Derivatives of alkylpiperazine- and alkylhomopiperazinecarboxylates, obtaining them and their use as ferment faah inhibitors

FIELD: chemistry, pharmaceutical.

SUBSTANCE: invention pertains to compounds with formula I , where: n is an integer equal 1 or 2; p is an integer from 1 to 7; A is chosen from one or more radicals X and/or Y; X represents methylene group, substituted when necessary by one or two C1-6-alkyl groups; Y represents C2-alkenyl, C2-alkenyl; G represents a single bonds, oxygen or C=O. The compound can be used as ferment FAAH inhibitor for pain killing, inflammation or nerve-degenerative diseases. Description is given of the method of obtaining compounds, pharmaceutical compositions based on them and their use.

EFFECT: design of a method of obtaining alkylhomopiperazinecarboxylates and their use for pain killing, treating inflammation or nervous degenerative diseases.

11 cl, 2 tbl, 7 ex

 

The invention relates to a derivative alkylpiperazine and alkylphenolethoxylates, their reception and therapeutic use.

To date, known derivatives of phenylalkylamines, dioxane-2-allylcarbamate and 1-piperazine - 1-homopiperazines described in the publications WO2004/067498 A, WO2004/020430 A and PCT/FR2004/00328 respectively, as inhibitors of the enzyme FAAH (hydrolases fatty acid amides).

However, there is still a need in the discovery and development of compounds for inhibitors of the enzyme FAAH. Compounds of the present invention meet this goal.

Compounds of the present invention correspond to the General formula (I)

where n is an integer equal to 1 or 2;

p is an integer variable from 1 to 7;

A is selected from one or more of the radicals X, Y and/or Z;

X represents a methylene radical, optionally substituted by one or two radicals With1-6-alkyl, C3-7-cycloalkyl or3-7-cycloalkyl-C1-3-alkylen;

Y represents a radical With2-albaniles, optionally substituted by one or two radicals With1-6-alkyl, C3-7-cycloalkyl or3-7-cycloalkyl-C1-3-alkylen and radical2-akinyan;

Z represents a radical which ormula:

o represents an integer variable from 1 to 5;

r and s are integers and are defined so that r+s is an integer variable from 1 to 5;

G represents a simple bond, oxygen atom or sulfur, a group SO, SO2C=O or CH(OH);

R1represents the radical R4substituted with one or more radicals R5and/or R6;

R4represents a radical selected from the radicals phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolin, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, diphenylmethyl, chinoline, tetrahydroquinoline, ethenolysis, tetrahydroisoquinoline, hintline, honokalani, phthalazine, cinnoline, naphthyridine, benzofuranyl, dihydrobenzofuranyl, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indanyl, indazoles, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, benzotriazolyl, benzoxazolyl, benzothiazolyl pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isooxazolyl, isothiazolinones;

R5PR is dstanley a halogen atom or a cyano, the nitrogroup, a radical With1-6-alkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl,1-6-foralkyl,1-6-feralcode,1-6-vertially, NR7R8, NR7COR8, NR7CO2R8, NR7SO2R8, COR7, CO2R7, CONR7R8, SO2R7, SO2NR7R8or-O-(C1-3-alkylen);

R6represents a phenyl radical, phenyloxy, benzyloxy, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl; radical or radicals R6optionally have substituents of one or more identical or different from each other radicals R5;

R7and R8represent independently of one another a hydrogen atom or a radical C1-6-alkyl or form together with the atom or atoms to which they are attached, a cycle selected from azetidine, pyrrolidine, piperidine, research, thiomorpholine, azepine, piperazine; this cycle can optionally have substituents of the radicals With1-6-alkyl or benzyl;

R2represent a hydrogen atom or a radical C1-6-alkyl;

R3represents a hydrogen atom or a radical C1-6-alkyl, C3-7-cycloalkyl or3-7-cycloalkyl-C1-3-alkyl.

Within the present invention compounds of General formula (I) can, after vetelino, to have several identical or different radicals A.

Among the compounds of General formula (I) first subgroup of compounds consists of compounds in which:

n is an integer equal to 1 or 2;

p is an integer variable from 1 to 7;

A is selected from one or more of the radicals X and/or Y;

X represents a methylene group, optionally substituted by one or two radicals With1-6-alkyl, in particular methyl group;

Y represents a radical With2-albaniles and radical2-akinyan;

G represents a simple bond, oxygen atom or the group C=O;

R1represents the radical R4substituted with one or more radicals R5and/or R6;

R4represents a radical selected from the radicals phenyl, naphthyl, diphenylmethyl, chinoline, indolyl, pyrazolyl, isoxazolyl, pyrimidinyl, thiazolyl;

R5represents a halogen atom, in particular chlorine, fluorine, bromine or iodine, or a cyano, a radical With1-6-alkyl, in particular methyl, isopropyl or tert-butyl,1-6-alkoxy, in particular methoxy,1-6-foralkyl, in particular trifluoromethyl,1-6-feralcode, in particular formatosi, or-O-(C1-3-alkylen), in particular-och2O-;

Rsub> 6represents a phenyl radical, naphthyl or benzyloxy;

R2represents a hydrogen atom or a radical C1-6-alkyl;

R3represent a hydrogen atom or a radical C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkyl.

Among the compounds of General formula (I), a second subgroup of compounds consists of compounds in which:

n is an integer equal to 1;

p is an integer variable from 1 to 4;

A is selected from one or more of the radicals X and/or Y;

X represents a methylene group, optionally substituted by one or two radicals With1-6-alkyl, in particular methyl group;

Y represents a radical With2-akinyan;

G represents a simple bond or an oxygen atom;

R1represents the radical R4substituted with one or more radicals R5and/or R6;

R4represents a radical selected from the radicals phenyl, naphthyl, isoxazolyl;

R5represents a halogen atom, in particular chlorine or fluorine, or a cyano, a radical With1-6-alkoxy, in particular methoxy, radical1-6-foralkyl, in particular trifluoromethyl;

R6represents a phenyl group;

R2represent the ATO is hydrogen or a radical With 1-6-alkyl;

R3represent a hydrogen atom or a radical C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkyl.

Among the compounds of General formula (I) the third subgroup of compounds consists of compounds in which:

n, p, A, X, Y, Z,o, r, s, G, R1, R4, R5, R6, R7and R8same as above for the General formula (I) or subgroups presented previously;

R2represents a hydrogen atom;

R3represents a hydrogen atom or a radical C1-6-alkyl, in particular methyl, radical3-7-cycloalkyl, in particular cyclopropyl, or a radical With3-7-cycloalkyl-C1-3-alkyl, in particular-CH2-cyclopropyl.

Among the compounds of General formula (I) can be given the following connections:

- 2-(methylamino)-2-oxoethyl-4-(2-diphenyl-3-retil)piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-(2-diphenyl-4-retil)piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[2-(1-naphthyl)ethyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-{2-[3-(4-chlorophenyl)isoxazol-5-yl]ethyl}piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-{2-[5-(4-chlorophenyl)isoxazol-3-yl]ethyl}piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-(3-diphenyl-3-ylpropyl)piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-(3-diphenyl-4-ylpropyl)Pipa is Azin-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-(3-diphenyl-3-yl-1,1-dimethylpropyl)piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(3'-chlorodiphenyl-3-yl)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(4'-chlorodiphenyl-3-yl)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(3'-methoxybiphenyl-3-yl)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(4'-methoxybiphenyl-3-yl)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(3'-chlorodiphenyl-4-yl)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(4'-chlorodiphenyl-4-yl)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(2-naphthyl)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-{3-[5-(4-chlorophenyl)isoxazol-3-yl]propyl}piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[4-(3-chlorophenyl)butyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[4-(4-chlorophenyl)butyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-{4-[3-trifluoromethyl)phenyl]butyl}piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-{4-[4-trifluoromethyl)phenyl]butyl}piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-{4-[4-trifluoromethyl)phenyl]but-3-in-1-yl}piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[5-(3-chlorophenyl)Penta-4-in-1-yl]PI is erasin-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[5-(2,4-dichlorophenyl)Penta-4-in-1-yl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[5-(2,5-dichlorophenyl)Penta-4-in-1-yl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[5-(3,4-dichlorophenyl)Penta-4-in-1-yl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[5-(3-chloro-4-forfinal)Penta-4-in-1-yl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(2-chlorophenoxy)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(3-chlorophenoxy)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(4-chlorophenoxy)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(2,3-dichlorophenoxy)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(2,4-dichlorophenoxy)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(2,5-dichlorophenoxy)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(2,6-dichlorophenoxy)propyl]piperazine-1-carboxylate;

- 2-(methylamino)-2-oxoethyl-4-[3-(3,5-dichlorophenoxy)propyl]piperazine-1-carboxylate.

Compounds of General formula (I) may contain one or more asymmetric carbon atoms. They can exist in the form of enantiomers or diastereoisomers. Compounds of General formula (I) can equally exist in the form ofCIS-(Z)-orTRANS-(E)stereoisomers. These stereoisomers, enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, form part of the invention.

Compounds of General formula (I) can equally exist in the form of bases or acid additive salts. Such additive salt form part of the invention.

As these salts, the corresponding image obtained with pharmaceutically acceptable acids and salts of other acids used, for example, for the purification or separation of compounds of formula (I) in equally form part of the invention.

Compounds of General formula (I) can be in the form of a hydrate or of a solvate and in the form of aggregates or combinations with one or more water molecules or with a solvent. Such hydrate and solvate are equally part of the invention.

Within the present invention it is accepted that:

- Ct-zwhere t and z can take values from 1 to 7, means a carbon chain which can have from t to z carbon atoms, for example With1-3is a carbon chain which can have from 1 to 3 carbon atoms;

- alkyl means saturated aliphatic linear or branched radical, for example a radical With1-6-alkyl represents a linear or branched carbon chain containing from 1 to 6 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-is util, pentyl, hexyl;

- alkylene means a saturated linear or branched divalent radical, for example a radical With1-3-alkylene represents a linear or branched divalent carbon chain containing from 1 to 3 carbon atoms, in particular methylene, ethylene, 1-mutilation, propylene;

- cycloalkyl means a cyclic alkyl radical, for example a radical With3-7-cycloalkyl represents the carbon cycle, containing from 3 to 7 carbon atoms, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;

- albaniles means unsaturated aliphatic divalent radical of 2 carbon atoms, in particular ethylene;

- C2-akinyan means the radical-S≡ -;

- alkoxy means the radical-O-alkyl with saturated aliphatic linear or branched chain;

- thioalkyl means the radical-S-alkyl with saturated aliphatic linear or branched chain;

- foralkyl means an alkyl radical in which one or more hydrogen atoms replaced by fluorine atom;

- feralcode means CNS radical, in which one or more hydrogen atoms replaced by fluorine atom;

- vertially means touchily radical, in which one or more hydrogen atoms replaced by fluorine atom;

the halogen atom sachetti, chlorine, bromine or iodine.

Compounds of the present invention can be obtained in various ways, illustrated by the following schema.

So, by the first method (scheme 1) compounds of General formula (I) can be obtained by bringing into interaction amine of General formula (IV)in which R1, G, A, p and n are the same as those in General formula (I), with a carbonate of General formula (IIIa), in which V represents a hydrogen atom or a nitro-group, R is the same as specified in the General formula (I), and R represents a methyl or ethyl group. Ester carbamino acid of General formula (II)obtained in the same way, later converted into a compound of General formula (I), aminolysis an amine of General formula R3NH2in which R3the same as specified in the General formula (I). The reaction aminolysis can be carried out in a solvent such as methanol or ethanol, or a mixture of solvents, such as methanol and tetrahydrofuran.

Scheme 1

Another method (scheme 2) obtain compounds of General formula (I) consists in bringing into interaction derivative of piperazine or homopiperazine General formula (VII), in which PG represents a protective group such as tert-butyloxycarbonyl (Boc), with a carbonate of General formula (IIIb), in which V represents sobo is a hydrogen atom or a nitro-group, and R2and R3are the same as those in General formula (I), with the subsequent removal of the protective group of the obtained compound, for example, in the presence of hydrochloric acid in a solvent such as isopropanol. Amid carbamino acid of General formula (V)obtained in the same way, turn subsequently in connection with the General formula (I) interaction with a derivative of General formula (VI)in which R1, G, p and A are the same as those in General formula (I), and W represents a chlorine atom, bromine or iodine, or mesilate, or toilet. The reaction of N-alkylation may be carried out in a solvent such as acetonitrile or toluene, in the presence of a base such as potassium carbonate or diisopropylethylamine.

Scheme 2

Compounds of General formula (I), (II) and (IV)in which R1represents a radical of the type aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl, can be obtained similarly by the interaction of the corresponding compounds of General formula (I), (II) and (IV)in which R4substituted by chlorine atom, bromine, iodine or tripersonality in the position in which shall be entered the radical R6with a derivative of an aryl - or heteroarylboronic acid under Suzuki reaction conditions (Chem. Rev. 1995,95, 2457-2483) or a derivative of an aryl - or Goethe is oail-trialkylamine in accordance with the terms of the Stille reaction (Angew. Chem. Int. Ed. 1986,25, 504-524).

The carbonates of General formula (IIIa) and (IIIb) may be obtained from any described in the literature, for example, the interaction of the corresponding alcohol of General formula HOCHR2COOR, in which R represents a methyl or ethyl group, or HOCHR2CONHR3in which R3the same as specified in the General formula (I)with phenyl - or 4-nitrophenylphosphate in the presence of a base such as triethylamine or diisopropylethylamine.

Compounds of General formula (IV), (VI) and (VII) as amines of General formula R3NH2for which you do not see the way to obtain, are commercially available or described in the literature, or can be obtained according to various methods described in the literature or known to the person skilled in the technical field.

The object of the present invention in one of its other aspects are equally the compounds of formula (II) and (V). These compounds are used as an intermediate in the synthesis of compounds of formula (I).

The following examples are given to illustrate the preparation of some compounds of the present invention. The examples are not exhaustive and is provided only to illustrate the present invention. The results of microanalysis, IR spectra and NMR and/or LC-MS (liquid chromatography with mass spectrometric analysis) confirm page is cture and purity of the compounds obtained.

PF (° (C) means melting temperature in degrees Celsius. The numbers indicated in parentheses in the titles of the examples correspond to the numbers in the first column of the following table.

Example 1 (compound No. 85)

2-(methylamino)-2-oxoethyl-TRANS-4-(3-phenylprop-2-EN-1-yl)piperazine-1-carboxylate

1.1. 2-(Ethoxy)-2-oxoethyl-TRANS-4-(3-phenylprop-2-EN-1-yl)piperazine-1-carboxylate

Heated at 80°C overnight, the solution of 1.40 g (6,93 mmol)TRANS-1-cinnamylpiperazine and 1,74 g (7,76 mmol) of ethyl{[(phenoxy)carbonyl]oxy}acetate (J. Med. Chem., 1999, 42, 277-290) in 15 ml of toluene. Is evaporated to dryness and treated with 50 ml of ethyl acetate. Water washed 2 times with 20 ml of 1 times 10 ml of a saturated aqueous solution of sodium chloride. Dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel by elution with a mixture of cyclohexane and ethyl acetate in the ratio of 50/50, then ethyl acetate and get 0,814 g of the product as a pale yellow oil.

1.2. 2-(Methylamino)-2-oxoethyl-TRANS-4-(3-phenylprop-2-EN-1-yl)piperazine-1-carboxylate

Dissolve 0.8 g (2.4 mmol) of 2-(ethoxy)-2-oxoethyl-TRANS-4-(3-phenylprop-2-EN-1-yl)piperazine-1-carboxylate, obtained in stage 1.1, 10 ml of 2 M solution of methylamine (20 mmol) in methanol. Stand for half an hour at room temperature and evaporated DOS is ha. The residue is purified by chromatography on silica gel by elution first with ethyl acetate, then with a mixture of ethyl acetate and methanol in a ratio of 90/10. Get 0,548 g of white powder.

Melting point (°C): 109-111

LC-MS: M+H = 318

1H NMR (DMSO-d6): δ (ppm): 7,80 (broad, 1H); 7,50-to 7.15 (m, 5H); 6,55 (d, 1H); of 6.25 (dt, 1H); however, 4.40 (s, 2H); 3.40 in (m, 4H); 3,10 (d, 2H); 2,60 (d, 3H); 2.40 a (m, 4H).

Example 2 (compound No. 99)

2-(methylamino)-2-oxoethyl-4-{3-[3-(trifluoromethyl)phenyl]prop-2-in-1-yl}diazepan-1-carboxylate

2.1. 4-{3-[3-(Trifluoromethyl)phenyl]prop-2-in-1-yl}-1,4-diazepan-1-carbaldehyde

Heated at 80°C a mixture of 1.28 g (10 mmol) of 1,4-diazepan-1-carbaldehyde and 0.33 g (11 mmol) of paraformaldehyde in 13 ml of dioxane to obtain a homogeneous solution. Add a solution of 1.70 g (10 mmol) 3-triftormetilfullerenov in 7 ml of dioxane and is 1.81 g (10 mmol) of the diacetate of copper. Heated at 80°C for 4 hours. Cooled to room temperature and dissolved in 75 ml of ethyl acetate. The organic phase is washed with 25 ml of 30%ammonia solution, then saturated aqueous sodium chloride. Dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel by elution with a mixture of dichloromethane, methanol and 30%aqueous ammonia solution in the ratio 98/2/0,2, then the ratio 96/4/0,4 and 94/6/0,6 and obtain 2.67 g of product in the form of W is logo oil.

2.2. 4-{3-[3-(Trifluoromethyl)phenyl]prop-2-in-1-yl}-1,4-diazepan

Dissolve 2,63 g (8,48 mmol) 4-{3-[3-(trifluoromethyl)phenyl]prop-2-in-1-yl}-1,4-diazepan-1-carbaldehyde obtained in stage 2.1, 7.5 ml of methanol. Add 3.5 ml of 35%aqueous sodium hydroxide solution (30 mmol) and refluxed for 3 hours. Cool to room temperature. Dissolved in 20 ml of water and 75 ml of dichloromethane. Decanted, and then extracted from the aqueous phase with dichloromethane 2 times 25 ml of the organic phase is Washed with 25 ml water, then with 25 ml of a saturated aqueous solution of sodium chloride. Dried over sodium sulfate and evaporated to dryness to obtain 2.25 g of product as a red oil, which is used in this form in the next stage.

2.3. 2-(Ethyloxy)-2-oxoethyl-4-{3-[3-(trifluoromethyl)phenyl]prop-2-in-1-yl}-1,4-diazepan-1-carboxylate

Heated at 60°C overnight, the solution of 2.25 g (of 7.95 mmol) 4-{3-[3-(trifluoromethyl)phenyl]prop-2-in-1-yl}-1,4-diazepan obtained in stage 2.2, and $ 2.68 g (11.9 mmol) of ethyl{[(phenyloxy)carbonyl]oxy}acetate in 10 ml of toluene. Add 5 g of silicon dioxide and evaporated to dryness. The residue is purified by chromatography on silica gel by elution with a mixture of cyclohexane and ethyl acetate in the ratio of 60/40, then in the ratio of 40/60, then ethyl acetate and get to 2.42 g of the product as an orange oil.

2.4. 2-(Amino)-2-oxoethyl-4-{3-[3-(triform the Teal)phenyl]prop-2-in-1-yl}-1,4-diazepan-1-carboxylate

Dissolve 0,77 g (of 1.87 mmol) 2-(ethyloxy)-2-oxoethyl-4-{3-[3-(trifluoromethyl)phenyl]prop-2-in-1-yl}-1,4-diazepan-1-carboxylate, obtained in stage 2.3, in 14 ml of a 7 M solution of ammonia (98 mmol) in methanol. Incubated over night at room temperature, then added 2 g of silica and evaporated to dryness. The residue is purified by chromatography on silica gel by elution with a mixture of dichloromethane, methanol and 30%aqueous ammonia solution in the ratio 97/3/0,3, then the ratio 95/5/0,5 and 93/7/0,7. Then recrystallized from a mixture of ethyl acetate and diisopropyl ether and receive 0,57 g of white crystals.

Melting point (°C): 102-104

LC-MS: M + H = 384

1H NMR (CDCl3) δ (ppm): of 7.70 (s, 1H); at 7.55 (m, 2H); was 7.45 (d, 1H); x 6.15 (m broad, 1H); 5,50 (m broad, 1H); with 4.65 (s, 2H); 3,65 (m+s, 6H); 2,85 (m, 4H); 1,95 (m, 2H).

Example 3 (compound No. 130)

2-(methylamino)-2-oxoethyl-4-{2[(4-chlorophenyl)oxy]ethyl}piperazine-1-carboxylate

3.1. 2-(methylamino)-2-oxoethyl-4-nitrophenylarsonic

To a suspension 2,62 g (29.4 mmol) of 2-hydroxy-N-methylacetamide and 16.5 g (58,7 mmol) diisopropylethylamine on the media (Ps-DIEA d Argonaut, specific capacity = of 3.56 mmol/g) in 250 ml of dichloromethane is added in small portions at room temperature to 5.93 g (29.4 mmol) of 4-nitrophenylphosphate. Then stirred apparatus with orbital rotation at room temperature is over 16 hours. Filter out osmol, washed with 150 ml dichloromethane and concentrate the filtrate under reduced pressure. Get 6 g of the product as a pale yellow solid, which is used in this form in the next stage.

3.2. 1,1-Dimethylethyl-2-(methylamino)-2-oxoethylidene-1,4, in primary forms

To a cooled to 0°C to a solution of 1.1 g (3 mmol) of 2-(methylamino)-2-oxoethyl-4-nitrophenylarsonic obtained in stage 3.1, in 10 ml of 1,2-dichloroethane are added dropwise at a temperature of approximately 0°C a solution of 0.53 g (2,85 mmol) 1,1-dimethylaminopropan-1-carboxylate in 5 ml of dichloroethane. Further stirred at a temperature of 0°C for 1 hour, then at room temperature for 3 hours.

Concentrate under reduced pressure. The residue is purified by chromatography on silica gel by elution with a mixture of cyclohexane and ethyl acetate in a ratio of 20/80, gradually increasing the proportion of ethyl acetate in order to complete the elution only ethyl acetate. Then triturated in diisopropyl ether and receive and 0.61 g of the product as a white solid, which is used in this form in the next stage.

3.3. Hydrochloride of 2-(methylamino)-2-oxoethylidene-1-carboxylate

To a solution of 2.68 g (8.9 mmol) of 1,1-dimethylethyl-2-(methylamino)-2-oxoethylidene-1,4-in primary forms obtained at the stage 3.2, in 25 ml dichloromethane was added 25 ml of 6 N. p is the target of hydrochloric acid in isopropanol. Then stirred at room temperature for 1 hour. Separate the organic phase by filtration through a hydrophobic cartridge and concentrated under reduced pressure. After grinding in isopropanol gain of 2.05 g of product.

Melting point (°C): 167 -169°C

3.4. 2-(Methylamino)-2-oxoethyl-4-{2[(4-chlorophenyl)oxy]ethyl}piperazine-1-carboxylate

Heated at 85°C for 16 hours the solution 0,073 g (0.3 mmol) of the hydrochloride of 2-(methylamino)-2-oxoethylidene-1-carboxylate, obtained in stage 3.3, 0,13 g (0.9 mmol) of potassium carbonate and 0,069 g (0.29 mmol) of 1-(2-bromoethoxy)-4-chlorobenzene in 3 ml of acetonitrile.

After cooling to room temperature, filtered the solid phase through the cartridge, equipped with a porous glass plate and containing celite. Washed with acetone and concentrated under reduced pressure. After chromatography was carried out on silica gel by elution with a mixture of dichloromethane and methanol in a ratio of 95/5 followed by crystallization from diisopropyl ether get 0,089 g of the product as a white solid.

LC-MS: M+H = 356

Melting point (°C): 159-161°C

1H NMR (CDCl3) δ (ppm): to 7.25 (DD, 2H); 6,85 (DD, 2H); 6,05 (broad, 1H); 4,60 (s, 2H); 4,10 (t, 2H); 3,55 (m, 4H); 2,90 (d, 3H); to 2.85 (t, 2H); 2,60 (m, 4H).

Example 4 (compound No. 25)

2-(Methylamino)-2-oxoethyl-4-(2-naphthalene-2-retil)piperazine-1-carbox ilat

To a cooled to 0°C to a solution of 0.13 g (0.75 mmol) of 2-naphthalene-2-retinol and to 0.19 ml (1.13 mmol) of diisopropylethylamine in 7.5 ml of dichloromethane is added 0,07 ml (0.9 mmol) chloride methanesulfonyl. Then stirred in the cold for 0.5 hour, then at room temperature for 2 hours. Concentrate under reduced pressure.

Treat the residue with 5 ml of acetonitrile, was added 0.12 g (0.5 mmol) of the hydrochloride of 2-(methylamino)-2-oxoethylidene-1-carboxylate obtained in example 3.3, and 0.20 g (1.5 mmol) of potassium carbonate. Heated at 70°C for 16 hours. After cooling to room temperature, concentrated under reduced pressure. The residue is suspended in dichloromethane and washed with saturated sodium bicarbonate solution, then water. Separate the organic phase by filtration through a hydrophobic membrane and concentrated under reduced pressure. After chromatography was carried out on silica gel by elution with a mixture of dichloromethane and methanol in a ratio of 95/5 followed by crystallization from diisopropyl ether get 0,069 g of the product as a white solid.

LC-MS: M+H = 356

Melting point: 133-135°C

1H NMR (CDCl3) δ (ppm): a 7.85 (m, 3H); the 7.65 (s, 1H); 7,55-7,30 (m, 3H); 6,05 (broad, 1H); 4,60 (s, 2H); 3,55 (m, 4H); 3,05-to 2.65 (m, 7H); to 2.55 (m, 4H).

Example 5 (compound No. 50)

Hydrochloride of 2-(methylamino)-2-oxoethyl-4-(3-diphenyl-3-yl-1,1-dimethylpropyl)piperazine-1-carboxylate

5.1. 1-(2,2-Dimethylpropanoyl)-4-(1,1-dimethylpropyl-2-in-1-yl)piperazine

Dissolve 0,756 g (6 mmol) of 1,1-dimethylpropyl-2-in-1-ilaclama (J. Org. Chem. 1994, 59, 2282-2284) and 2,235 g (12 mmol) of 1,1-dimethylaminopropan-1-carboxylate in 9 ml of tetrahydrofuran, then added 0,059 g (0.6 mmol) of copper chloride. Refluxed for 3 hours. After cooling to room temperature, add 100 ml of ethyl acetate, 10 ml of 1 N. aqueous sodium hydroxide solution and 2 ml of 30%ammonia solution. Decanted organic phase was washed with water 2 times 10 ml, then 10 ml of a saturated aqueous solution of sodium chloride. Dried over sodium sulfate and evaporated. The residue is purified by chromatography on silica gel by elution with a mixture of cyclohexane and ethyl acetate in a ratio of 85/15, then in the ratio of 75/25 and 65/35 and obtain 1.19 g (4,71 mmol) of the product as a pale yellow solid.

Melting point: 106-109°C

5.2. 1-(3-Diphenyl-3-yl-1,1-dimethylpropyl-2-in-1-yl)-4-(2,2-dimethylpropanoyl)piperazine

Dissolve 1,05 g (4.5 mmol) of 3-bromodiphenyl and 0.9 g (3.6 mmol) of 1-(2,2-dimethylpropanoyl)-4-(1,1-dimethylpropyl-2-in-1-yl)piperazine obtained in stage 5.1, 0.75 ml (5,38 mmol) of triethylamine and 0,028 g (0.11 mmol) of triphenylphosphine in 8 ml of tetrahydrofuran is. In an argon atmosphere is added 0.126 g (0.18 mmol) of the complex dichloride bis(triphenylphosphine)palladium. Stirred for 15 min, then add 0,014 g (0.07 mmol) modestou copper. Further stirred at room temperature for 4 hours, then at 60°C during the night. After cooling to room temperature, dissolved in 25 ml ethyl acetate and filtered through a paper filter. Washed the solid with ethyl acetate 4 times in 10 ml. was Added to the filtrate to 4 g of silica and evaporated to dryness. Purify by chromatography on silica gel by elution with a mixture of cyclohexane and ethyl acetate in a ratio of 90/10, then in the ratio of 80/20 and 70/30 and get 0,90 g (2.22 mmol) of the product as an orange oil.

5.3. 1,1-Dimethylethyl-4-(3-diphenyl-3-yl-1,1-dimethylpropyl)piperazine-1-carboxylate

Dissolve 0.87 g (2,15 mmol) 1-(3-diphenyl-3-yl-1,1-dimethylpropyl-2-in-1-yl)-4-(2,2-dimethylpropanoyl)piperazine obtained in stage 5.2, in a mixture of 5 ml of methanol and 15 ml of ethyl acetate. Add 0.2 g of platinum oxide is added and stirred in a hydrogen atmosphere under a pressure of 40 psi for 6 hours. Filtered through filter paper and washed with ethyl acetate 3 times in 10 ml. was Added to the filtrate 2 g of silica and evaporated to dryness. Purify by chromatography on silica gel by elution with a mixture of cyclohexane and ethyl acetate in a ratio of 90/10, then in a ratio of 85/15 is 80/20 and obtain 0.36 g (0.88 mmol) of the product as a colourless oil.

5.4. 1-(3-Diphenyl-3-yl-1,1-dimethylpropyl)piperazine

Add to 0.65 ml (8.4 mmol) triperoxonane acid to a solution of 0.35 g (0.86 mmol) of 1,1-dimethylethyl-4-(3-diphenyl-3-yl-1,1-dimethylpropyl)piperazine-1-carboxylate, obtained in stage 5.3, in 5 ml of dichloromethane. Stirred for 2 hours, then add one more to 0.65 ml triperoxonane acid. Additionally stirred for 2 hours, then dissolved in 10 ml of 1,2-dichloroethane and evaporated to dryness. Treat the residue with a mixture of 50 ml of dichloromethane and 20 ml of 15%aqueous sodium hydroxide solution. Decanted and extracted from the aqueous phase with dichloromethane 2 times with 20 ml.

The organic phase is washed with 10 ml of water, then 20 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate, evaporated and obtain 0.25 g (0.81 mmol) of the product as a yellow oil.

5.5. Hydrochloride of 2-(methylamino)-2-oxoethyl-4-(3-diphenyl-3-yl-1,1-dimethylpropyl)piperazine-1-carboxylate

Heated at 60°C overnight, the solution of 0.25 g (0.81 mmol) of 1-(3-diphenyl-3-yl-1,1-dimethylpropyl)piperazine obtained in stage 5.4 and 1.5 g (1,22 mmol) of ethyl{[(phenyloxy)carbonyl]oxy}acetate, then evaporated to dryness. Dissolve the residue with a mixture of 4 ml of 2 M solution of dimethylamine (8 mmol) in tetrahydrofuran and 2 ml of methanol. Stand over night, then add 1 g of silica and evaporated. The product cleans chromatogr is via on silica gel by elution with a mixture of dichloromethane and methanol in a ratio of 98/2, then in the ratio of 96/4 and 94/6 and get to 0.23 g (0.54 mmol) of the product as a colourless gum.

Dissolve the product in 5 ml of ethyl acetate and added 1 ml of 5 n hydrochloric acid in isopropanol. Is evaporated to dryness. Handle the balance of 15 ml of hot ethyl acetate. Filtered the solid, washed with ethyl acetate 2 times in 3 ml dry out and get 0,215 g (0.46 mmol) of the product as a white powder.

LC-MS: M+H = 424

Melting point: 212-216°C (decomposition)

1H NMR (CDCl3) δ (ppm): 12,50 (broad, 1H); at 7.55 (d, 2H); 7,40 (m, 6H); then 7.20 (d, 1H); 6,05 (broad, 1H); 4,60 (s, 2H); 4,30-4,10 (m, 4H); 3,55 (d broad, 2H); 3,05-2,75 (m+d, 5H); to 2.15 (m, 2H); 1.70 to (s, 8H).

Example 6 (compound No. 29)

2-(Methylamino)-2-oxoethyl-4-{2-[3-(4-chlorophenyl)isoxazol-5-yl]ethyl}piperazine-1-carboxylate

6.1. 2-[3-(4-Chlorophenyl)isoxazol-5-yl]ethanol

Added dropwise and 1.63 ml (11,58 mmol) of triethylamine to a solution of 1.18 ml (15,57 mmol) buta-4-in-1-ol and 2.0 g (10,52 mmol) chloride 4-chloro-N-hydroxybenzotriazole (J. Med. Chem. 1998, 41, 4556-4566) in 30 ml of dichloromethane, cooled in a bath with ice. Incubated over night at room temperature. Add 50 ml of dichloromethane and washed with water 2 times 50 ml, then 50 ml of a saturated aqueous solution of sodium chloride. Dried over sodium sulfate and evaporated. The residue is purified by chromatography on what silicagel by elution with a mixture of cyclohexane and ethyl acetate in a ratio of 80/20, then in the ratio of 70/30 and obtain 1.1 g (4,91 mmol) of the product a white solid.

Melting point: 65-67°C

6.2. 2-(Methylamino)-2-oxoethyl-4-{2-[3-(4-chlorophenyl)isoxazol-5-yl]ethyl}piperazine-1-carboxylate

To a solution 0,100 g (0,447 mmol) 2-[3-(4-chlorophenyl)isoxazol-5-yl]ethanol obtained in stage 6.1, and 0,082 ml (0.47 mmol) of diisopropylethylamine in 5 ml of dichloromethane was added 0.036 ml (0,469 mmol) chloride methanesulfonyl. Stirred at room temperature for 4 hours, then washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Concentrate under reduced pressure. Treat the residue with 5 ml of acetonitrile, add 0,107 g (0.45 mmol) of the hydrochloride of 2-(methylamino)-2-oxoethylidene-1-carboxylate obtained in example 3.3, and 0,186 g (1.35 mmol) of potassium carbonate. Heated at 75°C for 16 hours. After cooling to room temperature, concentrated under reduced pressure. Treat the residue with ethyl acetate and washed with water, then saturated aqueous sodium chloride. Is evaporated and the residue purified by chromatography on silica gel by elution with dichloromethane, then with a mixture of dichloromethane and methanol in a ratio of 90/10. Get 0,054 g (0,132 mmol) of the product as a white solid.

LC-MS: M+H = 407

Melting point: 130-132°C

sup> 1H NMR (DMSO-d6) δ (ppm): a 7.85 (d, 2H); 7,75 (array, 1H); at 7.55 (d, 2H); 6,85 (s, 1H); however, 4.40 (s, 2H); 3.40 in (m, 4H); 2.95 and (t, 2H); 2,70 (t, 2H); to 2.55 (d, 3H); 2.40 a (m, 4H).

Example 7 (compound No. 52)

2-(Methylamino)-2-oxoethyl-4-[3-(3'-chlorodiphenyl-3-yl)propyl]piperazine-1-carboxylate

7.1. 3-(3-Bromophenyl)propan-1-ol

To a suspension of 1.84 g (8 mmol) of 3-(3-bromophenyl)propionic acid and of 0.91 g (24 mmol) of sodium borohydride in 20 ml of THF, cooled to 0°C, add small portions of 3.2 ml (25 mmol) of complex cryptosporidiosis ether. Then stirred in the cold for 1 hour, then at room temperature for 16 hours. Cooled the reaction mass to 0°C and neutralized to pH=7˜8 Appendix 1 N. aqueous sodium hydroxide solution. Concentrate under reduced pressure, then the residue is treated with water. Extracted with dichloromethane and dried over sodium sulfate. After filtration the organic phase is concentrated under reduced pressure. Gain of 1.62 g (7,53 mmol) of product in the form of oils, which are used in this form in the next stage.

7.2. 2-(Methylamino)-2-oxoethyl-4-[3-(3-bromophenyl)propyl]piperazine-1-carboxylate

To a solution of) 0.157 g (6.7 mmol) of 3-(3-bromophenyl)propan-1-ol, obtained in stage 7.1, and 1.73 ml (10.1 mmol) of diisopropylethylamine in 38 ml of dichloromethane, cooled to 0°C, was added 0.63 ml (8,14 mmol) PI is ristoro methanesulfonyl. Then stirred in the cold for 0.5 hour, then at room temperature for 2 hours. Concentrate under reduced pressure, then the residue is suspended in 35 ml of acetonitrile. Gain of 1.34 g (to 5.35 mmol) of the hydrochloride of 2-(methylamino)-2-oxoethylidene-1-carboxylate obtained in example 3.3, and 2.2 g (16 mmol) of potassium carbonate. Heated at 75°C for 16 hours. After cooling to room temperature, concentrated under reduced pressure, then the residue is treated with water. Extracted with ethyl acetate and dried over sodium sulfate. After filtration the organic phase is concentrated under reduced pressure. Purify by chromatography on silica gel by elution with a mixture of dichloromethane and methanol in a ratio of 98/2. After crystallization from diisopropyl ether obtain 0.84 g (2.10 mmol) of white crystals.

7.3. 2-(Methylamino)-2-oxoethyl-4-[3-(3'-chlorodiphenyl-3-yl)propyl]piperazine-1-carboxylate

To a suspension of 0.14 g (0.35 mmol) of 2-(methylamino)-2-oxoethyl-4-[3-(3-bromophenyl)propyl]piperazine-1-carboxylate, obtained in stage 7.2, in a mixture of 4 ml of toluene and 0.6 ml of ethanol was added 0.08 g (0.07 mmol) tetrakis(triphenylphosphine)palladium, of 1.05 ml (2.1 mmol) of aqueous 2 M sodium carbonate solution and 0.22 g (1.4 mmol) of 3-chlorobenzylamino acid. Heated at 150°C microwave radiation for 5 min and secrete organic is kind of phase by filtration through a cartridge, equipped with a porous glass plate and containing celite and sodium sulfate. Washed with toluene and concentrate the filtrate under reduced pressure. The product was then purified by chromatography on silica gel by elution with a mixture of ethyl acetate and methanol in a ratio of 90/10. Then treated with n-heptane and get 0,086 g (0.18 mmol) of the product as white crystals.

LC-MS: M+H = 430

Melting point: 82-85°C

1H NMR δ (ppm): 7,35 (m, 8H); 6,05 (broad, 1H); and 4.6 (s, 2H); 3,55 (m, 4H); 2,85 (d, 3H); to 2.75 (t, 2H); of 2.45 (m, 6H); 1,9 (m, 2H).

Table 1, below, is given to illustrate the chemical structures and physical properties of some compounds according to the present invention. In the column "base or salt", "base" denotes a compound in the form of free base, whereas "HCl" represents a compound in the form of hydrochloride.

td align="center"> 1td align="center"> 64td align="center"> C≡H2td align="center"> H
Table 1< / br>
No.R1G[A]pnR2R3PF (°C) (or M+H)Base or salt
12-F-phenyllinkCH21HCH3196-200HCl
22-Cl-phenyllinkCH21HCH3212-217HCl
33-F-phenyllinkCH21HCH3161-166HCl
43-I-phenyllinkCH21HCH3(418)base
53-Cl-phenyllinkCH21HCH3203-207HCl
64-Cl-phenyllinkCH21HCH3112-115HCl
74-CH3O-phenyllinkCH21HCH3155-159HCl
84-(fenilin2O)-phenyllinkCH21HCH3172-178HCl
94-(CH3)2CH-phenyllinkCH2HCH3104-108HCl
103-phenyl-phenyllinkCH21HCH3111-114HCl
114-phenyl-phenyllinkCH21HCH3173-179HCl
12naphthalen-1-yllinkCH21HCH3143-145base
13naphthalen-2-yllinkCH21HCH3184-186HCl
14phenyllink(CH2)21HCH3167-169base
153-Br-phenyllink(CH2)21HCH3(384)base
164-Br-phenyllink(CH2)21HCH3 (384)base
174-CH3O-phenyllink(CH2)21HCH3124-126base
183-phenyl-phenyllink(CH2)21HCH3118-120base
194-phenyl-phenyllink(CH2)21HCH3148-150base
20naphthalen-1-yllink(CH2)21HH125-127base
21naphthalen-1-yllink(CH2)21HCH3109-112base
22naphthalen-1-yllink(CH2)21HCH2CH3113-115base
23naphthalen-1-yllink(CH2)21 Hcyclopropyl125-127base
24naphthalen-1-yllink(CH2)21HCH2-cyclopropyl113-115base
25naphthalen-2-yllink(CH2)21HCH3133-135base
26naphthalen-2-yllink(CH2)22HH115-119base
27indol-3-yllink(CH2)21HCH3121-123base
283-(4-Cl-phenyl)-1H-methylpyrazole-5-yllink(CH2)21HCH3141-143base
293-(4-Cl-phenyl)-isoxazol-5-yllink(CH2)21HCH3130-132base
305-(4-Cl-phenyl)isoxazol--Il link(CH2)21HCH3146-148base
316-(4-Cl-phenyl)-pyrimidine-4-yllink(CH2)21HCH3132-134base
321,1-diphenylmethyllink(CH2)21HCH386-88base
33phenyllink(CH2)31HCH3315-317HCl
343-Cl-phenyllink(CH2)31HCH385-87base
354-Cl-phenyllink(CH2)31HCH3115-117base
363-Br-phenyllink(CH2)31HCH3(398)base
37 4-Br-phenyllink(CH2)31HCH3(398)base
383-CN-phenyllink(CH2)31HCH3107-109base
393-CF3-phenyllink(CH2)31HCH398-100base
404-CF3-phenyllink(CH2)31HCH385-87base
412-Cl,4-Cl-phenyllink(CH2)31HCH3103-105base
422-Cl,5-Cl-phenyllink(CH2)31HH128-130base
432-Cl,5-Cl-phenyllink(CH2)31HCH3121-123base
44pyrimidine-2-yllink(CH2)31HCH3103-105base
45pyrimidine-5-yllink(CH2)31HCH3116-118base
46the thiazole-2-yllink(CH2)31HCH383-85base
472-phenyl-phenyllink(CH2)31HCH3(396)base
483-phenyl-phenyllink(CH2)31HCH399-101base
494-phenyl-phenyllink(CH2)31HCH3110-113base
503-phenyl-phenyllink(CH2)2-C(CH3)21HCH3 212-216HCl
514-phenyl-phenyllink(CH2)2-C(CH3)21HCH3101-103base
523-(3-Cl-phenyl)-phenyllink(CH2)31HCH382-85base
533-(4-Cl-phenyl)-phenyllink(CH2)31HCH3136-138base
543-(3-CH3O)phenyl-phenyllink(CH2)31HCH3(426)base
553-(4-CH3O)phenyl-phenyllink(CH2)31HCH3135-137base
563-(3-CN-phenyl)-phenyllink(CH2)31HCH3152-154base
573-(4-CN-phenyl)-phenyllink 2)31HCH3137-139base
584-(3-Cl-phenyl)-phenyllink(CH2)31HCH3101-103base
594-(4-Cl-phenyl)-phenyllink(CH2)31HCH3125-128base
604-(3-CH3O)phenyl-phenyllink(CH2)31HCH397-100base
614-(4-CH3O)phenyl-phenyllink(CH2)31HCH3128-130base
624-(3-CN-phenyl)-phenyllink(CH2)31HCH3108-110base
634-(4-CN-phenyl)-phenyllink(CH2)31HCH3148-150base
naphthalen-1-yllink(CH2)31HCH3104-106HCl
65naphthalen-2-yllink(CH2)31HCH3110-112base
663-(4-Cl-phenyl)-1H-methylpyrazole-5-yllink(CH2)31HCH3157-159base
675-(4-Cl-phenyl)isoxazol-3-yllink(CH2)31HCH3125-127base
683-(4-Cl-phenyl)isoxazol-5-yllink(CH2)31HH132-134base
693-(4-Cl-phenyl)isoxazol-5-yllink(CH2)31HCH3108-110base
703-(naphthalen-2-yl)isoxazol-5-yllink(CH2)31 HCH371-73base
711,1-di-(4-F-phenyl)methyllink(CH2)31HCH3(446)base
723-Cl-phenyllink(CH2)41HCH3103-105base
734-Cl-phenyllink(CH2)41HCH3120-122base
743-CN-phenyllink(CH2)41HCH3127-129base
753-CF3-phenyllink(CH2)41HCH398-100base
764-CF3-phenyllink(CH2)41HCH3129-131base
77pyrimidine-2-yllink(CH2 41HCH3141-143base
78pyrimidine-5-yllink(CH2)41HCH3114-116base
79the thiazole-2-yllink(CH2)41HCH393-95base
80naphthalen-1-yllink(CH2)41HCH390-92base
81naphthalen-2-yllink(CH2)41HCH3109-111base
822-phenyl-phenyllink(CH2)41HCH392-94base
833-phenyl-phenyllink(CH2)41HCH397-99base
84phenyllink CH=CHCH2(E)1HH115-117base
85phenyllinkCH=CHCH2(E)1HCH3109-111base
863-Cl-phenyllinkC≡H21HCH3114-116base
874-Cl-phenyllinkC≡H21HCH3127-129base
883-CF3-phenyllinkC≡H21HCH3131-133base
894-CF3-phenyllinkC≡H21HCH3125-127base
903-CN-phenyllinkC≡H21HCH3134-140base
91pyrimidine-2-yllink1HCH3137-139base
92pyrimidine-5-yllinkC≡H21HCH3151-153base
93the thiazole-2-yllinkC≡H21HCH3111-113base
94naphthalen-1-yllinkC≡H21HCH3131-134base
95naphthalen-2-yllinkC≡H21HCH3(366)base
962-phenyl-phenyllinkC≡H21HCH3(392)base
973-phenyl-phenyllinkC≡H21HCH3125-127base
984-phenyl-phenyllink C≡(CH3)21HCH3.137-139base
993-CF3-phenyllinkC≡H22HH102-104base
1003-CF3-phenyllinkC≡H22HCH392-94base
1013-Cl-phenyllinkC≡CH2)21HCH3115-117base
1024-Cl-phenyllinkC≡CH2)21HCH3141-143base
1033-CF3-phenyllinkC≡CH2)21HCH393-95base
1044-CF3-phenyllinkC≡CH2)21HCH3142-144base
105 3-CN-phenyllinkC≡CH2)1HCH3144-146base
106pyrimidine-2-yllinkC≡CH2)21HCH3120-122base
107pyrimidine-5-yllinkC≡CH2)21HCH3159-161base
108the thiazole-2-yllinkC≡CH2)21HCH3103-105base
109naphthalen-1-yllinkC≡CH2)21HCH399-101base
110naphthalen-2-yllinkC≡CH2)21HCH3140-142base
1112-phenyl-phenyllinkC≡CH2)21HCH3base
1123-phenyl-phenyllinkC≡CH2)21HCH3102-104base
1133-Cl-phenyllinkC≡CH2)31HCH379-81base
1144-Cl-phenyllinkC≡CH2)31HCH3126-128base
1152-F,4-Cl-phenyllinkC≡CH2)31HCH3131-133base
1162-Cl,4-F-phenyllinkC≡CH2)31HCH3133-135base
1172-Cl,4-Cl-phenyllinkC≡CH2)31HCH3133-135base
1182-Cl,5-Cl-phenyllinkC≡CH2)3 1HCH3110-112base
1193-Cl,4-Cl-phenyllinkC≡CH2)31HCH3119-121base
1203-Cl,4-F-phenyllinkC≡CH2)31HCH398-100base
121phenylO(CH2)21HCH3233-235base
1222-Cl-phenylO(CH2)21HH90-92base
1232-Cl-phenylO(CH2)21HCH3184-186HCl
1242-CN-phenylO(CH2)21HCH3109-111base
1253-Cl-phenylO(CH2)21H>300HCl
1263-Cl-phenylO(CH2)21HCH3105-107base
1273-CN-phenylO(CH2)21HCH3141-143base
1284-F-phenylO(CH2)21HCH3134-136base
1294-Cl-phenylO(CH2)21HH115-117base
1304-Cl-phenylO(CH2)21HCH3159-161base
1314-CN-phenylO(CH2)21HH145-147base
1324-CN-phenylO(CH2)21HCH3138-140base
1334-(CH3)2C-phenylO(CH2)21HCH3111-113HCl
1344-CF3-phenylO(CH2)21HH104-106base
1354-CF3O-phenylO(CH2)21HH96-98base
1364-CF3O-phenylO(CH2)21HCH393-96base
1372-Cl,3-Cl-phenylO(CH2)21HH136-138base
1382-Cl,3-Cl-phenylO(CH2)21HCH3132-134base
1392-Cl,4-Cl-phenylO(CH2)21HH178-180base
140 2-Cl,4-Cl-phenylO(CH2)21HCH3102-104base
1413-Cl,4-Cl-phenylO(CH2)21HCH3128-130base
1423-Cl,4-Cl-phenylO(CH2)21HH126-128base
1433-Cl,5-Cl-phenylO(CH2)21HCH3111-113base
1443-CF3,5-CF3-phenylO(CH2)21HCH3137-139base
1453,4-(OCH2O)-phenylO(CH2)21HCH3139-141base
1463-phenyl-phenylO(CH2)21HH120-122HCl
147 3-phenyl-phenylO(CH2)21HCH3143-145HCl
1484-phenyl-phenylO(CH2)21HH238-240base
1494-phenyl-phenylO(CH2)21HCH3130-132base
150naphthalen-1-ylO(CH2)21HH116-118base
151naphthalen-1-ylO(CH2)21HCH3135-137base
152naphthalen-2-ylO(CH2)21HH88-90base
153naphthalen-2-ylO(CH2)21HCH3118-120base
154the quinoline-6-yl (CH2)21HH203-205base
155the quinoline-6-ylO(CH2)21HCH3126-128base
156the quinoline-8-ylO(CH2)21HCH399-101base
157phenylO(CH2)31HCH3103-105base
1582-Cl-phenylO(CH2)31HCH3119-121base
1593-Cl-phenylO(CH2)31HCH395-97base
1604-Cl-phenylO(CH2)31HCH3116-118base
1612-Cl,3-Cl-phenylO(CH2)3 1HCH3110-112base
1622-Cl,4-Cl-phenylO(CH2)31HCH3115-117base
1632-Cl,5-Cl-phenylO(CH2)31HCH3134-136base
1642-Cl,6-Cl-phenylO(CH2)31HCH3100-102base
1653-Cl,5-Cl-phenylO(CH2)31HCH3121-123base
166phenylC=O(CH2)21HCH3141-143base
1674-Cl-phenylC=O(CH2)21HCH3172-174base
168phenylC=O(CH2)31 HCH3110-112base

Compounds of the present invention were the subject of pharmacological trials which allowed to determine the effect of inhibition of the enzyme FAAH (hydrolases fatty acid amides).

Inhibitory activity was determined by radiodermatitis test based on measuring the product of hydrolysis (ethanolamine [1-3H]) of anandamide [ethanolamine 1-3H] the enzyme FAAH(Life Sciences (1995), 56, 1999-2005andJournal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734).So, the brain of mice (without cerebellum) were removed and conserved at -80°C. Membrane homogenates were prepared before use by homogenization of tissues transmitter station in a buffer solution of Tris-HCl 10 mm (pH=8)containing 150 mmol NaCl and 1 mmol EDTA. Then the enzymatic reaction was performed in 70 μl of buffer solution containing bovine serum albumin without fatty acids (1 mg/ml). Sequentially added compound of various concentrations of anandamide [ethanolamine 1-3H] (specific activity 15-20 CI/mmol)diluted with 10 µl of chilled anandamide, and the membrane preparation (400 g frozen for testing tissue). After soaking for 15 min at 25°C enzymatic reaction was stopped by adding 140 μl of a mixture of chloroform/methanol (2:1). The mixture is stirred during the course the e 10 min, then centrifuged for 15 min at 3500 g. To aliquots (30 μl) of the aqueous phase, containing ethanolamine [1-3H], spent liquid scintillation.

In these conditions, the most active compounds of the present invention show CI50(concentration inhibiting 50% of the enzymatic activity of FAAH) from 0.001 to 1 mmol, inclusive.

In table 2, below, are given the values CI50for some compounds of the present invention.

Table 2
The connection numberCI50
210,072 µmol
480,050 µmol
490,032 µmol

It therefore appears that the compounds of the present invention have inhibitory action on the enzyme FAAH.

Activityin vivocompounds of the present invention was evaluated by test analgesic effect.

So, intraperitoneal (I.P. Pavlova.) PBQ (phenylbenzophenone, 2 mg/kg in 0.9%sodium chloride solution containing 5% ethanol) male OF1 mice weighing 25 to 30 g were causing abdominal stretch, about 30 twists or reductions during the period from 5 to 15 min after injection. Compound was administered orally (p.o.)or administered intraperitoneally (I.P. Pavlova.) in the form of a suspension of Tween 80 to a concentration of 0.5% for 60 or 120 min before the introduction of the PBQ. In these conditions, the most active compounds of the present invention is reduced from 35 to 70% the number of contractions caused by the introduction of PBQ, in doses ranging from 1 to 30 mg/kg. For example, compound No. 49 and No. 69 table reduced by 43 and 47%, respectively, the number of contractions caused by PBQ, at the dose of 10 mg/kg by oral administration for 120 minutes

The enzyme FAAH(Chemistry and Physics of Lipids,(2000), 108, 107-121) catalyzes the hydrolysis of endogenous derivatives of amides and esters of various fatty acids, such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamide, N-oleoylethanolamide, oleamide or 2-arachidonoylglycerol. These compounds exhibit various pharmacological activity, interacting with receptors cannabinoids and vanilloids. Compounds of the present invention block this path of degradation and increase the level of contents in the tissues of data endogenous substances. They can be used in this aspect for the prevention and treatment of pathologies which shows the use of endogenous cannabinoids and/or any other substrates, metabolisable enzyme FAAH. As examples, you can specify the following diseases and painful conditions: pain, especially acute or chronic pain of neurogenic type: migraine, neuropathic pain, including forms associated with the herpes virus and di is beta, acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome, acute or chronic peripheral pain, dizziness, vomiting, nausea, in particular resulting from chemotherapy, difficulty eating, in particular anorexia and cachexia of various nature, neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasticity, compulsive and obsessive behavior, Tourette's syndrome, all forms of depression and mental disorders of any nature and origin, impaired health, psychosis, acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's Hutchinson, damage associated with cerebral ischemia and cranial bone and brain injuries, epilepsy, sleep disorders, including seizures sleep apnea, cardiovascular disease, in particular hypertension, cardiac arrhythmia, arteriosclerosis, heart attack, ischemia of the heart, renal ischemia, cancers: benign skin tumors, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medulloepithelioma, neuroblastomas, tumors of embryonic origin, astrocytomas who we are, astroblastoma, ependymomas, oligodendrogliomas, plexus tumor, neuroepithelioma, tumor epiphysis, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanoma, sanomi), disorders of the immune system, especially autoimmune diseases: psoriasis, lupus erythematous, connective tissue disease or diffuse connective tissue disease, syndrome Charger, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis, the reaction of rejection of the transplant, diseases affecting plasmocytoma system, allergic diseases: hypersensitivity, immediate or delayed-type allergic rhinitis or conjunctivitis, contact dermatitis, parasitic, viral or bacterial infectious diseases: AIDS, meningitis, inflammatory diseases, particularly diseases of the joints: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome, osteoporosis, eye diseases: hypertension eye, glaucoma, lung diseases: diseases of the respiratory tract, bronchial constriction, cough, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema, gastrointestinal ill the of: irritable bowel syndrome, inflammatory intestinal disease, ulcers, diarrhea, urinary incontinence and bladder inflammation.

The use of compounds of the present invention in the form of a pharmaceutically acceptable base, an acid additive salt, hydrate or MES for obtaining a medicinal product intended for the treatment of the aforementioned pathologies, equally form part of the invention.

The object of the invention are equally medicines, including compound of formula (I) or pharmaceutically acceptable acid additive salt, or hydrate, or MES the compounds of formula (I). Data drug not find use in therapy, especially in the treatment of the aforementioned disorders.

The present invention in one of its aspects relates to pharmaceutical compositions comprising as active substance, at least a compound of formula (I) according to the present invention. Data pharmaceutical compositions contain an effective dose of a compound of the present invention or pharmaceutically acceptable acid additive salt, or hydrate, or MES-mentioned compounds and optionally one or more pharmaceutically acceptable excipients.

These fillers selected from traditional fillers, known special is that in this field of technology in accordance with the desired pharmaceutical form and route of administration.

In the pharmaceutical compositions of the present invention, intended for the introduction of oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, intradermal, intra-lungs, intraocular or rectally, the previously mentioned active substance of the formula (I) or its acid salt additive, possible MES or hydrate, can be administered in the dosage form of the standard dose in a mixture with conventional pharmaceutical excipients animals and humans for the prophylaxis or treatment of the aforementioned disorders or diseases.

Appropriate dosage forms standard dose for administration include forms for oral administration such as tablets, capsules, soft or hard gelatin shell, powders, granules, chewing gum, and solutions or suspensions for oral administration, the forms for receiving sublingual, transbukkalno, vnutritrahealno, intraocular, intranasal, intra-lungs, molds for injection subcutaneously, intramuscularly or intravenously and forms for administration rectally or vaginally. For topical use the compounds of the present invention can be applied in the form of creams, lipsticks and lotions.

As an example, a pharmaceutical form of STD is bound doses of the compounds of the present invention in tablet form can include the following connections:

The connection according to the present invention50.0 mg
Mannitol223,75 mg
Sodium, croscarmellose6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

Mentioned dosage forms standard dose dosed to get a daily dose in the range of from 0.01 to 20 mg of active ingredient per kg of body weight in accordance with the galenical form.

There may be special cases in which establish dose increased or decreased, these doses are equally form part of the present invention. According to accepted practice, the appropriate dose for each patient is determined by the physician according to the method of administration, the weight and response of the patient.

The present invention in one of its other aspects equally relates to a method of treatment of the aforementioned pathologies, which includes the introduction of an effective dose of the compounds of the present invention, one of its pharmaceutically acceptable acid additive salts of MES or hydrate mentioned connection.

1. The compound corresponding to formula (I)

where n is an integer equal to 1 or 2;

p is an integer ranging from 1 to 7;

And selected from one or more of the radicals X and/or Y;

X represents a methylene group substituted with one or two1-6-alkyl groups;

Y is either a2-albaniles or2-akinyan;

G represents a simple bond, oxygen atom or the group C=O;

R1represents the radical R4substituted with one or more radicals R5and/or R6;

R4represents a radical selected from phenyl, pyrimidinyl, thiazolyl, pyrazolyl, isoxazolyl, naphthalenyl, diphenylmethyl, chinoline, indolyl;

R5represents a halogen atom or a cyano, C1-6-alkyl, C1-6-alkoxy, C1-6-foralkyl,1-6-feralcode or-O-(C1-3-alkylene)-O;

R6represents phenyl, benzyloxy, naphthalenyl, radical or radicals R6optionally have substituents of one or more identical or different from each other radicals R5;

R2represent a hydrogen atom;

R3represent a hydrogen atom or a radical of the Sabbath. 1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkyl,

in the form of a base, an acid additive salt, hydrate or MES.

2. The compound of formula (I) according to claim 1, characterized in that

n is an integer equal to 1 or 2;

p is an integer variable from 1 to 7;

And selected from one or more of the radicals X and/or Y;

X represents a methylene group, optionally substituted by one or two radicals C1-6-alkyl;

Y represents a radical With2-albaniles and radical2-akinyan;

G represents a simple bond, an oxygen atom or a group C=0;

R1represents the radical R4substituted with one or more radicals R5and/or R6;

R4represents a radical selected from the radicals phenyl, naphthyl, diphenylmethyl, chinoline, indolyl, pyrazolyl, isoxazolyl, pyrimidinyl, thiazolyl;

R5represents a halogen atom or a cyano, a radical C1-6-alkyl, C1-6-alkoxy, C1-6-foralkyl,1-6-feralcode or-O-(C1-3-alkylen);

R6represents a phenyl radical, naphthyl or benzyloxy;

R2represent a hydrogen atom;

R3represent a hydrogen atom or a radical C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkyl,

a base, an acid additive salt, hydrate or MES.

3. The compound of formula (I) according to claim 1 or 2, characterized in that

n is an integer equal to 1;

p is an integer variable from 1 to 4;

And selected from one or more of the radicals X and/or Y;

X represents a methylene group, optionally substituted by one or two radicals With1-6-alkyl;

Y represents a radical With2-akinyan;

G represents a simple bond or an oxygen atom;

R1represents the radical R4substituted with one or more radicals R5and/or R6;

R4represents a radical selected from the radicals phenyl, naphthyl, isoxazolyl;

R5represents a halogen atom or a cyano, a radical C1-6-alkoxy, C1-6-foralkyl;

R6represents a phenyl group;

R2represents a hydrogen atom;

R3represents a hydrogen atom or a radical C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkyl;

a base, an acid additive salt, hydrate or MES.

4. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 3, comprising a stage consisting in linolite of ester carbamino acid of General formula (II)

where R1, R2, G, A, p and n are the same as those in General formula (I) according to claim 1, and R represents a methyl or ethyl group, an amine of General formula R3NH2in which the radical R3the same as specified in the General formula (I).

5. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 3, comprising a stage consisting in converting the amide carbamino acid of General formula (V)

where R2, R3and n are the same as those in General formula (I) according to claim 1, interaction with a derivative of General formula R1-G-[A]p-W (VI)in which R1, G, p and a are the same as those in General formula (I) according to claim 1, and W represents a chlorine atom, bromine or iodine, or mesilate or toilet.

6. The compound corresponding to General formula (II)

where R1, R2, G, R, m and n are the same as those in General formula (I) according to claim 1, and R represents a methyl or ethyl group.

7. The compound corresponding to General the th formula (V)

where R2, R3and n are the same as those in General formula (I) according to claim 1.

8. The compound of formula (I) according to any one of claims 1 to 3 in the form of a pharmaceutically acceptable base, an acid additive salt, hydrate or MES for its use as a medicinal product intended for the prevention or treatment of pathologies involving endogenous cannabinoids and/or any other substances, metabolisable enzyme FAAH.

9. Pharmaceutical composition containing at least one compound of formula (I) according to any one of claims 1 to 3 in the form of a pharmaceutically acceptable base, an acid additive salt, hydrate or MES, and optionally one or more pharmaceutically acceptable excipients intended for the prevention or treatment of pathologies involving endogenous cannabinoids and/or any other substances, metabolisable enzyme FAAH.

10. The use of the compounds of formula (I) according to any one of claims 1 to 3 in the form of a pharmaceutically acceptable base, an acid additive salt, hydrate or MES for obtaining a medicinal product intended for the prevention or treatment of pathologies involving endogenous cannabinoids and/or any other substances, metabolisable enzyme FAAH.

11. The use of compounds which ia of the formula (I) according to any one of claims 1 to 3 in the form of a pharmaceutically acceptable base, an acid additive salt, hydrate or MES for obtaining a medicinal product intended for the prevention or treatment of acute or chronic pain, dizziness, vomiting, nausea, difficulty eating, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular disease, renal ischemia, cancers, disorders of the immune system, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, eye diseases, pulmonary diseases, respiratory diseases, gastrointestinal diseases or inflammation of the bladder.



 

Same patents:

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

FIELD: medicine, pharmacology.

SUBSTANCE: medicine composition, possessing nootropic activity, represents 40% ethanolic extract of herb material, comprising grass of cottonweed, roots of Baikal scutellaria, sprouts of Pentaphylloides fruticosa, rhizome of officinal burnet, roots of deviating peony, fruits of rose, and grass of knotweed, cut to 1-3 mm pieces. The extraction is carried out at raw material to extragent proportion 1:10 and temperature 18-20°C.

EFFECT: medicine develops antiamnesic effect.

6 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine and pediatrics. The method consists of clinical examination of a child and carrying out of therapeutic procedures. There are determined abnormalities in immunologic state of main cell markers: total leukocyte count, lymphocytes CD3, CD4, CD4/CD8, CD19, classes A, M, G of antibodies levels; antibodies to chlamydia, HSV (herpes simplex virus), CMV (cytomegalovirus), toxoplasma, toxocaria, lamblia, opisthorchis. Drug dosage regimen for children under four years is as follows: polyoxidonium intranasal by 5 drops 30 minutes before meal once a day for 2 days, then 2 days break, the course total duration is 20 days; administration of succinic acid by 25 mg after meal in the morning and at noon for 5 days, then 2 days break. Children four to seven years proposed to take bronchomunal P by 3.5 mg before meal every morning for 1 month; succinic acid by 50 mg twice a day as above; and ribomunil by 75 mg before meal in the morning, during first month on 4 first days of each week, and during 2nd to 6th months on 4 first days of each month. Regimen for children seven to eleven years is as follows: cyclopheron 12.5% by 2 ml once a day on 1st, 2nd, 3rd, 4th, 6th, 8th, 11th, 14th, 17th, 21st, and 25th day, then once a week for 2 months; methyluracil by 50 mg after meal three times a day for 1 month; cod-liver oil with garlic by 1 dragee after meal three times a day for 10 days; and succinic acid by 75 mg twice a day as above. Regimen for children eleven to sixteen years is as follows: timaline by 0.01 g intramuscularly by 2 ml for 20 days; cod-liver oil with garlic by 2 dragee after meal three times a day for 10 days; biologically active additive "Karvipar" by 1 dessert-spoon three times a day for 2 weeks; and succinic acid by 100 mg twice a day as above. Immune state correction course is carried out in late autumn and in early spring, in other time polyvitamins are administered every month.

EFFECT: providing of health state stabilisation in ICP children, reducing any complications.

1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, particularly to drug preparation of deanol aceglumate. An injection drug formulation is proposed, containing ingredients as follows: deanol aceglumate, sugars (sorbitol, xylitol, and others), aminoacetic versene, optionally succinic acid, malic acid, and N-dimethylaminoethanol. It was demonstrated, that the injection drug formulation of deanol aceglumate shows neuroprotective action and can be applied to acute cerebral circulation injury, preventing from cerebral ischemia damage.

EFFECT: generation of stable and sterile injection drug formulation of deanol aceglumate, suitable for applying in diabetes cases.

3 cl, 4 ex, 2 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, particularly to drug substance - deanole aceglumate. Solid dosage drug formulation of deanole aceglumate is proposed, that is suitable for manufacturing of capsules and tablets; it contains ingredients as follows: 2-(dimethylamino)ethanol, N-acetyl-L-glutamic acid, cellulose derivatives, calcium carbonate, colloid silicon dioxide, starch, talcum, magnesium stearate, sweetener, aromatiser, and aminoacetic acid.

EFFECT: stable solid dosage drug formulation of deanole aceglumate is developed.

2 cl, 6 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns biochemistry, particularly biologically active peptides with stress-protection effect, which can be applied in medicine and pharmaceutics. The invention extends the range of safe substances stress resistance of an organism to include cyclopeptides I and II featuring the following aminoacid sequence: Cyclo(Gly1-Lys2-Val3-Leu4-Lys5-Lys6-Arg7-Arg8)n, where n = 2-3.

EFFECT: extension of the range of safe substances enhancing stress resistance of an organism.

5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new enantiomers of (+)-and(-)-trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indol and method of its obtaining. Being optical antipodes for each other, enantiomers exhibit different biological activity and can be applied as an active component in pharmaceutical compositions of nootropic and sedative action for treatment of different individual status of patients.

EFFECT: obtaining of the claimed compound.

1 ex, 5 tbl, 5 cl

FIELD: chemistry.

SUBSTANCE: invention concerns new enantiomers of (+)-and(-)-trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indol and method of its obtaining. Being optical antipodes for each other, enantiomers exhibit different biological activity and can be applied as an active component in pharmaceutical compositions of nootropic and sedative action for treatment of different individual status of patients.

EFFECT: obtaining of the claimed compound.

1 ex, 5 tbl, 5 cl

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: this invention concerns medical products, specifically application of oxcarbasepine which has particles of average size 2 to 12 mcm and maximal sieving remains through sieve aperture size 40 mcm not exceeding 5% for medical product applied for management, preventions or treatments of attacks for requiring patient. Besides, present invention concerns oral dosed form including oxcarbasepine with characteristics specified above, packed together with written instructions.

EFFECT: provided oxcarbasepine action regardless of meals.

10 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine and pediatrics. The method consists of clinical examination of a child and carrying out of therapeutic procedures. There are determined abnormalities in immunologic state of main cell markers: total leukocyte count, lymphocytes CD3, CD4, CD4/CD8, CD19, classes A, M, G of antibodies levels; antibodies to chlamydia, HSV (herpes simplex virus), CMV (cytomegalovirus), toxoplasma, toxocaria, lamblia, opisthorchis. Drug dosage regimen for children under four years is as follows: polyoxidonium intranasal by 5 drops 30 minutes before meal once a day for 2 days, then 2 days break, the course total duration is 20 days; administration of succinic acid by 25 mg after meal in the morning and at noon for 5 days, then 2 days break. Children four to seven years proposed to take bronchomunal P by 3.5 mg before meal every morning for 1 month; succinic acid by 50 mg twice a day as above; and ribomunil by 75 mg before meal in the morning, during first month on 4 first days of each week, and during 2nd to 6th months on 4 first days of each month. Regimen for children seven to eleven years is as follows: cyclopheron 12.5% by 2 ml once a day on 1st, 2nd, 3rd, 4th, 6th, 8th, 11th, 14th, 17th, 21st, and 25th day, then once a week for 2 months; methyluracil by 50 mg after meal three times a day for 1 month; cod-liver oil with garlic by 1 dragee after meal three times a day for 10 days; and succinic acid by 75 mg twice a day as above. Regimen for children eleven to sixteen years is as follows: timaline by 0.01 g intramuscularly by 2 ml for 20 days; cod-liver oil with garlic by 2 dragee after meal three times a day for 10 days; biologically active additive "Karvipar" by 1 dessert-spoon three times a day for 2 weeks; and succinic acid by 100 mg twice a day as above. Immune state correction course is carried out in late autumn and in early spring, in other time polyvitamins are administered every month.

EFFECT: providing of health state stabilisation in ICP children, reducing any complications.

1 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, in particular to ophthalmology. Patients with ablatio retinae in postoperational period are prescribed additionally polyoxidonium 0.006 g in 200 ml of haemodesum intravenously once a day, 5-day course, and cavinton 10 mg intravenously in dropper in 200 ml of isotonic solution of sodium chlorine once a day, 5-day course. Method allows for increasing vision acuity, increasing percentage of ablation retinae bearing, expanding field of vision, increasing light sensitivity of retina, to reducing number of relapses, improving indices of T-cell link of immunity, reducing terms of medications intake and reducing cost of treatment.

EFFECT: increase in vision acuity, expansion of field of vision, reduction of number of relapses, reduction of terms of medications intake and reduction of cost of treatment for patients with ablation retinae.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the new pyridine and new pyrimidine derivative, their pharmaceutically accepted salt or hydrate of the general formula (I): . The invention also relates to the pharmaceutical composition, which possesses the inhibiting activity with respect to the receptor of the growth factor of hepatocytes; to the inhibitor of the receptor of the growth factor of hepatocytes, the inhibitor of angiogenesis, the antitumor drug, the inhibitor of cancerous metastatic spreading, that contains the pharmacologically effective dose of the said compounds, its pharmaceutically acceptable salt or hydrate.

EFFECT: inhibitory activity.

27 cl, 45 tbl, 540 ex

FIELD: medicine.

SUBSTANCE: invention can be used for treatment of polypous rhinosinusitis. For this purpose medicine preparation "Longidasa" is applied as injections to polyp tissue dosed 3000 UN per procedure. Course of 5-10 procedures is performed every 5 days. Thus total dose makes 15000 to 30000 UN.

EFFECT: this therapy raises efficiency of non-surgical nose polyp treatment, and increases the disease remission period.

2 ex

FIELD: medicine.

SUBSTANCE: can be used as method of treatment of osteomyelitis and septic arthritis, caused by bacterial agents, including with plural medicinal resistance. For this purpose mammal is introduced with pharmacologically effective amount of tigecycline separately or in combination with ryphampycine antibiotic. This agent is also offered also for manufacturing of medical products for treatment of given diseases.

EFFECT: invention provides increased efficiency of bone, marrow and joints infection treatment to preferential tigecycline distribution through bone tissue, marrow and synovial fluid.

48 cl, 5 dwg, 11 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel piperazine derivatives with the general formula where R1 is benzofuranyl, inolyl or quinolinyl possibly substituted with one or more halogens; trifluoromethyl; -C1-6alkyl, possibly substituted with COOR15; -C1-6alkoxi, possibly substituted with COOR15; C1-6alkenyl; NR15R16; or C1-6alkylthio groups; and where R15 and R16 independently represent hydrogen, C1-6alkyl or C3-8cycloalkyl or can be condensed together with forming the 5-7-membered non-aromatic heterocyclic ring, possibly discontinued by the O or S atoms and possibly substituted with halogen, C1-6alkyl or -C1-6alkylC1-6alkoxi group; Z is the bind or CO; m is 0 or 2; n is 0; r is 0; p is 1; R3 is -(CH2)q-NR11R12, where q is 3; and NR11 R12 is a pirrolidinyl, piperidinyl, azepanyl or azokanyl, possibly substituted with one or more than one C1-6alkyl group; or their pharmaceutically acceptable salts. The pharmaceutical compositions based on the compounds I and their application in production of the pharmaceuticals, are described.

EFFECT: compounds can be used in treatment of neurodegenerative disorders including Alzheimer's disease.

10 cl, 503 ex

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