Method for preparing 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chromane

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]chromane of the formula (I): and its salts. Method involves direct reaction of 5-(4-fluorophenyl)pyridine-3-carbaldehyde of the formula (II): with 2-aminomethylchromane or its salts under reductive conditions resulting to formation of compound of the formula (I). Synthesized compound of the formula (I) is converted to one of its salts by treatment with acid. Method provides simplifying process based on decreasing amount of by-side products formed.

EFFECT: improved method of synthesis.

8 cl, 2 dwg, 4 ex

 

The invention relates to a method for producing 2-[5-(4-forfinal)-3-pyridylmethylamine]chromane formula I

including enantiomerically pure compounds of the formula I and their salts, which is characterized by the fact that 5-(4-forfinal)pyridine-3-carbaldehyde is subjected to a direct reaction with 2-aminomethylpropanol or its salts in reductive conditions with a compound of formula I and the compound obtained of the formula I, if necessary, converted into one of its salts by treatment with acid.

The compound 2-[5-(4-forfinal)-3-pyridylmethylamine]chroman described in the patent US 5767132 as well as the racemates and enantiomerically pure compounds. Also in the patent US 5767132 described obtaining physiologically acceptable salts (column 9, line 6-32) and the method of obtaining (examples 5 and 19).

2-[5-(4-Forfinal)-3-pyridylmethylamine]chroman formula I and salts thereof are selective antagonists of D2-dopamine receptor and receptor antagonists of 5-HT1A. Therefore, they are acceptable for use for the preparation of medicines for the prevention and/or treatment of secondary diseases after a heart attack brain (cerebral haemorrhage), for example, shock and cerebral ischemia, for the prevention and control of diseases of the brain, for example, migraine, treatment of anxious, tense, depress the active state, sexual disorders caused by the Central nervous system, disorders of sleep and eating, or for the treatment of psychosis, such as schizophrenia, schizoaffective psychosis or cyclothymia.

The term "anxiety" also refers panic syndromes with and without pathological fear of open spaces (agoraphobia), compulsive disorder or obsessive personality changes, specific anxiety disorder, social anxiety disorder, acute stress disorder, posttraumatic stress disorder, generalized anxiety disorder, anxiety disorder, caused by substances and also anxiety disorder as a result of disease.

2-[5-(4-Forfinal)-3-pyridylmethylamine]chroman formula I and salts thereof are also suitable to eliminate the impairment of cognitive ability, to improve learning ability and memory and for the treatment of Alzheimer's disease. They can also be used for the treatment of side effects in the treatment of hypertension, endocrinology and gynecology, for example, for the treatment of acromegaly, hypogonadism, secondary of amenorrhea, premenstrual syndrome or undesired puerperal lactation.

Connections can be used as active ingredients of drugs in the treatment of people in veterin the series. In addition, they can be used as intermediate products for the preparation of further active ingredients of medicines.

As 2-[5-(4-forfinal)-3-pyridylmethylamine]chroman, in particular (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chroman, but also (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]chroman, and their salts are very promising as active ingredients of drugs, obtaining these compounds is of considerable interest.

The object of the present invention therefore is to identify new and effective options for the synthesis of compounds specified above.

Known methods of synthesis of 2-[5-(4-forfinal)-3-pyridylmethyl-aminomethyl]chromane as racemate and enantiomerically pure compounds described in patent US 5767132, examples 5 and 19, 2-aminomethylpropanol as a racemate, and enantiomerically pure compounds, or a corresponding salt of these compounds, is subjected to reaction with 3-(chloromethyl)-5-(4-forfinal)pyridine. However, the starting material 3-(chloromethyl)-5-(4-forfinal)pyridine irritates the skin and can cause allergic reactions. Moreover, haleamano connection, such as, for example, 3-(chloromethyl)-5-(4-forfinal)pyridine, have the ability to exothermic decomposition as alkylating and capable of alkylation functional group compatible with the about are present in one molecule (literature: Chem. - lng. - Tech. 1979, 51, 928-933).

Consequently, the invention relates to a method for producing 2-[5-(4-forfinal)-3-pyridylmethylamine]chromane formula I

and its salts, which is characterized by the fact that

(1) 5-(4-forfinal)pyridine-3-carbaldehyde of the formula II

subjected to direct reaction with 2-aminomethylpropanol or its salts in reductive conditions with a compound of formula I, and (2) the compound obtained of the formula I is converted into one of its salts by treatment with acid.

The advantage of the new method compared with the method described in patent US 5767132, consists in reducing by-products by suppressing double alkylation. After completion of the reaction conversion of the active ingredient does not contain by-products, having two arylpyrimidine radical, which simplifies the purification of the active component.

Compared with the options of obtaining secondary amines described in the standard literature by reaction of aldehydes with primary amines (literature: Houben-Weyl, Methods der oganischen Chemie [Methods of organic chemistry], volume 11/1), is not necessary in the method in accordance with the invention forcibly remove water to obtain aldimine as an intermediate product. Instead, aldehyde, in accordance with the invention, 5-(4-shall terphenyl)pyridine-3-carbaldehyde, can communicate directly with 2-aminomethylpropanol in reducing conditions.

The advantage of regenerating aminating that occurs under standard conditions, therefore, consists of fewer reagents and to reduce the heat load that is required. It also occurs as a result of the reduction of impurities and adverse reactions. In particular, the heating for several hours in a solvent forming an azeotrope with the addition of a catalyst, for example, acids, such as p-toluoyltartaric, is not necessary. Common adverse effects of thermally loaded aldehydes are, for example, the disproportionation between alcohol and acid or oligomerization with removal of water, for example, to obtain the substituted of trioxane.

In addition, it was found that the reactive form 2-aminomethyl-chromane (free base) cannot be obtained separately, but instead can be obtained in situ directly with stable during storage of the salt form of the amine. Pass allocate the free base implies that at least you need one liquid/liquid separation. This addition is limited to the consumption of solvent.

Consequently, the invention relates to a method as described above, kharakterizuyushchegosya, that reactive form 2-aminomethylpropanol receive in situ from a salt of 2-aminomethylpropanol. More suitable salts of 2-aminomethylpropanol is maleate 2-aminomethylpropanol, hydrochloride 2-aminomethylpropanol and carbonate 2-aminomethylpropanol. Additional benefits in accordance with the invention is the application of the hydrochloride of 2-aminomethylpropanol.

2-[5-(4-Forfinal)-3-pyridylmethylamine]chroman formula I contain a chiral center in the 2nd position with romanovas patterns and can therefore exist in racemic or optically active form. Under the scope of formula I fall and racemates, and enantiomerically pure compounds (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chroman and (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]chroman. The racemates, including racemic compound 2-[5-(4-forfinal)-3-pyridyl-methylaminomethyl]chroman, can be separated mechanically or chemically to the isomers by methods known per se. The diastereomers are preferably formed from the racemic mixture by reaction with optically active authorizing agent. Examples of suitable resolving agents are optically active acids, such as D - and L-forms of tartaric acid, diatsetilvinny acid, dibenzoyltartaric acid, almond acid, malic acid, lactic acid or the amino acid is, or the various optically active camphorsulfonic acids, such as β-camphorsulfonic acid.

Also advantage is the chromatographic separation of enantiomers using a column Packed optically active authorizing agent (for example, dinitrobenzonitrile); an example of a suitable eluent is a mixture of hexane/isopropanol/acetonitrile, for example, at a volume ratio 82:15:3, or, as described, for example, in WO 97/47617. Separation of diastereoisomers may also be carried out using standard purification processes, such as, for example, fractionated crystallization (literature: A. Collet, S.H. Wilen, Enantiomers, Racemates and Resolutions, Wiley (new York) 1981).

Also, it is certainly possible to obtain optically active compounds of formula I using the methods mentioned above by applying a 2-aminomethyl-chromane, which is already optically active [(R)-2-aminomethylpropanol or (S)-2-aminomethylpropanol].

Racemic compound 2-aminomethylpropanol is commercially available or can be obtained by known methods of synthesis.

(R)- or (S)-2-Aminomethylpropanol can be obtained by known methods of synthesis.

Receiving can be done, for example, from commercially available chroman-2-carboxylic acid by the following reaction:

(1) reaction with thionyl chloride is getting chloride carboxylic acid,

(2) reaction with a chiral amine with getting diastereomeric mixture carboxamide,

(3) separation of the diastereomers using the conventional methods described above,

(4) recovery diastereomeric carboxamide to the corresponding N-substituted 2-aminomethylpropanol, and

(5) dealkylation, for example, by catalytic hydrogenation to obtain enantiomerically pure 2-aminomethylpropanol. Can be obtained either (R) or (S) enantiomer, depending on the configuration of the chiral amine.

The invention relates to a method for producing (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane formula 1A

and its salts, which is characterized by the fact that

(1) 5-(4-forfinal)pyridine-3-carbaldehyde of the formula II

subjected to direct reaction with (R)-2-aminomethylpropanol or its salts in reducing conditions to obtain compounds of formula 1A, and

(2) the compound obtained of the formula 1A turn into one of its salts by treatment with acid. (S) enantiomer of compound I receive a similar way, using (S)-2-aminomethylpropanol.

Alternatively, (R)-2-aminomethylpropanol can also be obtained by reaction of racemic 2-aminomethylpropanol with (S)-R-tailpole with subsequent separation of the racemate by means of crystallization. Rest rimasti two diastereoisomeric salts racemic amine with enantiomerically pure N-tosyl-(S)-Proline is so different, that pure (R)/(S) diastereoisomer of formula III may be obtained by conventional crystallization. Consequently, the formed (R)-2-amino-methylpropan N-(toluensulfonyl)-(S)-prolinate have been obtained of the formula III

Enantiomerically pure (R)-2-aminomethylpropanol later release of the compounds of formula III by alkaline extraction. (S)-2-aminomethylpropanol get a similar way, using (R)-N-tailpole.

In addition, the invention relates to a method for producing (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane or its salts, which is characterized by the fact that apply (S)-aminomethane obtained from racemic aminomethylpropanol separation of the racemate using (R)-N-tailpole.

The invention relates to diastereomeric salt (S)-2-aminomethylpropanol N-(toluensulfonyl)-(R)-prolinate have been obtained.

The compound of formula III is an important intermediate product in the synthesis of (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane and its salts, as described above.

In addition, the invention relates to a method for producing (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane or its salts, as described above, which is characterized by the fact that the use of (R)-aminomethane obtained from racemic aminomethylpropanol separation of the racemate using (S)-N-tailpole.

Also the invention is tositsa to diastereomeric salt of (R)-2-amino-methylchromone N-(toluensulfonyl)-(S)-prolinate have been obtained.

Obtaining (R)-2-aminomethylpropanol N-(toluensulfonyl)-(S)-prolinate have been obtained and subsequent alkaline extraction described in example 4. X-ray diffraction analysis of the salt shown in figures 1 and 2. Corresponding to the configuration of the two asymmetric centers can be confirmed by figures 1 and 2. The configuration of (R)-2-aminomethylpropanol can be deduced from the absolute configuration of the natural amino acid (S)-Proline.

Fig. 1 (1): x-ray analysis of (R)-2-aminomethylpropanol N-(toluensulfonyl)-(S)-prolinate have been obtained;

Fig. 2 (2): x-ray analysis of (R)-2-aminomethylpropanol N-(toluensulfonyl)-(S)-prolinate have been obtained.

5-(4-Forfinal)pyridine-3-carbaldehyde can be obtained by known methods of synthesis. The receiving may be performed, for example, from commercially available 5-(4-forfinal)nicotinic acid by the following reaction:

(1) recovery of under-5-(4-forfinal)-3-hydroxymethylpropane, for example, in the presence of borhydride, and then

(2) oxidation of the alcohol using, for example, manganese dioxide (MnO2), with the required aldehyde.

In addition, the alternative is to obtain aldehyde by restoring 3-cyano-5-(4-forfinal)pyridine, for example, by hydrogenation or using hydrides, such as diisobutylaluminium or lithium tri-tertbutoxycarbonyl.

The reaction of 5-(4-CFT is henyl)pyridine-3-carbaldehyde hydrochloride 2-amino-methylchromone, in particular, hydrochloride (R)-2-aminomethylpropanol, carried out in the reducing reaction conditions, for example, in the presence of borhydride or hydrogenating catalysts.

Acceptable borhydride are lithium borohydride, sodium borohydride, cyanoborohydride sodium borohydride or potassium borohydride in polymeric carriers, such as Amberlyst A-26 NR4form. Especially preferred is sodium borohydride, which first reacts with methanol to obtain trimethoxyborohydride.

Any solvent is suitable for the reaction in the presence of borohydride, provided that it does not interact with the source material. More preferred are proton solvents, for example alcohols, such as ethanol or methanol, or mixtures thereof.

Suitable reaction temperatures are between 0° and 70°preferably between 10 and 50°more preferably between 20 and 35°C.

The invention also relates to a method as described above, characterized in that the reaction is carried out in the presence of borohydride.

The reaction of 5-(4-forfinal)pyridine-3-carbaldehyde hydrochloride 2-amino-methylchromone, in particular the hydrochloride of (R)-2-aminomethylpropanol, similarly, can be carried out in the presence of hydrogen gas and hydrogenation catalysts.

Suitable gidaro is the following catalysts are, for example, the metals of the eighth subgroup, such as Raney Nickel, palladium or platinum. Palladium and platinum catalysts may be present on the media, for example, on charcoal, calcium carbonate, barium sulfate or strontium carbonate in the form of their oxides, such as platinum oxide, or well in partial form.

The reaction preferably takes place at a pressure of from 1 to 200 bar and in the temperature range between -80° and +150°S, more preferably at room temperature and atmospheric pressure.

Suitable solvents are, for example, alcohols such as methanol, ethanol or isopropanol, carboxylic acids such as acetic acid, esters such as ethyl acetate, or ethers, such as tetrahydrofuran (THF) or dioxane. It is also possible to use a mixture of the above solvents, if necessary, a mixture of solvents containing water.

In addition, the invention relates to method described above, which is characterized by the fact that the reaction is carried out in the presence of hydrogen and a hydrogenating catalyst.

The obtained base of formula I can be converted with the use of acid into the associated acid additive salt. Acceptable acids for this reaction are those which form a physiologically acceptable salt. Thus depict assetsa possible to use inorganic acids, for example sulfuric acid, halogenation acid, such as hydrochloric acid or Hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, furthermore organic acids, in particular aliphatic, alicyclic, analiticheskie, aromatic or heterocyclic monobasic or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, acetic acid, propionic acid, pavlikova acid, diethyloxalate acid, malonic acid, succinic acid, Emelyanova acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionate acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinamide acid, methane - or econsultancy acid, ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-toluensulfonate, naphthalenamine - and-disulfonate acid, or laurylsulphate acid.

In a preferred embodiment of the invention, the salt formation is carried out in ethanol by precipitation with hydrochloric acid (37%), receiving the hemihydrate of the dihydrochloride of 2-[5-(4-forfinal)-3-pyridylmethylamine]chromane, Pologi the rat dihydrochloride (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane or dihydrochloride hemihydrate (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]-chromane.

The invention relates to a method as described above, characterized by the fact that they are dihydrochloride (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane or dihydrochloride (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane.

Also in the preferred embodiment of the invention, the salt formation is carried out at -5°by adding the stoichiometric amount of 37%aqueous hydrochloric acid to a 7%solution of the base in ethanol, obtaining hydrochloride (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane or hydrochloride (S)-(+)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane.

The invention relates to a method as described above, characterized in that the receive hydrochloride (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane.

Even without further comment it is assumed that the average specialist in this field can use the above description in its broadest scope. Preferred embodiments of, thus, will be considered as illustrative disclosure, which may not be restricted in any way.

All temperatures above and below in degrees Celsius °C. In the following examples, "conventional treatment" means that if necessary, add water, pH, depending on the composition of the final product, base is t, if necessary, to a value from 2 to 10, the mixture is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate and evaporated, and the product was then purified using chromatography on silica gel and/or crystallization.

Example 1

of 20.3 g of the hydrochloride of (R)-2-aminomethylpropanol bring in 150 ml of ethanol and added dropwise with stirring to 36.8 g of a 20%aqueous solution of ethoxide sodium in ethanol. To the suspension is added to 20.5 g of 5-(4-forfinal)pyridine-3-carbaldehyde with 35°and the mixture is stirred for additional 3 hours. After addition of 4.2 g of sodium borohydride, the mixture is stirred for additional 4 hours and then drops added 62 ml of water at room temperature. Then the pH of the reaction mixture is brought to pH 4 using 37%hydrochloric acid for one hour. The crystals are filtered, washed with ethanol and dried under reduced pressure, getting to 27.2 g of the hydrochloride of (R)-(-)-2-[5-(4-forfinal)-3-pyridyl-methylaminomethyl]chroman (yield 69%).

Example 2

20,27 g of the hydrochloride of 2-aminomethylpropanol bring in 130 g of methanol and then added to 20.4 g of a 30%aqueous solution of sodium methylate in methanol. Add 20,43 g of 5-(4-forfinal)pyridine-3-carbaldehyde to a colorless suspension at 35°and the mixture is stirred for 1.5 hours before adding parts 4,20 g b is rhytida sodium. After 15 hours add is 56.4 ml of water and the pH of the mixture was adjusted to pH 2 using 37%hydrochloric acid. After cooling the suspension to 0°With, the crystals are filtered, washed with methanol and dried under reduced pressure, obtaining of 28.2 g of the hydrochloride of 2-[5-(4-forfinal)-3-pyridylmethylamine]chroman (yield 64%).

Example 3

5,07 g (R)-2-aminomethylpropanol and of 5.00 g of 5-(4-forfinal)-pyridine-3-carbaldehyde are dissolved in 38 ml of THF and then with stirring, add 6 g of 5% palladium on charcoal. The mixture hydronaut at room temperature under atmospheric pressure with stirring. After completion of hydrogen absorption, the catalyst is filtered off, getting 8,66 g (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane by removal of the solvent by distillation (yield 68%).

Example 4

(1) 45,0 g (S)-Proline was added to a solution of 31.0 g of NaOH in 300 ml of water. After dissolution of the solids add 74,6 g p-toluensulfonate and the mixture was stirred at 70°C for 4 hours. The mixture is then cooled to room temperature, add 30 ml of 37%hydrochloric acid and the solution extracted some time with methyl tributyl ether. The combined organic phase is evaporated and the residue is dissolved in 60 ml of ethanol. Then this mixture is slowly added dropwise to a solution of 42.2 g rat-2-aminomethylpropanol in 200 ml of e is anola. The precipitate is filtered off, washed with ethanol and dried, getting to 43.0 g (R)-2-aminomethylpropanol N-(toluensulfonyl)-(S)-prolinate have been obtained (77% of theory), is shown in Fig. 1 and 2.

(2) of 20.4 g (R)-2-aminomethylpropanol N-(toluensulfonyl)-(S)-prolinate have been obtained are suspended in 60 ml of toluene and extracted with a solution 2,07 g NaOH in 40 ml of water. Then add to 20.5 g of 5-(4-forfinal)-pyridine-3-carbaldehyde and stirred the mixture for 1.5 hours at 35°C. the Aqueous phase re-extracted with toluene and evaporated together with the first organic phase. The residue is dissolved in 500 ml of ethanol and then added 4,88 g 37%hydrochloric acid. After stirring at room temperature, the suspension is cooled to -10°and the crystalline solid is filtered off, getting to 7.95 g of the hydrochloride of (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane after drying to constant weight (85% of theory).

The substance is enantiomerically pure according to HPLC.

Data HPLC:

Column: Daicel Crownpak CR(+) (150*4 mm, the filler 5 μm)

Mobile phase: 90% water (adjusted to pH 2.0 using HClO4), 10% methanol

The flow rate: 1.2 ml/min

Retention time: 53 minutes

1. The method of obtaining 2-[5-(4-forfinal)-3-pyridylmethylamine]chromane formula I

and its salts, characterized in that

(1) 5-(-forfinal)pyridine-3-carbaldehyde of the formula II

subjected to direct reaction with 2-aminomethylpropanol or its salts in reductive conditions with a compound of formula I, and

(2) the compound obtained of the formula I is converted into one of its salts by treatment with acid.

2. The method according to claim 1, characterized in that the reactive form 2-aminomethylpropanol receive in situ from a salt aminomethylpropanol.

3. The method according to claim 1 or 2, characterized in that the reaction is carried out in the presence of borohydride.

4. The method according to claim 1 or 2, characterized in that the reaction is carried out in the presence of hydrogen and a hydrogenating catalyst.

5. The method according to claim 1 or 2, characterized in that the receive (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chroman or its salts.

6. The method according to claim 1 or 2, characterized in that the use of (R)-aminomethane obtained from racemic aminomethylpropanol separation of the racemate using (S)-N-tailpole.

7. The method according to claim 1 or 2, characterized in that the receive hydrochloride (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chromane.

8. The method according to claim 1 or 2, characterized in that the dihydrochloride of (R)-(-)-2-[5-(4-forfinal)-3-pyridylmethylamine]chroman. pyridylmethylamine]chromane.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-cyano-4-fluoropyrrolidine of the formula (I): or its pharmaceutically acceptable salt wherein A represents group of the general formula (II): wherein B represents carbonyl or sulfonyl group; R1 represents (C1-C6)-alkyl that can be optionally substituted with group chosen from the group comprising -OH or atoms of fluorine, chlorine, bromine or iodine, phenyl optionally substituted with -CN or morpholinyl group, or if B represents carbonyl then R1 can mean hydrogen atom; R2 represents (C1-C6)-alkyl optionally substituted with hydroxyl group or hydrogen atom. Compounds of the formula (I) are inhibitors of enzyme dipeptidyl peptidase IV that allows its using in pharmaceutical composition that is designated for treatment of insulin-dependent diabetes mellitus (diabetes of type 1), non-insulin-dependent diabetes mellitus (diabetes of type 2), diseases associated with resistance to insulin or obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

8 cl, 8 tbl, 11 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new benzofuran derivatives of formula 1 , wherein X represents group of formula -N= or -CH=; Y represents optionally substituted amino group, optionally substituted cycloalkyl group, or optionally substituted saturated heterocycle; A represents direct bond, carbon chain optionally containing double bond in molecular or in the end(s) thereof, or oxygen atom; R1 represents hydrogen, halogen, lower alkoxy, cyano, or amino optionally substituted with lower alkyl B represents optionally substituted benzene ring of formula ; and R2 represents hydrogen or lower alkyl; or pharmaceutically acceptable salt thereof. Invention also relates to pharmaceutical composition containing abovementioned compounds, uses thereof and method for thrombosis treatment.

EFFECT: new compounds for thrombosis treatment.

27 cl, 2 tbl, 429 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 2-phenylaminoimidazoline phenylketone that can be used as IP antagonists. Invention describes 2-phenylaminoimidazoline phenylketone of the general formula (I): wherein R1 mean optionally substituted aryl wherein R1 is optionally substituted with 1, 2 or 3 substitutes chosen independently from series including alkoxy-group, aryl aryloxy-, aralkyloxy-group, halogen atom, ethylenedioxy-group or optionally substituted heterocyclyl that means a monovalent saturated carbocyclic radical comprising from 3 to 7 atoms in cycle and comprising one or two heteroatoms chosen independently from nitrogen and oxygen atoms, and can be optionally substituted with one or more substitutes chosen independently from alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkyl sulfonyl, furanyloxy-group; R2 means hydrogen atom; A means -C(O)-(CH2)n- or -C(O)-CH2-O-; index n means a whole number from 2 to 6, or its pharmaceutically acceptable salt or solvate. Invention provides preparing novel compounds showing useful biological properties.

EFFECT: valuable properties of compounds.

16 cl, 1 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel amino- and hydroxy-derivatives of phenyl-3-aminomethylquinolone-2 of the general formula (1):

wherein R1, R2, R3 and R4 are independently similar or different and R1 is chosen from hydrogen atom (H), Alk, OAlk; R2 is chosen from H, Alk, OAlk, -OCF3; R3 is chosen from H, Alk, OAlk, -SCH3; R4 is chosen from H. Alk, OAlk, or R2 and R3 are chosen from -(CH2)3, -OCH2O-, -OCH2CH2O-; R5 means H or Alk; R6, R7 and R9 mean H; R8 is chosen independently from the following substitutes:

wherein n = 1, 2, 3; Het represents furan; R represents hydrogen atom or alkyl. In case of hydroxy-derivatives at least one among R6, R7, R8 or R9 is -OH and other represent H. Also, invention relates to methods for synthesis of these compounds and to a pharmaceutical composition based on these compounds inhibiting activity of NO-synthase. Invention provides preparing novel compounds and pharmaceutical compositions based on thereof in aims for treatment of diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

32 cl, 1 tbl, 132 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzopyrane substituted with secondary amines comprising tetrazole, their stereoisomers or their pharmaceutical acceptable salts of the formula (I): wherein R1 represents hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom, -CF3, -NO2, -CN, -ORa, -NH2, or -OS(O)lRa under condition that Ra represents hydrogen atom (H) or unbranched or branched (C1-C4)-alkyl; l means a whole number 0-2; R2 represents -CH2ORa, under condition that Ra has values given above; Rb and Rc represent independently unbranched or branched (C1-C4)-alkyl; R3 represents -OH or under condition that Ra has values given above; R4 and R5 represent independently H, F, Cl, Br, unbranched or branched (C1-C3)-alkyl, -ORa, -CF3, -OCF3, -NO2, or -SO3Ra under condition that Ra has values given above; R6 represents H, unbranched or branched (C1-C3)-alkyl; n and m mean independently a whole number 0-2; * represents chiral carbon atom. Also, invention relates to a method of synthesis of these compounds and a pharmaceutical composition based on thereof. Invention provides preparing novel derivatives of benzopyrane possessing antioxidant activity.

EFFECT: improved preparing method, valuable properties of compounds and pharmaceutical compositions.

15 cl, 14 tbl, 118 ex

FIELD: organic chemistry, medicine, virology, pharmacy.

SUBSTANCE: invention relates to new non-nucleoside inhibitors of reverse transcriptase activity of the formula (1): wherein R1 represents oxygen atom (O), sulfur atom (S); R2 represents optionally substituted nitrogen-containing heterocycle wherein nitrogen atom is at position 2 relatively to the bond with (thio)urea; R3 represents hydrogen atom (H), (C1-C3)-alkyl; R4-R7 are chosen independently from hydrogen atom (H), (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, halogen-(C1-C6)-alkyl, (C1-C6)-alcanoyl, halogen-(C1-C6)-alcanoyl, (C1-C6)-alkoxy-, halogen-(C1-C6)-alkoxy-group, hydroxy-(C1-C)-alkyl, cyano-group, halogen atom, hydroxy-group; X represents group of the formula: -(CHR8)-D-(CHR8)m- wherein D represents -O or -S-; R8 represents hydrogen atom (H); n and m represent independently 0, 1 or 2, and to its pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition based on these compounds possessing inhibitory effect with respect to activity of HIV-1 reverse transcriptase, and to using these compounds in preparing medicinal agents used in treatment of HIV-1 and to intermediates compounds.

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

45 cl, 1 tbl, 57 ex

FIELD: organic chemistry, chemical technology, medicine, endocrinology, biochemistry.

SUBSTANCE: invention relates to a method for preparing compound of the formula (I) wherein R1 and R2 represent independently of one another hydrogen atom or methyl; R3, R4, R5 and R6 represent independently of one another hydrogen atom (H), halogen atom, formyl group, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkylenyloxycarbonyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C4)-alkylcarbonylamido-group, (C3-C7)-cycloalkylcarbonylamido-group, phenylcarbonylamido-group, benzyl, phenyl or naphthyl wherein benzyl, phenyl and naphthyl are substituted optionally and independently of one another with substitutes in amount up to two and chosen independently from halogen atom, (C1-C6)-alkyl substituted optionally with fluorine atoms in amount up to three, (C1-C6)-alkoxy-group substituted optionally with fluorine atoms in amount up to three and (C1-C4)-alkoxy-(C1-C4)-alkyl. Proposed method involves the following successive stages: (a) interaction of compound of the formula (II) wherein R3, R4, R5 and R6 are determined independently as given above with lithium-organic compound in the presence of sulfur source in medium of the first reactively inert solvent to form the reactive intermediate compound of the formula (IIa) (b) interaction of indicated reactive intermediate compound of the formula (IIa) with compound of the formula (III) to form compound of the formula (IV) (c) interaction of indicated compound of the formula (IV) with alkaline (C1-C2)-alkoxide in (C1-C2)-alkanol medium to form derivative of simple ether of the formula (V) wherein Alk represents (C1-C2)-alkyl; (d) interaction of indicated compound of the formula (V) with mineral acid to form compound of the formula (VI) and (e) oxidation of compound of the formula (VI) in the second reactively inert solvent to form compound of the formula (I). Prepared pyridazinone compounds are effective inhibitors of aldose reductase activity and can be used in prophylaxis and/or treatment of diabetes mellitus complications, such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. Also, invention relates to new intermediate compounds of the formula (IV) used in synthesis of indicated inhibitors of aldose reductase, to a method for synthesis of compound of the formula (IV) and a method for synthesis of preferable pyridazinone compound of the formula (XI) .

EFFECT: improved preparing method, valuable medicinal properties of compounds and agents.

10 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of aminoquinoline and aminopyridine. Invention describes compounds of the general formula (I): wherein R1 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R2 means hydrogen atom or direct or branched (C1-C4)-alkyl group; R3 means hydrogen atom or direct or branched (C1-C4)-alkyl group or phenyl group, thienyl group or furyl group optionally substituted with one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group or halogen atom; R4 and R5 form in common 1,3-butadienyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group or halogen atom; R6 means hydrogen atom or cyano-group; R7 means hydrogen atom or direct or branched (C1-C4)-alkyl group, phenyl group, benzyl group, thienyl group, or furyl group optionally substituted with methylenedioxy-group or one or more direct or branched (C1-C4)-alkyl group, direct or branched (C1-C4)-alkoxy-group, hydroxy-group, trifluoromethyl group, cyano-group or halogen atom; X means -NH-group, -NR8-group or sulfur atom, or oxygen atom, or sulfo-group, or sulfoxy-group wherein R8 means direct or branched (C1-C4)-alkyl group or (C3-C6)-cycloalkyl group; n = 0, 1 or 2, and their salts. Also, invention describes a method for preparing compounds of the formula (I). a pharmaceutical composition based on thereof, using compounds of the formula (I) as antagonists of A3 receptors for preparing a pharmaceutical composition used in treatment of different diseases (variants), compounds of the formula (IA), (II), (III) and (IV) given in the invention description. Invention provides preparing new compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

15 cl, 6 tbl, 6 dwg, 172 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: bioactive compounds.

SUBSTANCE: invention relates to new 3-phenyl-1,2,4-benzotriazines and their derivatives of general formula 1

wherein R1 and R2 are independently fluorine or C1-C4-alkoxy, optionally substituted with halogen or tetrahydrofuryl. Compounds of present invention are useful in treatment and prophylaxis of diseases, induced by pathogenic for human and animals viruses including pathogenic for human orthopoxviruses, as well as postvaccinal sequelae.

EFFECT: compounds with improved antiviral activity.

1 cl, 12 ex, 7 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

Up!