Derivatives of benzimidazole and pharmaceutical composition comprising a prodrug of a proton pump inhibitor

C07D417/14 - containing three or more hetero rings

C07D409/14 - containing three or more hetero rings

C07D401/14 - containing three or more hetero rings

C07D401/12 - linked by a chain containing hetero atoms as chain links

C07D235/28 - Sulfur atoms

A61P1/04 - for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

A61K31/4184 -

(57) Abstract:

The invention relates to the field of chemistry, particularly the proton pump inhibitors. Describes benzimidazole derivatives:

Het₁-X-S(O)-Het₂,

where Het₁has the structure

X has the structure

Het₂has the structure

R₁, R₂and R₃independently selected from hydrogen, alkyl containing 1-10 carbon atoms, fluoro-substituted alkyl containing 1-10 carbon atoms, alkoxy with 1-10 carbon atoms and fluorinated alkoxy with 1-10 carbon atoms; R₆to R₉independently selected from hydrogen, alkyl with 1-10 carbon atoms, of halogensubstituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms and halogen-substituted alkoxy with 1-10 carbon atoms; R₁₀denotes hydrogen, alkyl with 1-10 carbon atoms; R₁₅has the formula

in which R₁₇means 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 alkyl of 1-10 carbon atoms, F, Cl, Br, J, NO₂CN, Oxoalkyl, NH₂alkylamino, dialkylamino, where in these Soulkilling, alkylamino and dialkylamino each of the said alkyl group contains 1-10 carbon atoms, carbarnoyl, N-substituted carbarnoyl, alkylsulphonyl with 1-10 carbon atoms, and (alkoxycarbonyl)alkoxygroup in each of these alkoxygroup contain 1-10 carbon atoms, (alkoxycarbonyl)altergroup in each of said alkoxy or alkyl group containing 1-10 carbon atoms, (carbarnoyl)alkoxy with 1-10 carbon atoms, (N-allylcarbamate)alkoxy with 1-10 carbon atoms, (N,N-dialkylamino)alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carbarnoyl)poly(alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carbarnoyl)alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbarnoyl]alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbarnoyl]alkoxy with 1-10 carbon atoms, [N-(substituted aryl)carbarnoyl]alkoxy with 1-10 carbon atoms, and poly(alkoxy)group in each of the specified alkoxygroup contains 1-10 carbon atoms, cyclic polyalkoxy, guanidinium, raidgroup, dialkylamino-poly(alkoxy)group, [N-(carbamoylmethyl)carbarnoyl]alkoxy, [N-(carbamoyl]alkyl]carbarnoyl]alkoxy, (sulfonato)alkyl, (sulfonato)alkoxy, [N-(sulfonate)alkyl]amido, (substituted)maleimido-, (substituted)succinimide, [(three-alkyl)ammonium]alkoxy; and R₂₁means (aryl)alkyl, (heteroaryl)alkyl, phenyl, naphthyl or heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and these phenyl, naftalina or heteroaryl groups are substituted or unsubstituted 1-5 groups R₁₇or pharmaceutically acceptable salts of these compounds. Also describes pharmaceutical compositions based on derivatives of benzimidazole. The technical result obtained new compounds with useful biological properties. 9 C. and 7 C.p. f-crystals, 4 PL.

The scope to which the invention relates

This invention relates to prodrugs of proton pump inhibitors, used as antiulcer agents. More specifically, this invention relates to prodrugs, which are slowly hydrolyzed, giving the proton pump inhibitors, which inhibit exogenous or endogenous secretion “stomach” (hydrochloric) acid and, therefore, can be used for the prevention and treatment of inflammatory diseases of the gastro-intestinal is benzimidazole, designed for the inhibition of acid secretion in the stomach, are described in U.S. Patents№4045563, 4255431, 4628098, 4686230, 4758579, 4965269, 5021433, 5430042 and 5708017. Inhibitors of acid secretion in the stomach benzimidazole type of work due to endure rearrangement with the formation of teofilina particles, which are then covalently associated with gastric H,K-ATPase, an enzyme involved in the final stages of formation of the proton in the parietal cells and thus inhibit the enzyme. Compounds that inhibit gastric enzyme H,K-ATPase, well-known in this area as “proton pump inhibitors (PPI).

Some of benzimidazole compounds able to inhibit gastric H,K-ATPase, have found practical application as drugs in medicine and is known under names such as lansoprazole (LANSOPRAZOLE, U.S. Patent 4628098), omeprazole (OMEPRAZOLE, U.S. Patent 4255431 and 5693818), pantoprazole (PANTOPRAZOLE, U.S. Patent 4758579) and rabeprazole (RABEPRAZOLE, U.S. Patent 5045552). Diseases that are treated with proton pump inhibitors and specifically the four above-mentioned pharmaceutical preparations include, among others, peptic ulcer, thermal burn, reflux esophagitis, erosive esophagitis, neyazvennoi the traditional pump is a step forward in the field of medicine and veterinary medicine, in General, they are not without weaknesses or deficiencies. The disadvantages of the currently used drugs type of proton pump inhibitors (PPI) can be best explained if a more detailed description of the method steps of the disease or condition under which they are applied, and the circumstances of their application. Thus, diseases caused by acid include, without limitation, erosive esophagitis, gastro-oesophageal reflux, gastric ulcer and duodenal ulcer, non-ulcer dyspepsia and Helicobacter pylori infection. Modern therapy of all diseases, except bacterial infection N. pylori, includes the use of drugs to suppress secretion; the above proton pump inhibitors are one type of such medicines.

Currently used proton pump inhibitors are paradimethylaminobenzaldehyde (or compounds of similar structure) with PK_and4,0-5,0. The mechanism of action requires accumulation in the acid space of the parietal cells (secretory canadian, pH 1.0) and subsequent catalyzed by hydrogen ion transformations in reactive teofilina particles, the method is Tim mechanism currently used drugs type PPI require special protection to the stomach, to remain active for absorption in the duodenum. For this reason, and because of the sensitivity to decomposition in the acidic environment of the stomach receptors PPI drugs for oral administration is usually covered intersolubility shell. The need for intersolubility shell is a disadvantage, because intersolubility shell road and moisture sensitive.

Due to the requirements of accumulation in the acid space of the parietal cell acid secretion is necessary for the effectiveness of drugs type of PPI. It was found that the half-period of the existence of these drugs in plasma is 60-90 minutes. All the acid pumps are not active at any time, probably only about 75% active average over time, when lekarstvennyy the drug is in the blood after oral intake. Also experimentally found that when the currently used treatment - oral once daily - maximum inhibition of stimulated acid is about 66%. This is caused by a combination of short-time existence of a medicinal product, a limited number of acid pumps, active during the presentation of Lech is the substance of the secretion of acid in the nighttime when evening oral administration, since the drug disappears from the plasma over time, the secretion of acid is set after midnight. Ideal for healing when caused by acid diseases and for treatment of infections of N. pylori (in combination with antibiotics), as well as to relieve symptoms of non-ulcer dyspepsia would be a complete inhibition of acid secretion. In the case of the currently used drugs type PPI this is achieved only by intravenous infusion; in the case of the drug OMEPRAZOLE (omeprazole) for this you need an intravenous infusion of 8 mg per hour. It is clear that the technique requires the drug or drugs that act on the mechanism of PPI drugs that reach complete inhibition or near complete inhibition of acid secretion when administered orally.

Oral modern dosage forms currently used drugs type of PPI is achieved partial inhibition of the secretion of acid and less than 24 hours, 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 the cells on the surface of the intestine is about 72 hours. Nesomnenno that prolonged healing time these preparationyou emphasizes the need for the drug or drugs, acting on the mechanism of PPI drugs, which would allow to achieve complete inhibition of acid secretion in oral or close to it.

As another comment on the merits of the region, to which the invention relates, applicants propose a General concept of prodrugs, which are well known in the art. Prodrugs are derivatives of drugs, which, after introduction into the body become physiologically active form. The transformation can be spontaneous, such as hydrolysis in physiological environment, or may kataliziruetsa enzymes. From a large volume of scientific literature on the prodrugs in General, the following examples: Design of Prodrugs (H. Bundgaard 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.) Chem. Abstracts 123, 17593b (Thomson et al.).

As far as we know atento US describe the connection which may act as prodrugs of certain proton pump inhibitors. Specifically, U.S. Patent No. 4686230 (Rainer et al.) describes derivatives of paradimethylaminobenzaldehyde, which include the group denoted by R₅when one of the benzimidazole nitrogen atoms, R₅the group is expected cleaved in ambient conditions or under the action of the enzyme, giving the corresponding compound with a free N-H bond (see section 3 of U.S. Patent No. 4686230). U.S. patent No. 5021433 (Alminger et al.), 4045563 (Berntsson et al.), 4965269 (Brznbstrxm et al.) also describe paradimethylaminobenzaldehyde in which one nitrogen atom of benzimidazole fragment carries the Deputy, which is cleaved under the influence of the environment or enzyme.

This invention represents a contribution in this area of technology, as it encompasses prodrugs of the best structure for medicines type of proton pump inhibitors and include evidence of the suitability of the prodrugs according to the invention for use as prodrugs of proton pump inhibitors with increased effectiveness in treatment caused by acid of diseases caused by prolonged lifetime inhibitors proton us the uly 1

Het₁-X-S(O)-Het₂,

in which Het₁choose from the formulas shown below:

X is selected from formulas

and Het₂choose from formulas

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

R₁, R₂and R₃independently selected from hydrogen, alkyl containing 1-10 carbon atoms, fluoro-substituted alkyl containing 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, fluorinated alkoxy with 1-10 carbon atoms, alkylthio with 1-10 carbon atoms, fluoro-substituted, alkylthio with 1-10 carbon atoms, alkoxyalkyl with 2-10 carbon atoms, alkylamino, dialkylamino containing each of the alkyl groups mentioned alkylamino and dialkylamino 1-10 carbon atoms, halogen, phenyl, alkyl substituted phenyl, alkoxy-substituted phenyl, funeralcare, and each of the alkyl groups in the above substituted phenyl, the alkoxy-substituted phenyl, funeralcare contains 1-10 carbon atoms, piperidino, morpholino or two of R₁, R₂and R₃groups together forming a 5 - or 6-membered cycle containing 0 or 1 gettername atoms, fluoro-substituted alkyl with 1-10 carbon atoms, phenylalkyl, naphtylamine and heteroalkyl, and alkyl in the above phenylalaninol, naphthylamines and heteroalkyl group contains 1-10 carbon atoms;

R₆means hydrogen, halogen, alkyl with 1-10 carbon atoms, fluoro-substituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms or fluorinated alkoxy with 1-10 carbon atoms;

with R₆to R₉independently selected from hydrogen, halogen, alkyl with 1-10 carbon atoms, of halogensubstituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms, halogen-substituted alkoxy with 1-10 carbon atoms, alkylsulphonyl, alkoxycarbonyl, and an alkyl group in the specified alkylcarboxylic and alkoxycarbonyl contains 1-10 carbon atoms, oxazolyl, imidazolyl, thiazolyl, morpholinyl, piperazinil, pyrazinyl, pyrazolyl or any two adjacent substituent groups R₆-R₉can form a loop, which, optionally, may include a heteroatom selected from N, S and O, and this cycle may in addition be substituted;

R₁₀denotes hydrogen, alkyl with 1-10 carbon atoms, or R₁₀moored, halogen, alkyl with 1-10 carbon atoms and of halogensubstituted alkyl with 1-10 carbon atoms;

R₁₅choose from the following formula:

where R₁₆means 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 R₁₇groups;

R₁₇means 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, NO₂CN, Oxoalkyl, NH₂alkylamino, dialkylamino, where in these Soulkilling, alkylamino and dialkylamino each of the said alkyl group contains 1-10 carbon atoms, in addition, R₁₇means ureido (RNHCONH-), guanidines, carbarnoyl, N-substituted carbarnoyl, alkylsulphonyl with 1-10 carbon atoms, with carbonyl)altergroup in each of said alkoxy or alkyl group containing 1-10 carbon atoms, (carbarnoyl)alkoxy with 1-10 carbon atoms, (N-allylcarbamate)alkoxy with 1-10 carbon atoms, (N,N-dialkylamino)alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carbarnoyl)poly(alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carbarnoyl)alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbarnoyl]alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbarnoyl]alkoxy with 1-10 carbon atoms, [N-(heteroaryl)carbarnoyl]alkoxy with 1-10 carbon atoms, [N-(substituted aryl)carbarnoyl]alkoxy with 1-10 carbon atoms, and poly(alkoxy)group in each of the specified alkoxygroup contain 1-10 carbon atoms, cyclic polyalkoxy (such as a fragment of the crown ether), guanidinium, raidgroup, dialkylamino-poly(alkoxy)group, [N-(carbamoylmethyl)carbarnoyl]alkoxy, [N-(carbamoylmethyl)carbarnoyl]alkyl, [N-[[N-(heteroaryl)carbarnoyl]alkyl]carbarnoyl]alkoxy, [N-[[N-(substituted heteroaryl)carbarnoyl]alkyl]carbarnoyl]alkoxy, [(three-alkyl)ammonium]alkoxy, (sulfonato)alkyl, (sulfonato)alkoxy, [N-(sulfonate)alkyl]amido, (substituted)maleimido-, (substituted)succinimido;

R₁₈independently selected from H, alkyl with 1-10 carbon atoms and phenyl;

R₁₉and R₂₀₁₉and R₂₀together with the N atom form a 4-10-membered cycle which may contain one heteroatom selected from N, O or S, with the specified N-heteroatom is unsubstituted or substituted alkyl group with 1-10 carbon atoms or aryl or heteroaryl group,

R₂₁means alkyl, (aryl)alkyl, (heteroaryl)alkyl, phenyl, naphthyl or heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and these phenyl, naftalina or heteroaryl groups are substituted or unsubstituted 1-5 groups R₁₇,

Y represents O or =NR₁₆,

or pharmaceutically acceptable salts of these compounds.

Compounds according to the invention are sulfoxidov and have an asymmetric center at the sulfur atom. As pure enantiomers, racemic mixtures and non-equilibrium mixture of the two isomers are included in the scope of this invention. Some compounds according to the invention can contain one or more asymmetric carbon atoms (for example, a branched alkyl group) and some other compounds can have a second sulfoxide group, introducing one asymmetric center at the sulfur atom. Optical isomers, racemates, di prodrugs drug type proton pump inhibitors, applicable for the inhibition of the secretion of acid in the stomach. Compounds according to the invention have increased resistance in the form of tablets or capsules, resistant to acid, have excellent bioavailability and half-life of elimination from plasma, up to 5-6 hours, which is considerably higher than the half-period of the existence of plasma used previously proton pump inhibitors.

Detailed description of the invention

The chemical structure of 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 according to the invention are paradimethylaminobenzaldehyde or compounds of closely related structure, wherein the benzimidazole nitrogen atoms have substituents group (indicated at R₁₅in the formula 1), which is gradually cleaved under physiological conditions and thus gives paradimethylaminobenzaldehyde connection (or connection close structure) with a free N-H group in benzimidazole (or related) fragment. Thus obtained is a splitting of R₁₅group connection then undergoes acid catalyzed over-current protecti and gastric acid. Therefore, new compounds according to this invention containing the group R₁₅are prodrugs of compounds of inhibitorof proton pumps, which also can be represented by formula 1, in which, however, R₁₅the group will denote hydrogen.

From the prodrugs of this invention preferred are those compounds in which paradimethylaminobenzaldehyde or related structure of the fragment is also preferred in the previous technique. In other words, the preferred prodrugs of this invention are prodrugs of the preferred themselves inhibitors of the proton pump.

Now, as to the specific meaning of the symbols in the formula 1, preferred are those compounds according to this invention, in which the fragment labeled Het₁represents a pyridyl having as substituents alkyl, O-alkyl and/or O-alkyl fluoride group. The most preferred substituents in the pyridine fragment, denoted by R₁, R₂and R₃in formula 1, a is CH₃O, CH₃-, CF₃CH₂Oh - and CH₃O(CH₂)₃O-.

The fragment indicated in the formula 1 X HR₁₀group preferably is in a-position to the nitrogen atom in the pyridine fragment. Also preferred compounds where X is an ortho-phenylene or substituted ortho-phenylene; in the most preferred compounds, X represents methylene.

With regard to the group indicated in the formula 1 Het₂this fragment preferably is a substituted benzimidazole. Group R₆-R₉preferably is selected from hydrogen, chlorine and fluorine derivatives of alkoxygroup, with hydrogen, chlorine, CF₂and CH₃About - are even more preferred.

Now, as for the groups denoted by R₁₅in formula 1, the specialists in the art it is obvious that this group represents a new structural feature of this invention. Among the groups R₁₅refer to note to the Formula 1, the preferred arylsulfonyl group (denoted by R₂₁(R₁₇)SOY-, where Y denotes O). In arylsulfonyl groups, aryl fragment (R₂₁) preferably represents a phenyl, a substituted or unsubstituted group R₁₇. When the phenyl group (R₂₁is Samusenko is l, triptoreline, di-(lower alkyl)amino, lower alkoxycarbonyl, ureido (RNHCONH-), guanidines, carbarnoyl, N-substituted carbarnoyl, (N-substituted carbarnoyl)alkyl, di-(lower alkylamino)alkoxy, (morpholine-4-yl)alkoxy, (morpholine-4-yl)polyalkoxy, di-(lower alkylamino)alkyl, poly(alkoxy)alkoxy, cyclic poly(alkoxy), (carbarnoyl)alkoxy, [N-(lower alkyl)carbarnoyl]alkoxy, [N,N-(lower dialkyl)carbarnoyl]alkoxy, (N,N-dialkylamino)alkyl, [N-(heteroaryl)carbarnoyl]alkyl, [N-(heteroaryl)carbarnoyl]alkoxy, [N-(aryl)carbarnoyl]alkoxy, [N-[(N-substituted carbarnoyl)alkyl]carbarnoyl] alkoxy, (sulfonato)alkyl, (sulfonato)alkoxy, [N-(sulfonate)alkyl]amido, (substituted)maleimido-, (substituted)succinimido and [(three-alkyl)ammonium]alkoxy. Even more preferably, when the phenyl group is unsubstituted (R₁₇means H or a substituent in the phenyl (R₂₁) a group selected from Cl, Br, F, methyl, methoxy, trifluoromethyl, triptoreline, dimethylamino, etoxycarbonyl, carbarnoyl, guanidines, ureido, (carbarnoyl)methoxy, [N-(pyridyl)carbarnoyl]methoxy, morpholinyl, (morpholine-4-yl)alkoxy, [(morpholine-4-yl)alkoxy], alkoxy, 2-(dimethylamino)ethoxy, [N-[(carbarnoyl)methyl]carbarnoyl]methoxy, sodium(sulfonato)alkoxy, (trimethylol is only one substituent R₁₇(other than hydrogen) phenyl (R₂₁) fragment, and preferably, when the substituent R₁₇is in position pair (1,4) or meta (1,3) in relation to sulfonylurea (SO₂) group.

In other embodiments, compounds according to the invention is unstable under physiological conditions substituent R₁₅represents sulfonyloxy group indicated in the notes to formula 1 as R₁₆(R₁₇)SO-. The preferred groups for the combination of R₁₆(R₁₇) are the same groups as for the combination of R₂₁(R₁₇even more preferred are phenyl, 4-were, 4-methoxyphenyl and 4-triptoreline. In this drill the lower alkyl or lower alkoxy contains 1 to 6 carbon atoms.

In other embodiments, compounds according to the invention is unstable under physiological conditions substituent R₁₅it forms the basis of manniche denoted by R₁₉R₂₀N-C(R₁₈)₂in connection with formula 1. In these compounds of the type of manniche R₁₈preferably denotes H or lower alkyl, most preferably H or methyl. Group R₁₉R₂₀N preferably represent di-(lower alkyl)amino, N-Succinimidyl, N-morpholinyl, N-piperidino below and denoted respectively by formulas 2 to 8 and 8A:

The most preferred groups for the combination of R₁₉R₂₀N this invention are dimethylamino, N-morpholino and N-piperidinyl.

The most preferred compounds according to the invention are those compounds in which a fragment of the proton pump inhibitor is the same as in the widely used proton pump inhibitors, also known as lansoprazole (LANSOPRAZOLE), omeprazole (OMEPRAZOLE), pantoprazole (PANTOPRAZOLE and rabeprazole (RABEPRAZOLE), in which the group R₁₅represents benzosulfimide group, monosubstituted or 4 (para) or in the 3 (meta) position of CL, Br, F, CH₃CH₃OH, CF₃, CF₃OH, (CH₃)₂N, NH₂CO, NH₂CONH, NH₂C(=NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, poly(alkoxy), PA^+-ABOUT₃S-CH₂CH₂CH₂-OH, X^-(CH₃)₃N⁺CH₂CH₂O- (X denotes an anion such as halogen ion), NH₂COCH₂O, (pyridyl)NHC₂O, NH₂COCH₂, NH₂COCH₂O (CH₃)₂N₂or tO. These compounds depicted by formulas 9, 10, 11 and 12, respectively, where R₁₇* represents the specified Cl,Halina, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, poly(alkoxy), PA^+-ABOUT₃S-CH₂CH₂CH₂-O, X^-(CH₃)₃N⁺CH₂CH₂O- (X denotes an anion such as halogen ion), NH₂COCH₂O, (pyridyl)N₂O NH₂COCH₂, NH₂COCH₂O, (CH₃)₂N₂or tO in position 4 (para) or 3 (meta) of the phenyl ring, and where the numbering in the benzimidazole system shown in formulas. In the formula 10 CH₃About the group can occupy position 5 or 6 in the benzimidazole fragmente, and in the formula 11 CF₂HO group can occupy position 5 or 6 benzimidazole fragment.

Compounds according to the invention include

2-[[(3-chloro-4-morpholine-2-pyridyl)methyl]sulfinil]-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-editio-3-methyl-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

2-[(3-methoxyphenyl)methylsulfinyl]imidazol[5,4-C]pyridine,

2-[(3-methoxyphenyl)methylsulfinyl]imidazol[4,5-C]pyridine

and 2-[(3-methoxyphenyl)matilal the quiet compounds are monosubstituted or in position 4 (pair), or in position 2 (meta) group with substituents Cl, Br, F, CH₃CH₃OH, CF₃, CF₃OH, (CH₃)₂N, NH₂CO, NH₂CONH, NH₂C(=NH)NH, 4-morpholino, 2-(4-morpholinyl)ethoxy, 2-[2-(4-morpholinyl)ethoxy]ethoxy, 3-(4-morpholinyl)propoxy, NH₂PINES₂Oh, (pyridyl)N₂O, NH₂COCH₂, NH₂COCH₂O, (CH₃)₂N₂, PA^+-ABOUT₃S-CH₂CH₂CH₂-OH, (CH₃)₃N⁺CH₂CH₂O - or EtOCO.

Examples of the most preferred in the present compounds according to the invention is as follows:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1-(p-permentantly)-2-[(3-methyl-4-(2’,2’,2’-triptoreline)-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-deformedarse-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

1-(p-methylbenzenesulfonyl)-2-[(3-methyl-4-(2’,2’,2’-triptoreline)-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-deformedarse-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

1-(p-methoxybenzenesulfonyl)-2-[(3-methyl-4-(2’,2’,2’-triptoreline)-2-pyridyl)methylsulfinyl]-1 is ffinal]-1H-benzimidazole,

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

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

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

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

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

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

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

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

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

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

1-("ptx2">

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

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

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

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

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

1-(pyridine-3-sulfonyl)-2-[[(3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(pyridine-3-sulfonyl)-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(pyridine-3-sulfonyl)-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

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

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

N-[4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenyl]urea,

N-[4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl} sulfinil)benzimidazole-1-yl]sulfonyl}phenyl]urea,

N-[4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinil}-5-(deformedarse)-benzimidazole-1-yl]sulfonyl}phenyl]urea,

N-[4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinil}-6-(deformedarse)-benzimidazole-1-yl]sulfonyl}phenyl]urea,

15-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-[(5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-[(6-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl} sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl}sulfinil)benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]Sul is etil]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-{4-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl)methyl}sulfinil)benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

1-[[4-{3-(morpholine-4-yl)propoxy}phenyl]sulfonyl]-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-[[4-{3-(morpholine-4-yl)propoxy}phenyl]sulfonyl]-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

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

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

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-2-[[[(4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

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

1-[2-acetamido-4-methyl-5-triazolylmethyl]-5-methoxy-2-[[(3,5 methyl-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]sulfinil]-1H-benzimidazole,

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

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

1-(thiophene-2-sulfonyl)-2-[[[(4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-(thiophene-2-sulfonyl)-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(thiophene-2-sulfonyl)-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(thiophene-2-sulfonyl)-2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

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

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

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

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

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

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

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

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

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

1-(pyridine-3-sulfonyl]-2-[[(3-methyl-4-methoxypropane-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-[4-(morpholine-4-yl)phenylsulfonyl]-2-[[[(4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-benzazolyl-2-[[(3-chloro-4-morpholine-2-pyridyl)methyl]sulfinil]-5-methoxy-(1H)-benzimidazole,

1-benzazolyl-2-[[[(4-(3-methoxypropane)-3-methyl-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

1-benzazolyl-2-[(shall final]imidazole[4,5-C]pyridine,

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

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

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

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-2-[(3-methoxyphenyl)methylsulfinyl]imidazol[5,4-C]pyridine,

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

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

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

1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[(4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-[[2-{2-(morpholine-4-yl) who ptx2">

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

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

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

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

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

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

Compounds according to the invention, in which the group R₁₅means arylsulfonyl group, can be obtained by the reaction of 2-pyridylmethylamine-1H-benzimidazole derivative (or similar structure compounds containing in the imidazole fragment free NH-group, with arylsulfonamides. In the broad sense of the benzimidazole or close on the structure of the compound that is the source containing the free NH-group, can be represented by formula 1 in which R₁₅means N. Similarly, the reagent arylsulfonate describes formRegion scheme 1 shows a method of obtaining examples of preferred compounds according to the invention by the reaction of 2-pyridylmethylamine-1H-benzimidazole derivative of formula 13 with benzosulphochloride formula 14 in the presence of an appropriate base. The reaction is generally 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 group values of R₁-R₃, R₆-R₉and R₁₇given in the explanation of formula 1. As can be seen from the reaction scheme 1, reaction with benzosulfimide can give two isomeric or tautomeric product depending on the nature and position of substituents R₆-R₉in the benzimidazole fragment. Two isomeric product (which may simply be the tautomers) are shown by formulas 15 and 16.

Derivatives benzosulfimide formula 14 can be obtained by well-known in the art methods.

Experts in the art know that 2-pyridylmethylamine-1H-benzimidazole derivative of formula 13 are well known in the technique as inhibitors of the hydrogen pump and described, for example, in U.S. Patent 4686230 (Rainer et al.) and in published international application WO 97/48380 (Astra Aktiobiolag). The original substances covered by formula 14, include known drugs: lansoprazole (U.S. Patent 4628098), omeprazole (U.S. Patent 4255431 and 5693818), pantoprazole (U.S. Patent 4758579) and rabeprazole (Pacou, for example, as described in U.S. 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 this is not shown in the reaction scheme for producing compounds according to the invention, in which in accordance with the formula 1 R₁₅means R₂₁(C₆H₄)SOY and Y represents =NR₁₆in the reaction with compounds of formula 13 instead of the reagent of formula 14 is used reagent of formula R₂₁(C₆H₄)S(O)(Cl)NR₁₆. The reagent of formula R₂₁(C₆H₄)S(O)(Cl)NR₁₆you can get izvestnimi in the technique of ways, for example, as written in the tutorial, Comprehensive Organic Functional Group Transformations, Volume 7, Editors-in-Chief A. R. Katritzky, O. Meth-Cohn and C. W. Rees (Pergamon).

Instead of the free benzimidazole compounds of formula 13 in the reaction with a derivative of benzosulfimide (vinylsulfonylacetamido) formula 14 you can use the corresponding salts, such as salts of sodium, potassium, magnesium (and others), also getting examples of compounds according to the invention corresponding to formula 15 and 16.

In reaction scheme 2 shows an alternative method of obtaining the examples connected phenylbenzimidazole-2-pyridylmethylene compounds of formulas 17 and 18 in the respective sulfoxidov. Specialists in the art will see that the formulas 17 and 18 depict isomeric compounds, which may be different or identical (tautomers), depending on the nature and position of substituents R₆-R₉. The oxidation can be carried out in a known technique oxidants used to obtain sulfoxidov, such as hydrogen peroxide, m-chloroperoxybenzoic acid and iodosobenzene can serve this purpose. The oxidation reaction is usually carried out in a neutral aprotic solvent such as methylene chloride. Sulfides of formulas 17 and 18 can be obtained by benzolsulfonate (by analogy with the reaction of scheme 1) sulphides containing free benzimidazole NH-group, or their respective salts. Last sulfides (formula 17) and (18) can be obtained known in the art methods.

Compounds according to the invention, where physiologically unstable group R₁₅is R₁₆(R₁₇)SO(sulfinil) by the formula 1, can be obtained by reactions analogous to reaction scheme 1, except that instead of arylsulfonamides used arylsulfonate formula R₁₆(R₁₇)SOCl. The reaction arylsulfonate usually carried out in the presence of organic >R₁₇)SOCl can be obtained from the appropriate sulfinol acid or salt of formula R₁₆(R₁₇)SO₂Na treatment with thionyl chloride. View full analogy with the reactions of sulfonylurea scheme 1 reaction sulfanilamide not shown in the diagram.

Compounds according to the invention, in which the physiologically unstable group R₁₅together with 2-pyridylmethylamine-1H-benzimidazole derivative (or similar structure compounds) form the basis of manniche, you can get in terms of widely used and known in the art to obtain manniche. Description of the specific conditions obtaining prodrugs type of manniche given in the article Bundgaard et al. in Methods in Enzymology 112, pp.347-359. Getting prodrugs type of manniche according to this invention includes heating a mixture of an amine of formula R₁₉R₂₀NH with aldehyde or ketone of the formula OC(R₁₈)₂in alcohol, water, dioxane or other suitable solvent. The meaning of the symbols is given in the explanation of formula 1.

Reaction scheme 3 illustrates the receive data in the examples of compounds of the type of manniche according to the invention derived from 2-pyridylmethylamine-1H-benzimidazole of formula 13 with formaldehyde't give two isomeric product formulas 19 and 20, respectively. Two products can be identical (tautomeric) depending on the nature and position of substituents R₆-R₉.

The compounds of formula 19 and formula 20 can be obtained, and preferably get an alternative method involving the reaction of N-geometrically sodium salt of the compounds of formula 13 or tetramoriini salt of the compounds of formula 13 with a compound of formula 13 in the presence of tert.-the butyl sodium. N-chlorotrianisene received as described Boehme et al. (Chemische Berichte, vol. 93, pp. 1305-1309 (1960) and Chemische Berichte, vol. 95, pp. 1849-1858 (1962)) and the salt of the Tetra(alkyl)ammonium of formula 13 was obtained by the method described in U.S. Patent 5021433. For example, tetrabutylammonium salt of 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-5-methoxy-1H-benzimidazole receive as described in U.S. Patent 5021433 and used in situ. Tetrabutylammonium salt of 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-5-methoxy-1H-benzimidazole is reacted with 1-chloromethyl-N,N-dimethylamine in methylene chloride with the formation of a mixture of 1-(N,N-dimethylamino)methyl-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-5-methoxy-1H-benzimidazole and 1-(N,N-dimethylamino)methyl-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl] sulfinil]-6-methoxy-1H-benzimidazole. 1-(Heteroaryl-N-MEM. For example, a mixture of 1-(benzotriazol-1-yl)methyl-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-5-methoxy-1H-benzimidazole and 1-(benzotriazol-1-yl)methyl-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-6-methoxy-1H-benzimidazole obtained by reaction of the sodium salt of 2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-5-methoxy-1H-benzimidazole with 1-chloromethyl-1H-benzotriazole.

Another method of preparing compounds of formula 19 and formula 20 is a 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 receive according to the method described in the European patent 279149 (Alminger et al.). For example, a mixture of 1-chloromethyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-chloromethyl-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinil]-1H-benzimidazole is reacted with morpholine, giving a mixture of 1-(morpholine-4-yl)methyl-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(morpholine-4-yl)methyl-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinil]-1H-benzimidazole.

A significant advantage of seediness, spontaneously hydrolyses in mammals (including humans). The hydrolysis can be carried out chemically or enzymatically. Since the compounds according to this invention spontaneously secrete an active form of drugs - proton pump inhibitors - hydrolysis in vivo, it is possible to achieve a longer existence medicinal substance in the body in an effective concentration. Therefore, the compounds of this invention are prodrugs that are converted to active drug substances, hydrolyses in the body that provides the prolongation of the effective concentration. The duration of the inhibitory activity due to spontaneous hydrolysis of the compounds according to this invention provides a more effective inhibition of acid secretion in the stomach, which gives the opportunity to better treat due to the acid of the disease. Compounds according to this invention can be input for the inhibition of secretion (hydrochloric) acid in the stomach orally. 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 dosage is the organisations according to the invention is mixed with pharmaceutically acceptable excipients, which are the true well-known in the art. Specifically, the drug for the systematic introduction can be prepared in the form of powder, pills, tablets, or so on, or in the form of a syrup or elixir suitable for oral administration. The description of the substances commonly used for the preparation of tablets, powders, pills, syrups and elixirs can be found in some books and textbooks, are well known in the art, for example in Remington''s Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pennsylvania.

Compounds according to this invention can be combined with a number of well-known proton pump inhibitors such as LANSOPRAZOLE, OMEPRAZOLE, PANTOPRAZOLE or RABEPRAZOLE, creating a combination of drug-prodrug, and this combination can be entered for the inhibition of the secretion of acid in the stomach. I.e., the first proton pump inhibitor (drug) inhibits the secretion of acid in the stomach of a patient. The above-mentioned and widely used proton pump inhibitors have a half-life of elimination from plasma 60-90 minutes. As the effective concentration of the proton pump inhibitor (drug substance) is reduced due to metabolism, the compounds of this izobreteniya in mammals, including humans.

The lack of modern proton pump inhibitors is that for therapy by injection in liquid form, they must be reconstituted from lyophilized powder in an environment with a high pH value of about 9.5. Prodrugs of this invention overcome the disadvantages of requiring the environment to play (reconstruction) with such a high pH value, as compounds according to this invention can be recreated in the form of injectable fluid environment with an approximate pH value of 6.0 to 8.5. Specialist in the art will quickly appreciate that for introduction into liquid form as an injection liquid, which recreates the medicinal substance is a pharmaceutically priemlemim aqueous solution, which is itself known in the art. Such pharmaceutically acceptable solutions used for the introduction of drugs in injectable form, as described, for example, in the textbook of Pharmaceutical Dosage Forms Parenteral Medications, Volume 1, Edited by K. E. Avis, H. A. Lieberman and L. Lachman (1992)).

Among the advantages of drug type pre-proton pump inhibitors (P-PPI) in this invention is their ability to more effectively treat erosive esophagitis and less severe less severe reflux reflux disease) requires the prevention of reflux of stomach contents at pH 3.0 and even at lower pH values. Modern medicines PPI-drugs allow deviation acidity to pH<2, several times a day, resulting in moderate and weak intensity decrease symptoms. But healing requires increasing the pH to >4.0 for about 16 hours or more. If, as in modern conventional PPI-turalei, in the other 8 hours is episodic acidity pH 3.0 or below, patients continue to complain of pain. More effective and more prolonged acid suppression drugs according to this invention leads, apparently, to a much better treatment of this disease, as well as more rapid healing due to acid erosion and all ulcers.

Medicinal substances such pre-proton pump inhibitors (P-PPI) according to this invention provide the possibility of improved dual therapy for the destruction of N. pylori. Synergies PPI-dependent cell division antibiotics, such as amoxicillin (biosynthesis of cell walls) and clarithromycin (protein synthesis), increases the pH of the surface of the stomach, which allows greater part of the population of bacteria under division during the presentation of the antibiotic of the stomach cavity. However, their action proton pump (P-PPI) according to this invention can continuously increase the value of the pH inside the stomach to neutral with modern treatment with taking once a day. Therefore, it is expected 100% destruction of bacteria in dual therapy prodrugs according to the invention (for example, a prodrug of omeprazole according to the invention) plus an effective antibiotic, such as amoxicillin.

Even monotherapy for the destruction of H. pylori, apparently, successful drug substances such as pre-proton pump inhibitors (P-PPI) according to this invention. In the absence of acid enzyme of H. pylori urease increases the pH to >8,3 that is toxic to the body. PPI in modern recipe inhibit the growth or presence of the body in the cavity due to the increase in value internalnode pH to neutral. The increase within 24 hours the pH to neutral, which is achieved by means of drugs in this invention, apparently, leads to a “self-liquidation” of bacteria.

About 30% of patients gastrointestinal disorders have symptoms without measurable underlying disease (non-ulcer dyspepsia). The most likely cause of these symptoms is increased gastro-intestinal afferent nerve sensitivity to “stomach” the acid. Only the elimination of the acid removes the (easier) these symptoms, and this can be achieved is Ana with specific examples. Some compounds according to the invention were tested using one or more tests that demonstrate gastric antisecretory activity. Compounds according to the invention is not directly inhibited K⁺dependent ATP-hydrolysis gastric H,K-ATPase. However, after hydrolysis of the compounds of this invention were strong inhibitors of the activity of the gastric H,K-ATPase. This is consistent with the known fact that the compounds obtained by hydrolysis, such as lansoprazole, omeprazole, pantoprazole and rabeprazole, are well-known inhibitors of H,K-ATPase. For example, 1-benzazolyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole was tested for inhibitory activity of gastric H,K-ATPase. First, this compound does not inhibit gastric H,K-ATPase. However, the activity of the gastric H,K-ATPase inhibited spontaneous as the flow of hydrolysis of this compound in aqueous solution at pH 7.4. After hydrolysis in the course of 5.75 h at pH 7.4, the connection is inhibited 91% of the activity of the gastric H,K-ATPase, as well as 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (OMEPRAZOLE), which was a product of the hydrolysis. It was found that 1-benzo is si-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (omeprazole) with a half-life existence (t_1/2) 30,5 hour at C and pH 7.4.

When a mixture of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide and 2-{4-[(6-methoxy-2-([(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide administered orally to male rats, 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole (omeprazole) nepreryvno stood in 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]-sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide. As a control, when OMEPRAZOLE was administered to male rats, OMEPRAZOLE completely disappeared from plasma for 1.5 hours. The bioavailability of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide was higher than the bioavailability omeprazole by oral administration.

When a mixture of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide and 2-{4-[(6-metocean was administered to male rats, the secretion of acid in the stomach markedly and continuously inhibited. 5 hours after oral administration of the mixture of 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]-sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide gave a maximum of 90% inhibition of the secretion of gastric acid stimulated by histamine, whereas OMEPRAZOLE was given only 45% inhibition. It was reported that the yield of 50-60% inhibition of gastric acid was achieved in 4 to 6 hours after intravenous administration of OMEPRAZOLE (Katashima et al., Drug metabolism and Disposition, vol. 23, 718-723, 1995). Perhaps a lower degree (45%) inhibition of gastric acid after administration of OMEPRAZOLE in this experiment compared with the data (50-60%) reported Katashima et al. caused by the difference in the way of introduction. However, it is well known that the efficacy of OMEPRAZOLE when administered orally without intersolubility shell is significantly lower than with intravenous or intradermal both in rats and in dogs (Larsson et al., Scand. J. Gastroenterology; vol. 20 (suppl. 108), 23-25, 1985). Compounds according to this invention do not require intersolubility shell for sesitive inhibition of pancreatic secretion of acid. The maximum inhibition obtained with compounds 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]-sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide after 5 hours, shows that the compounds according to the invention is continuously transformed in vivo into the corresponding PPI, which inhibit the secretion of gastric acid.

Description of the specific variants of the invention and experiment

The intermediate compounds

The standard example 1: Obtain [(morpholine-4-yl)alkoxy]benzene-4-sulfonyl chloride

[(Morpholine-4-yl)alkoxy]benzene-4-sulfonyl chloride is produced by chlorosulfonylisocyanate 4-[(phenoxy)alkoxy]research using chlorosulfonic acid in the presence of methylene chloride or chloroform. In this reaction, the chloroform or methylene chloride is necessary in order to avoid cleavage of the ether link alkoxybenzenes fragment chlorosulfonic acid.

[3-(Morpholine-4-yl)propoxy]benzene-4-sulfonyl chloride is produced by chlorosulfonylisocyanate 4-(3-phenoxypropan)of the research using chloral the l) N-(3-phenoxypropan)the research in 20 ml of chloroform added slowly at-10C 2 ml of chlorosulfonic acid (30 mmol) and stirred for 30 minutes The reaction mixture was stirred at room temperature for 5 hours. The chloroform is distilled off from the lower layer. The bottom layer is treated with crushed ice to obtain a solid residue. To a mixture of ice and the solid product add 10 g of sodium phosphate (trehosnovnogo) and stirred while cooling. Chlorosulfonyl compound is extracted with methylene chloride (300 ml). Extract methylene chloride dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Obtain 1.6 g of [3-(morpholine-4-yl)propoxy]benzene-4-sulfonyl chloride.

[2-(Morpholine-4-yl)ethoxy]benzene-4-sulfonyl chloride is obtained using N-(2-phenoxyethyl)the research on reactions similar to those described above. For example, 7.2 g of HCl salt of N-(2-phenoxyethyl)of the research re-suspended in 20 ml of methylene chloride and slowly introducing 7 ml of chlorosulfonic acid, cooling jacket with ice. The reaction mixture is stirred at 0C for 2 h, then at room temperature overnight. The reaction mixture was added methylene chloride (350 ml) and decompose the excess chlorosulfonic acid by adding Lesnoy water (about 100 grams). The aqueous layer was adjusted to pH 8.5 with concentrated solution of sodium carbonate when cooled eh what of 8.1 g of [2-(morpholine-4-yl)ethoxy]benzene-4-sulfonyl chloride. So pl. 48-50C.

N-(2-Phenoxyethyl)morpholine receive a modified method Grail et al. (Journal of American Chemistry Society, 1952, 74, 1313-1315). For example, 9.2 grams of phenol and 18.6 g of the HCl salt of N-(2-chloroethyl)the research is dissolved in 120 ml of isopropanol and added under cooling 12 g of potassium hydroxide. The reaction mixture is refluxed for 12 hours. A solid residue (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). Layer methylene chloride again washed with a solution of 0.1 N sodium carbonate in 10% NaCl solution. The layer of methylene chloride dried over anhydrous magnesium chloride and evaporated under reduced pressure. The remaining syrup was dissolved in 100 ml of 1.5 N Hcl solution and washed with 100 ml of chloroform. The aqueous layer was treated with 100 ml of toluene and remove the water by distillation in the apparatus of the Dean-stark. The remaining toluene layer is cooled to obtain a crystalline residue, which is separated by filtration. Obtain 12 g of the HCl salt of N-[(2-phenoxy)ethyl]the research (yield 50%).

N-[3-Phenoxy)propyl]morpholine is obtained by reaction of 3-(phenoxy)propyl bromide with morpholine. For example, 3-(phenoxy)propyl bromide (7.8 ml, 50 mmol) is added to morpholine (8 ml) in Nichelino refluxed for 4 hours. The toluene is removed by distillation under reduced pressure. The residue is treated with methylene chloride (200 ml) and water (200 ml). Layer methylene chloride, dried and concentrated. The residue is treated with a mixture of methylene chloride-heptane to obtain 4-[3-phenoxy)propyl]the research.

[2-{2-(Morpholine-4-yl)ethoxy}ethoxy]benzene-4-sulfonyl chloride is obtained using 4-[2-[2-(phenoxy)ethoxy]ethyl]the research on reactions similar to those described above. For example, 2-(phenoxy)ethanol (4.0 ml) is added to 5.5 g of the hydrochloride of N-(2-chloroethyl)the research and 6 g of tert.-butoxide of sodium in 70 ml of toluene. The reaction mixture is refluxed for 16 hours. Add EtOAc (100 ml) and washed with water (200 ml). The organic layer was separated and again extracted with 0.5 N Hcl solution (120 ml). The aqueous layer was again washed with chloroform (30 ml), then bring the pH to 10.5 by the addition of NaOH solution. The product, [2-[2-(morpholine-4-yl)ethoxy]ethoxy]benzene, extracted from the water methylene chloride (200 ml). The organic layer is washed again with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product, [2-[2-(morpholine-4-yl)ethoxy]ethoxy]benzene, obtained as a yellow syrup (5,4 g). TLC analysis shows 99% purity, and the structure is confirmed with panel chloride.

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

The standard example 2: Obtain [2-(dimethylamino)ethoxy]phenyl-4-sulfonyl chloride

2 g of N,N-dimethyl-N-[(2-phenoxy)ethyl]amine dissolved in 10 ml of methylene chloride and slowly while cooling with ice add 3 ml of chlorosulfonic acid. The mixture is stirred at room temperature for 3 hours and poured on ice. Add methylene chloride (100 ml) and the aqueous layer was neutralized with concentrated sodium carbonate solution, maintaining the temperature at 4C. Layer x(dimethylamino)ethoxy]phenyl-4-sulfonyl chloride.

The standard example 3: Obtaining N-[4-(chlorosulfonyl)phenyl]urea

N-[4-Chlorosulfonyl)phenyl]urea receive 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) is added to urea (2.7 g) in the bath with ice, then heated at 60C for 3 hours. The syrup is poured with good stirring on crushed ice. The solid precipitate was separated and dried in vacuum. Get 2,3, T. pl. 138-S.

The standard example 4: Obtaining N-[(p-chlorosulfonyl)phenyl]research

N-[(p-Chlorosulfonyl)phenyl]morpholine synthesized by a modified method 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 while cooling jacket with ice. The reaction mixture is stirred at the boil under reflux for 7 hours. The brown syrup was poured with stirring in methylene chloride (150 ml) and crushed ice (100 g) and neutralized with saturated sodium phosphate, trehosnovnoy, cooling bath with ice. Separate the layer of methylene chloride, dried over anhydrous magnesium sulfate. The organic solvent evaporated under LASS="ptx2">

The standard example 5: Receiving pyridine-3-sulphonylchloride

Pyridine-3-sulphonylchloride get method 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 petaluridae phosphorus is added to a suspension of 15 g of pyridine-3-sulfonic acid in 30 ml of phosphorus oxychloride and heated at 120C for 12 hours. The reaction mixture is concentrated by distillation under reduced pressure and treated with toluene. The obtained solid residue is collected and dried in vacuum. Obtain 16.7 g of product. So square 138-S.

The standard example 6: Obtain m-(chlorosulfonyl)benzo-15-crown-5-ether

It chilled with ice to a solution of benzo-15-crown-5-ether (53,6 mg, 2 mmol) in 5 ml of chloroform added slowly while cooling bath of ice 0.3 ml of chlorosulfonic acid (4.5 mmol). The reaction mixture was stirred in a bath with ice for 2 hours and then 5 hours at room temperature. The reaction mixture is poured on crushed ice and extracted with methylene chloride (50 ml). The combined organic layer is dried over magnesium chloride and evaporated. Get 374 mg of the product. So pl. 79-S.

m-(Chlorosulfonyl)benzo-15-crown-5-ether get, using the methodology described above. A yield of about 46%. So pl. 1082 g of the HCl salt of 2-(phenoxyacetyl)aminopyridine (5 mmol), re-suspended in 10 ml of methylene chloride and added dropwise while cooling in an ice bath to 2 ml of chlorosulfonic acid with the formation of a transparent solution. The solution was stirred at room temperature for 3 hours. The reaction mixture was poured with good stirring into ice-cold water to obtain white solids. The precipitate is filtered off, washed with acetonitrile and dried in vacuum. Obtain 0.65 g of solid substance. So pl. 170-C (with decomposition).

The standard example 8: obtain the HCl-salt of N-[n-(chlorosulfonyl)phenylmethyl]-N,N-dimethylamine

1.5 ml of N,N-dimethylbenzylamine (10 mmol) dissolved in 6 ml of methylene chloride and added dropwise while cooling in an ice bath to 2 ml of chlorosulfonic acid. The reaction mixture is heated at 40 ° C for 40 min and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and poured on ice to obtain a solid precipitate, which is collected and dried in vacuum. Obtain 1.6 g (59,2%) of the HCl salt of N-[n-(chlorosulfonyl)phenylmethyl]-N,N-dimethylamine.

The standard example 9: Obtain 2-[p-(chlorosulfonyl)phenoxy]-ndimethylacetamide

3.0 g of 2-(phenoxy)ndimethylacetamide dissolved in 10 ml of methylene chloride and slowly at 0C add 6 ml of chlorosulfonic acid. The reaction mixture was stirred at room temperature for 10 hours. Methylene chloride evaporated when onigen is in vacuum. Gain of 3.9 g of the product. So pl. 166-C (with decomposition).

The standard example 10: Obtain N-(p-chlorosulfonylphenyl)-pyridine chloride

p-(Chloromethyl)benzosulphochloride (2.2 g) dissolved in acetonitrile (20 ml) - methylene chloride (20 ml) and added dropwise pyridine (1.9 ml). The reaction mixture is refluxed for 3 hours. Brown syrup is separated from the solvent and lyophilizers in vacuum. Get a reddish-brown product (2.9 g). So pl. 105-S.

The standard example 11: Obtain p-(dimethylamino)benzazolyl chloride

N,N-dimethylaniline (8 ml) was dissolved in 20 ml of chloroform and slowly cooling added chlorosulfonic acid (20 ml). The reaction mixture is refluxed for 6 hours. The reaction mixture is cooled and poured on ice (100 g). Add methylene chloride (120 ml) and the aqueous layer was neutralized with concentrated sodium carbonate solution, maintaining the temperature below 4C. The organic layer is again washed with ice, of 0.1 N sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure. The remaining product is crystallized from a mixture of ethyl ether-heptane with SS="ptx2">

The standard example 12: Obtaining N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]ndimethylacetamide

a) Obtaining N-(carbamoylmethyl)-2-(phenoxy)ndimethylacetamide.

HCl-salt glycinamide (5 g) re-suspended in 200 ml of methylene chloride and 14 ml of triethylamine at 4C. Add slowly with good stirring, phenoxyacetate (6 ml). 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 filter cake is washed with water and dried in vacuum to obtain 7.5 g of the product, N-(carbamoylmethyl)-2-(phenoxy)ndimethylacetamide. The filtrate is washed with water and 0.1 N solution of sodium carbonate. The filtrate is concentrated and treated with ether to obtain additional product, N-(carbamoylmethyl)-2-(phenoxy)ndimethylacetamide. So square 138-140 C.

b) Obtaining N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]ndimethylacetamide.

N-(carbamoylmethyl)-2-(phenoxy)ndimethylacetamide (2,08 g) re suspension in 30 ml of methylene chloride and slowly cooling added chlorosulfonic acid (6 ml). The reaction mixture was stirred at room temperature during the Shem mixing on crushed ice (60 g) with a solid white color, which is separated by filtration and washed with ice water. The solid product is dried in vacuum, obtaining 2,78 g of N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]ndimethylacetamide. So pl. 97-100C (with decomposition).

Example 1

1-Benzazolyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole and 1-benzazolyl-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) was dissolved in 20 ml of methylene chloride and 0,140 ml of triethylamine. The solution is cooled to 0-4C in the bath with ice. Add slowly benzosulphochloride (96 mg, 0.55 mmol) and stirred at 0-4C control by TLC (manifesting the 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 is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue is crystallized from a mixture of methylene chloride-ethyl ether-heptane, getting 127 mg of product. So pl. 87-89S (with decomposition). To the remaining organic layer add Hecht is a mixture of 1-benzazolyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole and 1-benzazolyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (3:2 ratio by NMR).

1H NMR (Dl₃, ): 8,10-of 8.15 (m, 3H), 7,45-7,80 (m, 5H), to 7.0, and 7.1 (m, 1H), 4,8-5,0 (2 kV, AV, total 2H), 3,83 and to 3.92 (2s, total 3H), of 3.75 (s, 3H), 2,31 (s, 3H), of 2.23 (s, 3H).

Method B: a Mixture of 1-benzazolyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole and 1-benzazolyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole obtained by interaction of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole with benzosulphochloride, as described in method A. 1-Benzazolyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole allocate using column chromatography on silica gel and used in the next stage as follows. 1-Benzazolyl-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-20C. Slowly add a solution of methylene chloride (5 ml) containing m-chlormadinone acid (60% purity, quantity, equivalent to 1 mmol). The reaction is controlled 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 is dried over anhydrous magnesium sulfate and concentrate under the Tang, giving 397 mg of product (yield 82%), 1-benzazolyl-5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole and 1-benzazolyl-6-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole.

Examples 2-19

The compounds shown in Examples 2-19 below, obtained using the method As described in Example 1. 2-Paradimethylaminobenzaldehyde compounds interact with the corresponding arylsulfonamides, giving the corresponding 1-arylsulfonyl-2-pyridylmethylamine, which are shown in Table 1 and represented by formula 21:

Example 20

Sodium salt sesquihydrate 5-deformedarse-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (432 mg, 1 mmol) is suspended in 30 ml of methylene chloride in the presence of anhydrous sodium carbonate (100 mg). To the suspension is added 4-chlorobenzenesulfonamide (211 mg, 1 mmol) and stirred at 4C overnight. The organic layer is separated by filtration and concentrated under reduced pressure. The obtained solid residue is crystallized from a mixture of methylene chloride-ethyl ether-heptane. Obtain 417 mg isomers, 1-(4-chlorobenzenesulfonyl)-5-deformedarse the STI-2-pyridyl)methylsulfinyl]-1H-benzimidazole (5:4 ratio by NMR). The yield of 74.5%. So pl. 82-83 C get.

1H NMR (Dl₃, ): 8,05-of 8.15 (m, 2H), and 8.0 (d, 1H), 7,78-7,81 (m, 1H), 7,45-to 7.6 (m, 2H), 7,2-7,3 (m, 1H), 6,80-for 6.81 (d, 1H), 6,5-6,6 (d, 1H), 4,9-5,0 (sq. 2H), 3,93 (s, 3H).

Examples 21-24

The compounds listed in Table 2 and represented by formula 20, is obtained using the method described in Example 20.

Example 25

1-(Pyridine-3-sulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(pyridine-3-sulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-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. Add pyridine-3-sulphonylchloride (195 mg) and stirred in a bath with ice for 3 hours. The layer of methylene chloride was washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium bicarbonate. The layer of methylene chloride dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The obtained residue solidified upon treatment with a mixture of methylene chloride-ethyl ether-heptane, giving 372 mg of product, which is a mixture of 1-(pyridine-3-sulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridi ffinal]-1H-benzimidazole (ratio 3:1 by NMR). So pl. 136-C (with decomposition).

1H NMR (Dl₃, ): of 2.27 (s, 3H), of 2.35 (s, 3H), 3,82 (s, 3H), 3,86, and 3,93 (2s, total 3H), 5,04-5,17 (square AB, 2H), 7,01-7,02 (DD, 1H), 7,47-7,56 (m, 2H), to 7.67-7,71 (d, 1H), 8,15 (s, 1H), 8,51-8,55 (DD, 1H), cent to 8.85-8,88 (d, 1H), 9,34 (s, 1H).

Example 26

1-(Pyridine-3-sulfonyl)-2-[[(3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil]-1H-benzimidazole

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

1H NMR (Dl₃, ): 2,35 (s, 3H), of 4.38 figure-4.49 (q, 2H), 4,98-5,22 (square AB, 2H), 6.73 x (d, 1H), 7,41-7,56 (m, 3H), 7,80-8,02 (DD, 2H), 8,23 (s, 1H), charged 8.52 (DD, 1H), 8,87 (DD, 1H), 9,36 (s, 1H).

Example 27

1-(Pyridine-3-sulfonyl)-5-(diformate-2-pyridyl)methyl]sulfinil]-1H-benzimidazole

5-(Deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole (383 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. Add pyridine-3-sulphonylchloride (195 mg) and stirred in a bath with ice for 5 hours. The layer of methylene chloride was washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M sodium bicarbonate. The layer of methylene chloride dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The obtained residue solidified upon treatment with a mixture of methylene chloride-ethyl ether-heptane, giving 397 mg of a mixture of 1-(pyridine-3-sulfonyl)-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(pyridine-3-sulfonyl)-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole (ratio 3:2 by NMR). So pl. 127-C (with decomposition).

Example 28

Obtaining 1-(morpholine-4-yl)phenylsulphonyl-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(morpholine-4-yl)phenylsulfonyl-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole

270,8 mg of 4-(p-chlorosulfonyl)phenylmorpholine add to 344 mg of 5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole in 20 of the night. The layer of methylene chloride was washed with water and dried over anhydrous magnesium sulfate. The organic layer evaporated. The obtained residue lyophilizer in vacuum to obtain 425 mg of the above product (1:1 ratio by NMR). So pl. 76-C (with decomposition).

Example 29

Obtaining N-[4-[[5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]benzimidazole-1-yl]sulfonyl]phenyl]urea and N-[4-[[6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]benzimidazole-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. Add methylene chloride (20 ml) and washed with water and 0.1 M sodium bicarbonate solution. The organic layer is dried over anhydrous magnesium sulfate and evaporated. The residue is dissolved in 2 ml methylene chloride and add ethyl ether for crystallization. The crystals are separated and dried. Obtain 190 mg of the product. The product is a mixture of N-[4-[[5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]-sulfinil]benzimidazole-1-yl]who were radioactive]phenyl]urea (4:3 ratio by NMR). So pl. 154-C (with decomposition).

1H NMR (Dl₃, ): 2,19 (s, 3H), 2.20 2,321 (2s, total 3H), of 3.69 and 3.70 (2s, total 3H), 3,76, and the 3.89 (2s, total 3H), 4.75 V-4,94 (square AB, 2H), 5,6-5,7 (ush, NH₂,), 6,95-was 7.08 (d, 1H), 7,05 (s, 1H), 7,43-7,86 (m, 5H), to 8.12 (s, 1H), 9,0 (ush, NH).

Example 30

Obtaining N-[4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenyl]urea

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

1H NMR (Dl₃, ): of 2.25 (s, 3H), 4,37 was 4.42 (sq. 2H), 4,6-4,85 (square AB, 2H), to 6.67 (d, 1H), 7,35-7,42 (m, 2H), to 7.61 to 7.75 (m, 3H), 7,89-with 8.05 (m, 2H), 8,27 is 8.38 (m, 2H).

Example 31

Getting 15-[(5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl the l)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]annulene

170 mg of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole and 190 mg m-(chlorosulfonyl)benzo-15-crown-5-ether was 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 is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain a syrup that lyophilizer. Obtain 210 mg of the above product mixture 15-[(5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]annulene and 15-[(6-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl]methyl}sulfinil)-benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]annulene (1:1 ratio by NMR). Lyophilized product is so pl. 76-80 ° C with decomposition.

1H NMR (Dl₃, ): of 2.21 (s, 3H), 2,31 (s, 3H), 3,68-to 3.73 (m, 8H), 3,74 (s, 3H), 3,84-a 3.87 (m, 4H), 3,90 (s, 3H), 4,10-4,13 (m, 4H), 4,81-4,95 (kV, AV, 2H), at 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

Getting 15-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]annulene

2-[[(3-Methyl-4-(2,2,2-triptoreline)-2-pyridyl)m is 190 mg m-(chlorosulfonyl)benzo-15-crown-5-ether. The reaction mixture was stirred at room temperature overnight. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated to obtain a syrup that lyophilizer. Obtain 231 mg of the above product. Lyophilized product is so pl. 76-80 ° C with decomposition.

1H NMR (Dl₃, ): of 2.33 (s, 3H), 3,66-to 3.73 (m, 8H), 3,83-a 3.87 (m, 4H), 4,10-4,12 (m, 4H), 4,35-to 4.41 (q, 2H), 4,84-of 5.05 (square AB, 2H), is 6.61 (d, 1H), 6,86 (d, 1H), 7,37 was 7.45 (m, 2H), 7,56 (s, 1H), 7,71-7,74 (DD, 2H), 7,95 (d, 1H), 8,23 (d, 1H).

EXAMPLE 33

Getting 2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)the ndimethylacetamide

170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)ndimethylacetamide add 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 is dried over anhydrous magnesium sulfate and evaporated. The obtained residue lyophilizer in vacuum with p the-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide and 2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide (2:1 ratio by NMR). So pl. 76-80C.

1H NMR (Dl₃, ): 2.21 and 2.23 to (2s, total 3H), 2,32 (s, 3H), 3,74 and 3.75 (2s, total 3H), 3,83 and 3,93 (2s, total 3H) and 4.65 (s, 2H), a 4.83-4.92 in (sq. AB, 2H), 6,99-7,11 (m, 5H), 7,46 (d, 1H), 7.68 per-7,88 (m, 2H), 8,75 (ush, NH).

Example 34

Getting 2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide

2-[[(3-Methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil]-1H-benzimidazole (185 mg) was dissolved in 20 ml of methylene chloride and 0.2 ml of triethylamine and added to 170 mg of 2-[p-(chlorosulfonyl)-phenoxy]-N-(2-pyridyl)ndimethylacetamide. The reaction mixture is washed with water. The organic layer is dried over anhydrous magnesium sulfate and evaporated. The obtained residue lyophilizer to obtain 237 mg of the above product. So pl. 78-81s with.

1H NMR (CDCl₃, ): 2,31 (s, 3H), 4,34-and 4.40 (q, 2H), 4,71 (s, 2H), 4,84-of 5.05 (square AB, 2H), 6,62 (d, 1H), to 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 (ush, NH).

Example 35

5-(Deformedarse)-2-[[(3,�ylamine and added to 170 mg of 2-[p-(chlorosulfonyl)-phenoxyacetyl]aminopyridine. The reaction mixture is washed with water. The organic layer is dried over anhydrous magnesium sulfate and evaporated. The obtained residue lyophilizer to obtain 187 mg of the above product, which is a mixture 2-{4-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl] phenoxy} ndimethylacetamide and 2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}-benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)ndimethylacetamide (2:1 ratio by NMR). So pl. 95-S.

1H NMR (Dl₃, ): 3,90 (s, 3H), 3,93 (s, 3H), of 4.67 (s, 2H), 4,85-5,00 (square AB, 2H; with equal 1H), from 6.25 to 6.80 (m, 1H), was 7.08 (m, 3H), 7,29-7,40 (d, 1H), 7,58-7,80 (m, 2H), 7,97-8,16 (m, 3H), by 8.22 (d, 1H), 8.30 to (d, 1H), 8,82 (ush, NH).

Example 36

Obtaining 1-[4-(3-(morpholine-4-yl)propoxy)benzazolyl]-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-[4-(3-(morpholine-4-yl)propoxy)benzazolyl]-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole

180 mg of 4-(3-(morpholine-4-yl)propoxy)benzosulfimide added to a solution of 190 mg of 5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole in 10 ml of methylene chloride and 0.5 ml of triethylamine. The reaction mixture was stirred over night and about the products (1:1 ratio by NMR).

Example 37

Obtaining 1-[4-[3-(morpholine-4-yl)propoxy]benzazolyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-[4-[3-(morpholine-4-yl)propoxy]benzazolyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole

2000 mg of 4-[3-(morpholine-4-yl)propoxy]benzosulfimide 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 is concentrated and treated acylovir ether to obtain a solid residue. The solid residue is crystallized from a mixture of methylene chloride and ether. Obtain 210 mg of the above product mixture in the ratio 1:1 5-methoxy and 6-methoxy-compounds. So pl. 98-1 0 2 (decomposition).

1H NMR (Dl₃, ): 1,97-2,05 (m, 2H), 2,09 (s, 3H), of 2.20 (s, 3H), 3,05 is 3.15 (m, 6N), to 3.58 (s, 3H), 3,65-of 3.80 (m, 4H), 3,81, and to 3.92 (2s, total 3H), 3,82-of 3.95 (t, 2H), 4,73-4,94 (kV, AV, 2H), 6,62 (d, 1H), 6.89 in-6,91 (d, 2H), 7,4-7,6 (m, 3H), 7,79 to 8.0 (m, 2H), 8,17 (s, 1H).

Example 38

Obtaining 1-[[(N,N-dimethylamino)methyl]benzene-4-sulfonyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-[[(N,N-dime the CLASS="ptx2">

120 mg of N-[[n-(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 layer of methylene chloride was washed with water and 0.1 N sodium bicarbonate solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue lyophilizer in vacuum to obtain 245 mg of the above product (1:1 ratio by NMR).

Example 39

Obtaining 1-[2-acetamido-4-methyl-5-triazolylmethyl]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]]-1H-benzimidazole and 1-[2-apetito-4-methyl-5-triazolylmethyl]-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 are dissolved in 10 ml of methylene chloride and 0.4 ml of triethylamine and added 128 mg of 2-acetamido-4-methyl-5-thiazolecarboxamide. The reaction mixture was stirred at room temperature for 15 hours. Spot product appears just above the position of the 5-methoxy-2-[(3,5-dimethyl-what nitrile-methanol 100:10:5). The product distinguish using column chromatography on silica gel. Obtain 145 mg of the above product.

Example 40

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

1H NMR (Dl₃, ): of 2.20 (s, 3H), of 2.30 (s, 3H), of 3.73 (s, 3H), 3,83 and 3,91 (2s, total 3H), 4.80 to 4,92, (kV, AV, 2H), 7,00-7,10 (m, 2H), 7,47 (s, 1H), to 7.67-of 7.69 (m, 2H), 7,97-to 7.99 (d, 1H), 8,13 (s, 1H).

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

172 mg of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole are dissolved in 10 ml of methylene chloride and 0.2 ml of triethylamine. Add 95 mg phenylmethylsulfonyl. The reaction mixture was stirred at room temperature for 36 hours. The layer of methylene chloride was washed with water and concentrated under reduced pressure. The obtained residue lyophilizer in vacuum to obtain 205 mg of the above product, a mixture of 1-(phenylmethylsulfonyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(phenylmethylsulfonyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole (ratio 2:1 by NMR). So pl. 130C (with decomposition).

Example 42

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

103 mg of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole was dissolved in 2 ml of chloroform and 0.1 ml of triethylamine. Add slowly to the bath with ice 1-propanesulfonate (0,042 ml). The reaction mixture was stirred at room temperature for 3 hours. Orme magnesium sulfate and concentrated under reduced pressure. The obtained residue solidified upon treatment with a mixture of chloroform-ethyl ether-hexane to obtain 128 mg (95%) of the above product (ratio 3:2). So pl. 96-100C.

Example 43

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

103 mg of 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole was dissolved in 2 ml of chloroform and 0.1 ml of triethylamine. Add slowly to the bath with ice 1-butanesulfonate (0,042 ml). The reaction mixture was stirred at room temperature for 3 hours. The organic layer was washed with cold of 0.1 N sodium bicarbonate solution. The chloroform layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue solidified upon treatment with a mixture of chloroform-ethyl ether-hexane to obtain 130 mg (93%) of the above product (ratio 3:2). So pl. 54-S.

Example 44

Obtaining 1-(isopropylphenyl)-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(isopropylphenyl)-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-p is nil]-1H-benzimidazole was dissolved in 2 ml of chloroform and 0.1 ml of triethylamine. Add slowly in a bath with ice isopropylacetanilide (0,042 ml). The reaction mixture was stirred at room temperature for 24 hours. The organic layer is concentrated under reduced pressure and subjected to column chromatography on silica gel. Allocate 78 mg of the above product (1:1 ratio). So pl. 105-C (with decomposition).

Example 45

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

120 mg of p-(N,N-dimethylamino)benzosulfimide add 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 layer of methylene chloride was washed with water and 0.1 N sodium bicarbonate solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue lyophilizer in vacuum to obtain 215 mg (93%) of the above product (1:1 ratio). So pl. 92-S.

1H AMR-of 6.61 (m, 2N), of 6.96-7,07 (m, 1H), of 7.48 and to 7.68 (2D, total 1H), a 7.85-of 7.90 (m, 3H), by 8.22 (s, 1H).

Example 46

Obtaining N-[4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenyl]urea

128 mg of N-[4-(chlorosulfonyl)phenyl]urea added to 191 mg sodium salt of 2-[(3-methyl-4-methoxypropane-2-pyridyl)methylsulfinyl]-1H-benzimidazole 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. Add methylene chloride (20 ml) and washed with water and 0.1 M sodium bicarbonate solution. The organic layer is dried over bezvadnym magnesium sulfate and evaporated. The residue is dissolved in a minimal amount of acetonitrile and add ethyl ether for crystallization. The crystals are separated and dried. Obtain 190 mg of the above product.

1H NMR (Dl₃, ): 2,03-2,07 (m, 2H), 2,18 (s, 3H), 3,34 (s, 3H), 3,52-of 3.54 (t, 2H), 4,05-4,08 (t, 2H), 4,76-5,00 (kV, AV, 2H), 5,50-5,61 (ush, NH₂), 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

Obtaining 1-(pyridine-3-sulfonyl]-2-[[[3-methyl-4-(3-methoxypropane)-2-pyridyl]methyl]sulfinil]-1H-benzimidazole

100 mg of pyridine-3-sulphonylchloride on the si 0.15 ml of triethylamine and 10 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight. Add methylene chloride (20 ml) and washed with water and 0.1 M sodium bicarbonate solution. The organic layer is dried over anhydrous magnesium sulfate and evaporated. The residue is dissolved in a minimal amount of acetonitrile and add ethyl ether to precipitate. The solid precipitate was separated and dried to obtain 127 mg of the above product.

1H NMR (Dl₃, ): 1,97-2,10 (m, 2H), of 2.21 (s, 3H), at 3.35 (s, 3H), 3,51 is 3.57 (t, 2H), 4.04 the-4,07 (t, 2H), 4,82-5,14 (kV, AV, 2H), 6.73 x (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

Getting 2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenoxy)-N-(2-pyridyl)ndimethylacetamide

170 mg of 2-[p-(chlorosulfonyl)phenoxy]-N-(2-pyridyl)ndimethylacetamide add to 191 mg sodium salt of 2-[[[3-methyl-4-(3-methoxypropane)-2-pyridyl]methyl]sulfinil]-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 is dried over anhydrous magnesium sulfate and evaporated. The obtained residue lyophilizer in vacuum with getting 244 mg of the above produce), with 4.64 (s, 2H), a 4.83-5,02 (square AB, 2H), to 6.67 (d, 1H), 7,07-7,10 (m, 3H), 7,32-7,49 (m, 3H), 7,70-of 7.82 (m, 2H), to 7.99 (d, 1H), 8,14-8,30 (m, 4H), 8,77 (ush, NH).

Example 49

Obtaining 1-[4-(morpholine-4-yl)phenylsulfonyl]-2-[[[(4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole

136 mg of 4-[(p-chlorosulfonyl)phenyl]the research add to 191 mg sodium salt of 2-[[[3-methyl-4-(3-methoxypropane)-2-pyridyl]-methyl]-sulfinil]-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 is dried over bezvadnym magnesium sulfate and evaporated. The obtained residue lyophilizer in vacuum to obtain 224 mg of the above product. So pl. 93-C (with decomposition).

1H NMR (Dl₃, ): 2,02-to 2.06 (m, 2H), and 2.26 (s, 3H), 3,2-3,3 (m, 4H), to 3.35 (s, 3H), 3,50-of 3.53 (t, 2H), 3.75 to of 3.80 (m, 4H), 4.04 the-4,08 (t, 2H), 4,71-4,79 (kV, AV, 2H), of 6.71 (d, 1H), 7,26-7.5 (m, 4H), 7,8 and 8.1 (m, 2H), of 8.27 (d, 1H).

Example 50

Obtaining 1-[{2-(morpholine-4-yl)ethoxy}phenyl-4-sulfonyl]-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole

136 mg of 4-[2-[(p-chlorosulfonyl)phenoxy]ethyl]the research add to 191 mg sodium salt 2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]su the room temperature during the night. The reaction mixture is washed with water. The organic layer is dried over anhydrous magnesium sulfate and evaporated. The obtained residue lyophilizer in vacuum to obtain 234 mg of the above product.

1H NMR (Dl₃, ): 2,05-2,10 (m, 2H), and 2.27 (s, 3H), of 2.56 (m, 4H), 2,79-2,82 (t, 2H), 3,35 (s, 3H), 3,53 of 3.56 (t, 2H), 3,69-and 3.72 (m, 4H), 4,07-4,10 (t, 2H), 4,12-to 4.15 (t, 2H), 4,81-4,99 (kV, AV, 2H), of 6.68 (d, 1H), 6,95 (d, 2N), of 7.36-7,46 (m, 2H), 7,81 (d, 1H), of 8.06 (d, 2H), 8,21 (d, 1H).

Example 51

Obtaining 1-(thiophene-2-sulfonyl)-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole

92 mg of thiophene-2-sulphonylchloride add to 191 mg sodium salt 2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-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 is dried over anhydrous magnesium sulfate and evaporated. The obtained residue lyophilizer in vacuum to obtain 215 mg of the above product. So pl. 147-150C.

1H NMR (Dl₃, ): 2,00-of 2.08 (m, 2H), and 2.27 (s, 3H), at 3.35 (s, 3H), 3,53 of 3.56 (s, 2H), 4,07-4,10 (t, 2H), a 4.83-5,00 (kV, AV, 2H), to 6.67 (d, 1H), 7,08-7,10 (t, 1H), 7,42-7,49 (m, 2H), 7.68 per-of 7.70 (d, 1H), 7,82-to 7.84 (d, 1H), 8,00-8,03 (m, 2H), 8,18 (d, 1H).

Example 52

94 mg of benzosulfimide add to 191 mg sodium salt 2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-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 is dried over anhydrous magnesium sulfate and evaporated. The resulting residue is crystallized from a mixture of acetonitrile-ethyl ester. Obtain 210 mg of the above product. So pl. 126-S.

1H NMR (CDCl₃, ): 1,97-of 2.09 (m, 2H), and 2.27 (s, 3H), 3,34 (s, 3H), 3,52 is 3.57 (t, 3H), 4,05-4,10 (t, 3H), 4,81-5,03 (kV, AV, 2H), 6,66 (d, 1H), 7,38-7,53 (m, 4H), to 7.61-the 7.65 (t, 1H), 7,80 (d, 1H), 8,00 (d, 1H), 8,11-8,16 (m, 3H).

Example 53

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. Add 2-[p-(chlorosulfonyl)phenoxy]ndimethylacetamide (250 mg). The reaction mixture was stirred at room temperature overnight. The reaction is controlled by moving, washed with a small amount of methylene chloride and dried in vacuum to obtain 415 mg of the above product (the ratio of 5-methoxy and 6-methoxy 3:2). So pl. 159-C (with decomposition).

1H NMR (DMSO-d6, ): to 2.13 (s, 3H), of 2.25 (s, 3H), of 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-to 7.18 (m, 3H), 7,34-7,40 (m, 1H), 7,60-of 7.90 (m, 2H), 8,12-8,18 (m, 2H).

Example 54

Getting 2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide

2-[[(3-Methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil]-1H-benzimidazole (370 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. Add 2-[p-(chlorosulfonyl)phenoxy]ndimethylacetamide (250 mg). The reaction mixture was stirred at room temperature for 24 hours. The solid precipitate was separated, washed with methylene chloride and dried in vacuum. Obtain 378 mg of the above product. So pl. 162-C (with decomposition).

1H NMR (DSO-d6, ): of 2.21 (s, 3H), 4,55 (s, 2H), 4,86-5,15 (kV, 2N, q 2N), of 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

Getting 2-{4-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide and 2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)met who yl)methyl]sulfinil]-1H-benzimidazole (383 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. Add 2-[p-(chlorosulfonyl)phenoxy]ndimethylacetamide (250 mg). The reaction mixture was stirred at room temperature for 24 hours. The solid precipitate was separated, washed with methylene chloride and dried in vacuum. Receive 413 mg of the above product (1:1 ratio). So pl. 125-C (with decomposition).

Example 56

Getting 2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide

Sodium salt 2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole (382 mg) is added to methylene chloride (45 ml) and triethylamine (0.1 ml). Add 2-[p-(chlorosulfonyl)phenoxy]ndimethylacetamide (250 mg). The reaction mixture was stirred at room temperature overnight. The reaction mixture is washed with water. The organic layer is dried over anhydrous magnesium sulfate and evaporated. The resulting residue is crystallized from a mixture of acetonitrile-ethyl ester. Receive 437 mg of the above product. So pl. 148-C (with decomposition).

1H NMR (DMSO-d6, ): 1,93-of 1.97 (m, 2H), 2,18 (s, 3H), at 3.35 (s, 3H), 3.46 in (t, 2H), 4,06 (t, 2H), 4,56 (s, 2H), a 4.83-5,13 (kV, AV, 2H), 6,85 (d, 1H), 7,16 (d, 2H), 7,41-of 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

Obtaining 1-[{2-(morpholine-4-yl)ethoxy}',2,2 triptoreline)-2-pyridyl]methyl]sulfinil]-1H-benzimidazole (370 mg) was dissolved in 20 ml of methylene chloride and 1 ml of triethylamine. Add [2-(morpholine-2-yl)ethoxy]phenyl-4-sulphonylchloride (273 mg) and stirred at room temperature overnight. The layer of methylene chloride was washed with an aqueous solution consisting of 0.1 M NaCl, and ice in 0.1 M sodium bicarbonate solution. The layer of methylene chloride dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The obtained residue lyophilizer with getting 515 mg of the above product.

1H NMR (CDCl₃, ): of 2.33 (s, 3H), 2,50-2,52 (m, 4H), 2,78-of 2.81 (t, 2H), 3,70-3,74 (m, 4H), 4,12-to 4.15 (t, 2H), 4,84-5,02 (kV, AV, 2H), 6,63 (d, 1H), 6,69 (d, 2H), 7,38-7,49 (m, 2H), 7,81 (d, 1H), to 7.99 (d, 1H), 8,04 (d, 2H), compared to 8.26 (d, 1H).

Example 58

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

137 mg of [2-(morpholine-2-yl)ethoxy]phenyl-4-sulphonylchloride add 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 water rest Privat. The obtained residue lyophilizer in vacuum to obtain 224 mg of the above product (1:1 ratio).

1H NMR (CDCl₃, ): 2,22 (s, 3H), of 2.30 (s, 3H), 2,50 is 2.51 (m, 4H), and 2.79 (t, 2H), 3,69-3,74 (m, 4H; s, 3H), 3,82 and 3,91 (2s, total 3H), of 4.12 (t, 2H), 4,78-4,94 (kV, AV, 2H), 6,93-was 7.08 (m, 3H), 7,46 (s, 1H), 7.68 per-7,86 (DD, 1H), 8,00-of 8.04 (m, 2H), 8,17 (s, 1H).

Example 59

Getting 1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[(3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole

2-[[[3-Methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl]sulfinil]-1H-benzimidazole (185 mg) was dissolved in 20 ml of methylene chloride and 0.5 ml of triethylamine. Add 2-[2-(morpholine-4-yl)ethoxy]-ethoxyphenyl-4-sulphonylchloride (163 mg) and stirred at room temperature overnight. The layer of methylene chloride was washed with an aqueous solution consisting of 0.1 M NaCl and 0.1 M NaHCO₃. The layer of methylene chloride dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is subjected to preparative TLC. Obtain 198 mg of the above product.

1H NMR (CDCl₃, ): 2,30 (s, 3H), 2,48 (m, 4H), 2,58 (t, 2H), 3,64-of 3.77 (m, 8H), 4,10 (t, 2H), 4,34-and 4.40 (q, 2H), 4,81-5,01 (kV, AV, 2H), 6,62 (d, 1H), 6,94 (d, 2H), 7,35-7,47 (m, 2H), 7,78 (d, 1H), of 7.96 (d, 1H), 8,02 (d, 2H), by 8.22 (d, 1H).

the XI-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole

162 mg of 2-[2-(morpholine-4-yl)ethoxy]ethoxyphenyl-4-sulphonylchloride add 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 is dried over anhydrous magnesium sulfate and evaporated. The resulting residue is dried in vacuum to obtain 254 mg of the above product (1:1 ratio).

1H NMR (CDCl₃, ): of 2.21 (s, 3H), to 2.29 (s, 3H), 2.49 USD of $ 2.53 (m, 2H), 2,69-2,78 (m, 4H), 3,67-to 3.89 (m, 8H; C, 3H; s, 3H), 4,07 is 4.13 (m, 2H), 4,76-4,93 (kV, AV, 2H), 6,92-7,00 (m, 2H), 7.23 percent (d, 1H), 7,44 (d, 1H), the 7.65 a 7.85 (DD, 1H), 7,98-8,03 (m, 2H), 8,15 (s, 1H).

Example 61

Getting 1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole

Sodium salt of 2-[(3-methyl-4-methoxypropane-2-pyridyl]methyl-sulfinil]-1H-benzimidazole (191 mg) was dissolved in 20 ml of methylene chloride and 0.1 ml of triethylamine. Add 2-[2-morpholine-4-yl)ethoxy]ethoxyphenyl-4-sulphonylchloride (163 mg) and stirred at room temperature overnight. Layer methylene chloride industry is blockhead magnesium. The solvent is evaporated under reduced pressure. The obtained residue lyophilizer with getting 253 mg of the above product.

1H NMR (Dl₃, ): 1,99-2,03 (m, 2H), of 2.21 (s, 3H), 2,46 (t, 2H), by 2.55 (t, 2H), to 2.67 (t, 2H), 3,29 (s, 3H), 3,48-of 3.53 (m, 2H), 3,64-3,68 (m, 6N), to 3.73-3,74 (m, 2H), was 4.02-4,07 (m, 4H), 4,74 is equal to 4.97 (kV, AV, 2H), 6,62 (d, 1H), 6,89-6,92 (d, 2H), 7,31-7,42 (m, 2H), of 7.75 (d, 1H), to 7.93 (d, 1H), 8,02 (d, 2H), 8,13 (d, 1H).

Example 62

Obtaining N-(carbamoylmethyl)-2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl] phenoxy} ndimethylacetamide and N-(carbamoylmethyl)-2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}the ndimethylacetamide

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. Add tert.-piperonyl sodium (55 mg) and N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]ndimethylacetamide (160 mg). The reaction mixture was stirred at 30 ° C for 36 hours. The reaction mixture is filtered. The filtrate is concentrated and treated with ethyl ether to obtain a precipitate. The solid residue is separated and dried in vacuum. Get 253 mg of the above product (1:1 ratio).

Method 2: 5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylallyl)-2-[4-(chlorosulfonyl)phenoxy]ndimethylacetamide (160 mg). The reaction mixture was stirred at 30 ° C for 36 hours. The reaction mixture is treated by adding 80 ml of methylene chloride and washed with 7% NaCl and 0.1 N sodium bicarbonate solution. The layer of methylene chloride dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The obtained residue lyophilizer to obtain 213 mg of the above product (1:1 ratio).

1H NMR (DMSO-d6, ): and 2.14 (s, 3H), of 2.25 (s, 3H), 3,34 (ush, -NH, -NH₂), 3,66 (d, 2H), 3,70 (s, 3H), 3,88 (s, 3H), of 4.67 (s, 2H), 4,81-5,08 (kV, AV, 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

Obtaining N-(carbamoylmethyl)-2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl}sulfinil)benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide

2-[[[3-Methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl]sulfinil]-N-benzimidazole (185 mg) was dissolved in 20 ml of methylene chloride and 0.5 ml of triethylamine and add N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]ndimethylacetamide (158 mg). The reaction mixture was stirred at room temperature for 24 hours. To the reaction mixture are added methylene chloride (100 ml). The reaction mixture is washed with saturated NaCl solution and 0.1 N sodium bicarbonate solution. The layer of methylene chloride was separated and dried over baie remainder, which lyophilizer in vacuum. Obtain 237 mg of the above product.

1H NMR (DMSO-d6, ): of 2.23 (s, 3H), 3,36 (ush, -NH, -NH₂), 3,66 (d, 2H), 3,66 (d, 2H), 4,67 (s, 2H), 4,84-5,17 (m, 2H, q, AB, 2H), 6,99-8,35 (m, 10H, aromatic. N).

Example 64

Obtaining N-(carbamoylmethyl)-2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl)methyl}sulfinil)benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide

Sodium salt 2-[[[(4-(3-methoxypropane)-3-methyl-2-pyridyl]-methyl]sulfinil-1H-benzimidazole (190 mg) was dissolved in 20 ml of methylene chloride and 0.5 ml of triethylamine and add N-(carbamoylmethyl)-2-[4-(chlorosulfonyl)phenoxy]ndimethylacetamide (160 mg). The reaction mixture was stirred at room temperature for 24 hours. To the reaction mixture are added methylene chloride (100 ml). The reaction mixture is washed with saturated NaCl solution and 0.1 N sodium bicarbonate solution. The layer of methylene chloride was separated and dried over anhydrous magnesium sulfate. Methylene chloride evaporated under reduced pressure to get syrupy residue, which lyophilizer in vacuum. Obtain 215 mg of the above product.

1H NMR (DMSO-d6, ): 1,94-of 1.97 (m, 2H), 2,19 (s, 3H), 2,22 (s, 3H), 3.46 in (t, 2H), to 3.67 (d, 2H), 4,06 (t, 2H), and 4.68 (s, 2H), 4,84-5,14 (kV, AV, 2H), 6,85 (d, 1H), 7,21 (d, 2H), 7,42-of 7.55 (m, 2H), 7,80 (d, 1H)imethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(benzotriazol-1-yl)methyl-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-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. Add tert.-piperonyl sodium (55 mg) and 1-(chloromethyl)-1H-benzotriazol (85 mg). The reaction mixture was stirred at 30 ° C for 3 days. TLC analysis (showing 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]-sulfinil]-1H-benzimidazole above 5-methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole. Indicated in the title product purified preparative TLC. Obtain 195 mg of the product, a mixture of 1-(benzotriazol-1-yl)methyl-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole and 1-(benzotriazol-1-yl)methyl-6-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole (ratio 3:2).

1H NMR (Dl₃, ): of 2.21 (s, 3H), 2,24 (s, 3H), 3,70 (s, 3H), 3,79 and 3,86 (2s, total 3H), 4,85-5,08 (kV, AV, 2H), 6,65 (d, 2H, N-CH₂-N), 6,89-to 8.12 (m, 8H).

Example 66

Obtaining 1-(benzotriazol-1-yl)methyl-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole

Sodium salt 2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]-methyl]sulfinil]-1H-benzimidazole (190 mg) is more at 30 ° C for 3 days. TLC analysis shows a single spot of product. The reaction mixture is filtered. The filtrate is concentrated under reduced pressure and treated with a mixture of ethyl ether-heptane. The resulting solid precipitate was separated and dried to obtain pure 1-(benzotriazol-1-yl)methyl-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole (212 mg).

1H NMR (Dl₃, ): 2,05-of 2.08 (m, 2H), of 2.21 (s, 3H), 3,34 (s, 3H), of 3.54 (t, 2H), 4,08 (t, 2H), 4,86-5,16 (kV, AV, 2H), 6,69-6,70 (d, 2H, N-CH₂-N), 7,00-8,15 (m, 10H).

Example 67

Getting diethyl [5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]benzimidazole-1-yl]phosphate

5-Methoxy-2-[(3,5-dimethyl-4-methoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole (172 mg) was dissolved in 50 ml methylene chloride and 0.5 ml of triethylamine. Add diethylphosphate (87 mg). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture is washed with saturated NaCl solution and twice with 0.1 N sodium bicarbonate solution. The layer of methylene chloride was separated and dried over anhydrous magnesium sulfate. Methylene chloride evaporated under reduced pressure, giving siropoobraznoy substance, 215 mg of product. Syrupy product is slowly destroyed.

1H NMR (CD IS), 8,18 (s, 1H).

Chemical stability

Chemical stability of the compounds according to the invention is studied kinetically at low concentrations when S in the buffer solution of 0.2 M NaCl, 50 mm sodium phosphate, pH 7.4, 2% bovine serum albumin, 5-10% methanol. According to the measurements of the compounds of Example 1 and Example 19 had a half-period of the existence of (t_1/2) 3 CHS,5 hours and 3.5 CAS,3 hours, respectively. The compound of Example 1 has a slightly higher solubility in aqueous buffer than the compound from Example 19. It was found that the solubility of these compounds affects the rate of hydrolysis.

The stability of compounds in relation to acid examined in 95% methanol containing 0.1 N Hcl. About 90% of the compound of Example 1 remained intact (without decomposition) after 2.25 hours in this solution.

Biological tests

Inhibition of ATPase activity determined using isolated vesicles of the stomach of the pig. Gastric N. K-ATPase (10 µg) thermostatically when S in solution (1 ml) containing 0.25 M sucrose, 20 mm Pipes/Tris, pH 7.4, 0.15 M KS1, 2 mm MgCl₂valinomycin 2 µg/ml and compounds according to the invention in different concentrations. Intervals add ATP (up to 2 for measuring parentingebony activity use the drug from a previous techniques without labile benzimidazole group at the nitrogen atom (for example, OMEPRAZOLE or LANSOPRAZOLE). At first (before they undergo hydrolysis) samples with a content of 10, 20, 50 and 100 μm of the compound of Example 1 did not inhibit the enzymatic activity. However, after 80 minutes, the 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 of OMEPRAZOLE (control) and 10 μm of the compound from Example 1, the same level of inhibition achieved through of 5.75 hours of hydrolysis.

The relative concentration of omeprazole in plasma of rats

Adult male rats, strain Sprague-Dawley, was used to determine the concentration of OMEPRAZOLE in plasma. All rats in one day were deprived of food but not water. Presents compounds (2 mg/kg of body weight of the rat) orally administered to male (weighing 250-270 g) and intervals taking samples. The blood samples are centrifuged and the plasma is selected. Plasma is extracted with 0.5 ml of methylene chloride. Methylene chloride is evaporated, blowing nitrogen/air. The residue is dissolved in 0.5 ml of 40% acetonitrile in 10 mm phosphate buffer (pH 7.4). OMEPRAZOLE quantitatively determined by HPLC. As control of orally administered OMEPRAZOLE (4 mg/kg of body weight of the rat).

The relative concentration of OMEPRAZOLE, mystie on the secretion of gastric acid in male rats, in consciousness

Took male rats (strain Sprague-Dawley). OMEPRAZOLE (2 mg) or the compound of Example 33 (1 mg) resuspending in 1 ml of 15% sugar and 20 mm nutrifaster buffer pH 7.4. OMEPRAZOLE (2 mg/kg) or the compound of Example 33 (1 mg/ml) administered orally. Intervals (2, 3.5 and 5 hours) the abdominal cavity of the rat cut and are ligated pylorus is preserved under weak ether anesthesia. Histamine (2 mg/kg) is injected intravenously to stimulate acid. Immediately the abdominal cavity is closed. An hour later, the stomach removed after ligature of the esophagus. Gastric juice is collected and quantity (yield) of the acid is determined by titration with a solution of 0.1 N NaOH. In the control experiment administered orally 1 ml of 15% sugar and 20 mm phosphate buffer solution without adding any substances (inhibitors). The amount of acid that is defined as described above, shows the maximum westminsterabbey secretion of gastric acid. The percentage inhibition is calculated as the ratio of reaction (values) of the test compounds and the control experiment. Further calculations made on the basis of average values (reactions) in a group of 3-4 rats.

Inhibition of the secretion of gastric acid through certain intervening with OMEPRAZOLE. The maximum inhibition by the compound of Example 33 is achieved after 5 hours, which shows that the compound according to the invention continuously into corresponding PPI in vivo and inhibits the secretion of gastric acid.

1. Derivatives of benzimidazole

Het₁-X-S(O)-Het₂,

where Het₁has the structure

X has the structure

Het₂has the structure

R₆- R₉independently selected from hydrogen, alkyl with 1-10 carbon atoms, of halogensubstituted alkyl with 1-10 carbon atoms, alkoxy with 1-10 carbon atoms and halogen-substituted alkoxy with 1-10 carbon atoms;

R₁₀denotes hydrogen, alkyl with 1-10 carbon atoms;

R₁₅has the formula

in which R₁₇means alkyl with 1-10 carbon atoms, halogen-substituted alkyl with 1-10 carbon tomatnyi atoms, halogensubstituted alkylthio with 1-10 carbon atoms, alkoxycarbonyl with 1-10 carbon atoms, halogen-substituted alkoxycarbonyl with 1-10 carbon atoms, F, Cl, Br, J, NO₂CN, Oxoalkyl, NH₂alkylamino, dialkylamino, where in these Soulkilling, alkylamino and dialkylamino each of the said alkyl group contains 1-10 carbon atoms, carbarnoyl, N-substituted carbarnoyl, alkylsulphonyl with 1-10 carbon atoms, and (alkoxycarbonyl)alkoxygroup in each of these alkoxygroup contain 1-10 carbon atoms, (alkoxycarbonyl)altergroup in each of said alkoxy or alkyl group containing 1-10 carbon atoms, (carbarnoyl)alkoxy with 1-10 carbon atoms, (N-allylcarbamate)alkoxy with 1-10 carbon atoms, (N,N-dialkylamino)alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carbarnoyl)poly(alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carbarnoyl)alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbarnoyl]alkyl with 1-10 carbon atoms, [N-(heteroaryl)carbarnoyl]alkoxy with 1-10 carbon atoms, [N-(substituted aryl)carbarnoyl]alkoxy with 1-10 carbon atoms, and poly(alkoxy)group in each of the specified alkoxygroup containing the group, [N-(carbamoylmethyl)carbarnoyl]alkoxy, [N-(carbamoylmethyl)carbarnoyl]alkyl, [N-[[N-(heteroaryl)carbarnoyl]alkyl]carbarnoyl]alkoxy, [N-[[N-(substituted heteroaryl)carbarnoyl]alkyl]carbarnoyl]alkoxy, (sulfonato)alkyl, (sulfonato)alkoxy, N-[(sulfonato)alkyl]amido, (substituted)maleimido-, (substituted)succinimide, [(three-alkyl)ammonium]alkoxy;

R₂₁means (aryl)alkyl, (heteroaryl)alkyl, phenyl, naphthyl or heteroaryl containing 1-3 heteroatoms independently selected from N, O and S, and these phenyl, naftalina or heteroaryl groups are substituted or unsubstituted 1-5 groups R₁₇,

or pharmaceutically acceptable salts of these compounds.

2. Connection on p. 1, characterized in that X represents CH₂group.

3. Connection on p. 1, wherein R₂₁means phenyl, pyridyl, thiophenyl, thiazolyl or imidazolyl.

4. Derivatives of benzimidazole

characterized in that

R₁* denotes methyl, methoxy or chlorine;

R₂* denotes methoxy, 2,2,2-triptoreline, (2,2,3,3,4,4-heptafluorobutyl)hydroxy or CH₃O(CH₂)₃About;

R₃* denotes H or methyl;

2">

R₁₅has the formula

in which R₁₇means 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, NO₂CN, Oxoalkyl, NH₂alkylamino, dialkylamino, where in these Soulkilling, alkylamino and dialkylamino each of the said alkyl group contains 1-10 carbon atoms, in addition, R₁₇means carbarnoyl, N-substituted carbarnoyl, alkylsulphonyl with 1-10 carbon atoms, and (alkoxycarbonyl)alkoxygroup in each of these alkoxygroup contain 1-10 carbon atoms, (alkoxycarbonyl)altergroup in each of said alkoxy or alkyl group containing 1-10 carbon atoms, (carbarnoyl)alkoxy with 1-10 carbon atoms, (N-allylcarbamate)alkoxy with 1-10 carbon atoms, (N,N-dialkylamino)alkoxy with 1-10 carbon atoms, (N-substituted or unsubstituted carbarnoyl)poly(alkoxy with 1-10 carbon atoms, (N-Zam is diversified atoms, [N-(heteroaryl)carbarnoyl]alkoxy with 1-10 carbon atoms, [N-(substituted aryl)carbarnoyl]alkoxy with 1-10 carbon atoms, and poly(alkoxy)group in each of the specified alkoxygroup contains 1-10 carbon atoms, cyclic polyalkoxy, guanidinium, raidgroup, dialkylamino-poly(alkoxy)group, [N-(carbamoylmethyl)carbarnoyl]alkoxy, [N-(carbamoylmethyl)carbarnoyl]alkyl, [N-[[N-(heteroaryl)carbarnoyl]alkyl]carbarnoyl]alkoxy, [N-[[N-(substituted heteroaryl)carbarnoyl]alkyl]carbarnoyl]alkoxy, [(three-alkyl)ammonium]alkoxy, (sulfonato)alkyl, (sulfonato)alkoxy, N-[(sulfonato)alkyl]amido, (substituted)maleimido-, (substituted)succinimido;

or pharmaceutically acceptable salts of the compounds.

5. Connection on p. 4, wherein R₂₁(R₁₇means phenyl, thienyl or pyridyl, substituted or unsubstituted group R₁₇.

6. Connection on p. 5, wherein R₁₇vybiraem, carbarnoyl, guanidines, ureido, (carbarnoyl)alkoxy, [N-(heteroaryl)carbarnoyl]alkoxy, morpholinyl, (morpholine-4-yl)alkoxy, [(morpholine-4-yl)alkoxy]alkoxy, (di-(lower alkyl)amino)alkoxy, [N-[(carbarnoyl)alkyl]carbarnoyl]alkoxy, poly(alkoxy), sodium (sulfonato)alkoxy, (ammonium)alkoxy and a cyclic Tetra - or Penta-ethylenoxy, the terms lower alkyl or lower alkoxy, each identify groups containing 1-6 carbon atoms.

7. Connection on p. 6, wherein R₂₁is unsubstituted or the fact that R₁₇selected from CL, Br, F, lower alkyl, lower alkoxy, trifluoromethyl, di(lower alkyl)amino, lower alkoxycarbonyl, carbarnoyl, guanidines, ureido, (carbarnoyl)methoxy, [N-(pyridyl)carbarnoyl]methoxy, morpholinyl, (morpholine-4-yl)alkoxy, [(morpholine-4-yl)alkoxy]alkoxy, 2-(dimethylamino)ethoxy, [N-[(carbarnoyl)methyl]carbarnoyl]methoxy, poly(alkoxy) and cyclic Tetra - or Penta-ethylenoxide, the terms lower alkyl or lower alkoxy, each define a group containing 1-6 carbon atoms.

8. Connection on p. 4, selected from the group consisting of

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

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

1-benzazolyl-2-[(3-methyl-4-(2^',2^',2^'-triptoreline)-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-deformedarse-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

1-(p-brabanthallen)-2-[(3-methyl-4-(2',2',2'-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

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

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

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

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

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

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

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

1-(p-permentantly)-2-[(3-methyl-4-(2',2',2'-triptoreline)-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-deformedarse-2-[(3,4-dimethoxy-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

1-(p-methylbenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

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

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

1-(p-methoxybenzenesulfonyl)-2-[(3-methyl-4-(2',2',2'-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

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

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

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

1-(3-trifloromethyl)-2-[(3-methyl-4-(2',2',2'-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

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

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

1-(p-trifloromethyl)-2-[(3-methyl-4-(2',2',2'-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

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

1-(p-dimethylaminobenzylidene)-2-[(3-methyl-4-(2',2',2'-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

1-(p-ethoxycarbonylphenyl)-2-[(3-methyl-4-(2',2',2^'-triptoreline)-2-pyridyl)methylsulfinyl]-1H-benzimidazole,

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

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

1-(pyridine-3-sulfonyl)-2-[[(3-methyl-4-(2,2,2-triptoreline)-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(pyridine-3-sulfonyl)-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(pyridine-3-sulfonyl)-6-(deformedarse)-2-[[(3,4-d is,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

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

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

N-[4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenyl]urea,

N-[4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenyl]urea,

N-[4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinil}-5-(deformedarse)-benzimidazole-1-yl]sulfonyl}phenyl]urea,

N-[4-{[2-{[(3,4-di(methoxy)-2-pyridyl)methyl]sulfinil}-6-(deformedarse)-benzimidazole-1-yl]sulfonyl}phenyl]urea,

15-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl} sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-[(5-methoxy-2-{[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfone the l]sulfinil}benzimidazole-1-yl)sulfonyl]-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

15-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]-1,2,3,4,5,6,7,8,9,10,11,12,13-criticalities[and][15]Annalen,

2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-{4-[(5-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-{4-[(6-methoxy-2-{[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenoxy)ndimethylacetamide,

2-(4-{[2-({[3-methyl-4-(2,2,2-triability)-2-(4-{[2-({[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenoxy)ndimethylacetamide,

2-{4-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-{4-[(5-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy}ndimethylacetamide,

2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil} benzimidazole-1-yl)sulfonyl]phenoxy}-N-(2-pyridyl) acetamide", she

N-(carbamoylmethyl)-2-{4-[(6-(deformedarse)-2-{[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil}benzimidazole-1-yl)sulfonyl]phenoxy} ndimethylacetamide,

2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenoxy)ndimethylacetamide,

2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenoxy)-N-(2-pyridyl)acetamide", she

N-(carbamoylmethyl)-2-(4-{[2-({[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl}sulfinil)benzimidazole-1-yl]sulfonyl}phenoxy)ndimethylacetamide,

1-[[4-{3-(morpholine-4-yl)propoxy}phenyl]sulfonyl]-5-(diphenyl]sulfonyl]-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

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

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

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

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

1-[4-[2-(morpholine-4-yl)ethoxy]phenylsulfonyl]-2-[[[3-metalfoil]-5-methoxy-2-[[(3,5-dimethyl-4-methoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

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

1-(thiophene-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]sulfinil]-1H-benzimidazole,

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

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

1-(thiophene-2-sulfonyl)-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-(thiophene-2-sulfonyl)-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(thiophene-2-sulfonyl)-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-(thiophene-2-sulfonyl)-2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

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

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

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

1-(pyridine-3-sulfonyl)-2-[[(3-methyl-4-methoxypropane-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-[4-(morpholine-4-yl)phenylsulfonyl]-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-benzazolyl-2-[[(3-chloro-4-morpholine-2-pyridyl)methyl]sulfinil]-5-methoxy-(1H)-benzimidazole,

1-benzazolyl-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

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

1-benzazolyl-2-[(3-methoxyphenyl)methylsulfinyl]imidazole[5,4-C]pyridine,

1-benzazolyl-2-[(3-methoxyphenyl)methylsulfinyl]imidazole[4,5-C]pyridine,

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

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

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

1-[4-[2-(morpholine-the l)ethoxy]phenylsulfonyl]-2-[{2-(dimethylamino)phenyl}methylsulfinyl]-1H-benzimidazole,

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

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

1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[4-(3-methoxypropane)-3-methyl-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-5-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-lH-benzimidazole,

1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-6-(deformedarse)-2-[[(3,4-dimethoxy-2-pyridyl)methyl]sulfinil]-1H-benzimidazole,

1-[[2-{2-(morpholine-4-yl)ethoxy}ethoxy]phenyl-4-sulfonyl]-2-[[[3-methyl-4-(2,2,2-triptoreline)-2-pyridyl]methyl]sulfinil]-1H-benzimidazole,

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

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

9. The compound of the formula

in which R₁₅choose from the groups (1) to(9) shown below

10. CLASS="ptx2">

11. The compound of the formula

in which R₁₅choose from the groups (1) to(15) shown below

and isomers of compounds of this formula in which R₁₅linked to the nitrogen atom in position 3 of the benzimidazole fragment.

12. The compound of the formula

in which R₁₅choose from the groups (1) to(4) shown below

and isomers of compounds of this formula in which R₁₅linked to the nitrogen atom in position 3 of the benzimidazole fragment.

13. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a prodrug of a proton pump inhibitor under item 1.

14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a prodrug of a proton pump inhibitor under item 4.

15. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a prodrug of a proton pump inhibitor according to any one of paragraphs.8-12.

16. The pharmaceutical composition according to any one of paragraphs.13-15 containing liquid activated for injection mammal having a pH value not exceeding 8,5 ed

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