EA016814B1 - Isotopically substituted proton pump inhibitors - Google Patents

Abstract

The invention relates to benzimidazoles of Formula (1)where definitions of R1, R2, R3, R4 are given in the description and to pharmaceutical acceptable salts, solvates and solvates of the salts thereof, in which at least one hydrogen atom in R1, R2, R3, R4 groups or in any of R1, R2, R3 and R4 combination is replaced by a deuterium atom. Pharmaceutical compositions comprising such compounds as well as intermediates are also proposed.

Description

SUMMARY OF THE INVENTION

The present invention relates to isotope-substituted proton pump inhibitors and their (K) and (8) enantiomers. These compounds can be used in pharmacology to obtain pharmaceutical compositions.

BACKGROUND OF THE INVENTION

Pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, as described, for example, in patents EP-A0005129, EP-A-0166287, EP-A-0174726, EP-A-0254588 and EP-A-0268956, play an important role in the treatment of disorders associated with increased secretion of acid of gastric juice, due to their inhibitory effect against H ⁺ / K ⁺ -ATPase.

Examples of active compounds of this group that are commercial products or are undergoing clinical trials include 5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2pyridinyl) methylsulfinyl] -1H-benzimidazole (INN (international non-proprietary name ): omeprazole), (8) -5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy-2- [ (3,4-Dimethoxy-2-pyridinyl) methylsulfinyl] -1Nbenzimidazole (INN: pantoprazole), 2- [3-methyl-4- (2,2,2-trifluoroethoxy-2-pyridinyl) methylsulfinyl] 1H-benzimidazole (INN : lans prazol), 2 - {[4- (3-methoxypropoxy-3-methylpyridin-2-yl) methyl] sulfinyl} -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 above sulfinyl derivatives, in connection with their mechanism of action, are also called proton pump inhibitors or abbreviated ΡΡΙ.

Description of the Related Art

Patent I8 6818200 describes dihydropyridine compounds and antibiotics in which at least one hydrogen atom is replaced by a deuterium atom. Deuterated compounds are prepared by reacting the H-form of the compounds with a mixture of deuterium oxide and a suitable catalyst in closed vessels under harsh conditions, i.e. at elevated temperatures (60-80 ° C) and for a long time (up to 190 hours). This patent also describes the effect of H / ϋ exchange on certain pharmaceutical properties of such compounds.

Description of Embodiments of the Present Invention

It has been unexpectedly found that isotopically substituted compounds, described in detail below, have a significant effect on the inhibition of acid secretion.

The present invention relates to compounds of General formula 1

Where

R1 is hydrogen or C1-C ₄ alkoxy,

R2 is _C1-C4 alkyl or _C1-C4 alkoxy,

R3 is _C1-C4 alkyl, C1-C ₄ alkoxy or C ₂ -C ₈ alkoxyalkoxy,

R4 is hydrogen or _C1-C4 alkyl,

Ζ means CH or N and to pharmaceutically acceptable salts, solvates, preferably hydrates, and solvates, preferably hydrates, salts of these compounds, in which at least one hydrogen atom in the groups K1, K2, K3, K4 or in any combination K1, K2, K3 and K4 are replaced by a deuterium atom.

_C1-C4 alkyl refers to an alkyl group with straight or branched chain group having from 1 to 4 carbon atoms. Examples of such groups include butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl, and preferably methyl.

_C1-C4 alkoxy is a group which, besides the oxygen atom contains one of the aforementioned groups, _C1-C4 alkyl groups or fluorinated _C1-C4 alkyl. Examples of the groups _C1-C4 alkoxy include butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, preferably methoxy and ethoxy. Examples of fluorinated groups, _C1-C4 alkyl include 2,2,3,3,3-pentafluoropropyl, 2,2,3,3tetraftorpropil, 1- (trifluoromethyl) -2,2,2-trifluoroethyl, 2,2,3,3 , 4,4,4-heptafluorobutyl and preferably 2,2,2-trifluoroethyl and difluoroethyl.

C2-C8 alkoxyalkoxy means a group which, in addition to the oxygen atom, contains internal alkylene containing C1-C4 alkylene groups, and an end alkyl group that contains C1-C4 alkyl groups and is connected to the internal alkylene group via an oxygen atom. Examples of such groups include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxypropoxy, ethoxyisopropoxy, isopropoxymethoxy, propoxymethoxy, methoxybutoxy, methoxyisobutoxy, propoxyethoxy, isopropoxyethoxy, propoxypropoxy, isopropoxyisoxypropoxy, ethoxypropoxy-ethoxypropoxy, butoxypropoxy, ethoxypropoxy, butoxy preferably methoxypropoxy.

- 1 016814

The term salts used in this context means all salts of inorganic and organic bases, especially alkali metal salts, such as lithium, sodium and potassium salts, or alkaline earth metal salts, such as magnesium and calcium salts, as well as other pharmaceutically acceptable salts, such as, for example, aluminum or zinc salts. Most preferred are sodium and magnesium salts.

Pharmaceutically unacceptable salts, which are obtained in the initial stages, for example, as intermediates in the preparation of the compounds of the present invention on an industrial scale and which are also included in the scope of the present invention, can be used to prepare pharmaceutical compositions and converted into pharmaceutically acceptable salts according to standard procedures.

Those skilled in the art will recognize that if the compounds of the present invention and their salts are isolated in crystalline form, they may contain various amounts of solvents. The present invention also includes all solvates, and especially hydrates, of compounds of formula 1, as well as all solvates, and especially all hydrates of salts of compounds of formula 1. The term solvates includes all pharmaceutically acceptable solvents included in such solvates.

The term deutero, as used in this context, means a deuterium atom ([ ² H]). Similarly, the prefixes bis or di and three or tris respectively mean the presence of two or three, for example, deuterium atoms in a particular group, for example 1,1-dideutero-2,2,2-trifluoroethoxy or trideuteromethoxy.

Preferred compounds of the formula 1 included in the scope of the present invention are those in which at least one hydrogen atom in the C3 group is replaced by a deuterium atom, and C3 is C ₄ -C ₂ alkoxy or C ₂ -C ₅ alkoxyalkoxy.

Preferred are compounds of formula 1 in which R2 is _C1-C4 alkyl, and RS is C ₂ -C ₈ alkoxyalkoxy, wherein at least one hydrogen atom of R2, or R2 and RS of RS is replaced by deuterium atom.

Preferred are compounds of formula 1 wherein R1 is C ₄ -C ₄ alkoxy, R2 and R4 are _C1-C4 alkyl, and RS is _C1-C4 alkoxy, wherein at least one hydrogen atom of R1, RS, K4 or in any combination of K1, KZ and K4 replaced by a deuterium atom.

Also preferred are compounds of formula 1 in which K1 is hydrogen, methoxy or difluoromethoxy, K2 is methyl or methoxy, KZ is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen or methyl, with at least one hydrogen atom in the composition of CG replaced by a deuterium atom.

Also preferred are compounds of formula 1 in which K2 is methyl, KZ is methoxypropoxy, and Ζ is CH, with at least one hydrogen atom in K2, KZ or K2 and KZ replaced by a deuterium atom.

Also preferred are compounds of formula 1 in which K1 is methoxy, K2 and K4 are methyl, and KZ is methoxy, with at least one hydrogen atom in K1, KZ, K4 or in any combination of K1, KZ and K4 replaced by deuterium atom. Possible combinations include K1 and KZ, K1 and K4, KZ and K4, K1 and KZ and K4.

Also preferred are compounds of formula 1 in which K1 is methoxy, K2 is methyl, KZ is methoxy, K4 is methyl, K1 is hydrogen, K2 is methyl, and KZ is 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen or in which K1 is difluoromethoxy, K2 is methoxy, C3 is methoxy, and K4 is hydrogen, with at least one hydrogen atom in the C3 replaced by a deuterium atom.

Also preferred are compounds of formula 1 in which K1 is methoxy, K2 is methyl, KZ is methoxy, and K4 is methyl, or in which K1 is hydrogen, K2 is methyl, and KZ is 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen, or in which K1 is difluoromethoxy, K2 is methoxy, KZ is methoxy, and K4 is hydrogen, with at least two hydrogen atoms in the KZ replaced by deuterium atoms.

More preferred are compounds of formula 1 in which R2 is _C1-C4 alkyl, and RS is C ₂ -C ₈ alkoxyalkoxy, wherein all hydrogen atoms in the composition K2, K2 or RS and R4 are replaced by deuterium atoms.

More preferred are compounds of formula 1 wherein R1 is C ₁ -C ₄ alkoxy, R2 and R4 are _C1-C4 alkyl, and RS is a C ₄ -C ₄ alkoxy, wherein all hydrogen atoms in R1 composition, RS, K4 or in any combination, K1, KZ and K4 are replaced by deuterium atoms. Possible combinations include K1 and KZ, K1 and K4, KZ and K4, K1 and KZ and K4.

More preferred are compounds of formula 1 in which all of the hydrogen atoms in the C3 are replaced by deuterium atoms and the C3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy.

Compounds of formula 1 are also more preferred in which K2 is methyl, KZ is methoxypropoxy, and С is CH, all hydrogen atoms in K2, KZ or K2 and

- 2 016814

K3 replaced by deuterium atoms.

Compounds of formula 1 are also more preferred in which K1 is methoxy, K2 and K4 are methyl, and K3 is methoxy, with all hydrogen atoms in K1, K3, K4 or any combination of K1, K3 and K4 being replaced with deuterium atoms. Possible combinations include K1 and K3, K1 and K4, K3 and K4, K1 and K3 and K4.

Compounds of the formula 1 are also more preferred in which K1 is hydrogen, methoxy or difluoromethoxy, K2 is methyl or methoxy, K3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen or methyl, with all hydrogen atoms in the composition K3 replaced by deuterium atoms.

Also preferred are compounds of formula 1 in which K1 is methoxy, K2 is methyl, K3 is methoxy, and K4 is methyl, or in which K1 is hydrogen, K2 is methyl, and K3 is 2,2,2-trifluoroethoxy or methoxypropoxy , K4 means hydrogen, or in which K1 means difluoromethoxy, K2 means methoxy, K3 means methoxy, and K4 means hydrogen, all of the hydrogen atoms in K3 are replaced by deuterium atoms.

The most preferred compounds are 5-methoxy-2 - [(4-trideuteromethoxy-3,5dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-methoxy-2 - [(4-dideuteromethoxy-3,5-dimethyl-2 -pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-trideuteromethoxy-2 - [(4-methoxy-3,5-dimethyl2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-trideuteromethoxy-2 - [(4-trideuteromethoxy-3 , 5dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-trideuteromethoxy-2 - [(4-dideuteromethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1 H-benzimidazole, 5-methoxy-2- [(3-methyl-4trideuteromethoxy-5-three nuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-trideuteromethoxy-2 - [(3-methyl-4-trideuteromethoxy-5-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1Nbenzimidazole, 2 - [(3-methyl- 4- (1,1-dideutero-2,2,2-trifluoroethoxy) -2-pyridinyl) methylsulfinyl] -1benzimidazole, 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] - 1benzimidazole, 5-difluoromethoxy-2 - [(3-methoxy-4-dideuteromethoxy-2-pyridinyl) methylsulfinyl] -1benzimidazole, 5-difluoromethoxy-2 - [(3-trideuteromethoxy-4-methoxy-2-pyridinyl) methylsulfinyl] - 1benzimidazole, benzimidazole, benzimidazole, benzimidazole, finyl} -1H-benzimidazole, 2 - {[4- (3-trideuteromethoxyhexadeuteropropoxy) -3-trideuteromethylpyridin-2-yl] methylsulfinyl} -1H-benzimidazole, 5-methoxy-2 - ((4-trideuterome 3,5-dimethyl-2pyridylmethyl) sulfinyl) -1H-imidazo [4,5-b] pyridine, 5-trideuteromethoxy-2 - ((4-trideuteromethoxy3,5-dimethyl-2-pyridylmethyl) sulfinyl) -1H-imidazo [ 4,5-b] pyridine, 5-methoxy-2 - ((3-methyl-4-trideuteromethoxy-5-trideuteromethyl-2-pyridyl) methylsulfinyl) -1H-imidazo [4,5-b] pyridine or 5-trideuteromethoxy -2 - ((3-methyl-4-trideuteromethoxy-5-trideuteromethyl-2-pyridyl) methylsul bfinyl) -1 Nimidazo [4,5-b] pyridine.

The term hydrogen atom replaced by a deuterium atom used in the present invention means the degree of deuteration of at least 80% of the material in which all of the indicated hydrogen atoms are replaced

5-difluoromethoxy-2 - [(3-dideuteromethoxy-4-methoxy-2-pyridinyl) methylsulfinyl] -1H5-difluoromethoxy-2 - [(3,4- (bis (trideuteromethoxy) -2-pyridinyl) methylsulfinyl] -1H5- difluoromethoxy-2 - [(3,4- (bis (dideuteromethoxy) -2-pyridinyl) methylsulfinyl] -1H2 - {[4- (3-trideuteromethoxyhexadeuteropropoxy) -3-methylpyridin-2-yl] methylsulane on deuterium atoms. For example, if the substituent K2 or K3 means a methoxy group in which all 3 hydrogen atoms are replaced by deuterium atoms, then according to the above definition it should be understood that at least 80% of all K2 or K3 methoxy groups in the material means -ΟΟ.Ό _3. The rest up to 100% includes -ΟΟΗΌ ₂ , -ΟΟΗ ₂ Ό or -OSH ₃ .

The preferred degree of deuteration is the replacement of at least 90% of certain hydrogen atoms in the material with deuterium atoms. A more preferred degree of deuteration is the replacement of at least 92% of certain hydrogen atoms in the material with deuterium atoms. An even more preferred degree of deuteration is the replacement of at least 94% of certain hydrogen atoms in the material with deuterium atoms and the most preferred degree of deuteration is the replacement of at least 96% of certain hydrogen atoms in the material with deuterium atoms.

The compounds of the present invention are chiral compounds. Therefore, the present invention relates to racemates and enantiomers, as well as mixtures thereof in any desired ratio. Therefore, from a medical point of view, the introduction of certain chiral compounds in the form of one or the other enantiomer is preferable, and the enantiomers of the compounds of formula 1, preferably enantiomers practically containing no other corresponding enantiomer of the opposite configuration, are preferred.

Thus, on the one hand, compounds in the configuration (8) of the general formula 1a are particularly preferred.

B2 "s

- 3 016814 where K1, K2, KZ, K4 and Ζ are as defined above.

First of all, preferred compounds in configuration (8) of the present invention are (8) -5-methoxy-2 - [(4-trideuteromethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, (8) - 5-trideuteromethoxy-2 - [(4-trideuteromethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, (8) -5-methoxy-2 - [(4-dideuteromethoxy-3,5-dimethyl -2-pyridinyl) methylsulfinyl] -1H-benzimidazole, (8) -5-trideuteromethoxy-2 - [(4-dideuteromethoxy-3,5-dimethyl-2pyridinyl) methylsulfinyl] -1H-benzimidazole, (8) -5-trideuteromethoxy -2 - [(4-methoxy-3,5-dimethyl-2pyridinyl) methylsulfinyl] -1H- benzimidazole, (8) -5-methoxy-2 - [(3-methyl-4-trideuteromethoxy-5-trideuteromethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, (8) -5-trideuteromethoxy-2 - [(3 -methyl-4-trideuteromethoxy-5-trideuteromethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole or (8) -5 difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridylmethyl) sulfinyl] -1H-benzimidazole, ( 8) 5-difluoromethoxy-2 - [(3-methoxy-4-dideuteromethoxy-2-pyridylmethyl) sulfinyl] -1H-benzimidazole and solvates, preferably hydrates of these compounds, salts of these compounds and solvates, preferably hydrates of salts associated compounds. On the other hand, particularly preferred are compounds in configuration (K) of general formula 1b

where K1, K2, K3, K4 and Ζ are as defined above.

First of all, preferred compounds in configuration (K) of the present invention are (K) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridylmethyl) sulfinyl] -1Nbenzimidazole, (K) -5-difluoromethoxy- 2 - [(3-methoxy-4-dideuteromethoxy-2-pyridylmethyl) sulfinyl] -1Nbenzimidazole and solvates, preferably hydrates of these compounds, salts of these compounds and solvates, preferably hydrates of salts of these compounds.

The separation of these compounds of formula 1 into enantiomers is carried out according to various methods, for example, as described in the application for the grant of international patent \ ¥ 0 92/08716 or column chromatography. In another embodiment, the compounds of formulas 1a and 1b are prepared by the chiral oxidation of sulfides, as described in applications for the grant of international patent \ ¥ О 96/02535 or \ УО 2004/052881.

Salts of compounds of formulas 1, 1a and 1b are prepared by standard methods by reacting compounds of formulas 1, 1a and 1b, which are weak acids, with suitable bases, for example, alkali metal hydroxides or alkoxides, such as sodium hydroxide or sodium methoxide, or alkoxides alkaline earth metals such as magnesium methoxide. For example, magnesium salts of compounds of formulas 1, 1a and 1b, which are preferred in addition to sodium salts, are obtained by a standard method by reacting compounds of formulas 1, 1a and 1b with a magnesium base, for example magnesium alkoxide, or from a readily soluble salt of a compound of formulas 1, 1a and 1b (e.g., sodium salt) using a magnesium salt in water or in mixtures of water with polar organic solvents (e.g., alcohols, preferably methanol, ethanol or isopropanol, or ketones, preferably acetone).

The term compounds in the configuration (8) used in the present invention means compounds in the configuration (8), practically containing no compounds in the configuration (K).

The term “practically free” as used in this context means that compounds in configuration (8) and / or their salts, solvates or solvates of salts contain less than 10 wt.% Of compounds in configuration (K) and / or their salts, solvates or solvates salts. Preferably, the term “substantially free” means that the compounds in configuration (8) and / or their salts, solvates or solvates of salts contain less than 5 wt.% Of the compounds in configuration (K) and / or their salts, solvates or solvates of salts.

More preferably, the term “substantially free” as used in this context means that the compounds in configuration (8) and / or their salts, solvates or solvates of salts contain less than 2 wt.% Of compounds in configuration (K) and / or their salts, solvates or solvate salts. In the most preferred embodiment, the term “substantially free” means that the compounds in configuration (8) and / or their salts, solvates or solvates of salts contain less than 1 wt.% Of compounds in configuration (K) and / or their salts, solvates or solvates of salts.

The term compounds in the configuration (K) used in the present invention means compounds in the configuration (K), practically containing no compounds in the configuration (8).

The term “practically free” as used in this context means that compounds in configuration (K) and / or their salts, solvates or solvates of salts contain less than 10 wt.% Of compounds in configuration (8) and / or their salts, solvates or solvates salts. Preferably, the term “substantially free” means that compounds in configuration (K) and / or their salts, solvates or solvates of salts contain less than 5 wt.% Of compounds in configuration (8) and / or their salts, solvates or

- 4 016814 solvates of salts. More preferably, the term "substantially free" as used in this context means that compounds in configuration (K) and / or their salts, solvates or solvates of salts contain less than 2 wt.% Of compounds in configuration (B) and / or their salts, solvates or solvate salts. In the most preferred embodiment, the term “substantially free” means that compounds in configuration (K) and / or their salts, solvates or solvates of salts contain less than 1 wt.% Of compounds in configuration (B) and / or their salts, solvates or solvates of salts.

Another object of the present invention are compounds of formula 2

where K1, K2, K3, K4 and Ζ have the meanings as described above, and where at least one hydrogen atom in the composition of K1, K2, KZ and K4 or in any combination thereof is replaced by a deuterium atom, as well as their salts, such like hydrochloride, sulfate, phosphate or other salts of acids, and their solvates. Such compounds are used to prepare compounds of the general formula 1, 1a or 1b. The compounds of formula 2 are primarily suitable as starting material for an oxidation reaction to form compounds of formulas 1, 1a or 1b.

Another object of the present invention are compounds of formula 3

O) where X is a halogen or activated alcohol derivative, and K2, KZ and K4 are as defined above, and where at least one hydrogen atom in K2, K3 and / or K4 is replaced by a deuterium atom.

Preferred are compounds of formula 3 in which K2 is methyl or methoxy, KZ is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen or methyl, with at least one hydrogen atom in K3 being replaced by a deuterium atom.

More preferred are compounds of formula 3 in which K2 is methyl, K3 is methoxy, K4 is methyl, or K2 is methoxy, K3 is methoxy, K4 is hydrogen, or K2 is methyl, K3 is 2,2,2-trifluoroethoxy or methoxypropoxy , K4 means hydrogen, and at least one hydrogen atom in the composition of K3 is replaced by a deuterium atom.

Even more preferred are compounds of formula 3 in which K2 is methyl, K3 is methoxy, K4 is methyl, or K2 is methoxy, K3 is methoxy, K4 is hydrogen, or K2 is methyl, K3 is 2,2,2-trifluoroethoxy or methoxypropoxy, K4 means hydrogen, with at least two or all of the hydrogen atoms in K3 being replaced by deuterium atoms.

The term halogen used in the present invention means iodine, bromine, chlorine or fluorine. Preferably X is chlorine. The activated alcohol derivative is an alkyl sulfonate, for example mesylate, or an arylsulfonate, for example tosylate or bezylate, or perfluoroalkanesulfonate, for example trifluoromethanesulfonate.

The object of the present invention in relation to compounds of formula 3 is a compound of formula 3 a

K2 K5

where X, K2 and K4 are as defined above, K5 is chloro or nitro, with at least one hydrogen atom in K2 and / or K4 being replaced by a deuterium atom.

Preferred are compounds of formula 3a, wherein K2 is methyl or methoxy, K4 is hydrogen or methyl, with at least one hydrogen atom in K2 and / or K4 being replaced by a deuterium atom.

More preferred are compounds of formula 3a, where K2 and K4 are methyl and at least one hydrogen atom in K2 and / or K4 is replaced by a deuterium atom.

Compounds of formula 3 are used to prepare compounds of formulas 1, 1a or 1b. Preferably, the nitrogen atom in the compound of formula 3 is first quaternized, and then the resulting compound is reacted with compounds of formula 4

where K1 and Ζ have the meanings described above, whereby compounds of the formula 2 are obtained, as described above.

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Compounds of formula 3a are used to prepare compounds of formula 2a.

where K1, K2, K5, K4 and Ζ have the meanings as described above, with at least one hydrogen atom in the composition of K1, K2, K4 or any combination of K1, K2 and K4 replaced by a deuterium atom. Preferably, the nitrogen atom in the compound of formula Za is quaternized first, and then the resulting compound is reacted with compounds of formula 4

where K.1 and Ζ have the meanings described above, whereby the compounds of formula 2a are obtained as described above.

Compounds of formula 2a are used to prepare compounds of formula 2 by replacing the K5 residue with the K3 residue, the meanings of which are described above, provided that none of the hydrogen atoms in K1, K2, or K4 are replaced with a deuterium atom, and at least one atom hydrogen in the short circuit is replaced by a deuterium atom.

Another object of the present invention are compounds of formula 4

where K1 is C ₄ -C ₄ alkoxy, Ζ is C — H or Ν, with at least one hydrogen atom in K1 being replaced by a deuterium atom. Preferably, K1 is methoxy. Such compounds are used to prepare compounds of formula 1 or 2.

More preferred are compounds in which K1 is methoxy and all of the hydrogen atoms in K1 are replaced by deuterium atoms.

Deuterated homologs of proton pump inhibitors, for example, K / 8 pantoprazole and 8 pantoprazole, are obtained by oxidation of the corresponding thio compounds according to the methods described in the literature, for example, in the article by KOY et al., 1. Meb. SNSS .. 35, 1049 (1992) either in the application for the grant of patent XUO 2004/052881, or by exchanging halogen for trideuteromethoxy in the corresponding sulfoxides containing as a substituent a halogen atom (e.g. chlorine, bromine or nitro) in the position of the final group of trideuteromethoxy, primarily in position 4 of the pyridine ring. Similarly, the exchange of a halogen atom with a group of dodeuteromethoxy or monodeuteromethoxy leads to the formation of corresponding deuterated compounds.

Similarly, thio compounds are obtained by exchanging a halogen atom to a mono-, di- or trideuteromethoxy group at the position of the final mono-, di- or trideuteromethoxy substituent or by condensation of 5-difluoromethoxy-2-mercaptobenzimidazole and correspondingly substituted 2-chloromethyl-3methoxy-4-triridine chloride.

The compound of formula 1 is obtained according to the following scheme:

Salts of sulfoxides and inorganic bases are obtained according to standard methods by the interaction of sulfoxides with the corresponding hydroxides or alkoxides in organic solutions

- 6 016814 substances or mixtures of organic solvents with water.

In another embodiment, salts are prepared by reacting sulfoxides with alkali metal hydroxides to form an alkali metal salt (Na, K, L1) and then reacting, for example, with magnesium, calcium, aluminum and zinc salts.

The following examples are intended to illustrate in detail the present invention without limiting the scope of the invention. The other compounds described above are prepared according to the procedures described.

Examples

Methanol-b4, in which the percentage of deuterium is Ό> 99.8 atom%, was used as an agent for the introduction of trideuteromethoxy groups. The content of the isomer of the trideuteromethoxy group in all final products is> 98.0% according to NMR and MS. Subsequently, deuterium-containing agents were used, such as methanol-b2 (percentage Ό> 98.0 atom%) and methanol-b1 (percentage Ό> 98.0 atom%). The content of isomers of diditeromethoxy and monodeuteromethoxy groups in the final products is> 96.0% according to NMR and MS.

Example 1. 5-Difluoromethoxy- (K / 8) -2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

A sodium hypochloride solution (10% solution, 3.3 mmol) was added with stirring over 1 to 2 hours to a suspension of 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole ( 1.0 g, 2.7 mmol) in water (20 ml), 2-propanol (10 ml) and a solution of sodium hydroxide (0.5 ml 40% solution, 7.1 mmol) at 30-35 ° C. After 30-60 minutes at this temperature, sodium thiosulfate (0.3 g dissolved in water (5 ml)) was added and stirred for another 15-30 minutes.

The reaction mixture was concentrated in vacuo (30-40 ° C) to approximately one third of the original volume, and water (approximately 70 ml) was added.

After the aqueous phase was extracted with dichloromethane (2x10 ml), dichloromethane (50 ml) was added again and the pH was adjusted to 7-8 by adding an aqueous solution of potassium dihydrogen phosphate with stirring. The phases were separated, the aqueous phase was extracted once with dichloromethane (20 ml), the combined organic phases were washed with water (20 ml), dried over magnesium sulfate and filtered, to give a solution of the crude title compound.

By adding petroleum ether (50:70, 150 ml) and concentrating on a rotary evaporator in vacuo at 30-40 ° C to about 30 ml, the solid precipitate was separated by filtration, washed with 50:70 petroleum ether (20 ml) and dried in vacuum ( 35 ° C, 5 h), whereby the title compound 5-difluoromethoxy- (B / 8) -2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole was obtained as a solid off white. 1 _square 135-136 ° С (decomp.), Yield (1.0 g, 95% of theory).

Ή-NMR (400 MHz, DMSO ά-6): δ 3.78 (8, 3H, OMe), 4.68 (b, 1H, 1 (CHa, CH) 13 Hz, 8-CH ₂ -Py), 4.73 (b, 1H, 1 (CH, CH) 13 Hz, 8-CH ₂ -Pu), 7.10 (b, 1H, 1 (H5 ', H6') 5 Hz, H5 '), 7, 18 (broad b, 1H, H6), 7.24 (1, 1H, 1 (H, P) 74 Hz, OCHP ₂ ), 7.4 (broad 8, 1H, H4), 7.70 (broad .8, 1Н, Н7), 8.15 (b, 1Н, 1 (Н6 ', Н5') 5 Hz, Н6 '), 13.7 (8, 1Н, НН).

- 7 016814

Example 2. 8 (-) - 5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (2.0 g) was suspended at room temperature in methyl isobutyl ketone (20 ml) in a mixture with bis (Upyrrolidinamide) (+) - L-tartaric acid (2.3 g) and zirconium (IV) n-propoxide (1.0 g, 70% in propanol). The mixture was heated at 40 ° C. for 1 hour, whereby an almost clear solution was obtained. After cooling to room temperature, Ν-ethyldiisopropylamine (0.07 ml) and cumene hydroperoxide (1.05 ml) were added. The mixture was stirred at room temperature until oxidation was complete (10-24 h, reaction progress was monitored by TLC). The clear solution was diluted with methyl isobutyl ketone (10 ml) and the reaction was stopped by adding sodium thiosulfate (0.08 g) in saturated sodium bicarbonate solution (14 ml) and stirred for another 2 hours. After phase separation, the mixture was washed twice with saturated sodium bicarbonate solution (5 ml). Water (15 ml) was added to the methyl isobutyl ketone phase and the pH was adjusted to 13 with the addition of a 40 wt.% Sodium hydroxide solution. After phase separation, the methyl isobutyl ketone phase was extracted with water (5 ml) at pH 13. The aqueous phases were combined and evaporated at 40 ° C under reduced pressure, then the reagent NuDo §creg Ce11 was added as an auxiliary agent for filtering (0.05 g) and after stirring for 1 h at 2025 ° C was separated by filtration. The crude title compound was precipitated at 40-45 ° C. while 10% acetic acid was added to the filtrate to a pH of 9.0. The mixture was stirred for another 12 hours and the pH was monitored. The resulting beige crystals were separated by filtration and washed with water (10 ml), whereby the title compound (1.6 g, 75% of theory) was obtained, optical purity was> 98%.

For additional purification, (-) - trideuteriopantoprazole was dissolved in a water / aqueous sodium hydroxide mixture at pH 13 and again precipitated with the addition of acetic acid (10%) to pH 9.0.

Recrystallization from dichloromethane / tert-butyl methyl ether gave the title compound 8 (-) - 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as a solid off white. 1 _pl 146-148 ° C (decomp.), Yield (1.6 g).

Example 3. Synthesis of the starting compound 2-chloromethyl-3-methoxy-4-trideuteromethoxypyridinium

Preparation of 3-methoxy-2-methyl-4-trideuteromethoxypyridine Ν-oxide

4-chloro-3-methoxy-2-methylpyridine Ν-oxide (10 g) and sodium trideuteromethanolate (6.2 g) in тер 4 deuteromethanol (20 ml) were heated under reflux. After 15 hours, the solvent was evaporated in vacuo, the residue was extracted with hot toluene (50 ml), and the insoluble residue was filtered off. When diisopropyl ether was added to the filtrate, a precipitate was obtained, which was dried in vacuo to give 3-methoxy-2-methyl-4-trideuteromethoxypyridine Ν-oxide (8.1 g) as a light brown powder, which was used in the next step.

Preparation of 2-hydroxymethyl-3-methoxy-4-trideuteromethoxypyridine

The compound (8.1 g) obtained in the previous step was dissolved in acetic anhydride (50 ml) and heated at 90 ° C for 2 hours. After evaporation in vacuo, the dark oily residue was shaken in a mixture with 2N. ΝαΟΗ (20 ml) for 2 hours at 80 ° C. After cooling, the product was extracted with dichloromethane, dried (K ₂ CO 3) and concentrated in vacuo to reduce the volume, then petroleum ether (50:70) was added, filtered and dried in vacuo to give 2-hydroxy-3-methoxy-4 trideuteromethoxypyridine as a light brown solid (5.5 g), which was used in the next step.

Preparation of 2-chloromethyl-3-methoxy-4-trideuteromethoxypyridinium chloride

The compound obtained in the previous step (5.5 g) was dissolved in anhydrous dichloromethane (40 ml), and thionyl chloride (3 ml) was added dropwise with stirring. The mixture was heated to 20 ° C and after 3 hours it was evaporated to dryness in vacuo.

After adding toluene (20 ml), the title compound 2-chloromethyl-3methoxy-4-trideuteromethoxypyridinium chloride (6.6 g) was obtained as a pale brown solid.

The compound synthesized by this method contains some difficult to separate impurities, but which can be used in the following steps to obtain compounds of general formula (2) and, ultimately, compounds of general formula (1). For highly purified compounds of the general formula (1), it is most preferable to use the deuterioalkoxylation method in the same manner as described in Examples 9 and 35.

Example 4. 4-Chloro-2-chloromethyl-3-methoxypyridinium chloride

A solution of 4-chloro-3-methoxy-2-methylpyridine Ν-oxide (19.2 kg, 111 moles) in toluene (148 L) at 8595 ° С was added over 5-7 hours to acetic anhydride (71 L). The reaction mixture was concentrated in vacuo at approximately 60 ° C, the resulting distillate (170 L) was discarded. Toluene (160 L) was added to the residue and concentrated again, the resulting distillate (160 L) was discarded. The indicated operation was repeated once more. Then, toluene (14 L) and 40% aqueous solution of ΝαΟΗ (14.6 L) were added at 35-45 ° C and

- 8 016814 the reaction mixture was kept at the indicated temperature for 2-3 hours. If the pH of the mixture was less than 13, the ΝαΟΗ solution was continued and the mixture was heated for another 2 hours. The resulting two-phase reaction mixture was diluted with toluene (26 L) and saturated aqueous sodium bicarbonate solution (26 L), the phases were separated and the aqueous layer was extracted three times with toluene (26 L and 2x 13 L). The combined organic phase was washed with saturated aqueous sodium bicarbonate (13 L) and concentrated in vacuo at 50-65 ° C, the resulting distillate (115 L) was discarded. After diluting the residue with toluene (100 L), the mixture was concentrated again and the resulting distillate (100 L) was discarded.

The resulting solution of 4-chloro-2-hydroxymethyl-3-methoxypyridine (~ 30%) was diluted with CH ₂ Cl ₂ (48 L). Then, DMF (65.5 g, 0.896 mol) and thionyl chloride (11.1 kg, 93.2 mol) were added in one portion over 3-5 hours at 15-30 ° C. After stirring for another 1.5 hours, the mixture was evaporated and the resulting distillate (45 L) was discarded. Toluene (20 L) was added to the residue and the resulting distillate (20 L) was again discarded. Then, ethanol (1.5 L) was added to the resulting viscous suspension. 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 as an off-white solid. 1 _square 132 ° C, yield (15.0 kg, 59%).

Ή-NMR (200 MHz, C1AT): δ 4.19 (8, 3H), 5.14 (8, 2H), 7.92 (b, 6.0 Hz, 1H), 8.59 (b, 6 , 0 Hz, 1H), 11.64 (broad 8, 1H), LC-MS: 192/194/196 MH ⁺ .

Example 5. 4-Chloro-2-chloromethyl-3-trideuteromethoxypyridinium chloride

The starting compound Ν-oxide of 4-chloro-2-methyl-3-trideuteromethoxypyridine was obtained in the same way as described in method Ό to obtain a non-deuterated analogue, as described in article 1. Meb. S'11st .. 35, 1049-1057 (1992). The reaction of 3-hydroxy-2-methyl-4-pyrone with trideuterioiodomethane in the presence of potassium carbonate in DMF gave 2-methyl-3-trideuteriummethoxy-4-pyrone (yield 8396%), the resulting product was heated in a mixture with ammonia at 150 ° С in ethanol and crystallized from a 4: 1 acetone / isopropanol mixture to give 4-hydroxy-2-methyltrideuteromethoxypyridine (yield 52-60%). The resulting product was treated with phosphorus oxychloride and 4-chloro-2-methyltrideuteromethoxypyridine was obtained (yield 64-81%). Subsequent oxidation with hydrogen peroxide in acetic acid gave 4-chloro-2-methyl-3-trideuteromethoxypyridine Ν-oxide as a pale yellow solid (yield 87-89%). 4-Chloro-2-hydroxymethyl-3-trideuteromethoxypyridine was converted in the same manner as described in Example 4 to give 4-chloro-2-chloromethyl-3trideuteromethoxypyridinium chloride as colorless crystals. 1 _square 129-130 ° C, yield (19.6 g, 42%).

Example 6. 2-Chloromethyl-3,4-bis (trideuteromethoxy) pyridinium chloride

2-methyl-3,4-bis (trideuteromethoxy) pyridine Ν-oxide (yield 23.5 g, 96%) was obtained in the same manner as described above in Example 3, from 3,4-chloro-2-methyl Ν-oxide -3-trideuteromethoxypyridine (25.3 g, 144 mmol, synthesis see Example 5), the resulting product was converted to 2-hydroxymethyl-3,4bis (trideuteromethoxy) pyridine (yield 13.0 g, 56%) and finally 2 -chloromethyl-3,4bis (trideuteromethoxy) pyridinium chloride (yield 15.4 g, 89%) in the form of off-white crystals.

Example 7. 5-Difluoromethoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzimidazole

A solution of 4-chloro-2-chloromethyl-3-methoxypyridinium chloride (10.0 kg, 43.8 mol) in water (20 l) at 5565 ° C was added to the mixture of 5-trideuteromethoxy-1H-benzimidazole-for 2–3 hours 2-thiol (8.84 kg, 40.9 mol), toluene (43 L), water (21 L) and 40% aqueous solution No. 1OH (10.3 kg, 103 mol). Stirring was continued at 60 ° C for 2-3 hours, then the reaction mixture was cooled to 10-15 ° C. The precipitate was separated by centrifugation, washed with toluene (16 L) and resuspended in water (122 L). After centrifugation, the residue was washed with water (32 L) and dried at 35 ° C in vacuo to give 5-difluorormoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate 4.6%) as a off-white solid. 1 _W. 95-99 ° C, yield (14.2 kg, 92%).

Ή-NMR (200 MHz, DMSO-66): δ 3.55 (broad 8, ^ + Н ₂ О), 3.92 (8, 3Н), 4.79 (8, 2Н), 6.97 ( bb, 8.6 Hz, 2.3 Hz, 1H), 7.16 (1, 74.8 Hz, 1H), 7.28 (b, 2.2 Hz, 1H), 7.47 (b, 8 7 Hz, 1H), 7.55 (b, 5.3 Hz, 1H), 8.25 (b, 5.2 Hz, 1H), LC-MS: 372/374 MH ⁺ .

Example 8. 5-Difluoromethoxy-2 - [(4-chloro-3-trideuteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole

As the starting compound, 4-chloro-2-chloromethyl-3trideuteromethoxypyridinium chloride (5.00 g, 21.6 mmol) was used and 5-difluoromethoxy-2 - [(4chloro-3-trideuteromethoxy-2-pyridinyl) methylthio] -1H monohydrate was obtained -benzimidazole (KE 4.7%) as a off-white solid. 1 _square 94-99 ° C, yield (7.24 g, 85%), as described in example 7.

Ή-NMR (200 MHz, DMSO-b ₆ ): δ 4.79 (8, 2H), 6.98 (bb, 8.7 Hz, 2.3 Hz, 1H), 7.16 (1, 74, 8 Hz, 1H), 7.28 (b, 2.0 Hz, 1H), 7.47 (b, 8.6 Hz, 1H), 7.55 (b, 5.2 Hz, 1H), 8, 25 (b, 5.2 Hz, 1H), 12.75 (broad 8, 1H), LC-MS: 375/377 MH ⁺ .

Example 9. 5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole

Methanol-b4 (2.26 kg, 62.7 mol) was added at 15-30 ° C for 30-60 minutes in a mixture of tert-butoxide

- 9 016814 sodium (6.00 kg, 62.4 mol) and DMA (27 L). After heating the resulting mixture to 57-65 ° C, a solution of 5-difluoromethoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1Nbenzimidazole monohydrate (6.08 kg, 15.6 mol) was added to it. in DMA (10 L) for 30-60 minutes. Stirring was continued at 57-65 ° C for approximately 10 hours. The reaction mixture was cooled to 20-30 ° C and diluted with water (21 L), then the pH of the mixture was adjusted to 7-8 with the addition of a 20% aqueous HC1 solution (7.5 l). The product was precipitated by adding water (75 L) for 4 hours. The resulting suspension was heated at 35-45 ° C for

1.5 hours, then cooled to 10-15 ° C. The resulting suspension was centrifuged, washed with water (58 L), suspended again in water (78 L) and centrifuged, washed with water (58 L) to give 5 difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylthio] - 1H-benzimidazole as a brown moistened substance. Yield (10.4 kg, 91%), KR 49.7%.

A sample of the moistened product (16.2 g, CR 49.7%) was dried at 25 ° C in vacuo to give an amorphous solid, upon crystallization from toluene (30 ml), anhydrous 5 difluoromethoxy-2 - [(3-methoxy-4) was obtained -trideuteromethoxy-2-pyridinyl) methylthio] - 1H-benzimidazole as an off-white solid (5.80 g, 71% yield, 1 _pl . 115-116 ° C).

Я-NMR (200 MHz, DMSO-6): δ 3.82 (8, 3H), 4.68 (8, 2H), 6.97 (st, 8.6 Hz, 2.1 Hz, 1H), 7.08 (st, 5.6 Hz, 1H), 7.16 (1, 74.8 Hz, 1H), 7.28 (br. 8, 1H), 7.47 (br., ~ 8, 3 Hz, 1H), 8.16 (s, 5.6 Hz, 1H), 12.75 (broad 8, 1H), LC-MS: 371 MH ⁺ .

Example 10. 5-Difluoromethoxy-2 - [(3-methoxy-4-diddeteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole

The starting compounds used were 5-difluoromethoxy-2 - [(4-chloro-3-methoxy2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (28.6 g, 73.4 mmol) and methanol-2 (10.0 g , 294 mmol) and 5-difluoromethoxy-2 - [(3-methoxy-4-dideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was obtained as a moistened brownish solid, yield (46.4 g, 82%) , CR 51.6%, as described in example 9.

Ή-NMR (400 MHz, DMSO-6): δ 3.81 (8, 3H), 3.86 (8, 1H), 4.67 (8, 2H), 6.97 (s, 8.4 Hz , 2.0 Hz, 1H), 7.08 (st, 5.5 Hz, 1H), 7.16 (1, 74.7 Hz, 1H), 7.21-7.53 (broad t, 2H ), 8.16 (s, 5.5 Hz, 1H), 12.78 (broad 8, 1H), LC-MS: 370 MH ⁺ .

Example 11. 5-Difluoromethoxy-2 - [(3-methoxy-4-monodeuteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole

The starting compounds used were 5-difluoromethoxy-2 - [(4-chloro-3-methoxy2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (29.5 g, 75.6 mmol) and methanol-1 (10.0 g , 303 mmol) and 5-difluoromethoxy-2 - [(3-methoxy-4-monodeuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was obtained as a moistened brownish solid, yield (50.3 g, 89%) , CR 50.8%, as described in example 9.

Ή-NMR (200 MHz, DMSO-6): δ 3.82 (8, 3H), 3.88 (8, 2H), 4.67 (8, 2H), 6.98 (st, 8.6 Hz , 2.2 Hz, 1H), 7.08 (st, 5.6 Hz, 1H), 7.15 (1, 74.8 Hz, 1H), 7.22-7.53 (broad t, 2H ), 8.16 (s, 5.6 Hz, 1H), 12.79 (broad 8, 1H), LC-MS: 369 MH ⁺ .

Example 12. 5-Difluoromethoxy-2 - [(4-methoxy-3-trideuteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole

The starting compounds used were 5-difluoromethoxy-2 - [(4-chloro-3-trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (6.97 g, 17.7 mmol) and methanol (2.28 g, 71 , 2 mmol) and 5-difluoromethoxy-2 - [(4-methoxy-3-trideuteromethoxy-2-pyridinyl) methylthio] 1H-benzimidazole was obtained as a moistened brownish solid, yield (7.01 g, 87%), CR 19.1%, as described in example 9.

Я-NMR (200 MHz, DMSO-6): δ 3.89 (8, 3H), 4.68 (8, 2H), 6.97 (st, 8.6 Hz, 2.0 Hz, 1H), 7.08 (st, 5.5 Hz, 1H), 7.16 (1, 74.7 Hz, 1H), 7.18-7.47 (broad t, 2H), 8.16 (st, 5 6 Hz, 1H), 12.76 (broad 8, 1H), LC-MS: 371 MH ⁺ .

Example 13. 5-Difluoromethoxy-2 - [(3,4-bis (trideuteromethoxy) -2-pyridinyl) methylthio] -1Nbenzimidazole

2-Chloromethyl-3,4-bis (trideuteromethoxy) pyridinium chloride (15.4 g, 66.8 mmol) was added portionwise at 50-55 ° C over 30 min in a mixture of 5-difluoromethoxy-1H-benzimidazole-2-thiol ( 14.5 g, 66.8 mmol), ethanol (133 ml) and 2M aqueous NaOH solution (73.5 ml, 147 mmol). Stirring was continued at 50-55 ° C for 1-2 hours, then ethanol was removed by evaporation in vacuo at 40 ° C. The resulting aqueous emulsion was diluted with water (50 ml) and extracted with dichloromethane three times (165 ml each). The combined organic phase was washed with 0.1 M aqueous NaOH solution (165 ml), dried over Na ₂ 8O ₄ and evaporated to dryness to give 5-difluoromethoxy-2 - [(3,4-bis (trideuteromethoxy) -2pyridinyl) methylthio] -1H-benzimidazole as a brown oil, yield (23.8 g, 95%).

Example 14. rac-5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl1-1H-benzimidazole (preparative)

An aqueous solution of sodium hypochlorite (10.5 kg, 10% solution, 14.2 mol) was added at 25-35 ° C for 3-4 hours in a solution of 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy- 2-pyridinyl) methylthio] -1H

- 10 016814 benzimidazole (10.4 kg, KE 49.7%, 14.2 mol) and a 40% aqueous solution of ΝαΟΗ (2.84 kg) in a mixture of water (49 L) and isopropanol (49 L). Stirring at 25-35 ° C was continued for 0.5-1 h, then the reaction was stopped with the addition of a 1% aqueous solution _of Ν α ₂ 8 ₂ Ο ₃ (4.3 L). Then the mixture was evaporated at 30-45 ° C in vacuo and the resulting distillate (65 L) was discarded. After dilution with water (55 L), the mixture was again evaporated and the resulting distillate (8-10 L) was discarded. At a reaction temperature of 40-45 ° C., a 10% aqueous solution of acetic acid (approximately 13 L) was added over a period of 1.5 hours to a pH of 8.5-9.5. Crystallization was carried out by slowly lowering the pH to 6.8-7.2 with the addition of a 10% aqueous solution of acetic acid (approximately 0.6 L). After cooling to 20-25 ° C, the crude product was separated by filtration and washed with water (7.5 L) and again dissolved in a mixture of water (80 L), 40% aqueous solution of ΝαΟΗ (1.6 L) and Να ₂ 8 ₂ Ο ₃ , (60 g). The resulting opalescent aqueous solution was washed twice with M1BC (12 L) and clarified with the addition of the NoDo reagent (0.40 kg), the pH of the mixture was adjusted to 9.0-9.5 with the addition of a 10% aqueous solution of acetic acid (approximately 8 L) at 40 -45 ° C. After crystal formation, 10% acetic acid was again added to pH 9.0-9.5. It was then centrifuged at 20–25 ° C, washed with water (7.5 L) and dried in vacuum at 50 ° C to give rac-5-difluoromethoxy-2 - [(3methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl ] -1H-benzimidazole as a dirty white solid. 1 _square 134-135 ° C (decomp.), Yield (3.59 kg, 65%).

Я-NMR (400 MHz, DMSO-b6): δ 3.78 (q, 3H), 4.67 (b, 13.1 Hz, 1H), 4.73 (b, 13.1 Hz, 1H), 7.10 (b, 5.5 Hz, 1H), 7.18 (broad b, 8.7 Hz, 1H), 7.24 (1, 74.4 Hz, 1H), 7.44 (br. q, 1H), 7.70 (broad s, 1H), 8.15 (b, 5.5 Hz, 1H), 13.73 (broad s, 1H), LC-MS: 387 MH ⁺ .

Example 15. rac-5-Difluoromethoxy-2 - [(3-methoxy-4-diditeromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

As the starting compound, the moistened product 5-difluoromethoxy-2 - [(3methoxy-4-dideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (32.7 g, KE 51.6%, 42.8 mmol) was used and obtained rac-5-difluoromethoxy-2 - [(3-methoxy-4-diddeteromethoxy-2-pyridinyl) methylsulfinyl] -1Nbenzimidazole as an off-white solid. 1 _square 133-135 ° C (decomp.), Yield (10.8 g, 65%), as described in example 14.

Я-NMR (200 MHz, DMSO-b6): δ 3.32 (br.s, MH + H ^), 3.77 (q, 3H), 3.86 (q, 1H), 4.65 (b , 13.1 Hz, 1H), 4.73 (b, 13.1 Hz, 1H), 7.10 (b, 5.5 Hz, 1H), 7.15 (b, 8.8 Hz, 2, 4 Hz, 1H), 7.23 (1, 74.4 Hz, 1H), 7.44 (b, 2.2 Hz, 1H), 7.69 (b, 8.8 Hz, 1H), 8, 15 (b, 5.5 Hz, 1H), LC-MS: 386 MH ⁺ .

Example 16. rac-5-Difluoromethoxy-2 - [(3-methoxy-4-monodeuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

As the starting compound, the moistened product 5-difluoromethoxy-2 - [(3methoxy-4-monodeuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (34.8 g, KE 50.8%, 46.5 mmol) was used and obtained rac-5-difluoromethoxy-2- [(3-methoxy-4-monodeuteromethoxy-2-pyridinyl) methylsulfinyl] 1H-benzimidazole as an off-white solid. 1 _square 134-135 ° C (decomp.), Yield (14.0 g, 78%), as described in example 14

Я-NMR (200 MHz, DMSO-b6): δ 3.78 (q, 3H), 3.88 (q, 2H), 4.66 (b, 13.2 Hz, 1H), 4.73 (b , 13.1 Hz, 1H), 7.10 (b, 5.6 Hz, 1H), 7.16 (bb, 8.8 Hz, 2.4 Hz, 1H), 7.24 (1, 74, 4 Hz, 1H), 7.45 (b, 2.2 Hz, 1H), 7.69 (b, 8.8 Hz, 1H), 8.15 (b, 5.5 Hz, 1H), 13, 77 (broad s, 1H), LC-MS: 385 MH ⁺ .

Example 17. rac-5-Difluoromethoxy-2 - [(4-methoxy-3-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

The wetted product 5-difluoromethoxy-2- [(4methoxy-3-trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (3.00 g, KE 19.1%, 6.55 mmol) and after crystallization from TBME (10 ml) gave rac-5-difluoromethoxy-2 - [(4-methoxy-3trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid. 1 _square 133-134 ° C (decomp.), Yield (1.83 g, 72%) as described in Example 38.

Я-NMR (200 MHz, DMSO-b6): δ 3.90 (q, 3H), 4.66 (b, 13.1 Hz, 1H), 4.73 (b, 13.1 Hz, 1H), 7.10 (b, 5.6 Hz, 1H), 7.15 (bb, 8.9 Hz, 2.4 Hz, 1H), 7.24 (1, 74.4 Hz, 1H), 7.45 (b, 2.1 Hz, 1H), 7.69 (b, 8.8 Hz, 1H), 8.15 (b,

5.5 Hz, 1H), 13.77 (br.s, 1H), LC-MS: 387 MH ⁺ .

Example 18. rac-5-Difluoromethoxy-2 - [(3,4-bis (trideuteromethoxy) -2-pyridinyl) methylsulfinyl] 1 H-benzimidazole

As the starting compound, 5-difluoromethoxy-2 - [(3,4-bis (trideuteromethoxy) 2-pyridinyl) methylthio] -1H-benzimidazole (23.8 g, 63.7 mmol) was used and after crystallization from diisopropyl ether (700 ml) gave rac-5-difluoromethoxy-2 - [(3,4-bis (trideuteromethoxy) -2pyridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid, yield (20.9 g, 84%), as described in example 38.

Example 19. The sodium salt of rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy2-pyridinyl) methylsulfinyl] -1H-benzimidazole monohydrate

A 40% aqueous NaH solution (0.85 kg, 8.50 mol) was added over 10-30 minutes at 15-30 ° C to a solution of rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2 -pyridinyl) methylsulfinyl] -1Nbenzimidazole (3.29 kg, 8.51 mol) in acetone (18 L). The resulting suspension was heated at 50-55 ° C to

- 11 016814 formation of a clear solution. Crystallization of the product was carried out under slow cooling to 10-15 ° C for approximately 12 hours. The solid was separated by filtration and washed with acetone (1.7 L), then recrystallized from a mixture of acetone / water, 32: 1 (19 L). It was then dried at 50 ° C in vacuo to give rac-5-difluoromethoxy-2 - [(3-methoxy-4trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate as an off-white solid. 1 _square 151-152 ° C (decomp.), CT 4.3%, yield (2.93 kg, 81%).

Я-NMR (200 MHz, DMSO-b6): δ 3.78 (8, 3H), 4.34 (b, 12.9 Hz, 1H), 4.68 (b, 12.9 Hz, 1H), 6.72 (bb, 8.6 Hz, 2.4 Hz, 1H), 7.02 (1, 75.8 Hz, 1H), 7.07 (b, 5.6 Hz, 1H), 7.24 (b, 2.2 Hz, 1H), 7.44 (b, 8.6 Hz, 1H), 8.22 (b,

5.5 Hz, 1H), LCMS: 409 MH ⁺ , 387 MH ⁺ .

Example 20. The sodium salt of rac-5-difluoromethoxy-2 - [(3-methoxy-4-didideteromethoxy2-pyridinyl) methylsulfinyl] -1H-benzimidazole monohydrate

As the starting compound, rac-5-difluoromethoxy-2 - [(3-methoxy-4-deuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (8.10 g, 21.0 mmol) was used and the rac-5 sodium salt monohydrate was obtained -difluoromethoxy-2 - [(3-methoxy-4-dideuterium-methoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid. 1 _square 150152 ° C (decomp.), CR 4.8%, yield (6.05 g, 68%), as described in example 19

Я-NMR (200 MHz, DMSO-b6): δ 3.77 (8, 3H), 3.85 (8, 1H), 4.36 (b, 12.9 Hz, 1H), 4.66 (b , 12.9 Hz, 1H), 6.73 (bb, 8.6 Hz, 2.4 Hz, 1H), 7.02 (1, 75.8 Hz, 1H), 7.07 (b, 5, 6 Hz, 1H), 7.25 (b, 2.3 Hz, 1H), 7.45 (b, 8.6 Hz, 1H), 8.22 (b, 5.5 Hz, 1H), LC- MS: 408 MHA ⁺ , 386 MH ⁺ .

Example 21. The sodium salt of rac-5-difluoromethoxy-2 - [(3-methoxy-4 monodeuterium methoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole monohydrate

As the starting compound, rac-5-difluoromethoxy-2 - [(3-methoxy-4 monodeuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (10.2 g, 26.5 mmol) was used and the rac-5 sodium salt monohydrate was obtained -difluoromethoxy-2 - [(3-methoxy-4-monodeuteromethoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid. 1 _square 151152 ° C (decomp.), Raman 4.1%, yield (8.95 g, 79%), as described in Example 19.

Я-NMR (200 MHz, DMSO-b6): δ 3.78 (8, 3H), 3.88 (8, 2H), 4.34 (b, 12.9 Hz, 1H), 4.68 (b , 12.9 Hz, 1H), 6.73 (bb, 8.6 Hz, 2.4 Hz, 1H), 7.03 (1, 75.8 Hz, 1H), 7.08 (b, 5, 5 Hz, 1H), 7.24 (b, 2.2 Hz, 1H), 7.44 (b, 8.6 Hz, 1H), 8.22 (b, 5.5 Hz, 1H), LC- MS: 407 MHA ⁺ , 385 MH ⁺ .

Example 22. Rac-5-difluoromethoxy-2 sodium salt monohydrate - [(3,4-bis (trideuteromethoxy) -2pyridinyl) methylsulfinyl] -1H-benzimidazole

M Aqueous solution No. 1OH (8.92 ml, 53.5 mmol) was added over 15 minutes at 15-25 ° C to a solution of rac-5-difluoromethoxy-2 - [(3,4-bis (trideuteromethoxy) -2- pyridinyl) methylsulfinyl] -1H-benzimidazole (21.0 g, 53.9 mmol) in ethanol / dichloromethane (6: 1, 725 ml). After stirring for another 10 minutes at room temperature, the majority of the solvent was removed by evaporation. The resulting concentrate (115 g) was diluted with diisopropyl ether (1.7 L), while a certain amount of the waxy residue did not dissolve and the yellow transparent supernatant was separated by decantation. Another portion of diisopropyl ether (3.4 L) was added to the solution, and the product was obtained as a precipitate. The suspension was cooled to 0 ° C and the solid was filtered off, washed with diisopropyl ether (100 ml) and dried at 40 ° C in vacuo to give rac-5-difluoromethoxy-2 - [(3,4-bis (sodium) monohydrate trideuteromethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid (CR 4.0%), yield (18.9 g, 82%).

Я-NMR (400 MHz, DMSO-b6): δ 4.32 (b, 12.9 Hz, 1H), 4.70 (b, 12.9 Hz, 1H), 6.72 (bb, 8.6 Hz, 2.4 Hz, 1H), 7.04 (1, 75.8 Hz, 1H), 7.08 (b, 5.5 Hz, 1H), 7.23 (b, 2.4 Hz, 1H ), 7.44 (b, 8.6 Hz, 1H), 8.22 (b, 5.5 Hz, 1H), LC-MS: 412 MАа ⁺ , 390 MН ⁺ .

Example 23. The sesquirate hydrate of the sodium salt of rac-5-difluoromethoxy-2 - [(3-methoxy-4trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

The rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt monohydrate (2.93 kg, 6.87 mol) was dissolved at 48-55 ° C. in a mixture of isopropanol (12 L) and water (0.50 L). After treating the mixture with the NoDo 8iret Ce1 reagent (56 g) and cooling to 18-25 ° С, crystallization was carried out by adding seed crystals of the compound sample, then it was stirred for 40 hours at 18-25 ° С and for 5 hours at 10-15 ° FROM. After centrifugation and drying in vacuo at 45 ° C, one-and-a-half sodium hydrate of rac-5-difluoromethoxy-2 - [(3methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole was obtained as a white solid. 1 _square 140-142 ° С (decomp.), KR 6.6%, yield (2.28 kg, 78%).

Example 24. The magnesium dihydrate of the salt of bis- [rac-5-difluoromethoxy-2 - [(3-methoxy-4trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole]

A solution of the sodium salt of rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole (500 mg, CR 4.3%, 1.17 mmol) in water (10.0 ml) was filtered. After cooling to room temperature, anhydrous magnesium chloride (61.4 mg, 0.644 mmol) in 1.0 ml of water was added to the solution. The resulting suspension was stirred at room temperature in

- 12 016814 for another 18 hours, then the mixture was cooled to 0 ° C and filtered. The filtrate residue was resuspended in water (7.5 ml), filtered, washed with water (5.0 ml) and dried at 40 ° C. in vacuo to give bis [rac-5-difluoromethoxy-2- [magnesium salt dihydrate] (3-Methoxy-4-trideuterium-methoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole] as a white solid. ( _pl . 180-182 ° C (decomp.), CR 4.7%, HPLC: 99.5% a / a, yield (369 mg, 76%).

Example 25. (8) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (product preparation on a preparative scale using a wet sample)

Moistened 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole (382 g, CR 47.6%, 0.540 mol) was suspended at room temperature in methyl isobutyl ketone (2.44 L) in a mixture with bis- (No. pyrrolidinamide) (+) - L-tartaric acid (55.0 g). The mixture was heated to 40 ° C. and approximately 1.25 L of solvent was evaporated in vacuo to remove water. Then zirconium (IV) n-propoxide (24.0 ml, 70% solution in n-propanol) was added and stirred at 40 ° С for more than one hour. After cooling to 30 ° С, Ν-ethyldiisopropylamine (6.5 ml) was added ) and cumene hydroperoxide (103 ml, approximately 80% solution). The mixture was stirred for approximately 18 hours at 30 ° C until complete consumption of the starting material according to TLC. The clear reaction mixture was diluted with methyl isobutyl ketone (500 ml) and the reaction was stopped by adding sodium thiosulfate (7.0 g) in a saturated solution of sodium bicarbonate (800 ml). The phases were separated, the organic layer was washed twice with saturated sodium bicarbonate solution (400 ml). Water (1.5 L) was added to the organic phase and the pH was adjusted to 13 with the addition of a 40% aqueous sodium hydroxide solution. The organic layer was extracted with water (400 ml) at pH 13. After adding the reagent NuDo 8ireg Ce1 (5.0 g), the pH of the combined aqueous phase was adjusted to 9 by adding a 10% aqueous solution of acetic acid at 40-45 ° C. After the product precipitated, the mixture was stirred for another 12 hours, while the pH of the mixture was periodically adjusted to 9. The precipitate was filtered off and washed with water (200 ml). A crude product was obtained (yield 160 g, 75%), optical purity was> 98%.

The crude product was purified by dissolving in dichloromethane (2.0 L) and the resulting solution was washed with water (400 ml). Crystallization was performed from TBME (final volume approximately 1.1 L). The crystals were filtered off at approximately 0 ° C., washed with TBME (400 ml) and dried at 30 ° C. in vacuo to give (8) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2pyridinyl) methylsulfinyl ] -1H-benzimidazole as a dirty white solid. 1 _square 146148 C (decomp.), KR 0.8%, yield (135 g, 64%).

Chiral HPLC: enantiomeric purity (s)> 98.0%, optical rotation: [a] _s -98 ° (MeOH, s 0.50).

Ή-NMR (200 MHz, DMSO-b6): δ 3.41 (broad 5, ΝΗ + Η ₂ Ο), 3.77 (5, 3H), 4.65 (b, 13.0 Hz, 1H) 4.73 (b, 13.1 Hz, 1H), 7.09 (b, 5.6 Hz, 1H), 7.15 (b, 8.9 Hz, 2.4 Hz, 1H), 7, 23 (I, 74.4 Hz, 1H), 7.44 (b, 2.1 Hz, 1H), 7.68 (b, 8.9 Hz, 1H), 8.14 (b, 5.5 Hz) , 1H), LC-MS: 387 MH ⁺ .

Example 26. (K) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

As the starting compound, 5-difluoromethoxy-2 - [(3-methoxy-4trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (70.7 g, КР 47.6%, 100 mmol) and bis-ζ-pyrrolidinamide) ( -) - E-tartaric acid (10.3 g, 40.0 mmol) as a chiral ligand and after crystallization from TBME, (K) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2pyridinyl) was obtained methylsulfinyl] -1H-benzimidazole as an off-white solid. 1 _square 140142 ° C (decomp.), KR 0.8%, yield (22.2 g, 57%), as described in example 25.

Chiral HPLC: e> 98.0%, optical rotation [a] _s + 97 ° (MeOH, s 0.50).

Я-NMR (200 MHz, DMSO-b6): δ 3.77 (5, 3H), 4.65 (b, 13.2 Hz, 1H), 4.73 (b, 13.1 Hz, 1H), 7.09 (b, 5.5 Hz, 1H), 7.16 (broad b, -10.3 Hz, 1H), 7.23 (I, 74.4 Hz, 1H), 7.44 (broad .5, 1H), 7.68 (broad 5, 1H), 8.14 (b, 5.5 Hz, 1H), 13.73 (broad 5, 1H), LC-MS: 387 MH ⁺ .

Example 27. Sodium salt of (8) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole

To a suspension of (8) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (100 g, 0.259 mol) in a mixture of methyl isobutyl ketone (750 ml), isopropanol (75 ml) and water (5.0 ml) was added at room temperature a 40% aqueous solution No. 1OH (18.1 ml, 259 mmol). After heating to 50 ° C, a clear solution was obtained in which the reagent NuDo 8ireg Ce1 (10.0 g) was added. The product crystallized upon cooling to room temperature and then to 0 ° C. The crystals were separated by filtration, washed with methyl isobutyl ketone (3 times 40 ml) and dried at 35 ° C in vacuo to give the sodium salt of (8) -5-difluoromethoxy-2 - [(3-methoxy-4trideuteromethoxy-2-pyridinyl) methylsulfinyl ] -1H-benzimidazole as a white hygroscopic solid. 1 _square 105-106 ° C (decomp.), KR 10.3%, yield (105 g, 89%).

Chiral HPLC: e> 99.0%, optical rotation: [a] _s -94 ° (MeOH, s 0.50).

- 13 016814

Example 28. Sodium salt of (K) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole

As the starting compound, (K) -5-difluoromethoxy-2 - [(3-methoxy-4trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (15.5 g, 40.1 mmol) was used and the sodium salt was obtained (K ) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as a white hygroscopic solid. 1 _square 98-103 ° C (decomp.), CR 11.3%, yield (17.4 g, 94%), as described in Example 27.

Chiral HPLC: e> 98.0%, optical rotation: | α | v.) + 91 ° (MeOH, s 0.50).

Example 29. The magnesium salt trihydrate of bis - [(8) -5-difluoromethoxy-2 - [(3-methoxy-4trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole]

As the starting compound, the sodium salt of (8) -5-difluoromethoxy-2 - [(3methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (500 mg, CR 10.3%, 1.10 mmol) was used and the bis - [(8) -5-difluoromethoxy-2 - [(3-methoxy-4-trideterium-methoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole] magnesium salt trihydrate was obtained as a white solid. 1 _square 169-175 ° C (decomp.), CR 6.4%, yield (350 mg, 75%), as described in Example 24.

Chiral HPLC: e> 99.0%, optical rotation: | α | v.) -122 ° (MeOH, s 0.50).

Example 30. The magnesium salt trihydrate bis - [(K) -5-difluoromethoxy-2 - [(3-methoxy-4trideiummethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole]

The starting compound used was the sodium salt of (K) -5-difluoromethoxy-2 - [(3methoxy-4-trideuteriummethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (2.30 g, CR 11.3%, 5.00 mmol) and the magnesium salt trihydrate of bis - [(K) -5-difluoromethoxy-2 - [(3-methoxy-4trideiummethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole] was obtained as a white solid. 1 _square 141-145 C (decomp.), CR 6.9%, yield (1.23 g, 58%), as described in Example 24.

Chiral HPLC: e> 99.0%, optical rotation: | α | v.) + 120 ° (MeOH, s 0.50).

Example 31. Synthesis of the starting compound 5-trideuteromethoxy-1H-benzimidazole-2-thiol. Preparation of 4-trideuteromethoxynitrobenzene.

To a solution of sodium hydroxide (15.6 g, 390 mmol) in a mixture of methanol-64 (47.4 ml, 1.17 mol) and THF (50 ml), a 1-fluorine solution was added over 2 hours at 15-25 ° C. -4-nitrobenzene (50.0 g, 354 mmol) in THF (200 ml). The resulting suspension was stirred for another 3 hours at room temperature, then 10% aqueous HC1 solution (100 ml) and toluene (150 ml) were added. The organic phase was separated and evaporated to dryness, to give 4-trideuteromethoxynitrobenzene as a brown oil, which crystallized upon storage. 1 _sh . 48-51 ° C, yield (56.6 g, quantitative).

Ή-NMR (200 MHz, DMSO-66): δ 7.15 (t, 2H), 8.22 (t, 2H), GC-MS: 156 M ⁺ .

Preparation of 4-trideuteromethoxyacetanilide

10% Pb / C (3.6 g soaked in water), 4-trideuteromethoxynitrobenzene (72.5 g, 464 mmol) and isopropanol (508 ml) were charged into the autoclave. After purging the mixture with nitrogen (4 times), the resulting mixture was stirred in a hydrogen atmosphere under pressure (3-4 bar) at 50-60 ° C until the consumption of hydrogen ceased (for approximately 2.5 hours). The reaction mixture was cooled to room temperature and acetic anhydride (62.5 ml, 580 mmol) was added, stirred for another 4 hours, the catalyst was filtered off and washed with hot 2-propanol (270 ml, approximately 60 ° C). The combined filtrates were concentrated in vacuo to approximately 150 ml, methylcyclohexane (350 ml) was added, the resulting suspension was cooled to 10 ° C. The suspension was filtered and dried at 45 ° C. in vacuo to give 4-trideuteromethoxyacetanilide as a grayish solid. 1 _sh . 125 127 ° C, yield (67.0 g, 86%).

Я-NMR (200 MHz, DMSO-66): δ 2.00 (q, 3H), 6.85 (t, 2H), 7.47 (t, 2H), 9.74 (broad k, 1H) LC-MS: 169 MH ⁺ .

Preparation of 2-nitro-4-trideuteromethoxyaniline

A 50% aqueous solution of nitric acid (63.0 ml, 654 mmol) was added at 10-15 ° C for 1.5 hours in a solution of 4-trideuteromethoxyacetanilide (50.0 g, 297 mmol) in acetic acid (175 ml). Stirring was continued for 18 hours at room temperature. Then was added a 20% aqueous NaOH solution (671 ml) over about 1 hour at 15-20 ° C. The resulting brown suspension was heated at 50 ° C for 20 hours, then the pH was adjusted to 8 with the addition of a 20% aqueous HC1 solution (49 ml). The crude product was obtained by cooling the mixture to 10 ° C, the precipitate was filtered off, washed with water, the filter cake was suspended at 60 ° C in isopropanol (200 ml) and water (300 ml) was added over 1 h, the temperature of the mixture was maintained from 50 to 60 ° C, the mixture was evaporated and the resulting distillate (190 ml) was discarded. The resulting suspension was cooled to 10 ° C., filtered and washed with water (60 ml), dried at 30 ° C. in vacuo to give 2-nitro-4trideuteromethoxyaniline as a red solid. 1 _square 120-122 ° C, yield (46.7 g, 92%).

Ή-NMR (200 MHz, DMSO-66): δ 7.00 (b, 9.3 Hz, 1H), 7.16 (bb, 9.3 Hz, 2.9 Hz, 1H), 7.24 ( broad broad, 2H), 7.37 (6, 2.9 Hz, 1H), GC-MS: 171 M ⁺ .

- 14 016814

Preparation of 5-trideuteromethoxy-1H-benzimidazole-2-thiol

10% Pb / C (2.23 g soaked in water), 2-nitro-4-trideuteromethoxyacetanilide (45.6 g, 267 mmol) and isopropanol (460 ml) were charged into the autoclave. After thoroughly purging the mixture with nitrogen (4 times), the resulting mixture was stirred in a hydrogen atmosphere under pressure (3-4 bar) at 4050 ° C until the consumption of hydrogen ceased (for about 6 hours). Then, potassium salt of O-ethylxanthic acid (51.2 g, 319 mmol) was added and the reaction mixture was heated under reflux for 23 h, water (340 ml) was added and the pH was adjusted to 12.5 with the addition of a 20% aqueous solution of ΝαΟΗ ( 10 ml), then the main amount of isopropanol was removed by evaporation (460 ml). The resulting dark suspension was treated with charcoal (10 g), clarified by filtration and washed with toluene (350 ml), and a precipitate was obtained by adding a 20% aqueous solution of HC1 (53 ml), which was separated by filtration at 0 ° C, washed with water (100 ml) and dried at 35 ° C. in vacuo to give 5-trideuteromethoxy-1H-benzimidazole-2-thiol as an off-white solid. 1 _square 247-250 ° C, yield (45.5 g, 93%).

Ή-NMR (400 MHz, DMSO-66): δ 6.67 (b, 2.3 Hz, 1H), 6.72 (bb, 8.7 Hz, 2.4 Hz, 1H), 7.03 ( b, 8.6 Hz, 1H), 12.36 (broad 8, 1H), 12.40 (broad 8, 1H), LC-MS: 184 MH ⁺ .

Example 32. Synthesis of the starting compound 4-chloro-2-chloromethyl-3,5-dimethylpyridinium

Preparation of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine

A solution of 4-chloro-2,3,5-trimethylpyridine Ν-oxide (60.0 g, 350 mmol) in toluene (920 ml), preheated to 60 ° C, was added to acetic anhydride (232 ml) at 90-95 ° C for 7 hours. The reaction mixture was concentrated by evaporation in vacuo at 60 ° C, the resulting distillate (820 ml) was discarded. Toluene (840 ml) was added to the residue, and the solvent (940 ml) was removed by evaporation. Then, toluene (180 ml) and 40% aqueous solution No. 1OH (80 ml) were added, then the reaction mixture was heated at 50 ° C for approximately 15 hours. After addition of saturated aqueous sodium bicarbonate solution (120 ml), the phases were separated and the aqueous layer was again extracted with toluene (80 ml). The combined organic phase was washed with saturated aqueous sodium bicarbonate (120 ml) and evaporated to dryness to give 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine as a brown oil, which solidified upon storage, yield (61.8 g , (quantitative)).

Я-NMR (200 MHz, DMSO-b6): δ 2.30 ( ₈ , 3H), 2.36 ( ₈ , 3H), 4.58 (broad 8, 2H), 5.11 (broad 8, 1H), 8.27 ( ₈ , 1H), LC-MS: 172/174 MH ⁺ .

Preparation of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride

To a solution of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine (60.7 g, 354 mmol) and DMF (0.25 ml, 3.54 mmol) in toluene (200 ml) was added over 2 hours at 15 -30 ° C thionyl chloride (26.9 ml, 371 mmol). The mixture was stirred for another 2 hours at room temperature and ethanol (6 ml) was added until a viscous suspension was obtained. The solid was filtered off at 10 ° C, washed with toluene (80 ml) and dried at 40 ° C in vacuo to give 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride as an off-white solid. 1 _square 195-196 ° C, yield (66.5 g, 84%).

Я-NMR (200 MHz, DMSO-b6): δ 2.36 ( ₈ , 3H), 2.46 ( ₈ , 3H), 4.93 ( ₈ , 2H), 8.44 ( ₈ , 1H), 8 79 (broad 8, 1H), LC-MS: 190/192/194 MH ⁺ .

Example 33. 5-Trideuteromethoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole

A solution of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride (12.6 g, 55.6 mmol) in water (21 ml) was added at 55-65 ° C over 2 hours to a mixture of 5-trideuteromethoxy-1H- benzimidazole-2-thiol (9.50 g, 51.8 mmol), toluene (47 ml), water (23 ml) and 40% aqueous solution No. 1OH (14 ml). Stirring was continued at 60 ° C for 16 hours, then the reaction mixture was cooled to approximately 10 ° C. The precipitate was filtered off, washed with toluene (17 ml) and resuspended in water (132 ml), the suspension was filtered, then washed with water (70 ml) and dried at 35 ° C in vacuo to give 5-trideuteromethoxy-2 - [(( 4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole (KG 50%) as an off-white solid. 1 _square 99-102 ° C, yield (15.1 g, 82%).

Ή-NMR (200 MHz, DMSO-b6): δ 2.30 (8, 3H), 2.43 (8, 3H), 4.72 (8, 2H), 6.76 (bb, 8.7 Hz) , 2.5 Hz, 1H),

6.97 (broad 8, 1H), 7.35 (b, 8.7 Hz, 1H), 8.28 (8, 1H), 12.47 (broad.8, 1H), LC-MS: 337/339 MH ⁺ .

Example 34. 5-Methoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole

5-methoxy-1H-benzimidazole-2-thiol (24.0 g, 111 mmol) was used as the starting compound to give 5-methoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) monohydrate methylthio] -1Nbenzimidazole (KG 5.2%) as an off-white solid. 1 _square 100-102 ° C, yield (34.8 g, 89%), as described in example 33.

Ή-NMR (200 MHz, DMSO-b6): δ 2.30 (8, 3H), 2.43 (8, 3H), 4.72 (8, 2H), 6.76 (bb, 8.7 Hz) , 2.5 Hz, 1H),

6.98 (broad 8, 1H), 7.35 (b, 8.7 Hz, 1H), 8.28 (8, 1H), 12.41 (broad 8, 1H), LC-MS: 334/336 MH ⁺ .

Example 3 5. 5-Trideuteromethoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylthio] -1Nbenzimidazole

To a solution of 5-trideuteromethoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1Nbenzimidazole monohydrate (5.20 g, 14.7 mmol) in ΝΜΡ (30 ml) was added at 60- 65 ° C. in 10 equal portions over 1.5 hours solid sodium methoxide (5.80 g, 104 mmol). Stirring was continued at 60 ° C for

- 15 016814 h, then the reaction mixture was heated at 70 ° C for 24 h and finally at 80 ° C for 4 h. After dilution with water (200 ml) and addition of 10% aqueous HC1 (10 ml), the resulting dark brown solution the colors were extracted twice with toluene (100 + 40 ml). The combined organic phase was washed successively with 5% aqueous NaOH solution (2x200 ml) and water (100 ml), then the solution was evaporated to dryness. The precipitate was transferred into hot toluene (50 ml), clarified by filtration and evaporated again to dryness. The product was crystallized from TBME / toluene, 10: 1 (33 ml) to give 5trideuteromethoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole as a white solid colors. 1 _square 120-121 ° C, yield (2.27 g, 46%).

Ή-NMR (200 MHz, DMSO-b6): δ 2.20 (8, 3H), 2.27 (8, 3H), 3.73 (8, 3H), 4.65 (8, 2H), 6 75 (bb, 8.7 Hz,

2.5 Hz, 1H), 6.97 (br 8, 1 H), 7.35 (b, 8.7 Hz, 1 H), 8.17 (8, 1 H), 12.44 (br. 8, 1H), LC-MS: 333 MH ⁺ .

Example 36. 5-Trideuteromethoxy-2 - [(3,5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylthio] 1 H-benzimidazole

A solution of sodium trideuteromethoxide was prepared by adding methanol-b4 (1.70 ml, 41.5 mmol) at 50 ° C for 30 min to a suspension of sodium hydride (60% solution in mineral oil, 1.70 g, 41.5 mmol) in ΝΜΡ (12 ml). After heating to 60 ° C, a solution of 5-trideuteromethoxy 2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (2.10 g, 5.92 mmol) in ΝΜΡ (4 ml). Stirring was continued first at 70 ° C. for 24 hours, then at 85 ° C. for 5 hours. The reaction mixture was treated in the same manner as described in Example 35, whereby 5trideuteromethoxy-2 - [(3,5-dimethyl- 4-trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole as a white solid. 1 _square 120-121 ° C, yield (0.55 g, 28%).

Ή-NMR (200 MHz, DMSO-b6): δ 2.20 (8, 3H), 2.27 (8, 3H), 4.64 (8, 2H), 6.75 (bb, 8.7 Hz , 2.4 Hz, 1H),

6.89-7.38 (broad t, 2H), 8.17 (8, 1H), 12.42 (broad 8, 1H), LC-MS: 336 MH ⁺ .

Example 37. 5-Methoxy-2 - [(3,5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylthio] -1Nbenzimidazole

5-methoxy-2 - [(4-chloro-3,5-dimethyl-2pyridinyl) methylthio] -1H-benzimidazole monohydrate (24.0 g, 68.2 mmol) was used as the starting compound, and 5-methoxy-2 was obtained - [(3,5-Dimethyl-4trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole as a white solid. 1 _square 119-121 ° C, yield (8.72 g, 38%), as described in example 36.

¹ H-NMR (200 MHz, DMSO-b6): δ 2.20 (8, 3H), 2.27 (8, 3H), 3.77 (8, 3H), 4.64 (8, 2H), 6.75 (bb, 8.7 Hz,

2.5 Hz, 1H), 6.98 (broad 8, 1H), 7.35 (broad b, 8.6 Hz, 1H), 8.17 (8, 1H), 12.43 (broad 8, 1H), LC-MS: 333 MH ⁺ .

Example 38. rac-5-Trideuteromethoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] 1 H-benzimidazole

5-Trideuteromethoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylthio] - 1H-benzimidazole (1.50 g, 4.51 mmol) was dissolved in CH ₂ Cl ₂ (15 ml) and cooled to a temperature of from -55 to -40 ° C. A solution of 3-chloroperoxybenzoic acid (77% aqueous solution, 1.12 g, 5.00 mmol) in CH2C12 (8 ml) was slowly added to the resulting solution at the indicated temperature at the indicated temperature. The mixture was kept at a temperature of from -55 to -40 ° C, and then, while heating the mixture to approximately 0 ° C, triethylamine (0.87 ml, 6.28 mmol) was successively added and a mixture of 6% aqueous solution of Na ₂ CO ₃ and 2% an aqueous solution of Na ₂ 8 ₂ About ₃ (1: 1, 10 ml). Stirring was continued for 1 h at room temperature. The phases were separated and the organic layer was washed twice with a mixture of a 6% aqueous solution of Na ₂ CO ₃ and a 2% aqueous solution of Na ₂ CO ₃ (1: 1) and once with water (10 ml), then the solution was evaporated to dryness. The resulting residue was crystallized from ethyl acetate (6.0 ml) to give rac-5-trideuteromethoxy-2 - [(4-methoxy3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as a white solid. 1 _square 150-152 ° C (decomp.), Yield (1.27 g, 81%).

Ή-NMR (200 MHz, DMSO-b6): δ 2.17 (8, 3H), 2.20 (8, 3H), 3.69 (8, 3H), 4.67 (b, 13.6 Hz , 1H), 4.77 (b,

13.5 Hz, 1H), 6.92 (bb, 8.9 Hz, 2.4 Hz, 1H), 7.09 (br 8, 1 H), 7.54 (br b, 8.9 Hz, 1 H ), 8.18 (8, 1H), 13.39 (broad 8, 1H), LC-MS: 349 MH ⁺ .

Example 39. rac-5-Trideuteromethoxy-2 - [(3,5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

As the starting compound, 5-trideuteromethoxy-2 - [(3,5-dimethyl-4trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (1.20 g, 3.57 mmol) was used and rac-5trideuteromethoxy-2- was obtained [(3,5-Dimethyl-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as a white solid. 1 _square 147-148 ° C (decomp.), Yield (0.90 g, 72%), as described in Example 38.

Я-NMR (200 MHz, DMSO-b6): δ 2.16 (8, 3H), 2.20 (8, 3H), 4.67 (b, 13.5 Hz, 1H), 4.77 (b 13.5 Hz, 1H),

6.90-7.55 (broad t, 3H), 8.18 (8, 1H), 13.39 (broad 8, 1H), LC-MS: 352 MH ⁺ .

Example 40. rac-5-Methoxy-2 - [(3,5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] 1 H-benzimidazole

As the starting compound, 5-methoxy-2 - [(3,5-dimethyl-4-trideuteromethoxy-2pyridinyl) methylthio] -1H-benzimidazole (1.00 g, 3.01 mmol) was obtained and rac-5-methoxy- 2 - [(3,5-dimethyl

- 16 016814

4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as a white solid, 1 _pl . 14З-144 ° С (decomp.), Yield (0.86 g, 82%), as described in Example З8.

'H-NMR (200 MHz, DMSO-y6): δ 2.17 (q, ZN), 2.20 (q, ZN), Z, 81 (k, ZN), 4.67 (y, 1Z, 6 Hz, 1H), 4.77 (th,

1H, 5 Hz, 1H), 6.90-7.55 (broad t, H), 8.18 (q, 1 H), 1 H, 40 (broad h, 1 H), LC-MS: З49 MN ⁺ .

Example 41. The sodium salt of (8) -5-trideuteromethoxy-2 - [(3, 5-dimethyl-4-trideuteromethoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole

5-Trideuteromethoxy-2 - [(H, 5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (H, 02 g, 9.00 mmol) and bis (Y-pyrrolidinamide) (+) Β-tartaric acid (0.92 g, 3, 60 mmol) was suspended at room temperature in 3 ml of methyl isobutyl ketone. The mixture was heated to 40 ° C and approximately 8 ml of solvent (water) was removed by evaporation in vacuo. Then zirconium (IV) n-propoxide (0.40 ml, 70% solution in n-propanol, 0.90 mmol) was added and the mixture was stirred at 40 ° C for one more hour. After cooling to 3 ° C, Ν- was added ethyldiisopropylamine (0.11 ml, 0.63 mmol) and cumene hydroperoxide (1.52 ml, ~ 80% solution, 8.55 mmol). After stirring for approximately 20 hours at 3 ° C, the clarified reaction mixture was diluted with methyl isobutyl ketone (8.5 ml) and the reaction was stopped by adding sodium thiosulfate (0.11 g) in saturated sodium bicarbonate solution (15 ml). After phase separation, the organic phase was washed twice with saturated sodium bicarbonate solution (7.5 ml each). Water (25 ml) was added to the organic phase, and the pH of the mixture was adjusted to 12.5-1Z with the addition of 40% aqueous solution #JUN (0.71 ml). The organic layers were extracted twice with water (7.5 ml) at a pH of 12.5-1Z (if necessary, 40% aqueous solution No. YUN was added). The combined organic phase was washed with dichloromethane (15 ml). The pH was adjusted to 10 with potassium dihydrogen phosphate and the aqueous solution was extracted with dichloromethane (once 40 ml and twice 10 ml). The organic phase was evaporated to dryness to give (8) -5-trideuteromethoxy-2 - [(3, 5-dimethyl-4 trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as a brown oil, which was further purified to give appropriate sodium salt.

Then the crude product was transferred to methyl isobutyl ketone (15 ml) and isopropanol (1.5 ml), 40% aqueous solution #NO (0.63 ml) was added and the resulting suspension was cooled to 0 ° C. The solid was separated by filtration, washed with methyl isobutyl ketone (twice in 2.0 ml) and dried at 45 ° C in vacuo to give the sodium salt of (8) -5-trideuteromethoxy-2 - [(3, 5-dimethyl-4trideuteromethoxy-2 -pyridinyl) methylsulfinyl] -1H-benzimidazole as a off-white solid. ! _pl . 224-225 ° C (decomp.), KG 1.5%, yield (2.05 g, 61%).

Chiral HPLC: e> 97.0%, optical rotation: [a] _s -44 ° (MeOH, s 0.5Z), [a] _s + 3 ° C (H ₂ O, s 0, S9).

^! H-NMR (200 MHz, DMSO-Y6): δ 2.18 (q, 3H), 2.21 (k, 3H), 4, 99 (d, 12.9 Hz, 1H), 4.6З (d , 12.9 Hz, 1H), 6.54 (st, 8.7 Hz, 2.5 Hz, 1H), 6.98 (st, 2.5 Hz, 1H), 7, Z2 (broad, 8.6 Hz, 1H), 8.2Z (q, 1H).

Example 42. The magnesium salt of bis - [(8) -5-trideuteromethoxy-2 - [(3, 5-dimethyl-4-trideuteromethoxy-2pyridinyl) methylsulfinyl] -1H-benzimidazole]

The sodium salt of (8) -5-trideuteromethoxy-2 - [(3, 5dimethyl-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (200 mg, KG 1.5%, 0.528 mmol) was used as the starting compound. and the bis - [(8) -5-trideuteromethoxy-2 - [(3, 5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole] magnesium salt was obtained as a white solid. 1 _square 161-162 ° C (decomp.), KG 1.5%, yield (1Z2 mg, 68%), as described in example 24.

Chiral HPLC: e> 97.0%, optical rotation: [a] _s -120 ° (MeOH, s 0.50).

The following compounds of general formula (1) were obtained in the same manner as described above, but using a combination of the above methods.

For example, by reacting 4-chloro-2-chloromethyl-3-methylpyridinium chloride with 1H-benzimidazole-2-thiol, 2 - [(4-chloro-3-methyl-2-pyridinyl) methylthio] -1H- was obtained in the same manner as in Example 7 benzimidazole. The specified compound, for example, was reacted with 1,1-dideutero-3-methoxy-1-propanol or 1,1-dideutero-2,2,2-trifluoroethanol in the same manner as described in example 9, whereby 2 - [( 4- (1,1-Dididetero-3-methoxyprop-1-hydroxy) -3-methyl-2pyridinyl) methylthio] -1H-benzimidazole and 2 - [(4- (1,1-dididetero-2,2,2- trifluoroethoxy) -Z-methyl-2pyridinyl) methylthio] -1H-benzimidazole, respectively. Finally, the oxidation of these compounds was carried out similarly to that described in Example Z8, whereby rac-2 - [(4- (1,1-dididetero-Zmethoxypropane-1-hydroxy) -Z-methyl-2-pyridinyl) methylsulfinyl] was obtained -1H-benzimidazole and rac-2 - [(4- (1,1 diddetero-2,2,2-trifluoroethoxy) -3-methyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, respectively, each of which represents a compound general formula (1).

In another example, 4-chloro-2-chloromethyl-3, 5-dimethylpyridinium chloride was reacted with 5methoxy-1H-imidazo [4,5-b] pyridin-2-thiol in the same manner as described in example 3P, and 5methoxy was obtained -2 - [(4-chloro-3, 5-dimethyl-2-pyridinyl) methylthio] -1H-imidazo [4,5-b] pyridine. The specified compound was reacted with methanol-4, similarly to that described in example C6, and 5methoxy-2 - [(3, 5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylthio] -1H-imidazo [4, 5-b] pyridine, which in turn was oxidized in the same manner as described in Example Z8, whereby rac-5-17 016814 methoxy-2 - [(3,5-dimethyl-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl was obtained ] -1H-imidazo [4,5-b] pyridine, which is the main compound of the general formula (1).

Industrial applicability

The compounds of general formula 1 and their salts and solvates, preferably hydrates, and solvates, preferably salt hydrates (in this context, the compounds of the present invention) are characterized by the presence of suitable pharmaceutical properties, which allows them to be used as commercial products. First of all, they have a pronounced inhibitory effect on the secretion of acid of the gastric juice and a significant protective effect on the gastrointestinal tract in warm-blooded animals, primarily humans. The compounds of the present invention are characterized by high selectivity, high duration of action, extremely high bioavailability, the same metabolic profile in various organisms, the absence of significant side effects and a wide range of therapeutic effects.

The term gastrointestinal protective effect, as used in this context, means the prevention and treatment of gastrointestinal disorders, especially gastrointestinal inflammatory disorders and foci (such as, for example, gastric ulcer, duodenal ulcer, gastritis, gastric syndrome due to increased acid secretion or the action of pharmaceutical compositions, gastroesophageal reflux disease (GERD), Crohn's disease, inflammatory bowel disease (ΙΒΌ)) caused, for example, by microorg nism (for example, Neusobacillus pylori), bacterial toxins, pharmaceutical compositions (for example, anti-inflammatory and antirheumatic drugs), chemicals (for example, ethanol), stomach acid, or stress.

Using various models to determine antiulcer and antisecretory properties, it was unexpectedly found that the compounds of the present invention have significant advantages over the compounds described in the prior art, especially with regard to their pharmacokinetic properties. Such improved pharmacokinetic properties make it possible, for example, to reduce the amount of the compound of the present invention necessary for treatment or prophylaxis, or to provide a longer effect when the same amount of the compound of the present invention is administered compared to the compounds described in the prior art. In this regard, the compounds of the present invention have an advantage in terms of patient safety or from an economic point of view, for example, in relation to the cost of drugs, etc. Due to these properties, the compounds of the present invention are primarily suitable for use in medicine and veterinary medicine, i.e., primarily for the treatment and / or prevention of disorders in the gastrointestinal tract.

Thus, the present invention also provides the use of the compounds of the present invention for the treatment and / or prevention of the above diseases.

The present invention also provides the use of the compounds of the present invention for the preparation of pharmaceutical compositions for the treatment and / or prophylaxis of the above diseases.

The present invention also provides pharmaceutical compositions comprising the compounds of the present invention. First of all, the present invention provides pharmaceutical compositions for oral administration in solid form, containing compounds of formulas 1, 1a or 1b in the form of their salts, especially in the form of a sodium or magnesium salt, and / or in the form of a hydrate of said salt.

Pharmaceutical compositions are prepared according to standard procedures. The compounds of the present invention as pharmaceutical compositions are used individually or, preferably, in combination with suitable excipients or carriers in the form of tablets, coated tablets, capsules, suppositories, plasters (for example, as transdermal therapeutic systems), emulsions, suspensions or solutions, the content of the active component in which is preferably from about 0.1 to about 95%, and if necessary, receive pharmaceutical dosage forms (n for example, sustained release forms or enteric forms) which contain the appropriate excipients and carriers which are selected depending on the active ingredient and / or the desired period before the onset of action and / or on the duration of action.

Excipients or carriers intended for the desired pharmaceutical compositions are known to those skilled in the art. In addition to solvents, gelling agents, suppository bases, tablets and other carriers for the active ingredients, for example, antioxidants, dispersing agents, emulsifying agents, anti-foaming agents, unpleasant taste masking agents, preservatives, solubilizing agents, colorants or, previously total permeation accelerating agents and complexing agents (e.g. cyclodextrins).

The compounds of the present invention can be administered orally, parenterally or under

- 18 016814 dermal method.

It has been found that when administered to humans to provide the desired result, it is preferable to administer the compounds of the present invention by the oral route in a daily dose of from about 0.01 to about 1, preferably from about 0.02 to about 0.5, and especially from about 0.04 up to about 0.3 mg / kg body weight (based on the weight of the compounds of the present invention in free form, i.e. not in salt form), if necessary in the form of several doses, preferably from 1 to 4 single doses. When administered parenterally, similar or (especially if the active compounds are administered intravenously) lower doses are used. The optimal doses and route of administration of the active compounds required in each case are determined by those skilled in the art.

Another object of the present invention is a pharmaceutical composition containing one or more compounds of the present invention in a mixture with one or more standard excipients, wherein a single dose comprises from about 2 to 60 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition containing one or more compounds of the present invention in a mixture with one or more standard excipients, wherein a single dose comprises about 4 to 40 mg of the compound in free form.

Another object of the present invention is the use of the compounds of the present invention for the treatment of disorders of the gastrointestinal tract.

Another object of the present invention is the use of the compounds of the present invention for the treatment of gastrointestinal disorders in patients suffering from a slow metabolism.

Another object of the present invention is the use of the compounds of the present invention for the treatment of gastrointestinal disorders in patients at risk of adverse effects of other drugs.

Another object of the present invention is the use of the compounds of the present invention for the treatment of gastrointestinal disorders in patients requiring inhibition of acid secretion over an extended period of time.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients suffering from a slow metabolism, and containing one or more compounds of the present invention in a mixture with one or more standard excipients, wherein a single dose comprises from about 2 to 60 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients suffering from a slow metabolism, and containing one or more compounds of the present invention in a mixture with one or more standard excipients, and a single dose includes from about 4 up to 40 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients at risk of adverse effects of other drugs and containing one or more compounds of the present invention in a mixture with one or more standard excipients, wherein a single dose comprises from about 2 to 60 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients at risk of adverse effects of other drugs and containing one or more compounds of the present invention in a mixture with one or more standard excipients, and a single dose includes approximately from 4 to 40 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients requiring inhibition of acid secretion for an extended period of time, and containing one or more compounds of the present invention in a mixture with one or more standard excipients, a single dose includes from about 2 to 60 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients requiring inhibition of acid secretion for an extended period of time, and containing one or more compounds of the present invention in a mixture with one or more standard excipients, moreover, a single dose includes from about 4 to 40 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients suffering from a slow metabolism, and containing in solid dosage form for oral administration one or more

- 19 016814 lei of the present invention or a hydrate of said salts in a mixture with one or more standard excipients, wherein a single dose comprises from about 2 to 60 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients suffering from a slowed metabolism, and containing in solid dosage form for oral administration one or more salts of the present invention or a hydrate of said salts in a mixture with one or more standard excipients, and a single dose includes from about 4 to 40 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients at risk of negative effects of other drugs and containing in solid dosage form for oral administration one or more salts of the present invention or a hydrate of said salts in a mixture with one or more than standard excipients, with a single dose comprising from about 2 to 60 mg of the compound in free form.

Another object of the present invention is a pharmaceutical composition intended for the treatment of gastrointestinal disorders in patients at risk of negative effects of other drugs and containing in solid dosage form for oral administration one or more salts of the present invention or a hydrate of said salts in a mixture with one or more standard excipients, wherein a single dose comprises from about 4 to 40 mg of the free form compound.

Another object of the present invention is a pharmaceutical composition for treating gastrointestinal disorders in patients requiring inhibition of acid secretion for an extended period of time, and containing in solid dosage form for oral administration one or more salts of the present invention or a hydrate of said salts in a mixture with one or more standard excipients, wherein a single dose comprises about 2 to 60 mg of the compound in free form IU.

Another object of the present invention is a pharmaceutical composition intended for the treatment of disorders of the gastrointestinal tract in patients requiring inhibition of acid secretion for an extended period of time, and containing in solid dosage form for oral administration one or more salts of the present invention or a hydrate of these salts in a mixture with one or more standard excipients, wherein a single dose includes about 4 to 40 mg of the compound in free form.

If the compounds of the present invention are intended for the treatment of the above diseases, the pharmaceutical compositions may also include one or more pharmaceutically active ingredients from other groups of pharmaceutical compositions. Examples include tranquilizers (e.g., from the benzodiazepine group, e.g. diazepam), antispasmodic drugs (e.g., bioethamiverin or camilofin), anticholinergic drugs (e.g., oxyphencyclimine or phencarbamide), and local painkillers (e.g., tetracaine or procaine), and optionally , vitamins or amino acids.

In the present context especially be mentioned a combination of compounds of the present invention with other pharmaceuticals which form buffer or neutralize gastric acid or which inhibit acid secretion, such as, for example, antacids (such as, for example, magaldrate) or blockers of H ₂ (for example, cimetidine, ranitidine), and with gastrin antagonists designed to enhance the main effect as an additional effect and / or to eliminate or reduce side effects or to accelerate the onset of action. It should also be mentioned fixed or free combinations with non-steroidal anti-inflammatory drugs (such as, for example, etofenamate, diclofenac, indomethacin, ibuprofen or piroxicam) intended to prevent damage to the gastrointestinal tract caused by non-steroidal anti-inflammatory drugs, or combinations with compounds that alter motility in the gastrointestinal tract, or with compounds that reduce the incidence of temporary relaxation of the lower esophageal sphincter (TOBOK), or with bacterial substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, nitroimidazoles or bismuth salts), intended to suppress Neusobacillus and other. Antibacterial components in the combination include, for example, meslocillin, ampicillin, amoxicillin, cephalotin, cefoxitin, cefotaxime, imipenem, gentamicin, amikacin, erythromycin, ciprofloxacin, metronidazycin, amlithromycin + or combinations thereof (e.g. .

In combination therapy, the compounds of the present invention are administered separately, sequentially, simultaneously or alternately (for example, in the form of combined dosage forms, in the form of separate dosage forms, in the form of a combination of separate dosage forms, in the form of fixed or unfixed combinations, in the form of sets of components or mixtures ) with one or more

- 20 016814 less standard drugs, such as described above.

The term combination used in this context means a fixed combination, an unfixed combination or a set of components.

The term fixed combination means a combination in which the first active ingredient and the second active ingredient are included in the same dosage form. One example of a fixed combination is a pharmaceutical composition in which said first active ingredient and said second active ingredient are present as a mixture for simultaneous administration, such as a composition. Another example of a fixed combination is a pharmaceutical composition in which said first active ingredient and said second active ingredient are included in a single dosage form, rather than as a mixture.

The term “component kit” means a combination in which said first active ingredient and said second active ingredient are present in several dosage forms. One example of a kit is a combination in which said first active ingredient and said second active ingredient are present in separate dosage forms. Kit components can be entered individually, sequentially, simultaneously, or alternately.

Pharmacology

Metabolism in liver microsomes Materials and methods

Pantoprazole or the compounds described in examples 1 or 2 (each at a concentration of 10 μM) were incubated with liver microsomes (all preparations of Oep Tey. Except for the product Μίηί Ρί§ of TEVi) at a protein concentration of 1 mg / ml, in a buffer solution of 100 mm Tris -CH1, pH 7.4, 1 mM NADPH ₂ . The reaction was stopped after 90 minutes with liquid nitrogen, the starting compound was detected by HPLC (eluent: 10 mM KH ₂ PO ₄ , pH 7.4, gradient from 20 to 44% acetonitrile).

Table 1. The metabolism of N-pantoprazole compared with deuterated compounds (example 1, 2) in microsomes after 90 min of incubation (depending on the type of animal)

Kind of animal The degree of metabolism of the compound in% n- pantoprazole Example 1 Example 2 Example 1 / pantoprazole Example 2 / pantoprazole Rat 61 35 17 0.57 0.28 Dog twenty 12 10 0.60 0.50 Man 28 14 fifteen 0.50 0.54 Mouse 62 36 17 0.58 0.27 The guinea pig 78 59 54 0.75 0.69 A monkey 73 47 35 0.64 0.48 Dwarf pig 26 nineteen nineteen 0.73 0.73

Metabolic clearance

To evaluate the properties of the compounds of the present invention, the intrinsic clearance of the compounds was determined in the presence of recombinant human cytochrome P450 (RMS), i.e. in the presence of isoenzymes SUR1A2, SUR2S8, SUR2S19, SUR2I6, SUR3A4 and SUR3A5.

Materials and methods

The compounds described in examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41, and the non-deuterated racemic omeprazole, its (8) enantiomer, non-deuterated pantoprazole and its enantiomers were incubated in a buffer solution containing 1 nmol / ml recombinant P450 (Surekh, Eipbee, IR), 4 mg / ml microsomal protein, 100 mM Tris-HC1 pH 7.4 and 1 mM NADPH for 0, 3, 6, 12, 15 or 30 min at 37 ° FROM. Incubation was performed in triplicate. When incubating in the presence of СУР2С19, the concentration of P450 was reduced to 0.5 nmol / ml and the incubation time interval was 0, 1, 2, 3, 4, and 5 min. Own clearance was determined by reducing the content of the starting compound. The content of omeprazole and deuterated analogues was determined by HPLC. The lower detection limit of this method, taking into account the variability of the results, was 17.6 μl / min / nmol P450.

results

It was established that in the presence of СУР2С19 and СУР3А4, the oxidative metabolism of omeprazole, pantoprazole and their deuterated analogues occurs. In the presence of all other isoenzymes of cytochrome P450 (СУР1А2, СУР2С8, СУР2С9, СУР2И6, СУРАА), none of the compounds metabolizes (when the content is above the detection limit).

Kinetics of the formation of 5-hydroxyomeprazole and 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2pyridyl) methyl] sulfinyl] -1H-benzimidazole

After assessing the metabolic clearance of the compounds of the present invention in the presence of P450 enzymes, the kinetics of formation of the main metabolite identified in the human body, i.e. 5-hydroxyomeprazole (5-methoxy-2 - [[(4-methoxy-3-methyl-5-hydroxymethyl-2pyridinyl) methyl] sulfinyl] -1H-benzimidazole for omeprazole and 5- (difluoromethoxy) -2 - [[(3 methoxy 4

- 21 016814 sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole for pantoprazole). The formation of 5-hydroxyomeprazole and 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1Nbenzimidazole mainly occurs in the presence of СУР2С19. The combined fractions of previously frozen human hepatocytes were used as a more advanced системыη νίΐΓΟ system compared to microsomes from the human liver, because all the main enzymes that are involved in the metabolism of drugs (phase I, phase II, hydrolases) are functional in this ίη νίΐΓΟ system.

Materials and methods

The compounds described in examples 17, 19, 20, 21, 27, 28, 38, 39, 40 and 41, and the non-deuterated racemic omeprazole, its (8) enantiomer, non-deuterated pantoprazole and its enantiomers were incubated in Krebs-Henseleit buffer solution ( КНВ), containing 84 μg / ml amikacin, 1 mM calcium chloride, 20 mM HEPE8, 4.2 μM heptonic acid, 28.5 mM sodium bicarbonate and pre-frozen human hepatocytes (pooled fractions from 10 donors, from , MI И8Л) at a concentration of 10 cells / ml. The time dependence of the formation of 5hydroxyomeprazole and 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1Nbenzimidazole (M2) was linear under the indicated conditions for a period of time up to 60 min The dependence of the rate of formation of 5-hydroxyomeprazole was determined at 10 different concentrations of the compound (0, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, 100, 200 and 2500 μM) during incubation for 60 min at 37 ° C in duplicate. The dependence of the content of 5- (difluoromethoxy) -2 - [[(3-methoxy-4sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (M2) was determined at 9 different concentrations of the compound (0, 0.5, 1.0 , 2.5, 5.0, 10.0, 25.0, 50.0 and 100 μM) by double incubation for 60 min at 37 ° C in double repetition. The amount of 5-hydroxyomeprazole was determined by LCMS / MS. As an internal standard, 5-hydroxyomeprazole from the company Waterschwab AB, Lipb, 8 ueben was used. and 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1Nbenzimidazole (M2) from human urine. The concentration at which half of the maximum formation rate (K _M ) and maximum formation rate (ν ^) is observed was determined by nonlinear regression analysis according to the Michaelis-Menten equation. Own clearance (C ^ was calculated by dividing ν ^ by Km.

results

The compounds described in examples 39 and 40, both deuterated at position 4 of methoxypyridinyl, have formation rates of approximately 1.5 times lower than undeuterated omeprazole. There is no difference in the CM values of racemic [ ¹ H], [ ² H3] and [ ² H6] omeprazole analogues, which exceeded the experimental variability of the results (Fig. 1). A decrease in the rate of formation of 5-hydroxyomeprazole is observed for the compound described in example 40, but unexpectedly is not observed for the compound described in example 38 (Fig. 1). Moreover, there is no difference in the rates of formation of [ ² H3] omeprazole deuterated at the 4-position of methoxypyridyl (Example 40) and [ ² H6] omeprazole, also deuterated at the 5-position of methoxybenzimidazole (Example 41, Fig. 3). Formation of 5-hydroxyomeprazole from racemic | 'H | omeprazole and its (8) enantiomer is characterized by stereospecific differences, because the difference in the values of K _M and ν _{ιηαχ of} racemic and (8) -omeprazole exceeds experimental variability. Replacement of 6 atoms [ ^! H] on the [ ² H] atoms in the position of 4-methoxypyridinyl and 5-methoxybenzimidazole in the composition of (8) -omeprazole (Example 41) does not affect the intrinsic clearance (Ο _ιηί ) of 5-hydroxyomeprazole (Fig. 3).

It was found that at a substrate concentration of more than 100 mM, inhibition of the formation of 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (M2) from pantoprazole is observed, its enantiomers and from the compounds described in examples 17, 19, 20, 21, 27 and 28. Thus, the results obtained by incubation at a substrate concentration of 100 and 250 μM were excluded from the calculation of K _M and ν _ιηαχ . The formation of M2 from racemic [ ¹ H] pantoprazole and enantiomers is characterized by stereospecific differences (Fig. 2A). The formation rates of racemic (B) and (8) analogs (examples 19, 27 and 28), deuterated in the 4-methoxypyridyl position, are at least 2.5 times lower compared to their non-deuterated analogues (Fig. 2B) . The intrinsic clearance of racemic (B) and (8) analogues (examples 19, 27 and 28), deuterated at the 4-methoxypyridyl position, is at least 4.7 times lower than their non-deuterated analogues (Table 2 ) The stereospecific differences in the formation of M2, which are observed for analogues of [ ¹ H] pantoprazole, are less pronounced compared to analogues deuterated at the 4-methoxypyridyl position (Fig. 2B). It was unexpectedly found that the decrease in the rate of formation of M2 compared with non-deuterated compounds depends on the position of the trideuteromethoxy group in the pyridyl residue of the molecule (Fig. 4). The increase in the number of [ ¹ H] atoms replaced by [ ² H] atoms in the position of the 4-methoxypyridyl molecule ([ ¹ H], [ ² H3], example 21, [ ² H2], example 20 and [ ² H ₃ ] example 19 ), leads to a decrease in the rate of formation of M2.

- 22 016814

Table 2. Own clearance (C1 _t1 ) in the combined fractions of human hepatocytes after incubation in the presence of pantoprazole and the compounds of the present invention

Compound Own clearance C1 | _{P (} (μl / min / 10 cells) Own clearance C1 | c ₍ racemic omeprazole in total% Racemic omeprazole 2.0 one hundred Example 40 1.4 69 Example 38 2.1 107 Example 39 1.4 69 Sodium salt (8) = omeprazole 0.7 37 Example 41 0.8 40 C1 ( _P (racemic pantoprazole in total% Sodium salt of racemic pantoprazole, 1.5 N ₂ O 27.9 one hundred Example 19 5.1 eighteen Example 17 22.0 79 Example 20 13.5 48 Example 21 17.7 63 C1 | p ((K) -pantoprazole in total% Sodium salt (K.) of pantoprazole, 1.5 N ₂ O 25.7 one hundred Example 28 5.5 21 C1] _P1 (H) -pantoprazole in total% Sodium salt of (8) pantoprazole, 1.5 N ₂ O 16.1 one hundred Example 27 3.4 21

CLAIM

Claims (27)

1. Compounds of General Formula 1 H2 from where CT is hydrogen or C1-C ₄ alkoxy, R2 is _C1-C4 alkyl or _C1-C4 alkoxy, R3 is _C1-C4 alkyl, C1-C ₄ alkoxy or C ₂ -C ₈ alkoxyalkoxy, R4 is hydrogen or _C1-C4 alkyl, Ζ means CH or N and pharmaceutically acceptable salts, solvates and solvates of salts of these compounds in which at least one hydrogen atom in the groups K1, K2, K3, K4 or in any combination of K1, K2, K3 and K4 is replaced by deuterium atom. 2. Compounds of formula 2 wherein R1 is hydrogen or C1-C ₄ alkoxy, R2 is _C1-C4 alkyl or _C1-C4 alkoxy, R3 is _C1-C4 alkyl, C1-C ₄ alkoxy or C ₂ -C ₈ alkoxyalkoxy, R4 is hydrogen or _C1-C4 alkyl, Ζ means CH or Ν, where at least one hydrogen atom in the composition of K1, K2, K3 and K4 or in any combination thereof is replaced by a deuterium atom. 3. The compounds according to claim 1 or 2, in which at least one hydrogen atom in the composition of K3 is replaced by - 23 016814 deuterium atom and R3 represents a _C1-C2 alkoxy or C ₂ -C ₅ alkoxyalkoxy. 4. The compounds according to claim 1 or 2, in which K1 is hydrogen, methoxy or difluoromethoxy, K2 is methyl or methoxy, KZ is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen or methyl, at least one hydrogen atom in K3 is replaced by a deuterium atom. 5. The compounds according to claim 1 or 2, in which K3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, with all the hydrogen atoms in K3 being replaced by deuterium atoms. 6. The compounds according to claim 1 or 2, in which K1 is hydrogen, methoxy or difluoromethoxy, K2 is methyl or methoxy, K3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen or methyl, all hydrogen atoms in K3 are replaced by deuterium atoms. 7. The compounds according to claim 1, in which K1 is methoxy, K2 is methyl, K3 is methoxy, K4 is methyl, or in which K1 is hydrogen, K2 is methyl, K3 is 2,2,2-trifluoroethoxy or methoxypropoxy, K4 means hydrogen, or in which K1 is difluoromethoxy, K2 is methoxy, K3 is methoxy, and K4 is hydrogen, with at least one hydrogen atom in K3 being replaced by a deuterium atom. 8. The compounds of claim 7, wherein K1 is hydrogen, K2 is methyl, K3 is 2,2,2 trifluoroethoxy or methoxypropoxy, K4 is hydrogen, or in which K1 is difluoromethoxy, K2 is methoxy, K3 is methoxy, and K4 is hydrogen and at least one hydrogen atom in K3 is replaced by a deuterium atom. 9. The compounds according to claim 1, in which K1 is methoxy, K2 is methyl, K3 is methoxy, and K4 is methyl, or in which K1 is hydrogen, K2 is methyl, and K3 is 2,2,2 trifluoroethoxy or methoxypropoxy, K4 means hydrogen, or in which K1 means difluoromethoxy, K2 means methoxy, K3 means methoxy, and K4 means hydrogen, all of the hydrogen atoms in K3 are replaced by deuterium atoms. 10. The compounds of claim 1, wherein K1 is hydrogen, K2 is methyl, and K3 is 2,2,2 trifluoroethoxy or methoxypropoxy, K4 is hydrogen, or in which K1 is difluoromethoxy, K2 is methoxy, K3 is methoxy, and K4 is hydrogen, and all the hydrogen atoms in K3 are replaced by deuterium atoms. 11. (K / 8) -5-Methoxy-2 - [(4-trideuteromethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1Nbenzimidazole and pharmaceutically acceptable salts, solvates and solvates of salts of this compound. 12. (K / 8) -2- [3-Methyl-4 - ((1,1-dideutero-2,2,2-trifluoroethoxy) -2-pyridinyl) methylsulfinyl] -1benzimidazole and pharmaceutically acceptable salts, solvates and solvates thereof salts of said compound. 13. (K / 8) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridyl) methylsulfinyl] -1Nbenzimidazole and pharmaceutically acceptable salts, solvates and solvates of salts of this compound. 14. (K / 8) -2 - {[4- (3-Trideuteromethoxyhexadeuteropropoxy) -3-methylpyridin-2-yl] methylsulfinyl} -1Nbenzimidazole. 15. (K / 8) -5-Methoxy-2 - ((4-trideuteromethoxy-3,5-dimethyl-2-pyridylmethyl) sulfinyl) -1 Nimidazo [4,5-b] pyridine. 16. 8 (-) - 5-Methoxy-2 - [(4-trideuteromethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1Nbenzimidazole and pharmaceutically acceptable salts, solvates and solvates of salts of this compound. 17. (8) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridylmethyl) sulfinyl] -1Nbenzimidazole and pharmaceutically acceptable salts, solvates and solvates of salts of said compound. 18. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 or 3-17, in admixture with one or more pharmaceutically acceptable excipients. 19. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 or 3-17 in a mixture with one or more pharmaceutically acceptable excipients, wherein a single dose is about 2 to 60 mg of a compound of general formula 1. 20. The use of the compounds according to any one of claims 2 to 6 to obtain a compound of formula 1, as described in any claims 1 or 3-17. 21. The compounds of formula 3 where X is a halogen or activated alcohol derivative selected from the group consisting of alkyl sulfonate, aryl sulfonate or perfluoroalkanesulfonate, R2 is _C1-C4 alkyl or _C1-C4 alkoxy, R3 is _C1-C4 alkyl, C1-C ₄ alkoxy or C ₂ -C ₈ alkoxyalkoxy, R4 is hydrogen or _C1-C4 alkyl, where at least one hydrogen atom of R2, R3, R4 or any combination of R2, R3 and R4 is replaced by deuterium atom. 22. The compound according to item 21, in which X means a halogen, which is selected from iodine, bromine, fluorine or chlorine. - 24 016814 23. The compound according to one of paragraphs.21 or 22, in which K2 is methyl or methoxy, K3 is methoxy, 2,2,2-trifluoroethoxy or methoxypropoxy, K4 is hydrogen or methyl, with at least one hydrogen atom in the composition of KZ replaced by a deuterium atom. 24. The compound according to item 23, in which all the hydrogen atoms in the composition of K3 are replaced by deuterium atoms. 25. The use of a compound according to any one of claims 21-24 for the preparation of a compound of formula (1) or (2) as described in any claims 1-17. 26. The use of a compound according to any one of claims 1 or 3-17 for the manufacture of a medicament for the treatment and / or prophylaxis of gastrointestinal disorders. 27. The use of a compound according to any one of claims 1 or 3-17 for the treatment and / or prevention of disorders of the gastrointestinal tract.