Derivatives of pyridine

 

(57) Abstract:

Usage: in medicine, as a substance inhibiting the activity of H+-K+- adenosinetriphosphatase. The inventive product is a derivative of pyridine f-ly I, where R1and R2is hydrogen, lower alkoxy, halogenated lower alkoxycarbonyl, carboxy or halogen, X is a group-0-, -S - or-NR3where R3is hydrogen or alkali metal, lower alkyl or lower alkoxycarbonyl, Z is a group-O-(CH2)p-OR4where R4is hydrogen, alkyl or benzyl; p is an integer from 1 to 3; group-O(CH2)q-R5where q is an integer from 1 to 3, R5halogen, lower alkoxycarbonyl, phenyl or pyridyl; group f-ly-O-(CH2)r-O-(CH2)s-OR6where r and s is an integer from 1 to 5, R6is hydrogen or lower alkyl; group f-l II, III, IV and V, where t is an integer from 0 to 2; A is a group f-ly VI, where B is the group of f-crystals-NH or S; A is lower alkyl, pyridyl or furyl or a group of f-crystals VII, where R7is hydrogen, w is an integer 0 or 1; or Z is a group OR9where R9is hydrogen , lower alkyl or phenyl; n is an integer from 0 to 2, m is an integer from 2 to 10; I and K is hydrogen or lower alkyl. table 4. Structure f-l I, II, III, IV, V, VI and VII:

Describes derivatives pyridine duodenal ulcer, known collectively as peptic ulcers, are localized ulceration of the mucous membrane of the duodenum or stomach, respectively, which expose underlying layers of the intestinal wall the influence of acid secretions of the stomach and the proteolytic enzyme pepsin. I believe that they owe their origin to the autolysis that occurs when an imbalance between aggressive factors such as acid or pepsin, and defensive factors, such as the resistance of the mucous membranes, mucous secretion, blood flow or regulation of the duodenum. Peptic ulceration are the most common disease of the gastrointestinal tract and it is estimated approximately from 10 to 20% of the adult male population suffer from peptic ulcer in one or another period of his life.

Peptic ulcer cure or prevent, in principle, medical treatment and suggested many drug treatment, among which there are drugs with a high degree of efficiency.

Clinically useful drugs include N2-blocking agents such as cimetidine and ranitidine, as antiulcer p is involved in the parietal cells of the stomach, can effectively inhibit the secretion of gastric acid in mammals, including humans, so expect a new class of anti-ulcer funds from this point of view comes into being. More specifically, it was proposed a great variety of compounds having a benzimidazole structure. Among these compounds is omeprazole, currently in active development, as the most promising compound [1] this patent describes compounds with methoxy group at the 4-position of the pyridine ring, and among them, omeprazole, having the formula

next, 2-(4-methoxyethoxymethyl-2-yl)methylsulfinyl-5-methyl-1H-benzimidazole, the sample is received.

Known related compounds benzimidazole type, having antiulcer activity, in which the 4th position of the pyridine ring substituted by alkoxyalkyl, in which each alkoxygroup contains 1-2 carbon atoms. In the example, this patent describes 2-(3,5-dimethyl-4-methoxyethoxymethyl-2 - yl)methylsulfinyl-5 - phenyl-1H-benzimidazole. Also described other substitutions at different positions benzimidazole and pyridine rings. Data biological tests indicate significant Biol which laboratory animals, when the 4th position of the pyridine ring substituted by a methoxy group.

Known other compounds imidazole type, in which the substituent in the 4-position of the pyridine ring is benzyloxy [2]

The present invention discloses a new class of compounds with higher antiulcer activity than omeprazole, which is currently regarded as the most significant connection among the benzimidazole compounds of the type having antiulcer activity. As a result of intensive studies, it was found that the compounds represented by formula I are more potent in suppressing secretion of gastric acid in comparison with omeprazole. The present invention is based on this discovery.

The present invention includes a class pyridine derivatives represented by the General formula I:

CH (I) in which R1and R2may be the same or different, and each represents a hydrogen atom, lower alkyl, lower alkoxygroup, halogenated lower alkyl, lower alkoxycarbonyl or carboxyl group, or halogen atom, X stands for a group represented by the formula: -0, -S - or (where R< / BR>
and it is:

1) a group of the formula:- (CH2)p-OH,R4where p is an integer from 1 to 3, and R4a hydrogen atom or a lower alkyl, aryl or kalkilya group,

2) a group of the General formula: -O-(CH2)g-R5where g is an integer from 1 to 3, and R5halogen atom or alkoxycarbonyl, aryl or heteroaryl group,

3) a group of the General formula: -O-(CH)r-OH)(CH2)S-O-R6where r and S each independently from each other represents an integer from 1 to 5, and R6a hydrogen atom or lower alkyl,

4) a group of the formula

-N

5) a group of the formula

-N

6) a group of the formula

NS

7) a group of the formula

A where t is an integer from zero to 2, and a represents a group of General formula:

where the group of formula: -NH-, -O - or-S-), lower alkyl, alkoxycarbonylmethyl, pyridyl or furyl or a group of the General formula:

(CH2)

8) a group of General formula

CH in which R8acetoxy or lower alkyl, or

9) a group of the General formula: -OR9where R9a hydrogen atom or a lower alkyl or aryl,

n is an integer from 0 to 2, m is an integer from 2 to 10 and

I and K, which may be the same or different, each represents a hydrogen atom or lower alkyl, provided th number from 3 to 10, and their pharmaceutically acceptable salts.

The same definitions for R1, R2, X, n, I, K, Z and m used in the description and in the claims.

In the definition of compounds of General formula I, the lower alkyl group mentioned in connection with the definition for R1, R2, R3, R4, R6, A, R7, R8, I and the compound I according to the invention, can be an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms. Examples include methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl, among which the most preferred methyl and ethyl groups.

Lowest alkoxygroup and lower alkoxides lower alkoxycarbonyl groups defined above in connection with R1and R2may be alkoxygroup, derived from the above lower alkyl group. Methoxy - and ethoxypropan are the most preferred.

The halogen atom defined above, includes chlorine, bromine, iodine or fluorine.

Aryl group, as defined previously in connection with R4and R5may be a phenyl, talila, xilian, naphthyl or the like, ptx2">

Examples of arylalkyl defined earlier in connection with R4include benzyl and fenetylline group.

Examples of the heteroaryl group defined above in relation to R5include pyridyloxy and follow group.

When defining Z in the General formula I group 1, 2, 3, 4, 5, and 9 are preferred. The most preferred group 9. As for R1and R2, the preferred hydrogen atoms for both radicals, as well as the combination of lower alkyl, including methyl, R1and hydrogen for R2. X is preferably-NH3where R3means hydrogen. A preferred value for n units. The preferred values of I and K are both hydrogen, or when I is lower alkyl, the number of which is methyl, and j is a hydrogen atom, or when I atom of hydrogen, and lower alkyl, for example methyl. Thus, I and independently of one another are preferably hydrogen or stands, most preferably I represents methyl, and hydrogen.

A first preferred class of compounds among the compounds of General formula I represented by the following formula:

(where R1, R2, I, m and R9have the same sachets both hydrogen atoms, or R1mean 5-lower alkoxygroup, 5-lower alkyl or 5-halogenated lower alkyl, and R2the hydrogen. The preferred Deputy I is hydrogen or methyl, the preferred value for m is in the range from 3 to 10, most preferred is 3, and the preferred R9as the Deputy is lower alkyl, incidentally methyl or aryl. Among these features, for compounds of formulas And the preferred combination is that, when R1and R2both are represented by hydrogen, I is methyl, m is 3 or R9methyl.

The second group of preferred compounds are combinations of the mentioned substituents, when both R1and R2are hydrogen, I is hydrogen, m is 3 and R9methyl.

The third group of preferred compounds falling under formula A, is that when both R1and R2both signify hydrogen, I is methyl, m is two, or R9benzyl.

The second class of compounds falling within General formula I, represented by the following formula:

(in which R1, R2, I, p, m, and R4are the same values that have been defined for them previously). In the formula In the preferred h is PU, 5-lower alkyl or 5-halogenated lower alkyl, and R2the hydrogen. The preferred value of m is from 2 to 3, the preferred value for R is 2 or 3, and the preferred substituent R4is methyl or benzyl. Of these features for a formula In the most preferred combination is that, when R1represents 5-methyl, R2hydrogen, I, methyl, m is 2, p is 2 and R4means methyl.

Examples of pharmaceutically acceptable salts include salts of inorganic acids, such as hydrochloride, hydrobromide, sulphates and phosphates, organic acid salts such as acetate, maleate, tartrate, methanesulfonate, bansilalpet and toluensulfonate and salts of amino acids such as arginine, aspartic acid and glutamic acid.

Some compounds according to the invention may form a salt with a metal such as sodium, potassium, calcium or magnesium. These metal salts are also included in the pharmaceutically acceptable salts according to the invention. For example, compounds represented by the General formula I, in which X stands for a group and R3represents a hydrogen atom, or compounds represented by the General formula I, in which Z denotes Grupp> Because the connection according to the invention may also exist in the form of a hydrate or stereoisomer, of course, that these hydrates and stereoisomers are also included in the scope of the invention.

The action of the compounds according to the invention will be described with reference to the following pharmacological experiments.

Pharmacological experiment. Ingibirovanie activity N+- +adenosinetriphosphatase.

(I) obtaining the N+- +adenosinetriphosphatase.

Obtained from the glands of the fundus of the stomach of fresh gastric mucosa of pigs by the modified method of Saccomani and co-authors (see Biochem and Biophys. Acta 464, 313, 1977).

(2) Measurement of activity of N+- +adenosinetriphosphatase.

The connection according to the invention were incubated at various concentrations in 40 mmol of Tris-HCl buffer solution having a pH 7,40, together with the N+- +adenosinetriphosphatase and 10 μg/ml of protein at 37aboutC for 30 min, followed by addition of 15 mmol of potassium chloride. After 10 min the reaction adenosinetriphosphatase were initiated by addition of 3 mmol of magnesium chloride and ATP. After 10 min determined the amount of released inorganic phosphor is the form of a solution in methanol.

The inhibitory activity was determined by subtracting the amount of released inorganic acids observed in the case of adding a solution of the test compound, the amount allocated to the control, which was only added solvent, to determine the difference, and dividing this difference by the last number. The inhibitory activity is shown in table.1 values inhibitory concentration IR50.

The results of tests of the connection 19 of the invention and three comparative compounds a, b and C (see tab.2), also expressed in the form of inhibitory activity, calculated as follows:

inhibitory activity of 100 where a AND N+- +ATP activity in the absence of test compounds

IN THE N+- +ATP activity in the presence of test compounds.

From the experimental results it is seen that the compounds according to the invention have a high inhibitory effect on the activity of N+- +adenosinetriphosphatase and highly stable, so that they can effectively suppress the secretion of acids and therefore are effective for the treatment and prevention of peptic ulcers in humans and animals.

Then soedinenie in this field.

Used dogs with chronic gastric fistula. The test compound was administered intraduodenally such dog 4 mg/kg Through 1; 24; 48 and 72 h after the introduction of the dog intramuscularly, inetsirovali pentagastrin (6 μg kg-1). Determined the secretion of gastric acid and determined the allocation of its percentage compared with the control. The results of this test are presented in table. 4.

From these results we can determine that within one hour from intraduodenal injection of stimulation pentagastrinom the secretion of gastric acid completely inhibited in both tests with the connection 19, and omeprazole. In this test, the selection of the acid with the compound 19 was 61,9 and 121,5% in comparison with the control group, respectively, after 24 and 48 hours on the other hand, in the same with the use of omeprazole secretion of gastric acid was 108,4% after 72 h In both cases, as with the connection 19 and omeprazole, took 48 and 72 h, respectively, for recovery of acid secretion.

Pharmacological experiment 2. Ingibiruyushee effect on the secretion of gastric acid.

Used dogs with chronic gastric fistula. The secretion of gastric is in every dog intraduodenal introduced each of the test compounds, and one hour after injection was determined by the amount of gastric acid, allocated to each experimental dog. The results were compared with the control group, which did not enter the test compounds, and showed inhibition in percentage values.

Inhibitory effect on stimulated histamine secretion of gastric acid in dogs with chronic gastric fistula presented in table.3. Values inhibitory dose EID50calculated by curve dose-inhibition of the test compounds was $ 59.9 mg/kg for compounds 19 and to 112.2 mg/kg of omeprazole, which indicated that compound 19 was two times more potent than omeprazole. Compound 19 is shown in the table.2 experiment 1 in example 33.

The results of the three pharmacological experiments described above show that the compound according to the invention exhibits a significant inhibitory effect on the activity of N+- +-adenosinetriphosphatase.

Among these compounds, compound 19 has unexpectedly more selenopyran inhibitory activity on secretion of gastric acid in comparison with omeprazole, which itself is a highly effective inhibitor should be noted, the proposed connection unexpectedly exhibits a more rapid recovery and resumption of gastric secretion than omeprazole.

Currently, it is believed that the inhibitor N+- +-adenosinetriphosphatase has a stronger activity of inhibiting secretion of gastric acid than H2-blocking the connection, so he in the future has the opportunity to take the first place as protivojazvennogo tools.

But although desirable stronger inhibitory activity against the secretion of gastric acid, prolonged inhibition of the secretion of gastric acid is not preferred for antiulcer funds. For example, it causes the rapid expansion of enterochromaffin cells and the formation of carcinoid occurring as a result of hypergastrinemia, as described in "Degistion" Vol. 35, suppel. I, pages 42-55 (1986), the increase in bacterial flora of the stomach and the endogenous production of N-nitro compounds, as described in "But. Med I." Vol. 289, page 717 (1984), and difficulty in determining appropriate dosing regimen.

Thus, the most preferred is an inhibitor of H+- +-adenosinetriphosphatase with great ability who was lodales when using compound 19 (working example 33), which is a characteristic connection according to the invention, hound dogs that oral was administered 10 mg/kg / day during the week, and on rats, which were administered orally 50 mg/kg per day for one week.

Compound 19 has a significant inhibitory effect on the activity of N+- +-adenosinetriphosphatase in combination with the desired ability to quickly restore the secretion of gastric acid.

Compound 19 as a characteristic connection according to the invention, thus is effective for the treatment or prevention of peptic ulcers (ulcers of the stomach and duodenum ulcers) in animals, including humans.

The compound is administered for the treatment or prevention of peptic ulcers or orally in the form of powder, granules, capsules or syrup, or parenterale in the form of injections, or as external drug or drops, or as suppositories. Although the dose varies considerably depending on the symptom, age and type of sores (ulcers), it can be approximately from 0.01 to 200 mg/kg, preferably from 0.05 to 50 mg/kg and more preferably from 0.1 to 10 mg/kg / day and may be administered in a single dose or in the form of fractional doses, for example, from 2 to 4 times a day.

Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, whereas the binder include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, Arabian gum, tragakant, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethyl and polyvinylpyrrolidone. Examples of the dispersing means include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, acidic calcium carbonate, calcium citrate, dextrin and pepsin, whereas the lubricant include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. The coloring agent may be any substance that is permitted as an additive to the medication. Examples of flavoring means includes cocoa powder, mint tra the uly can be if necessary, coated with sugar, gelatin or the like.

Injecting the drug can be prepared by mixing the active ingredient with regulating the pH value of the medium, a buffer, a stabilizer, a solvent or the like, and processing the mixture by conventional means for obtaining intramuscular, subcutaneous or intravenous injection of the drug.

The connection can be obtained in various ways, typical examples of which are described below.

The method of obtaining AND

SH (II) where R1, R2and X have the meanings given above

YCH (III) where m, Z, I and K have the meanings defined above, Y is a halogen atom or sulfonyloxy,

< / BR>
That is, the compound represented by the General formula II is subjected to interaction with a halide or a sulfonate represented by the General formula III, to obtain the compounds represented by the General formula I, which is the target compound according to the invention.

Examples of the halogen atom mentioned in connection with the definition of Y include chlorine, bromine and iodine, while examples of sulfonyloxy include alkylsulfonates, such as methylsulfonate and ethylsulfonyl is SS="ptx2">

The above reaction is preferably performed in the presence of an acid acceptor. Examples of the acid acceptor include carbonates and acid carbonates of alkali metals such as potassium carbonate, sodium carbonate and acid sodium carbonate, hydroxide of alkali metals such as sodium hydroxide and potassium hydroxide and organic amines such as pyridine and triethylamine. Examples of the solvent used in the reaction include alcohols such as methyl and ethyl alcohols, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and mixtures thereof with water.

Temperautre reaction can be from -40aboutC to the boiling point of the used solvent, preferably from 0 to 60aboutC.

The obtained compound (I') can be easily oxidized in his alvinlee derivative (I), which is the target compound according to the invention, corresponding to the compound of General formula I, in which n is 1.

This oxidation can be performed in the usual way using an oxidant such as hydrogen peroxide, peracetic acid, m-chlormadinone acid, sodium hypochlorite or hypobromite sodium. The solvent used in the oxidation process, usually VIIa can be from -70aboutC to the boiling point of the used solvent, preferably -60 25aboutC.

In addition, the sulfonic derivative, which is the target compound according to the invention, corresponding to the compound of General formula I, in which n is 2, can be obtained, for example, in the following way:

where R1, R2, X, I, m and Z have the meanings previously defined.

I.e., thioester derivative represented by the General formula (I'), which is the target compound according to the invention, oxidized before it sulfonic derivative represented by the General formula (I'"), which is another target connection according to the invention.

More precisely sulfonic derivative of the formula I, which is the target compound according to the invention can be obtained by dissolving the compounds of formula I in a solvent selected from among aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, water, alcohols, such as methanol, ethanol, ethyl acetate, acetone, acetic acid, and the like to obtain a solution, adding at least double the equivalent is s, sodium hypochlorite, m-periodate sodium and the like, to the solution under ice cooling or at room temperature, and the interaction of the compounds of formula I with an oxidizing agent.

Alternative sulfonic derivative of the formula I can be obtained as described above in a solvent such as chloroform, by adding an oxidizing agent such as m-chlormadinone acid, to obtain the solution, and interaction sulfoxide derivative of the formula I with an oxidizing agent.

The method of obtaining Century

where R1, R2, X, m, I, K and Z have the meanings previously defined, and Hal means a halogen atom.

I.e., the target compound represented by the General formula I can be obtained by the interaction of the halide represented by the General formula IV with an alcohol, mercaptan or amine represented by the General formula Z-H (formula V). This reaction is preferably carried out in the presence of an acid acceptor. Examples of the acid acceptor include carbonates and acid carbonates of alkali metals such as potassium carbonate and sodium carbonate, hydroxide of alkali metals such as sodium hydroxide and potassium hydroxide and triethylamine. Examples of solvents used in reccntly homologues, such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethylsulfoxide and hexamethylene phosphoric acid. The reaction can be carried out either under ice cooling or at a temperature not exceeding the boiling point of the solvent used.

The compound obtained of the formula I', which is the target compound according to the invention, can be oxidized in his alvinlee derivative represented by the General formula I, in a manner analogous to the previously described method of obtaining A.

The method of obtaining With.

The connection represented by the General formula I, where X stands for a group represented by the formula (in which R3is a group selected from among specific to it earlier values, with the exception of a hydrogen atom) can be obtained in the following way:

where R1, R2, n, I, K, m and Z have the meanings previously defined, and Hal means a halogen atom, and R3is a group selected from the values defined above for R3in formula I, with the exception of the hydrogen atom, i.e., lower alkyl, phenyl, benzyl or lower alkoxycarbonyl group.

I.e., the compound represented by the General formula I, which is the target what rmulas VI with halide, represented by the General formula VII, in the usual way.

The condensation can be carried out in the absence of any solvent or in an organic solvent, inert under the conditions of condensation, selected from benzene, ethanol, xylene, tetrahydrofuran, chloroform, carbon tetrachloride, dimethylformamide and the like, either at room temperature or under ice cooling or heating for several hours in the usual way. Condensation can be accelerated by using dehydrohalogenating agent selected from inorganic salts, such as acid sodium carbonate, potassium carbonate, sodium carbonate and caustic soda or organic bases, such as triethylamine, pyridine, pyrimidine and diethylaniline.

Next, thioester derivative represented by the General formula I, in which n is zero, obtained by condensation of the compounds represented by the General formula VI, where n is equal to zero, with a halide of the formula VII, can be easily oxidized to the corresponding sulfoxide derivative (n = one) or sulfon (n = two), in a way similar to that described.

) where m, Z, I, K, and Y have the meanings previously defined.

Stage 1. Oxide one alcohol, represented by the General formula IX, in the presence of a base with the formation of alkoxybenzenes represented by the General formula X.

Examples of bases include alkali metal hydrides such as sodium hydride and potassium hydride, alkali metals such as metallic sodium, sodium alcoholate such as sodium methylate and hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide. The reaction can be carried out either in the absence of solvent or in an organic solvent selected from ethers such as tetrahydrofuran and dioxane, ketones, such as acetone and methyl ethyl ketone, homologues of benzene, such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethyleneamine phosphoric acid and the like, at a temperature of from cooling with ice to the boiling point of the used solvent.

Stage 2. Alkoxybenzenes General formula X obtained in stage 1, is heated in acetic anhydride at a temperature of from 60 to 100aboutWith to get acetoxypiperidine derivative represented by the General formula XI.

Stage 3. Acetoxypiperidine derivative of the formula XI obtained in stage 2, round hydrolysis is usually carried out under alkaline conditions.

Stage 4. 2-Hydroxymethylimidazole derivative of formula XII obtained in stage 3, Ganoderma, for example, glorieuses means, such as chloride thionyl, 2-geluidsisolerende derivative represented by the General formula III. In this galoidirovaniya used as a solvent, for example chloroform or dichloromethane. Next, 2-hydroxymethylimidazole derivative of formula XII interacts with reactive sulphonylchloride, such as methanesulfonamido to obtain sulfonylacetonitrile represented by the General formula III. In this reaction the solvent used, for example, chloroform, dichloromethane, simple ether, tetrahydrofuran, pyridine or benzene.

Alternative compound represented by the General formula X used in the described method, can be obtained in the following way:

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< / BR>
Stage 1. The connection represented by the General formula VIII, in which Hal means a halogen atom such as chlorine atom, is subjected to condensation with a compound represented by the General formula XIII, the usual way of obtaining the compound represented by General formula XIV.

The condensation is preferably carried out in the presence of bases is their as metallic sodium, of hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide, and the like. The condensation is carried out either in the absence of solvent or in a solvent selected from ethers such as tetrahydrofuran and dioxane, ketones, such as acetone and methyl ethyl ketone, homologues of benzene, such as benzene, toluene and xylene, acetonitrile, dimethylformamide, dimethyl sulfoxide, hexamethyleneamine phosphoric acid and the like, at a temperature suitably selected in the range of from cooling with ice to the boiling point of the used solvent.

Stage 2. Received alkoxybenzenes formula XIV restore in the compound of formula XV. More precisely alkoxybenzenes formula XIV hydronaut in the presence of a catalyst 10% palladium on coal in a mixture of acetic anhydride and acetic acid to obtain the recovered product of formula XV.

Stage 3. The resulting compound of formula XV halodrol, for example, with gloriouse agent such as thionyl chloride, to obtain the 2-galogenoproizvodnykh represented by the General formula XVI. When this galoidirovaniya in the solvent used, for example, chloroform or dichloromethane.

Stage 4. The resulting connection with obtaining connection represented by the General formula XVII. This reaction is preferably carried out in the presence of an acid acceptor as in the reaction described in the method of obtaining Century

Stage 5. The compound obtained of the formula XVII are oxidized using an oxidizing agent such as hydrogen peroxide, peracetic acid or m-chlormadinone acid to obtain the corresponding N-oxide derivative.

Alternative compound represented by the General formula III used in the method of getting And as a starting compound can be obtained in the following way:

where Hal means a halogen atom, and Z and m have the previously defined values.

The connection represented by the General formula XII, halodrol, for example, glorieuses means, such as chloride thionyl, at a temperature of from 0aboutWith up to room temperature to obtain halogenopyrimidines derivative represented by the General formula III. When galoidirovaniya in the solvent used, for example, chloroform or dichloromethane.

The compound of formula IV used in the method of getting In as a starting compound can be obtained, for example, in the following way:

< / BR>
where Hal sacredscience General formula XIV, turn to the appropriate acetylate formula XVIII in the usual way. In this reaction using, for example, acetic anhydride or acetyl chloride.

Stage 2. The resulting acetylate hydrolyzing in the presence of acid or base to obtain the corresponding delovogo derivative of formula XIX.

Stage 3. Dialogue derivative of formula XIX halodrol, for example, glorieuses agent such as chloride thionyl, obtaining dihalogenide represented by the General formula XX. When this galoidirovaniya in the solvent used, for example, chloroform or dichloromethane.

Stage 4. The resulting dihalogenide formula XX is subjected to interaction with the compound represented by General formula II, with getting sulfide derivative represented by General formula IV.

This reaction is carried out in the presence of an acid acceptor selected from carbonates and acid carbonates of alkali metals such as potassium carbonate and sodium carbonate, alkali hydroxide, such as sodium hydroxide and potassium hydroxide. Examples of solvents used in the reaction include alcohols such as ethanol and methanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide and the of varicella, preferably from 40 to 60aboutC.

The alternate connection of the formula IV used in the method of getting In as a starting compound can be obtained in the following way:

where Hal means a halogen atom, and other symbols have the previously defined values.

I.e., the compound of formula IV can be obtained by gorodilova the compounds of formula I""', which is the target compound according to the invention and obtained by a method of receiving And conventional method. More precisely, the connection represented by the General formula (I""', halodrol, for example, glorieuses agent such as chloride thionyl, receiving a halide represented by the General formula IV. In this process haloiding as a solvent is preferably used chloroform or dichloromethane, and the reaction temperature maintained within the range from room temperature to 80aboutC.

The following examples of the preparation related to the preparation of raw materials for use in obtaining the target compounds according to the invention.

Example of getting 1. Synthesis of N-oxide of 4-(2-benzyloxyethyl)-2,3-dimethylpyridin - on

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1,82 g (of 79.13 mmol) of sodium was added to 50 ml benzyloxyethyl the temperature was added 5.0 g (31,76 mmol) of N-oxide of 4-chloro-2,3-dimethylpyridine. The resulting mixture was stirred at 110aboutWith one and a half hours, cooled to room temperature and filtered to remove insoluble phase. The filtrate was absorbed on silica gel with dichloromethane. The silica gel was treated with 5-30% ethyl acetate in hexane to extract benzyloxyethanol. Then the obtained silica gel was treated with 5-30% methanol in ethyl acetate and got to 7.15 g of N-oxide of 4-(2-benzyloxyethyl)-2,3-dimethylpyridine in the form of butter.

An NMR spectrum on nuclei1N (l) : 2,20 (s, 3H) 2,47 (C. 3H) of 3.8 to 4.0 (m, 2H), 4,1 of 4.25 (m, 2H) 4,6 (S. 2N) of 6.65 (d, I 7,03 Hz, 1H) 7,33), 5N) to 8.12 (d, I 7,03 Hz, 1H).

Example of getting a 2. Synthesis of 4-(2-benzyloxyethyl)-2-oxymethyl-3-methylpyridin - on

< / BR>
A mixture containing 6.5 g of N-oxide of 4-(2-benzyloxyethyl-2,3-dimethylpyridine and 56 ml of acetic anhydride was stirred at 80-90aboutWith 1 hour and distilled to remove acetic anhydride. The obtained residue was poorly podslushivaet aqueous solution of sodium carbonate and was extracted with ethyl ketone. The extract was dried over magnesium sulfate and distilled to remove ethyl ketone. Thus was obtained 7.0 g of 2-acetoxymethyl-4-(2-benzyloxyethyl)-3-methylpyridine. This intermediate compound was dissolved in 90 ml of ethanol is added followed what was agarawala with methyl ethyl ketone. Thus obtained extract was dried over magnesium sulfate and got to 5.4 g of 4-(2-benzyloxyethyl)-2-hydroxymethyl - 3-methylpyridine.

Range1N-f NMR (CDCl3) : 2.06 (C. 3H) 3,7 3,95 (m, 2H) 4,0 4,3 (m, 2H) 4,6 (C. 4H) 6,70 (l, I of 6.7 Hz, 1H) 7,33 (5H C.) of 8.27 (d, j=6,7 Hz, 1H).

Example of getting a 3. Synthesis of 4-(2-benzyloxyethyl)-2-chloromethyl-3-methylpyridin - on

< / BR>
to 5.3 g of 4-(2-benzyloxyethyl)-2-hydroxymethyl-3-methylpyridine was dissolved in 60 ml of chloroform to obtain a solution. To the resulting solution was added dropwise under ice cooling was added a solution of 5.8 g of chloride tiomila in 40 ml of chloroform. The resulting mixture was stirred at room temperature for 7 h and distilled under reduced pressure to obtain a residue. To the residue was added 200 ml of 2 N. of an aqueous solution of sodium carbonate. The resulting mixture was extracted with chloroform and the extract was dried over magnesium sulfate, and distilled to remove chloroform. Received 6.3 g of target compound indicated in the title of the example.

An NMR spectrum on nuclei1H (CDCl3) : 2,27 (C. 3H) 3,5 4,25 (m, 4H) 4,56 (C. 2H) 4,66 (C. 2H) 6,7 (D. I 5,71 Hz, 1H), 7,30 (5H C.) of 8.27 (D. I 5,71 Hz, 1H).

P R I m e R 1. 2-[{4-(2-Benzyloxyethyl)-3-methylpyridin-2-yl}-methylthio] gasoline - midazol.

< / BR>
A mixture containing 40 ml of ethanol was stirred while heating to 60aboutWith one and a half hours and distilled under reduced pressure to remove ethanol. The obtained residue was subjected to chromatography on a column of silica gel. The column was treated with 30-60% ethyl acetate in n-hexane and was obtained 2.0 g of the target compound as white crystals.

An NMR spectrum on nuclei1N (DCl3) : 2,8 (C. 3H) 3,8 3,9 (m, 2H) 4,15 of 4.25 (m, 2H) 4,37 (C. 2H) 4,62 (C. 2H) 6,74 (D. I, 5.7 Hz, 1H) 7,11 the 7.65 (m N) 8,32 (D. I 5,71 Hz, 1H).

P R I m e R 2. 2-[{(4-(2-benzyloxyethyl)-3-methylpyridin-2-yl}-methylsulphonyl] benzimidazole.

< / BR>
0.98 tiefer, obtained above, was dissolved in 40 ml of dichloromethane to obtain a solution. To the solution in portions at a temperature of from -30 to -40aboutWith added 521 mg m-chlormadinone acid followed by the addition 461 mg diethylamine. The resulting mixture was heated to 0aboutWith the subsequent addition of 20 ml of 1N. an aqueous solution of sodium carbonate. The resulting mixture was stirred 30 min and was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled to remove dichloromethane. The obtained residue was led from a mixture of dichloromethane-ether and received 0,78 g of target compound in the form of crystals.

M+1(UP>H (CDCl3) : 2,2 (C. 3H) 3,65 (3,98 (m, 2H) 4,04 to 4.28 (m, 2H) 4,59 (C. 2H) 4,78 (C. 2H) 6,98 (m I and 4.6 Hz, 1H) 7,05 of 7.8 (m N) by 8.22 (D. I and 4.6 Hz, 1H) 7,05 of 7.8 (m N) by 8.22 (D. I and 4.6 Hz, 1H) 13,6 (W, s, 1H).

P R I m e R s 3-5. The following compounds were obtained by the method similar to that described in example 1 or 2.

P R I m e R 3. 2-[{4-(2-benzyloxyethyl)-3-methylpyridin-2-yl} methylsulfinyl}-5-methoxy-1H-benzimidazole.

< / BR>
An NMR spectrum on nuclei1H (CDCl3) : 2,13 (C. 3H) of 3.78 (SD 3H) 3,62 3,90 (m, 2H) 4,1 4,3 (m, 2H) 4,5 (S. 2N) 4,7 (C. 2H) 6,76 for 7.12 (m, 3H) 7.23 percent (5H C.) of 7.48 (D. I and 9.1 Hz, 1H) 8,14 (D. I and 7.9 Hz, 1H).

P R I m e R 4. 2-[{4-(2-benzyloxyethyl)-3-methylpyridin-2-yl}methylsulfinyl] 5-trifluoromethyl-1H-benzimidazole.

< / BR>
An NMR spectrum on nuclei1H (CDCl3) : 2,18 (C. 3H) 3,7 to 3.92 (m, 2H) 4,1 4,34 (m, 2H) 4,58 (C. 2H) 4,78 (C. 2H), 6,94 (D. I 5,71 Hz, 1H) to 7.32 (5H C.) to 7.59 (D. I 8,79 Hz, 1H), 7,83 (D. I 8,79 Hz, 1H) 7,99 (C. 1H) 8,17 (D. I 5,71 Hz, 1H).

P R I m e R 5. 2-[{4-(2-(2-methoxyethoxy))-ethoxy-3-methylpyridin-2-yl} methylsulfinyl]-5-trifluoromethyl-1H-benzimidazole.

< / BR>
Sodium salt 2-[{ 4-(2-(2-methoxyethoxy))ethoxy-3-methylpyridin-2-yl} methylsulfinyl]-1H-benzimidazole.

< / BR>
0.45 g 2-[{4-(2-(2-methoxyethoxy))ethoxy-3-methylpyridin-2-yl}methylthio] benzimidazole was dissolved in 40 ml of dichloromethane to obtain a solution. the m by adding 0.16 g of triethylamine. The resulting mixture was heated to 0aboutAnd then added 20 ml of 1N. an aqueous solution of acid sodium carbonate. The resulting mixture was stirred 30 min and was extracted with dichloromethane. The extract was dried over magnesium sulfate and distilled to remove dichloromethane. To the obtained residue was added 12 ml of 0.1 G. of an aqueous solution of sodium hydroxide. The resulting mixture was stirred at room temperature for one hour followed by addition of absolute ethanol. The resulting mixture was evaporated to dryness under reduced pressure. The obtained residue was led from a mixture of ethanol-ether and received at 0.42 g of target compound in the form of sodium salt.

An NMR spectrum on nuclei1N (DMCO-d6) : 2,16 (C. 3H) 3,25 (C. 3H) 3,3 3,9 (m 6N) of 4.0 to 4.14 (m, 2H) 4,55 (AB square I of 13.18 Hz, 13,55 Hz, 2H) 6,8 6,9 (m, 3H) 7,4 7,5 (DD. I 6,15 Hz, is 3.08 Hz, 2H) 8,28 (D. I at 5.27 Hz, 1H).

P R I m e R s 7-10. The following compounds were obtained by the method similar to that described in example 6.

P R I m e R 7. Sodium salt of 5-methoxy-2-[{4-(2-(2-methoxyethoxy))ethoxy-3-methyl - pyridine-2-yl} methylsulfinyl]-1H-benzimidazole.

< / BR>
An NMR spectrum on nuclei1N (CD3OD) : 2,14 (C. 3H) 3,34 (C. 3H) to 3.6 (m, 4H) 3,84 (C. 5H) 4,18 (m, 2H) 6,76 (DD. I 9,36 Hz, 2,52 Hz, 1H) 6,9 (D. I 5,76 Hz, 1H) 7,14 (D. I 2,52 Hz, 1H), 7.5 (a D. I 9,36 Hz, methylsulfinyl]-1H-benzimidazole.

< / BR>
The NMR spectrum of nuclei 1H (DMSO-d6) : 2,16 (C. 3H) 3,4 3,9 (m 6N) 3,96 to 4.28 (m, 2H) 4,49 (C. 2H) 4,6 (AB square I of 12.6 Hz, 12,85 Hz, 2H) of 6.8 to 7.2 (m, 3H) 7,29 (C. 5N) to 7.5 (DD. I 5,16 Hz, 3,03 Hz, 2H) 8,25 (D. I 5,71 Hz, 1H).

P R I m e R 9. Sodium salt 2-[{4-(2-(2-benzyloxyethyl))ethoxy-3-methylpyridin-2-yl} methylsulfinyl]-5-methoxybenzimidazole.

< / BR>
An NMR spectrum on nuclei 1H (DMSO-d6) : 2,16 (C. 3H) 3,63 (m, 4H) 3,74 (C. 3H) of 3.85 (m, 2H) 4,18 (m, 2H) 4,49 (C. 2H) 4,55 (AB square I of 13.18 Hz, 13,55 Hz, 2H) 6,6 (DD. I 9,35 Hz, 3,20 Hz, 1H) 7.03 is (D. I 2,63 Hz, 1H) 6.89 in (D. I 5,72 Hz, 1H) compared to 8.26 (D. I 5,72 Hz, 1H).

P R I m e R 10. Sodium salt 2-[{4-(2-(2-benzyloxyethyl)ethoxy-3-methylpyridin-2-yl} methylsulfinyl]-5-triftoratsetata.

< / BR>
An NMR spectrum on nuclei 1H (DMSO-d6) : 2,16 (C. 3H) 3,62 (I. 4H) 3,79 (m, 2H) 4,48 (C. 2H) 4,57 (AB kV, I of 13.18 Hz, 12,29 Hz, 2H) 6,93 (D. I 5,71 Hz, 1H) 7,16 (DD, I 8.35 Hz, 1.75 Hz, 1H) 7,29 (C. 5H) 7,62 (D. I 8.35 Hz, 1H) 8,28 (D. I 5,71 Hz, 1H).

Example 4. N-oxide of 4-(2-acetoxy)-2,3-dimethylpyridine.

< / BR>
4,60 g (0.2 mol) of metallic sodium was dissolved in 80 ml of ethylene glycol under ice cooling to a solution. This solution was stirred in nitrogen atmosphere at 100aboutC for 1 h followed by the addition 15,76 g (0.1 mol) of N-oxide of 4-chloro-2,3-dimethylpyridine when on origonaly to the dry residue to remove the ethylene glycol. The obtained residue was purified by chromatography on a column of silica gel (solvent was a mixture of chloroform-methanol 19:1) and received 13,28 g of 4-(2-acetoxy)-2,3-dimethylpyridine in the form of N-oxide, which is the white crystals.

An NMR spectrum on nuclei1N (SD3OD) : 2,29 (C. 3H) 2,55 (C. 3H) 3,39 (so 2N) 4,20 (so 2N)? 7.04 baby mortality (A. N) 8,18 (A. N).

Example of getting a 5. N-oxide of 4-(2-chloroethoxy)-2,3-dimethylpyridine.

< / BR>
1.0 ml of chloride tiomila was gradually added to a solution of 0.92 g (5 mmol) of 4-(2-acetoxy)-2,3-dimethylpyridine N-oxide in 10 ml of chloroform under cooling with ice. The resulting mixture was heated for 2 h under reflux, left to cool, neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted twice with 100 ml of methyl ethyl ketone. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on a column of silica gel (solvent mixture of chloroform and methanol in the ratio 19:1) and was obtained 0.56 g of N-oxide of 4-(2-chloroethoxy)-2,3-dimethylpyridine in the form of colorless crystals.

An NMR spectrum on nuclei1N (l3) : 2,24 (C. 3H) 2,54 (C. 3H) 3,86 (so 2N) 4,28 (so 2N) 6,62 (A. N) 8,17 (A. N).

Example of getting a 6. N-oxide-2,3-dim-dimethylpyridine, of 0.30 g (3 mmol) of succinimide, of 0.48 g (3.5 mmol) of potassium carbonate and 30 ml of methyl ethyl ketone was heated under reflux for 2 hours, left to cool and filtered. The filtrate is evaporated to dryness to remove methyl ethyl ketone. The obtained residue was purified by chromatography on a column (solvent a mixture of chloroform and methanol in the ratio 19:1) and was obtained 0.12 g of N-oxide, 2,3-dimethyl-4-(2-succinimides)pyridine in the form of white crystals.

An NMR spectrum on nuclei1N (l3) : 2,12 (C. 3H) 2,49 (C. 3H) 2,73 (C. 4H) 3,80 4,25 (m, 4H) 6,51 (D. H) 8.03 (A. N).

Example of getting a 7. 2-Chloromethyl-3-methyl-4-(2-succinimides)pyridine

< / BR>
0.12 g of N-oxide, 2,3-dimethyl-4-(2-succinimides)pyridine was dissolved in 5 ml of acetic anhydride to obtain a solution. This solution was stirred at 100aboutHalf an hour and cooled, followed by adding 30 ml of ethanol. The resulting mixture was stirred at room temperature for half an hour and person to distil to remove solvent. Thus was obtained 0.14 g of the crude 2-acetoxymethyl-3-methyl-4-(2-succinimides)pyridine in the form of butter.

An NMR spectrum on nuclei1N (l3) : 2,10 (C. 3H) 2,14 (C. 3H) 2,72 (C. 4H) 3,72 4,24 (m, 4H) 5,15 (C. 2H) 6,61 (A. N) 8,24 (A. N).

This acetoxymethyl 100aboutWith in half an hour, cooled, neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted twice with 100 ml of chloroform. The obtained extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and was obtained 0.12 g of the crude 2-hydroxymethyl-3-methyl-4-(2-succinimides)pyridine as colorless crystals.

An NMR spectrum on nuclei1N (l3) : 1,93 (C. 3H) 2,68 (C. 4H) 3,80-4,22 (m, 4H) 4,56 (C. 2H) 6,59 (D. 1H) 8,21 (A. N).

This crude hydroxymethylene derivative was dissolved in 5 ml of chloroform to obtain a solution. To this solution was added dropwise under ice cooling 0.11 g of chloride tiomila. The resulting mixture was heated under reflux for half an hour, cooled, neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted twice with 100 ml of chloroform. The obtained extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in vacuum. Received 0.07 g of 2-chloromethyl-3-methyl-4-(2-succinimides)pyridine in the form of white polikristallov.

An NMR spectrum on nuclei1N (l3) : 2,15 (C. 3H) 2,68 (C. 4H) 3,80 4,20 (m, 4H) 4,60 (C. 2H) 6,61 (A. N) by 8.22 (A. N).

P R I m e R 11. 2-[{3-Methyl-4-(2-actinomycetaceae, 0.06 g (0.21 mmol) of 2-chloromethyl-3-methyl-4-(2-succinimides)pyridine, 0.03 g (0.21 mmol) of potassium carbonate and 10 ml of methyl ethyl ketone was heated under reflux in nitrogen atmosphere for 3 h, cooled and filtered. The filtrate was concentrated and dried in vacuum followed by the addition of water. The mixture three times was extracted with 50 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on a column of silica gel. Was obtained 0.08 g of 2-[{3-methyl-4-(2-succinimides)pyridine-2-yl}methylthio]-1H - benzimidazole in the form of white crystals.

An NMR spectrum on nuclei1N (l3) : 2,09 (C. 3H) 2.63 in (C. 4H) 3,72 of 4.16 (m, 4H) 4,27 (C. 2H) 6,53 (A. N) 6,90 7,50 (m, 4H) 8,13 (A. N).

P R I m e R 12. 2-[{3-Methyl-4-(2-succinimides)pyridine-2-yl}methylsulfinyl] -1H-benzimidazole.

< / BR>
0.18 g of 95% m-chlormadinone acid was gradually added to a solution of 0.40 g (1 mmol) 2-[{3-methyl-4-(2-succinimides)pyridine-2-yl}methylthio] -1H - benzimidazole in 20 ml of dichloromethane at -60aboutWith to obtain a mixture. The mixture was stirred for half an hour followed by the addition of 0.15 g of triethylamine. The resulting mixture was heated to -10aboutWith, then added 30 ml of a saturated aqueous solution of acid carbonate is hatom magnesium and filtered. The filtrate was concentrated and dried in vacuum to obtain the crude product. The crude product was led from a mixture dichloromethylsilane ether and was obtained 0.36 g of 2-[{3-methyl-4-(2-succinimides)pyridine-2-yl} methylsulfinyl - 1H-benzimidazole in the form of white crystals.

An NMR spectrum on nuclei1N (l3) : 2,12 (C. 3H) 2,73 (C. 4H) 3,83 the 4.29 (m, 4H) 4,56 to 4.92 (m, 2H) 6,65 (A. N) 7,17 7,72 (m, 4H) 8,25 (A. N).

P R I m e p 13. 5-Methoxy-2-[{3-methyl-4-(2-succinimides)pyridine-2-yl} methylthio]-1H-benzimidazole.

< / BR>
The target compound was obtained by a method similar to that described in example 11.

An NMR spectrum on nuclei1N (l3) : 2,20 (C. 3H) 2,74 (C. 4H) 3,84 (C. 3H) 3,88 ( of 4.38 (m, 4H) 4,35 (S. 2N) of 6.71 (A. N) 6,80 of 7.48 (m, 3H) 8,35 (A. N).

P R I m e R 14. 2-[{3-Methyl-4-(2-succinimides)pyridine-2-yl}-methylthio]-5 - trifluoromethyl-1H-benzimidazole.

F3C

The specified connection was obtained in a manner analogous to the one described in example 11.

An NMR spectrum on nuclei1N (l3) : 2,22 (C. 3H) 2,75 (C. 4H) 3,88 4,08 (m, 2H) 4,08 to 4.28 (m, 2H) 46,45 (C. 2H) 6.73 x (A. N) 7,32 ( 7,86 (m, 3H) 8,32 (A. N).

P R I m e R 15. 5-Methoxy-2-[{3-methyl-4-(2-succinimides)pyridine-2-yl} methylsulfinyl]-1H-benzimidazole.

< / BR>
The specified connection is 3) : 2,13 (C. 3H) 2,74 (C. 4H) 3,86 (C. 3H) 3,60 4,30 (m, 4H) 4,50 4,90 (m, 2H) 6,65 (A. N) 6,80 to 7.68 (m, 3H) 8,25 (A. N).

P R I m e R 16. 2-[{3-Methyl-4-(2-succinimides)pyridine-2-yl}methylsulfinyl] -1H-5-triftoratsetata.

< / BR>
The specified connection was obtained in a manner analogous to the one described in example 12.

An NMR spectrum on nuclei1N (l3) : 2,23 (C. 3H) 2,75 (C. 4H) 3,80 of 4.45 (m, 4H) 4,67 (m, 2H) 6,74 (A. N) 7,30 8,00 (m, 3H) of 8.37 (A. N).

Example of getting 8. N-oxide, 2,3-dimethyl-4-(2-pyridylmethylene)pyridine.

< / BR>
0.39 g of 60% sodium hydride was added to a suspension of 1.20 g (6.5 mmol) of N-oxide of 4-(2-acetoxy)-2,3-dimethylpyridine in 40 ml of tetrahydrofuran under ice cooling in a nitrogen atmosphere to obtain a mixture. This mixture was stirred for half an hour followed by the addition of 0.83 g (6.5 mmol) of 2-chloromethylpyridine. The resulting mixture was heated under reflux for 8 h, cooled and filtered. The filtrate was concentrated and purified by chromatography on a column of silica gel (solvent was a mixture of ethyl acetate n-hexane in the ratio of 4: 1 and chloroform-methanol in the ratio 19:1). Received and 0.61 g of N-oxide, 2,3-dimethyl-4-(2-pyridylmethylene)pyridine.

An NMR spectrum on nuclei1N (l3) : 2,20 (C. 3H) 2,50 (C. 3H) 3,80 of 4.04 (m, 2H) 4.04 the 4,28 (is imitatsiei)Piri - DIN.

< / BR>
Mixture of 0.60 g of N-oxide, 2,3-dimethyl-4-(2-pyridylmethylene)Piri - DIN in acetic anhydride, stirred at 100aboutHalf an hour and was cooled, then added 40 ml of ethanol. The resulting mixture was stirred for half an hour at room temperature and distillation solvent was removed. The residue was dried in vacuum and got to 0.47 g of the crude 2-acetoxy-3-methyl-4-(2-pyridylmethylene)pyridine in the form of butter.

This crude intermediate was dissolved in 1 N. hydrochloric acid to obtain a solution. This solution was stirred at 100about1 h, cooled, neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted twice with 50 ml dichloromethane. Extract stitched over magnesium sulfate and filtered. The filtrate was concentrated and purified by chromatography on a column of silica gel (solvent was ethyl acetate) was obtained 0.40 g of 2-hydroxymethyl-3-methyl-4-(2-pyridylmethylene)pyridine as colorless polikristallov.

P R I m e R 17. 2-[{3-Methyl-4-(2-pyridylmethylene)pyridine-2-yl}methylthio]-1H - benzimidazole.

< / BR>
0.71 g (5 mmol) of chloride tiomila was added to a solution of 0.40 g (1.5 mmol) of 2-hydroxymethyl-3-methyl-4-(2-pyridyloxy-ethoxy)pirotechnia reaction mixture was neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted four times with 50 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The obtained filtrate was concentrated and dried in vacuum and received at 0.42 g of the crude 2-chloromethyl-3-methyl-4-(2-pyridyloxy - ethoxy)pyridine in the form of polikristallov.

A mixture containing 0.40 g of this crude intermediate compound 0.18 g of 2-mercapto-1H-benzimidazole to 0.19 g of potassium carbonate and 30 ml of methyl ethyl ketone was heated under reflux in nitrogen atmosphere for 2 hours, cooled and filtered. The filtrate was concentrated and purified by chromatography on a column of silica gel (solvent mixture of ethyl acetate n-hexane). Received of 0.38 g of 2-[{ 3-methyl-4-(2-pyridylmethylene)pyridine-2-yl} meth-ylthio]-1H - benzimidazole as colourless oil.

An NMR spectrum on nuclei1N (l3) : of 2.26 (SD 3H) 3,80 of 4.04 (m, 2H) 4,10 to 4.28 (m, 2H) 4,35 (C. 2H) 4,70 (C. 2H), 6,70 (A. N) 6,94 7,20 (m, 7H) 8,25 (A. N) 8,45 (A. N).

P R I m e R 18. 2-[{3-Methyl-4-(2-pyridylmethylene)pyridine-2-yl}metilsulfate - Neil]-1H-benzimidazole.

< / BR>
0.16 g m-chlormadinone acid was added to a solution of 0.38 g of 2-[{3-methyl-4-(2-pyridylmethylene)pyridine-2-yl}IU - tilty]-1H - benzimidazole in 20 ml of dichloromethane at -60aboutC in nitrogen atmosphere to obtain a mixture. This mixture was stirred for half an hour. At the end of reactivities 30 ml of a saturated aqueous solution of acid sodium carbonate. The resulting mixture was stirred at room temperature for half an hour and was extracted three times with 50 ml dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated and dried in vacuum to obtain the crude product. This crude compound was led from a mixture dichloromethylsilane ether and was obtained 0.31 g of 2-[{3-methyl-4-(2-pyridylmethylene)pyridine-2-yl} methylsulfinyl] 1H-benzimidazole in the form of white crystals.

An NMR spectrum on nuclei1N (l3) : 2,17 (C. 3H) 3,83 4,06 (m, 2H) 4,06 4,34 (m, 2H) 4.72 in (S. 2N) with 4.64 4,84 (m, 2H) 6,70 (A. N) 7,047,80 (m, 7H) of 8.27 (A. N) 8,55 (A. N).

Example 10. N-oxide, 2,3-dimethyl-4-[2-(2-pyrrolidone)ethoxy]pyridine.

< / BR>
0,42 g of sodium hydride was added to 30 ml of N,N-dimethylformamide at room temperature to obtain a mixture. This mixture was cooled to 0aboutWith the subsequent addition of 0.74 g of 2-pyrrolidone. The resulting mixture was stirred at 0aboutWith one and a half hours and cooled to room temperature followed by the addition of 1.17 g of N-oxide of 4-(2-chloroethoxy)-2,3-dimethylpyridine. The resulting mixture was stirred at a temperature of 60-80aboutWith 5 hours and cooled, followed by adding 20 ml of a saturated aqueous solution of acid sodium carbonate. Was polistirolo to obtain the crude product. This crude product was purified by chromatography on a column of silica gel and obtained 430 mg N-oxide, 2,3-dimethyl-4-[-2-(2-pyrrolidone)ethoxy]pyridine in the form of yellow crystals.

An NMR spectrum on nuclei1N (l3) : 2,2 (C. 3H) 2,54 (C. 3H) 1,9 2,5 (m, 4H) 3,57 (so I 7 Hz, 2H) of 3.73 (so I 6 Hz, 2H) 4,1 6 (D. I6 Hz, 2H) 6,65 (D. I 7 Hz, 1H) 8,15 (doctor I7 Hz, 1H).

Example of getting 11. 2-Chloromethyl-3-methyl-4-[-2-(2-pyrrolidone)ethoxy] Piri - DIN.

< / BR>
10 ml of acetic anhydride was added to 0.65 g of N-oxide, 2,3-dimethyl-4-[2-(2-pyrrolidone)ethoxy] pyridine at room temperature to obtain a mixture. This mixture was stirred at a temperature of 90about2 h followed by the addition of ethanol. The resulting mixture was kept under reduced pressure and got 0,79 g of the crude 2-acetoxymethyl-3-methyl-4-[2-(2-Pirro - don)ethoxy]pyridine.

20 ml of 1 N. hydrochloric acid was added to this crude intermediate compound to obtain a mixture. This mixture was stirred at 100about2 h, cooled, neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and received 510 mg of the crude 2-hydroximino1N (l3) : 2,04 (C. 3H) of 1.9 to 2.6 (m, 4H) to 3.58 (so I 7 Hz, 2H) of 3.73 (so I 6 Hz, 2H) 4,65 (C. 2H) 6,7 (doctor I7 Hz, 1H) 8.3 (the D. I 7 Hz, 1H).

500 g of this crude intermediate was dissolved in 10 ml of dichloromethane to obtain a solution. To this solution at -20aboutWith added dropwise 1.19 g of chloride tiomila. The resulting mixture was stirred at room temperature for 30 min, neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and got 0,57 mg of the crude 2-chloromethyl-3-methyl-4-[2-(2-pyrrolidon)ethoxy]pyridine in the form of butter.

An NMR spectrum on nuclei1N (l3) : 2,25 (C. 3H) 1,8 2,5 (m, 4H) 3,54 (so I 7 Hz, 2H) 3,68 (so I 6 Hz, 2H) 4,1 (so I 6 Hz, 2H) 6,62 (D. I, 6 Hz, 1H) by 8.22 (D. I, 6 Hz, 1H).

P R I m e R 19. 2-[3-Methyl-4-{2-(2-pyrrolidone)ethoxy}pyridine-2-yl]methylthio-1H - benzimidazole.

< / BR>
20 ml of methyl ethyl ketone was added to the mixture containing 0.55 g of 2-chloromethyl-3-methyl-[2-(2-pyrrolidone)ethoxy] pyridine, 0.3 g 2-mercapto-1H-benzimidazole and 0.33 g of potassium carbonate to obtain a mixture. This mixture was heated under reflux for 2 hours and filtered. The filtrate was concentrated to obtain the crude is I in the form of pale yellow crystals.

An NMR spectrum on nuclei1N (l3) : of 2.26 (SD 3H) 1,8 2,5 (m, 4H) 3,57 (so I 7 Hz, 2H) 3,7 (so I 6 Hz, 2H) 4,13 (so I 6 Hz, 2H) 4,34 (C. 2H) 6,66 (D. I, 6 Hz, 1H) 7,0 at 7.55 (m, 4H) 8,25 (D. I, 6 Hz, 1H).

P R I m e R 20. 5-Methoxy-2-[3-methyl-4-{2-(2-pyrrolidone)ethoxy}pyridine-2-yl] methylthio-1H-benzimidazole.

< / BR>
The specified connection was obtained by the method similar to that described in example 19.

An NMR spectrum on nuclei1N (l3) : 2,24 (C. 3H) 1,9 2,5 (m, 4H) 3,56 (so I 7 Hz, 2H) 3.72 points so I 6 Hz, 2H) 3,83 (C. 3H) 4,17 (so I 6 Hz, 2H) 4,4 (S. 2N) of 6.6 to 7.5 (m, 4H) 8,35 (D. I, 6 Hz, 1H).

P R I m e R 21. 2-[3-Methyl-4-{2-(2-pyrrolidon)ethoxy}pyridine-2-yl]methylthio-5 - trifluoromethyl-1H-benzimidazole.

< / BR>
The specified connection was obtained in a manner analogous to the one described in example 19.

An NMR spectrum on nuclei1N (l3) : 2,28 (C. 3H) 1,9 to 2.55 (m, 4H) 3,57 (so I 7 Hz, 2H) 3,74 (so I 6 Hz, 2H) 4,2 (so I 6 Hz, 2H) 4,4 (C. 2H) 6,7 7 (D. I, 6 Hz, 1H) 7,27 a 7.85 (m, 3H) scored 8.38 (D. I, 6 Hz, 1H).

P R I m e R 22. 2-[3-Methyl-4-{2-(2-pyrrolidone)ethoxy}pyridine-2-yl]metilsulfate-Nile - 1H-benzimidazole.

< / BR>
0.27 g of 2-[3-methyl-4-{ 2-(2-pyrrolidone)ethoxy}pyridine-2-yl]methylthio-1H - benzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. To this solution at -60aboutWith added 0.12 g of 95% m-chlormadinone acid. spent aqueous solution of acid sodium carbonate. The resulting mixture was extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain the crude product. This crude product was led from a mixture of dichloromethane-ether and was obtained 0.18 g of the target compound.

An NMR spectrum on nuclei1N (l3) : 2,18 (C. 3H) 1,9 2,5 (m, 4H) 3,53 (so I 7 Hz, 2H) of 3.73 (so I 6 Hz, 2H) 4,16 (so I 6 Hz, 2H) 4,74 (Avcv, I 14 Hz, 16 Hz, 2H) 6,7 (D. I, 6 Hz, 1H) of 7.2 to 7.7 (m, 4H) 6,25 (D. I, 6 Hz, 1H).

P R I m e R 23. 5-Methoxy-2-[3-methyl-4-{-(2-pyrrolidone)ethoxy}pyridine-2-yl] methylsulfinyl-1H-benzimidazole.

< / BR>
The specified connection was obtained in a manner analogous to the one described in example 22.

An NMR spectrum on nuclei1N (l3) : 2,17 (C. 3H) 1,9 2,5 (m, 4H) 3,88 of 3.78 (m, 4H) 3,8 (C. 3H) 4,1 (so I 6 Hz, 2H) 4,66 (AB square I 13 Hz, 12, 4 Hz, 2H) 6,6 (D. I, 6 Hz, 1H) 6,77 to 7.6 (m, 3H) 8,17 (D. I, 6 Hz, 1H).

P R I m e R 24. 2-[3-Methyl-4-{2-(2-pyrrolidone)ethoxy}pyridine-2-yl]metilsulfate-Neil-5 - trifluoromethyl-1H-benzimidazole.

< / BR>
The specified connection was obtained in a manner analogous to the one described in example 22.

An NMR spectrum on nuclei1N ( l3) : 2,17 (C. 3H) of 1.8 to 2.55 (m, 4H) of 3.4 to 3.8 (m, 4H) 4,75 (AB square I of 14.3 Hz, 17.5 Hz, 2H) 6,69 (D. I, 6 Hz, 1H) 7.24 to 8,0 e (m, 3H) 8,2 (D. I6 Hz, 1H).

An example of polucheniya 4-(2-hydroxy)-2,3-dimethylpyridine to obtain a solution. The solution was stirred at 90about2 h followed by the addition of ethanol. The resulting mixture was distilled under reduced pressure and obtained 4-(2-acetoacetate)-2-acetoxymethyl-3-methylpyridin.

20 g of sodium hydroxide, 20 ml of water and 50 ml of ethanol was added to this intermediate compound to obtain a mixture. This mixture was stirred at room temperature for 10 min and drove to remove ethanol, followed by adding 50 ml of a saturated aqueous solution of common salt. The resulting mixture was extracted with 2-butanol. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain 20 g of 4-(2-hydroxyethoxy)-2-hydroxymethyl-3-methylpyridine.

An NMR spectrum on nuclei1N (l3) : 2,02 (C. 3H) 3,9 4,2 (m, 4H) 4,50 (C. 2H) 6,63 (D. I, 6 Hz, 1H) 8,15 (D. I, 6 Hz, 1H).

11.9 g of the obtained 4-(2-hydroxyethoxy)-2-hydroxymethyl-3-methylpyridine was dissolved in 200 ml of dichloromethane to obtain a solution. To this solution was added dropwise at 0aboutWith 24 ml of chloride tiomila. The resulting mixture was stirred at room temperature for 2 hours and distilled under reduced pressure to remove the dichloromethane and excess chloride tiomila. To the residue was added saturated the t was dried over magnesium sulfate and filtered. The filtrate was concentrated and got to 10.9 g of 2-chloromethyl-4-(2-hydroxyethoxy)-3-methyl - pyridine.

An NMR spectrum on nuclei1N (l3) : 2,3 (C. 3H) 3,9 4,2 (m, 4H) 4,69 (C. 2H) 6.73 x (D. I, 6 Hz, 1H) 8.3 (the doctor I Hz, 1H).

P R I m e R 25. 2-[4-(2-hydroxyethoxy)-3-methylpyridin-2-yl]methylthio-5-methoxy - 1H-benzimidazole.

< / BR>
60 ml of ethanol was added to the mixture containing 0.7 g of 2-chloro-4-(2-hydroxyethoxy)-3-methylpyridine, 0,63 g 2-mercapto-5-methoxy-1H-benzimidazole and 0.16 g of sodium hydroxide to obtain a mixture. This mixture was stirred at 60about1 h, concentrated, purified by chromatography on a column of silica gel and got a 1.08 g of the specified target compounds.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,2 (C. 3H) 3,72 (C. 3H) 3,6 4,1 (m, 4H) 4,6 (C. 2H) 6,6 to 7.35 (m, 4H) 8,14 (D. I, 6 Hz, 1H).

P R I m e R 26. 2-[4-(2-hydroxyethoxy)-3-methylpyridin-2-yl]methylthio-1H-gasoline - imidazol

< / BR>
Specified target compound was obtained by a method similar to that described in example 25.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,24 (C. 3H) 3,6 4,18 (m, 4H) 4,7 (C. 2H) 6,93 (D. I, 6 Hz, 1H) 7,0 7,6 (m, 4H) 8,25 (D. I, 6 Hz, 1H).

P R I m e R 27. 2-[4-(2-hydroxyethoxy)-3-methylpyridin-2-yl]methylthio-5-Cryptor - methyl - 1H-benzimidazole

< / BR>
Specified target SUB>6) : 2,25 (C. 3H) 3,6 4,2 (m, 4H) 4,75 (S. 2N) of 6.96 (D. I, 6 Hz, 1H) 7,3 7,9 (m, 3H) 8,25 (D. I, 6 Hz, 1H).

P R I m e R 28. 2-[4-(2-hydroxyethoxy)-3-methylpyridin-2-yl]metalocalpyse - toxi - 1H-benzimidazole.

< / BR>
0.9 g of 2-[4-(2-hydroxyethoxy)-3-methylpyridin-2-yl]methylthio-5-methoxy-1H - benzimidazole was dissolved in a mixture containing 5 ml of methanol and 80 ml of dichloromethane to obtain a solution. To this solution at -60aboutWith added 0.51 g m-chlormadinone acid. The resulting mixture was stirred at a temperature of from -50 to -40aboutWith four and a half hours, followed by addition of 0.33 g of triethylamine. To the mixture was added saturated aqueous solution of acid sodium carbonate, and the resulting mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and obtained the crude product. This crude product was led from a mixture of dichloromethane-isopropyl ether and was received of 0.58 g of the specified target compounds.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,17 (C. 3H) 3,8 (C. 3H) 3,6 4,18 (m, 4H) 4,73 (AB square I 14 Hz 8 Hz, 2H) of 6.8 to 7.6 (m, 4H) 8,21 (D. I, 6 Hz, 1H).

P R I m e R 29. 2-[4-(2-hydroxyethoxy)-3-methylpyridin-2-yl]methylsulfinyl-1H - benzimidazole.

OF
THE M+1: 332.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,17 (C. 3H) 3,6 4,2 (m, 4H) 4,74 (C. 2H) 6,95 (D. I, 6 Hz, 1H) 7,18 to 7.77 (m, 4H) were 8.22 (D. I, 6 Hz, 2H).

P R I m e R 30. 2-[4-(2-hydroxyethoxy)-3-methylpyridin-2-yl]methylsulfinyl-5-trifluoromethyl-1H-benzimidazole

< / BR>
Specified target compound was obtained by a method similar to that described in example 28.

Example of receipt 13. N-oxide-4-(3-methoxypropane)-2,3-dimethylpyridine

< / BR>
2.0 g (22 mmol) of 3-methoxypropanol was dissolved in 50 ml of DMSO to obtain a solution. To this solution at room temperature was added 2.7 g (66 mmol) of sodium hydride. The resulting mixture was stirred at 60about1 h and cooled to room temperature followed by the addition of 3.0 g (19 mmol) of N-oxide of 4-chloro-2,3-dimethylpyridine. The resulting mixture was stirred at 40aboutWith 1 h After completion of the reaction, the reaction mixture was distilled to remove the dimethyl sulfoxide. The obtained residue was purified by chromatography on a column of silica gel and got 760 mg of 4-(3-methoxypropane)-2,3-pyridine in the form of N-oxide.

An NMR spectrum on nuclei1N (l3) : 2,1 (m, 2H) 2,2 (C. 3H) 2,54 (C. 3H) 3,35 (C. 3H) 3,55 (so I 6 Hz, 2H) 4,1 (so I 6 Hz, 2H) 6,65 (D. I 7,4 Hz, 1H) 8,16 (D. I 7,4 Hz, 1H).

Example the floor is 3.6 mmol) of N-oxide of 4-(3-methoxypropane)-2,3-dimethylpyridine for the reaction at 90aboutC for 1 h, the Reaction mixture was distilled to remove acetic anhydride followed by the addition of saturated aqueous solution of acid sodium carbonate. The resulting mixture was extracted with chloroform. The extract was concentrated and received 700 mg of 2-acetoxymethyl-4-(3-methoxypropane)-3 - methylpyridine as a brown oil.

To the above 2-acetoxymethyl-4-(3-methoxypropane)-3-methylpyridine was added 500 mg of sodium hydroxide and 15 ml of ethanol. The resulting mixture was stirred at 50aboutWith 1 h after completion of the reaction, the reaction mixture was distilled to remove ethanol and then adding water. The resulting mixture was extracted with chloroform. The chloroform layer was concentrated and received 450 mg of 2-hydroxymethyl-4-(3-methoxypropane)-3-methylpyridine as a brown oil.

An NMR spectrum on nuclei1N (l3) : 2,04 (C. 3H) 2,1 (m, 2H) 3,35 (C. 3H) 3,50 (so I 5.7 Hz, 2H) 4,12 (so I 5.7 Hz, 2H) with 4.64 (C. 2H) 6,7 (D. I 7 Hz, 1H) 8,24 (D. I 7 Hz, 1H).

450 mg of 2-hydroxymethyl-4-(3-methoxypropane)-3-methylpyridine, obtained above, was dissolved in 20 ml of dichloromethane to obtain a solution. To this solution at 0aboutWith dropwise added 760 mg chloride tiomila. The resulting mixture was stirred at komnatnogo of tonila. To the obtained residue was added a saturated aqueous solution of acid sodium carbonate. The resulting mixture was extracted with chloroform. The chloroform layer was concentrated and received 470 mg of 2-chloromethyl-4-(3-methoxypropane)-3-methylpyridine in the form of brown crystals.

An NMR spectrum on nuclei1N (l3) : 2,1 (m, 2H), and 2.27 (C. 3H) 3,36 (C. 3H) 3,56 (so I5,7 Hz, 2H) 4,12 (so I 5.7 Hz, 2H) 4,69 (S. 2N) of 6.71 (D. I 7 Hz, 1H) compared to 8.26 (D. I 7 Hz, 1H).

P R I m e R 31. 2-[{4-(3-methoxypropane)-3-methylpyridin-2-yl]methyl-thio] -1H - benzimidazole

< / BR>
20 ml of ethanol was added to the mixture containing 280 mg (1.8 mmol) of 2-mercapto-1H-benzimidazole, 470 mg (2 mmol) of 2-chloromethyl-4-(3-methoxypropane)-3-me - terpyridine and 100 mg (2.4 mmol) of sodium hydroxide. The resulting mixture was stirred at 50about3 hours After the reaction, the reaction mixture was distilled to remove ethanol. The obtained residue was purified by chromatography on a column of silica gel and got 590 mg of 2-[{4-(3-methoxypropane)-3-methylpyridin-2-yl} methylthio]-1H-benzimida - ash in the form of pale yellow crystals. An NMR spectrum on nuclei1N (l3) : 2,09 (so I 6,1 Hz, 2H) and 2.26 (C. 3H) 3,35 (C. 3H) 3,56 (so I 6,1 Hz, 2H) 4,13 (so I 6,1 Hz, 2H) 4,37 (C. 2H) 6,76 (D. I 6,1 Hz, 1H) 7,1 7,25 (m, 2H) 7.5 (a Shir.with. 2H) 8,33 (D. I 6,1 Hz, 1H).

P R I m e R 32. 2-{4-(3-Methoxyp the-2-yl}methylthio]-1H - benzimidazole was dissolved in the mixture, containing 100 ml of dichloromethane and 25 ml diethyl ether, to obtain a solution. To this solution in portions at a temperature of -45aboutWith added 2.83 g of 85% m-chlormadinone acid. After completion of the reaction the mixture was added 2 g of triethylamine, the resulting mixture was heated to -10aboutC, followed by adding 50 ml of 1 N. sodium hydroxide. The resulting mixture was stirred at room temperature for 30 minutes the Aqueous layer was twice washed with 20 ml dichloromethane and brought its pH to 112 M aqueous solution of ammonium acetate. The aqueous layer was extracted three times with 50 ml dichloromethane. The obtained dichloromethane layer twice washed with 50 ml saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and distilled to remove dichloromethane. The obtained oily product was led from a mixture of dichloromethane-ether and got to 4.17 g of the specified target compound as white crystals. The melting point 99-110aboutC (with decomposition).

An NMR spectrum on nuclei1N (l3) : 1,83 of 2.09 (m, 2H) 2,13 (C. 3H) 3,34 (C. 3H) 3,52 (so I 6.2 Hz, 2H) 4,05 (so I 6.2 Hz, 2H) 4,79 (C. 2H) 6,70 (D. I, 5.7 Hz, 1H) 7,07 7,30 (m, 2H) 7,30 7,60 (Shir.with. 2H) of 8.27 (D. I, 5.7 Hz, 1H).

P R I m e R 33. Sodium salt of 2-[{4-(3-methoxypropane)-3-methyl is-2-yl}methylthio] -1H - benzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. To this solution in portions at a temperature of -45aboutWith added 320 mg of 85% m-chlormadinone acid. After completion of the reaction the mixture was added 370 mg of triethylamine. The resulting mixture was heated to -10aboutWith the subsequent addition of a saturated aqueous solution of sodium carbonate. The resulting mixture was stirred at room temperature for 30 minutes and was extracted with dichloromethane. The extract was dried over magnesium sulfate and distilled to remove dichloromethane. Thus was obtained the crude product. This crude product was dissolved in 14.6 ml of 0.1 G. of an aqueous solution of sodium hydroxide to obtain a solution. This solution three times distilled together with 30 ml of ethanol to remove the water as an azeotropic mixture with ethanol, and dried in vacuum. To the obtained residue was added ether to precipitate white crystals. The crystals was three times washed with ether using decantation and dried in vacuum. Received 530 mg of sodium salt of 2-[{4-(3-methoxypropane)-3-methylpyridin-2-yl}IU-telcoline]-1H - benzimidazole. So pl. 140-141about(With Razlog.).

Mass spectrum M+1: 382.

An NMR spectrum on nuclei1H (DMSO-d6) : 1,99 (so I 6,1 Hz, 2H) 2,17 (C. 3H) 3,25 (C. 3H) 3,49 (so I 6,1 Hz, 2H) 4.09 to (so I 6,1 Hz, 2H) 4,56 (AB square I a 14.1 Hz, 21,3, Gclti] -1H - benzimidazole

< / BR>
80 ml of ethanol was added to the mixture containing 1.39 g (9,27 mmol) of 2-mercaptobenzimidazole, 2.0 g (9,27 mmol) of 2-chloromethyl-4-(3-hydroxypropoxy)-3-me-terpyridine and 0.44 g (11.1 mmol) of sodium hydroxide. The resulting mixture was stirred at 50aboutWith 1 h After the reaction, the reaction mixture was concentrated. The obtained residue was purified by chromatography on a column of silica gel and was obtained 1.7 g of the specified target compound, yield 56%

Mass spectrum M+1: 368

An NMR spectrum on nuclei1H (DMSO-d6) : 1,8 2,1 (m, 2H) 2,24 (C. 3H) 3,6 (so I 6 Hz, 2H) 4,2 (so I 6 Hz, 2H) 4,7 (C. 2H) 7,0 7,38 (m, 3H) 7,38 to 7.6 (m, 2H) 8,35 (D. I, 6 Hz, 1H).

P R I m e R 35. Sodium salt of 2-[{4-(3-hydroxypropoxy)-3-methylpyridin-2-yl}methylsulfinyl]-1H - benzimidazole

< / BR>
1.0 g (3.04 from mol) 2-[{4-(3-hydroxypropoxy)-3-methylpyridin-2-yl}methylthio]-1H - benzimidazole was dissolved in 100 ml of dichloromethane to obtain a solution. To this solution was added 580 mg of 90% m-chlormadinone acid at a temperature of -45aboutC. the resulting mixture was stirred 2 hours After completion of the reaction the mixture was added 470 mg of triethylamine. The resulting mixture was heated to -20aboutC, followed by adding 30 ml of a saturated aqueous solution of acid sodium carbonate. The MCA is Wali to obtain the crude product. The crude product was led from a mixture of dichloromethane-ether and received 830 mg of 2-[{4-(3-hydroxypropoxy)-3-methylpyridin-2-yl} matilal - vinyl] -1H - benzimidazole. This product was dissolved in 24 ml of 0.1 N. aqueous sodium hydroxide. The resulting solution was distilled with ethanol to remove the water in the form azeotropic mixtures with ethanol and dried under vacuum generated by the vacuum pump. To the obtained residue was added ether to precipitate colorless crystals. The crystals were separated by filtration. Thus received 860 mg of the specified target compounds with 77% yield.

An NMR spectrum on nuclei1H (DMSO-d6) : 1,7 2,1 (m, 2H) 2,16 (C. 3H) to 3.58 (so I 6 Hz, 2H) 4,12 (so I 6 Hz, 2H) 4,55 (AB square I 13 Hz, I 20 Hz, 2H) 6,7 7,0 (m, 3H) 7,3 7,6 (m, 2H) 8,27 (D. I, 6 Hz, 1H).

P R I m e R 36. 2-[{4-(2-chloroethoxy)-3-methylpyridin-2-yl}methylthio-1H-benzimida evil.

S

1.3 g of the crude 2-mercaptobenzimidazole, 20 g of the hydrochloride of 4-(2-chloroethoxy)-2-chloromethyl-3-methylpyridine and 11 g of sodium hydroxide was dissolved in 300 ml of ethanol to obtain a solution. This solution was stirred at 60aboutWith 2 hours and distilled under reduced pressure to remove ethanol. The obtained residue was chromatographically on a column of silica gel and was suirable 40% ethyl acetate in SS="ptx2">

An NMR spectrum on nuclei1N (l3) : of 2.24 (3H, s SN) of 3.80 (2H, so I 4 Hz, CH) 4,20 (2N, so I of 4.7 Hz, CH) and 4.40 (m, 2H, S, CH2) 6,62 (1H, d I 6 Hz) 7,00 7,40 (4H, m, Ar-H) 8,28 (1H, d I 6 Hz, PIR N, PIR-N).

P R I m e R 37. Sodium salt of 2-[{4-(2-methylthiouracil)-3-methylpyridin-2-yl} methylsulfinyl]-1H - benzimidazole

S

0.50 g of tiefer obtained in example 35 was dissolved in 20 ml of dichloromethane to obtain a solution. To this solution at a temperature of from -50 to -40aboutWith the parts added 0.36 g m-chlormadinone acid. After completion of the reaction the mixture at the same temperature of 0.21 g of triethylamine. The resulting mixture was heated to -20aboutC, followed by adding 20 ml of 1 N. aqueous solution of acid sodium carbonate. The resulting mixture was stirred 30 min and was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled to remove dichloromethane.

The crude sulfoxide was dissolved in 10 ml of ethanol followed by addition of 1 g of 15% aqueous solution of methylmercaptide sodium. The resulting mixture was stirred at 80aboutWith 4 hours and distilled to remove solvent. The residue was chromatographically on a column of silica gel and obtain the pure product. To this product was added to 7.2 ml of 1 N. aqueous sodium hydroxide and 20 ml of ethanol. The resulting mixture was evaporated to dryness under reduced pressure and got 460 mg of the specified target compounds.

Mass spectrum M+1: 384.

An NMR spectrum on nuclei1H (DMSO-d6) : to 2.18 (3H, s CH), 2,90 (2N, so I 7 Hz, CH) 4,24 (2N, so I 7 Hz, CH), 4,78 (2H, S. CH) 6,80 of 7.60 (4H, m, Ar-H) 6,98 (N, d I 6 Hz, PIR N) 8,30 (1H, d I 6 Hz, PIR-N).

P R I m e R 38. 2-[{4-(2-phenoxyethoxy)-3-methylpyridin-2-yl}methylthio] -1H - benzimidazol

< / BR>
A mixture containing 1.0 g of [4-(2-phenoxyethoxy)-3-methylpyridin-2-yl]methanol, of 0.60 ml chloride tiomila and 12 ml of dichloromethane maintained at 40aboutC for 60 min for reaction. The reaction mixture was distilled to remove solvent. Thus was obtained a residue in the form of a brown syrup. To the residue was added 50 ml of ethanol, 0,70 g of sodium hydroxide and 1.2 g of 2-mercaptobenzimidazole. The resulting mixture was heated at 70aboutWith 2 hours and distilled to remove the ethanol. The obtained residue was chromatographically on a column of silica gel and was suirable 30% ethyl acetate in hexane and then ethyl acetate was obtained 1.2 g of the specified target compound as a white solid.

An NMR spectrum on nuclei1
< / BR>
0,70 g tiefer obtained in example 37 was dissolved in 200 ml of dichloromethane to obtain a solution. To this solution in portions at a temperature of from -30 to -40aboutWith added 0.39 g m-chlormadinone acid. After the reaction in the reaction mixture at the same temperature was added 0.12 g of triethylamine. The resulting mixture was heated from -10aboutWith up to 10aboutWith 30 min. the Resulting dichloromethane layer was washed with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and distilled to remove dichloromethane. The obtained residue was dissolved in a mixture containing 20 ml of ethanol and 1.8 ml of aqueous sodium hydroxide to obtain a solution. This solution is evaporated to dryness under reduced pressure. The residue was led from a mixture of ethanol-ether and received and 0.61 g of the specified target compound as a brown solid.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,17 (3H, s) 4,32 (4H, s) 4,36 (1H, d) I 13 Hz) and 4.68 (1H, d I 13 Hz) 6,74 7,44 (10H, m) by 8.22 (1H, d I 6 Hz).

P R I m e R 40. 2-[{4-(2-(2-haritaki)-3-methylpyridin-2-yl}methylthio]-1H - benzimidazole and 2-[{4-(2-(2-acetoxy)ethoxy-3-)- methylpyridin-2-yl}methylthio] 1H-benzimidazole

S

< / BR>
of 0.54 g of sodium hydroxide was added to ethanol[2-hydroxyethoxy)ethoxy-3-methyl - pyridine, which was obtained by chlorination of 2-hydroxymethyl-4-[2-(2-hydroxyethoxy)ethoxy]-3-methylpyridine and 2.0 g of 2-mercapto-1H-benzimidazole to obtain a mixture. This mixture was stirred at 60aboutWith one and a half hours, cooled and distilled under reduced pressure to remove ethanol. The obtained residue was chromatographically on a column of silica gel and was suirable a mixture of ethyl acetate with n-hexane and then with a mixture of methanol-ethyl acetate. Received 1.0 g 2-[{4-(2-(2-chloroethoxy)ethoxy)-3-methylpyridin-2-yl}-methylthio]-1H - gasoline - imidazole.

An NMR spectrum on nuclei1N (l3) : 2,28 (C. 3H) 3,56 of 4.04 (m 6N) 4,04 4,32 (m, 2H) 4,4 (C. 2H) 6,76 (D. I, 6 Hz, 1H) 7,08 to 7.32 (m, 3H) 7,4 7,56 (m 2N) at 8.36 (D. I, 6 Hz, 1H) and 1.9 g 2-[{4-(2-(2-hydroxyethoxy)ethoxy)-3-methylpyridin-2-yl}methylthio] 1H-benzimidazole.

An NMR spectrum on nuclei1N (l3) : 2,24 (C. 3H) 3,56 to 4.28 (m, 8H) 4,4 (C. 2H) 6,12 (D. I 7 Hz, 1H)? 7.04 baby mortality to 7.32 (m, 2H) 7,4 to 7.68 (m, 2H) 8,32 (D. I 7 Hz, 1H).

P R I m e R 41. Sodium salt 2-[{4-(2-(2-chloroethoxy)ethoxy)-3-methylpyridin-2 - yl}-methylsulfinyl] -1H-benzimidazole

< / BR>
0,57 g m-chlormadinone acid in parts was added to a solution of 1.0 g 2-[{ 4-(2-) (2-chloroethoxy)ethoxy-3-methylpyridin-2-yl} methylthio]-1H - benzimidazole in 80 ml of dichloromethane under stirring and dehydration at -50aboutC. Receiving the temperature. The resulting mixture was podslushivaet 2 N. aqueous sodium carbonate solution at -10aboutWith and was extracted with dichloromethane. The extract was dried over magnesium sulfite and distilled to remove dichloromethane. Thus received in the remainder of 1.0 g of product. This residue was dissolved in 26 ml of 0.1 N. aqueous sodium hydroxide with subsequent addition of ethanol. The resulting mixture was distilled under reduced pressure. To the obtained residue was added ethanol, and the mixture was again distilled under reduced pressure to obtain a residue. To this residue was added ether and was obtained 1.07 g of crystals.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,17 (C. 3H) 3,56 of 3.96 (m 6N) of 4.0 to 4.28 (m, 2H) 4,04 (D. I and 12.6 Hz, 1H) 4,68 (D. I and 12.6 Hz, 1H) 6,76 of 8.04 (m, 3H) of 7.36 to 7.6 (m, 2H) compared to 8.26 (D. I, 6 Hz, 1H).

P R I m e R 42. 2-[{4-(3-ethoxy)propoxy-3-methylpyridin-2-yl}methylthio] -1H - benzimidazole

< / BR>
A mixture containing 4,2 G4-(3-ethoxypropane)-3-methylpyridin-2-yl}methyl ether methanesulfonate of 1.87 g of 2-mercaptobenzimidazole and 30 ml of ethanol was stirred at room temperature for 1 hour and distilled to remove the ethanol. The obtained residue was chromatographically on their column of silica gel and was obtained 0.88 g of target compound and 5.1 g of methansulfonate target compound.

Range C, 2H) 4,36 (C. 2H) 6.73 x (D. I, 5.7 Hz, 1H) 6,97 7,20 (m, 2H) 7,32 of 7.55 (m, 2H) 8,31 (D. I, 5.7 Hz, 1H).

P R I m e R 43. Sodium salt of 2-[{4-(3-ethoxypropane)-3-methylpyridin-2-yl}IU-telcoline]-1H - benzimidazole

< / BR>
0.6 g of 2-[{4-(3-methylpyridin-2-yl}methylthio]-1H-benzimidazole was dissolved in 30 ml of dichloromethane to obtain a solution. To this solution at -45aboutWith added and 0.37 g of 85% m-chlormadinone acid. After 2 h, to the mixture was added of 0.43 g of triethylamine, followed by addition of 30 ml of a saturated aqueous solution of acid sodium carbonate. The resulting mixture was vigorously stirred at room temperature for 1 h and was extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was dissolved in 16 ml of 0.1 N. aqueous sodium hydroxide and the resulting solution was distilled to remove water. The residue was dried under reduced pressure and was led out of the ether. Received of 0.54 g of the target compound.

An NMR spectrum on nuclei1H (DMSO-d6) : 1,11 (so I 7,0 Hz, 3H) 1,7 (2,1 (m, 2H) 2,15 (C. 3H) of 3.2 to 3.5 (m, 4H) 3,65 (C. 3H) 4.09 to (I. I6,2 Hz, 2H) 4,49 (AB square I and 11.8 Hz, 17,0 Hz, 2H) 6,65 to 7.0 (m, 3H) of 7.2 to 7.6 (m, 2H) 8,2 (D. I and 5.6 Hz, 1H).

P R I m e R 44. 2-[{4-(3-methoxyethoxy)propoxy-3-methylpyridin-2-yl}-mate the CSOs ether methanesulfonate, 0,76 g of 2-mercaptobenzimidazole, 0.29 grams of sodium hydroxide and 50 ml of ethanol was stirred at room temperature for 1 hour and distilled to remove the ethanol. The resulting residue was purified on a column of silica gel by chromatography and was obtained 1.4 g of the target compound.

An NMR spectrum on nuclei1N (l3) : 1,9-2,2 (m, 2H) and 2.26 (C. 3H) 3,33 (C. 3H) of 3.73 (so I 8,1 Hz, 2H) 4,16 (so I 6,1 Hz, 2H) to 4.38 (C. 2H) 4,62 (C. 3H) 6,76 (D. I, 5.7 Hz, 1H) 7,0 7,2 (m, 2H) 7,3 7,6 (m 2N) to 8.34 (D. I, 5.7 Hz, 1H).

P R I m e R 45. Sodium salt of 2-[{4-(3-methoxyethoxy)propoxy-3-metylene - DIN-2-yl}methylsulfinyl] -1H-benzimidazole

< / BR>
0.6 g of 2-[{4-(3-methoxyethoxy)propoxy-3-methylpyridin-2-yl}methylthio]-1H - benzimidazole was dissolved in 40 ml of dichloromethane to obtain a solution. To this solution at a temperature of -45aboutWith added 0.35 g of 85% m-chlormadinone acid. After 2 h the mixture at -30aboutWith added 0.64 g of triethylamine, followed by addition of 40 ml of a saturated aqueous solution of acid sodium carbonate. The resulting mixture was vigorously stirred at room temperature for 30 minutes and was extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. The residue was dissolved in 14.4 ml of 0.1 N. the aqueous hydroxide Nati, was led from the ether and received 0,57 g of target compound.

An NMR spectrum on nuclei1H (DMSO-d6) : 1,9 2,2 (m, 2H) 2,17 (C. 3H) 3,22 (C. 3H) 3,63 (so I 5.7 Hz, 2H) 4,12 (so I 5.7 Hz, 2H) 4,56 (S. 2N) TO 4.41 4,85 (2N) 6,84 (to 7.1 (m, 3H) 7,4 a 7.62 (m, 2H) compared to 8.26 (D. I 6,1 Hz, 1H).

P R I m e R 46. 2-[{4-(2-methoxyethoxy)ethoxy-3,5-dimethylpyridin-2-yl} methyl - thio]-1H - benzimidazole

< / BR>
The mixture containing the 3.0 G4-(2-methoxyethoxy)ethoxy-3,5-dimethylpyridin-2-yl} methyl ether methanesulfonate, 1,17 g of 2-mercaptobenzimidazole and 30 ml of ethanol was stirred at room temperature for 1 hour and distilled to remove the ethanol. The residue was purified by chromatography on a column of silica gel and was obtained 0.9 g of the target compound.

An NMR spectrum on nuclei1N (l3) : 2,28 (C. 3H) 2,33 (C. 3H) 3,37 (c. 3H)of 3.5 to 3.9 (m 6N) 3,9 4,2 (m, 2H) 4,37 (S. 2N) of 7.1 to 7.3 (m, 3H) 7,3 the 7.65 (m, 2H) 8,24 (C. 1H).

P R I m e R 47. Sodium salt of 2-[{4-(2-methoxyethoxy)ethoxy-3,5-dimethylene - DIN-2-yl}methylsulfinyl] -1H-benzimidazole

< / BR>
0.5 g of 2-[{4-(2-methoxyethoxy)ethoxy-3,5-dimethylpyridin-2-yl}methylthio] -1H - benzimidazole was dissolved in 30 ml of dichloromethane to obtain a solution. To this solution at -45aboutWith added 0.29 grams of 85% m-chlormadinone acid. After 2 h, to the mixture was added 0.34 triethylamine Toi temperature for 1 h and was extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was dissolved in 12 ml of 0.1 N. aqueous sodium hydroxide to obtain a solution. This solution was distilled to remove water. The obtained residue was dried under reduced pressure and was led out of the ether. Received 0,57 g of target compound.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,21 e (C. 6N) 3,25 (C. 3H) 3,3 3,7 (m 6N) of 3.7 to 4.0 (m, 2H) 4,39 (AB square I 13,2 Hz, 20.7 Hz, 2H) 6,65 of 6.9 (m, 2H) of 7.2 to 7.5 (m, 2H) 8,21 (C. 1H).

P R I m e R 48. 5-Carboxy-2-[{4-(2-benzyloxy)ethoxy-3-methylpyridin-2-yl} methylthio]-1H-benzimidazole

< / BR>
A mixture containing 1.26 g of 5-carboxymethylaminomethyl, 1.8 g of 4-(2-benzyloxyethyl)-2-chloromethyl-3-metylene - DIN, of 0.57 g of sodium hydroxide and 150 ml of methanol was stirred at 50aboutWith one and a half hours and distilled under reduced pressure to remove methanol. The obtained residue was purified by chromatography on a column of silica gel and recrystallized from methanol-ethyl acetate. Received 1.52 g of the target compound.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,25 (C. 3H) 3,65 of 3.9 (m, 2H) 4,1 4,3 (m, 2H) 4,58 (C. 2H) 4,74 (C. 2H) 6,95 (D. I, 5.7 Hz, 1H) 7,92 (C. 5H) 7,50 (D. I 8,3 Hz, 1H) 7,79 (DD. I 1.3 Hz, 8,3 Hz, 1H) 8,04 (C. 1H) 8,24 (D. I, 5.7 Hz, 1H).

An NMR spectrum on nuclei 1N (DSMO-d6) : 1,35 (so I 7,0 Hz, 3H) 2,25 (C. 3H) of 3.7 to 3.9 (m, 2H) 4,15 to 4.3 (m, 2H) 4,24 (square I 7,0 Hz, 2H) 4,57 (C. 2H) 4,75 (S. 2N) of 6.96 (D. I 5.7 Hz), 7,32 (C. 5H) 7,52 (D. I and 8.5 Hz, 1H) 7,79 (DD. I 1.3 Hz, 8.5 Hz, 1H) 8,05 (D. I, 1.3 Hz, 1H) 8,24 (D. I, 5.7 Hz, 1H).

P R I m e R 50. Sodium salt of 5-etoxycarbonyl-2-[{4-(2-benzyloxy)ethoxy-3-IU-terpyridine-2-yl} methylsulfinyl]-1H-benzimidazole

< / BR>
0.7 g of 5-etoxycarbonyl-2-[{4-(2-benzyloxy)ethoxy-3-methylpyridin-2-yl} methylthio] -1H-benzimidazole was dissolved in 50 ml dichloro the Noah acid. After 2 h the resulting mixture was heated to -30aboutWith the subsequent addition of 0.43 g of triethylamine. After 30 min the resulting mixture was heated to -10aboutAnd then added 50 ml of a saturated aqueous solution of acid sodium carbonate. The resulting mixture was vigorously stirred at room temperature for 30 minutes and was extracted with dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated, and the residue was dissolved in 10 ml of dichloromethane followed by addition of 0,056 g of 60% sodium hydride. The resulting mixture was stirred at room temperature for 30 minutes and distilled to remove dichloromethane. The resulting residue was led from the ether and received 0,59 g the specified connection.

An NMR spectrum on nuclei1H (DMSO-d6) : 1,34 (so I 7,0 Hz, 3H) 2,18 (C. 3H) of 3.7 to 3.9 (m, 2H) 4,1 4,3 (m, 2H) 4,24 (square I 7,0 Hz, 2H) 4,57 (C. 3H) 4,65 (C. 2H) 6,94 (D. I, 5.7 Hz, 1H) 7,30 (C. 5H) 7,50 7,86 (m, 3H) compared to 8.26 ( I 5.7 Hz, D. 1H).

P R I m e R 51. 2-[4-(4-methoxyphenoxy)pyridine-2-yl]methylthio-1H-benzimida evil

< / BR>
A mixture containing 2.55 g (of 0.017 mol) of 2-mercaptobenzimidazole, 5,09 g (0,022 mol) of 2-chloromethyl-4-(4-methoxyphenoxy)pyridine 0.84 g (at 0.020 mol) of 95% sodium hydroxide and 60 ml of ethanol was stirred at 40aboutWith an hour and a half. After completion of the reactions is the NCA from silica gel with a mixture of ethyl acetate and n-hexane) and received 4,13 g the specified connection.

An NMR spectrum on nuclei1H (DMSO-d6) : 1,431,84 (m, 4H) 3,21 (C. 3H) 3,31 (so I 6.2 Hz, 2H) 3,99 (so I 6.2 Hz, 2H) 4,59 (S. 2N) of 6.75 6.89 in (m, 1H)? 7.04 baby mortality 7,21 (m, 2H) 7,25 7,56 (m, 2H) 8,31 (D. I, 6.2 Hz, 1H).

P R I m e R 52. Sodium salt of 2-[4-(4-methoxyphenoxy)pyridine-2-yl]matilal-vinyl-1H-benzimidazole

CH

of 2.06 g (0,006 mol) of 2-[4-(4-methoxyphenoxy)pyridine-2-yl]methylthio-1H-benzimida-ash was dissolved in 80 ml of dichloromethane to obtain a solution. To this solution at -40aboutC in an atmosphere of nitrogen was added to 1.30 g (0,006 mol) of 80% m-chlormadinone acid and 5 ml of methanol. The resulting mixture was stirred one hour and a half. After completion of the reaction the mixture was added 1.0 g of triethylamine. The resulting mixture was heated to -10aboutC, followed by adding 50 ml of 2 N. of an aqueous solution of sodium carbonate. The resulting mixture was stirred at room temperature for 30 min and twice was extracted with 150 ml of dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent, and the resulting residue was dried in vacuum to obtain oil. This oil was dissolved in 54 ml of 0.1 N. aqueous sodium hydroxide with subsequent addition of ethanol. The resulting mixture was distilled to remove solvent. The resulting residue three respectr NMR nuclei1H (DMSO-d6) : 1,40 of 1.74 (m, 4H) 3,17 3,40 (m, 2H) 3,23 (C. 3H) 3,66 3,88 (m, 2H) 4,48 (AB square I of 12.5 Hz and 12.7 Hz, 2H) 6,60 7,00 (m, 3H), 7,35 7,58 (m, 2H) 8,32 (D. I and 6.6 Hz, 1H).

P R I m e R 53. 2-[4-(3-methoxypropane)pyridine-2-yl]methylthio-1H-benzimida evil

SCH

1,65 g (0,005 mol) of 2-[4-(3-methoxypropane)pyridine-2-yl]methylthio-1H-Benzema - dazole was dissolved in 50 ml of dichloromethane to obtain a solution. To this solution at -40aboutC in an atmosphere of nitrogen was added 1.08 g (0,005 mol) of 80% m-chlormadinone acid. The resulting mixture was stirred 15 min. After completion of the reaction the mixture was added 0.8 g of triethylamine. The resulting mixture was heated to -10aboutWith the subsequent addition of 30 ml of 2 N. of an aqueous solution of sodium carbonate. The resulting mixture was stirred at room temperature for 30 min and was extracted three times with 100 ml dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and dried in vacuum. The obtained residue was dissolved in 50 ml of 0.1 N. aqueous sodium hydroxide with subsequent addition of ethanol. The resulting mixture was distilled to remove solvent and the residue was washed with ether, dried in vacuum and received 1.70 g of the compound indicated in the title of example, in the form of white crystals.

P R I m e R 55. 2-[4-{3-(2-methoxyethoxy)propoxy-3-methylpyridin-2-yl] methylthio-1H - benzimidazole

S

2.24 g of triethylamine and 1.27 g of methanesulfonamide was added to a solution of 1.4 g of the crude 2-hydroxymethyl-4-{ 3-(2-methoxy)} -3-methylpyridine in dichloromethane at -30aboutC. the resulting mixture was gradually heated to room temperature followed by the addition of saturated aqueous solution of acid sodium carbonate. The resulting mixture was stirred 30 min and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove chloroform. Received of 1.9 g of crude [4-{ 3-(2-methoxyethoxy)propoxy} 3-methyl-pyridine-2-yl] methyl ester of methanesulfonate in the form of a red oil. To this oil was added 0,83 g 2-mercapto-1H-benzimidazole. The mixture was mixed with 20 ml of ethanol at room temperature for 30 min, then was added a saturated aqueous solution of acid sodium carbonate. The resulting mixture was stirred at room temperature for 30 min and extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to obtain a residue. The remainder tx2">

An NMR spectrum on nuclei1N (l3) : 2,12 (sq I x 6.15 Hz, 2H) 2,25 (C. 2H) 3,36 (C. 3H) to 3.56 (m, 2H) 3,66 (t I x 6.15 Hz, 2H) 4,14 (t I x 6.15 Hz, 2H) 4,37 (C. 2H) 6,77 (D. I 5,72 Hz, 1H) 7,1 7,25 (m, 2H) 7,52 (m, 2H) 8,33 (D. I 5,72 Hz, 1H).

P R I m e R 56. Sodium salt 2-[4-{3-(2-methoxyethoxy)propoxy}3-metylene - DIN-2-yl] methylsulphonyl-1H-benzimidazole

< / BR>
681 mg of 85% m-chlormadinone acid in parts was added to a solution of 1.3 g 2-[4-{3-(2-methoxyethoxy)propoxy}-3-methylpyridin-2-yl]methylthio - 1H-benzimidazole in 70 ml of dichloromethane under stirring, and remove moisture. The resulting mixture was stirred 30 min followed by the addition 483 mg of triethylamine. The resulting mixture was heated to -20aboutWith, then added 2 N. aqueous solution of sodium carbonate. The mixture was stirred at room temperature for 30 min and twice was extracted with chloroform. The extract was washed with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and drove away under reduced pressure to obtain crude oil. To this oil was added 30 ml of 0.1 N. aqueous sodium hydroxide and ethanol. The resulting mixture was distilled under reduced pressure and a temperature of 40aboutWith the removal of the environment. To the obtained residue was again added ethanol and the mixture was distilled at bonigen the tx2">

An NMR spectrum on nuclei1H (DMSO-d6) : 1,98 (sq I x 6.15 Hz, 2H) 2,15 (C. 3H) 3,22 (C. 3H) 3,47 (m, 4H) 3,56 (t I x 6.15 Hz, 2H) 4.09 to (so I x 6.15 Hz, 2H) 4,42 (AB square I of 13.18 Hz, = 14,74 Hz, 1H) 6,8 7,0 (m, 3H) 7,39 EUR 7.57 (m, 2H) 8,27 (D. I 5,71 Hz, 1H).

P R I m e R 57. 2-[{4-(4-methoxyphenoxy)-3-methylpyridin-2-yl}methylthio] -1H - benzimidazole

< / BR>
611 mg of triethylamine and 686 mg methanesulfonamide was added to a solution of 0.84 g of the crude 2-hydroxy-4-(4-methoxyphenoxy)-3-methylpyridine in 30 ml of dichloromethane at -20aboutWith stirring and removing moisture from the mixture. This mixture is gradually brought to room temperature, then was added a saturated aqueous solution of acid sodium carbonate. The mixture was stirred 30 min and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove chloroform. Thus was obtained a red oil. To this oil was added 580 mg of 2-mercapto-1H-benzimidazole and 30 ml of ethanol. The resulting mixture was stirred at room temperature for 30 min, podslushivaet 2 N. aqueous solution of sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove chloroform. The obtained residue was chromatographically on column UP>1
N (l3) : 1,4 of 2.16 (m, 4H) and 2.26 (C. 3H) 3,35 (C. 3H) 3,45 (so I 5,72 Hz, 2H) 4,06 (so I 5,72 Hz, 2H) 4,37 (C. 2H) 6,74 (D. I 5,71 Hz, 1H) 7,1 7,25 (m, 2H) of 7.48 7,56 (m, 2H) 8,33 (D. I 5,72 Hz, 1H).

Example of receipt 15.

[4-{ 3-(2-methoxyethoxy)propoxy} -3-IU - terpyridine-2-yl]methyl ester methanesulfonate

CH3--

2.24 g of triethylamine and 1.27 g of methanesulfonamide was added to a solution of 1.4 g of the crude 2-hydroxy-4-{ 3-(3-methoxyethoxy)}-3-methylpyridine in dichloromethane at -30aboutWith to obtain a mixture. This mixture was brought to room temperature followed by the addition of saturated aqueous solution of acid sodium carbonate. The resulting mixture was stirred 30 min and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove chloroform. Received of 1.9 g of the crude red oil.

P R I m e R 58. 2-[4-{3-(2-methoxyethoxy)propoxy}-3-methylpyridin-2-yl] methyl-thio-1H - benzimidazole

S

Mixture of 1.9 g of crude [4-{3-(2-methoxyethoxy)propoxy}-3-methyl - pyridine-2-yl] methyl ester of methansulfonate, or 0.83 g of 2-mercapto-1H-benzimidazole and 20 ml of ethanol was stirred at room temperature for 1 h, podslushivaet saturated aqueous acidic carbonate research Institute. The obtained residue was chromatographically on a column of silica gel and was suirable a mixture of ethyl acetate and n-hexane. Received 1.5 g of oily product.

An NMR spectrum on nuclei1N (l3) : 2,12 (square I of 6.2 Hz, 2H) 2,25 (C. 3H) 3,36 (C. 3H) 3,57 (m, 2H) 3,66 (so I 6.2 Hz, 2H) 4,14 (so I 6.2 Hz, 2H) 4,37 (C. 2H) 6,77 (D. I and 3.1 Hz, 1H) 7.15m (m, 2H) 7,53 (m, 2H) 8,39 (D. I and 3.1 Hz, 1H).

Example 16.

2-Chloromethyl-4-(4-methoxyphenoxy)Piri - DIN

< / BR>
5.6 g of the crude 2-hydroxymethyl-4-(4-methoxyphenoxy)pyridine was dissolved in 80 ml of chloroform to obtain a solution. To this solution was added dropwise a solution of 3.8 g of chloride tiomila in 10 ml of chloroform at 0aboutC for 1 h After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of acid sodium carbonate and twice was extracted with 200 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent. The obtained residue was dried in vacuum and received 5,09 g of the compounds in the form of crude oil.

An NMR spectrum on nuclei1N (l3) : 1,55 2,05 (m, 4H) 3,35 (C. 3H) 3,38 of 3.53 (m, 2H) 3,91 to 4.17 (m, 2H) br4.61 (C. 2H) 6,55 7,01 (m 2N) at 8.36 (D. I, 6.2 Hz, 1H).

Example of receipt 17.

2-Hydroxymethyl-4-(4-m acetic anhydride to obtain a solution. This solution was stirred at 100about1 h, cooled and distilled to remove solvent. To the residue was added 150 ml of 1 N. hydrochloric acid. The resulting mixture was stirred at 100about1 h, cooled, neutralized the acid with sodium carbonate and twice was extracted with 200 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent and the residue was dried in vacuum and got to 5.66 g of the compounds in the form of crude oil.

An NMR spectrum on nuclei1N (l3) : 1,58 of 2.08 (m, 4H) 3,32 of 3.54 (m, 2H) 3,34 (C. 3H) 3,82 of 4.16 (m, 2H) 4,69 (C. 2H) 5,02 (C. 1H) 6,54 to 6.88 (m, 2H) 8,30 (D. I, 6.2 Hz, 1H).

An example of obtaining 18.

1-Oxide 4-(4-methoxyphenoxy)-2-methylpyridine

< / BR>
6,77 g (0,065 mol) of 4-methoxybutanol was dissolved in 60 ml of DMSO to obtain a solution. To this solution at room temperature under nitrogen atmosphere was added 2.6 g (0,065 mol) of 60% sodium hydride. The resulting mixture was heated to 60aboutC, stirred for one hour and cooled to room temperature. To the mixture was added dropwise a solution of 4.66 g (to 0.032 mmol) of 1-oxide 4-chloro-2-methylpyridine in 20 ml dimethylsulfoxide. The mixture was stirred at 40aboutWith 1 h After savereide was added 150 ml of water. The resulting mixture 4 times was extracted with 200 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent. The residue was purified by chromatography on a column of silica gel (showed a mixture of ethyl acetate-methanol) and received of 5.06 g of the compounds in the form of butter.

An NMR spectrum on nuclei1N (l3) : 1,54 2,07 (m, 4H) 2,52 (C. 3H) 3,36 (C. 3H) 3,44 (so I 6.2 Hz, 2H) 4.01 (so I 6.2 Hz, 2H) 6,60 at 6.84 (m, 2H) 8,14 (D. I of 5.3 Hz, 1H).

Example obtain 19.

4-Methoxybutanol CH3OCH2CH CH2HE.

27,04 g (0.3 mol) of 1,4-butanediol was dissolved in 150 ml of tetrahydrofuran to obtain a solution. To this solution at 0aboutC in an atmosphere of nitrogen was added 7.2 g (0.18 mol) of 60% sodium hydride. The resulting mixture was heated under reflux for 1 h and was cooled to 0aboutC. To the mixture was added dropwise 21,73 g (0.15 mol) of 98% bromide. The mixture was stirred at a temperature of 30aboutC or lower within a half hour. After the reaction, the reaction mixture was filtered. The filtrate was distilled to remove solvent. To the residue was added 200 ml of water and the resulting mixture was washed with 200 ml of n-hexane and extragonadal 200 ml of chloroform 4 times. The extract was dried Saedinenie.

An NMR spectrum on nuclei1N( l3) : 1,54 of 1.80 (m, 4H) 1,71 (C. 1H) 3,32 (C. 3H) 3,34 to 3.73 (m, 4H).

An example of obtaining 20.

2-Chloromethyl-4-(3-methoxypropane)PI - ridin

< / BR>
The solution 2,60 g (6% of 0.022 mol) of chloride tiomila in 10 ml of chloroform was added dropwise to a solution of 3.64 g (0.018 mol) of 2-hydroxymethyl-4-methoxypiperidine in 60 ml of chloroform under cooling with ice. The resulting mixture was stirred 1 h, neutralized with a saturated aqueous solution of acid sodium carbonate and was extracted with chloroform. Chloroformate layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure received 3,23 g of the compounds in the form of a crude product.

An NMR spectrum on nuclei1N (l3) : 1,80 2,20 (m, 2H) 3,31 (C. 3H) 3,49 (I. I6,2 Hz, 2H) 4,07 (so I 6.2 Hz, 2H) 4,55 (C. 2H) 6,52 of 6.96 (m, 2H) compared to 8.26 (D. I of 5.3 Hz, 1H).

Example of getting a 21.

2-Hydroxymethyl-4-(3-methoxypropan-C)pyridine

< / BR>
of 4.05 g (0.02 mol) of 1-oxide 4-methoxypropane-2-methylpyridine was dissolved in 50 ml of acetic anhydride to obtain a solution. This solution was stirred at 90aboutHalf an hour and cooled followed by the addition of ethanol. The resulting mixture was concentrated under reduced pressure, then was decisively acid with sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent. So, got to 3.64 g of the crude specified connection.

An NMR spectrum on nuclei1N (PIF3) : 1,83 of 2.20 (m, 2H) 3,30 (C. 3H) 3,49 (so I5,3 Hz, 2H) 4,05 (so I at 5.3 Hz, 2H) with 4.64 (C. 2H) 4,70 (C. 1H) 6.48 in 6,86 (m, 2H) 8,21 (D. I, 6.2 Hz, 1H).

Example of getting a 22.

1-Oxide-4-(3-methoxypropane)-2-methyl - pyridine

< / BR>
of 5.85 g (0,065 mol) of methoxypropanol was dissolved in 60 ml of DMSO to obtain a solution. To this solution at room temperature under nitrogen atmosphere was added 2.6 g (0,065 mol) of sodium hydride. The resulting mixture was stirred at 60aboutFor half an hour. To the mixture under ice cooling was added dropwise a solution of 4.66 g (0,0325 mol) of 1-oxide 4-chloro-2-methylpyridine in 20 ml of dimethylsulfoxide. The mixture was stirred at 40aboutWith 1 h After termination of the reaction, the reaction mixture was concentrated under reduced pressure to obtain a solid substance. This solid matter was added 200 ml of water. The resulting mixture was extracted with chloroform, the extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and was purified by chromatography on a column of silica gel (a mixture of ethyl is 0 2,24 (m 2H) 2,48 (C. 3H) 3,31 (C. 3H) 3,48 (so I 6.3 Hz, 2H) was 4.02 (so I 6.3 Hz, 2H) 6,50 of 6.78 (m, 2H) 8,04 (D. I 7,2 Hz, 1H).

An example of retrieving 23.

1-Oxide 4-chloro-2-methoxypyridine

< / BR>
of 15.4 g (0.1 mol) of 1-oxide, 2-methyl-4-nitropyridine added to 78.5 per g (1 mol) of acetyl chloride at -10aboutC. the resulting mixture was stirred under ice cooling for half an hour. After completion of the reaction, the reaction mixture was added 300 ml of ice water. The resulting mixture was neutralized with sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and was purified by chromatography on a column of silica gel (a mixture of ethyl acetate, n-hexane and methanol). Received 4.7 grams of the specified connection.

An NMR spectrum on nuclei1N (l3) : 2,48 (C. 3H) 6,94 7,30 (m, 2H) 8,09 (D. I 7,2 Hz, 1H).

P R I m er 59. Sodium salt of 2-[{4-(4-methoxyphenoxy)-3-methylpyridin-2-yl}IU-telcoline]-1H - benzimidazole

< / BR>
0.4 g of 2-[{4-methoxybutan-3-methylpyridin-2-yl}methylthio]-1H-benzimidazole was dissolved in 40 ml of dichloromethane in the dehydration to obtain a solution. To this solution at -40aboutWith the parts added 227 mg m-chlormadinone acid. The resulting mixture was stirred 30 min, followed the line of sodium carbonate. The resulting mixture was stirred for 40 minutes and was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and distilled under reduced pressure to remove dichloromethane. Thus received of 0.43 g of oily product. This substance was dissolved in a mixture containing of 11.2 ml of 0.1 N. aqueous sodium hydroxide and 30 ml of ethanol, and the obtained solution was distilled under reduced pressure to remove solvent. To the residue was added ethanol and the resulting mixture was distilled under reduced pressure to remove solvent. The residue was led from a mixture of ethanol-ether and received 0,37 g of the compounds in the form of crystals.

An NMR spectrum on nuclei1H (DMSO-d6) : of 1.84 (m, 4H) 2,16 (C. 3H) 3,24 (C. 3H) 3,38 (so I 6.2 Hz, 2H) 4,06 (so I 6.2 Hz, 2H) 4,55 (AB square I 13,2 Hz, 18,1 Hz, 2H) 6,8 6,98 (m, 3H) 7,4 7,6 (m, 2H) 8,27 (D. I of 5.3 Hz, 1H).

An example of obtaining 24.

1-Oxide 4-(3-methoxypropane)-2,3,5-trimethylpyridine

< / BR>
4.5 g (0.05 mol) of methoxypropanol was dissolved in 45 ml of DMSO to obtain a solution. To this solution was added 2.0 g of 60% sodium hydride at room temperature in a nitrogen atmosphere. The resulting mixture was heated to 60aboutWith and paramashiva (0,025 mol) of 1-oxide 4-chloro-2,3,5-trimethylpyridine in 15 ml of dimethylsulfoxide. The resulting mixture was stirred at 60about5 h, cooled and distilled to dryness to remove the solvent. To the residue was added 200 ml of water. The resulting mixture was extracted five times with 150 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent. The residue was purified by chromatography on a column of silica gel (a mixture of ethyl acetate and n-hexane) and received 4,27 g of compound in the form of butter.

An example of obtaining 25.

2-Hydroxymethyl-4-(3-methoxypropan - XI)-3,4-dimethylpyridine

HO< / BR>
of 4.25 g (0.019 mol) of 1-oxide 4-(3-methoxypropane)-2,3,5-trimethylpyridine was dissolved in 40 ml of acetic anhydride to obtain a solution. This solution was stirred at 100about30 min, cooled and distilled to remove solvent. Thus obtained oil. To the oil was added 50 ml of 1 N. hydrochloric acid. The resulting mixture was stirred at 100about1 h, cooled, neutralized the acid with sodium carbonate and three times was extracted with 150 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent. The residue was dried in vacuum and received 4,70 g of the compounds in the form of crude oil.

With the S. 2H) 8,10 (C. 1H).

Example of receipt 26.

2-Chloromethyl-4-(3-methoxypropane)-3,5-dimethylpyridin

Cl< / BR>
4,70 g of the crude 2-hydroxymethyl-4-(3-methoxypropane)-3,5-dimethylpyridin - on was dissolved in 50 ml of chloroform to obtain a solution. To this solution at 0aboutWith was added dropwise a solution of 2.7 g of chloride tiomila in 10 ml of chloroform, the mixture was stirred at 0aboutWith 1 h After completion of the reaction, the reaction mixture was neutralized with a saturated aqueous solution of acid sodium carbonate and twice was extracted with 150 ml of chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent. The obtained residue was dried in vacuum and got to 4.52 g of the compounds in the form of crude oil.

An NMR spectrum on nuclei (l3) : 1,70 2,20 (m, 2H) and 2.26 (C. 3H) 2,34 (C. 3H) 3,38 (C. 3H) 3,61 (so I 6.2 Hz, 2H) 3,91 (I. I6,2 Hz, 2H) 4,67 (C. 2H) 8,18 (C. 1H).

P R I m e R 60. 2-[4-(3-methoxypropane)-3,4-dimethylpyridin-2-yl]methyl-thio-1H - benzimidazole

< / BR>
A mixture containing 2.25 g (0.015 mol) of 2-mercaptobenzimidazole, 4.52 g (0,0185 mol) of 2-chloromethyl-4-(3-methoxypropane)-3,5-dimethylpyridine, 0,63 g (0.015 mol) of 95% sodium hydroxide and 50 ml of ethanol was stirred at 40aboutWith 6 hours of FIA on a column of silica gel (a mixture of ethyl acetate and n-hexane) and got to 4.62 g of compound as pale yellow oil.

P R I m e R 61. Sodium salt of 2-[4-(3-methoxypropane)-3,4-dimethylpyridin-2-yl]methylsulfinyl - 1-benzimidazole.

< / BR>
1.5 g of 2-[4-(3-methoxypropane)-3,4-dimethylpyridin-2-yl] methylthio-1H - benzimidazole was dissolved in 80 ml of dichloromethane at moisture removal for a solution. To the solution in portions at -40aboutWith added 870 mg m-chlormadinone acid. The resulting mixture was stirred 30 min, then was added 599 mg of triethylamine. The mixture was heated to -20aboutC, followed by adding 80 ml of 2 N. of an aqueous solution of sodium carbonate. The resulting mixture was stirred 1 h and was extracted with dichloromethane. The extract was washed with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and distilled under reduced pressure. Was obtained 1.4 g of crystals. 800 mg of the crystals was dissolved in a mixture containing 21,4 ml of 0.1 N. aqueous sodium hydroxide and ethanol. The resulting solution was distilled under reduced pressure to remove solvent. The residue was dissolved in ethanol and the solution was distilled under reduced pressure to remove solvent. The obtained residue was led from a mixture of ethanol-ether and received 800 mg of crystals.

An NMR spectrum on nuclei1H (DMSO-d6) : 1,94 (the Queen. I (S. 1H).

P R I m e R 62. 2-[4-[3-(2-methoxyethoxy)methoxypropane]-3-methylpyridin-2-yl] methylthio-1H-benzimidazole

< / BR>
1.8 g of 2-hydroxymethyl-4-[3-{ (2-methoxyethoxy)methoxy}propoxy]-3 - methylpyridine was dissolved in 40 ml dichloromethane at removing moisture to obtain a solution and then adding 2,47 g of triethylamine. To the mixture was added with ice cooling in parts of 1.4 g of methanesulfonamide. The mixture was stirred 30 min, podslushivaet saturated solution (water) carbonic acid and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure. The residue was dissolved in 30 ml of ethanol followed by the addition 917 mg of 2-mercapto-1H-benzimidazole and 367 mg of sodium hydroxide. The mixture was stirred at room temperature for 30 minutes and distilled under reduced pressure to remove ethanol. The residue was chromatographically on a column of silica gel and was suirable a mixture of ethyl acetate and n-hexane. Was obtained 2.1 g of the compounds in the form of tiefer.

An NMR spectrum on nuclei1N (l3) : 2,11 (the Queen. I 6,2 Hz, 2H) 2,25 (C. 3H) 3,35 (C. 3H) to 3.58 (m, 4H) 3,75 (so I 6.2 Hz, 2H) 4,13 (so I 6.2 Hz, 2H) 4,33 (C. 2H) 4,71 (C. 2H) 6.75 in (D. N. 5.7 Hz, 1H) and 7.1 to 7.3 (m, 2H) and 7.4 to 7.6 (m, 2H) 8,32 (D. I, 5.7 Hz, 1H).

P R I m e R 63. R> 1.1 g 2-[4-[3-{ (2-methoxyethoxy)methoxypropane]-3-methylpyridin-2-yl] methylthio-1H-benzimidazole was dissolved in 80 ml of dichloromethane at moisture removal for a solution. To this solution at -40aboutWith the parts added 544 mg m-chlormadinone acid. The resulting mixture was stirred 30 min followed by the addition 379 mg of triethylamine. The resulting mixture was heated to -20aboutWith, then added 40 ml of 2 N. of an aqueous solution of sodium carbonate. The mixture was stirred 30 min and was extracted with chloroform. The extract was washed with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and distilled under reduced pressure to remove solvent. The residue was dissolved in a mixture containing 24 ml of 0.1 N. aqueous sodium hydroxide and 40 ml of ethanol. The resulting aqueous solution was distilled under reduced pressure to remove solvent, followed by addition of 40 ml of ethanol. The mixture was again distilled under reduced pressure to remove ethanol. The residue was led from a mixture of ethanol-ether and received 0,98 g of target compound.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,02 (Queen, I 6,2 Hz, 2H) 2,17 (C. 3H) 3,23 (C. 3H) to 3.49 (m, 4H) 3,65 (so I 6.2 Hz, 2H) 4,12 (so I 6.2 Hz, 2H) 4,56 (AB square I to 21.1 Hz, is 16.8 Hz, 2H) 4,62 (C. 2H),3-dimethylpyridin

< / BR>
of 0.49 g of sodium hydride was gradually added at room temperature in a nitrogen atmosphere to a solution of 1.0 g of N-oxide of 4-(2-acetoxy)-2,3-dimethylpyridine in 40 ml of dimethylformamide. After cessation of foaming to the resulting mixture at a temperature of -50aboutWith added 1 ml brumptomyia. The resulting mixture was gradually heated and stirred at 15-20aboutWith 3 hours To the mixture was added ethanol to absorb the excess sodium hydride. To the mixture was added 5 ml of 1 N. aqueous hydrochloric acid and after the resulting mixture was passed gaseous nitrogen removal brumptomyia. To the mixture was added water. The resulting mixture was extracted with chloroform and the extract was dried over magnesium sulfate and distilled under reduced pressure to remove solvent. The residue was chromatographically on a column of silica gel, was suirable chloroform containing 1-5% methanol, and was obtained 0.6 g of the specified connection.

An NMR spectrum on nuclei1N (l3) : 2,24 (C. 3H) 2,56 (C. 3H) 4,24 (m, 5H) 5,3 (D. I 55,8 Hz, 2H) 6,54 (D. I, 6.2 Hz, 1H) 8,12 (D. I, 6.2 Hz, 1H).

An example of retrieving 28.

4-(2-Formatosi)ethoxy-2-hydroxy-methyl-3-methylpyridin

< / BR>
The mixture containing the crude N-oxide of 4-(2-formatosi)ethoxy-2,3-dimethylpyridin shivali at a temperature of from 90 to 100aboutC for 40 min and distilled under reduced pressure to remove acetic anhydride. The remainder poorly alkalizing 2 N. aqueous solution of sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove solvent. The residue was dissolved in 30 ml of ethanol, followed by addition of 0.33 g of sodium hydroxide. The resulting mixture was stirred at room temperature for 30 min, slightly podslushivaet saturated aqueous ammonium chloride and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled under reduced pressure to remove solvent. The residue was chromatographically on a column of silica gel and was suirable a mixture of ethyl acetate and n-hexane. Received 1.2 g of the compounds in the form of crystals.

An NMR spectrum on nuclei1N (l3) : 2,0 (C. 3H) to 4.17 (m, 4H) with 4.64 (S. 2N) are 5.36 (D. I 56,3 Hz, 2H) of 6.71 (D. I, 5.7 Hz, 1H) 8,30 (D. I, 5.7 Hz, 1H).

An example of obtaining 29.

4-(2-formatosi)ethoxy-3-metylene - DIN-2-yl}methyl ether of methansulfonate

CH3--O-

160 mg methanesulfonamide was added dropwise to a solution of 0.2 g of 4-(2-formatosi)ethoxy-2-hydroxymethyl-3-Meile - ridine and 143 mg tritely to room temperature, was podslushivaet saturated aqueous solution of acid sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and distilled to remove solvent. Received of 0.38 g of the compounds in the form of crude oil.

An NMR spectrum on nuclei1N (l3) : 2,30 (C. 3H) is 3.08 (C. 3H) 4,2 (m, 4H) 5,4 (D. I 55,8 Hz, 2H) 5,38 (C. 2H) 6,84 (D. I, 6 Hz, 1H) at 8.36 (D. I, 6 Hz, 1H).

P R I m e R 64. 2-[{4-(2-formatosi)ethoxy-3-methylpyridin-2-yl}methylthio]-1H - benzimidazole

< / BR>
A mixture containing neojidannyi-(2-formatosi)ethoxy-3-methylpyridin-2-yl} methyl ether of methansulfonate derived from 0.6 g of 4-(2-formatosi)ethoxy-2-hydroxymethyl-3-methylpyridine, 0,42 g 2-mercapto-1H-benzimidazole and 30 ml of ethanol was stirred at room temperature for 30 minutes and distilled under reduced pressure to remove ethanol. The obtained residue was chromatographically on a column of silica gel and was suirable a mixture of methanol-ethyl acetate. Received 0.3 g of an oil product.

An NMR spectrum on nuclei1N (l3) : 2,25 (C. 3H) 2,98 (C. 3H) 4,13 (m, 4H) to 4.41 (C. 2H) 5,33 (D. I 56,3 Hz, 2H) 6,72 (D. I, 5.7 Hz, 1H) 7,1 7,2 (m 2N) is 7.4 to 7.6 (m, 2H) 8,32 (D. I, 5.7 Hz, 1H).

P R I m e R 65. Sodium salt of 2-[{4-(2-formatosi)ethoxy-3-methylpyridin-2-yl}methylsulfinyl] 1H-Ben is toxi-3-methylpyridin-2-yl - methylthio]-1H - benzimidazole in 30 ml of dichloromethane under stirring, and the removal of moisture at a temperature of -40aboutC. the resulting mixture was stirred 30 min followed by the addition of 129 mg of triethylamine. The mixture was heated to room temperature, slightly podslushivaet saturated aqueous solution of acid sodium carbonate and was extracted with chloroform. The extract was dried over magnesium sulfate and person to distil under reduced pressure to remove solvent. The obtained residue was dissolved in 30 ml of anhydrous tetrahydrofuran in a nitrogen atmosphere to obtain a solution. To this solution at -20aboutWith added and 36.2 g of 60% sodium hydride. After the disappearance of the foam mixture was distilled under reduced pressure to remove tetrahydrofuran. The residue was led from anhydrous ether and was obtained 260 mg of target compound in the form of crystals.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,18 (C. 3H) 4,14 (m, 4H) 4,56 (AB square I 13,2 Hz, 21,3 Hz, 2H) lower than the 5.37 (D. I 56,7 Hz, 2H) 6,8 7,0 (m, 3H) 7,4 7,5 (m, 2H) 8,29 (D. I of 5.3 Hz, 1H).

P R I m e R 66. 2-[[4-{2-(1H-benzimidazole-2-ylthio)ethoxy}2,3-methylpyridin-2-yl] methylthio]-1H-benzimidazole

S

Mixture of 1.34 g (0,004 mol) 2-[{4-(2-chloroethoxy)-3-methylpyridin-2-yl} methylthio} -1H-benzimidazole of 0.53 g (0,0035 mol) 2-mercapto-1H-benzimidazole 0.17 g (0,004 mol) of 95% sodium hydroxide and 30 ml of ethanol was stirred at 80on the spending was distilled to remove solvent. The residue was purified by chromatography on a column of silica gel (a mixture of ethyl acetate and n-hexane) and got a 1.08 g of the compounds in the form of white crystals.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,15 (C. 3H) of 3.73 (so I 7,1 Hz, 2H) 4,23 (so I 7,1 Hz, 2H) 4,68 (S. 2N) of 6.96 7,22 (m, 5H) 7,32 rate of 7.54 (m, 4H) 8,25 (D. I of 5.3 Hz, 1H).

P R I m e R 67. Disodium salt 2-[[4-{2-(1H-benzimidazole-2-ylsulphonyl)ATOC si}-3-methylpyridin-2 - yl]methylsulfinyl]-1H-benzimidazole

< / BR>
0,90 g (0.002 mol) 2-[[4-{2-(1H-benzimidazole-2-ylthio)ethoxy}-3-methylpyridin-2-yl] methylthio}-1H-benzimidazole suspended in 40 ml of dichloromethane to obtain a suspension. To the suspension was added methanol until then, until it becomes transparent. To the resulting mixture in a nitrogen atmosphere at a temperature of -60aboutWith added 0,43 g (0.002 mol) of 80% m-chlormadinone acid. The mixture was stirred for half an hour. After completion of the reaction the mixture was added 0.5 g of triethylamine. The resulting mixture was heated to -10aboutC, followed by adding 30 ml of a saturated aqueous solution of sodium carbonate. The mixture was stirred at room temperature for half an hour and was filtered. The filtrate three times was extracted with 100 ml dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate is purplenum ethanol. The resulting mixture was distilled to remove solvent. The residue was washed with ether and was obtained 0.15 g of the target specified connection in the form of yellow crystals.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,18 (C. 3H) 3,20 of 3.75 (m, 2H) 4,19 4,74 (m, 4H) 6,68 was 7.08 (m, 5H) 7,16 7,53 (m, 4H) 8,20 (D. I, 6.2 Hz, 1H).

P R I m e R 68. 2-[[4-(2-(benzothiazol-2-yl)ethoxy-3-methylpyridin-2-yl] methylthio] 1H-benzimidazole

< / BR>
Mixture of 1.34 g (0,004 mol) 2-[{4-(2-chloroethoxy)-3-methylpyridin-2-yl} methylthio] -1H-benzimidazole, 0,59 g (0.035 mol) of 2-mercaptobenzothiazoles, 0.17 g (0,004 mol) of 95% sodium hydroxide and 30 ml of ethanol was stirred at 80about16 hours After completion of the reaction, the reaction mixture was filtered to remove inorganic substances. The filtrate was distilled to remove solvent and the residue was purified by chromatography on a column of silica gel (a mixture of ethyl acetate and n-hexane) was obtained 1.20 g of the compounds in the form of white crystals.

An NMR spectrum on nuclei1H (DMSO-d6) : 2,08 (C. 3H) 3,79 (so I 6.2 Hz, 2H) 4,40 (I. I6,2 Hz, 2H) 4,60 (C. 2H) 6,88 (7,21 (m, 3H) 7,22 to 7.50 (m, 4H) 7,68 of 8.00 (m, 2H), 8,16 (D. I, 6.2 Hz, 1H).

P R I m e R 69. Sodium salt 2-[[4-{2-(benzothiazole-2-ylsulphonyl)ethoxy}-3-IU-terpyridine-2-yl] methylsulfinyl]-1H-benzimidazole

< / BR>
0,93 g is l dichloromethane. To the resulting suspension was added methanol until then, until it became transparent. To the mixture was added in a nitrogen atmosphere at a temperature of -60aboutWith, of 0.43 g of 80% m-chlormadinone acid. The mixture was stirred for half an hour. After completion of the reaction the mixture was added 0.6 g of triethylamine, and the resulting mixture was heated to -10aboutC, followed by adding 30 ml of a saturated aqueous solution of acid sodium carbonate. The mixture was stirred at room temperature for half an hour and twice was extracted with 100 ml dichloromethane. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove solvent. 0.8 g of the obtained residue was dissolved in 0.1 G. of sodium hydroxide with subsequent addition of ethanol. The mixture was distilled to remove solvent. The residue was washed with ether and received 0,69 g the specified connection.

An NMR spectrum on nuclei1H (DMSO-d6) : to 2.06 (C. 3H) 3,66 of 4.00 (m, 2H) 4,19 a 4.86 (m, 4H) 6,74? 7.04 baby mortality (m, 3H) 7,15 rate of 7.54 (m, 4H) of 7.96 to 7.64 (m, 2H) 8,21 (D. I, 6.2 Hz, 1H).

Connection examples 70-91 obtained by the method similar to those described above.

P R I m e R 70. 2-[{4-(2-furylmethyl)ethoxy-3-methylpyridin-2-yl} methylsulfinyl]-1H-benzimidazole

< / BR>
NMR-spectrum 5.4 Hz, 1H).

P R I m e R 71. 2-[{4-(2-(1,1-Dioxothiazolidine))ethoxy-3-methylpyridin-2-yl} methylthio]-1H-benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 2,21 (C. 3H) 2,99 (so I 5.8 Hz, 2H) 3,07 (C. 8H) 4,16 (so I 5.8 Hz, 2H) 4,68 (C. 2H) 6,95 (D. I 6,1 Hz, 1H) 6,95 to 7.2 (m, 2H) 7,3 7,5 (m, 2H) 8,2 (D. I 6,1 Hz, 1H).

P R I m e R 72. 2-[{3-methyl-4-(2-methylsulphonyl)ethoxy}pyridine-2-yl] methylthio-1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 2,28 (C. 3H) is 3.08 (C. 3H) 3.72 points so I 6.2 Hz, 2H) 3,66 (so I 6.2 Hz, 2H) 3,94 (S. 2N) of 6.8 to 7.6 (m, 7H) 8,6 (D. I, 5.7 Hz, 1H).

P R I m e R 73. 2-[{4-(2-ethoxycarbonylmethoxy)ethoxy-3-methylpyridin-2-yl} methylsulfinyl]-1H-benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 1,22 (so I was 7.2 Hz, 3H) 2,16 (C. 3H) 3,16 to 3.58 (m, 2H) 3,64 4,6 (m 6N) 4,76 (S. 2N)? 7.04 baby mortality (D. I 7 Hz, 1H) 7,16 of 7.24 (m, 2H) 7,32 7,80 (m, 2H) 8,24 (D. I 7 Hz, 1H).

P R I m e R 75. 2-[[3-methyl-4-{(2-phenylthio)ethoxy}pyridine-2-yl]methylthio] -1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1N (l3) : 2,08 (C. 3H) 3,24 (so I 6,1 Hz, 2H) 4,06 (so I 6,1 Hz, 2H) to 4.38 (C. 2H) 6,52 (D. I, 5.8 Hz, 1H)? 7.04 baby mortality of 7.64 (m, 10H) 8,23 (D. I, 5.8 Hz, 1H).

P R I m e R 76. 2-[[3-methyl-4-{2-pyridylthio)ethoxy}pyridine-2-yl]methylthio]-1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 2,14 (C. 3H) 3,6 (so I 6,1 Hz, 2H) 4,32 (I. I6,1 Hz, 2H) 4,7 (C. 2H) 7,0 7,8 (silicasol

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 2,16 (C. 3H) 2,64 (C. 3H) and 3.16 (m, 2H) of 4.44 (m, 2H) 4,78 (C. 2H) 7,0 (D. I, 5.8 Hz, 1H) 7,4 7,5 (m, 2H) of 7.5 to 7.7 (m, 2H) 8,2 (D. I, 5.8 Hz, 1H).

P R I m e R 78. 2-[4-{(2-benzylthio)ethoxy}-3-methylpyridin-2-yl]methylthio] -1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 2,24 (C. 3H) 2,84 (so-called I 5.8 Hz, 2H) 4,18 (so I 5.8 Hz, 2H) 4,68 (C. 2H) 6,86 (D. I and 6.5 Hz, 1H) 7,0 7,54 (m N) 8,23 (D. I and 6.5 Hz, 1H).

P R I m e R 79. 2-[{4-(2-methoxy)propoxy-3-methylpyridin-2-yl}-methylsulphonyl]-1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 2,0 (so I 7.5 Hz, 2H) 2,2 (C. 3H) 3,28 (C. 3H) 3,5 (so I 7.5 Hz, 2H) 4.09 to (so I 7.5 Hz, 2H) 5,06 (C. 2H) 6,92 (D. I of 5.4 Hz, 1H) 7,35 7,52 (m 2N) of 7.64 and 7.8 (m, 2H) 8,03 (D. I of 5.4 Hz, 1H).

P R I m e R 80. 5-methoxy-2-{4-(3-methoxypropane)-3-methylpyridin-2-yl} methyl-thio-1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1N (l3) : 1,92 of 2.18 (m, 2H) 2,22 (C. 3H) 3,31 (C. 3H) 3,52 (so I 6,1 Hz, 2H) 3,80 (C. 3H) 4.09 to (so I 6,1 Hz, 2H) 4,30 (C. 2H) 6,64 for 6.81 (m, 2H) 6,97 (D. I, 2.2 Hz, 1H) 7,33 (D. I 8,5 Hz) of 8.25 (D. I, 5.7 Hz, 1H).

P R I m e R 81. 5-methyl-2-{4-(3-methoxypropane)-3-methylpyridin-2-yl} methylthio - 1H-benzimidazole

< / BR>
An NMR spectrum on nuclei1N (l3) : 1,942,19 (m, 2H) 2,22 (C. 3H) 2,42 (C. 3H) 3,31 (C. 3H) 3,52 (so I 6,1 Hz, 2H) 4,08 (so I 6,1 Hz, 2H) or 4.31 (C. 2H) 6,67 (D. I, 5.7 Hz, 1H) 6,807,00 (m, 1H) 7,157,40 (m, 2H) 8,23 (D. I 5,>/BR>< / BR>
An NMR spectrum on nuclei1N (l3) : 1,952,17 (m, 2H) 2,24 (C. 3H) 2,34 (C. 6N) 3,35 (C. 3H) 3,55 (so I 6.2 Hz, 2H) 4,12 (I. I6,2 Hz, 2H) 4,35 (C. 2H) 6,74 (D. I 5.7 Hz), 7,29 (C. 2H) 8,32 (D. I, 5.7 Hz).

P R I m e R 83. 2-chloro-2-{4-(3-methoxypropane)-3-methylpyridin-2-yl} methylthio-1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1N (l3) : 1,932,18 (m, 2H) 2,25 (C. 3H) 3,35 (C. 3H) 3,56 (so I 6.2 Hz, 2H) 4,13 (so I 0.6 Hz, 2H) 4,36 (C. 2H) 6,76 (D. I, 5.7 Hz, 1H) 7,10 (DD. I 8,8 Hz, 2.2 Hz, 1H) 7,42 (D. I, and 8.8 Hz, 1H) 7,50 (D. I, 2.2 Hz, 1H) 8,31 (D. I, 5.7 Hz, 1H).

P R I m e R 84. 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl}methylthio-5 - trifluoromethyl-1H-benzimidazole

< / BR>
An NMR spectrum on nuclei1N (l3) : 1,922,19 (m, 2H), and 2.27 (C. 3H) 3,36 (C. 3H) 3,56 (so I 5,9 Hz, 2H) 4,15 (so I 6,1 Hz, 2H) to 4.38 (C. 2H) 6,79 (D. I, 5.7 Hz, 1H) 7.23 percent of 7.60 (m, 2H) 7,71 (C. 1H) 8,35 (D. I 5,76 Hz, 1H).

P R I m e R 85. Sodium salt of 5-methoxy-2-{4-(3-methoxypropane)-3-metylene - DIN-2-yl} methylsulfinyl-1H-benzimidazole

< / BR>
An NMR spectrum on nuclei 1H (DMSO-d6) : 1,84 of 2.06 (m, 2H) 2,14 (C. 3H) 3,25 (C. 3H) 3,49 (so I 6.2 Hz, 2H) 3,72 (C. 3H) 4.09 to (I. I6,2 Hz, 2H) 4,53 (AB square I of 12.7 Hz and 18.0 Hz, 2H) 6,54 (DD. I was 8.8 Hz, 2.6 Hz, 1H) 6,91 (D. I, 5.7 Hz, 1H) 7,00 (D. I of 2.6 Hz, 1H) 7,34 (D. I, and 8.8 Hz, 1H) 8,27 (D. I, 5.7 Hz, 1H).

P R I m e R 86. Sodium salt of 5-methyl-2-{4-(3-methoxypropane)-3-methylpyridin - 2 - yl}methylsulfinyl - 1H-benzimidazole
I6,2 Hz, 2H) 4,53 (AB square I of 12.8 Hz, 17.3 Hz, 2H) of 6.71 (DD. I 7,9 Hz, 1.5 Hz, 1H) 6,91 (D. I, 5.7 Hz, 1H) 7,26 (C. 1H) 7,35 (D. I and 7.9 Hz, 1H) 8,27 (D. I, 5.7 Hz, 1H).

P R I m e R 87. Sodium salt of 5,6-dimethyl-2-{4-(3-methoxypropane)-3-metylene - DIN-2-yl} methylsulfinyl-1H-benzimidazole

< / BR>
An NMR spectrum on nuclei 1H (DMSO-d6) : 1,82 of 2.08 (m, 2H) 2,13 (C. 3H), and 2.27 (C. 6N) 3,24 (C. 3H) 3,47 (so I was 6.6 Hz, 2H) 4,08 (I. I6,7 Hz, 2H) 4,54 (AB square I 13,0 Hz, and 19.8 Hz, 2H) 6,90 (D. I, 5.7 Hz, 1H) 7,25 (C. 2H) compared to 8.26 (D. I, 5.7 Hz, 1H).

P R I m e R 88. Sodium salt of 5-chloro-2-{4-(3-methoxypropane)-3-methylpyridin-2-yl}methylsulfinyl - 1H-benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 1,80 to 2.06 (m, 2H) 2,13 (C. 3H) 3,25 (C. 3H) 3,48 (so I 6.2 Hz, 2H) 4.09 to (so I 6.2 Hz, 2H) 4,54 (AB square I is 12.9 Hz, I is 15.3 Hz, 2H) 6,656,92 (m 2N) of 7.25 to 7.50 (m, 2H) 8,27 (D. I of 5.3 Hz).

P R I m e R 89. Sodium salt of 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl} methylsulfinyl-5 - trifluoromethyl-1H-benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 1,84 of 2.06 (m, 2H) 2,14 (C. 3H) 3,25 (C. 3H) 3,48 (so I 6.2 Hz, 2H) 4.09 to (so I 6,1 Hz, 2H) 4,56 (AB square I 13,2 Hz and 13.5 Hz, 2H) 6,92 (D. I of 5.3 Hz, 1H) 7,01 7,22 (m, 1H) 7,45 of 7.82 (m, 2H) 8,21 (D. I of 5.3 Hz, 1H).

P R I m e R 90. 2-{4-methoxypropane-5-methylpyridin-2-yl}methylthio-1H-Benzema - dasol

< / BR>
An NMR spectrum on nuclei1N (l3) : 1,90 of 2.24 (m, 2H) 2,16 (C. 3H) 3,31 (C. 3H) 3,51 (so I 6,2 G3-methoxypropane)-5-methylpyridin-2-yl} methylsulfinyl-1H - benzimidazole

< / BR>
An NMR spectrum on nuclei1H (DMSO-d6) : 1,56 of 1.87 (m, 2H) 2,00 (C. 3H) 3,16 (C. 3H) 3,20 and 3.72 (m, 4H) 6,16 6,60 (m 2N) of 6.49 (C. 1H) 6,68 6,92 (m, 2H) 7,28 to 7.50 (m, 2H) 8,13 (C. 1H).

P R I m e R 92. 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl}methyldibenzo - azole

S

A mixture containing 0.8 g of 2-chloromethyl-4-(3-methoxypropane)-3-methylpyridine hydrochloride, 0.5 g of 2-mercaptobenzothiazoles, 0.36 g of sodium hydroxide and 30 ml of ethanol was stirred at room temperature for 6 h and distilled under reduced pressure to remove ethanol. The residue was purified by chromatography on silica gel and got 0,85 g target specified connection in the form of pale yellow crystals.

An NMR spectrum on nuclei1N (l3) : 1,92,2 (m, 2H) 2,30 (C. 3H) 3,35 (C. 3H) 3,56 (so I 6,1 Hz, 2H) 4,10 (so I 6,1 Hz, 2H) 4,81 (C. 2H) 6,70 (D. I, 5.7 Hz, 1H) 7,1 7,5 (m, 2H) 7,57,9 (m, 2H) 8,29 (D. I, 5.7 Hz, 1H).

P R I m e R 93. 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl} methylsulfonylbenzoyl

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0.6 g of 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl}methyldibenzothiophene was dissolved in 20 ml of dichloromethane to obtain a solution. To the solution at a temperature of -45aboutWith added 0.36 g of 80% m-chlormadinone acid. After an hour, to the mixture was added 0.34 g of triethylamine and 30 ml of a saturated aqueous solution of sour is elali, twice washed with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. The residue was purified by chromatography on a column of silica gel and was obtained 0.17 g of the compound indicated in the title of the example as white crystals.

An NMR spectrum on nuclei1N (l3) : 1,95 of 2.18 (m, 2H) 2,20 (C. 3H) 3,34 (C. 3H) 3,54 (so I 6,1 Hz, 2H) 4,10 (so I 6,1 Hz, 2H) 4,67 (S. 2N) of 6.71 (D. I, 5.7 Hz, 1H) 7,40 to 7.0 (m, 2H) 7,92 to 8.20 (m, 2H) 8,25 (D. I, 5.7 Hz, 1H).

P R I m e R 94. 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl}methylthio-1 - methylbenzimidazole

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0.5 g of 2-{4-(3-hydroxypropoxy)-3-methylpyridin-2-yl}methylthio-1H-benzimidazole was dissolved in 30 ml of dimethylformamide to obtain a solution. To the solution at 0aboutWith added 0.24 g of 60% sodium hydride. The resulting mixture was stirred at 40about1 h and was again cooled to 0aboutWith the subsequent addition iodotope bromide. The mixture was stirred at room temperature for 3 hours Then to the mixture was added saturated aqueous ammonium chloride solution to terminate the reaction. The reaction mixture was distilled under reduced pressure to remove solvent and purified by chromatography on a column of silica gel. Received 0.3 g : 1,95 of 2.21 (m, 2H) 2,30 (C. 3H) 3,35 (C. 3H) 3,54 (so I 6.2 Hz, 2H) 3,67 (C. 3H) 4,10 (I. I6,2 Hz, 2H) 4,80 (C. 2H) 6,68 (D. I, 5.7 Hz, 1H) 7,16 7,30 (m, 3H) 7,80 EUR 7.57 (m, 1H) 8,29 (D. I, 5.7 Hz, 1H).

P R I m e R 95. 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl}methylsulfinyl-1 - methylbenzimidazole

< / BR>
0.25 g of 2-{4-(3-methoxypropane)-3-methylpyridin-2-yl}methylthio-1 - methylbenzimidazole was dissolved in 20 ml of dichloromethane to obtain a solution. To the solution at -50aboutWith added 0.18 g of 80% m-chlormadinone acid. The resulting mixture was stirred 1 h followed by the addition of 0.14 g of triethylamine and 20 ml of a saturated aqueous solution of acid sodium carbonate. The mixture was stirred at room temperature for 1 h Dichloromethane layer separated was washed twice with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. The residue was purified by chromatography on a column of silica gel and was obtained 0.12 g of the compounds in the form of pale yellow crystals.

An NMR spectrum on nuclei1N (l3) : 1,932,12 (m, 2H) 2,22 (C. 3H) 3,33 (C. 3H) 3,53 (so I 6.2 Hz, 2H) 3,98 (C. 3H) 4,06 (I. I6,2 Hz, 2H) 4,96 (C. 2H) 6,65 (D. I, 5.7 Hz, 1H) 7,25 7,40 (m, 3H) 7,75 7,87 (m, 1H) 8,15 (D. I5,7 Hz, 1H).

P R I m e R 96. 1-etoxycarbonyl-2-{4-3-methylpropoxy)-3-metylene the ol was dissolved in 10 ml of dimethylformamide to obtain a solution. To this solution at 0aboutWith added 0,23 g of a 60% aqueous hydride natra. The resulting mixture was stirred 15 minutes To the mixture was added dropwise at 0aboutWith 0.4 g of ethyl ester of carbonic acid. The resulting mixture was stirred at room temperature for 1 h To this mixture was added saturated aqueous ammonium chloride solution to terminate the reaction. The reaction mixture was extracted with chloroform. The extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by chromatography on a column of silica gel and got 0,82 g of the compounds in the WDA white crystals.

An NMR spectrum on nuclei1N (l3) : 1,50 (so I 7,0 Hz, 3H) 1,95 2,20 (m, 2H) 2,32 (C. 3H) 3,36 (C. 3H) 3,56 (so I 6.2 Hz, 2H) 4,10 (so I 6.2 Hz, 2H) 4,54 (square I 7,0 Hz, 2H) 4,77 (C. 2H) 6,69 (D. I, 5.7 Hz, 1H) and 7.1 to 7.4 (m, 2H) and 7.4 to 7.7 (m, 1H) 7,7 to 7.95 (m, 1H) 8,30 (D. I, 5.7 Hz, 1H).

P R I m e R 97. 1-etoxycarbonyl-2-{4-(3-methoxypropane)-3-methylpyridin-2-yl} methylsulfonylbenzoyl

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0.6 g of 1-etoxycarbonyl-2-{ 4-(3-methoxypropane)-3-methylpyridin-2-yl} methylthiopyrimidine was dissolved in 20 ml of dichloromethane to obtain a solution. To the solution at -45aboutWith added 0.4 g m-chlormadinone acid. After 1 h, to the mixture was added 0.3 g three the temperature 30 minutes The dichloromethane layer was separated, twice washed with a saturated aqueous solution of acid sodium carbonate, dried over magnesium sulfate and filtered. The filtrate was concentrated and the obtained residue. The residue was purified by chromatography on a column of silica gel and was obtained 0.21 g of the compound indicated in the title of example, in the form of a yellow oil.

An NMR spectrum on nuclei1N (l3) : 1,54 (so I 7,0 Hz, 3H) 1,99 of 2.20 (m, 2H) 2,30 (C. 3H) 3,35 (C. 3H) 3,55 (so I 6.2 Hz, 2H) 4,06 (so I 6.2 Hz, 2H) br4.61 (square I 7,0 Hz, 2H) 4,74 (AB square I of 12.8 Hz, 8.6 Hz, 2H) 6,60 (D. I, 5.7 Hz, 1H) 7,3 7,5 (m, 2H) 7,7 8,0 (m, 2H) 8,03 (D. I, 5.7 Hz, 1H).

DERIVATIVES of PYRIDINE of General formula I

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where R1and R2the same or different, each is hydrogen, lower alkoxy, halogenated lower alkyl, lower alkoxycarbonyl, carboxyl group, or a halogen;

X group of formula: -O-, -S-

or

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where R3hydrogen or alkali metal, lower alkyl or lower alkoxycarbonyl;

The Z group of the General formula

-O-(CH2)p-OR4,

where p is an integer from 1 to 3;

R4hydrogen, lower alkyl or benzyl;

a group of General formula

-O-(CH2)q-R5,

where q is an integer from 1 to 3;

R5halogen, lower alkoxycarbonyl, fairies s are each an integer from 1 to 5,

R6hydrogen or lower alkyl;

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where t is an integer from 0 to 2;

And a group of General formula

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where In the group of the formula-NH - or-S-,

or a lower alkyl, pyridyl or furyl or a group of the formula

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where R7hydrogen;

w is an integer of zero or 1;

a group of General formula-OR9,

where R9hydrogen, lower alkyl or phenyl;

n is an integer from 0 to 2;

m is an integer from 2 to 10;

J and K may be the same or different, are each hydrogen or lower alkyl, provided that when Z is a group of the formula-OR9where R9- a lower alkyl, m is an integer from 3 to 10, provided that when Z is a group of the formula-O-(CH2)qR5where q is an integer from 1 to 3, R5phenyl, m is an integer from 5 to 10.

 

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