RU2232159C2 - Derivatives of benzimidazole and pharmaceutical compositions comprising prodrug of proton pump inhibitor - Google Patents

Abstract

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to inhibitors of proton pump. Invention describes derivatives of benzimidazole of the formula: Het₁-X-S(O)-Het₂ wherein Het₁ has structure:

X has structure:

Het₂ has structure:

R₁, R₂, R₃ are taken independently among hydrogen atom, alkyl comprising 1-10 carbon atoms, fluoro-substituted alkyl comprising 1-10 carbon atoms, alkoxy-group with 1-10 carbon atoms and fluoro-substituted alkoxy-group with 1-10 carbon atoms; R₆-R₉ are taken among hydrogen atom, alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon atoms, alkoxy-group with 1-10 carbon atoms and halogen-substituted alkoxy-group with 1-10 carbon atoms; R₁₀ means hydrogen atom, alkyl with 1-10 carbon atoms; R₁₅ has formula:

wherein R₁₇ means alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon atoms, alkoxy-group with 1-10 carbon atoms, halogen-substituted alkoxy-group with 1-10 carbon atoms, alkylthio-group with 1-10 carbon atoms, halogen-substituted alkylthio-group with 1-10 carbon atoms, alkoxycarbonyl with 1-10 carbon atoms, halogen-substituted alkoxycarbonyl with 1-10 carbon atoms, F, Cl, Br, J, NO₂, CN, OCO-alkyl, NH₂, alkylamino- and dialkylamino-group wherein indicated alkyl groups comprise 1-10 carbon atoms, carbamoyl, N-substituted carbamoyl, alkylcarbonyl with 1-10 carbon atoms. (Alkoxycarbonyl)-alkoxy-groups in each of indicated alkoxy-groups comprise 1-10 carbon atoms, (alkoxycarbonyl)-alkyl groups in each of indicated alkoxy-group or alkyl group comprise 1-10 carbon atoms, (carbamoyl)-alkoxy-group with 1-10 carbon atoms, (N-alkylcarbamoyl)-alkoxy-group with 1-10 carbon atoms, (N,N-dialkylcarbamoyl)-alkoxy-group with 1-10 carbon atoms, (N-substituted or unsubstituted carbamoyl)poly(alkoxy)-group with 1-10 carbon atoms, (N-substituted or unsubstituted carbamoyl)-alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbamoyl]-alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbamoyl]-alkoxy-group with 1-10 carbon atoms, [N-(substituted aryl)carbamoyl]alkoxy-group with 1-10 carbon atoms being poly(alkoxy)-group in each indicated alkoxy-groups comprises 1-10 carbon atoms, cyclic polyalkoxy-group, guanidinyl-group, ureido-group, dialkylamino-poly(alkoxy)-group, [N-(carbamoylalkyl)carbamoyl]-alkoxy-group, [N-(carbamoylalkyl)carbamoyl]-alkyl, [N-[[N-(heteroaryl)carbamoyl]alkyl)carbamoyl]-alkoxy-group, [N-[[N-(substituted heteroaryl)carbamoyl]alkyl]carbamoyl]-alkoxy-group, (sulfonato)-alkyl, (sulfonato)-alkoxy-group, N-[(sulfonato)alkyl]-amido-group, (substituted)maleimido-group, (substituted)succinimido-group, [(trialkyl)ammonium]alkoxy-group; R₂₁ means (aryl)alkyl, (heteroaryl)alkyl, phenyl, naphthyl or heteroaryl comprising 1-3 heteroatoms taken independently among N, O and S wherein indicated phenyl, naphthyl or heteroaryl groups are substituted or unsubstituted 1-5 groups R₁₇; or pharmaceutically acceptable salts of indicated compounds. Invention describes also pharmaceutical compositions based on derivatives of benzimidazole. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

16 cl, 4 tbl, 67 ex

Description

FIELD OF THE INVENTION

The present invention relates to prodrugs of proton pump inhibitors useful as antiulcer agents. More specifically, this invention relates to prodrugs that slowly hydrolyze to produce proton pump inhibitors that inhibit exogenously or endogenously the secretion of “gastric” (hydrochloric) acid and, therefore, can be used to prevent and treat inflammatory diseases of the gastrointestinal tract in mammals, including man.

Brief Description of the Related Art

Derivatives of benzimidazole designed to inhibit the secretion of acid in the stomach are described in US Pat. which then covalently bind to gastric H, K-ATPase, an enzyme involved in the final stage of proton formation in parietal cells, and thus inhibit the enzyme. Compounds that inhibit the gastric enzyme H, K-ATPase, are generally known in the art as “proton pump inhibitors” (PPI).

Some of the benzimidazole compounds capable of inhibiting gastric H, K-ATPase have found practical use as medicines in medicine and are known by such names as lansoprazole (LANSOPRAZOLE, US Patent 4,628,098), omeprazole (OMEPRAZOLE, US Patents 4,255,431 and 5,693,818), pantoprazole (PANTOPRAZOLE, US Patent 4,758,579) and rabeprazole (RABEPRAZOLE, US Patent 5,045,552). Diseases that are treated with proton pump inhibitors, and specifically the four drugs listed above, include, but are not limited to, peptic ulcer, thermal burn, reflux esophagitis, erosive esophagitis, non-ulcer dyspepsia, Helicobacter pylori infection, rhinitis and asthma.

Although drugs such as proton pump inhibitors are a step forward in the field of medicine and veterinary medicine, they are generally not without weaknesses or weaknesses. The disadvantages of currently used drugs such as proton pump inhibitors (PPIs) can best be explained by describing in more detail the mode of action, disease or condition in which they are used, and the circumstances of their use. Thus, acid-related diseases include, but are not limited to, erosive esophagitis, gastroesophageal reflux, gastric and duodenal ulcers, non-ulcer dyspepsia, and Helicobacter pylori infection. Modern therapy for all diseases except bacterial infection of H. pylori includes the use of drugs designed to suppress secretion; the above proton pump inhibitors are one type of this kind of drug.

Currently used proton pump inhibitors are pyridylmethylsulfinylbenzimidazoles (or compounds of similar structure) with pK _a 4.0-5.0. The mechanism of their action requires the accumulation in the acidic space of the parietal cell (secretory Canadian, pH about 1.0) and the subsequent conversion of the hydrogen ion catalyzed into reactive thiophilic particles capable of inhibiting gastric ATPase, an enzyme that effectively inhibits gastric secretion. In accordance with this mechanism, currently used PPI drugs require special protection of the stomach in order to remain active for absorption in the duodenum. For this reason and because of sensitivity to digestion in the acidic environment of the stomach, PPI receptors for oral administration are usually enteric coated. The need for an enteric coating is a disadvantage because the enteric coating is expensive and sensitive to moisture.

Due to the requirement of accumulation in the acidic space of the parietal cell, acid secretion is necessary for the effectiveness of PPI drugs. It was found that the half-life of these drugs in plasma is 60-90 minutes. All acid pumps are not active at any time, most likely only about 75% are active on average during the time when the drug is in the blood after oral administration. It was also experimentally found that with the currently used treatment - oral administration once a day - the maximum inhibition of stimulated acid is about 66%. This is due to the combination of a short half-life of the drug, a limited number of acid pumps active during the presentation of the drug, and a turnover of acid pumps.

In today's practice, it is impossible to control acid secretion at night with evening oral administration, since the drug disappears from plasma with time, acid secretion is established after midnight. Complete inhibition of acid secretion would be ideal for healing in acid-related diseases and for treating H. pylori infection (in combination with antibiotics), as well as for alleviating the symptoms of non-ulcer dyspepsia. In the case of currently used drugs such as PPI, this is achieved only with intravenous infusion; in the case of OMEPRAZOLE (omeprazole), this requires an intravenous infusion of 8 mg per hour. It is clear that the technique requires a drug or drugs that act according to the mechanism of PPI drugs that achieve complete inhibition or come close to complete inhibition of acid secretion when taken orally.

With the oral administration of modern dosage forms of currently used PPI preparations, incomplete inhibition of acid secretion is achieved for less than 24 hours, the therapy used to heal ulcers in the stomach and duodenum is from 4 to 8 weeks. And this despite the fact that the generation time of cells on the surface of the intestine is about 72 hours. There is no doubt that the long healing time of these drugs is currently caused by the inadequacy between acid suppression and acid-induced damage. The above emphasizes the need for a drug or drugs that act according to the mechanism of PPI drugs, which would allow to achieve complete inhibition of acid secretion when taken orally or close to it.

As a further remark on the merits of the field to which the invention relates, applicants offer a general concept of prodrugs that are well known in the art. Prodrugs are derivatives of the drugs themselves, which after administration into the body turn into physiologically active forms. The conversion may be spontaneous, such as hydrolysis in a physiological environment, or may be catalyzed by enzymes. From the large body of scientific literature on prodrugs in general, we cite the following examples: Design of Prodrugs (Bundgaard H. ed.), 1985, Elsevier Science Publishers B.V. (Biomedical Division), Chapter 1; Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities (Hans Bundgaard); Bundgaard et al. Int. J. of Pharmaceutics 22 (1984), 45-56 (Elsevier); Bundgaard et al. Int. J. of Pharmaceutics 29 (1986), 19-28 (Elsevier); Bundgaard et al. J. Med. Chem. 32 (1989), 2503-2507; Chem. Abstracts 93, 137935y (Bundgaard et al.); Chem. Abstracts 95, 138493f (Bundgaard et al.); Chem. Abstracts 95, 138592n (Bundgaard et al.); Chem. Abstracts 110, 57664p (Alminger et al.); Chem. Abstracts 115, 64029s (Buur et al.); Chem. Abstracts 115, 189582y (Hansen et al.); Chem. Abstracts 117, 14347q (Bundgaard et al.); Chem. Abstracts 117, 55790x (Jensen et al.) And Chem. Abstracts 123, 17593b (Thomson et al.).

As far as applicants are aware, proton pump inhibitor prodrugs are not currently used. However, several US patents describe compounds that can act as prodrugs of certain proton pump inhibitors. Specifically, US Patent No. 4,662,230 (Rainer et al.) Describes pyridylmethylsulfinylbenzimidazole derivatives that include a group designated R ₅ at one of the benzimidazole nitrogen atoms, the R ₅ group is expected to cleave under ambient conditions or under the action of the enzyme to give the corresponding compound with a free NH bond (see section 3 of US Pat. No. 4,662,230). US Patent Nos. 5021433 (Alminger et al.), 4045563 (Berntsson et al.), 4965269 (Brznbstrxm et al.) Also describe pyridylmethylsulfinyl benzimidazoles in which one nitrogen atom of the benzimidazole moiety carries a substituent which is cleaved off under the influence of the environment or the enzyme.

This invention is a contribution to the art as it encompasses better-structured prodrugs for drugs such as proton pump inhibitors and includes evidence of the suitability of the prodrugs of the invention for use as prodrugs of proton pump inhibitors with increased efficacy in the treatment of acid-related diseases due to prolonged life proton pump inhibitors in the body.

SUMMARY OF THE INVENTION

This invention relates to compounds of the formula 1

Het ₁ -XS (O) -Het ₂ ,

in which Het _{1 is} selected from the formulas shown below:

X is selected from the formulas

and Het ₂ are selected from the formulas

where N in the benzimidazole moiety means that one of the carbon atoms may be substituted by an unsubstituted nitrogen atom;

R ₁ , R ₂ and R _{3 are} independently selected from hydrogen, alkyl containing 1-10 carbon atoms, fluoro substituted alkyl containing 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, fluoro substituted alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, fluorine-substituted alkylthio with 1-10 carbon atoms, alkoxyalkoxy with 2-10 carbon atoms, alkylamino and dialkylamino containing in each alkyl group of the indicated alkylamino and dialkylamino groups 1-10 carbon atoms, halogen, phenyl, alkyl substituted phenyl, alkoxy substituted phenyl, phenylal Coxy, wherein each of the alkyl groups in said substituted phenyl, alkoxy substituted phenyl and phenylalkoxy contains 1-10 carbon atoms, piperidino, morpholino or two of the R ₁ , R ₂ and R ₃ groups, together forming a 5- or 6-membered ring, containing 0 or 1 heteroatom selected from N, S and O;

R ₄ and R _{5 are} independently selected from hydrogen, alkyl with 1-10 carbon atoms, fluorine substituted alkyl with 1-10 carbon atoms, phenylalkyl, naphthylalkyl and heteroalkyl, and the alkyl in these phenylalkyl, naphthylalkyl and heteroalkyl groups contains 1-10 carbon atoms;

R ₆ means hydrogen, halogen, alkyl with 1-10 carbon atoms, fluoro substituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms or fluoro substituted alkoxy with 1-10 carbon atoms;

from R ₆ to R _{9 are} independently selected from hydrogen, halogen, alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, halogen-substituted alkoxy with 1-10 carbon atoms, alkylcarbonyl, alkoxycarbonyl wherein the alkyl group in said alkylcarbonyl and alkoxycarbonyl contains 1-10 carbon atoms, oxazolyl, imidazolyl, thiazolyl, morpholinyl, piperazinyl, pyrazinyl, pyrazolyl or any two adjacent substituents from the groups R ₆ -R ₉ can form a ring which, if necessary however, may include a heteroatom selected from N, S, and O, and said cycle may further be substituted;

R ₁₀ means hydrogen, alkyl with 1-10 carbon atoms or R ₁₀ may form an alkylene chain together with R ₃ ;

R ₁₁ and R _{12 are} independently selected from hydrogen, halogen, alkyl with 1-10 carbon atoms and halogen-substituted alkyl with 1-10 carbon atoms;

R _{15 is} selected from the following formulas:

where R ₁₆ means alkyl with 1-10 carbon atoms, morpholino, piperidino, phenyl, naphthyl or heteroaryl with 1-3 heteroatoms selected from N, O or S, and these morpholino, piperidino, phenyl, naphthyl or heteroaryl groups are unsubstituted or substituted with 1-5 R ₁₇ groups;

R ₁₇ means alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, halogen-substituted alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, halogen-substituted alkylthio with 1- 10 carbon atoms, alkoxycarbonyl with 1-10 carbon atoms, halogen-substituted alkoxycarbonyl with 1-10 carbon atoms, F, Cl, Br, J, NO ₂ , CN, OSOalkyl, NH ₂ , alkylamino and dialkylamino, where in the indicated OSOalkyl, alkylamino and dialkylamino groups each of these alkyl groups contains 1-10 angles native atoms, in addition, R ₁₇ means ureidoil (RNHCONH-), guanidinyl, carbamoyl, N-substituted carbamoyl, alkylcarbonyl having 1-10 carbon atoms, (alkoxycarbonyl) alkoxy groups of each of said alkoxy groups contain 1-10 carbon atoms, ( alkoxycarbonyl) alkyl groups in each of the indicated alkoxy or alkyl groups contain 1-10 carbon atoms, (carbamoyl) alkoxy with 1-10 carbon atoms, (N-alkylcarbamoid) alkoxy with 1-10 carbon atoms, (N, N-dialkylcarbamoyl) alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carb amoyl) poly (alkoxy) with 1-10 carbon atoms, (N-substituted or unsubstituted carbamoyl) alkyl with 1-10 carbon atoms, [N- (heteroaryl) carbamoyl] alkyl with 1-10 carbon atoms, [N- (heteroaryl ) carbamoyl] alkoxy with 1-10 carbon atoms, [N- (heteroaryl) carbamoyl] alkoxy with 1-10 carbon atoms, [N- (substituted aryl) carbamoyl] alkoxy with 1-10 carbon atoms, wherein the poly (alkoxy) group each of these alkoxy groups contains 1-10 carbon atoms, cyclic polyalkoxy (such as a crown ether fragment), guanidinyl group, ureido group, dialkyl aminopoly (alkoxy) group, [N- (carbamoylalkyl) carbamoyl] alkoxy, [N- (carbamoylalkyl) carbamoyl] alkyl, [N - [[N- (heteroaryl) carbamoyl] alkyl] carbamoyl] alkoxy, [N- [ [N- (substituted heteroaryl) carbamoyl] alkyl] carbamoyl] alkoxy, [(tri-alkyl) ammonium] alkoxy, (sulfonato) alkyl, (sulfonato) alkoxy, [N- (sulfonato) alkyl] amido, (substituted) maleimido , (substituted) succinimido;

R ₁₈ independently selected from H, alkyl with 1-10 carbon atoms and phenyl;

R ₁₉ and R _{20 are} independently selected from H, alkyl with 1-10 carbon atoms and halogen substituted alkyl with 1-10 carbon atoms, or R ₁₉ and R ₂₀ together with the N atom form a 4-10 membered ring, which may include another heteroatom selected from N, O or S, wherein said N-heteroatom is an unsubstituted or substituted alkyl group with 1-10 carbon atoms or an aryl or heteroaryl group,

R ₂₁ means alkyl, (aryl) alkyl, (heteroaryl) alkyl, phenyl, naphthyl or heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, wherein said phenyl, naphthyl or heteroaryl groups are substituted or unsubstituted 1- 5 groups R ₁₇ ,

Y means O or = NR ₁₆ ,

or pharmaceutically acceptable salts of these compounds.

The compounds of the invention are sulfoxides and have an asymmetric center on the sulfur atom. As pure enantiomers, racemic mixtures and nonequilibrium mixtures of two isomers are included in the scope of this invention. Some compounds of the invention may contain one or more asymmetric carbon atoms (for example, in a branched alkyl group) and some other compounds may have a second sulfoxide group introducing another asymmetric center on the sulfur atom. Optical isomers, racemates, diastereomers and mixtures thereof are also included in the scope of the invention.

The compounds of the invention behave as prodrugs of drugs, such as proton pump inhibitors, which are useful for inhibiting acid secretion in the stomach. The compounds of the invention have increased stability in the form of tablets or capsules, are resistant to acid, have excellent bioavailability and a half-life from plasma of up to 5-6 hours, which is significantly higher than the half-life of previously used proton pump inhibitors in plasma.

DETAILED DESCRIPTION OF THE INVENTION

The chemical structure of the compounds according to the invention is shown and fully described in the section “Summary of the invention” in the explanation of formula 1. As can be seen from this formula, the compounds of the invention are pyridylmethylsulfinyl benzimidazoles or compounds of a closely related structure, characterized in that the benzimidazole nitrogen atoms have a group as substituents (designated R ₁₅ in formula 1) that gradually cleaved under physiological conditions and thus gives piridilmetilsulfinilbenzimidazolnoe compound (Cpd or ix similar structure) with a free NH- group in the benzimidazole (or related) moiety. Thus obtained — by splitting the R ₁₅ group — the compound then undergoes acid-catalyzed rearrangement, and the thiophilic groups formed in this way inhibit H, K-ATPase, an enzyme involved in the formation of gastric acid. Therefore, the novel compounds of this invention containing the R ₁₅ group are prodrugs of proton pump initiator compounds, which can also be represented by formula 1, in which, however, the R ₁₅ group will mean hydrogen.

Of the prodrugs of this invention, those compounds are preferred in which a pyridylmethylsulfinylbenzimidazole or structurally similar moiety is also preferred in the prior art. In other words, preferred prodrugs of this invention are prodrugs of preferred proton pump inhibitors per se.

Now, with regard to the specific meaning of the symbols in Formula 1, those compounds of this invention are preferred in which the moiety designated Het ₁ is pyridyl having substituents an alkyl, O-alkyl and / or O-fluoroalkyl group. The most preferred substituents in the pyridine moiety designated R ₁ , R ₂ and R ₃ in formula 1 are CH ₃ O—, CH ₃ -, CF ₃ CH ₂ O— and CH ₃ O (CH ₂ ) ₃ O—.

The fragment indicated in Formula 1 X is preferably a methylene (—CH ₂ -) group or —CHR ₁₀ group, and the methylene or —CHR ₁₀ group is preferably located at the α-position relative to the nitrogen atom in the pyridine moiety. Also preferred are compounds wherein X is ortho-phenylene or substituted ortho-phenylene; in the most preferred compounds, X is methylene.

As for the group indicated in formula 1 Het ₂ , this fragment is preferably a substituted benzimidazole. R ₆ -R ₉ groups are preferably selected from hydrogen, chlorine and fluoro-substituted alkoxy groups, with hydrogen, chlorine, CF ₂ and CH ₃ O— being even more preferred.

Now, with regard to the group indicated by R ₁₅ in the formula 1, it is obvious to those skilled in the art that this group is a fundamentally new structural feature according to the invention. Among the R ₁₅ groups represented in the explanation of Formula 1, arylsulfonyl groups (designated R ₂₁ (R ₁₇ ) SOY-, where Y is O) are preferred. In arylsulfonyl groups, the aryl moiety (R ₂₁ ) is preferably phenyl substituted or unsubstituted on the R ₁₇ group. When the phenyl group (R ₂₁ ) is substituted, then the substituent (R ₁₇ ) is preferably selected from Cl, Br, F, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, di- (lower alkyl) amino, lower alkoxycarbonyl, ureidoyl (RNHCONH- ), guanidinyl, carbamoyl, N-substituted carbamoyl, (N-substituted carbamoyl) alkyl, di- (lower alkylamino) alkoxy, (morpholin-4-yl) alkoxy, (morpholin-4-yl) polyalkoxy, di- (lower alkylamino ) alkyl, poly (alkoxy) alkoxy, cyclic poly (alkoxy), (carbamoyl) alkoxy, [N- (lower alkyl) carbamoyl] alkoxy, [N, N- (lower dialkyl) carbamo yl] alkoxy, (N, N-dialkylcarbamoyl) alkyl, [N- (heteroaryl) carbamoyl] alkyl, [N- (heteroaryl) carbamoyl] alkoxy, [N- (aryl) carbamoyl] alkoxy, [N - [(N- substituted carbamoyl) alkyl] carbamoyl] alkoxy, (sulfonato) alkyl, (sulfonato) alkoxy, [N- (sulfonato) alkyl] amido, (substituted) maleimido-, (substituted) succinimido and [(tri-alkyl) ammonium] alkoxy. Even more preferably, when the phenyl group is unsubstituted (R ₁₇ is H) or the substituent in the phenyl (R ₂₁ ) group is selected from Cl, Br, F, methyl, methoxy, trifluoromethyl, trifluoromethoxy, dimethylamino, ethoxycarbonyl, carbamoyl, guanidinyl, ureidoyl, (carbamoyl) methoxy, [N- (pyridyl) carbamoyl] methoxy, morpholinyl, (morpholin-4-yl) alkoxy, [(morpholin-4-yl) alkoxy], alkoxy, 2- (dimethylamino) ethoxy, [N- [ (carbamoyl) methyl] carbamoyl] methoxy, sodium (sulfonato) alkoxy, (trimethylammonium) alkoxy, poly (alkoxy) and cyclic tetra- or penta-ethyleneoxy gr oops. Preferably, when there is only one substituent R ₁₇ (other than hydrogen) in the phenyl (R ₂₁ ) fragment, and it is preferable when the substituent R ₁₇ is in the position of steam (1,4) or meta (1,3) relative to sulfonyl (SO ₂ ) group.

In other embodiments of the compounds of the invention, the physiologically unstable substituent R ₁₅ is a sulfinyl group, designated R ₁₆ (R ₁₇ ) SO- in the explanation of Formula 1. Preferred groups for the combination of R ₁₆ (R ₁₇ ) are the same groups as for the combination of R ₂₁ (R ₁₇ ), phenyl, 4-methylphenyl, 4-methoxyphenyl and 4-trifluoromethylphenyl are even more preferred. In this detail, lower alkyl or lower alkoxy contains 1-6 carbon atoms.

In other embodiments of the compound of the invention, the physiologically unstable substituent R ₁₅ forms a Mannich base designated R ₁₉ R ₂₀ NC (R ₁₈ ) ₂ - in connection with formula 1. In these compounds of the type of Mannich bases R ₁₈ preferably means H or lower alkyl, most preferably H or methyl. The groups R ₁₉ R ₂₀ N are preferably di- (lower alkyl) amino, N-succinimidyl, N-morpholinyl, N-piperidinyl, N- (N-4-methyl) hexahydropyrazinyl, N, N-phenyl, methylamino, N-tetrahydroporrolyl and N- (benzotriazol-1-yl), as shown below and indicated by the formulas 2-8 and 8a, respectively:

The most preferred groups for the combination of R ₁₉ R ₂₀ N- according to this invention are dimethylamino, N-morpholino and N-piperidinyl.

The most preferred compounds of the invention are those in which the proton pump inhibitor fragment is the same as the widely used proton pump inhibitors known as lansoprazole (LANSOPRAZOLE), omeprazole (OMEPRAZOLE), pantoprazole (PANTOPRAZOLE) and rabeprazole (RABEPRAZOLE) in which the group R ₁₅ represents a benzenesulfonyl group monosubstituted either in 4 (pair) or in 3 (meta) position on Cl, Br, F, CH ₃ , CH ₃ O, CF ₃ , CF ₃ O-, (CH ₃ ) ₂ N, NH ₂ CO, NH ₂ CONH, NH ₂ C (= NH) NH, 4-morpholino, 2- (4-morpholinyl) ethoxy, 2- [2- (4-morpholinyl) ethoxy] ethoxy and, 3- (4-morpholinyl) propoxy, poly (alkoxy), Na ^{+ -} O ₃ S-CH ₂ CH ₂ CH ₂ -O, X ^- (CH ₃ ) ₃ N ⁺ CH ₂ CH ₂ O- (X is anion, such as a halogen ion), NH ₂ COCH ₂ O, (pyridyl) NHCOCH ₂ O, NH ₂ COCH ₂ , NH ₂ COCH ₂ O (CH ₃ ) ₂ NH ₂ or EtOCO. These compounds are depicted by formulas 9, 10, 11 and 12, respectively, where R ₁₇ * represents the indicated Cl, Br, F, CH ₃ , CH ₃ O, CF ₃ , CF ₃ O-, (CH ₃ ) ₂ N, NH ₂ CO, NH ₂ CONH, NH ₂ C (= NH) NH, 4-morpholino, 2- (4-morpholinyl) ethoxy, 2- [2- (4-morpholinyl) ethoxy] ethoxy, 3- (4-morpholinyl) propoxy , poly (alkoxy), Na ^{+ -} O ₃ S-CH ₂ CH ₂ CH ₂ -O, X ^- (CH ₃ ) ₃ N ⁺ CH ₂ CH ₂ O- (X denotes an anion, such as a halogen ion), NH ₂ COCH ₂ O, (pyridyl) NCHOS ₂ O NH ₂ COCH ₂ , NH ₂ COCH ₂ O, (CH ₃ ) ₂ NCH ₂ or EtCO groups at position 4 (pair) or 3 (meta) phenyl ring and where the numbering in the benzimidazole system is shown in the formulas. In formula 10, CH ₃ O-group may occupy position 5 or 6 in the benzimidazole fragment, and in formula 11 CF _{2 the} HO group may occupy position 5 or 6 of the benzimidazole fragment.

Compounds of the invention include

2 - [[(3-chloro-4-morpholin-2-pyridyl) methyl] sulfinyl] -5-methoxy- (1H) benzimidazole,

2 - [[[4- (2,2,3,3,4,4,4-heptafluorobutyl) oxy] -2-pyridyl] methylsulfinyl] -1H-thieno [3,4-d] imidazole,

2 - [[(4-ethithio-3-methyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

2 - [(3-methoxyphenyl) methylsulfinyl] -1H-benzimidazole,

2 - [(3-methoxyphenyl) methylsulfinyl] imidazole [5,4-c] pyridine,

2 - [(3-methoxyphenyl) methylsulfinyl] imidazole [4,5-c] pyridine

and 2 - [(3-methoxyphenyl) methylsulfinyl] -5-nitro-benzimidazole,

in which in position 1 is a group R ₁₅ . The group R ₁₅ in these compounds is a monosubstituted at either position 4 (pair) or position 2 (meta) group with the substituents Cl, Br, F, CH ₃ , CH ₃ O, CF ₃ , CF ₃ O-, (CH ₃ ) ₂ N, NH ₂ CO, NH ₂ CONH, NH ₂ C (= NH) NH, 4-morpholino, 2- (4-morpholinyl) ethoxy, 2- [2- (4-morpholinyl) ethoxy] ethoxy, 3 - (4-morpholinyl) propoxy, NH ₂ COCH ₂ O, (pyridyl) NHCOCH ₂ O, NH ₂ COCH ₂ , NH ₂ COCH ₂ O, (CH ₃ ) ₂ NH ₂ , Na ^{+ -} O ₃ S-CH ₂ CH ₂ CH ₂ —O, (CH ₃ ) ₃ N ⁺ CH ₂ CH ₂ O— or EtOCO group.

Examples of the currently most preferred compounds of the invention are as follows:

1-benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-chlorobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-chlorobenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-chlorobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-chlorobenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-bromobenzenesulfonyl) -2 [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-bromobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-bromobenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-bromobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-bromobenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-bromobenzenesulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-fluorobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-fluorobenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-fluorobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-fluorobenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-fluorobenzenesulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methylbenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methylbenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methylbenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methylbenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methylbenzolsulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methoxybenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methoxybenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methoxybenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methoxybenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-methoxybenzolsulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (3-trifluoromethylbenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (3-trifluoromethylbenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (3-trifluoromethylbenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (3-trifluoromethylbenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (3-trifluoromethylbenzenesulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2, -trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-trifluoromethoxybenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-trifluoromethoxybenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-trifluoromethoxybenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-trifluoromethoxybenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-trifluoromethoxybenzenesulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-dimethylaminobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-dimethylaminobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-dimethylaminobenzenesulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-ethoxycarbonylbenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (p-ethoxycarbonylbenzenesulfonyl) -2 - [(3-methyl-4- (2 ’, 2’, 2’-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1- (pyridin-3-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (pyridin-3-sulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (pyridin-3-sulfonyl) -2 - [[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (pyridin-3-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (pyridin-3-sulfonyl) -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- [4 - [(morpholin-4-yl) phenyl] sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- [4 - [(morpholin-4-yl) phenyl] sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

N- [4 - [[5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea,

N- [4 - [[6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea,

N- [4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenyl] urea,

N- [4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenyl] urea,

N- [4 - {[2 - {[(3,4-di (methoxy) -2-pyridyl) methyl] sulfinyl} -5- (difluoromethoxy) benzimidazol-1-yl] sulfonyl} phenyl] urea,

N- [4 - {[2 - {[(3,4-di (methoxy) -2-pyridyl) methyl] sulfinyl} -6- (difluoromethoxy) benzimidazol-1-yl] sulfonyl} phenyl] urea,

15 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5,6, 7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled,

15 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4, 5,6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled,

15 - [(5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5, 6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled,

15 - [(6-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5, 6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled,

15 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5,6, 7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled,

15 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5,6, 7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled,

2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2- pyridyl) acetamide,

N- (carbamoylmethyl) -2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide

2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sylphinyl} benzimidazole-1-yl) sylphonyl] phenoxy} -N- (2- pyridyl) acetamide,

N- (carbamoylmethyl) -2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide

2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- ( 2-pyridyl) acetamide,

N- (carbamoylmethyl) -2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl} sulfinyl) benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide

N- (carbamoylmethyl) -2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide

N- (carbamoylmethyl) -2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide

N- (carbamoylmethyl) -2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl) methyl} sulfinyl) benzimidazol-1-yl) sulfonyl] phenoxy} acetamide,

1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H -benzimidazole,

1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H -benzimidazole,

1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -2 - [(3-methyl-4-methoxypropoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole,

1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -2 - [(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methylsulfinyl] - 1H-benzimidazole,

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole ,

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole ,

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole ,

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] - 1H-benzimidazole,

1 - [{N, N-dimethylamino) methyl} benzene-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole ,

1- [2-acetamido-4-methyl-5-thiazolylsulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole,

1- (thiophen-2-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole,

1 - [{N, N-dimethylamino) methyl} benzene-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole ,

1- [2-acetamido-4-methyl-5-thiazolylsulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole,

1- (thiophen-2-sulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole,

1- (thiophen-2-sulfonyl) -2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole,

1- (thiophen-2-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (thiophen-2-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (thiophen-2-sulfonyl) -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (thiophen-2-sulfonyl) -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole,

1- (phenylmethylsulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (n-propanesulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (n-butanesulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (isopropylsulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [(N, N-dimethylamino) benzene-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (phenylmethylsulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (n-propanesulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (n-butanesulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (isopropylsulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [(N, N-dimethylamino) benzene-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (pyridin-3-sulfonyl] -2 - [[(3-methyl-4-methoxypropoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- [4- (morpholin-4-yl) phenylsulfonyl] -2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-2 - [[(3-chloro-4-morpholin-2-pyridyl) methyl] sulfinyl] -5-methoxy- (1H) benzimidazole,

1-benzenesulfonyl-2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] imidazolo [5,4-c] pyridine,

1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] imidazolo [4,5-c] pyridine,

1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] -5-nitro-benzimidazole,

1-benzenesulfonyl-2 - [{2- (dimethylamino) phenyl} methylsulfinyl] -1H-benzimidazole,

1-benzenesulfonyl-2 - [[[4- (2,2,3,3,4,4,4-heptafluorobutyl) oxy] -2-pyridyl] methyl] sulfinyl] -1H-thieno [3,4-d] imidazole

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [(3-methoxyphenyl) methylsulfinyl] imidazole [5,4-c] pyridine,

1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [{2- (dimethylamino) phenyl} methylsulfinyl] -1H-benzimidazole,

1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl ] sulfinyl] -1H-benzimidazole,

1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2- pyridyl] methyl] sulfinyl] -1H-benzimidazole,

1- (benzotriazol-1-yl) methyl-5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (benzotriazol-1-yl) methyl-6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (benzotriazol-1-yl) methyl-2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole,

diethyl [5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] phosphate,

1- (4-acetaminobenzenesulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole,

1- (4-acetaminobenzenesulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole.

Compounds of the invention in which the R ₁₅ group is an arylsulfonyl group can be prepared by reacting 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives (or structurally similar compounds) containing a free NH group in the imidazole moiety with an arylsulfonyl chloride. In a broad sense, benzimidazole or a structurally similar compound that is the starting one containing a free NH group can be represented by formula 1 in which R ₁₅ is H. Similarly, the arylsulfonyl chloride reagent is described by the formula R ₂₁ (R ₁₇ ) SO ₂ Cl, where the groups R ₂₁ and R ₁₇ are defined as in the explanation of formula 1. in the reaction scheme 1 shows a method for obtaining examples of preferred compounds of the invention by reacting the 2-pyridylmethylsulfinyl-1H-benzimidazole derivative of formula 13 with a benzenesulfonyl chloride of formula 14 in the presence of a responsible foundation. The reaction is usually carried out in an inert organic solvent, such as methylene chloride, in the presence of an organic base, such as triethylamine. For compounds of formula 13 and formula 14, the values of the groups R ₁ -R ₃ , R ₆ -R ₉ and R ₁₇ are given in the explanation of formula 1. As can be seen from reaction scheme 1, the reaction with benzenesulfonyl can give two isomeric or tautomeric products, depending on the nature and position of the substituents R ₆ -R ₉ in the benzimidazole fragment. Two isomeric products (which may simply be tautomers) are shown by formulas 15 and 16.

Derivatives of benzenesulfonyl chloride of the formula 14 can be obtained by methods well known in the art.

Specialists in the art know that 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives of formula 13 are well known in the art as hydrogen pump inhibitors and are described, for example, in US Pat. No. 4,686,230 (Rainer et al.) And published international application WO 97/48380 (Astra Aktiobiolag). Starting materials covered by Formula 14 include known drugs: lansoprazole (US Pat. No. 4,628,098), omeprazole (US Pat. Nos. 4,255,431 and 5,693,818), pantoprazole (US Pat. No. 4,758,579) and rabeprazole (US Pat. No. 5,045,552). Therefore, the starting compounds of formula 13 can be obtained in accordance with modern technology, for example, as described in US Patents 4686230, 4628098, 4255431, 4758579, 5045552, international application WO 97/48380, Journal of Medicinal Chemistry, 32, 1970-1977 (1989 ), Chem. Pharm. Bull. 38. 2853-2858 (1990), J. Med. Chem., 34, 1049-1062 (1991), Journal of Medicinal Chemistry, 35, 1049-1057 (1992) and Journal of Medicinal Chemistry, 35, 438-450, 91992).

Although not shown in the reaction scheme, to obtain compounds of the invention in which, in accordance with formula 1, R ₁₅ is R ₂₁ (C ₆ H ₄ ) SOY and Y is = NR ₁₆ , in a reaction with compounds of formula 13 instead of a reagent of formula 14 a reagent of the formula R ₂₁ (C ₆ H ₄ ) S (O) (Cl) NR _{16 is used} . The reagent of the formula R ₂₁ (C ₆ H ₄ ) S (O) (Cl) NR ₁₆ can be obtained by methods known in the art, for example, as described in the textbook Comprehensive Organic Functional Group Transformations, Volume 7, Editors-in-Chief AR Katritzky, O Meth-Cohn and CW Rees (Pergamon).

Instead of the free benzimidazole compounds of formula 13 in reaction with a benzenesulfonyl chloride (phenylsulfonyl chloride) derivative of formula 14, corresponding salts, such as sodium, potassium, magnesium (and others) salts can be used, also obtaining examples of compounds of the invention corresponding to formulas 15 and 16.

Reaction Scheme 2 shows an alternative method for preparing the examples of the compounds of the invention depicted by formulas 15 and 16. This reaction involves the oxidation of the corresponding 1- (N) -phenylsulfonylbenzimidazolyl-2-pyridylmethyl sulfide compounds of the formulas 17 and 18 into the corresponding sulfoxides. Those skilled in the art will see that formulas 17 and 18 depict isomeric compounds that may be different or identical (tautomers) depending on the nature and position of the substituents R ₆ -R ₉ . The oxidation can be carried out with oxidizing agents known in the art and used to produce sulfoxides, for example hydrogen peroxide, m-chloroperoxybenzoic acid and iodosobenzene can serve this purpose. The oxidation reaction is usually carried out in an aprotic neutral solvent, such as methylene chloride. Sulphides of formulas 17 and 18 can be obtained by benzenesulfonylation (by analogy with the reaction in Scheme 1) of sulfides containing a free benzimidazole NH group or their corresponding salts. The latter sulfides (formulas 17 and 18) can be obtained by methods known in the art.

Compounds of the invention where the physiologically unstable R ₁₅ group is R ₁₆ (R ₁₇ ) SO (sulfinyl) according to formula 1, can be prepared by reactions similar to the reactions in scheme 1, except that instead of arylsulfonyl chloride, arylsulfinyl chloride of formula R ₁₆ (R ₁₇ ) SOCl. The arylsulfonation reaction is usually carried out in the presence of an organic base in a solvent such as dioxane, tetrahydrofuran or alcohol. An arylsulfinyl chloride of formula R ₁₆ (R ₁₇ ) SOCl can be prepared from the corresponding sulfinic acid or salt of formula R ₁₆ (R ₁₇ ) SO ₂ Na by treatment with thionyl chloride. Due to complete analogy with the sulfonylation reactions of Scheme 1, sulfinylation reactions are not shown in the scheme.

Compounds of the invention in which the physiologically unstable R ₁₅ group together with 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives (or structurally similar compounds) form a Mannich base can be prepared under conditions widely used and known in the art for the preparation of Mannich bases. The specific conditions for the production of prodrugs such as Mannich bases are described in Bundgaard et al. in Methods in Enzymology 112, pp. 347-359. The preparation of Mannich base type prodrugs of the present invention involves heating a mixture of an amine of formula R ₁₉ R ₂₀ NH with an aldehyde or ketone of formula OC (R ₁₈ ) ₂ in alcohol, water, dioxane, or another suitable solvent. The meaning of the symbols is given in the explanation of the formula 1.

Reaction Scheme 3 illustrates the preparation of the data in examples of compounds of the Mannich base type of the invention from 2-pyridylmethylsulfinyl-1H-benzimidazole derivatives of formula 13 with formaldehyde as aldehyde and dimethylamine as amine. As can be seen in the reaction scheme, this reaction can also produce two isomeric products of formulas 19 and 20, respectively. The two products may be identical (tautomeric) depending on the nature and position of the substituents R ₆ -R ₉ .

Compounds of Formula 19 and Formula 20 can be prepared and are preferably prepared by an alternative method, comprising reacting N-halomethyldialkylamines with the sodium salt of a compound of Formula 13 or with the tetraammonium salt of a compound of Formula 13 or with a compound of Formula 13 in the presence of sodium tert-butylate. N-chloromethyldialkylamines were prepared as described by Boehme et al. (Chemische Berichte, vol. 93, pp. 1305-1309 (1960) and Chemische Berichte, vol. 95, pp. 1849-1858 (1962)) and the tetra (alkyl) ammonium salt of formula 13 were prepared according to the method described in US Pat. 5021433. For example, the tetrabutylammonium salt of 2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -5-methoxy-1H-benzimidazole is prepared as described in US Pat. No. 5,021,433 and is used in situ. The tetrabutylammonium salt of 2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -5-methoxy-1H-benzimidazole reacts with 1-chloromethyl-N, N-dimethylamine in methylene chloride to form a mixture 1- (N, N-dimethylamino) methyl-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -5-methoxy-1H-benzimidazole and 1- (N, N- dimethylamino) methyl-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -6-methoxy-1H-benzimidazole. 1- (Heteroaryl-N-methyl) -2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] - (5 and 6-methoxy) -1H-benzimidazole are obtained in a similar manner. For example, a mixture of 1- (benzotriazol-1-yl) methyl-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -5-methoxy-1H-benzimidazole and 1- (benzotriazole -1-yl) methyl-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -6-methoxy-1H-benzimidazole is obtained by the reaction of the sodium salt 2 - [[(3,5 -dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -5-methoxy-1H-benzimidazole with 1-chloromethyl-1H-benzotriazole.

Another method for preparing compounds of formula 19 and formula 20 is the reaction of 1-chloromethyl-2 - [(2-pyridyl) methylsulfinyl] -1H-benzimidazole compounds with dialkylamines such as morpholine, dimethylamine, pyrrolidine and piperidine. 1-Chloromethyl-2 - [(2-pyridyl) methylsulfinyl] -1H-benzimidazole compounds are prepared according to the method described in European Patent 279149 (Alminger et al.). For example, a mixture of 1-chloromethyl-5-methoxy-2 - [[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1-chloromethyl-6-methoxy-2- [ [(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole reacts with morpholine to give a mixture of 1- (morpholin-4-yl) methyl-5-methoxy-2 - [[( 4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (morpholin-4-yl) methyl-6-methoxy-2 - [[(4-methoxy-3,5 dimethyl-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole.

A significant advantage of the compounds of this invention is that they can release active forms of proton pump inhibitors, spontaneously hydrolyzing in mammals (including humans). Hydrolysis can be carried out chemically or enzymatically. Since the compounds of this invention spontaneously excrete the active form of drugs — proton pump inhibitors — during in vivo hydrolysis, it is possible to achieve a longer life of the drug substance in the body at an effective concentration. Therefore, the compounds of this invention are prodrugs that are converted into active drug substances, hydrolyzed in the body, which ensures prolonged effective concentration. The duration of the inhibitory activity due to spontaneous hydrolysis of the compounds of this invention provides a more effective inhibition of acid secretion in the stomach, which makes it possible to better treat acid-related diseases. The compounds of this invention can be administered orally to inhibit the secretion of (hydrochloric) acid in the stomach. The usual daily dose of the compounds depends on various factors, such as the individual need of each patient. In general, the interval of oral and parenteral dosages is 5-100 mg per day.

Those skilled in the art will readily understand that for oral administration, the compounds of the invention are mixed with pharmaceutically acceptable excipients, which themselves are well known in the art. Specifically, a medicament for systemic administration may be prepared in the form of a powder, pill, tablet, or the like. or in the form of a syrup or elixir suitable for oral administration. A description of the substances commonly used to make tablets, powders, pills, syrups and elixirs can be found in some books and textbooks well known in the art, for example, Remington’s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania.

The compounds of this invention can be combined with a number of known proton pump inhibitors, for example LANSOPRAZOL, OMEPRAZOL, PANTOPRAZOL or RABEPRAZOL, creating a drug-prodrug combination, and this combination can be administered to inhibit acid secretion in the stomach. Those. first, a proton pump inhibitor (drug) inhibits acid secretion in the patient’s stomach. The aforementioned and widely used proton pump inhibitors have a half-life of elimination from plasma of 60-90 minutes. As the effective concentration of the proton pump inhibitor (drug) decreases due to metabolism, the compounds of this invention (prodrugs) are continuously hydrolyzed and provide and maintain the concentration of the new active inhibitor in mammals, including humans.

The disadvantage of modern proton pump inhibitors is that for injection therapy in liquid form, they must be reconstituted from lyophilized powder in a medium with a high pH value of about 9.5. The prodrugs of this invention overcome the disadvantages of requiring a medium for reproduction (reconstruction) with such a high pH value, since the compounds of this invention can be reconstituted in the form of an injectable liquid in a medium with an approximate pH of 6.0-8.5. One of ordinary skill in the art will quickly appreciate that for administration in liquid form as an injection, the liquid that reconstitutes the drug is a pharmaceutically acceptable aqueous solution, which is itself known in the art. Such pharmaceutically acceptable solutions used for injectable drug administration are described, for example, in the Pharmaceutical Dosage Forms textbook (Parenteral Medications, Volume 1, Edited by K. E. Avis, H. A. Lieberman and L. Lachman (1992)).

Among the benefits of drugs like the proton pump pre-inhibitors (P-PPI) of this invention are their ability to more effectively treat erosive esophagitis, as well as less severe reflux diseases. This is because the effective treatment of erosive esophagitis (and the easier course of less severe reflux diseases) requires the prevention of reflux of the contents of the stomach at pH 3.0 and even at lower pH values. Modern PPI drugs tolerate acidity deviation up to pH <2 several times a day, which leads to a moderate and slight decrease in the intensity of symptoms. However, healing requires raising the pH to> 4.0 for about 16 hours or more. If, as with modern ordinary PPI teralia, in the remaining 8 hours there is an episodic acidity of pH 3.0 or lower, patients continue to complain of pain. A more effective and more prolonged suppression of acid by the drugs of this invention appears to lead to a significantly better treatment for this disease, as well as to faster healing of acid-caused erosion and all ulcers.

Medicinal substances such as the proton pump pre-inhibitors (P-PPI) of the present invention provide an opportunity for improved dual therapy to kill H. pylori. The synergism of PPI and cell division-dependent antibiotics such as amoxacillin (cell wall biosynthesis) and clarithromycin (protein synthesis) leads to an increase in the pH of the surface of the stomach, which allows most of the bacterial population to be in the division stage during the presentation of the antibiotic of the stomach cavity. However, their effect on the pH inside the stomach is limited by their plasma life. Medicines such as proton pump pre-inhibitors (P-PPI) of the present invention can continuously increase the pH inside the stomach to close to neutral with current once-daily treatment. Therefore, 100% killing of bacteria is expected with dual therapy with the prodrugs of the invention (e.g., the omeprazole prodrug of the invention) plus an effective antibiotic such as amoxicillin.

Even monotherapy to kill H. pylori appears to be successful with drugs like the proton pump pre-inhibitors (P-PPI) of the present invention. It is in the absence of acid that H. pylori urease enzyme raises the pH of the medium to> 8.3, which is toxic to the body. PPI in a modern formulation inhibits the growth or presence of an organism in a cavity due to an increase in the antranal pH to near neutral. The increase in pH within 24 hours to neutral, which is achieved using the drugs of this invention, apparently leads to the "self-destruction" of bacteria.

Approximately 30% of patients with gastrointestinal disorders have symptoms without a quantifiable underlying disease (non-ulcer dyspepsia). The most likely cause of these symptoms is an increased gastrointestinal afferent nerve sensitivity to gastric acid. Only the elimination of acid relieves (alleviates) these symptoms, and this can be achieved using the drugs of this invention.

The following tests and results are described with specific examples. Some compounds of the invention have been tested using one or more tests that demonstrate gastric antisecretory activity. The compounds of the invention did not directly inhibit K ⁺ -dependent ATP hydrolysis of gastric H, K-ATPase. However, after hydrolysis, the compounds of this invention were potent inhibitors of gastric H, K-ATPase activity. This is consistent with the known fact that compounds obtained by hydrolysis, for example lansoprazole, omeprazole, pantoprazole and rabeprazole, are well known inhibitors of H, K-ATPase. For example, 1-benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole was tested for the inhibitory activity of gastric H, K-ATPase. At first, this compound did not inhibit gastric H, K-ATPase. However, the activity of gastric N, K-ATPase was spontaneously inhibited as the hydrolysis of this compound occurred in an aqueous solution at pH 7.4. After hydrolysis for 5.75 hours at pH 7.4, this compound inhibited 91% of the activity of gastric H, K-ATPase, as well as 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl ) methylsulfinyl] -1H-benzimidazole (OMEPRAZOL), which was the product of hydrolysis. It was found that 1-benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole was hydrolyzed to 5-methoxy-2 - [(3,5- dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (omeprazole) with a half-life of (t _1/2 ) 3 ± 0.5 hours at 37 ° C and a pH of 7.4.

When a mixture of 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide and 2- {4 - [(6-methoxy-2 - ([(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide was administered orally to male rats, 5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (omeprazal) continuously released into the plasma for more than 4 hours as a result of hydrolysis of 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] -sulfinyl} -benzimidazole- 1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide and 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide. As a control, when omeprazole was administered to male rats, omeprazole completely disappeared from the plasma in 1.5 hours. Bioavailability 2- {4 - [(5-methoxy-2 - {[(( 3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide was higher than the oral bioavailability of omerazrazole.

When a mixture of 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide and 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide was orally administered to a male rat, acid secretion in the stomach was markedly and continuously inhibited. 5 hours after oral administration, a mixture of 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] -sulfinyl} benzimidazol-1-yl) sulfonyl ] phenoxy} -N- (2-pyridyl) acetamide and 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazole- 1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide gave a maximum of 90% inhibition of histamine stimulated gastric acid secretion, while OMEPRAZOL gave only 45% inhibition. A 50-60% inhibition of gastric acid was reported to be achieved 4-6 hours after intravenous administration of OMEPRAZOLE (Katashima et al., Drug metabolism and Disposition, vol. 23, 718-723, 1995). Perhaps a lower degree (45%) of gastric acid inhibition after administration of OMEPRAZOLE in this experiment compared with the data (50-60%) reported by Katashima et al. caused by differences in route of administration. However, it is well known that the efficacy of Omeprazole when administered orally without an enteric coating is significantly lower than when administered intravenously or intradermally in both rats and dogs (Larsson et al., Scand. J. Gastroenterology; vol. 20 (suppl. 108) 23-25, 1985). The compounds of this invention do not require an enteric coating to protect against acid catalyzed decomposition. In addition, the compounds of this invention provide continuous inhibition of pancreatic acid secretion. The maximum inhibition obtained using the compounds 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide and 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] -sulfinyl} benzimidazole- 1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide after 5 hours, shows that the compounds of the invention are continuously converted in vivo to the corresponding PPIs that inhibit gastric acid secretion.

Description of specific embodiments of the invention and experiment

Preparation of Intermediates

Standard Example 1: Preparation of [(morpholin-4-yl) alkoxy] benzene-4-sulfonyl chloride

[(Morpholin-4-yl) alkoxy] benzene-4-sulfonyl chloride is prepared by chlorosulfonylation of 4 - [(phenoxy) alkoxy] morpholine using chlorosulfonic acid in the presence of methylene chloride or chloroform. In this reaction, chloroform or methylene chloride is necessary in order to avoid cleavage of the ether bond of the alkoxybenzene fragment with chlorosulfonic acid.

[3- (Morpholin-4-yl) propoxy] benzene-4-sulfonyl chloride is prepared by chlorosulfonylation of 4- (3-phenoxypropyl) morpholine using chlorosulfonic acid in the presence of methylene chloride or chloroform.

For example, to a solution of 2.2 g (10 mmol) of N- (3-phenoxypropyl) morpholine in 20 ml of chloroform, 2 ml of chlorosulfonic acid (30 mmol) is added slowly at -10 ° C and stirred for 30 minutes. The reaction mixture was stirred at room temperature for 5 hours. Chloroform is distilled off from the bottom layer. The bottom layer is treated with crushed ice to obtain a solid residue. 10 g of sodium phosphate (tribasic) are added to a mixture of ice and a solid product and stirred while cooling. The chlorosulfonyl compound is extracted with methylene chloride (300 ml). The methylene chloride extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 1.6 g of [3- (morpholin-4-yl) propoxy] benzene-4-sulfonyl chloride are obtained.

[2- (Morpholin-4-yl) ethoxy] benzene-4-sulfonyl chloride is prepared using N- (2-phenoxyethyl) morpholine by a reaction similar to that described above. For example, 7.2 g of the HCl salt of N- (2-phenoxyethyl) morpholine is resuspended in 20 ml of methylene chloride and 7 ml of chlorosulfonic acid is slowly added, cooling with an ice jacket. The reaction mixture was stirred at 0 ° C. for 2 hours, then at room temperature overnight. Methylene chloride (350 ml) was added to the reaction mixture and the excess chlorosulfonic acid was decomposed by adding lelac water (about 100 g). The aqueous layer was adjusted to pH 8.5 with a concentrated sodium carbonate solution under ice-cooling. Methylene chloride was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain 8.1 g of [2- (morpholin-4-yl) ethoxy] benzene-4-sulfonyl chloride. Mp 48-50 ° C.

N- (2-Phenoxyethyl) morpholine was prepared according to a modified procedure by Grail et al. (Journal of American Chemistry Society, 1952, 74, 1313-1315). For example, 9.2 g of phenol and 18.6 g of the N- (2-chloroethyl) morpholine HCl salt are dissolved in 120 ml of isopropanol and 12 g of potassium hydroxide are added with cooling. The reaction mixture was refluxed for 12 hours. The solid precipitate (KCl) is filtered off. The filtrate is subjected to distillation. The remaining product is treated with 150 ml of 1 N NaOH, then extracted with methylene chloride (200 ml). The methylene chloride layer was again washed with a solution of 0.1 N sodium carbonate in a 10% NaCl solution. The methylene chloride layer was dried over anhydrous magnesium chloride and evaporated under reduced pressure. The remaining syrup is dissolved in 100 ml of a 1.5 N HCl solution and washed with 100 ml of chloroform. The aqueous layer was treated with 100 ml of toluene and water was removed by distillation in a Dean-Stark apparatus. The remaining toluene layer is cooled to obtain a crystalline residue, which is separated by filtration. 12 g of HCl salt of N - [(2-phenoxy) ethyl] morpholine are obtained (yield 50%).

N- [3-Phenoxy) propyl] morpholine is prepared by reacting 3- (phenoxy) propyl bromide with morpholine. For example, 3- (phenoxy) propyl bromide (7.8 ml, 50 mmol) is added to morpholine (8 ml) in toluene (50 ml) and refluxed overnight. A solution of NaOH (2 g of NaOH in 20 ml of water) was added and the mixture was further refluxed for 4 hours. Toluene is removed by distillation under reduced pressure. The residue is taken up in methylene chloride (200 ml) and water (200 ml). The methylene chloride layer was dried and concentrated. The residue was treated with methylene chloride-heptane mixture to give 4- [3-phenoxy) propyl] morpholine.

[2- {2- (Morpholin-4-yl) ethoxy} ethoxy] benzene-4-sulfonyl chloride is prepared using 4- [2- [2- (2-phenoxy) ethoxy] ethyl] morpholine by a reaction similar to that described above. For example, 2- (phenoxy) ethanol (4.0 ml) is added to 5.5 g of N- (2-chloroethyl) morpholine hydrochloride and 6 g of sodium tert.-butoxide in 70 ml of toluene. The reaction mixture was refluxed for 16 hours. EtOAc (100 ml) was added and washed with water (200 ml). The organic layer was separated and extracted again with 0.5 N HCl solution (120 ml). The aqueous layer was again washed with chloroform (30 ml), then the pH was adjusted to 10.5 by addition of a NaOH solution. The product, [2- [2- (morpholin-4-yl) ethoxy] ethoxy] benzene, was extracted from water with methylene chloride (200 ml). The organic layer was washed again with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product, [2- [2- (morpholin-4-yl) ethoxy] ethoxy] benzene, was obtained as a yellow syrup (5.4 g). TLC analysis showed 99% purity, and the structure was confirmed by NMR. A syrupy product is used in situ to produce [2- {2- (morpholin-4-yl) ethoxy} ethoxy] benzene-4-sulfonyl chloride.

5.0 g of 2- [2- (morpholin-4-yl) ethoxy] benzene is dissolved in 70 ml of methylene chloride. In an ice bath, chlorosulfonic acid (7 ml) is slowly added. The reaction mixture was stirred at room temperature overnight. Two layers are separated. The chloroform layer, the top layer, is removed. A light brown lower layer is added to 100 g of crushed ice. Methylene chloride (200 ml) was added, and concentrated sodium carbonate solution was added slowly at 4 ° C with good stirring to pH 9. The methylene chloride layer was separated, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. A yellow syrup is obtained which is dried under vacuum. 3.8 g of [2- {2- (morpholin-4-yl) ethoxy} ethoxy] benzene-4-sulfonyl chloride are obtained.

Standard Example 2: Preparation of [2- (dimethylamino) ethoxy] phenyl-4-sulfonyl chloride

2 g of N, N-dimethyl-N - [(2-phenoxy) ethyl] amine is dissolved in 10 ml of methylene chloride and 3 ml of chlorosulfonic acid is added slowly under ice-cooling. The mixture was stirred at room temperature for 3 hours and poured onto ice. Methylene chloride (100 ml) was added and the aqueous layer was neutralized with a concentrated sodium carbonate solution, maintaining the temperature at 4 ° C. The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. 0.8 g of [2- (dimethylamino) ethoxy] phenyl-4-sulfonyl chloride are obtained.

Standard Example 3: Preparation of N- [4- (chlorosulfonyl) phenyl] urea

N- [4-Chlorosulfonyl) phenyl] urea is obtained in a known manner (R.J. W. Cremlyn, D. Leonard and R. Motwani, 91973, J. Chem. Soc., Perkin I, 500-503).

Chlorosulfonic acid (4.4 ml) was added to urea (2.7 g) in an ice bath, then heated at 60 ° C for 3 hours. The syrup is poured on crushed ice with good stirring. The solid precipitate was separated and dried in vacuo. Obtain 2.3 g. So pl. 138-141 ° C.

Standard Example 4: Preparation of N - [(p-chlorosulfonyl) phenyl] morpholine

N - [(p-Chlorosulfonyl) phenyl] morpholine is synthesized according to a modified method of Cremlyn et al. (R.J. Cremlyn, J.P. Bassin, S. Farouk, M. Potterton and T. Mattu (1992), Phosphorus, Sulfur and Silicon, Vol. 73, pp. 107-120).

10 g of 4-phenylmorpholine in 50 ml of chloroform is added to 25 ml of chlorosulfonic acid under cooling with an ice jacket. The reaction mixture was stirred at reflux for 7 hours. The brown syrup is poured with stirring into methylene chloride (150 ml) and crushed ice (100 g) and neutralized with saturated sodium phosphate, tribasic, while cooling with an ice bath. A layer of methylene chloride was separated, dried over anhydrous magnesium sulfate. The organic solvent was evaporated under reduced pressure to give a yellow solid which was dried in vacuo. 6.1 g of product are obtained. Mp 154-156 ° C.

Standard Example 5: Preparation of Pyridin-3-Sulfonyl Chloride

Pyridine-3-sulfonyl chloride is prepared according to the method of Alo et al. (B.I. Alo, O.B. Familoni, F. Marsais and G. Queguiner (1992), Journal of Heterocyclic Chemistry, vol. 29, pp. 61-64).

24 g of phosphorus pentachloride are added to a suspension of 15 g of pyridin-3-sulfonic acid in 30 ml of phosphorus oxychloride and heated at 120 ° C for 12 hours. The reaction mixture was concentrated by distillation under reduced pressure and treated with toluene. The resulting solid residue was collected and dried in vacuo. 16.7 g of product are obtained. Mp 138-141 ° C.

Standard Example 6: Preparation of m- (chlorosulfonyl) benzo-15-crown-5-ether

To an ice-cooled solution of benzo-15-crown-5-ether (53.6 mg, 2 mmol) in 5 ml of chloroform was added slowly while cooling with an ice bath 0.3 ml of chlorosulfonic acid (4.5 mmol). The reaction mixture was stirred in an ice bath for 2 hours and then 5 hours at room temperature. The reaction mixture was poured onto crushed ice and extracted with methylene chloride (50 ml). The combined organic layer was dried over magnesium chloride and evaporated. 374 mg of product is obtained. Mp 79-84 ° C.

m- (Chlorosulfonyl) benzo-15-crown-5-ether is prepared using the procedure described above. The yield is about 46%. Mp 108-110 ° C.

Standard Example 7: Preparation of 2- [p- (Chlorosulfonyl) phenoxy] -N- (2-pyridyl) acetamide

1.32 g of the HCl salt of 2- (phenoxyacetyl) aminopyridine (5 mmol) is resuspended in 10 ml of methylene chloride and 2 ml of chlorosulfonic acid are added while cooling in an ice bath to form a clear solution. The solution was stirred at room temperature for 3 hours. The reaction mixture was poured with good stirring into ice water to give a white solid. The precipitate was filtered off, washed with acetonitrile and dried in vacuo. 0.65 g of solid is obtained. Mp 170-175 ° C (with decomposition).

Standard Example 8: Obtaining the HCl salt of N- [p- (chlorosulfonyl) phenylmethyl] -N, N-dimethylamine

1.5 ml of N, N-dimethylbenzylamine (10 mmol) is dissolved in 6 ml of methylene chloride and 2 ml of chlorosulfonic acid are added in an ice bath while cooling. The reaction mixture is heated at 40 ° C. for 40 minutes and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and poured onto ice to obtain a solid precipitate, which was collected and dried in vacuo. Obtain 1.6 g (59.2%) of the HCl salt of N- [p- (chlorosulfonyl) phenylmethyl] -N, N-dimethylamine.

Standard Example 9: Preparation of 2- [p- (chlorosulfonyl) phenoxy] acetamide

3.0 g of 2- (phenoxy) acetamide was dissolved in 10 ml of methylene chloride and 6 ml of chlorosulfonic acid was added slowly at 0 ° C. The reaction mixture was stirred at room temperature for 10 hours. Methylene chloride was evaporated under reduced pressure. The remaining product is poured onto crushed ice. The solid residue was filtered off and dried in vacuo. 3.9 g of product are obtained. Mp 166-171 ° C (with decomposition).

Standard Example 10: Preparation of N- (p-chlorosulfonylphenylmethyl) -pyridinium chloride

p- (Chloromethyl) benzenesulfonyl chloride (2.2 g) was dissolved in acetonitrile (20 ml) - methylene chloride (20 ml) and pyridine (1.9 ml) was added. The reaction mixture was refluxed for 3 hours. The brown syrup is separated from the solvent and lyophilized in vacuo. A reddish brown product (2.9 g) is obtained. Mp 105-108 ° C.

Standard Example 11: Preparation of p- (Dimethylamino) benzenesulfonyl chloride

N, N-dimethylaniline (8 ml) was dissolved in 20 ml of chloroform, and chlorosulfonic acid (20 ml) was added slowly with cooling. The reaction mixture was refluxed for 6 hours. The reaction mixture was cooled and poured onto ice (100 g). Methylene chloride (120 ml) was added and the aqueous layer was neutralized with a concentrated sodium carbonate solution, keeping the temperature below 4 ° C. The organic layer was washed again with ice, 0.1 N sodium bicarbonate and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure. The remaining product is crystallized from ethyl ether-heptane to give a yellowish green substance. Obtain p- (dimethylamino) benzenesulfonyl chloride (4.2 g). Mp 108-111 ° C.

Standard Example 12: Preparation of N- (carbamoylmethyl) -2- [4- (chlorosulfonyl) phenoxy] acetamide

a) Preparation of N- (carbamoylmethyl) -2- (phenoxy) acetamide.

The glycinamide HCl salt (5 g) was resuspended in 200 ml of methylene chloride and 14 ml of triethylamine at 4 ° C. Phenoxyacetyl chloride (6 ml) is added slowly with good stirring. The reaction mixture was stirred at room temperature for 3 hours, then refluxed for 3 hours. The reaction mixture is cooled to obtain a crystalline precipitate, which is separated by filtration. The filtered precipitate was washed with water and dried in vacuo to give 7.5 g of the product, N- (carbamoylmethyl) -2- (phenoxy) acetamide. The filtrate is washed with water and 0.1 N sodium carbonate solution. The filtrate was concentrated and treated with ether to give an additional product, N- (carbamoylmethyl) -2- (phenoxy) acetamide. Mp 138-140 ° C.

b) Preparation of N- (carbamoylmethyl) -2- [4- (chlorosulfonyl) phenoxy] acetamide.

N- (carbamoylmethyl) -2- (phenoxy) acetamide (2.08 g) was re-suspended in 30 ml of methylene chloride and chlorosulfonic acid (6 ml) was added slowly with cooling. The reaction mixture was stirred at room temperature for 2 hours. After standing for 10 minutes without stirring, two layers are separated. The bottom layer was poured with good stirring on crushed ice (60 g) to obtain a white solid, which was separated by filtration and washed with ice-cold water. The solid was dried in vacuo to give 2.78 g of N- (carbamoylmethyl) -2- [4- (chlorosulfonyl) phenoxy] acetamide. Mp 97-100 ° C (with decomposition).

Example 1

1-Benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole and 1-benzenesulfonyl-6-methoxy-2 - [(3,5-dimethyl -4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole

Method A: 5-Methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (172 mg, 0.5 mmol) is dissolved in 20 ml of methylene chloride and 0.140 ml of triethylamine . The solution is cooled to 0-4 ° C in an ice bath. Benzenesulfonyl chloride (96 mg, 0.55 mmol) was added slowly and stirred at 0-4 ° C with TLC control (developing solvent system: chloroform-methanol (10: 1) and acetonitrile-chloroform (1: 1)). After completion of the reaction, the organic layer was washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium phosphate, pH 8.5. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was crystallized from methylene chloride-ethyl ether-heptane, to give 127 mg of the product. Mp 87-89 ° C (with decomposition). Heptane was added to the remaining organic layer to give a second crop (104 mg). After combining the precipitates, 231 mg of product is obtained (95% yield). The product is a mixture of 1-benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole and 1-benzenesulfonyl-6-methoxy-2 - [(3 , 5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (3: 2 ratio by NMR).

1 H NMR (CDCl ₃ , δ): 8.10-8.15 (m, 3H), 7.45-7.80 (m, 5H), 7.0-7.1 (m, 1H), 4, 8-5.0 (2 q, 2AB, total 2H), 3.83 and 3.92 (2s, total 3H), 3.75 (s, 3H), 2.31 (s, 3H), 2.23 (s, 3H).

Method B: Mixture of 1-benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole and 1-benzenesulfonyl-6-methoxy-2 - [(3 , 5-Dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole is prepared by reacting 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole with with benzene sulfonyl chloride as described in method A. 1-Benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole was isolated by silica gel column chromatography and used in next stage next mod Zom. 1-Benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (318 mg, 1 mmol) in 30 ml of methylene chloride is cooled to -20 ° C . A methylene chloride solution (5 ml) containing m-chloroperbenzoic acid (60% purity, equivalent to 1 mmol) was slowly added. The reaction is monitored by TLC. After 5 hours, the organic layer was washed with an aqueous solution of 0.1 M sodium bicarbonate and 50 mm sodium thiosulfate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained solidifies upon treatment with a mixture of methylene-ethyl ether-heptane chloride to give 397 mg of the product (82% yield), 1-benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole and 1-benzenesulfonyl-6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole.

Examples 2-19

The compounds shown in Examples 2-19 below are prepared using method A described in Example 1. 2-Pyridylmethylsulfinylbenzimidazole compounds are reacted with the corresponding arylsulfonyl chloride to give the corresponding 1-arylsulfonyl-2-pyridylmethylsulfinylbenzimidazoles, which are shown in Table 21 and:

Example 20

Sodium salt of 5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole sesquihydrate sodium salt (432 mg, 1 mmol) was suspended in 30 ml of methylene chloride in the presence of anhydrous sodium carbonate (100 mg). 4-Chlorobenzenesulfonyl chloride (211 mg, 1 mmol) was added to the suspension and stirred at 4 ° C. overnight. The organic layer was separated by filtration and concentrated under reduced pressure. The resulting solid residue was crystallized from methylene chloride-ethyl ether-heptane. 417 mg of isomers are obtained, 1- (4-chlorobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole and 1- (4-chlorobenzenesulfonyl) -6-difluoromethoxy- 2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (5: 4 ratio by NMR). Yield 74.5%. Mp 82-83 ° C.

1 H NMR (CDCl ₃ , δ): 8.05-8.15 (m, 2H), 8.0 (d, 1H), 7.78-7.81 (m, 1H), 7.45-7, 6 (m, 2H), 7.2-7.3 (m, 1H), 6.80-6.81 (d, 1H), 6.5-6.6 (d, 1H), 4.9- 5.0 (q, 2H); 3.93 (s, 3H).

Examples 21-24

The compounds listed in Table 2 and represented by formula 20 are prepared using the method described in Example 20.

Example 25

1- (Pyridin-3-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (pyridin-3-sulfonyl ) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

5-Methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (344 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. Pyridine-3-sulfonyl chloride (195 mg) was added and stirred in an ice bath for 3 hours. The methylene chloride layer is washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium bicarbonate. The methylene chloride layer is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained solidifies upon treatment with a mixture of methylene-ethyl ether-heptane chloride to give 372 mg of a product which is a mixture of 1- (pyridin-3-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4- methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (pyridin-3-sulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (3: 1 ratio by NMR). Mp 136-138 ° C (with decomposition).

1 H NMR (CDCl ₃ , δ): 2.27 (s, 3H), 2.35 (s, 3H), 3.82 (s, 3H), 3.86 and 3.93 (2s, total 3H), 5.04-5.17 (q. AB, 2H), 7.01-7.02 (dd, 1H), 7.47-7.56 (m, 2H), 7.67-7.71 (d , 1H), 8.15 (s, 1H), 8.51-8.55 (dd, 1H), 8.85-8.88 (d, 1H), 9.34 (s, 1H).

Example 26

1- (Pyridin-3-sulfonyl) -2 - [[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

2 - [[(3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (370 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. Pyridin-3-sulfonyl chloride (195 mg) was added and stirred in an ice bath for 5 hours. The methylene chloride layer is washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium bicarbonate. The methylene chloride layer is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained solidifies upon treatment with a mixture of methylene-ethyl ether-heptane chloride and gives 348 mg of 1- (pyridin-3-sulfonyl) -2 - [[(3-methyl-4- (2,2,2-trifluoroethoxy) -2- pyridyl) methyl] sulfinyl] -1H-benzimidazole. Mp 118-120 ° C (with decomposition).

1 H NMR (CDCl ₃ , δ): 2.35 (s, 3H), 4.38-4.49 (q, 2H), 4.98-5.22 (q, AB, 2H), 6.73 ( d, 1H), 7.41-7.56 (m, 3H), 7.80-8.02 (dd, 2H), 8.23 (s, 1H), 8.52 (dd, 1H), 8 87 (dd, 1H); 9.36 (s, 1H).

Example 27

1- (Pyridin-3-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (pyridin-3-sulfonyl) - 6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

5- (Difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (383 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. Pyridin-3-sulfonyl chloride (195 mg) was added and stirred in an ice bath for 5 hours. The methylene chloride layer is washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium bicarbonate. The methylene chloride layer is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue obtained solidifies upon treatment with a mixture of methylene-ethyl ether-heptane chloride to give 397 mg of a mixture of 1- (pyridin-3-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl ] sulfinyl] -1H-benzimidazole and 1- (pyridin-3-sulfonyl) -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (ratio 3 : 2 by NMR). Mp 127-128 ° C (with decomposition).

Example 28

Preparation of 1- (morpholin-4-yl) phenylsulfonyl-5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (morpholin-4 -yl) phenylsulfonyl-6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

270.8 mg of 4- (p-chlorosulfonyl) phenylmorpholine is added to 344 mg of 5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole in 20 ml methylene chloride and 0.5 ml of triethylamine. The reaction mixture was stirred at room temperature overnight. The methylene chloride layer was washed with water and dried over anhydrous magnesium sulfate. The organic layer was evaporated. The resulting residue was lyophilized in vacuo to give 425 mg of the above product (1: 1 ratio by NMR). Mp 76-79 ° C (with decomposition).

Example 29

Preparation of N- [4 - [[5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea and N- [ 4 - [[6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea

128 mg of N- [4- (chlorosulfonyl) phenyl] urea is added to 172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole in a mixture of 0.5 ml of triethylamine and 10 ml of methylene chloride-acetonitrile (50/50). The reaction mixture was stirred at room temperature overnight. Methylene chloride (20 ml) was added and washed with water and a 0.1 M sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in 2 ml of methylene chloride and ethyl ether was added to crystallize. The crystals are separated and dried. 190 mg of product are obtained. The product is a mixture of N- [4 - [[5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] -sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea and N- [4 - [[6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea (ratio 4 : 3 by NMR). Mp 154-158 ° C (with decomposition).

1 H NMR (CDCl ₃ , δ): 2.19 (s, 3H), 2.20 and 2.321 (2s, total 3H), 3.69 and 3.70 (2s, total 3H), 3.76 and 3, 89 (2s, total 3H), 4.75-4.94 (q, AB, 2H), 5.6-5.7 (br, NH ₂ ), 6.95-7.08 (d, 1H) 7.05 (s, 1H), 7.43-7.86 (m, 5H), 8.12 (s, 1H), 9.0 (br, NH).

Example 30

Preparation of N- [4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenyl] urea

2 - [[(3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (185 mg) is dissolved in 30 ml of methylene chloride and 0.4 ml of triethylamine and add to 128 mg of N- [4- (chlorosulfonyl) phenyl] urea. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with water and a 0.1 M sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 2 ml of methylene chloride and ethyl ether was added to precipitate. 125 mg of the above product are obtained. Mp 115 ° C (with decomposition).

1 H NMR (CDCl ₃ , δ): 2.25 (s, 3H), 4.37-4.42 (q, 2H), 4.6-4.85 (q, AB, 2H), 6.67 ( d, 1H), 7.35-7.42 (m, 2H), 7.61-7.75 (m, 3H), 7.89-8.05 (m, 2H), 8.27-8, 38 (m, 2H).

Example 31

Preparation of 15 - [(5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5 , 6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled and 15 - [(6-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2 -pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5,6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] canceled

170 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole and 190 mg of m- (chlorosulfonyl) benzo-15-crown-5-ether are dissolved in 0 , 2 ml of triethylamine and 20 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a syrup, which was lyophilized. 210 mg of the above product are obtained, a mixture of 15 - [(5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1.2 , 3,4,5,6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled and 15 - [(6-methoxy-2 - {[(4-methoxy-3 , 5-dimethyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5,6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled (1: 1 ratio by NMR). The lyophilized product has a melting point of 76-80 ° C with decomposition.

1 H NMR (CDCl ₃ , δ): 2.21 (s, 3H), 2.31 (s, 3H), 3.68-3.73 (m, 8H), 3.74 (s, 3H), 3 84-3.87 (m, 4H), 3.90 (s, 3H), 4.10-4.13 (m, 4H), 4.81-4.95 (q, AB, 2H), 6 84 (d, 1H), 7.00-7.07 (dd, 1H), 7.25 (d, 1H), 7.42-7.72 (m, 3H), 8.15 (s, 1H) )

Example 32

Preparation of 15 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4 , 5,6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] canceled

2 - [[(3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (185 mg) is dissolved in 20 ml of methylene chloride and 0.2 ml of triethylamine and m- (chlorosulfonyl) benzo-15-crown-5-ether is added to 190 mg. The reaction mixture was stirred at room temperature overnight. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give a syrup, which was lyophilized. Receive 231 mg of the above product. The lyophilized product has so pl. 76-80 ° C with decomposition.

1 H NMR (CDCl ₃ , δ): 2.33 (s, 3H), 3.66-3.73 (m, 8H), 3.83-3.87 (m, 4H), 4.10-4, 12 (m, 4H), 4.35-4.41 (q, 2H), 4.84-5.05 (q. AB, 2H), 6.61 (d, 1H), 6.86 (d, 1H), 7.37-7.45 (m, 2H), 7.56 (s, 1H), 7.71-7.74 (dd, 2H), 7.95 (d, 1H), 8.23 (d, 1H).

EXAMPLE 33

Preparation of 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide and 2- { 4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide

170 mg of 2- [p- (chlorosulfonyl) phenoxy] -N- (2-pyridyl) acetamide is added to 172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] - 1H-benzimidazole dissolved in methylene chloride (15 ml) and triethylamine (0.4 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized in vacuo to give 244 mg of the above product, which is a mixture of 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide and 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1- il) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide (2: 1 ratio by NMR). Mp 76-80 ° C.

1 H NMR (CDCl ₃ , δ): 2.21 and 2.23 (2s, total 3H), 2.32 (s, 3H), 3.74 and 3.75 (2s, total 3H), 3.83 and 3.93 (2s, total 3H), 4.65 (s, 2H), 4.83-4.92 (sq. AB, 2H), 6.99-7.11 (m, 5H), 7.46 (d, 1H), 7.68-7.88 (m, 2H), 8.75 (br, NH).

Example 34

Preparation of 2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide

2 - [[(3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (185 mg) is dissolved in 20 ml of methylene chloride and 0.2 ml of triethylamine and 2- [p- (chlorosulfonyl) phenoxy] -N- (2-pyridyl) acetamide is added to 170 mg. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized to give 237 mg of the above product. Mp 78-81 ° C.

1 H NMR (CDCl ₃ , δ): 2.31 (s, 3H), 4.34-4.40 (q, 2H), 4.71 (s, 2H), 4.84-5.05 (q, AB, 2H), 6.62 (d, 1H), 7.09 (d, 2H), 7.29-7.47 (m, 2H), 7.62-7.80 (m, 2H), 7 98 (d, 1H), 8.11 (d, 2H), 8.20-8.29 (m, 4H), 8.92 (br, NH).

Example 35

Preparation of 2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide and 2- {4- [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide

5- (Difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (192 mg) is dissolved in 20 ml of methylene chloride and 0.2 ml of triethylamine and added to 170 mg 2- [p- (chlorosulfonyl) phenoxyacetyl] aminopyridine. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized to give 187 mg of the above product, which is a mixture of 2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazole-1 -yl) sulfonyl] phenoxy} acetamide and 2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide (2: 1 ratio by NMR). Mp 95-101 ° C.

1 H NMR (CDCl ₃ , δ): 3.90 (s, 3H), 3.93 (s, 3H), 4.67 (s, 2H), 4.85-5.00 (q AB, 2H; s, equal to 1H), 6.25-6.80 (m, 1H), 7.08 (m, 3H), 7.29-7.40 (d, 1H), 7.58-7.80 (m , 2H), 7.97-8.16 (m, 3H), 8.22 (d, 1H), 8.30 (d, 1H), 8.82 (br, NH).

Example 36

Preparation of 1- [4- (3- (morpholin-4-yl) propoxy) benzenesulfonyl] -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- [4- (3- (morpholin-4-yl) propoxy) benzenesulfonyl] -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

180 mg of 4- (3- (morpholin-4-yl) propoxy) benzenesulfonyl chloride was added to a solution of 190 mg of 5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H- benzimidazole in 10 ml of methylene chloride and 0.5 ml of triethylamine. The reaction mixture was stirred overnight and washed with water. The organic layer was concentrated and lyophilized in vacuo. Get 210 mg of the above mixture of products (1: 1 ratio by NMR).

Example 37

Preparation of 1- [4- [3- (morpholin-4-yl) propoxy] benzenesulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H -benzimidazole and 1- [4- [3- (morpholin-4-yl) propoxy] benzenesulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

2000 mg of 4- [3- (morpholin-4-yl) propoxy] benzenesulfonyl chloride is added to a solution of 200 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole in 10 ml of methylene chloride and 0.5 ml of triethylamine. The reaction mixture was stirred overnight and washed with water, the organic layer was concentrated and treated with ethyl ether to obtain a solid residue. The solid residue is crystallized from a mixture of methylene chloride and ether. Get 210 mg of the above product, a mixture in a 1: 1 ratio of 5-methoxy and 6-methoxy compounds. Mp 98-102 ° C (with decomposition).

1 H NMR (CDCl ₃ , δ): 1.97-2.05 (m, 2H), 2.09 (s, 3H), 2.20 (s, 3H), 3.05-3.15 (m, 6H), 3.58 (s, 3H), 3.65-3.80 (m, 4H), 3.81 and 3.92 (2s, total 3H), 3.82-3.95 (t, 2H) ), 4.73-4.94 (q, AB, 2H), 6.62 (d, 1H), 6.89-6.91 (d, 2H), 7.4-7.6 (m, 3H) ), 7.79-8.0 (m, 2H), 8.17 (s, 1H).

Example 38

Preparation of 1 - [[(N, N-dimethylamino) methyl] benzene-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H -benzimidazole and 1 - [[(N, N-dimethylamino) methyl] benzene-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

120 mg of N - [[p- (chlorosulfonyl) phenyl] methyl] -N, N-dimethylamine is added to 172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] - 1H-benzimidazole dissolved in 20 ml of methylene chloride and 0.5 ml of triethylamine. The reaction mixture was stirred at room temperature for 16 hours. The methylene chloride layer is washed with water and 0.1 N sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was lyophilized in vacuo to give 245 mg of the above product (1: 1 ratio by NMR).

Example 39

Preparation of 1- [2-acetamido-4-methyl-5-thiazolylsulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole and 1- [2-apetamido-4-methyl-5-thiazolylsulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole

172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole is dissolved in 10 ml of methylene chloride and 0.4 ml of triethylamine and 128 mg of 2-acetamido- 4-methyl-5-thiazolylsulfonyl chloride. The reaction mixture was stirred at room temperature for 15 hours. The product stain appears slightly above the position of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole on TLC (developing solvent: methylene chloride-acetonitrile-methanol 100: 10: 5). The product was isolated by silica gel column chromatography. 145 mg of the above product are obtained.

Example 40

Preparation of 1- (thiophen-2-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole and 1- (thiophen-2-sulfonyl ) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole

172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole was dissolved in 10 ml of methylene chloride and 0.2 ml of triethylamine. 95 mg of thiophene-2-sulfonyl chloride are added. The reaction mixture was stirred at room temperature for 16 hours. The methylene chloride layer was washed with water and concentrated under reduced pressure. The resulting residue was crystallized from acetonitrile-ethyl ether-hexane. 225 mg of the above product are obtained, a mixture of 1- (thiophen-2-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1 - (thiophen-2-sulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (7: 1 NMR). Mp 86-90 ° C.

1 H NMR (CDCl ₃ , δ): 2.20 (s, 3H), 2.30 (s, 3H), 3.73 (s, 3H), 3.83 and 3.91 (2s, total 3H), 4.80-4.92, (q, AB, 2H), 7.00-7.10 (m, 2H), 7.47 (s, 1H), 7.67-7.69 (m, 2H) 7.97-7.99 (d, 1H); 8.13 (s, 1H).

Example 41

Preparation of 1- (phenylmethylsulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (phenylmethylsulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole was dissolved in 10 ml of methylene chloride and 0.2 ml of triethylamine. 95 mg of phenylmethylsulfonyl chloride is added. The reaction mixture was stirred at room temperature for 36 hours. The methylene chloride layer was washed with water and concentrated under reduced pressure. The resulting residue was lyophilized in vacuo to give 205 mg of the above product, a mixture of 1- (phenylmethylsulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (phenylmethylsulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (2: 1 ratio by NMR). Mp 130 ° C (with decomposition).

Example 42

Preparation of 1- (n-propanesulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (n-propanesulfonyl) -6 -methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

103 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole is dissolved in 2 ml of chloroform and 0.1 ml of triethylamine. 1-Propanesulfonyl chloride (0.042 ml) was added slowly in an ice bath. The reaction mixture was stirred at room temperature for 3 hours. The organic layer was washed with a cold 0.1 N sodium bicarbonate solution. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue solidifies upon treatment with a mixture of chloroform-ethyl ether-hexane to give 128 mg (95%) of the above product (3: 2 ratio). Mp 96-100 ° C.

Example 43

Preparation of 1- (n-butanesulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (n-butanesulfonyl) -6 -methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

103 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole is dissolved in 2 ml of chloroform and 0.1 ml of triethylamine. 1-Butanesulfonyl chloride (0.042 ml) was added slowly in an ice bath. The reaction mixture was stirred at room temperature for 3 hours. The organic layer was washed with a cold 0.1 N sodium bicarbonate solution. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue solidifies upon treatment with a mixture of chloroform-ethyl ether-hexane to give 130 mg (93%) of the above product (3: 2 ratio). Mp 54-56 ° C.

Example 44

Preparation of 1- (isopropylsulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (isopropylsulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

103 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole is dissolved in 2 ml of chloroform and 0.1 ml of triethylamine. Isopropylsulfonyl chloride (0.042 ml) was added slowly in an ice bath. The reaction mixture was stirred at room temperature for 24 hours. The organic layer was concentrated under reduced pressure and subjected to silica gel column chromatography. 78 mg of the above product are isolated (1: 1 ratio). Mp 105-108 ° C (with decomposition).

Example 45

Preparation of 1 - [(N, N-dimethylamino) benzene-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1 - [(N, N-dimethylamino) benzene-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

120 mg of p- (N, N-dimethylamino) benzenesulfonyl chloride is added to 172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole dissolved in 20 ml of chloride methylene and 0.5 ml of triethylamine. The reaction mixture was stirred at room temperature for 16 hours. The methylene chloride layer is washed with water and 0.1 N sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was lyophilized in vacuo to give 215 mg (93%) of the above product (1: 1 ratio). Mp 92-96 ° C.

1 H NMR (CDCl ₃ , δ): 2.24 (s, 3H), 2.30 (s, 3H), 3.02 (s, 3H), 3.03 (s, 3H), 3.75 (s , 3H), 3.83 and 3.92 (2s, total 3H), 4.77-4.94 (2xx AB and A'B ', total 2H), 6.57-6.61 (m, 2H ), 6.96-7.07 (m, 1H), 7.48 and 7.68 (2d, total 1H), 7.85-7.90 (m, 3H), 8.22 (s, 1H) .

Example 46

Preparation of N- [4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenyl] urea

128 mg of N- [4- (chlorosulfonyl) phenyl] urea is added to 191 mg of 2 - [(3-methyl-4-methoxypropoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole sodium salt in a mixture of 0.1 ml of triethylamine and 10 ml of methylene chloride-acetonitrile (50/50). The reaction mixture was stirred at room temperature overnight. Methylene chloride (20 ml) was added and washed with water and a 0.1 M sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in a minimum amount of acetonitrile and ethyl ether was added to crystallize. The crystals are separated and dried. 190 mg of the above product are obtained.

1 H NMR (CDCl ₃ , δ): 2.03-2.07 (m, 2H), 2.18 (s, 3H), 3.34 (s, 3H), 3.52-3.54 (t, 2H), 4.05-4.08 (t, 2H), 4.76-5.00 (q, AB, 2H), 5.50-5.61 (br, NH ₂ ), 6.69 (d , 1H), 7.33-7.37 (m, 3H), 7.51 (d, 1H), 7.65 (d, 1H), 7.81 (d, 2H), 7.98 (d, 1H), 8.17 (d, 1H), 8.97 (s, -NH-).

Example 47

Preparation of 1- (pyridin-3-sulfonyl] -2 - [[[3-methyl-4- (3-methoxypropoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole

100 mg of pyridine-3-sulfonyl chloride is added to 191 mg of sodium salt of 2 - [[[3-methyl-4- (3-methoxypropoxy) -2-pyridyl] methyl] -sulfinyl] -1H-benzimidazole in a mixture of 0.15 ml of triethylamine and 10 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. Methylene chloride (20 ml) was added and washed with water and a 0.1 M sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The residue was dissolved in a minimum amount of acetonitrile and ethyl ether was added to precipitate. The solid precipitate was separated and dried to give 127 mg of the above product.

1 H NMR (CDCl ₃ , δ): 1.97-2.10 (m, 2H), 2.21 (s, 3H), 3.35 (s, 3H), 3.51-3.57 (t, 2H), 4.04-4.07 (t, 2H), 4.82-5.14 (q, AB, 2H), 6.73 (d, 1H), 7.41-7.56 (m, 3H), 7.80-8.02 (dd, 2H), 8.23-8.87 (m, 3H), 9.34 (s, 1H).

Example 48

Preparation of 2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenoxy) -N- (2-pyridyl ) acetamide

170 mg of 2- [p- (chlorosulfonyl) phenoxy] -N- (2-pyridyl) acetamide is added to 191 mg of the sodium salt of 2 - [[[3-methyl-4- (3-methoxypropoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole in methylene chloride (15 ml) and triethylamine (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized in vacuo to give 244 mg of the above product. Mp 78-81 ° C (with decomposition).

1 H NMR (CDCl ₃ , δ): 2.00-2.10 (m, 2H), 2.27 (s, 3H), 3.35 (s, 3H), 3.52-3.57 (t, 2H), 4.06-4.10 (t, 2H), 4.64 (s, 2H), 4.83-5.02 (q. AB, 2H), 6.67 (d, 1H), 7 07-7.10 (m, 3H), 7.32-7.49 (m, 3H), 7.70-7.82 (m, 2H), 7.99 (d, 1H), 8.14 -8.30 (m, 4H); 8.77 (br, NH).

Example 49

Preparation of 1- [4- (morpholin-4-yl) phenylsulfonyl] -2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole

136 mg of 4 - [(p-chlorosulfonyl) phenyl] morpholine is added to 191 mg of the sodium salt of 2 - [[[3-methyl-4- (3-methoxypropoxy) -2-pyridyl] methyl] -sulfinyl] -1H-benzimidazole in methylene chloride (15 ml) and triethylamine (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized in vacuo to give 224 mg of the above product. Mp 93-96 ° C (with decomposition).

1 H NMR (CDCl ₃ , δ): 2.02-2.06 (m, 2H), 2.26 (s, 3H), 3.2-3.3 (m, 4H), 3.35 (s, 3H), 3.50-3.53 (t, 2H), 3.75-3.80 (m, 4H), 4.04-4.08 (t, 2H), 4.71-4.79 ( q, AB, 2H), 6.71 (d, 1H), 7.26-7.5 (m, 4H), 7.8-8.1 (m, 2H), 8.27 (d, 1H) .

Example 50

Preparation of 1 - [{2- (morpholin-4-yl) ethoxy} phenyl-4-sulfonyl] -2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H -benzimidazole

136 mg of 4- [2 - [(p-chlorosulfonyl) phenoxy] ethyl] morpholine is added to 191 mg of the sodium salt of 2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] - 1H-benzimidazole in methylene chloride (15 ml) and triethylamine (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized in vacuo to give 234 mg of the above product.

1 H NMR (CDCl ₃ , δ): 2.05-2.10 (m, 2H), 2.27 (s, 3H), 2.56 (m, 4H), 2.79-2.82 (t, 2H), 3.35 (s, 3H), 3.53-3.56 (t, 2H), 3.69-3.72 (m, 4H), 4.07-4.10 (t, 2H) 4.12-4.15 (t, 2H), 4.81-4.99 (q, AB, 2H), 6.68 (d, 1H), 6.95 (d, 2H), 7.36 -7.46 (m, 2H), 7.81 (d, 1H), 8.06 (d, 2H), 8.21 (d, 1H).

Example 51

Preparation of 1- (thiophen-2-sulfonyl) -2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole

92 mg of thiophene-2-sulfonyl chloride is added to 191 mg of 2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole sodium chloride in methylene chloride (15 ml) and triethylamine (0.1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized in vacuo to give 215 mg of the above product. Mp 147-150 ° C.

1 H NMR (CDCl ₃ , δ): 2.00-2.08 (m, 2H), 2.27 (s, 3H), 3.35 (s, 3H), 3.53-3.56 (s, 2H), 4.07-4.10 (t, 2H), 4.83-5.00 (q, AB, 2H), 6.67 (d, 1H), 7.08-7.10 (t, 1H), 7.42-7.49 (m, 2H), 7.68-7.70 (d, 1H), 7.82-7.84 (d, 1H), 8.00-8.03 ( m, 2H), 8.18 (d, 1H).

Example 52

Preparation of 1-benzenesulfonyl-2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole

94 mg of benzenesulfonyl chloride is added to 191 mg of 2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole sodium salt in methylene chloride (15 ml) and triethylamine (0, 1 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was crystallized from acetonitrile-ethyl ether. Get 210 mg of the above product. Mp 126-128 ° C.

1 H NMR (CDCl ₃ , δ): 1.97-2.09 (m, 2H), 2.27 (s, 3H), 3.34 (s, 3H), 3.52-3.57 (t, 3H), 4.05-4.10 (t, 3H), 4.81-5.03 (q, AB, 2H), 6.66 (d, 1H), 7.38-7.53 (m, 4H), 7.61-7.65 (t, 1H), 7.80 (d, 1H), 8.00 (d, 1H), 8.11-8.16 (m, 3H).

Example 53

Preparation of 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide and 2- { 4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide

5-Methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (344 mg) was dissolved in 40 ml of methylene chloride and 1 ml of triethylamine. 2- [p- (Chlorosulfonyl) phenoxy] acetamide (250 mg) was added. The reaction mixture was stirred at room temperature overnight. The reaction was monitored by TLC (developing solvent: chloroform: acetonitrile: methanol (100: 10: 7)). The solid precipitate was separated by filtration, washed with a small amount of methylene chloride and dried in vacuo to give 415 mg of the above product (5-methoxy / 6-methoxy 3: 2 ratio). Mp 159-161 ° C (with decomposition).

1 H NMR (DMSO-d6, δ): 2.13 (s, 3H), 2.25 (s, 3H), 3.69 (s, 3H), 3.78 and 3.88 (2s, total 3H) 4.56 (s, 2H), 4.82-5.04 (2q, AB, 2H), 7.05-7.18 (m, 3H), 7.34-7.40 (m, 1H) 7.60-7.90 (m, 2H); 8.12-8.18 (m, 2H).

Example 54

Preparation of 2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide

2 - [[(3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (370 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. 2- [p- (Chlorosulfonyl) phenoxy] acetamide (250 mg) was added. The reaction mixture was stirred at room temperature for 24 hours. The solid precipitate was separated, washed with methylene chloride and dried in vacuum. Get 378 mg of the above product. Mp 162-166 ° C (with decomposition).

1 H NMR (DMSO-d6, δ): 2.21 (s, 3H), 4.55 (s, 2H), 4.86-5.15 (q, 2H and q, 2H), 6.99 (d , 1H), 7.16 (d, 2H), 7.39-7.58 (m, 2H), 7.79 (d, 1H), 7.97-8.03 (m, 2H), 8, 17 (d, 2H).

Example 55

Preparation of 2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide and 2- {4- [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide

5- (Difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (383 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. 2- [p- (Chlorosulfonyl) phenoxy] acetamide (250 mg) was added. The reaction mixture was stirred at room temperature for 24 hours. The solid precipitate was separated, washed with methylene chloride and dried in vacuum. 413 mg of the above product are obtained (1: 1 ratio). Mp 125-128 ° C (with decomposition).

Example 56

Preparation of 2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide

Sodium salt of 2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (382 mg) was added to methylene chloride (45 ml) and triethylamine (0.1 ml ) 2- [p- (Chlorosulfonyl) phenoxy] acetamide (250 mg) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was crystallized from acetonitrile-ethyl ether. Obtain 437 mg of the above product. Mp 148-153 ° C (with decomposition).

1 H NMR (DMSO-d6, δ): 1.93-1.97 (m, 2H), 2.18 (s, 3H), 3.35 (s, 3H), 3.46 (t, 2H), 4.06 (t, 2H), 4.56 (s, 2H), 4.83-5.13 (q, AB, 2H), 6.85 (d, 1H), 7.16 (d, 2H) 7.41-7.60 (m, 2H), 7.79 (d, 1H), 7.89 (d, 1H), 8.00-8.02 (d, 1H), 8.16-8 18 (d, 2H).

Example 57

Preparation of 1 - [{2- (morpholin-4-yl) ethoxy} phenyl-4-sulfonyl] -2 - [(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methylsulfinyl] - 1H-benzimidazole

2 - [[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (370 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. [2- (Morpholin-2-yl) ethoxy] phenyl-4-sulfonyl chloride (273 mg) was added and stirred at room temperature overnight. The methylene chloride layer is washed with an aqueous solution consisting of 0.1 M NaCl and ice-cold 0.1 M sodium bicarbonate solution. The methylene chloride layer is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was lyophilized to give 515 mg of the above product.

1 H NMR (CDCl ₃ , δ): 2.33 (s, 3H), 2.50-2.52 (m, 4H), 2.78-2.81 (t, 2H), 3.70-3, 74 (m, 4H), 4.12-4.15 (t, 2H), 4.84-5.02 (q, AB, 2H), 6.63 (d, 1H), 6.69 (d, 2H), 7.38-7.49 (m, 2H), 7.81 (d, 1H), 7.99 (d, 1H), 8.04 (d, 2H), 8.26 (d, 1H) )

Example 58

Preparation of 1 - [{2- (morpholin-4-yl) ethoxy} phenyl-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole and 1 - [{2- (morpholin-4-yl) ethoxy} phenyl-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl ]] - 1H-benzimidazole

137 mg of [2- (morpholin-2-yl) ethoxy] phenyl-4-sulfonyl chloride is added to 172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H- benzimidazole in methylene chloride (15 ml) and triethylamine (0.4 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was lyophilized in vacuo to give 224 mg of the above product (1: 1 ratio).

1 H NMR (CDCl ₃ , δ): 2.22 (s, 3H), 2.30 (s, 3H), 2.50-2.51 (m, 4H), 2.79 (t, 2H), 3 69-3.74 (m, 4H; s, 3H), 3.82 and 3.91 (2s, total 3H), 4.12 (t, 2H), 4.78-4.94 (q, AB , 2H), 6.93-7.08 (m, 3H), 7.46 (s, 1H), 7.68-7.86 (dd, 1H), 8.00-8.04 (m, 2H) ), 8.17 (s, 1H).

Example 59

Preparation of 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -2 - [(3-methyl-4- (2,2,2-trifluoroethoxy) -2- pyridyl) methylsulfinyl] -1H-benzimidazole

2 - [[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole (185 mg) was dissolved in 20 ml of methylene chloride and 0.5 ml of triethylamine. 2- [2- (Morpholin-4-yl) ethoxy] ethoxyphenyl-4-sulfonyl chloride (163 mg) was added and stirred at room temperature overnight. The methylene chloride layer is washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M NaHCO ₃ . The methylene chloride layer is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was subjected to preparative TLC. 198 mg of the above product are obtained.

1 H NMR (CDCl ₃ , δ): 2.30 (s, 3H), 2.48 (m, 4H), 2.58 (t, 2H), 3.64-3.77 (m, 8H), 4 10 (t, 2H), 4.34-4.40 (q, 2H), 4.81-5.01 (q, AB, 2H), 6.62 (d, 1H), 6.94 (d) , 2H), 7.35-7.47 (m, 2H), 7.78 (d, 1H), 7.96 (d, 1H), 8.02 (d, 2H), 8.22 (d, 1H).

Example 60

Preparation of 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl ) methyl] sulfinyl] -1H-benzimidazole and 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -6-methoxy-2 - [[(3,5- dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

162 mg of 2- [2- (morpholin-4-yl) ethoxy] ethoxyphenyl-4-sulfonyl chloride is added to 172 mg of 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole in methylene chloride (15 ml) and triethylamine (0.5 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was dried in vacuo to give 254 mg of the above product (1: 1 ratio).

1 H NMR (CDCl ₃ , δ): 2.21 (s, 3H), 2.29 (s, 3H), 2.49-2.53 (m, 2H), 2.69-2.78 (m, 4H), 3.67-3.89 (m, 8H; s, 3H; s, 3H), 4.07-4.13 (m, 2H), 4.76-4.93 (q, AB, 2H ), 6.92-7.00 (m, 2H), 7.23 (d, 1H), 7.44 (d, 1H), 7.65-7.85 (dd, 1H), 7.98- 8.03 (m, 2H); 8.15 (s, 1H).

Example 61

Preparation of 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl ] sulfinyl] -1H-benzimidazole

Sodium salt of 2 - [(3-methyl-4-methoxypropoxy-2-pyridyl] methyl-sulfinyl] -1H-benzimidazole (191 mg) was dissolved in 20 ml of methylene chloride and 0.1 ml of triethylamine. 2- [2-Morpholine was added. -4-yl) ethoxy] ethoxyphenyl-4-sulfonyl chloride (163 mg) and stirred at room temperature overnight. The methylene chloride layer is washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M NaHCO ₃ . The methylene chloride layer is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was lyophilized to give 253 mg of the above product.

1 H NMR (CDCl ₃ , δ): 1.99-2.03 (m, 2H), 2.21 (s, 3H), 2.46 (t, 2H), 2.55 (t, 2H), 2 67 (t, 2H), 3.29 (s, 3H), 3.48-3.53 (m, 2H), 3.64-3.68 (m, 6H), 3.73-3.74 (m, 2H), 4.02-4.07 (m, 4H), 4.74-4.97 (q, AB, 2H), 6.62 (d, 1H), 6.89-6.92 (d, 2H), 7.31-7.42 (m, 2H), 7.75 (d, 1H), 7.93 (d, 1H), 8.02 (d, 2H), 8.13 ( d, 1H).

Example 62

Preparation of N- (carbamoylmethyl) -2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy } acetamide and N- (carbamoylmethyl) -2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl ] phenoxy} acetamide

Method 1: 5-Methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (172 mg) was dissolved in 20 ml of methylene chloride. Sodium tert-butoxide (55 mg) and N- (carbamoylmethyl) -2- [4- (chlorosulfonyl) phenoxy] acetamide (160 mg) are added. The reaction mixture was stirred at 30 ° C for 36 hours. The reaction mixture is filtered. The filtrate was concentrated, treated with ethyl ether to obtain a precipitate. The solid residue is separated and dried in vacuo. 253 mg of the above product is obtained (1: 1 ratio).

Method 2: 5-Methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (172 mg) was dissolved in 20 ml of methylene chloride and 0.4 ml of triethylamine. N- (carbamoylmethyl) -2- [4- (chlorosulfonyl) phenoxy] acetamide (160 mg) was added. The reaction mixture was stirred at 30 ° C for 36 hours. The reaction mixture was treated with 80 ml of methylene chloride and washed with 7% NaCl and 0.1 N sodium bicarbonate. The methylene chloride layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was lyophilized to give 213 mg of the above product (1: 1 ratio).

1 H NMR (DMSO-d6, δ): 2.14 (s, 3H), 2.25 (s, 3H), 3.34 (br, -NH, -NH ₂ ), 3.66 (d, 2H) 3.70 (s, 3H), 3.88 (s, 3H), 4.67 (s, 2H), 4.81-5.08 (q, AB, 2H), 7.05-7.22 (m, 3H), 7.35 (s, 1H), 7.89 (dd, 1H), 8.14-8.18 (m, 2H), 8.32 (s, 1H).

Example 63

Preparation of N- (carbamoylmethyl) -2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl} sulfinyl) benzimidazol-1-yl) sulfonyl ] phenoxy} acetamide

2 - [[[3-Methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -H-benzimidazole (185 mg) is dissolved in 20 ml of methylene chloride and 0.5 ml of triethylamine and N- (carbamoylmethyl) -2- [4- (chlorosulfonyl) phenoxy] acetamide (158 mg) was added. The reaction mixture was stirred at room temperature for 24 hours. Methylene chloride (100 ml) was added to the reaction mixture. The reaction mixture was washed with saturated NaCl and 0.1 N sodium bicarbonate. The methylene chloride layer was separated and dried over anhydrous magnesium sulfate. Methylene chloride was evaporated under reduced pressure to give a syrupy residue, which was lyophilized in vacuo. Get 237 mg of the above product.

1 H NMR (DMSO-d6, δ): 2.23 (s, 3H), 3.36 (br, -NH, -NH ₂ ), 3.66 (d, 2H), 3.66 (d, 2H) 4.67 (s, 2H), 4.84-5.17 (m, 2H and q, AB, 2H); 6.99-8.35 (m, 10H, aromatic H).

Example 64

Preparation of N- (carbamoylmethyl) -2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl) methyl} sulfinyl) benzimidazol-1-yl) sulfonyl] phenoxy} acetamide

Sodium salt of 2 - [[[(4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl-1H-benzimidazole (190 mg) was dissolved in 20 ml of methylene chloride and 0.5 ml of triethylamine and added N- (carbamoylmethyl) -2- [4- (chlorosulfonyl) phenoxy] acetamide (160 mg). The reaction mixture was stirred at room temperature for 24 hours. Methylene chloride (100 ml) was added to the reaction mixture, and the reaction mixture was washed with saturated NaCl solution. and 0.1 N sodium bicarbonate solution. The methylene chloride layer is separated and dried over anhydrous magnesium sulfate. Evaporated methylene chloride It is removed under reduced pressure to give a syrupy residue which is lyophilized in vacuo to give 215 mg of the title product.

1 H NMR (DMSO-d6, δ): 1.94-1.97 (m, 2H), 2.19 (s, 3H), 2.22 (s, 3H), 3.46 (t, 2H), 3.67 (d, 2H), 4.06 (t, 2H), 4.68 (s, 2H), 4.84-5.14 (q, AB, 2H), 6.85 (d, 1H) 7.21 (d, 2H), 7.42-7.55 (m, 2H), 7.80 (d, 1H), 7.91 (d, 1H), 8.02 (d, 1H), 8.18 (d, 2H).

Example 65

Preparation of 1- (Benzotriazol-1-yl) methyl-5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole and 1- (benzotriazole-1 -yl) methyl-6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole

5-Methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (172 mg) was dissolved in 20 ml of methylene chloride. Sodium tert-butoxide (55 mg) and 1- (chloromethyl) -1H-benzotriazole (85 mg) are added. The reaction mixture was stirred at 30 ° C for 3 days. TLC analysis (developing solvent: chloroform-methanol 15: 1) shows one main spot 1- (benzotriazol-1-yl) methyl-5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2- pyridyl) methyl] -sulfinyl] -1H-benzimidazole above 5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole. The title product was purified by preparative TLC. 195 mg of product is obtained, a mixture of 1- (benzotriazol-1-yl) methyl-5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl-] sulfinyl] -1H-benzimidazole and 1- (benzotriazol-1-yl) methyl-6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole (3: 2 ratio).

1 H NMR (CDCl ₃ , δ): 2.21 (s, 3H), 2.24 (s, 3H), 3.70 (s, 3H), 3.79 and 3.86 (2s, total 3H), 4.85-5.08 (q, AB, 2H), 6.65 (d, 2H, N-CH ₂ -N), 6.89-8.12 (m, 8H).

Example 66

Preparation of 1- (Benzotriazol-1-yl) methyl-2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole

The 2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole sodium salt (190 mg) was dissolved in 20 ml of methylene chloride. 1- (Chloromethyl) -1H-benzotriazole (85 mg) was added. The reaction mixture was stirred at 30 ° C for 3 days. TLC analysis shows one stain of the product. The reaction mixture is filtered. The filtrate was concentrated under reduced pressure and treated with ethyl ether-heptane. The resulting solid precipitate was separated and dried to give pure 1- (benzotriazol-1-yl) methyl-2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole ( 212 mg).

1 H NMR (CDCl ₃ , δ): 2.05-2.08 (m, 2H), 2.21 (s, 3H), 3.34 (s, 3H), 3.54 (t, 2H), 4 08 (t, 2H), 4.86-5.16 (q, AB, 2H), 6.69-6.70 (d, 2H, N-CH ₂ -N), 7.00-8.15 (m, 10H).

Example 67

Preparation of diethyl [5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] phosphate

5-Methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole (172 mg) was dissolved in 50 ml of methylene chloride and 0.5 ml of triethylamine. Diethyl chlorophosphate (87 mg) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with saturated NaCl and twice with 0.1 N sodium bicarbonate. The methylene chloride layer was separated and dried over anhydrous magnesium sulfate. Methylene chloride was evaporated under reduced pressure to give a syrup-like substance, 215 mg of product. The syrupy product slowly breaks down.

1 H NMR (CDCl ₃ , δ): 1.28-1.38 (m, 6H), 2.10 (s, 3H), 2.19 (s, 3H), 3.60 (s, 3H), 3 83 (s, 3H), 4.20-4.28 (m, 4H), 4.72-4.87 (q, AB, 2H), 6.91 (d, 2H), 7.7 (d , 1H), 7.92 (s, 1H), 8.18 (s, 1H).

Chemical stability

The chemical stability of the compounds of the invention is studied kinetically at a low concentration at 37 ° C in a buffer solution of 0.2 M NaCl, 50 mM sodium phosphate, pH 7.4, 2% bovine serum albumin, 5-10% methanol. According to measurements, the compounds of Example 1 and Example 19 have a half-life of (t _1/2 ) 3 hours ± 0.5 hours and 3.5 hours ± 0.3 hours, respectively. The compound of Example 1 has a slightly higher solubility in an aqueous buffer than the compound of Example 19. It was found that the solubility of these compounds affects the rate of hydrolysis.

The acid resistance of the compounds was tested in 95% methanol containing 0.1 N Hcl. About 90% of the compound from Example 1 remained intact (without decomposition) after 2.25 hours in this solution.

Biological tests

Inhibition of ATPase activity is determined using isolated porcine stomach vesicles. Gastric N. K-ATPase (10 μg) was thermostated at 37 ° C in a solution (1 ml) containing 0.25 M sucrose, 20 mM Pipes / Tris, pH 7.4, 0.15 M KCl, 2 mM MgCl ₂ , valinomycin 2 μg / ml and the compounds of the invention in various concentrations. ATP (up to 2 mM) is added at certain intervals and thermostated (incubated) for 15 minutes and the amount of phosphate released is measured. As a control for measuring the enzyme-inhibiting activity, a drug from the previous technique is used without a labile group at the benzimidazole nitrogen atom (for example, OMEPRAZOL or LANSOPRAZOL). First (before they undergo hydrolysis), samples containing 10, 20, 50, and 100 μM of the compound from Example 1 did not inhibit the enzymatic activity. However, after 80 minutes, a sample containing 10 μg of the compound of Example 1 inhibits 10%, and a sample of 50 μM inhibits 50%. In samples containing 10 μM OMEPRAZOLE (control) and 10 μM of the compound from Example 1, the same level of inhibition is achieved after 5.75 hours of hydrolysis.

The relative concentration of omeprazole in rat plasma

Adult male rats, the Sprague-Dawley strain, were used to determine the plasma concentration of OMEPRAZOLE. All rats were deprived of food, but not water, for one day. Presented compounds (2 mg / kg rat weight) are orally administered to males (weighing 250-270 g) and samples are taken at certain intervals. Blood samples are centrifuged and plasma taken. Plasma is extracted with 0.5 ml of methylene chloride. Methylene chloride is evaporated by purging with nitrogen / air. The residue was dissolved in 0.5 ml of 40% acetonitrile in 10 mM phosphate buffer (pH 7.4). OMEPRAZOLE is quantified by HPLC. As a control, OMEPRAZOLE (4 mg / kg rat weight) is orally administered.

The relative concentration of OMEPRAZOLE released into the plasma (arbitrary units) is presented in table 3.

Inhibitory effect on gastric acid secretion in male conscious rats

Male rats (strain Sprague-Dawley) were taken. OMEPRAZOLE (2 mg) or the compound from Example 33 (1 mg) are resuspended in 1 ml of 15% sugar and 20 mM sodium phosphate buffer pH 7.4. OMEPRAZOLE (2 mg / kg) or the compound of Example 33 (1 mg / ml) is administered orally. At certain intervals (2, 3.5, and 5 hours), the rat abdominal cavity is cut and the pylorus is ligated under mild ether anesthesia. Histamine (2 mg / kg) is injected intravenously to stimulate acid. Immediately close the abdominal cavity. An hour later, the stomach is removed after ligation of the esophagus. Gastric juice is collected and the amount (yield) of acid is determined by titration with a solution of 0.1 N NaOH. In a control experiment, 1 ml of 15% sugar and 20 mM phosphate buffer solution are orally administered without the addition of any substances (inhibitors). The amount of acid determined by the method described above shows the maximum histamine-stimulated secretion of gastric acid. The percent inhibition is calculated as the ratio of the reaction (value) of the test compound to the control experiment. Further calculations are done based on the average values (reactions) in a group of 3-4 rats.

Inhibition of gastric acid secretion at specific intervals is shown in table 4.

The compound of Example 33 had prolonged inhibition compared with OMEPRAZOL. The maximum inhibition of the compound from Example 33 is achieved after 5 hours, which shows that the compound of the invention is continuously converted to the corresponding PPI in vivo and inhibits gastric acid secretion.

Claims (16)

1. Derivatives of benzimidazole Het ₁ —X — S (O) —Het ₂ , where het ₁ has a structure

X has the structure

Het ₂ has a structure

R ₁ , R ₂ and R _{3 are} independently selected from hydrogen, alkyl containing 1-10 carbon atoms, fluorine substituted alkyl containing 1-10 carbon atoms, alkoxy with 1-10 carbon atoms and fluorine substituted alkoxy with 1-10 carbon atoms; R ₆ - R _{9 are} independently selected from hydrogen, alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms and halogen substituted alkoxy with 1-10 carbon atoms; R ₁₀ means hydrogen, alkyl with 1-10 carbon atoms; R ₁₅ has the formula

in which R ₁₇ means alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, halogen-substituted alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, halogen-substituted alkylthio with 1-10 carbon atoms, alkoxycarbonyl with 1-10 carbon atoms, halogen-substituted alkoxycarbonyl with 1-10 carbon atoms, F, Cl, Br, J, NO ₂ , CN, OSOalkyl, NH ₂ , alkylamino and dialkylamino, where in the indicated OSOalkyl, alkylamino and dialkylamino groups each of these alkyl groups contains it has 1-10 carbon atoms, carbamoyl, N-substituted carbamoyl, alkylcarbonyl with 1-10 carbon atoms, moreover, (alkoxycarbonyl) alkoxy groups in each of said alkoxy groups contain 1-10 carbon atoms, (alkoxycarbonyl) alkyl groups in each of said alkoxy or the alkyl group contains 1-10 carbon atoms, (carbamoyl) alkoxy with 1-10 carbon atoms, (N-alkylcarbamoyl) alkoxy with 1-10 carbon atoms, (N, N-dialkylcarbamoyl) alkoxy with 1-10 carbon atoms, (N -substituted or unsubstituted carbamoyl) poly (alkoxy) with 1-10 carbon atom mi, (N-substituted or unsubstituted carbamoyl) alkyl with 1-10 carbon atoms, [N- (heteroaryl) carbamoyl] alkyl with 1-10 carbon atoms, [N- (heteroaryl) carbamoyl] alkoxy with 1-10 carbon atoms, [N- (substituted aryl) carbamoyl] alkoxy with 1-10 carbon atoms, the poly (alkoxy) group in each of these alkoxy groups containing 1-10 carbon atoms, cyclic polyalkoxy, guanidinyl group, ureido group, dialkylamino-poly (alkoxy) group, [N- (carbamoylalkyl) carbamoyl] alkoxy, [N- (carbamoylalkyl) carbamoyl] alkyl, [N - [[N- (heteroaryl) carbamoyl] alkyl] ka rbamoyl] alkoxy, [N - [[N- (substituted heteroaryl) carbamoyl] alkyl] carbamoyl] alkoxy, (sulfonato) alkyl, (sulfonato) alkoxy, N - [(sulfonato) alkyl] amido, (substituted) maleimido-, ( substituted) succinimido, [(tri-alkyl) ammonium] alkoxy; R ₂₁ means (aryl) alkyl, (heteroaryl) alkyl, phenyl, naphthyl or heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, wherein said phenyl, naphthyl or heteroaryl groups are substituted or unsubstituted 1-5 groups R ₁₇ , or pharmaceutically acceptable salts of these compounds. 2. The compound according to claim 1, characterized in that X represents a CH ₂ group. 3. The compound according to claim 1, characterized in that R ₂₁ means phenyl, pyridyl, thiophenyl, thiazolyl or imidazolyl. 4. Derivatives of benzimidazole

characterized in that R ₁ * means methyl, methoxy or chlorine; R ₂ * means methoxy, 2,2,2-trifluoroethoxy, (2,2,3,3,4,4-heptafluorooctyl) oxy or CH ₃ O (CH ₂ ) ₃ O; R ₃ * means H or methyl; R ₆ * means H, a methoxy or difluoromethoxy group at position 5 or 6 of the benzimidazole moiety; R ₁₅ has the formula

in which R ₁₇ means alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, halogen-substituted alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, halogen-substituted alkylthio with 1-10 carbon atoms, alkoxycarbonyl with 1-10 carbon atoms, halogen-substituted alkoxycarbonyl with 1-10 carbon atoms, F, Cl, Br, J, NO ₂ , CN, OSOalkyl, NH ₂ , alkylamino and dialkylamino, where in the indicated OSOalkyl, alkylamino and dialkylamino groups each of these alkyl groups contains um 1-10 carbon atoms, in addition, R ₁₇ is carbamoyl, N-substituted carbamoyl, alkylcarbonyl having 1-10 carbon atoms, (alkoxycarbonyl) alkoxy groups of each of said alkoxy groups contain 1-10 carbon atoms, (alkoxycarbonyl) alkyl groups in each of the indicated alkoxy or alkyl groups contains 1-10 carbon atoms, (carbamoyl) alkoxy with 1-10 carbon atoms, (N-alkylcarbamoyl) alkoxy with 1-10 carbon atoms, (N, N-dialkylcarbamoyl) alkoxy with 1- 10 carbon atoms, (N-substituted or unsubstituted carbamoyl) poly (alkox ) with 1-10 carbon atoms, (N-substituted or unsubstituted carbamoyl) alkyl with 1-10 carbon atoms, [N- (heteroaryl) carbamoyl] alkyl with 1-10 carbon atoms, [N- (heteroaryl) carbamoyl] alkoxy with 1-10 carbon atoms, [N- (substituted aryl) carbamoyl] alkoxy with 1-10 carbon atoms, the poly (alkoxy) group in each of these alkoxy groups containing 1-10 carbon atoms, cyclic polyalkoxy, guanidinyl group, ureido group, dialkylamino poly (alkoxy) group, [N- (carbamoylalkyl) carbamoyl] alkoxy, [N- (carbamoylalkyl) carbamoyl] alkyl, [N - [[N- (hetero aryl) carbamoyl] alkyl] carbamoyl] alkoxy, [N - [[N- (substituted heteroaryl) carbamoyl] alkyl] carbamoyl] alkoxy, [(tri-alkyl) ammonium] alkoxy, (sulfonato) alkyl, (sulfonato) alkoxy, N - [(sulfonate) alkyl] amido, (substituted) maleimido-, (substituted) succinimido; R ₂₁ means (aryl) alkyl, (heteroaryl) alkyl, phenyl, naphthyl or heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, wherein said phenyl, naphthyl or heteroaryl groups are substituted or unsubstituted 1-5 groups R ₁₇ , or pharmaceutically acceptable salts of said compound. 5. The compound according to claim 4, characterized in that R ₂₁ (R ₁₇ ) means phenyl, thienyl or pyridyl, substituted or unsubstituted with a group R ₁₇ . 6. The compound according to claim 5, characterized in that R _{17 is} selected from Cl, Br, F, lower alkyl, lower alkoxy, trifluoromethyl, trifluoromethoxy, di- (lower alkyl) amino, lower alkoxycarbonyl, carbamoyl, guanidinyl, ureido, ( carbamoyl) alkoxy, [N- (heteroaryl) carbamoyl] alkoxy, morpholinyl, (morpholin-4-yl) alkoxy, [(morpholin-4-yl) alkoxy] alkoxy, (di- (lower alkyl) amino) alkoxy, [N - [(carbamoyl) alkyl] carbamoyl] alkoxy, poly (alkoxy), sodium (sulfonato) alkoxy, (trimethylammonium) alkoxy and cyclic tetra- or penta-ethyleneoxy, the terms lower alkyl or lower alkoxy , each, define groups containing 1-6 carbon atoms. 7. The compound according to claim 6, characterized in that R ₂₁ is unsubstituted or in that R _{17 is} selected from Cl, Br, F, lower alkyl, lower alkoxy, trifluoromethyl, di- (lower alkyl) amino, lower alkoxycarbonyl, carbamoyl , guanidinyl, ureido, (carbamoyl) methoxy, [N- (pyridyl) carbamoyl] methoxy, morpholinyl, (morpholin-4-yl) alkoxy, [(morpholin-4-yl) alkoxy] alkoxy, 2- (dimethylamino) ethoxy, [N - [(carbamoyl) methyl] carbamoyl] methoxy, poly (alkoxy) and cyclic tetra- or penta-ethyleneoxy groups, wherein the terms lower alkyl or lower alkoxy each define groups containing 1-6 carbon atoms. 8. The compound according to claim 4, selected from the group consisting of 1-benzenesulfonyl-5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-2 - [(3-methyl-4- (2 ^' , 2 ^' , 2 ^' -trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-chlorobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-chlorobenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-chlorobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-chlorobenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-bromobenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-bromobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-bromobenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-bromobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-bromobenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-bromobenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-fluorobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-fluorobenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-fluorobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-fluorobenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-fluorobenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methylbenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methylbenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methylbenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methylbenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methylbenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methoxybenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methoxybenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methoxybenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methoxybenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-methoxybenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (3-trifluoromethylbenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (3-trifluoromethylbenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (3-trifluoromethylbenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (3-trifluoromethylbenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (3-trifluoromethylbenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-trifluoromethoxybenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-trifluoromethoxybenzenesulfonyl) -6-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-trifluoromethoxybenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-trifluoromethoxybenzenesulfonyl) -6-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-trifluoromethoxybenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-dimethylaminobenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-dimethylaminobenzenesulfonyl) -5-difluoromethoxy-2 - [(3,4-dimethoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-dimethylaminobenzenesulfonyl) -2 - [(3-methyl-4- (2 ', 2', 2'-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-ethoxycarbonylbenzenesulfonyl) -5-methoxy-2 - [(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (p-etoksikarbonilbenzolsulfonil) -2 - [(3-methyl-4- (2 ', ^2', 2-trifluoroethoxy) -2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1- (pyridin-3-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (pyridin-3-sulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (pyridin-3-sulfonyl) -2 - [[(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (pyridin-3-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (pyridin-3-sulfonyl) -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- [4 - [(morpholin-4-yl) phenyl] sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- [4 - [(morpholin-4-yl) phenyl] sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, N- [4 - [[5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea, N- [4 - [[6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] benzimidazol-1-yl] sulfonyl] phenyl] urea, N- [4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenyl] urea, N- [4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenyl] urea, N- [4 - {[2 - {[(3,4-di (methoxy) -2-pyridyl) methyl] sulfinyl} -5- (difluoromethoxy) benzimidazol-1-yl] sulfonyl} phenyl] urea, N- [4 - {[2 - {[(3,4-di (methoxy) -2-pyridyl) methyl] sulfinyl} -6- (difluoromethoxy) benzimidazol-1-yl] sulfonyl} phenyl] urea, 15 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4,5,6, 7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled, 15 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} -1,2,3,4, 5,6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled, 15 - [(5-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] -1,2,3,4,5, 6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled, 15 - [(6-methoxy-2 - {[(4-methoxy-3,5-dimethyl-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] -1,2,3,4,5, 6,7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled, 15 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] -1,2,3,4,5,6, 7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled, 15 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] -1,2,3,4,5,6, 7,8,9,10,11,12,13-tridecahydrobenzo [a] [15] is canceled, 2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide, 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2- pyridyl) acetamide, N- (carbamoylmethyl) -2- {4 - [(5-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide, 2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sylphinyl} benzimidazole-1-yl) sylphonyl] phenoxy} -N- (2- pyridyl) acetamide, N- (carbamoylmethyl) -2- {4 - [(6-methoxy-2 - {[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide 2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenoxy) acetamide, 2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenoxy) -N- ( 2-pyridyl) acetamide, N- (carbamoylmethyl) -2- (4 - {[2 - ({[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenoxy) acetamide, 2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide, 2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide N- (carbamoylmethyl) -2- {4 - [(5- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide, 2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide, 2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} -N- (2-pyridyl) acetamide N- (carbamoylmethyl) -2- {4 - [(6- (difluoromethoxy) -2 - {[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl} benzimidazol-1-yl) sulfonyl] phenoxy} acetamide, 2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenoxy) acetamide, 2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenoxy) -N- (2-pyridyl) acetamide N- (carbamoylmethyl) -2- (4 - {[2 - ({[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl} sulfinyl) benzimidazol-1-yl] sulfonyl} phenoxy) acetamide, 1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H -benzimidazole, 1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H -benzimidazole, 1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -2 - [(3-methyl-4-methoxypropoxy-2-pyridyl) methylsulfinyl] -1H-benzimidazole, 1 - [[4- {3- (morpholin-4-yl) propoxy} phenyl] sulfonyl] -2 - [(3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl) methylsulfinyl] - 1H-benzimidazole, 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole, 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole , 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole , 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] - 1H-6-benzimidazole, 1 - [{(N, N-dimethylamino) methyl} benzene-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H- benzimidazole 1- [2-acetamido-4-methyl-5-thiazolylsulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole, 1- (thiophen-2-sulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole, 1 - [{(N, N-dimethylamino) methyl} benzene-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H- benzimidazole 1- [2-acetamido-4-methyl-5-thiazolylsulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole, 1- (thiophen-2-sulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methylsulfinyl]] - 1H-benzimidazole, 1- (thiophen-2-sulfonyl) -2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole, 1- (thiophen-2-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (thiophen-2-sulfonyl) -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (thiophen-2-sulfonyl) -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (thiophen-2-sulfonyl) -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2-pyridyl] methyl] sulfinyl] -1H-benzimidazole, 1- (phenylmethylsulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1 - [(N, N-dimethylamino) benzene-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (phenylmethylsulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1 - [(N, N-dimethylamino) benzene-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (pyridin-3-sulfonyl) -2 - [[(3-methyl-4-methoxypropoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- [4- (morpholin-4-yl) phenylsulfonyl] -2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-2 - [[(3-chloro-4-morpholin-2-pyridyl) methyl] sulfinyl] -5-methoxy- (1H) benzimidazole, 1-benzenesulfonyl-2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] imidazolo [5,4-c] pyridine, 1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] imidazolo [4,5-c] pyridine, 1-benzenesulfonyl-2 - [(3-methoxyphenyl) methylsulfinyl] -5-nitro-benzimidazole, 1-benzenesulfonyl-2 - [{2- (dimethylamino) phenyl} methylsulfinyl] -1H-benzimidazole, 1-benzenesulfonyl-2 - [[[[4- (2,2,3,3,4,4,4-heptafluorobutyl) oxy] -2-pyridyl] methyl] sulfinyl] -1H-thieno [3,4-d ] imidazole, 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [(3-methoxyphenyl) methylsulfinyl] imidazole [5,4-c] pyridine, 1- [4- [2- (morpholin-4-yl) ethoxy] phenylsulfonyl] -2 - [{2- (dimethylamino) phenyl} methylsulfinyl] -1H-benzimidazole, 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -2 - [[[4- (3-methoxypropoxy) -3-methyl-2-pyridyl] methyl] sulfinyl] -1H-benzimidazole, 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -5- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -lH-benzimidazole, 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -6- (difluoromethoxy) -2 - [[(3,4-dimethoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1 - [[2- {2- (morpholin-4-yl) ethoxy} ethoxy] phenyl-4-sulfonyl] -2 - [[[3-methyl-4- (2,2,2-trifluoroethoxy) -2- pyridyl] methyl] sulfinyl] -1H-benzimidazole, 1- (4-acetaminobenzenesulfonyl) -5-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole, 1- (4-acetaminobenzenesulfonyl) -6-methoxy-2 - [[(3,5-dimethyl-4-methoxy-2-pyridyl) methyl] sulfinyl] -1H-benzimidazole. 9. The compound of the formula

in which R _{15 is} selected from groups (1) - (9) shown below

10. The compound of the formula

in which R _{15 is} selected from groups (1) to (8) shown below

11. The compound of the formula

in which R _{15 is} selected from groups (1) to (15) shown below

and isomers of compounds of this formula in which the R ₁₅ group is bonded to the nitrogen atom at position 3 of the benzimidazole moiety. 12. The compound of the formula

in which R _{15 is} selected from groups (1) - (4) shown below

and isomers of compounds of this formula in which the R ₁₅ group is bonded to the nitrogen atom at position 3 of the benzimidazole moiety. 13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a prodrug of a proton pump inhibitor according to claim 1. 14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a prodrug of a proton pump inhibitor according to claim 4. 15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a prodrug of a proton pump inhibitor according to any one of claims 8-12. 16. The pharmaceutical composition according to any one of paragraphs.13-15, containing a liquid activated for injection by a mammal, having a pH value not exceeding 8.5 units.