Benzimidazole derivatives, compositions containing said derivatives, production and use thereof

FIELD: chemistry.

SUBSTANCE: present invention relates to a compound of formula: which is N-{2-tert-butyl-1-[(4,4-diflurocyclohexyl)methyl]-1H-benzimidazol-5-yl}ethanesulfonamide and its pharmaceutically acceptable salt, their diastereomers, enantiomers or their mixture. The invention also relates to use of this compound in making a medicinal agent with modulator activity of CB1 receptors; to a pharmaceutical composition based on this compound; to a method of modulating CB1 receptors, based on use of effective quantities of this compound, as well as to a method of producing the compound described above.

EFFECT: obtaining a new derivative of benzimidazole with useful biological activity.

8 cl, 1 tbl, 28 ex

 

BACKGROUND of the INVENTION

1. The scope of the invention

The invention relates to therapeutic compounds, pharmaceutical compositions containing these compounds, methods for their manufacture and their use. In particular, the present invention relates to compounds that may be effective in the treatment of pain, cancer, scattered sclerosis, Parkinson's disease, horii's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and/or cardiovascular disorders.

2. Discussion of relevant technical solutions

Pain is an important area of research for many years. It is well known that ligands of cannabinoid receptors (e.g., receptor CB1, receptor SV2), including agonists, antagonists and inverse agonists, cause pain in different animal models by interacting with receptors CB1and/or CB2. Typically, receptors CB1mainly localized in the Central nervous system and receptors SV2localized mainly in the periphery and is confined largely to cells and tissues, the origin of which is associated with the immune system.

Although agonists of the receptor CB1such as Δ9-tetrahydrocannabinol (Δ9-THC) and anadamide, useful models anti is acceptee in mammals, they tend to have undesirable side effects on the Central nervous system (CNS), such as psychoactive side effects, the potential for abuse, drug dependence and tolerance, etc. Know that these unwanted side effects are mediated by receptors CB1localized in the Central nervous system. However, there is evidence that agonists CB1acting at peripheral sites, or with limited CNS exposure can eliminate pain in humans or animals with significantly improved overall in vivo profile.

Therefore, there is a need for new ligands of the receptor CB1such as agonists, which are useful for the treatment of pain or other treatment-related pain symptoms or diseases with reduced or minimal unwanted side effects on the Central nervous system.

DESCRIPTION INCARNATIONS

In the present invention proposed ligands of the receptor CB1that can be useful in the treatment of pain and/or other related symptoms or diseases.

The term "Cm-n" or "Cm-ngroup"used alone or as a prefix, refers to any group having m to n carbon atoms.

The term "alkyl"used alone or as suffix or prefix, refers to a monovalent saturated pleva Oradea the radical with a straight or branched chain, containing from 1 to about 12 carbon atoms. Illustrative examples of Akilov include, without limiting them With1-4alkyl groups such as methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, butyl, isobutyl, tert-butyl.

The term "cycloalkyl," used alone or as suffix or prefix, refers to a saturated monovalent containing ring hydrocarbon radical containing at least 3 and up to about 12 carbon atoms. Examples of cycloalkyl include, without limiting them With3-7cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and saturated cyclic and bicyclic terpenes. Cycloalkyl may be unsubstituted or may be substituted by one or two suitable substituents. Preferably cycloalkyl represents a monocyclic or bicyclic ring.

The term "alkoxy"used alone or as suffix or prefix, refers to radicals of the General formula-O-R, where R represents alkyl. Examples of alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy.

The halogen includes fluorine, chlorine, bromine and iodine.

"CT" or "CT" means room temperature.

In one aspect of the embodiment of the invention is a compound of which ormula I, its pharmaceutically acceptable salts, diastereomers, enantiomers or mixtures thereof:

where

G is selected from-O-, -CHF -, and-CF2-;

R1selected from C1-6the alkyl and C3-6cycloalkyl;

R2selected from-H and methyl; and

R3, R4and R5independently selected from fluorescent and bromide.

In another embodiment, these compounds can be compounds of formula I, where

G is selected from-O -, and-CF2-;

R1selected from C1-6the alkyl and C3-6cycloalkyl;

R2selected from-H and methyl; and

R3, R4and R5independently selected from fluorescent and bromide.

Another embodiment of the present invention is a compound of formula I, where

G is selected from-O -, and-CF2-;

R1selected from C1-4the alkyl and C3-4cycloalkyl;

R2selected from-H and methyl; and

R3, R4and R5independently selected from fluorescent and bromide.

Another embodiment of the present invention is a compound of formula I, where

G represents-O-;

R1selected from ethyl, propyl and cyclopropyl;

R2selected from-H and methyl; and

R3, R4and R5independently selected from fluorescent and methyl, and R3, R4and R5are the same.

Another embodiment of the present invention is a compound of formula I,

where

G represents-CF2-;

R1selected from ethyl, propyl and cyclopropyl;

R2selected from-H and methyl; and

R3, R4and R5independently selected from fluorescent and methyl, and R3, R4and R5are the same.

Another embodiment of the present invention is a compound of formula I,

where

G represents-CHF-;

R1selected from ethyl, propyl, tert-butyl and cyclopropyl;

R2selected from-H and methyl; and

R3, R4and R5independently selected from fluorescent and methyl, and R3, R4and R5are the same.

In another embodiment R1in the formula I is selected from ethyl, propyl, tert-butyl and cyclopropyl.

In another embodiment G in formula I is-CHF -, or-CF2-.

In another embodiment R3, R4and R5in the formula I is selected from fluorescent and methyl, and R3, R4and R5are the same.

In another embodiment of the connection according to the invention can be selected from

N-[2-tert-butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylcyclohexylamine;

N-[2-tert-butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylpropan-1-sulfonamida;

N-[2-tert-butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylbutane-1-sulfonamida;

N-{2-tert-Buti is-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylbutane-1-sulfonamida;

N-methyl-N-[1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-yl]propane-1-sulfonamida;

N-methyl-N-[1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-yl]cyclopropanecarboxamide;

N-[2-tert-butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylpentan-1-sulfonamida;

N-[2-tert-butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylethanolamine;

N-[2-tert-butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N,2-DIMETHYLPROPANE-2-sulfonamida;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylpropan-1-sulfonamida;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylethanolamine;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}propane-1-sulfonamida;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}methanesulfonamide;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}acanalonia;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}cyclopropanecarboxamide;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylcyclohexylamine;

N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-2-methylpropan-2-sulfonamida;

N-[1-[(4,4-diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazo is l-5-yl]cyclopropanecarboxamide;

N-[1-[(4,4-diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]acanalonia;

N-[1-[(4,4-diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]-2-methylpropan-2-sulfonamida;

N-[2-(1,1-dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylethanolamine;

N-[2-(1,1-dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylpropan-1-sulfonamida;

N-[2-(1,1-dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylcyclohexylamine;

N-{2-tert-butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}acanalonia;

N-{2-tert-butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}cyclopropanecarboxamide;

N-{2-tert-butyl-1-[(4-forcelogix)methyl-1H-benzimidazole-5-yl}-2-methylpropan-2-sulfonamida;

and their pharmaceutically acceptable salts.

In yet another embodiment of the invention the proposed compound selected from

and their pharmaceutically acceptable salts.

It is clear that when the connection is really the image the structure contain one or more chiral centers, compounds according to the invention can exist in enantiomeric or diastereomeric forms or in the form of a racemic mixture, or can be allocated in the form of enantiomeric or diasteriomeric forms or in racemic mixtures. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof of compounds of formula I. the Optically active forms of the compounds according to the invention can be obtained, for example, chiral chromatographic separation of a racemate, by synthesis from optically active starting compounds or asymmetric synthesis according to the methods described below.

You should also take into account that some compounds of the present invention may exist as geometric isomers, for example E and Z isomers of alkenes. The present invention covers any geometrical isomer of compounds of formula I. it Should be borne in mind that the present invention encompasses tautomers of the compounds of formula I.

It is also clear that some compounds of the present invention may exist in solvated, for example hydrated, as well as in resolutional forms. It should be borne in mind that the present invention encompasses all such solvated forms of the compounds of formula I.

In the scope of the present invention also includes salts of the compounds fo the mules I. In General, pharmaceutically acceptable salts of the compounds of the present invention can be obtained using standard techniques, well known in this field, for example by communicating sufficiently basic compound, for example, alkylamine, with a suitable acid, such as Hcl or acetic acid, to provide a physiologically acceptable anion. Possible can be also obtaining the corresponding alkali metal salt (such as sodium, potassium or lithium) or alkaline earth metal (such as calcium) by treating the compounds of the present invention, respectively having an acidic proton, such as a carboxylic acid or a phenol with one equivalent of hydroxide or alkoxide (such as ethoxide or methoxide) alkali metal or alkaline-earth metal or organic amine (such as choline or meglumine) in the aqueous medium, followed by purification by standard methods.

In one embodiment of the above compound of formula 1 can be transformed into its pharmaceutically acceptable salt or MES, in particular in salt accession acids, such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulfonate or p-toluensulfonate.

The inventors have discovered that the connection is in according to the invention have activity as pharmaceuticals, in particular are modulators or ligands, such as agonists, partial agonists, inverse agonists or antagonists of receptors CB1. More specifically, the compounds according to the invention show selective activity as agonists of the receptors CB1and useful in therapy, in particular to facilitate various pain conditions such as chronic pain, neuropathic pain, acute pain, pain caused by cancer, pain caused by rheumatoid arthritis, migraine, visceral pain, and so forth. However, you should not interpret this list as exhaustive. Additional compounds of the present invention is useful for other painful conditions, which has taken place or are involved in dysfunction of the receptors CB1. In addition, the compounds according to the invention can be used to treat cancer, multiple sclerosis, Parkinson's disease, horii's chorea, Alzheimer's disease, anxiety disorders, gastrointestinal disorders and cardiovascular disorders.

Compounds according to the invention are useful as immunomodulators, especially in autoimmune diseases, such as arthritis, skin grafts, organ transplants and similar surgical situations, collagen diseases, various allergies, for use as antitumor AG is now and antiviral agents.

Compounds according to the invention are useful in disease States in which degeneration or dysfunction of cannabinoid receptors has taken place or is involved in that sense. This may include the use of labeled isotopes versions of the compounds according to the invention in diagnostic methods and imaging applications such as positron emission tomography (PET).

Compounds according to the invention are useful for the treatment of diarrhea, depression, anxiety and stress-related disorders such as posttraumatic stress disorder, panic disorder, generalized anxiety disorder, social phobia and obsessive-compulsive disorder, urinary incontinence, premature ejaculation, various mental illnesses, cough, lung edema, various gastro-intestinal disorders, e.g. constipation, functional gastrointestinal disorders such as irritable bowel syndrome or functional dyspepsia, Parkinson's disease and other disorders of motility, traumatic brain damage, stroke, cardiotoxic after myocardial infarction, spinal cord and drug abuse, including treatment of abuse of alcohol, nicotine, opioids and other drugs, and to treat disorders of the sympathetic nervous system, such as hypertension.

p> Compounds according to the invention are useful as analgesic agents for use during General anesthesia and monitored anesthesia. Combinations of agents with different properties are often used to balance the effects required to maintain the state of anesthesia (such as amnesia, analgesia, muscle relaxation and sedation). Included in this combination are inhaled anesthetics, sleeping pills, anxiolytics, neuromuscular blockers and opioids.

Also in the scope of the invention includes the use of any of the above compounds of formula 1 for the manufacture of a medicine for the treatment of any condition described above.

Another aspect of the invention is a method of treatment of a subject suffering from any condition as described above, comprising the administration to a patient in need of such treatment, an effective amount of the compound of the above formula I.

Thus, according to the invention proposed compound of formula 1 or its pharmaceutically acceptable salt or MES, as defined here above for use in therapy.

In another aspect of the present invention proposed the use of the compounds of formula 1 or its pharmaceutically acceptable salt or MES, as defined here above, in the manufacture of medicinal environments is TBA for use in therapy.

In the context of the present invention, the term "therapy" also includes "prevention", if there is no specific guidance on the opposite. The terms "therapeutic" and "therapeutically" should be interpreted accordingly. The term "therapy" in the context of the present invention also includes the introduction of an effective amount of the compounds of the present invention to facilitate or existing painful conditions, acute or chronic, or recurrent condition. It also covers preventive therapy for prevention of recurrent States and long-term therapy of chronic disorders.

Compounds of the present invention are useful in therapy, in particular in therapy of various pain conditions including, but not limited to, acute pain, chronic pain, neuropathic pain, back pain, pain caused by cancer and visceral pain.

When applying for therapy in a warm-blooded animal, such as man, the connection according to the invention can be introduced in the form of a conventional pharmaceutical composition by any route including orally, intramuscularly, subcutaneously, topically, intranasally administered intraperitoneally, intraorale, intravenously, epidurally, intrathecally, transdermal, intracerebroventricularly and by injection into the joints.

In about the nom embodiment of the invention, the route of administration may be oral, intravenous or intramuscular.

The dosage will depend on the route of administration, severity of disease, age and weight of the patient, and other factors normally considered by the attending physician when determining an individual mode and dose level, the most suitable for a particular patient.

For preparing pharmaceutical compositions from the compounds according to this invention, inert, pharmaceutically acceptable carriers can be solid or liquid. Drugs in solid form include powders, tablets, dispersible granules, capsules, pills and suppositories.

A solid carrier can be one or more substances which may also act as diluents, corrigentov, soljubilizatory, lubricants, suspendresume agents, binders or leavening agents for tablets. The carrier can also be an encapsulating material.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground connection according to the invention or an active component. In tablets, the active ingredient is mixed with carrier having the necessary binding properties in suitable proportions and pressed to the desired shape of the desired size.

For preparation of compositions in the form of suppositories first melted low-melting wax, such as mesh of glycerides of fatty acids and cocoa butter and dispersed active ingredient, for example by stirring. The molten homogeneous mixture is then poured into forms appropriate size and allow it to cool and harden.

Suitable carriers are magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragakant, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like.

It is implied that the term "composition" includes the preparation of the active ingredient with encapsulating substance as a carrier providing a capsule in which the active component (with other carriers) is surrounded by carrier, which, consequently, is together with him. Similarly, this term covers the wafer.

Tablets, powders, pills and capsules can be used in solid dosage forms suitable for oral administration.

Compositions in liquid form include solutions, suspensions and emulsions. For example, solutions of the active compounds in sterile water or in aqueous propylene glycol may be liquid preparations suitable for parenteral administration. Liquid compositions can also be prepared in the form of the drug in an aqueous solution of polyethylene glycol.

Aqueous solutions for oral administration can be sentence is Owlery by dissolving the active component in water and adding suitable colorants, corrigentov, stabilizers and thickeners, if necessary. Aqueous suspensions for oral administration can be produced by dispersing finely ground active component in water together with a viscous substance, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other suspendresume agents known in the field of preparation of pharmaceutical products.

Depending on the method of administration of the pharmaceutical composition preferably contains from 0.05% to 99% wt.(percent by weight), more preferably from 0.10 to 50% wt. compounds according to the invention, all percentages by weight are calculated on the total weight of the composition.

A therapeutically effective amount for the practical use of the present invention can be determined using known criteria, including the age, weight and response of the individual patient, and interpreted in the context of the disease that is being treated or which warn specialist in this field.

In the scope of the present invention includes any compounds of formula I, as defined above, for the manufacture of a medicinal product.

Also in the scope of the present invention includes any compounds of formula I for the manufacture of Lek is stannage tools for the treatment of pain.

In addition, the proposed application of any of the compounds of formula I for the manufacture of a medicine for the treatment of various pain conditions including, but not limited to, acute pain, chronic pain, neuropathic pain, back pain, pain caused by cancer and visceral pain.

Another aspect of the invention is a method of treatment of a subject suffering from any of the States described above, wherein the patient in need of such treatment is administered an effective amount of the compound of the above formula I.

In addition, the proposed pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier.

In particular, the proposed pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, for therapy, more particularly for the treatment of pain.

Also proposed pharmaceutical composition comprising a compound of formula I or its pharmaceutically acceptable salt together with a pharmaceutically acceptable carrier, for use in any of the States described above.

The following aspect of the present invention, a method for producing compounds of the present invention.

In one GP is owenii of the invention, a method for obtaining compounds of formula I:

including the interaction of the compounds of formula II with the compound of the formula III

where R1, R2, R3, R4, R5and G are as defined above.

Compounds of the present invention can also be obtained according to the ways of synthesis, as they are presented in Schemes 1, 2 and 3.

Biological assessment

Binding to receptors hCB1and hCB2

Membranes containing the human receptor CB1from Receptor Biology (hCB1or human receptor SV2from BioSignal (hCB2), thawed at 37°C., passed 3 times through a needle with a blunt end 25-th size, diluted in buffer for binding of cannabinoids (50 mm Tris, 2.5 mm EDTA (ethylenediaminetetraacetic acid), 5 mm MgCl2and 0.5 mg/ml BSA (bovine serum albumin that do not contain fatty acids, pH 7.4) and distribute aliquots containing the appropriate amount of protein in 96-well plates. IC50compounds according to the invention with respect to hCB1and h2estimate of 10-point curves dose-response, constructed for samples with3H-CP55,940 at 20000-25000 dpm (disintegrations per minute) per well (by 0.17 to 0.21 nm) in a final volume of 300 ál. General and nespec the specific binding determined in the absence and in the presence of 0.2 μm HU210, respectively. Tablets shaken on a vortex and incubated for 60 minutes at room temperature, filtered through Unifilters GF/B (pre-soaked in 0.1% polyethylenimine) on a Tomtec harvester or Packard using 3 ml of wash buffer (50 mm Tris, 5 mm MgCl2, 0.5 mg BSA pH 7.0). The filters are dried for 1 h at 55°C. the Radioactivity (cpm (counts per minute)) counted in the TopCount (Packard) after adding 65 μl/well scintillation fluid MS-20.

The binding of GTPγS hCB1and hCB2

Membranes containing the human receptor CB1from Receptor Biology (hCB1or human receptor SV2(BioSignal), thawed at 37°C., passed 3 times through a needle with a blunt end 25-th size and bred in the buffer for the binding of GTPγS (50 mm Hepes, 20 mm NaOH, 100 mm NaCl, 1 mm EDTA, 5 mm MgCl2, a pH of 7.4, 0.1% BSA). EC50and Emaxcompounds according to the invention is evaluated according to 10-point curves dose-response, constructed for samples of 300 μl with the appropriate amount of membrane protein and 100000-130000 dpm (disintegrations per minute) GTPg35S per well (0,11-0,14 nm). The initial and maximum stimulated binding determined in the absence and in the presence of 1 μm (h2) or 10 μm (hCB1) Win 55212-2, respectively. Membrane preincubated for 5 minutes with 56,25 μm (h2or 112,5 μm (hCB1) GDP (guanozintrifosfat), and then distribute the tablets (the end is th GDP concentration of 15 μm (h 2) and 30 μm (h1)). Tablets shaken on a vortex and incubated for 60 minutes at room temperature, filtered through filters Unifilters GF/B (pre-soaked in water) on a Tomtec harvester or Packard using 3 ml of wash buffer (50 mm Tris, 5 mm MgCl2, 50 mm NaCl, pH 7.0). The filters are dried for 1 h at 55°C. the Radioactivity (cpm) counting in a TopCount (Packard) after adding 65 μl/well scintillation fluid MS-20. Studies antagonist treatment carried out in the same way, except that (a) the curve dose of agonist-response receive in the presence of constant concentration of antagonist or (b) curve dose of the antagonist is answered in the presence of constant concentration of agonist.

Based on the above analyses determine the dissociation constant (Ki) for specific compounds according to the invention in relation to a specific receptor, using the following equation:

Ki=IC50/(1+[rad]/Kd),

where IC50means the concentration of the compounds according to the invention, in which was observed a 50% substitution;

[rad] mean standard or reference concentration of radioactive ligand in the moment; and

Kd denotes the dissociation constant of the radioactive ligand in relation to a specific receptor.

Defined using the above-described analyses of Ki with respect to human is a mini-receptors SV 1for a number of compounds according to the invention has a value in the range between 3 nm and 195 nm. EC50for these compounds is in the range between 2,3 nm and 300 nm. Emaxfor these compounds is in the range between 109% and 144%. EU50for N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}ethane-sulfonamida is 13.5 nm.

Conditions of analysis for measuring the solubility

Prepare the initial solution of 30 mm in DMSO (dimethyl sulfoxide) and then aliquots of 25 μl added to 96-well plate and incubated at 40°C for 4 hours. To the incubated connection add 250 ál of sodium phosphate buffer (pH 7.4) and then mixed at 1200 rpm for 24 h, using an Eppendorf Thermomixer at 25°C. After mixing, the solution is transferred into a 96-well filter tablet Whatman GF/B and then filtered under vacuum. The supernatant is then injected into the instrument LC/MS (liquid chromatography/mass spectrometry) analysis and definition is done using 1-point calibration for interest connection.

Analysis of metabolic stability in liver microsomes of rats and humans

A solution of 500 μl of 100 μm of compound in DMSO incubated with human liver microsomes or rats (843 μl of microsomes from 0,5618 mg/ml in 30 ml of 0.1 M KN2RHO4buffer pH 7.4) at 37°C for 10 min in 96-well deep plate. To start is eacli added NADPH (nicotine-imidazenil-dinucleotides, 46 μl) at a concentration of 8.33 mg/ml in 100 mm KN2RHO4buffer with pH 7.4. The reaction mixture was transferred to 384-well plate containing acetonitrile for quenching the reaction at the points 0, 10, 20, 30 minuteto 384-well plate was centrifuged for 30 min at 9000 g at 4°C, and samples from it were analyzed by LC/MS (model: Eclipse XDB C18). Three standard were analyzed by LC/MS as a positive control. The data were processed following the standard procedure. The metabolic stability of the tested compounds was expressed as μl/min/mg.

In addition, using one or more of the above analyses was determined metabolic stability (hClint and rClint) and solubility (water) of a number of compounds according to the invention. It was found that the selected compounds have improved metabolic stability and/or solubility in water. Metabolic stability and solubility of selected compounds illustrated in Table 1 below.

Table 1
Metabolic stability (hClint and rClint) and solubility
Solubility (M)hClint (µl/min/mg)rClint (µl/min/mg)
3,E-0610,698,04
7,E-065,7611,74
4,E-067,4123,38
0,00000593to 7.7710,24
0,0000518555,27<4,0
0,0003533375,7262,60
0,000000618,0315,36
0,00000051<4,0006,87
0,00023307<4,00N/O
0,0001541811,51N/O

EXAMPLES

The invention hereinafter disclosed in more detail in the following Examples, which describe the ways in which the compounds of the present invention can be obtained, purified, analyzed and subjected to biological evaluation, and which should not be understood as limiting the invention.

Example 1

N-[2-tert-Butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylcyclopentanone

Stage A: N-[2-tert-Butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylcyclopentanone

2-tert-Butyl-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine (for more see the following stage B-E) (50 mg, 0,166 mmol) and catalytic amount of DMAP (4-dimethylaminopyridine) was dissolved in 5 ml of DCM (dichloromethane). Was added dropwise cyclopropanesulfonyl (30 mg, 0,216 mmol) and the solution was stirred at RT (room temperature) overnight. The solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. The product on which imali by HPLC (high performance liquid chromatography with reversed phase, using a mixture of 10-70% CH2SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA (triperoxonane acid) salt. Yield: 56 mg (65%).1H NMR (400 MHz, METHANOL-D4) δ 0.90-0.94 (m, 2 H), 0.97-1.02 (m, 2 H), 1.53-1.59 (m, 2 H), 1.59-1.65 (m, 2 H), 1.69 (s, 9 H), 2.36-2.42 (m, 1 H), 2.60-2.65 (m, 1 H), 3.36 (m, 2 H), 3.43 (s, 3 H), 3.94 (d, J=to 3.58 Hz, 1 H), 3.96 (d, J=3,07 Hz, 1 H), 4.55 (d, J=7.68 per Hz, 2 H), 7.74 (dd, J=8,96, is 2.05 Hz, 1 H), 7.81 (d, J=1,54 Hz, 1 H), 7.98 (d, J=8,96 Hz, 1 H); MS (ESI) mass spectrometry with electrospray ionisation) (M+N)+406,0.

Stage B: Methyl-(4-fluoro-3-nitrophenyl)carbamate

Methylchloroform (13,2 ml, 170,2 mmol) was added dropwise to a cold (0°C.) dichloromethane (200 ml) solution of 4-fluoro-3-nitroaniline (24,15 g 154,7 mmol) and DIPEA (N,N-diisopropylethylamine, 35 ml, 201 mmol). The reaction mixture was stirred at RT over night. The solution is then diluted with 200 ml dichloromethane and washed with 2 M HCl, brine and dried over anhydrous gSO4. The solvent is evaporated and the product was used directly in the next stage without additional purification. Output: 35.5 g (99%).1H NMR (400 MHz, CHLOROFORM-D) δ 3.81 (s, 3 H), 7.02 (s, 1 H), 7.23 (m, 1 H), 7.72 (d, J=8,59 Hz, 1 H), 8.17 (dd, J=6.35mm, of 2.64 Hz, 1 H).

Stage b: Methyl-{3-nitro-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}carbamate

Methyl-(4-fluoro-3-nitrophenyl)carbamate (2.0 g, to 9.32 mmol) and 4-aminomethyl the-tetrahydropyran (1.28 g, of 11.2 mmol) was stirred in 50 ml tO containing TEA (triethylamine, 2.0 ml, 14.0 mmol) at 75°C for 48 h, the solvent is evaporated. The residue was dissolved in tO and washed with aqueous 5%S4, saturated aqueous Panso3, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel, using as eluent a mixture of 1:1 / hexane: tO. Output: 2,53 g (88%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.42 (m, 2 H), 1.73 (d, J=1,76 Hz, 1 H), 1.76 (d, J=1,95 Hz, 1 H), 1.88-2.01 (m, 1 H), 3.22 (dd, J=6,74, to 5.57 Hz, 2 H), 3.42 (m, 2 H), 3.78 (s, 3 H), 4.01 (d, J=4,30 Hz, 1 H), 4.04 (d, J=3,51 Hz, 1 H), 6.48 (.s, 1H), 6.85 (d, J=9,37 Hz, 1 H), 7.65 (.s, 1 H), 8.03-8.09 (m, 2 H).

Stage D: Methyl-{3-amino-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}carbamate

Methyl-{3-nitro-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}-carbamate (2,53 g, 8,18 mmol) was dissolved in 50 ml of EtOAc containing a catalytic amount of 10% Pd/C. the Solution was shaken in an atmosphere of H2(40 pound-force per square inch (276 kPa)using the apparatus for Parr hydrogenation (Parr), over night at RT. The solution was filtered through celite and the solvent evaporated. Output: to 2.29 g (99%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.40 (m, 2 H), 1.70-1.74 (m, 1 H), 1.74-1.77 (m, 1 H), 1.81-1.92 (m, 1 H), 2.99 (d, J=6,64 Hz, 2 H), 3.34 (.s, 2 H), 3.41 (m, 2 H), 3.74 (s, 3 H), 3.99 (d, J=3,51 Hz, 1 H), 4.02 (d, J=3,51 Hz, 1 H), 6.38 (.s, 1 H), 6.55-6.60 (m, 1 H), 6.62-6.68 (m, 1 H), 6.95 (.s, 1 H).

Stage D: Methyl-[2-tert-BU the Il-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]carbamate

Methyl-{3-amino-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}-carbamate (to 2.29 g, 8.20 mmol) and DMAP (0.20 g, of 1.64 mmol) was dissolved in 75 ml of DCM (dichloromethane). Was added dropwise trimethylacetylchloride (1,10 ml of 9.02 mmol) and the solution was stirred at RT for 2 h the Solution was washed in an aqueous solution of NaHCO3, brine and dried over anhydrous gSO4. The residue was dissolved in 25 ml of Asón and was heated at 125°C for 1 h using a Personal Chemistry microwave device. The solvent is evaporated. The residue was dissolved in EtOAc and washed with aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel, using as eluent a mixture of 4:3 / hexane:acetone. Output: 1,81 g (64%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.48-1.54 (m, 4 H), 1.56 (s, 9 H), 2.23-2.35 (m, 1 H), 3.27-3.35 (m, 2 H), 3.78 (s, 3 H), 3.96 (t, J=2,93 Hz, 1 H), 3.99 (t, J=3,03 Hz, 1 H), 4.18 (d, J=7,42 Hz, 2 H), 6.63 (.s, 1 H), 7.24-7.28 (m, 1 H), 7.41 (.s, 1 H), 7.61 (d, J=1,95 Hz, 1 H).

Stage E: 2-tert-Butyl-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine

Methyl-[2-tert-butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]carbamate (1.80 g, to 5.21 mmol) was dissolved in 75 ml of THF (tetrahydrofuran) at 0°C. was Added dropwise a mixture of 1M HCl/diethyl ether (7.3 ml, 7,29 mmol) and the solution was stirred at 0°C for 15 minutes Slowly add the Yali LiAlH 4(988 mg, 26,1 mmol) and the solution was stirred at RT over night. The reaction mixture was extinguished at 0°C by adding Meon (5 ml)and then water (10 ml)and the solution was left to mix at RT for 30 minutes was Added anhydrous Na2SO4(10 g) and the solution was stirred at RT for a further 30 minutes the Solution was filtered and the solvent evaporated. The residue was dissolved in tO and washed with an aqueous solution Panso3, brine and dried over anhydrous gS4. The solvent is evaporated. Yield: 1.54 g (98%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.49-1.53 (m, 4 H), 1.53-1.57 (m, 9 H), 2,22-2.32 (m, 1 H), 2.87 (s, 3 H), 3.26-3.35 (m, 2 H), 3.95 (t, J=3,03 Hz, 1 H), 3.97-4.00 (m, 1 H), 4.13 (d, J=7,42 Hz, 2 H), 6.61 (dd, J=8,59, of 2.15 Hz, 1 H), 6.99 (d, J=1,95 Hz, 1 H), 7.11 (d, J=8,59 Hz, 1 H).

Example 2

N-[2-tert-Butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylpropan-1-sulfonamide

2-tert-Butyl-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine (for more see Stage B-E from Example 1) (50 mg, 0,166 mmol) and catalytic amount of DMAP were dissolved in 5 ml DCM. Was added dropwise 1-propanesulfonate (0,024 ml, 0,216 mmol) and the solution was stirred at RT for 3 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous gSO4. The product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3CN/H2O, and lyophilize is ovali obtaining specified in the title compound as the corresponding TFA salt. Yield: 60 mg (69%);1H NMR (400 MHz, METHANOL-D4) δ 1.02 (t, J=7,42 Hz, 3 H), 1.54-1.59 (m, 2 H), 1.60-1.66 (m,2 H), 1.69(s,9 H), 1.76-1.83 (m, 2 H), 2.36-2.42 (m, 1 H), 3.09-3.13 (m, 2 H), 3.36 (m, 2 H), 3.40 (s, 3 H), 3.94 (d, J=to 3.58 Hz, 1 H), 3.95 (d, J=to 3.58 Hz, 1 H), 4.55 (d, J=7.68 per Hz, 2 H), 7.70 (dd, J=8,6, is 2.05 Hz, 1 H), 7.81 (d, J=1,79 Hz, 1 H), 7.98 (d, J=8,96 Hz, 1 H); MS (ESI) (M+H)+408,0.

Example 3

N-[2-tert-Butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylbutane-1-sulfonamide

2-tert-Butyl-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine (for more see Stage B, C, G, D and E of Example 1) (38 mg, 0,126 mmol) and 1-butanesulfonate (0,025 ml, 0,189 mmol) was stirred in 3 ml of DCM containing a catalytic amount of DMAP, at RT over night. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-60% CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 39 mg (58%).1H NMR (400 MHz, METHANOL-D4): δ 0.88-0.94 (m, 3 H), 1.43 (m, 2 H), 1.53-1.59 (m, 2 H) 1.59-1.66 (m, 2 H), 1.69 (s, 9 H), 1.71-1.77 (m, 2 H), 2.35-2.42 (m, 1 H), 3.10-3.16 (m, 2 H), 3.35 (m, 2 H), 3.40 (s, 3 H), 3.93 (d, J=3.12 Hz, 1 H), 3.96 (d, J=3,71 Hz, 1 H), 4.54 (d, J=7,42 Hz, 2 H), 7.69 (dd, J=8,98, of 2.15 Hz, 1 H), 7.81 (d, J=1,56 Hz, 1 H), 7.97 (d, J=8,98 Hz, 1 H); MS (ESI) (M+H)+422,2; Analyt. Rasch. for C22H35N3About3S + 1,3 TFA + 1,2H2O: C, 49,96; H, 6,60; N, 7,10. Found: C, 49,98; H, To 6.67; N, 6,83.

Example 4

N-{2-tert-Butyl-1-[(4,4-d is forcelogix)methyl]-1H-benzimidazole-5-yl}-N-methylbutane-1-sulfonamide

Stage A: N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylbutane-1-sulfonamide

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-N-methyl-1H-benzimidazole-5-amine (for more see the following Stage B, C, D, E, f and G) (46 mg, 0,137 mmol) and 1-butanesulfonate (0,063 ml, 0,411 mmol) was stirred in 3 ml of DCM containing a catalytic amount of DMAP, at RT for 6 h, the Solvent evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-75% CH3SP/H2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 48 mg (62%).1H NMR (400 MHz, METHANOL-D4): δ 0.92 (t, J=to 7.32 Hz, 3 H), 1.43 (m, 2 H), 1.52-1.63 (m, 2 H), 1.69 (s, 9 H), 1.70-1.76 (m, 4 H), 1.76-1.84 (m, 2 H), 2.02-2.12 (m, 2 H), 2.22-2.31 (m, 1 H), 3.10-3.17 (m, 2 H), 3.41 (s, 3 H), 4.56 (d, J=a 7.62 Hz, 2 H), 7.69 (dd, J=8,98, of 2.15 Hz, 1 H), 7.82 (d, J=1,76 Hz, 1 H), 7.96 (d, J=9,18 Hz, 1 H); MS (ESI) (M+H)+456.

Stage B: tert-Butyl[(4,4-diverticulosis)methyl]carbamate

4-N-BOC-aminomethylpyrrolidine (1,00 g, 4.4 mmol) was dissolved in 30 ml of DCM at 0°C. was Added dropwise DAST (diethylaminomethyl TRIFLUORIDE, a 1.45 ml, 11.0 mmol) and the solution was stirred at RT over night. The solution is washed with aqueous 5%solution of KHSO4, saturated aqueous Panso3brine and was dried to the anhydrous gSO 4. The crude product was purified by flash chromatography on silica gel, using as eluent a mixture of 3:1 / hexane: tO. Output: 508 mg (46%).1H NMR (400 MHz, CHLOROFORM-D): δ 1.19-1.36 (m, 2 H), 1.44 (s, 9 H), 1.51-1.56 (m, 1 H), 1.59-1.75 (m, 2 H), 1.75-1.84 (m, 2 H), 2.01-2.16 (m, 2 H), 3.03 (t, J=6,54 Hz, 2 H), 4.62 (Sirs, 1 H).

Stage b: [(4,4-Diverticulosis)methyl]amine hydrochloride

tert-Butyl[(4,4-diverticulosis)methyl]carbamate (505 mg, 2.03 mmol) was stirred in 5 ml of 1M HCl/AcOH at RT for 2 h the Solvent is evaporated. The residue was washed with diethyl ether, filtered and dried. Yield: 330 mg (88%).1H NMR (400 MHz, METHANOL-D4): δ 1.28-1.40 (m, 2 H), 1.71-1.82 (m, 2 H), 1.84 (d, J=3.12 Hz, 2 H), 1.86-1.89 (m, 1 H), 2.03-2.15 (m, 2 H), 2.85 (d, J=7.03 is Hz, 2 H).

Stage D: Methyl-(4-{[(4,4-diverticulosis)methyl]amino}-3-nitrophenyl)carbamate

Followed the same methodology as in Stage b of Example 1 using [(4,4-diverticulosis)methyl]amine hydrochloride (210 mg, 1.12 mmol), methyl-(4-fluoro-3-nitrophenyl)carbamate (200 mg, 0,934 mmol) and TEA (0,390 ml, 2,80 mmol) in 10 ml tO. The crude product was purified by flash chromatography on silica gel using a mixture of 5% diethyl ether/DCM as eluent. Yield: 200 mg (62%).1H NMR (400 MHz, CHLOROFORM-D): δ 1.34-1.47 (m, 2 H), 1.65-1.75 (m, 2 H), 1.78-1.85 (m, 1 H), 1.90-1.93 (m, 1 H), 1.94-1.97 (m, 1 H), 2.10-2.21 (m, 2 H), 3.23 (dd, J=6,64, to 5.66 Hz, 2 H), 3.78 (s, 3 H), 6.48 (.s, 1 H), 6.83 (d, J=9,18 Hz, 1 H), 7.66 (the .s, 1 H), 8.05 (.s, 1 H), 8.07 (d, J=2,54 Hz, 1 H).

Stage D: Methyl-(3-amino-4-{[(4,4-diverticulosis)-methyl]amino}phenyl)carbamate

Followed the same methodology as in Stage g of Example 1, using methyl-(4-{[(4,4-diverticulosis)methyl]amino}-3-nitrophenyl)carbamate (200 mg, 0,583 mmol) and a catalytic amount of 10% Pd/C in 20 ml tO. Output:

185 mg (99%). MS (ESI) (M+H)+314,29.

Stage E: Methyl-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}carbamate

Methyl-(3-amino-4-{[(4,4-diverticulosis)methyl]amino}phenyl)-carbamate (185 mg, 0,590 mmol) and DMAP (15 mg, the amount of 0.118 mmol) was dissolved in 10 ml DCM. Was added dropwise trimethylacetylchloride (0,080 ml, 0,649 mmol) and the solution was stirred at RT for 2 h the Solution was washed with an aqueous solution Panso3, brine and dried over anhydrous MgSO4. The solvent is evaporated. The residue was dissolved in 4 ml of DCE was added P2O5(catalytic) and the solution was heated at 125°C for 1 h using a Personal Chemistry microwave device. The solution was washed with an aqueous solution NaHC3, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using a mixture of 50-75% tO / hexane. Yield: 122 mg (54%);1H NMR (400 MHz, CHLOROFORM-D): δ 1.43-1.52 (m, 2 H), 1.55 (s, 9 H), 1.57-1.66 (m, 2 H), 1.67-1.74 (m, 2 H), 2.08-2.18 (m, 3 H), 3.79 (s, 3 ), 4.19 (d, J=7,42 Hz, 2 H), 6.63 (.s, 1 H), 7.23 (d, J=8,79 Hz, 1 H), 7.37-7.46 (m, 1 H), 7.62 (d, J=1,76 Hz, 1 H).

Stage G: 2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-N-methyl-1H-benzimidazole-5-amine

Methyl-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}carbamate (115 mg, 0,303 mmol) was dissolved in 10 ml of THF (tetrahydrofuran) at 0°C. was Added 1M HCl/diethyl ether (0,425 ml, 0,424 mmol) and the solution was stirred at 0°C for 15 minutes was Slowly added LiAlH4(57 mg, of 1.52 mmol) and the solution was stirred at RT over night. The reaction mixture was extinguished at 0°C by adding Meon (1 ml) and water (2 ml). Added anhydrous Na2SO4(5.0 g) and the solution was stirred at RT for 30 min the Solution was filtered and the solvent evaporated. The residue was dissolved in EtOAc and washed with saturated aqueous NaHC3, brine and dried over anhydrous gS4. Yield: 95 mg (93%).1H NMR (400 MHz, CHLOROFORM-D): δ 1.41-1.51 (m, 2 H), 1.54 (s, 9 H), 1.57-1.67 (m, 2 H), 1.68-1.76 (m, 3 H), 2.07-2.17 (m, 3 H), 2.87 (s, 3 H), 4.15 (d, J=7,42 Hz, 2 H), 6.61 (dd, J=8,59, of 2.34 Hz, 1 H), 7.01 (d, J=1,95 Hz, 1 H), 7.09 (d, J=8,59 Hz, 1 H).

Example 5

N-Methyl-N-[1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-yl]propane-1-sulfonamide

Stage A: N-Methyl-N-[1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-yl]propane-1-sulfonamide

P is opan-1-sulphonylchloride (27 μl, 34 mg, 0.24 mmol) was added to a solution of N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-amine (63 mg, 0.20 mmol) (see following steps B, C, D, E, f and G to obtain), DIPEA (49 μl, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 ml) at 0°C. the Reaction mixture was stirred over night at room temperature, diluted with DCM (50 ml), washed with saturated Panso3(2×10 ml) and dried over Na2SO4. The crude product was purified by MPLC (liquid chromatography medium pressure)using a mixture of Gex./tO (1:1)on silica gel to obtain 40 mg (47%) indicated in the title compound as a white solid.1H NMR (400 MHz, METHANOL-D4): δ 1.00 (t, J=7,42 Hz, 3 H), 1.38-1.53 (m, 4 H), 1.70-1.88 (m, 2 H), 2.15-2.30 (m, 1 H), 3.01-3.11 (m, 2 H), 3.28-3.33 (m, 2 H), 3.35 (s, 3 H), 3.88-3.91 (m, 2 H), 4.30 (d, J=a 7.62 Hz, 2 H), 7.55 (dd, J=8,79, to 1.76 Hz, 1 H), 7.75 (d, J=8,98 Hz, 1 H), 7.82 (d, J=1,56 Hz, 1 H). MS (ESI) (M+H)+=420,0. Analyte. Rasch. for C18H24F3N3About3S + 0,20 H2O + 0,30 CH3HE (432,68): C, 50,80; H, 5,96; N, 9,71; found: C, 50,79; H, 5,91; N, RS 9.69.

Stage B. N-(4-fluoro-3-nitrophenyl)ndimethylacetamide

4-Fluoro-3-nitro-aniline (45,0 g, in 0.288 mol) was added in portions to acetic anhydride (150 ml) at room temperature. The reaction mixture was stirred at room temperature for 2 h White solid was collected and dried in vacuum to obtain specified what about the title compound (42,0 g, 70%).1H NMR (400 MHz, CHLOROFORM-D): δ 2.23 (s, 3 H), 7.26 (m, 1 H), 7.50 (s broad, 1 H), 7.87 (m, 1 H), 8.23 (dd, J=6,44, by 2.73 Hz, 1 H).

Stage b: N-(4-fluoro-3-nitrophenyl)-N-methylacetamide

Sodium hydride (4,22 g, 60%, 106 mmol) was added in portions to a solution of N-(4-fluoro-3-nitrophenyl)ndimethylacetamide (13,9 g, 70 mmol) in THF (200 ml) at 0°C. Under stirring for 20 min was added itmean (18.5 g, 130 mmol). The reaction mixture was stirred at room temperature for 2 h, extinguished saturated Panso3(30 ml) and was extracted with tO (3×100 ml). The combined organic phases were washed with saturated NaCl (2×50 ml). After filtration and evaporation was received of 13.1 g (88%) indicated in the title compound as a yellow solid.1H NMR (400 MHz, CHLOROFORM-D): δ 1.92 (s, 3 H), 3.30 (s, 3 H), 7.38 (s, 1 H), 7.52 (s, 1 H), 7.95 (s, 1 H).

Stage, N-methyl-N-{3-nitro-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}ndimethylacetamide

4-Aminomethylpyridine (10.0 g, 86,5 mmol) was added to a mixture of N-(4-fluoro-3-nitrophenyl)-N-methylacetamide (15.6 g, 73,3 mmol) and TEA (triethylamine, 15.3 ml, 11.1 g, 110 mmol) in tO (300 ml) at room temperature. The reaction mixture was heated under reflux for 6 hours After evaporation of the ethanol, the residue was dissolved in tO (400 ml), washed with H2About (3×50 ml), saturated NaCl (3×50 ml), and dried over Na2SO4. After filtration of the evaporation got to 21.7 g (96%) indicated in the title compound as a red-orange solid. 1H NMR (400 MHz, CHLOROFORM-D): δ 1.38-1.52 (m, 2 H), 1.72-1.81 (m, 2 H), 1.90 (s, 3 H), 1.93-2.02 (m, 1 H), 3.23 (s, 3 H), 3.23-3.27 (m, 2 H), 3.36-3.49 (m, 2 H), 4.01-4.07 (m, 2 H), 6.91 (d, J=9,18 Hz, 1 H), 7.29 (dd, J=remaining 9.08, 2.64 Hz, 1 H), 8.05 (d, J=2,34 Hz, 1 H), 8.22 (t, J=lower than the 5.37 Hz, 1 H). MS (ESI) (M+H)+=309,12.

Stage D. N-{3-Amino-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}-N-methylacetamide

N-Methyl-N-{3-nitro-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]-phenyl}ndimethylacetamide (21,7 g, 70.5 mmol) was first made in ethyl acetate (500 ml) with 10% Pd/C (1.0 g) as a catalyst at 30-40 pound-force per square inch (207-276 kPa) H2in Parr shaker for 18 h at room temperature. After filtration through celite and evaporation got a 19.6 g (100%) of a purple solid.1H NMR (400 MHz, CHLOROFORM-D): δ 1.35-1.50 (m, 2 H), 1.67 (s, 1 H), 1.73-1.81 (m, 2 H), 1.88 (s, 3 H), 1.88-1,99 (m, 1 H), 3.04 (d, J=6,64 Hz, 2 H), 3.20 (s, 3 H), 3.33-3.48 (m, 4 H), 3.97-4.08 (m, 2 H), 6.54 (d, J=1,76 Hz, 1 H), 6.60-6.63 (m, 2 H); MS (ESI) (M+H)+: 278,7.

Stage E. N-Methyl-N-[1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-yl]ndimethylacetamide

A solution of N-{3-amino-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}-N-methylacetamide hydrochloride (2,77 g, 10 mmol) in triperoxonane acid (60 ml) was heated to the boil for 18 hours After evaporation of the solvent the residue was dissolved in tO (200 ml), washed 2 N. NaOH (2×10 ml) and dried over Na2SO4. The crude product was purified by MPLC, use the Zuya tO on silica gel, getting 3,18 g (90%) indicated in the title compounds as white solids. MS (ESI) (M+H)+=356,02.

Stage g of N-Methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-amine

N-Methyl-N-[1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-yl]ndimethylacetamide (3,18 g of 8.95 mmol) was dissolved in hydrochloric acid (37%, 60 ml) and then heated overnight at 95°C. After evaporation the residue was treated with 20 ml of 2 N. NaOH, and was extracted with tO (4×50 ml). The combined organic phases were washed with brine (20 ml) and dried over Na2SO4. After evaporation got 2,80 g (100%) specified in the header of the product in the form of purple-white solid, which was used directly in Stage 3. MS (ESI) (M+H)+=314,20.

Example 6

N-Methyl-N-[1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-yl]cyclopropanesulfonyl

Followed the method of Example 5 using cyclopropanesulfonyl (34 mg, 0.24 mmol), N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-2-(trifluoromethyl)-1H-benzimidazole-5-amine (63 mg, 0.20 mmol) (for more see the stage W in example 1), DIPEA (49 μl, 36 mg, 0.28 mmol) and DMAP (5 mg, 0.04 mmol) in DCM (6 ml) at 0°C. the Crude product was purified by MPLC using a mixture of Gex./tO (1:1) on silica gel, receiving 81 mg (97%) specified in sialometaplasia in the form of a white solid. 1H NMR (400 MHz, METHANOL-D4): δ 0.85-0.92 (m, 2 H), 0.93-1.01 (m, 2 H), 1.37-1.52 (m, 4 H), 2.18-2.31 (m, 1 H), 2.55-2.65 (m, 1 H), 3.30-3.36 (m, 2 H), 3.38 (s, 3 H), 3.86-3.95 (m, 2 H), 4.32 (d, J=a 7.62 Hz, 2 H), 7.58 (dd, J=8,89, is 2.05 Hz, 1 H), 7.76 (d, J=8,79 Hz, 1 H) 7.86 (d, J=1.5 Hz, 1 H). MS (ESI) (M+H)+=418,0. Analyte. Rasch. for C18H22F3N3O3S + 0,10 N2O + 0,20 CH3HE (425,66): C, 51,36; N, THE 5.45; N, 9,87; found: C, 51,39; N, 5,49; N, 9,92.

Example 7

N-[2-tert-Butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylpentan-1-sulfonamide

2-tert-Butyl-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine (65 mg, 0,216 mmol) and catalytic amount of DMAP were dissolved in 3 ml of DCE. Was added n-intercolonial (44 mg, 0,259 mmol) and the solution was stirred at RT for 4 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 89 mg (75%).1H NMR (400 MHz, METHANOL-

D4) δ 0.89 (t, J=7,13 Hz, 3 H), 1.26-1.34 (m, 2 H), 1.34-1.43 (m, 2 H), 1.52-1.58 (m, 2 H), 1.58-1.66 (m, 2 H), 1.69(s, 9H), 1.71-1.80(m, 2 H), 2.34-2.43 (m, 1 H), 3.09-3.16 (m, 2 H), 3.36 (td, J=11,47, of 2.64 Hz, 2 H), 3.40 (s, 3 H) 3.93 (d, J=3.12 Hz, 1 H), 3.95-3.97 (m, 1 H), 4.55 (d, J=a 7.62 Hz, 2 H), 7.69 (dd, J=remaining 9.08, is 2.05 Hz, 1 H), 7.81 (d, J=1,56 Hz, 1 H), 7.97 (d, J8,59 Hz, 1 H); MS (ESI) (M+H)+km 436.0; Analyt. Rasch. (%) for C23H37N3O3S + 1,1 TFA + 0,9 H2O; C, 52,43; H, 6,97; N, 7,28. Found: C, 52,39; H, Of 6.96; N, 7,43.

Example 8

N-[2-tert-Butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylethanolamine

2-tert-Butyl-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine (50 mg, 0,166 mmol) and catalytic amount of DMAP were dissolved in 3 ml of DCE. Added acanaloniidae (0,020 ml, 0,215 mmol) and the solution was stirred at RT for 12 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/H2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 70 mg (83%).1H NMR (600 MHz, CD3OD) δ 1.31 (t, J=7,30 Hz, 3 H), 1.53-1.58 (m, 2 H), 1.58-1.65 (m, 2 H), 1.69 (s, 9 H), 2.35-2.42 (m, 1 H), 3.16 (m, 2 H), 3.35 (m, 2 H), 3.41 (s, 3 H), 3.94 (d, J=3,84 Hz, 1 H), 3.95 (d, J=3,84 Hz, 1 H), 4.54 (d, J=7.68 per Hz, 2 H), 7.69 (dd, J=a 9.09, with 1.92 Hz, 1 H), 7.81 (d, J=1,79 Hz, 1 H), 7.97 (d, J=8,96 Hz, 1 H); MS (ESI) (M+H)+394,0; Analyt. Rasch. (%) for C20H31N3About3S + 1,4 TFA: C, 49,50; N, 5,90; N, 7,60. Found: C, 49,51; N, 6,00; N, 7,24.

Example 9

N-[2-tert-Butyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N,2-DIMETHYLPROPANE-2-sulfonamide

2-tert-Butyl-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine (50 mg, 0,166 mmol) and DMAP (20 mg, 0,166 mmol) was dissolved in 3 ml of DCM. Added tert-butylsulfonyl (0,027 ml, 0,215 mmol) and the solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. Added 3-chloroperoxybenzoic acid (37 mg, 0,166 mmol) and the solution was stirred at RT for 1 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous gS4. The product was purified by HPLC with reversed phase, using a mixture of 10-70%

CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 34 mg (38%).1H NMR (400 MHz, METHANOL-D4) δ 1.37 (s, 9 H), 1.52-1.58 (m, 2 H), 1.59-1.66 (m, 2 H), 1.69 (s, 9 H), 2.34-2.44 (m, 1 H), 3.36 (m, 2 H), 3.48 (s, 3 H), 3.93 (d, J=3,32 Hz, 1 H), 3.95-3.97 (m, 1 H), 4.54 (d, J=a 7.62 Hz, 2 H), 7.78 (dd, J=remaining 9.08, is 2.05 Hz, 1 H), 7.92 (d, J=2,15 Hz, 1 H), 7.96 (d, J=9,18 Hz, 1 H); MS (ESI) (M+H)+422,0.

Example 10

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylpropan-1-sulfonamide

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-N-methyl-1H-benzimidazole-5-amine (45 mg, 0,134 mmol) and catalytic amount of DMAP were dissolved in 3 ml of DCE. Added propanesulfonate (0,020 ml, 0,174 mmol) and the solution per Merivale at RT for 4 hours The solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous gS4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 55 mg (74%).1H NMR (400 MHz, METHANOL-

D4) δ 1.00 (t, J=7,42 Hz, 3 H), 1.51-1.60 (m, 2 H), 1.66 (s, 9 H), 1.68-1.73 (m, 2 H), 1.73-1.81 (m, 4 H), 2.00-2.11 (m, 2 H), 2.18-2.29 (m, 1 H) 3.06-3.12 (m, 2 H), 3.38 (s, 3 H), 4.54 (d, J=a 7.62 Hz, 2 H), 7.67 (dd, J=remaining 9.08, is 2.05 Hz, 1 H), 7.79 (d, J=1,56 Hz, 1 H), 7.94 (d, J=8,98 Hz, 1 H); MS (ESI) (M+H)+442,0; Analyt. Rasch. (%) for C22H33N3O2SF2+ 1,0 TFA + 1,6 H2O: C, 49,32; H, 6.42 PER; N, 7,10. Found: C, Of 49.39; H, 6,66; N, Of 6.71.

Example 11

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylethanolamine

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-N-methyl-1H-benzimidazole-5-amine (49 mg, 0,146 mmol) and catalytic amount of DMAP were dissolved in 3 ml of DCM. Added acanaloniidae (0,018 ml, 0,190 mmol) and the solution was stirred at RT for 12 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/H2Oh, and liofilizirovanny with receiving the receiving specified in the title compound as the corresponding TFA salt. Yield: 58 mg (73%).1H NMR (600 MHz, MeOD) δ 1.31 (t, J=7,42 Hz, 3 H), 1.34-1.41 (m, 2 H), 1.54-1.62 (m, 2 H), 1.69 (s, 9 H), 1.72-1.80 (m, 2 H), 2.03-2.11 (m, 2 H), 2.23-2.30 (m, 1 H), 3.17 (q, J=7,25 Hz, 2 H), 3.41 (s, 3 H), 4.56 (d, J=7.68 per Hz, 2 H), 7.70 (dd, J=8,96, is 2.05 Hz, 1 H), 7.82 (d, J=2,05 Hz, 1 H), 7.96 (d, J=8,96 Hz, 1 H); MS (ESI) (M+H)+428,0.

Example 12

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}propane-1-sulfonamide

Stage A: N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}propane-1-sulfonamide

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-amine (for more see the following steps B-D) (45 mg, 0,140 mmol) and catalytic amount of DMAP were dissolved in 3 ml of DCM. Added propanesulfonate (0,020 ml of 0.182 mmol) and the solution was stirred at RT for 4 h the Solution was washed with a saturated aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 39 mg (51%).1H NMR (600 MHz, CD3OD) δ 1.00 (t, J=at 7.55 Hz, 3 H), 1.53-1.61 (m, 2 H), 1.67 (s, 9 H), 1.70-1.77 (m, 3 H), 1.77-1.85 (m, 3 H), 2.02-2.11 (m, 2 H), 2.22-2.29 (m, 1 H), 3.08-3.13 (m, 2 H), 4.53 (d, J=7,42 Hz, 2 H), 7.41 (dd, J=a 9.09, with 1.92 Hz, 1 H), 7.75 (d, J=1,79 Hz, 1 H), 7.89 (d, J=which 9.22 Hz, 1 H); MS (ESI) (M+H)+428,0.

Study the B: N-(4-{[(4,4-diverticulosis)methyl]amino}-3-nitrophenyl)ndimethylacetamide

N-(4-Fluoro-3-nitrophenyl)ndimethylacetamide (1,15 g of 5.84 mmol) and [(4,4-diverticulosis)methyl]amine hydrochloride (1.30 grams, to 7.59 mmol) was stirred in 30 ml tO containing TEA (2,40 ml, 17.5 mmol)at 80°C for 48 hours, the Solvent is evaporated. The residue was dissolved in tO and washed with aqueous 5%solution S4, saturated aqueous Panso3, saturated aqueous NaCl, and dried over anhydrous Na2SO4. The product was led from tO. The remains of the above mother liquor was purified by flash chromatography on silica gel using a mixture of 2:1 / hexane:acetone as eluent. Yield: 1.50 g (78%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.33-1.47 (m, 2 H), 1.66-1.77 (m, 2 H), 1.77-1.86 (m, 1 H), 1.89-1.93 (m, 1 H), 1.93-1.97 (m, 1 H), 2.10-2.17 (m, 2 H), 2.18 (s, 3 H), 3.23 (dd, J=6,74, USD 5.76 Hz, 2 H), 6.83 (d, J=9,37 Hz, 1 H), 7.15 (s, 1 H), 7.80 (dd, J=9,18, of 2.54 Hz, 1 H), 8.09 (d, J=2,54 Hz, 2 H).

Stage b: N-(3-Amino-4-{[(4,4-diverticulosis)methyl]amino}-phenyl)ndimethylacetamide

N-(4-{[(4,4-diverticulosis)methyl]amino}-3-nitrophenyl)ndimethylacetamide (1.48 g, to 4.52 mmol) was dissolved in 50 ml tO containing a catalytic amount of 10% Pd/C. the Solution was shaken in the apparatus for hydrogenation Parra in the atmosphere of H2(45 pounds-force per square inch, 310 kPa) at RT for 24 h the Solution was filtered through celite and the solvent evaporated. Output: 1,32 g (98%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.31-1.43 (m, 2 H), 1.64-173 (m, 2 H), 1.74-1.82 (m, 1 H), 1.89-1.93 (m, 1 H), 1.93-1.96 (m, 1 H), 2.08-2.17 (m, 5 H), 3.00 (d, J=6,64 Hz, 2 H), 3.27-3.46 (m, 2 H), 6.55 (d, J=8,40 Hz, 1 H), 6.70 (dd, J=8,40, of 2.34 Hz, 1 H), 7.01 (s, 1 H), 7.13 (d, J=2,34 Hz, 1 H).

Stage D: N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}ndimethylacetamide

N-(3-Amino-4-{[(4,4-diverticulosis)methyl]amino}phenyl)ndimethylacetamide (1,32 g of 4.44 mmol) was dissolved in 100 ml of DCM containing DMAP (108 mg, 0.89 mmol). Was added dropwise trimethylacetylchloride (of 0.60 ml, 4,88 mmol) and the solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution of NaHCO3, saturated aqueous NaCl, and dried over anhydrous

Na2SO4. Part of the product precipitated during the washing and filtration. The organic phases are evaporated and combined with the precipitate. The product was dissolved in 30 ml of Asón and placed 6 resealable tubes (5 ml/tube). Each tube was heated at 150°C. in a Personal Chemistry microwave device within 2.5 hours Fractions were combined and the solvent evaporated. The product was dissolved in tO and washed with an aqueous solution Panso3, saturated aqueous NaCl, and dried over anhydrous Na2SO4. The product was purified by flash chromatography on silica gel using a mixture of 2:1 acetone:hexane as eluent. Output: 1,11 g (68%).1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.49 (m, 2 H), 1.52 (s, 9 H), 1.60-1.65 (m, 2 H), 1.67-1.77 (m, 1 H) 1.96-2.06 (m, 3H),2.11 (s, 3 H), 2.15-2.23 (m, 1 H), 4.28 (d, J=a 7.62 Hz, 2 H), 7.35-7.39 (m, 1 H), 7.40-7.44 (m, 1 H), 7.85 (d, J=1,76 Hz, 1 H).

Stage D: 2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-amine

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}ndimethylacetamide (500 mg, 1.37 mmol) was dissolved in 10 ml of a mixture 1:1 / tO:2 M HCl. The solution was divided in two resealable tubes (5 ml/tube). Each tube was heated at 120°C. in a Personal Chemistry microwave device within 1 h Fractions were combined and the solvent evaporated. The residue was diluted with 2 M NaOH and was extracted (3X) tO. The organic phase is washed with saturated aqueous NaCl and dried over anhydrous Na2SO4. The solvent is evaporated. Yield: 440 mg (99%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.40-1.52 (m, 2 H), 1.52-1.54 (m, 9 H), 1.56-1.66 (m, 4 H), 1.68-1.75 (m, 2 H), 2.07-2.17 (m, 3 H), 4.14 (d, J=a 7.62 Hz, 2 H), 6.65 (dd, J=8,50, 2.25 Hz, 1 H), 7.04-7.09 (m, 2 H).

Example 13

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}methanesulfonamide

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-amine (40 mg, 0,124 mmol) and catalytic amount of DMAP were dissolved in 3 ml of DCM. Added methanesulfonamide (0,012 ml, 0,149 mmol) and the solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution of NaHCO3, brine and dried over anhydrous gS4. Dissolve the ü evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/N2O, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 50 mg (79%).1H NMR (600 MHz, MeOD) δ 1.53-1.61 (m, 2 H), 1.67 (s, 9 H), 1.71-1.76 (m, 3 H), 1.76-1.82 (m, 1 H), 2.04-2.11 (m, 2 H), 2.23-2.29 (m, 1 H), 3.01 (s, 3 H), 4.54 (d, J=7.68 per Hz, 2 H), 7.42 (dd, J=which 9.22, is 2.05 Hz, 1 H), 7.75 (d, J=1,79 Hz, 1 H), 7.91 (d, J=8,96 Hz, 1 H); MS (ESI) (M+H)+400,0; Analyt. Rasch. (%)

C19H27N3O2SF2+ 1,9 TFA + 0,1 H2O: C, 44,32; H, 4.75 V; N, 6,80. Found: C, 44,34; H, 4,78; N, 6,55.

Example 14

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}econsultant

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-amine (440 mg, 1.37 mmol) and DMAP (165 mg, 1.37 mmol) was dissolved in 50 ml DCM. Was added dropwise acanaloniidae (0,170 ml, 1.78 mmol) and the solution was stirred at RT for 2.5 h the Solution was washed with a saturated aqueous solution Panso3, saturated aqueous NaCl, and dried over anhydrous Na2SO4. The product was purified by flash chromatography on silica gel using tO as eluent. Fractions evaporated and the residue was dissolved in 25 ml of Meon. Was added dropwise TFA (0,155 ml of 2.06 mmol) and the solution was stirred at RT for 30 minutes, the Solvent evaporated and the product was besieged in diethyl ether to obtain specified in the connection header as its soo is relevant TFA salt. Output: 565 mg (78%).1H NMR (400 MHz, METHANOL-D4) δ 1.29 (t, J=7,42 Hz, 3 H), 1.48-1.60 (m, 2 H), 1.64 (s, 9 H), 1.66-1.72 (m, 2 H), 1.73-1.82 (m, 2 H), 1.99-2.09 (m, 2 H), 2.18-2.28 (m, 1 H), 3.11 (m, 2 H), 4.50 (d, J=a 7.62 Hz, 2 H), 7.38 (dd, J=the remaining 9.08, is 2.05 Hz, 1 H), 7.72 (d, J=2,15 Hz, 1 H), 7.85 (d, J=8,98 Hz, 1 H); MS (ESI) (M+H)+414,0.

Example 15

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}cyclopropanesulfonyl

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-amine (300 mg, 0,934 mmol) and DMAP (115 mg, 0,934 mmol) was dissolved in 10 ml DCM. Added cyclopropanesulfonyl (170 mg, to 1.21 mmol) and the solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. The product was purified by flash chromatography on silica gel using tO as eluent. Fractions evaporated and the residue was dissolved in 25 ml of Meon. Was added dropwise TFA (0,143 ml of 1.86 mmol) and the solution was stirred at RT for 30 minutes, the Solvent evaporated and the product was besieged in diethyl ether to obtain specified in the title compound as its corresponding TFA salt. Yield: 390 mg (77%).1H NMR (400 MHz, METHANOL-D4) δ 0.91-0.97 (m, 2 H), 1.02-1.08 (m, 2 H), 1.48-1.60 (m, 2 H), 1.65 (s, 9 H), 1.67-1.75 (m, 3 H), 1.75-1.82 (m, 1 H), 2.00-2.10 (m, 2 H), 2.18-2.28 (m, 1 H), 2.53-2.61 (m, 1 H), 4.50 (d, J=7,42 Hz, 2 H), 7.42 (dd, J=8,98, 2.15 Hz, 1 H), 7.74 (d, J=1,56 Hz, 1 H), 7.85 (d, J=8,79 Hz, 1 H); MS (ESI) (M+H)+426,0; Analyt. R is SSC. (%) for C21H29N3O2SF2+ 1,0 TFA; C, 51,20; H, THE CEILING OF 5.60; N, 7,79. Found: C, 51,38; H, To 5.66; N, 7,56.

Example 16

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-N-methylcyclopentanone

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-amine (65 mg, 0,202 mmol) and catalytic amount of DMAP were dissolved in 5 ml DCM. Added cyclopropanesulfonyl (34 mg, 0,242 mmol) and the solution was stirred at RT for 6 h, the Solution was washed with a saturated aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. The solvent is evaporated. The residue was dissolved in 5 ml of DMF at 0°C was added NaH (12 mg, 0,303 mmol). The solution was stirred at 0°C for 15 minutes was Added methyliodide (0,025 ml, 0,404 mmol) and the solution was stirred at RT for 2 h, the Reaction mixture was extinguished saturated aqueous Panso3and the solvent evaporated. The product was dissolved in tO and washed with water rostrom Panso3, saturated aqueous NaCl, and dried over anhydrous Na2SO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/N2O, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 60 mg (54%).1H NMR (600 MHz, CD3OD) δ 0.90-0.94 (m, 2 H), 0.97-1.01 (m, 2 H), 1.54-1.62 (m, 2 H), 1.68 (s, 9 H), 1.73-1.81 (m, 4 H), 2.03-2.11 (m, 2 H), 2.23-2.30 (m, 1 H). 2.59-2.65 (m, 1 H), 3.43 (s, 3 H), 4.56 (d, J=7.68 per Hz, 2 H), 7.72 (d, J=for 9.47 Hz, 1 H), 7.81 (s, 1 H), 7.95 (d, J=8,96 Hz, 1 H); MS (ESI) (M+N)+440,0.

Example 17

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}-2-methylpropan-2-sulfonamide

2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-amine (66 mg, 0,205 mmol) and DMAP (25 mg, 0,205 mmol) was dissolved in 5 ml DCM. Added tert-butylsulfonyl (0,031 ml, 0,246 mmol) and the solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. Added 3-chloroperoxybenzoic acid (90 mg, 0,410 mmol) and the solution was stirred at RT for 12 h the Solution was washed with a saturated aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. The product was purified by HPLC with reversed phase, using a mixture of 10-70%

CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 55 mg (48%).1H NMR (400 MHz, METHANOL-D4) δ 1.35 (s, 9 H), 1.49-1.60 (m, 2 H), 1.64 (s, 9 H), 1.68-1.75 (m, 3 H), 1.76-1.82 (m, 1 H), 2.00-2.09 (m, 2 H), 2.19-2.28 (m, 1 H), 4.50 (d, J=7,42 Hz, 2 H), 7.42 (dd, J=remaining 9.08, 2.05 Hz, 1 H), 7.81-7.86 (m, 2 H); MS (ESI) (M+H)+442,0; Analyt. Rasch. (%) for C22H33N3O2SF2+ 1,2 TFA + 0,2 H2O; C, 50,35; H, OF 5.99; N, 7,22. Found: C, 50,36 H, 5,73; N, 7,08.

Example 18

N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]cyclopropanesulfonyl

Stage A: N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]cyclopropanesulfonyl

N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]ndimethylacetamide (for more see next stage B) (95 mg, 0,256 mmol) was heated in 5 ml of a mixture 1:1 / 2 M HCl:EtOH at 120°C for 1 h using a Personal Chemistry microwave device. The solvent is evaporated. The residue was podslushivaet using 2 M NaOH and was extracted (3X) tO. The organic phase is washed with saturated aqueous NaCl and dried over anhydrous Na2SO4. The solvent is evaporated. The product was dissolved in 5 ml of DCM containing DMAP (31 mg, 0,256 mmol), was added cyclopropanesulfonyl (53 mg, 0.384 mmol). The solution was stirred at RT for 3 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous gSO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 35 mg (25%).1H NMR (400 MHz, METHANOL-D4) δ 0.88-0.95 (m, 2 H), 0.98-1.03 (m, 2 H), 1.39-1.51 (m, 2 H), 1.1-1.68 (m, 3 H), 1.70-1.79 (m, 1 H), 2.03 (s, 2 H), 2.15 (s, 1 H), 2.23 (m, 3 H), 2.47-2.55 (m, 1 H), 4.35 (d, J=a 7.62 Hz, 2 H), 7.39 (dd, J=8,79, of 1.95 Hz, 1 H), 7.65 (d, J=8,79 Hz, 1 H), 7.67 (d, J=2,15 Hz, 1 H); MS (ESI) (M+H)+43,0; Analyt. calculated (%) for C19H23N3O2SF4+ 0,7 TFA; C, 47,74; H AND 4.65; N, 8,19. Found: C, 47,88; H, To 4.68; N, 8,19.

Stage B: N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]ndimethylacetamide

N-(3-Amino-4-{[(4,4-diverticulosis)methyl]amino}phenyl)ndimethylacetamide (99 mg, of 0.333 mmol), DIPEA (0,087 ml, 0,500 mmol), HATU (O-(7-asobancaria-1-yl)-N,N,N,N'-tetramethylurea hexaflurophosphate, 140 mg, 0,366 mmol) and 2,2-deformationof acid (40 mg, 0,366 mmol) was stirred in 5 ml of DMF at RT for 1 h the Solvent is evaporated. The residue was dissolved in 3 ml ice Asón and was heated at 80°C for 2 hours the Solvent is evaporated. The product was dissolved in tO and washed with an aqueous solution Panso3, saturated aqueous NaCl, and dried over anhydrous Na2SO4. The product was purified by flash chromatography on silica gel using tO as eluent. Yield: 100 mg (81%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.39-1.52 (m, 2 H), 1.57-1.63 (m, 1 H), 1.64-1.71 (m, 3 H), 2.06-2.16 (m, 3 H), 2.22 (s, 3 H), 2.29 (m, 3 H), 4.25 (d, J=7,42 Hz, 2 H), 7.31 (s, 1 H), 7.35 (d, J=8,79 Hz, 1 H), 7.60 (dd, J=8,89, to 1.86 Hz, 1 H), 7.86 (d, J=1,76 Hz, 1 H).

Example 19

N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]econsultant

N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]ndimethylacetamide (80 mg, 0,215 mmol) was heated in 5 ml of a mixture 1:1 / 2 M HCl: EtOH at 120°C for 1 h using a Personal Chemistry microwave device. The solvent is evaporated. The residue was podslushivaet using 2 M NaOH and was extracted (3X) tO. The organic phase is washed with saturated aqueous NaCl and dried over anhydrous Na2SO4. The solvent is evaporated. The product was dissolved in 5 ml of DCM containing DMAP (31 mg, 0,256 mmol), was added acanaloniidae (0,026 ml, 0,280 mmol). The solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution of NaHCO2, brine and dried over anhydrous gS4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/H2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 22 mg (19%).1H NMR (400 MHz, METHANOL-D4) δ 1.29 (t, J=7,42 Hz, 3 H), 1.36-1.49 (m, 2 H), 1.58-1.66 (m, 3 H), 1.67-1.78 (m, 1 H), 1.96-2.06 (m, 2 H), 2.11-2.15 (m, 1 H), 2.21 (m, 3 H), 3.04 (m, 2 H), 4.33 (d, J=a 7.62 Hz, 2 H), 7.34 (dd, J=8,98, of 1.95 Hz, 1 H), 7.64 (dd, J=5,47, 3,32 Hz, 2 H); MS (ESI) (M+H)+421,9; Analyt. the expect.(%) for C18H23N3O2SF4+ 0,8 TFA + 0,1 H2O: C, 45,76; N, 4,70; N, 8,17. Found: C, 45,73; N, To 4.52; N, 7,80.

Example 20

N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]2-methylpropan-2-sulfonamide

N-[1-[(4,4-Diverticulosis)methyl]-2-(1,1-dottorati)-1H-benzimidazole-5-yl]ndimethylacetamide (185 mg, 0,498 mmol) was heated in 5 ml of a mixture 1:1 / 2M HCl: tO at 120°C for 1 h using a Personal Chemistry microwave device. The solvent is evaporated. The residue was podslushivaet using 2 M NaOH and was extracted (3X) tO. The organic phase is washed with saturated aqueous NaCl and dried over anhydrous Na2SO4. The solvent is evaporated. The residue was dissolved in 5 ml of DCM was added tert-butylsulfonyl (0.075 ml, 0,598 mmol) and DMAP (25 mg, 0,498 mmol). The solution was stirred at RT for 1 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. Added 3-chloroperoxybenzoic acid (225 mg, 0,996 mmol) and the solution was stirred at RT for 4 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. The product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3CN/H2O, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 70 mg (25%).1H NMR (400 MHz, METHANOL-D4) δ 1.33 (s, 9 H), 1.37-1.49 (m, 2 H), 1.60-1.65 (m, 3 H), 1.68-1.78 (m, 1 H), 1.97-2.06 (m, 2 H), 2.11-2.14 (m, 1 H), 2.21 (m, 3 H), 4.32 (d, J=a 7.62 Hz, 2 H), 7.40 (dd, J=8,89, is 2.05 Hz, 1 H), 7.59 (d, J=8,79 Hz, 1 H), 7.70 (d, J=1,95 Hz, 1 H); MS (ESI) (M+H)+449,8.

Por the measures 21

N-[2-(1,1-Dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylethanolamine

Stage A. N-[2-(1,1-dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylethanolamine

Acanaloniidae (55 μl, of 0.58 mmol) was added to a solution of 2-(1,1-dottorati)-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine (150 mg, 0.48 mmol) and DMAP (71 mg, of 0.58 mmol) in DCM (15 ml) at ambient temperature. The reaction mixture was stirred overnight and the solvent evaporated. The product was purified by preparative HPLC with reversed phase, using MeCN gradient from 10 to 90% in water, to obtain the TFA salt specified in the title compounds as white solids. Yield: 70 mg (28%);1H NMR (400 MHz, CD3OD) δ 1.24-1.37 (m, 3 H), 1.36-1.53 (m, 4 H), 2.12-2.32 (m, 3 H), 3.05-3.17 (m, 2 H), 3.25-3.31 (m, 2 H), 3.33 (d, J=3,71 Hz, 1 H), 3.36 (s, 2 H), 3.89 (m, 2 H), 4.33 (d, J=7,42 Hz, 2 H), 7.49 (dd, J=8,79, of 1.95 Hz, 1 H), 7.69 (d, J=8,98 Hz, 1 H), 7.77 (d, J=1,76 Hz, 1 H); MS (ESI) (M+H)+402,0.

Stage B. N-{5-[Acetyl(methyl)amino]-2-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}-2,2-deferrable

HATU (1.44 g, of 3.78 mmol) and N-{3-amino-4-[(tetrahydro-2H-Piran-4-ylmethyl)amino]phenyl}-N-methylacetamide (1,00 g of 3.60 mmol) (for more see Example 1, stage B-D) was added to a solution of 2,2-diperbarui acid (0.40 g, 3.60 m is ol) and DIPEA (0.75 ml, 4,32 mmol) in DMF (100 ml) at room temperature. The reaction mixture was stirred over night. The solvent is evaporated and the crude product was isolated in tO. The organic phase is washed with water, saturated solution Panso3and brine. The organic layer was dried over anhydrous PA2SO4and filtered. The solvent is evaporated to obtain specified in the title compound, which was used in the next stage without additional purification. Output: 1,00 g (75%); MS (ESI) (M+N)+: 370,2.

Stage C. N-[2-(1,1-Dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylacetamide

N-{5-[Acetyl(methyl)amino]-2-[(tetrahydro-2H-Piran-4-ylmethyl)amino]-phenyl}-2,2-deferrable (1,00 g, 2,70 mmol) was heated to 90°C over night in acetic acid (20 ml). The solvent is evaporated. The crude product was purified by flash chromatography on silica gel using Meon 3.5% acetone, 8% in DCM as eluent, obtaining specified in the header connection. Output: 0,48 g (50%); MS (ESI) (M+H)+: 352,0.

Stage, 2-(1,1-dottorati)-N-methyl-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-amine

N-[2-(1,1-Dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylacetamide (0,48 g, 1.37 mmol) was heated to 80°C over night in concentrated HCl (80 ml). The reaction mixture Oh what was Adali to 0°C and brought to a slightly alkaline pH with NaOH solution. The compound was extracted with EtOAc (3X) and the combined organic layers were washed with brine, dried over anhydrous Na2SO4and filtered. The solvent is evaporated to obtain specified in the title compound, which was used in the next stage without additional purification. Output: 0,42 g (98%); MS (ESI) (M+H)+: 310,2.

Example 22

N-[2-(1,1-Dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylpropan-1-sulfonamide

Following the methodology stage As in Example 21 and using propanesulfonate (65 μl, of 0.58 mmol), obtained TFA salt specified in the title compounds as white solids. Yield: 68 mg (26%);1H NMR (400 MHz, CD3OD) δ 1.02 (t, J=7,42 Hz, 3 H), 1.40-1.54 (m, 4 H), 1.74-1.87 (m, 1 H), 2.17-2.34 (m, 3 H), 3.05-3.15 (m, 2 H), 3.32-3.37 (m, 2 H), 3.37 (s, 3 H), 3.85-3.97 (m, 2 H), 4.35 (d, J=a 7.62 Hz, 2 H), 7.50 (dd, J=8,89, is 2.05 Hz, 1 H), 7.71 (d, J=8,79 Hz, 1 H), 7.78 (d, J=1,95 Hz, 1 H); MS (ESI) (M+H)+416,0; Analyt. calculated for C19H27F2N3O3S + 0,1 MeCN: C, 54,96; N, 6,56; N, 10,35. Found: C, 55,02; N, 6,40; N, 10,24.

Example 23

N-[2-(1,1-Dottorati)-1-(tetrahydro-2H-Piran-4-ylmethyl)-1H-benzimidazole-5-yl]-N-methylcyclopentanone

Following the methodology stage As in Example 21, using cyclopropanesulfonyl (81 μl, of 0.58 mmol) and heated to 60°C during the night, received a TFA salt specified in the header joint is in the form of a white solid. Yield: 135 mg (52%);1H NMR (400 MHz, CD3OD) δ 0.85-0.93 (m, 2 H), 0.93-1.03 (m, 2 H), 1.39-1.55 (m, 4H), 2.24 (m, 3H), 2.55-2.66 (m, 1 H), 3.31-3.38 (m, 3 H), 3.39 (s, 3 H), 3.86-3.97 (m, 2 H), 4.36 (d, J=7,42 Hz, 2 H), 7.52 (dd, J=8,79, 2,15 Hz, 1 H), 7.70 (d, J=8,79 Hz, 1 H), 7.81 (d, J=2,15 Hz, 1 H); MS (ESI) (M+H)+414,0; Analyt. calculated for C19H25F2N3O3S + 0,1 H2O: C, 54,95; H, 6,12; N, 10,12. Found: C, 54,91; H, 6,09; N, 9,68.

Example 24

N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}econsultant

Stage A: N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}econsultant

2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-amine (for more see the following steps B-E) (60 mg, 0,198 mmol) and DMAP (24 mg, 0,198 mmol) was dissolved in 5 ml DCM. Added acanaloniidae (0,025 ml, 0,257 mmol) and the solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/H2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 50 mg (50%).1H NMR (400 MHz, METHANOL-D4) δ 1.29 (t, J=7,42 Hz, 3 H), 1.34-1.41 (m, 2 H), 1.43-1.51 (m, 1 H), 1.53-1.62 (m, 1 H), 1.63-1.66 (m, 9 H), 1.69-1.75 (m, 2 H), 1.96-2.04 (m, 1 H), 2.06-2.12 (m, 2 H), 3.12 (q, J=742 Hz, 2 H), 4.44-4.49 (m, 2 H), 7.39 (dd, J=remaining 9.08, is 2.05 Hz, 1 H), 7.73 (d, J=2,15 Hz, 1 H), 7.85 (d, J=9,18 Hz, 0.7 H), 7.85-7.88 (d, J=9,18 Hz, 0.3 H); MS (ESI) (M+H)+396.0; Analyt. calculated (%) for C20H30N3O2SF + 1,3 TFA + 0,5 H2O: C, 49,11; H, OF 5.89; N, 7,60. Found: C, 49,10; H, Of 5.84; N, 7,52.

Stage B: tert-Butyl[(4-forcelogix-3-EN-1-yl)methyl]carbamate

4-N-BOC-aminomethylpyrrolidine (4,95 g and 21.8 mmol) was dissolved in 80 ml of THF. Was added dropwise DAST (4.3 ml, to 32.7 mmol) and the solution was stirred at 50°C for 5 hours, the Solvent evaporated and the product was purified by flash chromatography on silica gel using a mixture of 3:1 / hexane:tO as eluent. Output: 1,62 g (30%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.36-1.42 (m, 1 H), 1.44 (s, 9 H), 1.70-1.80 (m, 2 H), 1.82-1.90 (m, 1 H), 2.09-2.17 (m, 1 H), 2.17-2.29 (m, 2 H), 3.04-3.11 (m, 2 H), 4.61 (s, 1 H), 5.11-5.15 (m, 0.5 H), 5.16-5.19 (m, 0.5 H).

Stage b: [(4-Forcelogix-3-EN-1-yl)methyl]amine hydrochloride

tert-Butyl[(4-forcelogix-3-EN-1-yl)methyl]carbamate (1,62 g, 7,06 mmol) was stirred in 25 ml of 1 M HCl/AcOH at RT for 2 h, the Solvent evaporated and the product was besieged in diethyl ether, filtered and dried in vacuum. Yield: 1.13 g (97%).1H NMR (400 MHz, METHANOL-D4) δ 1.44-1.53 (m, 1 H), 1.80-1.89 (m, 2 H), 1.90-1.98 (m, 1 H), 2.16-2.23 (m, 2 H), 2.26-2.34 (m, 1 H), 2.88 (d, J=6.25 Hz, 2 H), 5.12-5.19 (m, 1 H).

Stage G: N-(4-{[(4-Forcelogix-3-EN-1-yl)methyl]amino}-3-nitrophenyl)ndimethylacetamide

N-(4-Fluoro-3-nitrophenyl)ndimethylacetamide (460 mg, 2.32 mmol) and [(4-forcelogix-3-EN-1-yl)methyl]amine hydrochloride (350 mg, 2,11 mmol) was stirred in 20 ml of tO containing TEA (0,735 ml, 5,28 mmol)at 75°C for 48 hours, the Solvent is evaporated. The residue was dissolved in tO and washed with aqueous 5%KHSO4, saturated aqueous NaHCO3, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using a mixture of 2:1 / hexane:acetone as eluent. Output: 553 mg (85%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.51-1.61 (m, 1 H), 1.84-1.93 (m, 1 H), 1.96-2.03 (m, 2 H), 2.16-2.18 (m, 3 H), 2.22-2.32 (m, 3 H), 3.26 (m, 2 H), 5.19 (m, 1 H), 6.84 (d, J=9,37 Hz, 1 H), 7.21 (s, 1 H), 7.79 (dd, J=9,18, of 2.54 Hz, 1 H), 8.09 (d, J=2,54 Hz, 2 H).

Stage D: N-(3-Amino-4-{[(4-forcelogix)methyl]amino}phenyl)ndimethylacetamide

N-(4-{[(4-Forcelogix-3-EN-1-yl)methyl]amino}-3-nitrophenyl)ndimethylacetamide (340 mg, 1.11 mmol) was dissolved in 25 ml tO containing a catalytic amount of 10% Pd/C. the Solution trachial in an atmosphere of H2(40 pound-force per square inch (275,6 kPa)using the apparatus for hydrogenation Parra, CT within 48 hours the Solution was filtered through celite and the solvent evaporated. Output: 308 mg (99%). MS (ESI) (M+H)+279,95.

Stage E: N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}ndimethylacetamide

N-(3-Amino-4-{[(4-forcelogix)methyl]amino}f the Nile)ndimethylacetamide (300 mg, 1.07 mmol) and DMAP (25 mg, 0,214 mmol) was dissolved in 10 ml DCM. Was added dropwise trimethylacetylchloride (0,145 ml, 1.18 mmol) and the solution was stirred at RT for 1 h the Solution was washed in an aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. The residue was dissolved in 5 ml of Asón and was heated at 150°C for 2.5 h using a Personal Chemistry microwave device. The solvent is evaporated. The residue was dissolved in tO and washed in an aqueous solution of NaHCO3, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography on silica gel using a mixture of 2:1 / acetonemia as eluent. Output: 196 mg (53%).1H NMR (400 MHz, CHLOROFORM-D) δ 1.14-1.25 (m, 2 H), 1.37-1.45 (m, 1 H), 1.43-1.51 (m, 1 H), 1.54-1.57 (m, 9 H), 1.70-1.78 (m, 2 H), 1.70-1.77 (m, 1 H), 2.02-2.08 (m, 1 H), 2.10-2.17 (m, 1 H), 2.19-2.21 (m, 3H), 4.12-4.19 (m, 2 H), 4.53 (m, 0.3 H), 4.73 (m, 0.3 H), 4.78 (m, 0.2 H), 4.90 (m, 0.2 H), 7.21-7.29 (m, 1 H), 7.30 (s, 1 H), 7.50-7.57 (m, 1 H), 7.64-7.67 (m, 1 H).

Stage G: 2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-amine

N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}ndimethylacetamide (190 mg, 0,550 mmol) was heated in 5 ml of a mixture 1:1 / 2 M HCl:tO at 120°C for 1 h using a Personal Chemistry microwave ustroystvo. The solvent is evaporated. The residue was podslushivaet using 2 M NaOH and was extracted (3X) tO. The organic phase is washed with saturated aqueous NaCl and dried nadaswaram Na 2SO4. The solvent is evaporated. Yield: 154 mg (92%).1H NMR (400 MHz, METHANOL-D4) δ 1.28-1.39 (m, 2 H), 1.41-1.50 (m, 1 H), 1.53-1.59 (m, 1 H), 1.61-1.64 (m, 9 H), 1.69 (d, J=7,81 Hz, 2 H), 1.95-2.03 (m, 0.7 H), 2.05-2.11 (m, 2 H), 2.13-2.22 (m, 0.3 H), 4.37-4.44 (m, 2.7 M), 4.47-4.56 (m, 0.3 H), 7.11 (t, J=2,05 Hz, 0.5 H) 7.13 (t, J=2,05 Hz, 0.5 H), 7.15-7.18 (m, 1 H), 7.67-7.73 (m, 1 H).

Example 25

N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}cyclopropanesulfonyl

2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-amine (56 mg, 0,199 mmol) and DMAP (25 mg, 0,199 mmol) was dissolved in 5 ml DCM. Added cyclopropanesulfonyl (42 mg, 0,298 mmol) and the solution was stirred at RT for 3 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous gSO4. The solvent is evaporated and the product was purified by HPLC with reversed phase, using a mixture of 10-70% CH3SP/H2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 58 mg (56%).1H NMR (400 MHz, METHANOL-D4) δ 0.91-0.98 (m, 2 H), 1.03-1.09 (m, 2 H), 1.32-1.43 (m, 2 H), 1.45-1.52 (m, 1 H), 1.54-1.62 (m, 1 H), 1.64-1.67 (m, 9 H), 1.68-1.76 (m, 1 H), 1.97-2.05 (m, 1 H), 2.06-2.13 (m, 2 H), 2.54-2.62 (m, 1 H), 4.44-4.50 (m, 2 H), 4.53 (m, 0.5 H), 4.73 (m, 0.5 H), 7.43 (dd, J=remaining 9.08, is 2.05 Hz, 1 H), 7.75 (d, J=1,95 Hz, 1 H), 7.83-7.89 (m, 1 H); MS (ESI) (M+H)+408,0.

Example 26

N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}-2-methylpropan-2-sulfonamide

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2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-amine (53 mg, 0,175 mmol) and DMAP (21 mg, 0,175 mmol) was dissolved in 5 ml DCM. Added tert-butylsulfonyl (0,026 ml, 0,210 mmol) and the solution was stirred at RT for 1 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. Added 3-chloroperoxybenzoic acid (78 mg, 0,350 mmol) and the solution was stirred at RT for 2 h the Solution was washed with a saturated aqueous solution Panso3, brine and dried over anhydrous MgSO4. The product was purified by HPLC with reversed phase, using a mixture of 10-70%

CH3SP/N2Oh, and liofilizirovanny obtaining specified in the title compound as the corresponding TFA salt. Yield: 47 mg (50%).1H NMR (400 MHz, METHANOL-D4) δ 1.36 (s, 9 H), 1.38-1.44 (m, 2 H), 1.44-1.51 (m, 1 H), 1.54-1.60 (m, 1 H), 1.63-1.66 (m, 9 H), 1.69-1.75 (m, 2 H), 1.96-2.04 (m, 1 H), 2.06-2.14 (m, 2 H), 4.42-4.48 (m, 2 H), 4.53 (m, 0.5 H), 4.72 (m, 0.5 H), 7.42 (dd, J=8,98, of 2.15 Hz, 1 H), 7.79-7.86 (m, 2 H); MS (ESI) (M+H)+424,0.

Example 27

N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}econsultant

Stage A. N-{2-tert-Butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}econsultant

N-{2-{[(4,4-diverticulosis)methyl]amino}-5-[(ethylsulfonyl)amino]-phenyl}-2,2-timetype UNAMID (22,3 g, 0,051 mol) (for more see the following steps B-D), PTSA (para-toluensulfonate acid)×H2O (10.8 g, 0,057 mol) and DMSO (100 ml) were mixed together and heated to 120°C during the night. Cooled to room temperature, the reaction mixture was poured into cold water (600 ml). The product was extracted with DCM (5×200 ml). The combined organic phases were washed with saturated solution of NaHCO3(4×200 ml), brine and dried over anhydrous Na2SO4. The solvent was removed and the crude product was purified on silica gel (tO:hexane 1:1) by flash chromatography (and was treated with activated charcoal) to give N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}acanaloniidae (18,4 g) as a white solid.

Stage B. N-(4-Fluoro-3-nitrophenyl)econsultant

EtSO2Cl (a 21.5 ml, 0.22 mol) was added dropwise to a mixture of 4-fluoro-3-nitroaniline (29,6 g at 0.19 mol) and pyridine (100 ml) at 0°C. the Reaction mixture was left to warm to room temperature and was stirred overnight. The reaction mixture was diluted tO (1 liter). The resulting solution was washed 2 N. HCl (4×200 ml), saturated solution Panso3(4×200 ml) and water (4×200 ml). The organic phase was dried over anhydrous Na2SO4and solvent was removed to obtain specified in the header of the product in the form of a beige solid substances is (46,3 g).

Stage C. N-(4-{[(4,4-Diverticulosis)methyl]amino}-3-nitrophenyl)econsultant

N-(4-Fluoro-3-nitrophenyl)econsultant (26 g, 0,107 mol), [(4,4-diverticulosis)methyl]amine (approx. 15 g), DIPEA (20 ml) and DMSO (100 ml) were mixed together and heated to 65°C over night. Added ethanolamine (5 g) and the reaction mixture was stirred until complete disappearance of N-(4-fluoro-3-nitrophenyl)acanaloniidae (approx. 4-5 hours). Cooled to room temperature, the reaction mixture was poured into cold water (900 ml). The product was extracted with DCM (5×200 ml). The combined organic phases are washed 2 N. HCl (3×200 ml) and dried over anhydrous Na2SO4. The solvent was removed and the crude product was purified on silica gel by flash chromatography (this material can be recrystallized using a mixture tO and hexane) to obtain specified in the header of the product (24.2 g) as an orange solid.

Stage, N-(3-amino-4-{[(4,4-diverticulosis)methyl]amino}phenyl)econsultant

N-(4-{[(4,4-Diverticulosis)methyl]amino}-3-nitrophenyl)econsultant (23,4 g) and Pd/C 10% in tO (800 ml) were shaken together for the night in an atmosphere of H2(50 pound-force per square inch (344,5 kPa)) in the apparatus for hydrogenation Parra. The reaction mixture was diluted Meon (400 ml) and filtered through with the second celite. The solvent was removed to give the desired specified in the header of the product (22,2 g) as a beige solid.

Stage D. N-{2-{[(4,4-diverticulosis)methyl]amino}-5-[(ethylsulfonyl)amino]phenyl}-2,2-dimethylpropanamide

A solution of tert-BuCOCl (7.6 g, 0,063 mol) in DCM (150 ml) was slowly added to a solution of N-(3-amino-4-{[(4,4-diverticulosis)methyl]amino}phenyl)acanaloniidae (22 g, 0,063 mol) and Et3N (9.7 ml, 0,069 mol) in DCM (500 ml) at 0°C. the Reaction mixture was stirred for 3 hours at 0°C. was Added DCM (300 ml) and water (200 ml). The organic layer was separated and washed with water (3×200 ml), brine and dried over anhydrous Na2SO4. The solvent was removed and the crude product was purified on silica gel by flash chromatography (tO:hexane, 1:1) to obtain specified in the header of the product (23.3 g) in the form of a beige solid.

Example 28. N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}econsultant (isomers)

N-{2-tert-Butyl-1-[(4-forcelogix)methyl]-1H-benzimidazole-5-yl}econsultant (60 mg, TFA salt, 0,117 mmol) was separated on chiral AD column, using a mixture of 10% tO / hexane (0.1% diethylamine), receiving respectively isomer And (16 mg) and isomer B (31 mg).

Isomer A:1H NMR (400 MHz, METHANOL-D4) δ 1.30 (t, J=7,42 Hz, 3 H), 1.41-1.52 (m, 3 H), 1.54-1.63 (m, 3 H), 1.65 (s, N), 1.97-2.05 (m, 2 H), 2.15-2.24 (m, 1 H), 3.13 (q, J=7,29 Hz, 2 H), 4.47 (d, J=a 7.62 Hz, 2 H), 4.72 (s, 0.5 H), 4.85 (s, 0.5 H), 7.38 (dd, J=8,98, of 2.15 Hz, 1 H), 7.73 (d, J=1,95 Hz, 1 H), 7.85 (d, J=8,98 Hz, 1 H); MS (ESI) (M+H)+395,8; chiral AD 15%tO/hexane with 0.1% DEA) k'=2,97.

Isomer B:1H NMR (400 MHz, METHANOL-D4) δ 1.30 (t, J=to 7.32 Hz, 3 H), 1.34-1.39 (m, 2 H), 1.39-1.45 (m, 2 H), 1.65 (s, 9 H), 1.70-1.75 (m, 2 H), 2.06-2.13 (m, 3 H), 3.13 (q, J=7,42 Hz, 2 H), 4.37-4.43 (m, 0.5 H), 4.45 (d, J=a 7.62 Hz, 2 H), 4.49-4.56 (m, 0.5 H), 7.39 (dd, J=remaining 9.08, is 2.05 Hz, 1 H), 7.73 (d, J=2,15 Hz, 1 H), 7.84 (d, J=9,18 Hz, 1 H); MS (ESI) (M+H)+395,8; Analyt. calculated for C20H30N3O2SF + 1,2 TFA + 0,2 H2O: C, 50, 20MM; N, 5,94; N, 7,84. Found: C, 50,13; N, Of 5.81; N, 7,74; chiral AD 15%tO/hexane with 0.1% DEA) k'=3,81.

IsomerKi hCB1(nm)AS hCB1(nm)Emax hCB1(%)Rest. pH 7.4 µm)hClint µl/min/mg)
A148--64-
In14,8a 4.91033817,7

1. The compound of the formula

representing the Wallpaper N-{2-tert-butyl-1-[(4,4-diverticulosis)methyl]-1H-benzimidazole-5-yl}econsultant, and its pharmaceutically acceptable salt, its diastereoisomers, enantiomers or mixtures thereof.

2. The compound according to claim 1 for use as a drug with activity modulator CB1receptors.

3. The use of compounds according to claim 1 in the manufacture of a medicine for the treatment of pain.

4. The use of compounds according to claim 1 in the manufacture of medicinal products for the treatment of anxiety disorders.

5. The use of compounds according to claim 1 in the manufacture of a medicinal product for the treatment of cancer, multiple sclerosis, Parkinson's disease, Huntington's disease, Alzheimer's disease, gastrointestinal disorders and cardiovascular disorders.

6. Pharmaceutical composition having activity modulator CB1receptors containing the compound according to claim 1 and a pharmaceutically acceptable carrier.

7. Method of modulating CB1receptors, including the stage of introducing a therapeutically effective amount of a compound according to claim 1.

8. The method of obtaining the compounds of formula

including the interaction of the compounds of formula II with the compound of the formula III

where G represents-CF2-;
R1represents ethyl;
R2represents-H; and
R3, R4and R5ezavisimo represent methyl.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: in substituted N-[ω-azol-1-yl)alkyl]benzolsulfamides , X and Y represent CH-group, n stands for 2 or 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, n stands for 3, R - similar or different stand for alkyl group with number of carbon atoms from 2 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 2 to 4, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, where X stands for CH-group, Y stands for nitrogen atom, n stands for 2, R - similar or different stand for alkyl group with number of carbon atoms from 2 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, n stands for 3 or 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, where X and Y simultaneously are chain C-CH=CH-CH=CH-C constituting together annelated with heterocycle ring, n stands for whole number from 2 to 4, R - similar or different stand for alkyl group with number of carbon atoms from 1 to 4, perfluoralkyl group with number of carbon atoms from 1 to 4, perfluoralkoxy group with number of carbon atoms from 1 to 4, nitro group, alkoxycarbonyl group with number of carbon atoms from 1 to 4, and their salts, methods of their obtaining and application as anti-aggregation preparations. Anti-aggregation activity of N-[ω -azol-1-yl)alkyl]benzolsulfamides, of general formula I, for instance, hydrochloride of N-[4-(1H-triasol-1-yl)butyl]-n-methylbenzolsulfumide (35) is higher than of etalon dazoxyben.

EFFECT: increase of anti-aggregation activity.

4 cl, 5 tbl, 5 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel α-(N-sulfonamido)acetamides of the formula (I) or their optical isomers wherein values R1, R, R2 and R3 are given in the invention claim. Proposed compounds are inhibitors of production of β-amyloid peptide and can be used for inhibition of production of β-amyloid peptide. Also, invention relates to pharmaceutical composition based on these compounds and to a method for inhibition of production of β-amyloid peptide.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein A means benzene ring optionally substituted with one or more the following groups: -OR2 wherein R2 mean linear or branched (C1-C5)-alkyl; X means -CH=, -CH2-, -N= or -NH-radical; Y means radical -CH2, oxygen or sulfur atom or group -NR7 wherein R7 means hydrogen atom or linear or branched (C1-C5)-alkyl; R1 means hydrogen atom, linear or branched (C1-C5)-alkyl, and to pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition showing anti-diabetic activity. The pharmaceutical composition comprises compound of the general formula (I) as an active component and an inert excipient. Invention provides bicyclic derivatives of guanidine eliciting anti-diabetic activity.

EFFECT: valuable medicinal properties of compounds and composition.

8 cl, 2 tbl, 4 ex

The invention relates to a new benzimidazole derivative of the formula (I), where a represents a single bond or C1-2-alkylenes group; R6is a hydrogen atom or a C1-4is an alkyl group; b - C2-3-alkylenes group; X represents an oxygen atom, each of R1and R2is a hydrogen atom; E is C1-2-alkylenes group; R3is a phenyl group (this phenyl group may be optionally substituted by halogen atom), each of R4and R5that are independent from each other, represents a hydrogen atom or a C1-4is an alkyl group; D - C1-2-alkylenes group and Ar is a phenyl group (this phenyl group may be optionally substituted by a halogen atom, a C1-4is an alkyl group, a C1-4-alkoxygroup or triptorelin group)

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula , where R1 is -O-X, where X is -(CH2)m-(CR9R10)p-(CH2)n-Z-(CH2)q-W, where m, n and q are independently equal to zero or assume values from 1 to 5; p equals 0 or 1; R9 and R10 are independently hydrogen, hydroxy, halogen, lower alkyl, lower alkoxy or cycloalkyl; or R9 and R10 together represent alkylene, which together with the carbon atom to which the are bonded, form an aryl; Z is a bond or O, W is aryl; R2 is hydrogen; L is a bond; R3 is hydrogen; R4 is hydrogen; R5 and R6 are independently hydrogen; R7 is hydrogen, halogen, hydroxy, trifluromethyl, lower alkyl, lower alkoxy, alkanoyl, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, carboxy, alkoxycarbonyl; or R5 and R6 together represent -(CH2)1-2-; Y is -(CH2)r-, -O-(CH2)r, -(CH2)r-O-, where r equals zero or assumes values from 1 to 3; Q together with atoms to which it is bonded form an aryl, pyridyl, pyrimidinyl, thienyl, furyl, pyrroliyl or indolyl ring; or to its pharmaceutically acceptable salts. The invention also relates to a method of inhibiting rennin activity in mammals, to a pharmaceutical composition, as well as to application.

EFFECT: obtaining new biologically active compounds with inhibitory activity towards renin.

23 cl, 52 ex

FIELD: medicine.

SUBSTANCE: there is offered application of glutaric acid derivatives of general formula where R1 = imidazole, indole, R2 = COOH, H, or its pharmaceutically acceptable salt as an antiarrhythmic drug (versions), a medical product, a pharmaceutical composition and method of appropriate prescription. There is presented effectiveness of Nαglutaryl-L-histidine, Nαglutaryl-L-tryptophan in arrhythmia caused by adrenal heart rhythm disorder, in nicotine arrhythmia and acute occlusive myocardium disorder.

EFFECT: effective in arrhythmia.

5 cl, 6 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to cardiology and endocrinology, and concerns normalisation of thromboplastin formation in patients suffering from arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated static and dynamic physical exercises, and also introduction of pioglitazone in a dose 30 mg once in the morning and a lisinopril in a dose 10 mg once a day in the morning during 1.5 months.

EFFECT: complex of specific medical agents and physical activity combined with empirically specified duration of treatment provides normalisation of thromboplastin formation that in turn reduces risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology and cardiology, and concerns correction of blood microvesicle level in arterial hypertension. That is ensured by introduction of lisinopril in a dose 10 mg once in the morning and amlodipine in a dose 5 mg once in the morning within at least 5 weeks. Introduction of specific preparations throughout empirically specified time of treatment ensures complete normalisation of blood microvesicle level.

EFFECT: invention allows reducing risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to haematology, cardiology and endocrinology, and concerns correction of blood microvesicle level in arterial hypertension with impaired glucose tolerance. That is ensured by integrated treatment including graduated physical exercises, and introduction of Fosinopril in a dose 10 mg once in the morning and pioglitazone in a dose 30 mg once in the morning. Therapeutic course is at least 7 weeks.

EFFECT: complex of drug-free modalities and specific pharmacological preparations combined with empirically specified time of treatment provides maintained optimum microvesicle level that in turn allows considerably reducing risk of thrombotic complications in given group of patients.

1 ex

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely haematology, cardiology and endocrinology and concerns correction of blood microvesicle level in arterial hypertension (AH) and pancreatic diabetes type II (PD II). That is ensured by integrated therapy involving graduated physical exercises, as well as introduction of lisinopril in a dose 10 mg once in the morning, amlodipine in a dose 5 mg once in the morning and pioglitazone in a dose 30 mg once in the morning for therapeutic course at least 7 weeks.

EFFECT: complex of specific medical preparations and physical exercises combined with empirically specified duration of treatment provides effective correction of blood microvesicle level and, thereby, reduced risk of thrombotic complications in given group of patients.

1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula II or their pharmaceutically acceptable salts, where R1 is H or C1-C10 alkyl; R2 is H or C1-C10 alkyl; n ranges from 0 to 4; p ranges from 0 to 1; R3 and R4 represent H, as well as to pharmaceutical compositions based on said derivatives and methods of treating cardiac arrhythmia using these compositions.

EFFECT: increased effectiveness of composition and method of treatment.

15 cl, 12 dwg, 3 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to cardiology, and concerns treatments of cardiovascular diseases that is ensured by introduction of a composition containing stem cells and undifferentiated precursors prepared of adipose tissue by separating mature adipocytes and connective tissue.

EFFECT: that ensures restoration of blood circulation in ischemic region.

28 cl, 7 ex, 12 dwg

FIELD: medicine.

SUBSTANCE: invention concerns medicine, namely application of sodium thiosulphate as a hypolipidemic and antiatherosclerotic agent for oral introduction to treat dislipoproteinemia and atherosclerosis.

EFFECT: there is disclosed hypolipidemic and antiatherosclerotic agent.

5 tbl

FIELD: medicine.

SUBSTANCE: invention refers to medical products and concerns a pharmaceutical tablet, contains a therapeutically effective dose of crystalline telmisartan sodium salt of fusion temperature 245±5°C and diuretic hydrochlorothiaside, as well as one or more adjuvants used to prepare medical products. There is also disclosed method for making thereof. According to the invention, the pharmaceutical tablets are storage-stable.

EFFECT: intended for prevention or treatment of diseases wherein application of angiotensin II antagonists ensures the therapeutic effect.

23 cl, 7 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely oncology and can be used for treating prostate intraepithelial neoplasia. The methods according to the invention involve introduction of a composition containing therapeutically effective amounts of supercritical extracts of rosemary, turmeric, origanum and ginger; and therapeutically effective amounts of water-alcohol extracts of holy basil, ginger, turmeric, Scutellaria baicalensis, rosemary, green tea, Polygonum cuspidatum, Coptis chinensis and barberry.

EFFECT: invention allows inhibiting growth of intraepithelial neoplasia cells due to antineoplastic activity of herbal extracts of the composition, inhibition of cyclooxygenase 2 and induction of apoptosis.

43 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to oncology, and can be used for optimisation of treatment tactics in case of Hodgkin's lymphoma in children and teenagers. Method is realised in the following way. Such unfavourable prognostic factors as: age over 10 years, IV stage of disease, conglomerate dimensions more than 5 cm and/or value of mediastinal-thoracic index greater than 0.33, number of affected zones more than 4, symptoms of intoxication and biological activity of process. After that three risk groups are determined by the sum of detected unfavourable factors. In the first group, if 0-2 factors are detected, 2 cycles of polychemotherapy in accordance with regimen VBVP are carried out, in the second group, if 3-4 risk factors are detected - 4 cycles in alternating regimen VBVP-ABVD-VBVP-ABVD, in the third group, if 5-6 factors are detected - 6 cycles in alternating regimen VBVP-ABVD-VBVP-ABVD-VBVP-ABVD. Two weeks after carrying out polychemotherapy in all groups irradiation of all earlier affected zones is performed.

EFFECT: method allows to reduce risk of post-cytostatic and radiation complications development due to reduction of treatment loading in patients.

1 tbl, 1 dwg, 2 ex

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