustment to pH 7 with 2N aqueous hydrochloric acid the mixture is stirred for a further hour at 20-25 *C. The precipitate is filtered off over a suction filter, rinsed with water (200 mL) in several portions and dried (35 *C, 20 mbar, 20 hours). The dried crude product (22 g) is dissolved in toluene (250 mL) at 80-85 *C and aluminium oxide (Merck, 90 active basic; 10 g) is added. After stirring for 30 minutes at the stated temperature the mixture is filtered and the clear filtrate is concentrated in vacuo (40-50 *C) to a volume of 50 mL. By cooling to 10 *C for 2 hours a colorless precipitate separates out which is filtered off over a suction filter, rinsed with toluene (10 mL) and dried (40 *C, 20 mbar, 20 hours). 16 g (80 % of theory) of the title compound 5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2 pyridinyl)methylthio]-1 H-benzimidazole are obtained as offwhite crystalline solid of m.p. 119 - 120 *C. Alternative synthesis of example 3 2.12 g of 2-chloromethyl-3-methoxy-4-trideuteriomethoxypyridinium chloride are added to a solution of 2.08 g of 2-mercapto-5-difluoromethoxy-1 H-benzimidazole in 40 mL of ethanol and 20 mL of 1N so dium hydroxide solution, the mixture is stirred at 20 *C for 2 hours and then at 40 *C for a further hour. Ethanol is distilled off on a rotary evaporator (10 mbar/40 *C) and the colorless precipitate which thereby separates out is filtered off over a suction filter. It is rinsed with 1N sodium hydroxide solution and water and dried. After recrystallization from toluene according to example 3 the title compound is obtained as offwhite crystalline solid, yield 2.9 g; mp 118 - 120 *C. Example 4 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-trisdeuteromethoxypyridine N-oxide as a light brown powder. It was subsequently used in the following step. Preparation of 2-hydroxymethyl-3-methoxy-4-trideuteriomethoxypyridine WO 2007/012651 PCT/EP2006/064669 - 12 The product (8.1 g) from the previous step was dissolved in acetic anhydride (50 mL) and was heated at 90 *C for 2 hours. After evaporation in vacuo, the dark oily residue was agitated with 2N NaOH (20 mL) for 2 hours at 80 *C. After cooling the product was extracted into dichloromethane, dried (K 2

CO

3 ), 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 *C while stirring. The mixture was allowed to warm up to 20 *C 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, ulti mately, 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 3 and 14. Example 5 Synthesis of Sodium (S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2 pyridinyl)methylsulphinyl]-1 H-benzimidazolide} hydrate 5,0 g of (S) {[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1 H benzimidazole} are suspended in 25 ml of isobutyl methyl ketone (MIBK) and 2,5 ml of 2-propanol and heated to an internal temperature of 45*C. The suspension is stirred at this temperature for 15 min. At 45*C, 1,25 g of 40% (w/w) aqueous sodium hydroxide solution and 0,25 ml of water are slowly added dropwise to this suspension. The solution is slowly cooled to room temperature. Between 45 and 30*C crystallization, which can be accelerated by seeding, sets in. The resulting suspension is stirred at an internal temperature of < 20*C for another 18 h. The suspension is then filtered, and the crystals are washed with 2 ml of MIBK. Drying is carried out in a vacuum drying cabinet at < 50 mbar and 35*C. The title compound is achieved as white to off white crystalline solid; yield 5.9 g, 99 % of theory; the water content is between 12 to 14 % corresponding to a trihydrate; m. p.: decomposition starts at 95 *C., purity HPLC > 99.7 %, chiral HPLC > 98.0% ee; [a] 2 % = -89,0* (c = 0.5, MeOH).

WO 2007/012651 PCT/EP2006/064669 - 13 Example 6 Synthesis of Sodium (R/S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2 pyridinyl)methylsulphinyl]-1 H-benzimidazolide} hydrate 9,5 g of {[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulphinyl]-1 H benzimidazole} are suspended in 57 ml of acetone and heated to an internal temperature of 45*C. The suspension is stirred at this temperature for 15 min. At 45 *C, 2,4 g of 40% (w/w) aqueous sodium hydroxide solution is slowly added to this suspension. The solution is slowly cooled to room tempera ture. Between 30 and 25 *C crystallization, which can be accelerated by seeding, sets in. 4 ml of water is added. The resulting suspension is stirred at an internal temperature of < 20*C for 18 h. The sus pension is then filtered, and the crystals are washed with 5 ml of acetone. Drying is carried out in a vacuum drying cabinet at < 50 mbar and 40 *C. The title compound is achieved as white to off white crystalline solid; yield 8.8 g, 88 % of theory; The water content is 5,2 %, by Karl Fischer titration, corre sponding to a monohydrate; m.p.: 155 - 158*C (decomposition), purity > 99.3 % by HPLC. 1 H-NMR (200 MHz, DMSO-d6): 8= 3.78 (s, 3H), 4.34 (d, 12.9 Hz, 1H), 4.68 (d, 12.9 Hz, 1H), 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 7 Synthesis of Magnesium (S)-bis-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2 pyridinyl)methylsulphinyl]-1 H-benzimidazolide} hydrate 3,0 g of sodium (S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2 pyridinyl)methylsulphinyl]-1 H-benzimidazolide} (calculated as anhydrous substance) are suspended in 26 ml of water. The suspension is heated to 35-40*C and stirred for another 10 min. This gives a clear solution. The clear solution is cooled to 22-27*C. 1.43 g of magnesium chloride hexahydrate are dis solved in 10 ml of water, and at room temperature and with stirring, this solution is slowly added drop wise to the sodium salt solution. The resulting suspension is then stirred at room temperature for an other 18 h. The suspension is, filtered, and the product is washed twice with 10 ml of water. Drying in a vacuum drying cabinet at < 50 mbar and 40-45*C gives 2.2 g (74 %) of the title compound of m. p.: decomposition starts at 169 *C; water content 6.4 % by Karl Fischer titration, corresponding to a tri hydrate; purity >99.7 % HPLC, chiral HPLC > 99.0% ee; [a] 20 D = -122* (c = 0.5, MeOH). Example 8 Synthesis of Magnesium (R/S)-bis-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2 pyridinyl)methylsulphinyl]-1 H-benzimidazolide} hydrate WO 2007/012651 PCT/EP2006/064669 - 14 3,0 g of sodium (R/S)-{[5-(difluoromethoxy)]-2-[(3-methoxy-4-trideuteriomethoxy-2 pyridinyl)methylsulphinyl]-1 H-benzimidazolide} (calculated anhydrous substance) are suspended in 26 ml of water. The suspension is heated to 35-40*C and stirred at 35-40*C for another 10 min. This gives a clear solution. The clear solution is cooled to 22-27*C. 1.43 g of magnesium chloride hexahydrate are dissolved in 10 ml of water, and at room temperature and with stirring, this solution is slowly added dropwise to sodium salt solution. The resulting suspension is then stirred at room temperature for an other 4 h. The suspension is filtered, and the product is washed twice with 15 ml of water. Drying in a vacuum drying cabinet at < 50 mbar and 40-45*C gives 2.1 g (70 %) of the title compound of m.p. 179 181 *C (decomposition). Water content 4.7 %, by Karl Fischer titration corresponding to a dihydrate, purity: 99.5% HPLC. Example 9 4-Chloro-2-chloromethyl-3-methoxypyridinium chloride At 85-95 *C, a solution of 4-chloro-3-methoxy-2-methylpyridine-N-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 *C, the reaction mixture was concentrated until about 170 L had been distilled off. Toluene (160 L) was added and 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 *C 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 hours. 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 three times 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 *C 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

CH

2 Cl 2 (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 *C. After stirring for additional 1.5 h, about 45 L of solvents were distilled off. Toluene (20 L) was added and 20 L of solvents were again removed by distillation. Then, ethanol (1.5 L) was added to the resulting thick slurry. The solids were filtered off at 10-15 *C, washed with toluene (17 L) and dried in vacuo at 30 *C to give 4-chloro-2-chloromethyl-3-methoxypyridinium chlo ride as an off-white solid (m. p. 132 *C); yield 15.0 kg (59%). 1 H-NMR (200 MHz, CDCl 3 ): 8= 4.19 (s, 3H), 5.14 (s, 2H), 7.92 (d, 6.0 Hz, 1H), 8.59 (d, 6.0 Hz, 1H), 11.64 (br s, 1H); LC-MS: MH* = 192/194/196. Example 10 WO 2007/012651 PCT/EP2006/064669 - 15 4-Chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride Starting material, 4-chloro-2-methyl-3-trideuteriomethoxypyridine-N-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 *C 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-N-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 9 to give 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride as a colorless crystalline solid (m. p. 129-130 *C); yield 19.6 g (42%). Example 11 2-Chloromethyl-3,4-bis(trideuteriomethoxy)pyridinium chloride According to the procedure as described under Example 4 above, 4-chloro-2-methyl-3 trideuteriomethoxypyridine-N-oxide (25.3 g, 144 mmol; for preparation see Example 10) was converted into 2-methyl-3,4-bis(trideuteriomethoxy)pyridine-N-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 12 5-Difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1 H-benzimidazole At 55-65 *C, 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-difluoromethoxy-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 *C was continued for 2-3 h before the reaction mixture was cooled to 10-15 *C. 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 *C 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 *C); yield 14.2 kg (92%).

WO 2007/012651 PCT/EP2006/064669 - 16 1 H-NMR (200 MHz, DMSO-d6): 8= 3.55 (br s, NH + H 2 0), 3.92 (s, 3H), 4.79 (s, 2H), 6.97 (dd, 8.6 Hz, 2.3 Hz, 1H), 7.16 (t, 74.8 Hz, 1H), 7.28 (d, 2.2 Hz, 1H), 7.47 (d, 8.7 Hz, 1H), 7.55 (d, 5.3 Hz, 1H), 8.25 (d, 5.2 Hz, 1 H); LC-MS: MH* = 372/374. Example 13 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, Example 10) and following the procedure described under Example 12, 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 *C); yield 7.24 g (85%). 1 H-NMR (200 MHz, DMSO-d6): 5= 4.79 (s, 2H), 6.98 (dd, 8.7 Hz, 2.3 Hz, 1H), 7.16 (t, 74.8 Hz, 1H), 7.28 (d, 2.0 Hz, 1 H), 7.47 (d, 8.6 Hz, 1 H), 7.55 (d, 5.2 Hz, 1 H), 8.25 (d, 5.2 Hz, 1 H), 12.75 (br s, 1 H); LC-MS: MH* = 375/377. Example 14 Alternative process for 5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio] 1 H-benzimidazole At 15-30 *C, 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 *C, 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 *C was continued for about 10 h. The reac tion mixture was cooled to 20-30 *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 *C for 1.5 h before being chilled to 10-15 *C. 5 difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylthio]-1 H-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 *C 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]-1H-benzimidazole as an off-white solid (5.80 g, 71% recovery, m. p. = 115-116 *C).

WO 2007/012651 PCT/EP2006/064669 - 17 1 H-NMR (200 MHz, DMSO-d6): 8= 3.82 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.1 Hz, 1H), 7.08 (d, 5.6 Hz, 1H), 7.16 (t, 74.8 Hz, 1H), 7.28 (br s, 1H), 7.47 (br d, -8.3 Hz, 1H), 8.16 (d, 5.6 Hz, 1H), 12.75 (br s, 1 H); LC-MS: MH* = 371. Example 15 5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylthio]-1 H-benzimidazole Starting from 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl)methylthio]-1H-benzimidazole mono hydrate (28.6 g, 73.4 mmol) and methanol-d2 (10.0 g, 294 mmol), the procedure described under Example 14 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%). 1 H-NMR (400 MHz, DMSO-d6): 5= 3.81 (s, 3H), 3.86 (s, 1H), 4.67 (s, 2H), 6.97 (dd, 8.4 Hz, 2.0 Hz, 1H), 7.08 (d, 5.5 Hz, 1H), 7.16 (t, 74.7 Hz, 1H), 7.21-7.53 (br m, 2H), 8.16 (d, 5.5 Hz, 1H), 12.78 (br s, 1 H); LC-MS: MH* = 370. Example 16 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]-1H-benzimidazole mono hydrate (29.5 g, 75.6 mmol) and methanol-d1 (10.0 g, 303 mmol), the procedure described under Example 14 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%). 1 H-NMR (200 MHz, DMSO-d6): 8= 3.82 (s, 3H), 3.88 (s, 2H), 4.67 (s, 2H), 6.98 (dd, 8.6 Hz, 2.2 Hz, 1H), 7.08 (d, 5.6 Hz, 1H), 7.15 (t, 74.8 Hz, 1H), 7.22-7.53 (br m, 2H), 8.16 (d, 5.6 Hz, 1H), 12.79 (br s, 1 H); LC-MS: MH* = 369. Example 17 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]-1H benzimidazole mono hydrate (6.97 g, 17.7 mmol) and methanol (2.28 g, 71.2 mmol), the procedure described under Example 14 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%).

WO 2007/012651 PCT/EP2006/064669 - 18 1 H-NMR (200 MHz, DMSO-d6): 8= 3.89 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.0 Hz, 1H), 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 18 5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylthio]-1 H-benzimidazole At 50-55 *C, 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 *C was continued for 1-2 h before ethanol was removed by distillation under vacuum at 40 *C. 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 0.1M aqueous NaOH (165 mL), dried over Na 2

SO

4 , and evaporated to dryness to give 5-difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2 pyridinyl)methylthio]-1 H-benzimidazole as a brown oil; yield 23.8 g (95%). Example 19 rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole - large scale procedure At 25-35 *C, 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]-1H benzimidazole (10.4 kg, KF = 49.7%, 14.2 mol) and 40% aqueous NaOH (2.84 kg) in a mixture of wa ter (49 L) and isopropanol (49 L). Stirring at 25-35 *C was continued for 0.5-1 h before the reaction was quenched by addition of 1% aqueous Na 2

S

2

O

3 (4.3 L). Then, about 65 L of solvents were distilled off at 30-45 *C 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 *C, 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 *C, crude product was filtered off and wahed with water (7.5 L) and re-dissolved in a mixture of water (80 L), 40% aqueous NaOH (1.6 L) and Na 2

S

2

O

3 (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 *C. 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 *C including an aqueous rinse (7.5 L) and drying in vacuo at about 50 *C gave rac-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole as an off-white solid (m. p. = 134-135 *C, decomp.); yield 3.59 kg (65%).

WO 2007/012651 PCT/EP2006/064669 - 19 1 H-NMR (400 MHz, DMSO-d6): 8= 3.78 (s, 3H), 4.67 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.5 Hz, 1H), 7.18 (br d, 8.7 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.44 (br s, 1H), 7.70 (br s, 1H), 8.15 (d, 5.5 Hz, 1H), 13.73 (br s, 1H); LC-MS: MH* = 387. Example 20 rac-5-Difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole Starting from wet 5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylthio]-1H benzimidazole (32.7 g, KF = 51.6%, 42.8 mmol) and following the procedure described under Example 19, rac-5-difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H benzimidazole was obtained as an off-white solid (m. p. = 133-135 *C, decomp.); yield 10.8 g (65%). 1 H-NMR (200 MHz, DMSO-d6): 5= 3.32 (br s, NH + H 2 0), 3.77 (s, 3H), 3.86 (s, 1H), 4.65 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.5 Hz, 1H), 7.15 (dd, 8.8 Hz, 2.4 Hz, 1H), 7.23 (t, 74.4 Hz, 1H), 7.44 (d, 2.2 Hz, 1H), 7.69 (d, 8.8 Hz, 1H), 8.15 (d, 5.5 Hz, 1H); LC-MS: MH* = 386. Example 21 rac-5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteromethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole Starting from wet 5-difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylthio]-1H benzimidazole (34.8 g, KF = 50.8%, 46.5 mmol) and following the procedure described under Example 19, 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 *C, decomp.); yield 14.0 g (78%). 1 H-NMR (200 MHz, DMSO-d6): 5= 3.78 (s, 3H), 3.88 (s, 2H), 4.66 (d, 13.2 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.6 Hz, 1H), 7.16 (dd, 8.8 Hz, 2.4 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.45 (d, 2.2 Hz, 1H), 7.69 (d, 8.8 Hz, 1H), 8.15 (d, 5.5 Hz, 1H), 13.77 (br s, 1H); LC-MS: MH* = 385. Example 22 rac-5-Difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole Starting from wet 5-difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridinyl)methylthio]-1H benzimidazole (3.00 g, KF = 19.1%, 6.55 mmol) and following the procedure described under Example 23, rac-5-difluoromethoxy-2-[(4-methoxy-3-trideuteriomethoxy-2-pyridiny)methylsulfinyl]-1H- WO 2007/012651 PCT/EP2006/064669 - 20 benzimidazole was obtained, after crystallization from TBME (10 mL); as an off-white solid (m. p. = 133-134 *C, decomp.); yield 1.83 g (72%). 1 H-NMR (200 MHz, DMSO-d6): 8= 3.90 (s, 3H), 4.66 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.6 Hz, 1H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.45 (d, 2.1 Hz, 1H), 7.69 (d, 8.8 Hz, 1H), 8.15 (d, 5.5 Hz, 1H), 13.77 (br s, 1H); LC-MS: MH* = 387. Example 23 rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole 5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylthio]-1 H-benzimidazole (23.8 g, 63.7 mmol) was dissolved in CH 2 Cl 2 (210 mL) and cooled to -55 to -40 *C. At this temperature, a solu tion of 3-chloroperoxybenzoic acid (wet, 77% strength, 15.8 g, 70.5 mmol) in CH 2 Cl 2 (110 mL) was slowly added over 1.5 h. After one more h at -55 to -40 *C, triethylamine (12.3 mL, 88.5 mmol) and a 1:1 mixture of 6% aqueous Na 2

CO

3 and 2% aqueous Na 2

S

2

O

3 (140 mL) were successively added while allowing the mixture to warm to about 0 *C. Stirring was continued for 1 h at ambient tempera ture. The phases were separated, and the organic layer was washed twice with a 1:1 mixture of 6% aqueous Na 2

CO

3 and 2% aqueous Na 2

S

2

O

3 and once with water (140 mL each) before being evapo rated to dryness. After crystallization from diisopropyl ether (700 mL), rac-5-difluoromethoxy-2-[(3,4 bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole was obtained as an off-white solid; yield 20.9 g (84%). Example 24 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 6 gave rac-5 difluoromethoxy-2-[(3-methoxy-4-dideuteriomethoxy-2-pyridinyl)methysulfinyl]-1 H-benzimidazole so dium salt mono hydrate as an off-white solid (m. p. = 150-152 *C (decomp.), KF = 4.8 %); yield 6.05 g (68%). 1 H-NMR (200 MHz, DMSO-d6): 8= 3.77 (s, 3H), 3.85 (s, 1H), 4.36 (d, 12.9 Hz, 1H), 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 25 WO 2007/012651 PCT/EP2006/064669 - 21 rac-5-Difluoromethoxy-2-[(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H 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 6 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 *C (decomp.), KF = 4.1%); yield 8.95 g (79%). 1 H-NMR (200 MHz, DMSO-d6): 8= 3.78 (s, 3H), 3.88 (s, 2H), 4.34 (d, 12.9 Hz, 1H), 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 26 rac-5-Difluoromethoxy-2-[(3,4-bis(trideuteriomethoxy)-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole sodium salt mono hydrate At 15-25 *C, 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 H-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 super natant 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 *C, and the solids were filtered off, washed with diisopropyl ether (100 mL) and dried at 40 *c in vacuo to give rac-5 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%). 1 H-NMR (400 MHz, DMSO-d6): 8= 4.32 (d, 12.9 Hz, 1H), 4.70 (d, 12.9 Hz, 1H), 6.72 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.04 (t, 75.8 Hz, 1H), 7.08 (d, 5.5 Hz, 1H), 7.23 (d, 2.4 Hz, 1H), 7.44 (d, 8.6 Hz, 1H), 8.22 (d, 5.5 Hz, 1H); LC-MS: MNa* = 412, MH* = 390. Example 27 rac-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole sodium salt sesqui hydrate At 48-55 *C, 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 WO 2007/012651 PCT/EP2006/064669 - 22 (12 L) and water (0.50 L). After treatment with Hyflo Super Cel (56 g) and cooling to 18-25 *C, crystalli zation 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 *C. Centrifugation and drying at 45 *C in vacuo gave rac-5 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 *C (decomp.), KF = 6.6%); yield 2.28 kg (78%). Example 28 (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 *C 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 *C was contin ued for one more hour. After cooling to 30 *C, N-ethyldiisopropylamine (6.5 mL) and cumene hydrop eroxide (103 mL, -80% strength) were added. After stirring for about 18 h at 30 *C, 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 bicar bonate 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 ad justed 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 Cel (5.0 g), the pH of the combined aque ous phase is adjusted to about 9 by addition of 10% aqueous acetic acid at 40 - 45 *C. Once precipita tion 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 includ ing 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 *C, washed with TBME (400 mL), and dried at 30 *C in vacuo to give (S)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteromethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole as an off-white solid (m. p. 146-148 *C (decomp.); KF = 0.8%); yield 135 g (64 %). Chiral HPLC: > 98.0% ee; optical rotation: [a]o = -98* (MeOH, c = 0.50). 1 H-NMR (200 MHz, DMSO-d6): 5= 3.41 (br s, NH + H 2 0), 3.77 (s, 3H), 4.65 (d, 13.0 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.09 (d, 5.6 Hz, 1H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1H), 7.23 (t, 74.4 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.68 (d, 8.9 Hz, 1H), 8.14 (d, 5.5 Hz, 1H); LC-MS: MH* = 387.

WO 2007/012651 PCT/EP2006/064669 - 23 Example 29 (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]-1H 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 28 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 *C (decomp.); KF = 0.8%); yield 22.2 g (57 %). Chiral HPLC: > 98.0% ee; optical rotation: [a]o = +97* (MeOH, c = 0.50). 1 H-NMR (200 MHz, DMSO-d6): 8= 3.77 (s, 3H), 4.65 (d, 13.2 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 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 30 (R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole sodium salt trihydrate Starting from (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H benzimidazole (15.5 g, 40.1 mmol) and following the procedure described under Example 5, (R)-5 difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H-benzimidazole so dium salt trihydrate was obtained as a white solid (m. p. 98-103 *C (decomp.); KF = 11.3%); yield 17.4 g (94 %). Chiral HPLC: > 98.0% ee; optical rotation: [a]o = +91* (MeOH, c = 0.50). Example 31 Bis-[(R)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methysulfinyl]-1 H benzimidazole] magnesium salt trihydrate Starting from (R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1H benzimidazole sodium salt (2.30 g, KF = 11.3 %, 5.00 mmol) and following the procedure described under Example 7, bis-[(R)-5-difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2- WO 2007/012651 PCT/EP2006/064669 - 24 pyridinyl)methylsulfinyl]-1 H-benzimidazole] magnesium salt trihydrate was obtained as a white solid (m. p. 141-145 *C (decomp.); KF = 6.9%); yield 1.23 g (58 %). Chiral HPLC: > 99.0% ee; optical rotation: [a]o = +120* (MeOH, c = 0.50).

WO 2007/012651 PCT/EP2006/064669 - 25 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 phar macological 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 warm blooded 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 metabolization 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 gas trointestinal disorders, in particular gastrointestinal inflammatory disorders and lesions (such as, for example, Ulcus ventriculi, Ulcus duodeni, gastritis, irritable bowel owing to an increased production of acid or as a result of medicaments, GERD, Crohn's disease, IBD) which may be caused, for example, by microorganisms (for example Helicobacter pylori), bacterial toxins, medicaments (for example cer tain 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 metabolization properties. These improved metabolization properties allow for example a reduction of the amount of a compound according to the invention, which is needed for treatment or prophylaxis. Or by using the same amount of the com pound 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 of the invention for the treatment and/or prophylaxis of the abovementioned diseases. The invention also embraces the use of the compounds of the invention for preparing pharmaceutical compositions used for the treatment and/or prophylaxis of the abovementioned diseases. The invention also provides pharmaceutical compositions comprising the compounds of the invention. In particular, the invention provides pharmaceutical compositions containing the compounds of formu lae 1, 1a or 1b in the form of their pharmaceutically acceptable salts, in particular in the form of a so dium or magnesium salt, and/or in the form of a hydrate of such salt.

WO 2007/012651 PCT/EP2006/064669 - 26 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 of the invention can be administered orally, parenterally or percutaneously. Prefera bly, the compounds of the invention are administered orally. 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 com pound"], if appropriate in the form of a plurality of, preferably 1 to 4, individual doses, to obtain the de sired result. For parenteral treatment, it is possible to use similar or (in particular when the active com pounds 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 com pound 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 com prises from about 4 to about 40 mg of the free compound. A further aspect of the invention is the use of the compounds according to the invention for treating gastrointestinal disorders. A further aspect of the invention is the use of the compounds according to the invention for the manu facture of pharmaceutical composition for the treatment or prophylaxis of gastrointestinal disorders.

WO 2007/012651 PCT/EP2006/064669 - 27 A further aspect of the invention is a method of treating gastrointestinal disorders by administering a pharmaceutical composition comprising one or more compounds according to the invention. A further aspect of the invention is the use of the compounds according to the invention for treating gastrointestinal disorders in patients who are slow metabolizers. A further aspect of the invention is the use of the compounds according to the invention hereof for treating gastrointestinal disorders in patients who have a risk of drug interactions. A further aspect of the invention is the use of the compounds according to the invention for treating gastrointestinal disorders in patients who need an inhibition of acid secretion for an extended period of time. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk of drug interactions, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk of drug interactions, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound.

WO 2007/012651 PCT/EP2006/064669 - 28 A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising one or more compound according to the invention together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising in an oral solid application form a pharma ceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free com pound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who are slow metabolizers, comprising in an oral solid application form a pharma ceutically salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk for drug interactions, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free com pound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who have a risk for drug interactions, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hydrate thereof together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free com pound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hy drate thereof together with one or more customary auxiliaries, where the single dose comprises from about 2 to about 60 mg of free compound. A further aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who need an inhibition of acid secretion for an extended period of time, comprising in an oral solid application form a pharmaceutically acceptable salt according to the invention or a hy drate thereof together with one or more customary auxiliaries, where the single dose comprises from about 4 to about 40 mg of free compound.

WO 2007/012651 PCT/EP2006/064669 - 29 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 medicaments. Examples that may be mentioned include tranquilizers (for exam ple 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 in vention 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 H 2 blockers (e.g., ci metidine, ranitidine), and with gastrin antagonists with the aim to enhance the main action in an addi tive 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 dam age caused by the NSAIDs, or with compounds, which modify gastrointestinal motility, or with com pounds, 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 combina tion 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 amox icillin + 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 combi nation" 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 WO 2007/012651 PCT/EP2006/064669 - 30 the said first active ingredient and the said second active ingredient are present separately. The com ponents of the kit-of-parts may be administered separately, sequentially, simultaneously or chronologi cally staggered.

WO 2007/012651 PCT/EP2006/064669 - 31 Pharmacology Metabolization in liver microsomes Materials and methods Pantoprazole or examples 1 or 2 (10 pM 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 de tected by HPLC (10 mM KH 2

PO

4 , pH 7.4, acetonitril gradient 20-44 %). Table 1: Metabolization of H-pantoprazole versus deutero-compounds (example 1, 2) with microsomes after 90 minutes incubation time (species dependent). Species Percent of compound metabolized H-Pantoprazole Example 1 Example 2 Eantoprazole Pant prazole Rat 61 35 17 0,57 0,28 Dog 20 12 10 0,60 0,50 Human 28 14 15 0,50 0,54 Mouse 62 36 17 0,58 0,27 Guinee pig 78 59 54 0,75 0,69 Monkey 73 47 35 0,64 0,48 Mini Pig 26 19 19 0,73 0,73 Metabolic clearance In order to evaluate the properties of the compounds according to the invention the compounds' intrin sic clearances in recombinant human cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were determined, in comparison to the non-deuterated compounds. Materials and methods Compounds as described in examples 5, 6, 22, 24, 25 and 30 and further [ 1 H]racemic pantoprazole sodium sesquihydrate and the corresponding S- and R-enantiomers were incubated in a buffer con taining 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. The intrinsic clearance was determined based on the rate of disappear ance of parent compound. Pantoprazole and the deuterated analogues were determined by HPLC-UV. The lower limit of assay resolution based on experimental variability was 17.6 pl/min/nmol P450.

WO 2007/012651 PCT/EP2006/064669 - 32 Results CYP2C19 and CYP3A4 were found to contribute to the oxidative metabolism of pantoprazole and its deuterated analogues. All other cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any of the compounds investigated above the lower limit of assay resolution. Formation kinetics of pantoprazole M2 (5-(difluoromethoxy)-2-r[(3-methoxy-4-sulfate-2-pyridyl) methyllsulfinvll-1 H-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. M2 (5 (difluoromethoxy)-2-[[(3-methoxy-4-sulfate-2-pyridyl)-methyl]sulfinyl]-1H-benzimidazole) was deter mined. Because the generation of M2 involves the oxidation of the 4-methoxy-pyridyl group by CYP2C19 and subsequent conjugation with 3'-phosphoadenosine-5'-phosphosulfate (PAPS) by an unidentified sulphotransferase, human cryopreserved hepatocytes were used since both phase I and phase II enzymes are functional in this in vitro system. Materials and method Compounds as described in examples 5, 6, 22, 24, 25 and 30 and further racemic [ 1 H]pantoprazole sodium sesquihydrate and the corresponding S- and R-enantiomers were incubated in Krebs Henseleit Puffer (KHB), containing 84 pg/mL amikacin, 1 mMol/L calcium chloride, 20 mMol/L Hepes, 4.2 pMol/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. M2 formation rate under these conditions was linear up to 60 min. The M2 formation rate was determined at nine different compound concentrations (0, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0 and 100 pMol/L) incubated in duplicate for 60 min at 37* C. M2 was quantified using LC-MS/MS. M2 isolated from human urine was used as an external standard. The concentration to reach the half-maximal formation rate (KM-value) and the maximal formation rate (Vmax) were obtained by non-linear regression analysis using the Michaelis Menten equation. The intrinsic clearance (Clint) was obtained dividing Vmax over KM. Results The formation of M2 from pantoprazole, its enantiomers and from compounds as described in exam ples 5, 6, 22, 24, 25 and 30 appeared to be inhibited by substrate concentrations above 100 pM. Therefore, the data for incubations with 100 and 250 pM substrate concentrations were excluded from the calculation of Km and Vmx.. The formation of M2 from racemic [ 1 H]pantoprazole and enantiomers exhibited stereospecific differences (Figure 1A). Racemic, (R), and (S)-analogues (examples 6, 30 and WO 2007/012651 PCT/EP2006/064669 - 33 5) 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 1 B). The intrinsic clearances of race mic, (R), and (S)-analogues deuterated in the 4-methoxy-pyridyl position (examples 6, 30 and 5) 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 1 B). 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 2). Increasing the number of [ 1 H] atoms substituted by [ 2 H] atoms in the 4-methoxy-pyridyl position of the molecule ([ 1 H], [ 2

H

1 ] example 25, [ 2

H

2 ] example 24, and [ 2

H

3 ] example 6) decreased M2 formation rates (Figure 3). Table 2: Intrinsic clearance (Clint)) in pooled human hepatocytes obtained upon incubation with pantoprazole and compounds according to the invention. Compound Clint [p1/min/10 6 cells] % E Clint rac. pantoprazole rac. pantoprazole Na 1.5 H 2 0 27.9 100 Example 6 5.1 20 Example 22 22.0 79 Example 24 13.5 48 Example 25 17.7 63 % E Clint (R)-pantoprazole (R)-pantoprazole Na 1.5 H 2 0 25.7 100 Example 30 5.5 21 % E Clint (S)-pantoprazole (S)-pantoprazole Na 1.5 H 2 0 16.1 100 Example 5 3.4 21

Claims

1. Compounds of the general formula 1 R2 R3 H NN R1 N 0 in which R1 is difluoromethoxy R2 is methoxy R3 is methoxy and salts, solvates, preferably hydrates and solvates, preferably hydrates of the salts thereof, wherein at least one of the hydrogen atoms of R1, R2, R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom.

2. Compounds of formula 2 R2 R3 H R1 S N2 RI N in which R1 is difluoromethoxy, R2 and R3 are methoxy and salts, solvates or solvates of the salts thereof, wherein at least one of the hydrogen atoms of R1, R2, R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom.

3. Compounds according to claim 1 or 2 wherein at least one hydrogen atom of R2, R3 or R2 and R3 is replaced by a deuterium atom.

4. Compounds according to claim 1 or 2 wherein R1 is deuteriodifluoromethoxy.

5. Compounds according to claim 1 or 2 wherein R2, R3 or R2 and R3 is trideuteriomethoxy.

6. Compound according to claim 1 or 2 wherein R1 is difluoromethoxy, R2 is methoxy and R3 is trideuteriomethoxy.

7. Compounds according to claim 1 or 2 wherein R2, R3 or R2 and R3 is dideuteriomethoxy. WO 2007/012651 PCT/EP2006/064669 - 35

8. Compound according to claim 1 or 2 wherein R1 is difluoromethoxy, R2 is methoxy and R3 is dideuteriomethoxy.

9. Compound according to claim 1 or 2 wherein R1 is difluoromethoxy and wherein R2 and R3 are trideuteriomethoxy.

10. (R/S)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole and pharmaceutically acceptable salts, solvates or solvates of pharmaceutically acceptable salts thereof.

11. S(-)-5-Difluoromethoxy-2-[(3-methoxy-4-trideuteriomethoxy-2-pyridinyl)methylsulfinyl]-1 H benzimidazole and pharmaceutically acceptable salts, solvates or solvates of pharmaceutically acceptable salts thereof.

12. Pharmaceutical composition comprising one or more compound, pharmaceutically acceptable salt or solvate according to any of claims 1 or 3 to 11 together with one or more pharmaceuti cally acceptable excipients.

13. Pharmaceutical composition comprising one or more compound, pharmaceutically acceptable salt or solvate according to any of claims 1 or 3 to 11 together with one or more pharmaceuti cally acceptable excipients wherein the single dose comprises from about 2 to 60 mg of the compound of formula 1.

14. Use of a compound according to any of claims 1 or 3 to 11 for treating and/or prophylaxis of gastrointestinal disorders.

15. Use of a compound according to any of claims 2 to 9 for manufacture of a compound of formula 1 as defined in any of claims 1 or 3 to 9.

16. Compound of formula 3 R2 R3 \ / (3) X N in which X is a halogen R2 and R3 are methoxy wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deuterium atom. WO 2007/012651 PCT/EP2006/064669 - 36

17. Compounds according to claim 16, wherein X is iodine, bromine, fluorine or chlorine.

18. Compound according to claim 16, wherein X is chlorine.

19. Compound according to one of claims 16 to 18, wherein R2, R3 or R2 and R3 is trideute riomethoxy.

20. Compound according to one of claims 16 to 18, wherein R2, R3 or R2 and R3 is dideute riomethoxy.

21. Use of a compound according to any of claims 16 to 20 for manufacture of a compound of for mula 1 or 2 as defined in any of claims 1 to 9.

22. Process for the manufacture of a compound of formula 1 as defined in any of claims 1 or 3 to 9 comprising the step of oxidizing a compound of formula 2 as defined in any of claims 2 to 9.

23. Process according to claim 22, wherein the compound of formula 2 as defined in any of claims 2 to 9 is produced by a process of quaternizing a compound of formula 3 as defined in any of claims 16 to 20 and subsequent reacting the obtained quaternized compound of formula 3 with a compound of formula 4 H N (4) R/1 SH R I N wherein R1 is difluoromethoxy or deuteriodifluoromethoxy.

24. Process for the manufacture of a compound of formula 2 as defined in any of claims 2 to 7 com prising the steps of: quaternizing a compound of formula 3 as defined in any of claims 16 to 20 and subsequent reacting the obtained quaternized compound of formula 3 with a compound of for mula 4 H N (4) R/1 SH R I N wherein R1 is difluoromethoxy or deuteriodifluoromethoxy.

25. Use of a compound according to any of claims 1 or 3 to 9 for the manufacture of a medicament for treating and/or prophylaxis of gastrointestinal disorders.