Derivatives of benzimidazole and pharmaceutical composition based on thereof

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

 

The technical field

This invention relates to new derivatives of benzimidazole and, in particular, to new derivatives of benzimidazole and their pharmaceutically acceptable salts, having the activity of glucose-lowering in blood or PDE5-inhibitory activity. In addition, the present invention relates to pharmaceutical compositions containing, as active ingredient, such benzimidazole derivatives or their salts.

Description of the invention

The object of the invention is the provision of new benzimidazole derivatives and their pharmaceutically acceptable salts, and pharmaceutical compositions that contain, as the active ingredient, such benzimidazole derivatives or their pharmaceutically acceptable salts, and which are useful for the prevention and treatment of impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy and so on), syndrome of insulin resistance (e.g., violations of the insulin receptor, syndrome Rabson-Mendenhall, leprechaunism (leprechaunism), Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence, the syndrome is Cushing, acromegaly and so on), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, and so on), hyperglycemia (e.g., abnormal sugar metabolism, such as malnutrition, etc), hypertension, angina, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc), tubulocystic disorders (e.g., nephropathy, caused by FK506, cyclosporin, etc), renal failure, atherosclerosis, stenosis of the vessel (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructi (e.g., bronchitis, asthma, chronic asthma, allergic asthma), and so on), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of interopability (e.g., syndrome Hyper sensitive enteropathy, and so on), impotence (e.g., organic impotence, psychic impotence, etc), nephritis, cachexia (e.g., progressive weight loss due to lipolysis, MOLISA, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc), pancreatitis, or restenosis after RTSA.

This is the inventors propose a new derivative of benzimidazole, represented by the following formula (I)and its pharmaceutically acceptable salt, and a pharmaceutical composition containing a specified compound or its pharmaceutically acceptable salt as an active ingredient, which is used for the prevention and treatment of impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc), syndrome of insulin resistance (e.g., violations of the insulin receptor, the syndrome Rabson-Mendenhall, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence, Cushing's syndrome, acromegaly, etc), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc), hyperglycemia (e.g., abnormal sugar metabolism, such as malnutrition, etc), hypertension, angina, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc), tubulocystic disorders (e.g., nephropathy, caused by FK506, cyclosporin, etc), renal defects in the accuracy, atherosclerosis, stenosis of the vessel (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructi (e.g., bronchitis, asthma, chronic asthma, allergic asthma), and so on), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of interopability (e.g., syndrome Hyper sensitive enteropathy, and so on), impotence (e.g., organic impotence, psychic impotence, etc), nephritis, cachexia (e.g., progressive weight loss due to lipolysis, m & e(cyto)Lisa, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc), pancreatitis, or restenosis after RTSA.

where R1represents a hydrogen atom, a lower alkyl group, lower alkoxy group or a lower alkylthio group;

R2represents an aromatic lower alkyl group which may be substituted by one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, nitro group, lower alkoxycarbonyl group, an aromatic group, an aromatic lower alkyloxy group, a lower cycloalkane-lower alkyl groups, aromatic h is SSA alkyl group, aromatic lowest alkenylphenol group, an aromatic lower alkenylphenol group, an aromatic hydroxy lower alkyl group, a lower cycloalkyl-lower alkyloxy group, alkenylphenol group, a lower alkoxy group, a lower alkylthio group, lower alkanesulfonyl group, lower alkanesulfonyl group and lower alkanesulfonyl group;

R3represents an alkyl group, a hydroxy lower alkyl group, alkenylphenol group, an aromatic group, a halogenated aromatic group, a lower alkyl aromatic group, lower alkenyl aromatic group, an aromatic lower alkyl group or aromatic lowest alkenylphenol group; and

-X-represents a crosslinking group represented by any one of the following formulas (II)-(VI):

In the above formula (I), R1preferably represents a lower alkyl group, and X represents a crosslinking group represented by the above formula (V).

Derivatives of benzimidazole, provided by the present invention, can be obtained according to the following reaction scheme ((a)-(m)).

where R1, R2and R3have the same meanings as described above, R represents a protective group for carboxyl group, and Z represents a halogen atom.

The compound (I) can be converted into Compound (2) by hydrolysis of its base, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. (reaction scheme (a)). The compound (3) can be obtained by treating Compound (2) an activator carboxylic acid represented by N,N'-carbonyl diimidazol, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or salt it, dicyclohexylcarbodiimide, isobutylacetate chloride, isobutyryl chloride, pivaloyl chloride, isobutyl by chloroformiate, diphenylphosphoryl azide or diethyl-cyanoformate, with subsequent interaction with the corresponding sulfonamide in the presence of a base, represented by databaseconnection, triethylamine, 4-dimethylaminopyridine, N,N'-dimethylaniline, pyridine, N-methylmorpholine, N-ethylpiperidine, potassium hydroxide, sodium hydroxide, the potassium phosphate, potassium bicarbonate, potassium carbonate, sodium carbonate, sodium hydride, t-piperonyl is Aliya, the sodium methylate or sodium ethylate (reaction scheme (b)). The compound obtained by the reaction between Compound 2 and activator of carboxylic acid may be isolated or it can not be selected.

The compound (6) can be obtained by the interaction of the Compound (2) with aminosulfonates in the presence of carbonyldiimidazole, etc. (reaction scheme (g)).

Compound (7) can be obtained by reacting compound (2) with hydrazine with one of its protected amino groups in the presence of carbonyldiimidazole etc. and processing the obtained product in acidic conditions (reaction scheme (h)). Compound (7) can be converted into the Compound (8) by its interaction with sulfonyl chloride or the like in the presence of a base, such as triethylamine, etc. (reaction scheme (i)).

The compound (2) can be converted into the Compound (9) by reacting it with diphenylphosphoryl azide and alcohol in the presence of a base, such as triethylamine, etc. (reaction scheme (j)). Compound (9) can be converted into a Compound (10) treatment in acidic conditions (reaction scheme (k)). The compound (10) can be converted into the Compound (11) by its interaction with sulfonyl the isocyanate (reaction scheme (1)), and Compound (12) by reacting with isocyanate (reaction scheme (m)), respectively.

Used the terms "sulfonamides", "aminosulfonyl", "sulfonyl chlorides", "sulfonyl isocyanates and isocyanate" refers to such groups having the above-described substituent R3where the functional group, if it is present on its carbon atom, may be protected or unprotected. The compound (3)having a protected functional group, can be converted into the desired compound by removing the protection.

The compound (2) can be transformed into the corresponding gelegenheid represented by the Compound (4)by its interaction with thionyl chloride, thionyl bromide, trichloride phosphorus, pentachloride phosphorus, phosphorus oxychloride, oxalyl chloride or tribromide phosphorus, etc. (reaction scheme (C)). The compound (3) can be synthesized from Compounds (4) and sulfonamida in the presence or in the absence of a base (reaction scheme (d)).

The compound (5) can be synthesized by reacting Compound (4) with ammonia or ammonia water (reaction Scheme (e)). The compound (5) can also be synthesized from Compound (1) and ammonia or ammonia water. Alternatively, the Compound (5) can be obtained by reacting the intermediate compound that is produced from Compound (2) and activator carboxylic acid according to the reaction scheme (b)with ammonia or ammonia water. The compound (3) can also be synthesized from Compound (5) and sulfonyl chloride in the presence or in the absence of the core is of (reaction Scheme (f)).

When R1, R2or R3has the reactive substituent in any of the compounds from the Compounds (1) to Compound (12), the Deputy may be replaced by another during the stages (a) through (m) or at the final stage.

If required, the intermediate compound obtained in the above stages can be optionally purified before they are subjected to the next stage, using any standard treatment, including, for example, recrystallization, column chromatography, thin-layer chromatography, high performance liquid chromatography, etc. in Addition, if required, the final products of the compounds of the present invention can be optionally purified by any conventional treatment, which is used in the field of purification of organic compounds and which includes, for example, recrystallization, column chromatography, thin-layer chromatography, high performance liquid chromatography, etc. To identify these compounds, use any of these methods: NMR spectroscopy, mass spectrometry, IR spectroscopy, elemental analysis, measurement of the melting point and other.

Following are preferred examples and details mentioned here different definitions that are within the scope of the present invention.

Used herein, the term alkyl is Naya group means a linear or branched alkyl group, having from 1 to 20 carbon atoms, including methyl group, ethyl group, n-sawn group, ISO-sawn group, n-boutelou group, ISO-boutelou group, sec-boutelou group, tert-boutelou group, n-pentelow group, ISO-pentelow group, sec-pentelow group, 2,2-dimethylpentyl group, 2-methylbutyl group, n-hexoloy group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethyl-1-methylpropyloxy group, n-heptylene group, 1-methylhexanoic group, 2-methylhexanoic group, 3-methylhexane group, 4-methylhexanoic group, 5-methylhexanoic group, 1-ethylpentane group, 2-ethylpentane group, 1,1-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, n-aktiline group, 1-methylheptenone group, 2-methylheptane group 3-methylheptenone group, 4-methylheptane group, 5-methylheptanoic group, 6-methylheptanoic group, 1-ethylhexyloxy group, 2-ethylhexyloxy group, 1,1-diethylhexyl group, 2,2-diethylhexyl group, 3,3-diethylhexyl group, n-naniloa group, 1-methylaniline group, 2-methylaniline group, 3-methylaniline group, 4-meta octillo group, 5-methylaniline group, 6-methylaniline group, 7-methylaniline group, 1-etilefrine group, 2-etilefrine group, 1,1-dimethylheptyl group, 2,2-dimethylheptyl group, 3,3-dimethylheptyl group, n-decile group, 1-methylnonanoic group, 2-methylnonane group, 3-methylnonane group, 4-methylnonanoic group, 1-atrakcyjny group, 2-atrakcyjny group, n-undecyloxy group, n-dodecyloxy group, n-tridecanol group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-octadecyl group, etc. are Preferably used those groups which have from 2 to 8 carbon atoms.

The term "lower" means the number of carbon atoms from 1 to 6. Preferred examples of the lower alkyl group include alkyl group with straight or branched chain such as methyl, ethyl, n-through out-through n-boutelou, ISO-boutelou, second-boutelou, tert-boutelou, n-pentelow, ISO-pentelow, second-pentelow, tert-pentelow, 2-methylbutyl, n-hexoloy, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyloxy, or the like, More preferred group, having from 1 to 3 carbon atoms.

The term "hydroxy lower al the ilen group" means the above lower alkyl group, which is connected with a hydroxyl group, including 1-hydroxyethylene, 2-hydroxyethylene, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxybutyl, 2-hydroxy-boutelou, 3-hydroxybutyl, 4-hydroxybutyl, 1-hydroxypentanal, 2-hydroxypentanal, 3-hydroxypentanal, 4-hydroxypentanal, 5-hydroxypentanal, 1-hydroxyhexyl, 2-hydroxyhexyl, 3-hydroxyhexyl, 4-hydroxyhexyl, 5-hydroxyhexyl, 6-hydroxyhexyloxy, 3,4-dihydroxybutyl, 2,4-dihydroxyphenyl, 1,3,5-trihydroxysilyl, (2-hydroxy-1-methyl)ethyl, (1-hydroxy-2-methyl)through (2-hydroxy-2-methyl)through (2-hydroxymethyl)through (3-hydroxy-1-methyl)through (4-hydroxy-1-methyl)boutelou, (1-hydroxy-3-methyl)boutelou, (2-hydroxy-3-methyl)boutelou, (3-hydroxy-3-methyl)boutelou, (3-hydroxymethyl)boutelou, (1-hydroxy-4-methyl)pentelow, (2-hydroxy-4-methyl)pentelow, (3-hydroxy-4-methyl)pentelow, (4-hydroxy-4-methyl)pentelow, (4-hydroxymethyl)pentelow, (1,1-dimethyl-2-hydroxy)ethyl, (1,1-dimethyl-2-hydroxy)through (1,1-dimethyl-3-hydroxy)through (1,1-dimethyl-2-hydroxy)boutelou, (1,1-dimethyl-3-hydroxy)boutelou, (1,1-dimethyl-4-hydroxy)boutelou, (1-hydroxy-1-methyl)boutelou, (2,2-dimethyl-1-hydroxy)boutelou, (2,2-dimethyl-3-hydroxy)boutelou, (2,2-dimethyl-4-hydroxy)boutelou (2-hydroxymethyl-2-methyl)boutelou, (3,3-dimethyl-1-hydroxy)boutelou, (3,3-dimethyl-2-hydroxy)boutelou, (3,3-dimethyl-4-hydroxy)boutelou, (3-hydroxymethyl-3-methyl)boutelou, etc.

Used herein, the term "Alchemilla group" means a linear or branched alkenylphenol group having from 2 to 20 carbon atoms including vinyl group, propenyloxy group, 2-propenyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-methyl-1-propenyloxy group, 2-methyl-1-propenyloxy group, 1-methyl-2-propenyloxy group, 2-methyl-2-propenyloxy group, 1-pentanediol group, 2-pentanediol group, 3-pentanediol group, 4-pentanediol group, 1-methyl-1-butenyloxy group, 2-methyl-1-butenyloxy group, 3-methyl-1-butenyloxy group, 2-methyl-2-butenyloxy group, 3-methyl-2-butenyloxy group, 2-methyl-3-butenyloxy group, 1,3-butadienyl group, 3-methyl-3-butenyloxy group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 2-methyl-1-pentanediol group, 3-methyl-1-pentanediol group, 4-methyl-1-pentanediol group, 1-heptenyl group, 1-octenidine group, 1-moneyline group, 1-dianilino group, 1-undecenyl group, 1-dodecyloxy group, 1-tridactylous group, 1-tetradecanol group, 1-pentadecanol group, 1-hexadecanethiol group, 1-octadecenyl group, and d Preferably groups having from 2 to 8 carbon atoms.

Used herein, the term "lower Alchemilla group" preferably includes a straight chain or branched chain lower alkenylphenol group, such as ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1,4-methylpentene, etc.

The halogen atom includes fluorine atoms, chlorine, bromine and iodine, and its preferred examples are fluorine atoms, chlorine and bromine.

Halo-lower alkyl group means the above lower alkyl group substituted by the above-described halogen atom, including vermeil, deformity, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, methyl bromide, dibromomethyl, tribromoethyl, iodomethyl, 1-foretel, 1-chloroethyl, 1-bromacil, 2-foretel, 2-chloroethyl, 2-bromacil, 1,1-dottorati, 1,1-dichloroethyl, 1,1-dibromoethyl, 2,2-dottorati, 2,2-dichloroethyl, 2,2-dibromoethyl, 1,2-dottorati, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2,2-triptorelin heptapteridae, 1-forproper, 1-chloropropyl, 1-bromopropyl, 2-forprofit, 2-chloropropyl, 2-bromopropyl, 3-forproper, 3-chloropropyl, 3-bromopropyl, 1,1-direcror, 1,1-dichloropropyl, 1,1-dibromopropyl, 1,2-direcror, 1,2-dichloropropyl, 1,2-dibromopropyl, 2,3-direcror, 2,3-dichloropropyl, 2,3-dip propyl, 3,3,3-cryptochromes, 2,2,3,3,3-pentafluoropropyl, 2-terbutyl, 2-chlorobutyl, 2-bromobutyl, 4-terbutyl, 4-chlorobutyl, 4-bromobutyl, 4-iodobutyl, 3,4-dichloroethyl, 2,4-dibromophenyl, 3,3,4,4,4-PENTACARBONYL, 2,2,3,3,4,4,4-heptafluorobutyl, performatic, 2-terpencil, 2-chloropentyl, 2-bromopentyl, 5-terpencil, 5-chloropentyl, 3-iodophenyl, 5-bromopentyl, 2-forexer, 2-chlorhex, 2-bromohexyl, 6-fluoro-hexyl, 6-chlorhex, 6-bromohexyl, 1,3,5-triptorelin, perferences, etc.

The lower alkoxy group means a straight chain or branched chain CNS group having up to 6 carbon atoms, including methoxy, ethoxy, n-propyloxy, and propyloxy, n-Butylochka, and bucalossi, sec-Butylochka, t-Butylochka, n-pentyloxy, and-pentyloxy, sec-pentyloxy, 2,2-dimethylpropylene, 2-methylbutoxy, n-hexyloxy, out-hexyloxy, t-hexyloxy, sec-hexyloxy, 2-methylendioxy, 3 methylpentane, 1 ethylbutyrate, 2-ethylbutylamine, 1,1-dimethylbutylamino, 2,2-dimethylbutylamino, 3,3-dimethylbutylamino, 1-ethyl-1-methylpropyloxy, etc.

Lower alkoxycarbonyl group means a carbonyl group, which is connected above the lower CNS group, including methoxycarbonyl, etoxycarbonyl, n-propylenecarbonate, and propylenecarbonate, n-butyloxycarbonyl, and butyloxycarbonyl, second-butyloxycarbonyl, t-butyloxycarbonyl, n-pentyloxybenzoyl, the-pentyloxybenzoyl, second-pentyloxybenzoyl, t-pentyloxybenzoyl, 2,2-dimethylpropyleneurea, 2-motivationskurser, n-hexyloxymethyl, and hexyloxybenzoyl, t-hexyloxybenzoyl, second-hexyloxyphenyl, 2-methylbenzyloxycarbonyl, 3-methylbenzyloxycarbonyl, 1-ethylbutylamine, 2-ethylbutylamine, 2,2-dimethylbutylamine, 3,3-dimethylbutylamine, 1-ethyl-1-methylpropyloxy, etc.

Lower cycloalkane-lower alkyl group means the above lower alkyl group having associated with it cycloalkane group having 3 to 7 carbon atoms, for example, cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy, cycloheptylamine, etc. are Examples of such groups include (cyclopropylamino)methyl, 2-(cyclopropylamino)ethyl, (cyclobutylamine)methyl, 3-(cyclobutylamine)propyl, cyclopentylmethyl, 2-(cyclopentyloxy)ethyl, 4-(cyclopentyloxy)butyl, (cyclohexyloxy)methyl, 1-(cyclohexyloxy)ethyl, 2-(cyclohexyloxy)ethyl, 3-(cyclohexyloxy)propyl, 2-(cyclohexyloxy)propyl, 1-(cyclohexyloxy) propyl, 4-(cyclohexyloxy)butyl, 3-(cyclohexyloxy) butyl, 2-(cyclohexyloxy)butyl, 6-(cyclohexyloxy)hexyl, 1-(cyclohexyloxy)butyl, (cyclohexyloxy)methyl, etc

Lowest cycloalkyl-lower alkyloxy group means the above lower alkoxy group having associated with it cloulkili group, having 3 to 7 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. are Examples of this group include (cyclopropylmethyl)hydroxy, (2-cyclopropylethyl)hydroxy, (cyclobutylmethyl)oxy, (3-cyclobutylmethyl)hydroxy, (cyclopentylmethyl)hydroxy, (2-cyclopentylmethyl)hydroxy, (4-cyclopentylmethyl)hydroxy, (cyclohexylmethyl)hydroxy, (1-cyclohexylethyl)hydroxy, (2-cyclohexylethyl)oxy, (3-cyclohexylprop)hydroxy, (2-cyclohexylprop)hydroxy, (1-cyclohexylprop)hydroxy, (4-cyclohexylmethyl)oxy, (3-cyclohexylmethyl)hydroxy, (2-cyclohexyl-

butyl)hydroxy, (6-cyclohexyloxy)hydroxy, (1-cyclohexylmethyl)hydroxy, cycloheptylmethyl, etc.

Lower alkylthio group means a straight chain or branched chain, alkylthio group having up to 6 carbon atoms, including methylthio, ethylthio, n-propylthio, and propylthio, n-butylthio, and butylthio, sec-butylthio, t-butylthio, n-pentylthio, and pentylthio, sec-pentylthio, 2,2-dimethylpropylene, 2-methylbutyl, n-hexylthio, and-hexylthio, t-hexylthio, second-hexylthio, 2-methylphenylthio, 3-methyl-lentilly, 1 ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, etc. are Preferred groups having from 1 to 4 carbon atoms, such as methylthio, ethylthio, n-propylthio, and propylthio, n-butylthio, and butylthio, sec-butyl is IO or t-butylthio.

Lower alkanesulfonyl group means a straight chain or branched chain alkanesulfonyl group with its alkyl part containing up to 6 carbon atoms, including methanesulfonyl, econsulting, 1-propanesulfonyl, 2-propanesulfonyl, 1-butanesulfonyl, 2-butanesulfonyl, 1,1-dimethylethanolamine, 1-(2-methylpropan)sulfinil, 1-pentanesulfonic, 2-pentanesulfonic, 3-pentanesulfonic, 1-(3-methylbutane)sulfinil, 1,1-dimethylpropylene, 1-hexanesulfonic, 2-hexanesulfonic, 3-hexanesulfonic, 1-(2-methylpentan)sulfinil, 1-(3-methylpentan)sulfinil, 1-(4-methylpentan) sulfinil, 2-ethylbutane-1-sulfinil, 3-ethylbutane-1-sulfinil, 1,1-dimethylbutan-1-sulfinil, 2,2-dimethylbutan-1-sulfinil, 3,3-dimethylbutan-1-sulfinil, 1-ethyl-1-methyl-propane-1-sulfinil, etc.

Lower alkanesulfonyl group means a straight chain or branched chain alkanesulfonyl group with its alkyl part containing up to 6 carbon atoms, including methanesulfonyl, econsultancy, 1-propanesulfonyl, 2-propanesulfonyl, 1-butanesulfonyl, 2-butanesulfonyl, 1,1-dimethylaminoethanol, 1-(2-methylpropane)-sulfonyl, 1-pentanesulfonic, 2-pentanesulfonic, 3-pentanesulfonic, 1-(3-methylbutane)sulfonyl, 1,1-dimethylpropylene, 1-hexanesulfonic, 2-hexanesulfonic, 3-hexanesulfonic, 1-(2-methylpentan)sulfonyl, 1-(3-METI the pentane)-sulfonyl, 1-(4-methylpentan) sulfonyl, 2-ethylbutane-1-sulfonyl, 3-ethylbutane-1-sulfonyl, 1,1-dimethylbutan-1-sulfonyl, 2,2-dimethylbutan-1-sulfonyl, 3,3-dimethylbutan-1-sulfonyl, 1-ethyl-1-methyl-propane-1-sulfonyl, etc.

The aromatic group means an aryl or heterocyclic aromatic group. In this description, the aryl group means a group having from 6 to 10 carbon atoms, such as phenyl, naphthyl, or the like When it comes to the term "naftalina group", it includes 1-raftiline and 2-raftiline group. Heterocyclic aromatic group means an unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom, such as oxygen atoms, sulfur and nitrogen, including pyrrolyl, imidazolyl, furyl, thienyl, thiazolyl, pyridyl, benzimidazolyl, benzofuran, indolyl, benzothiazyl, hinely, ethanolic, thiophene, furanyl, etc. Position substituted heteroatom, as described above, the aromatic ring is not particularly limited.

Halo-aromatic group means the above-described aromatic group substituted by the above-described halogen atom, including 2-forfinal, 2-chlorophenyl, 2-bromophenyl, 2-iodophenyl, 3-forfinal, 3-chlorophenyl, 3-bromophenyl, 3-iodophenyl, 4-forfinal, 4-chlorophenyl, 4-bromophenyl, 4-iodophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 4-br the m-2-chlorophenyl, 4-iodo-2-chlorophenyl, 1 does not depend-2-yl, 2-chloronaphthalene-1-yl, 5-chloronaphthalene-1-yl, 6-chloronaphthalene-1-yl, 4-chloroisoquinoline-8-yl, 2-chlorhydrin-4-yl, 4-bromoisoquinoline-1-yl, 5-chlorothiophene-2-yl, 5-bromothiophene-2-yl and 5-chlorothiophene-3-yl, etc.

Aromatic lower alkyl group means a lower alkyl group, which is connected with the above-described aromatic group, including benzyl, 1-phenylethyl, 2-phenylethyl, phenylpropyl, phenylbutyl, fenilpentil, phenylgesic, naphthylmethyl, naphtalate, naftilamin, naphthylmethyl, naphthylmethyl, nattinger, pyridylmethyl, pyridylethyl, chenailler, ISO-chenailler, etc. Aromatic group may be substituted by a halogen atom or a group such as lower alkyl, halo-lower alkyl, nitro, lower alkoxycarbonyl, an aromatic group, an aromatic lower alkyloxy, lower cycloalkane-lower alkyl, an aromatic lower alkyl, aromatic lowest alkenyl, aromatic lowest quinil, aromatic hydroxy-lower alkyl, lower cycloalkyl-lower alkyloxy, lower alkenyl, lower alkoxy, lower alkylthio, lower alkanesulfonyl, lower alkanesulfonyl, or lower alkanesulfonyl.

Lower alkyl aromatic group means the above-described aromatic group, which is connected with the above-described lower alkyl group, including 2-were, 3-were, 4-were, 2,3-dimethy is phenyl, 2,4-dimetilfenil, 2,5-dimetilfenil, 2,6-dimetilfenil, 3,4-dimetilfenil, 3, 5dimethylphenyl, 2,3,5,6-tetramethylene, pentamethylene, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-n-propylphenyl, 2-and-propylphenyl, 3-n-propylphenyl, 3-and-propylphenyl, 4-n-propylphenyl, 4-and-propylphenyl, 2,4,6-tri-and-isopropylphenyl, 2-n-butylphenyl, 2-and-butylphenyl, 2-t-butylphenyl, 3-n-butylphenyl, 3-and-butylphenol, 3-t-butylphenyl, 4-n-butylphenyl, 4-and-butylphenyl, 4-t-butylphenyl, 4-n-pentylphenol, 4-and-pentylphenol, 4-t-pentylphenol, 4-n-hexylphenyl, 2-methylnaphthalene-1-yl, 3-methylnaphthalene-1-yl, 4-methylnaphthalene-1-yl, 5-methylnaphthalene-1-yl, 6-methylnaphthalene-1-yl, 7-methylnaphthalene-1-yl, 8-methylnaphthalene-1-yl, 1-methylnaphthalene-2-yl, 3-methylnaphthalene-2-yl, 4-methylnaphthalene-2-yl, 5-methylnaphthalene-2-yl, 6-methylnaphthalene-2-yl, 7-methylnaphthalene-2-yl, 8-methylnaphthalene-2-yl, 5, 8-dimethylnaphthalene-1-yl, 5,8-dimethylnaphthalene-2-yl, etc.

Aromatic hydroxy lower alkyl group means the above-described aromatic group, with which the above lower alkyl group linked through an oxygen atom, including (phenyloxy)methyl, (1-naphthyloxy)methyl, (2-naphthyloxy)methyl, 1-(phenyloxy)ethyl, 2-(phenyloxy)ethyl, 1-(1-naphthyloxy)ethyl, 1-(2-naphthyloxy)-ethyl, 2-(1-naphthyloxy)ethyl, 2-(2-naphthyloxy)ethyl, 1-(phenyloxy)propyl, 2(phenyloxy)propyl, 3-(phenyloxy)propyl, 1-(1-naphthyloxy)propyl, 1-(2-naphthyloxy) propyl, 2-(1-naphthyloxy)propyl, 2-(2-naphthyloxy)propyl, 3-(naphthyloxy)propyl, 3-(2-naphthyloxy)propyl, 4-(vinyloxy)butyl, 5-(phenyloxy)pentyl, 6-(phenyloxy)hexyl, etc.

Aromatic lower alkyloxy group means the above-described aromatic group, which is connected above the lower CNS group, including benzyloxy, 1-naphthylmethyl, 2-naphthylmethyl, (1-phenylethyl)oxy, (2-phenylethyl)oxy, (1-Nettleton-1-yl)oxy, (2-Nettleton-1-yl)oxy, (1-Nettleton-2-yl)oxy, (2-Nettleton-2-yl)oxy, (1-phenylpropyl) hydroxy, (2-phenylpropyl)hydroxy, (3-phenylpropyl)hydroxy, (1-navipromo-1-yl)oxy, (2-navipromo-1-yl)oxy, (1-navipromo-2-yl)oxy, (2-naphthyl-propan-2-yl)oxy, (1-navipromo-3-yl)oxy, (2-navipromo-3-yl)oxy, (4-phenylbutyl)hydroxy, (2-attibute-4-yl)hydroxy, (5-fenilpentil)hydroxy, (2-afterparty-5-yl)hydroxy, (6-phenylhexa)hydroxy, (1-natterjacks-6-yl)oxy, etc.

Aromatic lowest Alchemilla group means the above lower alkenylphenol group, which is connected with the above-described aromatic group, including 1-phenylethenyl, 2-phenylethenyl, 1-phenyl-1-propenyl, 2-phenyl-1-propenyl, 3-phenyl-1-propenyl, 1-phenyl-2-propenyl, 2-phenyl-2-propenyl, 3-phenyl-2-propenyl, 1-phenyl-1-butenyl, 2-phenyl-1-butenyl, 4-phenyl-2-butenyl, 3-phenyl-2-propenyl, 2-phenyl-1-pentenyl, 2-phenyl-3-pentenal, 2-phenyl-1-pentenyl, 2-phenyl-1-hexenyl, etc.

Lower alkenyl aromatic group means the above-described aromatic group, which svetamaytala group, having from 2 to 6 carbon atoms, including 2-vinylphenol, 3-vinylbenzyl, 4-vinylbenzyl, 3-isopropylphenyl, 4-isopropylphenyl, 4-allylphenol, 4-(1-butenyl)phenyl, 4-(2-butenyl)phenyl, 4-(1,3-butadienyl)phenyl, 4-(3-butenyl)phenyl, 4-(1-pentenyl)phenyl, 5-(1-hexenyl)phenyl, etc.

Aromatic lowest Alchemilla group means alkylamino group having from 2 to 6 carbon atoms, which is connected with the above-described aromatic group, including phenylethynyl, 3-phenyl-1-PROPYNYL, 3-phenyl-1-butenyl, 4-phenyl-1-butenyl, 4-phenyl-2-butenyl, 1-phenyl-2-pentenyl, 1-phenyl-4-pentenyl, 6-phenyl-1-hexenyl, etc.

Preferred salts of benzimidazole derivatives of the present invention are non-toxic, ordinary, their pharmaceutically acceptable salts. For example, mentioned are salts derived from bases, and salts accession acid derivatives, which include, for example, their salts with

inorganic bases, such as salts with alkali metals (e.g. sodium, potassium), salts with alkaline earth metals (e.g. calcium, magnesium); ammonium salts; salts with organic amines (e.g. triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine,N,N'-dibenziletilendiaminom); salts with inorganic acids (e.g. hydrochloric acid, Hydrobromic acid, chamois is th acid, phosphoric acid); salts with organic carboxylic acids (e.g. formic acid, acetic acid, triperoxonane acid, maleic acid, tartaric acid); salts with sulfonic acids (for example, methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid); salts with basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid), etc.

Compounds of the invention can contain one or more chiral centers, so they can represent enantiomers or diastereomers. Few compounds containing alkenylphenol group, may also be CIS - or TRANS-isomers. In both cases, each of these isomers and their mixtures are included in the scope of this invention.

Compounds of the invention may also exist as tautomers, and each of such tautomers and their mixtures are included in the scope of this invention.

Compounds of the invention and their salts can be MES, which are also included in the scope of the invention. Solvent for MES is preferably a hydrate or ethanol.

Specific examples of the compounds of the present invention include 1-(isoquinoline-3-ylmethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-((4-chloroisoquinoline-3-yl)methyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-((1-br is naftalin-2-yl)methyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-

1-pentane)sulfonylamino)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonyl carbarnoyl)-

2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl) -2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)-benzimidazole, 6-(benzensulfonamidelor)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole, 6-(N'-botanicalvegetational)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 6-((n-butylaminoethyl)-carbarnoyl)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-[N'-(4-methylphenylsulfonyl)ureido]benzimidazole, 1-(2,4-dichlorobenzyl) -2-methyl-6-(N'-phenylurea)benzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(1-pentacarbonyliron) benzimidazole, 1-(2-chloro-4-(trifluoromethyl)-benzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-6-((5-chlorothiophene-2-yl) sulfonylamino)-2-methylbenzamide is angry 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)-benzimidazole, 1-(4-bromo-2-Chlorobenzyl) -2-methyl-6-((4-methylbenzoyl) sulfonylamino) benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol)benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-6-((5-chlorothiophene-2-yl)-sulfonylamino)-2-methylbenzimidazole, 1-(4-benzyloxy-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(4-benzyloxy-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino) benzimidazole, 6-((5-bromothiophene-2-yl) sulfonylamino) -1-(2, 4-dichlorobenzyl) -2-methylbenzimidazole,6-((5-bromothiophene-2-yl)sulfonylamino)-1-(2-chloro-4-phenylbenzyl)-2-methylbenzimidazole, 1-(2-chloro-4-(cyclohexylmethoxy)benzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(2-chloro-4-(cyclohexylmethoxy)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 6-((5-chlorothiophene-2-yl)sulfonylamino)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole, 1-(4-bromo-2-Chlorobenzyl)-6-((5-bromothiophene-1-yl)sulfonylamino)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)-

the benzimidazole, 1-(2-chloro-4-bromobenzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)-benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino) -benzimidazole, (+)-1-(1-2,4-dichlorophenyl)-ethyl) -2-methyl-6-(1-pentanesulfonate) benzimidazole, (-)-1-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((1-Penta-4-ene)sulfonylamino)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((E)-1-Penta-4-ene}sulfonylamino) benzimidazole, 1-(2-chloro-4-nitrobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-phenylethylene)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino) -benzimidazole, 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methyl-6-((4-methylbenzoyl)-sulfonylamino)benzimidazole, 1-(2-chloro-4-(2-phenylethyl)-benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(4-t-butylthio-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(4-t-butylthio-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl)-sulfonylamino)benzimidazole, 1-(2-chloro-4-(phenoxymethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(phenoxymethyl)-benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(cyclohexylmethyl)-benzyl)-2-methyl-6-((4-methylbenzoyl)-sulfonylamino)b is silicasol, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((n-intramyocellular)carbarnoyl)benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(((4-(were)aminosulfonyl)carbarnoyl)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((4-(were)aminosulfonyl)carbarnoyl)benzimidazole, 1-(2-chloro-4-iodobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-iodobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-ethoxybenzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(2-chloro-4-ethoxybenzyl)-2-methyl-6-((4-methylbenzoyl) sulfonylamino)benzimidazole, 1-(2-chloro-4-(1-pentanesulfonate)benzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino) benzimidazole, (R)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, (S)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole (showing a longer retention time under the liquid chromatography), optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy~1-pentane)Sul is Vilcabamba)-2-methylbenzimidazole) (demonstrating a shorter retention time under the liquid chromatography), optically active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylamino) -2-methylbenzimidazole (demonstrating a longer retention time under the liquid chromatography), optically active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole (demonstrating a shorter retention time under the liquid chromatography), 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-((4-methylbenzoyl)sulfonylamino)-benzimidazole, 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-6-(pentacarbonyliron)benzimidazole, 1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino) benzimidazole, 1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methyl-6-(1-pentacarbonyliron)benzimidazole, 1-(2-chloro-4-(furan-2-yl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(furan-2-yl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-6-((E)-1-penten-1-sulfonylamino)benzimidazole, 1-(2-chloro-4-(phenylethynyl)-benzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol)benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-6-((4-vinylbenzyl)sulfonylamino)-2-methylbenzimidazole, 1-(2-chloro-4-((E)2-phenylethenyl)-benzyl)-6-((E)-1-penten-1-sulfonylamino)-2-methylbenzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol) benzimidazole, 1-(4-Butylochka-2-Chlorobenzyl)-6-(1-pentanesulfonate)-2-methylbenzimidazole, 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, etc.

Derivatives of benzimidazole and their pharmaceutically acceptable salts of the present invention, as mentioned above, are effective for prophylaxis and treatment of various diseases, for example, impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc), syndrome of insulin resistance (e.g., violations of the insulin receptor, the syndrome Rabson-Mendenhall, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome Cushing syndrome, acromegaly, etc), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc), hyperglycemia (e.g., abnormal sugar metabolism, such as violations of p is Tania, etc), hypertension, angina, pulmonary hypertension, congestive heart failure, glomerulopathy (e.g., diabetic glomerulosclerosis, etc), tubulo-intestinal disorders (e.g., renovate caused FK506, cyclosporin, etc), renal failure, atherosclerosis, stenosis of the vessel (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructi (e.g., bronchitis, asthma, chronic asthma, allergic asthma), and so on), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders interopability (e.g., syndrome Hyper sensitive enteropathy, and so on), impotence (e.g., organic impotence, psychic impotence, etc) and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic violation of osteogenesis, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc), nephritis, cachexia (e.g., progressive weight loss due to lipolysis, MOLISA, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc), punk is eatit, or restenosis after RTSA based on their cGMP-PDE (especially PDE-V)-inhibitory activity, which relaxes the smooth muscle activity, bronchodilating activity, vasodilating activity, activity, suppressive cells, smooth muscle, and anti-allergic activity.

For the use of benzimidazole derivatives of the present invention for treatment of diseases or disorders such as those mentioned above, they can be prepared in pharmaceutical compositions, normal forms, which contain, as active ingredient, any of the derivatives together with pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid fillers, and which are suitable for oral administration, parenteral administration or external application. The pharmaceutical compositions can be any of the solid forms such as tablets, granules, powders, capsules, etc. or may be in any liquid forms such as solutions, suspensions, syrups, emulsions, soft drinks, etc.

If necessary, the pharmaceutical composition can optionally contain a pharmaceutical additive, stabilizer, wetting agent, and, in addition, any conventional additive, such as, for example, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, powdered gypsum, Saha is oz, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, etc.

A number of the above mentioned derivative of the present invention to be used, will vary depending on the age and condition of the patient, the type and condition of diseases or disorders and derived type to be used. In General, for oral administration, the dose can be derived from 1 to 100 mg/kg; and for intramuscular injection or intravenous injection, it may be from 0.1 to 10 mg/kg. Such standard dose can be administered to the patient from one to four times per day.

Brief description of drawings Figure 1 shows the chemical formulas of compounds(13)-(16).

Figure 2 shows the chemical formulas of compounds(17)-(20).

Figure 3 shows the chemical formulas of compounds(21)-(24).

Figure 4 shows the chemical formulas of compounds(25)-(28).

Figure 5 shows the chemical formulas of compounds(29)-(32).

6 shows the chemical formulas of compounds(33)-(36).

Fig.7 shows the chemical formulas of compounds(37)-(40).

Fig shows the chemical formulas of compounds(41)-(44).

Fig.9 shows the chemical formulas of compounds(45)-(48).

Figure 10 shows the chemical formulas of compounds(49)-(52).

11 shows the chemical formulas of compounds(53)-(56).

Figure 1 shows the chemical formulas of compounds(57)-(60).

Fig shows the chemical formulas of compounds(61)-(64).

Fig shows the chemical formulas of compounds(65)-(68).

Fig shows the chemical formulas of compounds(69)-(72).

Fig shows the chemical formulas of compounds(73)-(76).

Fig shows the chemical formulas of compounds(77)-(80).

Fig shows the chemical formulas of compounds(81)-(84).

Fig shows the chemical formulas of compounds(85)-(88).

Fig shows the chemical formulas of compounds(89)-(92).

Fig shows the chemical formulas of compounds(93)-(96).

Fig shows the chemical formula of compound (97) (98).

The best way of carrying out the invention

The present invention is illustrated more specifically by the following examples. However, the present invention is not limited to this only.

Example Obtain 1

Obtain ethyl 4-(acetylamino)-3-((isoquinoline-3-yl-methyl)amino)benzoate

A mixture of ethyl 4-(acetylamino)-3-aminobenzoate (1,11 g), 3-(methyl bromide)isoquinoline (1,37 g), sodium carbonate (0.74 g), sodium iodide (0.15 g), ethyl acetate (10 ml) and water (2.5 ml) was stirred at 70°C for 20 hours. In the reaction mixture, water is added, and the mixture is extracted with ethyl acetate. After the organic layer is dried and concentrated and the residue purified using column chromatography on silica gel (eluate: methanol/ethyl acetate=1/9), produces the desired compound, ethyl 4-(acetylamino)-3-((isoquinoline-3-ylmethyl)-amino)benzoate (0,91 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): to 1.37 (3H, t, J=7,1 Hz), 2,69 (3H, s), 4,36 (2N, K, J=7,1 Hz), the 5.65 (2H,s),? 7.04 baby mortality (1H,s), 7,60-7,66 (3H, m), 7,76 (1H, d, J=8.5 Hz), to 7.99 (2H,m), of 8.06 (1H, d, J=1.1 Hz), the 9.25 (1H, s).

Example of Getting 2

Obtain ethyl 4-(acetylamino)-3-(((4-chloroisoquinoline-3-yl)methyl)amino)benzoate

According to the method of Example 1, Receipt, receive the desired compound, ethyl 4-(acetylamino)-3-(((4-chloroisoquinoline-3-yl)methyl)amino)benzoate (0,536 g), using ethyl 4-(acetylamino)-3-aminobenzoate (0,524 g), 4-chloro-3-(chloromethyl) isoquinoline (0.50 g), sodium carbonate (0,300 g) and sodium iodide (0,071 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): to 1.38(3H, t, J=7.0 Hz), is 2.30(3H, s), 4,35(2N, K, J=7,1 Hz), 4.72 in(2N, C), 4,91(1H, CL), 7,58 (1H, d, J=7.8 Hz), 7,68 (2H, m), a 7.85 (2H, m), 8,01(2H, m), compared to 8.26(1H, d, J=6.4 Hz), 9,16(1H, s).

Example for the preparation of 3

Getting 6-(etoxycarbonyl)-1-(isoquinoline-3-ylmethyl)-2-methylbenzimidazole

A mixture of ethyl 4-(acetylamino)-3-((isoquinoline-3-ylmethyl)amino)benzoate (from 0.90 g)obtained in Example Obtain 1, conc. HCl (1 ml) and ethanol (10 ml) is heated at a temperature of education phlegmy within 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The obtained extract was concentrated, receiving remueve connection, 6-(etoxycarbonyl)-1-(isoquinoline-3-ylmethyl)-2-methylbenzimidazole (0,92 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): of 1.41 (3H, t, J=7,1 Hz), 2,70 (3H, s), 4,36 (2N, K, J=7,1 Hz), the 5.65 (2H, s),? 7.04 baby mortality (1H, s), 7,60-7,66 (3H, m), to 7.77 (1H, d, J=6.8 Hz), to 7.99 (2H, m), 8,07 (1H, d, J=1.3 Hz), the 9.25 (1H, s).

Example 4

Obtaining 1-((4-chloroisoquinoline-3-yl)methyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

According to the method described in the Example of a 3, this compound is synthesized from ethyl 4-(acetylamino)-3-(((4-chloroisoquinoline-3-yl)methyl)amino)benzoate.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): to 1.38 (3H, t, J=7,1 Hz), was 2.76 (3H, s), 4,34 (2N, K, J=7,1 Hz), 5,77 (2H, s), 7,69 (2H, m), 7,86 (2H, m), 7,94 (2H, m), 8,13 (1H, d, J=1.3 Hz), of 8.28 (1H, d, J=8,4 Hz), 8,98 (1H, s).

Example of Getting 5

Obtaining 6-carboxy-1-(isoquinoline-3-ylmethyl)-2-methylbenzimidazole

A mixture of 6-(etoxycarbonyl)-1-(isoquinoline-3-ylmethyl)-2-methylbenzimidazole (0,91 g)obtained in Example Receiving 3, aqueous 10% sodium hydroxide (10 ml) and ethanol (10 ml) is heated at a temperature of education phlegmy for 1 hour. The reaction mixture once acidified by adding conc. HCl (2 ml) and then neutralized aqueous saturated sodium bicarbonate solution. The precipitated crystals are collected and dried, obtaining a desired compound, 6-carboxy-1-(isoquinoline-3-ylmethyl)-2-methylbenzene the azole (0,79 g).

[Physico-chemical characteristics of connection]

H=NMR (DMCO-d6that δ m.g.): of 2.66 (3H, s), of 5.75 (2H, s), 7,58 (1H, d, J=8,4 Hz), the 7.65 (1H, t, J=7,1 Hz), 7,72 (1H, s), 7,76 (2H, m), to 7.93 (1H, d, J=8,3 Hz), of 8.09 (2H, m), 9.28 are (1H, s).

An example of Obtaining 6

Obtaining 6-carboxy-1-((4-chloroisoquinoline-3-yl)methyl)-2-methylbenzimidazole

This compound is synthesized from 1-((4-chloroisoquinoline-3-yl)methyl) -6-(etoxycarbonyl)-2-methylbenzimidazole according to the method described in Example Receipt 5.

[Physico-chemical characteristics of connection]

1H=NMR (DMCO-d6that δ m.g): at 2.59 (3H, s), 5,90 (2H, s)to 7.50 (1H, d, J=8,4 Hz), 7,44 (1H, DD, J=8.4 and 1,3 Hz), 7,79 (1H, t, J=7.5 Hz), to 7.99 (2H, m), 8,15 (1H, d, J=8.1 Hz), compared to 8.26 (1H, d, J=8.5 Hz), 9,13 (1H, s).

Example of Getting 7

Obtaining 1-((1-does not depend-2-yl)methyl)-6-carboxy-2-methylbenzimidazole

The crude product of the desired compound, ethyl 4-(acetylamino)-3-(((1-does not depend-2-yl)methyl)amino)benzoate, receive by way of Example, Obtain 1 using ethyl 4-(acetylamino)-3-aminobenzoate (0.50 g), 1-bromo-2-(methyl bromide) naphthalene (0,81 g), sodium carbonate (0,38 g) and sodium iodide (0.10 g).

This product is immediately converted into 1-((1-does not depend-2-yl)methyl)-6-carboxy-2-methylbenzimidazole (0,514 g) by the method of Example for the preparation of 3, and then by way of Example, Get 5.

[Physico-chemical characteristics of connection]

1H=NMR (DMCO-d6that δ m.g): of 2.56 (3H, s), of 5.84 (2H, s), is 6.61 (1H, d, J=8,Hz), 7,63 (1H, t, J=7.8 Hz), 7,66 (1H, d, J=8.5 Hz), of 7.75 (1H, t, J=7.8 Hz), 7,81 (1H, d, J=8.6 Hz), 7,86 (1H, d, J=8.6 Hz), 7,95 (1H, d, J=8,2 Hz), to 7.99 (1H, s), 8,30 (1H, d, J=8.6 Hz), 12,69 (1H, s).

Example Obtain 8

Obtain 1-(2,4-dichlorobenzyl)-6-(hydrazinophenyl)-2-methylbenzimidazole

A mixture of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (597 mg)as obtained in Example Receiving 14, 1,1'-carbonyldiimidazole (433 mg) and digidratirovannogo N,N-dimethylformamide (6.0 ml) was stirred at room temperature for 1 hour. In the reaction solution add databaseconnect (0,40 ml) and tertbutoxycarbonyl (353 mg). The mixture was stirred at 100°C for 4 hours. After cooling, the mixture was added water (30 ml), adjusted pH to 4 with Hcl and extracted with a mixed solvent of chloroform/methanol (4/1). The organic layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The obtained residue was washed with simple ether, obtaining 1-(2,4-dichlorobenzyl)-6-(hydrazinophenyl)-2-methylbenzimidazole in the form of a light yellow powder (250 mg).

[Physico-chemical characteristics of connection]

1H=NMR (DMCO-d6) 2,52 (3H, s), 5,64 (2H, s), 6,51 (1H, d, J=8 Hz), 7,34 (1H, d, J=8 Hz), the 7.65 (1H, d, J=8 Hz), 7,72 (1H, d, J=8 Hz), of 7.90 (1H, s).

Example of Getting 9

Getting 6-(tert-butoxycarbonylamino)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole

A mixture of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzo is idazole (200 mg), as received in the Sample Receiving 14, tert-butyl alcohol (5.7 ml), diphenylphosphoryl azide (1,54 ml), triethylamine (1.0 ml) and 1,4-dioxane (20 ml) is heated at a temperature of education phlegmy within 12 hours. The reaction solution allow to cool, diluted with ethyl acetate and washed sequentially with saturated aqueous sodium bicarbonate three times and with water once. The organic layer is evaporated to dryness under reduced pressure, and the residue is purified column chromatography on silica gel (chloroform/methanol=200/1 as eluate)to give 6-(tert-butoxycarbonylamino) -1-(2,4-dichlorobenzyl)-2-methylbenzimidazole in the form of a white powder (2.15 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMCO-d6): 1,42 (N, C)to 2.42 (3H, s), of 5.40 (2H, s), 6,44 (1H, d, J=8 Hz), 7,12 (1H, d, J=8 Hz), 7,32 (1H, d, J=8 Hz), 7,42 (1H, d, J=8 Hz), 7,49 (1H, CL), 7,72 (1H, s), 9,27 (1H, CL).

Example 10

Obtain 6-amino-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

6-(tert-Butoxycarbonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (2,05 g)obtained in Example Receiving 9, dissolved in 4N HCl/ethyl acetate (20 ml) and stirred at room temperature for 1 hour. The reaction mixture is evaporated to dryness under reduced pressure, and the residue extracted using chloroform and saturated aqueous sodium bicarbonate. The organic layer is dried over sulfate mA the of and evaporated to dryness under reduced pressure, getting 6-amino-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole in the form of a white powder (1.52 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMCO-d6): of 2.38 (2H, s), 5,32 (2H, s), 6,32 (1H, s), to 6.43 (1H, d, J=8 Hz), 6.48 in (1H, d, J=8 Hz), 7,22 (1H, d, J=8 Hz), 7,33 (1H, DD, J=8, 2 Hz), 7,72 (1H, d, J=8 Hz).

Example of Getting 11

Getting 2-chloro-1-((methanesulfonate)methyl)-4-(trifluoromethyl)-benzene

Methanesulfonyl chloride (1.1 ml) is added, dropwise, to a solution of 2-chloro-4-(trifluoromethyl)benzyl alcohol (2.64 g) and anhydrous triethylamine (2.3 ml) in anhydrous dichloromethane (30 ml) in a stream of nitrogen under ice cooling, and the mixture is stirred for 30 minutes under the same conditions. The reaction mixture was successively washed with water, aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The filtrate is concentrated and receiving 2-chloro-1-((methanesulfonate)-methyl)-4-(trifluoromethyl)benzene in the form of white crystals (3.62 in).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3): is 3.08 (3H, s), lower than the 5.37 (2H, s), 7,58 (1H, d, J=8 Hz), the 7.65 (1H, d, J=8 Hz), of 7.70 (1H, s).

Example 12

Obtain ethyl 4-(acetylamino)-3-((2-chloro-4-(trifluoromethyl)benzyl)amino)benzoate

Ethyl 4-(acetylamino)-3-((2-chloro-4-(trifluoromethyl)benzyl) amino) benzoate obtained as white crystals (915 mg) of ethyl 4-(acetylamino)-3-aminobenzoate 700 mg) and 2-chloro-1-((methanesulfonate)methyl)-4-(trifluoromethyl)benzene (909 mg) in the same way, as in the Example of a 1 except for using N,N-dimethylformamide as solvent and potassium carbonate as the base.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3): of 1.33 (3H, t, J=7 Hz), of 2.25 (2H, s), or 4.31 (2H, K, J=8 Hz), 4,53 (3H, s), 7,33 (1H, s), 7,40 (1H, d, J=8 Hz), 7,46-of 7.55 (3H, m), 7,68 (1H, s).

Example of Getting 13

Obtaining 6-carboxy-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methylbenzimidazole

Performing sequentially the methods of Examples 3 and 5 Receive, receive a 6-carboxy-1-(2-chloro-4-(trifluoromethyl)-benzyl)-2-methylbenzimidazole (777 mg) as white crystals from 4-(acetylamino)-3-((2-trifluoromethyl)benzyl)amino)benzoate (910 mg)as obtained in Example 12.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6): of 2.51 (3H, s), 5,71 (2H, s), 6,63 (1H, d, J=8 Hz), 7,63 (2H, t, J=8 Hz), 7,82 (1H, d, J=8 Hz), 8,01 (2H, s).

Example of Getting 14

<the First stage>

Obtain ethyl 4-(acetylamino)-3-nitrobenzoate

Acetyl chloride (62 ml) is added, dropwise, to a mixture of ethyl 4-amino-3-nitrobenzoate (142 g), N,N-dimethylaniline (110 ml) and toluene (940 ml) in a bath of ice. After stirring the mixture at 50°C for 3 hours, it is cooled. There is added water (142 ml)to stop the reaction. Toluene layer was separated and the organic layer washed with diluted hydrochloric acid and then with water. the donkey concentration of the organic layer to approximately 1/3 volume, there is added hexane (284 ml) for crystallization. The crystals are collected by filtration and washed with hexane, obtaining a desired compound, ethyl 4-(acetylamino)-3-nitrobenzoate (157,7 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): to 1.42 (3H, t, J=7,1 Hz), of 2.33 (3H, s), 4,42 (2N, K, J=7,1 Hz), of 8.28 (1H, DD, J=2.1 and a 8.9 Hz), 8,89 (1H, d, J=2.1 Hz), 8,91 (1H, d, J=8,9 Hz), 10,55 (1H, CL).

<a Second phase>

Obtain ethyl 4-(acetylamino)-3-aminobenzoate

A mixture of wet crystals of 4-(acetylamino)-3-nitrobenzoate (45,3 g, purity: 66,2%), ethanol (to 191.6 g), water (31,9 g) and palladium-on-carbon (palladium content: 5%, water content: 50%, 3.0 g) was stirred at 40°C for 19 hours in a hydrogen atmosphere. The catalyst was collected by filtration and washed with a mixed solvent of ethanol / water (1/9, 30,0). The filtrate is concentrated, and there is added dropwise, at 50°With added t-butyl methyl ether (33,0 g), and the mixture is cooled to 10°to carry out crystallization. The crystals are collected and washed with t-butyl methyl ether (30.0 g), and dried at 60°With under reduced pressure. Thus, getting ethyl 4-(acetylamino)-3-aminobenzoate (18.2 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): of 1.27 (3H, t), is 2.05 (3H, s), 4,23 (2N, K), 5,19 (2H, s), 7,13 (1H, d, J=8,2 Hz), 7,35 (1H, s), 7,47 (1H, d, J=8,2 Hz), 9,19 (1H, s).

<a Third step>

Obtain ethyl 4-(acetylamino)-3-((2,4-dichlorobenzyl)-amino)benzoate

In the same manner as in Example Obtain 1, get desired compound (46,8 g) of ethyl 4-(acetylamino)-3-aminobenzoate (40 g), 2,4-dichlorobenzyl chloride (42.2 g), potassium carbonate (30 g) and sodium iodide (8.1 g).

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): to 1.37 (3H, t, J=7,1 Hz), 2,23 (ZN, C), 4,30 (2N, K, J=7,1 Hz), to 4.38 (1H, d, J=5.3 Hz), to 4.41 (2H, d, J=5,GC), 7,18 (1H, d, J=8,3 Hz), 7,31 (1H, d, J=8,3 Hz), 7/39 (1H, d, J=7,3 Hz), 7,42 (1H, d, J=2.0 Hz), 7,46 (1H, d, J=8,2 Hz), 7,51 (1H, d, J=8,2 Hz).

<Fourth and fifth stage>

Obtaining 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

In the same manner as in the Example of a 3 and then in the Example of a 5, get the required connection (to 34.7 g) of ethyl 4-(acetylamino)-3-((2,4-dichlorobenzyl)amino)benzoate (40 g) 1-(2,4-dichlorobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 2,52 (3H, s), 5,62 (2H, s), 6,53 (1H, d, J=8.5 Hz), 7,33 (1H, DD, J=8.5 and 2.1 Hz), to 7.64 (1H, d, J=8,4 Hz), 7,74 (1H, d, J=2.2 Hz), 7,81 (1H, DD, J=8.4 and 1,4 Hz), 7,98 (1H, s), 12,74 (1H, CL).

Example Get 15

<the First stage>

Receiving N-t-butylmethylamine

Methanesulfonyl chloride (229 g) is added dropwise to the solution (800 ml) of t-butylamine (420 g) in chloroform under cooling in a bath of ice in the Techa is their 90 minutes. After stirring for 3 hours at room temperature, the solution is heated at a temperature of education phlegmy for 1 hour. The resulting reaction mixture is cooled with ice, make acidic by adding diluted hydrochloric acid, and extracted with chloroform. The organic layer is washed with water and dried over sodium sulfate. The resulting solution distil under reduced pressure, obtaining N-t-butylmethylamine (244 g) as a white solid. This product is immediately subjected to the next stage.

<a Second phase>

Receiving N-t-butyl-2-hydroxy-1-pentanesulfonate

2.0m solution diisopropylamide lithium in a mixture of heptane/tetrahydrofuran/ethylbenzene (400 ml) is cooled to (45-50° (C) in nitrogen atmosphere. There dropwise within 20 minutes, add a solution (100 ml) of N-t-butylmethylamine (55,0 g) in tetrahydrofuran. After increasing the temperature up to 5°C, within 1 hour, the solution is again cooled to -65°C. To the resulting solution was added, dropwise, a solution of n-butyl aldehyde (28.8 g) in tetrahydrofuran (100 ml) for 30 minutes. The solution is stirred for 18 hours while gradually increasing the temperature to room temperature. The resulting reaction solution was poured into excess dilute hydrochloric acid while cooling with ice, to make it the sour, and extracted with ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrated under reduced pressure, obtaining a solid crude product. Thereto was added with stirring hexane (300 ml). Thus obtained crystals are collected by filtration, washed with hexane and dried under reduced pressure, obtaining N-t-butyl-2-hydroxy-1-pentanesulfonate (46.2 g) as white crystals.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): of 0.95 (3H, t, J=7.0 Hz), 1.39 in (N, s), 1.41 to 1,49 (3H, m), 1,60 (1H, m)and 3.15 (2H, m), or 3.28 (1H, d, J=2.1 Hz), 4,20 (1H, m), 4,48 (1H, s).

<a Third step>

Receiving N-t-butyl-2-benzoyloxy-1-pentanesulfonate

In nitrogen atmosphere, benzoic acid (92,8 g) is added gradually to a mixture of N,N'-carbonyldiimidazole (123,3 g) and tetrahydrofuran (500 ml) for 10 minutes at room temperature. After stirring for 1 hour at room temperature, there are added dropwise a solution of N-t-butyl-2-hydroxy-1-pentanesulfonate (84,9 g) in tetrahydrofuran (300 ml) for 15 minutes. Then there are added dropwise a solution of diazabicyclo (57,9 g) in tetrahydrofuran (200 ml) for 35 minutes, and the resulting solution was stirred for 17 hours at room temperature. The reaction mixture was decanted into a mixture of ice-water, acidified by adding rubbable the Noah hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, and concentrated under reduced pressure, obtaining N-t-butyl-2-benzoyloxy-1-pentanesulfonate (132,8 g) as a yellowish brown oil.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g)as 0.96 (3H, t, J=7.4 Hz), 1,32 (N, s), 1.41 to 1,49 (2H,m), a 1.75-to 1.87 (2H,m), 3,30 (1H, DD, J=14.7 and 3,8gts), 3,49 (1H, DD, J=14.7 and 7,5Hz), to 4.41 (1H,s), 5,63 (1H,m), 7,45 (2H, t, J=7,7 Hz), EUR 7.57 (1H, m), with 8.05 (2H, d, J=8,2 Hz).

<Fourth stage>

Getting 2-benzoyloxy-1-pentanesulfonate

Triperoxonane acid (200 ml) are added to N-t-butyl-2-benzoyloxy-1-pentanesulfonate (132,8 g). After stirring for 32 hours at room temperature, the solution is concentrated under reduced pressure. After further adding triperoxonane acid (100 ml) and stirring for 16 hours at room temperature, the solution is concentrated under reduced pressure, obtaining an oily substance (165 g). This substance is dissolved in ethyl acetate and, after addition of saturated aqueous sodium bicarbonate solution, the solution is stirred for 15 minutes at room temperature. The organic layer was washed with 5% salt solution, dried over sodium sulfate and concentrated under reduced pressure, obtaining 2-benzoyloxy-1-Peninsula the amide (92,8 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 0,97 (3H, t, J=6.9 Hz), 1,39-of 1.55 (2H, m), 1,73-of 1.81 (1H,m), 1,82 is 1.91 (1H,m), 3,39 (1H, DD, J=14,8 and 3,5Hz), 3,52 (1H, DD, J=14,8 and 8,2 Hz), 5,00 (2H,s), 5,67 (1H,m),7,46 (2H, t, J=7,8 Hz), to 7.59 (1H, t, J=7.4 Hz), with 8.05 (2H, DD, J=8.5 and 1,2 Hz).

<Fifth stage>

Getting 6-((2-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole

6-Carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (50,3 g)as obtained in Example get to 14, and N, N'-carbonyldiimidazole (48,7 g) are added to N, N-dimethylformamide (400 ml) and stirred for 30 minutes at 40°and then for 30 minutes at room temperature. 2-Benzoyloxy-1-pentanesulfonate (81,4 g) and databaseconnect (of 45.7 g) add dropwise, and the solution is stirred for 22 hours at room temperature. The reaction solution is cooled with ice, acidified by adding hydrochloric acid, and extracted with chloroform. The organic layer is washed with water, dried over sodium sulfate and concentrate under reduced pressure. To the thus obtained oily substance (156 g) added acetonitrile (100 ml) and isopropyl ether (500 ml). The resulting mixture was heated to 60°and allow to cool to room temperature. The precipitated crystals are collected by filtration, washed with a mixed solution of acetonitrile (50 ml) and from propilovogo ether (200ml), and dried under reduced pressure, obtaining 6-((2-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (52,2 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g):of 0.85 (3H, t, J=7,3 Hz), 1,31 (2H, m), 1,74(2N, K, J=6.4 Hz), 2,47 (3H, s), 3,93 (1H, d, J=15,0 Hz), 4,11 (1H, DD, J=15.1 and 8,GC), 5,41-5,58 (3H, m), 6,36 (1H, d, J=8,4 Hz), 7,24 (2H, t, J=7,7 Hz), 7,30 (1H, d, J=8,4 Hz), was 7.45 (1H, t, J=7.4 Hz), to 7.59 (1H, d, J=8.5 Hz), 7,74 (4H, m), of 7.97 (1H, s), 12,01 (1H, CL).

Example 16

<the First stage>

Getting 4-penten-1-sulfonate sodium

5-Bromo-1-penten (199,74 g), sodium sulfite (202,67 g) and water (650ml) is mixed at room temperature. When the forming temperature phlegmy, the solution is stirred for 19 hours. After cooling to room temperature, there is added t-butyl methyl ether. The separated aqueous layer was concentrated and dehydration azeotrope with toluene. Thus, receive a 4-penten-1-sulfonate sodium (1)containing inorganic substances (387,51 g) as a white solid.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 1,60-to 1.67 (2H, m), 2.05 is (2N, K, J=7,2 Hz), 2,38-to 2.42 (2H, m), 4.92 in-5,00 (2H, m), 5,72-of 5.81 (1H, m).

<a Second phase >

Getting 4-penten-1-sulphur chloride

The phosphorus oxychloride (570,02 g) are added to 4-penten-1-sulfonate sodium (199,18 g) at room temperature. After n is grovania at a temperature of education phlegmy, within 3 hours, the solution is cooled in a bath of ice. The reaction solution is added gradually to a large number of ice water. After extraction with diethyl ether, the organic layer washed with brine, dried with magnesium sulfate and concentrated under reduced pressure, obtaining 4-penten-1-sulfonyl chloride (106,31 g) as a dark brown oil.

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): 2,13-2,19 (2H, m), 2,28 (2N, K, J=6.9 Hz), 3,65-3,68 (2H, m), 5,10-5,14 (2H, m), 5,72-of 5.81 (1H, m).

<a Third step>

Receiving N-t-butyl-4-penten-1-sulfonamida

Solution (30 ml) of 4-penten-1-sulfonyl chloride (190,85 g) in chloroform is added dropwise to a solution (300 ml) of t-butylamine (289,70 g) in chloroform in the bath with ice for 1 hour and 20 minutes. After heating at a temperature of education phlegmy, within 3 hours, the solution is cooled, acidified by adding diluted hydrochloric acid, and extracted with chloroform. The organic layer is concentrated under reduced pressure to obtain a residue (USD 261.9 bn g)which is purified column chromatography on silica gel (eluate: ethyl acetate/hexane=1/1). Thus, the receive N-t-butyl-4-penten-1-sulfonamide (194,73 g) as an orange oil.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 1,37 (N, C), 1,89 is 1.96 (2H, m) 2,19 (2H, k, J=7,0 Hz), 3,01 was 3.05 (2H, m), 4,11 (1H, s), 5,03-5,09 (2H, m), 5,72-of 5.81 (1H, m).

<Fourth stage>

Receiving N-t-butyl-(3-(2-oxiranyl)-1-propane)sulfonamida.

m-Chloroperbenzoic acid (214,82 g) are added to a solution (600 ml) of N-t-butyl-4-pentane-1-sulfonamida (194,73 g) in methylene chloride in the bath with ice for 2 hours. After stirring for 5 hours in a bath with ice, the solution is stirred over night at room temperature. Add m-chloroperbenzoic acid (55,47 g) and the solution stirred overnight. The reaction mixture was filtered under reduced pressure and to the resulting filtrate add 5% aqueous solution of sodium bisulfite and saturated salt solution. Thus obtained solution is extracted with methylene chloride. The organic layer was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and concentrated under reduced pressure, obtaining t-butyl-(3-(2-oxiranyl)-1-propane)sulfonamide (166,61 g) as a pale yellow oil.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 1,38 (N, C), 1,50-of 1.62 (1H, m), 1,81 is 1.91 (1H, m), 1,95-of 2.05 (2H, m), 2.49 USD is 2.51 (1H, m), was 2.76 is 2.80 (1H, m), 2,92-2,96 (1H, m), 3,03-3,19 (2H, m)to 4.23 (1H, s).

<Fifth stage>

Receiving N-t-butyl-4-hydroxy-1-pentanesulfonate

In nitrogen atmosphere, a solution (200 ml) of N-t-butyl-(3-(2-oxiranyl)-1-propane)sulfonamida (83,36 g) in tetrahydrofuran on billaut dropwise to the solution (800 ml) of 1.0m of triethylcitrate lithium in tetrahydrofuran for 1 hour and stirred for 1 hour and 30 minutes. The reaction is stopped by adding 5% hydrochloric acid in the bath with ice. There is added concentrated hydrochloric acid to neutralize the reaction solution. The reaction solution is concentrated to about 1/2 volume and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrate under reduced pressure. To the obtained residue (92,21 g) added hexane (400 ml) and crystallization was initiated by adding seed crystals under stirring. Precipitated crystals are separated by filtration, washed with hexane and dried under reduced pressure, obtaining N-t-butyl-4-hydroxy-1-pentanesulfonate (57,07 g) as a white solid.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 1,22 (3H, d, J=6.3 Hz), 1,37 (N, C), and 1.54-of 1.62 (2H, m)of 1.66 (1H, CL), 1,86 is 2.00 (2H, m)to 3.09 (2H, t, J=7.8 Hz), 3,81-a 3.87 (1H, m), 4,19 (1H, CL).

<Sixth stage >

Receiving N-t-butyl-benzoyloxy-1-pentanesulfonate

In nitrogen atmosphere, N, N'-carbonyldiimidazole (152,07 g) are added to tertrahydrofuran ring solution (600 ml) benzoic acid (114,46 g) in the bath with ice and stirred for 1 hour. There is added N-t-butyl-4-hydroxy-1-pentanesulfonate (99,73 g) and databaseconnect (142,78 g) and stirred over night at room temperature. Under reduced pressure of approximately 1/2 volume of tetrahydrofuran is removed. The reaction solution is acidified with dilute hydrochloric acid in an ice bath and extracted with chloroform. After washing with saturated aqueous sodium bicarbonate solution, the organic layer is dried over magnesium sulfate and concentrate under reduced pressure. To the obtained residue (148,18 g) added hexane (500 ml) and t-butyl methyl ether (25 ml) and crystallization was initiated by adding the seed crystal. Precipitated crystals are separated by filtration, washed (hexane/t-butyl methyl ether=20/1) and dried under reduced pressure. Thus, the receive N-t-butyl-benzoyloxy-1-pentanesulfonate (137,89 g) as a pale yellow solid.

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): 1,33 (N, C)to 1.37 (3H, d, J=6,3 Hz), 1,76 of 1.99 (4H, m), 3,03-3,13 (2H, m), 4,12 (1H, s), 5,17-5,23 (1H, m), 7,42-7,46 (2H, m), 7,54-7,58 (1H, m), 8,02-of 8.04 (2H, m).

<Seventh stage>

Getting 4-benzoyloxy-1-pentanesulfonate

A mixture of N-t-butyl-4-benzoyloxy-1-pentanesulfonate (15.0 g) and triperoxonane acid (70 ml) is stirred overnight at room temperature. The reaction solution is concentrated under reduced pressure. To the residue is added water and chloroform. Then, there was added with stirring saturated aqueous sodium bicarbonate solution to bring the pH of the water solution until neutral. Layer x is orapharma dried over sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (eluate: ethyl acetate)to give 4-benzoyloxy-1-pentanesulfonate (11.1 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): to 1.38 (3H, d, J=6.2 Hz), 1.77 in-2,05 (4H, m), 3,17 (2H, m), 4.72 in (2H, CL), to 5.21 (1H, m), 7,44 (2H, t), EUR 7.57 (1H,t), 8,03 (2H, m).

<Eighth stage>

Getting 6-((4-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

N,N'-carbonyldiimidazole (6.60 g) are added to N,N-dimethylformamide solution (90ml) 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (10.2 g)obtained in Example 14 to Obtain, and stirred for 1 hour at room temperature. There is added 4-benzoyloxy-1-pentanesulfonic-

amide (11.1 g) and-diazabicyclo (6.20 g) and the solution stirred over night at 80°C. the Solvent is removed under reduced pressure. To make the solution homogeneous, to the residue add ethanol (100 ml) and water (50ml), and the pH adjusted to about 5 by adding dilute hydrochloric acid. Precipitated crystals are separated by filtration, washed with a mixed solution of ethanol and water (2/1) and dried under reduced pressure, obtaining 6-((4-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole (15,54 g). This product is immediately subjected to the next stage.

When the EP Get 17

<the First stage>

Receiving N-t-butyl-3-hydroxy-1-pentanesulfonate

In nitrogen atmosphere, a solution (520 ml), 1.6 M n-butyl lithium in hexane added slowly to the solution (480 ml) Diisopropylamine and (120 ml) in tetrahydrofuran at a temperature of from -60°-50°and the solution is stirred for 1 hour in a bath with ice. The solution is cooled to -50°and there is added dropwise a solution (100 ml) of N-t-butylmethylamine (60,0 g) in tetrahydrofuran within 45 minutes. The temperature of the solution increased to 0°C for 1 hour, and the solution is stirred for 45 minutes in the bath with ice. It is cooled to -40°and solution (50 ml) butilenica (42.9 g) in tetrahydrofuran put at temperatures from -40°C to -30°C. the solution Temperature is slowly increased to room temperature, and

the solution is stirred over night. The reaction is stopped by adding water in the bath with ice. The solution is acidified with dilute hydrochloric acid, and tertrahydrofuran ring layer is separated. The aqueous layer was extracted with chloroform. Tertrahydrofuran ring and water layers independently washed with saturated salt solution. The organic layers are combined, dried over sodium sulfate and concentrate under reduced pressure. To the thus obtained residue is added with t-butyl methyl ether (89 g). Crystallization initiate additionally adding hexane (200 ml). The crystals are collected by filtration, washed with a small amount of a mixed solution of t-butyl methyl ether and hexane (1/2) and dried under reduced pressure. Thus, the receive N-t-butyl-3-hydroxy-1-pentanesulfonate (60,6 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 0,97 (3H, t, J=7.4 Hz), 1,38 (N, C), 1,46-of 1.57 (2H,m)1,80 (1H, d, J=5,1 Hz), 1,81-1,89 (1H,m), 2.00 in 2,07 (1H,m), 3,14-3,30 (2H,m), 3,68 (1H, m), 4,20 (1H, s).

<a Second phase>

Receiving N-t-butyl-3-benzoyloxy-1-pentanesulfonate

In nitrogen atmosphere, N,N'-carbonyldiimidazole (90.0 g) are added to a solution of benzoic acid (67,7 g) in tetrahydrofuran (400 ml) in a bath with ice, and the solution is stirred for 1 hour at room temperature. N-t-butyl-3-hydroxy-1-pentanesulfonate (59.0 g) add back at room temperature. Then, databaseconnect (84.5 g) is added to the bath with ice. The mixture is stirred over night at room temperature. Approximately 1/2 volume of tetrahydrofuran is removed under reduced pressure. The reaction solution is acidified with dilute hydrochloric acid in an ice bath and extracted with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate. The precipitated solid is separated by filtration. After washing the organic layer with saturated saline solution and drying the th over sodium sulfate, the solvent is removed under reduced pressure, obtaining N-t-butyl-3-benzoyloxy-1-pentanesulfonate (90,42 g) in the form of oil.

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g):0,97 (3H, t, J=7.5 Hz), 1,33 (N,C), 1,67-of 1.81 (2H,m), 2,13-of 2.26 (2H,m), of 3.12 (2H,m), of 4.66 (1H, s), of 5.15 (1H,m), 7,44 (2H,m), 7,56 (1H,m), 8,01-of 8.04 (2H,m).

<a Third step>

Obtaining 3-benzoyloxy-1-pentanesulfonate

A mixture of N-t-butyl-3-benzoyloxy-1-pentanesulfonate (90,4 g) and triperoxonane acid (200 ml) is stirred overnight at room temperature. Triperoxonane acid is removed under reduced pressure and to the residue is added water and chloroform. Saturated aqueous sodium bicarbonate solution added with vigorous stirring until until the aqueous layer becomes neutral. After extraction with chloroform, the organic layer was washed with saturated saline solution, dried over sodium sulfate and concentrate under reduced pressure. The residue is purified column chromatography on silica gel (eluate: hexane/ethyl acetate=2/1 to 1/1)to give 3-benzoyloxy-1-pentanesulfonate (60,6 g) in the form of oil.

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): 0,99 (3H, t, J=7.5 Hz), or 1.77 (2H,m), and 2.26 (2H,m), up 3.22 (2H, t, J=8.0 Hz), of 4.77 (2H,s), 5,19 (1H, m), 7,46 (2H, t), to 7.59 (1H, t), of 8.04 (2H, DD, J=1,3 and 8.3 Hz).

<Fourth stage>

Getting freeway salt of 6-((3-benzoyloxy-1-pentane)-sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole N,N'-carbonyldiimidazole (10,48 g) are added to N,N-dimethylformamide solution (150 ml), 6-carboxy-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole (19,65 g)as in Example 14 to Obtain, and the solution is stirred for 1 hour at room temperature. 3-Benzoyloxy-1-pentanesulfonate (21,0 g) and databaseconnect (9,40 g) added and the solution stirred over night at 80°C. the Solvent is removed under reduced pressure. To the residue water is added to make a homogeneous solution, and the pH adjusted to about 6 by adding hydrochloric acid. Water is added and the solution extracted with ethyl acetate. The organic layer is concentrated under reduced pressure. To the obtained residue, add

the ethyl acetate and saturated aqueous sodium bicarbonate solution and the solution is stirred for 4 hours. The precipitated solid is separated by filtration, washed with water and ethyl acetate and dried under reduced pressure, obtaining the sodium salt of 6-((3-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (18,90 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): or 0.83 (3H, t, J=7,1 Hz)of 1.64 (2H,m)to 1.99 (2H,m), 2,47 (3H, m)to 3.09 (2H,m), of 5.03 (1H,m), the 5.51 (2H,s)6,40 (1H, D, J=8,3 Hz), 7,28 (1H, d, J=8.1 Hz), 7,49 (3H, m), 7,63 (1H,t), of 7.70 (1H,s), a 7.85 (2H,m), 7,94 (2H, d, J=7.5 Hz).

Example 1

Synthesis of 1-(isoquinoline-3-ylmethyl)-2-methyl-6-(1-pentane-sulfonylamino)benzimidazole (13)

N,N'-carbonyldiimidazole (0,324 g) are added to a solution of 6-carboxy-1-(isoquinoline-3-ylmethyl)2-methylbenzimidazole (0,413 g), obtained in Example 5 Obtaining, in N,N-dimethylformamide (10ml) all at once and the mixture is stirred at room temperature for 1.5 hours. Then, there is added 1-pentanesulfonate (0,302 g) and databaseconnect (0,304 g), and the mixture was stirred at 100°C for 6.5 hours. The reaction solution is concentrated and the concentrate added salt solution, and the mixture is extracted with chloroform. The organic layer is concentrated, and the residue is purified column chromatography on silica gel (eluate:methanol/chloroform=1/19) followed by recrystallization from hexane/ethyl acetate = 2/3)to give the desired compound, 1-(isoquinoline-3-ylmethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (13) (0,142 g).

[Physico-chemical characteristics of the compound (13)]

1H=NMR (DMSO-d6that δ m.g): 0,76 (3H, t, J=7,3 Hz), 1,22 (2H, m)of 1.33 (2H,m), of 1.65 (2H,m), 2,65 (3H,s), 3,47 (2H, t, J=7,7 Hz), 5,74 (2H,s), to 7.64 (2H, m), 7,76 (2H, m), 7,92 (1H, d, J=8,2 Hz), of 8.09 (1H, d, J=8,2 Hz), 8,23 (1H, d, J=1.2 Hz), 9,27 (1H, s), up 11,86 (1H, CL).

IR (Nujol): 1674 cm-1, TPL: 209-212°

Example 2

Synthesis of 1-((4-chloroisoquinoline-3-ylmethyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole (14)

In the same manner as in Example 1, to obtain the desired benzimidazole (14), using a carboxylic acid, obtained in Example 6 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (14)]

Ȋ 1H=NMR (DMSO-d6that δ m.g): 0,76 (3H, t, J=7,3 Hz), 1,22 (2H, m)is 1.31 (2H,m)of 1.64 (2H,m), of 2.56 (3H,s), of 3.45 (2H, t, J=7.9 Hz), of 5.92 (2H,s), a 7.62 (1H, d, J=7.5 Hz), of 7.75 (1H,m), 7,80 (1H, t, J=7,7 Hz), 8,00 (1H, t, J=7,7 Hz), 8,10 (1H, s), 8,16 (1H, d, J=8.1 Hz), of 8.27 (1H, d, J=8.5 Hz), 9,12 (1H,s), 11,84 (1H,CL), IR (Nujol); 1677 cm-1, TPL: 209-210°C

Example 3

Synthesis of 1-((1-does not depend-2-yl)methyl)-2-methyl-6-(1-pentane-

sulfonylamino) benzimidazole (15)

In the same manner as in Example 1, to obtain the desired benzimidazole (15), using the carboxylic acid obtained in Example 7 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (15)]

1H=NMR (DMSO-d6that δ m.g): 0,78 (3H, t, J=7,3 Hz), 1,19 of 1.28 (2H,m), of 1.28 and 1.35 (2H,m), 1,61 by 1.68 (2H,m), of 2.51 (3H,s), 3,47 (2H, t, J=7.8 Hz), of 5.81 (2H,s), 6,51 (1H, D, J=8.6 Hz), 7,63 (1H, t, J=7,7 Hz), 7,71 (1H, d, J=8.5 Hz), of 7.75 (1H, t, J=7.2 Hz), 7,82 (1H, d, J=8,4 Hz), 7,86 (1H, d, J=8.6 Hz), 7,95 (1H, d, J=8.1 Hz), 8,15 (1H,s), 8,31 (1H, d, J=8.6 Hz), 12,15 (1H,s).

IR (Nujol): 1688 cm-1, TPL: 260-263°C

Example 4

Synthesis of 1-(2, 4-dichlorobenzyl) -6-((2-hydroxy-1-pentanesulfonate)-2-methylbenzimidazole (16)

In the same manner as in Example 1, to obtain the desired benzimidazole (16), using the carboxylic acid obtained in Example 14 to Obtain, and 2-hydroxy-1-pentanesulfonate.

[Physico-chemical characteristics of the compound (16)]

1H=NMR (DMSO-d6that δ m.g): of 0.82 (3H, t, J=7,3 Hz), 1,22-is 1.51 (4H,m), 2.49 USD (3H,s), 3,51 (1H, DD, J=14,5 is a 4.1 Hz), 3,61 (1H, DD, J=14.5 and 7,3 Hz), of 3.95 (1H,m), 4,91 (1H,m), to 5.58 (2H, s), to 6.43 (1H, d, J=8,4 Hz), 7,32 (1H, DD, J=8.4 and 2.1 Hz), to 7.68 (1H, d, J=8.5 Hz), to 7.77(1H, m), 7,80 (1H, d, J=8,4 Hz), 8,10 (1H, s), 11,77 (1H, CL).

1H=NMR (CD2Cl2that δ m.g): of 0.90 (3H, t, J=7 Hz), of 1.30 and 1.80 (4H, m), of 2.56 (3H, s), up 3.6-3.7 (3H,m), 5,43 (2H,s), 6,37 (1H, d, J=8 Hz), 7,12 (1H, DD, J=8 and 2 Hz), 7,52 (1H, d, J=2 Hz), 7,69 (1H, DD, J=8 and 2 Hz), 7,76-7,79 (2H,m).

IR (Nujol): 1684, 1670 cm-1.

Mass: m/e 484 (M+1).

TPL: 228-230°C.

Example 4-2

Obtain 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)-sulfonylamino)-2-methylbenzimidazole (16)

6-((2-Benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (10,00 g)obtained in Example 15 to Obtain, dissolved in methanol (450ml) when heated, and the mixture is cooled to room temperature. To this solution was added 10% aqueous sodium hydroxide solution (7ml) and stirred for 1 hour at room temperature. Then, 10% aqueous sodium hydroxide solution (13,4ml) is added and stirred for 80 minutes at 50°when heated. Upon cooling the reaction solution with ice, it is added slowly IN hydrochloric acid (about 50 ml)to bring to a pH of 4-5, and methanol (300 ml) was removed under reduced pressure. The concentrated reaction solution (about 150 ml) is cooled with ice and the precipitated crystals are collected by filtration and washed successively with water (50ml) chloroform (50ml). After drying, the crystals by heating under reduced pressure, there is added acetone (450 ml), and heated to a temperature of education phlegmy within 30 minutes. The solution is again cooled to a temperature of ice. The crystals are collected by filtration and dried by heating under reduced pressure. Thus have 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole (16) (6.69 in).

[Physico-chemical characteristics of the compound (16)]

1H=NMR (DMSO-d6that δ m.g): of 0.82 (3H, t, J=7.2 Hz), 1,26 of 1.46 (4H,m), 2.49 USD (3H,s), 3,51 (1H, DD, J=14,5 and 4.1 Hz), 3,61 (1H, DD, J=14.5 and 7,3 Hz), of 3.96 (1H,CL), 4,91 (1H,CL), to 5.58 (2H,s), to 6.43 (1H, d, J=8,4 Hz), 7,32 (1H, DD, J=8.4 and 1,8gts), to 7.68 (1H, d, J=8,4 Hz), of 7.75 (1H, d, J=1.1 Hz), 7,80 (1H, d, J=8,4 Hz), 8,10 (1H,c), 11,77 (1H,CL).

IR (Nujol): 1684 cm-1.

TPL: 224,0-224,4°C.

Example 5

Synthesis of 1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)-sulfonylamino) -2-methylbenzimidazole (17)

In the same manner as in Example 1, to obtain the desired benzimidazole (17), using the carboxylic acid obtained in Example 14 to Obtain, and (4-hydroxy-1-pentane)of the sulfonamide.

[Physico-chemical characteristics of the compound (17)]

1h=NMR (CD2Cl2that δ m.g): to 1.15 (3H, t, J=7 Hz), of 1.55 (2H,m), 1,90 (2H,m), 2,58 (3H,s), of 3.60 (2H,m), 3,80 (1H,m), 5,44 (2H,s), 6,37 (1H, d, J=8 Hz), 7,12 (1H, DD, J=8 and 2 Hz), 7,52 (1H, d, J=2 Hz), 7,70 (1H, DD, J=8 and 2 Hz), 7,76-7,79 (2H, m), 8,40 (1H, CL).

1H=NMR (DMSO-d6that δm.g): 0,99 (3H, d, J=6.2 Hz), of 1.37 to 1.47 (2H,m), 1,66 and 1.80 (2H,m), 2.49 USD (3H,s), 3,50 (1H, t, J=7.8 Hz), 3,55 (1H,m), to 5.58 (2H,s), to 6.43 (1H, d, J=8,3 Hz), 7,32 (1H, DD, J=8.4 and 2.1 Hz), to 7.67 (1H, d, J=8,4 Hz), of 7.75 (1H, d, J=2.0 Hz), 7,80 (1H, d, J=8,4 Hz), 8,10 (1H,s), 11,84 (1H,CL).

IR (Nujol): 1694 cm-1.

TPL: 186,7-187,6°C.

Mass: m/e 484 (M+1).

Example 5-2

Obtain 1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)-sulfonylamino)-2-methylbenzimidazole (17)

A mixture of 6-((4-benzoyloxy-1-pentane)sulfonylamino)-1-

(2,4-dichlorobenzyl)methylbenzimidazole (15.0 g)as obtained in Example 16 to Obtain, sodium hydroxide (4,08 g), ethanol (80 ml) and water (120 ml) is stirred for 2 hours at 80°C. After neutralization reaction of hydrochloric acid, there is added water and carry out the extraction with ethyl acetate. The organic layer is washed twice with water, dried and concentrated. To the thus obtained residue added acetone (50 ml) and diethyl ether (75 ml).

The precipitated crystals are collected by filtration, washed with diethyl ether and dried, obtaining white crystals (4.2-d). Following the same method, white crystals (3.0 g) is obtained from 6-((4-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)methylbenzimidazole (5.0 g). Crystals unite (7.2 g) and they added a mixed solvent of acetone and water (acetone/water=9/1, 150 ml) and heated to 60°C to dissolve crystals. Water (400 ml) is added PR is 60° With, the solution is stirred for 1 hour and slowly cooled to room temperature. The precipitated crystals are collected by filtration and dried, obtaining 1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole (17) (6.2 g).

[Physico-chemical characteristics of the compound (17)]

1H=NMR (DMSO-d6that δ m.g); 0,99 (3H, D, J=6.2 Hz), of 1.37 to 1.47 (2H,m), 1,66 and 1.80 (2H,m), 2.49 USD (3H,s), 3,50 (1H, t, J=7.8 Hz), 3,55 (1H,m), to 5.58 (2H,s), to 6.43 (1H, d, J=8,3 Hz), 7,32 (1H, DD, J=8.4 and 2.1 Hz), to 7.67 (1H, d, J=8,4 Hz), of 7.75 (1H, d, J=2.0 Hz), 7,80 (1H, d, J=8,4 Hz), 8,10 (1H,s), 11,84 (1H,CL).

IR (Nujol): 1694 cm-1.

TPL: 186,7-187,6°C

Example 6

Synthesis of 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)-sulfonylamino) -2-methylbenzimidazole (18)

In the same manner as in Example 1, to obtain the desired benzimidazole (18), using the carboxylic acid obtained in Example 14 to Obtain, and (3-hydroxy-1-pentane)of the sulfonamide.

[Physico-chemical characteristics of the compound (18)]

1H=NMR (CD2Cl2that δ m.g): to 0.92 (3H, t, J=7 Hz), 1,40-1,90 (4H, m), to 2.57 (3H, s), 3,6-3,8 (3H, m), 5,44 (2H,s), 6,36 (1H, d, J=8 Hz), 7,11 (1H, DD, J=8 and 2 Hz), 7,53 (1H, d, J=2 Hz), 7,69 (1H, DD, J=8 and 2 Hz), 7,76-7,79 (2H,m), 8,40 (1H, CL).

1H=NMR (DMSO-d6that δ m.g): 0,80 (3H, t, J=7,3 Hz), 1,25-1,40 (2H,m)of 1.64 (1H,m)to 1.79 (1H,m), 2.49 USD (3H,s), 3,37-of 3.48 (1H,m)to 3.58 (1H,m), with 4.64 (1H,m), to 5.58 (2H,s), to 6.43 (1H, d, J=8,4 Hz), 7,32 (1H, d, J=8,3 Hz), to 7.67 (1H, d, J=8,3 Hz), of 7.75 (1H,s), 7,80 (1H, d, J=8,3 Hz), of 8.09 (1H, s), 11,85 (1H,CL).

IR (Nujl): 1694 cm -1. TPL: 205,5-206,0°C. Mass; m/e 484 (M+1),

Example 6-2

Obtain 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)-sulfonylamino)-2-methylbenzimidazole (18)

An aqueous solution (ml) sodium hydroxide (2,03 g) and methanol (105 ml) is added to the sodium salt of 6-((3-benzoyloxy-1-pentane)-sulfonylamino-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (15,55 g, 25,47 mmol)obtained in Example 17 to Obtain, and stirred for 6.5 hours at 60°C. the Reaction solution is cooled to room temperature, neutralized (pH 5) hydrochloric acid and extracted with chloroform. The solid obtained by removing the solvent, was dissolved in a mixed solvent of water (50ml) and methanol (160 ml) under heating. About 1/2 the volume of the methanol is removed under reduced pressure, and the resulting solution was let to stand for one day. The precipitated crystals are collected by filtration and dried, obtaining 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)-sulfonylamino)-2-methylbenzimidazole (18) (9.00 g).

[Physico-chemical characteristics of the compound (18)]

1H=NMR (DMSO-d6that δ m.g); to 0.80 (3H, t, J=7,3 Hz), 1,25-1,40 (2H,m)of 1.64 (1H,m)to 1.79 (1H,m), 2.49 USD (3H,s), 3,37-of 3.48 (1H, m)to 3.58 (1H,m), with 4.64 (1H,m), to 5.58 (2H,s), to 6.43 (1H, d, J=8,4 Hz), 7,32 (1H, d, J=8,3 Hz), to 7.67 (1H, d, J=8,3 Hz), of 7.75 (1H,s), 7,80 (1H, d, J=8,3 Hz), of 8.09 (1H,s), 11,85 (1H, CL).

IR (Nujol): 1694 cm-1. TPL: 205,5-206,0°C

Example 7

Synthesis of 1-(2-dichlorobenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)benzimidazole (19)

In the same way as in Example 1, to obtain the desired Benzimidazole (19), using carboxylic acid obtained in Example 14 to Obtain, and (1-Penta-1-ene)of the sulfonamide.

[Physico-chemical characteristics of the compound (19)]

1H-NMR (CD3OD, δ m.g): of 0.85 (3H, t, J=7.4 Hz), the 1.44 (2H,m)to 2.18 (2H,m), of 2.51 (3H,s)5,52 (2H,s), 6.48 in (1H, d, J=8,4 Hz), 6,59 (1H,m)6,91 (1H,m), 7,14 (1H, DD, J=8.4 and 2,2 Hz), 7,51 (1H, d, J=2.0 Hz), to 7.61 (1H, d, J=8.5 Hz), 7,73 (1H, DD, J=8.5 and 1.6 Hz), 7,87 (1H, s).

IR (Nujol): 1674 cm-1.

so pl.: 243-245°C.

Example 8

Synthesis of 6-(benzensulfonamidelor)-1-(2,4-dichlorobenzyl)-2-

methylbenzimidazole (20)

In the same way as in Example 1, receive required

the benzimidazole (20), using the carboxylic acid obtained

in Example 14 production, benzosulfimide.

[Physico-chemical characteristics of the compound (20)]

1H=NMR (DMSO-d6): 2,50 (3H,s), to 5.58 (2H,s)6,41 (1H, d, J=8.5 Hz), 7,31 (1H, d, J=8,4 Hz), to 7.59-7,76 (6N,m), 7,98 (2H, d, J=7.9 Hz), of 8.06 (1H, s), 12,38 (1H,CL).

IR (Nujol): 1684 cm-1.

TPL: of 230.5-234,0°C.

Example 9

Synthesis of 6-(N'-botanicalvegetational)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole (21)

In digidratirovannogo dichloromethane (5.0 ml) was dissolved 1-(2,4-dichlorobenzyl)-6-(hydrogencarbon)-2-methylbenzimidazole (246 mg)obtained in Example 8 to Obtain, and triethylamine (0,196 ml). Next there at room temperature is added dropwise n-Butana hanil chloride. After stirring for 2 hours, the reaction mixture was extracted using chloroform and water. The organic layer is dried over magnesium sulfate and evaporated to dryness under reduced pressure. The resulting residue is purified using thin-layer chromatography (chloroform/methanol=30/1 as the developing solvent) and then by recrystallization from ethyl acetate, getting 6-(N'-botanicalvegetational)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (21) (mg) as colorless crystals.

[Physico-chemical characteristics of compounds 21]

TPL: 208-210°C.

1H=NMR (DMSO-d6): to 0.97 (3H, t, J=6 Hz), 1,53 (2H,m), with 1.92 (2H,m)2,60 (3H,s), 3,55 (2H, t, J=Hz), 5,42 (2H,s), 6,30 (1H, d, J=8 Hz), 7,10 (1H, d, J=8 Hz), 7,52 (1H,s), 7,72 (1H, s), to 7.84 (2H,s).

Example 10

Synthesis of 6-((n-butylaminoethyl)carbarnoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (22)

In the same way as in Example 8 to Obtain, receive 6-((n-butylaminoethyl)carbarnoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (22) in the form of colorless crystals (271 mg) of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (200 mg) and N-(n-butyl)sulphonamide (182 mg).

[Physico-chemical characteristics of the compound (22)]

1H=NMR (DMSO-d6): 0,78 (3H, t, J=6 Hz), 1,24 (2H,m)of 1.42 (2H,m), 2,52 (3H,s), 2,90 (2H,m), 5,59 (2H,s), 6.48 in (1H, d, J=8 Hz), 7,33 (1H, d, J=8 Hz), of 7.64-7,83 (4H,m), 8,08 (1H, s).

Example 11

Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-[N'-(4-methylphenylsulfonyl)ureido]benzimidazole (23)

6-Amino-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (60mg)obtained in Example 10 to Obtain, dissolved in digidratirovannogo 1,4-dioxane (1.0 ml) and then there is added (4-methylphenylsulfonyl)isocyanate (mg). After stirring the mixture at room temperature for 1 hour, the precipitated crystals are collected by filtration and washed with 1,4-dioxane, getting 1-(2,4-dichlorobenzyl)-2-methyl-6-[N'-(4-methylphenylsulfonyl)ureido]-benzimidazole (23) in the form of a white powder (95 mg).

[Physico-chemical characteristics of the compound (23)]

1H=NMR (DMSO-d6): is 2.37 (3H,s), 2,42 (3H,s), 5,42 (2H,s), 6,46 (1H, d, J=8 Hz), 7,00 (1H, d, J=8 Hz), 7,29 (1H, d, J=8 Hz), 7,35-7,47 (4H,m), of 7.70 (1H,s), 7,80 (2H, d, J=8 Hz), 8,76 (1H,s).

Example 12

Synthesis of 1-(2,4-dichlorobenzyl) -2-methyl-6'-(N'-phenylurea) benzimidazole (24)

In the same way as in Example 11, to obtain 1-(2,4-dichlorobenzyl)-2-methyl-6-(N'-phenylurea)benzimidazole (24)

(177 mg) of 6-amino-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (157 mg) and phenylisocyanate (0.06 ml).

[Physico-chemical characteristics of the compound (24)]

1H=NMR (DMSO-d6): of 2.44 (3H,s), 5,44 (2H,s), of 6.50 (1H, d, J=8 Hz), 6,93 (1H, t, J=8 Hz), was 7.08 (1H, d, J=8 Hz), 7,25 (2H, t, J=8 Hz), 7,34 (1H, d, J=8 Hz), 7,41 (2H, d, J=8 Hz), 7,49 (1H, d, J=8 Hz), to 7.59 (1H,s), of 7.75 (1H,s), 8,58 (1H,s), 8,67 (1H,s).

Example 13

Synthesis of 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (25)

In the same way as in Example 1 to obtain 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (25) in the form of white crystals (mg) of 6-carboxy-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methylbenzimidazole (200mg), obtained in Example 13 to Obtain, and 1-pentanesulfonate (123 mg).

[Physico-chemical characteristics of the compound (25)]

1H=NMR (DMSO-d6): of 0.90 (3H, t, J=8 Hz), 1,20-1,40 (4H,m), 1,62-1,72 (2H,m)of 2.50 (3H, s)to 3.49 (2H, t, J=8 Hz), 5,70 (2H,s), 6,56 (1H, d, J=8 Hz), a 7.62 (1H, d, J=8 Hz), of 7.70 (1H, d, J=8 Hz), 7,82 (1H, d, J=8 Hz), 8,13 (1H,s)to 8.12 (1H,s). Mass (ESI): m/z 500 (M-H).

Example 14

Synthesis of 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)benzimidazole (26)

In the same way as in Example 1, get 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(((E)-1-Penta-ene)sulfonylamino)benzimidazole (26) in the form of white crystals (mg), using 6-carboxy-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-

the benzimidazole (200 mg)obtained in Example 13 to Obtain, and (1-Penta-1-ene)sulfonamide (121 mg).

[Physico-chemical characteristics of the compound (26)]

1H=NMR (DMSO-d6):0,84 (3H, t, J=8 Hz), 1,36-1,49 (2H,m), of 2.21 (2H, K, J=7 Hz), 2,50 (3H,s), 5,67 (2H,s), is 6.54 (1H, d, J=8 Hz), 6.73 x (1H, d, J=14 Hz), 6,80-of 6.90 (1H,m), 7,60 (1H, d, J=8 Hz), to 7.68 (1H, d, J=8 Hz), 7,78 (1H, d, J=8 Hz), 8,00 (1H,s), 8,07 (1H,s).

Mass (ESI): m/z 498 (M-H).

Example 15

Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol)benzimidazole (27)

In the same way as in Example 1, to obtain the desired benzimidazole (27), using the carboxylic acid obtained in Example 14 to Obtain, and (E)-2-phenylethanolamine.

[Physico-chemical ha is acteristic compound (27)]

1H=NMR (DMSO-d6that δ m.g): 2,48 (3H,s), to 5.57 (2H,s), 6.42 per (1H, d, J=8,4 Hz), 7,31 (1H, d, J=8,4 Hz), 7,41-7,52 (4H,m), to 7.61-to 7.68 (2H,m), 7,72-of 7.82 (4H,m), 8,11 (1H,s), 12,17 (1H,CL). IR (Nujol): 1674 cm-1.

TPL: 291-293°

Example 18 to Obtain

<the first stage >

Obtain ethyl 4-(acetylamino)-3-((2-chloro-4-phenylbenzyl)-amino)benzoate

In the same way as in Example 1, Receipt, receive the requested connection (3,10 g) of ethyl 4-(acetylamino)-3-aminobenzoate (2,22 g), 2-chloro-4-phenylbenzyl bromide (3,37 g) and potassium carbonate (1.66 g). [Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): of 1.36 (3H, t, J=7,1 Hz), with 1.92 (1H,CL), of 2.23 (3H, s), 4,2-4,6 (5H, m), 7,37 (1H, t, J=7,3 Hz), 7,41-7,58 (N,m)to 7.64 (1H,s),

<the Second and Third stages>

Obtaining 6-carboxy-1-(2-chloro-4-phenylbenzyl)-2-methylbenzimidazole

Following the methods of Example 3 Obtaining and Example 5 Obtaining consistently get the desired compound (2.50 g) of ethyl 4-(acetylamino)-3-((2-chloro-4-phenylbenzyl)amino)benzoate (3.00 g) in 1-(2-chloro~4-phenylbenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): in 2.68 (3H,s), 7,76 (2H,s), 6,79 (1H, d, J=8.1 Hz), 7,38 (1H, t, J=7.2 Hz), 7,45 (2H,t), 7,56 (1H, DD, J=1.7 and 8.1 Hz), to 7.67 (2H, d, J=7,4 Hz), 7,76 (1H, d, J=8.5 Hz), 7,86 (1H, d, J=1,7 Hz), to 7.93 (1H, d, J=8.5 Hz), 13,0 (1H,CL).

Example 16

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(1-pentanal phenylcarbamoyl)benzimidazole (28)

In the same way as in Example 1, to obtain the desired benzimidazole (28), using the carboxylic acid obtained in Example 18, 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (28)]

1H=NMR (DMSO-d6that δ m.g): 0,80 (3H, T, J=7,3 Hz), 1,20 of 1.28 (2H,m), 1,31-to 1.38 (2H,m), 1,63-1,71 (2H,m), of 2.54 (3H,s)to 3.49 (2H, t, J=7,7 Hz), the 5.65 (2H,s), of 6.50 (1H, d, J=8,2 Hz), 7,39 (1H, t, J=7,1 Hz), 7,46 (2N, t, J=7,6 Hz), 7,54 (1H, DD, J=8.0 and 1.6 Hz), 7,66 (2H, d, J=7.5 Hz), of 7.70 (1H, d, J=8.6 Hz), 7,81 (1H, DD, J=8.5 and 1.3 Hz), 7,87 (1H, d, J=1,8 Hz), 8,15 (1H,s)11,89 (1H,s). IR (Nujol); 1683 cm-1. TPL: 210-212,5°C.

Example 17

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)benzimidazole (29)

In the same way as in Example 1, to obtain the desired benzimidazole (29), using the carboxylic acid obtained in Example 18 to Obtain, and (1-Penta-1-ene)of the sulfonamide.

[Physico-chemical characteristics of the compound (29)]

1H=NMR (DMSO-d6that δ m.g): 0,84 (3H, t, J=7,3 Hz), to 1.38 to 1.47 (2H,m), of 2.21 (2H, Quartet, J=7.0 Hz), 2,52 (3H,s), 5,63 (2H, s), 6,47 (1H, d, J=8.1 Hz), 6.75 in (1H, d, J=15.2 Hz), 6,82-to 6.88 (1H,m), 7,38 (1H, t, J=7.2 Hz), was 7.45 (2H, t, J=7,6 Hz), 7,52 (1H, d, J=8.0 Hz), the 7.65 (2H, d, J=7.8 Hz), to 7.68 (1H, d, J=8.6 Hz), 7,78 (1H, d, J=8.6 Hz), 7,86 (1H,s)to 8.12 (1H,s)12,00 (1H, CL). IR (Nujol): 1672 cm-1.

TPL: 234-235°C.

Example 18

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-methylbenzoyl)-sulfonylamino)benzimidazole (30)

In the same way as in Example 1, receive benzimidazol (30), using the carboxylic acid obtained in Example 18 to Obtain, and (4 methylbenzol)of the sulfonamide.

[Physico-chemical characteristics of the compound (30)]

1H=NMR (DMSO-d6that δ m.g): 2,35(3H,s), of 2.51(3H,s), 5,63(2H,s), 6,46(1H, d, J=8.1 Hz), 7,37-7,40(3H,m), 7,45(2H, t, J=7,6 Hz), 7,51(1H, DD, J=8.0 and 1.6 Hz), 7,63-to 7.67(3H,m), 7,72 (1H, DD, J=8.5 and 1,4 Hz), 7,83-7,87 (3H, m), 8,08(1H, d, J=1.2 Hz), of 12.33 (1H,CL).

IR (Nujol): 1682 cm-1. TPL: 251,8-252,3°C.

Example 19

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((E)-phenylacetylcarbinol)benzimidazole (31)

In the same way as in Example 1, to obtain the desired benzimidazole (31), using the carboxylic acid obtained in Example 18 to Obtain, and ((E)-2-phenylethenyl)of the sulfonamide.

[Physico-chemical characteristics of the compound (31)]

1H=NMR (DMSO-d6that δ m.g): 2,52 (3H, s), 5,63 (2H,s), 6,46 (1H, d, J=8.1 Hz), of 7.36-7,47 (6N, m)to 7.50 (1H,s), 7,51 (1H, d, J=8.7 Hz), 7,60 (1H, d, J=15,5 Hz), to 7.64 (2H, d, J=8.6 Hz), to 7.67 (1H, d, J=8.6 Hz), 7,73 (2H, d, J=6.9 Hz), 7,80 (1H, d, J=8.6 Hz), the 7.85 (1H,s), 8,15 (1H,s), 12,15 (1H,CL). IR (Nujol): 1677 cm-1.

TPL: 267-268°C.

Example 20

Synthesis of 1-(2-chloro-4-phenylbenzyl)-6-((5-chlorothiophene-2-yl)sulfonylamino)-2-methylbenzimidazole (32)

In the same way as in Example 1, to obtain the desired benzimidazole (32), using carboxylic acid obtained in Example 18 to Obtain, and (5-chlorothiophene-2-yl)sulfonamide.

[Physico-chemical characteristics of the compound (32)]

ÈA; 1H=NMR (DMSO-d6that δ m.g): 2,61 (3H,s), 5,71 (2H,s), 6,63 (1H, d, J=7.8 Hz), 7,16 (1H, d, J=4.0 Hz), 7,38 (1H, t, J=7.2 Hz), 7,45 (2H, t, J=7,6 Hz), 7,53 (1H, d, J=8.1 Hz), 7,56 (1H,CL), 7,66 (2H, d, J=8.6 Hz), of 7.70 (1H, d, J=8.6 Hz), 7,86 (1H, d, J=1.5 Hz), 7,89 (1H, d, J=8,4 Hz), 8,13 (1H,s). IR (Nujol): 1691 cm-1.

TPL: 292-293°C.

Example 19 to Obtain

<the First stage >

Obtain ethyl 4-(acetylamino)-3-((4-bromo-2-Chlorobenzyl) -amino)benzoate

In the same way as in Example 1, Receipt, receive the desired compound (3.00 g) of ethyl 4-(acetylamino)-3-aminobenzoate (2,22 g), 4-bromo-2-Chlorobenzyl bromide (2,60 g) and potassium carbonate (1.66 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): of 1.23 (3H, d, J=7,1 Hz), 2,10 (3H, s), 4,18 (2N, K, J=7,1 Hz), 4,39 (2H, d, J=5.8 Hz), equal to 6.05 (1H, t, J=5.8 Hz), 6.89 in (1H, d, J=1.7 Hz), 7,19 (1H, DD, J=1.7 and 8.2 Hz), 7,35 (1H, d, J=8,3 Hz), 7,40 (1H, d, J=8,2 Hz), to 7.50 (1H, DD, J=1,8 and 8.3 Hz), of 7.75 (1H, d, J=1.7 Hz), 9,38 (1H, s).

<the Second and Third stages>

Obtaining 1-(4-bromo-2-Chlorobenzyl)-6-carboxy-2-methylbenzimidazole

Following the methods of Example 3 Obtaining and Example 5 Obtaining consistently get the desired compound (2,03 g) of ethyl 4-(acetylamino)-3-((4-bromo-2-Chlorobenzyl)amino)benzoate (3.00 g) in 1-(4-bromo-2-Chlorobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 2,50 (3H,s), to 5.58 (2H,s), of 6.45 (1H, d, J=8,4 Hz), was 7.45 (1H, DD, J=2.0 and 8.4 and the C), 7,63 (1H, d, J=8,4 Hz), 7,80 (1H, DD, J=1.4 and 8,4 Hz), to 7.84 (1H, d, J=2.0 Hz), of 7.97 (1H, d, J=1.4 Hz), 12.7mm (1H,CL).

Example 21

Synthesis of 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)

sulfonylamino)benzimidazole (33)

In the same way as in Example 1, to obtain the desired benzimidazole (33), using carboxylic acid obtained in Example 19 to Obtain, and (1-Penta-1-ene)of the sulfonamide.

[Physico-chemical characteristics of the Compound (33)]

1H=NMR (DMSO-d6that δ m.g); of 0.85 (3H, t, J=7,3 Hz), of 1.40 to 1.47 (2H,m), 2,22 (2H, Quartet, J=7.0 Hz), 2,48 (3H, s), of 5.55 (2H, s), 6,34 (1H, d, J=8,4 Hz), to 6.75 (1H, d, J=15.2 Hz), 6,82-to 6.88 (1H,m), 7,44 (1H, d, J=8,4 Hz), 7,66 (1H, d, J=8,4 Hz), to 7.77 (1H, d, J=8,4 Hz), the 7.85 (1H,s), of 8.06 (1H,s), 11,95 (1H,CL). IR (Nujol): 1678 cm-1. TPL: 254-255°C.

Example 22

Synthesis of 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl)-sulfonylamino)benzimidazole (34)

In the same way as in Example 1, to obtain the desired benzimidazole (34), using the carboxylic acid obtained in Example 19 to Obtain, and 4-methylbenzenesulfonamide.

[Physico-chemical characteristics of the Compound (34)]

1H=NMR (DMSO-d6that δ m.g): is 2.37 (3H,s), 2,47 (3H,s)5,54 (2H, s), 6,32 (1H, d, J=8,4 Hz), 7,40 (2H, d, J=8,2 Hz), the 7.43 (1H, DD, J=8.5 and 1.8 Hz), 7,63 (1H, d, J=8.5 Hz), 7,71. (1H, d, J=8,4 Hz), 7,84-7,88 (3H,m), of 8.04 (1H,s), 12,31 (1H,CL). TPL: 245-246°C.

Example 23

Synthesis of 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol) benzimidazole (35)

In the same way the AK in Example 1, get the desired benzimidazole (35), using the carboxylic acid obtained in Example 19 to Obtain, and ((E)-2-phenylethenyl)of the sulfonamide.

[Physico-chemical characteristics of the Compound (35)]

1H=NMR (DMSO-d6that δ m.g): 2,47 (3H,c)5,54 (2H,s), 6,34 (1H, d, J=8,4 Hz), 7,41 was 7.45 (4H,m), of 7.48 (1H, d, J=15,5 Hz), a 7.62 (1H, d, J=15,4 Hz), the 7.65 (1H, d, J=8.5 Hz), of 7.75 (2H, d, J=7.8 Hz), 7,79 (1H, d, J=8,6 Hz), a 7.85 (1H, d, J=1,8gts), 8,10 (1H,s), 12,18 (1H,CL). IR (Nujol): 1672 cm-1. TPL: 292,5-293,5°C.

Example 24

Synthesis of 1-(4-bromo-2-Chlorobenzyl)-6-((5-chlorothiophene-2-yl)sulfonylamino)-2-methylbenzimidazole (36)

In the same way as in Example 1, to obtain the desired benzimidazole (36), using the carboxylic acid obtained in Example 19 was received; (5-chlorothiophene-2-yl)sulfonamide.

[Physico-chemical characteristics of the Compound(36)]

1H=NMR (DMSO-d6that δ m.g): to 2.55 (3H,s), 5,62 (2H,s), 6.48 in (1H, d, J=8.5 Hz), 7,18 (1H, d, J=4.0 Hz), 7,44 (1H, DD, J=8,3 and 1.8 Hz), EUR 7.57 (1H,s), to 7.68 (1H, d, J=8.6 Hz), the 7.85-7,88 (2H, m), 8,07 (1H,s).

IR (Nujol): 1692 cm-1.

TPL: 308-309°C.

Obtaining a Sample of 20

<First, Second and Third stages >

Obtaining 1-(4-(benzyloxybenzyl)-2-Chlorobenzyl)-6-carboxy-2-methylbenzimidazole

Following the methods of Example 1, an example of 3 Receiving and sequentially Example 5 Get get desired compound (0.50 g) from ethyl 4-(acetylamino)-3-aminobenzoate (0.74 g), 4-(benzyloxybenzyl)-2-Harbin the sludge chloride, (1.07 g), potassium carbonate (0.55 g) and sodium iodide

(0.25 g) via ethyl 4-(acetylamino)-3-((4-(benzyloxybenzyl)-2-Chlorobenzyl)amino)benzoate and 1-(4-(benzyloxybenzyl)-2-Chlorobenzyl) -6-(etoxycarbonyl) -2-methylbenzimidazole.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): to 2.55 (3H,s), 5,09 (2H,s), of 5.55 (2H,s), 6,62 (1H, d, J=8,8 Hz), 6,92 (1H, DD, J=2.2 and an 8.8 Hz), 7,22 (1H, d, J=2.2 Hz), 7,29-7,42 (5H,m), 7,63 (1H, d, J=8,8 Hz), 7,80 (1H, DD, J=1,3 and 8.8 Hz), of 7.97 (1H,s), of 12.76 (1H,CL).

Example 25

Synthesis of 1-(4-benzyloxy-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (37)

In the same way as in Example 1, to obtain the desired benzimidazole (37), using the carboxylic acid obtained in Example 20 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (37)]

1H=NMR (DMSO-d6that δ m.g): 0,81 (3H, t, J=7.2 Hz), 1,22-to 1.38 (4H,m), 1,64-1,72 (4H,m), 2.49 USD (3H,s)to 3.49 (2H, t, J=7,7 Hz), 5,09 (2H,s), the 5.51 (2H,s), 6,46 (1H, d, J=8.7 Hz), 6.90 to (1H, DD, J=8.7 and 2,5Hz), 7,24 (1H, d, J=2.5 Hz), 7,31 (1H, t, J=7.0 Hz), 7,34-7,42 (4H,m), 7,66 (1H, d, J=8,4 Hz), 7,79 (1H, d, J=8,4 Hz), of 8.09 (1H,s), 11,88 (1H,CL). IR (Nujol): 1681 cm-1.

TPL: to 190.5-191,5°C.

Example 26

Synthesis of 1-(4-benzyloxy-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (38)

In the same way as in Example 1, to obtain the desired benzimidazole (38), using the carboxylic acid obtained in Example 20 to Obtain, and (4-methylb Sol)of the sulfonamide.

[Physico-chemical characteristics of the compound (38)]

1H=NMR (DMSO-d6that δ m.g): is 2.37 (3H,s), 2,47 (3H,s), to 5.08 (2H,s)5,49 (2H,s), to 6.43 (1H, d, J=8.7 Hz), to 6.88 (1H, DD, J=8.7 and 2,5Hz), of 7.23 (1H, d, J=2.6 Hz), 7,30-7,42 (7H,m), to 7.61 (1H, d, J=8.5 Hz), of 7.70 (1H, DD, J=8.5 and 1,GZ), a 7.85 (2H, d, J=8,3 Hz), 8,02 (1H,s), 12,35 (1H,CL).

IR (Nujol): 1710 cm-1.

TPL: 235,5-236,5°C.

Example 27

Synthesis of 6-((5-bromothiophene-2-yl)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (39)

In the same way as in Example 1, to obtain the desired benzimidazole (39), using the carboxylic acid obtained in Example 14 to Obtain, and (5-bromothiophene-2-yl)sulfonamide.

[Physico-chemical characteristics of the compound (39)]

1H=NMR (DMSO-d6that δ m.g): of 2.56 (3H,s), 5,64 (2H,s), 6,56 (1H, d, J=8.0 Hz), 7,28 (1H, d, J=4.0 Hz), 7,32 (1H, DD, J=8.4 and 2.1 Hz), 7,54 (1H, d, J=1.6 Hz), 7,69 (1H, d, J=8,5Hz), of 7.75 (1H, d, J=2.2 Hz), 7,86 (1H, d, J=7,7 Hz), 8,08 (1H,s).

IR (Nujol): 1699, 1683 cm-1TPL: 302-303°C.

Example 28

Synthesis of 6-((5-bromothiophene-2-yl)sulfonylamino)-1-(2-chloro-4-phenylbenzyl)-2-methylbenzimidazole (40)

In the same way as in Example 1, to obtain the desired benzimidazole (40), using the carboxylic acid obtained in Example 18 to Obtain, and (5-bromothiophene-2-yl)sulfonamide.

[Physico-chemical characteristics of the compound (40)]

1H=NMR (DMSO-d6that δ m.g): 2,61 (3H,s), 5,71 (2H,s), 6,63 (1H, d, J=8.0 Hz), 7,26 (1H, d, J=4.0 Hz), 7,38 (1H, t, J=7,3 Hz), 7,45 (2H, t, J=7.6 for the TS) 7,51-rate of 7.54 (2H,m), 7,66 (2H, d, J=7.5 Hz), 7,71 (1H, d, J=8.6 Hz), 7,86 (1H, d, J=1.7 Hz), 7,89 (1H, d, J=8.7 Hz), 8,14 (1H,s). IR (Nujol): 1700, 1684 cm-1TPL: 280-281°C.

Obtaining a Sample 21

<First, Second and Third stages>

Obtaining 6-carboxy-1-(2-chloro-4-(cyclohexylmethoxy) benzyl)-2-methylbenzimidazole

Following the methods of Example 1, Receipt, Example 3 Obtaining and Example 5, Obtain, receive the desired compound (0.52 g) of ethyl-4-(acetylamino)-3-aminobenzoate (of 0.333 g), 2-chloro-4-(cyclohexylmethoxy)benzylchloride (0,49 g), potassium carbonate (0.25 g) and sodium iodide (0.15 g) via ethyl 4-(acetylamino)-3-((2-chloro-4-(cyclohexylmethyl-

hydroxy)benzyl)amino)benzoate and 1-(2-chloro-4-(cyclohexylmethoxy) benzyl) -6-(etoxycarbonyl) -2-methylbenzimidazole.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 1,00 (2H,m)to 1.21 (3H,m), 1,61-1,83 (6N,m), 2,52 (3H,in), 3.75 (2H, d, J=6.4 Hz), the 5.51 (2H,s), 6,55 (1H, d, J=8.7 Hz), for 6.81 (1H, DD, J=2.4 and 8,GC), 7,10 (1H, d, J=2.4 Hz), to 7.61 (1H, d, J=8,4 Hz), 7,78 (1H, DD, J=1.4 and 8,4 Hz), 7,94 (1H,s)12,70 (1H,CL).

Example 29

Synthesis of 1-(2-chloro-4-(cyclohexylmethoxy)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (41)

In the same way as in Example 1, to obtain the desired benzimidazole (41), using the carboxylic acid obtained in Example 21 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (41)]

1H=NMR (DM what About the-d 6that δ m.g): 0,81 (3H, t, J=7,3 Hz), 0,95-of 1.03 (2H,m), 1,11-of 1.39(5H,m), 1.60-to of 1.78 (8H,m), 2.49 USD (3H,s)to 3.49 (2H, t, J=7,7 Hz in), 3.75 (2H, d, J=6, 4 Hz), of 5.50 (2H,S), 6,44 (1H, d, J=8.7 Hz), 6,80 (1H, DD, J=8.7 and 2.6 Hz), 7,12 (1H, d, J=2.6 Hz), 7,66 (1H, d, J=8.5 Hz), 7,78 (1H, DD, J=8.5 and 1.7 Hz), of 8.09 (1H, d, J=1.3 Hz), up 11,86 (1H,CL). IR (Nujol): 1700, 1666 cm-1. TPL: 184-185°C.

Example 30

Synthesis of 1-(2-chloro-4-(cyclohexylmethoxy)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (42)

In the same way as in Example 1, to obtain the desired benzimidazole (42), using a carboxylic acid, obtained in Example 21 to Obtain, and (4 methylbenzol)of the sulfonamide.

[Physico-chemical characteristics of the compound (42)]

1H=NMR (DMSO-d6that δ m.g): 0,95 was 1.04(2H,m), 1,09-of 1.26 (3H,m), 1.60-to 1,79(6N,m), is 2.37(3H,s), 2,47(3H,in), 3.75(2H, d, J=6.4 Hz), 5,49(2H,c), 6,41(1H, d, J=8.6 Hz), 6,79(1H, DD, J=8.6 and 2.5 Hz), 7,11(1H, d, J=2,6 Hz), 7,41(2H, d, J=8,2 Hz), a 7.62(1H, d, J=8.5 Hz), of 7.70(1H, d, J=8.0 Hz), 7,86(2H, d, J=8,2 Hz), of 8.04 (1H,s), 12,30 (1H, CL).

IR (Nujol): 1698 cm-1TPL: 228-230°C.

Example 31

Synthesis of 6-((5-chlorothiophene-2-yl)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (43)

In the same way as in Example 1, to obtain the desired benzimidazole (43), using the carboxylic acid obtained in Example 14 to Obtain, and (5-chlorothiophene-2-yl)sulfonamide.

[Physico-chemical characteristics of the compound (43)]

1H=NMR (DMSO-d6that δ m.g): to 2.57(3H,s), the 5.65(2H,s), 6,59(1H, d, J=8,4 Hz), 7,19(1H, d, J=4,1 Hz), 7,32(1H, DD, J=8.4 and 2.1 Hz), of 7.60(1H, d, J=3.6 Hz), of 7.70(1H, d, J=8.5 Hz), 7,76(1H, d, J=2.1 Hz), 7,88(1H, d, J=8.7 Hz), 8,10(1H,s). IR (Nujol): 1700, 1684 cm-1. TPL: 301-302°C.

Example 32

Synthesis of 1-(4-bromo-2-Chlorobenzyl)-6-((5-bromothiophene-2-yl)sulfonylamino)-2-methylbenzimidazole (44)

In the same way as in Example 1, to obtain the desired benzimidazole (44), using the carboxylic acid obtained in Example 19 was received; (5-bromothiophene-2-yl)sulfonamide.

[Physico-chemical characteristics of the compound (44)]

1H=NMR (DMSO-d6that δ m.g): to 2.55(3H,s), 5,62(2H,s), of 6.49 (1H, d, J=8,3 Hz), 7,29(1H, d, J=4.0 Hz), 7,44(1H, DD, J=8.4 and 1.9 Hz), 7,55(1H, d, J=3,9 Hz), 7,69(1H, d, J=8.5 Hz), the 7.85-7,88 (2H, m), of 8.09 (1H,s). IR (Nujol): 1700, 1684 cm-1.

TPL: 310.5 to-311,5°C.

Example 33

Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-vinylbenzyl)-sulfonylamino)benzimidazole (45)

In the same way as in Example 1, to obtain the desired benzimidazole (45)using carboxylic acid obtained in Example 14 to Obtain, and (4-vinylbenzyl)of the sulfonamide.

[Physico-chemical characteristics of the compound (45)]

1H=NMR (DMSO-d6that δ m.g): 2,47(3H,S), THE 5.45(1H, d, J=11,0Hz), to 5.57(2H,s), 6,01 (1H, d, J=17,7 Hz), 6,41(1H, d, J=8,4 Hz), for 6.81(1H, DD, J=17.7 and and 11,0Hz), 7,30(1H, DD, J=8.4 and 2,0Hz), to 7.64(1H, d, J=8,5 Hz), to 7.67-7,74 (4H,m), to 7.93 (2H, d, J=8,4 Hz), with 8.05 (1H,s). IR (Nujol): 1683 cm-1.

TPL: 213-214°C.

Example 34

Synthesis of 1-(2-chloro-4-bromobenzyl)-2-methyl-6-((4-vinylbenzyl)-sulfonylamino)benzimidazole (6)

In the same way as in Example 1, to obtain the desired benzimidazole (46), using the carboxylic acid obtained in Example 19 to Obtain, and (4-vinylbenzyl)of the sulfonamide.

[Physico-chemical characteristics of the compound (46)]

1H=NMR (DMSO-d6that δ m.g): the 2.46(3H,s), the 5.45 (1H, d, J=11,0Hz), of 5.55(2H, s), 6,01(1H, d, J=17.6 Hz), 6,33(1H, d, J=8,4 Hz), for 6.81(1H, DD, J=17,6 and 11,0 Hz), the 7.43 (1H, DD, J=8.4 and 2,0Hz), to 7.64(1H, d, J=8,5 Hz), to 7.67-7,73 (3H,m), a 7.85(1H, d, J=2.0 Hz), to 7.93(1H, d, J=8,4 Hz), with 8.05(1H, d, J=1.3 Hz).

IR (Nujol): 1683 cm-1.

TPL: 241 to 243°C.

Example 35

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-vinylbenzyl) sulfonylamino)benzimidazole (47)

In the same way as in Example 1, to obtain the desired benzimidazole (47), using the carboxylic acid obtained in Example 18 to Obtain, and (4-vinylbenzyl)of the sulfonamide.

[Physico-chemical characteristics of the compound (47)]

1H=NMR (DMSO-d6that δ m.g):of 2.51(3H,s), 5,42(1H, d, J=11,0 Hz), 5,62(2H,s), 5,97(1H, d, J=17,7 Hz), 6,46(1H, d, J=8.1 Hz), 6,78(1H, DD, J=a 17.6 and 10.9 Hz), 7,37(1H, t, J=7,1 Hz), 7,44 (2H, t, J=7.5 Hz), 7,51(1H, d, J=8,2 Hz), to 7.59-of 7.69(5H, m), 7,74(1H, d, J=8.5 Hz), to 7.84(1H,s), to $ 7.91(2H, d, J=8,3 Hz), 8,07 (1H,s).

IR (Nujol): 1694 cm-1.

TPL: 174-175°C.

Example 36

Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (48)

In the same way as in Example 1, to obtain the desired benzimidazole (48)using carboxylic acid obtained in the Use of the e 14 Receive and (4 methylbenzol)of the sulfonamide.

[Physico-chemical characteristics of the compound (48)]

1H=NMR (DMSO-d6that δ m.g):is 2.37 (3H,s)to 2.46(3H,s)to 5.56(2H,s)6,40(1H, d, J=8.5 Hz), 7,30(1H, DD, J=8.4 and 2.1 Hz), 7,40 (2H, d, J=8,3 Hz), 7,63(1H, d, J=8.5 Hz), 7,71(1H, DD, J=8.5 and 1.5 Hz), 7,74(1H, d, J=2.2 Hz), the 7.85(2H, d, J=8,3 Hz), of 8.04 (1H, d, J=1.2 Hz), 12,35(1H,CL).

IR (Nujol): 1684 cm-1.

TPL: 248-250°C.

Example 37

Synthesis of (+)-1-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (49)

(R)-3-((1-(2,4-dichlorophenyl)ethyl)amino)-4-nitrobenzoic acid is obtained from (R)-1-(2,4-dichlorophenyl)ethyl)amine (optical purity: 93% enantiomeric excess))obtained by the method described in laid the patent application in Japan (Japanese Patent Laid-open No. Hei 8-325213, and 3-fluoro-4-nitrobenzoic acid. After esterification of this compound in ethanol under acidic conditions with sulfuric acid, the resulting product restores the recovered iron and acetimidoyl acetylchloride in pyridine. Acetylated product cyclist using Hcl in ethanol and then hydrolyzing getting the corresponding carboxylic acid.

In the same way as in Example 1, to obtain the desired benzimidazole (49), using the thus obtained carboxylic acid and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (49)]

1H=NMR (DMSO-d6that δ m.g): 0,81 (3H,t), of 1.26(2H,m)of 1.36(2H,m), 1,6(2H,m), 1,95(3H, d, J=7,0 Hz), of 2.56(3H,s), of 3.48(2H,t), 6,01(1N, K, J=7,0 Hz), EUR 7.57-to 7.61 (2H,m), 7,63(1H, d, J=2.2 Hz), of 7.70(1H, d, J=8.5 Hz), of 7.75(1H,s), 7,87(1H, d, J=8.5 Hz), 11,93(1H,CL).

IR (Nujol): 1683 cm-1so pl.: 248,5-251°C.

[α]

25
D
: +12,7(0,31, Meon).

Optical purity: 90% (analyzed using liquid chromatography using Chiralpak AS).

Example 38

Synthesis of (-)-1-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (50)

(S)-3-((1-[2,4-dichlorophenyl)ethyl)amino)nitrobenzoic acid is obtained from (S)-1-(2,4-dichlorophenyl)ethyl)amine (optical purity: 96%, obtained by the method described in laid out the application for Pat. Japan No. Hei 8-325213, and 3-fluoro-4-nitrobenzoic acid. After esterification of this compound in ethanol under acidic conditions with sulfuric acid, the resulting product restores the recovered iron and acetimidoyl acetylchloride in pyridine. Acetylated product cyclist using Hcl in ethanol and then hydrolyzing getting the corresponding carboxylic acid.

In the same way as in Example 1, to obtain the desired benzimidazole (50)using the thus obtained carboxylic acid and 1-pentanesulfonate.

[Physico-chemical characteristics of compounds (50)]

1H=NMR (DMSO-d6that δm.g):0,81 (3H,t), of 1.26(2H,m)of 1.36(2H,m)

to 1.67(2H,m), 1,95(3H, d, J=7,0 Hz), of 2.56(3H,s), of 3.48(2H,t), 6,01(1N, K, J=7,0 Hz), EUR 7.57-to 7.61 (2H,m), 7,63(1H, d, J=2.2 Hz), of 7.70(1H, d, J=8.5 Hz), of 7.75(1H,s), 7,87(1H, d, J=8.5 Hz), 11,93(1H,SHS).

IR (Nujol): 1683 cm-1.

so pl.: 243-246°C.

[α]

25
D
: -7,99(0,31, Meon).

Example 39

Synthesis of 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((1-Penta-4-ene-sulfonylamino)benzimidazole (51)

In the same way as in Example 1, to obtain the desired benzimidazole (51), using the carboxylic acid obtained in Example 19 to Obtain, and (1-Penta-4-ene)of the sulfonamide.

[Physico-chemical characteristics of compounds (51)]

1H=NMR (DMSO-d6that δ m.g): 1,75-of 1.81 (2H,m), 2,12-to 2.18(2H,m)of 2.50(3H,s), 3,50(2H, t, J=7,7 Hz), equal to 4.97(1H, d, J=10.0 Hz), 5,10(1H, DD, J=1.7 and 18.2 Hz), to 5.56(2H,s), 5,70-5,79 (1H, m), 6,36(1H, d, J=8,4 Hz), 7,44(1H, DD, J=8.4 and 1.9 Hz), to 7.68(1H, d, J=8,4 Hz), 7,89(1H, DD, J=8.4 and 1,5Hz), 7,86(1H,d, J=2.0 Hz), 8,10(1H, d, J=1.4 Hz), 11,95(1H,CL).

IR (Nujol): 1687 cm-1.

so pl.: 196-198,5°C.

Example 40

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((1-Penta-4-ene-sulfonylamino)benzimidazole (52)

In the same way as in Example 1, to obtain the desired benzimidazole (52)using carboxylic acid obtained in Example 18 to Obtain, and (1-Penta-4-ene)of the sulfonamide.

[Physico-chemical characteristics of the compound (52)]

1H=NMR (DMSO-d that δ m.g): 1,75-of 1.81(2H,m), 2,11-2,17(2H,m), of 2.54(3H,s), 3,50(2H, t, J=7,7 Hz), 4,96(1H, d, J=10.3 Hz), 5,00(1H,DD, J=17,2 and 1.6 Hz), the 5.65(2H, s), 5,70-5,78 (1H, m), 6,50(1H, d,J=8.1 Hz), 7,39(1H, t, J=7,3 Hz), 7,46(2H, t, J=7.4 Hz), 7,54(1H,DD, J=8.1 and 1,8gts), 7,66(2H, d, J=7,7 Hz), of 7.70 (1H, d, J=8.5 Hz), 7,82(1H, DD, J=8.5 and 1.6 Hz), 7,86 (1H, d, J=1.7 Hz), 8,16(1H,s), 11,98 (1H,CL). IR (Nujol): 1682 cm-1so pl.: 180-185°C.

Example 22 to Obtain

<First, second and third stages>

Obtaining 6-carboxy-1-(2-chloro-4-nitrobenzyl)-2-methylbenzimidazole

Following the methods of Example 1, Receipt, Example 3 Obtaining and consistently of Example 5, Obtain, receive the requested connection (0,37 g) of ethyl 4-(acetylamino)-3-aminobenzoate (1,11 g), 2-chloro-4-nitrobenzyl chloride (1.29 g), potassium carbonate (1,38 g) and sodium iodide (0,30 g) via ethyl 4-(acetylamino)-3-((2-chloro-4-nitrobenzyl)amino)benzoate and

1-(2-chloro-4-nitrobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole. This product is immediately subjected to the next stage.

Example 41

Synthesis of 1-(2-chloro-4-nitrobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (53)

In the same way as in Example 1, to obtain the desired benzimidazole (53), using the carboxylic acid obtained in Example 22 To Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (53)]

1H=NMR (DMSO-d6that δ m.g): 0,80(3H, t, J=7,3 Hz), to 1.21 to 1.37 (4H, m), 1,62 by 1.68(2H,m), 2.49 USD(3H,s), 3,40-3,47 (2H,m), 5,72(2H, s), 6,62(1H, d, J=8.7 Hz), to 7.68(1H, d, J=8,5Hz), 7,81(1H, d,J=8,Hz), 8,06-8,10 (2H,m), 8,42(1H, d, J=2.3 Hz), 11,88 (1H,CL).

Example 23 to Obtain

<First and second stages>

Obtain 1-(2-chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

Following the methods of Example 1 Obtaining and Example 3 Obtaining consistently obtain the desired compound (2,75 g) of ethyl 4-(acetylamino)-3-aminobenzoate (2,44 g), 2-chloro-4-iodobenzyl bromide (4,53 g) and potassium carbonate (of 3.73 g) via ethyl 4-(acetylamino)-3-((2-chloro-4-iodobenzyl)amino)-benzoate.

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): of 1.39(3H, t, J=7.2 Hz), of 2.56(3H,s),to 4.38 (2H, K, J=7,2 Hz), 5,38(2H,s), 6,11(1H, d, J=8,2 Hz), 7,42 (1H, DD, J=8,2 and 1.5 Hz), of 7.75 (1H, d, J=8.5 Hz), of 7.75(1H, d, J=8.5 Hz), 7,82(1H, d, J=1,GZ), of 7.96(1H, DD, J=8.4 and 1,4 Hz).

<a Third step>

Obtain 1-(2-chloro-4-(phenylethynyl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

A mixture of 1-(2-chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,91 g), phenylacetylene (1,02 g), palladium acetate(II) (0,045 g), triphenylphosphine (0,105 g), three n-butylamine(1.12 g), copper iodide (I) (0,038 g) and N,N-dimethylformamide (5 ml) is stirred for 1 hour at 70°and for 30 minutes at 100°C. After cooling the reaction solution, add acetone and the solution is filtered through celite. The filtrate is concentrated and the resulting residue is dissolved in ethyl acetate followed by washing IN hydrochloric acid and 10%aqueous sodium hydroxide solution. The organic layer is dried and concentrated, obtaining the crude 1-(2-chloro-4-(phenylethynyl)benzyl)-6-(etoxycarbonyl)-2-methyl-

the benzimidazole. This product is immediately subjected to the next stage.

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): of 1.40 (3H, t, J=7.2 Hz), 2,61(3H,s), to 4.38(2H, K, J=7,1 Hz), 5,46(2H,s), to 6.39 (1H, d, J=8.1 Hz), 7,25 (1H, d, J=8,3 Hz), to 7.32 and 7.36(3H,m), of 7.48-7,52(2H,m), of 7.64 (1H, d, J=1.4 Hz), 7,81(1H, d, J=8.5 Hz), 7,95(1H,c), of 8.00 (1H, d, J=8,5 Hz).

<Fourth stage >

Obtaining 6-carboxy-1-(2-chloro-4-(phenylethynyl)benzyl)-2-methylbenzimidazole

In the same way as in Example 5 Obtaining, obtain the desired compound (0,100 g) of 1-(2-chloro-4-(phenylethynyl)-benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole obtained in the above stage.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 2,52(3H,s), to 5.66(2H,s), 6,55(1H, d, J=8.1 Hz), 7,38-7,44 (4H,m), 7,52-EUR 7.57 (2H,m), of 7.64(1H, d, J=8,4 Hz), 7,76 (1H, d, J=1.5 Hz), 7,80(1H, d, J=8,4 Hz), to 7.99(1H,s), 12,72 (1H,CL).

Example 42

Synthesis of 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-(1-Pentanesulfonate)benzimidazole (54)

In the same way as in Example 1, to obtain the desired benzimidazole (54)using carboxylic acid, obtained in Example 23 To Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (54)]

1H=NMR (DMSO-d6that δ m.g): 0,80(3 is, t, J=7,3 Hz), 1,21-to 1.38 (4H, m), 1,63-1,71 (2H,m), 2.49 USD(3H,s)to 3.49(2H, t, J=7,Hz), 5,63 (2H,s), 6,47(1H, d, J=8.0 Hz), 7,40-7,46(4H,m), 7,52-EUR 7.57 (2H,m), 7,b(1H, d, J=8,4 Hz), to 7.77-7,82 (2H,m)to 8.12 (1H, s), 11,90(1H,CL).

so pl.: 224-225°C.

Example 24 to Obtain

<the First stage >

Obtain 1-(2-chloro-4-(2-phenylethenyl)benzyl)-6-(taxicar-

bonyl)-2-methylbenzimidazole

A mixture of 1-(2-chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,91 g)obtained in Example 23 to Obtain, phenylacetylene (1.04 g), palladium acetate(II) (0,068 g), triphenylphosphine (0.16 g), three n-butylamine (1.12 g) and N,N-dimethylformamide (10ml) was stirred overnight at 60°C. After cooling, the reaction mixture was extracted with ethyl acetate and water. The organic layer is dried and concentrated. Thus obtained residue is dissolved in acetone and discolor activated carbon. The solid is removed by filtration and the filtrate is concentrated, obtaining the crude 1-(2-chloro-4-(2-phenylethenyl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0.68 g).

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): of 1.39(3H, t, J=7,1 Hz), 2,59(3H,c), 4,37 (2N, K, J=7,1 Hz), 5,46(2H,s)6,40(1H, d, J=8.0 Hz), 6,98 (1H, d, J=16.2 Hz), was 7.08(1H, d, J=16.2 Hz), 7,20(1H, d, J=8.0 Hz), 7,28(1H, t, J=7.4 Hz), was 7.36(2H, t, J=7.5 Hz), of 7.48 (2H, d, J=7.8 Hz), to 7.61(1H,s), 7,56(1H, d, J=8.5 Hz), of 7.96 (1H,s), of 8.00(1H, d, J=8,4 Hz).

<a Second phase>

Obtaining 6-carboxy-1-(2-chloro-4-(2-phenylethenyl)benzyl)-2-mate the benzimidazole

In the same way as in Example 5, Obtain, receive the requested connection (0,49 g) of 1-(2-chloro-4-(2-phenylethenyl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0.68 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): to 2.54 (3H, s), 5,62(2H,s), to 6.58(1H, d, J=8.1 Hz), 7,21(1H, d, J=16.5 Hz), 7,27(1H, t, J=7.5 Hz), 7,31 (1H, d, J=16.4 Hz), was 7.36(2H, t, J=7.5 Hz), 7,44(1H, d, J=8.1 Hz), EUR 7.57(2H, d, J=7,7 Hz), to 7.64(1H, d, J=8,4 Hz), 7,80 (2H, DD, J=8.4 and 1.5 Hz), of 7.97 (1H,s), 12,69(1H,CL).

Example 43

Synthesis of 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (55)

In the same way as in Example 1, to obtain the desired benzimidazole (55)using carboxylic acid, obtained in Example 24 To Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (55)]

1H=NMR (DMSO-d6that δ m.g): of 0.79 (3H, t, J=7,3 Hz), to 1.21 to 1.37 (4H,m), 1,63 is 1.70(2H,m), of 2.51(3H,s), of 3.48(2H, t, J=7,7 Hz), the ceiling of 5.60(2H,s), 6.48 in(1H, d, J=8,2 Hz), 7,21(1H, d, J=16.5 Hz), 7,27(1H, t, J=7,3 Hz), 7,31(1H, d, J=16.5 Hz), was 7.36(2H,t, J=7.5 Hz), 7,44 (1H, d, J=8.1 Hz), EUR 7.57(2H, d, J=8.0 Hz), to 7.68 (1H, d, J=8.5 Hz), 7,80(1H, d, J=8.5 Hz), 7,83(1H,c)to 8.12 (1H,s), 11,90 1H,CL).

so pl.: 242-243°C.

Example 44

Synthesis of 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (56)

In the same way as in Example 1, to obtain the desired benzimidazole (56)using carboxylic acid, obtained in Example 24 To Obtain, and (4-methylb Sol) of the sulfonamide.

[Physico-chemical characteristics of the compound (56)]

1H=NMR (DMSO-d6that δ m.g): 2,35 (3H,s), 2.49 USD(3H,s)., to 5.58 (2H, s), 6,46(1H, d, J=8.1 Hz), 7,21(1H, t, J=16.5 Hz), 7,28(1H, t, J=7.4 Hz), 7,31(1H, d, J=16.6 Hz), 7,34-7,44(6N,m), 7,58(2H, d, J=7,6 Hz), to 7.64(1H, d, J=8.5 Hz), 7,71(1H, d, J=8.6 Hz), of 7.82 (1H,s), a 7.85(1H, d, J=8,3 Hz), of 8.06(1H,s), 12,30 (1H,CL). so pl.: 250-252°C.

Example 25 to Obtain

<First and Second stages>

Obtaining 6-carboxy-1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methylbenzimidazole

A mixture of 1-(2-chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (1,21 g), 1-hexene(1.12 g), palladium acetate (11) (0.09 g), triphenylphosphine(0.21 g), tri-n-butylamine (1,49 g) and N,N-dimethylformamide (15ml) was stirred overnight at 60°C. the Reaction mixture was concentrated under reduced pressure and the resulting residue is purified column chromatography on silica gel (eluate: hexane/ethyl acetate=1/2)getting 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,99 g). In accordance with the method of Example 5 of Receipt, this product is immediately converted into the desired compound (0.64 g)containing about 10% of 6-carboxy-1-(2-chloro-4-(1-HEXEN-2-yl)benzyl)-2-methylbenzimidazole.

This connection is immediately subjected to the next stage.

Example 45

Synthesis of 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (57)

In the same way as in Example 1, get the appropriate Benson Gasol (57), using the carboxylic acid obtained in Example 25 and Get 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (57)]

1H=NMR (DMSO-d6that δ m.g): 0,70-0,90 (6N,m), 1,21-1,71 (10H, m), 1.91 a-2,17 (2H,m), 2.49 USD(3H,s), of 3.48(2H, t, J=7,Hz), 5,10-to 5.85 (3H,m), 6,33-6,41 (2H,m), 7.03 is-7,40 (1H,m), 7,53-to 7.59 (1H, m), to 7.67(1H, d, J=8,5 Hz), 7,79(1H, d, J=8.5 Hz), 8,10(1H,c), 11.87 per(1H,CL).

so pl.: 175-177°C.

Example 46

Synthesis of 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methyl-6-((4-

methylbenzol)sulfonylamino)benzimidazole (58)

In the same way as in Example 1, to obtain the desired benzimidazole (58)using carboxylic acid obtained in Example 25 was received; (4 methylbenzol)of the sulfonamide.

[Physico-chemical characteristics of the compound (58)]

1H=NMR (DMSO-d6that δ m.g): 0,81-of 0.91(3H,m), 1,23-to 1.60(4H,m), 1,90-2,17(2H,m), a 2.36(3H,s), 2,488 and 2,491 (3H, 2s), 5,08-5,86 (3H,m), of 6.31-6.42 per (2H,m), 7,02-7,38(1H,m), 7,39(2H,d, J=8.1 Hz), 7,52-of 7.60 (1H,m), 7,62(1H, d, J=8,4 Hz), 7,71(1H, d, J=8.6 Hz), the 7.85(2H, d, J=8.1 Hz), 8,02-8,07(1H, m), 12,31(1H, CL).

so pl.: 190-192°C.

Example 47

Synthesis of 1-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (59)

The platinum oxide (0,010 mg) are added to a solution (10 ml) of the Compound (55) (0.24 g) in acetic acid obtained in Example 43, and the mixture is stirred in hydrogen atmosphere (pressure of 1 atmosphere) at room temperature for 1.5 hours. After filtered off the insoluble ve is esta, the filtrate is concentrated under reduced pressure. The residue is recrystallized from a mixture of 2-propanol and water, getting the desired benzimidazole (59) (0,22 g).

[Physico-chemical characteristics of the compound (59)]

1H=NMR (DMSO-d6that δ m.g): 0,80(3H, t, J=7,1 Hz), 1,21-of 1.40(4H,m), 1,64-1,72 (2H,m), 2,48(3H,s)2,84(4H,s), 3,48

(2H, t,J=7,6 Hz), of 5.55(2H,s), to 6.39(1H, d, J=7.9 Hz), to 7.09 (1H, d, J=8.0 Hz), to 7.15(1H, t, J=7.5 Hz), 7,27(3H,m), 7,19 (2H, d, J=7.5 Hz), 7,24(2H, t, J=7.5 Hz), the 7.43(1H,s), to 7.67 (1H, d, J=8,3 Hz), 7,79 (1H, d, J=8.5 Hz), of 8.09(1H,c), 11,85 (1H,CL).

so pcs.: 187-189°C.

Example 26 to Obtain

<the First stage>

Obtaining 1-(4-t-butylthio-2-Chlorobenzyl)-6-(etoxycarbonyl) -2-methylbenzimidazole

A mixture of 1-(2-chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,702 g)obtained in Example 23 To Obtain, tetrakis(triphenylphosphine)palladium (0) (0,357 g), tri-n-butylamine (0,573 g), t-butylmercaptan (0,397 g) and N,N-dimethylformamide (3ml) was stirred overnight at 60°C. the Reaction mixture was concentrated under reduced pressure and the resulting residue is purified column chromatography on silica gel (eluate: hexane/ethyl acetate=1/1)to give 1-(4-t-butylthio-2-Chlorobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,500 g).

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): of 1.28(9H,c)of 1.39(3H,m), of 2.56(3H,s), 4,37(2H,m), 5,43(2H,s), 6,36(1H, d, J=8.0 Hz), 7,25(1H, DD, J=1.5 and 8.0 Hz), the 7.65(1H, d, J=1.5 Hz), of 7.75(1H, d, J=8.4 and the C), 7,94(1H,s), 8,00(1H, DD, J=1.4 and 8,4 Hz).

<a Second phase>

Obtaining 6-carboxy-1-(4-t-butylthio-2-Chlorobenzyl)-2-methylbenzimidazole

In the same way as in Example 5, Obtain, receive the requested connection (0,365 g) of 1-(4-t-butylthio-2-Chlorobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,500 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 1,21(N,C)of 2.51(3H,s), the 5.65(2H,s), 6,56(1H, d, J=8.0 Hz), was 7.36(1H, DD, J=1.6 and 8.0 Hz), a 7.62 (1H, d, J=1.6 Hz), 7,63(1H, d, J=8,4 Hz), 7,79(1H, d, J=8,4 Hz), of 7.97 (1H, s), 12.7mm(1H,CL).

Example 48

Synthesis of 1-(4-t-butylthio-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (60)

In the same way as in Example 1, to obtain the desired benzimidazole (60), using a carboxylic acid, obtained in Example 26 To Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of compounds (60)]

1H=NMR (DMSO-d6that δ m.g): 0,80(3H, t, J=7.2 Hz), 1,21-1,29 (11N,m)of 1.34(2H,m)to 1.67(2H,m), 2.49 USD(3H, s), 3,49(2H,m), 5,62(2H,s), 6,46(1H, d, J=8.0 Hz), was 7.36(1H, d, J=8.0 Hz), to 7.64 (1H,s), to 7.68(1H, d, J=8.5 Hz), 7,80(1H, d, J=8,5 Hz)to 8.12 (1H,s), 11,84 (1H,CL).

so pl.: 163-165°C.

Example 49

Synthesis of 1-(4-t-butylthio-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (61)

In the same way as in Example 1, to obtain the desired benzimidazole (61), using the carboxylic acid obtained in Example 26 To Obtain, and (4 methylbenzol)sulfones is.

[Physico-chemical characteristics of the compound (61)]

1H=NMR (DMSO-d6that δ m.g): 1,21(N,C), is 2.37(3H,s)to 2.46(3H,s), 5,61(2H,s), 6,44(1H, d, J=7.9 Hz), 7,35(1H, d, J=7.9 Hz), 7,40 (2H, d, J=8.1 Hz), to 7.61-to 7.67(2H,m), 7,71(1H,d), a 7.85(2H, d, J=8,3 Hz), with 8.05(1H,s), with 12.3(1H,CL).

TPL: 208,5-210,5°C.

Example 27 to Obtain

<the First stage>

Obtain ethyl 4-(acetylamino)-3-((2-chloro-4-(phenoxymethyl)benzyl)amino)benzoate

In the same way as in Example 1, Receipt, receive the desired compound (1.63 g) of ethyl 4-(acetylamino)-3-aminobenzoate (0,80 g), 2-chloro-4-(phenoxymethyl) benzyl chloride (0.96 g), sodium carbonate (0,47 g) and sodium iodide (0,30 g). The connection is immediately subjected to the next stage.

<a Second phase >

Obtain 1-(2-chloro-4-(phenoxymethyl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

In the same way as in Example 3, Obtain, receive a connection from ethyl 4-(acetylamino)-3-((2-chloro-4-(phenoxymethyl)benzyl)amino)benzoate (1.63 g). This connection is immediately subjected to the next stage.

<a Third step>

Obtaining 6-carboxy-1-(2-chloro-4-(phenoxymethyl)benzyl)-2-methylbenzimidazole

In the same way as in Example 5, Obtain, receive the requested connection (0,78 g) of 1-(2-chloro-4-(phenoxymethyl) -benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole obtained in the above stage.

[Physico-chemical characteristics of connection]

1 6that δ m.g): 2,52(3H,s), 5,07(2H,s), 5,61 (2H, s), 6,56(1H, d, J=7.8 Hz), 6,92(1H, t, J=7,1 Hz), 6,97(2H, d, J=7.5 Hz), 7,27(3H,m), a 7.62(2H,s), 7,79(1H, d, J=8.0 Hz), 7,95 (1H,s).

Example 50

Synthesis of 1-(2-chloro-4-(phenoxymethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (62)

In the same way as in Example 1, to obtain the desired benzimidazole (62)using carboxylic acid obtained in Example 27 To Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (62)]

1H=NMR (DMSO-d6that δ m.g): 0,80 (3H, t, J=7.2 Hz), 1,24(2H,m)of 1.34(2H,m)of 1.66(2H, m), 2.49 USD(MN)of 3.48(2H, t, J=7,7 Hz), 5,07(2H,s)5,59(2H,s), 6,46(1H, d, J=8.0 Hz), 6,92(1H, t, J=7,7 Hz), 6,97(2H, d, J=8.5 Hz), 7,27(3H,m), of 7.64(1H,s), to 7.67 (1H, d, J=8,4 Hz), 7,79(1H, d, J=8,4 Hz), 8,10(1H,s), up 11,86 (1H,CL).

so pl.: 169-173°C.

Example 51

Synthesis of 1-(2-chloro-4-(phenoxymethyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (63)

In the same way as in Example 1, to obtain the desired benzimidazole (63), using the carboxylic acid obtained in Example 27 To Obtain, and (4 methylbenzol) of the sulfonamide.

[Physico-chemical characteristics of the compound (63)]

1H=NMR (DMSO-d6that δ m.g): is 2.37(3H,s), 2,47(3H,s), 5,07(2H,s), to 5.58(2H,s), to 6.43(1H, d, J=7.8 Hz), 6,93(1H, t, J=7,3 Hz), 6,97 (2H, d, J=7.9 Hz), 7,27(3H,m), 7,39(2H, d, J=7,7 Hz), 7,63 (2H, m), 7,71(1H, d, J=8.5 Hz), the 7.85(2H, d, J=7.5 Hz), of 8.04 (1H,s), 12,31 (1H,CL). so pl.: 161 to 165°C.

Example 28 to Obtain

<the First stage>

Getting etil-(acetylamino)-3-((2-chloro-4-(cyclohexylmethyl)benzyl)amino)benzoate

In the same way as in Example 1 to Obtain, receive the requested connection (1,94 g) of ethyl 4-(acetylamino)-3-aminobenzoate (0,89 g), 2-chloro-4-(cyclohexylmethyl)benzyl chloride (1,09 g), sodium carbonate (0.51 g) and sodium iodide (0,30 g). This connection is immediately subjected to the next stage.

<a Second phase>

Obtain 1-(2-chloro-4-(cyclohexylmethyl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

In the same way as in Example 3, Obtain, receive the requested connection from ethyl 4-(acetylamino)-3-((2-chloro-4-(cyclohexylmethyl)benzyl)amino)benzoate (1,94 g). This connection is immediately subjected to the next stage.

<a Third step >

Obtaining 6-carboxy-1-(2-chloro-4-(cyclohexylmethyl) -benzyl)-2-methylbenzimidazole

In the same way as in Example 5, Obtain, receive the desired compound (1.13 g) of 1-(2-chloro-4-(cyclohexylmethyl) benzyl-6-(etoxycarbonyl)-2-methylbenzimidazole obtained in the above stage.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 1,17-1,24(5H,m)of 1.44(1H,m)of 1.62 (2H,m), is 1.81(2H,m)of 2.50(3H,s), of 4.44(2H,s)4,55(1H,m), to 5.58 (2H,s), of 6.52(1H, d, J=7,7 Hz), to 7.15(1H, d, J=8.0 Hz), 7,45 (1H,s), 7,60(1H, d, J=8,3 Hz), 7,78(1H, d, J=8,4 Hz), 7,92 (1H,s).

Example 52

Synthesis of 1-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (64)

In the same way as in PR is as 1, get the desired benzimidazole (64)using carboxylic acid obtained in Example 28 To Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (64)]

1H=NMR (DMSO-d6that δ m.g): 0,80 (3H, t, J=7.2 Hz), 1,15-1,30 (7H,m)of 1.34(2H,m)of 1.45(1H,m)of 1.66(4H,m), is 1.81(2H,m), 2.49 USD (3H,s), of 3.48(2H, t, J=7,7 Hz), of 4.45(2H,c), 4,56(1H, d, J=4.6 Hz), to 5.57(2H,c), to 6.43(1H, d, J=8.0 Hz), 7,16(1H, d, J=7.5 Hz), of 7.48(1H,s), to 7.67(1H, d, J=8,4 Hz), 7,79(1H, d, J=8,8 Hz), 8,09(1ns), 11.87 per (1H, CL). so pl.: 129-133°C.

Example 53

Synthesis of 1-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (65)

In the same way as in Example 1, to obtain the desired benzimidazole (65)using carboxylic acid obtained in Example 28 To Obtain, and (4 methylbenzol)of the sulfonamide.

[Physico-chemical characteristics of the compound (65)]

1H=NMR (DMSO-d6that δ m.g): 1,17-1,24 (5H, m)of 1.46(1H,m), and 1.63 (2H,m), equal to 1.82(2H,m), is 2.37(3H,s), 2,47(3H,s), of 4.45(2H,s), 4,56 (1H, d, J=7,1 Hz)to 5.56(2H,c), 6,41 (1H, d, J=7,7 Hz), to 7.15 (1H, d, J=8.0 Hz,), 7,40(2H, d, J=7.8 Hz), 7,47(1H,c), 7,63 (1H, d, J=8.5 Hz), 7,71(1H, d, J=8,4 Hz), a 7.85(2H, d, J=7,7 Hz), of 8.04(1H,s), 12, 29 (1H, CL), so pl.: 143-151°C.

Example 54

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((n-intramyocellular)carbarnoyl)benzimidazole (66)

In the same way as in Example 1, to obtain the desired benzimidazole (66)using carboxylic acid obtained in Example 18 to Obtain, and N-(n-pentyl)sulphonamide.

[Fizi what about the chemical characteristics of the compound (66)]

1H=NMR (DMSO-d6that δ m.g): to 0.73(3H, t, J=6.8 Hz), 1,09-to 1.21 (4H,m), 1,36-of 1.42 (2H,m), of 2.53(3H,s), of 2.86(2H, t, J=6.4 Hz), 5,63(2H,s), 6,51(1H, d, J=8,2 Hz), 7,38(1H, t, J=7,4 Hz), 7,45 (2H, t, J=7,5Hz), 7,53(1H, d, J=8.1 Hz), 7,62-of 7.70 (4H,m), 7,79(1H, d, J=8,4 Hz), the 7.85(1H,s)to 8.12(1H,s), 11,58 (1H,CL).

so pl.: of 193.5-195,2°C.

Example 55

Synthesis of 1-(2,4-dichlorobenzyl)-2-methyl-6-(((4-were) -

aminosulfonyl)carbarnoyl)benzimidazole (67)

In the same way as in Example 1, to obtain the desired benzimidazole (67), using the carboxylic acid obtained in Example 14 to Obtain, and N-(4-were)sulphonamide.

[Physico-chemical characteristics of the compound (67)]

1H=NMR (DMSO-d6that δ m.g): of 2.16(3H,s), 2,47(3H,s), of 5.53(2H, s), to 6.43(1H, d, J=8,4 Hz), 7,01(2H, d, J=8,4 Hz), 7,06(2H, d, J=8,4 Hz), 7,30(1H, DD, J=8.3 and 2,0Hz), to 7.61(1H, d, J=8,4 Hz), 7,69(1H, d, J=8.6 Hz), of 7.75(1H, d, J=2.0 Hz), of 7.96(1H,s), 10,30(1H,CL), 11,82(1H,CL).

so pl.: 190-191°C.

Example 56

Synthesis of 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((4-(were)aminosulfonyl)carbarnoyl)benzimidazole (68)

In the same way as in Example 1, to obtain the desired benzimidazole (68), using the carboxylic acid obtained in Example 18 to Obtain, and N-(4-were)sulphonamide.

[Physico-chemical characteristics of the compound (68)]

1H=NMR (DMSO-d6that δ m.g): 2,10(3H,s), 2.49 USD(3H,s), ceiling of 5.60(2H, s), of 6.49(1H, d, J=8.0 Hz), of 6.99(2H, d, J=8,4 Hz), 7,05(2H, d, J=8,4 Hz), 7,38(2H, t, J=7.4 Hz), was 7.45(1H, t, J=7.4 Hz), 7,52 (1H, DD, J=8.1 and 2.2 to Hz), the 7.65(3H,m), of 7.70(1H, DD, J=8.5 and 14 Hz), 7,86(1H, d, J=1,8 Hz), 8,01(1H,s), 10,31(1H,CL), 11,85(1H,CL).

so pl.: 182,5-183,5°C.

Example 29 to Obtain

Obtaining 6-carboxy-1-(2-chloro-4-iodobenzyl)-2-methylbenzene-

dazole

In the same way as in Example 5, Obtain, receive the requested connection (0,86 g) of 1-(2-chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole obtained in Example 23 was received.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 2,50(3H,s), to 5.57(2H,s), 6,28 (1H, d, J=8,3 Hz), to 7.59(1H, DD, J=8,2 and 1.6 Hz), 7,63(1H, d, J=8,4 Hz), 7,80(1H, DD, J=8.4 and 1.5 Hz), to 7.93(1H, d, J=1.6 Hz), of 7.96(1H, d, J=1.3 Hz), 12,70(1H,CL).

Example 57

Synthesis of 1-(2-chloro-4-iodobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (69)

In the same way as in Example 1, to obtain the desired benzimidazole (69)using the carboxylic acid obtained in Example 29 To Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (69)]

1H=NMR (DMSO-d6that δ m.g): 0,80(3H, t, J=7.4 Hz), 1,21-of 1.30 (2H,m), 1,31-of 1.39 (2H,m), 1,63-1,71 (2H,m), 2,48(3H,s)to 3.49 (2H, t, J=7,7 Hz)5,54(2H,c), 6,18(1H, d, J=8,2 Hz), to 7.59 (1H, d, J=8,3 Hz), to 7.67(1H, d, J=8,4 Hz), 7,79(1H, d, J=8,4 Hz), 7,95(1H,s), 8,08(1H,s), 11,88 (1H,CL) so pl.: 226-228,5°C.

Example 58

Synthesis of 1-(2-chloro-4-iodobenzyl) -2-methyl-6-((4-methylbenzoyl)sulfonylamino) benzimidazole (70)

In the same way as in Example 1, to obtain the desired benzimidazole (70), using the carboxylic acid is received in Example 29 To Obtain, and (4 methylbenzol)of the sulfonamide.

[Physico-chemical characteristics of compounds (70)]

1H=NMR (DMSO-d6that δ m.g): of 2.38(3H,s)to 2.46(3H,s)5,52(2H,s), x 6.15(1H, d, J=8,2 Hz), 7,40(2H, d, J=8,2 Hz), EUR 7.57(1H, DD, J=8,2 and 1.5 Hz), a 7.62(1H, d, J=8.5 Hz), of 7.70(1H, DD, J=8.5 and 1,5Hz), a 7.85(2H, d, J=8,3 Hz), 7,94 (1H, d, J=1.7 Hz), 8,03(1H,s), 12,34 (1H,CL). so pl.: 226-228,5°C.

Example 30 to Obtain

<the First stage>

Obtain ethyl 4-(acetylamino)-3-((2-chloro-4-ethoxybenzyl)amino)benzoate

In the same way as in Example 1, Receipt, receive the requested connection (1,34 g) of ethyl 4-(acetylamino)-3-aminobenzoate (1.12 g), 2-chloro-4-ethoxybenzyl chloride (0.96 g), sodium carbonate (0,80 g) and sodium iodide (0,38 g).

The connection is immediately subjected to the next stage.

<a Second phase>

Obtain 1-(2-chloro-4-ethoxybenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

In the same way as in Example 3, Obtain, receive the requested connection from ethyl 4-(acetylamino)-3-((2-chloro-4-ethoxybenzyl)amino)benzoate (1,34 g). The connection is immediately subjected to the next stage.

<a Third step>

Obtaining 6-carboxy-1-(2-chloro-4-ethoxybenzyl)-2-methylbenzimidazole

In the same way as in Example 5, Obtain, receive the requested connection (0,91 g) of 1-(2-chloro-4-(cyclohexylmethyl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole obtained in the above stage.

[Physico-chemical features : the tick of connection]

1H=NMR (DMSO-d6that δ m.g): of 1.27(3H, t, J=6.9 Hz), 2.49 USD(3H,c), 3,99(2N, K, J=6.9 Hz), 5,52(2H,c), 6,56(1H, d, J=6.4 Hz), for 6.81 (1H, d, J=6.8 Hz), to 7.09(1H, d, J=2.0 Hz), 7,66(1H,CL), 7,78 (1H,CL), to 7.99(1H,SHS), 12,69(1H,CL).

Example 59

Synthesis of 1-(2-chloro-4-ethoxybenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (71)

In the same way as in Example 1, to obtain the desired benzimidazole (71), using carboxylic acid obtained in Example 30 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of compounds (71)]

1H=NMR (DMSO-d6that δ m.g): 0,81 (3H, t, J=7,3 Hz), 1.27mm(5H,m)of 1.35(2H,m)to 1.67(2H,m), 2.49 USD(3H,s)to 3.49(2H, t, J=7,6 Hz), 3,99(2N, K, J=6.9 Hz), the 5.51(2H,s), 6,46(1H, d, J=8.6 Hz), to 6.80 (1H, d, J=8,6 Hz), 7,11(1H, d, J=1.3 Hz), 7,68 (1H,CL), 7,79 (1H, d, J=6,4 Hz)to 8.12(1H,s)11,89 (1H,CL). so pl.: 190-191°C.

Example 60

Synthesis of 1-(2-chloro-4-ethoxybenzyl)-2-methyl-6-((4-methylbenzoyl)-sulfonylamino)benzimidazole (72)

In the same way as in Example 1, to obtain the desired benzimidazole (72), using carboxylic acid obtained in Example 30 was received; (4 methylbenzol)of the sulfonamide.

[Physico-chemical characteristics of compounds (72)]

1H=NMR (DMSO-d6that δ m.g): of 1.27 (3H, t, J=6,8gts), is 2.37 (3H, s)to 2.46(3H,s), 3,99(2N, K, J=6,8 Hz), of 5.50(2H,s), 6.42 per (1H, d, J=8,4 Hz), 6,79(1H, d, J=7.9 Hz), 7,10(1H,s), 7,40(2H, d, J=7.9 Hz), 7,71(2N,SHS), a 7.85(2H, d, J=7.9 Hz), 8,15 (1H,CL) so pl.: 254-256°C.

Example 31 to Obtain

<the First stage>

Getting ethyl -(acetylamino)-3-((2-chloro-4(methoxycarbonyl)benzyl)amino)benzoate

In the same way as in Example 1, Receipt, receive the requested connection (5,00 g) of ethyl 4-(acetylamino)-3-aminobenzoate (4.44 g), 2-chloro-4-(methoxycarbonyl)benzyl chloride (6.85 g) and potassium carbonate (5.5 g).

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): of 1.34(3H, t, J=7.0 Hz), 2,24(3H,s), 3,91(ZN,C), or 4.31(2H, K, J=7,0 Hz), 4,45-a 4.53(3H,m), of 7.36 (2H,CL), was 7.45(2H, t, J=7,1 Hz), 7,51(1H, d, J=8,3 Hz), 7,87 (1H, d, J=8.0 Hz), 8,07(1H,c).

<a Second phase>

Obtain 1-(2-chloro-4-(methoxycarbonyl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

In the same way as in Example 3, Obtain, receive the requested connection (2,40 g) of ethyl 4-(acetylamino)-3-((2-chloro-4-(methoxycarbonyl)benzyl)amino)benzoate (5,00 g).

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): to 1.38(3H, t, J=7,1 Hz), to 2.57(3H,c), 3,91(3H, s), 4,37(2N, K, J=7,1 Hz), of 5.48(2H,s), 6,46 (1H, d, J=8.1 Hz), of 7.75(1H, DD, J=8.1 and 1,4 Hz), to 7.77(1H, DD, J=8.6 Hz), to $ 7.91(1H,s), 8,01(1H, DD, J=8.4 and 1.2 Hz), 8,14(1H, d, J=1,GC).

<a Third step>

Obtaining 6-carboxy-1-(2-chloro-4-carboxybenzoyl)-2-methylbenzimidazole

In the same way as in Example 5, Obtain, receive the desired compound (0.36 g) of 1-(2-chloro-4-carboxybenzoyl)-6-(etoxycarbonyl) -2-methylbenzimidazole (0,60 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): of 2.51(3H,s)5,69(2H,s), 6,59 (1H, d, J=8.1 Hz), the 7.65(1H, d, J=8,4 Hz), 7,76(1H, q, j =8.1 Hz), 7,80(1H, d, J=8,4 Hz), 7,98 (1H,s), 7,99 1H,s), 13, 02 (2H,CL).

Example 61

Synthesis of 1-(2-chloro-4-(1-pentanesulfonate)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (73)

In the same way as in Example 1, to obtain the desired benzimidazole (73), using the carboxylic acid obtained in Example 31 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (73)]

1H=NMR (DMSO-d6that δ m.g): 0,77-0,86 (6N,m), 1,20-of 1.39 (8H,m), 1,63 is 1.70 (4H,m), 2.49 USD(3H,s), 3.43 points-to 3.52 (4H,m), 5,67(2H,s), is 6.54(1H, D, J=7.9 Hz), of 7.70(1H, D, J=8,4 Hz), 7,75 (H, d, J=8.1 Hz), 7,81(1H, d, J=8,5Hz), 8,10(1H,s)to 8.12(1H,s), 11,95 (1H,CL).

so pl.: 254-255°C.

Example 62

Synthesis of 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole (74)

In the same way as in Example 1, to obtain the desired benzimidazole (74)using carboxylic acid obtained in Example 19 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (74)]

1H=NMR (DMSO-d6that δ m.g): of 0.82(3H, t, J=7.2 Hz), 1,22-of 1.29 (2H,m), 1,31-of 1.39(2H,m), 1,62 is 1.70 (2H,m)of 2.50(3H,s), 3,50 (2H, t, J=7,7 Hz), to 5.57(2H,c), 6,37(1H, d, J=8,4 Hz), was 7.45 (1H, DD, J=8.4 and 2,0Hz), to 7.68(1H, d, J=8.5 Hz), 7,80(1H, DD, J=8.4 and 1,5Hz), 7,87(1H, d, J=2.0 Hz), 8,10(1H, d, J=1.3 Hz), up 11,86(1H,CL) so pl.: 222-223°C.

Example 63

Synthesis of 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (75)

In the same way as in Example 1, get 1-(2-the ENT-4-(trifluoromethyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (75) (186 mg) as white crystals from 6-carboxy-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-benzimidazole (175 mg), received in the Receipt Example 13, and (4 methylbenzol)sulfonamida (121 mg).

[Physico-chemical characteristics of the compound (75)]

1H=NMR (Dl3that δ m.g): to 2.42(3H,s), of 2.56(3H,s), 5,44(2H,s)6,40(1H, d, J=8 Hz), 7,28-7,33 (3H,m), 7,70-7,80 (4H,m), 7,98 (2H, d, J=18 Hz). Mass (ESI): m/z 420 (M-H).

Example 64

Synthesis of 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)benzimidazole (76)

In the same way as in Example 1, get 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(4-vinylbenzyl)sulfonylamino)benzimidazole (76) (190 mg) as white crystals from 6-carboxy-1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methylbenzimidazole (175 mg)obtained in Example 13 to Obtain, and (4-vinylbenzyl)sulfonamida, (121 mg).

[Physico-chemical characteristics of the compound (76)]

1H=NMR (CDCl3that δ m.g): of 2.56(3H,s), 5,42(2H,s), the 5.45(1H, d, J=10 Hz), of 5.89(1H, d, J=16 Hz), 6,38(1H, d, J=8 Hz), 6,74(1H, DD, J=16,10 Hz), 7,29(1H, d, J=8 Hz), 7,53(2H, d, J=8 Hz), 7,66-7,79(5H,m), with 8.05(2H, s, J=8 Hz).

Mass (ESI): m/z 532 (M-N).

Example 32 to Obtain

<the First stage>

Obtaining (R)-3-hydroxy-1-(p-toluensulfonate)Bhutan

After adding pyridine (100 ml) to (R)-1,3-butanediol (86,0 g), the solution is cooled to -25°C in nitrogen atmosphere. A solution of p-toluensulfonyl chloride (200 g) in pyridine (200 ml) slowly add dropwise at a temperature in the range from -20 to -10°C. the Mixture is stirred for 1 hour at a temperature of from -20 to -10° C. a Small amount of water added to the reaction mixture to stop the reaction, and the solution is extracted with toluene and water. The organic layer is washed with water, dried over sodium sulfate and concentrated under reduced pressure, obtaining (R)-3-hydroxy-1-(p-toluensulfonate)butane (209 g) as a light brown oil. Thus obtained oil is used in the next stage, as such without purification.

<a Second phase >

Obtaining (R)-2-methyloxirane

A mixture of potassium hydroxide (180 g) and water (18.0 g) is heated at 150°to melt the potassium hydroxide. There are added dropwise (R)-3-hydroxy-1-(p-toluensulfonate)butane (209 g). The liquid is isolated from the reaction is collected by distillation at normal pressure in the receiver. Thus obtained light-brown liquid is left to stand overnight. The supernatant is collected, dried with potassium hydroxide and distil under normal pressure, obtaining (R)-2-methyloxiran (16.6 g). The oil obtained is immediately subjected to the next stage.

<a Third step>

Obtaining (R)-N-t-butyl-4-hydroxy-1-pentanesulfonate

A solution of 2.0 M of diisopropylamide lithium in a mixture of heptane/tetrahydrofuran/ethylbenzene (100 ml) is slowly added dropwise to a solution of N-t-butylmethylamine (15.1 g) in tetrahydrofuran (100 ml) under nitrogen atmosphere, for 1 hour at 50 to -20° C. After stirring for 1 hour and cooling to -50°With, there are added dropwise (R)-1-methyloxiran (8,51 g). After stirring for 5 days at room temperature, the solution is extracted with water and ethyl acetate. The organic layer is washed with water, dried over sodium sulfate and concentrate under reduced pressure. The residue is purified column chromatography on silica gel (eluate: hexane/ethyl acetate=1/2)to give crude (R)-N-t-butyl-4-hydroxy-1-pentanesulfonate (6.6 g) as a solid. This solid is dissolved by adding chloroform, and concentrated under reduced pressure. Thus obtained residue is crystallized by adding diethyl ether. The crystals are separated by filtration and dried under reduced pressure, obtaining (R)-N-t-butyl-4-hydroxy-1-pentanesulfonate (3,39 g) as white crystals.

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): 1,22(3H, d, J=6,1 Hz), 1,38(N,C), 1,53-and 1.63 (3H,m), 1.85 to 2,02 (2H,m)to 3.09 (2H, t, J=7.8 Hz), 3,80-a 3.87 (1H,m), 4,10(1H,CL).

<Fourth stage>

Obtaining (R)-t-butyl-4-benzoyloxy-1-pentanesulfonate

In the same way as in the sixth stage of Example 16 Get get desired compound (2.35 g) as a yellow oil from (R)-N-t-butyl-4-hydroxy-1-pentanesulfonate (1.50 g), benzoic acid (1,72 g), N,N-carbonyldiimidazole (to 2.29 g) and databits is condecine (0,92 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 1,33(N,C)to 1.37(3H, d, J=6.3 Hz), 1.77 in-2,02 (4H,m), 3,03-3,13 (2H,m), was 4.02(1H,CL), 5,17-5,22 (1H,m), 7,44(2H, t, J=7.8 Hz), 7,56(1H, t, J=7.4 Hz), 8,03 (2H, DD, J=1,4 and 8.3 Hz).

Optical purity: 97.2 per cent (its conditions HPLC: CHIRALPAK AD, hexane/ethanol=9/1, 1.0 ml/min, 254 nm,40°).

<Fifth stage>

Obtaining (R)-4-benzoyloxy-1-pentanesulfonate

In the same way as in the seventh stage of Example 16 Get get desired compound (1,62 g) as a pale yellow oil from (R)-N-t-butyl-4-benzoyloxy-1-pentanesulfonate (2.15 g).

[Physico-chemical properties of Connection]

1H=NMR (Dl3that δ m.g): to 1.38(3H, d, J=6.3 Hz), 1.77 in-2,03 (4H, m), 3,12-up 3.22 (2H,m), and 4.68(2H,CL), 5,18-5,24 (1H,m), 7,44 (2H, t, J=7.9 Hz), 7,56(1H, t, J=7.5 Hz), 8,03(2H, DD, J=1.4 and 8.0 Hz).

<Sixth stage>

Obtaining the sodium salt of (R)-6-((4-benzoyl-1-pentane)-sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

N,N-dimethylformamide is added to 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (1.28 g)obtained in Example 14 to Obtain, and N,N-carbonyldiimidazole (0.84 g), and the solution is stirred for approximately 30 minutes at room temperature. Then add databaseconnect (0,78 g) and (R)-4-benzoyloxy-1-pentanesulfonate (1.40 g) and the solution stirred for 15 hours at 80°C. the Mixture will contentresult and there is added ethanol (15 ml) and water (7.5 ml). After adjusting the pH to 5 with diluted hydrochloric acid, the solution is extracted with ethyl acetate. An aqueous solution of sodium bicarbonate added to the organic layer. After stirring the mixture for about 1 hour at room temperature, precipitated crystals are collected by filtration, washed with water and ethyl acetate and dried under reduced pressure, obtaining the sodium salt of (R)-6-((4-benzoyl-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-

methylbenzimidazole (1,82 g) in the form of slightly yellowish-white crystals.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 1,24(3H, d, J=6,8gts), 1,48 is 1.75 (4H,m), 2,47(3H,s), of 3.07(2H, t, J=7.8 Hz), 5,00-5,08 (1H, m), the 5.51(2H,s), 7,42-7,47 (3H,m), to 7.61(1H, t, J=7.4 Hz), 7,71(1H, d, J=2.2 Hz), 7,81-the 7.85(2H,m), 7,89(2H, DD, J=1.2 and 8.1 Hz).

Example 65

Obtaining (R) -1-(2,4-dichlorobenzyl) -6-((4-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole (77)

Sodium hydroxide (0,335 g), water (15ml) and ethanol (10 ml) is added to the sodium salt of (R)-6-((4-benzoyl-1-pentane)-sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (1.70 g)obtained in Example 32 to Obtain, and the mixture is stirred for 3 hours at 70°C. the Reaction solution is cooled to room temperature, and the pH adjusted to 5 with hydrochloric acid. The precipitated crystals are collected by filtration, washed with a mixed solution of ethyl is pirta and water (1:1,8ml) and dried at about 80° With under reduced pressure, getting white crude crystals (1.06 g). After dissolving the crude crystals (1,00 g) in acetone (20 ml)there is added diethyl ether (20ml) and the solution is stirred for some time. The precipitated crystals are collected by filtration, washed with diethyl ether and dried under reduced pressure, obtaining (R)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane) -sulfonylamino)-2-methylbenzimidazole (0,76 g, 56%). Crystals (168 mg) was dissolved in a mixed solution of acetone and water (9:1,4 ml) at 60°C in an oil bath. Water (10ml) is added slowly dropwise over there, to precipitate crystals. The mixture is stirred for 1.5 hours, while the solution is slowly cooled to room temperature. The precipitated crystals are collected by filtration and dried, obtaining white crystals of (R)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)-sulfonylamino)-2-methylbenzimidazole (77) (144 mg).

[Physico-chemical characteristics of compounds (77)]

1H=NMR (DMSO-d6that δ m.g): 1,00(3H, d, J=6,1 Hz), of 1.35 to 1.48 (2H,m), 1,65-of 1.85(2H,m), 2.49 USD(3H,s), 3,51(2H, t, J=7.9 Hz), of 3.56(1H,m), of 4.44(1H,CL), 5,59(2H,s), 6,44(1H, d, J=8,4 Hz), 7,33(1H, DD, J=8.4 and and 2.1 Hz), 7,69(1H, d, J=8.5 Hz), 7,76(1H, d, J=2.1 Hz), 7,81(1H, DD, J=8.4 and 1.5 Hz), 8,11(1H, d, J=1.5 Hz), up 11,86(1H,CL).

IR (Nujol): 1682 cm-1TPL: to 194.6-194,9°C.

Optical purity: 97.9% of its (retention time: 23,3 min, high-performance liquid chromatography, column: CHIRALCEL OD250 mm × 4.6 mm ⊘the diameter of the filler particles: 20 μm, eluate: hexane/ethanol/methanol/triperoxonane acid=85/10/5/0,1, flow rate: 1.0 ml/min, column temperature: room temperature).

Example 33 to Obtain

<the First stage>

Obtain (S)-3-hydroxy-1-(p-toluensulfonate)Bhutan

In the same way as in the first stage of Example 32 Get get desired compound (77,5 g) as a pale brown oil of (S)-1,3-butanediol (30.0 g) and p-toluensulfonyl chloride (69,8 g). Thus obtained oil immediately subjected to the next stage.

<a Second phase>

Obtain (S)-2-methyloxirane

In the same way as in the second step of Example 32 Get get desired compound (5,28 g) as a colourless oil of potassium hydroxide (74,7 g), water (7.0 g) and (S)-3-hydroxy-1-(p-toluensulfonate)butane (75,C g).

[Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): to 1.42(3H, d, J=6,1 Hz), 2,28-is 2.37(1H,m), 2,67-by 2.73 (1H,m), 4,47-of 4.54 (1H,m), 4,60-of 4.67(1H,m), 4,96-5,04 (1H,m).

<a Third step>

Obtain (S)-N-t-butyl-4-hydroxy-1-pentanesulfonate

In the same way as in the third stage of Example 32 Get get desired compound (1.98 g) as white crystals from N-t-butylmethylamine (9,86 g), a solution of 2.0 M of diisopropylamide lithium in a mixture of heptane/tetrahydrofuran/ethylbenzene (ml) and (S)-1-enthusiasm is cetana (4,54 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 1,22 (3H, d, J=6.3 Hz), l,37(9H,c), and 1.54-of 1.62 (2H,m), 1,64-of 1.73 (1H,CL), 1.85 to 2,02 (2H,m), is 3.08 (2H, t, J=7,7 Hz), 3,80-a 3.87(1H,m), 4,32(1H,CL).

<Fourth stage>

Obtain (S)-N-t-butyl-4-benzoyloxy-1-pentanesulfonate

In the same way as in the fourth step of Example 32 to Obtain, get the crude product as a yellow oil (to 2.29 g) of (S)-N-t-butyl-4-hydroxy-1-pentanesulfonate (1.50 g), benzoic acid (1,72 g), N,N'-carbonyldiimidazole (to 2.29 g) and databaseconnect (2.15 g). This product is dissolved in hot t-butyl methyl ether (4ml) and to this solution was added hexane (10ml) for crystallization. The crystals are collected by filtration, washed with hexane and dried, obtaining the desired compound (1.63 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 1,33 (N,C)to 1.37(3H, d, J=6.2 Hz), 1.77 in for 2.01(4H,m), 3,03-of 3.12(2H,m)4,06(1H,CL), 5,16-5,23 (1H,m), 7,44(2H, t, J=7,6 Hz), 7,55(1H, t, J=7.5 Hz), 8,03(2H, DD, J=8,1 and 0.8 Hz).

Optical purity; to 99.6% (HPLC: CHIRALPAK AD, hexane/ethanol=9/1, 1.0 ml/min, 254 nm, 40°).

<Fifth stage>

Obtain (S)-4-benzoyloxy-1-pentanesulfonate

In the same way as in the fifth stage of Example 32 Get get desired compound (1.28 g) as a pale yellow oil from (S)-N-t-butyl-4-benzoyl the si-1-pentanesulfonate (1.63 g).

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): to 1.38 (3H, d, J=6.2 Hz), 1,78 e 2.06(4H,m), 3,13-3,24 (2H,m), and 4.68(2H,CL), 5,18-5,24 (1H, m), 7,44(2H, t, J=7.9 Hz), 7,56(1H, t, J=7.4 Hz), 8,03(2H, DD, J=7.8 and 1.4 Hz).

<Sixth stage>

Obtain (S)-6-((4-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

N,N-dimethylformamide is added to 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (1.26 g)as obtained in Example 14 to Obtain, and N, N'-carbonyldiimidazole (0,80 g), and the mixture is stirred for approximately 30 minutes at room temperature. Then add databaseconnect (0.75 g) and (S)-4-benzoyloxy-1-pentanesulfonate (1.28 g) and the solution stirred for 14 hours at 90°C. the Mixture is concentrated and there is added ethanol (15 ml) and water (7,5ml). After adjusting the pH to 5 with diluted hydrochloric acid, the mixture is stirred for about 1 hour at room temperature. The precipitated crystals are collected by filtration, washed with a mixed solution of ethanol and water (1/1) and dried under reduced pressure, obtaining (S)-6-((4-benzoyloxy-1-pentane) sulfonylamino) -1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (1,91 g) as white crystals. This connection is immediately subjected to the next stage.

Example 66

Obtain (S)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)-sulfonylamino)-2-m is diversitate (78)

In the same manner as in Example 65, receive untreated

crystals (1.01 g) of (S)-6-((4-benzoyloxy-1-pentane)-sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole(1.88 g)as obtained in Example 33 to Obtain, sodium hydroxide (0,391 g), water (10ml) and ethanol (10ml). Crystals (0,72 g) dissolved in methanol (15 ml) at 70°and the mixture is cooled to room temperature under stirring. The precipitated crystals are collected by filtration and dried under reduced pressure, getting white crystals (mg). The crystals are dissolved in a mixed solution of acetone and water (9/1,8 ml) at 60°C. There is slowly added dropwise water (20 ml) to precipitate crystals. The mixture is stirred for 2 hours while the solution allow to slowly cool to room temperature. The precipitated crystals are collected by filtration and dried, obtaining white crystals of (S)-1-(2,4-dichlorobenzyl)-6-(4-hydroxy-1-pentanesulfonate)-2-methylbenzimidazole (78) (218 mg).

[Physico-chemical characteristics of compounds (78)]

1H=NMR (DMSO-d6that δ m.g): 1,00(3H, d, J=6,1 Hz), of 1.35 to 1.47 (2H,m), 1,65-of 1.85(2H,m), 2.49 USD(3H,s), 3,50(2H, t, J=7.9 Hz), of 3.56(1H,m), 4,43(1H,CL), 5,59(2H,s), 6,44(1H, d, J=8,4 Hz), 7,32(1H, DD, J=8.4 and and 2,0Hz), to 7.68(1H, d, J=8.5 Hz), of 7.75(1H, d, J=2.0 Hz), 7,81(1H, DD, J=8.4 and 1.0 Hz), 8,11(1H,s), 11,85 (1H, CL). IR (Nujol): 1682 cm-1.

so pl.: 195,0-195,8°C.

Optical purity: 99,7% (retention time: 20,5 min, Vysokoe the objective liquid chromatography, column: CHIRALCEL OD 250 mm ×4.6 mm ⊘the diameter of the filler particles: 20 μm, eluate: hexane/ethanol/methanol/triperoxonane acid=85/10/5/0,1, flow rate: 1.0 ml/min, column temperature: room temperature).

Example 34 to Obtain

Obtaining optically active 6-((2-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

6-((2-Benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole (mg)obtained in Example 15 to Obtain, dissolved in ethyl alcohol (ml) and subjected to high performance liquid chromatography (column: CHIRALPAK AD 250 mm ×10 mm ⊘the diameter of the filler particles: 20 μm, eluate: hexane/ethanol/triperoxonane acid=50/50/0,1, flow rate: 3.0 ml/min, column temperature: 40°C, volume of injected sample: 20 mg/1 ml × RS)to obtain an independently both of the optical isomers. The fraction containing the isomer with shorter retention time (420 ml), concentrated to about 1/2 volume. There is added chloroform (200 ml) and water (400 ml) and then added with stirring saturated aqueous sodium bicarbonate solution (10 ml)to bring the pH of the aqueous layer to 7. Then add IN hydrochloric acid (3 ml). The organic layer was separated, washed with water (200 ml), dried over sodium sulfate and concentrate under reduced pressure. Thus, the floor shall indicate the optically active isomer of 6-((2-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole with a shorter retention time (mg, retention time: 10,9 min) with an optical purity of 100% EE.

The fraction containing the isomer with a longer retention time (800ml), treated in the same manner as described above, and are optically active isomer of 6-((2-benzyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole with longer retention time (273 mg, retention time: 19,1 min) with an optical purity of 100% EE. These connections are immediately subjected to the next stage.

Example 67

Obtaining optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole with longer retention time (79)

Methanol (2 ml) and 10% aqueous sodium hydroxide solution (0.2 ml) are added to the optically active isomer of 6-(2-benzoyloxy-1-pentane)sulfonylamino-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole with a shorter retention time, as obtained in Example 34 to Obtain (277 mg)and the mixture stirred for 90 minutes at room temperature. Next there is added 10% aqueous sodium hydroxide solution (0,36 ml) and stirring is continued for 50 minutes when heated at 50°C. the Solution allow to cool for 70 minutes to room temperature and added IN hydrochloric acid (1.4 ml)and the resulting solution is cooled with ice. The precipitated crystals are collected by filtration, about what to see three times with water (2 ml) and twice with chloroform (1 ml) and dried by heating under reduced pressure, receiving optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole with a longer retention time on CHIRALPAK AD (79) (143 mg).

[Physico-chemical characteristics of compounds (79)]

1H=NMR (DMSO-d6that δ m.g): 0,81 (3H, t, J=7.2 Hz), 1,26 of 1.46 (4H,m), 2.49 USD(3H,s), 3,49(1H, DD, J=14,4 and 4.1 Hz)and 3.59(1H, DD, J=14.4 and 7.2 Hz), 3,95(1H,CL), the 4.90(1H,CL), to 5.57(2H,s), 6.42 per(1H, d, J=8,4 Hz), 7,32(1H, d, J=8,4 Hz), to 7.67(1H, d, J=8,4 Hz), of 7.75(1H,s), 8,79(1H, d, J=8,4 Hz), of 8.09(1H,s), 11,77 (1H,CL) so pl.: 183-185°C.

Optical purity: 100% (retention time: 22,3 min, high-performance liquid chromatography, column: CHIRALPAK AD 250 mm × 4.6 mm ⊘the diameter of the filler particles: 20 μm, eluate: hexane/ethanol/isopropanol/triperoxonane acid=85/10/5/0,1, flow rate: 1.0 ml/min, column temperature: room temperature).

Example 68

Obtaining optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole with a shorter retention time (80)

In the same manner as in Example 67, are optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)-sulfonylamino)-2-methylbenzimidazole with a shorter retention time on CHIRALPAK AD (80) (mg) of the optically active isomer of 6-((2-benzoyloxy-1-pentane)sulfonylamino) -1-(2,4-dichlorobenzyl)-2-methylbenzimidazole with a longer retention time, as is Holocene in Example 34 to Obtain (mg).

[Physico-chemical characteristics of compounds (80)]

1H=NMR (DMSO-d6that δ m.g): 0,81 (3H, t, J=7.2 Hz), 1,26 of 1.46 (4H,m), 2.49 USD(3H,s), 3,49(1H, DD, J=14,4 and 4.1 Hz)and 3.59(1H, DD, J=14.4 and 7.2 Hz), 3,95(1H,CL), the 4.90(1H,CL), to 5.57(2H,s), 6.42 per(1H, d, J=8,4 Hz), 7,32(1H, d, J=8,4 Hz), to 7.67(1H, d, J=8,4 Hz), of 7.75(1H,s), 8,79(1H, d, J=8,4 Hz), of 8.09(1H,s), 11,77(1H,CL) so pl.: 187-188°C.

Optical purity: 100% EE (retention time: 17,2min, high performance liquid chromatography, column: CHIRALPAK AD 250 mm × 4.6 mm ⊘the diameter of the filler particles: industry is 20 µm, eluate: hexane/ethanol/isopropanol/triperoxonane acid=85/10 /5/0,1, flow rate: 1.0 ml/min, column temperature: room temperature).

Example 35 to Obtain

Obtaining optically active 3-benzoyloxy-1-pentanesulfonate. 3-Benzoyloxy-1-pentanesulfonate (1.50 g)obtained in the third stage of Example 17 Getting, dissolved in a mixed solution of hexane and isopropyl alcohol (7/3,50ml). The solution is subjected to high performance liquid chromatography (column: CHIRALPAK AS 250 mm × 10 mm ⊘the diameter of the filler particles: 20 μm, eluate: hexane/I-propanol=7/3, flow rate: 5.0 ml/min, column temperature: 40°C, volume of injected sample: 1.0 to 1.2 ml × 22 times)to collect independently both optical isomers. After concentration of each fraction, there was added toluene (5 ml × 2 times). Faction again concentrated under reduced pressure is I. So, are optically active isomer of 3-benzoyloxy-1-pentanesulfonate with a shorter retention time (350 mg, retention time: 10,7 min optical purity: 99,08% EE)and isomer with a longer retention time (350 mg, retention time: 16,2 min optical purity: 99,57% EE). These connections are immediately subjected to the next stage.

Example 36 to Obtain

Obtaining the sodium salt of optically active 6-((3-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

N,N'-carbonyldiimidazole (0,209 g) are added to N,N'-dimethylformamide solution (2 ml), 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (in 0.288 g)as obtained in Example 14 to Obtain, and the mixture is stirred for 40 minutes at room temperature. To this mixture isomer

optically active 3-benzoyloxy-1-pentane sulfonamida with a shorter retention time (0,350 g)as obtained in Example 35 production, databaseconnect (0,196 g), and the solution is stirred for: night at 80°C. the Solvent is removed under reduced pressure and to the residue is added methanol (3 ml) and water (3 ml)to make the solution homogeneous. Then, pH was adjusted to about 6 with hydrochloric acid.

After adding water, the solution extracted twice with ethyl acetate and the organic layer concentrated under reduced Yes the tion. To the obtained residue is added ethyl acetate (5 ml) and saturated aqueous sodium bicarbonate solution (4ml). After stirring for 1 hour, the precipitated solid is collected by filtration, washed with water and ethyl acetate and dried, obtaining the sodium salt of optically active 6-((3-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl) -2-methylbenzimidazole (0,497 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): corresponds to the range of its racemate.

Example 37 to Obtain

Obtaining the sodium salt of optically active 6-((3-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole

In the same manner as in Example 36 to Obtain, receive sodium salt of optically active 6-((3-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0,436 g) of 6-carboxy-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (in 0.288 g)obtained in Example 14 to Obtain, N,N'-carbonyldiimidazole (0,209 g), optically active isomer of 3-benzoyloxy-1-pentane sulfonamida with longer retention time (0,305 g)obtained in Example 35 to Obtain, and databaseconnect (0,196 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): corresponds to the range of its racemate.

Example 69

Obtaining optical and active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylamino-2-methylbenzimidazole with longer retention time (81)

The mixture of sodium salts of optically active 6-((3-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole (0.400 g)obtained in Example 36 to Obtain, sodium hydroxide (0,053 g), water (1.7 ml) and methanol (2.7 ml) is stirred for 6.5 hours at 60°C. the Reaction solution is cooled to room temperature, and the pH was adjusted to 4-5 by addition of IN hydrochloric acid, thereby causing the precipitation of an oily material. After removal of the supernatant, the oily substance was washed with water (1 ml). To the oily substance, add water (1.7 ml) and methanol (6.5 ml) and heated at a temperature of education phlegmy to make the solution homogeneous. The solution is cooled to room temperature, precipitated crystals are collected by filtration, washed (methanol/water =3/1, 18 ml) and dried. To the thus obtained crystals add water (1,7ml) and methanol (6,5ml) and heated at a temperature of education phlegmy to make the solution homogeneous. The solution is cooled to room temperature and the precipitated crystals are collected by filtration, washed (methanol/water=3/1/10 ml) and dried. So, are optically active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylamino-2-methylbenzimidazole with a longer retention time on CHIRALCEL OD-RH (81) (mg) in the form of white crystals.

[Physico-helices the second connection feature (81)]

1H=NMR (DMSO-d6that δ m.g): corresponds to the range of its racemate, so pl.: 191,5-192,8°C.

Optical purity: 98,7% (retention time: 45,2min, high performance liquid chromatography, column: CHIRALCEL OD-RH, 150 mm × 4.6 mm ⊘the diameter of the filler particles: industry is 20 µm, the eluate; 0.6 M aqueous solution of hexaflurophosphate potassium (pH adjusted to 2.0 using a mixture of 85% phosphoric acid/acetonitrile=7/3, flow rate: 0,7ml/min, column temperature: 10°).

Example 70

Obtaining optically active 1-(2,4-dichlorobenzyl)-6-(3-hydroxy-1-pentane)sulfonylamino-2-methylbenzimidazole with a shorter retention time (82)

In the same manner as in Example 69, receive the desired compound with a shorter retention time on CHIRALCEL OD-RH (82) (118 mg) as white crystals of the sodium salt of optically active 6-((3-benzoyloxy-1-pentane)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methyl-benzimidazole (0.400 g)obtained in Example 37 to Obtain.

[Physico-chemical characteristics of compounds (82)]

1H=NMR (DMSO-d6that δ m.g): corresponds to the range of its racemate.

so pl.: 192,8-193, 6°C.

Optical purity: > 99% EE (retention time: 36,6 min,

high-performance liquid chromatography, column:

CHIRALCEL OD-RH, 150 mm × 4.6 mm ⊘the diameter of the filler particles: 20 μm, eluate: 0,1M aqueous solution hexaf is orthostate potassium (pH adjusted to 2/0 using a mixture of 85% phosphoric acid/acetonitrile=7/3, flow rate: 0.7 ml/min, column temperature: 10°).

Example 71

Obtain 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-((4-methylbenzoyl)sulfonylamino)benzimidazole (83)

A mixture of 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (0,082 g)obtained in Example 46, acetic acid (1 ml), ethyl acetate (4 ml) and platinum oxide (0.015 g) is stirred for 3 hours in hydrogen atmosphere. The solid is separated by filtration, the filtrate concentrated and purified by thin-layer chromatography on silica gel, obtaining 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-((4-methylbenzoyl)sulfonylamino)benzimidazole (83) (0,080 g).

[Physico-chemical characteristics of compounds (83)]

1H=NMR (DMSO-d6that δ m.g): of 0.82(3H,t), 1,23(6N,m)of 1.50(2H,m), is 2.37(3H,s)to 2.46(3H,s), 2,52(2H,m), of 5.53(2H,s), 6,33(1H,m),? 7.04 baby mortality(1H, t, J=8,2 Hz), 7,41(3H,m), 7,63(1H, d, J=8,2 Hz), of 7.70(1H, d, J=8.5 Hz), the 7.85(2H, d, J=8,3 Hz), of 8.04(1H, s), 12,29(1H,CL).

IR (Nujol): 1619 cm-1.

so pl.: 195-196,5°C.

Example 72

Obtain 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-6-(pentacarbonyliron)benzimidazole (84)

In the same manner as in Example 71, receive the requested connection (0,064 mg) of 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methyl-6-(pentacarbonyliron)benzimidazole (0,093 g)obtained in Example 45.

[Physico-chemical characteristics of compounds (84)]

1H=NMR (DMSO-d6that δm.g): 0,80(6N,m), 1,19-of 1.39 (10H, m)of 1.50(2H,m)to 1.67(2H,m), 2,48(3H,s), 2,53(2H,m), of 3.48(2H,m), of 5.55(2H,s), 6,36(1H, d, J=8.0 Hz), 7,05(1H, d, J=8.0 Hz), 7,39 (1H,s), to 7.67(1H, d, J=8.5 Hz), 7,79(1H, d, J=8.5 Hz), 8,10 (1H,s), up 11,86(1H, CL). IR (Nujol): 1669 cm-1so pl.: 167-169°C.

Example 38 to Obtain

<the First stage>

Obtain 1-(2-chloro-4-(thiophene-2-yl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

1-(2-Chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (1,00 g)obtained in Example 23 To Obtain, thiophene-2-borate (0.34 g), tetrakis(triphenylphosphine)palladium (IV) (0.06 g), 2M aqueous sodium carbonate solution (2.2 ml), toluene (3 ml) and ethanol (1 ml) are mixed and heated at a temperature of education phlegmy for 2.5 hours. Solution allow to cool to room temperature. After adding toluene (50 ml) and water (50 ml), the solution is filtered through celite. The organic layer is separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting oil is purified by recrystallization from a mixture of ethanol/water (15ml/15ml)to give the desired 1-(2-chloro-4-(thiophene-2-yl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,60 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): of 1.28(3H, t, J=7.0 Hz), of 2.54(3H,c), 4.26 deaths(2N, K, J=7,0 Hz), 5,63(2H,s), is 6.61(1H, d, J=8, 0 Hz), 7,13 (1H, d,J=4,0 Hz), 7,49(1H, d, J=8.0 Hz), EUR 7.57(1H, d, J=4, 2 Hz), 7,66 (1H, d, J=8,4 Hz), 7,81(1H, d, J=8,4 Hz), to 7.84 (1H,s), 8, 01 (1H,s).

<a Second phase>

Getting carboxy-1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methylbenzimidazole

1-(2-chloro-4-(thiophene-2-yl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0.6 g), 10% aqueous sodium hydroxide solution (2 ml) and ethanol (5 ml) are mixed and heated at a temperature of education phlegmy within 15 minutes.

After the solution given the opportunity to cool to room temperature, insoluble matter is removed by filtration through celite, the filtrate is brought to pH 6 IN hydrochloric acid (4 ml). The precipitated crystals are collected by filtration, washed with 50% aqueous ethanol and dried under reduced pressure, obtaining a desired compound, 6-carboxy-1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methylbenzimidazole (0,208 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 2,53(3H,s), 5,61(2H,s), 6,56(1H, d, J=8.1 Hz), 7,13(1H,m)to 7.50(1H, DD, J=1.8 and 8.1 Hz), 7,58(2H,m), to 7.61(1H, d, J=8,4 Hz), 7,80(1H, DD, J=1.4 and 8,4 Hz), to 7.84 (1H, d, J=1,8 Hz), of 7.97(1H,s).

Example 73

Obtain 1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methyl-6-

((4-methylbenzoyl)sulfonylamino)benzimidazole (85)

In the same way as in Example 1, to obtain the desired benzimidazole (85) of the carboxylic acid obtained in Example 38 was received; (4 methylbenzol)sulfonamida.

[Physico-chemical characteristics of the compound (85)]

1H=NMR (DMSO-d6that δ m.g); a 2.36(3H,s), 2.49 USD(3H,s)5,59(2H,s), of 6.45(1H, d, J=8.1 Hz), 7,13(1H,m), 7,38(2H, d, J=8,2 Hz), of 7.48 (1H, d, J=8,2 Hz), 7,58(2H,m), of 7.64(1H, d, J=8,5 Hz), 71 (1H, d, J=8.5 Hz), the 7.85(3H,m), 8,07(1H,s), 12,32 (1H, CL).

IR (Nujol): 1698 cm-1so pl.: 207,5-208,5°C.

Example 74

Obtain 1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (86)

In the same way as in Example 1, to obtain the desired benzimidazole (86) of the carboxylic acid obtained in Example 38 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of compounds (86)]

1H=NMR (DMSO-d6that δ m.g): of 0.79(3H, t, J=7,3 Hz), 1,24(2H,m)of 1.33(2H,m)of 1.66(2H,m), 2,52(3H,s), of 3.48 (2H, t, J=7,7 Hz), 5,61(2H,s),6.48 in(1H, d, J=8,2 Hz), 7,13(1H,m), 7,49(1H, d, J=8.1 Hz), 7,58(2H,m), 7,68(1H, d, J=8.5 Hz), 7,80(1H, d, J=8,4 Hz), 7,86(1H,s)to 8.12(1H,s), 11,88 (1H,CL). IR (Nujol): 1684 cm-1. so pl.: 213-216°C.

Example 39 to Obtain

<the First stage>

Obtain 1-(2-chloro-4-(furan-2-yl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

1-(2-Chloro-4-iodobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (1,00 g)obtained in Example 23 To Obtain, furan-2-boronic acid (0,30 g), tetrakis(triphenylphosphine)palladium (IV) (0.06 g), 2M aqueous sodium carbonate solution (2.2 ml), toluene (3 ml) and ethanol (1 ml) are mixed and heated at a temperature of education phlegmy for 2.5 hours. Solution allow to cool to room temperature and extracted with toluene (50 ml) and water (50 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. Obtained in this mod is the way the oil is recrystallized from a mixture of ethanol/water (20 ml/20 ml), getting the desired compound, 1-(2-chloro-4-(furan-2-yl)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0.73 g). [Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): of 1.27(3H, t, J=7,1 Hz), 2,53(3H,s), 4.26 deaths(2N, K, J=7,1 Hz), 5,63(2H,s), 6,59(1H, DD, J=3.3 and 1.8 Hz), of 6.65(1H, d, J=8.1 Hz), 7,05(1H, d, J=3.2 Hz), to 7.50 (1H, d, J=8.1 Hz), the 7.65(1H, d, J=8,4 Hz), of 7.75(1H,s), 7,80 (1H, d, J=8,4 Hz), 7,86(1H,s), of 8.00(1H,s).

<a Second phase>

Obtaining 6-carboxy-1-(2-chloro-4-(furan-2-yl)benzyl)-2-methylbenzimidazole

1-(2-Chloro-4-(thiophene-2-yl)benzyl-6-(etoxycarbonyl)-2-methylbenzimidazole (0.73 g, 1,mol), 10% aqueous sodium hydroxide solution (2 ml) and ethanol (15 ml) are mixed and heated at a temperature of education phlegmy for 1.5 hours.

Solution allow to cool to room temperature. the pH of the solution adjusted to rn IN hydrochloric acid (about 6 ml). After adding water (10 ml), the precipitated crystals are collected by filtration, washed with 50% aqueous ethanol and dried under reduced pressure, obtaining the required 6-carboxy-1-(2-chloro-4-(furan-2-yl)benzyl)-2-methylbenzimidazole (0,305 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 2,53(3H,s), 5,62(2H,s), 6,59(1H, m), 6,62(1H, d, 8.1 Hz), 7,05(1H, d, J=3.3 Hz), 7,54(1H, d, J=8.0 Hz), to 7.64(1H, d, J=8,4 Hz), of 7.75(1H,s), 7,80(1H, d, J=8,4 Hz), 7,86(1H,s), to 7.99(1H,s)12,70 (1H,CL).

Example 75

Obtain 1-(2-chloro-4-(furan-2-yl)benzyl)-2-methyl-6-(1-PE is consultonline)benzimidazole (87)

In the same way as in Example 1, to obtain the desired benzimidazole (87) of the carboxylic acid obtained in Example 39 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of compounds (87)]

1H=NMR (DMSO-d6that δ m.g): of 0.79(3H, t, J=7,3 Hz), 1,24(2H,m)of 1.35(2H,m)of 1.66(2H,m), of 2.51(3H,s), of 3.48(2H, t, J=7,7 Hz), the ceiling of 5.60(2H,s), 6,53(1H, d, J=8,2 Hz), 6,59(1H,m), 7,05(1H, d, J=3.3 Hz), 7,54(1H, d, J=8.1 Hz), to 7.68(1H, d, J=8.6 Hz), 7,76 (1H, c), 7,80(1H, d, J=8,4 Hz), 7,88(1H,s)to 8.12(1H,s), 11,90 (1H,CL).

IR (Nujol); 1690 cm-1. so pl.: 221,8-222,7°C

Example 76

Obtain 1-(2-chloro-4-(furan-2-yl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (88)

In the same way as in Example 1, to obtain the desired benzimidazole (88) of the carboxylic acid obtained in Example 39 to Obtain and (4-methylbenzoyl)sulfonamida.

[Physico-chemical characteristics of the compound (88)]

1H=NMR (DMSO-d6that δ m.g): a 2.36(3H,s)of 2.50(3H,s)5,59(2H,s), of 6.50(1H, d, J=8,2 Hz), 6,60(1H,m), 7,05(1H, d, J=3.2 Hz), 7,39 (2H, d, J=8.0 Hz), 7,53(1H, d, J=8.1 Hz), to 7.64(1H, d, J=8.5 Hz), 7,72(1H, d, J=8,4 Hz), 7,76(1H,s), a 7.85(2H, d, J=8,2 Hz), 7,87(1H,s), 8,07(1H,s), 12,31 (1H,CL) IR (Nujol): 1614 cm-1so pl.: 154,2-155,9°C.

Example 77

Obtain 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole (89)

In the same way as in Example 1, to obtain the desired benzimidazole (89) of the carboxylic acid obtained in Example 23 To Obtain, and (4-IU is albenza)sulfonamida.

[Physico-chemical characteristics of compounds (89)]

1H=NMR (DMSO-d6that δ m.g): was 2.34(3H,s), 2,47(3H,s), 5,61(2H,s), 6,44(1H, d, J=8.1 Hz), 7,37-7,44(6N,m), 7,52-EUR 7.57(2H, m), of 7.64 (1H, d, J=8,2 Hz), 7,72(1H, d, J=7,1 Hz), to 7.77(1H, d, J=1.7 Hz), the 7.85(2H, d, J=8,3 Hz), of 8.06(1H,s). IR (Nujol): 1682 cm-1. so pl.: 222,4-228,5°C.

Example 78

Obtain 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((E)-1-penten-1-sulfonylamino)benzimidazole (90)

In the same way as in Example 1, to obtain the desired benzimidazole (90) of the carboxylic acid obtained in Example 23 To Obtain, and 1-pentane-1-sulfonamida.

[Physico-chemical characteristics of the compound (90)]

1H=NMR (DMSO-d6that δ m.g): 0,85(3H, d, J=7,0 Hz), 1,43(2N, K, J=7,3 Hz), 2,22(2H,m), 5,62(2H,s), 6.48 in(1H, d, J=8,3 Hz), 6,76 (1H, d, J=14,9 Hz), for 6.81-6.89 in(1H,m), 7,39 was 7.45 (4H,m), 7,52-7,58(2H,m), to 7.67(1H, d, J=3,9 Hz), 7,78(2H,m), 8,10(1H,s), 11, 97 (1H,CL).

IR (Nujol): 1673 cm-1.

so pl.: 242,7-244,0°C.

Example 79

Obtain 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)benzimidazole (91)

In the same way as in Example 1, to obtain the desired benzimidazole (91) of the carboxylic acid obtained in Example 23 To Obtain, and (4-vinylbenzyl)sulfonamida.

[Physico-chemical characteristics of the compound (91)]

1H=NMR (DMSO-d6that δ m.g): 5,44(1H, d, J=11,0 Hz), 5,62(2H,c), of 5.99(1H, d, J=17,7 Hz), 6,44(1H, d, J=8.1 Hz), to 6.80(1H, DD, J=11,0, 17,GC), 7,38 was 7.45(4H,m), 7,52-7,56(2H,m), 7,62-7,74 (4H,m), and 7.7(1H, d, J=1.6 Hz), to 7.93(2H, d, J=8,4 Hz), 8,07 (1H,s), KZT 12.39(1H,CL). IR (Nujol): 1694 cm-1. so pl.: 237,5-238,5°C.

Example 80

Obtain 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((E)-2-

phenylacetylcarbinol)benzimidazole (92)

In the same way as in Example 1, to obtain the desired benzimidazole (92) of the carboxylic acid obtained in Example 23 To Obtain, and ((E)-2-phenylethenyl)sulfonamida.

[Physico-chemical characteristics of the compound (92)]

1H=NMR (DMSO-d6that δ m.g): 5,62(2H,s), of 6.45(1H, d, J=8,2 Hz), 7,38-7,47 (7H,m), 7,49(1H, d, J=15,GC), 7,53-7,58(2H,m), 7,63(1H, d, J=15,5 Hz), to 7.67(1H, d, J=8.5 Hz), 7,73-to 7.77(2H,m), 7,78(1H,s), 7,80(1H, d, J=8.5 Hz), 8,13(1H, s), 12,17(1H,CL). IR (Nujol): 1672 cm-1so pl.: 239,1-241,8°C.

Example 81

Obtain 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-6-((4-vinylbenzyl)sulfonylamino)-2-methylbenzimidazole (93)

In the same way as in Example 1, to obtain the desired benzimidazole (93) of the carboxylic acid obtained in Example 24 To Obtain, and (4-vinylbenzyl)sulfonamida.

[Physico-chemical characteristics of compounds (93)]

1H=NMR (DMSO-d6that δ m.g): of 5.39(1H, d, J=11,0 Hz), to 5.57(2H,c), 5,95(1H, d, J=17.6 Hz), of 6.45(1H, D, J=8.1 Hz), 6,77(1H, DD, J=a 17.6 and 10.9 Hz), 7,19(1H, d, J=6,5 Hz), 7,22-to 7.32(2H, m), of 7.36(2H, t, J=7,6 Hz), 7,42(1H, D, J=8.0 Hz), 7,54-to 7.64(5H, m), 7,74(1H, d, J=8,4 Hz), 7,81(1H,s), 7,89 (2H, d, J=8,3 Hz), 8,02 (1H,s). IR (Nujol): 1682 cm-1.

so pl.: 142,5-144,5°C.

Example 82

Obtain 1-(2-chloro-4-((E)-2-phenylethenyl)b is nil)-6-((E)-1-penten-1-sulfonylamino)-2-methylbenzimidazole (94)

In the same way as in Example 1, to obtain the desired benzimidazole (94) of the carboxylic acid obtained in Example 24 To Obtain, and 1-penten-1-sulfonamida.

[Physico-chemical characteristics of compounds (94)]

1H=NMR (DMSO-d6that δ m.g): 0,84(3H, t, J=7,3 Hz), 1,37-of 1.44 (2H,m), of 2.21(2H, K, J=6,8 Hz), of 2.51(3H,c), 5,59(2H,s), 6,46 (1H, d, J=8.1 Hz), 6.75 in(1H, d, J=15.2 Hz), 6,80-6,87(1H,m), 7,21(1H, d, J=16.4 Hz), 7,24-7,37(4H,m), the 7.43(1H, DD, J=8,2 1,5Hz), EUR 7.57(1H, d, J=7,4 Hz), 7,66(1H, d, J=8.5 Hz), 7,78 (1H, DD, J=8.4 and 1,5Hz), 7,83(1H, d, J=1.6 Hz), of 8.09(2H, d, J=1,4 Hz), 12,04(1H,CL). IR (Nujol): 1674 cmof -1so pl.: 224,5-227,5°C.

Example 83

Obtain 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol)benzimidazole 95)

In the same way as in Example 1, to obtain the desired benzimidazole (95) of the carboxylic acid obtained in Example 24 To Obtain, and ((E)-2-phenylethenyl)sulfonamida.

[Physico-chemical characteristics of compounds (95)]

1H=NMR (DMSO-d6that δ m.g): 2,50(3H,s)5,59(2H,s), 6,46(1H, d, J=8.1 Hz), 7,20(1H, d, J=16.4 Hz), 7,25-to 7.32 (2H, m), of 7.36(2H, t, J=7,7 Hz), 7,41 was 7.45(4H,m), 7,49(1H, d, J=15,4 Hz), EUR 7.57 (2H, d, J=7.9 Hz), a 7.62(1H, d, J=15,5 Hz), 7,66(1H, d, J=8.5 Hz), 7,74(2H, d, J=7.8 Hz), 7,80(1H, d, J=8.5 Hz), 7,82 (1H,s), 8,13(1H,s), 12,1(1H,CL). IR (Nujol): 1672 cm-1so pl.: 249,9-251,4°C.

Example 40 Get

<the First stage>

Obtain 1-(2-chloro-4-hydroxybenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

Ethyl 4-(acetylamino)-3-aminobenzoate (6,34 is), 4-acetoxy-2-Chlorobenzyl bromide (14.0 g), potassium carbonate (5,12 g) and sodium iodide (1.28 g) is added to ethyl acetate (35 ml) and water (13 ml) and the mixture is stirred for 15 hours at 70°C. the Organic layer was separated, washed with water and concentrated under reduced pressure. To the oily residue is added ethanol (30ml) and 35% hydrochloric acid (3.2 g), and the mixture is stirred for 3 hours at 70°C. After extraction of the reaction solution with ethyl acetate and water, the organic layer is separated and concentrated. The residue is crystallized by adding ethanol. Obtained by filtering the crystals are dried, obtaining 1-(2-chloro-4-hydroxybenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (1,53 g).

Separately, the filtrate concentrated and add ethanol to carry out crystallization. The crystals obtained by filtration, dried, obtaining 1-(2-chloro-4-hydroxybenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (4.72 in). [Physico-chemical characteristics of connection]

1H=NMR (CDCl3that δ m.g): of 1.39 (3H, t, J=7 Hz), 2,50(3H,s), 4,37 (2N, K, J=7,1 Hz), lower than the 5.37(2H,s), 6,14(1H, d, J=8,4 Hz), 6,47 (1H, DD, J=8.5 and 2,2 Hz), 7,01(1H, d, J=2.2 Hz), to 7.67(1H, d, J=8,4 Hz), of 7.96(1H, d, J=8,8 Hz), to 7.99(1H,s).

<a Second phase >

Obtaining 1-(4-Butylochka-2-Chlorobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

N,N-dimethylformamide (5 ml) is added 60% sodium hydride (0.20 g, oil); then gradually at room temperature until ablaut crystals of 1-(2-chloro-4-hydroxybenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,80 g). After stirring for 1 hour at room temperature, to the mixture is added n-butyl bromide (0.28 g, 4.14 mmol). After further stirring for 15 hours at room temperature, to the solution was added water and then ethyl acetate to carry out the extraction. The organic layer was separated, washed twice with water and concentrated, obtaining of 0.62 g of oil.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): of 0.95(3H, t, J=7.5 Hz), of 1.39(3H, t, J=7,3 Hz), 1,42 of 1.50 (2H,m), 1.70 to of 1.78 (2H, m), to 2.57(3H,s), 3,90 (2H, t, J=6.4 Hz), 4,37(2N, K, J=6.9 Hz), 5,38(2H,s), 6,37 (1H, d, J=8.6 Hz), 6,62(1H, DD, J=8.6 and 2,5Hz), 7,00(1H, d, J=2.5 Hz), 7,73(1H, d, J=8.5 Hz), of 7.96(1H,s), 7,98(1H, d, J=8.6 Hz).

<a Third step>

Obtaining 1-(4-Butylochka-2-Chlorobenzyl)-6-carboxy-2-methyl-

benzimidazole

Sodium hydroxide (0.17 g), ethanol (8ml) and water (4ml) are added to 1-(4-Butylochka-2-Chlorobenzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole (0,62 g) and the mixture is stirred for 4 hours at 80°C. the pH was adjusted to about 5 with 35% hydrochloric acid. The precipitated crystals are filtered and dried, obtaining crystals (0,42 g) 1-(4-Butylochka-2-Chlorobenzyl) -6-carboxy-2-methylbenzimidazole.

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): to 0.89(3H, t, J=7.5 Hz), 1,35-of 1.42 (2H,m), 1,60 by 1.68 (2H,m), 2,52 (3H, s), of 3.94 (2H, t, J=6.4 Hz), the 5.51 (2H,s), 6,56(1H,d, J=8.7 Hz),for 6.81(1H, DD, J=8.7 and 2,5Hz),7,10 (1, d, J=2.5 Hz), to 7.61(1H, d, J=8,4 Hz), 7,88(1H, DD, J=8.4 and 1,3), 7,94(1H, s), 12,68 (1H,CL).

Example 84

Obtaining 1-(4-Butylochka-2-Chlorobenzyl)-6-(1-pentanesulfonate)-2-methylbenzimidazole (96)

In the same way as in Example 1, to obtain the desired benzimidazole (96) of the carboxylic acid obtained in Example 40 Receiving, and 1-pentanesulfonate.

[Physico-chemical characteristics of the compound (96)]

1H=NMR (DMSO-d6that δ m.g): 0,81(3H, t, J=7.2 Hz), to 0.89(3H, t, J=7.4 Hz), 1,21-of 1.29 (2H,m), of 1.31-1.42 (4H,m), 1,61-1,71 (4H,m), 2.49 USD (3H,s)to 3.49(2H, t,J=7,7 Hz), of 3.94 (2H, t, J=6.5 Hz), of 5.50(2H,s), 6, 45(1H, d, J=8.7 Hz), for 6.81(1H, DD, J=8.7 and 2,5Hz), 7,12(1H, d, J=2.5 Hz), the 7.65(1H, d, J=8.5 Hz), 7,78(1H, DD, J=8.4 and 1.5 Hz), of 8.09 (1H,s), 12,24 (1H, CL).

IR (Nujol): 1674 cm-1. so pl.: 166,0-172,5°C.

Example 41 to Obtain

<the First stage>

Obtain 1-(2-chloro-4-(3-methylbutoxy)benzyl)-6-(etoxycarbonyl)-2-methylbenzimidazole

In the same way as in the second stage of Example 40 Get get desired compound (0,600 g) of 1-(2-chloro-4-hydroxybenzyl)-6-etoxycarbonyl-2-methylbenzimidazole (0,600 g) and 1-bromo-3-methylbutane.

[Physico-chemical characteristics of connection]

1H=NMR (Dl3that δ m.g): 0,94(6N, d, J=6,7 Hz)of 1.39(3H, t, J=7.0 Hz), 1,64 (1H,, J=6.6 Hz), 1,76 of-1.83 (1H,m), to 2.57(3H, s), 3,93(2H, t, J=6.6 Hz), 4,37(2H, K, J=7,1 Hz), 5,38(2H,c), 6,36(1H, d, J=8,6 Hz), 6,62(1H, DD, J=8.7 and 2.5 Hz), 7,00(1H, d, J=2.5 Hz), 7,73(1H, d, J=8.5 Hz), 7.95 is-of 8.04(2H, m).

<a Second phase>

Obtain 1-(2-chloro-4(3-methylbutoxy)benzyl)-6-Carbo-XI-2-methylbenzimidazole

In the same way as in the third stage of Example 40 Get get desired compound (0,509 g) of 1-(2-chloro-4-(3-methylbutoxy)benzyl)-6-etoxycarbonyl-2-methylbenzimidazole (0,600 g).

[Physico-chemical characteristics of connection]

1H=NMR (DMSO-d6that δ m.g): 0,89(6N, d, J=6,8gts), and 1.56(2H, K, J=6.6 Hz), 1,68-to 1.77 (1H,m), 2,52(3H,s), of 3.96(2H, t, J=6,7 Hz), 5,52(2H,s), 6,56(1H, d, J=8.7 Hz), PC 6.82(1H, DD, J=8.6 and 2.5 Hz), 7,12(1H, d, J=2,6 Hz), to 7.61(1H, d, J=8.5 Hz), 7,88 (1H, DD, J=8.5 and 1.6 Hz), 7,94(1H, d, J=1.3 Hz), 11,70 (1H,CL).

Example 85

Obtain 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole (97)

In the same way as in Example 1, to obtain the desired benzimidazole (97) of the carboxylic acid obtained in Example 41 to Obtain, and 1-pentanesulfonate.

[Physico-chemical characteristics of compounds (97)]

1H=NMR (DMSO-d6that δ m.g): 0,80(3H, t, J=7.2 Hz), to 0.88(6H, d, J=6.6 Hz), 1.26 in(2H,m)of 1.34(2H,m), and 1.56(2H,m)to 1.67(3H, m), 2.49 USD(3H,s), 3,47(2H, t, J=7,Hz), of 3.96(2H, t, J=6,GC), of 5.50 (2H,s), of 6.45(1H, d, J=8.7 Hz), for 6.81(1H, d, J=8.6 Hz), 7,13 (1H, d, J=2.4 Hz), the 7.65(1H, d, J=8.5 Hz), 7,78(1H, d, J=8,4 Hz), of 8.09(1H,s), 11.87 per (1H,CL). IR (Nujol): 1672 cm-1. so pl.: 178,1-179,0°C.

Example 86

Obtain 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-

((4-methylbenzoyl)sulfonylamino)benzimidazole (98)

In the same way as in Example 1, to obtain the desired benzimidazole (98) of the carboxylic acid obtained in Example 41 to Obtain, and 4-methylbenzoyl)sulfonamida.

[Physico-chemical characteristics of compounds (98)]

1H=NMR (DMSO-d6that δ m.g): 0,89(6N, d, J=6,GC), and 1.56 (2H,m), 1,72 (1H,m), of 2.38(3H,s), 2,47(3H,s), of 3.96(2H, t, J=6.5 Hz), 5,49(2H,s), to 6.43(1H, d, J=8.5 Hz), to 6.80 (1H, d, J=8.5 Hz), 7,13(1H,s), 7,41(2H, d, J=8,0 Hz), the 7.62 (1H, d, J=8,4 Hz), of 7.70(1H, d, J=8,2 Hz), 7,86 (2H, d, J=8,2 Hz), of 8.04 (1H,s).

IR (Nujol): 1606 cm-1. so pl.: 218-226°C.

Example tests: Test activity reduction of plasma glucose using db/db mice

Test connection

1-(isoquinoline-3-ylmethyl)-2-methyl-6-(1-pentanesulfonate)-benzimidazole (13)

Used by animals

Buy female mice of the age of five weeks [C57BL/KsJ-dbm db+/db+, C57BL/KsJ-dbm+m/+m (Jackson Laboratory), and incubated for 2 to 3 weeks. Then, these mice used in the test.

Obtaining funds

The test compound is mixed with powdered feed (CE-2, produced by Nippon Clea), using a mortar.

The ratio of mixing amounted to 0.01%. Mixed feed is changed twice a week. The amount of feed and the remaining number register, and the consumption calculated from the difference between them.

The program tests

db/db mice-females grouped according to body weight, the concentration of glucose in plasma and the concentration of triglycerides in the plasma. Then, the mixture containing the test compound is administered to mice for 14 days (ages 8 to 10 weeks). In the morning on day 7 and day 14, the AOC is ü selected from the orbital venous plexus, using a glass capillary tube, treated with heparin (heparinised) (Chase Heparinized Capillary Tubes), and the fraction of plasma obtained by separation by centrifugation. Measured concentrations of glucose, triglycerides and insulin in plasma on day 0 and on day 14, and the concentrations of glucose and triglycerides in plasma on day 7. Body weight was measured on day 0, day 7 and day 14. After the final blood collection, mice are killed, using the CO2gas.

Measurement method

Glucose in plasma is measured glucose oxydase method (Glucose CII-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.), using 10 to 15 μl of plasma. The concentration of triglyceride in the plasma is measured GPO-p-chlorphenamine method (Triglyceride G-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.) or GPO-DAOS method (Triglyceride E-Test Wako), using 10 to 15 μl of plasma. The above measurements performed immediately after blood collection. The concentration of insulin in plasma was measured by radioimmunoassay method of analysis (Phadesef Insulin RIA Kit, custom Cabi Pharmacia)using 20 μl of plasma (which can be stored at -20°).

Results

The difference in the concentrations of plasma glucose and triglyceride levels in plasma between groups of db/db mice and +/+ mice is defined as 100%, and calculate the degree (%) lower concentrations of plasma glucose and triglyceride in the plasma group, which injected the connection. As a result, when ispytav is radiated compound was administered at the dose of 10 mg/kg, activity reduction of plasma glucose was 44%, while the activity decrease in the concentration of triglycerides (TG) was 77%.

Industrial applicability

Offers new benzimidazole derivatives and their pharmaceutically acceptable salts. These compounds and their salts have activity in reducing blood sugar levels or PDE5-inhibitory activity, and are useful for the prevention and treatment of impaired glucose tolerance, diabetes (type II diabetes), diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic osteopenia, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc), syndrome of insulin resistance (e.g., violations of the insulin receptor, the syndrome Rabson-Mendenhall, leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence, Cushing's syndrome, acromegaly, etc), polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders (e.g., stenocardia, cardiac failure, etc), hyperglycemia (e.g., abnormal sugar metabolism, such as malnutrition, etc), or hypertension, or angina, hypertension, pulmonary hypertension, congestive heart failure, glomerulopathy (for example, d is emeticeski glomerulosclerosis, etc), tubulocystic disorders (e.g., retinopathy, caused by FK506, cyclosporin, etc), renal failure, atherosclerosis, stenosis of the vessel (e.g., after percutaneous arterioplasty), distal angiopathy, cerebral apoplexy, chronic reversible obstructi (e.g., bronchitis, asthma, chronic asthma, allergic asthma), and so on), autoimmune diseases, allergic rhinitis, urticaria, glaucoma, diseases characterized by disorders of interopability (e.g., syndrome Hyper sensitive enteropathy, and so on), impotence (e.g., organic impotence, psychic impotence, etc.), and diabetic complications (e.g., diabetic gangrene, diabetic arthropathy, diabetic violation of osteogenesis, diabetic glomerulosclerosis, diabetic nephropathy, diabetic dermopathy, diabetic neuropathy, diabetic cataract, diabetic retinopathy, etc), nephritis, cachexia (e.g., progressive weight loss due to lipolysis, m & e(cyto)Lisa, anemia, edema, anorexia, etc. associated with chronic diseases such as cancer, tuberculosis, endocrine disorder, AIDS, etc), pancreatitis or restenosis after RTSA.

Additional experimental data, see table 1.

Table 1

Additional experimental data
Conn. NoformulaThe feed mixture (2 weeks)Oral administration (2 weeks)
Dose (mg/kg)Red eye reduction. Blood sugar (%)Dose (mg/kg)Red eye reduction. Blood sugar (%)
(15)1087--
(22)1062--
(26)--378
(31)--193
(47)--163
(87)--178

1. A derivative of benzimidazole represented by the following formula (I)or its salt:

where R1represents a lower alkyl group, R2is aromatic Nissho the alkyl group, which may be substituted by one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, a nitro group, an aromatic group, an aromatic lower alkyloxy, lower cycloalkane-lower alkyl group, an aromatic lower alkyl groups, lower aromatic alkenylphenol group, an aromatic lower alkenylphenol group, an aromatic hydroxy lower alkyl group, a lower cycloalkyl-low alkyloxy, alkenylphenol group, lower alkoxygroup, low allylthiourea, and lower alkane-sulphonylchloride group;

R3represents an alkyl group, a hydroxy lower alkyl group, alkenylphenol group, an aromatic group, a halogenated aromatic group, a lower alkyl aromatic group, lower alkenyl aromatic group or an aromatic lower alkenylphenol group; X represents a linking group represented by any one of the following formulas (II)to(V):

2. A derivative of benzimidazole or its salt according to claim 1, where R1represents a lower alkyl group.

3. A derivative of benzimidazole or its salt according to claim 1, where X represents a crosslinking group represented by the formula (V).

4. Pharmaceutical composition for the prevention and treatment of impaired tolerance to Glu the Oze, diabetes, diabetic complications, insulin resistance syndrome, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders, hyperglycemia or hypertension, comprising as active ingredient a compound represented by the following formula (I)or its pharmaceutically acceptable salt:

where R1represents a lower alkyl group; R2represents an aromatic lower alkyl group which may be substituted by one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, a nitro group, an aromatic group, an aromatic lower alkyloxy, lower cycloalkane-lower alkyl group, an aromatic lower alkyl groups, lower aromatic alkenylphenol group, an aromatic lower alkenylphenol group, an aromatic hydroxy lower alkyl group, a lower cycloalkyl-low alkyloxy, alkenylphenol group, lower alkoxygroup, low ancilliary and lower alkanesulfonyl group;

R3represents an alkyl group, a hydroxy lower alkyl group, alkenylphenol group, an aromatic group, a halogenated aromatic group, a lower alkyl aromatic group, lower alkenyl aromatic the action group or an aromatic lower alkenylphenol group;

-X - represents a crosslinking group represented by any of the following formulas (II)to(V):

5. A derivative of benzimidazole or its salt according to claim 1, where R2represents an aromatic lower alkyl group which may be substituted by one or more groups selected from a halogen atom, alkyl group, aromatic group, alkenylphenol group, lower alkoxygroup, low ancilliary; R3represents an alkyl group, a hydroxy lower alkyl group, alkenylphenol group, an aromatic group, a lower alkyl aromatic group or an aromatic lower alkenylphenol group; X - represents a crosslinking group represented by the formula (V).

6. A derivative of benzimidazole or its salt according to claim 5, where R1represents a lower alkyl group, R2represents an aromatic lower alkyl group which may be substituted by one or more halogen atoms, and R3represents a hydroxy lower alkyl group or alkenylphenol group.

7. A derivative of benzimidazole or its salt according to claim 6, where R1represents a lower alkyl group, R2represents a benzyl group, naphthylmethyl group or ethanolimino group which may be substituted by one or more halogen atoms, and R3is hydroxy, n is SCHOU alkyl group or alkenylphenol group.

8. Pharmaceutical composition for the prevention and treatment of impaired glucose tolerance, diabetes, diabetic complications, insulin resistance syndrome, polycystic ovary syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders, hyperglycemia or hypertension, comprising as active ingredient benzimidazole derivative or its pharmaceutically acceptable salt according to claim 1, where R2represents an aromatic lower alkyl group which may be substituted by one or more groups selected from a halogen atom, alkyl group, aromatic group, alkenylphenol group, lower alkoxygroup, and low ancilliary; R3represents an alkyl group, a hydroxy lower alkyl group, alkenylphenol group, an aromatic group, a lower alkyl aromatic group or an aromatic lower alkenylphenol group; X - represents a crosslinking group represented by the formula (V).

9. The pharmaceutical composition of claim 8, where R1represents a lower alkyl group; R2represents an aromatic lower alkyl group which may be substituted by one or more halogen atoms, and R3represents a hydroxy lower alkyl group or alkenylphenol group.

10. The pharmaceutical composition according to claim 9, where R1is lower ALK is the function group, R2represents a benzyl group, naphthylmethyl group or ethanolimino group which may be substituted by one or more halogen atoms, and R3represents a hydroxy lower alkyl group or alkenylphenol group.

11. A derivative of benzimidazole or its salt according to claim 1, where R1represents a lower alkyl group, R2represents a benzyl group which may be substituted by one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, an aromatic group, a lower cycloalkane-lower alkyl groups, lower aromatic alkenylphenol group, an aromatic lower alkenylphenol group, alkenylphenol group, lower ancilliary and lower alkanesulfonyl group; R3represents an alkyl group, alkenylphenol group, an aromatic group, haloaromatic group, lower alkenyl aromatic group, a lower alkyl aromatic group or an aromatic lower alkenylphenol group.

12. A derivative of benzimidazole or its salt according to claim 11, where R1represents a methyl group; R2represents a benzyl group which may be substituted by one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, phenyl group, lower cycloalkane lower McIlroy group, phenyl lower alkenylphenol group, phenyl lower alkenylphenol group, alkenylphenol group, lower ancilliary and lower alkanesulfonyl group; R3represents an alkyl group, alkenylphenol group, phenyl group, thiophene group, a halo-phenyl group, lower alkenyl phenyl group, lower alkyl phenyl group or a phenyl lower alkenylphenol group.

13. The pharmaceutical composition according to claim 4, where R1represents a lower alkyl group, R2represents a benzyl group which may be substituted by one or more groups selected from a halogen atom, an alkyl group, a halo-lower alkyl group, an aromatic group, a lower cycloalkane-lower alkyl groups, lower aromatic alkenylphenol group, an aromatic lower alkenylphenol group, alkenylphenol group, a lower alkylthio group and lower alkanesulfonyl group; R3represents an alkyl group, alkenylphenol group, an aromatic group, a halo-aromatic group, lower alkenyl aromatic group, a lower alkyl aromatic group or an aromatic lower alkenylphenol group.

14. The pharmaceutical composition according to item 13, where R1represents a methyl group, R2represents a benzyl group which may be substituted by one or more groups, vibrancies of halogen atom, alkyl group, a halo-lower alkyl group, phenyl group, lower cycloalkane-lower alkyl group, phenyl lower alkenylphenol group, phenyl lower alkenylphenol group, alkenylphenol group, lower ancilliary and lower alkanesulfonyl group; R3represents an alkyl group, alkenylphenol group, phenyl group, thiophene group, a halo-phenyl group, lower alkenyl phenyl group, lower alkyl phenyl group or a phenyl lower alkenylphenol group.

15. A derivative of benzimidazole or its salt according to claim 1, which is selected from 1-(isoquinoline-3-ylmethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-((4-chloroisoquinoline-3-yl)methyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)-sulfonylamino)benzimidazole, 6-(N'-butanesulfonyl-hydrazinophenyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 6-((n-butylaminoethyl)carbarnoyl)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-[N'-(4-methylphenylsulfonyl)ureido]benzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(((E)-1-Penta-1-Yong)sulfonylamino) benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-((E) -2-phenylacetylcarbinol) benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonyl-carbarnoyl) benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((E)-2-Hairdryer who lettersultimate)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-6-((5-chlorothiophene-2-yl)sulfonylamino)-2-methylbenzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-(((E)-1-Penta-1-ene)sulfonylamino)benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol-carbarnoyl) benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-6-((5-chlorothiophene-2-yl)sulfonylamino)-2-methylbenzimidazole, 6-((5-bromothiophene-2-yl)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole,6-((5-bromothiophene-2-yl)sulfonylamino)-1-(2-chloro-4-phenylbenzyl)-2-methylbenzimidazole, 1-(2-chloro-4-(cyclohexylmethoxy)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole,1-(2-chloro-4-(cyclohexylmethoxy)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino) benzimidazole, 6-((5-chlorothiophene-2-yl)sulfonylamino)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(4-bromo-2-Chlorobenzyl)-6-((5-bromothiophene-1-yl)sulfonylamino)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-bromobenzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino) benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((1-Penta-4-ene)sulfonylamino)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((E)-1-Penta-4-ene) sulfonylamino) benzimidazole, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole -(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(1-HEXEN-1-yl)-benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(1-HEXEN-1-yl)benzyl)-2-methyl-6-((4-methylbenzoyl) sulfonylamino)benzimidazole, 1-(4-t-butylthio-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonic-carbarnoyl)benzimidazole, 1-(4-t-butylthio-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl) sulfonylamino)benzimidazole, 1-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-6-((4-methylbenzoyl) sulfonylamino)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((n-intramyocellular)carbarnoyl)benzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(((4-(were)aminosulfonyl)carbarnoyl)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(((4-were)-aminosulfonyl) carbarnoyl) benzimidazole, 1-(2-chloro-4-(1-pentane-sulfonylamino) benzyl)-2-methyl-6-(1-pentanesulfonic-carbarnoyl) benzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-((4-vinylbenzyl)-sulfonylamino)benzimidazole, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((4-methylbenzoyl) sulfonylamino)benzimidazole, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((E)-1-penten-1-sulfonylamino) benzimidazole, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((4-vinylbenzyl)sulfonylamino)Benzema is asola, 1-(2-chloro-4-(phenylethynyl)benzyl)-2-methyl-6-((E)-2-phenylacetylcarbinol) benzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)-benzyl)-6-((4-vinylbenzyl)sulfonylamino)-2-methylbenzimidazole, 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-6-((E)-1-penten-1-sulfonylamino)-2-methylbenzimidazole and 1-(2-chloro-4-((E)-2-phenylethenyl)benzyl)-2-methyl-6-(((E)-2-phenylethenyl) sulfonylamino) benzimidazole.

16. A derivative of benzimidazole or its salt according to claim 1, which is selected from 1-((1-does not depend-2-yl)-methyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, 6-(benzensulfonamidelor)-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-phenylbenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(4-benzyloxy-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(4-benzyloxy-2-Chlorobenzyl)-2-methyl-6-((4-methylbenzoyl) sulfonylamino)benzamides the La, 1-(2,4-dichlorobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, (+)-1-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, (-)-1-(1-(2,4-dichlorophenyl)ethyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-nitrobenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(phenoxymethyl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(phenoxymethyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino) benzimidazole, 1-(2-chloro-4-iodobenzyl) -2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(2-chloro-4-iodobenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-ethoxybenzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-ethoxybenzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino) benzimidazole, 1-(4-bromo-2-Chlorobenzyl)-2-methyl-6-(1-pentanesulfonate) benzimidazole, 1-(2-chloro-4-(trifter-methyl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, (R)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, (S)-1-(2,4-dichlorobenzyl)-6-((4-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole, optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole (displayed on the speaker a longer retention time under the liquid chromatography),

optically active 1-(2,4-dichlorobenzyl)-6-((2-hydroxy-1-pentane)sulfonylamino)-2-methylbenzimidazole (demonstrating a shorter retention time under the liquid chromatography),

optically active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane) sulfonylamino)-2-methylbenzimidazole (demonstrating a longer retention time under the liquid chromatography),

optically active 1-(2,4-dichlorobenzyl)-6-((3-hydroxy-1-pentane)sulfonylamino-2-methylbenzimidazole (demonstrating a shorter retention time under the liquid chromatography), 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(1-hexyl)benzyl)-2-methyl-6-(pentacarbonyliron)benzimidazole, 1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(2-chloro-4-(thiophene-2-yl)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(furan-2-yl)-benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole, 1-(2-chloro-4-(furan-2-yl)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfonylamino)benzimidazole, 1-(4-Butylochka-2-Chlorobenzyl)-6-(1-pentanesulfonate)-2-methylbenzimidazole, 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-(1-pentanesulfonate)benzimidazole and 1-(2-chloro-4-(3-methylbutoxy)benzyl)-2-methyl-6-((4-methylbenzoyl)sulfo ylcarbonyl)benzimidazole.

Priority from 27.06.1997:

Derivatives of benzimidazole of General formula (I) or its salts, where

R1represents a lower alkyl group,

R2represents an aromatic lower alkyl group which may be substituted by one or more groups selected from a halogen atom, a lower alkyl group, lower alkenylphenol group, an aromatic group, a lower alkoxy group, a lower alkylthio group,

R3represents an aromatic group, a lower alkyl group, lower alkenylphenol group, an aromatic lower alkenylphenol group,

-X - represents a crosslinking group of formula (V).

Pharmaceutical composition for the prevention and treatment of impaired glucose tolerance, diabetes, diabetic complications, insulin resistance syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders, hyperglycemia or hypertension.

Priority from 25.03.1998:

All other values radicals and disease - polycystic ovary syndrome.



 

Same patents:

The invention relates to organic chemistry and can find application in medicine

The invention relates to organic chemistry and can find application in medicine

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to new derivatives of amidine General formula (I’)

where it is:

in which R1, R2and R3HE or1-C6alkyl, C1-C6alkoxy, R4- H1-C6alkyl, R5- H1-C6alkyl or the radical:

where R10, R11and R12- OH or H, R13- H1-C6alkyl; or the radical:

where R18, R19and R20- H, HE, C1-C6alkyl, R21and R22- H, C1-C6alkyl, or R21-alkylsulfonyl, alkylsulfonyl, alkylaryl, and R22- H or the radical:

where T is -(CH2)k-, k = 1, 2, R27- H, C1-C6alkyl

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; b is a thiophene; W is absent or represents an Association or S; X represents a bond or a radical -(CH2)k-NR16-, -O-, -CO-, -NR16-CO-, and so forth, and k is 0 or 1; Y represents a bond or a radical selected from the radicals -(CH2)m-, -(CH2)m-O-(CH2)n, -(CH-Q-(CH2)n; and Q represents pieperazinove radical, m and n are equal to integers from 0 to 6; R16, R17, R18represent independently a hydrogen atom, or a salt of the compounds

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

The invention relates to the field of organic chemistry, specifically to new connections: dicyanodiamide, namely aralen-bis(2-aminothiophene-3-carbonitrile)am General formula

where R represents

Connection most effectively can be used as monomers for obtaining polyamides, polyazomethines and politician with phenylanaline groups with high values of viscosity and conductivity

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma

The invention relates to piperazine derivatives of General formula I, in which R1denotes pyridyl or phenyl, unsubstituted or once substituted Ph or 2 - or 3-Tiepolo, R2indicates Ph1or Het

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

The invention relates to new substituted phenyl derivatives, which are strong blockers chlorine ion channels and as such are useful in the treatment of sickle cell anemia, cerebral edema that accompanies ischemia or tumor, diarrhea, hypertension (diuretic), osteoporosis and to reduce the intraocular pressure for the treatment of disorders such as glaucoma
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