Benzimidazole derivative

FIELD: chemistry.

SUBSTANCE: compound has general formula (where R1 and R3 are identical or different, and each denotes a hydrogen atom or C1-6alkyl; R2 denotes, for example, 5,5-dimethyl-1,3-dioxan-2-yl, 5,7-dioxaspiro[2.5]oct-6-yl, 1,5,9-trioxaspiro [5.5]undec-3-yl, 2,2-dimethyl-1,3-dioxan-5-yl etc; R4, R5, R6 and R7 each denotes a hydrogen atom, a halogen atom, C1-6 alkyl, C1-6 halogenalkyl, C1-6 alkoxy, C1-6 halogenalkoxy etc, and W1 denotes a single bond, methylene or ethylene, or salt thereof.

EFFECT: compound has excellent inhibiting activity towards secretion of gastric hydrochloric acid and more effectively in preserving inhibiting activity towards secretion of gastric hydrochloric acid, can maintain pH in the stomach for a long period of time, is safe and has acceptable physical and chemical resistance.

40 cl, 4 tbl, 97 ex

 

DESCRIPTION

The technical field to which the invention relates.

The present invention relates to benzimidazole derivative or its salt, or their MES, useful as an inhibitor of the secretion of gastric acid.

The present invention relates to benzimidazole derivative or its salt, or their MES, useful as a therapeutic agent or prophylactic agent associated with acid diseases or symptoms (in particular, gastroesophageal reflux disease, symptomatic gastroesophageal reflux disease, stomach ulcer and duodenal ulcer).

Background of invention

Peptic ulcers, as is known, caused by the imbalance between aggressive factors such as acid and pepsin, and defensive factors, such as the flow of mucus and blood flow, leading to samoupravlenie.

Peptic ulcer is mainly treated by the methods of medical care, in which various methods are used by drug therapy. In particular, in recent years, we developed and found clinical use of the drug, capable, in particular, to inhibit N+/K+-ATPase, which is an enzyme present in the parietal cells and is responsible for the final stage of the secretion of gastric acid, thereby suppressing sec is Ezio gastric acid and inhibiting self-digestion. Examples of such drugs include omeprazole, esomeprazole, pantoprazole, lansoprazole and rabeprazole.

These drugs have excellent therapeutic effects, but there was still a need for the creation of medicines, more firmly inhibiting the secretion of gastric acid, more safely and to an appropriate degree of physico-chemically stable. In particular, it is also assumed that the efficiency of treatment of gastroesophageal reflux can be improved by maintaining high values of intragastric pH in a long time (non-patent document 1).

Connections, especially close to the present invention described in patent documents 1 and 2. However, the compounds disclosed in these patent documents, differ in chemical structure from the compounds specifically disclosed in this description of the present invention.

Patent document 1: WO 91/19712

Patent document 2: JP-A-59-181277

Non-patent document 1: Digestion 1992; 51 (suppl 1): 59-67

Disclosure of the invention

The problem solved by the invention

The present invention is to provide a novel compound having an excellent inhibitory effect against the secretion of gastric acid, useful as a therapeutic or profile of the optical means associated with acid diseases or symptoms and excellent in maintaining inhibitory effect against the secretion of gastric acid and thereby maintain high intragastric pH during long time.

Means for solving the problem

The authors of the present invention have conducted intensive research aimed at solving this problem. In the result, it was found that a derivative of benzimidazole with a new chemical structure, has excellent inhibitory effect against the secretion of gastric acid, is excellent in maintaining inhibitory effect against the secretion of gastric acid and thereby maintain high intragastric pH for a long time and is particularly useful as a therapeutic or prophylactic drug for gastroesophageal reflux disease, symptomatic gastroesophageal reflux, stomach ulcers and duodenal ulcers. On the basis of these findings, it was established the present invention.

More specifically the present invention relates to compounds having the following formula (1)or its salt, or their MES.

Formula 1

In addition, in accordance with the present invention offers a drug containing a compound that shown above formula (1)or its salt, or their MES.

In accordance with the present invention it is also proposed inhibitor of the secretion of gastric acid containing compound with the above four the Ulu (1), or its salt, or their MES.

In accordance with this invention features a pharmaceutical composition comprising a compound that shown above formula (1)or its salt, or MES, or the use of compounds, which have shown above formula (1)or its salt, or their MES to obtain a pharmaceutical composition.

And yet the present invention relates to a therapeutic agent or preventive agent associated with the acid of diseases or symptoms, such as stomach ulcers, duodenal ulcer, anastomotic ulcer, gastroesophageal reflux (including gastroesophageal reflux with frequent relapses and recurring symptoms)syndrome Zollinger-Ellison, symptomatic gastroesophageal reflux, endoscopy-negative gastroesophageal reflux, neurosignal gastroesophageal reflux, gastroesophageal regurgitation, NUD (non-ulcer dyspepsia), abnormal sensation in the throat, syndrome Berreta, NSAID-induced ulcer, gastritis, gastrointestinal bleeding, hemorrhagic gastritis, gastrointestinal bleeding, peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperacidity, dyspepsia, gastroparesis, plague older people, intractable ulcer, acute injury of the mucous membrane of the stomach, heartburn, heartburn disorder is pnoe in a dream, bruxism, gastralgia, feeling of heaviness in the stomach, retching and vomiting, nausea, arthrosis of the temporomandibular joint or erosive gastritis, containing a compound that shown above formula (1)or its salt, or their MES.

Preferred examples involving acid diseases or symptoms may include stomach ulcers, duodenal ulcer, anastomotic ulcer, gastroesophageal reflux syndrome Zollinger-Ellison, symptomatic gastroesophageal reflux, endoscopy-negative gastroesophageal reflux, neurosignal gastroesophageal reflux and acute injury of the gastric mucosa. More preferred examples may include gastroesophageal reflux, symptomatic gastroesophageal reflux, peptic ulcer and duodenal ulcer. More preferred examples may include (1) gastroesophageal reflux or symptomatic gastroesophageal reflux and (2) a stomach ulcer or a duodenal ulcer.

On the other hand, the present invention relates to bactericidal agent or auxiliary bactericidal agent againstHelicobacter pyloricontaining a compound that shown above formula (1)or its salt, or their MES.

Note that the above “prophylactic agent” includes the t in contrast to prophylactic, entered prior to the onset of the disease or symptom, supporting a therapeutic tool and a means to prevent relapse after treatment.

In addition, the above “auxiliary antibacterial agent” refers to a means of regulating work environment microbicides, which is difficult to work in acidic conditions to give the effect.

In the formula (1) R1and R3may be the same or different, and each represents a hydrogen atom or C1-C6 alkyl group, and R2represented by formula 2, which may contain 1-4 groups selected from the following group A1.

Formula 2

Group A1 is a group consisting of a halogen atom, C1-C6 alkyl groups, C1-C6 of alkoxygroup, C1-C6 halogenoalkanes group, C1-C6 alkoxy-C1-C6 alkyl group and a hydroxyl group.

R4, R5, R6and R7may be the same or different, and each represents a hydrogen atom, hydroxyl group, halogen atom, C1-C6 alkyl group, C1-C6 halogenating group, C1-C6 alkoxygroup or C1-C6 halogenlampe, or the combination of R5and R6is methylendioxy or Ethylenedioxy, and W1represents a single bond or C1-C8 unbranched who do extensive alkylenes group.

W2represents a hydrogen atom, C1-C6 alkyl group or a halogen atom (provided that the number of radicals W2in the benzene ring may be equal to 1-3, and they may be the same or different);

n1 is 1 to 5, n2 is 1 to 4, and n3 is 1 to 6.

Used in this description, the term "C1-C6 alkyl group" refers to an unbranched or branched alkyl group containing 1-6 carbon atoms, such as methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group, tert-bucilina group, n-pencilina group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, n-exilda group, isohexyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutyl group or 2-ethylbutyl group.

Used in this description, the term "halogen atom" refers to fluorine atom, chlorine atom, bromine atom and iodine atom.

Used in this description, the term "C1-C6 alkoxygroup" refers to an unbranched or branched alkoxygroup containing 1-6 carbon atom is in, such as a methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan, isobutoxy, second-butoxypropan, tert-butoxypropan, phenoxypropan, isobutoxide, 2-methylbutoxy, pointershape, hexyloxy, 4-methylphenoxy, 3-methylphenoxy, 2-methylphenoxy, 3,3-dimethylbutyramide, 2,2-dimethylbutyramide, 1,1-dimethylbutyramide, 1,2-dimethylbutyramide, 1,3-dimethylbutyramide or 2,3-dimethylbutyramide.

Used in this description, the term "C1-C6 halogenation group" refers to C1-C6 alkyl group containing 1-5 substituents of the above Halogens, for example, including monitoramento group, monochloromethyl group, monobromodiphenyl group, monoiodotyrosine group, deformational group, dichloromethylene group, dibromomethyl group, diabetology group, triptorelin group, trichlorethylene group, tribromaniline group, triameterene group, 1-foretelling group, 2-foretelling group, 2,2,2-triptorelin group, 1-chlorethylene group, 2-chloraniline group, 2,2,2-trichlorethylene group, 1-forproperty group, 2-bromopropyl group, 1-bromatology group, 1-chloraniline group and 1-perhexiline group.

Used in this description, the term "C1-C6 halogenlampe" refers to C1-Sarcoxie, containing 1-5 substituents of the above Halogens, for example, including monitormetriclog, monochlorotoluene, monobromoacetate, monoiodotyrosine, dipterocarp, dichloromethoxy, dibromochloropropane, diiodotyrosine, cryptometrics, trichlormethiazide, tribromaniline, triiodothyronine, 1-foratractorru, 2-foratractorru, 2,2,2-tripterocarpa, 1-chlorethoxyfos, 2-chlorethoxyfos, 2,2,2-trichlorethylene, 1-ferroelectic, 2-bromopropionyl, 1-brombutylruber, 1-Globetrotter and 1-forexbroker.

Used in this description, the term "C1-C6 alkoxy-C1-C6 alkyl group" refers to C1-C6 alkyl group, containing only one Deputy from the above-described C1-C6 of alkoxygroup, for example, including methoxymethyl group, ethoxymethyl group, propoxymethyl group, 2-methoxyaniline group, 2-ethoxyethylene group, 1-methoxyamino group, 3-methoxypropyl group, 3-ethoxypropanol group, 4-methoxybutyl group, 4-ethoxymethylene group, 4-propoxymethyl group, 5-methoxyphenyl group, 5-ethoxyphenyl group 5-propoxyphenyl group, 6-methoxyaniline group and 6-ethoxyaniline group.

As used in this description the term "C1-C8 unbranched and branched Allenova chain" refers to a methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene (1-mutilation), 1-methyltrienolone or 2-methyltryptamine.

"C1-C6 alkyl group" defined above, R1represents preferably a methyl group.

"C1-C6 alkyl group" defined above, R3represents preferably a methyl group.

"Halogen atom" mentioned above, R4, R5, R6and R7represents preferably a fluorine atom or chlorine and more preferably a fluorine atom.

"C1-C6 alkyl group" of the above R4, R5, R6and R7represents preferably methyl group or ethyl group, and more preferably methyl group.

"C1-C6 halogenation group" of the above R4, R5, R6and R7represents preferably monitoramento group, deformational group or triptorelin group, and more preferably monitoramento group.

"C1-C6 alkoxygroup" above R4, R5, R6and R7represents preferably a methoxy group or ethoxypropan and more preferably a methoxy group.

"C1-C6 halogenlampe" above R4, R5, R6and R7represents preferably monitormetriclog, monochloramine is oxygraph, dipterocarp, dichloromethoxy, cryptometrics or trichlormethiazide and more preferably monitormetriclog or deformations.

"Halogen atom" from group A1 represents preferably a fluorine atom.

"C1-C6 alkyl group" of the above groups A1 preferably represents methyl group, ethyl group, or through a group, more preferably methyl group or ethyl group, and most preferably a methyl group.

"C1-C6 alkoxygroup from the above group A1 preferably represents a methoxy group or ethoxypropan and more preferably a methoxy group.

"C1-C6 halogenation group" from the groups described above, A1 represents preferably pharmacylow group or deformational group, and more preferably pharmacylow group.

"C1-C6 alkoxy-C1-C6 alkyl group" from the groups described above, A1 represents preferably methoxymethyl group or ethoxymethyl group.

Above W1represents preferably a single bond, methylene group or ethylene group, and more preferably a methylene group.

"C1-C6 alkyl group" defined above W2represents preferably a methyl group.

"The atom halog is" above W 2represents preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom.

The number of substituents present in the benzene ring of the above W2is preferably one.

Above W2represents preferably a hydrogen atom.

Above n1 is preferably 1-3, and more preferably 1 or 2.

Above n2 is preferably 1 or 2 and more preferably 1.

Above n3 is preferably 1-4, and more preferably 1 or 2.

In this description of the structure of the compound, sometimes for convenience, represents a certain isomer, but the present invention covers all structural isomers such as geometric isomers, optical isomers, rotary isomers, stereoisomers, tautomers and mixtures of these isomers, and therefore is not limited to the typical formula. Accept any of these isomers or mixture of isomers. Therefore, the compound of the present invention may sometimes be an optically active substance and a racemic form, which do not limit the present invention and are included in the scope of the invention. The connection can sometimes have a crystal polymorphism, not limiting the present invention. Acceptable as a separate crystalline substance, and see what camping crystalline substances. In addition, examples of the compounds of the present invention may include anhydrous substances and solvate (in particular, hydrates). In the scope of the present invention can be also included so-called metabolite formed by the decomposition ofin vivocompounds (1) according to the present invention. In addition, the present invention encompasses compounds (so-called prodrugs)that form a connection (1) according to the present invention during metabolismin vivothrough oxidation, reduction, hydrolysis and conjugation, etc.

The compound of the present invention, presents shown above formula (1), forms a salt with the NH group in the 1st or 3rd position of the benzimidazole skeleton.

“Salt” is not particularly limited, if only she was a pharmaceutically acceptable. Examples of such salt include salts of inorganic bases, and salts of organic bases. Preferred examples of salts of inorganic bases include alkali metal salts such as sodium salt, potassium salt and lithium salt; salts of alkaline earth metals such as calcium salt and magnesium salt; salts of transition metals, such as zinc salt; aluminum salt and ammonium salt. Preferred examples of organic salts include diethylamine salt, diethanolamine salt, meglumine salt and N,N'-dibenzylethylenediamine the salt.

“MES” according to the present invention is not particularly limited, if only he was a pharmaceutically acceptable. Examples of such MES include hydrate, ethanol MES and acetone MES. A preferred example is a hydrate.

Of the compounds represented by formula (1) according to the present invention, preferred compounds include:

(2) connection, where R1represents a hydrogen atom or a methyl group, or its salt, or their MES;

(3) connection, where R1represents a methyl group, or its salt, or their MES;

(4) the compound, where R2represents a group represented by the formula 3

where W2represents a hydrogen atom, C1-C6 alkyl group or a halogen atom (provided that the number of radicals W2in the benzene ring may be equal to 1-3, and they may be the same or different);

n1 is 1 to 5, n2 is 1 to 4, and n3 equals 1-6,

group, optionally containing 1 or 2 groups selected from the group A2, consisting of a fluorine atom, methyl group, ethyl group, various groups, metoxygroup and mooftormetilnoy group;

or its salt, or their MES;

(5) the compound, where R2represented by formula 4

or its salt, or their MES;

(6) connection, where R2p is edstaven formula 5

or its salt, or their MES;

(7) the compound, where R3represents a hydrogen atom, or methyl group, or its salt, or their MES;

(8) the compound, where R3represents a methyl group, or its salt, or their MES;

(9) the compound, where R4represents a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxypropan, or a fluorine atom, or its salt, or their MES;

(10) the compound, where R4represents a hydrogen atom, methyl group, or a fluorine atom, or its salt, or their MES;

(11) the compound wherein R4represents a hydrogen atom, or its salt, or their MES;

(12) the compound wherein R5represents a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxypropan, or a fluorine atom, or its salt, or their MES;

(13) the compound, where R5represents a hydrogen atom, methyl group, or a fluorine atom, or its salt, or their MES;

(14) the compound, where R5represents a hydrogen atom, or its salt, or their MES;

(15) the compound, where R6represents a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxypropan, or a fluorine atom, or its salt, or their MES;

(16) the compound, where R6represents a hydrogen atom, methyl group, or a fluorine atom, or its salt, or their MES;

(17) the compound, where R6represents a hydrogen atom, or its salt, or their MES;

(18) the compound wherein R7represents a hydrogen atom, hydroxyl group, methyl group, ethyl group, methoxy group, ethoxypropan, or a fluorine atom, or its salt, or their MES;

(19) the compound wherein R7represents a hydrogen atom, methyl group, or a fluorine atom, or its salt, or their MES;

(20) the compound wherein R7represents a hydrogen atom, or its salt, or their MES;

(21) connection, where W1represents a single bond, methylene group, or ethylene group, or its salt, or their MES;

(22) connection, where W1represents a methylene group, or its salt, or their MES;

(23) connection, where W2represents a hydrogen atom, or its salt, or their MES;

(24) connection, where n1 is 1 to 3, or its salt, or their MES;

(25) connection, where n1 is 1 or 2, or its salt, or their MES;

(26) connection, where n2 is 1 or 2, or its salt, or their MES;

(27) connection, where n3 is 1 to 4, or its salt, or their MES; and

(28) connection, where n3 is 1 or 2, or its salt, or their MES.

In addition, predpochtitelno you can use the compound or its salt, or MES, which satisfy the following conditions in any combination: R1selected from (2) or (3); R2selected from (4) or (6); R3selected from (7) or (8); R4selected from (9)-(11); R5selected from (12)-(14); R6selected from (15)-(17); R7selected from (18)-(20), and W1selected from (21) or (22), W2selected from (23), n1 is selected from (24) or (25), n2 is selected from (26), n3 is selected from (27) or (28).

Of specific compounds, or their salts, or the solvate of those and other suitable compounds of the present invention include:

2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-(5,7-dioxaspiro[2.5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((3-methyl-4-(1,5,9-dioxaspiro[5.5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((3-methyl-4-(2-(8-methyl-1,4,7,9-tetraoxaspiro[4.5]Dec-8-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-(5,9-dioxaspiro[3.5]non-7-yloxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-(1,3-dioxolane-4-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-METI the pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-(5,9-dioxaspiro[3.5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4.5]Dec-8-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-(5,9-dioxaspiro[3.5]non-7-ylethoxy)pyridine-2-yl)methyl)sulfinil-1H-benzimidazole or

2-(((4-((5,5-debtor-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole; or a salt, or a solvate of those and other (in particular, dehydrat their sodium salts or hydrate of their sodium salts).

Other suitable compounds of the present invention include:

2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((4-(5,7-dioxaspiro[2.5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole;

2-(((3-methyl-4-(1,5,9-dioxaspiro[5.5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole or

2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole; or a salt, or a solvate of those and other (in particular, anhydrous sodium salt or the hydrate of their sodium salts).

Of optical isomers (exist) from the compounds represented above, more preferably used as a compound exhibiting higher the s inhibitory effect against the secretion of gastric acid, or the connection with the higher resistance inhibitory effect against gastric secretion of acid.

Advantages of the invention

The compound of the present invention exhibits an excellent inhibitory effect against gastric secretion of acid and higher resistance inhibitory effect against the secretion of gastric acid, supports high intragastric pH for a long time, more safely and to an appropriate degree of physico-chemically stable. Therefore, the compound is useful as a medicine, particularly as a therapeutic agent or prophylactic agent associated with acid diseases or symptoms and as a bactericidal agent or auxiliary microbicides againstHelicobacter pylori.

The best way of carrying out the invention

The compound of the present invention can be obtained by any of the methods described below, however, these methods of obtaining the present invention is not limited.

Connection (1) according to the present invention can be obtained by doing the following : A.

Formula 6

where R1, R2, R3, R4, R5, R6, R7and W1are the same as defined above, and X2 represents a leaving group.

Examples of leaving groups X2include sulfonyloxy, such as methanesulfonate, p-toluensulfonate, tripterocalyx, halogen groups such as chlorine, bromine and iodine, alloctype, such as atomic charges, tripterocalyx, propionyloxy, and preferably use methanesulfonate and p-toluensulfonate, chlorine or atomic charges.

The following describes the individual stages of the method A.

Stage A-1: Introduction of the leaving group or halogenoalkane

(1) the Reaction of introducing the leaving group

At this stage, the compound (3) is subjected to interaction with the agent for the introduction of the leaving group in the absence of solvent or in an inert solvent and in the presence of a base to obtain the compound (3a) or its salt.

Used here, the solvent is not particularly limited, if only he could, to some extent, dissolving the source material and does not inhibit the reaction. Examples of such a solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and benzotrifluoride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylated the Ministry of foreign Affairs, hexamethylphosphoric triamide; pyridine and a mixture of these solvents. Preferably use halogenated hydrocarbons, ethers, or a mixture of ethers and aromatic oglewood and most preferably dichloromethane, tetrahydrofuran or a mixture of tetrahydrofuran and toluene.

Examples of the agent for the introduction of the leaving group used in this reaction include sulfonylurea agents, such as methanesulfonate, p-toluensulfonate, triftormetilfullerenov, N-phenyl-bis(triptoreline). Preferably use methanesulfonate or p-toluensulfonate and most preferably methanesulfonanilide.

The examples used here, the base include tertiary alkylamines followed, such as trimethylamine and triethylamine; pyridine, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide. Preferably using triethylamine or sodium hydroxide, and most preferably is triethylamine.

The reaction temperature varies depending on the starting material, solvent, agent for the introduction of the leaving group and the Foundation. The reaction temperature is usually from -50°C to 100°C and preferably from -20°C to 40°C.

The reaction time varies depending on the starting material, solvent, agent for the introduction of the leaving group, the warping and the reaction temperature. The reaction time is usually from 15 minutes to 12 hours and more preferably from 30 minutes to 2 hours.

Obtained at this stage, the connection could not be allocated and directly processed in the next stage.

(2) Halogenoalkane (in the typical example described chlorination)

At this stage, the compound (3) is subjected to interaction with gloriouse agent in the absence of solvent or in an inert solvent and in the presence or in the absence of a basis of obtaining compound (3a).

Used here, the solvent is not particularly limited, if only he could, to some extent, dissolving the source material and does not inhibit the reaction. Examples of such a solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene and benzotrifluoride; and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol. Preferably use a halogenated hydrocarbon or an aromatic hydrocarbon, and most preferably dichloromethane, chloroform or toluene. Examples glorieuses agent used in this reaction include methanesulfonate, oxalicacid, thionyl chloride, oxychloride, the FOSFA the RA, trichloride phosphorus, pentachloride phosphorus and chloroethanol acid and preferably using thionyl chloride or chloroethanol acid. The examples used here, the base include tertiary alkylamines followed, such as trimethylamine and triethylamine; pyridine, etc. are Preferably used triethylamine.

The reaction temperature varies depending on the starting material, solvent and gloriouse agent. The reaction temperature is usually from -20°C to 30°C and preferably from 0°C to 10°C.

The reaction time varies depending on the starting material, solvent, glorieuses agent and the reaction temperature. The reaction time is usually from 10 minutes to 6 hours and preferably from 10 minutes to 2 hours.

At this stage, the connection could not be allocated and directly processed in the next stage.

Bromination performed using a reagent, such as bromide/red phosphorus, tribromide phosphorus and pentabromide phosphorus. Iodination perform using this reagent, as iodine/red phosphorus. Alternatively, the bromide and iodide can be obtained for interaction reagent such as sodium bromide and sodium iodide, respectively, with the leaving group, synthesized at the stage of A-1.

Stage-2: Lieterature

At this stage, the compound (2) was subjected to the Ute interaction with compound (3a) or its salt (in particular, hydrochloride(AMI)in the absence of solvent or in an inert solvent and in the presence or in the absence of a basis of obtaining compound (4).

Used here, the solvent is not particularly limited, if only he could, to some extent, dissolving the source material and does not inhibit the reaction. Examples of such a solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; aromatic hydrocarbons such as benzene and toluene; N,N-dimethylformamide; dimethylsulfoxide; water and a mixture of these solvents. Preferably use dichloromethane, alcohol, simple ester or mixture of simple ether and toluene, and most preferably methanol, tetrahydrofuran or a mixture of tetrahydrofuran and toluene.

The examples used here, the base include inorganic bases such as sodium hydride, potassium hydride, lithium carbonate, sodium carbonate, potassium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide; the authority of the economic base, such as N-methylmorpholine, triethylamine, Tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinedione, picoline, 4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). It is preferable to use an inorganic base such as sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide or potassium hydroxide or triethylamine, and most preferably sodium hydroxide or triethylamine.

The reaction temperature varies depending on the starting material, solvent and base and is usually from 0°C to 100°C and preferably from 10°C. to 50°C.

The reaction time varies depending on the starting material, solvent, base and reaction temperature and is usually from 30 minutes to 3 days.

Stage-3: Oxidation

At this stage, the compound (4) is subjected to interaction with the oxidant in the presence or in the absence of a solvent to obtain compound (1).

Used here, the solvent is not particularly limited, if only he could, to some extent, dissolving the source material and does not inhibit the reaction. Examples of such a solvent include alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; NITRILES, such as acetonitrile. It is preferable to use an aromatic hydrocarbon, an alcohol, a halogenated hydrocarbon or a mixture thereof, and most preferably toluene, a mixture of toluene and methanol or dichloromethane.

The examples used here, the oxidizing agent include hydrogen peroxide, tert-butylhydroperoxide, the hydroperoxide cumene, periodate sodium, peracetic acid, perventing acid, 3-chloroperbenzoic acid, a complex of hydrogen peroxide with urea ((NH2)2CO·H2O2). Preferably use the 3-chloroperbenzoic acid or the hydroperoxide cumene.

It should be noted that asymmetric oxidation can be performed by methods described in the following documents: WO96/02535, WO2001/83473, WO2004/087702, WO2004/052881, WO2004/052882, Adv. Synth. Catal. 2005, 347, 19-31, Chem. Rev. 2003, 103, 3651-3705, Tetrahedron Lett. 2004, 45, 9249-9252, Angew. Chem. Int. Ed. 2004, 43, 4225-4228 and Tetrahedron Asymmetry 2003, 14, 407-410.

In particular, asymmetric oxidation perform ongoing, is the group interaction of the compound (4) and oxidant in the presence of the agent for the induction of asymmetry or catalyst induction of asymmetry.

Examples of the oxidant include peroxides such as hydrogen peroxide, tert-butylhydroperoxide, urea hydroperoxide and the hydroperoxide cumene. In particular, when the agent for the induction of asymmetry or the catalyst induction of asymmetry containing titanium, zirconium or hafnium, then use hydroxyperoxide cumene. When it contains vanadium, use hydrogen peroxide.

The oxidizing agent used in this reaction, may be present in amounts exceeding the amount of the compound (4), preferably in the range of 1.01 to 10 molar equivalents. In particular, when the agent for the induction of asymmetry or the catalyst induction of asymmetry contains titanium, use 1.05 equivalents of oxidant. When the agent for the induction of asymmetry or the catalyst induction of asymmetry contains zirconium or hafnium, using 1.2 equivalents of oxidant. When it contains vanadium, usually using 1.1 equivalent of oxidant.

Examples of the specified agent for the induction of asymmetry or catalyst induction of asymmetry include:

(1) optically active titanium complexes, such as complexes of an optically active diol and alkoxide of titanium(IV) and water or alcohol;

(2) optically active zirconium complexes, such as complexes of an optically active diol and alkoxide of zirconium(IV) water may be present or not);

(3) the optical AK is positive others complex, such as complexes of an optically active diol and hafnium alkoxide(IV);

(4) optically active vanadium complex, such as complexes of an optically active Schiff bases and venodilatation;

(5) optically active iron complexes, such as complexes of an optically active Schiff bases and acetylacetonate Fe(III);

(6) optically active manganese complexes (for example, Salins(salen)manganese complex, such as complexes of an optically active Schiff bases and manganese; and

(7) optically active tungsten complexes, such as complexes of an optically active alkaloid of Cinchona and tungsten(III).

Examples of the optically active diol include:

(1) ALCALDIA, such as esters of tartaric acid, for example, (+) or (-) diethyltartrate, diethyltartrate, diisopropylate and dibutylated, and tartarate, such as tetramethylthiuram; and

(2) an aromatic diol, such as (R)- or (S)-binaphthol.

Examples of optically active Schiff bases include Schiff bases derived from substituted salicylic aldehydes, such as (S)-(-)-2-(3,5-di-tert-butylcyclohexylamine)-3,3-dimethyl-1-butanol and (1R,2S)-1-((2-hydroxy-3,5-di-tert-butylbenzamide)amino)indan-2-ol, and Schiff bases Salins-type.

When performing asymmetric oxidation add, if needed, basis. Examples of the use of the Foundation has been created especially not limit, if only it does not inhibit the reaction, and they include inorganic bases and organic bases, preferably tertiary amines, such as diisopropylethylamine and triethylamine, and most preferably diisopropylethylamine. The base is usually added in an amount of 0.1-1 equivalent relative to compound (4).

It should be noted that when using the agent for the induction of asymmetry or the catalyst induction of asymmetry, containing vanadium, base usually do not use.

Examples of the solvent used for asymmetric oxidation include aromatic hydrocarbons such as toluene, benzene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; and ethers, such as ethyl acetate. In particular, when using the agent for the induction of asymmetry or the catalyst induction of asymmetry containing titanium, zirconium or hafnium, preferably using toluene or tert-butyl methyl ether. When using the agent for the induction of asymmetry or the catalyst induction of asymmetry, containing vanadium, preferably using acetonitrile or dichloromethane. When using the catalyst induction of asymmetry containing titanium, effective is the addition of water. The amount of water, including the water contained in the solvent, the reagent (excluding oxidant) and su the stratum, preferably is in the range of 0.1 to 0.33 equivalent relative to compound (4) and most preferably in the range of 0.13-0.25 equivalent. The water content can be adjusted by molecular sieves 3A.

In the synthesis of complex alkoxide of titanium(IV) and alcohol as alcohol is advisable to use isopropanol in amounts of typically 1.2 equivalents relative to titanium.

The reaction temperature varies depending on the starting material, solvent and oxidant and is usually from -100°C to 100°C, preferably from -70°C to 70°C.

The reaction time varies depending on the starting material, solvent, oxidant, and the reaction temperature and is usually from 15 minutes to 72 hours, more preferably from 30 minutes to 24 hours.

Obtained as described above, the connection can be converted to a salt in the usual way. In particular, the compound (1) is subjected to interaction with base in the presence or in the absence of solvent. The solvent can be used acetonitrile; an alcohol such as methanol or ethanol; water, or a mixture of these solvents, preferably a mixture of ethanol and water. As a basis you can use an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; alkali earth metal hydroxide, such ka is magnesium hydroxide; and the alkoxide such as sodium methoxide, tert-piperonyl sodium tert-pentoxide, sodium or magnesium methoxide. It is preferable to use an aqueous solution of sodium hydroxide. The reaction temperature is usually from -50°C to 50°C, preferably from 10°C. to 40°C. the reaction Time is usually from 1 minute to 2 hours, preferably from 1 minute to 1 hour.

In accordance with another variant of a salt of an alkali metal such as sodium salt or potassium salt, can be subjected to a salt exchange reaction with a metal chloride or a metal sulfate such as barium chloride, magnesium chloride, magnesium sulfate or zinc sulfate, in the presence or in the absence of a solvent for the conversion into the corresponding metal salts such as barium salt, magnesium salt and zinc salt.

After oxidation of the compound (4) compound (1) may be subjected to transformation in Sol without allocations with obtaining metal salt.

As compounds (2) and compounds (3), which are intermediate compounds in the method, it is possible to use commercially available compounds or compounds readily obtained from commercially available(s) connection(s) in the traditional way, usually used by professionals. In particular, the compound (3) can be obtained by the method described below.

Formula 7

In this formula, R1, R2, R3and W1are the same as defined above, and X1represents a halogen atom, preferably a chlorine atom, a bromine atom or an iodine atom, and more preferably a chlorine atom.

The following describes the individual stages of the method Century.

Stage B-1: Halogenoalkane (in the typical example described chlorination)

At this stage, the compound (5) is subjected to interaction with gloriouse agent in the absence of solvent or in an inert solvent to obtain the compound (6).

At this stage of the reaction should preferably be conducted in gloriouse agent, usually without the use of solvent. However, when the solvent is not limited, if only he could, to some extent, dissolving the source material and does not inhibit the reaction. Examples of such a solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride, and ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol.

Examples glorieuses agent used in this reaction include acetylchloride, oxalicacid, thionyl chloride, phosphorus oxychloride, trichloride phosphorus and pentachloride phosphorus, and prepact the positive use acetylchloride.

The reaction temperature varies depending on the starting material, solvent and gloriouse agent and is usually from -50°C to 30°C and preferably from -30°C to 10°C.

The reaction time varies depending on the starting material, solvent, glorieuses agent and the reaction temperature and is usually from 30 minutes to 8 hours and preferably from 1 to 5 hours.

When do bromination, use this reagent, as acetylmuramic, bromovalerate, bromine/red phosphorus, tribromide phosphorus and pentabromide phosphorus. When do iodination, use this reagent, as iodine/red phosphorus, or perform bromination and subsequent implementation of the interaction with sodium iodide.

Stage-2: Reaction of the introduction of the group R2-W1-O

At this stage, the compound (6) is subjected to interaction with alcohol (7), i.e. the group R2-W1-OH (where R2and W1are the same as defined above), in the absence of solvent or in an inert solvent and in the presence of a base to obtain compound (8).

Used here, the solvent is not particularly limited, if only he could, to some extent, dissolving the source material and does not inhibit the reaction. Examples of such a solvent include aliphatic hydrocarbons such as hexane, heptane, ligroin and Petrola the initial broadcast; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; aromatic hydrocarbons such as benzene and toluene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide and N-organic; dimethylsulfoxide; water and a mixture of these solvents. Preferably use a sulfoxide, a simple ester or amide, and most preferably dimethyl sulfoxide.

The examples used here, the base include carbonates of alkali metals such as lithium carbonate, sodium carbonate and potassium carbonate; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; hydrides of alkali metals such as lithium hydride, sodium hydride and potassium hydride; alkoxides of alkali metals formed alkali metal; n-utility and diisopropylamide lithium. Preferably use a hydride of an alkali metal, and most preferably sodium hydride.

The reaction temperature varies depending on the starting material, solvent and base and with whom is usually from 0°C to 100°C and preferably from 10°C to 100°C in the case when the alcohol (7), that is, R2-W1-OH, is a primary alcohol, and from 50°C to 100°C when the specified alcohol is a secondary alcohol.

The reaction time varies depending on the starting material, solvent, base and reaction temperature and is usually from 15 minutes to 48 hours and more preferably from 30 minutes to 12 hours.

Stage-3: Rearrangement of the ester of acetic acid

At this stage the connection (8) is subjected to interaction with acetic anhydride in the absence of solvent and in the presence or in the absence of grounds with getting acetate of compound (3).

The examples used here, the base include tertiary amines such as trimethylamine, diisopropylethylamine and triethylamine, and pyridine, etc. are Preferably used triethylamine.

The reaction temperature varies depending on the starting material and solvent, and is usually from 20°C to 150°C and preferably from 20°C to 60°C in the presence of a base, and from 50°C to 100°C in the absence of base.

The reaction time varies depending on the starting material, solvent and reaction temperature and is usually from 10 minutes to 6 hours and preferably from 30 minutes to 5 hours.

Upon completion of the reaction, the residue obtained by distillation of acetic anhydride, usually directly used to follow is her stage. In accordance with another variant acetate is subjected to the operation stage a-2 method And obtaining the compound (4).

Stage-4: hydrolysis Reaction

At this stage, the compound obtained in stage B-3, is subjected to the interaction with base in the presence or in the absence of a solvent to obtain compound (3).

Used here, the solvent is not particularly limited, if only he could, to some extent, dissolving the source material and does not inhibit the reaction. Examples of such a solvent include water; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methylcellosolve; aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and dimethyl ether of diethylene glycol; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; amides, such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide and hexamethylphosphoric triamide; and a mixture of these solvents. Preferably use alcohol or mixture of alcohol and water, and most preferably a mixture of methanol and water.

The examples used here, the base including the Ute carbonates of alkali metals, such as lithium carbonate, sodium carbonate and potassium carbonate; hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkoxides of metals such as lithium methoxide, sodium methoxide, ethoxide sodium tert-piperonyl potassium; and Amici, such as aqueous ammonia and the mixture concentrated ammonia-methanol, etc. are Preferably used alkali metal hydroxide, and most preferably sodium hydroxide.

The reaction temperature varies depending on the starting material, solvent and base and is usually from 0°C to 60°C and preferably from 10°C. to 40°C.

The reaction time varies depending on the starting material, solvent, base and reaction temperature and is usually from 10 minutes to 6 hours.

In each of the above methods after the reaction at each stage of the target compound obtained from the reaction mixture using the traditional method.

For example, in the case when the entire reaction mixture is a solution of the target compound is obtained by returning the temperature of the reaction mixture to room if need be, or by cooling the reaction mixture on ice, the neutralization of acid, alkali, oxidant or reductant and the addition of water and an organic solvent, such as ethyl acetate, water-immiscible and nesposobnogo is to interact with the target compound, to separate the layer containing the target compound, and then adding a solvent immiscible with the received layer and unable to interact with the target compound, washing the layer containing the target compound, and separation of the specified layer. In addition, if the layer is an organic layer, the desired compound can be obtained by drying the organic layer with use of a dehydrating agent, such as potassium carbonate, anhydrous magnesium sulfate or anhydrous sodium sulfate, and distillation of the solvent. On the other hand, if the layer is an aqueous layer, the desired compound can be obtained by subjecting the layer to the stages of electric desalting and drying freeze.

In accordance with another variant, when the entire reaction mixture is a solution, and, if possible, the target compound can be obtained by distillation of other compounds (e.g., solvent, reagent) under normal or reduced pressure.

In addition, when only the target compound precipitates in the form of solids or the whole reaction mixture is liquid and only the target compound precipitates during the extraction process, the target compound can be obtained by filtering, washing the filtered target compounds suitable R is storyteller and drying. Next, the target compound can be obtained from the filtrate in the same manner as in the case when the entire reaction mixture is a solution.

In addition, when the reaction mixture in the form of a solid substance is present(ut) only the reagent(s) or catalyst, or when the entire reaction mixture is a solution and only the reagent(s) or catalyst deposited in the form of solids during the extraction process, and the target compound dissolved in the solvent, the target compound can be obtained by filtering the reagent(s) or catalyst, washing the filtered(s) of reagent(s) or catalyst suitable organic or inorganic solvent, an Association of wash liquid and filtrate, and processing the mixture in the same way, as in the case when the entire reaction mixture is a solution.

In particular, when all other target compounds in the reaction mixture does not inhibit the reaction of the next stage, the mixture can be used directly in the next stage without separation of target compounds.

To increase the purity of the target compound obtained in the above stage, can be appropriately applied the method of recrystallization, various chromatographic methods and the method of distillation.

When received from the connection is solid the purity of the target compounds usually increase the recrystallization method. In the method of recrystallization is possible to use a single solvent or a mixture of several solvents, directionspublic in relation to the target connection. In particular, the target compound can be recrystallized first dissolving it in the solvent or in a mixture of several solvents at room temperature or by heating and then cooling the resulting solution with ice water, etc., mixing it, or defending it one at room temperature, or by adding a solvent in which the target compound is dissolved with low solubility, and removing the crystallized target compound from a solution.

The purity of the target compound may be enhanced by various chromatographic methods. Usually used chromatography on a column of silica gel, using a weakly acidic silica gels, such as silica gel 60 (70-230 mesh or 340-400 mesh) manufactured by F. Merck Ltd., BW-300 (300 mesh) manufactured by F. Fuji SilysiChemical Ltd., or a disposable cartridge column with silica gel for liquid chromatography, medium-pressure column High Frash) production F. Yamazen Corporation. When the target compound is the main and excessively adsorbed by the above silica, applied forces is Kagel with propylamino coating (200-350 mesh) manufactured by F. Fuji Silysia Chemical Ltd. or NH silica gel using a single cartridge column with silica gel for liquid chromatography, medium pressure (High Frash, Amino) production F. Yamazen Corporation. Alternatively, when the target connection has bipolarity and should be allerban a highly polar solvent, such as methanol, can be used NAM-200H or NAM-300H (production Laboratory NAM). When the elution of the target compounds using any of the above mentioned silica and single solvent or a mixture of several solvents, directionspublic in relation to the target compound, and the solvent can be obtained target compound of high purity.

When the target compound is liquid, the purity of the target compound can be increased by distillation. When using the method of distillation target connection, you can distil under normal pressure or under reduced pressure at room temperature or when heated.

What I described above is a typical way to obtain the compounds (1). The initial compounds and reagents used for obtaining compounds of the present invention, can be salt or MES, such as hydrate vary depending on the source material and the solvent and does not limit the I, if only they could not inhibit the reaction. Needless to say that the solvent used varies depending on starting materials and reagents and are not particularly limited, but he would not inhibit the reaction and could to some extent dissolve the starting material. When the compound (1) according to the present invention can be obtained in a free form, it can be converted into a salt or MES, in which the compound (1) can be converted, in the usual way.

When the compound (1) according to the present invention are in the form of salt or MES compounds (1), salt or MES can be converted to the compound (1) free form in the usual way.

In addition, various isomers such as geometric isomers, optical isomers, rotary isomers, stereoisomers and tautomers) connection (1) according to the present invention purify and produce traditional partitioning methods, such as recrystallization method, a method diastereomeric salt, enzymatic separation method, various chromatographic methods such as thin layer chromatography, column chromatography and gas chromatography).

When the compound of the present invention is used as a drug, it is usually the compound is mixed with suitable additives for the manufacture of ready-p is the physical alteration of the dosage form. But it does not exclude the case of direct application of the compounds of the present invention as a medicine.

Examples of these additives include a filler, binder, grease, baking powder, dye, conditioner taste and smell, emulsifier, surfactant, solubilizer, suspendisse substance, isotonic agent, buffer, preservative, antioxidant, stabilizer and accelerator absorption, which is usually used in medicine. If required, they can be used in combination.

Examples of the filler include lactose, white sugar, glucose, corn starch, mannitol, sorbitol, starch, α-starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, alumosilicate magnesium and phosphate of calcium.

Examples of the binder include polyvinyl alcohol, methylcellulose, ethylcellulose, Arabian gum, tragakant, gelatin, shellac, hypromellose, hydroxypropylcellulose, sodium carboximetilzellulozu, polyvinylpyrrolidone and macrogol.

Examples of lubricants include magnesium stearate, calcium stearate, sodium fumarate, talc, polyethylene glycol and colloidal silicon dioxide.

Examples of the powder include Chris is aricescu cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, nitrosamino hydroxypropylcellulose, carboximetilzellulozu, calcium-carboximetilzellulozu, sodium-croscarmellose, carboximetilkrahmal, sodium carboximetilkrahmal.

Examples of the dye include pharmaceutically acceptable dyes, such as sesquioxide iron, yellow sesquioxide iron, Carmine, burnt sugar, β-carotene, titanium oxide, talc, Riboflavin-phosphate sodium and yellow aluminum lacquer.

Examples of enhancer taste and smell include cocoa powder, menthol, mpasm, menthol oil, bernasco camphor and cinnamon powder.

Examples of the emulsifier or surfactant include steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, glycerol monostearate, ester of sucrose and a fatty acid and an ester of glycerol and fatty acids.

Examples of the solubilizer include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, Polysorbate 80 and nicotinamide.

Examples of suspending substances include, in addition to the above-described surfactants, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroc ethylcellulose and hydroxypropylcellulose.

Examples of isotonic substances include glucose, sodium chloride, mannitol and sorbitol.

Examples of the buffer include phosphate, acetate, carbonate and citrate buffer solutions.

Examples of preservatives include methylparaben, propylparaben, chlorobutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid and sorbic acid.

Examples of the antioxidant include sulfite, ascorbate and α-tocopherol.

As examples of the stabilizer, you can specify the stabilizers commonly used in medicine.

As examples of absorption accelerator, you can specify the absorption accelerators commonly used in medicine.

Examples of the drug include oral contraceptives, such as tablet, powder, granule, capsule, syrup, toffee and fugitive drug; external preparations such as suppositories, ointment, eye ointment, band-AIDS, eye drops, nose drops, drops in the ear, poultices and lotion; and injectable preparations.

The above-mentioned oral contraceptives produce a suitable mixture of compounds of the present invention with the above additives. It should be noted that, if necessary, on the surface preparations may be coated.

External agents produce a suitable mixture of compounds of the present invention with the above additives, such in castnet is, as the filler, binder, improver of taste and smell, emulsifier, surfactant, solubilizer, suspendisse substance, isotonic agent, buffer, preservative, antioxidant, stabilizer and accelerator absorption.

Injectable drugs produce a suitable mixture of compounds of the present invention with the above additives, including, in particular, as an emulsifier, surfactant, solubilizer, suspendisse substance, isotonic agent, buffer, preservative, antioxidant, stabilizer and accelerator absorption.

When the compound of the present invention is used as a medicine, the dose will change depending on the symptom and age, but it is usually 0.15 to 5000 mg (preferably 0.5 to 1500 mg) in the case of oral contraceptives, 0.5 to 1500 mg, preferably 1.5 to 500 mg) in the case of an external preparation, 0.3 to 5000 mg (preferably 1-500 mg) in the case of injection of the drug. The dose may be entered at one time or divided for the introduction of 2-6 times per day. It should be noted that in cases of oral contraceptives and injectable dose means the entered number, and in the case of an external preparation, it is the amount that is actually absorbed into a living organism.

Connection (1) according to the present izaberete is s can be obtained by way described in the examples below. The effect of the compound can be confirmed by the method described below in the examples trials. These examples are described as illustrative examples and are in no way limit the present invention.

Below are the names of the commercially available starting materials and reagents used in the examples and their manufacturers. The names of the documents shown in the number of existing manufacturers, means that the connection receive in accordance with the method described in this document:

benzyloxyacetaldehyde (Aldrich),

2,2-dimethyl-1,3-propandiol (Kanto Chemical Co., Inc.)

monohydrate p-toluensulfonate acid (Tokyo Kasei Kogyo Co., Ltd.),

20% palladium hydroxide (Aldrich),

sodium hydride, in oil (Wako Pure Chemical Industries Ltd.),

acetone (Wako Pure Chemical Industries Ltd.)

1-oxide 4-chloro-2,3-dimethylpyridine (obtained from Sanyo Fine Co., Ltd., however, is a known compound disclosed in J. Med. Chem. 1998, 41, 1777-1788),

acetic anhydride (Kanto Chemical Co., Inc.)

5N aqueous solution of sodium hydroxide (Wako Pure Chemical Industries Ltd.),

1N aqueous solution of sodium hydroxide (Wako Pure Chemical Industries Ltd.),

the triethylamine (Kanto Chemical Co., Inc., or Wako Pure Chemical Industries Ltd.),

methanesulfonanilide (Tokyo Kasei Kogyo Co., Ltd.),

2-mercaptobenzimidazole (Tokyo Kasei Kogyo Co., Ltd.),

3-chloroperbenzoic acid (Tokyo Kasei Kogyo Co., Ltd.),

1,1-bis(hydroxymethyl)cyclopropane (Aldrich),

ethyl 3-oxohexanoate (ACROS),

ethylene glycol (Tokyo Kasei Kogyo Co., Ltd.),

sociallyengaged (Wako Pure Chemical Industries Ltd.),

1,3-dimensions-2-propanol (Aldrich),

the complex of sulfur trioxide and pyridine (Aldrich),

triethylorthoformate (Wako Pure Chemical Industries Ltd.),

triethylorthoformate (Tokyo Kasei Kogyo Co., Ltd.),

methylpropionate (Aldrich),

hydroxyacetone (Wako Pure Chemical Industries Ltd.),

the benzoyl chloride (Tokyo Kasei Kogyo Co., Ltd.),

D-(-)-diethyltartrate (Tokyo Kasei Kogyo Co., Ltd.),

toluene (digidrirovanny) (Kanto Chemical Co., Inc.)

isopropoxide titanium(IV) (Kanto Chemical Co., Inc. or Aldrich),

N,N-diisopropylethylamine (Aldrich or Nakarai Tesque),

the hydroperoxide cumene (Nakarai Tesque, Inc. or Aldrich),

L-(+)-diethyltartrate (Tokyo Kasei Kogyo Co., Ltd. or Aldrich),

2-(hydroxymethyl)-1,3-propandiol (E-MERCK or Aldrich),

tetrahydrofuran (digidrirovanny) (Kanto Chemical Co., Inc.)

1,3-defloration (SYNQUEST),

1,3-propandiol (Wako Pure Chemical Industries Ltd.),

((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methanol (Aldrich),

2,2-dimethyl-1,3-dioxane-5-he (Tokyo Kasei Kogyo Co., Ltd.),

benzylbromide (E-MERCK),

tetrabutylammonium (Tokyo Kasei Kogyo Co., Ltd.),

DOWEX(R) 50W-X8 (Muromachi Depending Kogyo Kaisha, Ltd.),

cyclobutanone (AVOCADO)

tetrahydro-4H-Piran-4-one (Tokyo Kasei Kogyo Co., Ltd.),

dichloromethane (digidrirovanny) (Kanto Chemical Co., Inc.)

70% of Perlina acid (Wako Pure Chemical Industries Ltd.),

2,3,5-kallidin (ACROS),

sulfuric acid (Junsei Chemical Co., Ltd.),

nitric acid, boiling (Wako Pure Chemical Industries Lt.),

acetylchloride (Junsei Chemical Co., Ltd.),

N,N-dimethylformamide (Wako Pure Chemical Industries Ltd.),

0,1N aqueous solution of sodium hydroxide (Wako Pure Chemical Industries Ltd.),

sodium hydroxide (Wako Pure Chemical Industries Ltd.),

p-toluensulfonate (Tokyo Kasei Kogyo Co., Ltd.),

thionyl chloride (Wako Pure Chemical Industries Ltd.),

tert-piperonyl potassium (Tokyo Kasei Kogyo Co., Ltd.),

pentaerythritol (Tokyo Kasei Kogyo Co., Ltd.),

triethylorthoformate (Tokyo Kasei Kogyo Co., Ltd.),

triethylenediamine (Tokyo Kasei Kogyo Co., Ltd.),

3-pentanon (Tokyo Kasei Kogyo Co., Ltd.),

Cyclopentanone (Tokyo Kasei Kogyo Co., Ltd.),

cyclohexanone (Tokyo Kasei Kogyo Co., Ltd.),

monoelemental 1,4-cyclohexandione (Tokyo Kasei Kogyo Co., Ltd.),

cyclopropanecarbonitrile (Tokyo Kasei Kogyo Co., Ltd.),

cyclobutanecarbonitrile (AVOCADO),

benzyloxyacetaldehyde (Aldrich),

1-benzyloxy-2-propanone (Aldrich),

picolina acid (Tokyo Kasei Kogyo Co., Ltd.),

1,3-pentanediol (Wako Pure Chemical Industries Ltd.),

2,2-dimethyl-1,3-propandiol(Kanto Chemical Co., Inc.)

ethylacetoacetate (Tokyo Kasei Kogyo Co., Ltd.),

methyl 4-methoxyacetate (Tokyo Kasei Kogyo Co., Ltd.),

ethyliodide (Wako Pure Chemical Industries Ltd.),

thionyl chloride (Wako Pure Chemical Industries Ltd.),

Diisopropylamine (Aldrich),

n-utility (Kanto Chemical Co., Inc.)

sociallyengaged (Wako Pure Chemical Industries Ltd.),

borohydride sodium (Kanto Chemical Co., Inc.)

2N aqueous solution of sodium hydroxide (Wako Pure Chemical Industries Ltd.),

gaseous hydrogen (TOMOE SHOKAI Co., LTD),

gaseous chloromethane acid is the TOMOE SHOKAI Co., LTD),

ethyl 3-oxopentanoate (Aldrich),

1-rambutan-2-he (Trans World Chemicals, Inc.),

potassium acetate (Wako Pure Chemical Industries Ltd.),

potassium carbonate (Kanto Chemical Co., Inc.)

methyl 4-methoxyacetate (Tokyo Kasei Kogyo Co., Ltd.),

dihydroxyacetone (E-MERCK),

pyridine (Wako Pure Chemical Industries Ltd.),

the benzoyl chloride (Tokyo Kasei Kogyo Co., Ltd.),

1,8-diazabicyclo[5.4.0]undec-7-ene (Aldrich),

nonfor-1-butanesulfonate (Tokyo Kasei Kogyo Co., Ltd.),

sodium benzoate (Kanto Chemical Co., Inc.)

TRIFLUORIDE (diethylamino)sulfur (FLUKA),

28% methanol solution of sodium methoxide (Wako Pure Chemical Industries Ltd.),

benzyloxyacetaldehyde (Aldrich),

3-hydroxy-2-methylpyridine (Aldrich),

N-phenyltrichlorosilane (Tokyo Kasei Kogyo Co., Ltd.),

(trimethylsilyl)acetylene (Aldrich),

chloride bis(triphenylphosphine)palladium(II) (N.E.CHEMCAT),

the copper iodide(I) (Kanto Chemical Co., Inc.)

tetrabutylammonium (1H tertrahydrofuran ring solution)(Aldrich),

10% palladium on carbon (N.E.CHEMCAT),

3,4-diamino-1-torbenson (Lancaster),

carbon disulphide (Wako Pure Chemical Industries Ltd.),

dimethylacetal formaldehyde (Tokyo Kasei Kogyo Co., Ltd.),

lithium bromide (Aldrich),

monohydrate p-toluensulfonate acid (Tokyo Kasei Kogyo Co., Ltd.),

2-methyl-6-nitroaniline (Wako Pure Chemical Industries Ltd.),

N-oxide, 4-nitro-2-picoline (Lancaster),

0,1N aqueous solution of sodium hydroxide (Wako Pure Chemical Industries Ltd.),

sodium hydroxide (Wako Pure Chemical Industries Ltd.),

p-toluensulfonate (Tokyo Kasei KogyoCo., Ltd.),

tert-piperonyl potassium (Tokyo Kasei Kogyo Co., Ltd.),

5,5-dimethyl-1,3-dioxane-2-ethanol (Aldrich),

clearinterval (Tokyo Kasei Kogyo Co., Ltd.),

2-hydroxymethyl-1,4-benzodioxan (Aldrich),

2-(allyloxy)ethanol (Tokyo Kasei Kogyo Co., Ltd.),

iodine (Wako Pure Chemical Industries Ltd.),

18-crown-6 (Wako Pure Chemical Industries Ltd.),

complex isopropoxide zirconium(IV) and isopropanol (Aldrich),

(-)-tetramethyl-(D)-tartarate (Tokyo Kasei Kogyo Co., Ltd.),

tetrabutoxide hafnium (Aldrich),

venodilatation (Aldrich),

(S)-(-)-2-(3,5-di-tert-butylcyclohexylamine)-3,3-dimethyl-1-butanol (Aldrich),

30% hydrogen peroxide (Kanto Chemical Co., Inc.)

3-amino-4-nitrotoluene (Aldrich),

2-methoxy-6-nitroaniline (J. of Chem. Soc. (1954) 2977-2978),

4-amino-3-nitrobenzotrifluoride (ACROS),

4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich),

DL-α-0-benzylglycine (SIGMA),

3-pentanon (Tokyo Kasei Kogyo Co., Ltd.),

1-benzyloxy-2-propanone (Aldrich),

(+)-1,4-dioxaspiro[4,5]decane-2-methanol (Aldrich),

4-benzyloxy-2-butanone (FLUKA),

(R)-(+)-1,2,4-butanetriol (Wako Pure Chemical Industries Ltd.),

(S)-(-)-1,2,4-butanetriol (Wako Pure Chemical Industries Ltd.),

methylacetoacetate (Tokyo Kasei Kogyo Co., Ltd.),

6,7-dihydro-1H-[1,4]like[2',3':4,5]benzo[D]imidazole-2-thiol (MAYBRIDGE),

5-nitro-1,3-benzodioxol (Tokyo Kasei Kogyo Co., Ltd.),

Tetramethylammonium (Aldrich),

triftormetilfullerenov anhydride (Aldrich),

methyl 2-cyclopentanecarboxylate (Aldrich),

mono-2.2-dimethyltrimethylene 1,4-cyclohexandione (Adrich),

ethyl 4-cyclohexanecarboxylate (Tokyo Kasei Kogyo Co., Ltd.),

diethylacetal of glycolaldehyde (Lancaster),

diethyl 1,1-cyclobutanedicarboxylate (Lancaster).

Examples

In the chemical formulas shown in the examples, the atom marked with footnotes *is an asymmetric atom.

Example 1: sodium salt of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 8

(1a) 2-((benzyloxy)methyl)-5,5-dimethyl-1,3-dioxane

Formula 9

To a mixture of benzyloxyacetaldehyde (5 g, 33.3 mmol), 2,2-dimethyl-1,3-propane diol (4,16 g, 40 mmol) and toluene (70 ml) was added monohydrate p-toluensulfonate acid (287 mg and 1.51 mmol) and boiled under reflux for 4 hours, removing water by means of the apparatus of the Dean-stark. After cooling the reaction mixture to room temperature, was added thereto triethylamine (4 ml) and the mixture was removed by evaporating the solvent. The residue was purified by chromatography on a column of silica gel (silica gel: 200 g, eluting solvent: ethyl acetate/heptane=1/9) to obtain the specified title compound (7.6 g, yield: 96,6%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; to 0.73 (3H, s)to 1.19 (3H, s), of 3.46 (2H, d, J=10 Hz), 3,55 (2H, d, J=4 Hz), to 3.64 (2H, d, J=10 Hz), 4,60 (2H, s), of 4.66 (1H, t, J=4 Hz), 7,26-to 7.35 (5H, m).

(1b) (55-dimethyl-1,3-dioxane-2-yl)methanol

Formula 10

2-((Benzyloxy)methyl)-5,5-dimethyl-1,3-dioxane (7.6 g, to 32.2 mmol)obtained in stage (1a), was mixed with 20% palladium hydroxide (700 mg) and ethyl acetate (70 ml). The mixture was stirred in an atmosphere of hydrogen overnight. The reaction mixture was allowed to stand for a further 5 days in the same atmosphere of hydrogen. The reaction vessel was purged with nitrogen, the catalyst was filtered and drove the solvent to obtain specified in the title compound (4 g, yield: 85%) as a white solid.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.75 (3H, s)of 1.20 (3H, s), 1,88-of 1.95 (1H, Shir), 3,47 (2H, d, J=10 Hz), 3,63-3,66 (4H, m), of 4.54 (1H, t, J=4 Hz).

(1c) 1-oxide 4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-2,3-dimethylpyridine

Formula 11

(5,5-Dimethyl-1,3-dioxane-2-yl)methanol (2 g, 13.7 mmol)obtained in stage (1b)was mixed with sodium hydride in oil (822 mg, of 20.6 mmol content 60%) and dimethylsulfoxide (20 ml). The mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 1-oxide 4-chloro-2,3-dimethylpyridine (2.16 g, 13.7 mmol) and the mixture was stirred at 50°C overnight and then allowed to stand for one day at room temperature. After distillation of DMSO to the residue was added methanol and NH silica gel and then drove methanol. The mixture of the reaction mixture NH silica gel was purified by chromatography on a column of silica gel (NH silica gel: 200 g, eluting solvent: ethyl acetate/heptane=1/1-4/1→methanol/ethyl acetate=1/9) to obtain the specified title compound (3.1 g, yield: 84,6%) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,70 (3H, s)of 1.12 (3H, s)a 2.12 (3H, s), of 2.34 (3H, s), 3,49 (2H, d, J=11 Hz)and 3.59 (2H, d, J=11 Hz), 4,06 (2H, d, J=4 Hz), 4,82 (1H, t, J=4 Hz), of 6.96 (1H, d, J=7 Hz), with 8.05 (1H, d, J=7 Hz).

(1d) (4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methanol

Formula 12

1-Oxide 4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-2,3-dimethylpyridine (3.1 g, 11.6 mmol)obtained in stage (1c), was mixed with acetic anhydride (9,87 ml, 104 mmol). After stirring the mixture at 85°C for 45 minutes, acetic anhydride was removed. The residue was dissolved in methanol (40 ml) and 5N aqueous sodium hydroxide solution (5.1 ml, 25.5 mmol) was added to the mixture while cooling on ice. The mixture was stirred at room temperature for one hour. Methanol and drove to the residue was added ice water, after which the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate. After removal of the solvent the mixture was purified by chromatography on a column of silica gel (silica gel: 120 g, eluting solvent: ethyl acetate/heptane=1/4-4/1) to obtain the specified title compound (1.23 g, yield: 39,7%) as light yellow is the asle.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.77 (3H, s)of 1.23 (3H, s)2,07 (3H, s), 3,52 (2H, d, J=12 Hz), of 3.69 (2H, d, J=12 Hz), 4,12 (2H, d, J=4 Hz)and 4.65 (2H, s), is 4.85 (1H, t, J=4 Hz), was 6.73 (1H, d, J=6 Hz), 8,30 (1H, d, J=6 Hz).

(1e) 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 13

(4-((5,5-Dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methanol (500 mg, of 1.87 mmol)obtained in stage (1d), was mixed with triethylamine (1.04 million ml of 7.48 mmol) and tetrahydrofuran (15 ml). The resulting mixture was cooled to -19°C and added to it methanesulfonanilide (217 μl, of 2.81 mmol), after which the mixture was stirred at -19°C for 30 minutes. Under the same conditions was added to the reaction mixture 2-mercaptobenzimidazole (309 mg, of 2.06 mmol). After stirring the reaction mixture overnight at room temperature was added to a mixture of methanol and NH silica gel, and then drove the solvent. The mixture of the reaction mixture and NH silica gel was purified by chromatography on a column of silica gel (silica gel: 80 g, eluting solvent: ethyl acetate/heptane=1/1-4/1→methanol/ethyl acetate=1/9) to obtain the specified title compound (599 mg, yield: 80.2 per cent) as a light red foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.71 (3H, s)of 1.13 (3H, s), of 2.21 (3H, s), 3,50 (2H, d, J=11 Hz)and 3.59 (2H, d, J=11 Hz), 4.09 to (2H, d, J=4 Hz), 4,69 (2H, s), 4,84 (1H, t, J=4 Hz), 6,98 (1H, d, J=6 Hz), 7,11 (2H, DD, J=3, 6 Hz), of 7.36-7,51 (2H, W), by 8.22 (H, d, J=6 Hz).

(1f) 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 14

2-(((4-((5,5-Dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (599 mg, 1.5 mmol)obtained in stage (1e), was mixed with methanol (5 ml) and toluene (15 ml) and the mixture was cooled to -50°C. To the mixture was slowly added dropwise 3-chloroperbenzoic acid (358 mg, 1.35 mmol, when the content of 65%), dissolved in a mixture of methanol and toluene, and the resulting mixture was stirred at a temperature of from -47 to -70°C for 3 hours. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over potassium carbonate and drove the solvent. The residue was purified by chromatography on a column of silica gel (NH silica gel: 40 g, eluting solvent: dichloromethane/heptane=7/3→methanol/dichloromethane=3/97-1/9). To the obtained product was added heptane (20 ml) and diethyl ether (2 ml), after which the precipitate was filtered. In this way it was obtained is listed in the title compound (475 mg, yield: 76,2%) as a pale orange solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.71 (3H, s)of 1.12 (3H, s), and 2.14 (3H, s), 3,49 (2H, d, J=11 Hz)and 3.59 (2H, d, J=11 Hz), 4.09 to (2H, d, J=4 Hz), 4,70 (1H, d, J=13 G is), 4,78 (1H, d, J=13 Hz), 4,84 (1H, t, J=4 Hz), 6,98 (1H, d, J=6 Hz), 7,25-to 7.32 (2H, m), 7,60-7,66 (2H, m), to 8.20 (1H, d, J=6 Hz).

(1g) sodium salt of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 15

2-(((4-((5,5-Dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (475 mg, to 1.14 mmol)obtained in stage (1f), was mixed with ethanol (15 ml). To the mixture was added 1N aqueous sodium hydroxide solution (1,14 ml, to 1.14 mmol) and drove the solvent. To the residue was added ethanol, the residue was dissolved and drove the solvent. This operation was repeated twice. To the residue was added diethyl ether and the resulting mixture was subjected to ultrasonic processing. The precipitate was filtered and dried his aspiration of fluid from receiving specified in the title compound (445 mg, yield: 89,2%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,70 (3H, s)of 1.13 (3H, s)to 2.18 (3H, s), 3,50 (2H, d, J=11 Hz)and 3.59 (2H, d, J=11 Hz), 4,08 (2H, d, J=4 Hz), 4,39 (1H, d, J=13 Hz), was 4.76 (1H, d, J=13 Hz), 4,84 (1H, t, J=4 Hz), 6,85 (2H,, DD, J=3, 6 Hz), to 6.95 (1H, d, J=6 Hz), the 7.43 (2H, DD, J=3, 6 Hz), of 8.27 (1H, d, J=6 Hz).

Example 2: sodium salt of 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 16

(2a) 6-((benzyloxy)methyl)-5,7-dioxaspiro[2,5]Octan

Formula 17

A mixture of benzyloxyacetaldehyde (5 g, 33.3 mmol), 1,1-bis(hydroxymethyl)cyclopropane (4,08 g, 40 mmol), monohydrate p-toluensulfonate acid (287 mg and 1.51 mmol) and toluene (70 ml) was boiled under reflux for 2 hours, removing water by means of the apparatus of the Dean-stark. After cooling the reaction mixture to room temperature, was added thereto triethylamine (4 ml) and drove the solvent. The residue was purified by chromatography on a column of silica gel (silica gel: 200 g, eluting solvent: ethyl acetate/heptane=5/95-1/9) to obtain specified in the connection header (6,1 g, output: 78,2%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,31-0,35 (2H, m), 0.67 and is 0.71 (2H, m), 3,26 (2H, d, J=12 Hz), 3,57 (2H, d, J=4 Hz), 4,14 (2H, d, J=12 Hz), 4,60 (2H, s), 4,82 (1H, t, J=4 Hz), 7,27-7,34 (5H, m).

(2b) 5,7-dioxaspiro[2,5]Oct-6-ylmethanol

Formula 18

6-((Benzyloxy)methyl)-5,7-dioxaspiro[2,5]octane (6,1 g, 26 mmol)obtained in stage (2a), was mixed with 20% palladium hydroxide (800 mg) and ethyl acetate (70 ml) and the mixture was stirred in an atmosphere of hydrogen for 24 hours. The reaction vessel was purged with nitrogen and the catalyst was filtered, and then drove the solvent to obtain specified in the title compound (3.7 g, yield: 98,7%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,33-0,37 (2H, m), 0,68 is 0.72 (2H, m), or 3.28 (2H, d, J=12 Hz) 3,68 (2H, d, J=4 Hz), 4,16 (2H, d, J=12 Hz), to 4.73 (1H, t, J=4 Hz).

(2c) 1-oxide 4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-2,3-dimethylpyridine

Formula 19

5,7-Dioxaspiro[2,5]Oct-6-ylmethanol (1.7 g, to 11.8 mmol)obtained in stage (2b), was mixed with sodium hydride in oil (708 mg of 17.7 mmol content 60%) and dimethylsulfoxide (20 ml) and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture were added 1-oxide 4-chloro-2,3-dimethylpyridine (1.86 g, and 11.8 mmol) and the mixture was stirred at 50°C during the night. After distillation of DMSO to the residue was added methanol and NH silica gel and methanol drove away. The mixture of the reaction mixture and NH silica gel was purified by chromatography on a column of silica gel (NH silica gel: 200 g, eluting solvent: ethyl acetate/heptane=1/1-4/1→methanol/ethyl acetate=1/9-1/4) to obtain the specified title compound (1.8 g, yield: 57,5%) as a red oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,36-0,40 (2H, m), 0,69-0,74 (2H, m), 2,22 (3H, s), of 2.53 (3H, s), 3,30 (2H, d, J=12 Hz), 4,11 (2H, d, J=4 Hz), 4,19 (2H, d, J=12 Hz), 5,00 (1H, t, J=4 Hz), of 6.68 (1H, d, J=7 Hz), 8,13 (1H, d, J=7 Hz).

(2d) (4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methanol

Formula 20

1-Oxide 4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-2,3-dimethylpyridine (1.8 g, is 6.78 mmol)obtained in stage (2c), was mixed with acetic anhydride (5,77 ml, 61 mmol). The mixture is eremetical at 85°C for 45 minutes, and then acetic anhydride drove away. The residue was cooled on ice and dissolved in methanol. To the resulting solution was added a 5N aqueous solution of sodium hydroxide (2,98 ml, 14.9 mmol) while cooling on ice and the mixture was stirred at room temperature for 2 hours. Methanol and drove to the residue was added water, then the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then drove the solvent. Conducted clearing chromatography on a column of silica gel (silica gel: 100 g, eluting solvent: ethyl acetate/heptane=1/4-4/1). To the purified product was added heptane (15 ml) and the mixture is boiled under reflux. Making sure that the solution has reached a homogeneous state, it is gradually cooled. Was filtered phase precipitate the product. In this way it was obtained is listed in the title compound (520 mg, yield: 28,9%) as a white solid.

1H NMR (400 MHz, CDCl3) δ ppm; 0,36-0,40 (2H, m), 0.70 to 0.74 and (2H, m)2,07 (3H, s), 3,30 (2H, d, J=11 Hz), 4,14 (2H, d, J=4 Hz), 4,20 (2H, d, J=11 Hz), with 4.64 (2H, s), a 4.86 (1H, Sirs), 5,02 (1H, t, J=4 Hz), was 6.73 (1H, d, J=6 Hz), 8,29 (1H, d, J=6 Hz).

(2e) 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 21

(4-(5,7-Dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methanol (520 mg, a 1.96 mmol)obtained the first stage (2d), was mixed with triethylamine (1,09 ml, to 7.84 mmol) and tetrahydrofuran (10 ml) and the resulting mixture was cooled to -19°C. To the mixture was added methanesulfonamide (228 μl, to 2.94 mmol) and stirred her at -19°C for 30 minutes. Under the same conditions to the reaction mixture were added 2-mercaptobenzimidazole (324 mg, of 2.16 mmol). After stirring the reaction mixture at room temperature for 2 days was added thereto methanol and NH silica gel and drove the solvent. The mixture of the reaction mixture and NH silica gel was purified by chromatography on a column of silica gel (silica gel: 80 g, eluting solvent: ethyl acetate/heptane=4/6-7/3→methanol/ethyl acetate=1/9) to obtain the specified title compound (629 mg, yield: 80,7%) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,31-0,36 (2H, m), 0.56 to 0,61 (2H, m), of 2.21 (3H, s), 3,26 (2H, d, J=12 Hz), 4,10-4,13 (4H, m), 4,69 (2H, s), 5,02 (1H, t, J=5 Hz), of 6.99 (1H, d, J=6 Hz), 7,11 (2H, DD, J=3, 6 Hz), 7,39-7,49 (2H,cm.), 8,23 (1H, d, J=6 Hz).

(2f) 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 22

2-(((4-(5,7-Dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (629 mg, was 1.58 mmol)obtained in stage (2e), was mixed with methanol (5 ml) and toluene (15 ml) and the mixture was cooled to -50°C. Then, to the mixture was slowly added dropwise 3-chloroperbenzoic acid (378 mg, of 1.42 mmol, when is the obsession 65%), dissolved in a mixture of methanol and toluene, and the resulting mixture was stirred at a temperature of from -47 to -70°C for 4 hours. Was added to the reaction mixture, saturated aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried over potassium carbonate and drove the solvent. The residue was purified by chromatography on a column of silica gel (NH silica gel: 40 g, eluting solvent: dichloromethane/heptane=7/3→methanol/dichloromethane=3/97-1/9) to obtain specified in the header of the compound (623 mg, yield: 95.4 percent) as a colorless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,31-0,36 (2H, m), 0.56 to 0,61 (2H, m), and 2.14 (3H, s), 3,26 (2H, d, J=11 Hz), 4,11-4,13 (4H, m), 4,70 (1H, d, J=14 Hz), 4,79 (1H, d, J=14 Hz), 5,02 (1H, t, J=4 Hz), of 6.99 (1H, d, J=6 Hz), 7,29 (2H, DD, J=3, 6 Hz), to 7.59-to 7.67 (2H, W), 8,21 (1H, d, J=6 Hz).

(2g) sodium salt of 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 23

2-(((4-(5,7-Dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (623 mg and 1.51 mmol)obtained in stage (2f), was mixed with ethanol (15 ml). To the mixture was added 1N aqueous sodium hydroxide solution (1,51 ml and 1.51 mmol) and drove the solvent. To the residue was added ethanol and drove him away. This operation was repeated twice. To the residue was added on the ethyl ester and the resulting mixture was subjected to ultrasonic processing. The precipitate was filtered and dried his aspiration of fluid from receiving specified in the title compound (553 mg, yield: 84,1%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,31-0,35 (2H, m), 0,57-0,61 (2H, m), are 2.19 (3H, s), 3,26 (2H, d, J=11 Hz), 4,10 (2H, d, J=5 Hz), 4,12 (2H, d, J=11 Hz), 4,37 (1H, d, J=13 Hz), 4,82 (1H, d, J=13 Hz), 5,02 (1H, t, J=5 Hz), at 6.84 (2H, DD, J=3, 6 Hz), to 6.95 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), of 8.27 (1H, d, J=6 Hz).

Example 3: sodium salt of 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 24

(3a) ethyl (2-propyl-1,3-dioxolane-2-yl)acetate

Formula 25

A mixture of ethyl 3-oxohexanoate (5 g, of 31.6 mmol), ethylene glycol (to 3.92 g, 63.2 mmol), triethylorthoformate (4.68 g, of 31.6 mmol) and monohydrate p-toluensulfonate acid (544 mg, of 2.86 mmol) was stirred at room temperature for 29 hours and 10 minutes. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (6.2 g, 97%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.93 (3H, t, J=7 Hz), of 1.27 (3H, t, J=7 Hz), of 1.39 to 1.48 (2H, m), of 1.78 (2H, t, J=8 Hz), 2,64 (2H, s), 3,94-was 4.02 (4H, m), is 4.15 (2H, q, J=7 Hz).

(3b) 2-(2-propyl-1,3-dioxolane-2-yl)ethanol

Formula 26

To tetrahydrofuranate (100 ml) suspension of sociallyengaged (1,17 g, 30.7 mmol) was added while cooling on ice tertrahydrofuran ring (20 ml) solution of ethyl (2-propyl-1,3-dioxolane-2-yl)acetate (6.2 g, 30.7 mmol)obtained in stage (3a). The mixture was stirred for 30 minutes while cooling on ice, was sequentially added water (1,17 ml) and 15% aqueous sodium hydroxide solution (1,17 ml) and water (3,51 ml) and the mixture was stirred for 10 minutes. Was added to a mixture of sodium sulfate, stirred the resulting mixture was subjected her to filtration through silica gel. The filtrate was concentrated under reduced pressure and the residue was dissolved in a solvent mixture containing n-heptane and ethyl acetate in the ratio 2:1, and the solution was subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=2/1) to obtain specified in the connection header (3,82 g, with 77.7%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.93 (3H, t, J=8 Hz), 1,33 was 1.43 (2H, m), 1,60-1,65 (2H, m), with 1.92 (2H, t, J=6 Hz), and 2.83 (1H, t, J=6 Hz), 3,74 (2H, q, J=6 Hz), 3.95 to a 4.03 (4H, m).

(3c) 1-oxide, 2,3-dimethyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine

Formula 27

To dimethylsulfoxide (22.5 ml) solution of 2-(2-propyl-1,3-dioxolane-2-yl)ethanol (1.5 g, 9,35 mmol)obtained in stage (3b), was added in a stream of nitrogen guy who reed sodium in oil (561 mg, 14 mmol content 60%) and 1-oxide 4-chloro-2,3-dimethylpyridine (1,33 g, 8,42 mmol) and the mixture was stirred at 60°C for 2 hours. The mixture was allowed to stand at room temperature for 3 days and concentrated her under reduced pressure. The residue is suspended in tetrahydrofuran. To the mixture was added NH silica gel, after which the mixture was concentrated to dryness and subjected to chromatography on a column of NH silica gel (eluting solvent: n-heptane/ethyl acetate/methanol=1/1/0→0/1/0→0/10/1) obtaining specified in the connection header (1,53 g, output: 58,2%) as a light brown oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.94 (3H, t, J=7 Hz), 1,38-1,49 (2H, m), 1,62-to 1.67 (2H, m), 2,14-of 2.20 (2H, m), are 2.19 (3H, s), of 2.53 (3H, s), 3,92-4,01 (4H, m), 4,10 (2H, t, J=7 Hz), only 6.64 (1H, d, J=7 Hz), 8,13 (1H, d, J=7 Hz).

(3d) (3-methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)acetate

Formula 28

1-Oxide, 2,3-dimethyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine (1,53 g, 5,44 mmol)obtained in stage (3c), was mixed with acetic anhydride (30 ml) and the mixture was stirred at 80°C during the night. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and then the resulting solution was subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1) to obtain specified in the header is connected to the I (1.19 g, 67,6%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.94 (3H, t, J=7 Hz), 1,39-1,49 (2H, m), 1,64 was 1.69 (2H, m), 2,12 (3H, s), 2,16-of 2.20 (2H, m)to 2.18 (3H, s), 3,93-4,00 (4H, m), of 4.12 (2H, t, J=7 Hz), 5,20 (2H, s), of 6.73 (1H, d, J=6 Hz), 8,31 (1H, d, J=6 Hz).

(3e) (3-methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methanol

Formula 29

(3-Methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)acetate (1.19 g, 3,68 mmol)obtained in stage (3d), was mixed with 1N aqueous sodium hydroxide solution (5 ml) and methanol (10 ml). The mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure. The residue is suspended in tetrahydrofuran, to the suspension was added sodium sulfate and the mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a solvent mixture containing heptane and ethyl acetate in the ratio 2:1, and the solution was subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=2/1) to obtain the specified title compound (0.88 g, 85%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.94 (3H, t, J=7 Hz), 1,39-1,49 (2H, m), 1,64 was 1.69 (2H, m), 2,03 (3H, s)to 2.18 (2H, t, J=7 Hz), 3,93-4,01 (4H, m), 4,14 (2H, t, J=7 Hz)and 4.65 (2H, s), 4,89 (1H, Sirs), was 6.73 (1H, d, J=6 Hz), 8,29 (1H, d, J=6 Hz).

(3f) 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole

Forms the La 30

(3-Methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl) methanol (450 mg, 1.6 mmol)obtained in stage (3e), was mixed with tetrahydrofuran (10 ml). The mixture was cooled on ice under nitrogen atmosphere. Was added triethylamine (0,446 ml, 3.2 mmol) and methanesulfonamide (0,186 ml, 2.4 mmol) and the mixture was stirred for 50 minutes under cooling on ice. To the reaction mixture were added 2-mercaptobenzimidazole (240 mg, 1.6 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture were added an aqueous solution of sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. After adding to the solution of the silica gel, the solution was concentrated. The obtained residue was subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the specified title compound (528 mg, 79.8 per cent) as a colourless viscous oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.94 (3H, t, J=7 Hz), 1,39 of 1.50 (2H, m), 1,63 by 1.68 (2H, m), of 2.20 (2H, t, J=7 Hz), and 2.26 (3H, s), 3,93-4,01 (4H, m)to 4.16 (2H, t, J=7 Hz), 4,37 (2H, s), is 6.78 (1H, d, J=6 Hz), 7,16-7,20 (2H, m,), 7,50-to 7.59 (2H, m), 8,35 (1H, d, J=6 Hz).

(3g) 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)is iridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 31

2-(((3-Methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole (482 mg, at 1.17 mmol)obtained in stage (3f), was dissolved in a mixture of toluene (30 ml) and methanol (3 ml). The mixture was cooled in nitrogen atmosphere. To the mixture was added a methanol solution (1.3 ml) of 3-chloroperbenzoic acid (311 mg, 1,17 mmol content 65%) when the internal temperature below -70°C and stirred at a temperature below -60°C for 2 hours. To the reaction mixture were added an aqueous solution of sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with saturated saline, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and subjected to chromatography on a column of silica gel, using NH silica gel (eluting solvent: methylene chloride/methanol=1/0→100/1→100/5) to obtain the specified title compound (323 mg, yield: 64.3 per cent).

1H NMR (400 MHz, DMSO-d6) of 0.85 (3H, t, J=7 Hz), 1,28-of 1.39 (2H, m), 1,55-1,60 (2H, m), 2,04 (2H, t, J=7 Hz), 2,10 (3H, s), 3,89-are 3.90 (4H, m), 4,08 (2H, t, J=7 Hz), and 4.68 (1H, d, J=13 Hz), of 4.77 (1H, d, J=13 Hz), to 6.95 (1H, d, J=6 Hz), 7,26-to 7.32 (2H, m), to 7.59-to 7.67 (2H, m), to 8.20 (1H, d, J=6 Hz).

(3h) sodium salt of 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 32

2-(((3-Methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole (323 mg, 0,752 mmol)obtained in stage (3g), was mixed with ethanol (15 ml) and 1N aqueous sodium hydroxide solution (0,752 ml, 0,752 mmol) and the mixture was stirred at room temperature for 10 minutes. Drove the solvent, the obtained residue was dissolved in ethanol and again drove the solvent. To the residue was added diethyl ether-ethanol-n-heptane, the mixture was mixed at room temperature and then filtered to obtain a solid substance. In this way it was obtained is listed in the title compound (315 mg, 92,8%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6); of 0.85 (3H, t, J=7 Hz), 1,29-of 1.39 (2H, m), 1.56 to and 1.63 (2H, m), is 2.05 (2H, t, J=7 Hz), of 2.15 (3H, s), 3,83-3,91 (4H, m), 4,07 (2H, t, J=7 Hz), and 4.40 (1H, d, J=13 Hz), was 4.76 (1H, d, J=13 Hz), 6,84-6,90 (2H, m), 6,92 (1H, d, J=5 Hz), 7,41-7,47 (2H, m), of 8.25 (1H, d, J=5 Hz).

Example 4: sodium salt of 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 33

(4a) of 1,3-bis(benzyloxy)acetone

Formula 34

To a dichloromethane (200 ml) solution of 1,3 dimensions-2-propanol (52 g, 191 mmol), triethylamine (130 ml, 933 mmol) and dimethyl sulfoxide (65 ml, 916 mmol) was added at 0°C the complex of sulfur trioxide is pyridine (131 g, 823 mmol) and the mixture was stirred at a temperature of from 0°C. to room temperature for 2 hours. To the mixture were added water and ethyl acetate. The organic layer is washed with 2N chloroethanol acid, water and aqueous salt solution, dried over anhydrous sodium sulfate and concentrated. The result is specified in the header connection (52,01 g, quantitative yield) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4.26 deaths (4H, s), 4,49 (4H, s), 7,25-7,38 (10H, m).

(4b) 2,2-bis((benzyloxy)methyl)-1,3-dioxolane

Formula 35

1,3-Bis(benzyloxy)acetone (30g, 111 mmol)obtained in stage (4a), was mixed with ethylene glycol (64 ml, 1,148 mmol), triethylorthoformate (19 ml, 114 mmol) and monohydrate p-toluensulfonate acid (591 mg, 3.11 mmol). The mixture was stirred at 50°C for 14 hours. To the mixture was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with water and salt solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=gradient 1/0-4/1) and the desired fractions were concentrated to obtain specified in the connection header (28,46 g, output: 81,6%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm of 3.45 (4H, C), 3,88 (4H, s), 4,50 (4H, s), 7,22-to 7.35 (10H, m).

(4c) 1,3-dioxolane-2,2-videotool

Formula 36

To an ethyl acetate (300 ml) solution of 2,2-bis((benzyloxy)methyl)-1,3-dioxolane (28.5 g, 90,7 mmol)obtained in stage (4b), was added palladium hydroxide (20 wt.% Pd (dry weight) on carbon, wet (maximum water 50%)) (2.5 g) and the mixture was stirred at room temperature for 39 hours in hydrogen atmosphere. After purging the reaction mixture with nitrogen, the catalyst was filtered from the reaction mixture and washed with ethyl acetate. The filtrate was concentrated. To the obtained residue was added ethyl acetate (300 ml) and palladium hydroxide (20 wt.% Pd (dry weight) on carbon, wet (maximum water 50%)) (2.5 g) and the mixture was stirred at room temperature for 26 hours in a hydrogen atmosphere. After purging the reaction mixture with nitrogen, the catalyst was filtered and washed with ethyl acetate. The filtrate was concentrated to obtain specified in the connection header (of $ 11.97 g, output: 98,4%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.32 (4H, d, J=6 Hz), 3,85 (4H, s), 4,63 (2H, t, J=6 Hz).

(4d) of methyl (8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)acetate

Formula 37

1,3-Dioxolane-2,2-videotool (4 g, to 29.8 mmol), which was obtained at a different time by a method similar to that described in stages (4a)-(4c), cm is stirred with methylpropionate (5.6 ml, to 44.6 mmol), triethylorthoformate (5,2 ml of 31.3 mmol) and monohydrate p-toluensulfonate acid (163 mg, 0,856 mmol). The mixture was stirred at room temperature for 3 hours. To the mixture was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with water twice and the aqueous salt solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=gradient 1/0-3/1-1/1) and the desired(s) fraction(s) was concentrated to obtain specified in the connection header (2,63 g, output: 35,8%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; from 0.84 (3H, t, J=7 Hz), a 1.75 (2H, q, J=7 Hz), was 2.76 (2H, s), of 3.56 (3H, s)to 3.58 (2H, d, J=12 Hz), 3,68 (2H, d, J=12 Hz), 3,80-to 3.89 (4H, m).

(4e) 2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethanol

Formula 38

To a solution in THF (40 ml) of methyl (8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)acetate (2,63 g of 10.7 mmol)obtained in stage (4d)was added at 0°C sociallyengaged (487 mg, 12.8 mmol) and the mixture was stirred at a temperature of from 0°C. to room temperature for 4 hours. To stop the reaction, to the mixture were added successively water (0.5 ml), 2 N. aqueous sodium hydroxide solution (0.5 ml), water (1.5 ml). Then to the mixture was added anhydrous sulfate n the sodium and celite and the resulting mixture was filtered through a glass filter and washed with ethyl acetate. The filtrate was concentrated to obtain specified in the connection header (2,34 g, quantitative yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.79 (3H, t, J=7 Hz), of 1.62 (2H, q, J=7 Hz), is 1.81 (2H, t, J=8 Hz), to 3.41 (2H, dt, J=6, 8 Hz), of 3.57 (4H, s), 3,83 (4H, s), the 4.29 (1H, t, J=6 Hz).

(4f) 1-oxide 4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-2,3-dimethylpyridine

Formula 39

To dimethylsulfoxide (20 ml) solution of 2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethanol (1,34 g, 6,14 mmol)obtained in stage (4e), was added sodium hydride in oil (295 mg, 7,37 mmol content 60%) at room temperature under nitrogen atmosphere. The mixture was stirred for 30 minutes in the same conditions. To the reaction mixture were added at room temperature 1-oxide 4-chloro-2,3-dimethylpyridine (1.06 g, of 6.75 mmol) and the resulting mixture was stirred at 60°C for 5.5 hours. The reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane, ethyl acetate/methanol=gradient 1/0-4/1) and the desired(s) fraction(s) was concentrated to obtain specified in the connection header (948 mg, yield: 45,5%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; or 0.83 (3H, t, J=7 Hz), at 1.73 (2H, q, J=7 Hz), is 2.09 (3H, s), 2,12 (2H, t, J=6 Hz), 2,32 (3H, s), 3,62 (4H, s), 3,80-3,88 (4H, m)4,06 (2H, t, J=6 Hz, 6,89 (1H, d, J=8 Hz), with 8.05 (1H, d, J=8 Hz).

(4g) (4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methanol

Formula 40

1-Oxide 4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-2,3-dimethylpyridine (947 mg, and 2.79 mmol)obtained in stage (4f), was mixed with acetic anhydride (10 ml). To the mixture was added triethylamine (0.6 ml, 4.3 mmol) and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated and to the residue was added methanol (10 ml) and then 5N aqueous solution of sodium hydroxide (7 ml) and the mixture was stirred at room temperature for one hour. To the mixture was added saturated aqueous solution of ammonium chloride (7 ml) and the pH of the resulting solution was brought to about 10. The reaction mixture was diluted with ethyl acetate and the organic layer washed with 2N aqueous sodium hydroxide solution, water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol=gradient 1/0-4/1) and the desired(s) fraction(s) was concentrated to obtain specified in the title compound (564 mg, yield: 59,6%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; from 0.84 (3H, t, J=7 Hz), 1,74 (2H, q, J=7 Hz), of 2.08 (3H, s), and 2.14 (2H, t, J=6 Hz), 3,63 (4H, s), 3,78-to 3.89 (4H, m), 4,08 (2H, t, J= Hz), 4,50 (2H, d, J=6 Hz), 4,96 (1H, t, J=6 Hz), make 6.90 (1H, d, J=6 Hz), to 8.20 (1H, d, J=6 Hz).

(4h) 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 41

To a solution in THF (10 ml) of (4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methanol (560 mg, of 1.65 mmol)obtained in stage (4g)was added at room temperature triethylamine (of 0.48 ml, 3,44 mol)was then added methanesulfonamide (0,19 ml, 2.45 mmol) under cooling in a bath of ice and salt and mixed in the same conditions for 30 minutes. Removing a bath of ice and salt, was added 2-mercaptobenzimidazole (248 g of 1.65 mmol) and the mixture was stirred at room temperature for 22 hours. After kontsentrirovanija reaction mixture, to the residue was added NH silica gel and the mixture was dried. The crude substance was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=1/0, gradient 1/1-0/1) and the desired(s) fraction(s) was concentrated. The obtained foamy product was dissolved in chloroform and the resulting solution was added diethyl ether. The obtained solid substance was collected by filtration to obtain specified in the title compound (410 mg, yield: 52,7%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; from 0.84 (3H, t, J=7 Hz), a 1.75 (2H, q, J=7 Hz), of 2.15 (2H, t, J= Hz), to 2.18 (3H, s), 3,63 (4H, s), 3,80-are 3.90 (4H, m), 4.09 to (2H, t, J=6 Hz), of 4.67 (2H, s), 6,93 (1H, d, J=6 Hz), 7,07-7,13 (2H, m), 7,35-7,51 (2H, m), by 8.22 (1H, d, J=6 Hz), 12,60 (1H, Sirs).

(4i) 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 42

To a solution in toluene (10,8 ml) and methanol (1.2 ml) of 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (380 mg, 0.81 mol)obtained in stage (4h), was added dropwise a solution of 3-chloroperbenzoic acid (192 mg, 0.73 mmol content 65%) in toluene (2.7 ml) and methanol (0.3 ml) at a temperature of from -70 to -60°C for 10 minutes in nitrogen atmosphere. The mixture was stirred for one hour at the same conditions. Stop reaction by addition of a saturated aqueous solution (15 ml) of sodium bicarbonate at the same temperature. The mixture was extracted with chloroform (50 ml) twice and the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (NH silica gel: an eluting solvent: ethyl acetate/methanol=gradient 1/0-4/1) and the desired fractions were concentrated. The obtained foamy product was perioadele chloroform and diethyl ether and filtered. The operation was repeated four times and the obtained solid substance was washed with diethylaluminum and then dried to obtain specified in the title compound (188 mg, 47,9% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; or 0.83 (3H, t, J=7 Hz), 1,74 (2H, q, J=7 Hz), 2,10 (3H, s), and 2.14 (2H, t, J=6 Hz), 3,63 (4H, s), 3,79-are 3.90 (4H, m), 4.09 to (2H, t, J=6 Hz), and 4.68 (1H, d, J=13 Hz), of 4.77 (1H, d, J=13 Hz), 6,93 (1H, d, J=6 Hz), 7.23 percent-to 7.32 (2H, m), 7,54-to 7.68 (2H, m), to 8.20 (1H, d, J=6 Hz).

(4j) sodium salt of 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 43

To an ethanol (2 ml) solution of 2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl) sulfinil)-1H-benzimidazole (188 mg, 0,39 mmol)obtained in stage (4i)was added at room temperature, 1N aqueous sodium hydroxide solution (386 μl, 0,39 mmol) and the mixture was stirred for 10 minutes and then concentrated. To the residue was added methanol and the mixture was concentrated. By repeating this operation, to the residue was added diethyl ether and the resulting suspension was allowed to stand. After removing the supernatant, the residue was dried by a vacuum pump to obtain specified in the title compound (190 mg, 96,6% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; from 0.84 (3H, t, J=8 Hz), a 1.75 (2H, q, J=8 Hz), 2,09-of 2.20 (5H, m), 3,63 (4H, m), 3,80-are 3.90 (4H, m), 4,08 (2H, t, J=6 Hz), 4,36 (1H, d, J=13 Hz), 4,79 (1H, d, J=13 Hz), 6,78-to 6.88 (2H, m), 6.89 in (1H, d, J=5 Hz), of 7.36-7,46 (2H, m), compared to 8.26 (1H, d, J=5 Hz).

Example 5: sodium salt of 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetrac is Aspiro[4,5]Dec-8-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 44

(5a) 2-oxopropanoic

Formula 45

To a solution of pyridine (25 ml) and THF (10 ml) hydroxyacetone (5 g, of 67.5 mmol) was added dropwise a benzoyl chloride (12 ml, 103 mmol) at 0°C under nitrogen atmosphere and the mixture was stirred for 43 hours at room temperature. To the reaction mixture were added ice, then diluted it with ethyl acetate. The organic layer was washed 1H chloroethanol acid, water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=gradient 1/0-1/1). The desired fractions were concentrated to obtain specified in the connection header (10,56 g of 87.8% yield) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; and 2.14 (3H, s), free 5.01 (2H, s), 7,51-7,58 (2H, m), 7,65-of 7.70 (1H, m), 7,95-of 8.00 (2H, m).

(5b) (8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methylbenzoate

Formula 46

2-Oxopropanoic (4 g, of 22.4 mmol)obtained in stage (5a), was mixed with 1,3-dioxolane-2,2-videoteam (3 g, of 22.4 mmol)obtained in stage (4c), triethylorthoformate (3.8 ml of 22.8 mmol) and monohydrate p-toluensulfonate acid (200 mg, 1.05 mmol). The mixture was stirred at room temperature for the of 13.5 hours. To the mixture was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with water twice and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=gradient 1/0-1/1) and the desired fractions were concentrated to obtain specified in the title compound (1.92 g, 29,1% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.41 (3H, s), 3,64 is 3.76 (4H, m), 3,80-3,88 (4H, m)to 4.33 (2H, s), 7,50-EUR 7.57 (2H, m), of 7.64-of 7.70 (1H, m), 7,92-of 8.00 (2H, m).

(5c) (8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methanol

Formula 47

To a solution in THF (10 ml) and methanol (5 ml) of (8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methylbenzoate (1.92 g, of 6.52 mmol)obtained in stage (5b), was added 1N aqueous sodium hydroxide solution (10 ml, 10 mmol) and the mixture was stirred at room temperature for one hour. The reaction mixture was extracted with dichloromethane (50 ml) four times, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=gradient 1/1-0/1) and the desired fractions were concentrated to obtain specified in the title compound (1.12 g, 900% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,24 (3H, s)to 3.33 (2H, d, J=6 Hz), 3,60 (4H, s), 3,80-of 3.85 (4H, m), to 4.81 (1H, t, J=6 Hz).

(5d) 1-oxide, 2,3-dimethyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methoxy)pyridine

Formula 48

To dimethylsulfoxide (15 ml) solution of (8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methanol (1,11 g of 5.82 mmol)obtained in stage (5c)was added at room temperature in a nitrogen atmosphere sodium hydride in oil (326 mg, 8,15 mmol content 60%). The mixture was stirred for 30 minutes in the same conditions. To the reaction mixture were added at room temperature 1-oxide 4-chloro-2,3-dimethylpyridine (917 mg, of 5.82 mmol) and the reaction mixture was stirred at 70°C for 4.5 hours. The reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol=gradient 1/0-5/2) and the desired fractions were concentrated to obtain specified in the title compound (1.20 g, 66,1% yield) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.42 (3H, s)a 2.12 (3H, s), of 2.33 (3H, s), 3,65 of 3.75 (4H, m), 3,85 (4H, s)4,07 (2H, s), 7,00 (1H, d, J=7 Hz), 8,07 (1H, d, J=7 Hz).

(5e) (3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methoxy)pyridin-2-yl)methanol

Formula 49

1-Oxide, 2,3-dimethyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methoxy)pyridine (1.20 g, 84 mmol), obtained in stage (5d), was mixed with acetic anhydride (10 ml). To the mixture was added triethylamine (0.8 ml, 5,74 mmol) and the mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated and to the residue was added methanol (10 ml). Then to the mixture was added 5N aqueous sodium hydroxide solution (7 ml) and stirred at room temperature for 30 minutes. To the mixture was added saturated aqueous solution of ammonium chloride (7 ml) and the pH was brought to about 10. The reaction mixture was diluted with ethyl acetate and the organic layer washed with 2N aqueous sodium hydroxide solution, water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol=gradient 1/0-4/1) and the desired(s) fraction(s) was concentrated to obtain specified in the title compound (312 mg, 26,1% yield) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; the 1.44 (3H, s), 2,11 (3H, s), 3,65 of 3.75 (4H, m), 3,85 (4H, s)4,08 (2H, s), 4,51 (2H, d, J=5 Hz), equal to 4.97 (1H, t, J=5 Hz), of 6.99 (1H, d, J=6 Hz), to 8.20 (1H, d, J=6 Hz).

(5f) 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 50

To a solution in THF (7 ml) (3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)m is toxi)pyridine-2-yl)methanol (312 mg, 1.00 mmol)obtained in stage (5e)was added at room temperature triethylamine (0,30 ml of 2.15 mmol)was then added methanesulfonamide (of 0.12 ml, 1.55 mmol) under cooling in a bath of ice and salt and the mixture was stirred for 30 minutes in the same conditions. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and salt solution, dried over anhydrous sodium sulfate and concentrated. The obtained residue was dissolved in ethanol (6 ml). To the resulting solution were added 2-mercaptobenzimidazole (150 mg, 1.00 mmol) and sodium hydroxide (160 mg, 4.00 mmol) and the mixture was stirred at room temperature for 16.5 hours. After concentration of the reaction mixture, to the residue was added NH silica gel and the mixture was dried. The crude product was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=1/0, gradient 1/1-0/1) and the desired fractions were concentrated to obtain specified in the title compound (377 mg, 85,0% yield) as a white foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; was 1.43 (3H, s), of 2.21 (3H, s), 3,66 is 3.76 (4H, m), 3,85 (4H, s), 4.09 to (2H, s), and 4.68 (2H, s), 7,02 (1H, d, J=6 Hz), 7,07-7,14 (2H, m), 7,37 is 7.50 (2H, m), by 8.22 (1H, d, J=6 Hz), 12,59 (1H, Sirs).

(5g) 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)labels and)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 51

To a solution in toluene (8.1 ml) and methanol (0.9 ml) of 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (372 mg, 0.84 mmol)obtained in stage (5f), was added dropwise a solution of 3-chloroperbenzoic acid (200 mg, 0.76 to mmol content 65%) in toluene (2.7 ml) and methanol (0.3 ml) at a temperature from -55 ° C to -50°C for 10 minutes in nitrogen atmosphere. The mixture was stirred at a temperature of from -60 to -50°C for 1.5 hours. Stop the reaction by adding 12 ml of a saturated aqueous solution of sodium bicarbonate at the same temperature. The mixture was extracted with 50 ml of chloroform twice, and then the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol=gradient 1/0-4/1) and the desired fractions were concentrated. The obtained white foam was perioadele chloroform and diethyl ether and filtered. The operation was repeated twice to obtain specified in the title compound (148 mg, 38.4% of output) in the form of a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; was 1.43 (3H, s), and 2.14 (3H, s), 3,65-of 3.77 (4H, m), 3,85 (4H, s), 4.09 to (2H, s), 4,69 (1H, d, J=14 Hz), 4,78 (1H, d, J=14 Hz), 7,02 (1H, d, J=6 Hz), 7,20-to 7.32 (2H, m), 7,53-of 7.70 (2H, m), to 8.20 (1H, d, J=6 Hz).

(5h) is trieva salt of 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 52

To an ethanol (4 ml) solution of 2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (147 mg, 0.32 mmol), obtained in stage (5g)was added at room temperature, 1N aqueous solution of sodium hydroxide (320 μl, 0.32 mmol) and the mixture was stirred for 10 minutes, after which it was concentrated. To the residue was added methanol and the mixture was concentrated. Repeating this operation twice, was added diethyl ether and the resulting suspension was allowed to stand. After removing the supernatant, the residue was dried by a vacuum pump to obtain specified in the title compound (147 mg, 95.4% of output) in the form of a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; was 1.43 (3H, s)to 2.18 (3H, s), 3,66 is 3.76 (4H, m), 3,85 (4H, s)4,07 (2H, s), 4,36 (1H, d, J=13 Hz), to 4.81 (1H, d, J=13 Hz), 6,78-to 6.88 (2H, m), of 6.99 (1H, d, J=6 Hz), 7,38-7,46 (2H, m), of 8.27 (1H, d, J=6 Hz).

Example 6: sodium salt of 2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 53

(6a) (2-methoxy-1,3-dioxane-5-yl)methanol

Formula 54

A mixture of 2-(hydroxymethyl)-1,3-propane diol (1.7 g, 16 mmol), triethylorthoformate (7 ml, 64.1 mmol) and monohydrate p-toluensulfonate acid (275 mg, 1.6 mmol) was stirred at room temperature for 22 the aces. To the reaction mixture were added triethylamine (447 μl) and the mixture was concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (1.4 g, 59.1% of output), representing a mixture (1:1) of CIS - and TRANS-forms, in the form of a light yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,85-1,92 (0,5H, m), 1.93 and-2,04 (0,5H, m), 3,34 (1,5H, s), 3,41 (1,5H, s), 3,62-a-3.84 (3H, m), 3,90 (1H, DD, J=4, 12 Hz), a 4.03 (1H, DD, J=6, 12 Hz), 4,27 (1H, DD, J=4, 12 Hz), 5,22 (0,5H, in), 5.25 (0,5H, s).

(6b) 1-oxide 4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-2,3-dimethylpyridine

Formula 55

To dimethylsulfoxide (10 ml) solution of (2-methoxy-1,3-dioxane-5-yl)methanol (2.0 g, 13.5 mmol)obtained by the method similar to that described in stage (6a), was added at room temperature sodium hydride in oil (770 mg, 14.9 mmol content 55%). To the mixture was added 1-oxide 4-chloro-2,3-dimethylpyridine (2,13 g, 13.5 mmol) and the mixture was stirred at 60°C for 2.5 hours. After cooling the reaction mixture to room temperature it was concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (1.8 g, 49.5% of output), representing a mixture (1:1) of CIS - and TRANS-forms, in the form of a yellow oil.

1H NMR (400 MHz, CDClsub> 3) δ ppm; 2,12-of 2.30 (1H, m), of 2.20 (3H, s)to 2.54 (3H, s), 3,41 (1,5H, s), 3.45 points (1,5H, C)of 3.77 (1H, DD, J=4, 12 Hz), 4,01 (1H, DD, J=4, 12 Hz), 4,08-4.26 deaths (3H, m), 4,39 (1H, DD, J=4, 12 Hz), 5,28 (0,5H, s), from 5.29 (0,5H, s), 6,65 (0,5H, d, J=8 Hz), 6,69 (0,5H, d, J=8 Hz), 8,15 (0,5H, d, J=8 Hz), 8,16 (0,5H, d, J=8 Hz).

(6c) (4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol

Formula 56

1-Oxide 4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-2,3-dimethylpyridine (1.8 g, of 6.68 ml)obtained in stage (6b), was mixed with acetic anhydride (8 ml). The mixture was stirred at 100°C for 2 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. To the obtained residue were added methanol (10 ml) and 5N aqueous sodium hydroxide solution (5 ml) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was allocated saturated salt solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and the residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain specified in the connection header (0,41 g, yield: 22.8 per cent), representing a mixture (1:1) of CIS - and TRANS-forms, in the form of a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 2,04 (3H, s), 2,12-2,22 (0,5H, m), 2,24-2,32 (0,5H, m), 3,41 (1,5H, s), 3,44 (1,5H, s), with 3.79 (1H, DD, J=4, 12 Hz, to 4.01 (1H, DD, J=4, 12 Hz), 4,10-4,20 (2H, m)to 4.23 (1H, d, J=8 Hz), to 4.38 (1H, DD, J=4, 12 Hz), of 4.66 (2H, s), a 4.86 (1H, Sirs), 5,28 (0,5H, C)of 5.29 (0,5H, s), 6.73 x (0,5H, d, J=8 Hz), 6,76 (0,5H, d, J=8 Hz), 8,31 (0,5H, d, J=8 Hz), 8,32 (0,5H, d, J=8 Hz).

(6d) 2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 57

To a solution of (4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol (0,41 g of 1.52 mmol)obtained in stage (6c), and triethylamine (of 1.06 ml, to 7.61 mmol) in tetrahydrofuran (digidrirovanny) (10 ml) was added dropwise methanesulfonanilide (176 μl, of 2.27 mmol) while cooling on ice in a nitrogen atmosphere. The mixture was stirred for 1.5 hours at the same conditions. To the mixture was added 2-mercaptobenzimidazole (228 mg, of 1.52 mmol) and stirred at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (324 mg, 53,1% yield), which was a mixture (1:1) of CIS - and TRANS-forms, in the form of a light yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; 2,12-of 2.24 (1H, m), and 2.27 (3H, s), 3,41 (1,5H, s), 3,44 (1,5H, s), with 3.79 (1H, DD, J=4, 12 Hz), was 4.02 (1H, DD, J=4, 12 Hz), 4,12-4,20 (2H, m), 4,27 (1H, d, J=8 Hz), to 4.38 (2H, s), 4,36-of 4.44 (1H, m), 5,27 (0,5H, C)of 5.29 (0,5H, s), 6,78 (0,5H, d, J=8 Hz), 6,82 (0,5H, d, J=8 Hz), 7,15-7,24 (2H, m), 7,43 is 7.50 (1H, m), 7,58-to 7.67 (1H, m), 8,35-8,44 (1H, m).

(6e) 2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 58

To a solution of 2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (324 mg, 807 μmol)obtained in stage (6d), in a mixture of toluene/methanol (10:1) (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (528 mg, 1,99 mmol content 65%) in a mixture of toluene/methanol (10:1) (5 ml) at a temperature of -50 to -60°C for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 2 hours in the same conditions. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (337 mg, 65.9% of output), representing a mixture (1:1) of CIS - and TRANS-forms, in the form of a light yellow foam.

MS m/e (ESI) 418 (MH)+, 440(MNa)+

(6f) sodium salt of 2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil-1H-benzimidazole

Formula 59

To an ethanol (10 ml) solution of 2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (222 mg, 532 mmol)obtained in stage (6e)was added at room temperature, 1N aqueous sodium hydroxide solution (532 μl, 532 mmol) and the mixture was stirred for one hour. The mixture was concentrated and the residue was dissolved in ethanol. Then was added to a mixture of diethyl ether and the mixture was subjected to ultrasonic processing. The obtained solid substance was collected by filtration in a nitrogen atmosphere. The solid was dried under reduced pressure to obtain specified in the title compound (234 mg, yield: 83.4%of), representing a mixture (1:1) of CIS - and TRANS-forms, as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,14-of 2.21 (1H, m)to 2.18 (3H, s), 3,66-3,74 (1H, m), 3.27 to (1,5H, s)3,28 (1,5H, s), 3,66 is 3.76 (1H, m), 3,88-Android 4.04 (2H, m), 4.09 to (1H, DD, J=4, 12 Hz), 4,16-to 4.23 (1H, m), 4,35 (1H, d, J=13 Hz), 4,82 (1H, d, J=13 Hz), 5,24 (0,5H, s), 5,27 (0,5H, s), 6,83 (2H, DD, J=3, 6 Hz), 6,93 (1H, d, J=6 Hz),7,41 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

MS m/e (ESI) 440(MNa)+

Example 7: sodium salt of 2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 60

(7a) (2,2-bis(permitil)-1,3-dioxane-5-yl)methanol

Formula 61

A mixture of 2-(g is proximity)-1,3-propane diol (2.2 g, of 20.7 mmol), 1,3-defloration (to 3.89 g, 41,4 mmol), triethylorthoformate (3,44 ml of 20.7 mmol) and monohydrate p-toluensulfonate acid (356 mg, 2,07 mmol) was stirred at 60°C for 10 hours. Upon completion of the reaction was added to the reaction mixture triethylamine (577 μl), after which it was concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (1.6 g, yield: 43,4%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,97-2,10 (1H, m), 3.72 points-is 3.82 (2H, m), a 3.87 (2H, DD, J=4, 12 Hz), 4,10 (2H, DD, J=4, 12 Hz), 4,46 (2H, DD, J=2, 48 Hz), of 4.57 (2H, DD, J=2, 48 Hz).

(7b) 1-oxide 4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-2,3-dimethylpyridine

Formula 62

To dimethylsulfoxide (10 ml) solution of (2,2-bis(permitil)-1,3-dioxane-5-yl)methanol (1.6 g, 8.98 mmol)obtained in stage (7a), was added at room temperature sodium hydride in oil (431 mg, 9,88 mmol content 55%). To the mixture was added 1-oxide 4-chloro-2,3-dimethylpyridine (1.42 g, 8.98 mmol) and the resulting mixture was stirred at 60°C for 2 hours. After cooling the reaction mixture to room temperature it was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol) to obtain specified in the header is VCE compound (1.63 g, output: 60,6%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 2,19 (3H, s), 2.26 and-a 2.36 (1H, m), of 2.54 (3H, s)to 3.99 (2H, DD, J=4, 12 Hz), 4,13 (2H, d, J=8 Hz), is 4.21 (2H, DD, J=4, 12 Hz), of 4.45 (2H, DD, J=2, 48 Hz), to 4.62 (2H, DD, J=2, 48 Hz), only 6.64 (1H, d, J=8 Hz), 8,14 (1H, d, J=8 Hz).

(7c) (4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol

Formula 63

1-Oxide 4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-2,3-dimethylpyridine (1.63 g, 5.37 mmol)obtained in stage (7b), was mixed with acetic anhydride (8 ml). The mixture was stirred at 100°C for 2 hours, cooled to room temperature, then concentrated under reduced pressure. To the obtained residue were added methanol (10 ml) and 5N aqueous sodium hydroxide solution (5 ml) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and the residue was distributed between saturated salt solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated and the residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the specified title compound (385 mg, yield of 23.6%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 2,04 (3H, s), 2,32-to 2.40 (1H, m)to 4.01 (2H, DD, J=4, 12 Hz), 4,16 (2H, d, J=8 Hz), is 4.21 (2H, DD, J=4, 12 Hz), 4,48 (2H, DD, J=2, 48 Hz), to 4.62 (2H, the d, J=2, 48 Hz), of 4.66 (2H, s), 4,84 (1H, Sirs), was 6.73 (1H, d, J=8 Hz), 8,31 (1H, d, J=8 Hz).

(7d) 2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 64

To a solution of (4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol (385 mg, of 1.27 mmol)obtained in stage (7c), and triethylamine (885 μl, 6,35 mmol) in tetrahydrofuran (digidrirovanny) (20 ml) was added dropwise methanesulfonanilide (177 μl, to 2.29 mmol) while cooling on ice in a nitrogen atmosphere. The mixture was stirred for 1.0 hour in the same conditions. To the reaction mixture were added 2-mercaptobenzimidazole (191 mg, of 1.27 mmol) and the mixture was stirred at room temperature for 10 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (305 mg, yield: 55,1%) as a pale yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; and 2.26 (3H, s), 2,30-of 2.38 (1H, m)to 4.01 (2H, DD, J=4, 12 Hz), 4,18 (2H, d, J=8 Hz), 4,22 (2H, DD, J=4, 12 Hz), to 4.38 (2H, s), 4,46 (2H, DD, J=2, 48 Hz), to 4.62 (2H, DD, J=2, 48 Hz), 6,79 (1H, d, J=8 Hz), 7,15-of 7.23 (2H, m), 7,42-7,50 (1H, m), 7,56-7,66 (1H, m), of 8.37 (1H, d, J=8 Hz).

(7e) 2-((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 65

To a solution of 2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (305 mg, 700 μmol)obtained in stage (7d), in a mixture of toluene/methanol (10:1) (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (167 mg, 630 μmol when the content of 65%) in a mixture of toluene/methanol (10:1) (5 ml) at a temperature of -50 to -60°C for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 2 hours in the same conditions. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (215 mg, yield: 68%) as a pale yellow foam.

MS m/e (ESI) 452(MH)+, 474(MNa)+

(7f) sodium salt of 2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 66

To an ethanol (10 ml) solution of 2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (215 mg, 476 mmol)obtained in stage (7e)was added at room temperature 1N odny solution of sodium hydroxide (476 μl, 476 μmol) and the mixture was stirred for one hour. After the mixture was concentrated and the residue was dissolved in ethanol, was added to a mixture of diethyl ether. The mixture was subjected to ultrasonic processing, and the obtained solid substance was collected by filtration in a nitrogen atmosphere. The solid was dried under reduced pressure to obtain specified in the title compound (193 mg, yield: 85,6%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,17 (3H, s), 2,18-of 2.28 (1H, m), 3,84-of 3.94 (2H, m), 4,06-4,18 (2H, m), of 4.12 (2H, d, J=8 Hz), 4,37 (1H, d, J=12 Hz), 4,50 (2H, d, J=47 Hz), 4,58 (2H, d, J=47 Hz), to 4.81 (1H, d, J=12 Hz), 6,80-make 6.90 (2H, m)6,94 (1H, d, J=8 Hz), 7,38-of 7.48 (2H, m), of 8.27 (1H, d, J=8 Hz).

Example 8: sodium salt of 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 67

(8a) ethyl (2-propyl-1,3-dioxane-2-yl)acetate

Formula 68

A mixture of ethyl 3-oxohexanoate (5 g, of 31.6 mmol), 1,3-propane diol (3,61 g, with 47.4 mmol), triethylorthoformate (5,78 ml, 34.8 mmol) and monohydrate p-toluensulfonate acid (272 mg, was 1.58 mmol) was stirred at room temperature for 22 hours. Upon completion of the reaction was added to the reaction mixture triethylamine (881 μl, 6,32 mmol), after which it was concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptan/ethyl acetate) to obtain the specified title compound (5.5 g, output: 80,5%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.94 (3H, t, J=7 Hz), of 1.27 (3H, t, J=7 Hz), 1,40-and 1.54 (2H, m), 1,55 by 1.68 (2H, m), 1,74-1,90 (2H, m), 2,82 (2H, s), a 3.87-4,06 (4H, m), is 4.15 (2H, q, J=7 Hz).

(8b) 2-(2-propyl-1,3-dioxane-2-yl)ethanol

Formula 69

To a solution of ethyl (2-propyl-1,3-dioxane-2-yl)acetate (5.5 g, and 25.4 mmol)obtained in stage (8a), in tetrahydrofuran (digidrirovanny) (30 ml) was added in portions sociallyengaged (578 mg, of 15.2 mmol) while cooling on ice and the mixture was stirred for one hour while cooling on ice. To the reaction mixture were added successively water (0.6 ml), 2N aqueous sodium hydroxide solution (0.6 ml) and water (1.8 ml) and the resulting mixture was filtered through celite. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (4.4 g, yield of 99.4%), which represented the crude product as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.97 (3H, t, J=7 Hz), 1,22-of 1.42 (4H, m), 1,82 is 2.00 (4H, m), 3,78-of 3.96 (4H, m), 3.96 points-4,08 (2H, m).

(8c) 1-oxide, 2,3-dimethyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine

Formula 70

To dimethylsulfoxide (20 ml) solution of (2-(2-propyl-1,3-dioxane-2-yl)ethanol (4.4 g, to 25.3 mmol)obtained in stage (8b)was added at room temperature sodium hydride in oil (1.1 g, to 25.3 mmol content 55%). To Speedball 1-oxide 4-chloro-2,3-dimethylpyridine (3,19 g, a 20.2 mmol) and the mixture was stirred at 60°C for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the specified title compound (3.9 g, yield: 52,2%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.96 (3H, t, J=7 Hz), of 1.34 to 1.48 (2H, m), 1,76-of 1.88 (2H, m), 2,14-of 2.26 (4H, m), of 2.54 (3H, s), 2,62 (3H, s), 3,82-are 3.90 (2H, m), 3,92-Android 4.04 (2H, m), 4,17 (2H, t, J=7 Hz), 6,69 (1H, d, J=8 Hz), 8,14 (1H, d, J=8 Hz).

(8d) (3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methanol

Formula 71

1-Oxide, 2,3-dimethyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine (3.9 g, 13,2 mmol)obtained in stage (8c), was mixed with acetic anhydride (16 ml). The mixture was stirred at 90°C for 2 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. To the obtained residue were added methanol (20 ml) and 5N aqueous sodium hydroxide solution (10 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue was allocated using saturated salt solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue of the imali chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate, the ethyl acetate/methanol) to obtain specified in the connection header (1,69 g, output: 43,3%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.96 (3H, t, J=7 Hz), of 1.35 to 1.48 (2H, m), 1,52-of 1.66 (2H, m), 1,72-of 1.88 (2H, m), 2,03 (3H, s), 2,22 (2H, t, J=7 Hz), 3,82-Android 4.04 (4H, m), 4,19 (2H, t, J=7 Hz)and 4.65 (2H, s), 6,77 (1H, d, J=8 Hz,), 8,29 (1H, d, J=8 Hz).

(8e) 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole

Formula 72

To a solution of (3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methanol (445 ml and 1.51 mmol)obtained in stage (8d), and triethylamine (1,05 ml of 7.55 mmol) in tetrahydrofuran (digidrirovanny) (30 ml) was added dropwise methanesulfonanilide (210 μl, of 2.72 mmol) while cooling on ice in a nitrogen atmosphere and the mixture was stirred for one hour at the same conditions. To the reaction mixture were added 2-mercaptobenzimidazole (227 mg and 1.51 mmol) and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate, ethyl acetate/methanol) to obtain the specified title compound (417 mg, yield: 64,6%) as a pale yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.96 (3H, t, J=7 Hz), of 1.35 to 1.47 (2H, m), 1,76-of 1.88 (4H, m), 2,22 (2H, t, J=7 Hz), of 2.25 (3H, s), 3,82-3,91 (2H, m), 3,92-4,00 (2H, m), 4,22 (2H, t, J=7 Hz), 4,37 (2H, s), PC 6.82 (1H, d, J=8 Hz,), 7,14-7,24 (2H, m), 7,50 to 7.62 (2H, m), 8,35 (1H, d, J=8 Hz).

(8f) 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 73

To a solution of 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole (417 mg, 975 mmol)obtained in stage (8e), in a mixture of toluene/methanol (10:1) (30 ml) was added dropwise a solution of 3-chloroperbenzoic acid (233 mg, 878 µmol when the content of 65%) in a mixture of toluene/methanol (10:1) (5 ml) at a temperature of -50 to -60°C for 5 minutes in a nitrogen atmosphere. The reaction mixture was stirred for 2 hours in the same conditions. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. After the organic layer was concentrated, the residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (311 mg, yield: 71.9 percent), as a pale yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.95 (3H, t, J=7 Hz), of 1.34 to 1.47 (2H, m), 1.70 to a 1.88 (4H, m), 2,17 (3H, s), measuring 2.20 (2H, t, J=7 Hz), 3,82-to 3.92 (2H, m), 3,92-4,00 (2H, m), 4,17 (2H, t, J=7 Hz)and 4.65 (1H, d, J=14 Hz), 4,82 (1H, d, J=14 Hz), 6,7 (1H, d, J=8 Hz), 7,28-7,38 (2H, m), 7,30 to 7.62 (2H, m), 8,30 (1H, d, J=8 Hz).

(8g) sodium salt of 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 74

To an ethanol (6 ml) solution of 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole (311 mg, 701 mmol)obtained in stage (8f)was added at room temperature, 1N aqueous sodium hydroxide solution (ál 701, 701 mmol) and the mixture was stirred for one hour. The mixture was concentrated and the residue was dissolved in ethanol. Adding to the obtained solution of diethyl ether, the solution was subjected to ultrasonic processing. The obtained solid substance was collected by filtration in a nitrogen atmosphere and dried under reduced pressure to obtain specified in the title compound (283 mg, yield: 86,7%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.87 (3H, t, J=7 Hz), 1,26-to 1.38 (2H, m), 1,48-of 1.64 (2H, m), 1,67-of 1.74 (2H, m), 2,12-of 2.20 (2H, m)of 2.16 (3H, s), 3,81 (4H, t, J=7 Hz), 4,07 (2H, t, J=7 Hz), to 4.38 (1H, d, J=13 Hz), 4,79 (1H, d, J=13 Hz), 6,82-of 6.90 (2H, m)6,91 (1H, d, J=8 Hz), of 7.36-to 7.50 (2H, m), of 8.25 (1H, d, J=8 Hz).

MS m/e (ESI) 466(MNa)+.

Example 9: sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 75

(9a) 2,2-dimethyl-1,3-dioxane-5-ol

Formula 76

To a solution of 2,2-dimethyl-1,3-dioxane-5-it (15 g, 0,115 mol) in diethyl ether (150 ml) was added sociallyengaged (of 4.38 g, 0,115 mol) at 0-8°C for one hour in nitrogen atmosphere. To the reaction mixture were added successively dropwise water (4,2 ml), 5N aqueous solution of sodium hydroxide (4,2 ml) and water (to 12.8 ml) at 0-10°C. the Mixture was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain specified in the title compound (14.2 g, 93,4%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; the 1.44 (3H, s)of 1.46 (3H, s), of 2,75 2,95 (1H, W), 3,51-3,55 (1H, m), 3,74-with 3.79 (2H, m), 4,05-4,10 (2H, m).

(9b) 5-(benzyloxy)-2,2-dimethyl-1,3-dioxane

Formula 77

To N,N-dimethylformamide (200 ml) solution of 2,2-dimethyl-1,3-dioxane-5-ol (7,1 g, 0,054 mol)obtained in stage (9a)was added at 0°C and sodium hydride in oil (2,81 g, 0,064 mol content 55%) and stirred. Once to the mixture was added at the same temperature benzylbromide (12.9 ml, to 0.108 mol) and tetrabutylammonium (220 mg, 0.001 mol), the mixture was stirred at room temperature for 1.5 hours. Was added to the reaction mixture water, after which the mixture was extracted with ethyl acetate three times. The organic layers were combined, washed five times with water and once with saturated saline, dried over anhydrous sodium sulfate and filtrowanie add NH silica gel, the mixture was concentrated and purified by chromatography on a column of silica gel (eluting solvent: heptane, heptane/ethyl acetate=9/1, 4/1, ethyl acetate) to obtain the specified title compound (6.5 g, 54,5%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.40 (3H, s)of 1.45 (3H, s), 3,50 of 3.56 (1H, m), of 3.77 (2H, DD, J=7, 12 Hz), 3,95 (2H, DD, J=4, 12 Hz), 4,58 (2H, s), 7,28-7,38 (5H, m).

(9c) of 2-(benzyloxy)propane-1,3-diol

Formula 78

To methanol (50 ml) solution of 5-(benzyloxy)-2,2-dimethyl-1,3-dioxane (6.5 g, 29.2 mmol)obtained in stage (9b)was added DOWEX(R) 50W-X8 (5 g) and the mixture was stirred at room temperature. After 2 hours the reaction mixture was filtered and concentrated to obtain specified in the title compound (5.0 g, 93,8%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; 3,60-the 3.65 (1H, m), 3,74 (2H, DD, J=5, 12 Hz), 3,82 (2H, DD, J=4, 12 Hz), of 4.67 (2H, s), 7,29-7,40 (5H, m).

(9d) 7-(benzyloxy)-5,9-dioxaspiro[3,5]nonan

Formula 79

To a round bottom flask containing a solution of 2-(benzyloxy)propane-1,3-diol (5.0 g, a 27.4 mmol)obtained in stage (9c), cyclobutanone (2,33 ml of 30.6 mmol) and monohydrate p-toluensulfonate acid (100 mg, of 0.53 mmol) in benzene (50 ml), was added the reflux condenser equipped with a water separator Dean-stark. The mixture was boiled under reflux for 2 hours. To the mixture was added triethylamine (0.4 ml, to 0.72 mmol) and concentrated her to obtain the crude product, the Crude product was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane, heptane/ethyl acetate=5/1) to obtain the specified title compound (6.3 g, yield: 98.2 per cent) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,70-to 1.79 (2H, m), 2,20-to 2.29 (4H, m), 3,44-3,50 (1H, m), 3,64 at 3.69 (2H, m)to 3.92 (2H, DD, J=4, 12 Hz), 4,58 (2H, s), 7,27-7,39 (5H, m).

(9e) 5,9-dioxaspiro[3,5]nonan-7-ol

Formula 80

To methanol (269 ml) solution of 7-(benzyloxy)-5,9-dioxaspiro[3,5]nonane (6.3 g, 26.9 mmol)obtained in stage (9d)was added 20% palladium hydroxide (630 mg) and the mixture was stirred for 13 hours in an atmosphere of hydrogen. The reaction vessel was purged with nitrogen and insoluble material was removed by filtration. The filtrate was concentrated to obtain the crude product. The crude product was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane, heptane/ethyl acetate=5/1) to obtain the specified title compound (3.42 g, output: 88,2%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,72-to 1.82 (2H, m), 2.21 are 2,31 (4H, m), 2.71 to 2,88 (1H, W), 3,50 of 3.56 (1H, m), 3,71 is 3.76 (2H, m), 3,93-3,98 (2H, m).

(9f) 1-oxide 4-(5,9-dioxaspiro[3,5]non-7-yloxy)-2,3-dimethylpyridine

Formula 81

To dimethylformamide (30 ml) solution of 5.9-dioxaspiro[3,5]nonan-7-ol (1.68 g, 11.7 mmol)obtained in stage (9e), was added at room temperature hydride is the atrium in oil (587 mg, 13.5 mmol content 55%). The mixture was stirred at room temperature for 50 minutes. Adding thereto 1-oxide 4-chloro-2,3-dimethylpyridine (1.84 g, 11.7 mmol), the mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, added to it dimethyl sulfoxide (30 ml) and the resulting mixture was stirred at 80°C. After 12 hours was added to the reaction mixture of sodium hydride in oil (587 mg, 13.5 mmol content 55%) and mixed it at 80°C. After one hour the reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate ethyl acetate/methanol=9/1) to obtain specified in the header of the compound (2.00 g, yield: 64,4%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,76-to 1.82 (2H, m), 2,24 (3H, s), 2,27 of-2.32 (4H, m), of 2.54 (3H, s), 3,85 (2H, DD, J=6, 12 Hz), 4,07 (2H, DD, J=3, 12 Hz), 4,24-4,30 (1H, m), 6,62 (1H, d, J=7 Hz), 8,16 (1H, d, J=7 Hz).

(9g) (4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methanol

Formula 82

1-Oxide 4-(5,9-dioxaspiro[3,5]non-7-yloxy)-2,3-dimethylpyridine (1,25 g, 4,71 mmol)obtained in stage (9f), was mixed with acetic anhydride (4,45 ml of 47.1 mmol). After stirring the mixture at room temperature for one hour it was cooled to 0°C. Add triethylamine (656 μl, 4,71 mmol), the mixture was stirred for one hour and stirred at on the th temperature for another one hour. After stirring at 50°C for 2 hours the reaction mixture was concentrated and the residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/heptane=1/3). To the obtained product was added methanol (30 ml) and 5N aqueous sodium hydroxide solution (2,24 ml, and 11.2 mmol) and the reaction mixture was stirred at room temperature for one hour. Was added to the reaction mixture, a saturated aqueous solution of ammonium chloride to bring the pH to about 9, and then the mixture was concentrated. The obtained residue was extracted with ethyl acetate three times. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated to obtain specified in the title compound (630 mg, yield: 49,6%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,77-of 1.85 (2H, m), of 2.08 (3H, s), 2.26 and to 2.35 (4H, m), 3,85 (2H, DD, J=6, 12 Hz), 4,11 (2H, DD, J=4, 12 Hz), to 4.38-of 4.44 (1H, m), and 4.68 (2H, s), 6,72 (1H, d, J=6 Hz), 8,31 (1H, d, J=6 Hz).

(9h) 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 83

Tertrahydrofuran ring solution (20 ml) of (4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methanol (630 mg, is 2.37 mmol)obtained in stage (9g), and triethylamine (0,66 ml, 4,74 mmol) was stirred at -10°C. After 10 minutes, add the Yali at the same temperature methanesulfonanilide (275 μl, of 3.56 mmol) and the resulting mixture was stirred at the same conditions for 30 minutes. Was poured into the reaction mixture saturated aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate twice and the organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated. To the residue was added dichloromethane (30 ml) to obtain a solution and then the solution was added at room temperature 2-mercaptobenzimidazole (354 mg, 2.36 mmol). In addition, was added triethylamine (0,493 ml, 3.54 mmol) and was additionally added methanol to dissolve the 2-mercaptobenzimidazole. After stirring the reaction mixture at room temperature for 2 hours was added to the reaction mixture NH silica gel, after which the mixture was concentrated. The residue was subjected to chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate=1/1, ethyl acetate) to obtain the specified title compound (690 mg, yield: 73,6%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,61 is 1.70 (2H, m), 2.13 and was 2.25 (4H, m), 2,22 (3H, s),of 3.77 (2H, DD, J=4, 12 Hz), was 4.02 (2H, DD, J=2, 12 Hz), of 4.44-4,48 (1H, m), and 4.68 (2H, s), 6,97 (1H, d, J=6 Hz), 7,07-7,13 (2H, m), 7,37 is 7.50 (2H, m), 8,21 (1H, d, J=6 Hz).

(9i) 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 84

To a solution of 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (290 mg, 0.73 mmol)obtained in stage (9h), in a mixture of toluene (30 ml)/methanol (3 ml) was added a solution of 3-chloroperbenzoic acid (174 mg, of 0.65 mmol content 65%) in a mixture of toluene/methanol (10:1) at -70°C in the atmosphere of nitrogen. After stirring the mixture at -50°C for one hour was added a saturated aqueous solution of sodium bicarbonate. After the mixture was heated to room temperature, it was extracted with ethyl acetate twice. The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate ethyl acetate/methanol=9/1). The fractions containing specified in the title compound were collected, using ethyl acetate, and concentrated. After the residue was added diethyl ether, drove the solvent to obtain specified in the title compound (230 mg, yield: 76,2%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,60-1,70 (2H, m), of 2.15 (3H, s), 2,12 was 2.25 (4H, m), of 3.73-3,81 (2H, m), 3,98-4,06 (2H, m), of 4.44 figure-4.49 (1H, m), 4,70 (1H, d, J=14 Hz), 4,78 (1H, d, J=14 Hz), 6,97 (1H, d, J=6 Hz), 7,25-to 7.32 (2H, m), 7,56-of 7.70 (2H, m), 8,19 (1H, d, J=6 Hz).

(9j) sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-Benson is desola

Formula 85

To an ethanol (20 ml) solution of 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (230 mg, 0,56 mmol)obtained in stage (9i)was added at room temperature, 1N aqueous sodium hydroxide solution (of 0.56 ml of 0.56 mmol). The mixture was stirred for one hour and then concentrated. After the residue was subjected to azeotropic distillation with ethanol twice, it is suspended in diethyl ether, the resulting solid substance was collected by filtration and dried to obtain specified in the title compound (190 mg, yield: 91%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,60-1,70 (2H, m), 2,13-of 2.27 (4H, m), 2,22 (3H, s), 3,74-3,81 (2H, m), 3,99-4,06 (2H, m), 4,37 (1H, d, J=13 Hz), 4,42-4,50 (1H, m), is 4.85 (1H, d, J=13 Hz), 6,82-to 6.88 (2H, m)6,94 (1H, d, J=6 Hz), 7,40-7,46 (2H, m), of 8.25 (1H, d, J=6 Hz).

Example 10: the sodium salt of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 86

(10a) 1,5,9-dioxaspiro[5,5]undec-3-ylmethanol

Formula 87

A mixture of 2-(hydroxymethyl)-1,3-propane diol (3.3 grams, and 31.1 mmol), tetrahydro-4H-Piran-4-it (3.12 g, and 31.2 mmol), monohydrate p-toluensulfonate acid (268 mg, of 1.41 mmol) and benzene (68,3 ml) was heated in a round bottom flask, equipped with a fridge and apparatus the atom Dean-stark within 6 hours. After cooling to room temperature was added to the reaction mixture triethylamine (1 ml) and the mixture was concentrated. The residue was purified by chromatography on a column of silica gel (silica gel: 200 g, eluting solvent: heptane, heptane/ethyl acetate=1/1, 1/3) to obtain the specified title compound (3.80 g, output: 64,9%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,67-1,82 (5H, m), 3,35-of 3.42 (2H, m), 3,49 is 3.57 (4H, m), the 3.65 (2H, DD, J=7, 12 Hz), 3,86 (2H, DD, J=4, 12 Hz), 4,56 (1H, t, J=5 Hz).

(10b) 1-oxide, 2,3-dimethyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine

Formula 88

To dimethylsulfoxide (30 ml) solution of 1,5,9-dioxaspiro[5,5]undec-3-ylmethanol (3.80 g, a 20.2 mmol)obtained in stage (10a)was added at room temperature sodium hydride in oil (770 mg, and 19.3 mmol content 60%). The mixture was stirred at room temperature for 30 minutes in nitrogen atmosphere. To the mixture was added 1-oxide 4-chloro-2,3-dimethylpyridine (2.6 g, 16.5 mmol) and stirred it at 60°C for 2.5 hours. After cooling to room temperature the reaction mixture was concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 200 g, eluting solvent: heptane, heptane/ethyl acetate=1/1, 1/3, ethyl acetate, ethyl acetate/methanol=10/1) to obtain specified in the connection header (3,38 g, the output is: 66,2%) as a pale yellow resin.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,78 (2H, t, J=5 Hz), of 1.85 (2H, t, J=5 Hz), 2,07-of 2.20 (1H, m)to 2.13 (3H, s)to 2.35 (3H, s), 3,52-of 3.60 (4H, m), 3,80 (2H, DD, J=6, 12 Hz), Android 4.04 (2H, DD, J=4, 12 Hz), 4,11 (2H, d, J=7 Hz), 6,97 (1H, d, J=7 Hz), 8,08 (1H, d, J=7 Hz).

(10c) (3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methanol

Formula 89

1-Oxide, 2,3-dimethyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine (of 3.31 g of 10.7 mmol)obtained in stage (10b), was mixed with acetic anhydride (30 ml, 331 mmol). The mixture was stirred at 85°C for 1 hour 55 minutes. After cooling to room temperature the reaction mixture was concentrated. To the obtained residue were added methanol (50 ml) and 5N aqueous solution of sodium hydroxide (30 ml, 150 mmol) and the mixture was stirred at room temperature for one hour. The reaction mixture was concentrated and the residue was distributed between water and ethyl acetate. The organic layer was washed two times with 1N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain specified in the title compound (1.97 g, yield: 59,5%) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,78 (2H, t, J=5 Hz), of 1.85 (2H, t, J=5 Hz), 2,09-of 2.20 (1H, m), 2,12 (3H, s), 3,50-3,62 (4H, m), 3,82 (2H, DD, J=6, 12 Hz), of 4.05 (2H, DD, J=4, 12 Hz), 4,14 (2H, d, J=7 Hz), a 4.53 (2H, d, J=6 Hz), 4,99 (1H, t, J=6 Hz), 6,97 (1H, d, J=6 Hz), 8,24 (1H, d, J=6 Hz).

(10d) of 2-(((3-methyl-4-(1,5,9-trioxa the IIR[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole

Formula 90

To a solution of (3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methanol (1.26 g, 4.07 mmol)obtained in stage (10c), and triethylamine (1.13 ml, 8,14 mmol) in dichloromethane (digidrirovanny) (20 ml) was added dropwise methanesulfonanilide (473 μl, 6,11 mmol) at 1-4°C for 20 minutes in nitrogen atmosphere. The mixture was stirred for 40 minutes under the same conditions. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was mixed with 2-mercaptobenzimidazole (595 mg, of 3.96 mmol). The mixture was stirred in methanol (15 ml) at room temperature for 17 hours and 45 minutes. Was added to the reaction mixture NH silica gel (10 g) and the mixture was concentrated. The residue was subjected to chromatography on a column of silica gel (silica gel: 15 g, eluting solvent: heptane/ethyl acetate=50/50, 25/75, ethyl acetate, ethyl acetate/methanol=10/1) to obtain the mixture specified in the title compound and 2-mercaptobenzimidazole. The mixture still was purified by chromatography on a column of silica gel (silica gel: 15 g, eluting solvent: heptane/ethyl acetate=50/50, 25/75, ethyl acetate, ethyl acetate/methanol=10/1). The resulting oil is suspended in hexane, conc is listed with obtaining specified in the connection header (994 mg, exit; 56,8%) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,78 (2H, t, J=5 Hz), of 1.85 (2H, t, J=5 Hz), 2,10-of 2.20 (1H, m), 2,22 (3H, s), 3,52-of 3.60 (4H, m), 3,82 (2H, DD, J=6, 12 Hz), of 4.05 (2H, DD, J=4, 12 Hz), 4,15 (2H, d, J=7 Hz), 4,70 (2H, s), of 6.99 (1H, d, J=6 Hz), 7,09-7,16 (2H, m), 7,38-7,53 (2H, W), of 8.25 (1H, d, J=6 Hz), br12.62 (1H Sirs).

(10e) 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 91

To a solution of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole (974 mg, 2.21 mmol)obtained in stage (10d), in a mixture of toluene (30 ml)-methanol (3 ml) was added dropwise a solution of 3-chloroperbenzoic acid (528 mg, 1,99 mmol content 65%) in a mixture of toluene (1 ml)-methanol (1 ml) at -65°C for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 55 minutes in the same conditions. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 20 g, eluting solvent: dichloromethane, dichloromethane/methanol=10/1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated. After the residue was added diethyl ether, drove the solvent to obtain specified the title compound (725 mg, output: 71,7%) as a pale grey solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,78 (2H, t, J=5 Hz), of 1.85 (2H, t, J=5 Hz), 2,05-of 2.21 (1H, m), and 2.14 (3H, s), 3,48-3,62 (4H, m), 3,81 (2H, DD, J=6, 12 Hz), of 4.05 (2H, DD, J=4, 12 Hz), 4,15 (2H, d, J=7 Hz), 4,71 (1H, d, J=14 Hz), 4,80 (1H, d, J=14 Hz), of 6.99 (1H, d, J=6 Hz), 7,26 and 7.36 (2H, m), 7,58-7,72 (2H, W), 8,23 (1H, d, J=6 Hz).

(10f) sodium salt of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 92

To an ethanol (15 ml) solution of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole (708 mg, 1.55 mmol)obtained in stage (10e)was added at room temperature, 1N aqueous sodium hydroxide solution (1,54 ml, 1.55 mmol in concentration 1,004 M) and the mixture was concentrated. The residue was subjected to azeotropic distillation with ethanol twice. After the residue is suspended in diethyl ether, subjected to ultrasound treatment and allowed to stand, the supernatant was removed. Described washing process was repeated two more times. The residue was dried under reduced pressure to obtain specified in the title compound (635 mg, yield: 85,4%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 1.79 (2H, t, J=5 Hz), of 1.85 (2H, t, J=5 Hz), 2,10-of 2.23 (1H, m), are 2.19 (3H, s), 3,50-3,62 (4H, m), 3,78-a 3.87 (2H, m), of 4.05 (2H, DD, J=4, 12 Hz), 4,14 (2H, d, J=7 Hz), and 4.40 (1H, d, J=13 Hz), 4,78 (1H, d, J=13 Hz), 6,2-of 6.90 (2H, m)of 6.96 (1H, d, J=6 Hz), 7,42-of 7.48 (2H, m), 8,29 (1H, d, J=6 Hz).

Example 11: the sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 93

(11a)(2,2-dimethyl-1,3-dioxane-5-yl)methanol

Formula 94

A mixture of 2-(hydroxymethyl)-1,3-propane diol (4.09 g, a 38.5 mmol), acetone (130 ml, 1768 mmol) and 70% perchloro acid (1,37 g of 9.55 mmol) was stirred at room temperature for 21 hours. After the pH of the reaction mixture brought concentrated aqueous ammonia to 9, the reaction mixture was concentrated. The residue was purified by chromatography on a column of silica gel (silica gel: 100 g, eluting solvent: heptane, heptane/ethyl acetate=1/3) to obtain the specified title compound (4.83 g, output: 85,8%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.29 (3H, s)of 1.30 (3H, s), 1,64-of 1.74 (1H, m), 3,35-to 3.41 (2H, m), 3,61 (2H, DD, J=7, 12 Hz), 3,82 (2H, DD, J=4, 12 Hz), of 4.54 (1H, t, J=5 Hz).

(11b) 1-oxide 2,3,5-trimethylpyridine

Formula 95

To a solution of 2,3,5-collidine (11,0 g, the 90.8 mmol) in dichloromethane (digidrirovanny) (150 ml) was added at 1°C in nitrogen atmosphere 3-chloroperbenzoic acid (24.8 g, for 93.4 mmol content 65%). The mixture was stirred while gradually raising the temperature to room temperature for 13.5 hours the century After concentrating the reaction mixture, the residue was purified by chromatography on a column of silica gel (NH silica gel: 200 g, eluting solvent: heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=20/1) to obtain neoimerologitismos the title compound as a pale yellow oil. After dilution of the crude product by ethyl acetate and saturated aqueous sodium hydrogen carbonate and the mixture was concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 300 g, eluting solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=20/1) to obtain specified in the connection header (11,0 g, output: 88,3%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.15 (3H, s), of 2.23 (3H, s), and 2.27 (3H, s), 6,97 (1H, s), to 7.99 (1H, s).

(11c) 1-oxide 2,3,5-trimethyl-4-nitropyridine

Formula 96

1-Oxide 2,3,5-trimethylpyridine (11,0 g, 80.2 mmol)obtained in stage (11b), was mixed with sulfuric acid (34,1 g, 348 mmol). After adding to the mixture dropwise boiling nitric acid (5.50 ml, 133 mmol) at room temperature and the mixture was stirred at 80°C for 9 hours. The reaction mixture was cooled to room temperature and then poured into ice. The resulting aqueous solution was extracted with chloroform three times. The organic layers were combined and who left the house taking over anhydrous magnesium sulfate, was filtered and concentrated to obtain specified in the connection header (to 13.6 g, yield: 93.1%) are in the form of a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.16 (3H, s), measuring 2.20 (3H, s), a 2.36 (3H, s), 8,35 (1H, s).

(11d) 1-oxide 4-chloro-2,3,5-trimethylpyridine

Formula 97

1-Oxide 2,3,5-trimethyl-4-nitropyridine (13,4 g, 73,6 mmol)obtained in stage (11c), was added to acetylchloride (80 ml, 1,125 mmol) at -30°C in nitrogen atmosphere. The mixture was stirred at a temperature of from -30°C. to room temperature for 4 hours and 20 minutes. After concentrating the reaction mixture, the residue was subjected to chromatography on a column of silica gel (NH silica gel: 300 g, eluting solvent: heptane, heptane/ethyl acetate=50/50, ethyl acetate, ethyl acetate/methanol=10/1) to obtain fractions containing pure specified in the header connection, and fractions containing crude specified in the header of the connection.

The fractions containing crude specified in the title compound were concentrated. The residue is suspended in ethyl acetate and the precipitate was collected by filtration and washed with ethyl acetate and diethyl ether to obtain specified in the connection header (sample A, was 1.58 g) as a white solid. The filtrate was concentrated. The residue was dissolved in chloroform and washed with saturated aqueous hydro is arbonate sodium, was dried over anhydrous sodium sulfate, filtered and concentrated. The residue is suspended in diethyl ether. The precipitate was collected by filtration, washed with diethyl ether to obtain specified in the connection header (sample B, 2,69 g) as a pale brown solid.

The fractions containing pure indicated in the title compound, was concentrated. The residue was dissolved in chloroform, washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain specified in the connection header (sample C, 6,56 g) in the form of not-quite-white solid.

The output specified in the title compounds 3 samples had a total of 85.7%.

Sample A:1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.24 (3H, s)to 2.35 (3H, s), 2,39 (3H, s), of 8.25 (1H, s).

Sample B:1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.24 (3H, s)to 2.35 (3H, s), 2,39 (3H, s), of 8.25 (1H, s).

Sample C:1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.24 (3H, s)to 2.35 (3H, s), 2,39 (3H, s), of 8.25 (1H, s).

(11e) 1-oxide 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-2,3,5-trimethylpyridine

Formula 98

To dimethylsulfoxide (50 ml) solution of (2,2-dimethyl-1,3-dioxane-5-yl)methanol (4,78 g, to 32.7 mmol)obtained in stage (11a)was added at room temperature sodium hydride in oil (1.26 g, 31,5 molpro content of 60%). The mixture was stirred at room temperature for 15 minutes in nitrogen atmosphere. To the mixture was added 1-oxide 4-chloro-2,3,5-trimethylpyridine (sample C, 4,50 g, 26,2 mmol)obtained in stage (11d), and the mixture was stirred at 60°C for 8 hours and 10 minutes. After cooling to room temperature the reaction mixture was concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 300 g, eluting solvent: heptane, heptane/ethyl acetate=1/1, 1/3, ethyl acetate, ethyl acetate/methanol=10/1) to obtain specified in the connection header (of 5.06 g, output: 68,6%) as a yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), is 2.05 and 2.13 (1H, m), and 2.14 (3H, s), 2,17 (3H, s), 2,31 (3H, s), of 3.77-3,86 (4H, m)to 4.01 (2H, DD, J=4, 12 Hz), 8,07 (1H, s).

(11f) (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol

Formula 99

1-Oxide 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-2,3,5-trimethylpyridine (of 5.06 g, 18 mmol)obtained in stage (11e), was mixed with acetic anhydride (50 ml, 529 mmol) and the mixture was stirred at 85°C. for 1.5 hours. After cooling to room temperature the reaction mixture was concentrated. To the residue was added methanol (50 ml) and 5N aqueous sodium hydroxide solution (50 ml, 250 mmol) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue distribution is ranged between water and ethyl acetate. The organic layer is washed with 1N aqueous sodium hydroxide solution twice and dried over anhydrous magnesium sulfate, filtered and concentrated to obtain specified in the connection header (3,02 g, output: 59,6%) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)to 1.37 (3H, s), 2,05-of 2.16 (1H, m), of 2.20 (6H, s), 3,82 (2H, DD, J=6, 12 Hz), 3,86 (2H, d, J=8 Hz), was 4.02 (2H, DD, J=4, 12 Hz), 4,51 (2H, d, J=6 Hz), to 4.98 (1H, t, J=6 Hz), 8,16 (1H, s).

(11g) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 100

To tertrahydrofuran ring solution (15 ml) of (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol (504 mg, to 1.79 mmol)obtained in stage (11f), and triethylamine (500 μl, 3.58 mmol) was added dropwise methanesulfonanilide (208 μl, 2,69 mmol) at 1-3°C for 15 minutes in nitrogen atmosphere. The reaction mixture was stirred for 1 hour 25 minutes in the same conditions. After adding 2-mercaptobenzimidazole (271 mg, 1.8 mmol) and the mixture was stirred at room temperature for 64 hours and 20 minutes. The reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (silica gel: 30 g, elwi the respective solvent: heptane/ethyl acetate=42/58, 22/78, ethyl acetate) to obtain the specified title compound (442 mg, yield: 59,7%) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,05-of 2.16 (1H, m), of 2.20 (3H, s), of 2.28 (3H, s), 3,81 (2H, DD, J=6, 12 Hz), a 3.87 (2H, d, J=7 Hz), was 4.02 (2H, DD, J=4, 12 Hz), 4,69 (2H, s), 7,09-7,16 (2H, m), 7,41-7,50 (2H, m), 8,18 (1H, s).

(11h) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 101

To a solution in a mixture of toluene (20 ml)-methanol (2 ml) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (424 mg, of 1.03 mmol)obtained in stage (11g), was added dropwise a solution of 3-chloroperbenzoic acid (246 mg, 0,927 mmol content 65%) in a mixture of toluene (1 ml)-methanol (1 ml) at -65°C for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 45 minutes in the same conditions. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 20 g, eluting solvent: dichloromethane, dichloromethane/methanol=10/1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated. To the obtained residue was added diethyl-the new ether. The precipitate was collected by filtration and washed with diethyl ether to obtain specified in the title compound (274 mg, yield: 61.9%) in the form of a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, s)of 1.36 (3H, s), 2,02 and 2.13 (1H, m)of 2.16 (3H, s), measuring 2.20 (3H, s), 3,74-a-3.84 (4H, m)4,00 (2H, DD, J=4, 12 Hz), 4,70 (1H, d, J=14 Hz), 4,79 (1H, d, J=14 Hz), 7,26-7,33 (2H, m), 7,60-7,70 (2H, m), 8,18 (1H, s).

(11i) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 102

To an ethanol (10 ml) solution of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (274 mg, 0,638 mmol)obtained in stage (11h), was added at room temperature, 1N aqueous sodium hydroxide solution (635 μl, 0,638 mmol in concentration 1,004 M) and the mixture was concentrated. The residue was subjected to azeotropic distillation with ethanol twice. After the residue is suspended in diethyl ether, the mixture was subjected to ultrasonic treatment and then concentrated to obtain specified in the title compound (260 mg, yield: 90.3 per cent) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,03 with 2.14 (1H, m), of 2.20 (3H, s), of 2.21 (3H, s), 3,76-a 3.87 (4H, m)4,00 (2H, DD, J=4, 11 Hz), 4,39 (1H, d, J=13 Hz), and 4.75 (1H, d, J=13 Hz), for 6.81-6,91 (2H, m), 7,40-of 7.48 (2H, m), 8,23 (1H, s).

Example 12: the sodium salt of 2-(((4-((2,2-dim the Teal-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 103

(12a) 1-oxide 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-2,3-dimethylpyridine

Formula 104

To dimethylsulfoxide (30 ml) solution of (2,2-dimethyl-1,3-dioxane-5-yl)methanol (3,27 g of 22.4 mmol), obtained separately as well as at the stage of (11a) in example 11, was added at room temperature sodium hydride in oil (837 mg, of 20.9 mmol content 60%). The mixture was stirred at room temperature for 15 minutes in nitrogen atmosphere. To the mixture was added 1-oxide 4-chloro-2,3-dimethylpyridine (3.03 g, 19.2 mmol) and the mixture was stirred at 60°C for 3 hours and 20 minutes. After cooling to room temperature the reaction mixture was concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 250 g, eluting solvent: ethyl acetate ethyl acetate/methanol=10/1) to obtain specified in the connection header (3,84 g, output: 74,8%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,31 (3H, s)of 1.35 (3H, s), 2.00 in a 2.12 (1H, m), 2,12 (3H, s), of 2.33 (3H, s), 3,74 (2H, DD, J=6, 12 Hz), of 3.97 (2H, DD, J=4, 12 Hz), 4,08 (2H, d, J=7 Hz), 6,94 (1H, d, J=7 Hz), with 8.05 (1H, d, J=7 Hz).

(12b) (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol

Formula 105

1-Oxide 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-2,3-dimethylpyridine (3,84 g, 14.4 mmol)obtained in which Tadei (12a), was mixed with acetic anhydride (50 ml, 530 mmol). The mixture was stirred at 85°C. for 1.5 hours. After cooling to room temperature the reaction mixture was concentrated. To the obtained residue were added methanol (50 ml) and 5N aqueous sodium hydroxide solution (20 ml, 100 mmol) and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated and the residue was distributed between water and ethyl acetate. The organic layer is washed with 1N aqueous sodium hydroxide solution twice, dried over anhydrous sodium sulfate, filtered and concentrated to obtain specified in the connection header (2,97 g, output: 77,2%) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,31 (3H, s)of 1.34 (3H, s), 2,03 with 2.14 (1H, m), 2,10 (3H, s), 3,76 (2H, DD, J=6, 12 Hz), 3,98 (2H, DD, J=4, 12 Hz), 4,10 (2H, d, J=7 Hz), 4,51 (2H, d, J=5 Hz), equal to 4.97 (1H, t, J=5 Hz), 6,95 (1H, d, J=6 Hz), by 8.22 (1H, d, J=6 Hz).

(12c) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 106

To a solution of (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol (1,03 g of 3.85 mmol)obtained in stage (12b), and triethylamine (1.07 ml, 7.7 mmol) in dichloromethane (digidrirovanny) (20 ml) was added dropwise methanesulfonanilide (447 μl, 5,78 mmol) at a temperature of from 1 to 4°C for 10 minutes in nitrogen atmosphere. The mixture is stirred for 1 hour and 25 minutes in the same conditions. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was mixed with 2-mercaptobenzimidazole (586 mg, 3.9 mmol) and the mixture was stirred in methanol (20 ml) at room temperature for 2 hours and 40 minutes. Was added to the reaction mixture NH silica gel (15 g), after which the mixture was concentrated. The residue was subjected to chromatography on a column of silica gel (NH silica gel: 20 g, eluting solvent: heptane/ethyl acetate=1/1, 1/3, ethyl acetate) to obtain the mixture specified in the title compound and 2-mercaptobenzimidazole. The mixture still was purified by chromatography on a column of silica gel (silica gel: 30 g, eluting solvent: heptane/ethyl acetate=50/50, 25/75, ethyl acetate) to obtain specified in the connection header (771 mg, yield: 50,1%) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,31 (3H, s)of 1.34 (3H, s), 2,03-to 2.15 (1H, m), of 2.20 (3H, s), 3,76 (2H, DD, J=6, 12 Hz), 3,98 (2H, DD, J=4, 12 Hz), 4,11 (2H, d, J=7 Hz), and 4.68 (2H, s), 6,97 (1H, d, J=6 Hz), 7,06-7,14 (2H, m,), 7,35-7,51 (2H, W), 8,23 (1H, d, J=6 Hz), 12,60 (1H, Shir. C).

(12d) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 107

To a solution in a mixture of toluene (45 ml)-methanol (5 ml) of 2-(((4-((2,2-dimethy who -1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (766 mg, 1.92 mmol)obtained in stage (12c), was added dropwise a solution of 3-chloroperbenzoic acid (459 mg, 1,73 mmol content 65%) in a mixture of toluene (0.5 ml)-methanol (0.5 ml) at -65°C for 5 minutes in a nitrogen atmosphere. The mixture was stirred at the same conditions for one hour and 20 minutes. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and chloroform (three times). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 30 g, eluting solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing specified in the title compound were collected, concentrated with obtaining specified in the title compound (688 mg, yield: 86.2 per cent) as a light brown foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,31 (3H, s)of 1.34 (3H, s), 2,03-2,12 (1H, m), 2,12 (3H, in), 3.75 (2H, DD, J=6, 12 Hz), 3,98 (2H, DD, J=4, 12 Hz), 4,11 (2H, d, J=7 Hz), 4,69 (1H, d, J=14 Hz), 4,78 (1H, d, J=14 Hz), 6,97 (1H, d, J=6 Hz), 7.24 to 7,34 (2H, m), EUR 7.57-of 7.70 (2H, m), to 8.20 (1H, d, J=6 Hz).

(12e) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 108

To an ethanol (10 ml) solution of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil-1H-benzimidazole (688 mg, of 1.66 mmol)obtained in stage (12d)was added at room temperature, 1N aqueous sodium hydroxide solution (1.65 ml of 1.66 mmol in concentration 1,004 M) and the mixture was concentrated. The residue was subjected to azeotropic distillation with ethanol twice. After the residue is suspended in diethyl ether, the mixture was subjected to ultrasound treatment and allowed to stand. Then remove the supernatant. Described washing process was repeated twice and the residue was dried under reduced pressure to obtain specified in the title compound (701 mg, yield: 96,5%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, s)of 1.34 (3H, s), 2,04 and 2.13 (1H, m), 2,17 (3H, s), 3.72 points-3,81 (2H, m), 3,98 (2H, DD, J=4, 12 Hz), 4,10 (2H, d, J=7 Hz), to 4.38 (1H, d, J=13 Hz), was 4.76 (1H, d, J=13 Hz), 6,80-6,89 (2H, m,), 6,94 (1H, d, J=5 Hz), 7,39-7,47 (2H, m), of 8.28 (1H, d, J=5 Hz).

Example 13: sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 109

(13a) 5,9-dioxaspiro[3,5]non-7-ylmethanol

Formula 110

A mixture of 2-(hydroxymethyl)-1,3-propane diol (5,58 g, for 52.6 mmol), cyclobutanone (3,69 g, for 52.6 mmol), monohydrate p-toluensulfonate acid (550 mg, 2.89 mmol) and benzene (92,9 ml) was heated in a round bottom flask, equipped with reflux condenser and the office of the Dean-stark for 8 hours 35 minutes. On the Les cooling the reaction mixture to room temperature, was added thereto triethylamine (1 ml) and the resulting mixture was concentrated. The residue was purified by chromatography on a column of silica gel (silica gel: 300 g, eluting solvent: heptane, heptane/ethyl acetate=1/1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated. The residue was dissolved in diethyl ether, after which the solution was concentrated to obtain specified in the connection header (between 6.08 g, output: 73,1%) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,58 by 1.68 (2H, m), 1,68-to 1.77 (1H, m), 2,07-of 2.16 (4H, m), 3,32-3,39 (2H, m), 3,52 (2H, DD, J=7, 12 Hz), of 3.78 (2H, DD, J=4, 12 Hz), 4,56 (1H, t, J=5 Hz).

(13b) 1-oxide 4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)-2,3,5-trimethylpyridine

Formula 111

To dimethylsulfoxide (20 ml) solution of 5.9-dioxaspiro[3,5]non-7-ylmethanol (2.20 g, a 13.9 mmol)obtained in stage (13a), was added at room temperature sodium hydride in oil (524 mg, 13,1 mmol content 60%). The mixture was stirred at room temperature for 45 minutes under nitrogen atmosphere. To the mixture was added 1-oxide 4-chloro-2,3,5-trimethylpyridine (sample C, was 1.94 g, 11.3 mmol)obtained in stage (11d) in example 11, and the mixture was stirred at 60°C for 2 hours and 50 minutes. After cooling to room temperature the reaction mixture was concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 100 g, eluting solvent: heptane, heptane/acilac is tat=1/1, ethyl acetate ethyl acetate/methanol=20/1) to obtain the specified title compound (1.97 g, yield: 59,4%) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,60-1,71 (2H, m), 2,07-2,22 (5H, m), 2,12 (3H, s)of 2.16 (3H, s), is 2.30 (3H, s), 3,74 (2H, DD, J=7, 12 Hz), of 3.78 (2H, d, J=7 Hz), of 3.94 (2H, DD, J=4, 12 Hz), with 8.05 (1H, s).

(13c) (4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methanol

Formula 112

1-Oxide 4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)-2,3,5-trimethylpyridine (1.97 g, 6,72 mmol)obtained in stage (13b), was mixed with acetic anhydride (20 ml, 212 mmol). The mixture was stirred at 85°C. for 1.5 hours. After cooling to room temperature the reaction mixture was concentrated. To the obtained residue were added methanol (20 ml) and 5N aqueous sodium hydroxide solution (20 ml, 100 mmol) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated and the residue was distributed between water and ethyl acetate. The organic layer is washed with 2N aqueous sodium hydroxide solution, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain specified in the connection header (1,69 g, output: 85,7%) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,60-1,70 (2H, m), 2,08 was 2.25 (5H, m)to 2.18 (6H, in), 3.75 (2H, DD, J=6, 12 Hz), 3,83 (2H, d, J=7 Hz), 3,95 (2H, DD, J=4, 12 Hz), 4,50 (2H, d, J=5 Hz), equal to 4.97 (1H, t, J=5 Hz), 8,14 (1H, s).

<> (13d) 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 113

To a solution of (4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methanol (450 mg, 1.53 mmol)obtained in stage (13c), and triethylamine (427 μl, of 3.06 mmol) in a mixture of dichloromethane (digidrirovanny) (15 ml) and tetrahydrofuran (5 ml) was added dropwise methanesulfonanilide (178 μl, 2.3 mmol) at a temperature of from 1 to 4°C for 10 minutes in nitrogen atmosphere. The mixture was stirred for 50 minutes in the same conditions. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was mixed with 2-mercaptobenzimidazole (235 mg, 1.56 mmol) and the mixture was stirred in methanol (20 ml) at room temperature for 2 hours and 30 minutes. Was added to the reaction mixture NH silica gel (15 g), after which it was concentrated. The residue was subjected to chromatography on a column of silica gel (silica gel: 30 g, eluting solvent: heptane/ethyl acetate=42/58, 22/78, ethyl acetate) to obtain the specified title compound (507 mg, yield: 77,9%) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,60-1,71 (2H, m), 2,08-2,22 (5H, m), are 2.19 (3H, s), of 2.28 (3H, s), 3,76 (H, DD, J=6, 12 Hz), a-3.84 (2H, d, J=7 Hz), 3,95 (2H, DD, J=4, 12 Hz), 4,69 (2H, s), 7,06-7,19 (2H, m), 7,37-7,56 (2H, W), 8,18 (1H, s), 12,60 (1H, Sirs).

(13e) 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 114

To a solution in a mixture of toluene (20 ml)-methanol (2 ml) of 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (499 mg, at 1.17 mmol)obtained in stage (13d), was added dropwise a solution of 3-chloroperbenzoic acid (280 mg, 1.05 mmol content 65%) in a mixture of toluene (1 ml)-methanol (1 ml) at -65°C for 5 minutes in a nitrogen atmosphere. The mixture was stirred at the same conditions for 55 minutes. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 20 g, eluting solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated. To the obtained residue was added diethyl ether, after which the mixture was concentrated to obtain specified in the title compound (445 mg, yield: 86,1%) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,60-1,70 (2H, m, 2.06 to of 2.23 (5H, m), and 2.14 (3H, s)to 2.18 (3H, s), 3,67-3,82 (4H, m), 3,93 (2H, DD, J=4, 12 Hz), 4,70 (1H, d, J=14 Hz), 4,78 (1H, d, J=14 Hz), 7,25-7,34 (2H, m), 7,58-of 7.70 (2H, m), 8,18 (1H, s).

(13f) sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 115

To an ethanol (10 ml) solution of 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (445 mg, 1.01 mmol)obtained in stage (13e), was added at room temperature, 1N aqueous sodium hydroxide solution (of 1.01 ml, 1.01 mmol in concentration 1,004 M) and the mixture was concentrated. The residue was subjected to azeotropic distillation with ethanol twice. After the residue is suspended in diethyl ether, the mixture was subjected to ultrasonic treatment and then concentrated to obtain specified in the title compound (420 mg, yield: 89,7%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,58 is 1.70 (2H, m), 2,07 was 2.25 (5H, m), 2,19 (6H, s), 3,68-3,82 (4H, m), of 3.94 (2H, DD, J=4, 12 Hz), 4,34-to 4.41 (1H, m), 4,70-of 4.77 (1H, m), 6,82-6,89 (2H, m), 7,41-7,47 (2H, m), by 8.22 (1H, s).

Example 14: sodium salt of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 116

(14a) 1-oxide 4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-2,3-dimethylpyridine

Formula 117

To dimethylsulfoxide (48 ml) solution of ((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methanol (4,87 g, and 39.7 mmol) was added at room temperature sodium hydride in oil (1.73 g, 39,6 mmol content 55%). To the mixture was added 1-oxide 4-chloro-2,3-dimethylpyridine (4.8 g, to 30.5 mmol) and the resulting mixture was stirred at 60°C for 2 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (10.5 g, yield: 136%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.40 (3H, s)of 1.45 (3H, s), of 2.21 (3H, s)to 2.54 (3H, s), 3,93 (1H, DD, J=6, 8 Hz), 4,01 (1H, DD, J=5, 10 Hz), 4,07 (1H, DD, J=5, 10 Hz), 4,17 (1H, DD, J=6, 8 Hz), 4,48 (1H, quintet, J=6 Hz), of 6.65 (1H, d, J=8 Hz), 8,15 (1H, d, J=8 Hz).

(14b) (4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methanol

Formula 118

1-Oxide 4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-2,3-dimethylpyridine (10.5 g, 41.5 mmol)obtained in stage (14a), was mixed with acetic anhydride (20 ml). The mixture was stirred at 80°C for one hour. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. To the obtained residue was added methanol (40 ml) and 5 N. aqueous sodium hydroxide solution (20 is l) and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue was distributed between saturated salt solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (3.77 g, output: 41,9%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.41 (3H, s)of 1.46 (3H, s), is 2.05 (3H, s), of 3.95 (1H, DD, J=6, 8 Hz), a 4.03 (1H, DD, J=5, 10 Hz), 4,11 (1H, DD, J=5, 10 Hz), 4,18 (1H, DD, J=6, 8 Hz), 4,49 (1H, quintet, J=6 Hz)and 4.65 (2H, s), 4,84 (1H, Sirs), of 6.71 (1H, d, J=8 Hz), 8,29 (1H, d, J=8 Hz).

(14c) 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 119

To a solution of (4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methanol (3.77 g, 14.9 mmol)obtained in stage (14b), and triethylamine (4,15 ml, to 29.8 mmol) in tetrahydrofuran (digidrirovanny) (50 ml) was added dropwise methanesulfonanilide (1.73 ml of 22.4 mmol) while cooling on ice in a nitrogen atmosphere and the mixture was stirred for 1.5 hours at the same conditions. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and drove the solvent. From the resulting mod is a (3.8 g, crude yield: 77%) took part, component 1.2 g (3.62 mmol), was dissolved in ethanol (20 ml), was added to the obtained solution of 2-mercaptobenzimidazole (598 mg, 3,98 mmol) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (580 mg, yield: 41,6%) as a pale yellow foam.

1H NMR (400 MHz, CD3OD) δ ppm; of 1.37 (3H, s)of 1.39 (3H, s), of 2.33 (3H, s), of 3.94 (1H, DD, J=6, 8 Hz), 4,19 (1H, DD, J=6, 8 Hz), 4,32 (1H, DD, J=5, 11 Hz), and 4.40 (1H, DD, J=4, 11 Hz), to 4.52-4,60 (1H, m), and 4.75 (2H, s), 7,25 (2H, DD, J=3, 6 Hz), 7,39 (1H, d, J=8 Hz), 7,53 (2H, DD, J=3, 6 Hz), of 8.47 (1H, d, J=8 Hz).

(14d) 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 120

To a solution in a mixture of toluene-methanol (10:1) (22 ml) of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (580 mg, 1.5 mmol)obtained in stage (14c), was added dropwise a solution of 3-chloroperbenzoic acid (353 mg, of 1.33 mmol content 65%) in a mixture of toluene-methanol (10:1) (11 ml) at te is the temperature from -50 to -60°C for 5 minutes in a nitrogen atmosphere. The mixture was stirred at the same conditions for 3 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (330 mg, yield: 54,8%) as a pale yellow foam. The compound obtained was converted into the sodium salt as described below and determined its structure.

(14e) sodium salt of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 121

To an ethanol (6 ml) solution of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (330 mg, 822 mmol)obtained in stage (14d)was added at room temperature, 1N aqueous sodium hydroxide solution (822 μl, 822 mmol) and the mixture was stirred for 30 minutes. After the mixture was concentrated and to the residue was added diethyl ether, and the mixture was subjected to ultrasonic processing. The obtained solid substance was collected by filtration in a nitrogen atmosphere. The solid was dried under reduced pressure to obtain specified in the title compound (314 mg, you who od: 90,2%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.30 (3H, s)of 1.36 (3H, s), are 2.19 (3H, s), 3,80 (1H, DD, J=6, 8 Hz), was 4.02-to 4.14 (3H, m), 4,37 (1H, d, J=14 Hz), 4,43 (1H, quintet, J=6 Hz), 4,79 (1H, d, J=14 Hz), 6,83 (2H, DD, J=3, 6 Hz), 6,93 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), at 8.36 (1H, d, J=6 Hz).

(14f) Optical isomer (short retention time) of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 122

To a solution of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (84 mg, 218 μmol)obtained in stage (14c), in a mixture of toluene (digidrirovanny)(0.5 ml) and water (1,73 µl, with 95.9 mmol) was added L+(-)-diethyltartrate (32,9 μl, 192 mmol) and the mixture was stirred at 50°C for 15 minutes in nitrogen atmosphere. To the reaction mixture was added isopropoxide titanium(IV) (28,3 µl, with 95.9 mmol) and the mixture was stirred for another hour. After the reaction mixture was cooled on ice, added to it N,N-diisopropylethylamine (33,4 μl, 192 mmol) was added dropwise in a nitrogen atmosphere hydroperoxide cumene (121 μl, 654 mmol content 80%) and the mixture was stirred at a temperature of from 0°C. to room temperature for 17 hours. Was added to the reaction mixture, a saturated aqueous solution of sodium bicarbonate and was extracted with her with ethyl acetate. The organic layer was dried over anhydrous sulfate Natrii drove away the solvent under reduced pressure. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (45 mg, yield: 51,4%) as a pale yellow foam. The compound obtained was converted into the sodium salt as described below and determined its structure.

(14g) sodium salt of an optical isomer (short retention time) of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 123

To an ethanol (3 ml) solution of the optical isomer (short retention time) of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (45 mg, 112 μmol)obtained in stage (14f)was added at room temperature, 1N aqueous solution of sodium hydroxide (112 μl, 112 mmol) and the mixture was stirred for 30 minutes. After the mixture was concentrated and to the residue was added diethyl ether, and the mixture was subjected to ultrasonic processing. The obtained solid substance was collected by filtration in a nitrogen atmosphere. The solid was dried under reduced pressure to obtain specified in the title compound (22 mg, yield: 46,4%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.30 (3H, s)of 1.35 (3H, s), are 2.19 (3H, s), 3,80(1H, DD, J=6, 8 Hz), was 4.02-to 4.14 (3H, m), 4,37 (1H, d, J=13 Hz), 4,42 (1H, quintet, J=5 Hz), 4,79 (1H, d, J=13 Hz), 6,83 (2H, DD, J=3, 6 Hz), 6,93 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.3 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 31.6 minutes, diastereomeric excess: 92%de.

(14h) optical isomer (long retention time) of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 124

To a solution of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (170 mg, 441 mmol)obtained in stage (14c), in a mixture of toluene (digidrirovanny)(1.0 ml) and water (3,5 μl, 194 mmol) was added D-(-)-diethyltartrate (66,6 μl, 389 mmol) and the mixture was stirred at 50°C for 15 minutes in nitrogen atmosphere. To the reaction mixture was added isopropoxide titanium(IV) (57,3 μl, 194 mmol) and the resulting mixture was stirred for another hour. After the reaction mixture was cooled on ice, added to it N,N-diisopropylethylamine (67,6 μl, 389 mmol) and the resulting mixture was added dropwise a hydroperoxide cumene (245 μl, of 1.32 mmol content 80%) in nitrogen atmosphere and the mixture was stirred at a temperature from 0°C up to matnog temperature for 17 hours. Was added to the reaction mixture, a saturated aqueous solution of sodium bicarbonate and was extracted with her with ethyl acetate. The organic layer was dried over sodium sulfate and drove away the solvent under reduced pressure. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (104 mg, yield: 58,7%) as a pale yellow foam. The compound obtained was converted into the sodium salt as described below and determined its structure.

(14i) sodium salt of the optical isomer (long retention time) of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 125

To an ethanol (3 ml) solution of the optical isomer (long retention time) of 2-(((4-(((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (104 mg, 259 μmol)obtained in stage (14h), was added at room temperature, 1N aqueous sodium hydroxide solution (259 μl, 259 μmol) and the mixture was stirred for 30 minutes. After the mixture was concentrated and to the residue was added diethyl ether, and the mixture was subjected to ultrasonic processing. The obtained solid substance was collected by filtration in a nitrogen atmosphere. Solid is emesto was dried under reduced pressure to obtain specified in the title compound (99 mg, yield: 90%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.30 (3H, s)of 1.35 (3H, s), are 2.19 (3H, s), 3,80 (1H, DD, J=6, 8 Hz), was 4.02-to 4.14 (3H, m), 4,37 (1H, d, J=13 Hz), 4,42 (1H, quintet, J=5 Hz), 4,79 (1H, d, J=13 Hz), 6,82-to 6.88 (2H, m), 6,93 (1H, d, J=6 Hz), 7,38-7,46 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.3 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 35.9 minutes, diastereomeric excess: 89%de.

Example 15: the sodium salt of the optical isomer (long retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 126

(15a) optical isomer (long retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 127

A suspension of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (250 mg, 0,626 mmol), obtained as described in stages (1a)-(1e) of example 1, and D-(-)-diethyltartrate (47 μl, 0,275 mmol) in a mixture of toluene (digidrirovanny) (2,8 ml)-water (1,4 μl, mmol 0,0777) was stirred at 50°C for 30 minutes in nitrogen atmosphere. Added to a mixture of toluene (digidrirovanny) (1.2 ml) ipermediali the mixture for 30 minutes in the same conditions. Added isopropoxide titanium(IV) (37 μl, 0.125 mmol) and the resulting mixture was stirred for one hour at the same conditions. After cooling the mixture to room temperature and added N,N-diisopropylethylamine (35 μl, 0,201 mmol) the resulting mixture was stirred for 10 minutes while cooling on ice. Once to the mixture was added dropwise a hydroperoxide cumene (360 μl, of 1.95 mmol content 80%) at an internal temperature of 0 ° to 2°C for 5 minutes, the mixture was stirred at an internal temperature of 0 ° to 3°C for 4 hours. After stopping the reaction with saturated aqueous sodium bicarbonate to the reaction mixture were added ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, saturated salt solution, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol=gradient 1/0-4/1). The desired fractions were concentrated to obtain specified in the title compound (203 mg, contents: 88,9%, yield: 69.4%) are in the form of a light brown foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; is 0.69 (3H, s), is 1.11 (3H, s)to 2.13 (3H, s), 3,48 (2H, d, J=11 Hz), to 3.58 (2H, d, J=11 Hz), 4,08 (2H, d, J=4 Hz), 4,69 (1H, d, J=14 Hz), of 4.77 (1H, d, J=14 Hz), a 4.83 (1H, t, J=4 Hz), 6,97 (1H, d, J=6 Hz), 7.24 to to 7.32 (2H, m) 7,58-to 7.67 (2H, m)to 8.20 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.) (0,46 ϕ×25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 18.9 minutes, enantiomeric excess: 87%ee.

(15b) the sodium salt of the optical isomer (long retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 128

To an ethanol (3 ml) solution of the optical isomer (long retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (200 mg, contents: 88,9%, 0,428 mmol)obtained in stage (15a)was added at room temperature, 1N aqueous sodium hydroxide solution (428 μl, 0,428 mmol) and the mixture was stirred for 10 minutes in those same conditions. After the mixture was concentrated and to the residue was added ethanol, and the mixture was subjected to azeotropic distillation and suspended in diethyl ether. The suspension was subjected to ultrasonic treatment and allowed to stand. Remove the supernatant and then the residue was dried to obtain specified in the title compound (145 mg, 77,4% yield) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.68 (3H, s), is 1.11 (3H, s), 2,17 (3H, s), 3,48 (2H, d,J=11 Hz), to 3.58 (2H, d, J=11 Hz), 4,06 (2H, d, J=4 Hz), 4,37 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), a 4.83 (1H, t, J=4 Hz), for 6.81-to 6.88 (2H, m), 6,93 (1H, d, J=6 Hz), 7,39-7,46 (2H, m), of 8.25 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.) (0,46 ϕ×25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 18.4 minutes, enantiomeric excess: 87,4%ee,

specific rotation: αD25,5=-123,83(c=0.5, EtOH).

Example 16: the sodium salt of the optical isomer (short retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 129

(16a) optical isomer (short retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 130

A suspension of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (250 mg, 0,626 mmol), obtained as described in stages (1a)-(1e) of example 1, and L-(+)-diethyltartrate (47 μl, 0,274 mmol) in a mixture of toluene (digidrirovanny)(4,0 ml)-water (1,4 μl, mmol 0,0777) was stirred at 50°C for 10 minutes in nitrogen atmosphere. Added isopropoxide titanium(IV) (37 μl, 0.125 mmol) and the resulting mixture was stirred for one hour at the same conditions. After the OHL is born of the mixture to room temperature, was added thereto, N,N-diisopropylethylamine (35 μl, 0,201 mmol) and the resulting mixture was stirred for 15 minutes under cooling on ice. Once to the mixture was added dropwise a hydroperoxide cumene (360 μl, of 1.95 mmol content 80%) at an internal temperature of 0 ° to 2°C for 5 minutes, the mixture was stirred at an internal temperature of 0 ° to 3°C for 4 hours. After stopping the reaction with saturated aqueous sodium bicarbonate to the reaction mixture were added ethyl acetate and water. The separated aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water and saturated saline, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol=gradient 1/0-4/1). The desired fractions were concentrated to obtain specified in the title compound (208 mg, contents: 90,9%, output: 72,7%) as a light brown foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; is 0.69 (3H, s), is 1.11 (3H, s)to 2.13 (3H, s), 3,48 (2H, d, J=11 Hz), to 3.58 (2H, d, J=11 Hz), 4,08 (2H, d, J=4 Hz), and 4.68 (1H, d, J=14 Hz), of 4.77 (1H, d, J=14 Hz), a 4.83 (1H, t, J=4 Hz), 6,97 (1H, d, J=6 Hz), 7,22-to 7.32 (2H, m), EUR 7.57-to 7.68 (2H, m), to 8.20 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(The results of the analysis is (a): retention time: 15.2 minutes enantiomeric excess: 84,2%ee.

(16b) sodium salt of an optical isomer (short retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 131

To an ethanol (3 ml) solution of the optical isomer (short retention time) of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (206 mg, contents: 90,9%, 0,451 mmol)obtained in stage (16a)was added at room temperature, 1N aqueous sodium hydroxide solution (451 μl, 0,451 mmol) and the mixture was stirred for 15 minutes in those same conditions. After the reaction mixture was concentrated and to the residue was added ethanol, and the mixture was subjected to azeotropic distillation and suspended in diethyl ether. The suspension was subjected to ultrasonic treatment and gave her to stand up. Remove the supernatant and then the residue was dried to obtain specified in the title compound (126 mg, and 63.9% yield) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; is 0.69 (3H, s), is 1.11 (3H, s), 2,17 (3H, s), 3,48 (2H, d, J=11 Hz), to 3.58 (2H, d, J=11 Hz), 4,06 (2H, d, J=4 Hz), 4,36 (1H, d, J=13 Hz), to 4.81 (1H, d, J=13 Hz), a 4.83 (1H, t, J=4 Hz), 6,79-6,87 (2H, m), 6,93 (1H, d, J=6 Hz), 7,37-7,46 (2H, m), of 8.25 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/et is Nol=4/1 (about./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 15.8 minutes, enantiomeric excess: 85,0%ee,

specific rotation: αD26,3=+116,94(c=0.5, EtOH).

Example 17: the sodium salt of the optical isomer (short retention time) of sodium salt of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 132

(17a) optical isomer (short retention time) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 133

To a solution of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole (300 mg, 679 mmol), separately obtained as described in stage (10a)-(10d) of example 10, a mixture of toluene (digidrirovanny)(1.5 ml)-water (1,47 µl of 81.5 mmol) was added L-(+)-diethyltartrate (51,2 μl, 299 μmol) and the mixture was stirred at 50°C for 5 minutes in a nitrogen atmosphere. Added isopropoxide titanium(IV) (40.1 per µl, 136 mmol) and the resulting mixture was stirred for another hour. After the mixture was cooled on ice and added N,N-diisopropylethylamine (37,8 μl, 217 mmol) was added dropwise hydroperoxide cumene (376 μl, 2.04 mmol content 80%) in nitrogen atmosphere, the mixture was stirred at which the temperature from 0°C. to room temperature for 5.5 hours. After adding a saturated aqueous solution of sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and drove away the solvent under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (256 mg, yield: 82,4%) as a pale yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.85 (2H, t, J=5 Hz), a 2.01 (2H, t, J=5 Hz), 2,12-of 2.21 (1H, m), of 2.21 (3H, s), 3,66-of 3.78 (4H, m), 3,86 (2H, DD, J=4, 12 Hz), 4,06-4,24 (4H, m), with 4.64 (1H, d, J=14 Hz), a 4.83 (1H, d, J=14 Hz), 6,77 (1H, d, J=6 Hz), 7,26-7,40 (2H, m), 7,50-7,80 (2H, W), 8,32 (1H, d, J=6 Hz).

(17b) sodium salt of an optical isomer (short retention time) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 134

To an ethanol (10 ml) solution of the optical isomer (short retention time) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole (256 mg, 599 mmol)obtained in stage (17a)was added at room temperature, 1N aqueous sodium hydroxide solution (559 µl, 559 μmol) and the mixture was stirred for 30 minutes. After the mixture was concentrated and to the residue was added diethyl ether, and the mixture was subjected to ul raspokoval processing. The obtained solid substance was collected by filtration in a nitrogen atmosphere. The solid was dried under reduced pressure to obtain specified in the title compound (147 mg, yield: 54,8%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,74 is 1.86 (4H, m), 2,08-of 2.23 (1H, m)to 2.18 (3H, s), 3,50-3,62 (4H, m), 3,76-a-3.84 (2H, m), was 4.02 (2H, DD, J=4, 12 Hz), 4,11 (2H, d, J=7 Hz), 4,37 (1H, d, J=13 Hz), to 4.81 (1H, d, J=13 Hz), 6,80-6,92 (2H, m), 6,93 (1H, d, J=6 Hz), 7,38-of 7.48 (2H, m), of 8.25 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 29,6 minutes, enantiomeric excess: 85,8%ee.

Example 18: the sodium salt of the optical isomer (long retention time) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 135

(18a) optical isomer (long retention time) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 136

To a solution of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)thio)-1H-benzimidazole (150 mg, 340 μmol), separately obtained as described in stage (10a)-(10d) of example 10, a mixture of olwal (digidrirovanny)(1.5 ml)-water (1,35 μl, 74,8 mmol) was added D-(-)-diethyltartrate (51,2 μl, 299 μmol) and the mixture was stirred at 50°C for 5 minutes in a nitrogen atmosphere. Added isopropoxide titanium(IV) (44,2 μl, 150 μmol) and the resulting mixture was stirred for another hour. After the mixture was cooled on ice, was added N,N-diisopropylethylamine (39,1 μl, 224 mmol) was added dropwise hydroperoxide cumene (188 μl, of 1.02 mmol content 80%) in nitrogen atmosphere, the mixture was stirred at a temperature of from 0°C. to room temperature for 7 hours. After the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and drove away the solvent under reduced pressure. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (68 mg, yield: 43,7%) as a pale yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.85 (2H, t, J=5 Hz), a 2.01 (2H, t, J=5 Hz), 2,12-2,22 (1H, m), of 2.21 (3H, s), 3,66-of 3.78 (4H, m)to 3.89 (2H, DD, J=4, 12 Hz), 4,06-4.26 deaths (4H, m)and 4.65 (1H, d, J=14 Hz), a 4.83 (1H, d, J=14 Hz), 6,79 (1H, d, J=6 Hz), 7,28-7,42 (2H, m), 7,50-7,80 (2H, W), with 8.33 (1H, d, J=6 Hz).

(18b) the sodium salt of the optical isomer (long retention time) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)IU the mud)sulfinil)-1H-benzimidazole

Formula 137

To an ethanol (10 ml) solution of the optical isomer (long retention time) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole (68 mg, 149 μmol)obtained in stage (18a)was added at room temperature, 1N aqueous sodium hydroxide solution (149 μl, 149 μmol) and the mixture was stirred for 30 minutes. After the mixture was concentrated and to the residue was added diethyl ether, and the mixture was subjected to ultrasonic processing. The obtained solid substance was collected by filtration in a nitrogen atmosphere. The solid was dried under reduced pressure to obtain specified in the title compound (36 mg, yield: 54,8%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; or 1.77 (2H, t, J=6 Hz)and 1.83 (2H, t, J=6 Hz), 2,08-of 2.23 (1H, m), 2,17 (3H, s), 3,50-3,60 (4H, m), 3,76-3,86 (2H, m), was 4.02 (2H, DD, J=4, 12 Hz), 4,11 (2H, d, J=7 Hz), 4,37 (1H, d, J=13 Hz), to 4.81 (1H, d, J=13 Hz), 6,85 (2H, DD, J=3, 6 Hz), 6,93 (1H, d, J=6 Hz), 7,42 (1H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 36.7 minutes, enantiomeric excess: 36%ee.

Example 19: the sodium salt of the optical isomer (long hold the project) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 138

(19a) optical isomer (long retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 139

A solution of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (444 mg, 1.07 mmol), separately obtained in the same way as described in the stages (11a)-(11g) of example 11, and D-(-)-diethyltartrate (80,6 μl, 0,471 mmol) in a mixture of toluene (digidrirovanny) (2,22 ml)-water (2,3 μl, mmol 0,128) was stirred at 50°C for 10 minutes in nitrogen atmosphere. Added isopropoxide titanium(IV) (63,2 μl, 0,214 mmol) and the resulting mixture was stirred for another hour at the same conditions. After the mixture was cooled to room temperature and was added N,N-diisopropylethylamine (59,6 μl, 0,342 mmol), the mixture was cooled to 0°C. After adding dropwise the hydroperoxide cumene (611 μl, of 3.31 mmol content 80%) for 5 minutes at 0-2°C and the mixture was stirred at 0-7°C for 3 hours 35 minutes in nitrogen atmosphere. After the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on Colo is ke silica gel (NH silica gel: 20g, eluting solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated to obtain specified in the title compound (388 mg, yield: 84.4 per cent) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, s)of 1.36 (3H, s), 2,02 and 2.13 (1H, m)of 2.16 (3H, s), measuring 2.20 (3H, s), 3,74-of 3.85 (4H, m)4,00 (2H, DD, J=4, 12 Hz), 4,70 (1H, d, J=14 Hz), 4,79 (1H, d, J=14 Hz), 7,26-7,34 (2H, m), to 7.59-7,70 (2H, m), 8,18 (1H, s).

HPLC:

(Conditions) column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=1/1 (vol./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 17.8 minutes, enantiomeric excess: 94,4%ee.

(19b) the sodium salt of the optical isomer (long retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 140

To an ethanol (10 ml) solution of the optical isomer (long retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (379 mg, 0,882 mmol)obtained in stage (19a)was added at room temperature, 1N aqueous sodium hydroxide solution (878 μl, 0,882 mmol in concentration 1,004 M) and the mixture was concentrated. The residue was subjected to azeotropic distillation with ethanol. the STATCOM suspended in diethyl ether, was subjected to ultrasonic treatment and then concentrated to obtain specified in the title compound (365 mg, yield: 91,7%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,03 and 2.13 (1H, m), of 2.20 (3H, s), of 2.21 (3H, s), 3,76-3,88 (4H, m)4,00 (2H, DD, J=4, 12 Hz), to 4.38 (1H, d, J=13 Hz), and 4.75 (1H, d, J=13 Hz), for 6.81-of 6.90 (2H, m), 7,40-7,47 (2H, m), 8,23 (1H, s).

HPLC:

(Conditions) column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=1/1 (vol./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 17.0 minutes, enantiomeric excess: 94,9%ee,

specific rotation: αD27,4=-76,29(c=0.5, EtOH).

Example 20: the sodium salt of the optical isomer (short retention time) of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 141

(20a) optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 142

A solution of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (591 mg, 1,43 mmol), separately obtained in the same way as described in the stages (11a)-(11g) of example 11, and L-(+)-diethyltartrate (108 μl, 0,629 mmol) in a mixture of toluene (dehydrated the bath) (2,96 ml)-water (3,09 μl, 0,172 mmol) was stirred at 50°C for 5 minutes in a nitrogen atmosphere. Added isopropoxide titanium(IV) (84,4 μl, 0,286 mmol) and the resulting mixture was stirred for one hour at the same conditions. After the mixture was cooled to room temperature and was added N,N-diisopropylethylamine (79,7 μl, 0,458 mmol), the mixture was cooled to 0°C. After adding dropwise the hydroperoxide cumene (816 μl, was 4.42 mmol content 80%) for 10 minutes at 0-1°C and the mixture was stirred for 3 hours and 10 minutes in the same conditions. After the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 20 g, eluting solvent: dichloromethane, dichloromethane/methanol=20/1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated to obtain specified in the title compound (498 mg, yield: 81,1%) as a colourless foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, s)of 1.36 (3H, s), 2,02-2,12 (1H, m)of 2.16 (3H, s), measuring 2.20 (3H, s), 3,74-a-3.84 (4H, m)4,00 (2H, DD, J=4, 12 Hz), 4,70 (1H, d, J=14 Hz), 4,79 (1H, d, J=14 Hz), 7,26-7,34 (2H, m), 7,58-7,70 (2H, m), 8,18 (1H, s).

HPLC:

(Conditions) column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 is m), eluent: hexane/ethanol=1/1 (vol./vol.), flow rate: 0.6 ml/min, detection: UV (254 nm).

(Results of analysis): retention time: 14.6 minutes, enantiomeric excess: 95,4%ee.

(20b) the sodium salt of the optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 143

To an ethanol (10 ml) solution of the optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (480 mg, 1.12 mmol)obtained in stage (20a)was added at room temperature, 1N aqueous sodium hydroxide solution (of 1.12 ml, 1.12 mmol in concentration 1,004 M) and the mixture was concentrated. The residue was subjected to azeotropic distillation with ethanol. The residue is suspended in diethyl ether, the suspension was subjected to ultrasonic treatment and then concentrated to obtain specified in the title compound (447 mg, yield: 88,4%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,03 with 2.14 (1H, m), of 2.21 (6H, s), 3,76-a 3.87 (4H, m)4,00 (2H, DD, J=4, 12 Hz), 4,39 (1H, d, J=13 Hz), 4,74 (1H, d, J=13 Hz), 6,82-of 6.90 (2H, m), 7,40-of 7.48 (2H, m), 8,23 (1H, s).

HPLC:

(Conditions) column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries Ltd.)(0,46 ϕ×25 cm), eluent: hexane/ethanol=1/1 (vol./vol.), flow rate: 0.6 ml/which in detection: UV (254 nm).

(Results of analysis): retention time: 14.4 minutes, enantiomeric excess: 95,4%ee.

Example 21: sodium salt of 2-(((4-(6,10-dioxaspiro[4,5]Dec-8-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 144

(21a) 6,10-dioxaspiro[4,5]Dec-8-ylmethanol

Formula 145

Repeating the same procedure as in stage (9d) of example 9 using 2-(hydroxymethyl)-1,3-propandiol and Cyclopentanone, obtaining specified in the title compound (2.8 g, yield: 87%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,51-of 1.55 (1H, m), 1,62-1,72 (4H, m), 1,83-of 1.94 (4H, m), of 3.73-of 3.80 (4H, m)to 3.99 (2H, DD, J=4, 12 Hz).

(21b) sodium salt of 2-(((4-(6,10-dioxaspiro [4,5]Dec-8-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 146

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using 6,10-dioxaspiro[4,5]Dec-8-ylmethanol obtained in stage (21a), with specified title compound (180 mg, total yield: 8,1%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,52-of 1.62 (4H, m), 1,75 is 1.86 (4H, m), 2,08-of 2.16 (1H, m), 2,17 (3H, s), 3.72 points-is 3.82 (2H, m), 3,92-was 4.02 (2H, m), 4.09 to (2H, d, J=7 Hz), 4,36 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), 6,83 (2H, DD, J=3, 6 Hz), 6,93 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), of 8.27 (1H, d, J=6 Hz).

Example 22: nutrie the traveler salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 147

Repeating the same procedure as in stage (21a) and (21b) of example 21, using 2-(hydroxymethyl)-1,3-propandiol and CYCLOBUTANE, obtaining specified in the title compound (265 mg, total yield: 6,2%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,58 is 1.70 (2H, m), 2.06 to 2,22 (5H, m), 2,17 (3H, s), 3,66 is 3.76 (2H, m), 3,86-of 3.96 (2H, m), 4,07 (2H, d, J=6 Hz), 4,37 (1H, d, J=13 Hz), 4,79 (1H, d, J=13 Hz), 6,85 (2H, DD, J=3, 6 Hz), 6,93 (1H, d, J=6 Hz), 7,44 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 23: sodium salt of 2-(((4-((2,2-diethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 148

(23a) (2,2-diethyl-1,3-dioxane-5-yl)methanol

Formula 149

Repeating the same procedure as in stage (9d) of example 9 using 2-(hydroxymethyl)-1,3-propandiol and 3-pentanone, obtaining specified in the title compound (1.5 g, yield: 46%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.87 (3H, t, J=7 Hz), to 0.88 (3H, t, J=7 Hz), 1,46-is 1.51 (1H, m)to 1.70 (2H, q, J=7 Hz), of 1.78 (2H, q, J=7 Hz), 3,70-3,88 (4H, m), 3.96 points-4,10 (2H, m).

(23b) sodium salt of 2-(((4-((2,2-diethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 150

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using the (2,2-diethyl-1,3-dioxane-5-yl)methanol obtained at the stage of (23a), with specified title compound (164 mg, total yield: 9,7%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,80 (6H, t, J=7 Hz), and 1.63 (2H, q, J=7 Hz), to 1.70 (2H, q, J=7 Hz), 2,01-2,12 (1H, m)to 2.18 (3H, s), 3,50-of 3.80 (2H, m), 3,94-4,20 (2H, m), of 4.12 (2H, d, J=7 Hz), 4,37 (1H, d, J=13 Hz), 4,81 (1H, d, J=13 Hz), at 6.84 (2H, DD, J=3, 6 Hz), 6,92 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 24: sodium salt of 2-(((3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 151

(24a) (1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol

Formula 152

A mixture of pentaerythritol (15 g, 110 mmol), triethylorthoformate (20.2 ml, 110 mmol) and monohydrate p-toluensulfonate acid (947 mg, 5.5 mmol) was stirred at 100°C for 30 minutes. The temperature of the mixture was then raised to 130°C and the mixture was stirred for 30 minutes. To the reaction mixture were added triethylamine (of 1.53 ml, 11 mmol) and the resulting mixture was concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (8.5 g, yield: 48,2%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm; about 1.47 (3H, s), of 3.46 (2H, d, J=4 Hz), was 4.02 (6H, s).

(24b) 1-oxide, 2,3-dimethyl-4-((1-methyl,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridine

Formula 153

To dimethylsulfoxide solution (30 ml) (1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol (4.5 g, 28.1 mmol)obtained in stage (24a)was added at room temperature sodium hydride in oil (1.29 g, 29.5 mmol content 55%). To the mixture was added 1-oxide 4-chloro-2,3-dimethylpyridine (3,99 g, to 25.3 mmol) and the mixture was stirred at 60°C for 3 hours. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol) to obtain specified in the connection header (7,46 g, yield: 81%) as a yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; a 1.50 (3H, s), measuring 2.20 (3H, s)to 2.54 (3H, s), of 3.77 (2H, s), 4,15 (6H, s), 6,53 (1H, d, J=6 Hz), 8,14 (1H, d, J=6 Hz).

(24c) (3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methanol

Formula 154

A mixture of 1-oxide, 2,3-dimethyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridine (6.4 g, of 22.8 mmol)obtained in stage (24b), and acetic anhydride (20 ml) was stirred at 80°C for one hour. After cooling to room temperature the reaction mixture was concentrated under reduced pressure. To the obtained residue were added methanol (30 ml) and 5N aqueous sodium hydroxide solution (10 ml) and the mixture is displaced is ivali at room temperature for 15 hours. The reaction mixture was concentrated and to the residue was added ethyl acetate. The mixture was washed with saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained residue (solid) was washed with diethyl ether and collected by filtration to obtain specified in the title compound (1.5 g, yield: 28,7%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm; a 1.50 (3H, s)2,04 (3H, s), 3,80 (2H, s), 4,15 (6H, s)and 4.65 (2H, s), of 4.77 (1H, Sirs), 6,60 (1H, d, J=6 Hz), 8,29 (1H, d, J=6 Hz).

(24d) 2-(((3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 155

To tertrahydrofuran ring solution (digidrirovanny, 20 ml) of (3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methanol (0,37 g of 1.32 mmol)obtained in stage (24c), and triethylamine (0,368 ml of 2.64 mmol) was added dropwise methanesulfonanilide (153 μl, to 1.98 mmol) in a nitrogen atmosphere at 1-4°C. the resulting mixture was stirred at the same conditions for 1.5 hours. Then to the mixture was added 2-mercaptobenzimidazole (204 mg, of 1.52 mmol) and the mixture was stirred at room temperature for 18 hours. After kontsentrirovanija the reaction mixture the residue was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/methanol to obtain specified in the title compound (230 mg, output: 40,9%) as a pale yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; a 1.50 (3H, s), and 2.27 (3H, s), 3,80 (2H, s), 4,15 (6H, s), to 4.38 (2H, s), of 6.65 (1H, d, J=6 Hz), 7,15-7,21 (2H, m), of 7.36-to 7.68 (2H, m), 8,35 (1H, d, J=6 Hz).

(24e) 2-(((3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 156

To a solution (20 ml) of 2-(((3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methyl)thio)-1H-benzimidazole (230 mg, 556 mmol)obtained in stage (24d), in a mixture of toluene-methanol (10:1) was added dropwise a solution (5 ml) of 3-chloroperbenzoic acid (133 mg, 0.5 mmol content 65%) a mixture of toluene-methanol (10:1) in nitrogen atmosphere at a temperature of -50 to -60°C for 5 minutes and the mixture was stirred at the same conditions for 3.5 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol) to obtain the specified title compound (143 mg, yield: 59,9%) as a pale yellow foam.

1H NMR (400 MHz, CDCl3) δ ppm; a 1.50 (3H, s), 2,17 (3H, s), 3,76 (2H, s), 4,12 (6H, s), 4,63 (1H, d, J=14 Hz), 4,79 (1H, d, J=14 Hz), 6,60 (1H, d, J=6 Hz), 7,30-7,38 (2H, m), 7,47-7,56 (1H, m), 7,6-7,86 (1H, m), 8,30 (1H, d, J=6 Hz), 11,05 (1H, Sirs).

(24f) sodium salt of 2-(((3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 157

To an ethanol (5 ml) solution of 2-(((3-methyl-4-((1-methyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (143 mg, 333 μmol)obtained in stage (24e), was added at room temperature, 1N aqueous sodium hydroxide solution (333 μl, 333 μmol) and the mixture was stirred for 0.5 hours. The mixture was concentrated and the residue was dissolved in ethanol. Then to the solution was added diethyl ether, and subjected to ultrasound treatment. The obtained solid was filtered under nitrogen atmosphere and dried under reduced pressure to obtain specified in the title compound (150 mg, yield: 100%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s), are 2.19 (3H, s)to 3.92 (2H, s), Android 4.04 (6H, s), 4,35 (1H, d, J=15 Hz), 4,82 (1H, d, J=15 Hz), PC 6.82-6.87 in (3H, m), 7,42 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 25: sodium salt of 2-(((4-(1,5-dioxaspiro[5,5]undec-3-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 158

(25a) 1.5-dioxaspiro[5,5]undec-3-ylmethanol

Formula 159

Repeating the same procedure as in stage (1a) the use of the 1, using 2-(hydroxymethyl)-1,3-propandiol and cyclohexanone, to obtain specified in the connection header (of 2.26 g, yield: 65%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,37 of 1.46 (2H, m), 1,47-of 1.57 (4H, m), by 1.68 to 1.76 (2H, m), 1.77 in-1,90 (3H, m), 3,74-3,81 (4H, m), was 4.02 (2H, DD, J=4, 12 Hz).

(25b) sodium salt of 2-(((4-(1,5-dioxaspiro[5,5]undec-3-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 160

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using 1.5-dioxaspiro[5,5]undec-3-ylmethanol obtained in stage (25a), with specified title compound (125 mg, total yield: 8,4%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.30 to 1.48 (6H, m), 1,64 to 1.76 (4H, m), 2.06 to to 2.15 (1H, m)to 2.18 (3H, s), of 3.73-3,82 (2H, m), 3.96 points-a 4.03 (2H, m), 4,11 (2H, d, J=7 Hz), of 4.44 (1H, d, J=13 Hz), to 4.81 (1H, d, J=13 Hz), 6.90 to-6,98 (3H, m), 7,47 (2H, DD, J=3, 6 Hz), of 8.25 (1H, d, J=6 Hz).

Example 26: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)oxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 161

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using 2,2-dimethyl-1,3-dioxane-5-ol obtained in stage (9a), with specified title compound (530 mg, total yield: 18%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ is d; of 1.34 (3H, s)of 1.40 (3H, s), of 2.23 (3H, s), with 3.79 (2H, DD, J=3, 12 Hz), of 4.12 (2H, DD, J=3, 12 Hz), 4,39 (1H, d, J=13 Hz), 4,46-of 4.54 (1H, m), 4,82 (1H, d, J=13 Hz), 6,86-6,94 (3H, m), 7,42-of 7.48 (2H, m), 8,23 (1H, d, J=6 Hz).

Example 27: sodium salt of 2-(((4-(1,4-dioxaspiro[4,5]Dec-8-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 162

(27a) 1,4-dioxaspiro[4,5]Decan-8-ol

Formula 163

Repeating the same method as in example 9a, using 1,4-monoethylether 1,4-cyclohexandione, obtaining specified in the title compound (2.6 g, yield: 79%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,53-1,71 (4H, m), 1.77 in-of 1.93 (4H, m), 3.75 to of 3.85 (1H, m), 3,93-of 3.96 (4H, m).

(27b) sodium salt of 2-(((4-(1,4-dioxaspiro[4,5]Dec-8-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 164

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using 1,4-dioxaspiro[4,5]Decan-8-ol, obtained in stage (27a), with specified title compound (230 mg, total yield: 7,3%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,57-of 1.94 (8H, m), 2,17 (3H, s), a 3.87 (4H, s), 4,35 (1H, d, J=13 Hz), 4,62-and 4.68 (1H, m), 4,79 (1H, d, J=13 Hz), at 6.84 (2H, DD, J=3, 6 Hz), 6,97 (1H, d, J=6 Hz), the 7.43 (2H, DD, J=3, 6 Hz), 8,23 (1H, d, J=6 Hz).

Example 28: sodium salt of 2-(((4-(2-(2,2-dimethyl-1,3-dioxane-5-yl)ethoxy)-3-methylpyridin-2-the l)methyl)sulfinil)-1H-benzimidazole

Formula 165

(28a) of 2-(2,2-dimethyl-1,3-dioxane-5-yl)ethanol

Formula 166

To acetone (30 ml) solution of 2-(hydroxymethyl)butane-1,4-diol (3.4 g, 28.3 mmol)obtained by the method described in J.Med.Chem., 30(9), 1636-1642 (1987), was added at room temperature monohydrate p-toluensulfonate acid (244 mg, and 2.83 mmol) and the mixture was stirred for 15 hours. To the reaction mixture were added triethylamine (394 μl, and 2.83 mmol) and the mixture was concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (1.0 g, yield: 22%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.42 (6H, s), 1,54-of 1.62 (2H, m), 1,90-2,02 (1H, m), to 3.58 is 3.76 (4H, m), of 3.94 (2H, DD, J=4, 12 Hz).

(28b) sodium salt of 2-(((4-(2-(2,2-dimethyl-1,dioxan-5-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 167

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6 using 2-(2,2-dimethyl-1,3-dioxane-5-yl)ethanol obtained in stage (28a), with specified title compound (58 mg, total yield: 2.0%) in the form of a light yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.28 (3H, s)of 1.34 (3H, s), 1,64-1,72 (2H, m), 1,83-of 1.92 (1H, m)of 2.16 (3H, s), 3,54-3,63 (2H, m), 3,83 (2H, DD, J=4, 16 Hz), 4,06 (2H, the, J=6 Hz), to 4.38 (1H, d, J=13 Hz), and 4.75 (1H, d, J=13 Hz), 6,85 (2H, DD, J=3, 6 Hz), 6,91 (1H, d, J=6 Hz), the 7.43 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 29: sodium salt of 2-(((4-((1-ethyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 168

(29a) (1-ethyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol

Formula 169

Repeating the same method as in example 24, using triethylenediamine (15 g, 110 mmol), to obtain the specified title compound (14 g, yield: 73%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.96 (3H, t, J=7 Hz), 1,71 (2H, q, J=7 Hz), 3,47 (2H, d, J=4 Hz), was 4.02 (6H, s).

(29b) sodium salt of 2-(((4-((1-ethyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 170

Repeating the same method as in example 24 using (1-ethyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol obtained in stage (29a), with specified title compound (145 mg, total yield: 1.7%) in the form of a light yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,86 (3H, t, J=7 Hz), 1,59 (2H, q, J=7 Hz), 2,19 (3H, s)to 3.92 (2H, s), Android 4.04 (6H, s), 4,35 (1H, d, J=13 Hz), 4,82 (1H, d, J=13 Hz), 6,80-of 6.90 (3H, m), 7,42 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 30: sodium salt of 2-(((3-methyl-4-(2-(2-methyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-is)methyl)sulfinil)-1H-benzimidazole

Formula 171

(30a) 2-(2-methyl-1,3-dioxane-2-yl)ethanol

Formula 172

Repeating the same procedure as in the stages (8a) and (8b) of example 8, using ethylacetoacetate, obtaining specified in the title compound (5.4 g, total yield: 49%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; for 1.49 (3H, s), at 1.91 (2H, t, J=6 Hz), 1,90-to 2.40 (2H, m)of 3.00 (1H, t, J=6 Hz), 3,80-4,06 (6H, m).

(30b) sodium salt of 2-(((3-methyl-4-(2-(2-methyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 173

Repeating the same procedure as in the stages (8c)-(8g) of example 8, using 2-(2-methyl-1,3-dioxane-2-yl)ethanol obtained in stage (30a), with specified title compound (113 mg, total yield: 2,5%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.39 (3H, s), 1,46 is 1.70 (2H, m), 2,12-2,19 (2H, m)of 2.16 (3H, s), 3,76-are 3.90 (4H, m), 4,11 (2H, t, J=7 Hz), to 4.38 (1H, d, J=13 Hz), 4,79 (1H, d, J=13 Hz), 6,82-6,92 (2H, m), 6.90 to (1H, d, J=6 Hz), 7,38-of 7.48 (2H, m), 8,24 (1H, d, J=6 Hz).

Example 31: sodium salt of 2-(((4-(2-(5,9-dioxaspiro[3,5]non-7-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 174

Repeating the same method as in example 28, using cyclobutanone, obtaining specified in the title compound (80 mg, total output is: 0,8%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,57-to 1.67 (4H, m), 1,86 is 1.96 (1H, m), 2.05 is-to 2.18 (4H, m)of 2.16 (3H, s), 3,40-3,50 (2H, m), 3,82 (2H, DD, J=4, 11 Hz), 4,06 (2H, t, J=7 Hz), to 4.38 (1H, d, J=13 Hz), 4,78 (1H, d, J=13 Hz), 6,85 (2H,, DD, J=3, 6 Hz), make 6.90 (1H, d, J=6 Hz), the 7.43 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 32: sodium salt of 2-(((4-(1,3-dioxane-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 175

(32a) 2-((benzyloxy)methyl)-1,3-dioxane

Formula 176

A mixture of benzyloxyacetaldehyde (3.6 g, 24 mmol), 1,3-propane diol (5,2 ml, 72 mmol), triethylorthoformate (4 ml, 24 mmol) and monohydrate p-toluensulfonate acid (414 mg, 2.45 mmol) was stirred at room temperature for 17 hours. To the reaction mixture were added triethylamine (669 μl, 4.8 mmol) and the mixture was concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (2.9 g, yield: 58%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,22 (1H, t, J=7 Hz), 2,04-of 2.20 (1H, m), 3,49 (2H, d, J=4 Hz), 3,80 (2H, dt, J=2, 12 Hz), 4,14 (2H, DD, J=5, 11 Hz), 4,59 (2H, s), was 4.76 (1H, t, J=4 Hz), 7,20-7,42 (5H, m).

(32b) 1,3-dioxane-2-ylmethanol

Formula 177

To methanol (50 ml) solution of 2-((benzyloxy)methyl)-1,3-dioxane (2.9 g, a 13.9 mmol)obtained in stage (32a), was added 10% PA is lady on carbon (760 mg) and the mixture was stirred at room temperature in a hydrogen atmosphere for 2 days. The reaction mixture was filtered through celite and washed with ethyl acetate. Then the solvent of the filtrate drove under reduced pressure to get crude specified in the title compound (860 mg, yield: 52,4%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,34-of 1.44 (1H, m)to 1.86 (1H, t, J=5 Hz), 2,04-of 2.20 (1H, m), of 3.60 (2H, DD, J=4, 6 Hz), 3,82 (2H, dt, J=2, 12 Hz), is 4.15 (2H, DD, J=5, 11 Hz), of 4.66 (1H, t, J=5 Hz).

(32c) sodium salt of 2-(((4-(1,3-dioxane-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 178

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using 1,3-dioxane-2-ylmethanol obtained in stage (32b), with specified title compound (148 mg, total yield: 10%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,33-of 1.42 (1H, m), 1,84-to 1.98 (1H, m)of 2.16 (3H, s), 3,74-a-3.84 (2H, m), 3,98-4,08 (4H, m), 4,37 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), to 4.92 (1H, t, J=4 Hz), at 6.84 (2H, DD, J=3, 6 Hz), 6,91 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), of 8.25 (1H, d, J=6 Hz).

Example 33: sodium salt of 2-(((3-methyl-4-((2-methyl-1,3-dioxane-2-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 179

(33a) (2-methyl-1,3-dioxane-2-yl)methanol

Formula 180

Repeating the same procedure as in the stages (32a) and (32b) of example 32, using 1-benzyloxy-2-ol is panon, obtaining specified in the title compound (1.51 g, total yield: 37%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; was 1.43 (3H, s), 1,92-of 2.20 (2H, m), 3,53 (2H, d, J=6 Hz), 3,86-4,06 (4H, m).

(33b) sodium salt of 2-(((3-methyl-4-((2-methyl-1,3-dioxane-2-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 181

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using (2-methyl-1,3-dioxane-2-yl)methanol obtained in stage (33a), with specified title compound (220 mg, total yield: 8,6%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; a 1.45 (3H, s), 1,57-to 1.67 (2H, m), are 2.19 (3H, s), 3,88 (4H, t, J=6 Hz), 4.09 to (2H, s), 4,36 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), at 6.84 (2H, DD, J=3, 6 Hz), 6,98 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), of 8.25 (1H, d, J=6 Hz).

Example 34: sodium salt of 2-(((3-methyl-4-(2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 182

(34a) 2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethanol

Formula 183

Repeating the same procedure as in the stages (8a) and (8b) of example 8, using ethylacetoacetate and 2,2-dimethyl-1,3-propandiol, obtaining specified in the connection header (7,3 g, total yield: 55%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,81 (3H, s)of 1.16 (3H, s)of 1.44 (3H, s) of 1.93 (2H, t, J=6 Hz), 3,06 (1H, t, J=6 Hz), 3,42 (2H, d, J=12 Hz), 3,68 (2H, d, J=12 Hz), 3,82-to 3.92 (2H, m).

(34b) sodium salt of 2-(((3-methyl-4-(2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 184

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6 using 2-(2,5,5-trimethyl-1,3-dioxane-2-yl)ethanol obtained in stage (34a), with specified title compound (196 mg, total yield: 7,2%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; or 0.83 (3H, s)to 0.94 (3H, s)to 1.38 (3H, s), 2,12-of 2.20 (2H, m)of 2.16 (3H, s), 3,39 (2H, d, J=11 Hz), 3,51 (2H, d, J=11 Hz), of 4.13 (2H, t, J=3 Hz), to 4.38 (1H, d, J=13 Hz), 4,78 (1H, d, J=13 Hz), at 6.84 (2H, DD, J=3, 6 Hz), to 6.88 (1H, d, J=6 Hz), 7,42 (2H, DD, J=3, 6 Hz), of 8.25 (1H, d, J=6 Hz).

Example 35: sodium salt of 2-(((3-methyl-4-(2-(6-methyl-5,7-dioxaspiro[2,5]Oct-6-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 185

(35a) of 2-(6-methyl-5,7-dioxaspiro[2,5]Oct-6-yl)ethanol

Formula 186

Repeating the same procedure as in the stages (8a) and (8b) of example 8, using ethylacetoacetate and 1,1-bis(hydroxymethylpropane), with specified title compound (2.9 g, total yield: 36%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,38 (2H, t, J=6 Hz), and 0.62 (2H, t, J=6 Hz), and 1.54 (3H, s)a 1.96 (2H, t, J=6 Hz), 3.04 from (1H, t, J=6 Hz), and 3.16 (2H, d, J=12 Hz), 384-3,92 (2H, m)4,20 (2H, d, J=12 Hz).

(35b) sodium salt of 2-(((3-methyl-4-(2-(6-methyl-5,7-dioxaspiro[2,5]Oct-6-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 187

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6 using 2-(6-methyl-5,7-dioxaspiro[2,5]Oct-6-yl)ethanol obtained in stage (35a), with specified title compound (163 mg, total yield: 5,5%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,34-of 0.50 (4H, m)of 1.46 (3H, s)to 2.18 (3H, s), 2,22 (2H, t, J=6 Hz), of 3.45 (2H, d, J=11 Hz), 3,76 (2H, d, J=11 Hz), of 4.16 (2H, t, J=7 Hz), 4,39 (1H, d, J=13 Hz), 4,78 (1H, d, J=13 Hz), 6,86 (2H, DD, J=3, 6 Hz), 6,91 (1H, d, J=6 Hz), the 7.43 (2H, DD, J=3, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 36: sodium salt of 2-(((4-(2-(2-(methoxymethyl)-1,3-dioxane-2-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 188

(36a) of 2-(2-(methoxymethyl)-1,3-dioxane-2-yl)ethanol

Formula 189

Repeating the same procedure as in the stages (8a) and (8b) of example 8, using methyl 4-methoxyacetate, obtaining specified in the title compound (4.5 g, total yield: 34%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,58 is 1.70 (1H, m), 1,80 is 1.96 (1H, m), 2,03 (2H, t, J=6 Hz), 2,86 (1H, t, J=6 Hz), 3.43 points (3H, s), 3,62 (2H, s), 3,76-a-3.84 (2H, m), 3,90-Android 4.04 (4H, m).

(36b) sodium salt of 2-(((4-(2-(2-(methoxymethyl)-1,3-dioxane-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 190

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6 using 2-(2-(methoxymethyl)-1,3-dioxane-2-yl)ethanol obtained in stage (36a), with specified title compound (304 mg, total yield: 7,0%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,50-1,70 (2H, m)of 2.16 (3H, s), measuring 2.20 (2H, t, J=7 Hz), 3,29 (3H, s), 3,52 (2H, s), 3,80-are 3.90 (4H, m), 4.09 to (2H, t, J=7 Hz), 4,37 (1H, d, J=13 Hz), 4,78 (1H, d, J=13 Hz), 6,83 (2H, DD, J=3, 6 Hz), 6.87 in (1H, d, J=6 Hz), 7,41 (2H, DD, J=3, 6 Hz), of 8.25 (1H, d, J=6 Hz).

Example 37: sodium salt of 2-(((4-((1-cyclopropyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 191

(37a) of the hydrochloride of methylcyclohexanecarboxylic

Formula 192

In a solvent mixture of cyclopropanecarbonitrile (15 g, 224 mmol), diethyl ether (200 ml) and methanol (10 ml) was introduced under cooling on ice, hydrogen chloride, and the mixture was stirred at room temperature for 17 hours. After the reaction mixture is kept under reduced pressure, the solvent, to the residue was added diethyl ether and the formed solid substance was collected by filtration in a nitrogen atmosphere to obtain specified in the title compound (29 g, output: 95,5%) as a pale yellow firm is about substance.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,10-1,24 (4H, m), 2.06 to of 2.38 (1H, m)to 3.99 (3H, s), and 10.8 (1H, Sirs), 12,1 (1H, Sirs).

(37b) (trimethoxysilyl)cyclopropane

Formula 193

To n-hexane solution (75 ml) of the hydrochloride of methylcyclohexanecarboxylic a (17.4 g, 128 mmol)obtained in stage (37a), was added methanol (25,9 ml, 640 mmol) and the mixture was stirred at room temperature for 3.5 days. Precipitated precipitated ammonium chloride was removed by filtration and the filtrate was concentrated under reduced pressure to get crude specified in the title compound (7.5 g, yield: 40%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,47-of 0.56 (2H, m), 0.58, up-to 0.67 (2H, m), 0,84-0,94 (1H, m), 3,29 (9H, s).

(37c) (1-cyclopropyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol

Formula 194

Repeating the same procedure as in stage (24a) of example 24 using (trimethoxysilyl)cyclopropane (9,8 g, and 67.2 mmol)obtained in stage (37b), with specified title compound (11.9 g, yield: 95%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,42-0,52 (2H, m), of 0.58 and 0.68 (2H, m), 0,86-to 0.96 (1H, m), of 3.46 (2H, s), was 4.02 (6H, s).

(37d) sodium salt of 2-(((4-((1-cyclopropyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 195

Repeating the same procedure as in the stages (24b)-(24f) of example 24, using (1-cyclopropyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol obtained in stage (37 ° C), with specified title compound (147 mg, total yield: 3,2%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,35-0,54 (4H, m), 1,06-of 1.18 (1H, m), are 2.19 (3H, s)to 3.92 (2H, s), Android 4.04 (6H, s), to 4.38 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), 6,82-6,94 (3H, m), 7,44 (2H, DD, J=3, 6 Hz), of 8.27 (1H, d, J=6 Hz).

Example 38: sodium salt of 2-(((4-((1-cyclobutyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 196

(38a) (1-cyclobutyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol

Formula 197

Repeating the same procedure as in the stages (37a)-(37c) of example 37, using cyclobutanecarbonitrile, obtaining specified in the title compound (15 g, total yield: 51%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,70-of 2.30 (7H, m), 3,47 (2H, s), a 4.03 (6H, s).

(38b) sodium salt of 2-(((4-((1-cyclobutyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 198

Repeating the same procedure as in the stages (24b)-(24f) of example 24, using (1-cyclobutyl-2,6,7-dioxabicyclo[2,2,2]Oct-4-yl)methanol obtained in stage (38), obtaining specified in the title compound (56 mg, 2,3%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,60 is 1.86 (4H, m), 1,94-2,07 (3H, m), are 2.19 (3H, s)to 3.92 (2H, s), of 4.05 (6H, s)to 4.33 (1H, d, J=13 Hz), a 4.83 (1H, d, J=13 Hz), 6,78-of 6.90 (3H, m), 7,38-of 7.48 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 39: sodium salt of 2-(((4-(2-(2-ethyl-1,3-dioxolane-2-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 199

(39a) ethyl (2-ethyl-1,3-dioxolane-2-yl)acetate

Formula 200

A mixture of ethyl 3-oxopentanoate (5 g, to 34.7 mmol), ethylene glycol (10.8 g, 174 mmol), triethylorthoformate (5,14 g, to 34.7 mmol) and monohydrate p-toluensulfonate acid (598 mg, 3.14 mmol) was stirred at room temperature overnight. To the reaction mixture was added heptane and ethyl acetate to obtain a solution, which is washed with water. The organic layer was washed with saturated saline, dried over magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in heptane and subjected to chromatography on a column of NH silica gel (eluting solvent: n-heptane/ethyl acetate=1/0→10/1) to obtain specified in the connection header (3,85 g, output: 58,9%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.94 (3H, t, J=8 Hz), of 1.27 (3H, t, J=7 Hz)and 1.83 (2H, q, J=8 Hz), 2,65 (2H, s), 3,89 of 4.3 (4H, m)to 4.15 (2H, q, J=7 Hz).

(39b) 2-(2-ethyl-1,3-dioxolane-2-yl)ethanol

Formula 201

To tetrahydrofuranate (50 ml) suspension of sociallyengaged (800 mg, 21.1 mmol) was added while cooling on ice, ethyl (2-ethyl-1,3-dioxolane-2-yl)acetate (3,85 g of 20.5 mmol). The mixture was stirred at room temperature for 1 hour and 30 minutes and cooled on ice. Then to the mixture were added successively water (0.8 ml), 15% aqueous sodium hydroxide solution (0.8 ml) and water (2.4 ml) under cooling on ice. Was added to a mixture of magnesium sulfate and the resulting mixture was filtered through silica gel. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (2.76 g, 92.1 per cent) in the form of oil.

1H NMR (400 MHz, CDCl3) δ ppm; to 0.92 (3H, t, J=8 Hz), 1,68 (2H, q, J=8 Hz), of 1.93 (2H, t, J=5 Hz), 2,82 (1H, t, J=5 Hz), 3,76 (2H, q, J=5 Hz), 3.96 points-of 4.05 (4H, m).

(39c) sodium salt of 2-(((3-methyl-4-(2-(2-propyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 202

Repeating the same procedure as in the stages (3c)-(3h) of example 3, using 1-oxide 4-chloro-2,3-dimethylpyridine and 2-(2-ethyl-1,3-dioxolane-2-yl)ethanol, obtaining specified in the title compound (422 mg, 6 stages: 25%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.87 (3H, t, J=8 Hz), 1,64 (2H, q, J=8 Hz), 2,07 (2H, t, J=7 Hz), 2,17 3H, C)3,85-of 3.94 (4H, m), 4.09 to (2H, t, J=7 Hz), and 4.40 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), 6,83-of 6.90 (2H, m)6,94 (1H, d, J=6 Hz), 7,41-7,49 (2H, m), of 8.27 (1H, d, J=6 Hz).

Example 40: sodium salt of 2-(((4-((2-ethyl-1,3-dioxolane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 203

(40a) 2-oxobutanoate

Formula 204

A mixture of 1-rambutan-2-it (10 g, 66,2 mmol), potassium acetate (7.8 g, 79,4 mmol) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 5 days. Was added to the reaction mixture water and the resulting mixture was extracted with diethyl ether twice. The organic layers were combined and washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (8,24 g) in the form of a mixture with N,N-dimethylformamide.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.10 (3H, t, J=7 Hz), and 2.14 (3H, s), a 2.45 (2H, q, J=7 Hz), of 4.66 (2H, s).

(40b) (2-ethyl-1,3-dioxolane-2-yl)acetate

Formula 205

A mixture of 2-oxobutyrate (4 g)obtained in stage (40a), ethylene glycol (of 7.82 g, 126 mmol), triethylorthoformate (of 3.73 g of 25.2 mmol) and monohydrate p-toluensulfonate acid (479 mg, 2,52 mmol) was stirred at room temperature overnight. To the reaction mixture were added water and et is latitat and distributed mixture. The aqueous layer was again extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of heptane-ethyl acetate and subjected to chromatography on a column of NH silica gel (eluting solvent: n-heptane/ethyl acetate=20/1→5/1) to obtain the specified title compound (1.4 g, output 2 stages: 25%).

1H NMR (400 MHz, CDCl3) δ ppm; of 0.93 (3H, t, J=7 Hz), at 1.73 (2H, q, J=7 Hz), is 2.09 (3H, s), 3.96 points-a 4.03 (4H, m), a 4.03 (2H, s).

(40c) (2-ethyl-1,3-dioxolane-2-yl)methanol

Formula 206

A mixture of methyl (2-ethyl-1,3-dioxolane-2-yl) acetate (1.39 g, 7,94 mmol), potassium carbonate (2,19 g, 15.9 mmol), tetrahydrofuran (20 ml) and water (10 ml) was stirred at room temperature for 6 hours and 50 minutes. The reaction mixture was concentrated under reduced pressure, to the residue was added ethyl acetate and the mixture was subjected to filtration through a pillow from the NH silica gel. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (0.75 g, 71,5%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.93 (3H, t, J=8 Hz), 1,71 (2H, q, J=8 Hz), 1,95-2,03 (1H, W), of 3.53 (2H, d, J=4 Hz), 3.96 points-4,06 (4H, m).

(40d) sodium salt of 2-(((4-((2-ethyl-1,3-dioxolane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 207

Repeating the same procedure as in the stages (3c)-(3h) of example 3, using 1-oxide 4-chloro-2,3-dimethylpyridine and (2-ethyl-1,3-dioxolane-2-yl)methanol, obtaining specified in the title compound (355 mg, 6 stages: 9,6%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.87 (3H, t, J=8 Hz), total 1.74 (2H, q, J=8 Hz), 2,17 (3H, s), a 3.87-4.00 points (4H, m), of 3.96 (2H, s), 4,39 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), 6,84-6,91 (2H, m)6,94 (1H, d, J=6 Hz), 7,41-7,47 (2H, m), of 8.25 (1H, d, J=6 Hz).

Example 41: sodium salt of 2-(((4-(2-(2-ethyl-1,3-dioxolane-2-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-4-methyl-1H-benzimidazole

Formula 208

Repeating the same procedure as in stage (39c), using 1-oxide 4-chloro-2,3-dimethylpyridine and 2-(2-ethyl-1,3-dioxolane-2-yl)ethanol, except that used 4-methyl-1H-benzimidazole-2-thiol obtained in stage (54a) of example 54, instead of 2-mercaptobenzimidazole on stage (39c) of example 39, obtaining specified in the title compound (490 mg, 6 furlongs: 27%) in powder form.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.85 (3H, t, J=8 Hz), of 1.62 (2H, q, J=8 Hz), was 2.05 (2H, t, J=7 Hz), 2,17 (3H, s), a 2.45 (3H, s), 3,83-to 3.92 (4H, m), 4,07 (2H, t, J=7 Hz), 4,42 (1H, d, J=13 Hz), and 4.75 (1H, d, J=13 Hz), 6,63 (1H, d, J=7 Hz), was 6.73 (1H, t, J=7 Hz), 6,91 (1H, d, J=6 Hz), 7,24 (1H, d, J=8 Hz), of 8.25 (1H, d, J=6 Hz).

Example 42: sodium salt of 2-(((4-((2-ethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Forms the La 209

(42a) 2-oxobutanoate

Formula 210

A mixture of 1-rambutan-2-she (7.2 g, while 47.7 mmol), sodium benzoate (7,56 g, a 52.4 mmol) and N,N-dimethylformamide (72 ml) was stirred at room temperature for 3 hours and 45 minutes. Was added to the reaction mixture of diethyl ether and the mixture was washed with water and saturated saline solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain specified in the title compound (9.5 g, quantitative) as a light brown oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.13 (3H, t, J=7 Hz), of 2.54 (2H, q, J=7 Hz), 4,89 (2H, s), 7,43-7,49 (2H, m), EUR 7.57 to 7.62 (1H, m), 8,08-to 8.12 (2H, m).

(42b) (2-ethyl-1,3-dioxane-2-yl)methylbenzoate

Formula 211

A mixture of 2-oxobutanoate (5 g, 26 mmol), 1,3-propane diol (5,94 g, 78 mmol), triethylorthoformate (3,85 g, 26 mmol) and monohydrate p-toluensulfonate acid (448 mg, 2.36 mmol) was stirred at room temperature for 3 hours and 30 minutes. Was added to the reaction mixture ethyl acetate and diethyl ether and the mixture was washed with water and saturated salt solution. The organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of heptane/ethyl acetate (12/1) and subjected to chromatography on to what the PMC with NH silica gel (eluting solvent: n-heptane/ethyl acetate=12/1) to obtain specified in the connection header (4,33 g, 65,5%) as a colourless viscous oil.

1H NMR (400 MHz, CDCl3) δ ppm; and 0.98 (3H, t, J=8 Hz), 1,63-to 1.87 (2H, m), 1,89 (2H, q, J=8 Hz), 3,90-4,06 (4H, m)to 4.52 (2H, s), 7,42-of 7.48 (2H, m), 7,54-of 7.60 (1H, m), 8,06-of 8.09 (2H, m).

(42c)(2-ethyl-1,3-dioxane-2-yl)methanol

Formula 212

A mixture of (2-ethyl-1,3-dioxane-2-yl)methylbenzoate (4,33 g, 17.3 mmol), potassium carbonate (4,95 g, or 35.9 mmol), tetrahydrofuran (50 ml) and water (20 ml) was stirred at room temperature for 11 hours. Added 5N aqueous sodium hydroxide solution (2 ml) and the mixture was stirred at room temperature for 7 hours, then was added methanol (50 ml) and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added ethyl acetate was removed by filtration of the insoluble material. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of heptane/ethyl acetate and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=2/1→1/1) to obtain the specified title compound (2.35 g, of 92.9%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; to 0.89 (3H, t, J=8 Hz), 1,52 is 1.60 (1H, m), 1,83-of 1.95 (4H, m)to 3.58 (2H, d, J=6 Hz), 3,86-4,01 (4H, m).

(42d) sodium salt of 2-(((4-((2-ethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

The form is and 213

Repeating the same procedure as in the stages (3c)-(3h) of example 3, using 1-oxide 4-chloro-2,3-dimethylpyridine and (2-ethyl-1,3-dioxane-2-yl)methanol, obtaining specified in the title compound (305 mg, 6 stages: 9,6%) as a solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; or 0.83 (3H, t, J=8 Hz), 1,51-1,71 (2H, m)and 1.83 (2H, q, J=8 Hz), of 2.15 (3H, s), 3,79-of 3.94 (4H, m), is 4.15 (2H, s), of 4.45 (1H, d, J=13 Hz), 4,78 (1H, d, J=13 Hz), 6,93-7,00 (2H, m),? 7.04 baby mortality (1H, d, J=5 Hz), 7,45-7,52 (2H, m), compared to 8.26 (1H, d, J=5 Hz).

Example 43: sodium salt of 2-(((4-(2-(2-(methoxymethyl)-1,3-dioxolane-2-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 214

(43a) of 2-(2-(methoxymethyl)-1,3-dioxolane-2-yl)ethanol

Formula 215

Repeating the same procedure as in the stages (39a) and (39b) of example 39, using methyl 4-methoxyacetate, obtaining specified in the connection header (5.3g, stage 2: 50%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; a 2.01 (2H, t, J=5 Hz), 2,74 is 2.80 (1H, W), to 3.38 (2H, s), 3,42 (3H, s), 3,74-of 3.80 (2H, W), 4,01-4,06 (4H, m).

(43b) sodium salt of 2-(((4-(2-(2-(methoxymethyl)-1,3-dioxolane-2-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 216

Repeating the same procedure as in the stages (5d)-(5h) of example 5, using 1-oxide 4-chloro-2,3-dimethylpyridine and 2-(2-(IU shall oxymethyl)-1,3-dioxolane-2-yl)ethanol obtaining specified in the title compound (312 mg, 5 stages of 3.9%) as a pale yellow foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,10 (2H, t, J=7 Hz), of 2.15 (3H, s), with 3.27 (3H, s), 3,30 (2H, s), 3,86-3,91 (4H, m), 4.09 to (2H, t, J=7 Hz), to 4.38 (1H, d, J=13 Hz), was 4.76 (1H, d, J=13 Hz), for 6.81-to 6.88 (2H, m), 6,92 (1H, d, J=6 Hz), 7,40-7,46 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 44: sodium salt of 2-(((4-((2-(permitil)-1,3-dioxane-2-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 217

(44a) (2-(hydroxymethyl)-1,3-dioxane-2-yl)methylbenzoate

Formula 218

To a solution of dihydroxyacetone (20 g, 222 mmol) in pyridine (200 ml) was added benzoyl chloride (from 25.8 ml, 222 mmol) while cooling on ice and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and to the residue was added ethyl acetate, water was added for dissolution. Separated the organic layer and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue is suspended in a mixture of n-heptane/ethyl acetate (1/1) and was removed by filtration of the insoluble material. The filtrate was concentrated and dissolved in ethyl acetate. To the resulting solution was added Seeley is aqel and the mixture was concentrated and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=3/1→2/1→1/1→0/1) to obtain a mixture (16.5 g), containing 3-hydroxy-2-oxopropanoic, in the form of a white solid.

The mixture of the mixture (0.5 g)containing 3-hydroxy-2-oxopropanoic, 1,3-propane diol (0,932 ml, 12.9 mmol), triethylorthoformate (0,428 ml, 2.58 mmol) and monohydrate p-toluensulfonate acid (44,5 mg, 0,234 mmol) was stirred at room temperature for 4 days. Another mixture consisting of a mixture (4 g)containing 3-hydroxy-2-oxopropanoic, 1,3-propane diol (7,46 ml, 12.9 mmol), triethylorthoformate (3.42 ml of 20.6 mmol) and monohydrate p-toluensulfonate acid (356 mg, of 1.87 mmol), stirred at 40°C during the night. Two reaction mixtures were combined, added water and ethyl acetate and the separated organic layer. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of n-heptane/ethyl acetate (2/1) and toluene and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=3/2) to obtain specified in the connection header (4,2 g).

1H NMR (400 MHz, CDCl3) δ ppm; 1,58-2,04 (2H, m), and 3.72 (2H, s), 3,92-3,99 (2H, m), 4,05 is 4.13 (2H, m), of 4.66 (2H, s), 7,41-of 7.48 (2H, m), 7,56-of 7.60 (1H, m), 8,02-8,07 (2H, m).

(44b) (2-(permitil)-1,3-dioxane-2-yl)methylbenzoate

Formula 219

To a solution of (2-(hydroxymethyl)-1,3-dioxane-2-yl)methylbenzoate (4,76 g of 18.8 mmol) in toluene (100 ml) was added to the 1,8-diazabicyclo[5,4,0]undec-7-ene (8,43 ml, of 56.4 mmol), the mixture was cooled on ice and added to it nonfor-1-butanesulfonate (5,06 ml of 28.2 mmol). The mixture was stirred while cooling on ice for 15 minutes and at 40°C for 20 hours and then stirred at room temperature for 8 days. The reaction mixture was extracted by adding water and ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and filtered through silica gel, after which the filtrate was concentrated. The residue was subjected twice chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=4/1) to obtain specified in the connection header (2,22 g, yield: 46.4 per cent).

1H NMR (400 MHz, CDCl3) δ ppm; 1,63-of 1.74 (1H, m),1,89 is 2.01 (1H, m), 3,93-4,01 (2H, m), 4,05 is 4.13 (2H, m), 4,56 (2H, d, J=47 Hz), of 4.66 (2H, d, J=2 Hz), 7,42-of 7.48 (2H, m), 7,54-to 7.61 (1H, m), 8,03-8,08 (2H, m).

(44c) (2-(permitil)-1,3-dioxane-2-yl)methanol

The formula 220

A mixture of (2-(permitil)-1,3-dioxane-2-yl)methylbenzoate (2,22 g, 8,73 mmol), methanol (20 ml) and 1N aqueous sodium hydroxide solution (13.1 ml) was stirred at room temperature overnight. To the reaction mixture was added ammonium chloride and concentrated. The residue is suspended in tetrahydrofuran and ethyl acetate, after which was added magnesium sulfate and the mixture was stirred for 5 minutes. After filtration through NH Seeley is aqel the filtrate was concentrated to obtain specified in the connection header (1,17 g, 89,3%) as a colourless liquid.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.65 and 1.75 (1H, m), 1.85 to a 1.96 (1H, m), 3,71 (2H, d, J=3 Hz), 3,94-of 4.05 (4H, m), of 4.57 (2H, d, J=47 Hz).

(44d) sodium salt of 2-(((4-((2-(permitil)-1,3-dioxane-2-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 221

Repeating the same procedure as in stage (1c)to(1g) of example 1, using 1-oxide 4-chloro-2,3,5-trimethylpyridine and (2-(permitil)-1,3-dioxane-2-yl)methanol, obtaining specified in the title compound (331 mg, 5 stages: 12%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,61-of 1.74 (2H, m), 2,22 (3H, in), 2.25 (3H, s), 3,86-of 3.95 (4H, m), of 3.96 (2H, s)to 4.41 (1H, t, J=13 Hz), with 4.64 (2H, d, J=47 Hz), and 4.75 (1H, d, J=13 Hz), for 6.81-to 6.88 (2H, m), 7,39-7,46 (2H, m), 8,21 (1H with).

Example 45: sodium salt of 2-(((4-((2-(permitil)-1,3-dioxolane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 222

(45a) (2-(permitil)-1,3-dioxolane-2-yl)methanol

Formula 223

Repeating the same procedure as in the stages (44a)-(44c)using dihydroxyacetone, except that instead of 1,3-propane diol used in example 44, used ethylene glycol, to obtain specified in the title compound (543 mg, total yield: 13.8 percent).

1H NMR (400 MHz, CDCl3) δ ppm; 1,70-1,82 (1H, W), 3,66 (2H, d, J=2 Hz), 4,06(4H, C)4,37 (2H, d, J=47 Hz).

(45b) sodium salt of 2-(((4-((2-(permitil)-1,3-dioxolane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 224

Repeating the same procedure as in the stages (3c)-(3h) of example 3, using 1-oxide 4-chloro-2,3-dimethylpyridine and (2-(permitil)-1,3-dioxolane-2-yl)methanol, obtaining specified in the title compound (140 mg, 6 stages 8,2%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.20 (3H, s), 3.95 to of 4.05 (4H, m), 4,10 (2H, d, J=2 Hz), to 4.38 (1H, d, J=13 Hz), 4,48 (2H, d, J=47 Hz), a 4.83 (1H, d, J=13 Hz), for 6.81-to 6.88 (2H, m), of 6.96 (1H, d, J=6 Hz), 7,39-7,46 (2H, m), 8,27 (1H, d, J=6 Hz).

Example 46) sodium salt of 2-(((4-((5,5-debtor-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 225

(46a) 2,2-ditropan-1,3-diltiazem

The formula is 226

A mixture of 2-oxoprop-1,3-dialdictate (10.6 g, of 60.8 mmol) and diethylaminoacetate (and 24.2 ml, 182 mmol) was stirred at room temperature for 4 days. The reaction mixture was diluted with ethyl acetate and cooled on ice, after which was added a saturated solution of sodium bicarbonate and separated the organic layer. The organic layer was washed twice with water, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure with what rucenim specified in the connection header (10.92 g, to 91.6%).

1H NMR (400 MHz, CDCl3) δ ppm; a 2.13 (6H, s), 4,35 (4H, t, J=12 Hz).

(46b) 2,2-ditropan-1,3-diol

Formula 227

A mixture of 2,2-ditropan-1,3-dialdictate (10,9 g, and 55.7 mmol), methanol (300 ml) and 28% methanol solution of sodium methoxide (32,2 g, 167 mmol) was stirred at room temperature for 2 hours. To the reaction mixture was added DOWEX 50W-X8 (100-200 mesh, H-form) to bring the pH to 5. The mixture was filtered and the filtrate was concentrated. To the obtained residue to dissolve) was added tetrahydrofuran and ethyl acetate. The solution was dried over magnesium sulfate and filtered, then the filtrate was concentrated. The residue was dissolved in ethyl acetate and filtered through filter paper of glass fiber. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (5.3g, 84,9%).

1H NMR (400 MHz, CDCl3) δ ppm; 2,07-of 2.20 (2H, W), to 3.92 (4H, dt, J=1, 12 Hz).

(46c) 2-((benzyloxy)methyl)-5,5-debtor-1,3-dioxane

Formula 228

A mixture of 2,2-ditropan-1,3-diol (1 g, 8.9 mmol), benzyloxyacetaldehyde (1,34 g, 8.9 mmol), monohydrate p-toluensulfonate acid (154 mg, 0.81 mmol) and toluene (20 ml) was boiled under reflux with unit Dean-stark within one hour. The resulting mixture was stirred at room temperature than is their night and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and to the solution was added silica gel. The resulting mixture was concentrated to dryness and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=10/1) to obtain the specified title compound (930 mg, 42.8 per cent).

1H NMR (400 MHz, CDCl3) δ ppm; 3,61 (2H, d, J=5 Hz), 3.75 to 3,88 (2H, m), 4,13-4,22 (2H, m), br4.61 (2H, s), was 4.76 (1H, t, J=5 Hz), 7,21-7,40 (5H, m).

(46d) (5,5-debtor-1,3-dioxane-2-yl)methanol

Formula 229

A mixture of 2-((benzyloxy)methyl)-5,5-debtor-1,3-dioxane (930 mg, 3,81 mmol), 20% palladium hydroxide (353 mg) and ethyl acetate (30 ml) was stirred in hydrogen atmosphere at room temperature for 4 hours and 25 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain specified in the title compound (572 mg, 97,4%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; and 3.72 (2H, d, J=5 Hz), 3,78-are 3.90 (2H, m), 4,16-to 4.23 (2H, m), 4,69 (1H, t, J=4 Hz).

(46e) sodium salt of 2-(((4-((5,5-debtor-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 230

Repeating the same procedure as in stage (1c)to(1g) of example 1, using 1-oxide 4-chloro-2,3-dimethylpyridine and (5,5-debtor-1,3-dioxane-2-yl)methanol, obtaining specified in the title compound (375 mg, 5 stages: 22,7%) in powder form.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,19 (3H, s), 4,00-of 4.25 (6H, m), to 4.38 (1H, d, J=13 Hz), a 4.83 (1H, d, J=13 Hz)to 5.17 (1H, t, J=4 Hz), for 6.81-6.87 in (2H, m), of 6.96 (1H, d, J=6 Hz), 7,39 was 7.45 (2H, m), of 8.27 (1H, d, J=6 Hz).

Example 47: sodium salt of 2-(((4-(2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-5-methyl-1H-benzimidazole

Formula 231

(47a) 5-methyl-1H-benzimidazole-2-thiol

Formula 232

First suspended 3-amino-4-nitrotoluene (6.3 g, up 41.4 mmol) and 10% palladium on carbon (900 mg) in methanol (70 ml) and the mixture was stirred in hydrogen atmosphere for 3 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration and washed with ethanol. To the reaction mixture was added carbon disulfide (20 ml) and the mixture was stirred at room temperature for 5 days. After kontsentrirovanija reaction mixture, to the residue was added diethyl ether. The obtained solid substance was collected by filtration to obtain specified in the connection header (6,1 g, output: 89,7%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.33 (3H, s), 6.90 to-6,93 (2H, m), 7,00 (1H, d, J=8 Hz).

(47b) sodium salt of 2-(((4-(2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-5-methyl-1H-benzimidazole

Formula 233

Repeating the same% the fool, as at the stages of (1e)-(1g) of example 1, using 5-methyl-1H-benzimidazole-2-thiol (309 mg, 1.88 mmol)obtained in stage (47a)and (4-(2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methanol (501 mg, 1.88 mmol), to obtain the specified title compound (118 mg) as a white solid. It should be noted that the curing operation specified in the title compounds were performed as follows. To the residue was added ether and the resulting mixture was brought ultrasonic wave. The resulting suspension was allowed to stand and then remove the supernatant. These operations were repeated two times. The precipitate was subjected to suction drying with obtaining specified in the connection header.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.27 (3H, s)of 1.33 (3H, s), 1,96-2,04 (2H, m)to 2.18 (3H, s), a 2.36 (3H, s)and 3.59 (1H, t, J=8 Hz), 4.04 the-4,14 (3H, m), is 4.21-4.26 deaths (1H, m), 4,37 (1H, DD, J=4, 13 Hz), 4,80 (1H, DD, J=2, 13 Hz), 6,69 (1H, d, J=8 Hz), 6,92 (1H, d, J=6 Hz), 7,22 (1H, s), 7,31 (1H, d, J=8 Hz), of 8.28 (1H, d, J=6 Hz).

Example 48: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-4-methoxy-1H-benzimidazole

The formula 234

(48a) 4-methoxy-1H-benzimidazole-2-thiol

Formula 235

A mixture of 2-methoxy-6-nitroaniline (1 g, 5,95 mmol), 10% palladium on carbon (300 mg) and methanol (25 ml) was stirred in hydrogen atmosphere for 4 hours. The reactions the config vessel was purged with nitrogen and the catalyst was removed by filtration. To the reaction mixture was added carbon disulfide (15 ml) and the mixture was stirred at room temperature overnight. To the reaction mixture were added triethylamine (1 ml) and stirred her at 50°C for 3 hours. After concentration of the reaction mixture, to the residue was added methanol (2 ml) and diethyl ether (20 ml). The obtained solid substance was collected by filtration to obtain specified in the title compound (950 mg, yield: 88,6%) as a pale orange solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 3,86 (3H, s), 6,74 (1H, d, J=8 Hz), 6.75 in (1H, d, J=8 Hz), 7,05 (1H, t, J=8 Hz).

(48b) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-4-methoxy-1H-benzimidazole

Formula 236

Repeating the same procedure as in the stages (1e)-(1g) of example 1, using 4-methoxy-1H-benzimidazole-2-thiol (260 mg, 1.44 mmol)obtained by the method of stages (48a)and (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol (350 mg, 1,31 mmol), to obtain the specified title compound (326 mg) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, t, J=6 Hz), 2.06 to and 2.14 (1H, m), of 2.20 (3H, s), 3.75 to of 3.80 (2H, m), 3,88 (3H, s), 3,97-4,01 (2H, m), 4,10 (2H, d, J=7 Hz), 4,35 (1H, d, J=13 Hz), a 4.83 (1H, d, J=13 Hz), 6,33 (1H, d, J=8 Hz), 6,74 (1H, t, J=8 Hz), 6,94 (1H, d, J=6 Hz), 7,05 (1H, d, J=8 Hz), of 8.27 (1H, d, J=6 Hz).

Example 49: sodium with the l 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-5-(trifluoromethyl)-1H-benzimidazole

Formula 237

(49a) 5-(trifluoromethyl)-1H-benzimidazole-2-thiol

Formula 238

A mixture of 4-amino-3-nitrobenzotrifluoride (7 g, 34 mmol), 10% palladium on carbon (1.3 g) and methanol (70 ml) was stirred in hydrogen atmosphere for 5 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration. To the reaction mixture was added carbon disulfide (30 ml) and the mixture was stirred at room temperature overnight, after which the reaction mixture was concentrated. To the residue was added methanol (60 ml), carbon disulfide (20 ml) and triethylamine (15 ml) and the mixture was stirred at 50°C during the night. After concentrating the reaction mixture, the residue was purified by chromatography on a column of silica gel (silica gel 200 g, eluting solvent: ethyl acetate/heptane=1/3→7/3. When ethyl acetate/heptane=7/3, in the eluting solvent was added a small amount of methanol) to obtain the specified title compound (5.3 g, yield: 71,4%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 7,29 (1H, d, J=8 Hz), 7,35 (1H, s), 7,45 (1H, d, J=8 Hz), 12,86 (1H, Sirs).

(49b) sodium salt of 2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-5-(trifluoromethyl)-1H-benzimidazole

Formula 239

Repeated the same process is ur, as at the stages of (1e)-(1g) of example 1, using 5-(trifluoromethyl)-1H-benzimidazole-2-thiol (137 mg, 0,626 mmol)obtained by the method of stages (49a)and (4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol (176 mg, 0,626 mmol), to obtain the specified title compound (104 mg) as a pale yellow solid. It should be noted that during curing is specified in the header connection to it was added heptane (10 ml) and diethyl ether (2 ml) and the mixture was subjected to ultrasonic processing.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,70 (3H, s), 1,10 (3H, s), measuring 2.20 (3H, s), of 2.21 (3H, s), 3,48 (2H, d, J=11 Hz), 3,57 (2H, d, J=11 Hz), 3,82 (2H, d, J=4 Hz), was 4.76 (1H, t, J=4 Hz), 7,14 (1H, DD, J=2, 8 Hz), to 7.59 (1H, d, J=8 Hz), to 7.77 (1H, s), 8,21 (1H, s).

Example 50: sodium salt of 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 240

Repeating the same procedure as in the stages (10d)-(10f) of example 10, using 2-mercaptobenzimidazole (291 mg, 1.94 mmol) and (4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)pyridine-2-yl)methanol (443 mg, of 1.76 mmol), to obtain the specified title compound (300 mg) as a white solid. It should be noted that in the same process as in stage (10d), to the reaction mixture were added 2-mercaptobenzimidazole and then 2 equivalents of triethylamine. The mixture was stirred at room temperature for 2 days.

1H NMR (400 MHz, DMSO-d6) δ ppm; between 0.30 to 0.34 (2H, m), of 0.56 to 0.60 (2H, m), 3,24 (2H, d, J=12 Hz)to 3.99 (2H, t, J=4 Hz), 4,08 (2H, d, J=12 Hz), 4,94 (1H, t, J=4 Hz), 6,85-to 6.88 (3H, m), 6,92 (1H, DD, J=3, 6 Hz), was 7.45 (2H, DD, J=3, 6 Hz), of 8.37 (1H, d, J=6 Hz).

Example 51: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-ethylpyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 241

(51a) 2-methylpyridin-3-yl triftorbyenzola

Formula 242

First, 3-hydroxy-2-methylpyridine (16.2 g, 148 mmol) and N-phenyltrichlorosilane cases (53.2 g, 149 mmol) was dissolved in dichloromethane (digidrirovanny) (450 ml). To the mixture was added triethylamine (31 ml, 222 mmol) in a nitrogen atmosphere at 1-3°C. the Mixture was stirred for 13 hours and 20 minutes by increasing the temperature to room temperature. The reaction mixture was washed two times with 1N aqueous sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered and concentrated to obtain specified in the title compound (34.3 g, output: 96,1%) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.54 (3H, s), 7,44-7,52 (1H, m), of 7.90-of 7.96 (1H, m), 8,56 at 8.60 (1H, m).

(51b) of 2-methyl-3-((trimethylsilyl)ethinyl)pyridine

Formula 243

First 2-methylpyridin-3-yl triftorbyenzola (34.3 g, 142 mmol), trimethylsilylacetamide (30 ml, 212 mmol), chloride bis(Trifan lfopen)palladium(II) (10.0 g, of 14.2 mmol) and copper iodide(I) (2,75 g, 14.4 mmol) was dissolved in N,N-dimethylformamide (150 ml). Then to the mixture was added triethylamine (43 ml, 309 mmol) under nitrogen atmosphere at room temperature. The mixture was stirred for 3 hours (was exothermic reaction). The reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride and the insoluble substance was removed by filtration. The organic layer of the filtrate was washed twice with a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain specified in the connection header (22,6 g, output: 84,1%) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.25 (9H, s), to 2.57 (3H, s), 7,22 (1H, DD, J=5, 8 Hz), 7,79 (1H, DD, J=2, 8 Hz), 8,43 (1H, DD, J=2, 5 Hz).

(51c) 3-ethyl-2-methylpyridin

Formula 244

First, 2-methyl-3-((trimethylsilyl)ethinyl)pyridine (22,6 g, 119 mmol) was dissolved in tetrahydrofuran (digidrirovanny) (200 ml). To the mixture was added tetrabutylammonium (1 N. tertrahydrofuran ring solution (150 ml, 150 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was distributed between ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed two R is over saturated aqueous ammonium chloride, was dried over anhydrous magnesium sulfate and person to distil using a rotary evaporator. To the fractions obtained were added 10% palladium on carbon (900 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 2 hours. The reaction mixture was filtered through anhydrous magnesium sulfate and celite. To the filtrate was added 10% palladium on carbon (810 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered through anhydrous magnesium sulfate and celite, then the filtrate was concentrated to obtain specified in the connection header (7,25 g, output: 51,1%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.16 (3H, t, J=8 Hz), a 2.45 (3H, s), 2,60 (2H, q, J=8 Hz), 7,14 (1H, DD, J=5, 7 Hz), 7,51 (1H, DD, J=1, 7 Hz), compared to 8.26 (1H, DD, J=1, 5 Hz).

(51d) 3-ethyl-2-methylpyridine 1-oxide

Formula 245

First, 3-ethyl-2-methylpyridine (7,25 g, to 59.8 mmol) was dissolved in dichloromethane (digidrirovanny) (100 ml) was added 3-chloroperbenzoic acid (19,0 g, 71,6 mmol, when the content of 65%) in nitrogen atmosphere at a temperature of cooling on ice. The mixture was stirred at room temperature for 90 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane and three times with chloroform. Institutions the institutions layers were combined, was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (silica gel: 100 g, eluting solvent: heptane, ethyl acetate/methanol=10/1) to obtain specified in the connection header (7,35 g, output: 89,6%) as a reddish solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 1.14 (3H, t, J=8 Hz), to 2.35 (3H, s)of 2.64 (2H, q, J=8 Hz), 7,12-7,24 (2H, m), 8,10-8,16 (1H, m).

(51e) 1-oxide 3-ethyl-2-methyl-4-nitropyridine

Formula 246

Cooling the mixture of 1-oxide 3-ethyl-2-methylpyridine (7,35 g, 53.6 mmol) and sulfuric acid (22.7 g, 231 mmol) in an ice bath, was added dropwise boiling nitric acid (to 3.64 ml, 87.9 mmol) and the mixture was stirred at 80°C for 8 hours. The reaction mixture was cooled to room temperature and then poured into ice. The resulting aqueous solution was extracted three times with chloroform. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain specified in the connection header (3,37 g, output: 34,5%) as a yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 1.21 (3H, t, J=7 Hz), a 2.45 (3H, s), 2,80 (2H, q, J=7 Hz), 7,88 (1H, d, J=7 Hz), at 8.36 (1H, d, J=7 Hz).

(51f) 1-oxide 4-chloro-3-ethyl-2-methylpyridine

Formula 247

First, 1-oxide, 3-ethyl-2-methyl-4-nitropyridine (3,37 g, 8.5 mmol) was added to acetylchloride (20 ml, 281 mmol) in a nitrogen atmosphere at -30°C. the Mixture was stirred at a temperature of from -30 to 0°C for 3 hours. After concentrating the reaction mixture, the residue was distributed between chloroform and saturated aqueous sodium bicarbonate. After insoluble matter was removed by filtration, the aqueous layer was extracted twice with chloroform. The organic layers were combined and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 100 g, eluting solvent: heptane, heptane/ethyl acetate=50/50) to obtain the specified title compound (2.10 g, yield: 66,1%) as a yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.10 (3H, t, J=8 Hz), 2,42 (3H, s), 2,77 (2H, q, J=8 Hz), 7,41 (1H, d, J=7 Hz), 8,16 (1H, d, J=7 Hz).

(51g) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-ethylpyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 248

Repeating the same procedure as in stage (10b) of example 10 and stages (11f)-(11i) of example 11, using 1-oxide 4-chloro-3-ethyl-2-methylpyridine, solketal and 2-mercaptobenzimidazole, obtaining specified in the title compound (122 mg, yield: 5,6%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.07 (3H, t, J=7 Hz), of 1.30 (3H, s)of 1.35 (3H, s), 2,60-and 2.83 (2H, m), 3,81 (1H, t, J=7 Hz), 4,01-4,18 (3H, what), 4,32-4,47 (2H, m), 4,67-of 4.77 (1H, m), 6,79-6,89 (2H, m), to 6.95 (1H, d, J=5H), 7,38-7,49 (2H, m), 8,29 (1H, d, J=5 Hz).

Example 52: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-5-fluoro-1H-benzimidazole

Formula 249

(52a) 5-fluoro-1H-benzimidazole-2-thiol

Formula 250

A mixture of 3,4-diamino-1-fervently (10 g, 79.3 mmol), carbon disulfide (70 ml, 1164 mmol) and methanol (100 ml) was stirred at room temperature for 86 hours and 50 minutes. After kontsentrirovanija reaction mixture, the residue is suspended in hexane. The precipitate was collected by filtration and washed with hexane to obtain specified in the title compound (13.1 g, yield: 98.2 per cent) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 6,90-6,99 (2H, m), 7,06-7,13 (1H, m), 12,58 (1H, s), was 12.61 (1H, s).

(52b) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-5-fluoro-1H-benzimidazole

Formula 251

Repeating the same procedure as in stage (10b) of example 10 and the stage (14b) of example 14, stage (5f) of example 5 stages (11h) and (11i) of example 11, using solketal, 1-oxide 4-chloro-2,3-dimethylpyridine and 5-fluoro-1H-benzimidazole-2-thiol, obtaining specified in the title compound (210 mg, yield: 14,1%) as a white solid. Should be about the mark, as a solvent used methanol instead of ethanol in the same operations phase (5f).

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.29 (3H, s), 1,30-1,40 (3H, m), 2,17 (3H, s), 3,80 (1H, DD, J=6, 8 Hz), 4,00-4,16 (3H, m), 4,37 (1H, d, J=13 Hz), 4,42 (1H, quintet, J=6 Hz), 4,70-rate 4.79 (1H, m), 6,62-of 6.73 (1H, m)6,94 (1H, d, J=5 Hz), 7,08-7,16 (1H, m), 7,33-the 7.43 (1H, m), of 8.27 (1H, d, J=5 Hz).

Example 53: sodium salt of 2-(((4-(1,3-dioxane-5-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 252

(53a) 1,3-dioxane-5-ylmethanol

Formula 253

A mixture of 2-(hydroxymethyl)-1,3-propane diol (a 3.06 g, 28.8 mmol), dimethylacetal formaldehyde (9 ml, 102 mmol), lithium bromide (488 mg, 5,62 mmol), monohydrate p-toluensulfonate acid (491 mg, 2.58 mmol) and dichloromethane (digidrirovanny) (15 ml) was stirred for 7 days. After adding triethylamine (1 ml) the reaction mixture was concentrated. The residue was purified by chromatography on a column of silica gel (silica gel: 100 g, eluting solvent: heptane, heptane/ethyl acetate=1/1, 1/3) to obtain specified in the connection header (1,37 g, output: 40,3%) as a colourless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,76 is 1.86 (1H, m)to 3.36 (2H, t, J=6 Hz), 3,57 (2H, DD, J=8, 11 Hz), 3,90 (2H, DD, J=4, 8 Hz), 4,58 (1H, t, J=6 Hz), 4,63 (1H, d, J=6 Hz), 4,79 (1H, d, J=6 Hz).

(53b) sodium salt of 2-(((4-(1,3-dioxane-5-ylethoxy)-3-methylpyridin-2-yl)methyl)shall sulfinyl)-1H-benzimidazole

Formula 254

Repeating the same procedure as in stage (10b) of example 10 and stages (11f)-(11i) of example 11, using 1,3-dioxane-5-ylmethanol, 1-oxide 4-chloro-2,3-dimethylpyridine and 2-mercaptobenzimidazole, obtaining specified in the header of the compound (927 mg, yield: 24,2%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,15-of 2.27 (1H, m), are 2.19 (3H, s), of 3.73-of 3.85 (2H, m), 3,98-4,06 (2H, m), 4,11 (2H, d, J=7 Hz), and 4.40 (1H, d, J=13 Hz), and 4.75 (1H, d, J=6 Hz), of 4.77 (1H, d, J=13 Hz), a 4.83 (1H, d, J=6 Hz), 6,80-6,91 (2H, m), of 6.96 (1H, d, J=6 Hz), 7,40-7,51 (2H, m), 8,30 (1H, d, J=6 Hz).

Example 54: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-4-methyl-1H-benzimidazole

Formula 255

(54a) 4-methyl-1H-benzimidazole-2-thiol

Formula 256

First, 2-methyl-6-nitroaniline (7 g, 46 mmol) and 10% palladium on carbon (900 mg) suspended in methanol (70 ml) and the mixture was stirred in hydrogen atmosphere for 5 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration. To the reaction mixture was added carbon disulfide (30 ml) and the mixture was stirred at room temperature overnight. After drove away the solvent under reduced pressure, to the residue was added diethyl ether. The obtained solid substance was collected by filtration receipt the m specified in the title compound (6.9 g, output: 92,7%) as a pale blue solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; is 2.37 (3H, s)6,91 (1H, t, J=8 Hz), 6,94 (1H, d, J=8 Hz), 7,00 (1H, d, J=8 Hz).

(54b) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-4-methyl-1H-benzimidazole

Formula 257

Repeating the same procedure as in the stages (11g)-(11i) of example 11, using 4-methyl-1H-benzimidazole-2-thiol, and (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol, obtaining specified in the title compound (327 mg, yield: 36,5%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2.05 is with 2.14 (1H, m), of 2.21 (3H, s), 2,48 (3H, s), 3.75 to 3,82 (2H, m), 3,97-was 4.02 (2H, m), 4,11 (2H, d, J=7 Hz), of 4.44 (1H, d, J=13 Hz), of 4.77 (1H, d, J=13 Hz), of 6.65 (1H, d, J=7 Hz), to 6.75 (1H, DD, J=7, 8 Hz), to 6.95 (1H, d, J=6 Hz), 7,26 (1H, d, J=8 Hz), 8,29 (1H, d, J=6 Hz).

Example 55: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-5-methyl-1H-benzimidazole

Formula 258

Repeating the same procedure as in the stages (11g)-(11i) of example 11, using 5-methyl-1H-benzimidazole-2-thiol, and (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol, obtaining specified in the title compound (330 mg, yield: 35,6%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2.06 to 2,1 (1H, m)2,17 (3H, s), a 2.36 (3H, s), 3.75 to 3,82 (2H, m), 3,97-was 4.02 (2H, m), 4,11 (2H, d, J=7 Hz), to 4.38 (1H, d, J=13 Hz), of 4.77 (1H, d, J=13 Hz), 6,69 (1H, DD, J=2, 8 Hz), to 6.95 (1H, d, J=6 Hz), 7.23 percent (1H, d, J=2 Hz), 7,32 (1H, d, J=8 Hz), 8,29 (1H, d, J=6 Hz).

Example 56: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-5-fluoro-1H-benzimidazole

Formula 259

Repeating the same procedure as in the stages (11g)-(11i) of example 11, using 5-fluoro-1H-benzimidazole-2-thiol, and (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol, obtaining specified in the title compound (169 mg, yield: 33.7%) of a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,03 and 2.13 (1H, m), of 2.20 (6H, s), 3,76-a 3.87 (4H, m)4,00 (2H, DD, J=4, 11 Hz), to 4.38 (1H, d, J=13 Hz), 4,74 (1H, d, J=13 Hz), 6,65-6,74 (1H, m), 7,10-7,17 (1H, m), of 7.36-the 7.43 (1H, m), by 8.22 (1H, s).

Example 57: sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 260

(57a) 1-oxide 4-chloro-2-methylpyridine

Formula 261

N-oxide, 4-nitro-2-picoline (20 g, 130 mmol) was added to acetylchloride (120 ml, 1688 mmol) in an atmosphere of nitrogen at -25°C. the Mixture was stirred at a temperature of from -30 to 5°C for 4 hours and 15 minutes. After the reaction mixture was diluted with ethyl acetate (150 ml) and chloroform (100 ml), the mixture is concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 200 g, eluting solvent: heptane, heptane/ethyl acetate=75/25, 50/50, 25/75, ethyl acetate, ethyl acetate/methanol=20/1) to obtain specified in the connection header (3,14 g) as a brown oil. At the same time received the crude product (about 17 g). The crude product was further purified by chromatography on a column of silica gel (NH silica gel: 300 g, eluting solvent: heptane, heptane/ethyl acetate=75/25, 40/60, 25/75, ethyl acetate) with a separate receipt specified in the connection header (5,39 g) as a brown oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.33 (3H, s), 7,41 (1H, DD, J=3, 7 Hz), to 7.68 (1H, d, J=3 Hz), of 8.25 (1H, d, J=7 Hz).

(57b) sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 262

Repeating the same procedure as in stage (10b) of example 10 and stages (11f)-(11i) of example 11, using 1-oxide 4-chloro-2-methylpyridine, 5,9-dioxaspiro[3,5]non-7-ylmethanol obtained in the same manner as at the stage of (13a), and 2-mercaptobenzimidazole, obtaining specified in the title compound (274 mg, yield: 11.4%) as a white solid. It should be noted that in the same operation as in stage (11g), after adding to the reaction mixture 2-mercaptobenzimidazole the mixture was stirred at on the th temperature for 1 day and then was added 2 equivalents of triethylamine, taken by alcohol, and the mixture was stirred at 50°C for 8 hours, 35 minutes and at room temperature for 84 hours and 40 minutes.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.64 (2H, quintet, J=8 Hz), 1,88-of 1.97 (1H, m), 2,13 (2H, t, J=8 Hz), of 2.15 (2H, t, J=8 Hz), 3,47-3,62 (3H, m), 3.75 to of 3.85 (3H, m), of 4.45 (1H, d, J=12 Hz), the 4.90 (1H, d, J=12 Hz), to 6.58 (1H, d, J=2 Hz), PC 6.82 (1H, DD, J=2, 6 Hz), 6,84-6,91 (2H, m), 7,42-of 7.48 (2H, m), 8,31 (1H, d, J=6 Hz).

Example 58: sodium salt of 2-(((4-(6,10-dioxaspiro[4,5]Dec-8-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 263

Repeating the same procedure as in stage (10b) of example 10 and stages (11f)-(11i) of example 11, using 1-oxide 4-chloro-2-methylpyridine, 6,10-dioxaspiro[4,5]Dec-8-ylmethanol obtained in the same manner as in stage (21a), and 2-mercaptobenzimidazole, obtaining specified in the title compound (427 mg, yield: 15.6%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,52-to 1.63 (4H, m), 1,73 is 1.86 (4H, m), 1,88-to 1.98 (1H, m), 3,52-3,66 (3H, m), 3,78-3,88 (3H, m), of 4.45 (1H, d, J=12 Hz), 4,59 (1H, d, J=12 Hz), 6,60 (1H, d, J=3 Hz), PC 6.82 (1H, DD, J=3, 6 Hz), 6,84-6,91 (2H, m), 7,42-7,49 (2H, m), 8,32 (1H, d, J=6 Hz).

Example 59: sodium salt of 2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 264

Repeating the same procedure as in stage (10b) of example 10 and stages (11f)-(11i) of example 11, using 1-oxide 4-PI is the p-2-methylpyridine, (2,2-bis(permitil)-1,3-dioxane-5-yl)methanol obtained in the same manner as at the stage of (7a)and 2-mercaptobenzimidazole, obtaining specified in the title compound (326 mg, yield: 12,5%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,02-2,12 (1H, m), 3,68-of 3.78 (3H, m), 3,90 (1H, DD, J=7, 10 Hz), 3,97-4,06 (2H, m), 4,40-4,65 (6H, m), of 6.66 (1H, d, J=2 Hz), 6,83-6,92 (3H, m), 7,43-to 7.50 (2H, m), a 8.34 (1H, d, J=6 Hz).

Example 60: sodium salt of 2-(((4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 265

Repeating the same procedure as in stage (10b) of example 10 and stages (11f)-(11i) of example 11, using 1-oxide 4-chloro-2-methylpyridine, 1,5,9-dioxaspiro[5,5]undec-3-ylmethanol obtained in the same manner as in stage (10a), and 2-mercaptobenzimidazole, obtaining specified in the title compound (313 mg, yield: 7.1%) as a white solid. It should be noted that in the same operation as in stage (11g), after adding to the reaction mixture 2-mercaptobenzimidazole the mixture was stirred at room temperature for 86 hours and 30 minutes, after which was added 2 equivalents of triethylamine in alcohol and the mixture was stirred at 50°C for 10 hours and at room temperature for 14 hours and 30 minutes.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,76 (2H, t, J=5 Hz), is 1.81 (2H, t, J=5 Hz), 1,91-2,02 (1H, m), 3,55 (4H, t, J=5Hz), to 3.58 of 3.75 (3H, m), 3,83-of 3.96 (3H, m), of 4.44 (1H, d, J=12 Hz), 4,58 (1H, d, J=12 Hz), only 6.64 (1H, d, J=2 Hz), 6,82-6,91 (3H, m), 7,43-7,49 (2H, m), with 8.33 (1H, d, J=6 Hz).

Example 61: sodium salt of 2-(((4-(2,3-dihydro-1,4-benzodioxin-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 266

Repeating the same procedure as in the stages (8c)-(8g) of example 8, using 2-hydroxymethyl-1,4-benzodioxan, obtaining specified in the title compound (141 mg, total yield: 3%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 2.20 (3H, s), 4,19 (1H, DD, J=7, 12 Hz), 4,30-4,34 (2H, m), to 4.38 (1H, DD, J=5, 13 Hz), 4,46 (1H, DD, J=2, 12 Hz), br4.61-4,63 (1H, m), 4,82 (1H, DD, J=5, 13 Hz), 6,82-6,93 (6H, m), 6,98 (1H, d, J=6 Hz), the 7.43 (2H, DD, J=3, 6 Hz), 8,29 (1H, d, J=6 Hz).

Example 62: sodium salt of 2-(((4-(1,4-dioxane-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 267

(62a) sodium salt of 2-iodomethyl-1,4-dioxane

Formula 268

To a solution of 2-(allyloxy)ethanol (14 g, 137 mmol) in acetonitrile (420 ml) was added sodium bicarbonate (34,6 g, 410 mmol) and iodine (104 g, 410 mmol) and the mixture was stirred at room temperature for 20 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. Then the organic layer was washed with an aqueous solution of sodium thiosulfate and a saturated saline solution,dried over magnesium sulfate, was filtered through a column of silica gel and the filtrate was concentrated to obtain specified in the title compound (26.5 g, yield 85%) as a yellow liquid.

1H NMR (400 MHz, CDCl3) δ ppm; 3,10 (2H, d, J=8 Hz), to 3.34 (1H, DD, J=8, 13 Hz), 3,66-3,98 (6H, m).

(62b) 2-hydroxymethyl-1,4-dioxane

Formula 269

2-iodomethyl-1,4-dioxane (15 g, 65,8 mmol)obtained in stage (62a), was added potassium acetate (64,6 g, 658 mmol), 18-crown-6 (1,74 g, to 6.58 mmol) and N,N-dimethylformamide (220 ml) and the mixture was stirred at 80°C for 24 hours. To the reaction mixture were added water and the mixture was extracted with ethyl acetate. The organic layers were combined and washed with water and saturated saline solution, dried over magnesium sulfate to obtain acetoxysilane (5 g). Acetoxysilane was dissolved in methanol (60 ml) and added dropwise chloroethanol acid (1 ml). The mixture was stirred at room temperature for 1 hour and at 40°C for 1 hour and then neutralized by adding triethylamine. The mixture was concentrated and the residue was extracted with ether. The insoluble substance was filtered, the filtrate was concentrated and the residue was purified by chromatography on a column of silica gel (silica gel: 500 ml, eluting solvent: heptane/ethyl acetate=3/2, 1/1, 0/1) to obtain the specified title compound (2.15 g, yield: 27%) in the form bestwe the Noah liquid.

1H NMR (400 MHz, CDCl3) δ ppm; 3,44-3,89 (9H, m).

(62c) 1-oxide 4-(1,4-dioxane-2-ylethoxy)-2,3-dimethylpyridine

Formula 270

Toluene solution of 2-hydroxymethyl-1,4-dioxane (2.24 g, 19 mmol)obtained in stage (62b), and 1-oxide 4-chloro-2,3-dimethylpyridine (2.5 g, 15.8 mmol) was heated to 140°C. To the solution was added over twice KOH (2 g, 34.8 mmol) and the resulting mixture was boiled under reflux at the same temperature for 3 hours, thereby removing water from the reaction system by the apparatus of the Dean-stark. To the reaction mixture were added by NH silica gel and the solvent was removed. A mixture of the crude reaction product and NH silica gel was subjected to purification by chromatography on a column of silica gel (NH silica gel, eluting solvent: ethyl acetate/methanol=9/1-4/1) to obtain the specified title compound (2.9 g, yield: 77%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,11 (3H, s), 2,32 (3H, s), 3,37-3,50 (2H, m), to 3.58-3,88 (5H, m), 4,01-was 4.02 (2H, m), 6,93 (1H, d, J=7 Hz), of 8.06 (1H, d, J=7 Hz).

(62d) sodium salt of 2-(((4-(1,4-dioxane-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 271

Repeating the same procedure as in the stages (8d)-(8g) of example 8 using 1-oxide 4-(4-(1,4-dioxane-2-ylethoxy))-2,3-dimethylpyridine obtained in stage (62c)on the doctrine stated in the title compound (385 mg, total yield: 24%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,17 (3H, s), 3,35-3,51 (2H, m), 3,59-3,90 (5H, m), was 4.02 (2H, Sirs), 4,36 (1H, d, J=12 Hz), 4,80 (1H, d, J=12 Hz), 6,83 (2H, DD, J=4, 6 Hz), 6,91 (1H, d, J=6 Hz), 7,42 (2H, DD, J=4, 6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 63: sodium salt of 2-(((4-(1,4-dioxane-2-ylethoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 272

Repeating the same procedure as in the stages (62a)-(62d) of example 62 using 1-oxide 4-chloro-2,3,5-trimethylpyridine, obtaining specified in the title compound (355 mg, total yield: 18%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 2.18 (3H, s), of 2.21 (3H, d, J=2 Hz), 3,29-3,82 (9H, m), 4,36 (1H, DD, J=2, 13 Hz), and 4.75 (1H, DD, J=2, 13 Hz), PC 6.82 (2H, DD, J=3, 6 Hz), 7,41 (2H, DD, J=3, 6 Hz), 8,19 (1H, s).

Example 64: sodium salt of 2-(((4-(2-(2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 273

Repeating the same procedure as in the stages (4f)to(4j) of example 4 (the operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid was not performed), using 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane, obtaining specified in the title compound (412 mg, total yield: 8,7%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,25 (3H, s)is 1.31 (3H, s), 1,90-2,04 (2H, m), 2,17(3H, C)of 3.57 (1H, t, J=8 Hz), 3,98-4.26 deaths (4H, m), 4,36 (0,5H, d, J=13 Hz), 4,37 (0,5H, d, J=13 Hz), 4,78 (0,5H, d, J=13 Hz), 4,78 (0,5H, d, J=13 Hz), 6,79-6,87 (2H, m)6,91 (1H, d, J=6 Hz), 7,37-7,47 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 65: sodium salt of 2-(((4-((2,2-diethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 274

(65a) of 4-((benzyloxy)methyl)-2,2-diethyl-1,3-dioxolane

Formula 275

To tertrahydrofuran ring solution (30 ml) DL-α-O-benzylglycine (3 g, 16.5 mmol) was added at room temperature 3-pentanon (17.5 ml, 165 mmol) and monohydrate p-toluensulfonate acid (300 mg, was 1.58 mmol) and the mixture was stirred at the same temperature for 22 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (5 ml) to bring the pH to about 8. The precipitate was removed by filtration and the filtrate was concentrated. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0-3/1). The desired fraction was concentrated to obtain specified in the connection header (2,77 g of 67.1% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,75-of 0.83 (6H, m), 1,46 is 1.58 (4H, m), 3,41-3,50 (2H, m), 3,52-to 3.58 (1H, m), 3.96 points-was 4.02 (1H, m), 4,15-to 4.23 (1H, m), of 4.49 (2H, s), 7,24 and 7.36 (5H, m).

(65b) (2,2-diethyl-1,3-dioxolane-4-yl)methanol

Formula 276

To a methanol (40 ml) solution of 4-((benzyloxy)methyl)-2,2-diethyl-1,3-dioxolane (2,77 g, 11.1 mmol)obtained in stage (65a), was added palladium hydroxide (20 wt.% Pd (dry weight) on carbon, wet (maximum water 50%)) (400 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 16 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration through celite, then washed with methanol. The filtrate was concentrated and dried under reduced pressure to obtain specified in the connection header (1,593 g, 89.6% of output) in the form of a colorless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.91 (3H, t, J=7 Hz), of 0.93 (3H, t, J=7 Hz), 1.60-to 1,72 (4H, m)to 1.86 (1H, t, J=6 Hz), 3,55-of 3.64 (1H, m), 3,67-a-3.84 (2H, m), 4,01-4,08 (1H, m), 4,20-to 4.28 (1H, m).

(65c) sodium salt of 2-(((4-((2,2-diethyl-1,3-dioxolane-4-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 277

Repeating the same procedure as in the stages (4f)to(4j) of example 4 (the operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid is not performed)using (2,2-diethyl-1,3-dioxolane-4-yl)methanol obtained in stage (65b), with specified title compound (418 mg, total yield: 14,3%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,78-to 0.88 (6H, m)and 1.51-of 1.66 (4H, m), 2,18 (1,5H, s), 2,18 (1,5H, C)3,76 (1H, t, J=8 Hz), was 4.02-4,20 (3H, m), 32-4,48 (2H, m)4,76 (0,5H, d, J=13 Hz), 4,78 (0,5H, d, J=13 Hz), 6,78-to 6.88 (2H, m)6,94 (1H, d, J=6 Hz), 7,37-7,47 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 66: sodium salt of 2-(((4-(1,3-dioxolane-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1 H-benzimidazole

Formula 278

(66a) 2-((benzyloxy)methyl)-1,3-dioxolane

Formula 279

A mixture of benzyloxyacetaldehyde (3 g, 20 mmol), ethylene glycol (1.23 ml, 22 mmol), monohydrate p-toluensulfonate acid (344 mg, 1.8 mmol) and toluene (15 ml) was stirred at 140°C for 2 hours and then stirred at 150°C for 3 hours. After the mixture was cooled on ice, was added to the reaction mixture of 2N aqueous sodium hydroxide solution and ethyl acetate. The organic layer was separated, washed with water (three times) and saturated salt solution. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0-9/1). The desired fractions were concentrated to obtain specified in the connection header (3,01 g, 77.5% of yield) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 3.45 (2H, d, J=4 Hz), 3,74-to 3.92 (4H, m), 4,51 (2H, s), to 4.98 (1H, t, J=4 Hz), 7.24 to 7,38 (5H, m).

(66b) 1,3-dioxolane-2-ylmethanol

Formula 280

To me annaloveme (100 ml) solution of 2-((benzyloxy)methyl)-1,3-dioxolane (3,01 g, of 15.5 mmol)obtained in stage (66a), was added palladium hydroxide (20 wt.% Pd (dry weight) on carbon, wet (maximum water 50%)) (300 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 15 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration through celite, then washed with methanol. The filtrate was concentrated and dried under reduced pressure to obtain specified in the connection header (1,57 g, 97,3% yield) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,89 (1H, Sirs), 3,66-and 3.72 (2H, m), 3,88-4,08 (4H, m), free 5.01 (1H, t, J=3 Hz).

(66c) sodium salt of 2-(((4-(1,3-dioxolane-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 281

Repeating the same procedure as in the stages (4f)to(4j)described in example (operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid is not performed)using 1,3-dioxolane-2-ylmethanol obtained in stage (66b), with specified title compound (411 mg, total yield: 17,2%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 2,17 (3H, s), of 3.80-4.00 points (4H, m), 4,07 (2H, d, J=4 Hz), 4,39 (1H, d, J=13 Hz), 4,79 (1H, d, J=13 Hz), of 5.24 (1H, t, J=4 Hz), 6,80-6,89 (2H, m)6,94 (1H, d, J=6 Hz), 7,38-7,46 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 67: sodium salt of 2-(((3-methyl-4-((2-methyl-1,3-dioxolane-2-yl)methoxy)pyridin-2-yl)m is Teal)sulfinil)-1H-benzimidazole

Formula 282

(67a) 2-((benzyloxy)methyl)-2-methyl-1,3-dioxolane

Formula 283

A mixture of 1-benzyloxy-2-propanone (4.94 g, to 30.1 mmol), ethylene glycol (20 ml, 359 mmol), triethylorthoformate (5 ml, to 30.1 mmol) and monohydrate p-toluensulfonate acid (130 mg, 0,683 mmol) was stirred at room temperature for 61,5 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (20 ml) and the mixture was extracted twice with chloroform (50 ml), the organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0-4/1). The desired fractions were concentrated to obtain specified in the connection header (5,67 g, 90,5% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.26 (3H, s)to 3.34 (2H, s), 3,85 (4H, s), 4,51 (2H, s), 7,22-7,38 (5H, m).

(67b) (2-methyl-1,3-dioxolane-2-yl)methanol

Formula 284

To methanol (100 ml) solution of 2-((benzyloxy)methyl)-2-methyl-1,3-dioxolane (5,66 g of 27.2 mmol)obtained in stage (67a), was added palladium hydroxide (20 wt.% Pd (dry weight) on carbon, wet (maximum water 50%)) (500 mg) and the mixture was stirred in hydrogen atmosphere at room temperature the re for 17 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration through celite, then washed with methanol. The filtrate was concentrated and dried under reduced pressure to obtain specified in the connection header (2,96 g of 92.1% yield) as a pale green oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.35 (3H, s), 1,82-1,90 (1H, W), of 3.54 (2H, d, J=6 Hz), to 4.01 (4H, s).

(67c) sodium salt of 2-(((3-methyl-4-((2-methyl-1,3-dioxolane-2-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 285

Repeating the same procedure as in the stages (4f)to(4j) of example 4 (the operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid was not performed), using (2-methyl-1,3-dioxolane-2-yl)methanol obtained in stage (67b), with specified title compound (263 mg, total yield: 12,9%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.39 (3H, s), are 2.19 (3H, s), 3,88-4,00 (4H, m), of 3.96 (2H, s), 4,37 (1H, d, J=13 Hz), 4,79 (1H, d, J=13 Hz), 6,78-to 6.88 (2H, m), 6,92 (1H, d, J=6 Hz), 7,37-7,46 (2H, m), of 8.25 (1H, d, J=6 Hz).

Example 68: sodium salt of 2-(((4-((2S)-1,4-dioxaspiro[4,5]Dec-2-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 286

Repeating the same procedure as in the stages (4f)to(4j) of example 4 (the operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid is not performed), using (+)-1,4-dioxaspiro[4,5]decane-2-methanol, obtaining specified in the header of the compound (500 mg, total yield: 16,8%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,24-to 1.63 (10H, m)to 2.18 (3H, s), 3,76-a-3.84 (1H, m), 4,01-to 4.14 (3H, m), 4,37 (0,5H, d, J=13 Hz), to 4.38 (0,5H, d, J=13 Hz), to 4.38-to 4.46 (1H, m), 4,77 (0,5H, d, J=13 Hz), 4,78 (0,5H, d, J=13 Hz), 6,79-6,87 (2H, m)6,94 (1H, d, J=6 Hz), 7,37-7,46 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 69: sodium salt of 2-(((3-methyl-4-(2-(2-methyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 287

(69a) 2-(2-(benzyloxy)ethyl)-2-methyl-1,3-dioxolane

Formula 288

A mixture of 4-benzyloxy-2-butanone (10 g, or 56.1 mmol), ethylene glycol (40 ml, 718 mmol), triethylorthoformate (9,3 ml of 55.9 mmol) and monohydrate p-toluensulfonate acid (290 mg, of 1.52 mmol) was stirred at room temperature for 13.5 hours. To the reaction mixture were added saturated aqueous solution of sodium bicarbonate (40 ml) and the mixture was extracted three times with chloroform (50 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (NH silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0-4/1). The desired fractions were concentrated to obtain specified in the connection header (10,08 g, 80.8% of output) in VI is e a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.23 (3H, s)to 1.86 (2H, t, J=7 Hz), of 3.48 (2H, t, J=7 Hz), 3.75 to 3,86 (4H, m), 4,42 (2H, s), 7,22 and 7.36 (5H, m).

(69b) 2-(2-methyl-1,3-dioxolane-2-yl)ethanol

Formula 289

To methanol (150 ml) solution of 2-(2-(benzyloxy)ethyl)-2-methyl-1,3-dioxolane (10.1 g, to 45.4 mmol)obtained in stage (69a), was added palladium hydroxide (20 wt.% Pd (dry weight) on carbon, wet (maximum water 50%)) (900 mg) and the mixture was stirred in hydrogen atmosphere at room temperature for 16 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration through celite, then washed with methanol. The filtrate was concentrated. The obtained residue was purified by chromatography on a column of silica gel (silica gel, eluting solvent: heptane/ethyl acetate=1/0→gradient 1/1-0/1). The desired fractions were concentrated to obtain specified in the title compound (3.5 g, 58,3% yield) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 1.21 (3H, s)of 1.73 (2H, t, J=7 Hz), 3,40-3,50 (2H, m), 3.75 to 3,86 (4H, m), 4,30 (1H, t, J=5 Hz).

(69c) sodium salt of 2-(((3-methyl-4-(2-(2-methyl-1,3-dioxolane-2-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 290

Repeating the same procedure as in the stages (4f)to(4j) of example 4 (the operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid n is performed), using 2-(2-methyl-1,3-dioxolane-2-yl)ethanol obtained in stage (69b), with specified title compound (410 mg, total yield: 14,4%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,31 (3H, s), of 2.08 (2H, t, J=7 Hz), of 2.15 (3H, s), a 3.87 (4H, s), 4,10 (2H, t, J=7 Hz), to 4.38 (1H, d, J=13 Hz), and 4.75 (1H, d, J=13 Hz), 6,77-6,89 (2H, m), 6,92 (1H, d, J=6 Hz), 7,35-7,49 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 70: sodium salt of an optical isomer of 2-(((3-methyl-4-((2-methyl-1,3-dioxolane-2-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 291

Sodium salt of 2-(((3-methyl-4-((2-methyl-1,3-dioxolane-2-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (racemate) (185 mg), obtained as described in stages (67a)-(67c), was dissolved in water. To the solution was added dichloromethane and a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted with further dichloromethane. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated.

To the obtained free form was added a small amount of diethylamine and the mixture was shared by HPLC (column: CHIRALCEL OD-H 2 φ × 25 cm (manufactured by Daicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol/diethylamine=80/20/0,1 (vol./about./vol.), flow rate: 9 ml/min, detection: 254 nm). On the other hand, in each of the test tubes for testing in advance was placed an aqueous solution of Ki is rockside sodium (100 ml). The fraction of the optical isomer with a short retention time and the fraction of the optical isomer with a long retention time separately concentrated and the residues were separately dissolved in water. To each solution was added dichloromethane and a saturated aqueous solution of ammonium chloride. The aqueous layers separated was extracted with further dichloromethane. The organic layers were separately combined, dried over anhydrous sodium sulfate and concentrated. As described above received a free form (59 mg) optical isomer with a short retention time and a free form (56 mg) optical isomer with a long retention time, each in the form of light-gray foam.

Every free form optical isomer was subjected to the same operation for obtaining sodium salt, as performed on stage (4j) (formation of the sodium salt), to obtain the sodium salt (58 mg) optical isomer with short retention times and the sodium salt (53 mg) optical isomer with a long retention time, each in the form of a light yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; charts of both isomers of the same sodium salt of 2-(((3-methyl-4-((2-methyl-1,3-dioxolane-2-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (racemate).

HPLC:

(Conditions) column: CHIRALCEL OD-H (manufactured by Daicel Chemical Industries, Ltd.)(0,46φ × 25 cm), eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.6 ml/min, detection: UV 254 nm).

(Results of analysis) the retention time of the sodium salt of the optical isomer with a short retention time: 16 minutes, enantiomeric excess: 100%ee; the retention time of the sodium salt of the optical isomer with a long retention time: 22 minutes, enantiomeric excess: 100%ee.

Example 71: sodium salt of 2-(((4-(2-((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 292

(71a) 2-((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)ethanol

Formula 293

A mixture of (R)-(+)-1,2,4-butanetriol (30 g, 283 mmol), acetone (200 ml, 2724 mmol) and monohydrate p-toluensulfonate acid (1.4 g, 7.36 mmol) was stirred at room temperature for 16.5 hours. To the reaction mixture were added triethylamine and the mixture was concentrated. The crude product was purified by chromatography on a column of silica gel (silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0→1/1→1/3). The desired fractions were concentrated to obtain specified in the connection header (29,9 g, 72,3% yield) as a colorless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.37 (3H, s)of 1.43 (3H, s), 1,78-of 1.95 (3H, m), 3,60 (1H, t, J=8 Hz), 3,76-of 3.85 (2H, m), 4.09 to (1H, DD, J=6, 8 Hz), 4,27 (1H, quintet, J=6 Hz).

(71b) sodium salt of 2-(((4-(2-((R)-2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 294

Repeating the same procedure as in the stages (4f)to(4j) of example 4 (at the stage of obtaining Pikalyovo alcohol was performing a recrystallization using heptane, and the operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid is not performed)using 2-((4R)-2,2-dimethyl-1,3-dioxolane-4-yl)ethanol obtained in stage (71a), with specified title compound (320 mg, total yield: 8,5%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.26 (3H, s), 1,32 (3H, s), 1.91 a-2,04 (2H, m), 2,17 (3H, s), of 3.57 (1H, t, J=7 Hz), 3,98-to 4.28 (4H, m), 4,36 (0,5H, d, J=13 Hz), 4,37 (0,5H, d, J=13 Hz), 4,80 (0,5H, d, J=13 Hz), 4,80 (0,5H, d, J=13 Hz), is 6.78-6.87 in (2H, m)6,91 (1H, d, J=6 Hz), of 7.36-7,46 (2H, m), of 8.25 (1H, d, J=6 Hz).

Example 72: sodium salt of 2-(((4-(2-((4S)-2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 295

(72a) 2-((4S)-2,2-dimethyl-1,3-dioxolane-4-yl)ethanol

Formula 296

To (S)-(-)-1,2,4-butanetriol (30 g, 283 mmol) was added acetone (200 ml) and the monohydrate p-toluensulfonate acid (1.4 g, 7.36 mmol) and the mixture was stirred at room temperature overnight. To the reaction mixture were added triethylamine (4 ml) and the mixture was concentrated. The residue was purified by chromatography on a column of silica gel (silica gel (350 g, eluting rest ritel: ethyl acetate/heptane=18/82→6/4) to obtain specified in the connection header (30,2 g, yield: 73%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.37 (3H, s)of 1.43 (3H, s)and 1.83 (2H, q, J=6 Hz), 2,20 (1H, t, J=6 Hz), 3,60 (1H, t, J=8 Hz), 3,80 (2H, q, J=6 Hz), 4.09 to (1H, DD, J=6, 8 Hz), 4,27 (1H, quintet, J=6 Hz).

(72b) sodium salt of 2-(((4-(2-((4S)-2,2-dimethyl-1,3-dioxolane-4-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 297

Repeating the same procedure as in the stages (4f)to(4j) of example 4 (at the stage of obtaining Pikalyovo alcohol was performing a recrystallization using heptane, and the operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid is not performed)using 2-((4S)-2,2-dimethyl-1,3-dioxolane-4-yl)ethanol obtained in stage (72a), with specified title compound (386 mg, total yield: 10,1%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,25 (3H, s)is 1.31 (3H, s), 1,90-of 2.05 (2H, m), 2,17 (3H, s), of 3.57 (1H, t, J=8 Hz), 4,00-4,27 (4H, m), 4,37 (0,5H, d, J=13 Hz), 4,37 (0,5H, d, J=13 Hz), 4,78 (0,5H, d, J=13 Hz), 4,78 (0,5H, d, J=13 Hz), 6,79-6,87 (2H, m)6,91 (1H, d, J=6 Hz), 7,38-7,46 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 73: sodium salt of 2-(((3-methyl-4-(2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 298

(73a) of methyl (8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)acetate

Formula 299

A mixture of 1,3-dioxol the n-2,2-videotool (4 g, to 29.8 mmol), obtained separately as well as on stages (4a)-(4c), methylacetoacetate with 4.9 ml of 45.4 mmol), triethylorthoformate (5,2 ml of 31.3 mmol) and monohydrate p-toluensulfonate acid (163 mg, 0,856 mmol) was stirred at room temperature for 3 hours. To the mixture was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed twice with water and brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0-3/1-1/1). The desired fraction was concentrated to obtain specified in the connection header (of 3.46 g, 50.0% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.41 (3H, s)of 2.75 (2H, s), of 3.57 (3H, s), 3,60 (2H, d, J=12 Hz), the 3.65 (2H, d, J=12 Hz), a-3.84 (4H, s).

(73b) 2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethanol

Formula 300

To a solution in THF (40 ml) of methyl (8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)acetate (of 3.46 g, 14.9 mmol)obtained in stage (73a)was added at 0°C sociallyengaged (679 mg, of 17.9 mmol) and the mixture was stirred at 0°C. to room temperature for 3 hours. After stopping the reaction by the sequential addition of water (0.68 ml), 2N aqueous sodium hydroxide solution (0.68 ml) and water (2 ml) to the resulting CME and was added anhydrous sodium sulfate and celite. The mixture was filtered through a glass filter. The precipitate was washed with ethyl acetate and concentrated to obtain specified in the connection header (2,96 g, 97,3% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.27 (3H, s), is 1.81 (2H, t, J=7 Hz), 3,44 (2H, dt, J=6, 7 Hz), 3,55 (2H, d, J=12 Hz), 3,60 (2H, d, J=12 Hz), 3.72 points-to 3.89 (4H, m), or 4.31 (1H, t, J=6 Hz).

(73c) sodium salt of 2-(((3-methyl-4-(2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 301

Repeating the same procedure as in the stages (4f)to(4j) of example 4, using 2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethanol obtained in stage (73b), with specified title compound (298 mg, total yield: 15.1%) in the form of a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 1.38 (3H, s), 2,11-of 2.20 (5H, m), 3,62 (2H, d, J=12 Hz), 3,66 (2H, d, J=12 Hz), 3,79-are 3.90 (4H, m), 4,11 (2H, t, J=7 Hz), 4,37 (1H, d, J=13 Hz), of 4.77 (1H, d, J=13 Hz), 6,80-6,87 (2H, m), 6.90 to (1H, d, J=6 Hz), 7,38 was 7.45 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 74: sodium salt of 5-methyl-2-(((3-methyl-4-(2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 302

Repeating the same procedure as in the stages (4f)to(4j) of example 4, using 2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethanol obtained in stage (73b), and 5-methyl-1H-benzimidazole-2-thiol, polucen the th stage (47a), obtaining specified in the title compound (188 mg, total yield: 12,4%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 1.38 (3H, s), 2,09-of 2.20 (5H, m), of 2.34 (3H, s), 3,62 (2H, d, J=12 Hz), 3,66 (2H, d, J=12 Hz), of 3.77-to 3.92 (4H, m), 4,10 (2H, t, J=6 Hz), 4,35 (1H, d, J=13 Hz), and 4.75 (1H, d, J=13 Hz), to 6.67 (1H, d, J=8 Hz), 6.89 in (1H, d, J=6 Hz), 7,20 (1H, s), 7,29 (1H, d, J=8 Hz), of 8.25 (1H, d, J=6 Hz).

Example 75: sodium salt of 2-(((4-(2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 303

Repeating the same procedure as in the stages (5d)-(5h) example 5 (operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid is not performed)using 2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethanol obtained in stage (73b), and 1-oxide 4-chloro-2-methylpyridine obtained in stage (57a), with specified title compound (860 mg, total yield: 20,2%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,31 (3H, s), is 2.05 (2H, t, J=7 Hz)and 3.59 (2H, d, J=12 Hz), to 3.64 (2H, d, J=12 Hz), 3,78-a 4.03 (6H, m), of 4.45 (1H, d, J=12 Hz), of 4.54 (1H, d, J=12 Hz), of 6.71-of 6.90 (4H, m), 7,37-of 7.48 (2H, m), 8,32 (1H, d, J=6 Hz).

Example 76: sodium salt of 2-(((4-(2-(9-methyl-1,5,8,10-tetraoxaspiro[5,5]undec-9-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 304

(76a) of 2,2-bis((benzyloxy)methyl)-1,3-dioxane

Formula 305

A mixture of 1,3-bis(benzyloxy)acetone (20 g, 73,9 mmol)obtained in the same manner as in stage (4a), 1,3-propane diol (54 ml, 747 mmol), triethylorthoformate (13 ml, 78.2 mmol) and monohydrate p-toluensulfonate acid (394 mg, 2,07 mmol) was stirred at 50°C for 14,5 hours. To the mixture was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with water and salt solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0-3/1). The desired fractions were concentrated to obtain specified in the connection header (17,46 g, 71,9% yield) as a pale yellow oil.

1H NMR (400 MHz, DMSO-d6) δ ppm and 1.60 (2H, quintet, J=6 Hz), 3,60 (4H, s), 3,82 (4H, t, J=6 Hz), 4,49 (4H, s), 7,22-to 7.35 (10H, m).

(76b) 1,3-dioxane-2,2-videotool

Formula 306

To an ethyl acetate (200 ml) solution of 2,2-bis((benzyloxy)methyl)-1,3-dioxane (17,46 g, 53.2 mmol)obtained in stage (76a), was added palladium hydroxide (20 wt.% Pd (dry weight) on carbon, wet (maximum water 50%)) (1.7 g) and the mixture was stirred in hydrogen atmosphere at room temperature for 46 hours. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration, and then prom is Vali with ethyl acetate. The filtrate was concentrated to obtain specified in the connection header (to 7.67 g, 97,3% yield) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; was 1.58 (2H, quintet, J=6 Hz), 3,47 (4H, d, J=6 Hz), 3,80 (4H, t, J=6 Hz), 4,43 (2H, t, J=6 Hz).

(76c) methyl (9-methyl-1,5,8,10-tetraoxaspiro[5,5]undec-9-yl)acetate

Formula 307

A mixture of 1,3-dioxane-2,2-videotool (4 g, 27 mmol)obtained in stage (76b), methylacetoacetate (4,4 ml of 40.8 mmol), triethylorthoformate (4.6 ml, 27.7 mmol) and monohydrate p-toluensulfonate acid (160 mg, 0,843 mmol) was stirred at room temperature for 4.5 hours. To the mixture was added saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed twice with water and salt solution, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by chromatography on a column of silica gel (silica gel, eluting solvent: heptane/ethyl acetate=gradient 1/0-4/1-1/1). The desired fractions were concentrated to obtain specified in the title compound (1.60 g, 24.1% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.39 (3H, s), 1,53-to 1.63 (2H, m), of 2.72 (2H, s), of 3.56 (3H, s), 3,70-3,86 (8H, m).

(76d) 2-(9-methyl-1,5,8,10-tetraoxaspiro[5,5]undec-9-yl)ethanol

Formula 308

To a solution in THF (20 ml) of methyl (9-is etil-1,5,8,10-tetraoxaspiro[5,5]undec-9-yl)acetate (1.6 g, 6.5 mmol)obtained in stage (76c)was added at 0°C sociallyengaged (300 mg, 7.9 mmol) and the mixture was stirred at 0°C. to room temperature for one hour. After stopping the reaction by the sequential addition of water (0.3 ml), 2N aqueous sodium hydroxide solution (0.3 ml) and water (0.9 ml) to the resulting mixture was added anhydrous sodium sulfate and celite. The mixture was filtered through a glass filter. The precipitate was washed with ethyl acetate and concentrated. The obtained residue was purified by chromatography on a column of silica gel (silica gel, eluting solvent: heptane/ethyl acetate=gradient 3/1-1/4). The desired fractions were concentrated to obtain specified in the title compound (950 mg, 67,0% yield) as a colorless oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,24 (3H, s), 1,53-to 1.63 (2H, m), of 1.78 (2H, t, J=7 Hz), 3.43 points (2H, dt, J=6, 7 Hz), 3,67-of 3.85 (8H, m), 4,30 (1H, t, J=6 Hz).

(76e) sodium salt of 2-(((4-(2-(9-methyl-1,5,8,10-tetraoxaspiro[5,5]undec-9-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 309

Repeating the same procedure as in the stages (5d)-(5h) example 5 (operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid is not performed)using 2-(9-methyl-1,5,8,10-tetraoxaspiro[5,5]undec-9-yl)ethanol obtained in stage (76d), with specified title compound (228 mg, total yield: 11.4%) as white is solid substances.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.28 (3H, s), 1,53-of 1.64 (2H, m), 2,02 (2H, t, J=7 Hz), 3,68-4,00 (10H, m), 4,46 (1H, d, J=12 Hz), of 4.54 (1H, d, J=12 Hz), 6,72-of 6.90 (4H, m), of 7.36-7,47 (2H, m), 8,32 (1H, d, J=6 Hz).

Example 77: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

Formula 310

Repeating the same procedure as in the stages (5f)-(5h) (operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid was not performed), using (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol obtained in stage (12b), and 6,7-dihydro-1H-[1,4]like[2',3':4,5]benzo[d]imidazole-2-thiol, with receipt in the title compound (137 mg, total yield: 25,8%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, s)of 1.35 (3H, s), 2,03 with 2.14 (1H, m)of 2.16 (3H, s), 3,70-3,82 (2H, m), 3,92-was 4.02 (2H, m), 4.09 to (2H, d, J=7 Hz), 4,14 (4H, s), 4,32 (1H, d, J=13 Hz), and 4.75 (1H, d, J=13 Hz), 6,83 (2H, ), 6,92 (1H, d, J=6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 78: 6-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-5H-[1,3]dioxolo[4,5-f]benzimidazole

Formula 311

(78a) 5,6-dinitro-1,3-benzodioxol

Formula 312

A mixture of 5-nitro-1,3-benzodioxole (10 g, to 59.8 mmol), Tetramethylammonium (10.6 g, with 77.7 mmol) and dichloromethane (100 ml) displaced ivali while cooling on ice and then added to it dropwise at a temperature below 0°C triftormetilfullerenov anhydride (13.1 ml, to 77.7 mmol). The mixture was stirred at room temperature for 30 minutes and boiled under reflux during the night. The reaction mixture was stirred under cooling on ice and added to it Tetramethylammonium (4,07 g, and 29.9 mmol) and triftormetilfullerenov anhydride (5,03 ml, and 29.9 mmol). The resulting mixture was stirred at 50°C for 6 hours. The reaction mixture was cooled to room temperature and was added a saturated aqueous solution of sodium bicarbonate and ice. The mixture was stirred and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, magnesium sulfate and filtered through silica gel. The filtrate was concentrated to obtain specified in the title compound (7.4 g, 58,3%) as a yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm; 6,27 (2H, s), 7,31 (2H, s).

(78b) of 1,3-benzodioxole-5,6-diamine

Formula 313

A mixture of 5,6-dinitro-1,3-benzodioxole (7,4 g, is 34.9 mmol)obtained in stage (78a), and 10% palladium on carbon (containing 50% water, 1,09 g), methanol (200 ml) and tetrahydrofuran (50 ml) was stirred in hydrogen atmosphere for 3 days. The reaction mixture was filtered and the filtrate was concentrated to obtain a mixture (6,48 g)containing specified in the title compound as a yellow solid substances is TBA.

1H NMR (400 MHz, DMSO-d6) δ ppm; 4,10 (4H, Sirs), 5,67 (2H,s), 6,23 (2H, s).

(78c) 5H-[1,3]dioxolo[4,5-f]benzimidazole-6-thiol

Formula 314

A mixture of (6,48 g)containing 1,3-benzodioxole-5,6-diamine obtained in stage (78b), was dissolved in methanol (100 ml). To the mixture was added carbon disulfide (30 ml) and the mixture was stirred at room temperature during the day. The reaction mixture was concentrated under reduced pressure. To the resulting solid residue was added ethyl acetate, and the mixture was filtered. The solid was washed by adding tetrahydrofuran, ethyl acetate and diluted chloroethanol acid and the insoluble substance was collected by filtration, dried under reduced pressure at room temperature for 2 hours in a desiccator to obtain specified in the title compound (3.8 g, 56.1 per cent from 5,6-dinitro-1,3-benzodioxole) as a brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 5.99 (2H,s), 6,74 (2H, s), 12,36 (2H, Sirs).

(78d) 6-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-5H-[1,3]dioxolo[4,5-f]benzimidazole

Formula 315

Repeating the same procedure as in the stages (5f)-(5h) of example 5 using (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methanol obtained in stage (12b), and 5H-[1,3]dioxolo[4,5-f]benzimidazo is l-6-thiol, obtained in stage (78c), with specified title compound (347 mg, total yield: 51,9%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, s)of 1.34 (3H, s), 2,03 and 2.13 (1H, m)of 2.16 (3H, s), 3,71-3,81 (2H, m), 3,93-was 4.02 (2H, m), 4.09 to (2H, d, J=7 Hz), 4,30 (1H, d, J=13 Hz), 4,80 (1H, d, J=13 Hz), of 5.82 (2H, s), 6.89 in (2H, ), 6,92 (1H, d, J=6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 79: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

Formula 316

(79a) of 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-N,N-diisopropylidene-2-carboxamide

Formula 317

A mixture of 4-chloro-N,N-diisopropylidene-2-carboxamide (5 g, to 20.8 mmol)obtained in the same manner as in stage (92a), (2,2-dimethyl-1,3-dioxane-5-yl)methanol (3,34 g of 22.8 mmol)obtained in the same manner as at the stage of (11a), potassium hydroxide (to 2.57 g, with 45.8 mmol) and toluene (50 ml) was boiled under reflux with unit Dean-stark for 7 hours and was stirred at room temperature for 3 days. The reaction mixture was washed with water and saturated saline solution, dried over magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was dissolved in a mixture of toluene-heptane-ethyl acetate and subjected to chromatography on a column of NH silica gel (E. giraudi solvent: n-heptane/ethyl acetate=2/1→1/1). The fraction containing the desired product were concentrated and the solid residue was washed with heptane and collected by filtration to obtain specified in the connection header (5,39 g, 73,9%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.09 (6H, d, J=7 Hz), of 1.23 (3H, s)of 1.36 (3H, s)of 1.43 (6H, d, J=6 Hz), 2,02-2,10 (1H, m), 3,51-the 3.65 (2H, m), 3,74 (2H, DD, J=6, 12 Hz), 3,98 (2H, DD, J=4, 12 Hz), 4,16 (2H, d, J=7 Hz), 6,95-7,00 (2H, m), with 8.33 (1H, d, J=6 Hz).

(79b) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

Formula 318

Repeating the same procedure as in the stages (92d) and (5f)-(5h) (operation resultant deposition rates at the stage of oxidation of 3-chloroperbenzoic acid was not performed), using 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-N,N-diisopropylidene-2-carboxamide obtained in stage (79a), and 6,7-dihydro-1H-[1,4]like[2',3':4,5]benzo[d]imidazole-2-thiol, obtaining specified in the title compound (373 mg, total yield: 40,8%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.30 (3H, s)of 1.33 (3H, s), 1,82-of 1.95 (1H, m), 3,53-to 3.73 (3H, m), 3,79-3,91 (3H, m), 4,14 (4H, s), to 4.38 (1H, d, J=12 Hz), of 4.54 (1H, d, J=12 Hz), 6,55-6,63 (1H, m), 6,74-6,86 (1H, m), 6,83 (2H, s), of 8.28 (1H, d, J=6 Hz).

Example 80: sodium salt of 2-(((4-(1,4-dioxaspiro[4,4]non-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 319

(80a) methyl 1,4-dioxaspiro[4,4]nonan-6-carboxylate

Formula 320

The reflux condenser equipped with a water separator Dean-stark, was added to the round bottom flask containing methyl 2-cyclopentanecarboxylate (2 ml, 16.2 mmol), ethylene glycol (994 μl, 17.8 mmol), monohydrate p-toluensulfonate acid (139 mg, 0.73 mmol) and benzene (30 ml). The mixture was boiled under reflux for 2 hours. To the reaction mixture were added triethylamine (0,22 ml) and the mixture was concentrated and purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/heptane=1/9, 1/1) to obtain specified in the connection header (2,12 g, yield 70,3%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,59-1,72 (1H, m), 1.77 in-to 1.98 (4H, m), 2.06 to to 2.18 (1H, m), with 2.93 (1H, t, J=8 Hz), 3,70 (3H, s), 3,86-4,06 (4H, m).

(80b) 1,4-dioxaspiro[4,4]non-6-ylmethanol

Formula 321

To a suspension of sociallyengaged (630 mg, of 16.6 mmol) in diethyl ether (30 ml) was added at 0°C methyl 1,4-dioxaspiro[4,4]nonan-6-carboxylate (3.1 g, of 16.6 mmol)obtained by the method of stages (80a). The mixture was stirred at room temperature for 3 hours. Sequentially added to the mixture at 0°C. water (0.6 ml), 5N aqueous sodium hydroxide solution (0.6 ml) and water (1.8 ml) and the mixture was filtered. After adding to the filtrate water was separated, organic the sky layer. The aqueous layer was extracted three times with ethyl acetate. The obtained extract was dried over sodium sulfate, concentrated under reduced pressure and was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/heptane=1/4, 1/1) to obtain the specified title compound (1.9 g, yield to 72.4%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,51-of 1.92 (6H, m), 2,11-to 2.18 (1H, m), 2,53-2,69 (1H, W), to 3.58-to 3.73 (2H, m), 3,88-was 4.02 (4H, m).

(80c) sodium salt of 2-(((4-(1,4-dioxaspiro[4,4]non-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 322

Repeating the same procedure as in the stages (14a)-(14e) of example 14, using 1,4-dioxaspiro[4,4]non-6-ylmethanol obtained in stage (80b), with specified title compound (383 mg, total yield of 5 stages: 14,6%) as a pale yellow solid. It should be noted that in the same process, both at the stage of (14c), as solvent instead of ethanol used methanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,42 and 1.80 (5H, m), 1,86 is 2.01 (1H, m), of 2.15 (3H, d, J=7 Hz), 2,28-to 2.41 (1H, m), 3,70-3,93 (5H, m), as 4.02 is 4.13 (1H, m), to 4.38 (1H, d, J=13 Hz), of 4.77 (1H, d, J=13 Hz), 6,79-6,87 (2H, m), 6.89 in (1H, DD, J=2, 6 Hz), 7,37-7,46 (2H, m), of 8.25 (1H, d, J=6 Hz).

Example 81: sodium salt of 2-(((4-((3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)oxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 323

(81a) 3,3-dimethyl-1,5-dioxaspiro[5,5]undecane-9-ol

Formula 324

To a suspension of sociallyengaged (748 mg, of 19.7 mmol) in tetrahydrofuran (40 ml) was added at 0°C tertrahydrofuran ring solution of mono-2,2-dimethyltrimethylene 1,4-cyclohexandione (3,9 g of 19.7 mmol). The mixture was stirred at room temperature for 3 hours. After the mixture was sequentially added at 0°C. water (0.7 ml), 5N aqueous sodium hydroxide solution (0.7 ml) and water (2.1 ml), the mixture was dried over sodium sulfate, filtered, concentrated under reduced pressure and was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/heptane=1/2, 1/1, 2/1) to obtain the specified title compound (3.6 g, yield: 91,2%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 0.97 (6H, s), 1,51 is 1.60 (4H, m), 1,74 is 1.86 (2H, m), 2,04 with 2.14 (2H, m), 3,50 (4H, d, J=4 Hz), 3,74-a-3.84 (1H, m).

(81b) sodium salt of 2-(((4-((3,3-dimethyl-1,5-dioxaspiro[5,5]undec-9-yl)oxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 325

Repeating the same procedure as in the stages (14a)-(14e) of example 14, using 3,3-dimethyl-1,5-dioxaspiro[5,5]undecane-9-ol, obtained in stage (81a), with specified title compound (275 mg, total yield of 5 stages: 3,3%) as a white solid. It should be noted that in t the who process, as at the stage of (14b), after addition of acetic anhydride was added to perform reaction 10 equivalents of triethylamine relative to the derived 1-oxide pyridine. In the same process, both at the stage of (14c), the solvent was using tetrahydrofuran instead of ethanol.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.90 (6H, s), 1,62-of 1.94 (8H, m)to 2.18 (3H, s), of 3.45 (4H, d, J=6 Hz), 4,35 (1H, d, J=13 Hz), 4,70-4,78 (1H, W), to 4.81 (1H, d, J=13 Hz), for 6.81-to 6.88 (2H, m), 6,97 (1H, d, J=6 Hz), 7,39-7,46 (2H, m), 8,23 (1H, d, J=6 Hz).

Example 82: sodium salt of 2-(((4-(1,4-dioxaspiro[4,5]Dec-8-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 326

(82a) 1,4-dioxaspiro[4,5]Dec-8-ylmethanol

Formula 327

The reflux condenser equipped with a water separator Dean-stark, was added to the round bottom flask containing ethyl 4-cyclohexanecarboxylate (5 ml, of 31.4 mmol), ethylene glycol (1,93 ml, 34.5 mmol), monohydrate p-toluensulfonate acid (200 mg, 1.05 mmol) and benzene (30 ml). The mixture was boiled under reflux for 3 hours. To the reaction mixture were added triethylamine (181 μl, 1.3 mmol) and the mixture was concentrated. Tertrahydrofuran ring solution of the crude substance was added at 0°C to a suspension of sociallyengaged (1.31 g, 34.5 mmol) in tetrahydrofuran (30 ml). After stirring the mixture at room t is mperature within 7 hours successively added to the mixture at 0°C water (1.3 ml), 5N aqueous sodium hydroxide solution (1.3 ml) and water (3.9 ml). After drying over sodium sulfate, the mixture was filtered. The filtrate was concentrated under reduced pressure and was purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/heptane=1/2, 1/1, 2/1) to obtain the specified title compound (4.6 g, yield: 85.1%) are in the form of a colorless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.20 and 1.33 (3H, m), 1,48-to 1.61 (2H, m), 1,74-to 1.82 (4H, m), 3,49 (2H, t, J=6 Hz), 3,92-of 3.96 (4H, m).

(82b) sodium salt of 2-(((4-(1,4-dioxaspiro[4,5]Dec-8-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 328

Repeating the same procedure as in the stages (14a)-(14b) of example 14 and stages (7d)-(7f) of example 7, using 1,4-dioxaspiro[4,5]Dec-8-ylmethanol obtained in stage (82a), with specified title compound (115 mg, total yield of 5 stages: 7,3%) as a white solid. It should be noted that in the same process as in stage (14b), after addition of acetic anhydride were added to perform the reaction of 2 equivalents of triethylamine relative to the derived 1-oxide pyridine.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,23-of 1.55 (4H, m), 1,65-1,89 (5H, m), are 2.19 (3H, s), 3,81-of 3.95 (6H, m), 4,36 (1H, d, J=13 Hz), a 4.83 (1H, d, J=13 Hz), 6,79-to 6.88 (2H, m), 6.90 to (1H, d, J=6 Hz), 7,38-7,46 (2H, m), 8,24 (1H, d, J=6 Hz).

Example 83: sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)p is ridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 329

(83a) 4-(5,9-dioxaspiro[3,5]non-7-yloxy)-N,N-diisopropylidene-2-carboxamide

Formula 330

Repeating the same procedure as in stage (92c) of example 92, using 5,9-dioxaspiro[3,5]nonan-7-ol, separately obtained by the method of stages (9a)-(9e) example 9 and 4-chloro-N,N-diisopropylidene-2-carboxamide obtained by the method of stages (92a) of example 92, obtaining specified in the connection header (1,69 g, yield 97%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.12 to 1.31 (6H, d, J=6 Hz), 1,74-to 1.82 (2H, m), 2,24-of 2.34 (4H, m), 3,45-3,63 (1H, m), 3.72 points-a 3.87 (1H, m), 3,90 (2H, DD, J=5, 12 Hz), 4,05-to 4.15 (2H, m), 4,36-of 4.44 (1H, m), to 6.88 (1H, DD, J=2, 6 Hz), to 6.95 (1H, d, J=2 Hz), 8,40 (1H, d, J=6 Hz).

(6H was absent because he was blocked by a peak of the content of H2O 1,4-1,7 ppm)

(83b) (4-(5,9-dioxaspiro[3,5]non-7-yloxy)pyridine-2-yl)methanol

Formula 331

To tertrahydrofuran ring solution (60 ml) of 4-(5,9-dioxaspiro[3,5]non-7-yloxy)-N,N-diisopropylidene-2-carboxamide (1,69 g is 4.85 mmol)obtained in stage (83a), added sociallyengaged (552 mg, 14.5 mmol) at a temperature of from -6 to -5°C and then the mixture was stirred at room temperature for 1 hour. To the mixture were added successively water (0,55 ml), 5N aqueous solution of sodium hydroxide (0,55 ml) and water (1.65 ml). After drying over sodium sulfate with the ect was concentrated under reduced pressure and was purified by chromatography on a column of silica gel (eluting solvent: heptane, the ethyl acetate/heptane=1/1, ethyl acetate) to obtain the specified title compound (560 mg, yield 45,9%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.65 (2H, quintet, J=8 Hz), and 2.14 (2H, t, J=8 Hz), of 2.23 (2H, t, J=8 Hz), of 3.77 (2H, DD, J=3, 13 Hz), 3,99-4,06 (2H, m), of 4.44 figure-4.49 (3H, m), PC 6.82 (1H, DD, J=2, 6 Hz), of 6.96 (1H, d, J=2 Hz), 8,25 (1H, d, J=6 Hz).

(83c) sodium salt of 2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 332

Repeating the same procedure as in the stages (9h)-(9j) of example 9, using (4-(5,9-dioxaspiro[3,5]non-7-yloxy)pyridine-2-yl)methanol obtained in stage (83b), with specified title compound (100 mg, the total yield of 3 stages: 50%) as a white solid. It should be noted that in the same process as in stage (9h), 2-mercaptobenzimidazole was added to the reaction mixture and the mixture was stirred at room temperature for 25 hours, after which was added 3 equivalents of potassium hydroxide relative to the alcohol. The mixture was allowed to react at room temperature for 6 hours.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,56 is 1.70 (2H, m), 2,04-of 2.24 (4H, m), 3,44-of 3.53 (1H, m), 3,60-and 3.72 (2H, m), 3,80 (1H, DD, J=2, 13 Hz), of 3.96 (1H, t, J=2 Hz), to 4.41 (1H, d, J=12 Hz), of 4.57 (1H, d, J=12 Hz), 6,55 (1H, d, J=3 Hz), for 6.81-6,91 (3H, m), 7,40-of 7.48 (2H, m), 8,31 (1H, d, J=6 Hz).

Example 84: sodium salt of 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)is iridin-2-yl)methyl)sulfinil)-5-fluoro-1H-benzimidazole

Formula 333

(84a) 2,2-diethoxyacetate

Formula 334

To a solution of pyridine (30 ml) diethylacetal glycolic aldehyde (19,8 g, 148 mmol)was added dropwise a benzoyl chloride (51,7 ml, 444 mmol) at a temperature of from -20 to 30°C. the Mixture was stirred at room temperature for 167 hours and 50 minutes. After adding methanol and water, the mixture was extracted with ethyl acetate. The obtained organic layer was washed saturated aqueous ammonium chloride, saturated aqueous sodium hydrogen carbonate and saturated saline. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure and was purified by chromatography on a column of silica gel (eluting solvent: heptane, ethyl acetate/heptane=1/9). Then again conducted clearing chromatography on a column of silica gel (eluting solvent: heptane, ethyl acetate/heptane=1/100, 1/30, 1/10) to obtain the specified title compound (34 g, output: 96,4%) as a pale green oil.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.24 (6H, t, J=7 Hz), to 3.58-3,68 (2H, m), 3.72 points-is 3.82 (2H, m), 4,34 (2H, d, J=6 Hz), a 4.83 (1H, t, J=6 Hz), 7,42-of 7.48 (2H, m), 7,54-of 7.60 (1H, m), 8,02-of 8.09 (2H, m).

(84b) 5,7-dioxaspiro[2,5]Oct-6-imetelstat

Formula 335

The reflux condenser equipped with a water separator Di is a stark, was added to the round bottom flask containing 2,2-diethoxyacetate (33 g, 139 mmol)obtained in stage (84a), 1,1-bis(hydroxymethyl)cyclopropane (15.6 g, 153 mmol), monohydrate p-toluensulfonate acid (2.64 g, a 13.9 mmol) and toluene (100 ml). The mixture was boiled under reflux for 2 hours and cooled to room temperature. To the reaction mixture were added triethylamine (10 ml), ethyl acetate (100 ml) and silica gel (50 g). The mixture was concentrated and purified by chromatography on a column of silica gel (eluting solvent: ethyl acetate/heptane=1/30, 1/10) to obtain specified in the connection header (25,5 g, yield 73,9%) as a pale yellow oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,32 to 0.39 (2H, m), 0,68-0,76 (2H, m), 3,29 (2H, d, J=12 Hz), 4,16 (2H, d, J=12 Hz), to 4.41 (2H, d, J=5 Hz), to 4.98 (1H, t, J=5 Hz), 7,40-7,46 (2H, m), 7,52-7,58 (1H, m), 8,04-of 8.09 (2H, m).

(84c) 5,7-dioxaspiro[2,5]Oct-6-ylmethanol

Formula 336

To a mixture of 5,7-dioxaspiro[2,5]Oct-6-imetelstat (25,1 g, 101 mmol)obtained in stage (84b), and methanol (150 ml) was added 2N aqueous sodium hydroxide solution (55,6 ml, 111 mmol) at an internal temperature of 0 ° to 4°C. After stirring the mixture at room temperature for 3 hours was added a saturated aqueous solution of ammonium chloride to bring the pH to about 9. The mixture was concentrated under reduced pressure to about the same amount of methanolic the residue was added ethyl acetate and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and then to the obtained aqueous layer was added sodium chloride. The mixture was extracted with ethyl acetate and then the organic layers were combined and washed with saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and was then removed by distillation, the solvent is obtaining specified in the title compound (10 g, yield: 68,6%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; 0,33-0,37 (2H, m), 0,68 is 0.72 (2H, m)to 1.87 (1H, t, J=6 Hz), or 3.28 (2H, d, J=11 Hz), 3,68 (2H, DD, J=4, 6 Hz), 4,16 (2H, d, J=11 Hz), to 4.73 (1H, t, J=4 Hz).

(84d) sodium salt of 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)pyridine-2-yl)methyl)sulfinil)-5-fluoro-1H-benzimidazole

Formula 337

Repeating the same procedure as in stage (79a) of example 79, the stage (92d) of example 92, stage (5f) of example 5 and stages (9i)-(9j) of example 9, using 5,7-dioxaspiro[2,5]Oct-6-ylmethanol obtained in stage (84c), with specified title compound (298 mg, total yield of 5 stages: 14,1%) as a white solid. It should be noted that in the same operation as in stage (92d), used ethanol instead of methanol. In the same operation as in stage (5f), used 5-fluoro-1H-benzimidazole-2-thiol obtained in stage (52a) of example 52, instead of 2-mercaptobenzimidazole.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,33 (2H, DD, J=7, 8 Hz), 0,5 (2H, DD, J=7, 8 Hz), 3,24 (2H, d, J=12 Hz), 3,92-Android 4.04 (2H, m), 4.09 to (2H, d, J=12 Hz), 4,43 (1H, d, J=12 Hz), 4,50 (1H, d, J=12 Hz), 4,94 (1H, t, J=4 Hz), 6,64-of 6.78 (1H, m), 6,80-6,98 (2H, m), 7,16 (1H, DD, J=2, 10 Hz), 7,42 (1H, d, J=5, 8 Hz), of 8.37 (1H, d, J=6 Hz).

Example 85: sodium salt of 2-(((4-(6,8-dioxaspiro[3,5]non-7-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 338

(85a) CYCLOBUTANE-1,1-videotool

Formula 339

Tertrahydrofuran ring solution (50 ml) of diethyl 1,1-cyclobutanedicarboxylate (equal to 4.97 g of 24.8 mmol) was cooled on ice. To the solution was added sociallyengaged (1.6 g, 42.2 per mmol). The reaction mixture was stirred at 0°C for 10 minutes and then stirred at room temperature for 15 minutes. Stop the reaction by adding a mixture of diethyl ether-water to the reaction mixture. The solution with the precipitated precipitated inorganic compounds were dried over anhydrous magnesium sulfate and drove away the solvent under reduced pressure to obtain specified in the connection header (2,88 g, 100%) as a colourless oil.

1H NMR (400 MHz, CDCl3) δ ppm; 1,77-to 1.82 (4H, m), 1,90 is 1.96 (2H, m), of 2.38 (2H, Sirs in), 3.75 (4H, s).

(85b) 7-((benzyloxy)methyl)-6,8-dioxaspiro[3,5]nonan

Formula 340

The mixture CYCLOBUTANE-1,1-videotool (2,88 g of 24.8 mmol)obtained in stage (85a), benzyloxyacetaldehyde (and 3.72 g, 24.8 mm is l), monohydrate p-toluensulfonate acid (214 mg, 1.13 mmol) and toluene (70 ml) was boiled under reflux for one hour, removing the water by means of the apparatus of the Dean-stark. The reaction mixture was cooled to room temperature and added to it triethylamine (3 ml), and then drove the solvent. The residue was purified by chromatography on a column of silica gel (silica gel: 200 g, eluting solvent: ethyl acetate/heptane=1/50→1/9) to obtain the specified title compound (3.8 g, yield: 48,7%) as a white solid.

1H NMR (400 MHz, CDCl3) δ ppm; and 1.54 (2H, t, J=8 Hz), 1,90 (2H, quintet, J=8 Hz), 2,10 (2H, t, J=8 Hz), 3,49 (2H, d, J=4 Hz), 3,52 (2H, d, J=11 Hz), 4,00 (2H, d, J=11 Hz), of 4.57 (2H, s), of 4.67 (1H, t, J=4 Hz), 7,25-7,33 (5H, m).

(85c) 6,8-dioxaspiro[3,5]non-7-ylmethanol

Formula 341

A mixture of 7-((benzyloxy)methyl)-6,8-dioxaspiro[3,5]nonane (3.8 g, of 15.3 mmol)obtained in stage (85b), 20% palladium hydroxide (800 mg) and ethyl acetate (70 ml) was stirred in hydrogen atmosphere overnight. The reaction vessel was purged with nitrogen and the catalyst was removed by filtration. The filtrate was concentrated to obtain specified in the title compound (2.0 g, yield: 82,6%) as a white solid.

1H NMR (400 MHz, CDCl3) δ ppm; and 1.56 (2H, t, J=8 Hz)and 1.83 (1H, t, J=4 Hz), with 1.92 (2H, quintet, J=8 Hz), 2,10 (2H, t, J=8 Hz), 3,54 (2H, d, J=11 Hz), of 3.60 (2H, t, J=5 Hz), was 4.02 (2H, d, J=11 Hz, 4,56 (1H, t, J=4 Hz).

(85d) sodium salt of 2-(((4-(6,8-dioxaspiro[3,5]non-7-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 342

Repeating the same procedure as in the stages (62c) and (8d)-(8g), using the alcohol obtained in stage (85c), with specified title compound (198 mg, total yield of 13.6%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,51 (2H, t, J=8 Hz), of 1.85 (2H, quintet, J=8 Hz), to 1.98 (2H, t, J=8 Hz), of 2.16 (3H, s), of 3.54 (2H, d, J=10 Hz), of 3.97 (2H, d, J=10 Hz)to 4.01 (2H, d, J=4 Hz), to 4.38 (1H, d, J=13 Hz), was 4.76 (1H, d, J=13 Hz), a 4.86 (1H, t, J=4 Hz), 6,83-6,85 (2H, m), 6,92 (1H, d J=6 Hz), 7,41-the 7.43 (2H, m), of 8.25 (1H, d, J=6 Hz).

Example 86: sodium salt of 2-(((4-(2-(5,5-dimethyl-1,3-dioxane-2-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 343

Repeating the same procedure as in stage (1c)to(1g) of example 1, using 5,5-dimethyl-1,3-dioxane-2-ethanol (1,00 g, 6,24 mmol), to obtain the specified title compound (138 mg, 0.31 mmol) as a beige solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 0.68 (3H, s)of 1.09 (3H, s), 1,96-2,07 (2H, m)of 2.16 (3H, s)to 3.41 (2H, d, J=11 Hz), 3,53 (2H, d, J=11 Hz), 4,10 (2H, t, J=6 Hz), to 4.38 (1H, d, J=13 Hz)and 4.65 (1H, t, J=5 Hz), 4,74 (1H, d, J=13 Hz), 6,79-to 6.88 (2H, m), 6.90 to (1H, d, J=6 Hz), 7,38-7,47 (2H, m), of 8.25 (1H, d, J=6 Hz).

Example 87: sodium salt of 2-(((4-(1,3-dioxolane-4-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-BAA is tinidazole

Formula 344

Repeating the same procedure as in stage (1c)to(1g) of example 1, using clearinterval (1,76 ml, 20.3 mmol), to obtain the specified title compound (87 mg, 0.22 mmol) as a beige solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; to 2.18 (3H, s), 3,68-3,74 (1H, m)to 4.01 (1H, t, J=8 Hz), 4,06-4,17 (2H, m), 4,33-4,43 (2H, m), 4,78 (1H, d, J=13 Hz), is 4.85 (1H, s), 4,94 (1H, s), 6,78-to 6.88 (2H, m), 6,93 (1H, d, J=6 Hz), of 7.36-7,46 (2H, m), compared to 8.26 (1H, d, J=6 Hz).

Example 88: sodium salt of an optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 345

The following describes another method of synthesis carried out in example 20.

(88a) optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 346

Toluene (4 ml) solution of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (500 mg, to 1.21 mmol), complex isopropoxide zirconium(IV) and isopropanol (295 mg, from 0.76 mmol) and N,N,N',N'-(-)-tetramethyl-(D)-tartramide (396 mg, 1.94 mmol) was stirred in the atmosphere nitrogen at 40°C for 1 hour. After cooling the solution to room temperature was added N,N-disop militiamen (91 μl, 0.52 mmol) and then to the mixture was added dropwise a hydroperoxide cumene (243 μl, of 1.32 mmol content 80%), after which the mixture was stirred at room temperature for 22 hours. Once added saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 30 g, eluting solvent: ethyl acetate ethyl acetate/methanol 7:3 gradient 1;1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated to obtain specified in the title compound (328 mg, yield: 63%) as a colourless foam.

HPLC:

(Conditions) column: CHIRALPAK IA (manufactured by Daicel Chemical Industries, Ltd.)(0,46 φ × 25 cm),

eluent: hexane/ethanol=3/2 (about./vol.), flow rate: 0.5 ml/min, detection: UV (254 nm).

(Results of analysis):

retention time: 17.5 minutes, enantiomeric excess: 99%ee.

(88b) sodium salt of an optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 347

Repeating the same procedure as in example 20b, for the formation of the three-the howl of salt with obtaining specified in the title compound (299 mg, yield: 88%) as a white solid.

HPLC:

(Conditions) column: CHIRALPAK IA (manufactured by Daicel Chemical Industries, Ltd.)(0,46 φ × 25 cm),

eluent: hexane/ethanol=3/2 (about./vol.), flow rate: 0.5 ml/min, detection: UV (254 nm).

(Results of analysis):

retention time: 18.0 minutes, enantiomeric excess: 99%ee.

specific rotation: αD22,4=+78,51 (c=0.5, EtOH).

Example 89) sodium salt of an optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 348

The following describes another method of synthesis carried out in example 20.

(89a) Optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 349

A mixture of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (500 mg, to 1.21 mmol) and N,N,N',N'-(-)-tetramethyl-(D)-tartramide (396 mg, 1.94 mmol) in toluene (4 ml) was dissolved by heating at 40°C for 10 minutes in nitrogen atmosphere. Was added to the mixture tetrabutoxide hafnium (315 μl, 0.78 mmol) and then stirred the mixture at the same temperature for one hour. After cooling the reaction mixture to room temperature N,N-diisopropylethylamine (90 μl, 0.52 mmol) and then was added dropwise a hydroperoxide cumene (267 μl, of 1.46 mmol content 80%), after which the mixture was stirred at room temperature for 22 hours. Once added saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution, the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel: 30 g, eluting solvent: ethyl acetate ethyl acetate/methanol 7:3 gradient 1;1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated to obtain specified in the title compound (206 mg, yield: 40%) as a colourless foam.

HPLC:

(Conditions) column: CHIRALPAK IA (manufactured by Daicel Chemical Industries, Ltd.)(0,46 φ × 25 cm),

eluent: hexane/ethanol=3/2 (about./vol.), flow rate: 0.5 ml/min, detection: UV (254 nm).

(Results of analysis):

retention time: 17.2 minutes, enantiomeric excess: 90%ee.

(89b) sodium salt of an optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 350

Repeating the same procedure as in example 20b, for the formation of sodium with and obtaining specified in the title compound (182 mg, yield: 84%) as a white solid.

HPLC:

(Conditions) column: CHIRALPAK IA (manufactured by Daicel Chemical Industries, Ltd.)(0,46 φ × 25 cm),

eluent: hexane/ethanol=3/2 (about./vol.), flow rate: 0.5 ml/min, detection: UV (254 nm).

(The results)

retention time: 18.1 minutes, enantiomeric excess: 89%ee.

Example 90: optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 351

The following describes another method of synthesis carried out in example 20a.

Into a flask were introduced (S)-(-)-2-(3,5-di-tert-butylcyclohexylamine)-3,3-dimethyl-1-butanol (115 mg, 0.35 mmol), venodilatation (64 mg, 0.24 mmol) and acetonitrile (0.8 ml) and the mixture was stirred at room temperature for 30 minutes. The mixture was added to dichloromethane (3 ml) solution of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (500 mg, to 1.21 mmol), prepared in another flask, and the resulting mixture was stirred at room temperature for 30 minutes. Was added an aqueous solution of hydrogen peroxide (150 μl), dividing the entire solution for 15 servings (10 µl per serving), for 20 hours and then the mixture was stirred for 24 hours. Once added 1N aqueous sodium hydroxide solution (3 ml) and the mixture re exively within 48 hours, was added to a mixture of saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium thiosulfate solution and then the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (NH silica gel 30 g, eluting solvent: ethyl acetate ethyl acetate/methanol 7:3 gradient 1;1). The fractions containing specified in the title compound was collected with ethyl acetate and concentrated to obtain specified in the title compound (76 mg, yield: 15%) as a colourless foam.

HPLC:

(Conditions) column: CHIRALPAK IA (manufactured by Daicel Chemical Industries, Ltd.)(0,46 φ × 25 cm),

eluent: hexane/ethanol=3/2 (about./vol.), flow rate: 0.5 ml/min, detection: UV (254 nm).

(The results)

retention time: 19.9 minutes, enantiomeric excess: 45%ee.

Example 91: sodium salt of an optical isomer of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 352

An ethanol solution of sodium salt (racemate) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole (192 mg) were prepared and divided HPLC (column: CHIRALCEL OD-H 2 φ × 25 cm (manufactured by Daicel Chemical Industries, Ltd.), mobile phase: ethanol/n-hexan/2, flow rate: 3.0 ml/min, wavelength of the detection: 254 nm). Immediately after receiving the fractions in each fraction was added 1N aqueous sodium hydroxide solution (1 ml). Collected respectively the fractions containing the optical isomers with short and long retention time, and shared them with ethyl acetate and saturated aqueous ammonium chloride. The organic layer of each fraction was dried over anhydrous sodium sulfate, concentrated and subjected to azeotropic distillation with diethyl ether.

The remainder of the optical isomer with a short retention time was subjected to the above operations fractionation by HPLC, separation, drying and concentration. The obtained residue was purified by chromatography on a column of silica gel (NH silica gel 20 g, eluting solvent: dichloromethane, dichloromethane/methanol=10/1). Then performed the same as described above, the operations of fractionation by HPLC, separation, drying, concentration and azeotropic distillation with diethyl ether to obtain free-form optical isomer (20 mg) with a short retention time in the form of a colorless solid.

The remainder of the optical isomer with a long retention time was subjected to the same, as described above, the operations of fractionation by HPLC, separation, drying, concentration and the zeotrope distillation with diethyl ether to obtain free-form optical isomer (14 mg) with a long retention time in the form of a colorless solid.

Each of the available optical isomers were subjected to conversion into the sodium salt in the same way as in stage (11i) of example 11, to obtain the sodium salt (18 mg) optical isomer with short retention times and the sodium salt (14 mg) optical isomer with a long retention time, both in the form of a colorless solid.

1H NMR(400 MHz, DMSO-d6): for the sodium salts of both optical isomers obtained the same data as in the case of sodium salt (racemate) of 2-(((3-methyl-4-(1,5,9-dioxaspiro[5,5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

HPLC:

(Conditions) column: CHIRALPAK IA (manufactured by Daicel Chemical Industries, Ltd.)(0,46 φ × 25 cm),

eluent: hexane/ethanol=4/1 (about./vol.), flow rate: 0.5 ml/min, detection: UV (280 nm).

(Results of analysis):

for the sodium salt of the optical isomer with a short retention time

retention time: 36 minutes, enantiomeric excess: >98,0%ee,

specific rotation: αD25,5=+107,73 (c=0,32, EtOH);

for the sodium salt of the optical isomer with a long retention time

retention time: 44 minutes, enantiomeric excess: >98,0%ee,

specific rotation: αD25,0=-115,85 (c=0,19, EtOH).

Example 92: sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-ethylpyridine-2-yl)methyl)sulfinil)-1H-benzimidazole is

Formula 353

(92a) 4-chloro-N,N-diisopropylidene-2-carboxamide

Formula 354

Thionyl chloride (60 ml, 823 mmol) was diluted with toluene (100 ml) and was heated to 45°C. To the mixture was added N,N-dimethylformamide (16 ml, 207 mmol) and the resulting mixture was stirred at the same conditions for one hour. To the mixture was added Pikalyovo acid (25 g, 203 mmol) and the resulting mixture was stirred at 80°C for 1 hour and 20 minutes. After the reaction mixture was concentrated and to the residue was added Diisopropylamine (185 ml, 807 mmol) and acetonitrile (500 ml), the mixture was stirred at room temperature for 21 hours and 30 minutes. After concentrating the reaction mixture, the residue was distributed between ethyl acetate and water. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain specified in the connection header (31.1 g, output: 63,6%) as a pale brown solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; a 1.11 (6H, d, J=7 Hz), USD 1.43 (6H, d, J=6 Hz), 3,54-3,66 (2H, m), 7,56 to 7.62 (2H, m), 8,51-8,56 (1H, m).

(92b) 4-chloro-3-ethyl-N,N-diisopropylidene-2-carboxamide

Formula 355

Tetrahydrofuranate solution (digidrirovanny) (50 ml) Diisopropylamine (1.35 g, 13.3 mmol) was added dropwise n-utility (a 1.6 M hexane solution of 6.75 ml, about 10.8 mmol) while cooling on ice in a nitrogen atmosphere and the resulting mixture was stirred at the same conditions for 30 minutes. After the reaction mixture was cooled to -70°C, was added to the mixture tertrahydrofuran ring solution of 4-chloro-N,N-diisopropylidene-2-carboxamide (2 g, 8,31 mmol)obtained in stage (92a), and the resulting mixture was stirred at -70°C for 1.5 hours. To the reaction mixture was added ethyliodide (798 μl, 10 mmol) and the resulting mixture was stirred at a temperature of from -70 to 0°C for 3 hours. To the reaction mixture were added saturated aqueous solution of ammonium chloride and was extracted with her with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on a column of silica gel (eluting solvent: heptane/ethyl acetate) to obtain the specified title compound (1.9 g, yield: 85.1%) are in the form of a light yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm;to 1.15 (6H, d, J=7 Hz), 1,25 (3H, t, J=7 Hz), was 1.58 (6H, d, J=7 Hz), 2,70-2,84 (2H, m), 3,42-of 3.60 (2H, m), 7,26 (1H, d, J=6 Hz), of 8.28 (1H, d, J=6 Hz).

(92c) 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-ethyl-N,N-diisopropylidene-2-carboxamide

Formula 356

To dimethylsulfoxide (20 ml) solution of 4-chloro-3-ethyl-N,N-diisopropyl ridin-2-carboxamide (1 g, 3.72 mmol)obtained in stage (92b), was added at room temperature sodium hydride in oil (195 mg, of 4.46 mmol content 55%). To the mixture was added (2,2-dimethyl-1,3-dioxane-5-yl)methanol (598 mg, 4.09 to mmol)obtained in example (11a), and the mixture was stirred at room temperature for 16.5 hours. Was added to the reaction mixture ethyl acetate. The mixture was washed twice with a saturated solution of salt. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was washed with diethyl ether obtaining specified in the title compound (520 mg, yield: 36,9%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm; 1,10-1,22 (9H, m)of 1.44 (3H, s), for 1.49 (3H, s), 1,58 (6H, d, J=7 Hz), 2,14-2,22 (1H, m), 2,55-of 2.66 (2H, m), 3.46 in-of 3.60 (2H, m), 3,86-3,98 (2H, m), 4,10-4.26 deaths (4H, m), 6,77 (1H, d, J=6 Hz), 8,32 (1H, d, J=6 Hz).

(92d) (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-ethylpyridine-2-yl)methanol

Formula 357

To tertrahydrofuran ring solution (10 ml) of 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-ethyl-N,N-diisopropylidene-2-carboxamide (520 mg, 1.37 mmol)obtained in stage (92c), added sociallyengaged (156 mg, 4,11 mmol) while cooling on ice and the mixture was stirred while cooling on ice for one hour. To the reaction mixture were added successively water (0.2 ml), 2N aqueous sodium hydroxide solution (0.2 ml) and water (0.6 ml). C is the mixture was filtered through celite and the filtrate kept at reduced pressure the solvent. To methanol (20 ml) solution of the residue was added borohydride sodium (51.8% of mg, 1.37 mmol) and the mixture was stirred at room temperature for 1 hour. Was added to the reaction mixture, a saturated solution of salt. The mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain the crude specified in the title compound (456 mg, yield: 118%) as a pale yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm; of 1.09 (3H, t, J=7 Hz), USD 1.43 (3H, s), for 1.49 (3H, s), 2,14-2,22 (1H, m), 2,52 (2H, q, J=7 Hz), 3,90 (2H, DD, J=5, 12 Hz), 4,08-4,22 (4H, m), 4,71 (2H, s)6,76 (1H, d, J=6 Hz), 8,31 (1H, d, J=6 Hz).

(92e) sodium salt of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-ethylpyridine-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 358

Repeating the same procedure as in the stages (6d), (6e) and (6f) of example 6, using (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-3-ethylpyridine-2-yl)methanol obtained in stage (92d), with specified title compound (159 mg, total yield: 25%) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.07 (3H, t, J=7 Hz), of 1.33 (3H, s)of 1.35 (3H, s), 2.06 to of 2.16 (1H, m), 2,62-2,82 (2H, m), of 3.78 (2H, DD, J=6, 12 Hz), 3,98 (2H, DD, J=4, 12 Hz), 4.09 to (2H, d, J=10 Hz), 4,36 (1H, d, J=13 Hz), of 4.77 (1H, d, J=13 Hz), 6,80-6,98 (2H, m), 6,93 (1H, d, J=6 Hz), 7,38-of 7.48 (2H, m), of 8.28 (1H, d, J=6 Hz).

Example 93: sodium salt of 2-(((4-((2,2-dimethyl,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

Formula 359

Repeating the same procedure as in the stages (5f)-(5h), using (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol, which was received, exposing monohydrate (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol obtained in the same manner as in example 96(5), azeotropic distillation with toluene, and 6.7-dihydro-1H-[1,4]like[2',3':4,5]benzo[d]imidazole-2-thiol, obtaining specified in the title compound (395 mg, total yield: 61.7 per cent) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.32 (3H, s)of 1.35 (3H, s), 2.00 in to 2.13 (1H, m)to 2.18 (6H, s), 3,69-3,86 (4H, m), 3,91-a 4.03 (2H, m), 4,14 (4H, s), or 4.31 (1H, d, J=12 Hz), 4,70 (1H, d, J=12 Hz), PC 6.82 (2H, s), 8,19 (1H, s).

Example 94: sodium salt of 2-(((3-methyl-4-(2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

The formula 360

Repeating the same procedure as in the stages (5d)-(5h), using 2-(8-methyl-1,4,7,9-tetraoxaspiro[4,5]Dec-8-yl)ethanol and 6,7-dihydro-1H-[1,4]like[2',3':4,5]benzo[d]imidazole-2-thiol obtained in (73b), with specified title compound (110 mg, contents: 93,5%, total yield: 9,2%) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.39 (3H, s), 2,05-of 2.23 (5H, m), 3,56-and 3.72 (4H, m), 3.75 to 3,93 (4H, m), as 4.02-4,22 (6H, m), or 4.31 (1H, d, J=13 Hz), 75 (1H, d, J=13 Hz), PC 6.82 (2H, s), to 6.88 (1H, d, J=5 Hz), 8,24 (1H, d, J=5 Hz).

Example 95: sodium salt of 2-(((4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole

Formula 361

Repeating the same procedure as in the stages (5f)-(5h), using (4-(5,7-dioxaspiro[2,5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methanol obtained in example (2d), and 6,7-dihydro-1H-[1,4]like[2',3':4,5]benzo[d]imidazole-2-thiol, obtaining specified in the title compound (364 mg, total of 55.6% yield) as a pale pink solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 0,26-0,40 (2H, m), from 0.50 to 0.66 (2H, m)of 2.16 (3H, s), 3,26 (2H, d, J=12 Hz), 4.09 to (2H, d, J=4 Hz), 4,12 (2H, d, J=12 Hz), 4,15 (4H, s)to 4.33 (1H, d, J=13 Hz), was 4.76 (1H, d, J=13 Hz), 5,02 (1H, t, J=4 Hz), 6,83 (2H, s)6,94 (1H, d, J=6 Hz), compared to 8.26 (1H, d, J=6 Hz).

Example 96: sodium salt of an optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 362

(1) Optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (429 mg, 1 mmol) was dissolved in ethanol (0,85 ml) and to the solution was added 1N aqueous sodium hydroxide solution (1 ml, 1 mmol). After the mixture was concentrated under reduced Yes is the population and to the residue was added ethanol (0,85 ml), the mixture was concentrated under reduced pressure. Added tetrahydrofuran (0,85 ml), then was added tert-butyl methyl ether (8 ml), making the mixture turbid (milky white). After the mixture was allowed to stand at room temperature overnight, the precipitate was collected by filtration to obtain specified in the title compound (191 mg, yield 42%) (sample A) in the form of a white solid.

(2) Optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (490 mg, to 1.14 mmol, enantiomeric excess: 98%ee) was dissolved in ethanol (0,98 ml) and to the solution was added 1N aqueous sodium hydroxide solution (1,14 ml, to 1.14 mmol). After the mixture was concentrated under reduced pressure and added to it the ethanol (0,98 ml), the mixture was concentrated under reduced pressure. This operation was repeated twice. After adding ethyl acetate (6 ml) to the mixture was added diluted specified in the title compound, obtained in stage (1) (sample A). The mixture was concentrated under reduced pressure. Adding ethyl acetate (8 ml), to the mixture was added diluted specified in the title compound, obtained in stage (1) (sample A), and gave the mixture to stand at room temperature for 1 hour 13 minutes. Added to a mixture of ethyl acetate (2 m is) and gave it to stand at room temperature overnight. The precipitate was collected by filtration to obtain specified in the title compound (309 mg, yield 60%)(sample B) in the form of white crystals.

(3) To ethanol (8 ml) solution of the optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (4 g, 9,31 mmol) was added 1N aqueous sodium hydroxide solution (9,31 mmol, 9,31 mmol). After stirring the mixture at the same conditions for 2 hours, drove away the solvent under reduced pressure. Was added to the residue ethanol (8 ml) and drove him away under reduced pressure. Repeating this operation twice, to the residue was added ethyl acetate (80 ml), was added as the seed crystal is specified in the header connection (sample B)obtained in stage (2), and the mixture was allowed to stand at room temperature overnight. After the mixture was still allowed to stand at 4°C overnight, the precipitate was collected by filtration to obtain specified in the title compound (1.1 g, yield: 25,9%) (sample C) as light yellow crystals. Part of the solvent from the resulting filtrate drove away under reduced pressure. The crystals obtained after the filtrate was allowed to stand at room temperature for 2 hours, collected by filtration to obtain specified the CSOs in the title compound (2.5 g, output: 59,5%) (sample D) in the form of light yellow crystals.

(4) To an ethanol (10 ml) solution of the optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (200 mg, 0,466 mmol, enantiomeric excess: 77,1%ee) was added at room temperature, 1N aqueous sodium hydroxide solution (466 μl, 0,466 mmol), after which the mixture was concentrated under reduced pressure. Adding ethanol (10 ml), the mixture was concentrated under reduced pressure. This operation was repeated twice. To the obtained residue was added ethyl acetate (40 ml) and the resulting suspension was dissolved in ethanol. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate (4 ml) and ethanol (2 ml). Then added as a seed specified in the header connection (sample D)obtained in stage (3), and the mixture was concentrated under reduced pressure. The residue was dissolved in 2-propanol (0.4 ml) and ethyl acetate (4 ml) and then diluted added is listed in the title compound (sample D)obtained in stage (3). Allowing the mixture to stand at room temperature, it was concentrated under reduced pressure. After the resulting mixture was dissolved in ethanol (0.2 ml) and ethyl acetate (3 ml), specified in the header connection (sample D)obtained in stage (3)was added at room is the temperature in diluted under stirring. After about 10 minutes the precipitate began to emerge. After further stirring for about 10 minutes the precipitate was collected by filtration to obtain specified in the title compound (44 mg, yield 21%)(sample E) in the form of white crystals.

(5) Optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (340 mg, 0,792 mmol, enantiomeric excess, 47%ee) was dissolved in ethanol (4.5 ml) at room temperature and the solution was added dropwise 1N aqueous sodium hydroxide solution (792 μl, 0,792 mmol). The mixture was concentrated at 40°C under reduced pressure. After adding ethanol (0.9 ml) and the mixture was concentrated under reduced pressure. This operation was repeated two times to azeotrope to remove water. Adding to a mixture of ethyl acetate, the mixture was stirred at room temperature, collected by filtration and washed with ethyl acetate (4.5 ml) to obtain specified in the connection header (sample F) (230 mg, yield 64,3%) as a pale yellow solid. The filtrate was subjected to the same operations with obtaining specified in the connection header (sample G)(47 mg, yield: 13,1%) as a pale yellow solid.

HPLC:

(Conditions) column: CHIRALPAK AD-H (manufactured by Daicel Chemical Industries, Ltd.)(0,46 φ × 25 cm),

eluent: hexane/ethanol=1/1 (vol./vol.), Corot flow: 0.6 ml/min, detection: UV 254 nm).

(Results of analysis):

sample B: retention time: 16.7 minutes, enantiomeric excess: 100%ee;

sample C: retention time: 17.2 minutes, enantiomeric excess: 100%ee;

sample D: retention time: 16,8 minutes, enantiomeric excess: 100%ee;

sample E: retention time: 18.0 minutes, enantiomeric excess: 100%ee;

sample F: retention time: 17.1 minutes, enantiomeric excess: 39%ee;

sample G: retention time: 17.1 minutes, enantiomeric excess: 62%ee.

Example 97: sodium salt of an optical isomer (short retention time) of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

(1) 1-oxide 2,3,5-trimethylpyridine

Formula 363

To acetic acid (1,43 kg, 23,83 mol) was added 2,3,5-trimethylpyridine (1,43 kg, 11,80 mol) over 15 minutes. After 15 minutes, was added dropwise 35% solution of hydrogen peroxide (1,38 kg 14,2 mol) for 30 minutes, after which the mixture was stirred at 90-95°C during the night. To the reaction mixture was added sodium sulfite (220 g). The reaction mixture was poured into a mixture of sodium carbonate (2.5 kg) and water (12 l) and the mixture was extracted with chloroform (3.0 l × 4). The obtained organic layer was concentrated until precipitation of crystals. To the precipitate was added n-hexane (2.5 l). The resulting mixture was stirred under cooling on ice for whom the night. The obtained crystals were filtered off to obtain the desired compound (1,53 kg).

(2) 1-oxide 2,3,5-trimethyl-4-nitropyridine

Formula 364

To 98% sulfuric acid (4,93 kg, to 49.3 mol) was added 1-oxide 2,3,5-trimethylpyridine (1,38 kg, 10.1 mol). After the resulting mixture was added dropwise over 50 minutes 97% nitric acid (1.44 kg), the mixture was heated at 85°C for 4 hours. The reaction mixture was poured into a mixture of ammonium hydrogen carbonate (10,6 kg) and water (9.0 l). The mixture was extracted with ethyl acetate (3.0 l × 3). The obtained organic layer was concentrated and dried in vacuum overnight to obtain the desired product (1.50 kg).

(3) 1-oxide 4-chloro-2,3,5-trimethylpyridine

Formula 365

To 1-oxide 2,3,5-trimethyl-4-nitropyridine (850 g of 4.67 mol) was added water (400 g) and 36% concentrated chloroethanol acid (1,69 kg) and the mixture was heated to 70°C. To the mixture was added N,N-dimethylformamide (115 ml) and then the resulting mixture was heated to 100°C. after the reaction, the reaction mixture was cooled to 20°C and was poured into a mixture of potassium carbonate (1,40 kg) and water (7 l). The mixture was extracted with chloroform (1.0 l × 3), the organic layer was dried over sodium sulfate and concentrated. The crude product was stirred for 2 hours in a mixture of diisopropyl ether (500 ml) and n-hexane (1.0 l) and then Khujand who have been filtering with suction. The obtained wet product was dried in vacuum overnight to obtain the desired product (666,4 g).

(4) 1-oxide 4-(2,2-dimethyl-1,3-dioxane-5-ylethoxy)-2,3,5-trimethylpyridine

Formula 366

A mixture of 1-oxide 4-chloro-2,3,5-trimethylpyridine (840 g), (2,2-dimethyl-1,3-dioxane-5-yl)methanol (688 g) and toluene (2,52 l) was boiled under reflux, removing water. Continuing azeotropic dehydration was added to the reaction mixture of potassium hydroxide (0,58 kg) for 3 hours and 45 minutes and continued azeotropic dehydration for 2.5 hours. The mixture was cooled to 30°C or below, and added to it in ethyl acetate (2.5 l) and 17% saline (3.5 l), after which the mixture was allowed to stand over night. An ethyl acetate layer was separated and the aqueous layer was extracted with ethyl acetate (1.0 l × 3). An ethyl acetate layers were combined, filtered through celite and concentrated under reduced pressure to obtain the desired product (1.20 kg).

(5) monohydrate (4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methanol

Formula 367

To a mixture of N-oxide of 4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-2,3,5-trimethylpyridine (1.20 kg) and sodium acetate (0.18 kg), heated at 50-60°C, was added dropwise acetic anhydride (1,10 kg) for 1.5 hours. After 0.5 hours the mixture was heated at 80°C for 4.5 hours and cooled until the internal temperature is s below 30°C or less, gave her to stand up and concentrated under reduced pressure. The obtained residue was dissolved in methanol (1.0 l) and the solution was added to a mixture of 48% aqueous sodium hydroxide solution (0,71 kg) and cold water (2,85 l) for one hour. After stirring at room temperature for 5 hours and 45 minutes, the mixture was concentrated under reduced pressure. To the residue obtained after concentration, was added water (3.0 l) and the mixture was extracted with toluene (2.3 l × 4). Toluene layers were combined and washed with water (1.2 l). The obtained organic layer was filtered through celite and concentrated. To the obtained residue was added at room temperature diisopropyl ether (1,15 l) and then add warm water (45°C, 74 ml). After precipitation of crystals, the mixture was stirred at 25°C for 1 hour. Vliv heptane (3.6 l), the mixture was stirred over night. The mixture was then stirred while cooling on ice for 5 hours, then was filtered to obtain yellow crystals. To the resulting yellow crystal was added diisopropyl ether (3.5 l) and the mixture was dissolved at 50°C. After insoluble matter was removed by filtration, the mixture was gradually cooled and allowed it to stand at 5°C during the night. The obtained crystals were filtered and washed with heptane (0.5 l) and the mixture was dried with air to obtain the desired product is (0,69 kg).

(6) 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 368

To the monohydrate (4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methanol (690 g) was added toluene to perform azeotropic dehydration (2,1 l × 5, 1,75 l × 1). To the obtained concentrated product was added toluene (393 ml) with a toluene solution (921 g) (4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methanol.

To a toluene solution (4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methanol (845,7 g, content: 61,7%, quantity: 521,8 g 1,855 mol) were added sequentially tetrahydrofuran (2609 ml), toluene (669 ml) and triethylamine (375,3 g 3,709 mol) in nitrogen atmosphere. The mixture was stirred while cooling with a mixture of dry ice/ethanol. 30 minutes after the start of cooling was added dropwise methanesulfonanilide (254,9 g, 2,226 mol) within 42 minutes. Upon completion of the drop addition, the mixture was stirred while cooling in an ice bath. After about 1.5 hours the mixture was poured tertrahydrofuran ring solution (3653 ml) 2-mercaptobenzimidazole (334,28 g, 2,226 mol) for 2 minutes and the mixture was stirred at room temperature for about 18 hours. In the reaction mixture is poured into toluene (3653 ml) and 20% (wt./wt.) an aqueous solution of sodium hydroxide (1852,4 g) and then added H2O (2322 ml). Thus was carried out by extraction and separation. The organic layer was washed twice with 20% (wt./wt.) aqueous solution of ammonium chloride (4174 g) and then H2O (4174 ml).

The obtained organic layer was concentrated under reduced pressure (40°C) to obtain a brown oily substance (2,40 kg, contains 1446 ml of toluene, 168 ml of tetrahydrofuran, the value provided by1H-NMR spectrum).

Collected in this way brown oil was transferred to a crystallization vessel, washed with toluene (119 ml) and the mixture was stirred at room temperature. After 10 minutes, poured tert-butyl methyl ether (134 ml) and the mixture was continuously stirred at room temperature. After 20 minutes, another was added tert-butyl methyl ether (127 ml) and the mixture was continuously stirred at room temperature. After 30 minutes, added dropwise within 20 minutes, tert-butyl methyl ether (266 ml) and the mixture was continuously stirred at room temperature. After a minute again started dropwise addition of tert-butyl methyl ether (522 ml). After 8 minutes saw the falling crystals. Dropwise addition was stopped for one hour and 20 minutes. After the resulting mixture was stirred at room temperature for 40 minutes, was added dropwise heptane (2348 ml) for one hour and 17 minutes and the mixture was stirred at room the th temperature during the night.

Approximately 15,5 hours after drip adding heptane precipitated precipitated crystals were subjected to filtration with suction, washed with a mixture of toluene/tert-butyl methyl ether/heptane (587 ml/391 ml/587 ml) and the mixture was dried in vacuum. Resulting crystals were dried air (50°C) to obtain the desired product.

Output: 619,0 g, content: 96,5%, quantity: 597,3 g, yield: 77.8% of (quantitative), purity according to HPLC: 98,0%.

<Conditions of the analysis by HPLC (control reaction, the measurement of the purity by HPLC and quantification)>:

column: YMC-Pack Pro C18 AS-302 (5 μm, 4.6 mm × 150 mm I.D.),

eluent: a solution (MeCN/20 mm AcONH4aq.= 100/900 (about./vol.), solution B (MeCN/20 mm AcONH4aq.= 800/200 (about./vol.)),

flow rate: 1.0 ml/min,

detection: UV 254 nm,

furnace temperature: 25°C,

sample temperature: 25°C,

gradient conditions (time/concentration of the solution (B): 0,01 min/0%→25 min/100%→30 min/100%→30,01 min/0%→40 min/stop

RT=18,4 min

(7) the crude sodium salt of the optical isomer (short retention time) of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 369

The water content of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole, toluene, diethyl L-(+)-tartrate and N,N-diisopropyl is the ethylamine, used in the reaction was determined by the method of Karl Fischer (total number 0,885 g).

Sequentially added 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole (580,3 g, content: 96.5%of that amount: 560, 0m g 1,354 mol), toluene (3864 ml) and H2O (2,81 g, 0,156 mol) under nitrogen atmosphere and the mixture was stirred under heating at 60°C. After 6 minutes to the resulting suspension was added diethyl L-(+)-tartrate (122,9 g, 0,596 mol) and washed reactive flask with toluene (560 ml). After 30 minutes confirmed the dissolution. After 8 minutes was added tetraisopropoxide titanium(IV) (77.0 g, 0,271 mol) and washed reactive flask with toluene (56 ml). The resulting mixture was stirred under heating at the same temperature for about one hour. The mixture was cooled to 8°C was added N,N-diisopropylethylamine (56,01 g, 0,742 mol), and then washed reactive flask with toluene (280 ml). After 10 minutes, was added dropwise over 47 minutes toluene solution (840 ml) of the hydroperoxide cumene (259,2 g 1,422 mol) and the mixture was stirred at 8°C for approximately 18,5 hours. Poured chilled 30% (wt./wt.) an aqueous solution of sodium thiosulfate (2240 g) and the mixture was stirred for 12 minutes, after which the water layer was removed. The organic layer was poured 4% (wt./wt.) an aqueous solution of sodium hydroxide (2240 g) and the mixture was stirred and allowed it to stand. Separated water lyrics by the second obtaining an aqueous solution of an optical isomer (short retention time) of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole, extracted aqueous solution of sodium hydroxide, in the form of a yellow-brown suspension. In toluene (7840 ml) was poured a solution of (2,98 kg) optical isomer (short retention time) of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole, extracted with an aqueous solution of sodium hydroxide, and the mixture was stirred. To the mixture was sequentially added with stirring 20% (wt./wt.) an aqueous solution of acetic acid (400 ml), 8% aqueous NaOH solution (50 ml) and 20% (wt./wt.) an aqueous solution of acetic acid (8 ml) and the pH was brought to 8.64. The mixture, allowing her to stand up, separated and the aqueous layer was removed. The organic layer is washed with 5% (wt./wt.) aqueous solution of salt (2240 g), separated with getting toluene extraction solution of the optical isomer (short retention time) of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (7,31 kg) (content: 567,7 g 1,322 mol) as a yellow-brown solution.

To the obtained toluene extraction solution was added during minutes to 28.3% methanol solution of sodium methoxide (to 245.6 g, 1,286 mol) with stirring at room temperature. Then to this solution was added dropwise over 3 minutes, tert-butyl methyl ether (1120 ml) and the mixture was stirred at room temperature. After 6 minutes confirmed the camping precipitation of crystals. The mixture was continuously stirred for about 30 minutes. Next was added dropwise over 2 hours and 40 minutes, tert-butyl methyl ether (7840 ml) and the mixture was continuously stirred at room temperature overnight.

After about 13 hours after was added dropwise tert-butyl methyl ether, precipitated precipitated crystals were subjected to filtration with suction, rinsed with a mixture of toluene/tert-butyl methyl ether (1047 ml/1193 ml) and dried in vacuum for 15 minutes. Obtained wet crystals were dried under reduced pressure (40°C) to obtain the desired product.

Output: 546,8 g, content: 101,7%, the number 546,8 g (content of 100%), output: 90,9% (quantitative), purity according to HPLC: 98.2 per cent, enantiomeric excess: 100%ee.

<Conditions of the analysis by HPLC (control reaction, the measurement of the purity by HPLC and quantification)>:

column: YMC-Pack Pro C18 AS-302 (5 μm, 4.6 mm × 150 mm I.D.),

eluent: A solution (MeCN/20 mm AcONH4aq.=100/900 (about./vol.), solution B (MeCN/20 mm AcONH4aq.=800/200 (about./vol.)),

flow rate: 1.0 ml/min,

detection: UV 254 nm,

furnace temperature: 25°C,

sample temperature: 25°C,

gradient conditions (time/concentration of the solution (B): 0,01 min/0%→25 min/100%→30 min/100%→30,01 min/0%→40 min/stop

RT=14,1 minutes

<Conditions of the analysis by HPLC (enantiomeric excess)>:

column: DAICE CHIRALPAK IA (4.6 mm × 250 mm I.D.),

eluent: EtOH/MTBE=150/850 (about./vol.),

flow rate: 1.0 ml/min,

detection: UV 284 nm,

furnace temperature: 25°C,

sample temperature: 25°C.

(8) purified sodium salt of the optical isomer (short retention time) of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole

Formula 370

To the crude optical isomer (short retention time) of sodium salt of 2-(((4-(2,2-dimethyl-1,3-dioxane-5-yl)methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (536,8 g, 1,189 mol) was added ethanol (1074 ml). The crude isomer was dissolved in ethanol at room temperature. The solution was poured tert-butyl methyl ether (1074 ml). Resulting solution was subjected to filtration with suction through a pillow Hyflo Super-Cel bed (107,4 g, washed successively with a mixture of ethanol/tert-butyl methyl ether (1074 ml/1074 ml) and tert-butyl methyl ether (537 ml)and was rinsed with a mixture of ethanol/tert-butyl methyl ether (215 ml/215 ml).

The resulting filtrate was transferred to a crystallization vessel and to full migration was washed with a mixture of ethanol/tert-butyl methyl ether (54 ml/54 ml), and then started mixing at room temperature. Then was added dropwise tert-butyl methyl ether (1610 ml) for 6 minutes and the mixture is continuously stirred the ri room temperature. 11 minutes was added dropwise tert-butyl methyl ether (268 ml) for 2 minutes and the mixture is continuously stirred. A minute later saw the falling crystals. The mixture was continuously stirred for 31 minutes and added to it dropwise tert-butyl methyl ether (268 ml) for 9 minutes. After stirring the mixture at room temperature for 8 minutes added dropwise tert-butyl methyl ether (8589 ml) for one hour and 10 minutes and the mixture was continuously stirred at room temperature.

After about 22 hours after the end of the drip adding tert-butyl methyl ether precipitated precipitated crystals were subjected to under a stream of nitrogen is filtered with suction, washed successively with a mixture of ethanol/tert-butyl methyl ether (107 ml/966 ml) and tert-butylmethylamine ether (1074 ml) and dried in vacuum for 8 minutes. From the obtained wet crystals (584,54 g) part of the wet crystals (531,10 g) was dried under reduced pressure (50°C) to obtain the desired product.

Output: 419,6 g, purity according to HPLC: 99.4 per cent.

<Conditions of the analysis by HPLC method (measurement of the purity by HPLC and quantification)>:

column: YMC-Pack Pro C18 AS-302 (5 μm, 4.6 mm × 150 mm I.D.),

eluent: A solution (MeCN/20 mm AcONH4aq.=100/900 (about./vol.), solution B (MeCN/20 mm AcONH4aq.=800/200 (about./vol.)),

flow rate: 1.0 ml/min,

det is sterowanie: UV 254 nm,

furnace temperature: 25°C,

sample temperature: 25°C,

gradient conditions (time/concentration of the solution (B): 0,01 min/0%→25 min/100%→30 min/100%→30,01 min/0%→40 min/stop

RT=14,1 minutes

Example a 1: 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 371

(1a) (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methylmethanesulfonate

Formula 372

(4-((2,2-Dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol (2.5 g, 8,35 mmol in water content 7,28%) was dissolved in toluene and the mixture was subjected twice azeotropic dehydration. The residue was dissolved in tetrahydrofuran (30 ml). To the solution was added triethylamine (2,33 ml of 16.7 mmol) and the mixture was stirred in nitrogen atmosphere while cooling on ice. Then was added dropwise methanesulfonanilide (0,766 ml, 10 mmol) with an internal temperature below 11.5°C for 2 minutes. The reaction mixture was stirred for 13 minutes under the same conditions, was diluted with ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate solution and saturated saline solution. The organic layer was dried over magnesium sulfate and filtered through silica gel and the filtrate was concentrated under reduced pressure to obtain specified in the connection header (2,8 is, 93,3%) as a pale orange solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)to 1.37 (3H, s), 2,07-to 2.15 (1H, m), of 2.23 (3H, s), and 2.26 (3H, s), up 3.22 (3H,s), 3,81 (2H, DD, J=6, 12 Hz), with 3.89 (2H, d, J=7 Hz), was 4.02 (2H, DD, J=4, 12 Hz), from 5.29 (2H, s), 8,24 (1H, ).

(1b) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 373

To a mixture of (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methylmethanesulfonate (500 mg, of 1.39 mmol), 2-mercaptobenzimidazole (209 mg, of 1.39 mmol) and tetrahydrofuran (5 ml) was added triethylamine (0,387 ml, 2,78 mmol) and the mixture was stirred at room temperature for 14 hours and 25 minutes. The reaction mixture was concentrated under reduced pressure, to the residue was added toluene, and 0.1 n aqueous solution of sodium hydroxide and the insoluble substance was removed by filtration. The organic layer was separated and the aqueous layer was again extracted with toluene. The organic layers were combined, washed with saturated saline solution, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of n-heptane/ethyl acetate (1/1) and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the specified title compound (549 mg, 95,5%) as a colourless viscous oil.

1H I Is R (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,05-of 2.16 (1H, m), of 2.20 (3H, s), of 2.28 (3H, s), 3,80 (2H, DD, J=6, 12 Hz), 3,86 (2H, d, J=7 Hz), 4,01 (2H, DD, J=4, 12 Hz), and 4.68 (2H, s), 7,08-7,14 (2H, m), 7,38-7,50 (2H, m), 8,17 (1H, s).

Example of getting a 2: 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 374

(2a) (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl 4-methylbenzenesulfonate

Formula 375

To tertrahydrofuran ring solution (30 ml) of (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol (738 mg, 2,61 mmol) was added powdered sodium hydroxide (313 mg, to 7.84 mmol) and the mixture was stirred at room temperature for 35 minutes. The mixture was still stirred for 10 minutes while cooling on ice and added p-toluensulfonate (1,09 g, 5,74 mmol) slowly within minutes. The reaction mixture was stirred at room temperature for 17 hours, 40 minutes and was diluted with tetrahydrofuran, and then was removed by filtration, the insoluble substance. To the filtrate was added silica gel and the mixture was concentrated and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1) to obtain specified in the connection header (1,00 g, 88%) as a white solid.

1H NMR (400 MHz, DMSO-d6) is ppm; of 1.33 (3H, s)to 1.37 (3H, s), 2,03-2,11 (1H, m)2,07 (3H, s)to 2.18 (3H, s)to 2.41 (3H, s), 3,76-3,81 (4H, m)4,00 (2H, DD, J=4, 12 Hz)to 5.13 (2H, s), 7,42 (2H, d, J=8 Hz), 7,73 (2H, d, J=8 Hz), 8,14 (1H, s).

(2b) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 376

To a mixture of (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl 4-methylbenzenesulfonate (457 mg, 1.05 mmol), 2-mercaptobenzimidazole (158 mg, 1.05 mmol) and tetrahydrofuran (5 ml) was added triethylamine (0,293 ml, 2.1 mmol) and the mixture was stirred at room temperature for 15 hours and 30 minutes. To the reaction mixture were added toluene and dilute aqueous sodium hydroxide solution and the organic layer was separated. The aqueous layer was again extracted with toluene. The organic layers were combined and washed with saturated saline solution, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of n-heptane/ethyl acetate (1/1) and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the specified title compound (419 mg, 96,5%) as a colourless viscous oil.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,05-of 2.16 (1H, m), of 2.20 (3H, s), of 2.28 (3H, s), 3,80 (2H, DD, J=6, 12 Hz), 3,86 (2H, d, J=7 Hz), 4,01 (2H, DD, J=4, 12 Hz), and 4.68 (2H, s), 7,08-7,14 (2H, m), 7,38-7,50 (2H, m), 8,17 (1H, s).

u> Example of getting 3: 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 377

(3a) 2-(chloromethyl)-(4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin

Formula 378

To a solution in toluene (16 ml) of (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methanol (800 mg, 2,85 mmol) was added triethylamine (0,397 ml, to 2.85 mmol) and the mixture was stirred in nitrogen atmosphere while cooling on ice. Was added dropwise thionyl chloride (0,208 ml, 2,85 mmol) for 2 minutes at an internal temperature below 7,7°C and the mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with ethyl acetate while cooling on ice and washed with a saturated aqueous solution of sodium bicarbonate and saline. The organic layer was dried over sodium sulfate and filtered using silica gel. The filtrate was concentrated under reduced pressure to obtain specified in the connection header (0,837 g, 98%) as a pale brown oily substance.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)to 1.37 (3H, s), 2,05-of 2.16 (1H, m), of 2.21 (3H, s), of 2.28 (3H, s), 3,81 (2H, DD, J=6, 12 Hz), 3,88 (2H, d, J=7 Hz), 4,01 (2H, DD, J=4, 12 Hz), was 4.76 (2H, s), 8,19 (1H, s).

(3b) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Fo the mule 379

To a mixture of 2-(chloromethyl)-(4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridine (837 mg, and 2.79 mmol), 2-mercaptobenzimidazole (419 mg, and 2.79 mmol) and sodium hydroxide (223 mg, to 5.58 mmol) was added methanol (20 ml) and the mixture was stirred at room temperature for 12 hours 55 minutes. The reaction mixture was concentrated under reduced pressure. To the residue was added toluene, and 0.1 n aqueous solution of sodium hydroxide and the insoluble substance was removed by filtration, after which the organic layer was separated. The aqueous layer was again extracted with toluene. The organic layers were combined and washed with saturated saline solution, dried over sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of n-heptane/ethyl acetate (1/1) and subjected to chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1→0/1) to obtain the specified title compound (980 mg, 84,9%) as a white foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,05-of 2.16 (1H, m), of 2.20 (3H, s), of 2.28 (3H, s), 3,81 (2H, DD, J=6, 12 Hz), 3,86 (2H, d, J=7 Hz), 4,01 (2H, DD, J=4, 12 Hz), and 4.68 (2H, s), 7,08-7,14 (2H, m), 7,38-7,50 (2H, m), 8,17 (1H, s).

Example 4: 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 380

(4a) (4-((2,2-dimethy who -1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)acetate

Formula 381

1-Oxide 4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)-2,3,5-trimethylpyridine (10.5 g, or 37.4 mmol) was dissolved in acetic anhydride (100 ml) and the solution was stirred at 85°C. for 1.5 hours. After concentrating the reaction mixture, the residue was purified by chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1→0/1) and the desired fraction was concentrated to obtain specified in the connection header (6,1 g, 50.4 per cent) as a pale yellow solid.

1H NMR (400 MHz, DMSO-d6) δ ppm; 1,31 (3H, s)of 1.35 (3H, s)2,04 (3H, s), is 2.05 and 2.13 (1H, m), 2,17 (3H, s), are 2.19 (3H, s), with 3.79 (2H, DD, J=6, 12 Hz), 3,85 (2H, d, J=7 Hz), 4.00 points (2H, DD, J=4, 12 Hz), 5,09 (2H, s), 8,17 (1H, ).

(4b) 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzimidazole

Formula 382

To dimethylsulfoxide (10 ml) solution of tert-butoxide potassium (262 mg, of 2.33 mmol) and 2-mercaptobenzimidazole (349 mg, of 2.33 mmol) was added (4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)acetate (500 mg, 1.55 mmol) and the mixture was stirred in nitrogen atmosphere at 150°C for 3 hours and 10 minutes. After cooling to room temperature the reaction mixture was diluted with toluene and washed with diluted aqueous sodium hydroxide solution and saturated saline solution, dried over sodium sulfate and filter the Lee. The filtrate was concentrated under reduced pressure. The residue was subjected twice chromatography on a column of silica gel (eluting solvent: n-heptane/ethyl acetate=1/1) to obtain the specified title compound (441 mg, 68,8%) as a white foam.

1H NMR (400 MHz, DMSO-d6) δ ppm; of 1.33 (3H, s)of 1.36 (3H, s), 2,05-of 2.16 (1H, m), of 2.20 (3H, s), of 2.28 (3H, s), 3,80 (2H, DD, J=6, 12 Hz), 3,86 (2H, d, J=7 Hz), 4,01 (2H, DD, J=4, 12 Hz), and 4.68 (2H, s), 7,08-7,14 (2H, m), 7,38-7,50 (2H, m), 8,17 (1H, s).

Experimental example 1 Inhibitory effect on secretion of gastric acid in dogs with chronic gastric fistula

(1) Method

The compounds described above in the examples investigated for inhibitory effects against secretion of gastric acid and persistent effect against the secretion of gastric acid, using the big dogs (body weight: 14-19 kg)with chronic gastric fistula. The experiment lasted for 2 days. On the first day continuously for 3 hours was administered intravenous histamine (50 or 75 mcg/kg/h). During the administration of histamine every 20 minutes took the gastric juice. One hour after the start of injection of histamine was administered the test compound (which was obtained in the above examples), suspended or dissolved in 0.5% solution of methylcellulose, with a volume of 0.1 ml/kg through a permanent catheter in the duodenum. The inhibiting effect of spitemare connection against the secretion of gastric acid was examined within 2 hours after injection. In the second day (i.e. 24 hours after injection of the test compounds) continuously for 2 hours was administered intravenous histamine. During the administration of histamine every 20 minutes took the gastric juice and checked the resistance of the inhibitory effect against gastric secretion of acid. After measuring the amount of gastric juice sample in 0.5 ml of gastric juice was titrated to pH 7.0 with a solution of 0.04 mol/l sodium hydroxide. Thus we measured the concentration of acid in the gastric juice. The release of gastric acid (allocated amount) was calculated by multiplying the volume of gastric juice on the concentration of the acid. Inhibitory effect against the secretion of gastric acid was estimated by the ratio (%) of inhibition of the secretion of gastric acid in the first day. Inhibitory effect (%) against the secretion of gastric acid was obtained by the following equation. When the number of animals was equal to 2 or more received an average value.

The inhibitory effect against gastric secretion of acid (%) = (A-B)/A × 100

[A]: the Release of gastric acid (allocated amount) for 20 minutes in a period of 40 minutes to an hour after the start of injection of histamine.

[B]: the Release of gastric acid for 20 minutes in a period of 1 hour and 40 minutes to two hours after administration of the test compounds.

Resistance inhibitory effect against gastric secretion assess the Wali coefficient (%) of inhibition of the secretion of gastric acid in the second day. Resistance (%) inhibitory effect against the secretion of gastric acid was obtained by the following equation:

Resistance (%) inhibitory effect against gastric secretion of acid = (C-D)/C × 100.

[C]: the Total number of ejection of gastric acid from the start of injection of histamine (on the first day, plus one hour).

[D]: the Total number of ejection of gastric acid from the start of injection of histamine (in the second day plus one hour).

(2) the Results

Table 1
ConnectionDose
(mg/kg, introduo-dealno)
The number of animalsInhibitory effect against the secretion of stomach acid
(%)
Resistance inhibitory effect against the secretion of stomach acid
(%)
Example 10,429476
Example 10,8210090
Example 20,2383 52
Example 20,4310090
Example 20,8210096
Example 30,8110086
Example 40,8110093
Example 50,8210089
Example 50,425461

Table 2
ConnectionDose
(mg/kg, introduo-dealno)
The number of animalsInhibitory effect against the secretion of stomach acid
(%)
Resistance is ingibiruyushchego effect against secretion of stomach acid
(%)
Example 60,8110089
Example 70,819990
Example 80,8110088
Example 90,8210090
Example 100,829890
Example 101,6110087
Example 110,437965
Example 110,8310089
Example 12110086
Example 130,8210074
Example 190,4413-4
Example 190,848256
Example 200,1486
Example 200,246546
Example 200,4109777
Example 200,8810089
Example 211,61100 94
Example 221,6110097
Example 231,6110092
Example 241,618880
Example 261,6110080
Example 271,6110092
Example 281,619477
Example 291,6110087
Example 301,6110095
Example 30 0,8110063
Example 311,6110097
Example 321,6110083
Example 331,6110084
Example 341,6110078
Example 361,6110090
Example 391,6110086

Table 3
ConnectionDose
(mg/kg, introduo-dealno)
The number of animalsIngibiruet the rd effect against secretion of stomach acid
(%)
Resistance inhibitory effect against the secretion of stomach acid
(%)
Example 401,6110092
Example 400,819966
Example 411,6110085
Example 420,816072
Example 460,8110095
Example 471,6110087
Example 500,817980
Example 511,61 10083
Example 521,6110087
Example 530,819987
Example 550,818375
Example 560,818474
Example 570,829883
Example 580,829577
Example 590,818977
Example 600,818974
Prima is 61 1,6210090
Example 640,8210078
Example 651,6110091
Example 661,6110079
Example 671,6110083
Example 691,6110078
Example 701,6110077
Example 701,6110064
Example 730,81 10094
Example 750,818575
Example 810,819670
Example 830,817194
Example 850,8110086
Example 860,8110075
Example 870,8110092

Example 1 fabrication: Capsule

Dissolved 30.0 g of 2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole (hereinafter referred to as "Compound A")and 8.1 g of ethyl cellulose (trade name: Etcel, manufacturer Dow Chemical Co.) and 16.2 g hydroxypropylcellulose (trade name: HPC-L, manufacturer Shin-Etsu Chemical C. Ltd.) in 489 g digidratirovannogo ethanol. The resulting solution was applied on 500,1 g of substance kernel Nonpareil 108 (trade name, manufacturer Freund Corporation), using machine Wurster-type for coating granules in a fluidized bed (trade name: Multiplex, Pawlek) and the mixture was dried to obtain granules.

Then was dissolved to 48.6 g of ethyl cellulose (trade name: Etcel, Dow Chemical Co.) and 291,9 g hydroxypropylcellulose (trade name: HPC-L, Shin-Etsu Chemical Co. Ltd.) in digidratirovannogo ethanol (6860 g). Next, in the obtained solution was dispersively 136,8 g of magnesium stearate (manufactured by Marin Klot) to obtain the film-forming solution. Previously obtained granules (554,4 g) was covered with the specified film-forming solution and dried to obtain granules with an intermediate coating layer.

In addition, dissolved 460,2 g phthalate of hydroxypropylmethylcellulose (trade name: HP-55S, Shin-Etsu Chemical Co. Ltd.) and 45.3 g diacetylene monoglyceride (trade name: Mybassett, manufacturer Quest International) in 80% aqueous ethanol (11045 g). Then obtained as described above, the ethanol was dispersively of 42.3 g of talc (trade name: Talc, manufacturer Matsumura Industry) and 24.3 g of titanium oxide (trade name: Titanium (IV) oxide, manufacturer Merck). Granules with an intermediate coating layer (1031,7 g) covered the obtained dispersion solution and dried to obtain granules with intersolubility the floor.

It is ranula with intersolubility coating (1603,8 g) was added 15.0 g of light anhydrous silicic acid (trade name: AEROSIL-200 (Japanese Pharmacopoeia), manufacturer Nippon Aerosil) and 15.0 g of talc (trade name Hi-filler#17, the manufacturer Matsumura Industry) and all were mixed using a balloon-type mixer (trade name: 2/5 L vessel-type mixer, manufacturer Toyo Packing) to obtain compound A which was loaded into the capsules in quantities of 1 mg/capsule.

Example 2 fabrication: Capsule

Granules were produced by following the recipe the same way as in example 1 production. Connection And loaded into capsules of 10 mg/capsule.

Table 4
Component
Nonpareil 108465,0
Layer the main components
Connection A500,0
Ethylcellulose135,0
HPC-L270,0
The intermediate layer
Ethylcellulose40,0
HPC-L240,0
Stearate Mg112,5
The outer layer
HP-55S380,0
Mybassett37,5
Talc35,0
The titanium oxide20,0
AEROSIL-20030,0
Talc30,0
Unit: g

Nonpareil 103 (trade name Freund Corporation)

Industrial applicability

Compounds of the present invention strongly inhibit the secretion of gastric acid, steadily inhibit the secretion of gastric acid, the more secure an appropriate degree of physico-chemically stable and therefore can be used as a drug, in particular a therapeutic drug or a preventive drug against diseases or symptoms associated with acid.

1. The compound represented by formula 1

where R1and R3may be the same or different, and each represents a hydrogen atom or C1-C6 alkyl group;
R2is subgrupo, represented by formula 2


or
where W2represents a hydrogen atom;
n1 is 1 to 5, n2 is 1 to 4, and n3 equals 1-6,
with this optional group contains 1-4 groups selected from group A1, consisting of a halogen atom, C1-C6 alkyl groups, C1-C6 alkoxygroup, C1-C6 halogenoalkanes group;
R4, R5, R6and R7may be the same or different, and each represents a hydrogen atom, halogen atom, C1-C6 alkyl group, C1-C6 halogenating group, C1-C6 alkoxygroup, or the combination of R5and R6is methylendioxy or Ethylenedioxy; and
W1represents a single bond or alkilinity group containing 1-8 carbon atoms;
or its salt.

2. The compound or its salt according to claim 1, where R1represents a hydrogen atom or methyl group.

3. Connection or Sol is according to claim 1, where R1represents a methyl group.

4. The compound or its salt according to any one of claims 1 to 3, where R2represents a group represented by the formula (3)


or
where W2represents a hydrogen atom;
n1 is 1 to 5, n2 is 1 to 4, and n3 is 1 to 6;
moreover, this group optionally contains 1 or 2 groups selected from group A1, consisting of a fluorine atom, methyl group, ethyl group, various groups, metoxygroup and mooftormetilnoy group.

5. The compound or its salt according to any one of claims 1 to 3, where R2represents a group represented by the formula (4)


what does

6. The compound or its salt according to any one of claims 1 to 3, where R is a group represented by the formula (5)
or

7. The compound or its salt according to any one of claims 1 to 3, where R3represents a hydrogen atom or methyl group.

8. The compound or its salt according to any one of claims 1 to 3, where R3represents a methyl group.

9. The compound or its salt according to any one of claims 1 to 3, where R4represents a hydrogen atom, methyl group, ethyl group, methoxy group, ethoxypropan or a fluorine atom.

10. The compound or its salt according to any one of claims 1 to 3, where R4represents a hydrogen atom, a methyl group or a fluorine atom.

11. The compound or its salt according to any one of claims 1 to 3, where R4represents a hydrogen atom.

12. The compound or its salt according to any one of claims 1 to 3, where R4represents a hydrogen atom, methyl group, ethyl group, methoxy group, ethoxypropan or a fluorine atom.

13. The compound or its salt according to any one of claims 1 to 3, where R4represents a hydrogen atom, a methyl group or a fluorine atom.

14. The compound or its salt according to any one of claims 1 to 3, where R4represents a hydrogen atom.

15. The compound or its salt according to any one of claims 1 to 3, where R6is the Wallpaper a hydrogen atom, methyl group, ethyl group, methoxy group, ethoxypropan or a fluorine atom.

16. The compound or its salt according to any one of claims 1 to 3, where R6represents a hydrogen atom, a methyl group or a fluorine atom.

17. The compound or its salt according to any one of claims 1 to 3, where R6represents a hydrogen atom.

18. The compound or its salt according to any one of claims 1 to 3, where R7represents a hydrogen atom, methyl group, ethyl group, methoxy group, ethoxypropan or a fluorine atom.

19. The compound or its salt according to any one of claims 1 to 3, where R7represents a hydrogen atom, a methyl group or a fluorine atom.

20. The compound or its salt according to any one of claims 1 to 3, where R7represents a hydrogen atom.

21. The compound or its salt according to any one of claims 1 to 3, where W1represents a single bond, methylene group or ethylene group.

22. The compound or its salt according to any one of claims 1 to 3, where W1represents a methylene group.

23. The compound or its salt according to any one of claims 1 to 3, where n1 is 1-3.

24. The compound or its salt according to any one of claims 1 to 3, where n1 is 1 or 2.

25. The compound or its salt according to any one of claims 1 to 3, where n2 is 1 or 2.

26. The compound or its salt according to any one of claims 1 to 3, where n3 is equal 1-4.

27. The compound or its salt according to any one of claims 1 to 3, where n3 is 1 or 2.

28. The compound or its salt according to claim 1, where the unity is selected from the following group, consisting of:
2-(((4-((5,5-dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-(5,7-dioxaspiro[2.5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((3-methyl-4-(1,5,9-dioxaspiro[5.5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-((2,2-dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((3-methyl-4-(2-(8-methyl-1,4,7,9-tetraoxaspiro[4.5]Dec-8-yl)ethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-(5,9-dioxaspiro[3.5]non-7-yloxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-(2-(8-ethyl-1,4,7,9-tetraoxaspiro[4.5]Dec-8-yl)ethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-(1,3-dioxolane-4-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-((2,2-bis(permitil)-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-(5,9-dioxaspiro[3,5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-((2-methoxy-1,3-dioxane-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((3-methyl-4-((8-methyl-1,4,7,9-tetraoxaspiro[4.5]Dec-8-yl)methoxy)pyridin-2-yl)methyl)sulfinil)-1H-benzimidazole,
2-(((4-(5,9-dioxaspiro[3.5]non-7-ylethoxy)pyridine-2-yl)methyl)sulfinil-1H-benzimidazole and
2-(((4-((5,5-debtor-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)met the l)sulfinil)-1H-benzimidazole.

29. 2-(((4-((5,5-Dimethyl-1,3-dioxane-2-yl)methoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole or its salt.

30. 2-(((4-(5,7-Dioxaspiro[2.5]Oct-6-ylethoxy)-3-methylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole or its salt.

31. 2-(((3-Methyl-4-(1,5,9-dioxaspiro[5.5]undec-3-ylethoxy)pyridine-2-yl)methyl)sulfinil)-1H-benzimidazole or its salt.

32. 2-(((4-((2,2-Dimethyl-1,3-dioxane-5-yl)methoxy)for 3,5-dimethylpyridin-2-yl)methyl)sulfinil)-1H-benzimidazole or its salt.

33. Drug as an inhibitor of the secretion of gastric acid containing compound or its salt according to any one of claims 1 to 32.

34. The inhibitor of the secretion of gastric acid containing compound or its salt according to any one of claims 1 to 32.

35. Therapeutic agent or prophylactic agent associated with the acid of diseases or symptoms, containing the compound or its salt according to any one of claims 1 to 32.

36. Therapeutic agent or prophylactic agent for p where associated with acid diseases or symptoms are stomach ulcers, duodenal ulcer, anastomotic ulcer, gastroesophageal reflux syndrome Zollinger-Ellison, symptomatic gastroesophageal reflux, endoscopy-negative gastroesophageal reflux, neurosignal gastroesophageal reflux, gastroesophageal regurgitation, NUD (non-ulcer dyspep the Oia), abnormal sensation in the throat, syndrome Berreta, NSAID-induced ulcer, gastritis, gastrointestinal bleeding, hemorrhagic gastritis, gastrointestinal bleeding, peptic ulcer, bleeding ulcer, stress ulcer, gastric hyperacidity, dyspepsia, gastroparesis, plague older people, intractable ulcer, acute injury of the mucous membrane of the stomach, heartburn, heartburn from the syndrome of sleep apnea, bruxism, gastralgia, feeling of heaviness in the stomach, retching and vomiting, nausea, arthrosis of the temporomandibular joint or erosive gastritis.

37. Therapeutic agent or prophylactic agent for p where associated with acid disease or symptom is stomach ulcers, duodenal ulcer, anastomotic ulcer, gastroesophageal reflux syndrome Zollinger-Ellison, symptomatic gastroesophageal reflux, endoscopy-negative gastroesophageal reflux, neurosignal gastroesophageal reflux or acute injury of the gastric mucosa.

38. Therapeutic agent or prophylactic agent for p where associated with acid diseases or symptoms are gastroesophageal reflux or symptomatic gastroesophageal reflux.

39. Therapeutic agent or prophylactic agent for p where associated with acid-related disease is euonymi are a stomach ulcer or duodenal ulcer.

40. A bactericidal agent or subsidiary is a bactericidal agent against Helicobacter pylori in the stomach, containing the compound or its salt according to any one of claims 1 to 32.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cycloalkene derivatives of formula (I) in which X and Y are a group, in which X and Y together with a carbon atom on ring B to which they are bonded form a ring A, X and Y together represent a ring B substitute, or each of X and Y is a hydrogen atom.

EFFECT: invention relates to a medicinal agent based on the said compounds, which has inhibitory effect on intracellular signal transduction or cell activation induced by an endotoxin.

21 cl, 3 tbl, 191 ex

FIELD: organic chemistry, insecticides.

SUBSTANCE: invention relates to compounds of formula I , wherein W is halogen, C1-C6-alkyl, C1-C6-alkoxy, C1-C4-haloalkyl or C1-C4-haloalkoxy; X is hydrogen, halogen, C1-C6-alkyl; Y is hydrogen, halogen, C1-C6-alkyl, C1-C4-haloalkyl, C1-C4-haloalcoxy or cyano; Z is hydrogen, halogen, etc.; G is halogen or nitro; meanings of the other substituents are as defined in specification. Also disclosed are methods for production of said compounds by interaction compounds of formula II with halogenation agents in presence of solvent and optionally of radical initiator of with fumed nitric acid in presence of solvent.

EFFECT: new compounds with insecticide activity.

17 cl, 20 tbl, 114 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: compounds have formula (lb) in which R1 denotes (1) -N(R1A)SO2-R1B, (2) -SO2NR1CR1D, (3) -COOR1E, (4) -OR1F, (5) -S(O)mR1G; (6) -CONR1HR1J, (7) -NR1K COR1L, or (8) cyano, where m equals 0, 1 or 2;X denote a bond or a spacer which contains 1-3 atoms as the backbone chain; ; R1A, R1B, R1C, R1D, R1E, R1F, R1G, R1H, R1J, R1K and R1L each independently denotes (1) a hydrogen atom, (2) a C1-8alkyl group which can have a substitute (substitutes) selected from a group comprising [1] a hydroxy group, [2] a carboxy group, [3] a C1-6alkoxy group which can be substituted with a halogen and [4] a mono- or disubstituted amino substituted C1-8alkyl group or (3) tetrahydropyran, piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl, and where R1C and R1D, or R1H and R1J together with a nitrogen atom to which they are bonded can form piperazine, piperidine, azetidine, pyrrolidine or morpholine, each of which can have a substitute (substitutes) selected from a group comprising hydroxy, halogen, C1-8alkanoyl and C1-10halogenalkyl; ring A is a benzene ring or a pyridine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl, nitro, C1-6alkoxy and halogen; ring B is a benzene ring, a pyridine ring or a pyrazine ring, each of which can have a substitute (substitutes) selected from a group comprising C1-8alkyl; R51 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (2) benzene, pyrazole, pyridine, isoxazole, thiophene, benzothiazole, each of which can have a substitute (substitutes) selected from a group comprising C1-4alkokyl, C1-6alkoxy, C1-6alkylthio, C1-6alkylthionyl, C1-6alkylsulphonyl and halogen; R52 denotes a hydrogen atom; R53 denotes (1) C1-8alkyl, C2-8alkenyl or C2-8alkynyl, each of which can have a benzene substitute (substitutes) or (3) benzene, pyrazole, pyridine, thiophene, benzodioxane, cyclohexan or tetrahydropyran, each of which can have a substitute (substitutes) selected from a group comprising [1] hydroxy group, [2] cyano, [3] carbamoyl, [4] aminocarbonyl, substituted with one or two substitutes selected from (a) hydroxy group, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group, (e) carboxyl and (f) C1-6alkoxycarbonyl, [5] carboxy, [6] halogen, [7] C1-6alkoxy, [8] C1-6alkylsulphonyl, [9] amino, [10] C1-6acylamino, [11] alkyl-sulphonylamino, [12] cyclic aminocarbonyl and [13] C1-8 hydrocarbon group substituted with 1 or 2 substitutes selected from (a) hydroxy, (b) amino, (c) C1-4alkoxy, (d) mono or disubstituted amine, substituted with a C1-8 hydrocarbon group and (e) aminocarbonyl, substituted with a C1-8 hydrocarbon group; to salts thereof, N-oxide thereof and solvate thereof. The invention also relates to a pharmaceutical composition based on said compound, having antagonistic activity towards CCR5, to use of formula (1b) compound to produce an agent for preventing or treating CCR5 related diseases. Novel compounds which have anti CCR5 activity are obtained and described. Said compounds are therefore useful in preventing and/or treating CCR5 related diseases, for example various inflammatory diseases, immunological diseases etc.

EFFECT: wider field of use of the compounds.

7 cl, 11 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: tricyclic compounds of formula I: $ substituted with heterocycle are disclosed, or pharmaceutically acceptable salt or solvate of specified compound, isomer or racemic mixture, where stands for optional double link, dotted line stands for link or does not stand for link, which results in double or single link according to requirements of valency and where A, B, G, M, X, J, n, Het, R3, R10, R11, R32 and R33 and other substituents are such as indicated in formula of invention. Invention also relates to pharmaceutical compositions, which contain them, method of thrombin receptor or cannabinoid receptor inhibition, and to method for treatment of disease related to thrombosis, atherosclerosis, restenosis, hypertension, stenocardia, arrhythmia, cardiac failure and cancer by administration of specified compounds.

EFFECT: production of compounds having properties of antagonists of thrombin receptors.

33 cl, 6 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new compounds of formula (1) or its pharmaceutically acceptable salts, with properties of antagonist CXCR2 of human neutrophils receptor. In formula (1) R1 represents a group selected from C1-8alkyl; where this group is possibly substituted with 1 substituent, independently selected from phenyl or 5-6-unit heteroaryl, containing 1-2 heteroatoms selected from N, S; where phenyl and heteroaryl are possibly substituted by 1, 2 or 3 substitutors, independently selected from halogeno, cyano, -OR4, -COOR7, -SO2R10, C1-6alkyl; X represents -CH2-, oxygen, sulfur; R2 represents C3-7carbocyclil, possibly substituted with 1, 2 or 3 substituents, independently selected from -OR4; or R2 represents 5-unit ring, containing 2 heteroatoms, selected from O, -NR8, and where this ring is possibly substituted with 1 substituent, independently selected from C1-3alkyl; or R2 represents group, selected from C1-8alkyla, where this group is substituted with 1, 2 or 3 substituents, independently selected from hydroxy, amino, C1-6alkoxy, C1-6alkylamino, di(C1-6alkyl)amino, N-C1-6alkylcarbamoyl, N,N-di(C1-6alkyl)carbamoyl, carboxy, -NR8COR9 and -CONR5R6; R3 represents group -NR5R6, or R3 represents phenyl, possibly condensed with 6-unit heterocyclil, containing nitrogen, naphthyl, 4-8-unit monocyclic heterocyclil, containing 1-3 heteroatoms, selected from N, O, S, possibly condensed with benzole ring or 3-unit nitrogen-containing ring, where heteroring may be non-saturated, partially or fully saturated, and one or more than one circular atom of carbon may form carbonyl group, and where each phenyl or heterocyclil group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, phenyl, 5-6-unit heteroaryl, containing 1-2 atoms of nitrogen, -OR4, -NR5R6, -CONR5R6, -COR7, -COR20, -COOR7, -NR8COR9, -SO2R10, -SO2NR5R6 or C1-6alkyl [possibly additionally substituted with 1, 2 or 3 substituents, independently selected from halogeno, cyano, -OR20, -COOR20, -NR18R19, -CONR18R19, phenyl or 5-6-unit of monocyclic heteroaryl, containing 1-2 heteroatoms O, N, S, or 10-unit bicyclic heteroaryl, containing 1 heteroatom O, where heteroring may be partially or fully saturated, and where each phenyl or heteroaryl is group possibly substituted with 1 or 2 substituents, independently selected from halogeno, cyano, nitro, -OR20, -NR5R6, -COOR7, -NR8COR9, 6-unit heterocyclil, containing two heteroatoms, selected from O and N, 5-unit heteroaryl, containing 3 heteroatoms N, C1-6alkyl (possibly additionally substituted with 1 substituent, independently selected from halogeno, cyano, nitro, -OR20, -COOR20; or R3 represents group, selected from C3-7carbocyclil, C1-8alkyl, where this group is possibly substituted with 1, 2 or 3 substituents, independently selected from halogeno, -OR4, -NR5R6; R4 represents hydrogen; R5 and R6 independently represent hydrogen or group, selected from C1-6alkyl and monocyclic 6-unit saturated heterocyclil containing 1 heteroatom N; where C1-6alkyl is possibly substituted with 1 substituent, independently selected from -NR15R16; or R5 and R6 together with atom of nitrogen, to which they are linked, form 4-7-unit saturated heterocyclic circukar system, possibly containing additional heteroatom, selected from oxygen, -SO(n)- (where n equals 0, 1 or 2) and atoms of nitrogen; R10 represents hydrogen or group, selected from C1-6alkyl; and each of R7, R8, R9, R15, R16, R17 independently represents hydrogen, C1-6alkyl; R18, R19 and R20 represent hydrogen or group, selected from C1-6alkyl, where this group is possibly substituted with 1 substituent, independently selected from -NR8R9, -CONR8R9.

EFFECT: production of new compounds, which may find application in production of medicinal agent for use in treatment of diseases and disorders mediated with chemokines, such as asthma, allergic rhinitis, chronic obstructive pulmonary disease, inflammatory intestine disease, irritable colon syndrome, osteoarthritis, osteoporosis, rheumatoid arthritis or psoriasis, and also for treatment of cancer.

12 cl, 155 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula (Ia) or their pharmaceutically acceptable salts, tautomers, or N-oxides, for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases. In formula (Ia) X stands for group R1-A-NR4; A stands for link, C=O, or NRg(C=O, where R8 stands for hydrogen or C1-3 alkyl; Y stands for link or alkylene chain, made of 1, 2 or 3 atoms of carbon; R1 stands for carbocyclic or heterocyclic group, containing from 3 to 12 circular units; or saturated C1-8hydrocarbyl group, optionally substituted with one or more substituents selected from halogen (for instance, fluorine), hydroxygroups, C1.4alkoxygroups, and carbocyclic or heterocyclic groups, and where 1 or 2 atoms of hydrocarbyl group carbon may be optionally substituted with atom or group selected from O, S, NH, SO, SO2; R2 stands for hydrogen or methyl; R3 is selected from hydrogen and carbocyclic or heterocyclic groups, containing from 3 to 6 circular units; and R4 stands for hydrogen or methyl. Specified carbocyclic and heterocyclic groups are determined in formula of invention and may be optionally substituted with groups specified in invention formula. Objects of invention are also a pharmaceutical composition based on proposed compounds, their application to produce medicinal agents and methods of their application.

EFFECT: production of pharmaceutical composition based on proposed compounds for use in prevention or treatment of unhealthy conditions or diseases, mediated with cyclin-dependent kinase and glycogen synthase-kinase-3, such as cancerous diseases.

48 cl, 6 tbl, 254 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: medicine-ligand conjugates are powerful cytotoxins in which the medicine is bonded to the ligand through a peptide, hydrazine or disulphide linker.

EFFECT: agents are highly effective.

63 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: described are novel derivatives of genera formula (1) (where A denotes an oxygen or sulphur atom, -CH2- or -NH- group; R1 denotes C1-6alkyl group, possibly substituted ; R1A denotes a hydrogen atom or a C1-6 alkyl group; or these two radicals together with a carbon atom to which they are bonded form a cyclic C3-6 alkyl group; R2 denotes a C1-6 alkyl group or a C3-6 cycloalkyl group; R3 denotes an aryl group or a heteroaryl group, which can be substituted; R4 denotes a hydrogen atom; R5 denotes C1-6 alkyl group, aryl or heteroaryl group, which can be substituted), a pharmaceutical composition containing said derivatives and intermediate compounds. Said compounds (1) can inhibit bonding between SIP and its receptor Edg-1 (SIP1).

EFFECT: possibility of use in medicine.

18 cl, 2 tbl, 28 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel anhydrous tetomilast type A crystalline form, having powder X-ray diffraction spectrum essentially the same as the powder X-ray diffraction spectrum having characteristic peaks at 2θ = 10.5°, 13.1°, 18.4°, 21.9° and 25.8°, pharmaceutical compositions based thereon and synthesis methods thereof.

EFFECT: considerable advantages in terms of industrial production owing to significantly better filterability.

8 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: novel compounds have general formula (1), or salts thereof:

, where R10 is cyclohexyl optionally substituted with a substitute selected from group A1, or cyclohexenyl optionally substituted with a substitute selected from group A1, R30, R31 and R32 denote hydrogen, R40 denotes C1-10alkyl optionally substituted with a substitute selected from group D1, n equals 0 or 1, X1 denotes nitrogen, and R20, R21, R22 and R23 independently denote hydrogen, except when R20, R21, R22 and R23 all denote hydrogen, C1-6 alkylthio optionally substituted with a substitute selected from group F1, C2-6 alkoxycarbonyl, C1-6 alkyl substituted with a substitute selected from group W1, C1-6 alkyl substituted with a substitute selected from group K1, C1-6 alkoxy substituted with a substitute selected from group W1, a 5-6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from W1, a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or S atoms, substituted with a substitute selected from group V1, pyridyl substituted with a substitute selected from group W1, phenyl,optionally substituted with a substitute selected from group W1, C2-7 alkenyl, optionally substituted with a substitute selected from group W1, C2-7 alkynyl optionally substituted with a substitute selected from group W1, a 3-6-member cycloalkyl optionally substituted with a substitute selected from group W1, a 5-6-member cyclalkenyl optionally substituted with a substitute selected from group W1, NR1XR2X, -CO-R1X, -CO-NR1XR2X, -NR1X-CO-R2X, -SO2-R3X or -O-SO2-R3X,where R1X is hydrogen or a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N and O atoms, R2X is a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, and R3X is C1-6 alkyl optionally substituted with a substitute selected from group F1; or R21 and R22 together form a ring selected from group Z1, where group A1 consists of C1-6 alkyl, group D1 consists of cyclopropyl and tetrahydropyranyl, group F1 consists of a halogen, group W consists of hydroxyl, C2-7 alkoxyalkyl, phenoxy, C2-7 alkoxycarbonyl, -NR6XR7X and -CO-NR6XR7X, where R6X and R7X independently denote hydrogen or C1-6 alkyl, group V1 consists of oxo (=O) and ethylenedioxy(-O-CH2CH2-O-), where ethylenedioxy is allowable only if a compound of two rings with one common atom forms together with a substituted 6-member heterocyclic group, group K1 consists of a 6-member heterocyclic group which is a non-aromatic saturated ring containing one or two heteroatoms selected from N or O atoms, group U1 consists of carboxyl, C1-6 alkoxy, phenyl and CO-NR8XR9X, where R8X and R9X denote hydrogen, and group Z1 consists of

, where R1Z denotes C1-6 alkyl or benzyl. The invention also pertains to a medicinal agent, a cell adhesion or cell infiltration inhibitor, as well as to therapeutic or prophylactic agents.

EFFECT: obtaining novel biologically active compounds having cell adhesion or cell infiltration inhibiting activity.

20 cl, 147 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry, namely to creation of gastroprotective medication, representing flavonoid of grass of Vicia varia 7-rutinoside diosmetin.

EFFECT: medication reduces area and number of ulcer defects of stomach mucous membrane, considerably reduces activity of lipid peroxidation in stomach and blood serum; reduced expression of stomach mucous membrane lesion.

1 ex, 2 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new imidazopyrazines of formula where Q1 and R1 have the values specified in the patent claim, and to their pharmaceutically acceptable salts showing IGF-1R enzyme inhibiting activity and applicable for treatment and/or prevention of various diseases and conditions which are sensitive to tyrosine kinase inhibition.

EFFECT: preparation of the compounds showing IGF-1R enzyme inhibiting activity.

27 cl, 294 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely - to physiotherapy and gastroenterology. A method involves the administration of ozonised low-mineralised water and the skin insonification following 2-3 minutes later within a stomach projection. As ozonised low-mineralised water, Obukhovskaya-13 water of ozone concentration 2.0 mg/l is administered in dosage 200.0 ml. The insonification is performed by a labile technique in a continuous generation mode for 5 minutes. For the first five procedures, power flux density is 0.4 Wt/cm2, and for the following procedures - 0.7 Wt/cm2. The procedures are daily. The therapeutic course is 7 procedures.

EFFECT: method provides higher clinical effectiveness ensured by higher epithelisation rate of erosive defects of the gastric mucosa.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to surgery, and can be used for the early postoperative prevention of acute gastroduodenal ulcers in patients with colorectal cancer. That is ensured by the preoperative detection of Helicobacter pylori infection. Then for 5-7 preoperative days, amoxicillin in daily dose 2 g and clarithromycin in daily dose 1 g are administered orally.

EFFECT: method provides the prevention of acute gastroduodenal ulcers in the declared group of patients regardless the presence of pathological changes in the upper gastrointestinal mucosa.

5 ex

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