Benzimidazole derivatives and application thereof for gamma-amino-butyric acid (gabaa) receptor complex modulation

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I): or to any of its stereoisomers, or to any mixture of their stereoisomers, or to their pharmaceutically acceptable salts where Ra, Rb and Rc independently represent hydrogen, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, arylalkyl, formyl or alkylcarbonyl; Rd represents a heteroaryl group; where said heteroaryl group means a 5-6-member aromatic heterocyclic group which contains one or two heteroatoms in the ring structure, specified from nitrogen (N) or sulphur (S) and where the heteroaryl group is optionally substituted with one or more substitutes independently specified from the group including: halogeno, hydrazino and alkoxy. Also the invention refers to a pharmaceutical composition, the application of a chemical compound under any of cl. 1-6, as well as to a method of GABAa-receptor complex modulation in the central nervous system.

EFFECT: preparation of the new biologically active compounds exhibiting gamma-amino-butyric acid (GABAa) receptor complex modulating activity in the central nervous system.

11 cl, 10 ex, 1 tbl

 

The SCOPE of the INVENTION

The invention relates to novel benzimidazole derivatives, pharmaceutical compositions containing these compounds, and to methods of treatment using them.

Compounds according to the invention are useful in treating diseases and disorders of the Central nervous system, which are sensitive to modulation of GABAA-receptor complex, and in particular to combat anxiety and related diseases.

PRIOR art

Modulatory sites on GABAA-receptor complex, such as, for example, the binding site of the benzodiazepine, is a target for anxiolytics, such as classical anxiolytic benzodiazepines. However, they are associated with a number of undesirable properties.

There are many isoforms of the receptor for GABAAeach receptor is a pentamers complex that includes a subunit derived from subunit isoforms α1-6that β1-3that γ1-3, δ, ε and θ. Classical anxiolytic benzodiazepines do not show selectivity for subtypes. It was assumed that one of the main elements of the shortcomings of classical benzodiazepines (such as sedation, dependence and cognitive impairment) associated with α1-subunit of the GABA receptorsA. Accordingly, it is expected that compounds with villages what aktivnosti against subunits α2 and/or α3 compared to the α1 subunit, have a better side effect profile.

Thus, there is a significant need for compounds with optimized pharmacological profile. In addition, there is a significant need for effective detection of compounds that do not have undesirable side effects associated with the same connection.

SUMMARY of the INVENTION

In the first aspect of the invention proposed compound of the Formula I

or its N-oxide, any of its isomers or any mixture of its isomers, or pharmaceutically acceptable salt,

where Ra, Rb, Rcand Rdare as defined below.

In the second aspect of the invention proposed pharmaceutical composition comprising a therapeutically effective amount of the compounds according to the invention or its N-oxide, any of its isomers or any mixture of its isomers, or pharmaceutically acceptable salts together with at least one pharmaceutically acceptable carrier, excipient or diluent.

In another aspect of the invention the application of the compounds according to the invention or its N-oxide, any of its isomers or any mixture of its isomers, or their pharmaceutically acceptable salts for the manufacture of pharmaceutical compositions for the treatment, is recuperate or alleviate symptoms of the disease, or disorder, or condition of a mammal, including a human, which disease, disorder or condition responsive to modulation of the GABA receptor complexAin the Central nervous system.

In another aspect the invention relates to a method to treat, prevent or ameliorate symptoms of disease or disorder, or condition of the body of an animal, including a human, which disorder, disease or condition responsive to modulation of GABAA-receptor complex in the Central nervous system, including the stage of introduction into the body of an animal, in need thereof, a therapeutically effective amount of the compounds according to the invention or its N-oxide, any of its isomers or any mixture of its isomers, or their pharmaceutically acceptable salts.

Other objects of the invention understood by a person skilled in the art from the following detailed description and examples.

DETAILED description of the INVENTION

Substituted benzimidazole derivatives

In the first aspect of the present invention proposed a compound of General formula (I)

or its N-oxide, any of its isomers or any mixture of its isomers,

or its pharmaceutically acceptable salt,

where

Ra, Rband Rcindependently from each other represents the t of a hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkenyl, quinil, hydroxy, alkoxy, alkoxyalkyl, arylalkyl, formyl, alkylsulphonyl or alkoxycarbonyl;

Rdrepresents a heteroaryl group;

where the heteroaryl group possibly substituted by one or more substituents independently selected from the group consisting of:

halogeno, hydroxy, R R"N-, group R R"N-alkyl, cyano, nitro, trifloromethyl, triptoreline, hydrazino, alkoxy, cycloalkane, alkyl, cycloalkyl, cycloalkenyl,alkenyl and quinil;

where R' and R" independently from each other represent hydrogen or alkyl.

In one embodiment Rarepresents hydrogen, alkyl or arylalkyl. In another embodiment Rarepresents hydrogen or alkyl. In a specific embodiment Rarepresents hydrogen. In another embodiment Rarepresents alkyl, such as methyl or ethyl. In another embodiment Rameans arylalkyl, such as phenylalkyl, such as benzyl.

In another embodiment Rbrepresents hydrogen, alkyl, alkoxy, arylalkyl, formyl or alkylsulphonyl. In another embodiment Rbrepresents hydrogen, alkyl, formyl or alkylsulphonyl. In a specific embodiment Rbrepresents hydrogen. In another embodiment Rbrepresents alkyl, Taco is as methyl or ethyl. In another embodiment Rbis arylalkyl, such as phenylalkyl, such as benzyl. In another embodiment Rbrepresents formyl or alkylsulphonyl, such as acetyl. In another embodiment Rbrepresents alkoxy, such as methoxy.

In another embodiment Rcrepresents hydrogen or alkyl. In a specific embodiment Rcrepresents hydrogen. In another embodiment Rcrepresents alkyl, such as methyl.

In another embodiment Rdrepresents a heteroaryl group selected from thiazolyl, pyridyl, pyrimidyl and pyrazinyl; where the heteroaryl group possibly substituted by one or more substituents independently selected from the group consisting of halogeno, hydrazino and alkoxy.

In another embodiment Rdrepresents a possibly substituted thiazolyl. In another embodiment Rdrepresents thiazolyl, such as thiazol-2-yl. In another embodiment Rdrepresents halogenoacetyl, such as chlorothiazole, such as 5-chlorothiazole-2-yl.

In another embodiment Rdrepresents a possibly substituted pyridyl. In another embodiment Rdrepresents pyridyl, such as pyridin-2-yl or pyridin-3-yl. In another embodiment Rdrepresents halogeno iridal, such as perperidis, such as 6-herperidin-3-yl or 2-herperidin-3-yl. In another embodiment Rdis hydrazinophenyl, such as 6-hydrazinopyridazine-3-yl. In another embodiment Rdis alkoxyphenyl, such as methoxyphenyl, such as 2-methoxypyridine-3-yl.

In another embodiment Rdrepresents a possibly substituted pyrimidyl. In another embodiment Rdis pyrimidyl, such as pyrimidine-5-yl. In another embodiment Rdis dialkoxybenzene, such as dimethoxypyrimidine, such as 2,4-dimethoxypyrimidine-5-yl

In another embodiment Rdrepresents a possibly substituted pyrazinyl. In another embodiment Rdis pyrazinyl, such as pyrazin-2-yl.

In another embodiment Ra, Rband Rcindependently of one another represent hydrogen, alkyl, cycloalkyl, cycloalkenyl, alkenyl, quinil, hydroxy, alkoxy, alkoxyalkyl, formyl, alkylsulphonyl or alkoxycarbonyl.

In another embodiment Rdrepresents a heteroaryl group;

where the heteroaryl group possibly substituted by one or more substituents independently selected from the group consisting of: halogen, hydroxy, R R"N-, group R R"N-alkyl, cyano, nitro, trifloromethyl, is reformatory, alkoxy, cycloalkane, alkyl, cycloalkyl, cycloalkenyl, alkenyl and quinil; where R' and R" independently from each other represent hydrogen or alkyl.

In a particular embodiment the chemical compound according to the invention is a

S-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine;

S-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]methylamine;

S-[1-(3-[6-Herperidin-3-yl]phenyl)-1H-benzimidazole-5-yl]methylamine;

S-[1-(3-[Pyridin-2-yl]phenyl)-1H-benzimidazole-5-yl]methylamine;

S-[1-(3-Pyrazin-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine;

1-[1-(3-Pyrazin-2-ylphenyl)-1H-benzimidazole-5-yl]ethylamine;

1-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethylamine;

1-{1-[3-(6-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;

1-{1-[3-(6-Hydrazinopyridazine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;

1-[1-(3-Pyrimidine-5-ylphenyl)-1H-benzimidazole-5-yl]ethylamine;

N-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]ndimethylacetamide;

N-[1-(3-Pyridin-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]ndimethylacetamide;

N-(1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide;

N-(1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide;

N-(1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide;

1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;

1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}is tiemin;

1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;

Methyl-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

Dimethyl-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

Benzyl-{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}amine;

Dibenzyl-{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}amine;

Methyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

Dimethyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

Ethyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

Diethyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

Benzyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

Dibenzyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;

O-Methyl-N-{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}hydroxylamine;

N-{1-[3-Thiazol-2-ylphenyl]-1H-benzimidazole-5-ylmethyl}formamide;

1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;

or its N-oxide, any of its isomers or any mixture of its isomers,

or their pharmaceutically acceptable salt.

In another specific embodiment the chemical compound

the invention is a

1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethanol;

or its N-oxide, any of its isomers or any mixture of its isomers,

or their pharmaceutically acceptable salt.

It is assumed that Liu is the first combination of two or more of the above-described embodiments included in the scope of the present invention.

The definition of the substituents

In the context of the invention, halogen represents fluorine, chlorine, bromine or iodine.

In the context of the invention, the alkyl group means a monovalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains from one to six carbon atoms (C1-6-alkyl), including pentyl, isopentyl, neopentyl, tertiary of pentyl, hexyl and isohexyl. In the preferred embodiment the alkyl represents a C1-4is an alkyl group containing butyl, isobutyl, secondary butyl and tertiary butyl. In yet another preferred embodiment of this invention the alkyl represents a C1-3-alkyl group, which, in particular, may represent a methyl, ethyl, propyl or isopropyl.

In the context of this invention Alchemilla group means a carbon chain containing one or more than one double bond, including dieny, triene and a polyene. In the preferred embodiment Alchemilla group according to the invention contains from two to six carbon atoms (C2-6alkenyl), including at least one double bond. In the preferred embodiment Alchemilla group according to the invention represents an ethynyl; 1 - or 2-propenyl; 1-, 2 - or 3-butenyl or 1,3-butadienyl; 1-, 2-, 3-, 4 - or 5-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatriene the L.

In the context of the invention Alchemilla group means a carbon chain containing one or more than one triple bond, including dieny, triinu and Polyany. In the preferred embodiment Alchemilla group according to the invention contains from two to six carbon atoms (C2-6-quinil), including at least one triple bond. In the preferred embodiment Alchemilla group according to the invention is ethinyl; 1 - or 2-PROPYNYL; 1-, 2 - or 3-butenyl or 1,3-butadienyl; 1-, 2-, 3-, 4-pentenyl or 1,3-pentadienyl; 1-, 2-, 3-, 4 - or 5-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatriene.

In the context of the invention cycloalkyl group is a cyclic alkyl group, preferably containing from three to seven carbon atoms (C3-7-cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkoxy means O-alkyl where alkyl is as defined above.

Alkoxyalkyl means alkoxy as defined above, and alkyl, as defined above, meaning, for example, methoxymethyl.

Cycloalkane means O-cycloalkyl where cycloalkyl is the same as defined above.

Cycloalkenyl means cycloalkyl, as defined above, and alkyl, as defined above, meaning, for example, cyclopropylmethyl.

In the context of this invention, heteroa the ilen group means an aromatic mono - or bicyclic heterocyclic group, which contains one or more heteroatom in the ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S).

Preferred monocyclic heteroaryl groups of the invention include aromatic 5 - and 6-membered monocyclic heterocyclic group including, for example, oxazolyl, isoxazolyl, thiazolyl, isothiazole, 1,2,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-oxadiazolyl, 1,2,5-thiadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl or pyrazinyl, but not limited to.

Preferred bicyclic heteroaryl groups of the invention include, for example, indolizinyl, indolyl, isoindolyl, indazoles, benzofuranyl, benzo[b]thienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzo[d]isothiazole, purinol, chinoline, ethenolysis, cinnoline, phthalazine, hintline, honokalani, 1,8-naphthyridine, pteridine and indenyl, but are not limited to.

Pharmaceutically acceptable salt

Chemical compound according to the invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre - or proletarienne form chemical compounds according to the invention.

Examples of pharmaceutically acceptable salts of accession on the hunger without limitation, non-toxic inorganic and organic salts of joining acids, such as hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconitate, ascorbate, bansilalpet, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonate, mandelate, methanesulfonate, derived naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-para-sulfonate and the like. Such salts can be obtained by methods well known and described in the art.

Other acids, such as oxalic acid, which can be regarded as a pharmaceutically unacceptable, can be useful in obtaining salts which are useful as intermediates in obtaining chemical compounds according to the invention and its pharmaceutically acceptable salts accession acid.

Examples of pharmaceutically acceptable cationic salts chemical compounds according to the invention include, without limitation, salts of sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine and ammonium and the like for chemical compounds according to the invention containing an anionic group. Such cationic salts can be obtained by methods well known and described in the art.

In the context of this invention "onieva the salts of N-containing compounds are also considered as pharmaceutically acceptable salts. Preferred "onevia salts include alkyl-onieva salt, cycloalkyl-onieva salt and cycloalkenyl-onieva salt.

Examples of pre - or proletarienne forms of chemical compounds according to the invention include examples of suitable prodrugs of the substances according to the invention, including compounds which are modified by one or more reactive or derivatizing groups of the parent compound. Of particular interest are the compounds which are modified by carboxyl group, hydroxyl group or amino group. Examples of suitable derivatives are the esters or amides.

Chemical compound according to the invention can be presented in a soluble or insoluble forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Soluble forms may also include hydrated forms, such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like In General soluble forms are considered equivalent to insoluble forms for the purposes of this invention.

Steric isomers

Specialist in the art it is clear that the compounds of the present invention can contain one or more than one chiral center, and that such compounds can exist in different stereoisomeric forms - including Aisne is tionery, diastereoisomer and CIS-TRANS isomers.

The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

Can be used in the methods of separation of optical isomers, known to experts in the art and understandable to the average person skilled in the art. Such methods include the methods discussed in J.Jaques, A.Collet, and S.Wilen "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).

Optically active compounds can also be obtained from optically active starting materials.

N-oxides

In the context of this invention an N-oxide means an oxide derived nitrogen-containing compounds, for example N-containing heterocyclic compounds capable of forming such N-oxides, and compounds containing one or more than one amino group. For example, N-oxide compounds containing pyridyl, can be a 1-oxypyridine-2, -3 or-4-ilen derived.

N-Oxides of the compounds according to the invention can be obtained by oxidation of the corresponding nitrogen base using a conventional oxidizing agent such as hydrogen peroxide, in the presence of acid, such as acetic acid, at elevated temperature, or by interaction with percolate, such as peracetic acid, in a suitable solvent, for example dichloromethane, ethyl acetate or methyl is cetate, or chloroform or dichloromethane with 3-chloroperoxybenzoic acid.

Labeled compounds

Compounds according to the invention can be used in labeled or unlabeled form. In the context of the invention in the labeled compound is one or more than one atom is replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. The introduction of the label provides the ability to easily quantitative detection of the specified connection.

Labeled compounds according to the invention can be useful as diagnostic tools, radioactive tracers or agents used for monitoring in various diagnostic methods, as well as for visualization of the receptor in vivo.

Labeled isomer according to the invention preferably contains at least one radionuclide as a label. All positron-emitting radionuclides are candidates for use. In the context of this invention, the radionuclide is preferably selected from the2H (deuterium),3H (tritium),13C,14C,131I125I123I, and18F.

Physical detection of labeled isomer of the present invention may be selected from positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic Rezo is annoy spectroscopy (MRS), magnetic resonance imaging (MRI) and computed axial x-ray tomography (CAT) or combinations thereof.

Ways to get

Chemical compounds according to the invention can be obtained by conventional methods of chemical synthesis, for example, described in the working examples. Source materials for the methods described in this application are well known or can be easily obtained by conventional means from commercially available chemicals.

In addition, one of the compounds according to the invention can be converted into another compound of the invention using conventional methods.

The final products described herein reactions can be isolated by conventional means, for example by extraction, crystallization, distillation, chromatography, etc.

The compounds of this invention may exist in resolutional, as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In General, the objectives of the present invention solvated forms are considered equivalent nonsolvated forms.

Biological activity

Compounds according to the invention can modulate GABAA-receptor complex. They can be tested for their ability to bind with GABAA-receptor complex, including its concrete the e subunit.

Compounds of the present invention, representing the ligands of the benzodiazepine binding site on the GABA receptorsAthus useful in the treatment and/or prevention of a number of disorders of the Central nervous system. Thus, in another aspect of the compounds according to the invention is considered useful for treatment, prevention or relief of symptoms of the disease, disorder or condition that is sensitive to modulation of GABAA-receptor complex in the Central nervous system.

In a particular embodiment of the compounds according to the invention is considered useful for treatment, prevention or relief of symptoms

- anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without panic disorder, animal and other phobias, including sociophobia, obsessive-compulsive disorder, and generalized or caused by taking psychoactive substance anxiety disorder;

- stress disorders, including post-traumatic and acute stress disorder;

- sleep disorders;

- memory disorders;

- nervousness;

- convulsive disorders such as epilepsy, convulsions, seizures or febrile convulsions in children;

- migraine;

- mood disorders;

- depressive or bipolar disorders, for example depress the AI, single-episode or recurrent major depressive disorder, estimatesare disorder, bipolar disorder, bipolar manic disorder type I and II, and cyclothymic disorder

- psychotic disorders, including schizophrenia;

- neurodegeneration arising from cerebral ischemia;

syndrome of attention deficit and hyperactivity disorder;

- pain and nociception, such as neuropathic pain;

- nausea, including acute, delayed and premature nausea, in particular nausea caused by chemotherapy or irradiation;

- motion sickness in transport, postoperative nausea and vomiting;

- eating disorders, including nervous anorexia and nervous bulimia;

- premenstrual syndrome;

neuralgia, such as trigeminal neuralgia;

muscle spasm or spasticity, e.g. in patients suffering from paralysis of the lower limbs;

effects of substance abuse or dependence, including alcohol withdrawal syndrome;

cognitive disorders such as Alzheimer's disease; and

- cerebral ischemia, stroke, brain injury;

noise in the ears;

- disorders of circadian rhythm, e.g. in subjects suffering from the effects of desynchronosis after transmural the data of the flight or shift work.

Preferred compounds according to the invention is considered useful for treatment, prevention or relief of symptoms of anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without panic disorder, animal and other phobias, including sociophobia, obsessive-compulsive disorder, and generalized or caused by taking psychoactive substance anxiety disorder.

In addition, the compounds according to the invention can be useful as a radio in assays to detect compounds which are able to bind to the human receptor GABAA.

At the present time discovered that a suitable dose of the active pharmaceutical ingredient (API) is in the range from about 0.1 to about 1000 mg API per day, more preferably from about 10 to about 500 mg API per day, most preferably from about 30 to about 100 mg API per day, however, depending on the particular method of administration, the form in which it is introduced, consider the testimony of the subject and especially body mass under consideration of the subject, and the preference and experience of the attending or veterinarian.

Preferred compounds according to the invention show a biological activity in submicromolar and micromolar is the range, i.e. from less than 1 to about 100 microns.

The pharmaceutical composition

In another aspect of the invention proposed new pharmaceutical compositions containing a therapeutically effective amount of a chemical compound according to the invention.

Although chemical compound according to the invention for use in therapy can be introduced in the form of the raw chemical compound, it is preferable to introduce the active ingredient, possibly in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and/or other conventional pharmaceutical auxiliary substances.

In the preferred embodiment of the proposed invention the pharmaceutical composition comprising a chemical compound according to the invention or its pharmaceutically acceptable salt or its derivative together with one or more pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic ingredients, known and used in the field of technology. The carrier(s) must be "acceptable" in the sense of compatibility with other ingredients and are not harmful to the recipient.

The pharmaceutical compositions according to the invention can provide a composition suitable for peroral the tion, rectal, bronchial, nasal, pulmonary, local (including transbukkalno and sublingual), transdermal, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral introduction, intraocular injection or infusion), or compositions in a form suitable for administration by inhalation or insufflation, including the introduction of powder and liquid spray, or using a long-release. Suitable examples of systems with long release include semi-permeable matrices of solid hydrophobic polymers containing a compound according to the invention, the matrix may be in the form of molded articles, e.g. films, or microcapsules.

Thus, a chemical compound according to the invention together with a conventional adjuvant, carrier or diluent may be placed in the form of pharmaceutical compositions and standard dosage forms. Such forms include solids, in particular tablets, filled capsules, powder and granulated forms, and liquids, in particular aqueous or nonaqueous solutions, suspensions, emulsions, elixirs, and capsules filled with them, all of which are intended for oral administration, suppositories for rectal injection is a sterile injectable solutions for parenteral use. Such pharmaceutical compositions and their standard dosage forms may contain conventional ingredients in conventional proportions, together with additional active compounds or active basis or without them, and such a standard dosage forms may contain any suitable effective amount of the active ingredient in accordance with the intended used range daily dose.

Chemical compound according to the present invention can be introduced in a wide range of dosage forms for oral and parenteral administration. Specialist in the art it is obvious that the following dosage forms may contain as an active ingredient a chemical compound according to the invention or a pharmaceutically acceptable salt of a chemical compound according to the invention.

For the manufacture of pharmaceutical compositions of chemical compounds according to the present invention, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. A solid carrier can be one or more than one substance, which may also act as diluents, flavoring agents, solubilization, lubricants, suspender the participating agents, binders, preservatives, tablet disintegrating agents, or encapsulating substances.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground active component.

In tablets, the active ingredient is mixed with carrier having the necessary binding capacity in suitable proportions and presova to the desired shape and size.

The powders and tablets preferably contain from five or ten to about seventeen percent of the active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, carboxymethylcellulose sodium, low-melting wax, cocoa butter and the like. It is assumed that the term "manufacturer" includes preparation in the form of a preparation of the active compound with encapsulating substance as a carrier with obtaining capsules where the active ingredient with the media or no media is surrounded by carrier, which is thus United with him. Similarly, included Sasha and tortillas. Tablets, powders, capsules, pills, sachets and cakes can be used as solid dosage forms suitable for oral administration.

For the manufacture of suppositories first melted low-melting the wax, such as a mixture of glycerides of fatty acids or cocoa butter, and the active component is homogeneous dispersed therein by stirring. The molten homogeneous mixture is then poured into forms convenient form, leave to cool and, thus, to harden.

Compositions suitable for vaginal administration, can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers which are known in the field of technology as appropriate.

Liquid preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, liquid preparations for parenteral injection may be made in the form of solutions in an aqueous solution of polyethylene glycol.

Thus, a chemical compound according to the present invention can be prepared in the form of a preparation for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in a standard dosage form in ampoules, pre-filled syringes, containers for infusion of a small volume or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous solvents, and which may contain agents used for preparation of the drug, such as suspendresume agents, stabilizers and/or dispersants. Alternatively, the active ingredient may be in powder form, prepared by aseptic selection of sterile solid or by lyophilization from solution, for reconstitution before use with a suitable diluent, such as sterile pyrogen-free water.

Aqueous solutions suitable for oral use can be obtained by dissolving the active component in water and adding, if necessary, suitable colorants, flavors, stabilizers and thickeners.

Aqueous suspensions suitable for oral use can be prepared by dispersing finely ground active component in water with viscous substance, such as natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose sodium, or other well-known suspendresume agents.

Also included are solid form preparations intended to become directly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to active component such preparations may contain colouring agents, corrigentov, stabilizers, buffet is s, artificial and natural sweeteners, dispersants, thickeners, soljubilizatory and the like.

For local injection into the epidermis chemical compound according to the invention can be made in the form of ointments, creams or lotions, or as a transdermal patch. Ointments and creams can be made, for example, aqueous or oily base with the addition of suitable thickeners and/or gelling agents. Lotions can be prepared with water or oil based and are generally also contain one or more than one emulsifier, stabilizer, dispersing agent, suspendisse agent, thickening agent or dye.

Compositions suitable for local injection in the mouth include pellet containing the active agent in a flavored basis, usually sucrose and Arabian gum or tragacanth gum; mints containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum; and dental elixirs containing the active ingredient in a suitable liquid carrier.

Solutions or suspensions used directly in the nasal cavity using conventional means, such as a dropper, pipette or spray. The composition can be represented as a single dose or mnogochasovoj form.

Introduction to the respiratory tract may also be achieved is by using aerosol drug in which the active ingredient in packing under pressure with a suitable propellant such as a chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. Aerosol for convenience may also contain a surfactant such as lecithin. The dose can be monitored by measuring valve.

Alternatively, the active ingredients may be offered in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, derivatives of starch, such as hypromellose and polyvinylpyrrolidone (PVP). For convenience powder carrier forms a gel in the nasal cavity. Powder composition may be presented in a standard dosage form, for example, capsules or cartridges, for example, from gelatin or blister packs from which the powder may be introduced using an inhaler.

In compositions intended for administration to the respiratory tract, including compositions for the intranasal route, the connection usually has a small particle size, for example about 5 μm or less. This particle size can be obtained by methods known in the technical field, for example by ICRI the organization.

If desired, can be used compositions adapted for long-term release of the active ingredient.

The pharmaceutical preparations are preferably in a standard dosage forms. In such form the preparation is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, where the package contains discrete quantities of preparation, such as Packed in vials or ampoules, tablets, capsules and powders. In addition, a standard dosage form can be a capsule, tablet, sachet or the cake or can be a suitable number of any of these packaged forms.

Tablets or capsules for oral administration and fluids for intravenous injection and continuous infusion are preferred compositions.

Additional details of methods of manufacture and introduction can be found in the latest edition Remington''s Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

A therapeutically effective dose refers to the amount of active ingredient which reduces the intensity of symptoms or condition. Therapeutic efficacy and toxicity, such as ED50(average effective dose) and LD50(median lethal dose), can the be determined using standard pharmaceutical procedures in cell cultures or experimental animals. The ratio of doses between therapeutic and toxic effects is a therapeutic index and can be expressed by the ratio LD50/ED50. Preferred are pharmaceutical compositions that demonstrate large therapeutic indices.

Enter the dose, of course, must be carefully chosen in accordance with age, weight and condition of the individual, which are treated, as well as by injection, dosage form and scheme of administration and the desired result, and the exact dose of course should be determined by a medical practitioner.

The actual dose will depend on the nature and severity of the disease, which is treatable and is at the discretion of the attending physician, and may vary the dose titration in the specific conditions of the invention to give the desired therapeutic effect. However, at present it is believed that therapeutic treatment is suitable pharmaceutical compositions containing from about 0.1 to about 500 mg of the active ingredient on the individual dose, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg.

The active ingredient can be introduced in one or several doses per day. In some cases, a satisfactory result may be the floor of the Chan at such low doses, as 0.1 µg/kg I.V (intravenous) and 1 mg/kg oral (P.O.). Currently, it is believed that the upper boundary of the range of doses of approximately 10 mg/kg I.V and 100 mg/kg P.O. Preferred ranges are from about 0.1 μg/kg to about 10 mg/kg/day centuries and from about 1 μg/kg to about 100 mg/kg/day P.O.

Methods of treatment

In another aspect of the invention, a method for treating, preventing or reducing the intensity of symptoms of such diseases or disorders, or body condition of the animal, including man, which is sensitive to modulation of GABAA-receptor complex in the Central nervous system, and where the method includes the introduction of such an animal, including a human, in need thereof, an effective amount of a chemical compound according to the invention.

Currently, it is believed that a suitable dose ranges are from 0.1 to 1000 mg per day, 10-500 mg per day, and especially 30-100 mg per day, usually depending on the specific route of administration, form in which the introduction, indications, in relation to whom the introduction, subject and body mass of the subject, and the preference and experience of the attending or veterinarian.

EXAMPLES

The invention is additionally illustrated with reference to the following examples, etc is what is not expected, that they in any way limit the claimed scope of the invention.

General: All reactions involving sensitive to air reagents or intermediate compounds were carried out under nitrogen atmosphere and anhydrous solvents. Magnesium sulfate or sodium sulfate was used as driers in the processing procedures and the solvents evaporated under reduced pressure.

Example 1

3-Nitro-4-(3-thiazol-2-ilfenomeno)benzoic acid

To a solution of 3-thiazol-2-ilfenomeno (14.0 g, 79 mmol) in anhydrous NMP (1-methyl-2-pyrrolidone (50 ml) was added 4-fluoro-3-nitrobenzoic acid (15.0 g, 127 mmol). The resulting mixture was stirred at 90°C during the night. The cooled reaction residue suspended in water and the solid was filtered, washed with water and dried in air to obtain the desired product (22,5 g, 83%).

3-Nitro-4-(3-brompheniramine)benzoic acid

It was prepared analogously from 4-fluoro-3-nitrobenzoic acid and 3-bromoaniline.

[3-Nitro-4-(3-thiazol-2-ilfenomeno)phenyl]methanol

The above product was dissolved in anhydrous tetrahydrofuran (THF) (150 ml) under nitrogen atmosphere. The solution was cooled to 0°C. and dropwise with stirring was added a 1 M solution of the complex of borane-THF in THF (132 ml). After the addition, the reaction mixture leaves the Yali mixed at ambient temperature over night. The solvent was removed in vacuum and the residue was distributed between water and dichloromethane. The organic layer was dried over magnesium sulfate and evaporated to dryness to obtain the target product (23.3 g, 77%).

[3-Nitro-4-(3-brompheniramine)phenyl]methanol

It was obtained analogously from 3-nitro-4-(3-brompheniramine)benzoic acid.

[3-Amino-4-(3-thiazol-2-ilfenomeno)phenyl}methanol

To a solution of the above product (17.8 g, 54,0 mmol) in a mixture of THF (100 ml) and ethanol (50 ml) was added hydrazine hydrate (11 ml, 217 mmol) and a catalytic amount of Raney Nickel. The mixture was stirred at ambient conditions overnight and then filtered through califirnia was evaporated to dryness to obtain the target product (15,8 g, 86%).

[3-Amino-4-(3-brompheniramine)phenyl]methanol

It was obtained similarly from [3-nitro-4-(3-brompheniramine)phenyl]methanol.

[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-yl]methanol

To a solution of the above product (15,8 g, 53,1 mmol) in anhydrous THF (100 ml) was added triethylorthoformate (18 ml, 0.11 mol) and a catalytic amount of para-toluensulfonate acid. The resulting solution was stirred while boiling under reflux for three hours and then the solvent was removed in vacuum. The residue was distributed between aqueous sodium carbonate and the mixture e is racette and methanol. The organic layer was dried over sodium sulfate and concentrated in vacuum. As a result of processing of the concentrate on silica gel by column chromatography, elwira a mixture of dichloromethane and methanol, was obtained the desired product (6.5 g, 40%).

[1-(3-Bromophenyl)-1H-benzimidazole-5-yl]methanol

It was obtained similarly from [3-amino-4-(3-brompheniramine)phenyl]methanol.

2-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione

To a chilled on ice, the mixture of the above product (6.5 g, 21.1 mmol), phthalimide (3.7 g, and 25.4 mmol) and triphenylphosphine in anhydrous THF (150 ml) dropwise with stirring for 15 min was added diethylazodicarboxylate (DEAD) (4,2 g, and 25.4 mmol). Stirring was continued for 30 min, after which the solvent was removed in vacuum. The residue is triturated with ethyl acetate and the resulting precipitate was filtered, washed with ethyl acetate and air-dried to obtain the target product (7.5 g, 81%).

2-[1-(3-Bromophenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione

It was obtained similarly from [1-(3-bromophenyl)-1H-benzimidazole-5-yl]methanol.

2-{1-[1-(3-Bromophenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione

It was obtained similarly from 1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethanol.

S-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine

To suspense the above product (7.5 g, to 17.2 mmol) in absolute ethanol (100 ml) was added hydrazine hydrate (3.5 ml of 68.7 mmol). The mixture was stirred while boiling under reflux for 1 hour and then left at ambient conditions overnight. The solvent was removed in vacuo, and the residue triturated with water to form a solid, which was purified column chromatography on silica gel using a mixture of dichloromethane and methanol (9:1 vol./about.) as eluent.

It is possible to obtain the target product as a white crystalline solid (3.8 g, 71%). The melting point of 99.7°C.

S-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]methylamine

It was obtained analogously from 2-[1-(3-(pyridin-3-yl)phenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione with the release of 26%. The melting point 107-110°C.

S-[1-(3-[6-Herperidin-3-yl]phenyl)-1H-benzimidazole-5-yl]methylamine

It was obtained analogously from 2-[1-(3-(6-herperidin-3-yl)phenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione with the release of 25%. The melting point 141-143°C.

S-[1-(3-Pyridin-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine

It was obtained analogously from 2-[1-(3-pyridin-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione with the release of 18%. The melting point 224-229°C.

S-[1-(3-Pyrazin-2-yl]phenyl)-1H-benzimidazole-5-yl]methylamine

It was obtained analogously from 2-[1-(3-(pyrazin-2-yl)phenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione with vyhoda is 22%. The melting point of 163-165°C.

1-[1-(3-Pyrazin-2-ylphenyl)-1H-benzimidazole-5-yl]ethylamine

It was obtained analogously from 2-[1-[1-(3-(pyrazin-2-yl)phenyl)-1H-benzimidazole-5-yl]ethyl]isoindole-1,3-dione. LC-ESI-HRMS (liquid chromatography-electrospray ionization-mass spectrometry high resolution) [M+H]+ shows 316,155 Yes. Designed 316,15622 Yes, the deviation of 3.9 million-1.

1-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethylamine

It was obtained analogously from 2-{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione to yield 10%. LC-ESI-HRMS of [M+H]+ shows 315,1604 Yes. Designed 315,160971 Yes, deviation -1,8 million-1.

1-{1-[3-(6-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine

It was obtained analogously from 2-(1-{1-[3-(6-herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)-isoindole-1,3-dione with the release of 15%. LC-ESI-HRMS of [M+H]+shows 333,1501 Yes. Designed 333,151549 Yes, a deviation of-4.3 million-1.

The main product (24%) this reaction consisted of 1-{1-[3-(6-Hydrazinopyridazine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine obtained in the form of a yellowish powder.

1-[1-(3-Pyrimidine-5-ylphenyl)-1H-benzimidazole-5-yl]ethylamine

It was obtained analogously from 2-{1-(3-pyrimidine-5-ylphenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione, the yield was 61%, in the form of a white powder.

N-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]ndimethylacetamide

the suspension of s-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine (0,70 g, 2.3 mmol) in dichloromethane (30 ml) dropwise with stirring was added acetic anhydride (2.4 ml, 2.5 mmol). After the addition stirring was continued for 30 min and the reaction mixture is washed twice with saturated aqueous sodium bicarbonate and once with water. The organic phase was dried over sodium sulfate and concentrated in vacuum. The concentrate was purified column chromatography on silica gel, elwira a mixture of dichloromethane, methanol and ammonia (9:1:0.1.about./vol.). It is possible to obtain the target product (0.52 g, 65%). The melting point 156,4°C.

N-[1-(3-Pyridin-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]ndimethylacetamide

It was obtained similarly from C-[1-(3-[pyridin-2-yl]phenyl)-1H-benzimidazole-5-yl]methylamine (0.06 g, 54%). LC-ESI-HRMS of [M+H]+ shows 34,1544 Yes. Designed 343,155886 Yes, a deviation of-4.3 million-1.

Example 2

2-[1-(3-(Pyridin-3-yl)phenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione

A mixture of 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione (1.10 g, 2.54 mmol), 3-pyridineboronic acid (0,47 g is 3.82 mmol), potassium carbonate (1.06 g, 7,63 mmol), 1,3-propane diol (0,92 ml, 12,72 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g) in a mixture of dimethoxyethane (20 ml) and water (10 ml) was stirred while boiling under reflux in a nitrogen atmosphere within 20 minutes the mixture was cooled and the volatile matter was removed under vacuum. Product is besieged from residual solvent and filtered, washed with water and dried in the air with the receipt of 0.56,

2-[1-(3-(6-Herperidin-3-yl)phenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione

It was obtained analogously from 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]-isoindole-1,3-dione and (6-fluoro-3-pyridine)Bronevoy acid.

2-{1-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione

It was obtained analogously from 2-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethyl}-isoindole-1,3-dione and 3-pyridineboronic acid.

2-(1-{1-[3-(6-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)isoindole-1,3-dione

It was obtained analogously from 2-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione and (6-fluoro-3-pyridine)Bronevoy acid.

2-{1-[1-(3-Pyrimidine-5-ylphenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione

It was obtained analogously from 2-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione and 5-pyrimidinemethanol acid.

2-[1-(3-(Pyridin-2-yl)phenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione

To a solution of 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione (1.0 g, 2,31 mmol) in anhydrous THF (20 ml) was added 2-tributylstannyl (of 0.82 ml, 2.54 mmol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0) (60 mg) and the resulting mixture was stirred while boiling under reflux in nitrogen atmosphere for 3 days. The reaction mixture was extinguished aqueous ammonia and was extracted uh what racedata. The organic extract was dried over magnesium sulfate and concentrated in vacuum. The concentrate was suirable through silica gel with ethyl acetate to obtain the desired product. 0.24 g (24%).

2-[1-(3-(Pyrazin-2-yl)phenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione

It was obtained analogously from 2-[1-(3-bromophenyl)-1H-benzimidazole-5-ylmethyl]isoindole-1,3-dione and 2-tributylstannyl.

2-[1-[1-(3-(Pyrazin-2-yl)phenyl)-1H-benzimidazole-5-yl]ethyl]isoindole-1,3-dione

It was obtained analogously from 2-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethyl}isoindole-1,3-dione and 2-tributylstannyl.

Example 3

1-[4-(3-Brompheniramine)-3-nitrophenyl]alanon

To a solution of 4-fluoro-3-nitroacetophenone (165 g, 0.9 mol) in NMP (350 ml) was added 3-bromaniline (98 ml, 0.9 mol) and triethylamine (125,4 ml, 0.9 mol) and the reaction mixture was stirred at 80°C for 6 hours and then was allowed to mix at room temperature over night. The resulting suspension was poured into a mixture of ice-water and the precipitate was filtered and sequentially washed with water and diethyl ether. As a result of air drying was obtained target product (262 g, 87%).

1-{4-[3-(5-Chlorothiazole-2-yl)phenylamino]-3-nitrophenyl}alanon

It was obtained analogously from 4-fluoro-3-nitroacetophenone and 3-thiazol-2-ilfenomeno with the release of 76%.

1-[3-Amino-4-(3-Bromphenol the but)phenyl]alanon

1-[4-(3-Brompheniramine)-3-nitrophenyl]alanon (75 g, 0.22 mol) was dissolved in THF (350 ml) and was first made by standard methods, using Raney Nickel as a catalyst, to obtain the desired diamine, which was used in the next stage without additional purification.

1-{3-Amino-4-[3-(5-chlorothiazole-2-yl)phenylamino]phenyl}alanon

It was obtained similarly from 1-{4-[3-(5-chlorothiazole-2-yl)phenylamino]-3-nitrophenyl}of ethanone.

1-[1-(3-Bromophenyl)-1H-benzimidazole-5-yl]alanon

It was obtained from 1-[3-amino-4-(3-brompheniramine)phenyl]ethanone (86,5 g, 0.28 mol) by treatment with triethylorthoformate in THF in the presence of para-toluensulfonate acid as described in Example 1.

1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}alanon

It was obtained similarly from 1-{3-amino-4-[3-(5-chlorothiazole-2-yl)phenylamino]phenyl}of ethanone.

1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethanol

To a solution of 1-{1-[3-(5-chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethanone (6.3 g, 17.8 mmol) in methanol (75 ml) was added sodium borohydride (0,91 g of 23.9 mmol) and the resulting mixture was stirred at room temperature under nitrogen atmosphere for 7 days. The reaction mixture was diluted with four volumes of water and was extracted with ethyl acetate. The organic extract was washed with brine, dried over magnesium sulfate and evaporated in vacuum to obtain the target product (4,95 g, 78%). LC-ESI-HRMS of [M+H]+ shows 356,0635 Yes. Designed 356,062436 Yes, a deviation of 3 million-1.

1-[1-(3-Bromophenyl)-1H-benzimidazole-5-yl]ethanol

It was obtained similarly from 1-[4-(3-brompheniramine)-3-nitrophenyl]ethanone.

Example 4

N-{1-[1-(3-Bromophenyl)-1H-benzimidazole-5-yl]ethyl}formamide

A mixture of 1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethanone (7.5 g, to 23.8 mmol), formamide (9,5 ml of 23.8 mmol) and formic acid (22,4 ml, 595 mmol) was stirred at 190°C for 7 hours. The cooled mixture decantation. The residue was podslushivaet by adding saturated aqueous sodium carbonate and was extracted with ethyl acetate. The organic extract was dried over magnesium sulfate and concentrated in vacuum. The concentrate was suirable through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (9:1:0.1.about./about.) to obtain the desired product (60%).

N-(1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide

To a solution of N-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethyl}formamide (0.2 g, of 0.65 mmol) in a mixture of dimethoxyethane, water and ethanol (4 ml, 7:3:2 vol./about./about.) was added 2-herperidin-3-Bronevoy acid (0.09 g, of 0.65 mmol), chloride bis(triphenylphosphine)palladium (II) (5 mg) and sodium carbonate (0.07 g, of 0.65 mmol) and the resulting mixture was heated to 160°With microwave radiation within 4 minutes the Cooled mixture was diluted with ethyl acetate and washed the water. In the drying over magnesium sulfate and processing column chromatography was obtained the desired product (150 mg, 67%). LC-ESI-HRMS of [M+H]+ shows 361,1451 Yes. Designed 361,146464 Yes, the deviation of 3.8 million-1.

N-(1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide

It was obtained similarly from N-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethyl}formamide and 2-methoxypyridine-3-Bronevoy acid with a yield of 77%. LC-ESI-HRMS of [M+H]+ shows 373,1666 Yes. Designed 373,166451 Yes, deviation 0.4 million-1.

N-(1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide

It was obtained similarly from N-{1-[1-(3-bromophenyl)-1H-benzimidazole-5-yl]ethyl}formamide and 2,4-dimethoxypyrimidine-5-Bronevoy acid with a yield of 81%. LC-ESI-HRMS of [M+H]+ shows 404,1729 Yes. Designed 404,172265 Yes, the deviation of 1.6 million-1.

1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine

A solution of N-(1-{1-[3-(2,4-dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide (0,53 g of 1.31 mmol) in hydrochloric acid (2.2 ml, 6 M) was stirred at 60°C for 3 hours. To the cooled solution was added ethyl acetate and aqueous sodium carbonate to an alkaline reaction. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated in vacuum. The concentrate was suirable through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (9:1:0.1.about./about.) received the eating of the desired product (0.12 g, 25%). LC-ESI-HRMS of [M+H]+ shows 376,1794 Yes. Designed 376,17735 Yes, the deviation of 5.4 million-1.

1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazol-5-yl}ethylamine

It was obtained similarly from N-(1-{1-[3-(2-methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide with the release of 31%. LC-ESI-HRMS of [M+H]+ shows 345,1733 Yes. Designed 345,171536 Yes, the deviation of 5.1 million-1.

(R)-1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine

It was obtained similarly from N-(1-{1-[3-(2-herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide; LC-ESI-HRMS of [M+H]+ shows 333,1525 Yes. Designed 333,151549 Yes, the deviation of 2.9 million-1.

Example 5

5-Chloro-2-(3-nitrophenyl)thiazole

To a stirred solution of 2-(3-nitrophenyl)thiazole (18,5 g of 89.7 mmol) in a mixture of chloroform (150 ml) and anhydrous DMF (40 ml) was slowly added sulfurylchloride (28,2 ml, 359 mmol). After adding the resulting mixture was stirred while boiling under reflux for 3 hours. The cooled mixture was concentrated under reduced pressure and the residue was distributed between water calcium chloride (3 M) and ethyl acetate. The organic layer is washed with aqueous sodium carbonate, dried over magnesium sulfate and evaporated to dryness to obtain the desired product. 20.6 g (80%).

3-Thiazol-2-elfenlied

To a solution of 5-chloro-2-(3-nitrophenyl)thiazole (20,0 g to 69.6 mmol) in THF (260 ml) was added hydrazine monohydrate (13,5 ml, 278 mmol) and Raney Nickel (2 g). The resulting mixture was stirred at ambient conditions for 1 hour and then filtered through celite. The filtrate was evaporated to dryness and distributed between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried over sodium sulfate and concentrated in vacuum. The concentrate was suirable through silica gel with a mixture of ethyl acetate and ligroin (1:3 vol./about.) to obtain the target product (10.6 g, 72%).

Example 6

A General method.

To a solution of amine in anhydrous DMF (10-20 ml / g amine) was added 1.1 equivalents of triethylamine and 1.5 equivalent of the appropriate alkylating agent. The resulting mixture was stirred at room temperature until complete consumption of the source materials (thin-layer chromatography (TLC) or LC-MS). The mixture was diluted with four volumes of water and was extracted with ethyl acetate. As a result of processing of the concentrated extract by column chromatography has been the target products.

In accordance with this method received the following connections:

Methyl[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin

and

Dimethyl[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin

Melting point: 235°C (hydrochloride) from n-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]methylamine and iodomethane.

Benzyl{1-[1(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}amine

LC-ESI-HRMS of [M+H]+ shows 405,2069 Yes. Designed 405,207921 Yes, deviation and 2.5 million-1

and

Dibenzyl{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}amine from 1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethylamine.

Methyl[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin

and

Dimethyl[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin

LC-ESI-HRMS of [M+H]+ shows 335,1313 Yes. Designed 335,133042 Yes, the deviation of 5.2 million-1.

Received from C-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine.

Ethyl[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin.

The melting point of 224°C. (as hydrochloride)

and

Diethyl[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin

The melting point of 152°C. (as hydrochloride).

Benzyl[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin

LC-ESI-HRMS of [M+H]+shows 397,1492 Yes. Designed 397,148692 Yes, the deviation of 1.3 million-1

and

Dibenzyl[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]Amin

The melting point of 126°C.

Example 7

O-Methyl-N-{1-[1-(3-pyridin-3-elfini)-1H-benzimidazole-5-yl]ethyl}hydroxylamine

To a solution of 1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethanone On-methyloxime (obtained as described in WO 96/33191) (0.88 g, 2.57 mmol) in dichloromethane (10 ml) was sequentially added pyridine-bananowy complex of 0.87 ml, to 8.57 mmol) and glacial acetic sour is at (2.5 ml). The resulting solution was stirred while boiling under reflux in nitrogen atmosphere for 4 days. To the cooled solution was added hydrochloric acid (5 ml, 1 M), stirring was continued for 30 min and the resulting mixture was concentrated in vacuum. The concentrate was distributed between ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate and suirable through silica gel with a mixture of ethyl acetate and methanol (9:1 vol./vol.). It is possible to obtain 27 mg of the target product. LC-ESI-HRMS of [M+H]+shows 345,1717 Yes. Designed 345,171536 Yes, deviation 0.5 million-1.

Example 8

N-{1-[3-(Thiazol-2-yl)phenyl]-1H-benzimidazole-5-ylmethyl}formamide

A solution of C-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine (1.4 g of 4.57 mmol) in formic acid (20 ml) was stirred while boiling under reflux for 3 hours. The mixture was evaporated in vacuo, and the residue was distributed between ethyl acetate and saturated aqueous sodium carbonate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (9:1 vol./about.) as the eluent, to obtain the target product 0.5 g (33%). LC-ESI-HRMS of [M+H]+ shows 335,095 Yes. Designed 335,096657 Yes, the deviation of 4.9 million .

Example 9

1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine

Stir a suspension of 1-{1-[3-(5-chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethanol (1.0 g, 2,80 mmol) in a mixture of anhydrous toluene (60 ml) and THF (10 ml) was cooled to WC and consistently added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 ml, to 3.36 mmol) and diphenylphosphoryl (0.95 g, to 3.36 mmol). Stirring was continued for 45 min at 10°C, after which the temperature was increased and the mixture was stirred while boiling under reflux for two days. The cooled mixture was concentrated in vacuo and the concentrate was distributed between ethyl acetate and saturated aqueous sodium carbonate. The organic extract was dried over magnesium sulfate, concentrated under reduced pressure and was suirable through silica gel with a mixture of dichloromethane, methanol and aqueous ammonia (9:1:0.1.about./about.) to obtain the desired product (0.75 g, 70%). LC-ESI-HRMS of [M+H]+shows 355,079 Yes. Designed 355,07842 Yes, the deviation of 1.6 million-1.

Example 10

Some of the amines described in the Examples above, exist in the form of racemic mixtures. Specific enantiomers can be obtained by using below presents the overall methodology, starting with commercially available (R)- and (S)-1-phenylethylamine.

Optically pure 1-(4-forfinal)ethylamine for iseut by acetylation with acetic anhydride and nitrious nitric acid. The resulting product interacts with the anion accordingly formirovanija 3-substituted aniline with getting nitroaniline, which, in turn, hydronaut and close the ring.

In accordance with this method are the following connections:

(R)-Benzyl{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}amine and

(S)-Benzyl{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}amine.

(R)-1-[1-(3-Pyrazin-2-ylphenyl)-1H-benzimidazole-5-yl]ethylamine and

(S)-1-[1-(3-Pyrazin-2-ylphenyl)-1H-benzimidazole-5-yl]ethylamine.

(R)-1-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethylamine and

(S)-1-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethylamine.

(R)-1-{1-[3-(6-Hydrazinopyridazine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine and

(S)-1-{1-[3-(6-Hydrazinopyridazine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine.

(R)-1-{1-[3-(6-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine and

(S)-1-{1-[3-(6-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine.

(R)-1-[1-(3-Pyrimidine-5-ylphenyl)-1H-benzimidazole-5-yl]ethylamine and

(S)-1-[1-(3-Pyrimidine-5-ylphenyl)-1H-benzimidazole-5-yl]ethylamine.

(R)-1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine salt chloride LC-ESI-HRMS of [M+H]+ shows 355,0795 Yes. Designed 355,07842 Yes, a deviation of 3 million-1; solid whitish; and

(S)-1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine salt chloride LC-ESI-HRMS of [M+H]+ shows 55,0788 Yes. Designed 355,07842 Yes, the deviation of 1.1 million-1; solid brown color.

(R)-N-(1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide, LC-ESI-HRMS of [M+H]+ shows 361,145 Yes. Designed 361,146464 Yes, deviation -4,1 million-1; white foam; and

(S)-N-(1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide LC-ESI-HRMS of [M+H]+ shows 361,1471 Yes. Designed 361,146464 Yes, the deviation of 1.8 million-1; whitish powder.

(R)-N-(1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide and

(S)-N-(1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide.

(R)-N-(1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide and

(S)-N-(1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide.

(R)-1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine and

(S)-1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine.

(R)-1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine and

(S)-1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine.

(R)-1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine and

(S)-1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine.

TEST METHODS

Test method 1

Inhibition of binding3H-flunitrazepam (3H-FNM) in vitro

The site of the GABA recognition and benzodiaz the new modulating fragment can be selectively marked 3H-flunitrazepam.

Tissue preparation

Unless otherwise stated, the drugs are prepared at 0-4°C. the cerebral Cortex of male Wistar rats (150-200 g) homogenized for 5-10 s in 20 ml of Tris-HCl (30 mm, pH 7.4) using a homogenizer (Ultra-Turrax. The suspension is centrifuged at 27000 × g for 15 min and the precipitate washed three times with buffer (centrifuged at 27000 × g for 10 min). The washed precipitate homogenized in 20 ml of buffer and incubated in a water bath (37°C) for 30 min to remove endogenous GABA and then centrifuged for 10 min at 27000 × g. The precipitate is then homogenized in buffer and centrifuged for 10 min at 27000 × g. The final precipitate resuspended in 30 ml of buffer and the product is frozen and stored at -20°C.

Analysis

The membrane preparation is thawed and centrifuged at 2°C for 10 min at 27000 × g. The precipitate washed twice with 20 ml of 50 mm Tris-citrate, pH of 7.1, using a homogenizer Ultra-Turrax and centrifuged for 10 min at 27000 × g. The final precipitate resuspended in 50 mm Tris-citrate, pH 7,1 (500 ml buffer g of original tissue), and then used for analysis of binding. Aliquots of 0.5 ml of tissue added to 25 μl of test solution and 25 μl of3H-FNM (1 nm, final concentration), mixed and incubated for 40 min at 2°C. non-specific binding determine using clonazepam (1 μm, final con is entrace). After incubation the sample add 5 ml of ice-cold buffer and poured directly onto a glass-fiber filters Whatman GF/C using suction and immediately washed with 5 ml ice-cold buffer. The amount of radioactivity on the filters is determined using conventional liquid scintillation counting. Specific binding represents the total binding minus nonspecific binding.

Results

Must be received 25-75%inhibition of specific binding before calculating IC50(concentration causing 50%inhibition).

The resulting test values are expressed as IC50(the concentration (μm) test substance which inhibits the specific binding3H-FNM 50%).

where

Corepresents specific binding in control assays and

Withxrepresents the specific binding in the test assay.

(Calculations assume normal kinetics in accordance with the law of mass).

The results of the tests in these experiments with a number of compounds according to the invention are presented in Table 1 below.

Table 1
The tested compounds is of Binding in vitro IC50(µm)
S-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazol-5-yl]methylamine0,011
N-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazol-5-ylmethyl]ndimethylacetamide0,024
N-{1-[3-(Thiazol-2-yl)phenyl]-1H-benzimidazole-5-ylmethyl}formamide0,0048

1. The compound of General formula (I)

or any of its stereoisomers or any mixture of its stereoisomers,
or its pharmaceutically acceptable salt,
where Ra, Rband Rcindependently of one another represent hydrogen, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, arylalkyl, formyl or alkylsulphonyl;
Rdrepresents a heteroaryl group;
where the heteroaryl group means a 5-6-membered aromatic heterocyclic group which contains one or two heteroatoms in its ring structure selected from nitrogen (N) or sulfur (S), and where the heteroaryl group possibly substituted by one or more substituents independently selected from the group consisting of halogeno, hydrazino and alkoxy.

2. The compound according to claim 1, where Rarepresents hydrogen, alkyl or arylalkyl.

3. The compound according to claim 1, where Rbis the Oh hydrogen, alkyl, alkoxy, arylalkyl, formyl or alkylsulphonyl.

4. The compound according to claim 1, where Rcrepresents hydrogen or alkyl.

5. The compound according to any one of claims 1 to 4, where Rdrepresents a heteroaryl group selected from thiazolyl, pyridyl, pyrimidyl and pyrazinyl;
where the heteroaryl group possibly substituted by one or more substituents independently selected from the group consisting of halogeno, hydrazino and alkoxy.

6. The compound according to claim 1, which represents the
S-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine;
S-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]methylamine;
S-[1-(3-[6-Herperidin-3-yl]phenyl)-1H-benzimidazole-5-yl]methylamine;
S-[1-(3-[Pyridin-2-yl]phenyl)-1H-benzimidazole-5-yl]methylamine;
S-[1-(3-Pyrazin-2-ylphenyl)-1H-benzimidazole-5-yl]methylamine;
1-[1-(3-Pyrazin-2-ylphenyl)-1H-benzimidazole-5-yl]ethylamine;
1-[1-(3-Pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethylamine;
1-{1-[3-(6-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;
1-{1-[3-(6-Hydrazinopyridazine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;
1-[1-(3-Pyrimidine-5-ylphenyl)-1H-benzimidazole-5-yl]ethylamine;
N-[1-(3-Thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]ndimethylacetamide;
N-[1-(3-Pyridin-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]ndimethylacetamide;
N-(1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide;
N-[1-{1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)f is rmaed;
N-(1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethyl)formamide;
1-{1-[3-(2,4-Dimethoxypyrimidine-5-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;
1-{1-[3-(2-Methoxypyridine-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;
1-{1-[3-(2-Herperidin-3-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;
Dimethyl-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;
Benzyl-{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}amine;
Dimethyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;
Ethyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;
Diethyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;
Benzyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;
Dibenzyl-[1-(3-thiazol-2-ylphenyl)-1H-benzimidazole-5-ylmethyl]amine;
O-Methyl-N-{1-[1-(3-pyridin-3-ylphenyl)-1H-benzimidazole-5-yl]ethyl}hydroxylamine;
N-{1-[3-(thiazol-2-yl)phenyl]-1H-benzimidazole-5-ylmethyl}formamide;
1-{1-[3-(5-Chlorothiazole-2-yl)phenyl]-1H-benzimidazole-5-yl}ethylamine;
or any of its stereoisomers or any mixture of its stereoisomers, or its pharmaceutically acceptable salt.

7. Pharmaceutical composition, which have activity as modulators of a receptor complex of gamma-aminobutyric acid (GABAAin the Central nervous system containing a therapeutically effective amount of a compound according to any one of claims 1 to 6 or of any of its stereoisomers, and any mixture of its stereoisomers, or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier, excipient or diluent.

8. The use of chemical compounds according to any one of claims 1 to 6 or of any of its stereoisomers or any mixture of its stereoisomers, or its pharmaceutically acceptable salt for the manufacture of drugs that have activity as modulators of a receptor complex of gamma-aminobutyric acid (GABAAin the Central nervous system.

9. The use of claim 8 for the manufacture of pharmaceutical compositions for the treatment, prevention or reduction of the intensity of symptoms of the disease or disorder, or condition of a mammal, where the disease, disorder or condition responsive to modulation of GABAA-receptor complex in the Central nervous system.

10. The use according to claim 9, where the disease, disorder or condition is an anxiety disorder, panic disorder with or without agoraphobia, agoraphobia without panic disorder, animal and other phobias, including sociophobia, obsessive-compulsive disorder, and generalized or caused by taking psychoactive substance anxiety disorder, stress disorder, post-traumatic and acute stress disorder, resstr istwa sleep, memory loss, nervous disorders, convulsive disorders, epilepsy, seizures, convulsions, febrile convulsions in children, migraine, mood disorders, depressive or bipolar disorder, depression, single episode major depressive disorder or recurrent major depressive disorder, delimitable disorder, bipolar disorder, bipolar manic disorder type I and II, cyclothymic disorder, psychotic disorders, including schizophrenia, neurodegeneration arising from cerebral ischemia, disorder attention deficit hyperactivity disorder, pain, nociception, neuropathic pain, nausea, acute, delayed and premature nausea, including nausea, caused by chemotherapy or radiation, motion sickness, postoperative nausea, vomiting, eating disorders, nervous anorexia, nervous bulimia, premenstrual syndrome, neuralgia, trigeminal neuralgia, muscle spasm, spasticity, for example in patients suffering from paralysis of the lower limbs, the effects of substance abuse or dependence on psychoactive substances, alcohol withdrawal syndrome, cognitive disorders, Alzheimer's disease, cerebral ischemia, stroke, brain injury, noise in the Shah, disorders of circadian rhythm, e.g. in subjects suffering from the effects of desynchronosis after transmeridian flight or shift work.

11. Method of modulating GABAA-receptor complex in the Central nervous system, including the stage of introducing a therapeutically effective amount of a compound according to any one of claims 1 to 6 or of any of its stereoisomers or any mixture of its stereoisomers, or its pharmaceutically acceptable salt.



 

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SUBSTANCE: medicine-ligand conjugates are powerful cytotoxins in which the medicine is bonded to the ligand through a peptide, hydrazine or disulphide linker.

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63 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

, in which A is a counter ion, a=1-3, b=0-3, X=1-6C alkyl, R1=1-6C alkyl, one or R2 and R3 is 1-6C alkyl and the other is XN+Hb(R1)3-b, or R2 and R3 form a methylenedioxy group, one or R4 and R5 is a halogen and the other is a halogen-substituted 1-6C alkyl, or R4 and R5 are bonded to form a 6-10C aromatic ring or a substituted 6-10C aromatic ring in which the substitute is selected from 1-6C alkoxy, halogen and halogen-substituted 1-6C alkyl. The invention also relates to a method of measuring content of analysed substance capable of ensuring proportional colour change as a result of a reaction in a biological fluid, involving the following steps: ensuring availability of the disclosed tetrazolium salt as an indicator and determination of concentration of the said analysed substance in the biological fluid using the said tetrazolium salt which is used as an indicator.

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

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29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. Disclosed compounds have inhibitory effect on CDK1 kinase and can be used to prepare medicinal agents for treating diseases associated with abnormal cell cycle development. In formula I , R1 is hydrogen, -C(O)OR9 or R2-(X)n-; X is (lower)alkylene, hydroxy(lower)alkylene, cyclised(lower)alkylne or mono- or dihalogen(lower)alkylene; R2 is a group, where denotes a phenyl or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from a group comprising oxygen, sulphur and nitrogen atoms; R5, R6 and R7 are independently selected from a group comprising hydroxy, hydrogen, (lower)alkyl, halogen and (lower)alkoxy; R4 is a halogen, , (O)k(CH2CH2O)y-R10, , -S-R12 or -O-(CH2)tR14, where denotes a phenyl, a cycloalkyl ring containing 3-6 carbon atoms, a 4-6-member heterocycloalkyl containing 3-5 carbon atoms and 1-2 heteroatoms selected from a group comprising oxygen, nitrogen and sulphur atoms; R9, R11, R15 and R16 independently denote (lower)alkyl; R10 and R12 denote (lower)alkyl; R14 denotes perfluoro(lower)alkyl or -NR15R16; R17 and R18 independently denote hydrogen, , F, OCH3 and -C(=O)CH3; n and k are equal to 0 or 1; m, w, y and z are equal an integer from 0 to 3; and t equals an integer from 0 to 6.

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65 cl, 1 tbl, 49 ex

FIELD: medicine, pharmaceutics.

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6 cl, 3 ex

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20 cl, 1 tbl, 133 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I) , where R1 is selected from group, including: phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, lower alkoxy group, halogen or lower halogenalkyl; naphtyl; tetrahydronaphtyl; C3-7cycloalkyl; -(CHR3)m-phenyl, where m stands for 1, 2, or 3; and phenyl is unsubstituted or mono-, di- or tri-substituted with lower alkoxy group, and where R3 is independently selected from hydrogen and lower alkyl; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; -(CH2)n-heteroaryl, where n stands for 1, 2 or 3; term "heteroaryl" relates to aromatic 5- or 6- member ring or bicyclic 9-member aromatic groups, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur, and heteroaryl is mono-, di- or tri-substituted independently with lower alkoxy group; and R2 is selected from group including: n-butyl; phenyl, unsubstituted or mono-, di- or tri-substituted independently with lower alkyl, halogen or lower alkoxy group; heteroaryl, where term "heteroaryl" relates to aromatic 5-member ring, which can include 1, 2 or 3 atoms, selected from nitrogen and/or sulphur; unsubstituted or mono-, di- or tri-substituted independently with lower alkoxy group; -C(O)-NR4R5; where R4 and R5 stand for lower alkyl or together with nitrogen atom, to which they are bound, form 5-member heterocycle, which can additionally contain heteroatom, selected from N or S, and to their pharmaceutically acceptable salts. Invention also relates to pharmaceutical composition.

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13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, pharmaceutical compositions based on the said compounds, as well as methods of using said compounds in preparing medicinal agents.

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12 cl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have inhibitory effect on CDK1 kinase. In formula I , R1 is hydrogen or R2-(X)n-; X is a lower alkylene or cyclic lower alkylene; R2 denotes ; where denotes phenyl; cycloalkyl containing 3-6 carbon atoms; 4-6-member heterocycloalkyl ring having 3-5 carbon atoms and 1-2 oxygen atoms; R5, R6 and R7 are independently selected from a group containing hydrogen or halide; R4 is hydrogen or -(O)k(CH2CH2O)y-R10; R19 is hydrogen; R20 is hydrogen or -C(O)-R11; R10 and R11 is a lower alkyl; n and k are equal to 0 or 1; y is an integer from 0 to 3.

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15 cl, 10 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

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32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): , optical isomers of said compounds, as well as salts thereof having peroxisome proliferator-activated receptor subtype y (PPARy) modulating property. Values of R1, R2, X, Ar1 and Ar2 are given in the formula of invention.

EFFECT: preparation of compositions based on said compounds, as well as use of said compounds in cosmetic and pharmaceutical industry.

11 cl, 30 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, and more specifically to novel ethyl 5-R1-7-R2-1'-benzyl-3,3-dimethyl-1,2' -dioxo-5'-phenyl- 1',2,2',3,4,10-hexahydro-1H-spiro[acridine-9,3'-pyrrol]-4'-carboxylates of formula , where R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br, and to a method for synthesis of the said compounds.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to heterocyclic compounds of formula I or their stereo isomer, tautomer or pharmaceutically acceptable salt or solvate, where W denotes -C(=S)- or -C(=O); X denotes -N(R5)-; U denotes a bond or -(C(R6)(R7))b- where b equals 1; R1, R2 and R5 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, cycloalkyl with 3-7 carbon atoms and other radicals given in claim 1 of the formula of invention; R3, R4, R6 and R7 are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; R15, R16 and R17 indicated below are independently selected from a group comprising H, alkyl with 1-6 carbon atoms, alkenyl with 2-6 carbon atoms, alkynyl with 2-4 carbon atoms, cycloalkyl with 3-7 carbon atoms, cycloalkylalkyl with 3-7 carbon atoms in the cycloalkyl part and 1-6 carbon atoms in the alkyl part and other radicals given in claim 1 of the formula of invention; or R15, R16 and R17 denote ; , where R23 denotes 0-2 substitutes, m equals 0 and n equals 1 or 2, and where all alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, alkenyl and alkynyl groups in R1, R2, R3, R4, R5, R6, R7 can be independently substituted with 1-3 R21 groups independently selected from alkyl with 1-6 carbon atoms, cycloalkyl with 3-7 carbon atoms, halogen, aryl with 6-10 carbon atoms; -CN, -OR15, -C(O)R15, -C(O)OR15, - C(O)N(R15)(R16), -S(O)2N(R15)(R16), -N(R15)(R16), -N(R15)C(O)R16, -CH2-N(R15)C(O)R16, - CH2-R15; -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17), -CH2-N(R15)C(O)N(R16)(R17), -N(R15)C(O)OR16, -CH2-N(R15)C(O)OR16, -N3, -NO2 and -S(O)2R15; and where alkyl with 1-6 carbon atoms and cycloalkyl with 3-7 carbon atoms are independently substituted or contain substitutes in form of 1-5 R22 groups, independently selected from a group comprising halogen, -CN or -OR15; R23 denotes alkyl with 1-6 carbon atoms; provided that if W denotes -C(O)- and U denotes a bond, then R1 does not denote, if needed, a substituted phenyl, provided that neither R1 nor R5 denotes alkyl disubstituted with -CO(O)R15 or -C(O)N(R15)(R16)) and (-N(R15)(R16), -N(R15)C(O)R16, -N(R15)S(O)R16, -N(R15)S(O)2R16, -N(R15)C(O)N(R16)(R17) or -N(R15)C(O)OR16) groups; provided that if R1 denotes methyl, R2 denotes H, W denotes C(O)- and U denotes a bond, then (R3, R4) does not denote (H, H), (phenyl, phenyl), (H, phenyl), (benzl, H), (benzyl, phenyl), (isobutyl, H), (isobutyl, phenyl), (OH-phenyl, phenyl), (halogenphenyl, phenyl) or (CH3O-phenyl, NO2-phenyl);provided that if R1 and R5 both denote H, W denotes -C(O)- and U denotes a bond, then (R3, R4) does not denote (substituted phenyl if needed, substituted benzyl if needed), (substituted phenyl if needed, heteroarylalkyl) or (heteroaryl, heteroarylalkyl); provided that if R1 denotes R21-aryl or R21 arylalkyl, where R21 denotes -OCF3, -S(O)2CF3, -S(O)2alkyl, -S(O)2CHF2, -S(O)2CF2CF3, -OCF2CHF2, -OCHF2, -OCH2CF3 or -S(O)2NR15R16; where R15 and R16 are independently selected from a group comprising H, said alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, R18-alkyl, R18-cycloalkyl, R18-heterocycloalkyl and R18 -aryl, and U denotes a bond; then R5 denotes H, where R18 is as defined in claim 1 of the formula of invention. The present invention also relates to a pharmaceutical composition based on the compound of formula , use of the formula I compound in preparing a medicinal agent.

EFFECT: novel heterocyclic derivatives of formula I, having aspartyl protease inhibiting properties, are obtained.

16 cl, 1 tbl

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