BRPI0614039A2 - isotopically substituted proton pump inhibitors - Google Patents

Abstract

ISOTOPICALLY REPLACED INHIBITORS FROM THE PROTON PUMP. The present invention relates to benzimidazoles of formula (1) and to pharmaceutical compositions comprising these compounds, and also to intermediates of formula (2 and 3).

Description

Report of the Invention Patent for "ISOTOPICALLY REPLACED PROTON PUMP INHIBITORS".

Invention Matter

The present invention relates to isotopically substituted proton pump inhibitors and their (R) and (S) enantiomers. These compounds may be used in the pharmaceutical industry to prepare pharmaceutical compositions.

Background of the Invention

Due to their inhibitory action of H + / K + -ATPase, pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, such as those known, for example, from EP-A-0005129, EP-A-0166287, EP-A-0174726, EP-A-0254588 and EP-A-0268956 are of considerable importance in the therapy of disorders associated with increased gastric acid secretion.

Examples of commercially available or clinically available active compounds of this group are 5-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (INN: omeprazole ), (S) -5-Methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (INN: esomeprazole), 5-difluoromethoxy-2 - [( 3,4-dimethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (INN: pantoprazole), 2- [3-methyl-4- (2,2,2-trifluorooxy) -2-pyridinyl) methylsulfinyl] -1 H-benzimidazole (INN: lansoprazole), 2 - {[4- (3-methoxypropoxy) -3-methylpyridin-2-yl] methylsulfinyl} -1H-benzimidazole (INN: rabeprazole) and 5-methoxy-2 - ((4-Methoxy-3,5-dimethyl-2-pyridylmethyl) sulfinyl) -1H-imidazo [4,5-b] pyridine (INN: tenatoprazole).

The sulfinyl derivatives mentioned above are also due to their mechanism of action, called proton pump inhibitors or, for short, PPI.

Description of Related Art

US 6,818,200 discloses dihydropyridine compounds and antibiotics wherein at least one hydrogen atom is replaced by one deuterium atom. Deuterated compounds are obtained by reaction of the H-form with mixtures of deuterium oxide and a suitable catalyst sealed in drastic reaction conditions, ie at elevated temperatures (60 - 80 ° C) and for extended reaction times (up to 190 hours). It further describes a certain influence on the pharmacological properties of these compounds due to H / D exchange.

Description of the Invention

It has now surprisingly been found that iso-topically substituted compounds described in detail below significantly influence inhibition of acid secretion.

The invention relates to compounds of general formula 1

<formula> formula see original document page 3 </formula>

Where

R1 is hydrogen or 1-4C-alkoxy

R2 is 1-4C-alkyl or 1-4C-alkoxy

R3 is 1-4C-alkyl, 1-4C-alkoxy or 2-8C-alkoxyalkoxy

R4 is hydrogen or 1-4C-alkyl

Z is C-H or N

and pharmaceutically acceptable salts, solvates, preferably hydrates, esolvates, preferably hydrates of salts thereof, wherein at least one hydrogen atom of R1, R2, R3, R4 or any combination of R1, R2, R3 and R4 is substituted by one. Deuterium atom.

1-4C-Alkyl represents straight or branched chain alkyl groups of 1 to 4 carbon atoms. Examples that may be mentioned are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and preferably the methyl group.

1-4C-Alkoxy represents a group which in addition to oxygen contains one of the above-mentioned 1-4C-alkyl groups or 1-4C-fluorinated alkyl groups. Examples of 1-4C-alkyl groups which may be mentioned are butoxy, isobutoxy, sec-butoxy, tert-butoxy, propoxy, isopropoxy, ethoxy groups and preferably the methoxy group. Examples of 1-4C-alkyl fluorinated groups are 2,2,3,3,3-pentafluorpropyl, 2,2,3,3-tetrafluorpropyl, 1- (trifluoromethyl) -2,2,2-trifluoroethyl, 2,2, 3,3,4,4,4-heptafluorbutyl and preferably 2,2,2-trifluoroethyl and difluoromethyl.

2-8C-Alkoxyalkoxy represents a group which in addition to the deoxygen atom contains an internal alkylene containing 1-AC alkylene groups and a terminal alkyl group containing 1-4C alkyl groups and are connected by an oxygen atom to the internal alkylene group. Examples are methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxypropoxy, ethoxyisopropoxy, isopropoxymethoxy, propoxymethoxy, methoxybutoxy, methoxyisobutoxy, isoproproxyoxypropoxy, propoxypropoxyoxyoxypropoxy, ethoxy-tert-butoxy and preferably methoxypropoxy.

According to the invention, within the meaning of salts are included all salts with inorganic and organic bases, in particular alkali metal bones such as lithium, sodium and potassium salts, or alkaline earth metal bones such as alkaline earth metals. magnesium and calcium salts, but also other pharmacologically compatible salts, such as, for example, aluminum salts or zinc salts. Particularly preferred are sodium salts and magnesium salts.

Pharmacologically incompatible salts, which may be obtained initially, for example, as process products in the production of compounds according to the invention on an industrial scale, which are also within the scope of the invention, are for the manufacture of pharmaceutical compositions. - converted to the pharmacologically tolerable salts by processes known to the person skilled in the art.

One skilled in the art knows that the compounds according to the invention and their salts, if, for example, they are isolated in crystalline form, may contain various amounts of solvents. The invention therefore also comprises all solvates and in particular all hydrates of the compounds of formula 1, and also all solvates and in particular all hydrates of the salts of the compounds of formula 1. Within the meaning of desolvates are included all pharmaceutically acceptable solvents which result in such For the nomenclature of the compounds according to the invention the terms "deuterium" or "deuterium" indicate a deuterium atom ([2H]). Also, the prefixes "bis" or "di" and "tri" or "tris" respectively indicates the occurrence of two or three, for example deuterium atoms in a specific group, ie 1,1-dehydro-2,2,2-trifluorooxy or trideuteriomethoxy.

Preferred within the scope of the invention are compounds of formula 1 wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom and R3 is a 1-2C alkoxy group or a 2-5C-alkoxyalkoxy group.

Preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and R3 is a 2-8C-alkoxyalkoxy group, wherein at least one of the hydrogen atoms of R2, R3 or R2 and R3 is replaced by a deedeutory atom. .

Preferred are compounds of formula 1 wherein R1 is a 1-4C alkoxy group, R2 and R4 are a 1-4C alkyl group and R3 is a 1-4C-alkoxy group, wherein at least one of the hydrogen atoms of R1, R3, R4 or any combination of R1, R3 and R4 is replaced by a deuterium atom.

Also preferred are compounds of formula 1 where R 1 is hydrogen, methoxy or difluoromethoxy, R 2 is methyl or methoxy, R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen or methyl and where at least one of the atoms of R3 hydrogen is replaced by a deuterium atom.

Other compounds of formula 1 wherein R2 is methyl, R3 is methoxypropoxy and Z is -C-H where at least one of the hydrogen atoms of R2, R3 or R2 and R3 is substituted with a deuterium atom are preferred.

Other compounds of formula 1 wherein R1 is methoxy, R2 and R4 are methyl and R3 is methoxy are preferred where at least one of the hydrogen atoms of R1, R3, R4 or any combination of R1, R3 and R4 is substituted. by a deuterium atom. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.

Also preferred are compounds of formula 1 where R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or where R1 is hydrogen, R2 is methyl, R3 is 2,2,2-trifluorooxy or methoxypropoxy, R4 is hydrogen or where R difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and where at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.

Other compounds of formula 1 are also preferred where R 1 is methoxy, R 2 is methyl, R 3 is methoxy, R 4 is methyl or where R 1 is hydrogen, R 2 is methyl, R 3 is 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen or where R 1 is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and where at least two of the hydrogen atoms of R3 are replaced by a deuterium atom.

More preferred are compounds of formula 1 wherein R2 is a 1-4C alkyl group and R3 is a 2-8C-alkoxyalkoxy group, wherein all the hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.

More preferred are compounds of formula 1 wherein R1 is a 1-4C alkoxy group, R2 and R4 are a 1-4C alkyl group and R3 is a 1-4C-alkoxy group, wherein all hydrogen atoms of R1, R3 , R4 or any combination of R1, R3 and R4 are replaced by deuterium atoms. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.

More preferred are compounds of formula 1 wherein all hydrogen atoms of R 3 are replaced by deuterium atoms and where R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy.

More preferred are other compounds of formula 1 wherein R2 is methyl, R3 is methoxypropoxy and Z is C-H where all hydrogen atoms of R2, R3 or R2 and R3 are replaced by deuterium atoms.

More preferred are other compounds of formula 1 wherein R1 is methoxy, R2 and R4 are methyl and R3 is methoxy, where all hydrogen atoms of R1, R3, R4 or any combination of R1, R3 and R4 are substituted by deuterium atoms. Possible combinations are R1 and R3, R1 and R4, R3 and R4, R1 and R3 and R4.

More preferred are also compounds of formula 1 wherein R 1 is hydrogen, methoxy or difluoromethoxy, R 2 is methyl or methoxy, R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen or methyl and where all hydrogen atoms of R 3 are More preferred are also compounds of formula 1 where R1 is methoxy, R2 is methyl, R3 is methoxy, R4 is methyl or where R1 is hydrogen, R2 methyl, R3 is 2,2,2-trifluorooxy or methoxypropoxy, R4 is hydrogen or where R1 is difluoromethoxy, R2 is methoxy, R3 is methoxy, R4 is hydrogen and where all hydrogen atoms of R3 are replaced by deuterium atoms.

More preferred are 5-methoxy-2 - [(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole, 5-methoxy-2 - [(4-dideu-teriomethoxy -3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-trideuterio-methoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole , 5-tri-deuteriomethoxy-2 - [(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-trideuteriomethoxy-2 - [(4-dideuteriomethoxy-3,5-dimethyl -2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-methoxy-2 - [(3-methyl-trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-trideuteriomethoxy-2 - [(3-methyl-trideuteriomethoxy-5-trideuthenylimidazole, 2- [3-methyl-(1,1-dideuterium-2,2,2-trifluorooxy) -2-pyridinyl) methylsulphenyl] -1 H -benzimidazole, 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-difluoromethoxy-2 - [(3-methoxy-4-dideuteriomethoxy -2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-difluoride methoxy-2 - [(3-trideuteriomethoxy-4-methoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole, 5-difluoromethoxy-2 - [(3-deuteriomethoxy-4-methoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-difluoromethoxy-2 - [(3,4-bis (trideuteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 5-difluoromethoxy-2 - [(3,4 -bis (dideuteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole, 2 - {[4- (3-trideuteriomethoxyhexadeuteriopropoxy) -3-methylpyridin-2-yl] methylsulfinyl} -1H-benzimidazole, 2- { [4- (3-trideuteriomethoxyhexadeuteriopropoxy) -3-tri-deuteriomethylpyridin-2-yl] methylsulfinyl} -1H-benzimidazole, 5-methoxy-2 - ((4-trideu-teriomethoxy-3,5-dimethyl-2-pyridylmethyl ) sulfinyl) -1H-imidazo [4,5-b] pyridine, 5-tri-deuteriomethoxy-2 - ((4-trideuteriomethoxy-3,5-limetyl-2-pyridylmethyl) sulfinyl) -1Hdazo [4,5- b] pyridine, 5-methoxy-2 - ((3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridylmethyl) sulfinyl) -1H-imidazo [4,5-b] pyridine or 5-trideuteriomethoxy-2- ( (3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridylmethyl ) sulfinyl) -1H-imidazo [4,5-b] pyridine.

According to the invention, the term "hydrogen atom substituted with a deuterium atom" should be considered to define a degree of deuteration of at least 80% of the crude material, where all of these correspondingly mentioned hydrogen atoms are replaced by deuterium atoms. . For example, if the substituent R2 or R3 refers to a methoxy group having the three "hydrogen atoms substituted by a deuterium atom" it is understood according to the above definition that at least 80% of all R2 or R3 methoxy groups in the raw material are OCD3. What is left to complete 100% includes -OCHD2, OCH2D or -OCH3.

A degree of deuteration of at least 90% for the specific hydrogen atom in the raw material is preferred, which means that at least 90% of the substituted hydrogen atoms must be deuterium atoms. More preferably is a degree of deuteration of at least 92% for the specific hydrogen atom in the crude material. Even more preferable is a degree of deuteration of at least 94% for the specific hydrogen atom in the crude material, and even more preferable is a degree of deuteration of at least 96% for the specific hydrogen atom in the crude material.

The compounds according to the invention are chiral compounds. The invention therefore relates to racemates as well as enantiomers and mixtures thereof in any desired proportion. In view of the fact that from a medical point of view it may be advantageous for certain chiral compounds to be administered in the form of either enantiomer, a preferred subject matter of the invention is the enantiomers of the compounds of formula 1. enantiomers preferably being substantially free of the respective other enantiomer of opposite configuration.

On the one hand, therefore, particularly preferred are those having the configuration (S) of general formula 1a.

<formula> formula see original document page 8 </formula>

where R1, R2, R3, R4 and Z have the meanings given above.

Particularly preferred compounds with (S) configuration within the scope of the invention are (S) -5-methoxy-2 - [(4-tri-deuteriomethoxy-3,5-dimethyl-2-pyridinyl) methyl] (S) compounds -5-tri-deuteriomethoxy-2 - [(4-trideuteriomethoxy-3,5-limethoxybenzimidazole, (S) -5-methoxy-2 - [(4 H -deuteriomethoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1H-benzimidazole, (S) -5-trideuteriomethoxy-2 - [(4-dideuteriomethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole, (S) -5-trideuteriomethoxy-2 - [(4-Methoxy-3,5H-methyl-2'-iridinyl) methylsulfinyl] -1H-benzimidazole, (S) -5-methoxy-2 - [(3-methyl-trideuteriomethoxy-54-pyridinyl) methylsulfinyl] ^^ zimidazole, (S) -5-trideuteriomethoxy-2 - [(3-methyl-4-trideuteriomethoxy-5-trideuteriomethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole or (S) -5-difluormethoxy-2-one [(3-Methoxy-4-trideuteriomethoxy-2-pyridylmethyl) sulfinyl] -1 H -benzimidazole, (S) -5-difluoromethoxy-2 - [(3-methoxy-4-dideuteriomethoxy-2-pyridylmethyl ) sulfinyl] -1H-benzimidazole solvates, preferably hydrates of these compounds, salts of these compounds and solvates, preferably hydrates of salts of these compounds.

On the other hand, compounds with the (R) configuration of formula 1b are particularly preferred.

<formula> formula see original document page 9 </formula>

where R1, R2, R3, R4 and Z have the meanings given above.

A particularly preferred compound of the (R) configuration within the scope of the invention is (R) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridylmethyl) sulfinyl] -1H-benzimidazole, (R) -5-Difluoromethoxy-2 - [(3-methoxy-4-dideuteromethoxy-2-pyridylmethyl) sulfinyl] -1H-benzimidazole and ossolvates, preferably hydrates of these compounds, salts of these compounds and solvates, preferably hydrates of the salts of these compounds.

Separation of the compounds of formula 1 into enantiomers may be carried out according to various procedures, for example as described in International Patent Application WO 92/08716 or by column chromatography. Alternatively, the compounds of formulas 1a and 1b may be obtained by chiral oxidation of the sulfides in the manner described in international patent applications WO96 / 02535 or WO 2004/052881.

Salts of the compounds of formulas 1, 1a and 1b are prepared by processes known per se by reaction of the compounds of formulas 1,1a, and 1b which may be considered as weak acids with suitable bases, for example with hydroxides. or alkali metal alkoxides, such as sodium hydroxide or sodium methoxide, or with alkaline earth metal alkoxides, such as magnesium methoxide. As an example, the magnesium salts of the compounds of formulas 1, 1a and 1b, which - in addition to the sodium salts - are the preferred salts, are prepared in a manner known by reaction of compounds of formulas 1, 1a and 1b with a base of magnesium, for example a magnesium alkoxide, or from a readily soluble salt of a compound of formulas 1, 1a and 1b (for example a sodium salt) using a magnesium salt in water or in organic solvent water mixtures polar (e.g. alcohols, preferably methanol, ethanol or isopropanol, or ketones, preferably acetone).

According to the invention, the term "(S) configuration compounds" includes "(S) configuration compounds being substantially free of (R) configuration compounds.

"Substantially free" in the context of the invention means that compounds with (S) configuration and / or their salts, solvates or desal solvates contain less than 10% by weight of compounds with (R) configuration and / or salts, solvates or solvates thereof. salts. Preferably, "substantially free" means that the compounds of (S) configuration and / or salt salts, solvates or solvates thereof contain less than 5% by weight of (R) configuration compounds and / or their salts, salt solvates or solvates. Most preferably, "substantially free" means that compounds with (S) configuration and / or their salts, solvates or salt solvates contain less than 2% by weight of (R) configuration compounds and / or salts thereof. , salts solvates or solvates. In the most preferred embodiment, "substantially free" means that compounds of (S) configuration and / or salt salts, solvates or solvates thereof contain less than 1% by weight of (R) configuration compounds and / or their salts, solvates or solvates of salts.

According to the invention, the term "(R) configuration compounds" includes "(R) configuration compounds being substantially free of (S) configuration compounds.

"Substantially free" in the context of the invention means that compounds with (R) configuration and / or their salts, solvates or desal solvates contain less than 10% by weight of compounds with (S) configuration and / or salts, solvates or solvates thereof. salts. Preferably, "substantially free" means that compounds of (R) configuration and / or salt salts, solvates or solvates thereof contain less than 5% by weight of (S) configuration compounds and / or salts thereof, salt solvates or solvates. Most preferably, "substantially free" means that compounds with (R) configuration and / or their salts, solvates or solvates thereof contain less than 2% by weight of compounds with (S) configuration and / or salts thereof. , salts solvates or solvates. In the most preferred embodiment, "substantially free" means that compounds with (R) configuration and / or salt salts, solvates or solvates thereof contain less than 1% by weight of (S) configuration and / or compounds thereof. salts, solvates or solvates of salts.

A further subject of the invention is the compounds of formula 2

<formula> formula see original document page 11 </formula>

where R1, R2, R3, R4 and Z have the meanings given above and where at least one of the hydrogen atoms of R1, R2, R3, R4 or any combination of R1, R2, R3 and R4 is replaced by a deuterium atom, and salts thereof, such as hydrochloride, sulfate, phosphate or other salts with acids, and their solvates. These compounds may be used for the production of compounds of formula 1.1a or 1b. The compounds of formula 2 are especially suitable as a starting material for an oxidation reaction resulting in compounds according to formulas 1.1a or 1b. Another aspect of the invention is compound of formula 3.

<formula> formula see original document page 12 </formula>

where X is a halogen or activated derivative of an alcohol and R2, R3 and R4 have the meanings given above and where at least one of the hydrogen atoms of R2, R3 and / or R4 is replaced by a deuterium atom.

Compounds of formula 3 wherein R 2 is methyl or methoxy, R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen or methyl and where at least one of the hydrogen atoms of R 3 is substituted by deuterium atoms are preferred.

More preferred are compounds of formula 3 wherein R 2 is methyl, R 3 is methoxy, R 4 is methyl or R 2 is methoxy, R 3 is methoxy, R 4 is hydrogen or R 2 is methyl, R 3 is 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen and wherein at least one of the hydrogen atoms of R3 is replaced by deuterium atoms.

Also more preferred are compounds of formula 3 wherein R2 is methyl, R3 is methoxy, R4 is methyl or R2 is methoxy, R3 is methoxy, R4 is hydrogen or R2 is methyl, R3 is 2,2,2-trifluorooxy or methoxypropoxy, R4 is hydrogen and where at least two or all of the hydrogen atoms of R3 are replaced by deuterium atoms.

For the purpose of the invention, halogen is iodine, bromine, chlorine and fluorine. Preferably X is chlorine. An activated derivative of an alcohol is an alkylsulfonate group, for example mesylate or an arylsulfonate group, for example tosylate or besylate, or a perfluoralkane sulfonate group, for example trifluoromethanesulfonate.

Related to a compound of formula 3 and therefore an aspect of the invention is a compound of formula 3a

<formula> formula see original document page 12 </formula>

where X, R2 and R4 have the meanings given above, R5 being chlorine or nitro and where at least one of the hydrogen atoms of R2 and / or R4 is replaced by a deuterium atom.

Compounds of formula 3a wherein R 2 is methyl or methoxy, R 4 is hydrogen or methyl and wherein at least one of the hydrogen atoms of R 2 and / or R 4 is substituted by deuterium atoms are preferred.

More preferred are compounds of formula 3a wherein R2 and R4 are methyl and where at least one of the hydrogen atoms of R2 and / or R4 is substituted by deuterium atoms.

The compounds of formula 3 may be used for the production of compounds of formula 1, 1a or 1b. Preferably the nitrogen atom compound of formula 3 is first quaternized and then reacted with compounds of formula 4.

<formula> formula see original document page 13 </formula>

where R1 and Z have the meaning given above, thus providing the compounds of formula 2 described above.

The compounds of formula 3a may be used for the production of compounds of formula 2a.

<formula> formula see original document page 13 </formula>

where R1, R2, R5, R4 and Z have the meanings given above and where at least one of the hydrogen atoms of R1, R2, R4 or any combination of R1, R2 and R4 is replaced by a deuterium atom.

Preferably the nitrogen atom of the compound of formula 3a is first quaternized and then reacted with compounds of formula 4.

<formula> formula see original document page 13 </formula>

where R1 and Z have the meaning given above, thus providing the compounds of formula 2a described above.

The compounds of formula 2a may be used for the production of compounds of formula 2 by substituting residue R5 for residue R3, both having the meanings described above. Provided that none of the hydrogens of R1, R2 or R4 is replaced by a deuterium atom, at least one of the hydrogen atoms of R3 is replaced by a deuterium atom.

Another aspect of the invention are compounds of formula 4.

<formula> formula see original document page 14 </formula>

where R1 is 1-4C alkoxy, Z is C-H or N and where at least one of the hydrogen atoms of R1 is replaced by a deuterium atom. Preferably R1 is methoxy. These compounds may be used for the production of compounds of formula 1 or 2.

More preferred are compounds where R1 is methoxy and where all hydrogen atoms of R1 are replaced by deuterium atoms.

Deuterium homologues of proton pump inhibitors and for example R / S pantoprazole and S-pantoprazole are prepared by oxidizing the corresponding thiocompounds according to methods known in the literature, for example Kohl et al. J. Med. Chem. 1992, 35, 1049 ff. or WO 2004/052881 or by exchanging halide for trideuteriomethoxy from the corresponding sulfoxides with a halogen substituent (e.g. chloro, bromo or nitro) at the position of the final trideuteriomethoxy group, in particular at position 4 of the pyridine group. Similar to that described above, an exchange of halogen for dideuteriomethoxy or monodeuteriomethoxy will lead to the corresponding deuterated compounds.

By analogy thiocompounds are prepared by exchanging halogen for mono-, di- or trideuteriomethoxy at the position of the final mono-, di- or trideuteriomethoxy substituent or by coupling 5-difluoromethoxy-2-mercaptobenzimidazole with 2-chloromethyl chloride. Correspondingly substituted -3-methoxy-4-trideuteromethoxy-pyridinium.The compound of formula 1 may be prepared according to the following reaction scheme:

<formula> formula see original document page 15 </formula>

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

Alternatively the salts are prepared by reaction of sulfoxides with alkaline hydroxides to give the corresponding alkaline salt (Na, K, Li) and further reaction with for example magnesium, calcium, aluminum, zinc salts.

The following examples serve to illustrate the invention in more detail without limiting it to the examples described. The other compounds mentioned above may be obtained using the methods described.

Examples

As trideuteriomethoxylating agent, methanol-d4 with> 99.8% D atoms was used. The isomeric purity of trideuthiomethoxy substituents in all resulting products was> 98.0% as determined by NMR and MS. As with other deuterating agents methanol-d 2 with> 98.0% D atoms, and methanol-d 1 with> 98.0% D atoms. Isomeric purity of dideuteriomethoxy and monodeuteriomethoxine substituents was> 96.0% as determined by NMR and MS.

Example 1

5-Difluoromethoxy (R / S) 2- 1- (3-Methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

<formula> formula see original document page 16 </formula>

A solution of sodium hypochlorite (10% solution) (3.3 mmol) is added for one to two hours to a suspension of 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio ] -1 H -benzimidazole (1.0 g, 2.7 mmol) in water (20 mL), 2-propanol (10 mL) and sodium hydroxide (0.5 mL 40% dissolution, 7.1 mmol) at 30 - 35 ° C with stirring. After 30 - 60 minutes at the set temperature sodium thiosulfate (0.3 g dissolved in 5 ml water) is added and stirring is continued for a further 15-30 minutes.

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

After extraction of the aqueous phase with dichloromethane (2 x 10 mlc) once again dichloromethane (50 ml) is added and the pH is adjusted 7 - 8 by the addition of potassium diacid phosphate with stirring. Separation of the phases, further extraction of the aqueous phase with dichloromethane (20 ml), washing of the combined organic phases with water (20 ml), drying with magnesium sulfate and filtering of the drying agent give a solution of the crude title compound.

Addition of petroleum ether (50/70; 150 ml) and concentration in a vacuum rotary evaporator at 30 - 40 ° C to about 30 ml of volume then filtration of precipitated solid, rinse with 50/70 petroleum ether (20 ml) and Vacuum drying (35 ° C, 5 hours) gives the title compound 5-difluoromethoxy (R / S) 2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as a solid whitish p. f. 135 - 136 ° C (de-comp.); yield 1.0 g (95% of theory).

1H-NMR (400 MHz, DMSO d-6): d = 3.78 (s, 3 H, OMe), 4.68 (d, 1H, J (CHa1 CHb) = 13 Hz, S-CH2-Py), 4.73 (d, 1H, J (CHb1 CHa) = 13 Hz, S-CH2 -Py), 7.10 (d, 1H, J (H5 ', H6') = 5 Hz1 H5 ') 7.18 (bd 1H, H6), 7.24 (t, 1H, J (H1F) = 74 Hz, OCHF2), 7.4 (bs, 1H, H4), 7.70 (bs, 1H, H7), 8.15 (d, 1H, J (H 6 ', H 5') = 5 Hz 1 H 6 '), 13.7 (s, 1H, NH).

Example 2

S (-) - 5-Difluoromethoxy-2 - [(3-methoxy-44rideuteriomethoxy-2'-iridinyl) methylsulfinyl] -1H-benzimidazole

At room temperature, 2.0 g of 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole is suspended in 20 ml of methyl isobutyl ketone along with bis- (N- (+) - L-Tartaric acid pyrrolidinamide (2.3 g) and zirconium (IV) n-propoxide (1.0 g, 70% in propanol). The mixture is heated to 40 ° C for one hour, resulting in the formation of a solution that is practically clear. After cooling to room temperature, N-ethyldiisopropylamine (0.07 ml) and cumene hydroperoxide (1.05 ml) are added. The mixture is stirred at room temperature until oxidation is complete (10 - 24 hours, monitored by TLC). The clear solution is diluted with 10 ml methyl isobutyl ketone and quenched with 0.08 g sodium thiosulfate in 14 ml saturated sodium bicarbonate solution and stirred for a further 2 hours. After phase separation the mixture is washed twice with 5 ml of saturated sodium bicarbonate solution. 15 ml of water is added to the methyl isobutyl ketone phase, and the pH is adjusted to pH = 13 using a 40% by weight solution of sodium hydroxide. After separation of the phases, the methyl isobutyl ketone phase is extracted with an additional 5 ml of water at pH 13. The aqueous phases are combined and at 40 ° C subjected to incipient distillation at reduced pressure. Hyflo Su-per Cell as filter aid (0.05 g) is added and after stirring for one hour at 20-25 ° C is filtered off. At 40 - 45 ° C, the crude title compound is precipitated by the addition of 10% acetic acid to the filtrate to pH = 9.0. The mixture is stirred for a further 12 hours during which the pH is monitored. The beige crystals are filtered off and washed with 10ml of water. The title compound is obtained in a yield of about 1.6 g (75% of theory) and an optical purity of> 98%.

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

Recrystallization from dichloromethane / tert-butyl methyl ether gives the title compound S (-) - 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole dep . m, 146-148 ° C (decomp.); yield 1.6 g.

Example 3

Synthesis of the starting material 2-chloromethyl-3-methoxy-4-trideuteriomethoxy pyridinium chloride

Preparation of 3-Methoxy-2-methyl-4-trideuteriomethoxypyridine N-oxide

4-Chloro-3-methoxy-2-methylpyridine N-oxide (10 g) and sodium trideuteriomethane (6.2 g) in deuteromethanol D4 (20 ml) were heated at reflux. After 15 hours the solvent was evaporated in vacuo, the residue extracted with hot toluene (50 ml) and insolubles removed by filtration. Addition of diisopropyl ether to the filtrate precipitated a solid, which after vacuum drying gave 8.1 g of 3-methoxy-2-methyl-4-trideuteriomethoxypyridine N-oxide as a light brown powder. He was subsequently using you in the next step.

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

The product (8.1 g) from the previous step was dissolved in anhydride acetic acid (50 ml) and heated at 90 ° C for 2 hours. After vacuum evaporation, the dark oily residue was stirred with 2 N NaOH (20 mL) for 2 hours at 80 ° C. After cooling the product was extracted into dichloromethane, dried (K 2 CO 3), and concentrated in vacuo to decrease volume. Addition of petroleum ether (50/70) gave, after filtration and vacuum drying 2-hydroxy-3-methoxy-4-trideuteriomethoxypyridine as a light brown solid (5.5 g) which was used in the next step.

Preparation of 2-Chloromethyl-3-methoxy-4-trideuteriomethoxy pyridinium chloride

The product from the previous step (5.5 g) was dissolved in dry dichloromethane (40 ml) and thionyl chloride (3 ml) was added dropwise at 5-10 ° C with stirring. The mixture was allowed to warm to 20 ° C and after 3 hours was evaporated under vacuum to dryness.

Addition of toluene (20 ml) gave 6.6 g of the title compound 2-chloromethyl-3-methoxy-4-trideuteriomethoxypyridinium chloride as a light brown solid.

The material synthesized in this manner contained some difficult to remove impurities which showed a tendency to be carried by the following steps leading to compounds of general formula (2) and finally general formula (1). For the preparation of compounds of formula (1) exceptionally high hardness, it is usually preferred however to use the deuterioalkylation method set forth in examples 9 and 35.

Example 4

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

At 85-95 ° C, a solution of 4-chloro-3-methoxy-2-methylpyridine - oxide (19.2 kg, 111 mmol) in toluene (148 l) was added over 5-7 hours at acetic anhydride (71 I). In vacuo at about 60 ° C, the reaction mixture was concentrated until about 170 l were distilled off. To-luene (160 ml) was added and once again the solvents were distilled off (160 l). This last operation was repeated once more. Then toluene (14 I) and 40% aqueous NaOH (14.6 I) were added at 35 - 45 ° C and the reaction mixture was kept at this temperature for 2 - 3 hours. If at this point the pH was below 13, more NaOH was added and heating continued for a further 2 hours. The resulting biphasic reaction mixture was diluted with toluene (26 I) and saturated aqueous sodium bicarbonate (26 I), the phases separated and the aqueous layer extracted three more times with toluene (26 I and 2 χ 13 I). Finally, the combined organic phase was washed with saturated aqueous sodium bicarbonate (13 l) and concentrated in vacuo at 50-65 ° C until about 115 l had been distilled off. After dilution with toluene (100 l), an additional 100 l of solvents were distilled off.

The resulting solution of 4-chloro-2-hydroxymethyl-3-methoxypyridine (-30% concentration) was diluted with CH 2 Cl 2 (48 l). DMF (65.5 g, 0.896mol) was added at one time and then thionyl chloride (11.1 kg, 93.2 mmol) for 3 - 5 hours at 15 - 30 ° C. After stirring for a further 1.5 hours, about 45 l of solvents were distilled off. Toluene (20 l) was added and once again 20 l of solvents were distilled off. Then ethanol (1.5 I) was added to the thick suspension resulting. The solids were filtered off at 10-15 ° C, washed with toluene (17 l) and vacuum dried at 30 ° C to give 4-chloro-2-chloromethyl-3-methoxypyridinium chloride as an off-white solid (mp 132 ° C). C) Yield 15.0 kg (59%).

1H-NMR (200 MHz, CDCl3): δ 4.19 (s, 3H), 5.14 (s, 2H), 7.92 (d, 6.0 Hz, 1H), 8.59 (d, 6 0.1 Hz, 1H), 11.64 (br s, 1H); LC-MS: MH + = 192/194/196.

Example 5

4-Chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride

The starting material, 4-chloro-2-methyl-3-trideuteriomethoxypyridine - was prepared according to method D for the undeuterated analogue in J.Med. Chem. 1992, 35, 1049-1057:

starting from 3-hydroxy-2-methyl-4-pyrone, conversion with trideuterium iodomethane in the presence of potassium carbonate in DMF gave 2-methyl-3-trideuteriomethoxy-4-pyrone (yield: 83-96%), which with heating with ammonia at 150 ° C in ethanol gave, after crystallization from 4: 1 acetone / isopropanol; 4-hydroxy-2-methyltrideuteriomethoxypyridine (yield: 52-60%). Treatment of this material with phosphorus oxychloride led to the formation of 4-chloro-2-methyltrideuteriomethoxypyridine (yield: 64-61%). Subsequent oxidation with hydrogen peroxide to acetic acid afforded 4-chloro-2-methyl-3-trideuteriomethoxypyridine - dx / c / o as a light yellow solid (yield: 87-89%).

Final transformations by 4-chloro-2-hydroxymethyl-3-trideuteriomethoxypyridine were carried out as described in Example 4 to give 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride as a colorless crystalline solid (mp 129-130 ° C). ); yield 19.6 g (42%).

Example 6 2-Chloromethyl-3) 4-bis (trideuteriomethoxy) pyridinium chloride

According to the procedure described in Example 3,4-chloro-2-methyl-3-trideuteriomethoxypyridine - / / dx / c / o (25.3 g, 144 mmols; for preparation see Example 5) was converted in 2-methyl-3,4-bis (trideuteriomethoxy) pyridine-N-oxide (yield: 23.5 g, 96%), which in turn gave 2-hydroxymethyl-3,4-bis (trideuteriomethoxy ) pyridine (yield: 13.0 g, 56%) and finally 2-chloromethyl-3,4-bis (trideuteriomethoxy) pyridinium chloride (yield: 15.4 g, 89%) as an off-white crystalline solid.

Example 7

5-Difluoromethoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzi-midazol

At 55-65 ° C, a solution of 4-chloro-2-chloromethyl-3-methoxypyridinium chloride (10.0 kg, 43.8 mo) in water (20 l) was added over 2 -3 hours to a mixture. of 5-trideuteriomethoxy-1H-benzimidazol-2-thiol (8.84 kg, 40.9 mo), toluene (43 I), water (21 I) and 40% aqueous NaOH (10.3 kg, 103 mol). Stirring at 60 ° C continued for 2 - 3 hours before the reaction mixture was cooled to 10 - 15 ° C. The precipitate was removed by centrifugation, washed with toluene (16 I) and resuspended in water (122 I). Centrifugation followed by an aqueous rinse (32 l) and drying at 35 ° C under vacuum of a 5-difluoromethoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzimidazole ( KF = 4.6%) as an off-white solid (mp 95-99 ° C), yield 14.2 kg (92%).

1H-NMR (200 MHz, DMSO-d6): δ 3.55 (br s, NH + H 2 O), 3.92 (s, 3H), 4.79 (s, 2H), 6.97 (dd, 8 , 6 Hz, 2.3 Hz, 1H), 7.16 (t, 74.8 Hz, 1H), 7.28 (d, 2.2 Hz1 1H), 7.47 (d, 8.7 Hz, 1H), 7.55 (d, 5.3 Hz, 1H), 8.25 (d, 5.2 Hz, 1H); LC-MS: MH + = 372/374.

Example 8

5-Difluoromethoxy-2 - [(4K; loro-3-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole

Starting from 4-chloro-2-chloromethyl-3-trideuteriomethoxypyridinium chloride (5.00 g, 21.6 mmols) and following the procedure described in Example 7, 5-difluoromethoxy-2 - [(4-chlorohydrochloride) 3-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (KF = 4.7%) was obtained as an off-white solid (mp 94-99 ° C); yield 7.24 g (85%).

1H-NMR (200 MHz, DMSO-d6): δ 4.79 (s, 2H), 6.98 (dd, 8.7 Hz, 2.3 Hz, 1H), 7.16 (t, 74.8 Hz, 1H), 7.28 (d, 2.0 Hz, 1H), 7.47 (d, 8.6 Hz, 1H), 7.55 (d, 5.2 Hz, 1H), 8.25 (d, 5.2 Hz, 1H); 12.75 (br s, 1H); LC-MS: MH + = 375/377.

Example 9

5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole

At 15-30 ° C, methanol-d 4 (2.26 kg, 62.7 mol) was added over 30 - 60 minutes to a mixture of sodium tert-butoxide (6.00 kg, 62.4 mmol) in DMAc (27 I). After heating to 57 - 65 ° C, a solution of 5-difluoromethoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (6.08 kg, 15.6 in DMAc (10 l) was added over 30-60 minutes. Stirring at 57-65 ° C continued for about 10 hours. The reaction mixture was cooled to 20-30 ° C and was diluted with water (21 l) before the pH was adjusted to 7-8 with 20% aqueous HCl (-7.5 l). Precipitation of the product was obtained by the addition of water (75 h) for about 4 hours. The resulting suspension was heated to 35 - 45 ° C for 1.5 hours before being cooled to 10 - 15 ° C. 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was obtained as a brownish water-wet solid by centrifugation including an aqueous rinse (58 l) , resuspension in water (78 I) and, again, centrifugation included another aqueous rinse (58 I); yield 10.4 kg, KF = 49.7% (91%).

Drying a sample of the water wet (16.2 g, KF = 49.7%) at 25 ° C under vacuum gave an amorphous solid, which with crystallization from toluene (30 ml) gave 5-difluoromethoxy-2- [ Water-free (3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole as an off-white solid (5.80 g, 71% recovery, mp = 115-116 ° C).

1H-NMR (200 MHz, DMSO-d6): δ 3.82 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.1 Hz, 1H), 7.08 (d, 5.6 Hz, 1H), 7.16 (t, 74.8 Hz, 1H), 7.28 (brs, 1H), 7.47 (br d, -8.3 Hz, 1H), 8.16 (d, 5.6 Hz, 1H), 12.75 (br s, 1H); LC-MS: MH + = 371.

Example 10

5-Difluoromethoxy-2 - [(3-methoxy-4'-lideuteriomethoxyl] -1H-benzimidazole

Starting from 5-difluoromethoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1 / - / - benzimidazole monohydrate (28.6 g, 73.4 mmols) and methanol-d2 (10 0.294 mmol), the procedure described in Example 9 was followed to give 5-difluoromethoxy-2 - [(3-methoxy-4-clideuteriomethoxy-2-pyridinyl) methylthio] -1 / - / - benzimidazole water-wet brown solid; yield 46.4 g, KF = 51.6% (82%).

1H-NMR (400 MHz, DMSO-d6): δ 3.81 (s, 3H), 3.86 (s, 1H), 4.67 (s, 2H), 6.97 (dd, 8.4 Hz , 2.0 Hz, 1H), 7.08 (d, 5.5 Hz, 1H), 7.16 (t, 74.7 Hz, 1H), 7.21-7.53 (br m, 2H) 8.16 (d, 5.5 Hz, 1H); 12.78 (br s, 1H); LC-MS: MH + = 370.

ExampleH

5-Difluoromethoxy-2 - [(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole

Starting from 5-difluoromethoxy-2 - [(4-chloro-3-methoxy-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (29.5 g, 75.6 mmols) and methanol-d1 (10.0g 303 mmoles), the procedure described in Example 9 was followed to give 5-difluoromethoxy-2 - [(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole as a water-wet brown solid; yield 50.3 g, KF = 50.8% (89%).

1H-NMR (200 MHz, DMSO-d6): δ 3.82 (s, 3H), 3.88 (s, 2H), 4.67 (s, 2H), 6.98 (dd, 8.6 Hz , 2.2 Hz, 1H), 7.08 (d, 5.6 Hz, 1H), 7.15 (t, 74.8 Hz, 1H), 7.22-7.53 (br m, 2H) 8.16 (d, 5.6 Hz 1H); 12.79 (br s, 1H); LC-MS: MH + = 369.

Example 12

5-Difluoromethoxy-2 - [(4-methoxy-3-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole

Starting from 5-difluoromethoxy-2 - [(4-chloro-3-trideu-teriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (6.97 g, 17.7 mmols) and methanol (2 28 g, 71.2 mmol), the procedure described in Example 9 was followed to give 5-lifluoromethoxy-2 - [(4-methoxy-3-trideuteriomethoxy-2'-iridinyl) methylthio] -1 / - / - benzimidazole as a water-wet brown solid; yield T10Ig1KF = Ig10Zo (ST0Zo).

1H-NMR (200 MHz, DMS0-d6): δ 3.89 (s, 3H), 4.68 (s, 2H), 6.97 (dd, 8.6 Hz, 2.0 Hz, 1H), 7.08 (d, 5.5 Hz, 1H), 7.16 (t, 74.7 Hz, 1H), 7.18-7.47 (br m, 2H), 8.16 (d, 5, 6 Hz, 1H); 12.76 (br s, 1H); LC-MS: MH + = 371.

Example 13

5-Difluoromethoxy-2 - [(3,4-bis (trideuteriomethoxy) -2-pyridinyl) methylthio] -1 / - / - benzimidazole

At 50-55 ° C, 2-chloromethyl-3,4-bis (trideuteriomethoxy) pyridinium chloride (15.4 g, 66.8 mmols) was slowly added over 30 minutes to a mixture of 5-difluoromethoxy-1 Benzimidazol-2-thiol (14.5 g, 66.8 mmol), ethanol (133 mL), and 2 M aqueous NaOH (73.5 mL, 147 mmol). Stirring at 50-55 ° C continued for 1-2 hours before ethanol was removed by vacuum distillation at 40 ° C. The remaining aqueous emulsion was diluted with water (50 mL) and extracted three times with dichloromethane (165 mL portions). The combined organic phase was washed with 0.1 M aqueous NaOH (165 mL), dried over NagSO4 and evaporated to dryness to give 5-difluoromethoxy-2 - [(3,4-bis (trideuteriomethoxy) -2-pyridinyl) methylthio] -1 / - / - benzimidazole as a maromor oil; yield 23.8 g (95%).

Example 14

rac-5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole - Large Scale Procedure

At 25-35 ° C, aqueous sodium hypochlorite (10.5 kg 10% concentration, 14.2 mol) was added over 3-4 hours to a solution of 5-difluoromethoxy-2 - [(3- methoxy-4-trideuteriomethoxy-2-dazole (10.4 kg, KF = 49.7%, 14.2 mol) and 40% aqueous NaOH (2.84 kg) in a mixture of water (49 I) and isopropanol ( Stirring at 25 - 35 ° C continued for 0.5 -1 hours before the reaction was quenched by the addition of 1% aqueous Na 2 S 2 O 3 (4.3 I). 65 I of 65 I solvents were distilled off at 30-45 DEG C. After dilution with water (55 I), a further portion of solvents (8-10 I) were distilled off. 40-45 ° C, 10% aqueous acetic acid (-13 l) was added over 1.5 hours until an pH of 8.5 - 9.5 was reached. Once crystallization was established, the pH was slowly adjusted to 6.8 - 7.2 by the addition of more 10% aqueous acetic acid (-0.6 I.) After cooling to 20-25 ° C, the The crude product was filtered off and washed with water (7.5 l) and redissolved in a mixture of water (80 l), 40% aqueous Na-OH (1.6 l) and Na 2 S 2 O 3 (60 g). The resulting lightly cloudy aqueous solution was washed twice with MIBK (12 l each) and clarified by treatment with Hyflo (0.40 kg) before the pH was adjusted to 9.0-9.5 by the addition of 10% aqueous acetic acid. (~ 8 l) at 40-45 ° C. As the product began to crystallize, more 10% acetic acid was added to continuously maintain a pH of 9.0 - 9.5. Finally, centrifugation at 20-25 ° Cincluding an aqueous rinse (7.5 l) and vacuum drying at about 50 ° C. Rac-5Kiifluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl ] -1H-benzimidazole as an off-white solid (mp = 134-135 ° C, de-comp.); yield 3.59 kg (65%).

1H-NMR (400 MHz1 DMSO-d6 δ 3.78 (s, 3H), 4.67 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.5 Hz, 1H), 7.18 (br d, 8.7 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.44 (br s, 1H), 7.70 (br s, 1H), 8.15 (d, 5.5 Hz, 1H), 13.73 (br s, 1H); LC-MS: MH + = 387.

Example 15

rac-5-Difluoromethoxy-2 - [(3-methoxy-4-dideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole

Starting from wet 5-difluoromethoxy-2 - [(3-methoxy-4-dideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (32.7 g, KF = 51.6%, 42.8 mmol) and following the procedure described in Example 14, rac-5-difluoromethoxy-2 - [(3-methoxy-4-dideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole was obtained as an off-white solid (mp = 133-135 ° C). ° C, decomp.); yield 10.8 g (65%).

1H-NMR (200 MHz, DMSO-d6): δ 3.32 (br s, NH + H 2 O), 3.77 (s, 3H), 3.86 (s, 1H), 4.65 (d, 13 , 1 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.10 (d, 5.5 Hz, 1 Η), 7.15 (dd, 8.8 Hz1 2.4 Hz1 1Η ), 7.23 (t, 74.4 Hz, 1Η), 7.44 (d, 2.2Hz, 1Η), 7.69 (d, 8.8Hz, 1Η), 8.15 ( d, 5.5 Hz, 1H); LC-MS: MH + = 386.

Example 16

rac-5-Difluoromethoxy-2 - [(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

Starting from wet 5-difluoromethoxy-2 - [(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (34.8 g, KF = 50.8%, 46.5 mmol) and following the procedure described in Example 14, rac-5-difluoromethoxy-2 - [(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole was obtained as an off-white solid (mp = 134-135 ° C, decomp.); yield 14.0 g (78%).

1H-NMR (200 MHz, DMSO-d6): δ 3.78 (s, 3H), 3.88 (s, 2H), 4.66 (d, 13.2 Hz, 1H), 4.73 (d , 13.1 Hz, 1H), 7.10 (d, 5.6 Hz, 1H), 7.16 (dd, 8.8 Hz, 2.4 Hz, 1H), 7.24 (t, 74.4 Hz , 1H), 7.45 (d, 2.2 Hz, 1H), 7.69 (d, 8.8 Hz, 1H), 8.15 (d, 5.5 Hz, 1H), 13.77 ( br s, 1H); LC-MS: MH + = 385.

Example 17

rac-5-Difluoromethoxy-2 - [(4-methoxy-3-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

Starting from wet 5-difluoromethoxy-2 - [(4-methoxy-3-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (3.00 g, KF = 19.1%, 6.55 mmol) and following the procedure described in Example 38, rac-5-difluoromethoxy-2 - [(4-methoxy-3-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole was obtained after crystallization from TBME (10 ml) as an off-white solid (mp = 133-134 ° C, decomp.); yield 1.83 g (72%).

1H-NMR (200 MHz, DMSO-d6): δ 3.90 (s, 3H), 4.66 (d, 13.1 Hz, 1H), 4.73 (d, 13.1 Hz1 1H), 7 , 10 (d, 5.6 Hz, 1H), 7.15 (dd, 8.9 Hz, 2.4 Hz, 1H), 7.24 (t, 74.4 Hz, 1H), 7.45 ( d, 2.1 Hz, 1H), 7.69 (d, 8.8 Hz, 1H), 8.15 (d,

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

Example 18

rac-5-Difluoromethoxy-2 - [(3,4-bis (trideuteriomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole

Starting from 5-difluoromethoxy-2 - [(3,4-bis (trideuteriomethoxy) -2-pyridinyl) methylthio] -1 / - / - benzimidazole (23.8 g, 63.7 mmol) and following the described procedure in Example 38, rac-5-difluoromethoxy-2 - [(3,4-bis (trideuthiomethoxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole was obtained after crystallization from diisopropyl ether (700 ml) as an off-white solid; yield 20.9 g (84%).

Example 19

Rac-5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium monohydrate

At 15-30 ° C, 40% aqueous NaOH (0.85 kg, 8.50 mol) was added over 10-30 minutes to a solution of rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideute -riomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (3.29 kg, 8.51 mo) emacetone (18 I). The resulting suspension was heated to 50-55 ° C until a clear solution was obtained. Crystallization of the product was obtained by cooling slowly to 10 - 15 ° C for about 12 hours. The solids were filtered off and washed with acetone (1.7 l) before being recrystallized from acetone / water 32: 1 (19 l). Finally, drying at 50 ° C under vacuum gave rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium salt hydrochloride as an off-white solid (mp = 151-152 ° C (decomp), KF = 4.3%); yield 2.93 kg (81%).

1H-NMR (200 MHz, DMSO-d6): δ 3.78 (s, 3H), 4.34 (d, 12.9 Hz, 1H), 4.68 (d, 12.9 Hz, 1H), 6.72 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.02 (t, 75.8 Hz, 1H), 7.07 (d, 5.6 Hz, 1H), 7.24 (d, 2.2 Hz, 1H); 7.44 (d, 8.6 Hz, 1H); 8.22 (d, 5.5 Hz1 1H); LC-MS: MNa + = 409, MH + = 387.

Example 20

[Α-S-Difluoromethoxy-4β-methoxy-4-dideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole sodium monohydrate

Starting from rac-5-difluoromethoxy-2 - [(3-methoxy-4-dideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (8.10 g, 21.0 mmol), the procedure described in Example 19 gave monohydrate of rac-5-difluoromethoxy-2 - [(3-methoxy-4H-dideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-midazole sodium salt as an off-white solid (mp = 150-152 ° C (decomp.), KF = 4.8%); yield 6.05 g (68%).

1H-NMR (200 MHz, DMSO-d6): δ 3.77 (s, 3H), 3.85 (s, 1H), 4.36 (d, 12.9 Hz, 1H), 4.66 (d , 12.9 Hz, 1H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.02 (t, 75.8 Hz, 1H), 7.07 (d, 5.6 Hz, 1H), 7.25 (d, 2.3 Hz, 1H), 7.45 (d, 8.6 Hz, 1H), 8.22 (d, 5.5 Hz, 1H); LC-MS: MNa + = 408, MH + = 386.

Example 21

Rac-5-Difluoromethoxy-2 - [(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole sodium salt monohydrateFrom rac-5 <lifluormethoxy-2 - [(3- methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole (10.2 g, 26.5 mmols), the procedure described in Example 19 gave racemic sodium salt monohydrate. 5-difluoromethoxy-2 - [(3-methoxy-4-monodeuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole as an off-white solid (mp = 151-152 ° C (decomp.), KF = 4.1% Yield 8.95 g (79%).

1H-NMR (200 MHz, DMSO-d6): δ 3.78 (s, 3H), 3.88 (s, 2H), 4.34 (d, 12.9 Hz, 1H), 4.68 (d , 12.9 Hz, 1H), 6.73 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.03 (t, 75.8 Hz, 1H), 7.08 (d, 5, 5 Hz, 1H), 7.24 (d, 2.2 Hz, 1H), 7.44 (d, 8.6 Hz, 1H), 8.22 (d, 5.5 Hz, 1H); LC-MS: MNa + = 407, MH + = 385.

Example 22

Rac-5-Difluoromethoxy-2 - [(3,4-bis (trideuteriomethoxy) -2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole sodium monohydrate

At 15-25 ° C, 6 M aqueous NaOH (8.92 ml, 53.5 mmol) was added over 15 minutes to a solution of rac-5-difluoromethoxy-2 - [(3,4-bis (trideuteriomethoxy) -2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole (21.0 g, 53.9 mmol) in a 6: 1 mixture of ethanol / dichloromethane (725 mL). After stirring for a further 10 minutes at room temperature, some of the solvents were distilled off. The resulting concentrate (115 g) was diluted with diisopropyl ether (1.7 l). Some of the dark waxy residue did not dissolve, and the clear yellow supernatant solution was removed by distillation. To this solution, a further portion of diisopropyl ether (3.4 l) was added to precipitate the product. The suspension was cooled to 0 ° C, and the solids were removed by filtration, washed with diisopropyl ether (100 ml) and dried at 40 ° C under vacuum to give rac-5Oifluormethoxy-2 - [(3) dehydrated salt monohydrate. 4,4-bis (trideuteriomethoxy) -2'-iridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid (KF = 4.0%); yield 18.9 g (82%).

1H-NMR (400 MHz, DMSO-d6): δ 4.32 (d, 12.9 Hz, 1H), 4.70 (d, 12.9 Hz, 1H), 6.72 (dd, 8.6 Hz, 2.4 Hz, 1H), 7.04 (t, 75.8 Hz, 1H), 7.08 (d, 5.5Hz, 1H), 7.23 (d, 2.4 Hz, 1H) 7.44 (d, 8.6 Hz, 1H); 8.22 (d, 5.5 Hz, 1H); LC-MS: MNa + = 412, MH + = 390.

Example 23

Rac-5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium salt sesquihydrate

At 48-55 ° C rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium monohydrate (2.93kg, 6.87 mol) was dissolved in a mixture of isopropanol (12 I) and water (0.50 I). After treatment with Hyflo Super Cell (56 g) and cooling to 18 - 25 ° C, crystallization was performed by seeding with an authentic product sample followed by stirring for 40 hours at 18 - 25 ° C and an additional 5 hours at 10 - 15 ° C. ° C. Centrifugation and drying at 45 ° C in vacuo gave rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt sesquihydrate as a solid white (mp = 140-142 ° C (decomp), KF = 6.6%); yield 2.28 kg (78%).

Example 24

Bis- [rac-5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole] Magnesium Salt Dihydrate

At 40 ° C a solution of rac-5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium salt (500mg, KF = 4.3% 1.17 mmol) in water (10.0 ml) was subjected to a clean filtration. After cooling to room temperature, a solution of anhydrous magnesium chloride (61.4 mg, 0.644 mmol) in 1.0 mL of water was added. The resulting suspension was stirred at room temperature for a further 18 hours before being cooled to 0 ° C and filtered. The filtrate cake was resuspended in water (7.5 mL), filtered, rinsed with water (5.0 mL) and dried at 40 ° C in vacuo to give bis- [rac-5-magnesium salt dihydrate. difluoromethoxy-2 - [(3-methoxy-44rideuteriomethoxy-2α)

midazol] as a white solid (m.p. 180-182 ° C (decomp.); KF = 4.7%; HPLC: 99.5% w / w); yield 369 mg (76%).

Example 25

(S) -5-Difluoromethoxy-2 - [(3H-hydroxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole - Large-scale procedure for undried starting material

At room temperature, 382 g of wet 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (KF = 47.6%, 0.540 mol) was suspended in 2, 44 I of methyl isobutyl ketone together with (+) - L-tartaric acid (N-pyrrolidinamide) combis- (55.0 g). The mixture was heated to 40 ° C and about 1.25 l of solvent was evaporated in vacuo to remove water. Then zirconium (IV) n-propoxide (24.0 mL, 70% in n-propanol) was added and stirring at 40 ° C was continued for an additional hour.

After cooling to 30 ° C, N-ethyldiisopropylamine (6.5 mL) and cumene hydroperoxide (103 mL, -80% concentration) were added. After stirring for about 18 hours at 30 ° C, TLC no longer indicated conversion of the starting material. The clear reaction mixture was diluted with 500 ml of methyl isobutyl ketone and quenched with 7.0 g of desodium thiosulfate in 800 ml of saturated sodium bicarbonate solution. After phase separation, the organic layer was washed twice with 400 ml saturated sodium bicarbonate solution. To the organic phase was added 1.5 l of water, and the pH was adjusted to pH = 13 using 40% aqueous sodium hydroxide. The organic layer was extracted with an additional 400 ml of water at pH 13. After treatment with Hyflo Super Cell (5.0 g), the pH of the combined pellet was adjusted to about 9 by the addition of 10% aqueous acetic acid at 40 ° C. - 45 ° C. Once precipitation of the product was established, the mixture was stirred for a further 12 hours with possible pH readjustment. The crude product (160 g, 75% yield) with an optical purity of> 98% was obtained by filtration including an aqueous rinse (200 ml).

To further increase the purity, the crude product was dissolved in dichloromethane (2.0 l) and washed with water (400 ml). Crystallization was achieved by solvent chase evaporation with TBME (final volume about 1.1 I). The crystals were filtered off at about 100 ° C washed with TBME (400 ml), and dried at 30 ° C under vacuum to give (S) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfimidazole as an off-white solid (mp 146-148 ° C (decomp.); KF = 0.8%); yield 135 g (64%).

Chiral HPLC:> 98.0% ee; optical rotation: [d [D = -98 ° (MeOH, c = 0.50).

1H-NMR (200 MHz, DMSO-d6): δ 3.41 (br s, NH + H 2 O), 3.77 (s, 3H), 4.65 (d, 13.0 Hz, 1H), 4, 73 (d, 13.1 Hz, 1Η), 7.09 (d, 5.6 Hz, 1H), 7.15 (dd, 8.9 Hz, 2.4 Hz1 1H), 7.23 (t, 74.4 Hz, 1H), 7.44 (d, 2.1 Hz, 1H), 7.68 (d, 8.9 Hz, 1H), 8.14 (d, 5.5 Hz, 1H); LC-MS: MH + = 387.

Example 26

(f) - 5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

Starting from 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1 H -benzimidazole (70.7 g, KF = 47.6%, 100 mmol) and using bis- (N (-) - D-tartaric acid-pyrrolidinamide (10.3 g, 40.0 mmol) as chiral ligand, the procedure described in Example 25 gave, after recrystallization from TBME, (/ 7) -5 -fluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole as an off-white solid (mp 140-142 ° C (decomp.); KF = 0.8 %); yield 22.2 g (57%).

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

1H-NMR (200 MHz, DMSO-d6): δ 3.77 (s, 3H), 4.65 (d, 13.2 Hz, 1H), 4.73 (d, 13.1 Hz, 1H), 7.09 (d, 5.5 Hz, 1H), 7.16 (br d, -10.3 Hz, 1H), 7.23 (t, 74.4 Hz, 1H), 7.44 (br s , 1H), 7.68 (br s, 1H), 8.14 (d, 5.5 Hz, 1H), 13.73 (br s, 1H); LC-MS: MH + = 387.

Example 27

(S) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium salt At room temperature a suspension of (S) -5- difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyrizol (100 g, 0.259 mol) in a mixture of methyl isobutyl ketone (750 mL), isopropanol (75 mL), and water (5.0 40% aqueous NaOH (18.1 ml, 259 mmol) was added After heating to 50 ° C a clear solution was obtained which was subjected to treatment with Hyflo Super Cel (10.0 g). Product crystallization was established with cooling to room temperature and brought to completion by cooling to 0 ° C. Finally, the crystals were removed by filtration, washed with methyl isobutyl ketone (3 portions, 40 ml each) and vacuum dried to give (S) -5KJifluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt as a white hygroscopic solid (mp 105-106 ° C). ° C (de-comp.); KF = 10.3%; yield 105 g (89%).

Chiral HPLC:> 99.0% ee; optical rotation: [α] D = -94 ° (MeOH, c = 0.50).

Example 28

(N-5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt

Starting from (?) - 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole (15.5 g, 40.1 mmols) and following the procedure described in the example 27, (6) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium salt was obtained as a white hygroscopic solid (mp 103 ° C (decomp.); KF = 11.3%); yield 17.4 g (94%).

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

Example 29

Bis - [(S) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole] magnesium salt trihydrate

Starting from (S) -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium salt (500 mg, KF = 10.3%, 1, 10 mmol) and following the procedure described in example 24, bis - [(S) -5-difluoromethoxy-2 - [(3-methoxy-4-trideu-teriomethoxy-2-pyridinyl) methylsulfinyl magnesium salt trihydrate ] -1 H -benzimidazole] was obtained as a white solid (mp 169-175 ° C (decomp.); KF = 6.4%); yield 350 mg (75%).

Chiral HPLC:> 99.0% ee; optical rotation: [α] D = -122 ° (MeOH, c = 0.50).

Example 30

Bis - [(R) -5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole] Magnesium salt trihydrate

Starting from (F ') - 5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole sodium salt (2.30 g, KF = 11.3%) , 5.00 mmols) and following the procedure described in Example 24, bis - [(6 ') -5-difluoromethoxy-2 - [(3-methoxy-4-trideuteriome-toxy-2-pyridinyl) magnesium salt trihydrate methylsulfinyl] -1H-benzimidazole] was obtained as a white solid (mp 141-145 ° C (decomp.); KF = 6.9%); yield 1.23 g (58%).

Chiral HPLC:> 99.0% ee; optical rotation: [α] 0 = + 120 ° (MeOH, c = 0.50).

Example 31

Synthesis of starting material 5-trideuteriomethoxy-1 H-benzimidazol-2-thiol

Preparation of 4-trideuteriomethoxy nitrobenzene

To a solution of sodium hydroxide (15.6 g, 390 mmol) in a mixture of methanol-d4 (47.4 mL, 1.17 mol) and THF (50 mL) was added a solution of 1-fluoro-4-nitrobenzene. (50.0 g, 354 mmol) in THF (200 mL) for 2 hours at 15 - 25 ° C. The resulting suspension was stirred for a further 3 hours at room temperature before addition of 10% aqueous HCl (100 mL) and toluene (150 mL). The organic phase was separated and evaporated to dryness to give 4-trideuteriomethoxy-nitrobenzene as a brown oil which crystallized on standing (m.p. 48-51 ° C); yield 56.6 g (quantitative). 1 H-NMR (200 MHz, DMSO-d 6): δ 7.15 (m, 2H), 8.22 (m, 2H); GC-MS: M + = 156.

Preparation of 4-trideuteriomethoxy acetanilide

An autoclave was charged with 10% Pd / C (3.6 g, wet with water), 4-trideuteriomethoxy nitrobenzene (72.5 g, 464 mmols) and isopropanol (508 ml). After careful nitrogen purging (4 times), the resulting mixture was stirred at a hydrogen pressure of 0.3 to 0.4 mPa (3 - 4bar) at 50 - 60 ° C until hydrogen absorption ceased (about than 2.5 hours).

The reaction mixture was cooled to room temperature and acetic anhydride (62.5 ml, 580 mmols) was added. Stirring was continued for a further 4 hours before the catalyst was filtered off and washed with hot 2-propanol (270 ml, about 60 ° C). The combined filtrates were concentrated in vacuo to about 150 mL, methylcyclohexane (350 mL) was added, and the resulting suspension was cooled to 10 ° C. Filtration and drying at 45 ° C under vacuum gave 4-trideuteriomethoxy acetanilide as an a-gray solid (m.p. 125-127 ° C); yield 67.0 g (86%).

1H-NMR (200 MHz, DMSO-d6): δ 2.00 (s, 3H), 6.85 (m, 2H), 7.47 (m, 2H), 9.74 (br s, 1H); LC-MS: MH + = 169.

Preparation of 2-nitro-4-trideuteriomethoxy aniline

At 10-15 ° C 50% aqueous nitric acid (63.0 mL, 654 mmols) was added over 1.5 hours to a solution of 4-trideuteriomethoxy acetanilide (50.0 g, 297 mmols) in acetic acid ( 175 ml). Stirring continued for 18 hours at room temperature. Then, 20% aqueous NaOH (671 mL) was added for about 1 hour at 15-20 ° C. The resulting brown suspension was heated at 50 ° C for 20 hours before the pH was adjusted to about 8 by the addition of 20% aqueous HCl (49 ml). The product was obtained by cooling to 10 ° C and filtration. After an aqueous rinse, the filtrate cake was suspended at 60 ° C in isopropanol (200 mL) and water (300 mL) was added over 1 hour. While maintaining the temperature between 50 and 60 ° C, 190 ml of solvents were distilled off.

The resulting suspension was cooled to 10 ° C, filtered and washed with water (60 ml) to give after drying at 30 ° C under vacuum 2-nitro-4-trideuteriomethoxy aniline as a red solid (mp 120-122 ° C). ); yield 46.7 g (92%).

1H-NMR (200 MHz, DMSO-d6): δ 7.00 (d, 9.3 Hz, 1H), 7.16 (dd, 9.3 Hz, 2.9 Hz, 1H), 7.24 ( br s, 2H), 7.37 (d, 2.9 Hz, 1H); GC-MS: M + = 171.Preparation of 5-trideuteriomethoxy-1 / - / - benzimidazole-2-thiol

An autoclave was charged with 10% Pd / C (2.23 g, wet with water), 2-nitro-4-trideuteriomethoxy acetanilide (45.6 g, 267 mmols) and isopropanol (460 ml). After careful nitrogen purging (4 times), the resulting mixture was stirred at a hydrogen pressure of 0.3 to 0.4 mPa (3-4 bar) at 40 - 50 ° C until hydrogen absorption ceased (about 6 ho-ras). Then, O-ethylxantic acid potassium salt (51.2 g, 319 mmols) was added and the reaction mixture was heated at reflux for 23 hours.

Water (340 mL) was added and the pH was adjusted to 12.5 with 20% aqueous NaOH (10 mL) before practically the amount of isopropanol (460 mL) was distilled off. The resulting dark suspension was treated with charcoal (10 g), clarified by filtration and washed with toluene (350 ml).

The product was precipitated by the addition of 20% aqueous HCl (53 ml) and isolated by filtration at 0 ° C. Rinsing with water (100 ml) and drying at 35 ° C and vacuum finally gave 5-trideuteriomethoxy-1 H -benzimidazol-2-thiol as an off-white solid (mp 247-250 ° C); yield 45.5 g (93%).

1H-NMR (400 MHz, DMSO-d6): δ 6.67 (d, 2.3 Hz, 1H), 6.72 (dd, 8.7 Hz, 2.4 Hz, 1H), 7.03 ( d, 8.6 Hz, 1H), 12.36 (br s, 1H), 12.40 (br s, 1H); LC-MS: MH + = 184.

Example 32

Synthesis of starting material 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride

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

At 90-95 ° C, a solution of 4-chloro-2,3,5-trimethylpyridine / V-ox / w / o (60.0 g, 350 mmols) in toluene (920 ml) was maintained at room temperature. At about 60 ° C, acetic anhydride (232 ml) was added over 7 hours. In a vacuum at about 60 ° C, the reaction mixture was concentrated until 820 ml were distilled off. Toluene (840 ml) was added and once again the solvents were distilled off (940 ml). Then toluene (180 ml) and 40% aqueous NaOH (80 ml) were added before the reaction mixture was heated at 50 ° C for about 15 hours. After addition of saturated aqueous sodium bicarbonate (120 mL), the phases were separated and the aqueous layer was extracted once again with toluene (80 mL). Finally, the combined organic phase was washed with saturated aqueous sodium bicarbonate (120ml) and evaporated to dryness to give 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine as a brown oil which solidified with the solvent. rest; yield61.8 g (quantitative).

1H-NMR (200 MHz, DMSO-d6): δ 2.30 (s, 3H), 2.36 (s, 3H), 4.58 (br s, 2H), 5.11 (brs, 1H), 8.27 (s, 1H); LC-MS: MH + = 172/174.

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

To a solution of 4-chloro-2-hydroxymethyl-3,5-dimethylpyridine (60.7g, 354mmol) and DMF (0.25ml, 3.54mmol) in toluene (200ml) was added. thionyl (26.9 ml, 371 mmol) for 2 hours at 15 - 30 ° C.

After stirring for a further 2 hours at room temperature, ethanol (6 ml) was added to the coarse suspension. The solids were removed by filtration at about 10 ° C, washed with toluene (80 ml) and dried at 40 ° C in vacuo to 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride as an off-white solid (m.p. 195-196 ° C); yield 66.5 g (84%).

1H-NMR (200 MHz, DMSO-d6): δ 2.36 (s, 3H), 2.46 (s, 3H), 4.93 (s, 2H), 8.44 (s, 1H), 8 , 79 (br s, 1H); LC-MS: MH + = 190/192/194.

Example 33

5-Trideuteriomethoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole

At 55-65 ° C, a solution of 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride (12.6 g, 55.6 mmols) in water (21 ml) was added over 2 hours to a mixture of 5-trideuteriomethoxy-1H-benzimidazol-2-thiol (9.50 g, 51.8 mmol), toluene (47 mL), water (23 mL) and 40% aqueous NaOH (14 mL). Stirring at 60 ° C continued for 16 hours before the reaction mixture was cooled to about 10 ° C. The precipitate was filtered off, washed with toluene (17 mL) and resuspended in water (132 mL). Filtration followed by an aqueous rinse (70 ml) and drying at 35 ° C under vacuum gave 5-trideuteriomethoxy-2 - [(4α; 3,5-dimethyl-2-pyridinyl) methylthio] -1 / - / - benzimidazole monohydrate (KF = 5.0%) as an off-white solid (mp 99-102 ° C); yield 15.1 g (82%). 1H-NMR (200 MHz1 DMSO-d6) δ 2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76 (dd, 8.7 Hz, 2.5 Hz, 1H), 6.97 (br s, 1H), 7.35 (d, 8.7 Hz 1H), 8.28 (s, 1H), 12, 47 (br s, 1H); LC-MS: MH + = 337/339.

Example 34

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

Starting from 5-methoxy-1H-benzimidazol-2-thiol (24.0 g, 111 mmol) and following the procedure described in example 33, 5-methoxy-2 - [(4 <; dimethyl-2 (Diridinyl) methylthio] -1H-benzimidazole (KF = 5.2%) was obtained as an off-white solid (mp 100-102 ° C); yield 34.8 g (89%).

1H-NMR (200 MHz, DMSO-d6): δ 2.30 (s, 3H), 2.43 (s, 3H), 4.72 (s, 2H), 6.76 (dd, 8.7 Hz , 2.5 Hz, 1H), 6.98 (br s, 1H), 7.35 (d, 8.7 Hz, 1H), 8.28 (s, 1H), 12.41 (br s, 1H); LC-MS: MH + = 334/336.

Example 35

5-Trideuteriomethoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole

At 60-65 ° C, to a solution of 5-trideuthiomethoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (5.20 g, 14.7 mmol) in NMP (30 mL) was added over 1.5 hours solid disodium methoxide (5.80 g, 104 mmol) in about 10 equal portions. Stirring at 60 ° C was continued for 16 hours, and then the reaction mixture was heated at 70 ° C for 24 hours and finally at 80 ° C for 4 hours. After dilution with water (200 mL) and addition of 10% aqueous HCl (10 mL), the resulting dark brown solution was extracted twice with toluene (100 + 40 mL). The combined organic phase was washed successively with 5% aqueous NaOH (2 x 200 mL) and water (100 mL) before being evaporated to dryness. The residue was taken up in hot toluene (50 ml), subjected to rapid filtration and, once again, evaporated to dryness. Finally, crystallization from 10: 1 TBME / toluene (33 ml) gave 6-trideuteriomethoxy-4-methoxy-SS-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole as a white solid (mp 120-121Â °). Ç); yield 2.27 g (46%). 1H-NMR (200 MHz, DMSO-δ): δ 2.20 (s, 3,), 2.27 (s, 3Η), 3.73 (s, 3Η), 4.65 (s, 2Η), 6.75 (dd, 8.7Hz, 2.5Hz, 1Η), 6.97 (br s, 1Η), 7.35 (d, 8.7Hz1) 1 δ), 8.17 (s, 1 Η), 12.44 (br s, 1H); LC-MS: MH + = 333.

Example 36

5Trideuteriomethoxy-2 - [(3,5 (Jimethyl-44rideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole

A solution of sodium trideuteriomethoxide was prepared by adding methanol-d4 (1.70 ml, 41.5 mmols) at about 50 ° C for 30 minutes to a suspension of sodium hydride (60% in mineral oil, 1%). 70 g, 41.5 mmol) in NMP (12 mL). After heating to 60 ° C, a solution of 5-trideuteriomethoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-benzimidazole monohydrate (2.10 g, 5.92 mmols) in NMP (4 ml) was added. Stirring was continued, first at 70 ° C for 24 hours, and then at 85 ° C for 5 hours. Following the treatment procedure described in example 35,5-trideuteriomethoxy-2 - [(3,5-dimethyl-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was obtained as a white solid (mp 120-121 ° C) Yield 0.55 g (28%).

1H-NMR (200 MHz, DMSO-d6): δ 2.20 (s, 3H), 2.27 (s, 3H), 4.64 (s, 2H), 6.75 (dd, 8.7 Hz , 2.4 Hz 1H), 6.89-7.38 (br m, 2H), 8.17 (s, 1H), 12.42 (br s, 1H); LC-MS: MH + = 336.

Example 37

5-Methoxy-2 - [(3,5-limethyl-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole

Starting from 5-methoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1 H -benzimidazole monohydrate (24.0 g, 68.2 mmols) and following the procedure described in example 36,5-methoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole was obtained as a white solid (mp 119-121 ° C); yield 8.72 g (38%).

1H-NMR (200 MHz, DMSO-d6): δ 2.20 (s, 3H), 2.27 (s, 3H), 3.77 (s, 3H), 4.64 (s, 2H), 6 , 75 (dd, 8.7 Hz, 2.5 Hz, 1H), 6.98 (br s, 1H), 7.35 (br d, 8.6 Hz, 1H), 8.17 (s, 1H ), 12.43 (br s, 1H); LC-MS: MH + = 333.

Example 38rac-5-Trideuteriomethoxy-2- (4-methoxy-3,5-limetyl-2-pyridinyl) methylsul-H-benzimidazole 5-Trideuteriomethoxy-2 - [(4-methoxy-3,5'-limetyl-2-pm 1 H-benzimidazole (1.50 g, 4.51 mmol) was dissolved in CH 2 Cl 2 (15 mL) and cooled to a temperature of -55 to -40 ° C. At this temperature, an acid solution 3-Chloroperoxybenzoic acid (wet, 77% concentration, 1.12 g, 5.00 mmol) in CH 2 Cl 2 (8 mL) was slowly added over 1.5 hours.

After an additional hour at a temperature of -55 to -40 ° C, triethylamine (0.87 ml, 6.28 mmol) and a 1: 1 mixture of 6% aqueous Na2CO3 and 2% aqueous Na2S2O3 were successively added while the eradicated mixture warms to about 0 ° C. Stirring was continued for 1 hour at room temperature. The phases were separated, and the organic layer was washed twice with a 1: 1 mixture of 6% aqueous Na 2 CO 3 and 2% aqueous Na 2 S 2 O 3 and once with water (10 ml each) before evaporating to dryness. . The resulting residue was crystallized from ethyl acetate (6.0ml) to give rac-5-trideuteriomethoxy-2 - [(4-methoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H- benzimidazole as a white solid (mp 150-152 ° C, decomp.); yield 1.27 g (81%).

1H-NMR (200 MHz, DMSO-d6): δ 2.17 (s, 3H), 2.20 (s, 3H), 3.69 (s, 3H), 4.67 (d, 13.6 Hz) , 1H), 4.77 (d, 13.5 Hz, 1H), 6.92 (dd, 8.9 Hz, 2.4 Hz, 1H), 7.09 (br s, 1H), 7.54 (br d, 8.9 Hz 1H), 8.18 (s, 1H), 13.39 (br s, 1H); LC-MS: MH + = 349.

Example 39

rac-5-Trideuteriomethoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole

Starting from 5-trideuteriomethoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (1.20 g, 3.57 mmols) and following the procedure described in the example 38, rac-5-trideuteriomethoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole was obtained as a white solid (mp 147-148 ° C, decomp.); yield 0.90 g (72%).

1H-NMR (200 MHz, DMSO-d6): δ 2.16 (s, 3H), 2.20 (s, 3H), 4.67 (d, 13.5 Hz, 1H), 4.77 (d 13.5 Hz, 1H), 6.90-7.55 (br m, 3H), 8.18 (s, 1H), 13.39 (br s, 1H); LC-MS: MH + = 352.Example 40

rac-5-Methoxy-2 - [(3,5'-dimethyl-tndeuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole

Starting from 5H7thioxy-2- (3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (1.00 g, 3.01 mmol) and following the procedure described in Example 38, rac-5-methoxy-2 - [(3,5-dimethyl-M-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole was obtained as a white solid (mp143-144 ° C decomp.); yield 0.86 g (82%).

1H-NMR (200 MHz, DMSO-d6): δ 2.17 (s, 3H), 2.20 (s, 3H), 3.81 (s, 3H), 4.67 (d, 13.6 Hz) , 1H), 4.77 (d, 13.5 Hz, 1H), 6.90-7.55 (br m, 3H), 8.18 (s, 1H), 13.40 (brs, 1H); LC-MS: MH + = 349.

Example 41

(S) -5-Trideuteriomethoxy-2 - [(3,5-dimethyl-4-trideu-teriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole sodium salt

At room temperature, 5-trideuteriomethoxy-2 - [(3,5-dimethyl-M-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-benzimidazole (3.02 g, 9.00 mmols) acid bis- (N-pyrrolidinamide) (+) - L-tartaric (0.92 g, 3.60 mmol) was suspended in 35 ml of methyl isobutyl ketone. The mixture was heated to 40 ° C and about 8 ml of solvent was evaporated in vacuo to remove water. Then zirconium (IV) n-propoxide (0.40 ml, 70% in n-propanol, 0.90 mmol) was added and stirring at 40 ° C continued for another hour. After cooling to 30 ° C, N-ethyldiisopropylamine (0.11 ml, 0.63 mmol) and cumene hydroperoxide (1.52 ml, -80% concentration, 8.55 mmol) were added. After stirring for about 20 hours at 30 ° C, clear reaction mixture was diluted with methyl isobutyl ketone (8.5 ml) and quenched with sodium thiosulfate (0.11 g) in saturated sodium bicarbonate solution (15 ml). . After phase separation, the organic layer was washed twice with saturated sodium bicarbonate solution (7.5 ml each). Water (25 ml) was added to the organic phase, and the pH was adjusted to pH = 1.25-13 using 40% aqueous NaOH (0.71 ml). The organic layer was extracted twice more with water (7.5 ml) at pH 12.5-13 (by the addition of a prerequisite 40% aqueous NaOH). The combined organic phase was washed with dichloromethane (15 mL). Then the pH was adjusted to about 10 with potassium diacid phosphate and the aqueous solution was extracted with dichloromethane (once 40 ml and twice 10 ml). Evaporation of the organic phase to dryness gave (S) -5-trideuteriomethoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole as a brown oil, which was still purified by the formation of the corresponding sodium salt.

To this end, the crude product was recovered in methyl isobutyl acetone (15 ml) and isopropanol (1.5 ml). Then 40% aqueous NaOH (0.63 mL) was added and the resulting suspension was cooled to 0 ° C. The solids were removed by filtration, washed with methyl isobutyl ketone (twice 2.0 ml) and dried at 45 ° C under vacuum to give (S) -5-trideuteriomethoxy-2 - [(3,5-dimethyl) trideuteriome

1 / - / - benzimidazole as an off-white solid (mp 224-225 ° C (decomp.), KF = 1.5%); yield 2.05 g (61%).

Chiral HPLC:> 97.0% ee; optical rotation: [α] D = -44 ° (MeOH, c = 0.53), [α] D = + 39 ° (H2O, c = 0.39).

1H-NMR (200 MHz, DMSO-d6): δ 2.18 (s, 3H), 2.21 (s, 3H), 4.39 (d, 12.9 Hz, 1H), 4.63 (d , 12.9 Hz, 1H), 6.54 (dd, 8.7 Hz, 2.5 Hz, 1H), 6.98 (d, 2.5 Hz, 1H), 7.32 (br d, 8, 6 Hz 1H), 8.23 (s, 1H).

Example 42

Bis - [(S) -5-Trideuteriomethoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1 / - / - benzimidazole] Magnesium Salt

Starting from (S) -5-trideuteriomethoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole sodium salt (200 mg, KF = 1.5%, 0.528 mmol) and following the procedure described in example 24, bis - [(S) -5-trideuteriomethoxy-2 - [(3,5-climethyl-4-trideuteromethoxy-2-pyridinyl) methylsulfinyl] -1 magnesium salt H-benzimidazole] was obtained as a white solid (mp 161-162 ° C (decomp.); KF = 1.5%); yield 132 mg (68%).

Chiral HPLC:> 97.0% ee; optical rotation: [α] D = -120 ° (MeOH, c = 0.50).

By appropriate combination of the procedures described above, other compounds of formula (1) are also accessible: For example, 4-chloro-2-chloromethyl-3-methylpyridinium chloride may be reacted with 1H-benzimidazole-2-thiol according to the procedure described in example 7 to give 2 - [(4-chloro-3-methyl-2-pyridinyl) methylthio] -1H-benzimidazole. Conversion of this product with, for example, 1,1-dideuterium-3-methoxy-1-propanol or 1,1-dideuterium-2,2,2-trifluoroethanol following the protocol described in example 9 then gives rise to formation of 2- [ (4- (1,1-dideuterium-3-methoxyprop-1-oxy) -3-methyl-2-pyridinyl) methylthio] -1H-benzimidazole and 2 - [(4- (1,1-dideuterium-2, 2,2-trifluorooxy) -3-methyl-2-pyridinyl) methylthio] -1H-benzimidazole, respectively. Finally, oxidation of these compounds according to the procedure used in 38 gives rac-2 - [(4- (1,1-deuterium-3-methoxypropan-1-oxide) -3-methyl-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole and rac-2 - [(4- (1,1-dideuthenium-2,2,2-trifluorooxy) -3-methyl-2-pyridinyl) methylsulfinyl] -1 H -benzimidazole, respectively representative of the compounds of formula (1).

As another example, 4-chloro-2-chloromethyl-3,5-dimethylpyridinium chloride may be reacted with 5-methoxy-1H-imidazo [4,5-b] pyridine-2-thiol according to the procedure described in Example 33 to give 5-methoxy-2 - [(4-chloro-3,5-dimethyl-2-pyridinyl) methylthio] -1H-imidazo [4,5-b] pyridine. Conversion of this product with methanol-d4 following the protocol described in example 36 gives rise to the formation of 5-methoxy-2 - [(3,5-dimethyl-trideuteriomethoxy-2-pyridinyl) methylthio] -1H-imidazo [4,5 -b] pyridine, which in turn may be oxidized according to the procedure used in example 38 to give rac-5-methoxy-2 - [(3,5-dimethyl-4-trideuteriomethoxy-2-pyridinyl ) methylsulfinyl] -1H-i [4,5- b] pyridine, that is, another compound of formula (1).

Commercial utility

The compounds of formula 1 and their salts and solvates, preferably hydrates, and the solvates, preferably salts hydrates (hereinafter "compounds of the invention") have useful pharmacological properties, making them commercially usable. In particular, they have a marked inhibitory effect on gastric acid secretion and excellent gastrointestinal protective action in warm-blooded animals, particularly in men. Accordingly, the compounds according to the invention are distinguished by highly selective action, advantageous duration of action, particularly high availability, a metabolism profile that is uniform among different individuals, a lack of significant side effects and a broad therapeutic spectrum.

In this context, "gastrointestinal protection" means the prevention and treatment of gastrointestinal disorders, in particular inflammatory gastrointestinal disorders and lesions (such as, for example, ulceraventricular, duodenal ulcer, gastritis, irritable bowel due to production acid enhancement or as a result of pharmaceutical compositions, GERD, Crohn's disease, IBD) which may be caused, for example, by microorganisms (eg Helicobacter pylori), bacterial toxins, pharmaceutical compositions (eg certain antiflogistics and antirheumatic drugs), chemicals (eg ethanol), gastric acid or stress.

With their excellent properties, the compounds according to the invention, in various models for the determination of antiulcerogenic and antisecretory properties, surprisingly proved to be markedly superior to the prior art compounds, in particular with regard to their pharmacokinetic properties. These improved pharmacokinetic properties allow for example a reduction in the amount of a compound according to the invention which is required for treatment or prophylaxis. Or by using the same amount of the inventive compound as that used for the prior art compounds, a longer duration of action can be obtained. Associated with these properties are advantages regarding patient safety or economic aspects, for example drug costs and so on. Because of these properties, the compounds according to the invention are quite suitable for use in human and veterinary medicine, where they are used in particular for the treatment and / or prophylaxis of gastro-testicular disorders.

Accordingly, the invention further provides the use of the compounds according to the invention for the treatment and / or prophylaxis of the diseases mentioned above. The invention also encompasses the use of the compounds according to the invention to prepare pharmaceutical compositions used for treatment and / or treatment. prophylaxis of the diseases mentioned above.

The invention also provides pharmaceutical compositions comprising the compounds according to the invention. In particular, the invention provides pharmaceutical compositions for oral use in solid form, containing the compounds of formulas 1, 1a or 1b in the form of their salts, in particular in the form of a sodium or magnesium salt, and / or in the form of a hydrate of such salt.

Pharmaceutical compositions are prepared by processes known per se which are familiar to one skilled in the art. As pharmaceutical compositions, the compounds according to the invention are employed as such or preferably in combination with pharmaceutical auxiliaries or vehicles in the form of tablets, coated tablets, capsules, suppositories, plasters (e.g. as TTS), emulsions, suspensions or solutions, where the active compound content advantageously ranges from about 0.1 to about 95% and where pharmaceutical dosage forms can be produced (eg slow-release forms ") or enteral forms) which, by appropriate choice of aids and vehicles, are adjusted to the active compound and / or the desired onset of action and / or duration of action.

Suitable auxiliaries or carriers for the desired pharmaceutical formulations are known to the person skilled in the art. In addition to solvents, gel formers, suppository bases, decompressed forming aids and other carriers for active compounds, for example, antioxidants, dispersants, emulsifiers, antifoams, flavor masking agents, preservatives, solubilizers, dyes or, in particular, permeation enhancers and complex formers (e.g. cyclodextrins).

The compounds according to the invention may be administered orally, parenterally or percutaneously.

In human medicine, it is generally advantageous to administer the compounds according to the invention when given orally in a daily dose of from about 0.01 to about 1, preferably about 0.02 to about 0. , And in particular about 0.04 to about 0.3 mg / kg body weight [calculated on the basis of the compounds according to the invention in free form, i.e. not in salt form (= "free compound" ], if appropriate in the form of a plurality of preferably 1 to 4 single doses, to achieve the desired result.For parenteral treatment, similar dosages may be used or (particularly when the active compounds are administered intravenously). Optical dosage and type of administration of the active compounds required in each case can be readily determined by one of ordinary skill in the art.

A further aspect of the invention is therefore a pharmaceutical composition comprising one or more compounds according to the invention together with one or more usual adjuvants, wherein the individual dose comprises from about 2 to about 60 mg of the product. free compound.

Another aspect of the invention is a pharmaceutical composition comprising one or more compounds according to the invention together with one or more usual adjuvants, wherein the individual dose comprises from about 4 to about 40 mg of the free compound.

Another aspect of the invention is the use of the compounds according to the invention to treat gastrointestinal disorders.

Another aspect of the invention is the use of the compounds according to the invention to treat gastrointestinal disorders in patients who have slow metabolism.

Another aspect of the invention is the use of the compounds according to the invention to treat gastrointestinal disorders in patients at risk of pharmacological interactions.

Another aspect of the invention is the use of the compounds according to the invention to treat gastrointestinal disorders in patients requiring inhibition of acid secretion for a prolonged period of time.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients having slow metabolism, comprising one or more compounds according to the invention together with one or more usual adjuvants, wherein the individual dose comprises from about 2 to about 2 about 60 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients with slow metabolism, comprising one or more compounds according to the invention together with one or more usual adjuvants, wherein the individual dose comprises from about 4 to about about 40 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients at risk of pharmacological interactions, comprising one or more compounds according to the invention together with one or more usual adjuvants, wherein the individual dosage comprises from about 2 to about 60 mg compostolivre.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients at risk of pharmacological interactions, comprising one or more compounds according to the invention together with one or more usual adjuvants, wherein the individual dose comprises from about 4 to about 40 mg compostolivre.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who require inhibition of acid secretion for an extended period of time, comprising one or more compounds according to the invention together with one or more usual adjuvants, where the dose The individual composition comprises from about 2 to about 60 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who require inhibition of acid secretion for an extended period of time, comprising one or more compounds according to the invention together with one or more usual adjuvants, where the dose The individual composition comprises from about 4 to about 40 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients having slow metabolism, comprising in an oral solid application form one or more salts according to the invention or a hydrate thereof together with one or more adjuvants. where the individual dose comprises from about 2 to about 60 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients having slow metabolism, comprising in an oral solid application form one or more salts according to the invention or a hydrate thereof together with one or more adjuvants. where the individual dose comprises from about 4 to about 40 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients at risk of pharmacological interactions, comprising in an oral solid application form one or more salts according to the invention or a hydrate thereof together with one or more usual adjuvants, where the individual dose comprises from about 2 to about 60 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients at risk of pharmacological interactions, comprising in an oral solid application form one or more salts according to the invention or a hydrate thereof together with one or more usual adjuvants, where the individual dose comprises from about 4 to about 40 mg of free compound.

Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who require inhibition of acid secretion for an extended period of time, comprising in one oral solid application form one or more salts according to the invention or a hydrate of the compounds. together with one or more usual aids, where the individual dose comprises from about 2 to about 60 mg of free compound. Another aspect of the invention is a pharmaceutical composition for treating gastrointestinal disorders for use in patients who require inhibition of acid secretion by a extended period of time, comprising in an oral solid application form one or more salts according to the invention or a hydrate thereof together with one or more usual adjuvants, wherein the individual dose comprises from about 4 to about 40 mg of free compound.

If the compounds according to the invention are used to treat the aforementioned diseases, the pharmaceutical preparations may also comprise one or more pharmacologically active ingredients from other groups of pharmaceutical compositions, examples which may be mentioned include tranquilizers (e.g. benzo-diazepines, eg diazepam), spasmolytic drugs (eg bietamiverine or camilofin), anticholinergic drugs (eg oxyphen-cyclimine or phencarbamide), local anesthetics (eg tetracaine or procaine), and optionally also enzymes, vitamins or amino acids.

In this context, we emphasize in particular the combination of the compounds according to the invention with other buffered drugs that neutralize gastric acid or inhibit acid secretion, such as, for example, antacids (such as, for example, magaldrate) or H2 blockers (eg, cimetidine, ranitidine), and with degastrin antagonists in order to increase the main action in the additive or superadditive sense and / or to eliminate or reduce side effects or to achieve a faster onset of action. We can also mention the free fixed or combination with NSAIDs (such as, for example, etophenamate, diclofenac, in-dometacin, ibuprofen or piroxicam) to prevent gastrointestinal injury caused by NSAIDs, or with compounds that modify gas-gastrointestinal motility, or with compounds. which reduce the incidence of transient lower esophageal sphincter relaxation (TLOSR), or with antibacterial substances (such as, for example, cephalosporins, tetracyclines, penicillins, macrolides, or bismuth salt) to control Helicobacter pylori. Participants of the antibacterial combination that may be mentioned include, for example, mezlocillin, ampicillin, amoxicillin, cephalothin, cefoxitin, cefotaxim, imipenem, gentamycin, amicacin, erythromycin, ciprofloxacin, metronidazole, clarithromycin and azithromycin, combinations with azithromycin, metronidazole or amoxicillin + clarithromycin).

In the practice of the present invention, the compounds of this invention may be administered in combination therapy separately, sequentially, simultaneously or chronologically (as for example as combined unit dosage forms, as separate unit dosage forms, as distinct unit dosage forms). -adjacent tapes, as fixed or non-fixed combinations, as a kit of parts or as mixtures) with one or more traditional therapeutic agents as mentioned above.

The term "combination" according to this invention may be present as a fixed combination, a non-fixed combination or a departes kit.

A "fixed combination" is defined as a combination where a first active ingredient and a second active ingredient are present together in a single dosage or in a single entity. An example of a "fixed combination" is a pharmaceutical composition wherein said first active ingredient and said second active ingredient are present in a concurrently administered mixture, such as in a formulation. Another example of a "fixed combination" is a pharmaceutical composition wherein said first active ingredient and said second active ingredient are present in a unit without being mixed.

A "kit of parts" is defined as a combination wherein said first active ingredient and said second active ingredient are present in more than one unit. An example of a "kit of parts" is a combination wherein said first active ingredient and said second active ingredient are present separately. The parts kit components can be administered separately, sequentially, simultaneously or chronologically.

Metabolism in liver microsomes

Materials and methods

Pantoprazole or examples 1 or 2 (10 μΜ each) were incubated with liver microsomes (source: all from GenTest except TEBU MiniPorco), 1 mg / ml protein incubation, 100 mM Tris-HCI, pH 7 0.1 mM NADPH2). The reaction was stopped 90 minutes after liquid nitrogen, the elemental compound was detected by HPLC (10 mMKH2PO4, pH 7.4, 20-44% acetonitrile gradient).

Table 1

Metabolism of H-pantoprazole versus deuterium compounds (e.g. 1,2) with microsomes after an incubation time of 90 minutes (species dependent).

<table> table see original document page 50 </column> </row> <table>

Metabolic clearance

To evaluate the properties of the compounds according to the invention intrinsic clearance in the isoenzymesCYP1A2, CYP2C8, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 of the recombinant human cytochrome P450 (CYP) family

Materials and methods

The compounds described in examples 17,19, 20, 21, 27, 28, 38,39, 40 and 41 undeuterated racemic omeprazole, its undeuterated epantoprazole (S) enantiomer and its enantiomers were incubated in a buffer containing 1 nmol / ml of recombinant P450 (Cypex, Dundee, UK), 4 mg / ml microsomal protein, 100mmols / l Tris-HCI (pH 7.4) and 1 mmol / l NADPH for 0, 3, 6, 12, and 15 or 30 minutes at 37 ° C. Incubations were performed in triplicate. For incubations with CYP2C19 the concentration of P450 was decreased to 0.5 nmol / ml and the incubation interval was changed to 0, 1, 2, 3, 4, and 5 minutes. Intrinsic clearance was determined based on the rate of disappearance of the elemental compound. Omeprazole and the deuterated analogs were determined by HPLC-UV. Lower limit of assay resolution based on experimental variability was 17.6 μΙ / min / nmol P450.

Results

CYP2C19 and CYP3A4 have been found to contribute to the oxidative metabolism of omeprazole, pantoprazole and their deuterated analogs. All other isoenzymes (CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP3A5) from the cytochrome P450 family did not contribute to the metabolism investigated. above the lower limit of assay resolution.

Formation kinetics of omeprazole 5-hydroxy-omeprazole and 5- (difluoromethoxy) -2-rr (3-methoxy-4-sulfate-2-pyridyl) methylsulfinyl-1H-benzimidazole

Following evaluation of the metabolic clearance of the compounds according to the invention by the P450 enzymes, the kinetics of formation of the major metabolite identified in humans, i.e. 5-hydroxy-omeprazole (5-methoxy-2 [[(4-methoxy- 3-methyl-5-hydroxymethyl-2-pyridinyl) methyl] suphinyl] -1H-benzimidazole) to omeprazole and 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) -methyl] sulfinyl] -1H-benzimidazole for pantoprazole. Generation of 5-hydroxy omeprazole and 5- {difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole is predominantly carried out by CYP2C19. Cryopreserved coagulated human hepatocytes are chosen as the most advanced in vitro system compared to human liver microsomes because all major drug metabolizing enzymes (phase I, phase II, hydrolases) are functional in this system in vitro.

Materials and methods

The compounds described in examples 17, 19, 20, 21, 27, 28, 38,39, 40 and 41 and undeuterated racemic omeprazole *, their undeuterated epantoprazole (S) enantiomer and their enantiomers were incubated in KrebsHenseleit Puffer (KHB), containing 84 μς / ιηΙ amikacin, 1 mmol / l calcium chloride, 20 mmols / l Hepes, 4.2 μπιοΙ / Ι hepatonic acid, 28.5 mmols / l sodium bicarbonate, and cryopreserved human hepatocytes (a combination of 10 donors, InVitro Technologies, Baltimore, MDUSA) at a concentration of 106 cells / ml. Formation rates of 5-hydroxy-omeprazole and 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (M2) under these conditions were linear up to 60 minutes. The formation rate of 5-hydroxy omeprazole was determined at ten different concentrations of the compound (0, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, 100.200 and 2500 μΜοΙε / Ι) incubated in duplicate for 60 minutes at 37 ° C. The formation rate of 5- (difluoromethoxy) -2 - [[[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (M2) was determined at nine different concentrations. (0, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0 and 100 μΜοΙ / Ι) incubated in duplicate for 60 minutes at 37 ° C C. 5-Hydroxy omeprazole was quantified using LC-MS / MS. 5-hydroxy-omeprazole purchased from Ramidius AB, Lund, Sweden and 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole ( M2) isolated from human urine were used as external reference. The concentration to reach the semi-maximal formation rate (KM value) and the maximal formation rate (Vmax) was obtained by nonlinear regression analysis using the Michaelis-Menten equation. Intrinsic clearance (CIint) was obtained by dividing Vmax by KM.

Results

Examples 39 and 40, both deuterated at the 4-methoxy-pyridinyl position showed formation rates that were about 1.5 times compared to undeuterated omeprazole. There were no differences between the Km values of racemic omperazole [1H], [2H3], and [2H6] analogs that exceeded experimental variability (Figure 1). Reduction in the deformation rate of 5-hydroxy-omeprazole was observed for example 40, but surprisingly not for example 38 (figure 1). Furthermore, there was no difference in formation rate between [2H3] omeprazole deuteradone 4-methoxy-pyridinyl position (example 40) and [2H6] omeprazole additionally deuterated at 5-methoxy-benzimidazole position (example 41, figure 3) . The formation of 5-hydroxy omeprazole from racemic [1H] omeprazole and its enantiomer (S) showed stereospecific differences, since the difference between Km and Vmax values of racemic omeprazole and ome-prazol (S) exceeded experimental variability. . Replacing six [1 H] atoms with [2 H] atoms at the 4-methoxy-pyridinyl and 5-methoxy-benzimidazole positions of (S) -omeprazole (example 41) did not alter the intrinsic clearance (ICm) of 5- hydroxy omeprazole (Figure 3).

The formation of 5- (difluoromethoxy) -2 - [[(3-methoxy-4-sulfate-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (M2) from pantoprazole, its enantiomers and from of the compounds described in examples 17, 19, 20, 21, 27 and 28 appeared to be inhibited by substrate concentrations above 100 μΜ. Therefore, data for incubations with substrate concentrations of 100 and 250μΜ were excluded from the calculation of Km and Vmax. M2 formation from racemic [1H] pantoprazole and enantiomers showed stereospecific differences (Figure 2A). Racemic analogs, (R), and (S) (examples 19, 27 and 28) deuterated at the 4-methoxy-pyridyl position showed formation rates that were at least 2.5 times reduced compared to their undeuterated equivalents (Figure 2B ). Intrinsic clearance of 4-methoxy-pyridyl, (R), and (S) -racemic analogues (examples 19, 27 and 28) were at least 4.7 times reduced compared to their undeuterated equivalents (Table 2). Stereospecific differences in M2 formation rates observed for [1H] pantoprazole analogs were less pronounced for deuterated analogs at the 4-methoxy pyridyl position (Figure 2B). Surprisingly, the reduction in the rate of formation of M2 compared to undeuterated compounds appears to be dependent on the position of the trideuteriomethoxy groups in the pyridyl portion of the molecule (Figure 2. The increase in the number of [1 H] atoms replaced by [2 H] 30 at 4-position methoxy-pyridyl of the molecule ([1H], [2H1] example 21, [2H2] example 20, and [2H3] example 19) decreased the formation rates of M2.Table 2:

Intrinsic clearance (CIint)) in coagulated human hepatocytes obtained by incubation with pantoprazole and compounds according to the invention.

<table> table see original document page 54 </column> </row> <table>

Claims (23)

1. Compounds of the general formula 1 <formula> formula see original document page 55 </formula> where R 1 is hydrogen or 1 -4C-alkoxyR 2 is 1 -4C-alkyl or 1 -4C-alkoxyR 3 is 1 -4C-alkyl, 1 - 4C-alkoxy or 2-8C-alkoxyalkoxyR4 is hydrogen or 1-4C-alkylZ is CH or Ne pharmaceutically acceptable salts, solvates and solvates thereof, wherein at least one hydrogen atom of R1, R2, R3, R4 or any combination of R1, R2, R3 and R4 is replaced by a deuterium atom. 2. Compounds of formula 2 <formula> formula see original document page 55 </formula> wherein R1 is hydrogen or 1-4C-alkoxy R2 is 1-4C-alkyl or 1-4C-alkoxyR3 is 1-4C-alkyl, 1- 4C-alkoxy or 2-8C-alkoxyalkoxyR4 is hydrogen or 1-4C-alkylZ is CH or Nd thereof, where at least one hydrogen atom of R1, R2, R3, R4 or any combination of R1, R2, R3 and R4 is substituted by a deuterium atom. Compounds according to claim 1 or 2, wherein at least one of the hydrogen atoms of R3 is replaced by a deuterium atom and R3 is a 1-2C alkoxy group or a 2-5C-alkoxyalkoxy group. Compounds according to claim 1 or 2, wherein R 1 is hydrogen, methoxy or difluoromethoxy, R 2 is methyl or methoxy, R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen or methyl and where at least one of the hydrogen atoms of R3 is replaced by deuterium atoms. Compounds according to claim 1 or 2, wherein R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy and wherein all R 3 hydrogen atoms are replaced by deuterium atoms. Compounds according to claim 1 or 2, wherein R 1 is hydrogen, methoxy or difluoromethoxy, R 2 is methyl or methoxy, R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen or methyl and where all atoms of hydrogen from R3 are replaced by deuterium atoms. 7. (R / S) -5-Methoxy-2 - [(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole and pharmaceutically acceptable salts, solvates and solvates thereof. 8. (R / S) -2- [3-Methyl-4- (1,1-deuterium-2,2,2-trifluorooxy) -2-pyridinyl) methylsulfinyl] -1H-benzimidazole and pharmaceutically acceptable salts, solvatos solvates salts thereof. 9. (R / S) - 5-Difluoromethoxy-2 - [(3-methoxy-4-trideuteriomethoxy-2-pyridinyl) methylsulfinyl] -1H-benzimidazole and pharmaceutically acceptable salts, solvates and solvates thereof . 10. (R / S) -2 - {[4- (3-Trideuteriomethoxyhexadeuteriopropoxy) -3-methyl-pyridin-2-yl] methylsulfinyl} -1H-benzimidazole. 11. (R / S) -5-Methoxy-2 - ((4-trideuteriomethoxy-3,5-dimethyl-2-pyridylmethyl) sulfinyl) -1H-imidazo [4,5-b] pyridine. 12. S (-) - 5-Methoxy-2 - [(4-trideuteriomethoxy-3,5-dimethyl-2-pyridinyl) methylsulfinyl] -1H-benzimidazole and pharmaceutically acceptable salts, solvates and solvates of the salts thereof. A pharmaceutical composition comprising one or more compounds as defined in any one of claims 1 or 3 to 12 together with one or more pharmaceutically acceptable excipients. A pharmaceutical composition comprising one or more compounds as defined in any one of claims 1 or 3 to 12 together with one or more pharmaceutically acceptable excipients wherein the individual dose comprises from about 2 to 60 mg of the compound of general formula 1. Use of a compound as defined in any one of claims 1 or 3 to 12 for the treatment and / or prophylaxis of gastrointestinal disorders. Use of a compound as defined in any one of claims 2 to 6 for the production of a compound of formula 1 as defined in any one of claims 1 or 3 to 6. 17. Compounds of formula 3 <formula> formula see original document page 57 </formula> where X is a halogen or an activated derivative of an alcohol R 2 is 1 -4C-alkyl or 1 -4C-alkoxyR 3 is 1 -4C-alkyl, 1 -4C-alkoxy or 2-8C-alkoxyalkoxyR4 is hydrogen or even 1-4C-alkylated, where at least one hydrogen atom of R2, R3, R4 or any combination of R2, R3 and R4 is replaced by one deuterium atom. Compounds according to claim 17, wherein X is a halogen selected from iodine, bromine, fluorine or chlorine. A compound according to claim 17, wherein X is an activated derivative of an alcohol selected from an alkylsulfonate group, an arylsulfonate group or a perfluoralkane sulfonate group. A compound according to any one of claims 17 to 19 wherein R 2 is methyl or methoxy, R 3 is methoxy, 2,2,2-trifluorooxy or methoxypropoxy, R 4 is hydrogen or methyl and wherein at least one of hydrogen moieties of R3 is replaced by deuterium atoms. A compound according to claim 20, wherein all hydrogen atoms of R 3 are replaced by deuterium atoms. Use of a compound as defined in any one of claims 17 to 21 for the production of a compound of formula 1 or 2 according to any one of claims 1 to 12. Use of a compound as defined in any one of claims 1 or 3 to 12 for the manufacture of a medicament for the treatment and / or prophylaxis of gastrointestinal disorders.