Alkylaminothiazole derivatives, synthesis method thereof and use thereof in therapy

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula (I), R1 denotes: C1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R1 and R2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C1-6-alkyl; one or another of radicals R4 and R5 is a group Z and one or another of radicals R4 and R5 is a -C(X)R6 group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R6 denotes a C1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

 

The object of the present invention are derivatives of alkylimidazole, obtaining them and their use in therapy.

Already known derivatives alkylimidazole described in documents WO 03/014095 A, WO 2004/009565 A and WO 2004/033439 A, are inhibitors of the formation of β-amyloid peptide (β-A4).

There is always a need for the development of substances which are inhibitors of the formation of β-amyloid peptide (β-A4). Compounds according to the invention meet this goal.

The first object of the invention are compounds corresponding to General formula (I):

in which:

R1means: either1-6-alkyl, in certain cases substituted one, two or three substituents selected from: halogen, trifloromethyl, hydroxy-group, With1-6-alkoxygroup,1-6-thioalkyl, thiophene or phenyl; or C3-7-cycloalkyl, thiophene, benzothiophene, pyridinyl, furanyl or phenyl; and the above-mentioned phenyl groups in certain cases can be substituted by one, two or three substituents selected from: halogen atom, a C1-6-alkyl, C1-6-alkoxygroup, hydroxy-group, methylendioxy, fenoxaprop or benzyloxy, or trifloromethyl;

R2and R2'denote, independently of one another, a hydrogen atom, halogen atom, hydro is the system of groups, With1-3-alkoxygroup,1-3-alkyl, C3-7-cycloalkyl, group O-C(O)-C1-6-alkyl, or R2and R2'together form oxoprop;

R3denotes a hydrogen atom, a C1-6-alkyl, in certain cases substituted hydroxyl group, With1-6-cycloalkyl or1-3-alkoxygroup;

one or the other of the radicals R4and R5represents a group Z

and one or the other of the radicals R4and R5represents a group-C(X)R6;

G represents a simple bond or a group-CH2-;

Y represents a simple bond, oxygen atom, sulfur atom, With1-4-alkylenes group or-N(W)-With1-4-Allenova group, in some cases, substituted hydroxy-group or1-3-alkoxygroup;

W denotes either a hydrogen atom or a C1-3-alkyl, in certain cases substituted by phenyl, or phenyl;

A and b represent, independently of one another, a hydrogen atom, a halogen atom, a hydroxy-group, With1-3-alkyl, C1-3-alkoxygroup, trifluoromethyl, cryptometer or-O-F2; provided that when Y represents a simple bond or an oxygen atom, and if the group Z is a group type

then As different from a hydrogen atom;

X denotes an atom color is Yes or sulfur atom;

R6stands With1-6-alkoxygroup, the hydroxy-group or-NR7R8;1-6-alkoxygroup in some cases substituted by phenyl;

R7and R8denote, independently of one another, or a hydrogen atom; or C1-6-alkyl group, in some cases replaced With3-7-cycloalkyl,3-7-cycloalkenyl,1-3-alkoxygroup, phenyl, morpholinyl or pyridinyl; or C3-7-cycloalkyl group1-6-alkoxygroup or phenyl; and With the above3-7-cycloalkyl and phenyl groups, in some cases, substituted by one or two groups selected from a halogen atom, hydroxy-group, With1-3-alkyl or C1-3-alkoxygroup; or

R7and R8together with the nitrogen atom which carries them, form aziridinyl, azetidinone, pyrolidine, piperidinyl, morpholinyl or benzamidenafil cycle.

Among the compounds of General formula (I) first subgroup of compounds is formed by compounds for which R1stands With1-6-alkyl or phenyl, in some cases substituted one, two or three halogen atoms.

Among the compounds of General formula (I), a second subgroup of compounds is formed by compounds for which R2and R2'denote, independently of one another, a hydrogen atom, GI is oxygraph or R 2and R2'together form oxoprop.

Among the compounds of General formula (I) the third subgroup of compounds is formed by compounds for which R3stands With1-6-alkyl.

Among the compounds of General formula (I) fourth subgroup of compounds is formed by compounds for which:

one or the other of the radicals R4and R5represents a group Z

and one or the other of the radicals R4and R5represents a group-C(X)R6;

G denotes a simple link;

Y represents a simple bond, oxygen atom, sulfur, With1-4-alkylenes group, more particularly a methylene group;

A and b represent, independently of one another, a hydrogen atom, a halogen, more specifically, fluorine, triptorelin group, cryptometer; provided that when Y represents a simple bond or an oxygen atom, and if the group Z is a group type

then As different from a hydrogen atom;

X denotes an oxygen atom or a sulfur atom;

R6stands With1-6-alkoxygroup, more specifically, a methoxy group or ethoxypropan.

Compounds for which at the same time A, B, W, X, Y, Z, R1, R2, R2', R3, R4, R5, R6, R7and R8are such, which is defined in the above subgroups of compounds form a fifth subgroup.

Among the compounds of General formula (I) and the above-mentioned subgroups sixth subgroup of compounds is formed by compounds for which:

R1stands With1-4-alkyl, preferably isopropyl, ortert-butyl, or phenyl substituted by two fluorine atoms; and/or

R2denotes a hydrogen atom or a hydroxy-group, and R2'denotes a hydrogen atom; and/or

R3stands With1-4-alkyl, preferably methyl, ethyl or propyl; and/or

X denotes a hydrogen atom.

In the framework of the present invention

- Ct-zwhere t and z take values from 1 to 7, see the carbon chain can contain from t to z carbon atoms, for example With1-3-carbon chain which may contain from 1 to 3 carbon atoms, With3-6-carbon chain which may contain from 3 to 6 carbon atoms,

under the alkyl understand the saturated aliphatic group, a linear or branched, for example, With1-6is an alkyl group represents a carbon chain containing from 1 to 6 carbon atoms, linear or branched, more specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,Deut-butyl,tert-butyl, ..., preferably, methyl, ethyl, propyl or isopropyl;

under alkylene understand divalent saturated alkyl group, lineynoye branched, for example, With1-3-alkylene represents a divalent carbon chain containing from 1 to 3 carbon atoms, linear or branched, more specifically, methylene, ethylene, isopropylene, propylene;

under cycloalkyl understand cyclic alkyl group, for example, With3-7-cycloalkyl represents a cyclic carbon chain containing from 3 to 7 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably, cyclopentyl or cyclohexyl;

under cycloalkenyl understand mono - or polyunsaturated cyclic alkyl group, for example, With3-7-cycloalkenyl represents a mono - or polyunsaturated cyclic carbon chain containing from 3 to 7 carbon atoms, more specifically, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, preferably, cyclopentenyl or cyclohexenyl;

under thioalkyl understand the group of S-alkyl with a saturated aliphatic chain, linear or branched;

under alkoxygroup understand the group-O-alkyl with a saturated aliphatic chain, linear or branched;

under a halogen atom understood fluorine, chlorine, bromine or iodine;

under "R2and R2'together form oxoprop" understand this group, so:

and

and

in the group Z is an aromatic groupis that one of the carbon atoms of the aromatic cycle can be replaced by a nitrogen atom in the position in which there is no substituent a or C.

Compounds of General formula (I) may contain one or more asymmetric carbon atoms. Therefore, they can exist in the form of antimirov or diastereoisomers. Mentioned inationary, diastereoisomer, as well as mixtures thereof, including racemic mixtures, are included in the invention. When the carbon atom carrying the R2and R2'and/or the carbon atom carrying the R3are asymmetric, preferred compounds of General formula (I), in which the carbon atom carrying the R2and R2'has the configuration (S) and/or the carbon atom carrying the R3has the configuration (S).

The compounds of formula (I) may exist in the form of bases or of salts of joining acids. Such additive salts are included in the invention.

The above-mentioned salts get, mostly, with pharmaceutically acceptable acids but the salts of other acids used, for example, for the purification or separation of compounds of formula (I), are also included in the invention.

Compounds of General formula (I) can be in the form of a hydrate or of a solvate, namely, in the form of aggregates or compounds with one or a number of the mi water molecules, or with the solvent. Such a hydrate and a solvate likewise included in the invention.

The second object of the present invention are methods for producing compounds of formula (I).

Thus, these compounds can be obtained by methods illustrated in the schemes below, the operating conditions which are customary for professionals.

The term "protective group" means a group, giving the ability to inhibit the reactivity of a functional group or provisions during the chemical reaction, which can affect which recreates the molecule after the rupture of chemical bonds according to methods known to the expert. Examples of protective groups, and how to protect and unprotect given, among other things, in the monograph byProtective groups in Organic Synthesis,Greene et coll., 2ndEd. (John Wiley & Sons, Inc., New York).

The values of A, B, W, X, Y, Z, R1, R2,R2', R3, R4, R5, R6, R7and R8in the compounds of formulas (II)-(XVIII)below are as defined for compounds of formula (I), unless another definition is not updated.

According to scheme 1 below, the compound of formula (I) can be obtained by peptide coupling of 2-aminothiazole formula (III) with acylaminoalkyl formula (II) operating conditions, a renowned expert who, for example, in the presence of hexaflurophosphate benzotriazol-1 yloxy-Tris(pyrrolidino)phosphonium (Rumor) or hexaphosphate benzotriazol-1 yloxy-Tris(dimethylamino)phosphonium (THIEF) and N-ethylmorpholine or N-methylmorpholine in an inert solvent, such as N,N-dimethylformamide, acetonitrile or dichloromethane at a temperature which can vary from 0°C to room temperature.

The compound of formula (II) can be obtained by peptide coupling of compounds of formula (IV) with a protected acid of formula (V), in which Pg represents a protective group, for example, benzyl, according to methods known to the expert, such as described above. The compound, thus obtained, is then released from the protection. When the protective group is benzyl, to obtain the compounds of formula (II) compound pre hydronaut, preferably in the presence of palladium on carbon in absolute ethanol under atmospheric pressure of hydrogen at room temperature.

SCHEME 1

Alternatively, the compound of formula (I) can be obtained according to scheme 2.

According to scheme 2, the following, the compound of formula (I) can be obtained by peptide coupling of compounds of formula (IV) with the amine of formula (VI) according to methods known to the expert, as, for example, in the presence of the Hydra is one of hydroxybenzotriazole peso (Bt) and hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (COMMERCIALS, HCl) (EDAK, Hcl).

SCHEME 2

The compound of formula (VI) can be obtained by peptide coupling of 2-aminothiazole formula (III) with the protected amine of formula (VII), in which Pg denotes a protective group, for example, N-tert-butyloxycarbonyl (SIDE)(Boc), according to methods known to the expert, such as described above. The compound, thus obtained, is then released from the protection. When the protective group is a SIDE, in order to obtain the compound of formula (VI), removing the protection is carried out by acid hydrolysis in the presence of gaseous hydrochloric acid, dissolved in an anhydrous solvent, or triperoxonane acid.

The compounds of formula (I)in which R2and R2'form oxoprop can be obtained by oxidation of compounds of formula (I)in which R2or R2'represents a hydroxy-group. The reaction can be carried out under conditions known to the expert, for example, with the reagent Tessa Martin (Dess Martin). Similarly, these compounds can be obtained by direct binding of the keto-acid of formula (IV)in which R2and R2'together form oxoprop, with an amine of formula (VI) under conditions known to the specialist. Methods of obtaining such ketoacids known to the expert.

The compounds of formula(III), in which R4=-C(O)-R6while R6represents a C1-6-alkoxygroup, can be obtained according to scheme 3, following.

SCHEME 3

According to scheme 3, the compound of formula (III) can be obtained by reaction of an aldehyde of formula (VIII)in which R5is as defined above, with methyldichlorosilane formula (IX)in which R6represents a C1-6-alkoxygroup, in some cases, substituted phenyl, and, for example, methylate or ethylate of sodium at 0°C according to the adaptation of the method described by Takeda (Takeda) (Bull. Chem. Soc. Jp., 1970, p. 2997). To obtain the compounds of formula (III), the resulting mixture of products (X) and (XI) is treated with thiourea in the presence of, for example, methanol or ethanol under reflux for 4 or 8 hours.

The compounds of formula (III)in which R4=-C(O)-R6while R6represents a hydroxy-group, can be obtained by hydrolysis of the above-mentioned compounds for which R6represents a C1-6-alkoxygroup, in some cases, substituted phenyl, in conditions known to the expert.

The compound of formula (III)in which R5=-C(O)-R6while R6represents a C1-6-alkoxygroup, can be obtained according to scheme 4, following.

SCHEME 4

According to scheme 4, the compound of formula (III) can be obtained by bromirovanii complex of β-keeeper formula (XIII), in which R6represents a C1-6-alkoxygroup, in some cases, substituted phenyl, obtaining the compounds of formula (XII), and subsequent reaction with thiourea according to the adaptation of the method described by Barton and colleagues (Barton et coll.) (J.C.S. Perkin I, 1982, p.159).

Complex of β-ketoester formula (XIII) can be obtained by reaction of a ketone of formula (XIV) with dialkylammonium formula (XVI)in which R6represents a C1-6-alkoxygroup, in some cases, substituted phenyl, according to the adaptation of the method described Crombie's colleagues (L. b-movies et coll.) (J.C.S. Perkin Trans I, 1987, p.323). Similarly, a complex of β-ketoester formula (XIII) can be obtained by reaction of the acid of formula (XV), activated carbonyl diimidazol (CBI) (CDI), with malonate formula (XVIa), in which R6represents a C1-6-alkoxygroup, in some cases, substituted phenyl, according to the adaptation of the method described, for example, Brooks and colleagues (D.W. Brooks et coll.) (Angew. Chem. Int. Ed., 1979, p.72).

The compound of formula (III) in which R5=-C(O)-R6while R6represents a hydroxy-group, can be obtained by hydrolysis of the above-mentioned compounds for which R6represents a C1-6-alkoxygroup in the us is the conditions, well-known specialist.

The compound of formula (III) in which R4or R5represents-C(O)-NR7R8can be obtained according to scheme 5.

SCHEME 5

According to scheme 5, the compound of formula (III) receive a peptide binding of the compounds of formula (XVII)in which R5or R4represents a carboxyl group and Pg is a protective group, such as the SIDE with the compound of the formula (XVIII) in the presence of, for example, the peso, and (COMMERCIALS, Hcl). The compound thus obtained, free from protection under conditions known to the specialist. The compound of formula (XVII), in which Pg represents a SIDE can be obtained by protecting the compounds of formula (III)in which R4or R5represents a group-C(O)R6and R6represents a C1-6-alkoxygroup, in some cases, substituted phenyl, the influence of di-tert-BUTYLCARBAMATE in anhydrous tetragidrofurane in the presence of dimethylaminopyridine at room temperature and subsequent hydrolysis of the carboxylate under conditions known to the expert, for example, lithium hydroxide in a mixture of tetrahydrofuran/water 7:3 (vol/about.) at 60°C.

Compounds of General formula (I)in which R4or R5represents a group-C(X)R6and X=S, can be obtained on the basis of relevant is the corresponding compounds of General formula (I) or (III), in which R4or R5represents a group-C(X)R6and X=Oh, transformation groups(Oh) in the CS group, for example, using a reagent of Lawesson (Lawesson) according to the method similar to the method described cava with colleagues (M.P. Cava et coll) Tetrahedron, 1985, p.5061.

In schemes 1-5 of the initial compounds and the reagents, in particular, the compounds of formula (III), (IV), (V), (VII), (VIII), (IX), (XIV), (XV), (XVI), (XVIa), (XVII) and (XVIII), when the retrieval method is not described, are available in the trade or described in the literature, or can be obtained by methods described in the literature or which are known to the expert.

For example, the compounds of formula (IV)in which R2or R2'represents a hydroxy-group, can be obtained by attaching trimethylsilylacetamide to the aldehyde according to the adaptation of the method described by Evans and colleagues (D.A. Evans et coll.) (J. C. S., Chem. Comm. 1973, p.55) or by the action of sodium nitrite on alpha-amino acid according to the adaptation of the method described Tire with colleagues (I. Shinn et coll.) (J. Org. Chem., 2000, p.7667).

For example, the compounds of formula (XV)in which Y=O, can be obtained according to the adaptation of the method described by Sindala with colleagues (Sindel et coll.) (Collect. csech. Tchecosl., 1982, p.72) or Acciona with colleagues (Atkison et coll.) (J. Med. Chem., 1983, p.1353).

For example, the compounds of formula (XV)in which Y is a group of type C1-4-alkalinous can b is to be obtained, for example, the adaptation of the method described Crowe and colleagues (Crow et coll.) (Austral. J. Chem., 1981, p.1037), or, alternatively, the reaction Suzuki (Suzuki) according to the adaptation of the method described by SCHACHEN with colleagues (Chahen et coll.) (Synlett, 2003, p.1668).

For example, the compounds of formula (XV), where Y=S, can be obtained according to the method described by Goldberg (Goldberg) (Chem. Ber., 1994, p.4526).

For example, the compounds of formula (XV)in which Y=N(W)can be obtained according to the method described Shano with colleagues (Chane et coll.) (Tetrahedron Letters, 1998, p.2933) or Samana (Chamain) (Tetrahedron Letters, 1998, p.4179) or Husam with colleagues (Huwe et coll.) (Tetrahedron Letters, 1999, p.683).

For example, the compounds of formula (XV)in which Y represents a simple bond, can be obtained by the reaction of Suzuki (Suzuki) under conditions known to the expert, for example, according to the method described by Deng and colleagues (Deng et coll.) Synthesis, 2003, p.337 or by Meyer and colleagues (Meier et coll.) Synthesis, 2003, p.551.

For example, the compounds of formula (VIII) can be obtained by reduction of compounds of formula (XV) under conditions known to the expert.

When the functional group the compound is reactive, for example, when R1contains a hydroxy-group, it may require a preliminary protection before the reaction. The expert can easily determine the necessity of preliminary protection.

The following examples describe the receipt is of some compounds according to the invention. These examples are not restrictive and only to illustrate the invention.

The numbers of the compounds given in the examples correspond to the numbers shown in the table following. Elemental microanalysis and analyses by NMR, IR spectrometry or LC-MS (LC-MS) liquid chromatography in combination with mass spectrometry) to confirm the structures of the compounds obtained.

Example 1: 2-{2-(S)-[2-(3,5-differenl)acetylamino]pentanoyl}amino-5-[2-(4-pertenece)phenyl]thiazole-4-methylcarbamoyl

Example 1.1: 2-(4-pertenece)benzoic acid

To a mixture of 120 g of 2-identies acid, 1 g of powdered copper and 54.4 g of 4-terfenol in 200 ml of N,N-dimethylformamide is added slowly to 100 g of potassium carbonate. Heat at 160°C for 4 hours, then allowed to cool before evaporation. The residue is extracted with distilled water, acidified with aqueous solution of 1 N. hydrochloric acid, then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, then concentrated. The target product is crystallized from a mixture of diethyl ether/pentane. Get 50 grams of white solid.

LC/MS: MN+=233

Example 1.2: 2-(4-pertenece)-O,N-dimethylbenzamide

It is astory 50 g of 2-(4-pertenece)benzoic acid, obtained in stage 1.1, 450 ml of N,N-dimethylformamide add to 29.7 g of hydroxybenzotriazole hydrate, then 37 g (COMMERCIALS, Hcl), 19 g (O,N-dimethylhydroxylamine, Hcl) and of 19.4 g of N-methylmorpholine. Stirred at room temperature for 16 hours. Is evaporated, extracted with ethyl acetate and washed 2 times with saturated aqueous solution of sodium chloride, 1 time with distilled water, 1 times with an aqueous solution of 1 M potassium hydrosulfate, then saturated aqueous sodium chloride. Dried over anhydrous sodium sulfate, then concentrated. Get 49 g colored oil, which is used in this state later.

LC/MS: MN+=276

Example 1.3: 2-(4-pertenece)benzaldehyde

To 100 ml of a solution 1M of sociallyengaged in tetrahydrofuran at 0°C. are added dropwise to 48.5 g of 2-(4-pertenece)-O,N-dimethylbenzamide obtained in stage 1.2, in 300 ml of anhydrous tetrahydrofuran. Stirred at 0°C for 1 hour, and then hydrolyzing dropwise 40 ml of an aqueous solution of 1M potassium hydrosulfate. Is evaporated, extracted with ethyl acetate, washed 2 times with an aqueous solution of 1M potassium hydrosulfate, then saturated aqueous sodium chloride. Dried over anhydrous sodium sulfate, then concentrated. Get 35 g colored oil.

LC/MS: MN+=217

NMR, 300 MHz (CDCl3), δ (ppm): 6,70-7,00 (m, 4 Prov.); 7,20-7,35 (m, 2H); at 7.55 (t, 1H); to 7.95 (d, 1H); 10,43 (s, 1H).

Example 1.4: 2-amino-5-[2-(4-pertenece)phenyl]thiazole-4-methylcarbamoyl

To a solution of 35 g of 2-(4-pertenece)benzaldehyde, obtained in stage 1.3, 400 ml of diethyl ether is added at 0°C 30 g methyldichlorosilane, then dropwise 325 ml of a solution of sodium methylate (0.5 M) in methanol. After 1 h at 0°C is evaporated only diethyl ether, keeping the methanol, add 11 g of thiourea and heated under reflux for 6 hours. The reaction mixture is evaporated to dryness, extracted it with ethyl acetate and washed with a 10%aqueous solution of ammonium hydroxide and then saturated aqueous sodium chloride. Dried the organic phase over anhydrous sodium sulfate, then concentrated. Extract the residue with 100 ml of diethyl ether and filtered through a glass filter. Get 30 grams of white solid.

LC/MS: MN+=345

NMR, 300 MHz (CDCl3), δ (ppm): 3,70 (s, 3H); 5,55 (Sirs, 2H); 6,55-to 6.80 (m,4H); 7,00 (d, 1H); 7,20 (m, 1H); 7,35-7,45 (m, 2H).

Example 1.5: 2-[2-(S)-pentanediamine]amino-5-[2-(4-pertenece)phenyl]thiazole-4-methylcarbamoyl

To 8.6 g of 2-amino-5-[2-(4-pertenece)phenyl]thiazole-4-methylcarbonate obtained at the stage of 1.4, in solution in 200 ml of N,N-dimethylformamide at 0°C. add to 2.75 g of N-methylmorpholine, 14,30 g of PyBOP, then 5,97 g(S)-SIDE-Norvaline. Give the reaction medium to return to ambient temperature, then stirred for 16 hours After evaporation of the extract residue with ethyl acetate and washed 2 times with saturated aqueous sodium bicarbonate solution, 2 times with water, 1 times with an aqueous solution of 1M potassium hydrosulfate, then saturated aqueous sodium chloride. Dried the organic phase over anhydrous sodium sulfate, then concentrated. Chromatografic the residue on a column of silica gel, elwira a mixture of ethyl acetate and petroleum ether 3:7 (vol./vol.). Obtain 8.5 g of a white solid.

LC/MS: MN+=544

NMR, 300 MHz (CDCl3), δ (ppm): 0,88 (t, 3H); to 1.38 (s, N); 1,39-1.55V (2m, 2H); to 1.75 (m, 2H); 3,35 (Sirs, 1H); 3,68 (s, 3H); to 4.28 (m, 1H); the 5.65 (d, 1H); 6,80-of 6.90 (m, 5H); 7,10 (t, 1H); 7,20-to 7.32 (m, 2H).

Mix of 6.5 g of the product obtained above in solution in 60 ml triperoxonane acid at room temperature for 30 min, then evaporated, the residue is extracted with ethyl acetate and washed 2 times with saturated aqueous sodium carbonate, then saturated aqueous sodium chloride. Dried the organic phase over anhydrous sodium sulfate, then evaporated to obtain 3.9 g of a white solid.

LC/MS: MN+=444

Example 1.6: 2-{2-(S)-[2-(3,5-differenl)acetylamino]pentanoyl}amino-5-[2-(4-pertenece)phenyl]thiazole-4-methylcarbamoyl

To 0.7 g of 2-amino-2[2-(S)-pentanediamine]-5-[2-(4-pertenece)phenyl]thiazole-4-methylcarbonate, obtained according to example 1.5, in solution in 30 ml of N,N-dimethylformamide at 0°C is added 0.20 g of N-methylmorpholine, 0,99 g of PyBOP, then 0.33 g of 3,5-dipertanyakan acid. Give the reaction medium to return to room temperature and stirred for 18 hours the reaction is Evaporated environment. The precipitate is extracted with ethyl acetate and washed 2 times with saturated aqueous sodium bicarbonate solution, 2 times with water, 1 times with an aqueous solution of 1M potassium hydrosulfate, then saturated aqueous sodium chloride. Dried the organic phase over anhydrous sodium sulfate, then concentrated. Chromatografic the residue on a column of silica, elwira a mixture of petroleum ether/ethyl acetate 1:1 (vol./about.) to obtain 0.56 g of a white solid.

LC/MS: MN+=558

An NMR spectrum described in the table (compound No. 13).

Example 2: 2-{2-(S)-[2-(S)-hydroxy-(3,3-dimethyl)bucillamine]pentanoyl}amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbazole (compound No. 19)

Example 2.1: (2 phenylthio)-O,N-diethylnicotinamide

(2 phenylthio)-O,N-diethylnicotinamide can be obtained according to the method similar to that described in stage 1.2 of example 1. On the basis of 20 g of 2-pertinacious acid gain of 21.9 g of colorless oil, which is used in this condition, consequently the AI.

LC/MS: MN+=275

NMR, 300 MHz (CDCl3), δ (ppm): 3,35 (Sirs, 3H); to 3.58 (Sirs, 3H); 7,35 (m, 3H); to 7.50 (m, 2H); of 7.60 (d, 2H); to 8.40 (d, 1H).

Example 2.2: (2 phenylthio)nicotinamidase

(2 phenylthio)nicotinamidase can be obtained according to the method similar to that described in stage 1.3 of example 1. According to 21.9 g (2 phenylthio)-O,N-diethylnicotinamide (amide Weinrebe (Weinreb)), obtained in stage 2.1, and 48 ml of a 1M solution of sociallyengaged in 300 ml of tetrahydrofuran, to obtain 16.6 g of a white solid.

NMR, 300 MHz (CDCl3), δ (ppm): 7,18 (m, 1H); 7,42 (m, 3H); EUR 7.57 (m, 2H); with 8.05 (d, 1H); 8,46 (d, 1H); 10,35 (s, 1H).

Example 2.3: 2-amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbazole (compound No. 19)

2-Amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbamoyl can be obtained according to the method similar to that described in stage 1.4 of example 1. On the basis of 16.5 g (2 phenylthio)nicotinanilide obtained in stage 2.2, 11.2 g of methyldichlorosilane and 150 ml of 0.5 M sodium methylate in 300 ml of diethyl ether, to obtain 19 g of a pale yellow solid.

LC/MS: MN+=344

NMR, 300 MHz (d6), δ (ppm): 3,41 (Sirs, 3H); of 3.60 (s, 3H); 7,20 (shirt, 1H); 7,38-of 7.48 (m, 5H); 7,65 (shirt, 1H); 8.30 to (shirt, 1H).

Example 2.4: 2-[2-(S)-pentanediamine]amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbamoyl

2-[2-(S)-pentanediamine]amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbamoyl can be obtained according to the method similar to that described in stage 1.5 of example 1. Based on 5,14 g 2-amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbamate obtained in example 2.3, and 3.58 g (S)-SIDE-Norvaline in the presence 8,58 g of PyBOP and 1.66 g of N-methylmorpholine in N,N-dimethylformamide at 0°C, obtain, after chromatography was carried out, 3.5 g of pale yellow solid.

LC/MS: MN+=542

NMR, 300 MHz (d6), δ (ppm): of 0.87 (t, 3H); 1,45 (s, N); to 1.70 (m, 2H); of 1.97 (m, 2H); and 3.72 (s, 3H); of 4.45 (m, 1H); 5,23 (m, 1H); 7,10 (m, 1H); 7,30 (m, 3H); 7,42 (m, 2H); 7,50 (d, 1H); 8,39 (d, 1H).

Dissolve 3.5 g amine obtained above in 150 ml of 4M hydrochloric acid in 1,4-dioxane and 20 ml of methanol. Stirred for 1 h 30 min at room temperature, then evaporated. Obtain 3.2 g of pale yellow solid.

LC/MS: MN+=442

Example 2.5: 2-{2-(S)-[2-(S)-hydroxy-(3,3-dimethyl)bucillamine]pentanoyl}amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbamoyl

2-{2-(S)-[2-(S)-hydroxy-(3,3-dimethyl)bucillamine]pentanoyl}amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbamoyl can be obtained according to the method similar to that described in stage 1.6 example 1. On the basis of 0.9 g of 2-[2-(S)-pentanediamine]amino-5-[2-(phenylthio)-3-pyridyl]thiazole-4-methylcarbonate obtained at stage 2.4, and 0.25 g (S)-2-hydroxy-3,3-dimetime what Laney acid in the presence of 1 g of PyBOP and 0.59 g of N-methylmorpholine in 90 ml of N,N-dimethylformamide at 0°C, receive, after chromatography was carried out on a column of silica gel, eluruumi a mixture of ethyl acetate/petroleum ether 7:3 (vol/vol.), 0.5 g of white powder.

LC/MS: MN+=557

An NMR spectrum described in the table (compound No. 19).

Example 3: 2-{2-(S)-[2-(3,5-differenl)acetylamino]pentanoyl}amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbazole (compound No. 5)

Example 3.1: 2-amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbamoyl

2-Amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbamoyl can be obtained according to the method similar to that described in stage 1.2-1.4 of example 1, according to 26.6 g of 4-trifluoromethyl-2-diphenylcarbinol acid. Amide Weinrebe (Weinreb) this restore acid to the aldehyde by sociallyengaged with getting to 18.7 g of clear yellow oil. The aldehyde (18 g) is injected into the reaction with 10.3 g of methyldichlorosilane in the presence of 144 ml of 0.5 M sodium methylate, then 4.7 g of thiourea in methanol at reflux. Obtain 16 g of a pale yellow solid.

LC/MS: MN+=379

Example 3.2: 2-[2-(S)-Pentanediamine]amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbamoyl

2-[2-(S)-Pentanediamine]amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbamoyl can be received is according to the mode similar to that described in stage 1.5 of example 1. On the basis of of 2.26 g of 2-amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbamate obtained in example 3.1, and 1.43 g (S)-SIDE-Norvaline, in the presence of 3.43 g Rover and 0.66 g of N-methylmorpholine in 120 ml of N,N-dimethylformamide at C, to receive, after chromatography on a column of silica gel, eluruumi a mixture of petroleum ether/ethyl acetate 8:2 (about./vol.), 2 g of pale yellow solid.

LC/MS: MN+=578

NMR 300 MHz (CDCl3) δ (ppm): to 0.92 (t, 3H); 1,45 (s, N); to 1.70 (m, 2H); of 1.80 (m, 2H); of 3.69 (s, 3H); however, 4.40 (m, 1H); 5,10 (m, 1H); 6,98 (m, 4H); 7,27 (m, 2H); to 7.32 (d, 2H).

Then the obtained compound is released from the protection 50 ml triperoxonane acid, following the method described in example 1.5. Receive 1 g of white foam.

LC/MS: MN+=478

Example 3.3: 2-{2(S)-[2-(3,5-Differenl)acetylamino]pentanoyl}amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbamoyl

2-{2(S)-[2-(3,5-Differenl)acetylamino]pentanoyl}amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbamoyl can be obtained according to the method similar to that described in stage 1.6 example 1. According to 0.94 g of 2-[2-(S)-pentanediamine]amino-5-[2-(4'-trifluoromethyl)diphenyl]thiazole-4-methylcarbonate obtained at the stage 3.2, and 0.18 g of 3,5-dipertanyakan acid in the presence of 0.55 g Rover and 0.11 g of N-methylmorpholine in 50 ml of N,N-dimethylformamide at 0°C, obtain, after chromatography on a number of the NECS with silica gel, eluruumi a mixture of ethyl acetate/ petroleum ether 7:3 (vol/vol.), 0.45 g of a white powder.

LC/MS: MN+=632

An NMR spectrum described in the table (compound No. 5).

The table that follows illustrates the chemical structures and physical properties of some examples of compounds according to the invention.

In the table below:

- (S) or (R) columns ("R3and R2, R2' " indicate the stereochemistry of the asymmetric carbon atom bearing R3or R2in the formula (I). To the carbon atom carrying the R2the indication (S) or (R) does not concern the case in which R2and R2' together form oxoprop;

- MN+represents the value of the mass compounds, protonated hydrogen atom (mass of compound + 1)determined by LC/MS.

Compounds according to the invention have formed the subject of pharmacological trials which have shown their use as therapeutically active substances.

In particular, they were tested with respect to their inhibitory effect on the production of β-amyloid peptide (β-A4).

β-Amyloid peptide (β-A4) represents a fragment of the more important protein precursor, called BIA (the precursor protein of amyloid) (APP (Amyloid Precursor Protein)). This last Avenue is dotiruetsja and is present in various tissue cells of the animal or human. However, its cleavage in the brain tissue enzymes type protease, leads to the formation of peptide β-A4, which is stored in the form of amyloid plaques. Two protease responsible for the production of amyloid peptide, known as beta-secretase and gamma secretase (Wolf MS, Secretase targets for Alzheimer's disease: identification and therapeutic potential, J. Med. Chem., 2001, 44(13), 2039-60).

It was shown that these gradual deposition of peptide β-A4 is neurotoxic and can play an important role in Alzheimer's disease.

Thus the compounds according to the present invention as an inhibitor of the production of β-amyloid peptide (β-A4) by inhibiting gamma-secretase can be used in the treatment of pathologies such as senile dementia, Alzheimer's disease, down's syndrome, Parkinson's disease, amyloid angiopathy, and/or cerebrovascular disorders, fronto-temporal dementia and the disease Peak, post-traumatic dementia, pathologies associated with inflammatory processes in the nervous system, Huntington's disease and Korsakov syndrome.

Tests were conducted according to the Protocol described below.

For cell testing β-amyloid use the cell line Cho-K1, together expressing ST from BIA (RDAs) and PS1 M146L clone 30-12. Cell line aimed at the inhibition of gamma-secretase. Presenilin Saint who is associated with the activity of gamma-secretase (Wolf MS, Haass C., The role of presenilins in gamma-secretase activity, J. Biol. Chem., 2001, 276(8):5413-6)) and its co-expression with amyloid protein or N-terminal fragment leads to increased secretion of peptide A1-42 (β-A4), thus generating a pharmacological tool to assess ingibirovanie compounds of formula (I) production of peptide β-A4. Seeding 96-hole tablets for cultivation is carried out at the rate of 1×105cells per well in 150 μl of incubation medium. The presence of a minimum percentage (1,3%) serum allows cell adhesion to plastic after 2-3 hours of incubation at 37°C in the presence of 5% CO2. Products (15 µl) test 10 μm in 1% DMSO (final concentration) and incubated for 24-25 hours at 37°C in the presence of 5% CO2at 100%humidity. After the 24-25-hour incubation cell supernatant (100 µl) was transferred into tablets ELISA processed breathtaking antibodies E (E, epitope: Aa1-17, INTERCHIM/SENETEK 320-10), to determine the content of amyloid peptides, secreted by cells in the presence of compounds according to the invention. In parallel process the range of control of the synthetic peptide, the peptide 1-40", with concentrations of 5 and 10 ng/ml Tablets ELISA incubated over night at 4°C.

The amount of bound peptide detects indirect sposobov the presence of the competitor, the corresponding truncated peptide, peptide 1-28 associated with Biotin, which is then detected using streptavidin linked to alkaline phosphatase. The substrate,p-nitrophenylphosphate (pNPPFASTp-Nitrophenyl Phosphate, Sigma N2770), gives a clear soluble yellow reaction product at 405 nm. The reaction stop solution in 0.1m EDD (EDTA). To do this, after fixing amyloid peptide in the tablet ELISA, 50 μl of the biotinylated peptide 1-28 added to 100 µl of distilled cellular fluid and incubated for 30 minutes at room temperature. Then the tablets ELISA washed 3 times. After drying the flip on the filter paper in the wells add 100 ál of streptavidin-alkaline phosphatase (Interchim/Jackson Immunoresearch Laboratories 016-050-084) and incubated 1 hour at room temperature. Tablets are again washed, then add the substrate of alkaline phosphatase (pNPP 1 mg/ml) at the rate of 100 μl per well. After incubation for 30 minutes at room temperature the reaction is stopped by adding 100 μl of 0.1 m add per well and perform reading at 405 nm.

The most active compound of the formula (I) according to the present invention have SE (concentration corresponding to the efficiency of 50%) is less than 500 nm, more particularly less than 100 nm. For example, compound No. 13 of table has SHE nm.

The results of biological tests show that the connection is Vlada inhibitors of the formation of β-amyloid peptide (β-A4).

Therefore, these compounds can be used for the treatment of pathologies in which the inhibitor of the formation of β-amyloid peptide (β-A4) brings therapeutic benefit. In particular, such pathologies are senile dementia, Alzheimer's disease, down's syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, fronto-temporal dementia and the disease Peak, post-traumatic dementia, pathologies associated with inflammatory processes in the nervous system, Huntington's disease and Korsakov syndrome.

The use of compounds according to the invention for obtaining a drug intended for the treatment of these pathologies is an integral part of the invention.

Similarly, the subject invention are drugs, which contain the compound of formula (I), or salt attaching the latter with a pharmaceutically acceptable acid, or a hydrate or MES the compounds of formula (I). These drugs are used in therapy, in particular in the treatment of the aforementioned disorders.

According to another of its aspects the present invention relates to pharmaceutical compositions containing as an active beginning at least one compound according to the invention. These pharmaceutical compositions contain an effective the ing the dose of a compound according to the invention, or a pharmaceutically acceptable salt, hydrate or MES aforementioned compounds and, in some cases, one or more pharmaceutically acceptable excipients.

The above-mentioned excipients chosen according to the pharmaceutical form and the desired method of administration, from the usual excipients known to the expert.

In the pharmaceutical compositions according to the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal introduction of the above-mentioned active principle of formula (I), its salt, its MES or its possible hydrate can be entered in one form of administration, mixed with classical pharmaceutical excipients, to animals and to humans for the prophylaxis or treatment of disorders or diseases mentioned above.

The corresponding one-forms introduction include forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules, chewing gum, and solutions or suspensions for oral administration; forms for sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal is doing. For topical application it is possible to use the compounds according to the invention in the form of creams, lipsticks or lotions.

As an example, one form of the introduction of the compounds according to the invention in the form of tablets may contain the following components:

connection according to the invention 50 mg;

- attracts 223,75 mg;

- sodium, croscarmellose 6.0 mg;

- corn starch 15,0 mg;

- hypromellose 2.25 mg;

- stearate 3,0 m

In order to obtain the desired prophylactic or therapeutic effect, the dose of the beginning of the current can vary from 0.1 to 200 mg per kg of body weight per day. Although the dosage will be examples for the situation in the middle may be special cases in which use higher or lower doses, these doses are equally belong to the invention. According to usual practice, the dosage appropriate to each patient is determined by the physician according to the method of administration, the weight and response of the above-mentioned patient.

Each single dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg of active beginning in combination with one or more pharmaceutical excipients. Specified single dose can be administered 1 to 5 times a day so to enter daily dose of from 0.5 to 5000 mg, preferably is from 0.5 to 2500 mg.

According to another aspect, the present invention relates to a method of treating the pathologies indicated above, which is the introduction of the compounds according to the invention, pharmaceutically acceptable salt or hydrate of the above-mentioned connection.

1. The connection that meets the General formula (I)

in which R1represents C1-6-alkyl or phenyl; and these phenyl groups substituted with two substituents selected from halogen atoms;
R2and R2' denote, independently of one another, a hydrogen atom or a hydroxy-group;
R3represents C1-6-alkyl;
one or the other of the radicals R4and R5represents a group Z

and one or the other of the radicals R4and R5represents a group-C(X)R6;
G denotes a simple link;
Y represents a simple bond, oxygen atom, sulfur atom, With1-4-alkylenes group;
A and b represent, independently of one another, a hydrogen atom, halogen, trifluoromethyl, cryptometer; provided that when Y represents a simple bond or an oxygen atom, and if the group Z is a group-type

then As different from a hydrogen atom;
X denotes an oxygen atom;
R6represents C1-6-Ala is xygraph;
in the form of a base or pharmaceutically acceptable salt accession acid.

2. The method of obtaining the compounds of formula (I) according to claim 1, comprising a stage consisting in the implementation of the peptide-binding compounds of the formula (IV)

with an amine of formula (VI)

in which R1, R2, R2' R3, R4, R5are as defined in formula (I) according to claim 1.

3. Medicinal product having the properties of an inhibitor of formation of β-amyloid peptide (β-A4), characterized in that it contains a compound of the formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt.

4. Pharmaceutical composition having the properties of an inhibitor of formation of β-amyloid peptide (β-A4)containing at least one compound of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt and, in some cases, one or more pharmaceutically acceptable excipients.

5. The compound of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt, designed to produce a medicinal product having the properties of an inhibitor of formation of β-amyloid peptide (β-A4).

6. The use of the compounds of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt to obtain, in addition to the public funds, designed for treatment of senile dementia, Alzheimer's disease, down syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, fronto-temporal dementia and disease Peak, post-traumatic dementia, pathologies associated with inflammatory processes in the nervous system, disease of Huntington's disease and/or Korsakov syndrome.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

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

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of general formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit the properties of glycine carrier 1 (GlyT-1) inhibitors. In formula I , R1 represents -OR1', -SR1' or morpholinyl; R1' represents lower alkyl, halogen-substituted lower alkyl, or represents -(CH2)n-lower cycloalkyl; R2 represents -S(O)2-lower alkyl, -S(O)2NH-lower alkyl, NO2 or CN; X1 represents CR3 or N; X2 represents CR3' or N; R3/R3' independently represent hydrogen, halogen, lower alkyl, CN, NO2, -S(O)2-phenyl, -S(O)2-lower alkyl, -S(O)2-pyridine-2, 3 or 4-yl, phenyl optionally substituted with one or two substitutes specified from the group consisting of NO2 or halogen, or represent halogen-substituted lower alkyl, or represent -C(O)-lower alkyl; n has a value of 0, 1 or 2. The invention also concerns a drug containing one or more compounds of the invention and pharmaceutically appropriate excipients.

EFFECT: preparation of the compounds exhibiting the properties of glycine carrier inhibitors.

20 cl, 1 tbl, 133 ex

FIELD: chemistry.

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

EFFECT: obtaining novel biologically active compounds, able to inhibit DPP-IV.

13 cl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel benzothiazinone derivatives of formula (I) and their use as antibacterial agents in infectious diseases caused by bacteria, especially mycobacterium tuberculosis (TB) and leprosy, in which R1 and R2 independently denote NO2, CN, CONR7R8, COOR9 CHO, halogen, SO2NR7R8, OCF3, trifluromethyl; R3 and R4 independently denote H or methyl; R5 and R6 independently denote a straight or branched aliphatic radical having 1-8 members in the chain, or R5 and R6 together denote a divalent radical -(CR92)m- or R5 and R6 together denote a divalent radical: R7, R8 and R9 independently denote H or a straight or branched aliphatic radical having 1-7 members in the chain, or phenyl.

EFFECT: design of an efficient method of obtaining benzothiazinone derivatives, a pharmaceutical composition having anti-mycobacterial activity.

12 cl, 6 tbl, 12 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (XXI) where values of R1, Y, Ra and Rb are given in subparagraphs 1 and 2 of the formula of invention, as phosphatidylinositol-3-kinase inhibitors, a pharmaceutical composition based on said compounds and their use.

EFFECT: compounds can be used for treating and preventing diseases mediated by phosphatidylinositol-3-kinase.

5 cl, 5 tbl, 146 ex

FIELD: medicine.

SUBSTANCE: there is described thiomorpholine compound presented by formula (I) wherein the ring A represents benzene ring; the ring B represents benzene ring; R1 represents hydrogen atom, R2 represents C1-6-alkyl group; R3a and R3b are identical or different, each representing hydrogen atom or C1-6-alkyl group, and n represents an integer equal to 2, or its pharmaceutically acceptable salt. There is also described method for making the compound of formula (1), a pharmaceutical composition and application of the compound of formula (1) for making a medical product used for treatment and prevention of the disease chosen from inflammation, allergic diseases, pain, migraine, neuralgia, itch, cough, central nervous system diseases, alimentary organ diseases, nausea, vomiting and urological disorders.

EFFECT: compounds exhibits affinity to neurokinine-1 receptor.

6 cl, 4 tbl, 16 ex

Gsk-3 inhibitors // 2379300

FIELD: medicine.

SUBSTANCE: invention concerns GSK-3 inhibitors of general formula (I), method for making thereof and based pharmaceutical compositions which can be used in medicine: formula I, where R1 means an organic group containing at least 8 atoms, chosen of C or O, including aromatic ring of phenyl, naphthyl or methylene dioxypjenyl, which is not bound directly with N through -C(O)- or oxygen; Ra, Rb, Rz, R3, R4, R5 and R6 represent hydrogen.

EFFECT: production of new biologically active compounds for treatment of GSK-3 mediated diseases.

28 cl, 13 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzyloxy-derivatives of general formula (I) , where R1 is a halogen; R2 is a 5-member heteroaryl group containing 2 or 3 heteroatoms selected from a group consisting of N, O or S, which can be substituted with R3, where R3 is a lower alkyl or -C(O)R; R is -NR'R" or lower alkoxy; R'/R" independently represent H; as well as to their pharmaceutically acceptable salts. Formula I compounds inhibit monoamine oxidase B.

EFFECT: compounds can be used for preparing a medicinal agent.

5 cl, 15 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: pharmacology.

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

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

19 cl, 3 tbl, 181 ex

FIELD: medicine.

SUBSTANCE: there are described 2-(R)-phenylpropionic acid derivatives of formula (1) and their pharmaceutically acceptable salts where R' is chosen from H, OH and provided R' represents H, R is chosen from H, C1-C5-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, thiazolyl, substituted CF3, the remained formula -CH2-CH2-Z-(CH2- CH2O)nR', where n is equal to 2, and Z represents oxygen, the remained formula - (CH2)n-NRaRb, the remained formula SO2Rd, provided R' represents OH, R is chosen from C1-C5alkyl. The compounds are applied to inhibit chemotactic activation of neutrophils (PMN leukocytes) induced by interaction of interleukine-8 (IL-8) and membrane receptors CXCR1 and CXCR2. The compounds are applied to prevent and treat the pathologies generated by specified activation. There are also described application of the compounds for manufacturing of medicinal agents for treating psoriasis, nonspecific ulcerative colitis, melanoma, angiogenesis, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, idiopathic fibrosis, glomerulonephritis and to prevent and treat the damages caused by ischemia and reperfusion, the pharmaceutical composition and method for making the compounds of formula (1) where R' represents H and R - group SO2Rd.

EFFECT: higher clinical effectiveness.

8 cl, 3 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: object of present invention is the following compounds: thiazol-2-ylamide 2-(3,4-dichlorophenoxy) hexanoic acid, 2-(4-fluorophenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-methoxyphenoxy)-K-pyridin-2-ylhexaneamide, 2-(3,4-dichlorophenoxy)-4-methyl-N,3-thiazol-2-ylpentaneamide, 2-(1,1'-biphenyl-4-yloxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(4-isopropylphenoxy)-N-1,3-thiazol-2-ylhexaneamide, 2-(3-methoxyphenoxy)-N-1,3-thiazol-2-ylhexaneamide, and others, named in the formula of invention. Present invention also relates to a pharmaceutical composition, which contains the invented compound as an active ingredient and use of compounds in preparing a medicinal agent which increases activity of glucose. The invention also pertains to a compound of formula (I) where G is -C(O)-; L1 is a direct bond, A is >N-, X is a direct bond, R1 is cyclohexyl, R3 is cyclohexyl, substituted with R34, R4 is hydrogen; R5 is thiazol-5-yl, substituted with R48.

EFFECT: obtaining compounds which can be used for preparing a medicinal agent which can be used for treating diseases caused by glucokinase deficiency, for preparing a medicinal agent for treating diseases where increased activity of glucokinase is favourable.

6 cl, 143 ex

FIELD: chemistry, medicine.

SUBSTANCE: in the general formula (I): X is oxygen atom; R1 is C1-10-alkyl , substituted if necessary by phenyl or thienyl group; or R1 is C3-7-cycloalkyl, thienyl, pyridinyl; the thienyl groups can be substituted if necessary by 1-2 C1-3-alkyl groups; phenyl can be substituted if necessary by 1-2 halogen atoms; R2 is C1-6-alkyl; or R2 is C3-7-cycloalkyl, phenyl or pyridinyl; phenyl if necessary can be substituted by one or more halogen atoms or by the CN, C1-3-alkyl, C1-3-alkoxyl, C1-3-fluoroalkyl groups; R3 is C1-6-alkyl; R4 is hydrogen atom or C1-6-alkyl; R5 and R5' are independently of each other the hydrogen atom, hydroxyl; or R5 and R5' form together the oxo-group; n is integer value in the range from 0 to 3; R6 is independently of each other hydrogen atom, halogen atom, C1-3-alkyl, C1-3-alkoxyl.

EFFECT: compounds of present invention can find application as pharmaceutical for pathology treatment where the inhibitor of β-amiloyd peptide β-A4 is useful.

8 cl, 1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: compounds of the invention have chemokine antagonistic properties and can be applied in treatment of immunoinflammatory diseases, such as atherosclerosis, allergy diseases. In general formula (I) R1 is hydrogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxyl, cyclopropylmethoxy group, (C1-C4)-alkylthio group; R2 is halogen atom, (C1-C8)-alkyl, perfluoro-(C1-C4)-alkyl, (C3-C10)-cycloalkyl, phenyl, (C1-C8)-alkoxyl, values of the other radicals are indicated in the claim of the invention.

EFFECT: improved properties.

14 cl, 7 tbl, 20 dwg, 17 ex

FIELD: chemistry, pharmaceutics.

SUBSTANCE: invention relates to novel compounds N(1,3-tiazol-2-yl)amides of 2-diphenylmethylenehydrazono-5,5-dimethyl-2,4-diooxohexane acid of formula (Ia, b): demonstration anti-inflammatory and analgetic activity. Invention also relates to method of their obtaining.

EFFECT: obtaining novel compounds.

2 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry.

SUBSTANCE: invention describes novel substituted benzoylcyclohexenones of the general formula (I): wherein values Q, Y, Z, R1-R5 and their possible tautomeric forms and their possible salts given in the invention claim. Invention proposes substituted benzoylcyclohexenones of the general formula (I) that possess the herbicide activity.

EFFECT: valuable property of compounds.

2 cl, 10 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to 2-heterocyclyl-1,2-ethanediol carbamates of the formula (I) , their enantiomers, enantiomeric mixtures or pharmaceutically acceptable salts wherein A means a heterocyclic fragment chosen from the following group:

B1 and B2 mean independently hydroxy-group or -OCONR1R2 under condition that B1 and B2 don't mean hydroxy-group simultaneously; R1 and R2 mean hydrogen atom; R3, R4 and R5 mean alkyl, halogen atom, trihalogenmethyl, trialkylmethyl, -NO2, -CN and phenyl. These compounds can be used in treatment of the central nervous system disorders being especially as anticonvulsants and anti-epileptic agents. Also, invention describes a pharmaceutical composition based on compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 1 tbl, 34 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I): wherein dashed lines present single or double bonds, and the values of radicals R1, R2, R3, R4 are described in cl. 1 of the patent claim. Besides the invention refers to application and a based pharmaceutical composition for prevention and treatment of neurodegenerative diseases and other diseases wherein cell dystrophy and/or cell loss (apoptosis) caused by free radicals act the main part.

EFFECT: production of new compounds and the based pharmaceutical composition which can find application in medicine for prevention and treatment of neurodegenerative diseases.

6 cl, 3 ex

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