New 2,3,4,5-tetrahydro-1-pyrido[4,3-b]indole derivatives and methods for using them

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to new 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole derivatives, which can be used for modulating histamine receptors in individuals or for treating neurodegenerative diseases. The above derivatives have formula , wherein R1 is specified in an alkyl, substituted alkoxy or phenyl, and aralalkyl; R2 is specified in an alkyl, C6-C14-aryl optionally substituted by 1 to 5 substitutes specified in alkoxy and alkyl; R3 is an alkyl; and R4 is an alkyl.

EFFECT: presented are the new compounds effective as histamine receptor modulators, and a based pharmaceutical composition.

20 cl, 1 tbl, 1 ex

 

The technical field to which the invention relates

New derivatives of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole according to the invention can find application as a new antihistamine or used for the treatment of neurodegenerative diseases.

Summary of the invention

Compounds of the General formula I are described as new modulators of the histamine receptors. The compounds according to the invention may also find application in the treatment nejrodegenerativnyh diseases.

The invention includes compounds of formula I,

in which

R1choose from alkyl, substituted alkyl and aralkyl; and

R2choose from alkyl, aryl and substituted aryl;

R3is alkyl; and

R4is alkyl;

or their pharmaceutically acceptable salts.

The invention also includes all salts of these compounds, solvates and hydrates of the above compounds. All tautomers are also included in the scope of this invention. The invention also includes any or all of the stereochemical forms, including enantiomeric or diastereomeric forms of the described compounds. If stereochemistry is not specified clearly in the chemical structure or name, it is understood that the structure or the name embraces all possible stereoisomers of the described compounds. Sun� forms of compounds, such as crystalline or non-crystalline forms, also included in the scope of the invention. The compositions containing the compound according to the invention, also refers to such as the composition is essentially pure compound, including its specific stereochemical form, or a composition comprising a mixture of compounds according to the invention in any ratio, including two or more stereochemical forms, such as racemic or racemic mixture. The compositions containing the compound of the invention and the filler is also included in the scope of this invention. Another aspect of the invention are compositions containing essentially pure compound according to the invention.

The invention is also directed to pharmaceutical compositions containing the compound of the invention and a pharmaceutically acceptable carrier and/or excipient. Method of modulating histamine receptors in an individual, comprising administering to the individual in need of this, the compounds according to the invention. Sets containing the compound of the invention and instructions for use are also included in the scope of this invention.

A detailed description of the invention

Definition

For purposes of this description, unless expressly stated otherwise, the use of nouns in the singular also includes the plural form number�.

The reference tag about in relation to the value or parameter includes (and describes) implementation options that are targeted at these value or parameter as such. For example, the definition relating to "about X" includes the description of "X".

Unless expressly stated otherwise, "individual", as used herein, refers to a mammal, including, but not limited to, human.

As used herein, "treatment" is an approach for obtaining beneficial or desired results, such as clinical result.

As used herein, the term "modulator of histamine receptors" refers to a compound that reduces or eliminates or increases or enhances the activity of histamine receptors. Basically, a "modulator of histamine receptors" includes both an antagonist of histamine receptors and agonist histamine receptors. In some embodiments, the modulator of histamine receptors reduces, or eliminates or increases or enhances the activity of histamine receptors reversible or irreversible manner. In some embodiments, the modulator of histamine receptors reduces the activity of histamine receptors, at least or about any value from 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% compared�Oia with the corresponding activity in the same individual before treatment with the modulator histamine receptors or compared to the corresponding activity in like individuals, not receiving the modulator histamine receptors. In some embodiments, the modulator of histamine receptors enhances the activity of histamine receptors, at least or about any value from 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100%, or 200% or 300% or 400% or 500%, or more, compared to the corresponding activity in the same individual before treatment with the modulator histamine receptors or compared to the corresponding activity in like individuals, not receiving the modulator histamine receptors. In some embodiments, the modulator of histamine receptors capable of binding to the active center of histamine receptor (for example, the binding site of the ligand). In some embodiments, the modulator of histamine receptors capable of binding to allosteric center of histamine receptor.

"Pharmaceutically acceptable salts" are those salts which retain at least a portion of the biological activity of free (not as a salt) compounds and can be used as drugs or pharmaceuticals for individuals. Such salts, for example, include: (1) acid additive salts formed from inorganic acids such as hydrochloric acid, Hydrobromic acid, Serna� acid, nitric acid, phosphoric acid, etc.; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example, alkali earth metal ion, an alkaline earth metal ion or aluminum ion, or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc., Pharmaceutically acceptable salts can be obtained in situ during the synthesis process or separately by the reaction of purified compounds according to the invention in the form of its free acid or base with a suitable organic or inorganic base or acid, respectively, with the release, so salt formed during subsequent purification. It should be understood that the mention of pharmaceutically acceptable salts include its shape, formed by adding a solvent, or its crystalline form, particularly solvates or polymorphs. Solvates contain either stoichiometric or non-stoichiometric amount �of astorias, and they are often formed during the crystallization process. Hydrates are formed when the solvent is water, or ALCOHOLATES are formed when the solvent is alcohol. Polymorphs include various configurations of the crystal structures of the same elemental composition of compounds. The polymorphs are usually characterized by different patterns of x-ray diffraction, infrared spectra, melting points, density, hardness, crystal form, optical and electrical properties, stability and solubility. Various factors, such as solvent for recrystallization, crystallization rate and storage temperature can cause the dominance of a single crystal form.

The term "filler" as used herein means an inert or inactive substance that can be used in the manufacture of a drug or pharmaceutical preparation such as a tablet containing a compound of the invention as the active ingredient. The term "filler" may encompass various substances, including without limitation any substance used as a binder, disintegrant, coating, processing aid for compression/encapsulation, cream or lotion, lubricant material, the Sol�ry for parenteral administration, materials for chewable tablets, sweetener or flavoring, suspendida/gelling agents or agents for wet granulation. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, acetate cellulose phthalate, ethylcellulose, gelmanova gum, maltodextrin, enteric coatings, etc.; technological additives for molding/encapsulation include, for example, calcium carbonate, dextrose, fructose dc (dc="directly compressible" directly press), honey, dc, lactose (anhydrous or monohydrate; optionally in combination with aspartame, cellulose or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, the sodium croscarmellose, gelmanova gum, sodium starch glycolate, etc.; creams and lotions include, for example, maltodextrin, carragenan, etc.; lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; materials for chewable tablets include, for example, dextrose, fructose dc, lactose monohydrate, optionally in combination with aspartame or cellulose), etc.; suspendida/gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fruit juice�RAM dc, sorbitol, sucrose, dc, etc.; and agents for wet granulation include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

"Alkyl" means and includes saturated linear, branched and cyclic hydrocarbon structures and combinations thereof. In particular, the alkyl groups contain 1-20 carbon atoms ("C1-C20alkyl"). More specifically, the alkyl groups contain 1-8 carbon atoms ("C1-C8alkyl), or 1-4 carbon atoms ("C1-C4alkyl"). When you mention the alkyl residue containing a certain number of carbon atoms, it is meant that covers all geometric isomers with this carbon atoms; thus, for example, "butyl" also implies n-butyl, sec-butyl, isobutyl, tert-butyl and cyclobutyl; "propyl" includes n-propyl, isopropyl and cyclopropyl. Examples of the groups denoted by this term are, such as methyl, tert-butyl, n-heptyl, octyl, cyclohexylmethyl, cyclopropyl, etc Cycloalkyl is a subfamily of alkyl and may consist of one ring, such as cyclohexyl, or a set of rings, such as adamantyl. Cycloalkyl containing more than one ring may be condensed, Spiro, or bridged structure, or their combination. In condensed ring structures one �whether multiple rings can be aryl or heteroaryl. Cycloalkyl having more than one ring where at least one ring is aromatic, can connect with the original structure or through a provision in the composition of the non-aromatic ring, or through a provision in the composition of the aromatic ring. In one embodiment, cycloalkyl having more than one ring where at least one ring is aromatic, attached to the original structure over the situation in the composition of non-aromatic rings. The preferred cycloalkyl represents a saturated cyclic hydrocarbon containing from 3 to 13 carbon atoms in the ring. A more preferable cycloalkyl is a saturated cyclic hydrocarbon containing from 3 to 7 carbon atoms in the ring ("C3-C7cycloalkyl"). Examples cycloalkyl groups include adamantyl, decahydronaphthalene, cyclopropyl, cyclobutyl, cyclopentyl, etc.

"Substituted alkyl" refers to alkyl group having from 1 to 5 substituents including, but not limited to, substituents, such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonyloxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonyl, aminocarbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, superseded by aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, thiol, thioalkyl,�ewenny of or unsubstituted alkenyl, the substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylations, etc.

"Aryl" or "Ar" refers to unsubstituted aromatic carbocyclic group containing a single ring (e.g. phenyl) or a lot of condensed rings (e.g. naphthyl or antril) in which the condensed ring may be aromatic or non-aromatic. In one embodiment, the aryl group contains from 6 to 14 ring carbon atoms. Aryl group containing more than one ring where at least one ring is non-aromatic, can connect with the original structure or through a provision in the composition of the non-aromatic ring, or through a provision in the composition of the aromatic ring. In one embodiment, the aryl group containing more than one ring where at least one ring is non-aromatic, attached to the original structure over the situation in the composition of non-aromatic rings.

"Substituted aryl" refers to aryl group containing from 1 to 5 substituents including, but not limited to, groups such as alkoxy, substituted alkoxy, acyl, acyloxy, carbonyloxy, acylamino, substituted or unsubstituted amino, aminoacyl, aminocarbonyl, AMI�carbonyloxy, heteroaryl, substituted heteroaryl, aryloxy, superseded by aryloxy, cyano, halogen, hydroxyl, nitro, carboxyl, Tilney, thioalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkylamino, substituted or unsubstituted heterocyclyl, substituted or unsubstituted Uralkaliy, aminosulfonyl, sulfonylamino, sulfonyloxy, oxo, carbonylations, etc.

"Aralkyl" refers to a residue in which an aryl fragment attached to the alkyl fragment and in which kalkilya group can be attached to the original structure or through aryl, or via an alkyl residue. Preferably, aralkyl is connected with the source structure via an alkyl residue. Specifically, Uralkalij groups are such groups in which the alkyl residue contains from 1 to 20 carbon atoms ("C1-C20aralkyl"). More specifically, Uralkalij groups are such groups in which the alkyl residue contains from 1 to 8 carbon atoms ("C1-C8aralkyl"). Even more specifically, Uralkalij groups are such groups in which the alkyl residue contains from 1 to 4 carbon atoms ("C1-C4aralkyl").

"Alkoxy" refers to the group "alkyl-O-". Specifically, alkoxy groups that are�their group, which contain from 1 to 20 carbon atoms ("C1-C20alkoxy"). More specifically, the alkoxy groups are those groups which contain from 1 to 8 carbon atoms ("C1-C8alkoxy") or 1 to 4 carbon atoms ("C1-C4alkoxy"). Alkoxygroup include as an example, methoxy, ethoxy, n-propoxy, ISO-propoxy, butoxy, tert - butoxy, Deut-butoxy, pentox, hexose, 1,2-Dimethylbutane, etc. "Alkenylacyl" refers to the group of alkenyl-O-" and "alkyloxy" refers to the group "alkenyl-O-".

"Halo" or "halogen" refers to a range of group 17 elements, having atomic number 9-85. Preferred galactography include fluorine, chlorine, bromine and iodine radicals.

The composition is "substantially pure" compound means that the composition contains not more than 15% or preferably no more than 10%, more preferably not more than 5% or even more preferably not more than 3% and most preferably not more than 1% impurity, where the impurity may be the compound in a different stereochemical form. For example, the composition is essentially pure S compound means that the composition contains not more than 15%, or not more than 10%, or not more than 5%, or no more than 3% or no more than 1% of the R form. All stereochemical variants of the compounds according to the invention means, and to�position, contains these options are covered by the invention, including but not limited to, compositions of enantiomers and/or diastereomers in any ratio, racemic, enantiomerically enriched, and other possible mixture of compounds according to the invention.

The compounds according to the invention

The compounds according to the invention is described in detail here, including a brief description of the invention and the attached claims. The invention includes the use of all compounds described herein, including any and all other stereoisomers, salts, hydrates and solvates of the compounds described as modulators of the histamine receptors.

The invention encompasses compounds of formula I,

in which:

R1choose from alkyl, substituted alkyl and aralkyl; and

R2choose from alkyl, aryl and substituted aryl;

R3is alkyl; and

R4is alkyl;

or their pharmaceutically acceptable salts.

In some embodiments, R1choose from alkyl, substituted alkyl and alkyl-phenyl. In some embodiments, R1selected from C1-C4of alkyl, substituted C1-C4the alkyl and C1-C4alkyl-phenyl. In some embodiments, R1selected from methyl, isopropyl, methoxymethyl and benzyl.

2choose from alkyl, phenyl and substituted phenyl. In some embodiments, R2selected from C1-C4of alkyl, phenyl and phenyl substituted C1-C4alkoxy or C1-C4alkyl group. In some embodiments, R2selected from methyl, phenyl, 4-methoxyphenyl and 4-methylphenyl.

In some embodiments, R3represents a C1-C4alkyl. In some embodiments, R3is bromide.

In some embodiments, R4represents a C1-C4alkyl. In some embodiments, R4is ethyl.

In one embodiment, R3is bromide, R4is ethyl, and R1and R2determined by any variant of this specification.

In some embodiments, R2is bromide, R3is bromide, R4is ethyl and R1choose from alkyl, substituted alkyl, and C1-C4aralkyl where kalkilya group attached to the parent molecule via an alkyl residue.

In some embodiments, R2is bromide, R3is bromide, R4is ethyl and R1selected from C1-C4of alkyl, substituted C1-C4the alkyl and C1-C4alkyl-phenyl.

In some embodiments, R2is bromide, R3is bromide, R4is ethyl and R1selected from methyl, isopropyl, methoxymethyl and benzyl.

In some embodiments, R1is bromide, R3is bromide, R4is ethyl and R2choose from alkyl, phenyl and substituted phenyl.

In some embodiments, R1is bromide, R3is bromide, R4is ethyl, and R2selected from C1-C4of alkyl, phenyl and phenyl substituted C1-C4alkoxy or C1-C4alkyl group.

In some embodiments, R1is bromide, R3is bromide, R4is ethyl, and R2selected from methyl, phenyl, 4-methoxyphenyl and 4-methylphenyl.

In some embodiments, the compound is selected from ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate; ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methylbutanoate; ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-phenylpropanoate; ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methoxypropionate; ethyl 2-(2-methyl-8-phenyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate; ethyl 2-(8-(4-methoxyphenyl)-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate; and e�Il 2-(2-methyl-8-p-tolyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate.

Described compounds may be present as salts, even if salt is not marked, and it should be understood that the invention embraces all salts, hydrates and solvates of the compounds described herein, and are not a salt, solvate and hydrate forms compounds that are clear to the person skilled in the art. Thus, it is understood that pharmaceutically acceptable salts of the compounds according to the invention is implied.

The pharmaceutical composition of any of the compounds described here are included in the scope of this invention. Thus, the invention includes pharmaceutical compositions containing a compound according to the invention, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and/or excipient. The pharmaceutical compositions according to the invention can be in a form suitable for oral, buccal, parenteral, nasal, local or rectilinearity, or a form suitable for administration by inhalation.

The compounds according to the invention can be used in a method for modulating histamine receptors.

General synthetic methods

The compounds according to the invention can be obtained in a number of ways, as outlined below. In the following descriptions of methods should be understood that the symbols when they are used in the depicted formula, pre�are the groups described above in connection with formula I or its variations, unless otherwise noted.

If you want to get individual enantiomer or connection, it can be distinguished from the corresponding mixture of enantiomers, using any suitable conventional technique of separation of enantiomers. For example, diastereomeric derivatives, such as salts, can be obtained by the reaction of a mixture of enantiomers such as the racemate, and the corresponding chiral compounds. The diastereomers can then be divided by conventional methods, for example by crystallization, and highlight the desired enantiomer. In another method of separation of the racemate can be separated, using chiral high-performance liquid chromatography. Alternative optional individual enantiomer can be obtained using an appropriate chiral intermediate connection in one of the described methods.

Chromatography, recrystallization, and other suitable methods of separation can also be used for intermediate or final products where it is desirable to obtain separate geometric isomers according to the invention or to purify the reaction product.

Method of synthesis of certain compounds according to the invention is shown in General method 1.

General method 1.

Connection structure 103 can be synthesized using a common Protocol with�of NASA according to the General method 1. Appropriately substituted compounds of structure 101, in which R2and R3are as described above, can interact in a standard alkylation conditions with an appropriately substituted compounds of structure 102, in which R1and R4are as described herein above, and X represents a halogen selected from Cl, Br and I, to obtain compounds of the structure 103.

In one embodiment, sodium hydride (260 mmol) was added to a solution of 101 in DMF (150 ml) with stirring and cooling. After 30 minutes the reaction mixture is added dropwise a solution of 102 (260 mmol) in DMF (20 ml) for 10-15 minutes. The resulting mixture was stirred at 70°C for 10 hours. The reaction mixture is evaporated to dryness under vacuum; the residue was poured into ice water (100 ml) and extracted with methylene chloride (3×100 ml). The organic extract is dried over anhydrous sodium sulfate, the solvent is evaporated under vacuum and the residue was recrystallized from benzene or chromatographic on a dry column in the system petroleum ether-ethyl acetate concentration gradient up to 15% of ethyl acetate with getting 103.

The method of synthesis of some compounds according to the invention is shown in General method 2a or 2b.

General method 2a.

Connection patterns 103 also can be synthesized using General �the Protocol of synthesis according to General method 2a. Appropriately substituted compounds of structure 201 in which R2is such as described above, can interact in a standard alkylation conditions with an appropriately substituted compounds of structure 102, in which R1and R4described herein above and X represents a halogen selected from Cl, Br and I with the formation of compounds of the structure 202. The interaction of compounds of structure 202 in the standard synthesis conditions of the Fischer indole with compounds of the structure 203 in which R2is such as described above, yields a compound of the structure 103.

General method 2b.

In another embodiment, the connection structure 103 can be synthesized according to the General Protocol for synthesis in accordance with the General method 2b. A solution of aniline (10 mmol), ester 102 (10 mmol) and ethyldiethanolamine (10 mmol) in THF (40 ml) was heated to reflux for 24 hours. The reaction mixture was poured into ice water (100 ml) and extracted with methylene chloride (4×50 ml). The organic extract is dried over anhydrous sodium sulfate, the solvent is evaporated under vacuum, the residue dissolved in ethanol and added an excess of a solution of hydrogen chloride in ether. Volatile components are removed under vacuum and the residue was recrystallized from ethanol-ether to obtain �connection patterns 200.

The connection 200 in the form of a hydrochloride (5.2 mmol) was added in one portion under cooling and vigorous stirring to 50 ml of a cold solution of potassium hydroxide in water (5.2 mmol). Amine was extracted with ether (3×50 ml), washed with water and saturated solution of sodium chloride and the extract dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, the residue dissolved in anhydrous THF (10 ml), and to the solution while cooling and stirring portions 14% solution of amylnitrite in alcohol (~7,2 mmol). The reaction mixture was kept for 12 hours at room temperature in the dark. Volatile components are removed under vacuum at a temperature of bath 40°C, and get a compound of formula 201. This compound is used in subsequent transformations without further purification.

Concentrated HCl (72 ml) and (portions with vigorous stirring) zinc dust (75 mmol) is added to a solution of nitrosamine 201 (9 mmol) in pure methanol (100 ml) cooled to -80°C in argon atmosphere. The reaction mixture was carefully stirred for 6-8 hours at a temperature of from -80°C to -70°C in argon atmosphere. The completeness of the reaction monitored by TLC. The excess zinc is filtered off, the residue was washed with methanol (20 ml), the filtrate is evaporated under vacuum at room temperature to a volume of ~20 ml was poured into ice water (100 ml) and �otshelushivaet by adding 24% aqueous ammonia solution (20 ml). The mixture was extracted with methylene chloride (4×50 ml), the extract washed with saturated sodium chloride solution (30 ml) and dried over anhydrous sodium sulfate. After removal of the solvent under vacuum, there was obtained compound of formula 202. This substance is used without further purification.

The coupling structure 203 (4 mmol) and catalytic amount of p-toluensulfonate acid is added to a solution of compound 202 (4 mmol) in benzene (10 ml) and the mixture is boiled for 8 hours with a nozzle Dean stark. The formation of hydrazone confirmed using LC-MS. The benzene is removed under reduced pressure, the residue dissolved in toluene (40 ml) was added Amberlist 15 (3 g), and the mixture was thoroughly stirred for 3 hours at 90-100°C. the Resin was filtered, washed with ethyl acetate (60 ml), the filtrate is evaporated under vacuum and the residue is subjected to chromatography on a column of silica gel in the system petroleum ether-ethyl acetate concentration gradient to 15% ethyl acetate, to produce a compound of formula 103.

The methods described above can be adapted, as is well known to experts in this field.

All the documents mentioned in the description entered here in by reference in full.

Table 1
Certain compounds of the invention
ConnectionNameStructure
1ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate
2ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methylbutanoate
3ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-phenylpropanoate

4ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methoxypropanol
5ethyl 2-(2-methyl-8-phenyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate
6ethyl 2-(8-(4-methoxyphenyl)-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate
7ethyl 2-(2-methyl�-8-p-tolyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate

Example 1. Determination of the ability of compounds of the invention are to contact histamine receptors

To assess the activity of the compounds according to the invention by a method of binding of the radioactive ligand used recombinant histamine H1 receptor human, murine ovarian cells of the Chinese hamster (Chinese hamster ovary, Cho) (De Backer MD et al. Biochem. Biophys. Res. Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50 mm Tris-HCl, pH 7.4, 2 mm MgCl2, 100 mm NaCl, 250 mm sucrose). Compounds of the invention were incubated with 1.2 nm [3N]pyrilamine for 180 minutes at 25°C. Nonspecific binding was assessed in the presence of 1 μm of pyrilamine. Proteins receptors was filtered and washed, the filters are then counted to determine specifically bound [3H]pyrilamine. Compounds were tested at a concentration of 1 μm or below, using 1% DMSO as a carrier. The results of biochemical tests can be represented as the percent inhibition of specific binding in percent.

To assess the activity of the compounds according to the invention by a method of binding of the radioactive ligand used recombinant histamine H2 receptor human, murine K1 cells Chinese hamster ovary (Chinese hamster ovary, Cho) (M. Rua Proc. Natl. Acad. Sci. USA. 87(5):1658, 1990) in 50 mm phosphate buffer, pH 7.4. Compounds of the invention were incubated with 0.1 nm [125I]of aminotetraline for 120 minutes at 25°C. Nonspecific binding was assessed in the presence of 3 μm of tiotidine. Proteins receptors was filtered and washed, the filters are then counted to determine specifically bound [125I]of aminotetraline. Compounds were tested at a concentration of 1 μm or below, using 1% DMSO as a carrier.

Although the above invention has been described in some detail as an illustration and example for purposes of clarity of understanding, the experts in this field it is obvious that in practice it is possible to carry out certain minor changes and modifications. Thus, the description and examples should not be construed as limiting the scope of the invention.

1. The compound of formula I,

in which:
R1chosen from alkyl, alkyl substituted with alkoxy or phenyl and aralkyl;
R2choose from alkyl, aryl containing from 6 to 14 ring carbon atoms, and aryl containing from 6 to 14 ring carbon atoms and 1 to 5 substituents selected from alkoxy and alkyl;
R3is alkyl; and
R4is alkyl;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, in which R1 chosen from alkyl, alkyl substituted with alkoxy and alkyl-phenyl.

3. The compound according to claim 2, in which R1selected from C1-C4of alkyl, C1-C4of alkyl, substituted alkoxy, and C1-C4alkyl-phenyl.

4. The compound according to claim 3 in which R1selected from methyl, isopropyl, methoxymethyl and benzyl.

5. The compound according to claim 1, in which R2choose from alkyl, phenyl and phenyl substituted alkoxy or alkyl.

6. The compound according to claim 5, in which R2selected from C1-C4of alkyl, phenyl and phenyl substituted C1-C4alkoxy or C1-C4the alkyl.

7. The compound according to claim 6, in which R2selected from methyl, phenyl, 4-methoxyphenyl and 4-methylphenyl.

8. The compound according to claim 1, in which R3represents a C1-C4alkyl.

9. The compound according to claim 8, in which R3is methyl.

10. The compound according to claim 1, in which R4represents a C1-C4alkyl.

11. The compound according to claim 10, in which R4represents ethyl.

12. The compound according to claim 1, in which R2is bromide, R3is bromide, R4is ethyl, and R1chosen from alkyl, alkyl substituted with alkoxy or phenyl, and C1-C4aralkyl.

13. The compound according to claim 12, in which R2is bromide, R3is bromide, R4�is ethyl, and R1selected from C1-C4of alkyl, C1-C4of alkyl, substituted alkoxy, and C1-C4alkyl-phenyl.

14. The compound according to claim 13, in which R2is bromide, R3is bromide, R4is ethyl, and R1selected from methyl, isopropyl, methoxymethyl and benzyl.

15. The compound according to claim 1, in which R1is bromide, R3is bromide, R4is ethyl, and R2choose from alkyl, phenyl and phenyl substituted alkoxy or alkyl.

16. The compound according to claim 15, in which R1is bromide, R3is bromide, R4is ethyl, and R2selected from C1-C4of alkyl, phenyl and phenyl substituted C1-C4alkoxy or C1-C4the alkyl.

17. The compound according to claim 16, in which R1is bromide, R3is bromide, R4is ethyl, and R2selected from methyl, phenyl, 4-methoxyphenyl and 4-methylphenyl.

18. Compound selected from ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate; ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methylbutanoate; ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-phenylpropanoate; ethyl 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-3-methoxypropionate; ethyl 2-(2-methyl-8-phenyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate; ethyl 2(8-(4-methoxyphenyl)-2-methyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate; and ethyl 2-(2-methyl-8-p-tolyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)propanoate.

19. Method of modulating histamine receptors in an individual, comprising administering to the individual in need of this, compounds according to any of claims.1-18.

20. Pharmaceutical composition having the properties of the modulator histamine receptors containing the compound according to any of claims.1 to 18 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to new quinolin-4-one derivatives of formula (1) or to its pharmaceutically acceptable salt, wherein R1 represents: (1) hydrogen, (2) C1-C6 alkyl, (35) carbamoyl-C1-C6 alkyl optionally containing morpholinyl-C1-C6 alkyl, or (36) phosphonoxy-C1-C6 alkyl optionally containing one or two C1-C6 alkyl groups on a phosphonoxy group; R2 represents: (1) hydrogen or (2) C1-C6 alkyl; R3 represents phenyl, thienyl or furyl, wherein a phenyl ring presented by R3, can be substituted by one C1-C6 alkoxy group; R4 and R5 are bound to form a group presented by any of the following formulas: , , , , , , or a group presented by the following formula: a group optionally containing one or more substitutes specified in a group consisting of C1-C6 alkyl groups and oxogroups; R6 represents hydrogen; and R7 represents C1-C6 alkoxy group. The invention also refers to a pharmaceutical composition based on the compound of formula , to a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method for preparing the compound of formula , as well as to specific compounds.

EFFECT: there are prepared new quinolin-4-one derivatives effective in treating neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases caused by mitochondrial dysfunction.

18 cl, 1 tbl, 257 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I, their pharmaceutically acceptable salts or N-oxides. In general formula , R1 represents C1-6alkoxy, such as methoxy or hydroxy; R2 represents C3-5cycloalkyl, which is optionally substituted by one substitute specified in R4, wherein R4 means C1-4alkyl, which is optionally substituted by hydroxy, C1-4alkoxy, group -OC(O)NR5R6, wherein each of R5 and R6 independently represents a hydrogen atom, C1-4alkyl, C3-6cycloalkyl, or R5 and R6 together with a nitrogen atom where they are attached to, form pyrrolidinyl, group -NHC(O)R7, wherein R7 means C1-4alkyl, C3-5cycloalkyloxy or pyrrolidinyl, or benzyloxygroup; -C(O)NR7R8, wherein each of R7 and R8 independently represents a hydrogen atom or C1-4alkyl, which in turn can be substituted by hydroxy, oxo, cyano, group -SO2C1-4alkyl, group -SO2NR11R12, wherein each of R11 and R12 independently represents a hydrogen atom or C1-4alkyl, group -NHSO2C1-4alkyl, group -NHC(O)C1-4alkyl, group -C(O)NR7R8, wherein R7 and R8 together with a nitrogen atom, where they are attached to, form morpholinyl, -OC(O)C2-6alkenyl, phenyl, pyridinyl or C3-6cycloalkyl, or R7 and R8 together with a nitrogen atom where they are attached to, form 5-6-merous cycle specified in morpholinyl, piperidinyl, piperazinyl substituted by C1-4alkyl, or pyrrolidinyl; -COOR7, wherein R7 means a hydrogen atom or C1-4alkyl; A represents phenyl optionally one or two-substituted by cyano, halogen, hydroxyl, C1-4alkyl, halogenC1-4alkyl, C1-4alkoxy, halogenC1-4alkoxy, C1-4alkoxyC1-4alkoxy, -SO2C1-4alkyl, group -C(O)OR3, wherein R3 means a hydrogen atom or C1-4alkyl, -C(O)R3, wherein R3 means C1-4alkyl, amino, C1-4alkylamino or diC1-4alkylamino, -NR5R6, wherein R5 and R6 independently mean hydrogen, -C(O)C1-4alkyl or -SO2C1-4alkyl, -C1-4alkylNR5R6, wherein R5 and R6 independently mean hydrogen or -SO2C1-4alkyl, or -C1-4alkylC(O)OR3, wherein R3 means C1-4alkyl, -SO2NR11R12, wherein R11 and R12 independently mean a hydrogen atom or C1-4alkyl substituted by hydroxy, or R11 and R12 together with a nitrogen atom where they are attached to, form morpholinyl; pyrrolidinyl optionally substituted by cyano; pyrimidinyl; thiophenyl optionally substituted by C1-4acyl; piperidinyl; 4,5-dihydro-2H-pyridazinone substituted by C1-4alkyl; dihydrobenzofuranone; oxoindanyl; or dihydro-oxoindolyl; X and Y represent either C and N, or N and C, respectively.

EFFECT: there are prepared new compounds, which possess the inhibitory activity on PDE4.

6 cl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compound of general formula (I) or to its pharmaceutically acceptable salt, acid salt or stereoisomer, where Y: NRa and N+R1R2X-; Z: bond, -(CH2)p, -CHOH, -CH=CH-, -C≡C-, -CONH- and -CO-; Rb: C1-C8 alkyl, C2-C8 alkenyl, C6-C10 aryl, -NR5R6,: , and ; with each alkyl, alkenyl and aryl, representing Rb, possibly, contains 1-3 substituents, selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C6-C10 aryl, 5-, 6- and 7-membered heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, halogen, -OH, -NH2, -CN and -NO2; Rc: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkinyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, C1-C4 alkoxy, C6-C10 aryl, 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, 9- and 10-membered bicyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; with C1-C6 alkyl, C2-C6 alkenyl C2-C6 alkinyl, C3-C10 cycloalkyl, C3-C8 cycloalkenyl, C6-C10aryl, 5-, 6-, 7-, 8-membered monocyclic heterocyclyl and 9- and 10-membered bicyclic heterocyclyl, representing Rc, possibly contain 1-5 substituents, selected from the group, consisting of C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy, C3-C6 cycloalkyl, C4-C8 cycloalkenyla, halogen, -OH, -NH2, C6-C10 (A)(A')(A")(A'")aryl, (A)(A')(A")(A'")heterocyclyl, containing 1-3 heteroatom, selected from nitrogen, oxygen and sulphur, NR14R15, (CH2)pNR14R15, -CN, -NO2, oxo, -COOR14, SOR14, SO2R14, SO2NR14R15, NR15SO2R16, COR14, CONR14R15 and NR15COR16; with each (A), (A'), (A") and (A'")independently absent or representing C1-C4 alkyl, and each heterocyclyl (A)(A')(A")(A'")heterocyclyl is independently selected from the group, consisting of 5-, 6-, 7- and 8-membered monocyclic heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur, and 9- and 10-membered bicyclico heterocyclyl, containing 1-3 heteroatoms, selected from nitrogen, oxygen and sulphur; the remaining radicals have values given in i.1;and on condition that, if Rc represents heterocyclyl, said heterocyclyl is bound directly through carbon atom of heterocyclyl ring. Invention also relates to particular compounds and to pharmaceutical composition based on formula (I) compound.

EFFECT: obtained are novel imidazopyrazine and imidazodiazepine derivatives, useful for prevention or treatment of disease or condition, severity of which is reduced by receptors to cannabinoids.

21 cl, 5 dwg, 4 tbl, 71 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new cyclic indolysincarboxamides and azaindolysincarboxamides of formulas Ia and Ib:

presented below, wherein the values of R, Ra, R10, R20, R30, R40, Y, n, p and q are specified in cl. 1 of formula. What is described is a method for preparing them.

EFFECT: compounds exhibit rennin-inhibitory activity that enables using them in the pharmaceutical composition and for treating hypertension.

11 cl, 4 tbl, 17 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a triazolopyridine compound of general formula [I] or a pharmaceutically acceptable salt, where the partial structural formula: is a group represented by any of the following formulae: or R1 is (1) a hydrogen atom, (2) C1-6alkyl group, (3) phenyl group or (4) C3-8cycloalkyl group; R2 is (1) a hydrogen atom, (2) C1-10alkyl group, (3) phenyl group, optionally substituted with identical or different 1-3 substitutes selected from the following groupB, (4) C3-8cycloalkyl group, (5) C3-8cycloalkenyl group, (6) thienyl group, optionally substituted with 1 substitute selected from halogen or C1-6alkyl group, (7) phenyl-C1-6alkyl group (wherein phenyl is optionally substituted with different or identical 1-2 substitutes selected from halogen, C3-8cycloalkyl or halogen-C1-6alkyl group) or (8) C3-8cycloalkyl-C1-6alkyl group; R3 is (1) a hydrogen atom, (2) a halogen atom, (3) C1-6alkyl group, (4) phenyl group (6) phenyl-C1-6alkyl group; and each of R4 and R5 are both hydrogen atoms or a group B: (a) a halogen atom, (b) C1-6alkyl group, (c) C3-8cycloalkyl group, (d) cyano group and (e) halogen-C1-6alkyl group. The invention also relates to the specific compounds, a pharmaceutical composition based on the compound of formula [I] and to use of the compound with the formula [I].

EFFECT: obtaining novel triazolopyrine compounds, having inhibitory activity on prolyl hydroxylase and capable of inducing erythropoietin production.

30 cl, 34 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrazolopyridine derivatives of formula (I) , a based pharmaceutical composition, and using them for treating and/or preventing disorders or conditions related to nictonamide adenine dinucleotide phosphatoxidase (NADPH-oxidase), as well as to a method for preparing them and an intermediate of formula (VIII) . In general formula (I), G1 is specified in H; and optionally substituted heteroaryl-C1-C6-alkyl; G2 is specified in H; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted C1-C6-alkylaryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-heterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G3 is specified in H; optionally substituted amino; optionally substituted aminoalkyl; optionally substituted aminocarbonyl; optionally substituted alkoxy, optionally substituted alkoxy-C1-C6-alkyl; optionally substituted carbonyl; optionally substituted C1-C6-alkyl; optionally substituted C2-C6-alkenyl; optionally substituted C2-C6-alkinyl; optionally substituted aryl; optionally substituted aryl-C1-C6-alkyl; optionally substituted C1-C6-alkylaryl: optionally substituted heteroaryl; optionally substituted C1-C6-alkylheteroaryl; optionally substituted heteroaryl-C1-C6-alkyl; optionally substituted C2-C6-alkenylaryl; optionally substituted aryl-C2-C6-alkenyl; optionally substituted C2-C6-alkenylheteroaryl; optionally substituted heteroaryl-C2-C6-alkenyl; optionally substituted C3-C8-cycloalkyl; optionally substituted C3-C8-heterocycloalkyl; optionally substituted C1-C6-alkyl-C3-C8-cycloalkyl; optionally substituted C3-C8-cycloalkyl-C1-C6-alkyl; optionally substituted C1-C6-alkyl-C3-C8-hterocycloalkyl and optionally substituted C3-C8-heterocycloalkyl-C1-C6-alkyl; G4 is specified in -NR2-C(O)-R1 and -(CHR3)m-(CH2)n-R4, G5 represents H.

EFFECT: preparing the pharmaceutical composition for treating and/or preventing the disorders and conditions related to nictonamide adenine dinucleotide phosphatoxidase.

16 cl, 3 tbl, 87 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein A1 represents N or C (A2); A2 represents H, F, Cl or CN; B1 represents H, OR1, SO2R1, NHR1, NHC(O)R1, F or Cl; D1 and E1 represents H or Cl; Y1 represents H, CN, NO2, F, Cl, Br, CF3, R17, OR17, SO2R17 or C(O)NH2; or Y1 and B1 together with atoms to which they are attached, represent 5- or 6-merous heteroarene having 2-3 nitrogen atoms, wherein heteroarene rings are unsubstituted or substituted by (O); G1 represents H; Z1 represents uncondensed phenylene substituted by OR41; R41 represents 6-merous heteroaryl having 1 N atom, wherein heteroaryl is condensed with R43A, R43A represents 5-merous heteroarene having 1 N atom; Z2 represents monocyclic 6-merous heterocycloalkylene having 1-2 N atoms and 0 double bonds; Z1A and Z2A are both absent; L1 represents -CH2-; Z3 represents R38 or R40; R38 represents uncondensed phenyl; R40 represents cycloalkyl, wherein cycloalkyl represents a monocyclic ring system having 3 to10 C atoms and 0 double bonds, cycloalkenyl, wherein cycloalkenyl represents monocyclic 6-merous ring having 1 heteroatom specified in a group consisting of O and N, and 1 double bond, wherein cycloalkenyl is uncondensed or condensed with R40A; R40A represents cycloalkane, wherein cycloalkane represents a monocyclic ring having 3-10 C atoms and 0 double bonds, or heterocycloalkane, wherein heterocycloalkane represents monocyclic 6-merous ring having 1 N atom and 0 double bonds (the rest substitutes are those as specified in cl. 1 of the patent claim). The invention also refers to compounds of formula

and a pharmaceutical composition containing an effective amount of the compound of formula (I) or (II) or its pharmaceutically acceptable salt.

EFFECT: compounds of formula (I) or (II) inhibiting the activity of anti-apoptotic Bcl-2 proteins.

6 cl, 5 tbl, 378 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to new quinolin-4-one derivatives of formula (1) or to its pharmaceutically acceptable salt, wherein R1 represents: (1) hydrogen, (2) C1-C6 alkyl, (35) carbamoyl-C1-C6 alkyl optionally containing morpholinyl-C1-C6 alkyl, or (36) phosphonoxy-C1-C6 alkyl optionally containing one or two C1-C6 alkyl groups on a phosphonoxy group; R2 represents: (1) hydrogen or (2) C1-C6 alkyl; R3 represents phenyl, thienyl or furyl, wherein a phenyl ring presented by R3, can be substituted by one C1-C6 alkoxy group; R4 and R5 are bound to form a group presented by any of the following formulas: , , , , , , or a group presented by the following formula: a group optionally containing one or more substitutes specified in a group consisting of C1-C6 alkyl groups and oxogroups; R6 represents hydrogen; and R7 represents C1-C6 alkoxy group. The invention also refers to a pharmaceutical composition based on the compound of formula , to a preventive and/or therapeutic agent based on the compound of formula (1), using the compound of formula (1), a method for preparing the compound of formula , as well as to specific compounds.

EFFECT: there are prepared new quinolin-4-one derivatives effective in treating neurodegenerative diseases, diseases caused by neurological dysfunction, or diseases caused by mitochondrial dysfunction.

18 cl, 1 tbl, 257 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of structural formula (I), which possesses phosphodiesterase 10 inhibitory activity. In formula (I), R1 represents hydrogen, halogen or lower alkyl; the ring A represents optionally substituted 6-10-merous monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as heteroatoms, or a group containing a cycloaliphatic 6-merous ring condensed with the above heteroaryl, which is specified in 6-merous cycloalkane and aliphatic 6-merous heterocyclic ring containing an oxygen atom; the ring B represents optionally substituted 4-6-merous monocyclic nitrogen-containing group, which can additionally contain an oxygen atom or a 3-6-merous monocyclic hydrocarbonic group, which can be optionally saturated; R3 represents hydrogen; lower alkyl optionally substituted by a substitute specified in lower alkoxy; or lower cycloalky. The R2,Y radicals, as well as substitutes of the rings A and B are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compound, to a method of treating or preventing schizophrenia, anxiety disorders, drug addiction, disorders with a symptom of cognition deficiency, affective disorder or mood episode, each of which is mediated by phosphodiesterase 10 activity.

20 cl, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present group of inventions refers to medicine, namely to neurology, and concerns treating vegetative-vascular dystonia, dizziness syndrome of various origins, and kinetosis. That is ensured by administering a therapeutic agent containing an activated-potentiated form of brain-specific protein S-100 antibody and using the activated-potentiated form of endothelial NO-synthase antibodies as an additional exalting agent.

EFFECT: invention provides the effective treatment of the above pathological conditions by the synergetic effect of the ingredients of the therapeutic agent.

9 cl, 16 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: claimed group of inventions relates to medicine, namely to neurology, and deals with treatment of Alzheimer's disease. For this purpose pharmaceutical composition, which contains activated potentiated form of antibodies to brain-specific protein S-100 and activated potentiated form of antibodies to endothelial NO-synthase, is introduced.

EFFECT: introduction of claimed composition provides efficient treatment of Alzheimer's disease due to synergic neuroprotective, anti-ischemic and anxiolytic action of composition components.

9 cl, 5 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention represents a liquid dosage form of a hopantenic acid calcium salt possessing nootropic activity, containing an effective amount of the hopantenic acid calcium salt and additive agents. It represents drops, and as additive agents, it contains benzoic acid, sodium saccharinate, an orange flavour, hydrochloric 1M, Trilon B and water.

EFFECT: higher active substance content by improving its organoleptic properties and reducing a viscosity of the liquid dosage form by reducing the content of viscosity-enhancing agents and increasing the water content.

2 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention can be used in chemical-pharmaceutical industry for preparing effective tranquilising salamide preparations and analgesics. What is presented is using salicyloyl morpholine sodium salt of formula (I) as a tranquilising, nootropic and analgesic agent possessing low gastric toxicity.

EFFECT: implementing the declared application with the therapeutic index of salicyloyl morpholine of formula (I) is 3 times higher than that of mexidole, and 9,5 times higher than that of aspirin.

5 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, chemical-pharmaceutical industry and concerns agents possessing the nootropic and neuromodulatory activity. A tabletted pharmaceutical composition possessingthe nootropic and neuromodulatory activity, characterised by the fact that as an active substance, it contains N-cabamoylmethyl-4-phenyl-2-pyrrolidone; the additives are lactose monohydrate, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide (aerosil) and calcium stearate. The tablets of the composition are prepared by direct compression.

EFFECT: produced preparation has a lower variability of the pharmacological action.

3 cl, 3 ex

FIELD: medicine.

SUBSTANCE: present invention refers to biotechnology, more specifically to granulocyte-macrophage colony-stimulating factor (GM-CSF) antagonists, and can be used in medicine. The invention consisting in using the GM-CSF specific antibody in treating or preventing multiple sclerosis in the patients with multiple sclerosis.

EFFECT: invention enables delaying the onset of multiple sclerosis recurrences.

9 cl, 5 dwg, 8 ex

Humanised antibody // 2538709

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to ophthalmology, and can be used for treating ocular diseases associated with amyloid-beta related pathological abnormalities/changes in the visual system tissues. That is ensured by administering a pharmaceutical composition, which contains a therapeutically effective amount of a humanised antibody or antigen-binding fragment, wherein the humanised antibody or its fragment is able to bind amyloid-beta. Presented are preventing, treating or relieving symptoms of an ocular disease, reducing the plaque load of retinal ganglion cells, diagnosing the ocular disease and diagnosing a predisposition to the ocular disease, prolonging the patient's sensitivity when treating with the pharmaceutical composition for treating the ocular disease.

EFFECT: group of inventions provides the effective treating of the above ocular pathology by using the composition containing the high-specific antibodies, which specifically recognise and bind to specific epitopes of various β-amyloid proteins.

20 cl, 18 dwg, 9 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: hepatoprotective effect in a chronic immobilisation stress is ensured by delta sleep inducing peptide having formula (NH2)Trp-Ala-Gly-Gly-Asp-Ala-Ser-Gly-Glu(COOH).

EFFECT: using the invention enables improving the metabolic processes and promotes the hepatic functional recovery in the chronic immobilisation stress.

1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

,

wherein pyridine rings A, B and C are independently unsubstituted or substituted by one or more substitutes independently specified in a group consisting of: C1-6-alkyl, halogen alkyl having 1-6 carbon atoms, Hal or OR13; L1 and L2 are independently specified in residues having formula or , wherein at least one of L1 or L2 has formula (b); R1 and R2 are independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; R3 is specified in hydrogen and C1-6-alkyl; R4, R5, R6 and R7 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R8, R9, R10 and R11 are independently specified in a group consisting of hydrogen and C1-6-alkyl; R12 is specified in a group consisting of hydrogen and C1-6-alkyl; R13 is independently specified in a group consisting of hydrogen, C1-6-alkyl and phenyl; p is equal to 1 or 2; q is equal to 0, 1 or 2, and Hal is specified in a group consisting of F, Cl, Br, and I, which can be used in treating a group of amyloid protein related disturbances and disorders.

EFFECT: preparing the compounds which can be used in treating a group of amyloid protein related disturbances and disorders.

17 cl, 1 dwg, 6 tbl, 13 ex

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