JP5289951B2 - Isotopically substituted pantoprazole - Google Patents

Description

  The present invention relates to isotopically substituted pantoprazole and its (R) -enantiomer and (S) -enantiomer. These compounds can be used in the pharmaceutical industry for the production of pharmaceutical compositions.

BACKGROUND OF THE INVENTION Due to their H ⁺ / K ⁺ -ATPase inhibitory action, pyridin-2-ylmethylsulfinyl-1H-benzimidazoles such as EP-A-0005129, EP-A-0166287, EP-A- The ones known from 0174726, EP-A-0254588 and EP-A-0268958 are of considerable importance in the treatment of diseases associated with increased gastric acid secretion.

  Examples of active compounds available commercially or in pharmaceutical clinical development are 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (INN: Omeprazole), (S) -5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl-sulfinyl] -1H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy -2-[(3,4-dimethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (INN: pantoprazole), 2- [3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole (INN: lansoprazole), 2-{[4 (3-Methoxypropoxy) -3-methylpyridin-2-yl] methylsulfinyl} -1H-benzimidazole (INN: rabeprazole) and 5-methoxy-2-((4-methoxy-3,5-dimethyl-2-) Pyridylmethyl) sulfinyl) -1H-imidazo [4,5-b] pyridine (INN: tenatoprazole).

  The sulfinyl derivative is also called a proton pump inhibitor or PPI for short because of its mechanism of action.

Description of Related Art US Pat. No. 6,818,200 discloses dihydropyridine compounds and antibiotics in which at least one hydrogen atom is replaced by a deuterium atom. The deuterated compound forms the H form and a mixture of deuterium oxide and a suitable catalyst under vigorous reaction conditions in a sealed vessel, ie at an elevated temperature (60-80 ° C.). Obtained by reacting for an extended reaction time (up to 190 hours). Furthermore, several effects on the pharmacological properties of these compounds by H / D exchange are disclosed.

DISCLOSURE OF THE INVENTION Surprisingly, it has now been found that the isomer-substituted compounds disclosed in detail below have a profound effect on the properties of these compounds with respect to inhibition of acid secretion.

［式中、Ｒ１が、ジフルオロメトキシであり、Ｒ２が、メトキシであり、Ｒ３が、メトキシである］で示され、Ｒ１、Ｒ２、Ｒ３の水素原子又はＲ１、Ｒ２及びＲ３の任意の組み合わせの水素原子の少なくとも１個が、重水素原子によって交換されている化合物並びに塩、溶媒和物、有利には水和物並びにその塩の溶媒和物、有利には水和物に関する。可能な組み合わせは、Ｒ１及びＲ２、Ｒ１及びＲ３、Ｒ２及びＲ３又はＲ１及びＲ２及びＲ３である。 The present invention relates to general formula 1

[Wherein R1 is difluoromethoxy, R2 is methoxy, R3 is methoxy], a hydrogen atom of R1, R2, R3, or hydrogen of any combination of R1, R2, and R3 It relates to compounds as well as salts, solvates, preferably hydrates and solvates of the salts, preferably hydrates, in which at least one of the atoms 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 scope of the salts, all salts with inorganic and organic bases, in particular salts with alkali metals, such as lithium salts, sodium salts and potassium salts, or alkaline earth metals are included. Circles such as magnesium and calcium salts, as well as other pharmacologically compatible salts such as aluminum or zinc salts are included. Particularly preferred are sodium and magnesium salts.

  For example, the pharmacologically unacceptable salts that can be obtained initially as process products in the industrial scale production of the compounds according to the invention are also within the scope of the invention, It is converted to a pharmacologically acceptable salt by methods known to those skilled in the art.

  It is known to the person skilled in the art that the compounds according to the invention and their salts may have various amounts of solvent, for example when they are isolated in crystalline form. The invention therefore also encompasses all solvates and especially all hydrates of the compounds of the formula 1, and also all solvates and especially all hydrates of the salts of the compounds of the formula 1 . Within the meaning of solvates are included any pharmaceutically acceptable solvent that results in such solvates.

  According to the invention, the term “at least one” refers to 1 to 3 hydrogen atoms of R 2 or R 3 that can be exchanged by deuterium atoms.

With respect to the nomenclature of the compounds according to the invention, the term “deutero” or “deuterio” should include the deuterium atom ([ ² H]). Similarly, the prefix “tri” or “tris” should refer to, for example, the presence of three deuterium atoms in a particular group, ie triduteriomethoxy.

Preferred within the scope of the invention are compounds in which 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 are
5-difluoromethoxy-2-[(3-methoxy-4-monodeteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole,
5-difluoromethoxy-2-[(3-methoxy-4-dideliomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole,
5-difluoromethoxy-2- [3-monodeteriomethoxy-4-methoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole,
5-difluoromethoxy-2-[(3-dideliomethoxy-4-methoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole,
5-difluoromethoxy-2-[(3,4-bis (monodeteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole, or 5-difluoromethoxy-2-[(3,4-bis ( Diduteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole.

  Further preferred are compounds wherein R2, R3 or R2 and R3 are trideteriomethoxy. More preferred are compounds wherein R3 is trideteriomethoxy.

Examples of such compounds are
5-difluoromethoxy-2-[(3-triduteriomethoxy-4-methoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole,
5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, or 5-difluoromethoxy-2-[(3,4-bis (tri Deuteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole.

  Most preferred is a compound wherein R1 is difluoromethoxy, R2 is methoxy, and R3 is diduteriomethoxy or triduteriomethoxy.

  Preferred is the sodium or magnesium salt of the compound of formula 1. Advantageously, the sodium salt is a monohydrate salt, and more preferred is a sesquihydrate salt. Advantageously, the magnesium salt is a trihydrate salt, and even more preferred is a dihydrate salt.

  The compounds according to the invention show greatly improved properties over known compounds with regard to their effects on gastric acid secretion.

  The compounds according to the invention are chiral compounds. Accordingly, the present invention relates to racemates and enantiomers and mixtures of any desired ratio thereof. In view of the fact that, from a medical point of view, certain chiral compounds may be preferred to be administered in the form of one enantiomer or the other enantiomer, the subject of the present invention is the enantiomer of the compound of formula 1, In this case, it is preferable that each other enantiomer having the opposite configuration is substantially free.

［式中、Ｒ１、Ｒ２及びＲ３が前記の意味を有する］で示される（Ｓ）−立体配置を有する化合物が特に好ましい。 Thus, on the other hand, the general formula 1a

A compound having an (S) -configuration represented by [wherein R1, R2 and R3 have the above-mentioned meanings] is particularly preferred.

  Particularly preferred compounds having the (S) -configuration within the scope of the present invention are the compounds (S) -5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridylmethyl) sulfinyl -1H-benzimidazole and solvates, preferably hydrates of the compounds, salts of the compounds and solvates, preferably hydrates of the salts of the compounds. Another particularly preferred compound having the (S) -configuration within the scope of the present invention is the compound (S) -5-difluoromethoxy-2-[(3-methoxy-4-dideliomethoxy-2-pyridyl) Methyl) sulfinyl] -1H-benzimidazole and solvates, preferably hydrates, salts of the compounds and solvates, preferably hydrates, of the compounds.

  Preference is given to the sodium or magnesium salt of the compound of formula 1a. Advantageously, the sodium or magnesium salt of the S-enantiomer is a trihydrate.

［式中、Ｒ１、Ｒ２及びＲ３が前記の意味を有する］で示される（Ｒ）−立体配置を有する化合物が特に好ましい。 On the other hand, the general formula 1b

A compound having the (R) -configuration represented by [wherein R1, R2 and R3 have the above-mentioned meanings] is particularly preferred.

  Particularly preferred compounds having the (R) -configuration within the scope of the present invention are the compounds (R) -5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridylmethyl) sulfinyl -1H-benzimidazole and solvates, preferably hydrates of the compounds, salts of the compounds and solvates, preferably hydrates of the salts of the compounds. Another particularly preferred compound having the (R) -configuration within the scope of the present invention is the compound (R) -5-difluoromethoxy-2-[(3-methoxy-4-dideliomethoxy-2-pyridyl) Methyl) sulfinyl] -1H-benzimidazole and solvates, preferably hydrates, salts of the compounds and solvates, preferably hydrates, of the compounds.

  Resolution of the compound of formula 1 into enantiomers can be accomplished according to various methods, for example as described in international patent application WO 92/08716 or by column chromatography. Alternatively, compounds of formulas 1a and 1b can be obtained by chiral oxidation of sulfides as described in international patent application WO 2004/052881.

  The salt of the compound of formula 1, formula 1a and formula 1b is obtained by a method known per se, a compound which can be regarded as a weak acid represented by formula 1, formula 1a and formula 1b and a suitable base, for example an alkali metal hydroxide. Alternatively, it is produced by reacting an alkoxide, such as sodium hydroxide or sodium methoxide, or an alkaline earth metal alkoxide, such as magnesium methoxide. As an example, magnesium salts (other than sodium salts), which are advantageous salts of compounds of formula 1, formula 1a and formula 1b, as known per se, compounds of formula 1, formula 1a and formula 1b, magnesium base, For example, by reacting with a magnesium alkoxide or from a readily soluble salt of a compound of formula 1, formula 1a or formula 1b (for example a sodium salt) using magnesium salt, water or water and a polar organic solvent (for example an alcohol, preferably Is prepared in a mixture with methanol, ethanol or isopropanol or ketone, preferably acetone).

  According to the present invention, "a compound having (S) -configuration" is understood to include "a compound having (S) -configuration substantially free of a compound having (R) -configuration". The

  In the context of the present invention, “substantially free” means that the compound having the (S) -configuration and / or a salt, solvate or solvate of the salt thereof has the (R) -configuration. And / or a salt thereof, a solvate thereof or a solvate of the salt thereof in an amount of less than 10% by mass. Advantageously, “substantially free” means that the compound having the (S) -configuration and / or their salts, solvates or solvates of the salts have the (R) -configuration. It means that the compound and / or salt, solvate or solvate of the salt thereof is contained in an amount of less than 5% by mass. More preferably, “substantially free” means that the compound having the (S) -configuration and / or a salt, solvate or solvate of the salt thereof has the (R) -configuration. It means that it contains less than 2% by mass of the compound and / or salt, solvate or solvate of the salt thereof. In a most preferred embodiment, “substantially free” means that the compound having the (S) -configuration and / or salt, solvate or solvate of the salt thereof has the (R) -configuration. And / or their salts, solvates or solvates of the salts thereof in an amount of less than 1% by mass.

  According to the present invention, “a compound having (R) -configuration” is understood to include “a compound having (R) -configuration substantially free of a compound having (S) -configuration”. The

  In the context of the present invention, “substantially free” means that the compound having the (R) -configuration and / or a salt, solvate or solvate of the salt thereof has the (S) -configuration. And / or a salt thereof, a solvate thereof or a solvate of the salt thereof in an amount of less than 10% by mass. Advantageously, “substantially free” means that the compound having the (R) -configuration and / or their salts, solvates or solvates of the salts have the (S) -configuration. It means that the compound and / or salt, solvate or solvate of the salt thereof is contained in an amount of less than 5% by mass. More preferably, “substantially free” means that the compound having the (R) -configuration and / or a salt, solvate or solvate of the salt thereof has the (S) -configuration. It means that it contains less than 2% by mass of the compound and / or salt, solvate or solvate of the salt thereof. In a most preferred embodiment, “substantially free” means that the compound having the (R) -configuration and / or a salt, solvate or solvate of the salt thereof has the (S) -configuration And / or their salts, solvates or solvates of the salts thereof in an amount of less than 1% by mass.

According to the invention, the term “hydrogen atoms exchanged by deuterium atoms” defines a degree of deuteration of at least 80% for the bulk material, with all these correspondingly raised. Hydrogen atoms should be understood as being exchanged by deuterium atoms. For example, when the substituent R 2 or R 3 refers to a methoxy group having all three “hydrogen atoms exchanged by deuterium atoms”, according to the above definition, all R 2 or R 3 in the bulk material It should be understood that at least 80% of the methoxy groups of are -OCD ₃ . Part up remaining 100%, including -OCHD _2, -OCH ₂ D or -OCH _3.

  Preferred is a degree of deuteration of at least 90% for a particular hydrogen atom in the bulk material, which means that at least 90% of the exchanged hydrogen atoms should be deuterium atoms. More preferred is a degree of deuteration of at least 92% for a particular hydrogen atom in the bulk material. Even more preferred is a degree of deuteration of at least 94% for a particular hydrogen atom in the bulk material, and most preferred a degree of deuteration of at least 96% for a particular hydrogen atom in the bulk material. It is.

［式中、Ｒ１、Ｒ２及びＲ３は、前記の意味を有し、かつＲ１、Ｒ２、Ｒ３の水素原子又はＲ１、Ｒ２及びＲ３の任意の組合せの水素原子の少なくとも１個が重水素原子によって交換されている］で示される化合物である。可能な組み合わせは、Ｒ１及びＲ２、Ｒ１及びＲ３、Ｒ２及びＲ３又はＲ１及びＲ２及びＲ３である。式２の化合物は、更に、その酸との塩、有利には塩酸塩、硫酸塩又はリン酸塩及び／又は溶媒和物である。これらの化合物は、一般式１、１ａ又は１ｂの化合物の製造のために使用することができる。式２の化合物は、式１、１ａ又は１ｂによる化合物をもたらす酸化反応のための出発材料として特に適している。 An additional inventive subject matter of the present invention is the formula 2

[Wherein R1, R2 and R3 have the above-mentioned meanings, and at least one of the hydrogen atoms of R1, R2 and R3 or any combination of R1, R2 and R3 is replaced by a deuterium atom. It is a compound shown by. Possible combinations are R1 and R2, R1 and R3, R2 and R3 or R1 and R2 and R3. The compound of formula 2 is furthermore a salt with its acid, preferably the hydrochloride, sulfate or phosphate and / or solvate. These compounds can be used for the preparation of compounds of general formula 1, 1a or 1b. The compounds of formula 2 are particularly suitable as starting materials for oxidation reactions that lead to compounds according to formula 1, 1a or 1b.

［式中、Ｘは、ハロゲン又はアルコールの活性化誘導体であり、かつＲ２及びＲ３は、前記の意味を有し、かつＲ２、Ｒ３又はＲ２及びＲ３の水素原子の少なくとも１個は重水素原子によって交換されている］で示される化合物である。 Another embodiment of the invention is a compound of formula 3

[Wherein X is an activated derivative of halogen or alcohol, and R2 and R3 have the above meaning, and at least one of the hydrogen atoms of R2, R3 or R2 and R3 is deuterium atom. It has been exchanged].

  For the purposes of the present invention, halogen is iodine, bromine, chlorine and fluorine. Preferably X is chlorine. For the purposes of the present invention, activated derivatives of alcohols are alkyl sulfonate groups such as mesylate groups or aryl sulfonate groups such as tosylate groups or besylate groups, or perfluoroalkane sulfonate groups such as trifluoromethane sulfonate.

［式中、Ｒ１は、前記の意味を有する］で示される化合物と反応させて、前記の式２の化合物が提供される。 Compounds of formula 3 can be used for the preparation of compounds of formula 1, 1a or 1b. Advantageously, the nitrogen atom of formula 3 is first quaternized, then the formula 4

[Wherein R1 has the above-mentioned meaning] is reacted with a compound represented by the above formula 2.

  R / S-pantoprazole and deuterium analogues of S-pantoprazole have been described in the literature, for example, J. Kohl et al. Med. Chem. 1992, 35, 1049ff or according to the methods known from WO 2004/052881 by oxidation of the corresponding thio compound or the corresponding sulfoxide, halogenated at the position of the last triduteriomethoxy group, in particular at the 4-position of the pyridine group Prepared from those with substituents (eg chloro, bromo or nitro) by halogen exchange for trideteriomethoxy.

  Similarly, a thio compound is correspondingly substituted by substitution of halogen with trideteriomethoxy at the position of the last trideteriomethoxy substituent or with 5-difluoromethoxy-2-mercaptobenzimidazole. Prepared either by coupling with chloromethyl-3-methoxy-4-triduteriomethoxy-pyridinium chloride. The disclosed production route can also be used to replace halogens by diduteriomethoxy or monodeteriomethoxy instead of trideteriomethoxy as described above. These syntheses result in correspondingly deuterated compounds.

Compounds of formula 1 can be prepared according to the following reaction scheme:

  Salts of sulfoxides and inorganic bases are prepared by reacting sulfoxides with the corresponding hydroxides or alkoxides in organic solvents or mixtures of organic solvents and water according to methods known from the literature.

  Optionally, the salt can be obtained by reacting a sulfoxide with an alkali hydroxide to obtain the corresponding alkali salt (Na, K, Li) and further reacting with, for example, a magnesium, calcium, aluminum, zinc salt. Manufactured.

  The following examples serve to illustrate the invention in more detail without limiting it. The novel compounds described by way of example as well as any salts, solvates, preferably hydrates or solvates of salts of these compounds, preferably hydrates of the salts of these compounds, Preferred invention subject.

Examples As a triduterio methoxylating agent, methanol-D4 having> 99.8 atomic% D was used. The isomeric purity of the triduteriomethoxy substituent in all resulting products was> 98.0% as measured by NMR and MS. As further deuterating agents, methanol-d2 with> 98.0 atomic% D and methanol-d1 with> 98.0 atomic% D were used. The isomeric purity of the diduteriomethoxy and monodeteriomethoxy substituents in the resulting product was> 96.0% as measured by NMR and MS.

Example 1
(R / S) -5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole solution of sodium hypochlorite (10% concentration) (3.3 mmol) was added over 5-1-2 hours over 5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (1.0 g, 2.7 mmol) in a slurry of water (20 mL), 2-propanol (10 mL) and sodium hydroxide (0.5 mL 40% strength solution, 7.1 mmol) stirred at 30-35 ° C. While adding. After 30-60 minutes at the indicated temperature, sodium thiosulfate (0.3 g dissolved in 5 mL of water) is added and stirring is continued for an additional 15-30 minutes.

  The reaction mixture is concentrated in vacuo (30-40 ° C.), brought to about one third of the original volume and water (about 70 mL) is added.

  After extraction of the aqueous phase with dichloromethane (2 × 10 mL each), dichloromethane (50 mL) is added again and the pH is adjusted to 7-8 by adding aqueous potassium dihydrogen phosphate with stirring. The crude title compound was obtained by phase separation, further extracting the aqueous phase once with dichloromethane (20 mL), washing the combined organic phases with water (20 mL), drying over magnesium sulfate, and filtering the desiccant. Solution is obtained.

  Petroleum ether (50/70; 150 mL) is added and concentrated in a rotary evaporator at 30-40 ° C. in vacuo to a volume of about 30 mL, followed by filtration of the precipitated solid and petroleum ether (50/70). 70; 20 mL) and dried in vacuo (35 ° C., 5 hours) to give the title compound, (R / S) -5-difluoromethoxy-2-[(3-methoxy-4-triduterio Methoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole is obtained as an off-white solid (melting point 135-136 ° C. (decomposition); yield 1.0 g (95% of theory)).

Example 2
(S) (−)-5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole 2.0 g of 5-difluoromethoxy at room temperature 2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole in (+)-L-tartaric acid bis (N-pyrrolidinamide) in 20 mL of methyl isobutyl ketone ) (2.3 g) and zirconium (IV) n-propoxide (1.0 g, 70% in propanol). The mixture is heated at 40 ° C. for 1 hour to form an almost clear solution. 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 oxidation is complete (10-24 hours, monitored by TLC). The clear solution is diluted with 10 ml methyl isobutyl ketone and quenched with 0.08 g sodium thiosulfate in 14 mL saturated sodium bicarbonate solution and stirred for another 2 hours. After phase separation, the mixture is washed twice with 5 ml of saturated sodium bicarbonate solution. 15 mL of water is added to the methyl isobutyl ketone phase and the pH is adjusted to pH = 13 using a 40% strength by weight aqueous solution of sodium hydroxide. After phase separation, the methyl isobutyl ketone phase is extracted with an additional 5 ml of water at pH 13. The aqueous phases are combined and initial distillation is performed at 40 ° C. under reduced pressure. Add Hyflo Super Cell (0.05 g) as filter aid and stir at 20-25 ° C. for 1 hour before filtering off. At 40-45 ° C., the crude title compound is precipitated by adding 10% strength acetic acid to the filtrate to pH = 9.0. The mixture is stirred for a further 12 hours while monitoring the pH. 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 optical purity> 98%.

  To increase purity, (−)-pantoprazole is dissolved in water / aqueous sodium hydroxide solution at pH = 13 and reprecipitated with acetic acid (10%) at pH = 9.0.

  Recrystallization from dichloromethane / t-butyl methyl ether gave the title compound, S (−)-5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole is obtained as an off-white solid (mp 146-148 ° C (decomposition); yield 1.6 g).

Example 3
5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole 2-[(4-chloro-3-methoxy-2-pyridinyl) methylthio]- Hydrogenation of 5-difluoromethoxy-1H-benzimidazole (20 g) in four portions at 50-60 ° C. over 30-60 minutes at 50 ° C. with sodium trideuterio methanolate (deuteromethanol D4 (7.8 g) Sodium (made from 8.6 g, 60% strength in paraffin)) is added to a solution in N-methylpyrrolidin-2-one (150 mL).

  After 4 hours at the indicated temperature, the reaction mixture is cooled to 20-25 ° C. and water (500 mL) is added over 1-2 hours with stirring. After adjusting to pH 7 with 2N aqueous hydrochloric acid, the mixture is stirred for an additional hour at 20-25 ° C.

  The precipitate is filtered off through 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 aluminum oxide (Merck, 90 active form; 10 g) is added. After stirring for 30 minutes at the specified 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. over 2 hours, a colorless precipitate separated out, which was filtered off through 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-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole, turned off white crystals Obtained as a crystalline solid (melting point: 119-120 ° C.).

Alternative Synthesis of Example 3 2.12 g 2-chloromethyl-3-m ethoxy-4-triduteriomethoxypyridinium chloride, 2.08 g 2-mercapto-5-difluoromethoxy-1H-benzimidazole Add to a solution dissolved in 40 mL of ethanol and 20 mL of 1N sodium hydroxide solution and stir the mixture at 20 ° C. for 2 hours and then at 40 ° C. for an additional hour. The ethanol is distilled off on a rotary evaporator (10 mbar / 40 ° C.) and the colorless precipitate thereby separated off is filtered off through 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 an off-white crystalline solid (yield 2.9 g; mp 118-120 ° C.).

Example 4
Synthesis of starting material, 2-chloromethyl-3-methoxy-4-triduteriomethoxypyridinium chloride Preparation of 3-methoxy-2-methyl-4-triduteriomethoxypyridine N-oxide 4-Chloro-3-methoxy- 2-Methylpyridine N-oxide (10 g) and sodium trideuterio methanolate (6.2 g) in deuteromethanol 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 insoluble material was filtered off. By adding diisopropyl ether to the filtrate, a solid precipitated and after it was dried in vacuo, 8.1 g of 3-methoxy-2-methyl-4-triduteromethoxypyridine N-oxide was diluted lightly. Obtained as a brown powder. It was subsequently used in the subsequent step.

Preparation of 2-hydroxymethyl-3-methoxy-4-triduteriomethoxypyridine The product from the previous step (8.1 g) was dissolved in acetic anhydride (50 mL) and heated at 90 ° C. for 2 hours. After evaporation in vacuo, the dark oily residue was stirred with 2N NaOH (20 mL) at 80 ° C. for 2 hours. After cooling, the product was reduced in volume by extraction in dichloromethane, drying (K ₂ CO ₃ ) and concentrating in vacuo. After addition of petroleum ether (50/70), after filtration and drying in vacuo, 2-hydroxy-3-methoxy-4-triduteriomethoxypyridine as a light brown solid (5.5 g) Obtained and used in the subsequent step.

Preparation of 2-chloromethyl-3-methoxy-4-triduteriomethoxypyridinium chloride The product from the previous step (5.5 g) was dissolved in anhydrous dichloromethane (40 mL) and thionyl chloride (3 mL) was added. Add dropwise at 5-10 ° C. with stirring. The mixture was allowed to warm to 20 ° C. and after 3 hours concentrated to dryness in vacuo.

  Toluene (20 mL) was added to give 6.6 g of the title compound, 2-chloromethyl-3-methoxy-4-triduteriomethoxypyridinium chloride, as a light brown solid.

  The material synthesized as described above contained some difficult impurities to remove. They have tended to lead to compounds of general formula (2) and ultimately to compounds of general formula (1) throughout the subsequent steps. For the preparation of compounds of general formula (1) with exceptionally high purity, it is therefore often preferred to carry out the deuterioalkoxylation characterized in Examples 3 and 14.

Example 5
Sodium (S)-{[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazolide} Synthesis of Hydrate 5 0.0 g of (S)-{[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole} Suspend in methyl ketone (MIBK) and 2.5 ml of 2-propanol and heat to an internal temperature of 45 ° C. The suspension is stirred for 15 minutes at the temperature. At 45 ° C., 1.25 g of 40% (w / w) aqueous sodium hydroxide and 0.25 ml of water are slowly added dropwise to the suspension. Cool the solution slowly to room temperature. Between 45-30 ° C., crystallization begins and can be promoted by sowing. The resulting suspension is stirred at an internal temperature of <20 ° C. for a further 18 hours. The suspension is then filtered and the crystals are washed with 2 ml MIBK. Drying takes place in a vacuum drying shelf at <50 mbar and 35 ° C. The title compound is obtained as a white to off-white crystalline solid; yield 5.9 g, 99% of theory; water content 12-14%, corresponding to trihydrate; melting point: 95 Decomposition started at ° C, purity HPLC> 99.7%, chiral HPLC> 98.0% ee; [α] ²⁰ _D = −89.0 ° (c = 0.5, MeOH).

Example 6
Sodium (R / S)-{[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazolide} Synthesis 9.5 g of {[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole} in 57 ml acetone. Suspend and heat to an internal temperature of 45 ° C. The suspension is stirred for 15 minutes at the temperature. At 45 ° C., 2.4 g of 40% (w / w) aqueous sodium hydroxide is slowly added to the suspension. Cool the solution slowly to room temperature. Between 30-25 ° C., crystallization begins, which can be promoted by sowing. Add 4 ml of water. The resulting suspension is stirred at an internal temperature of <20 ° C. for 18 hours. The suspension is then filtered and the crystals are washed with 5 ml of acetone. Drying takes place in a vacuum drying shelf at <50 mbar and 40 ° C. The title compound is obtained as a white to off-white solid; yield 8.8 g, 88% of theory; the moisture content is 5.2% by Karl Fischer titration, which corresponds to a monohydrate Melting point: 155-158 ° C. (decomposition), purity> 99.3% by HPLC.

Example 7
Magnesium (S) -bis {[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazolide} Synthesis of Hydrate 3.0 g of sodium (S)-{[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazolide} (anhydrous Is suspended in 26 ml of water. The suspension is heated to 35-40 ° C. and stirred for an additional 10 minutes. This gives a clear solution. The clear solution is cooled to 22-27 ° C. 1.43 g of magnesium chloride hexahydrate is dissolved in 10 ml of water and this solution is slowly added dropwise to the sodium salt solution at room temperature and with stirring. The resulting suspension is then stirred at room temperature for a further 18 hours. The suspension is filtered and the product is washed twice with 10 ml of water. Drying at <50 mbar and 40-45 ° C. in a vacuum drying cabinet yields 2.2 g (74%) of the title compound (melting point: 169 ° C. onset of decomposition; 4%, corresponding to trihydrate; purity> 99.7% HPLC, chiral HPLC> 99.0% ee; [α] ²⁰ _D = −122 ° (c = 0.5, MeOH).

Example 8
Magnesium (R / S) -bis {[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazolide} hydrate Synthesis of 3.0 g sodium (R / S)-{[5- (difluoromethoxy)]-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazo Lido} (calculated as anhydrous material) is suspended in 26 ml of water. The suspension is heated to 35-40 ° C. and stirred at 35-40 ° C. for an additional 10 minutes. This gives a clear solution. The clear solution is cooled to 22-27 ° C. 1.43 g of magnesium chloride hexahydrate is dissolved in 10 ml of water and this solution is slowly added dropwise to the sodium salt solution at room temperature and with stirring. The resulting suspension is then stirred for a further 4 hours at room temperature. 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 (melting point: 179-181 ° C. (decomposition)). Moisture content by Karl Fischer titration 4.7%, corresponding to dihydrate, purity: 99.5% HPLC.

Example 9
4-Chloro-2-chloromethyl-3-methoxypyridinium chloride At 85-95 ° C., 4-chloro-3-methoxy-2-methylpyridine-N-oxide (19.2 kg, 111 mol) in toluene (148 L). The solution dissolved in was added to acetic anhydride (71 L) over 5-7 hours. Under vacuum at about 60 ° C., the reaction mixture was concentrated until about 170 L was distilled off. Toluene (160 L) was added and the solvent was distilled off (160 L). This last task was repeated once more. Toluene (14 L) and 40% aqueous NaOH (14.6 L) were then added at 35-45 ° C. and the reaction mixture was held at the temperature for 2-3 hours. If the pH was less than 13 at this point, more NaOH was added and heating continued for more than 2 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 × 13 L). . Finally, the combined organic phases were washed with saturated aqueous sodium bicarbonate (13 L) and concentrated under vacuum at 50-65 ° C. until about 115 L was distilled off. After diluting with toluene (100 L), another 100 L of solvent was distilled off.

The resulting solution of 4-chloro-2-hydroxymethyl-3-methoxypyridine (˜30% concentration) was diluted with CH ₂ Cl ₂ (48 L). DMF (65.5 g, 0.896 mol) was added in one portion, followed by thionyl chloride (11.1 kg, 93.2 mol) at 15-30 ° C. over 3-5 hours. After further stirring for 1.5 hours, about 45 L of solvent was distilled off. Toluene (20 L) was added and again 20 L of solvent was removed by distillation. Ethanol (1.5 L) was then added to the resulting thick slurry. The solid was 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 chloride off-white. Obtained as a solid (melting point 132 ° C .; yield 15.0 kg (59%)).

Example 10
4-Chloro-2-chloromethyl-3-triduteriomethoxypyridinium chloride The starting material, 4-chloro-2-methyl-3-triduteriomethoxypyridine-N-oxide, is prepared according to J. Am. Med. Chem. Prepared according to Method D for the non-deuterated analog in 1992, 35, 1049-1057:
Starting with 3-hydroxy-2-methyl-4-pyrone, conversion with trideuterioiodomethane in the presence of potassium carbonate in DMF yields 2-methyl-3-trideteriomethoxy-4 Pyrone (yield: 83-96%) is obtained, which is heated in ethanol at 150 ° C. with ammonia and then crystallized from acetone / isopropanol 4: 1 before 4-hydroxy-2- Methyl-triduteriomethoxypyridine (yield: 52-60%) was obtained. Treatment of this material with phosphorus oxychloride resulted in the formation of 4-chloro-2-methyl-triduteriomethoxypyridine (yield: 64-81%). Subsequently, 4-chloro-2-methyl-3-triduteriomethoxypyridine-N-oxide was oxidized with hydrogen peroxide in acetic acid to give a slightly yellow solid (yield: 87-89%). ) Was obtained. The final transformation via 4-chloro-2-hydroxymethyl-3-triduteriomethoxypyridine was performed as described in Example 9 to give 4-chloro-2-chloromethyl-3-trimethyl. Deuteriomethoxypyridinium chloride was obtained as a colorless crystalline solid (mp 129-130 ° C .; yield 19.6 g (42%)).

Example 11
2-Chloromethyl-3,4-bis (triduteriomethoxy) pyridinium chloride According to the method described in Example 4 above, 4-chloro-2-methyl-3-triduteriomethoxypyridine-N-oxide ( 25.3 g, 144 mmol; see Example 10 for preparation) to convert 2-methyl-3,4-bis (triduteriomethoxy) pyridine-N-oxide (yield: 23.5 g, 96%) from which 2-hydroxymethyl-3,4-bis (trideteriomethoxy) pyridine (yield: 13.0 g, 56%) and finally 2-chloromethyl- 3,4-Bis (triduteriomethoxy) pyridinium chloride (yield: 15.4 g, 89%) was obtained as an off-white crystalline solid.

Example 12
5-Difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzimidazole at 55-65 ° C., 4-chloro-2-chloromethyl-3-methoxypyridinium chloride (10 Solution of 0.0 kg, 43.8 mol) in water (20 L) was added over a period of 2-3 hours over 5-difluoromethoxy-1H-benzimidazole-2-thiol (8.84 kg, 40.9 mol) To a mixture of toluene (43 L), water (21 L) and 40% aqueous NaOH (10.3 kg, 103 mol) was added. Stirring at 60 ° C was continued for 2-3 hours before the reaction mixture was cooled to 10-15 ° C. The precipitate was centrifuged, washed with toluene (16 L) and redissolved in water (122 L). Following centrifugation, washing with water (32 L) and drying in vacuo at 35 ° C., 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H Benzimidazole monohydrate (KF = 4.6%) was obtained as an off-white solid (melting point 95-99 ° C .; yield 14.2 kg (92%)).

Example 13
5-Difluoromethoxy-2-[(4-chloro-3-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole 4-chloro-2-chloromethyl-3-triduteriomethoxypyridinium chloride (5 5-difluoromethoxy-2-[(4-chloro-3-triduteriomethoxy-2-pyridinyl) according to the method described in Example 12, starting from 0.000 g, 21.6 mmol, Example 10). ) Methylthio] -1H-benzimidazole monohydrate (KF = 4.7%) was obtained as an off-white solid (mp 94-99 ° C .; yield 7.24 g (85%)).

Example 14
Alternative Method for 5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole At 15-30 ° C., methanol-d4 (2.26 kg) 62.7 mol) was added over 30-60 minutes to the mixture of sodium t-butoxide (6.00 kg, 62.4 mol) in DMAc (27 L). After heating to 57-65 ° C., 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (6.08 kg, 15.6 mol) ) In DMAc (10 L) was added over 30-60 minutes. Stirring at 57-65 ° C was continued for about 10 hours. The reaction mixture was cooled to 20-30 ° C. and diluted with water (21 L) before adjusting the pH to 7-8 with 20% aqueous HCl (˜7.5 L). Product precipitation was achieved by adding water (75 h) over about 4 hours. The resulting slurry was heated to 35-45 ° C. over 1.5 hours and then cooled to 10-15 ° C. 5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was rinsed with water as a brownish solid (58 L), Obtained by centrifugation with redissolution in water (78 L) and again with further water rinse (58 L) (yield 10.4 kg, KF = 49.7% (91%)).

  A sample of the wet product (16.2 g, KF = 49.7%) was dried in vacuo at 25 ° C. to give an amorphous solid, which was crystallized from toluene (30 mL) Anhydrous 5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was obtained as an off-white solid (5.80 g, 71% recovery, melting point) ˜115-116 ° C.).

Example 15
5-difluoromethoxy-2-[(3-methoxy-4-dideliomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2- Starting from pyridinyl) methylthio] -1H-benzimidazole monohydrate (28.6 g, 73.4 mmol) and methanol-d2 (10.0 g, 294 mmol), the method described in Example 14 was followed. In doing so, 5-difluoromethoxy-2-[(3-methoxy-4-dideliomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was converted to a watery brownish solid (yield 46.4 g, KF = 51.6% (82%)).

Example 16
5-difluoromethoxy-2-[(3-methoxy-4-monodeteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole 5-difluoromethoxy-2-[(4-chloro-3-methoxy-2- Starting from pyridinyl) methylthio] -1H-benzimidazole monohydrate (29.5 g, 75.6 mmol) and methanol-d1 (10.0 g, 303 mmol), the method described in Example 14 was followed. In doing so, 5-difluoromethoxy-2-[(3-methoxy-4-monodeteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was converted into a watery brownish solid (yield 50.3 g, KF = 50.8% (89%)).

Example 17
5-difluoromethoxy-2-[(4-methoxy-3-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole 5-difluoromethoxy-2-[(4-chloro-3-triduteriomethoxy 2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (6.97 g, 17.7 mmol) and methanol (2.28 g, 71.2 mmol) and subsequently described in Example 14. Thus, 5-difluoromethoxy-2-[(4-methoxy-3-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was converted into a watery brownish solid (yield 7 0.01 g, KF = 19.1% (87%)).

Example 18
5-Difluoromethoxy-2-[(3,4-bis (triduteriomethoxy) -2-pyridinyl) methylthio] -1H-benzimidazole 2-chloromethyl-3,4-bis (tri Deuteriomethoxy) pyridinium chloride (15.4 g, 66.8 mmol) was added over 30 minutes to 5-difluoromethoxy-1H-benzimidazol-2-thiol (14.5 g, 66.8 mmol), ethanol (133 mL). And was added in portions to a mixture of 2M aqueous NaOH (73.5 mL, 147 mmol). Stirring at 50-55 ° C. was continued for 1-2 hours before ethanol was removed by distillation at 40 ° C. under vacuum. The remaining aqueous emulsion was diluted with water (50 mL) and extracted three times with dichloromethane (165 mL portions). The combined organic phases were washed with 0.1 M aqueous NaOH (165 mL), dried over Na ₂ SO ₄ and evaporated to dryness to give 5-difluoromethoxy-2-[(3,4-bis ( Triduteriomethoxy) -2-pyridinyl) methylthio] -1H-benzimidazole was obtained as a brown oil (yield 23.8 g (95%)).

Example 19
rac-5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole-large scale method 25-35 ° C, aqueous sodium hypochlorite (10.5 kg, 10.2 mol at 10% concentration) over 5-4 hours over 5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H A solution of 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). Added. Stirring at 25-35 ° C. was continued for 0.5-1 h before the reaction was quenched by the addition of 1% aqueous Na ₂ S ₂ O ₃ (4.3 L). Then about 65 L of solvent was distilled off under vacuum at 30-45 ° C. After dilution with water (55 L), a further portion of solvent (8-10 L) was removed by distillation. While maintaining the reaction mixture at 40-45 ° C., 10% aqueous acetic acid (˜13 L) was added over 1.5 hours to pH 8.5-9.5. Once crystallization started, the pH was slowly adjusted to 6.8-7.2 by adding more 10% aqueous acetic acid (˜0.6 L). After cooling to 20-25 ° C., the crude product is filtered off and washed with water (7.5 L) and water (80 L), 40% aqueous NaOH (1.6 L) and Na ₂ S ₂ O ₃ Redissolved in a (60 g) mixture. The resulting slightly turbid aqueous solution was washed twice with MIBK (12 L each) and clarified by Hyflo treatment (0.40 kg) before the pH was adjusted by addition of 10% aqueous acetic acid (˜8 L). It adjusted to 9.0-9.5 at 40-45 degreeC. Once the product began to crystallize, an additional 10% acetic acid was added to continuously maintain a pH of 9.0-9.5. Finally, rac-5-difluoromethoxy-2-[(3-methoxy-4-trimethyl) is obtained by centrifuging, including rinsing with water (7.5 L) and drying at about 50 ° C. in vacuo. Deuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole was obtained as an off-white solid (melting point = 134-135 ° C. (decomposition); yield 3.59 kg (65%)).

Example 20
rac-5-Difluoromethoxy-2-[(3-methoxy-4-dideliomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole wet 5-difluoromethoxy-2-[(3-methoxy-4 -Diduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (32.7 g, KF = 51.6%, 42.8 mmol) and by carrying out the method described in Example 19. Rac-5-difluoromethoxy-2-[(3-methoxy-4-didetriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole is an off-white solid (melting point = 133-135 ° C. ( Decomposition); yield 10.8 g (65%)).

Example 21
rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole wet 5-difluoromethoxy-2-[(3-methoxy-4 By carrying out the method described in Example 19 starting from -monodeuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (34.8 g, KF = 50.8%, 46.5 mmol). Rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole is an off-white solid (melting point = 134-135 ° C. ( Decomposition); yield 14.0 g (78%)).

Example 22
rac-5-difluoromethoxy-2-[(4-methoxy-3-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole wet 5-difluoromethoxy-2-[(4-methoxy-3 Starting from -triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (3.00 g, KF = 19.1%, 6.55 mmol), carrying out the method described in Example 23. Rac-5-difluoromethoxy-2-[(4-methoxy-3-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole was crystallized off-white after crystallization from TBME (10 mL). As a solid (melting point = 133-134 ° C. (decomposition); yield 1.83 g (72%)). .

Example 23
rac-5-difluoromethoxy-2-[(3,4-bis (trideteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole 5-difluoromethoxy-2-[(3,4-bis ( Trideteriomethoxy) -2-pyridinyl) methylthio] -1H-benzimidazole (23.8 g, 63.7 mmol) was dissolved in CH ₂ Cl ₂ (210 mL) and brought to −55 ° C. to −40 ° C. Cooled down. At that temperature, a solution of 3-chloroperoxybenzoic acid (wet, 77% strength, 15.8 g, 70.5 mmol) in CH ₂ Cl ₂ (110 mL) was added slowly over 1.5 hours. . After more than 1 hour at −55 ° C. to −40 ° C., triethylamine (12.3 mL, 88.5 mmol) and 6% aqueous Na ₂ CO ₃ and 2% aqueous Na ₂ S ₂ O ₃ (140 mL) A 1: 1 mixture of was added continuously, warming the mixture to about 0 ° C. Stirring was continued for 1 hour at ambient temperature. The phases are separated and the organic layer is 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). And then evaporated to dryness. After crystallization from diisopropyl ether (700 mL), rac-5-difluoromethoxy-2-[(3,4-bis (trideteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole was turned off. Obtained as a white solid (yield 20.9 g (84%)).

Example 24
rac-5-difluoromethoxy-2-[(3-methoxy-4-dideliomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate rac-5-difluoromethoxy-2- [ Performing the method described in Example 6 starting from (3-methoxy-4-didetriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (8.10 g, 21.0 mmol). Rac-5-difluoromethoxy-2-[(3-methoxy-4-didetriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate is an off-white solid ( Melting point = 150-152 ° C. (decomposition), KF = 4.8%; yield 6.05 g (68%)) Obtained.

Example 25
rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate rac-5-difluoromethoxy-2- [ Performing the method described in Example 6 starting from (3-methoxy-4-monodeteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (10.2 g, 26.5 mmol). Rac-5-difluoromethoxy-2-[(3-methoxy-4-monodeteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate is an off-white solid ( Melting point = 151-152 ° C. (decomposition), KF = 4.1%; yield 8.95 g (79%)) It was obtained by.

Example 26
rac-5-Difluoromethoxy-2-[(3,4-bis (trideteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate 6-15M aqueous at 15-25 ° C. NaOH (8.92 mL, 53.5 mmol) is added over a period of about 15 minutes to rac-5-difluoromethoxy-2-[(3,4-bis (triduteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H. -Benzimidazole (21.0 g, 53.9 mmol) was added to a solution dissolved in a 6: 1 mixture of ethanol / dichloromethane (725 mL). Further, after stirring at room temperature for 10 minutes, most of the solvent was distilled off. The resulting concentrate (115 g) was diluted with diisopropyl ether (1.7 L). Some dark waxy residue remained undissolved and the clear yellow solution of the supernatant was decanted. To this solution, a further portion of diisopropyl ether (3.4 L) was added to precipitate the product. The suspension was cooled to 0 ° C. and the solid was filtered off, washed with diisopropyl ether (100 mL) and dried in vacuo at 40 ° C. to give rac-5-difluoromethoxy-2-[( 3,4-Bis (trideteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate is an off-white solid (KF = 4.0%; yield 18.9 g ( 82%)).

Example 27
rac-5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt sesquihydrate at 48-55 ° C., rac-5 Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate (2.93 kg, 6.87 mol) was added to isopropanol ( 12L) and water (0.50L). After treatment with Hyflo Super Cel (56 g) and cooling to 18-25 ° C., the crystallization is seeded with a reference sample of the product, followed by 18-25 ° C. for 40 hours and further at 10-15 ° C. This was achieved by stirring for 5 hours. Centrifugation and drying in vacuo at 45 ° C. gave rac-5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole Sodium salt The sesquihydrate was obtained as a white solid (melting point = 140-142 ° C. (decomposition), KF = 6.6%; yield 2.28 kg (78%)).

Example 28
(S) -5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole-large scale method for the desired starting material at room temperature 382 g of wet 5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (KF = 47.6%, 0.540 mol) Suspended in 2.44 L of methyl isobutyl ketone with (+)-L-tartaric acid bis (N-pyrrolidinamide) (55.0 g). The mixture was heated to 40 ° C. and about 1.25 L of solvent was evaporated under vacuum to remove water. Zirconium (IV) n-propoxide (24.0 mL, 70% in n-propanol) was then added and stirring at 40 ° C. was continued for more than 1 hour. After cooling to 30 ° C., N-ethyldiisopropylamine (6.5 mL) and cumene hydroperoxide (103 mL, ˜80% concentration) were added. After stirring for about 18 hours at 30 ° C., TLC showed no further conversion of starting material. The clear reaction mixture was diluted with 500 mL methyl isobutyl ketone and quenched with 7.0 g sodium thiosulfate in 800 mL 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 was added 1.5 L of water and the pH was adjusted to pH = 13 using 40% aqueous sodium hydroxide. The organic layer was further extracted with 400 mL water at pH 13. After treatment with Hyflo Super Cel (5.0 g), the pH of the combined aqueous phase was adjusted to about 9 by adding 10% aqueous acetic acid at 40-45 ° C. Once product precipitation began, the mixture was stirred for an additional 12 hours with occasional readjustment of the pH. A crude product (160 g, 75% yield) with optical purity> 98% was obtained by filtration with a water rinse (200 mL).

  To further increase the purity, the crude product was dissolved in dichloromethane (2.0 L) and washed with water (400 mL). Crystallization was achieved by solvent addition with TBME (final volume about 1.1 L). The crystals were filtered off at about 0 ° C., washed with TBME (400 mL) and dried in vacuo at 30 ° C. to give (S) -5-difluoromethoxy-2-[(3-methoxy-4 -Trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid (mp 146-148 ° C. (decomposition); KF = 0.8%; yield 135 g (64%)) Obtained.

Chiral HPLC:> 98.0% ee; optical rotation: [α] _D = −98 ° (MeOH, c = 0.50).

Example 29
(R) -5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole 5-difluoromethoxy-2-[(3-methoxy-4 -Trideteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (70.7 g, KF = 47.6%, 100 mmol) as a chiral ligand (-)-D-Tartrate (N-pyrrolidinamide) (10.3 g, 40.0 mmol) was used to perform the method described in Example 28, followed by (R) -5-difluoromethoxy- after recrystallization from TBME. 2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole is White solid was obtained as (mp 140-142 ° C. (decomposition);; KF = 0.8% yield 22.2g (57%)).

Chiral HPLC:> 98.0% ee; optical rotation: [α] _D = + 97 ° (MeOH, c = 0.50).

Example 30
(R) -5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt trihydrate (R) -5-difluoromethoxy As described in Example 5, starting from 2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (15.5 g, 40.1 mmol) By carrying out the process, (R) -5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt trihydrate Obtained as a white solid (melting point 98-103 ° C. (decomposition); KF = 11.3%; yield 17.4 g (94%)) .

Chiral HPLC:> 98.0% ee; optical rotation: [α] _D = + 91 ° (MeOH, c = 0.50).

Example 31
Bis-[(R) -5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole] magnesium salt trihydrate (R)- 5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt (2.30 g, KF = 11.3%, 5.00 mmol) ), Starting from bis [(R) -5-difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methyl Sulfinyl] -1H-benzimidazole] magnesium salt is a white solid (melting point 141-145 ° C. (decomposition); = 6.9%; obtained as a yield of 1.23g (58%)).

Chiral HPLC:> 99.0% ee; optical rotation: [α] _D = + 120 ° (MeOH, c = 0.50).

INDUSTRIAL APPLICABILITY Compounds of general formula 1 and their salts and solvates, preferably hydrates and solvates of these salts, preferably hydrates (hereinafter referred to as “compounds of the invention”) Have useful pharmacological properties that make them industrially available. In particular, they have a remarkable inhibitory action on gastric acid secretion and have an excellent gastrointestinal protective action in warm-blooded animals, especially humans. Here, the compounds according to the invention have a very selective action, an advantageous duration of action, in particular a high bioavailability, a uniform metabolic profile between different individuals, a lack of serious side effects and a wide range of treatments It is remarkable in terms of spectrum.

  In this context, “gastrointestinal protection” can be caused, for example, by microorganisms (eg Helicobacter pylori), bacterial toxins, pharmaceuticals (eg certain anti-inflammatory and anti-rheumatic drugs), chemicals (ethanol), gastric acid or stress Should be understood as the prevention and treatment of gastrointestinal diseases, especially gastrointestinal inflammatory diseases and lesions (eg gastric ulcer, duodenal ulcer, gastritis, increased production of acid or irritable bowel as a result of pharmaceuticals, GERD, Crohn's disease, IBD) is there.

  Along with their excellent properties, the compounds according to the invention are surprisingly clear over conventional compounds in various models for the measurement of anti-tumor development and anti-secretory properties, especially in terms of their metabolic properties Turned out to be excellent. These improved metabolic properties make it possible, for example, to reduce the amount of the compound according to the invention which is required for treatment or prevention. Alternatively, a longer duration of action can be achieved by using the same amount of a compound according to the invention as is done for a state of the art compound. In connection with these characteristics, it is preferred with respect to patient safety or economic aspects, such as drug costs. Because of these properties, the compounds according to the invention are very suitable for use in human medicine and veterinary medicine, where the compounds are used in particular for the treatment and / or prevention of gastrointestinal diseases.

  The invention therefore further provides the use of the compounds according to the invention for treating and / or preventing the above mentioned diseases.

  The invention also includes the use of a compound according to the invention for the manufacture of a pharmaceutical composition used for the treatment and / or prevention of the aforementioned diseases.

  The invention also provides a pharmaceutical composition comprising a compound according to the invention. In particular, the invention relates to compounds of formula 1, formula 1a or formula 1b in the form of their pharmaceutically acceptable salts, in particular in the form of sodium or magnesium salts and / or hydrates of such salts. The pharmaceutical composition containing the form is provided.

  The pharmaceutical composition is produced by a method known per se well known to those skilled in the art. As a pharmaceutical composition, the compounds according to the invention are used as such or in combination with suitable pharmaceutical auxiliaries or carriers, such as tablets, coated tablets, capsules, suppositories, patches (eg TTS), emulsions. The active compound content is preferably from about 0.1 to about 95%, and the exact active compound is determined by appropriate choice of auxiliaries and carriers. And / or and / or pharmaceutical dosage forms (eg, delayed release or enteric forms) that are closely matched to the desired onset of action and / or duration of action.

  Auxiliaries or carriers suitable for the desired pharmaceutical formulation are known to those skilled in the art. In addition to solvents for active compounds, gel formers, suppository bases, tableting aids and other carriers, for example, antioxidants, dispersants, emulsifiers, antifoaming agents, flavoring agents, preservatives, solubilizers Agents, colorants, or in particular penetration enhancers and complexing agents (eg cyclodextrins) can be used.

  The compounds according to the invention can be administered orally, parenterally or transdermally. Advantageously, the compounds of the invention are administered orally.

  In human medicine, in general, when the compound according to the invention is administered orally, it is about 0.01 to about 1 mg, preferably about 0.02 to about 0.5 mg, in particular about 0.04 per kg body weight. In a daily dose of ˜0.3 mg [calculated on the free form of the compound according to the invention, ie not in the salt form (= “free compound”)], optionally in multiple individual doses, advantageously 1 It has been found preferable to administer ˜4 individual doses to achieve the desired results. For parenteral treatment, similar doses or generally lower doses can be used (especially when the active compound is administered intravenously). The optimum dosage and dosage form of the active compound required in each case can be readily determined by one skilled in the art.

  Thus, a further aspect of the present invention contains one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 2 to about 60 mg of free compound. It is a pharmaceutical composition.

  A further aspect of the present invention is a pharmaceutical composition comprising one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 4 to about 40 mg of free compound. is there.

  A further aspect of the invention is the use of the compounds according to the invention for the treatment of gastrointestinal diseases.

  A further aspect of the invention is the use of a compound according to the invention for the manufacture of a pharmaceutical composition for the treatment or prevention of gastrointestinal diseases.

  A further aspect of the present invention is a method of treating gastrointestinal diseases by administering a pharmaceutical composition comprising one or more compounds according to the present invention.

  A further aspect of the invention is the use of a compound according to the invention for the treatment of gastrointestinal diseases in patients with slow metabolism.

  A further aspect of the invention is the use of the compounds according to the invention for the treatment of gastrointestinal diseases in patients at risk of drug interaction.

  A further aspect of the invention is the use of the compounds according to the invention for the treatment of gastrointestinal diseases in patients in need of long-term inhibition of acid secretion.

  A further aspect of the present invention is a slow metabolism, containing one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 2 to about 60 mg of free compound. A pharmaceutical composition for the treatment of gastrointestinal diseases for use in a patient.

  A further aspect of the present invention is a slow metabolism comprising one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 4 to about 40 mg of free compound. A pharmaceutical composition for the treatment of gastrointestinal diseases for use in a patient.

  A further aspect of the present invention is a drug interaction comprising one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 2 to about 60 mg of free compound. A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients at risk of.

  A further aspect of the present invention is a drug interaction comprising one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 4 to about 40 mg of free compound. A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients at risk of.

  A further aspect of the present invention is an extended composition containing one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 2 to about 60 mg of free compound. A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients in need of inhibition of acid secretion over a period of time.

  A further aspect of the present invention is an extended composition containing one or more conventional auxiliaries together with one or more compounds according to the present invention, wherein a single dose comprises from about 4 to about 40 mg of free compound. A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients in need of inhibition of acid secretion over a period of time.

  A further aspect of the invention comprises one or more conventional auxiliaries together with a pharmaceutically acceptable salt according to the invention or a hydrate thereof in an oral solid application form, wherein a single dose is A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients with slow metabolism, comprising about 2 to about 60 mg of free compound.

  A further aspect of the invention comprises one or more conventional auxiliaries together with a pharmaceutically acceptable salt according to the invention or a hydrate thereof in an oral solid application form, wherein a single dose is A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients with slow metabolism, comprising about 4 to about 40 mg of free compound.

  A further aspect of the invention comprises one or more conventional auxiliaries together with a pharmaceutically acceptable salt according to the invention or a hydrate thereof in an oral solid application form, wherein a single dose is A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients at risk of drug interaction, comprising about 2 to about 60 mg of free compound.

  A further aspect of the invention comprises one or more conventional auxiliaries together with a pharmaceutically acceptable salt according to the invention or a hydrate thereof in an oral solid application form, wherein a single dose is A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients at risk of drug interaction, comprising about 4 to about 40 mg of free compound.

  A further aspect of the invention comprises one or more conventional auxiliaries together with a pharmaceutically acceptable salt according to the invention or a hydrate thereof in an oral solid application form, wherein a single dose is A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients in need of inhibition of acid secretion over an extended period of time comprising about 2 to about 60 mg of free compound.

  A further aspect of the invention comprises one or more conventional auxiliaries together with a pharmaceutically acceptable salt according to the invention or a hydrate thereof in an oral solid application form, wherein a single dose is A pharmaceutical composition for the treatment of gastrointestinal diseases for use in patients in need of inhibition of acid secretion over an extended period of time comprising 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 contain one or more pharmacologically active ingredients from other pharmaceutical groups. Examples that may be mentioned are tranquilizers (eg benzodiazepines, eg diazepam), antispasmodics (eg vietamiberin or camilofin), anticholinergics (eg oxyphencyclimine or phencarbamide), local anesthetics (eg tetracaine or procaine) Optionally also contains enzymes, vitamins or amino acids.

In this connection, particular emphasis is given to the compounds according to the invention and other medicaments which buffer or neutralize gastric acid or inhibit acid secretion, such as antacids (eg magaldrate) or H ₂ blockers ( For example, cimetidine, ranitidine) and gastrin antagonists with the objective of enhancing the main action additively or superadditively and / or eliminating or reducing side effects or obtaining a more rapid onset of action. A fixed or free combination with an NSAID (eg etofenamate, diclofenac, indomethacin, ibuprofen or piroxicam) for preventing gastrointestinal disorders caused by the NSAID, or a fixed combination with a compound that alters gastrointestinal motility or Free combinations, or fixed or free combinations with compounds that reduce the incidence of transient lower esophageal sphincter relaxation (TLOSR), or antibacterial agents for the control of Helicobacter pylori (eg cephalosporins, tetracyclines) , Penicillins, macrolides, nitroimidazoles or bismuth salts). Suitable antibacterial combination partners that may be mentioned are, for example, mezlocillin, ampicillin, amoxicillin, cephalotin, cefoxitin, cefotaxime, imipenem, gentamicin, amikacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin, azithromycin and these Combinations (eg clarithromycin + metronidazole or amoxicillin + clarithromycin).

  In the practice of the invention, the compounds according to the invention may be used in combination therapy, separately, sequentially, simultaneously or offset in time (e.g. as a combined unit dosage form, as a separate unit dosage form, adjacent, discrete, As a unit dosage form, as a fixed or non-fixed combination, as a sub-kit or as a mixture), it may be administered together with one or more standard said therapeutic agents.

  The term “combination” according to the invention may exist as a fixed combination, a non-fixed combination or a dispensing kit.

  A “fixed combination” is defined as a combination in which a first active ingredient and a second active ingredient are present together in one unit dose or in a single entity. An example of a “fixed combination” is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in a mixture, for example for simultaneous administration in one preparation. Another example of a “fixed combination” is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in one unit without being mixed.

  A “split kit” is defined as a combination in which the first active ingredient and the second active ingredient are present in more than one unit. An example of the “split kit” is a combination in which the first active ingredient and the second active ingredient are present separately. The components of the dispensing kit may be administered separately, sequentially, simultaneously or offset in time.

Pharmacology Metabolism in Liver Microsomes Materials and Methods Pantoprazole or Example 1 or 2 (10 μM each) were incubated with liver microsomes (source: all from GenTest other than TEBU's minipig). Incubation was performed in 1 mg / ml protein, 100 mM Tris-HCl (pH 7.4), 1 mM NADPH ₂ . The reaction was stopped after 90 minutes with liquid nitrogen and the parent compound was detected by HPLC (10 mM KH ₂ PO ₄ , pH 7.4, acetonitrile gradient 20-44%).

Table 1:
Metabolism of H-pantoprazole versus deutero compounds (Examples 1, 2) after 90 minutes incubation time with microsomes (species dependence)

Metabolic clearance In order to evaluate the properties of the compounds according to the invention, the compound-specific clearance in recombinant human cytochrome P450 (CYP) isoenzymes CYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4 and CYP3A5 is not deuterated. Measured in comparison with

Materials and Methods The compounds described in Examples 5, 6, 22, 24, 25 and 30 and further [ ¹ H] racemic sodium pantoprazole sodium sesquihydrate and the corresponding S- and R-enantiomers, 37 ° C. in a buffer containing 1 nmol / mL recombinant P450 (Cypex, Dundee, UK), 4 mg / mL microsomal protein, 100 mmol / L Tris-HCl (pH 7.4) and 1 mmol / L NADPH. Incubated at 0, 3, 6, 12, and 15 or 30 minutes. Incubation was performed in triplicate. Intrinsic clearance was determined based on the disappearance rate of the parent compound. Pantoprazole and deuterated analogs were measured by HPLC-UV. The lower limit of assay sensitivity based on experimental variability was 17.6 μl / min / nanomolar P450.

Results CYP2C19 and CYP3A4 were found to contribute to the oxidative metabolism of pantoprazole and its deuterated analogs. All other cytochrome P450 isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) did not contribute to the metabolism of any compound investigated above the lower limit of assay sensitivity.

Formation kinetics of pantoprazole M2 (5- (difluoromethoxy) -2-[[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole P450 of metabolic clearance of compounds according to the invention Following enzyme-mediated evaluation, the major metabolite identified in humans, namely M2 (5- (difluoromethoxy) -2-[[(3-methoxy-4-sulfate-2-pyridyl) methyl] Sulfinyl] -1H-benzimidazole) was measured.M2 was formed by oxidation of the 4-methoxy-pyridyl group by CYP2C19 followed by 3′-phosphoadenosine-5′- by unidentified sulfotransferase. Freezes humans because it is involved in binding to phosphosulfate (PAPS) Hepatocytes were used because both Phase I and Phase II enzymes are functional in the in vitro system.

Materials and Methods The compounds 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, 84 μg / mL amikacin, 1 μmol / L calcium chloride, 20 mmol / L Hepes, 4.2 μmol / L hepatonic acid, 28.5 mmol / L sodium bicarbonate and human Incubated at a concentration of 10 ⁶ cells / mL in Krebs-Henseleit buffer (KHB) containing frozen hepatocytes (10 donor pools, InVitro Technologies, Baltimore, MD US). The M2 production rate under these conditions was linear up to 60 minutes. M2 production rate at 9 different compound concentrations (0, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0 and 100 micromol / L) Measurements were made by incubating in duplicate for 60 minutes at 37 ° C. M2 was quantified using LC-MS / MS. M2 isolated from human urine was used as an external standard. The concentration reaching the half-maximal production rate (K _M value) and the maximum production rate (V _max ) were obtained by nonlinear regression analysis using the Michaelis-Menten equation. Intrinsic clearance (Cl _int) was obtained by dividing the V _max in K _M.

Results Production of M2 from pantoprazole, its enantiomers and the compounds described in Examples 5, 6, 22, 24, 25 and 30 appeared to be inhibited by substrate concentrations higher than 100 μM. Therefore, data for incubation at substrate concentrations of 100μM and 250μM were excluded from the calculation of K _M and V _max. Production of M2 from racemic [ ¹ H] pantoprazole and enantiomers showed a stereospecific difference (FIG. 1A). The racemic (R) and (S) -analogues (Examples 6, 30 and 5 deuterated in the 4-methoxy-pyridyl position) are compared to their undeuterated counterparts. The production rate was reduced by at least 2.5 times (FIG. 1B). The intrinsic clearance of the (R) and (S) -analogues (Examples 6, 30 and 5) of racemic deuterated in the 4-methoxy-pyridyl position is their undeuterated equivalent. Compared to at least 4.7 times (Table 2). The stereospecific differences in M2 production rates observed for [ ¹ H] pantoprazole analogs were less pronounced for the analogs deuterated at the 4-methoxy-pyridyl position (FIG. 1B). Surprisingly, the reduction in M2 production compared to undeuterated compounds appears to be dependent on the position of the trideteriomethoxy group in the pyridyl part of the molecule (Figure 2). As the number of [ ¹ H] atoms replaced by [ ² H] atoms in the 4-methoxypyridyl position of the molecule increases ([ ¹ H], [ ² H ₁ ] Example 25, [ ² H ₂ ] Example 24) And [ ² H ₃ ] Example 6), the M2 production rate decreased (FIG. 3).

Table 2:
Intrinsic clearance (Cl _int ) in pooled human hepatocytes obtained by incubation with pantoprazole and a compound according to the invention

FIG. 1 shows (A) racemic [ ¹ H] pantoprazole and enantiomers, and (B) [ ² H ₃ ] pantoprazole (Example 6) and the corresponding enantiomers in pooled human frozen hepatocytes (FIG. 1). 2 is a graph showing the kinetics of M2 production from Examples 5 and 30). FIG. 2 shows racemic [ ¹ H] pantoprazole and deuterated at the 4-methoxy-pyridyl position (Example 6) or 3-methoxy-pyridyl position in pooled human frozen hepatocytes. FIG. 6 is a graph showing the kinetics of M2 production rate from [ ² H ₃ ] analogs deuterated at (Example 22). FIG. 3 shows [ ² H] versus kinetics of M2 production rate from racemic pantoprazole analogs ([ ¹ H] pantoprazole, Examples 25, 24 and 6) in pooled human frozen hepatocytes. It is a graph which shows an isotope effect.

Claims (25)

General formula 1

[Wherein R1 is difluoromethoxy, R2 is methoxy, R3 is methoxy], a hydrogen atom of R1, R2, R3, or hydrogen of any combination of R1, R2, and R3 at least one is a compound or salt are replaced by deuterium atoms, solvate, hydrate or solvate of a salt thereof, a hydrate of a salt of atoms. Formula 2

Wherein R1 is difluoromethoxy and R2 and R3 are methoxy, and at least one hydrogen atom of R1, R2, R3 or any combination of R1, R2 and R3 Or a salt, solvate or solvate of the salt in which is replaced by a deuterium atom.   The compound according to claim 1 or 2, wherein at least one hydrogen atom of R2, R3 or R2 and R3 is exchanged by a deuterium atom.   3. A compound according to claim 1 or 2, wherein R1 is deuteriodifluoromethoxy.   3. A compound according to claim 1 or 2, wherein R2, R3 or R2 and R3 are trideteriomethoxy.   3. A compound according to claim 1 or 2, wherein R1 is difluoromethoxy, R2 is methoxy and R3 is trideteriomethoxy.   3. A compound according to claim 1 or 2, wherein R2, R3 or R2 and R3 are diduteriomethoxy.   3. The compound according to claim 1 or 2, wherein R1 is difluoromethoxy, R2 is methoxy, and R3 is diduteriomethoxy.   3. A compound according to claim 1 or 2, wherein R1 is difluoromethoxy and R2 and R3 are trideteriomethoxy. (R / S) -5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole or a pharmaceutically acceptable salt, solvate Or a pharmaceutically acceptable salt solvate thereof. S (−)-5-Difluoromethoxy-2-[(3-methoxy-4-triduteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole or a pharmaceutically acceptable salt, solvate Or a pharmaceutically acceptable salt solvate thereof. 12. One or more pharmaceutically acceptable enhancers together with one or more compounds or pharmaceutically acceptable salts or solvates according to claim 1 or any one of claims 3-11. A pharmaceutical composition comprising a dosage form. 12. One or more pharmaceutically acceptable enhancers together with one or more compounds, pharmaceutically acceptable salts or solvates according to claim 1 or any one of claims 3-11. A pharmaceutical composition comprising a dosage form, wherein a single dose comprises from 2 to 60 mg of a compound of general formula 1. Use of the compound according to any one of claims 1 or 3 to 11 for the manufacture of a medicament for the treatment and / or prevention of gastrointestinal diseases.   Use of a compound according to any one of claims 2 to 9 for the preparation of a compound of formula 1 as defined in any one of claims 1 or 3 to 9. Formula 3

[Wherein X is halogen, R 2 and R 3 are methoxy, and at least one hydrogen atom of R 2, R 3, or R 2 and R 3 is replaced by a deuterium atom].   17. A compound according to claim 16, wherein X is iodine, bromine, fluorine or chlorine.   17. A compound according to claim 16, wherein X is chlorine.   19. A compound according to any one of claims 16 to 18, wherein R2, R3 or R2 and R3 are triduteriomethoxy.   19. A compound according to any one of claims 16 to 18, wherein R2, R3 or R2 and R3 are diduteriomethoxy.   Use of a compound according to any one of claims 16 to 20 for the preparation of a compound of formula 1 or formula 2 as defined in any one of claims 1 to 9.   A process for the preparation of a compound of formula 1 according to any one of claims 1 or 3 to 9, comprising the step of oxidizing a compound of formula 2 as defined in any one of claims 2 to 9. Method. 23. The method of claim 22, wherein the compound of formula 2 as defined in any one of claims 2 to 9 is the compound of formula 3 as defined in any one of claims 16 to 20. Quaternized and subsequently obtained the quaternized compound of formula 3 with formula 4

A process for producing a compound by reacting with a compound of the formula: wherein R1 is difluoromethoxy or deuteriodifluoromethoxy. A method for producing a compound of formula 2 as defined in any one of claims 2 to 7, wherein the compound of formula 3 as defined in any one of claims 16 to 20 is quaternized, And subsequently, the resulting quaternized compound of formula 3 and formula 4

A method comprising a step of reacting a compound of the formula: wherein R1 is difluoromethoxy or deuteriodifluoromethoxy.   Use of a compound according to any one of claims 1 or 3 to 9 for the manufacture of a medicament for the treatment and / or prevention of gastrointestinal diseases.

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