Method for preparing 3-aminorifampicine-s (variants)

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 3-aminorifampicin-S representing semi-product in synthesis of anzamycine antibiotics, such as rifabutin - an anti-tuberculosis antibiotic with prolonged effect. Invention describes a method for preparing3-aminorifampicin-S that involves interaction of 3-bromorifampicin-S with hexamethylenetetramine in the amount 2-6-fold molar excess of hexamethylenetetramine with respect to 3-bromorifampicin-S at temperature 40-65°C in organic solvent medium and isolation of the end product. Trichloroethylene is used as a solvent in preparing 3-aminorifampicin-S followed by its change for butyl acetate by addition of butyl acetate to reaction mass in the amount 2-5-fold excess with respect to trichloroethylene volume followed by distilling off trichloroethylene. Prepared 3-aminorifampicin-S butyl acetate solution is filtered through aluminum oxide layer and 3-aminorifmapicin-S is isolated by evaporation until dry. Also, invention describes variant of method for preparing 3-aminorifampicin-S. Invention provides reducing reaction time in preparing the end product, reduced cost and simplified reaction, enhanced yield and purity of the end product.

EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

 

The invention relates to the chemistry of heterocyclic compounds, in particular to a method for C-aminoaniline-S - an intermediate in the synthesis of antibiotics asamisimasa series, such as rifabutin - TB antibiotic prolonged action.

Described is a method of obtaining 3-aminoaniline-S direct replacement of the hydrogen of the amino group. Reagent for such an introduction of an amino group are alkali metal azides. Subsequent thermal decomposition in the environment of formamide or pyrrolidone and rearrangement of 3-azidoaniline-S leads to the target connection. Selection 3-aminoaniline-S carried out by chromatographic separation on a column of silica gel or by fractional crystallization from 2-methoxyethanol. The result is a pure substance with a yield of about 20-30% (US 4007169 from 1977).

There are also known methods for the preparation of 3-aminoaniline-S substitution of halogen by amino group. The amino compounds of galoidoproizvodnykh get action on them of sodium nitrite in the environment dimethyl-formamide, followed by reduction of 3-nitroaniline-S to the target product. The ambiguity of the process in this case defines and complex purification of 3-aminoaniline-S. the Output does not exceed 20% (US 4217277 from 1980).

The prototype of the present invention is a method of obtaining a 3-aminoaniline-S(DE No. 2847427 from 1979) by acid hydrolysis of the Quaternary salts of 3-romafamilie-S with hexamethylenetetramine in an environment of chloroform. After the reaction the excess of hexamethylenetetramine is separated by filtration, washed several times with the reaction mass with water, dried with anhydrous sodium sulfate, evaporated to dryness and the residue is recrystallized from 2-methoxyethanol. Get the target connection with the release of 76%. In case of carrying out the process in tetrahydrofuran output is 50%.

The disadvantages of the above methods, including nearest analogue, is a significant process duration (8 hours), its technological complexity associated with multi-stage selection 3-aminoaniline-S from the reaction mass, the recrystallization of an expensive solvent, namely 2-methoxyethanol, low yield of the target product and the impossibility of its use in the subsequent stages of the synthesis of rifabutin without additional purification.

The technical result achieved by the present invention is the reduction of the reaction time for the preparation of 3-aminoaniline-S (twice in comparison with the prototype), the simplification and reduction reactions, increase the yield of the target product containing 3-aminoaniline-S to 94%, and achieving such a degree of purity, in which the quality of the resulting 3-aminoaniline-S allows you to use it without additional purification in the subsequent stages of the synthesis of rifabutin.

Specified technology the economic result is achieved by 3 bromoethanol-S enter into interaction with hexamethylenetetramine in the number of two-to sixfold molar excess of hexamethylenetetramine in relation to 3-romafamilie-S, at a temperature of from 40 to 65°in the medium of organic solvent, with the solvent used trichloroethylene or ethyl acetate, are replacing trichloroethylene or ethyl acetate in butyl acetate by addition of butyl acetate to the reaction mass in an amount of twice the surplus to the five-fold excess relative to the amount of trichloroethylene or ethyl acetate, after which produce a distillation of trichloroethylene or ethyl acetate, filtered received butylacetate a solution of 3-aminoaniline-S through the layer of aluminum oxide and produce 3-aminobiphenyl-S by evaporation to dryness.

The invention is illustrated by the following examples.

Example No. 1. 10 g of 3-romafamilie-S and 6 g of hexamethylenetetramine is placed in a flask, poured 50 ml of trichloroethylene and with stirring, heated to 60°C. after 3 hours the reaction medium was added butyl acetate in the amount of 150 ml (ratio of trichloroethylene and butyl acetate 1:3), remove trichloroethylene by distillation, excess of hexamethylenetetramine and ammonium bromide is separated by filtration. The obtained filtrate is washed several times with water, filtered through a layer is aluminum oxide and evaporated to dryness. The weight of the obtained 3-aminoaniline-S is 8.2 g (yield 89%) with a basic substance content of 95% (HPLC).

Example No. 2. 10 g of 3-romafamilie-S and 5 g of hexamethylenetetramine is placed in a flask, poured 50 ml of ethyl acetate and heated with stirring to 60°C. after 3 hours the reaction medium was added butyl acetate in the amount of 150 ml (ratio of ethyl acetate and butyl acetate 1:3), remove the ethyl acetate by distillation, excess of hexamethylenetetramine and ammonium bromide is separated by filtration. The obtained filtrate is washed several times with water, filtered through a layer of aluminum oxide and evaporated to dryness. The weight of the obtained 3-aminoaniline-S is 8.1 g (yield 86%) with a basic substance content 93% (HPLC).

Example No. 3. 10 g of 3-romafamilie-S and 6 g of hexamethylenetetramine is placed in a flask, poured 50 ml of trichloroethylene and with stirring, heated to 60°C. after 3 hours to the reaction medium was added butyl acetate in the amount of 100 ml (ratio of trichloroethylene and butyl acetate 1:2), remove trichloroethylene by distillation, excess of hexamethylenetetramine and ammonium bromide is separated by filtration. The obtained filtrate is washed several times with water and filtered through a layer of aluminum oxide and evaporated to dryness. The weight of the obtained 3-aminoaniline-S is 7.2 g (yield 75%) with the content of the main exhibits is and 92% (HPLC).

Example No. 4. 10 g of 3-romafamilie-S and 5 g of hexamethylenetetramine is placed in a flask, poured 50 ml of ethyl acetate and heated with stirring to 60°C. after 3 hours the reaction medium was added butyl acetate in the amount of 100 ml (ratio of ethyl acetate and butyl acetate 1:2), removing the ethyl acetate by distillation, excess of hexamethylenetetramine and ammonium bromide is separated by filtration. The obtained filtrate is washed several times with water, filtered through a layer of aluminum oxide and evaporated to dryness. The weight of the obtained 3-aminoaniline-S is 7.1 g (yield 76%) with a basic substance content 93% (HPLC).

Examples No. 5-12, are shown in table 1, illustrate the 3 aminoaniline-S using as solvent trichloethylene in example 1 with the changes in the following parameters:

T - temperature of the reaction mixture;

t - heating time, h;

m is the ratio of trichloroethylene and butyl acetate.

Table No. 1
No.T °t, hmProduct weight g /Exit from theory, %The content in the main Islands, %
5553.51/48,3/9095
665 1/47,1/7293
7454.51/48,2/8895
8406.01/48,1/8695
9604.01/58,0/8894
10504.01/58,3/9095
11454.01/57,9/8595
12404.01/57,6/8295

Examples 13-20 shown in table 2, illustrate the 3 aminoaniline-S using as solvent of ethyl acetate according to example 2 with the changes in the following parameters:

T - temperature of the reaction mixture;

t - heating time, h;

m is the ratio of ethyl acetate and butyl acetate.

Table No. 2
No.T °t, hmProduct weight g /Exit from theory, %The content in the main Islands, %
13554.51/47,3/79 94
14653.51/47,1/7693
15455.01/47,2/7894
16406.01/47,1/7694
17604.01/57,0/7794
18505.01/57,3/7995
19456.01/56,9/7595
20406.01/56,6/7195

1. The method of obtaining 3-aminoaniline-S, including the interaction of 3-romafamilie-S with hexamethylenetetramine in the number of two-to sixfold molar excess of hexamethylenetetramine in relation to 3-romafamilie-S, at a temperature of 40-65°in the medium of organic solvent, and isolation of the target product, wherein when receiving a 3-aminoaniline-S as solvent using trichloroethylene, and then perform a replacement on butyl acetate by addition of butyl acetate to the reaction mass in an amount of twice the excess to pyatibrat the th excess in relation to the volume of trichloroethylene, then produce the Stripping of trichloroethylene, filtered received butylacetate a solution of 3-aminoaniline-S through the layer of aluminum oxide and produce 3-aminobiphenyl-S by evaporation to dryness.

2. The method of obtaining 3-aminoaniline-S, including the interaction of 3-romafamilie-S with hexamethylenetetramine in the number of two-to sixfold molar excess of hexamethylenetetramine in relation to 3-romafamilie-S, at a temperature of 40-65°in the medium of organic solvent, and isolation of the target product, wherein when receiving a 3-aminoaniline-S as the solvent used ethyl acetate, and then perform a replacement on butyl acetate by addition of butyl acetate to the reaction mass in an amount of twice the surplus to the five-fold excess relative to the amount of ethyl acetate, after which produce a distillation ethyl acetate, filtered received butylacetate a solution of 3-aminoaniline-S through the layer of aluminum oxide and produce 3-aminobiphenyl-S by evaporation to dryness.



 

Same patents:

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to methods for preparing derivatives of 3-aazidorifamycin S eliciting antibiotic properties. Method for preparing 3-azido-derivatives of rifamycin S involves interaction rifamycin S derivative with hydrazoic acid salt in solvent medium by stirring reagents at temperature from 0oC to 100oC for 0.5-2 h followed by extraction of the end product. 3-Halogen-derivative of rifamycin S is used as rifamycin S derivative. Simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 is used as a solvent. Sodium azide or potassium azide is used as hydrazoilc acid salt. Extraction of the end product is carried out by extraction with solvent not mixing with water or by dilution of reaction mixture with water followed by filtration. The claimed method provides enhancing the yield of the end product by 63-71% and to simplify the process of it isolating. Invention provides the enhancement of effectiveness of method for preparing 3-azido-derivatives of rifamycin S due to elevating yield of the end product and simplifying the process of its isolating.

EFFECT: improved preparing method.

1 tbl, 13 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

The invention relates to new compounds rifamitinov series formula:

< / BR>
A new connection can be used as an antibacterial and antituberculosis drug

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-aminorifamycin S of the formula (I) , eliciting antibiotic properties wherein X means NH2; Y = Z and mean hydrogen atom (H) or (CH3)2C<, or C6H5CH<, or C6H10<. Method for preparing 3-amino-derivatives of rifamycin S involves stirring 3-halogen-derivative of rifamycin S in solvent medium wherein solvent represents simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the following series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 with hydrazoic acid salt wherein sodium azide is used and stirring is carried out for 0.5-2 h. Then method involves the following conversion of obtained 30azido-derivative of rifamycin S to the end product using a reducing agent wherein mixture of zinc or iron with acetic acid is used, or hydrogen in the presence of palladium catalyst followed by treatment with oxidizing agent wherein ferric (III) chloride or manganese (IV) oxide is used, or hydrogen peroxide, or persulfates, or air. Extraction of the end product is carried out by extraction with organic solvent not mixing with water or by dilution of reaction mixture with water followed by crystallization of product. Invention provides the enhancement of method for preparing 3-amino-derivatives of rifamycin S due to elevating yield of the end product and process for it isolating.

EFFECT: improved preparing method.

1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, antibiotics.

SUBSTANCE: invention relates to methods for preparing derivatives of 3-aazidorifamycin S eliciting antibiotic properties. Method for preparing 3-azido-derivatives of rifamycin S involves interaction rifamycin S derivative with hydrazoic acid salt in solvent medium by stirring reagents at temperature from 0oC to 100oC for 0.5-2 h followed by extraction of the end product. 3-Halogen-derivative of rifamycin S is used as rifamycin S derivative. Simple aliphatic alcohols with carbon atom number from 1 to 5 or acetonitrile, or mixture of water and organic solvent not mixing with water taken among the series: ethyl acetate, methyl acetate, benzene or its mono- or dimethyl analogues, chlorinated hydrocarbons with carbon atom number from 1 to 3 is used as a solvent. Sodium azide or potassium azide is used as hydrazoilc acid salt. Extraction of the end product is carried out by extraction with solvent not mixing with water or by dilution of reaction mixture with water followed by filtration. The claimed method provides enhancing the yield of the end product by 63-71% and to simplify the process of it isolating. Invention provides the enhancement of effectiveness of method for preparing 3-azido-derivatives of rifamycin S due to elevating yield of the end product and simplifying the process of its isolating.

EFFECT: improved preparing method.

1 tbl, 13 ex

FIELD: organic chemistry, antibiotics, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing 3-aminorifampicin-S representing semi-product in synthesis of anzamycine antibiotics, such as rifabutin - an anti-tuberculosis antibiotic with prolonged effect. Invention describes a method for preparing3-aminorifampicin-S that involves interaction of 3-bromorifampicin-S with hexamethylenetetramine in the amount 2-6-fold molar excess of hexamethylenetetramine with respect to 3-bromorifampicin-S at temperature 40-65°C in organic solvent medium and isolation of the end product. Trichloroethylene is used as a solvent in preparing 3-aminorifampicin-S followed by its change for butyl acetate by addition of butyl acetate to reaction mass in the amount 2-5-fold excess with respect to trichloroethylene volume followed by distilling off trichloroethylene. Prepared 3-aminorifampicin-S butyl acetate solution is filtered through aluminum oxide layer and 3-aminorifmapicin-S is isolated by evaporation until dry. Also, invention describes variant of method for preparing 3-aminorifampicin-S. Invention provides reducing reaction time in preparing the end product, reduced cost and simplified reaction, enhanced yield and purity of the end product.

EFFECT: improved method for preparing.

2 cl, 2 tbl, 20 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new layers of acidic compounds with Formula I , where R2 is C1-6alkyl (possibly substituted and/or ending with one or more substitute, chosen from -OH, halogen, cyano, nitro and aryl) or aryl, where each aryl group, if not specifically mentioned, is possibly substituted by one or more substitutes, including -OH, cyano, halogen, nitro, C1-6alkyl, C1-6alkoxy, -N(R14a)R14b, -C(O)R14c, -C(O)OR14d, -C(O)N(R14e)R14f, -N(R14g)C(O)R14h, -N(R14m)S(O)2R13b, -S(O)2Rl3c and/or -OS(O)2R13d, where radicals from R13b to Rl3d independently represent C1-6alkyl; R14a and R14b independently represent H, C1-6alkyl, or jointly represent C3-6alkene, as a result, yielding a four-heptatomic nitrogen containing ring; radicals from R14c to R14m independently represent H or C1-6alkyl; A represents , where R16 represents unsubstituted C1-4alkyl, C1-4perfluoroalyl or phenyl, where the last group can be substituted with one or more substitutes, chosen from C1-6alkyl, halogen, nitro and C1-6alkoxy. The invention also relates to the method of obtaining Formula II compounds.

EFFECT: obtaining of new intermediate compounds and their use in special obtaining of formula II oxabispidin compounds, which can be used in the treatment of cardiac arrhythmia.

8 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to a compound with general formula where R' stands for phenyl, unsubstituted or substituted with one or more substitutes, chosen from a group comprising alkyl, alkoxy group, halogen, -(CH2)oOH, -C(O)H, CF3, CN, S-alkyl, -S(O)1,2-alkyl, -C(O)NR'R", -NR'R"; R2 and R3 independently stand for hydrogen, halogen, alkyl, alkoxy group, OCHF2, OCH2F, OCF3 or CF3 and R4 and R5 independently stand for hydrogen, -(CH2)2SCH3, -(CH2)2S(O)2CH3, -(CH2)2S(O)2NHCH3, -(CH2)2NH2, -(CH2)2NHS(O)2CH3 or -(CH2)2NHC(O)CH3, R' stands for hydrogen, alkyl, -(CH2)oOH, -S(O)2- alkyl, -S(O)-alkyl, -S-alkyl; R" stands for hydrogen or alkyl; o stands for 0, 1, 2 or 3. The invention also relates to use of formula I compounds in making medicinal preparations for treating schizophrenia, for treating positive and negative symptoms of schizophrenia and medicine for treating schizophrenia.

EFFECT: obtaining new compounds with useful biological properties.

55 cl, 421 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: invention relate to oxabispidinic compounds of formula I, ,where R1 is C1-12alkyl (where the given alky group is substituted with a group selected from phenyl, Het1, N(R5a)R6, -OR5c, -S(O)2N(R9b)R9c and -N(R9b)S(O)2R9d); R5a is H; R5c is C1-6alkyl (which is substituted with phenol) or phenyl; R6 is H or -C(O)OR10b; R10b is C1-6alkyl; R9b in each case where it is used in the given description of the invention represents H or C1-6alkyl; R9c and R9d in each case it is used in the given description of the invention independently presents C1-6alkyl (possibly substituted with one or more substitutes, selected from halogen or phenyl), phenyl or Het7, or R9c is H; R2 is H or OR13; R3 is H; R13 is H; Het1 and Het7 independently represent 5-12-member heterocyclic groups containing one or more heteroatoms, selected from oxygen and nitrogen, where these groups are possibly substituted with one or more substitutes selected from halogen and C1-6alkyl; A is a direct bond, -J-, J-S(O)2N(R19b)- or -J-N(R19c)S(O)2- (where in the last two groups -J is bonded to the nitrogen of an oxabispidinic ring); B is Z-{[C(O)]aC(H)(R20a)}b-, -Z-[C(O)]cN(R20b)-, -Z-N(R20c)S(O)2-, -Z-S(O)2N(R20d)-, -Z-S(O)n-, -Z-O- (where in the last six groups Z is bonded to a carbon atom, carrying R2 and R3), -N(R20e)-Z-, -N(R20f)S(O)2-Z-, -S(O)2N(R20g)-Z- or -N(R20h)C(O)O-Z- (where in the last four groups Z is bonded to a phenyl group which is possibly substituted with a R4 group); J is C1-6alkylene, possibly broken by a -S(O)2N(R19d)- or -N(R19e)S(O)2- group and/or possibly substituted with a substitute selected form -OH; Z is a direct bond or C1-4alkylene, possibly broken by a -N(R20i)S(O)2- or -S(O)2N(R20j)- group; a, b and c possibly represent 0 or 1; n is 0, 1 or 2; R19b-R19e in each case where used in the given description of the invention independently represents H or C1-6alkyl; R20a is H or together with the only substitute R4 on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, represents C2-4alkylene, possibly broken or ending with O, N(H) or N(C1-6alkyl) group; R20b is H or C1-6alkyl; R20c-R20j in each case when used in the given description of the invention independently represents H or C1-6alkyl; or R20g and R20i independently represent C1-6alkyl, substituted with 3,5-dimethylisoxazolyl; G is CH; R4 is one or more possible substitutes selected from cyano, halogen, C1-4alkyl and C1-6alkoxy, possibly substituted with one or more hanogen and a R4 substitute on the position of the phenyl group, which is an ortho-position relative the position where group B is bonded, together with R20a can represent C2-4alkylene; broken or ending with O or N(H) or a N(C1-6alkyl) group; R41-R46 independently represent H; where each phenyl group is possibly substituted with one or more substitutes selected from halogen, cyano, C1-6alkyl and C1-6alkoxy (where the last two groups are possibly substituted with one or more halogen atoms); or to their pharmaceutically acceptable salts. The invention also relates to methods of producing said compounds, as well as to a pharmaceutical composition based on said compounds, with HERG-channel blocking activity.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for preventing and treating arrhythmia, particularly cardiac and ventricular arrhythmia.

32 cl, 1 tbl, 15 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula (I) or their pharmaceutically acceptable salts, where symbols assume values given in the description, where the said compounds are chemokine receptor (CCR-1) antagonists. Also described is a method of inhibiting the chemokine receptor to reduce inflammation in mammals.

EFFECT: possibility of use in treating inflammatory diseases.

8 cl, 160 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel intermediate compounds - methyl 7-aryl-4,9-diaroyl-3-hydroxy-1-(2-hydroxyphenyl)-2,6-dioxo-1,7-diazaspiro[4.4]none-3,8-diene-8-carboxylates of formula III Ar1=Ar2=Ph, Ar3=C6H4Me-n (IIIa); and Ar1=C6H4Br-n, Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IIIb), for synthesis of methyl 6,9-diaryl-11-aroyl-2-(o-hydroxyphenyl)-3,4,10-trioxo-7-oxa-2,9-diazatricyclo[6.2.1.01,5]undec-6-ene-8-carboxylates of formula IV where Ar1=Ar2=Ph, Ar3=C6H4Me-n (IVa); Ar1=C6H4Br-n Ar2=C6H4OEt-n, Ar3=C6H4Me-n (IVb), which exhibit antimicrobial activity and are used as precursors for synthesis of novel heterocyclic systems, and a method for synthesis of said compounds.

EFFECT: compounds have high effectiveness.

5 cl, 1 tbl, 5 ex

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