Method for preparing 3-azido-derivatives of rifamycin s

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

 

The present invention relates to the field of chemical technology of organic substances, and in particular to methods for the preparation of 3-Isidorovich rifamycin S with the properties of antibiotics.

3 azido-derivatives of rifamycin S are important intermediate products in the production of 3-amino-rifamycin S interest and as an independent antibacterial agents (antibacterial activity higher than that of rifamycin S) and as starting compound to obtain numerous semisynthetic analogues of rifamycin S, which are used, for example, as an effective anti-TB drugs.

3 azido-derivatives of rifamycin S are solid orange color, insoluble in water, soluble in most common organic solvents, especially good in halogenated hydrocarbons. The structure of these compounds may be represented by the General formula I:

where X=N3Y=Z=H or (CH3)2With< or (C6H5CH< or (C6H10<.

Closest to the claimed technical essence and the achieved result is a method of obtaining 3-azido-rifamycin S (X=N3Y=Z=H, Pat. U.S. No. 4007169, C 07 D 498/08, 1975, prototype), including the interaction of rifamycin S with azide is the atrium in the solvent by stirring the reactants at a temperature from 0C to 100C for at least 0.5 hour. As solvents which are especially suitable for carrying out this reaction, marked dimethylformamide, methylformamide, dimethylsulfoxide, pyrrolidone and other solvents belonging to the group of bipolar aprotic solvents. After the reaction the product emit using either preparative column chromatography or fractional crystallization. The yield of the target product is 21%.

The disadvantages of the known method of obtaining 3-azido-rifamycin S should be attributed, primarily, low product yield, and the use of highly toxic and expensive solvents. In addition, if the reaction is the formation of a significant number of by-products. It should also be noted that the solutions of rifamycin derivatives in solvents such as dimethylformamide represent an increased danger for workers in chemical plants due to the fact that the dimethylformamide greatly increases the permeability of cell membranes. The disadvantages also include the use of column chromatography for separation of the target product that requires special equipment and usage is quite expensive sorbents, and also creates the problem of recycling (regeneration) of the spent sorbent.

The objective of the proposed technical solution is what I've increased the efficiency of the method of obtaining 3-azido-derivatives of rifamycin S due to the increase of the yield of the target product and facilitate its excretion.

The task is achieved in that in the method of obtaining 3-azido-derivatives of rifamycin S formula I:

where X=N3Y=Z=H or (CH3)2With< or (C6H5CH< or (C6H10<involving the interaction of 3-halogenated derivatives of rifamycin S in the medium of the solvent, which is used as a simple aliphatic alcohols with carbon atoms of 1 to 5 or acetonitrile or a mixture of water and water-immiscible organic solvent selected from the range: ethyl acetate, methyl acetate, benzene or mono - or dimethyl analogues, chlorinated hydrocarbons with carbon atoms of 1 to 3, with salt, attestations acid, which use sodium azide or potassium azide, at a temperature from 0C to 100C for 0.5-2 hours, the target product is removed by extraction with water-immiscible organic solvent or by dilution of the reaction mixture with water followed by filtration. Below is a diagram of the process:

From the chemical literature it is known that the halogen atom in gelegenheden, which are 3-halogenated derivatives of rifamycin S, fairly agile and can be replaced with a suitable substitute.

We have found that the interaction of 3-halogenated derivatives of reefs is of CIN S with sodium azide or potassium azide, conducted in the present conditions, leads to the rapid formation of 3-azido-derivatives of rifamycin S with a high output, while the target connection does not require treatment and can be directly used for subsequent transformations.

The proposed solution is new, involves an inventive step and is industrially applicable.

The essence of the proposed method is illustrated by examples of its implementation.

Example 1.

In a glass reactor equipped with a thermometer and a stirrer, placed 1500 ml of ethanol and added with stirring to 77.5 g (0.1 mol) 21,23-isopropylidenebis derived - bromo-rifamycin S, obtained according to the method described in Belgium patent No. 893873, and then poured a solution of 9.7 g (0.15 mol) of sodium azide in 30 ml of water. Stirred the reaction mass at a temperature of 20C for 2 hours, after which it is diluted with 3000 ml of water, the resulting product is filtered, washed with water and dried. Get 21,23-isopropylidenebis derived 3-azido-rifamycin S.

Output 21,23-isopropylidenebis derived 3-azido-rifamycin S 71,6 g (92%).

Data CHN analysis: From 62.1, N, 6,1, N 7,15, C40H48N4O12.

IR-spectrum: 2165 cm-1that confirms the presence of azido group.

range PMR: there is no signal for the proton at C(3).

High-performance liquid chromatography (HPLC): d is Genin.

Example 2

In a glass reactor equipped with a thermometer and stirrer was placed 500 ml of ethyl acetate and added with stirring 73,0 g (0.1 mol) 3-chlorophenesin S, obtained according to the method described in German patent No. 2548128, and then poured the solution of 12.1 g (0.15 mol) of potassium azide in 100 ml of water. Stirred the reaction mass at a temperature of 20C for 2 hours, after which the product is extracted with ethyl acetate, the organic phase is washed with water, dried with anhydrous sodium sulfate and evaporated under vacuum.

Output 3-azido-rifamycin S and 63.4 g (86%).

Data CHN analysis: 60.4, H, 6,0, N To 7.61 With37H44N4O12.

IR-spectrum: 2170 cm-1'that confirms the presence of azido group.

range PMR: there is no signal for the proton at C(3).

High-performance liquid chromatography (HPLC): homogeneous.

Example 3

In a glass reactor equipped with a thermometer and stirrer was placed 1500 ml of ethanol and added with stirring 91 g (0.1 mol) 21,23-benzylidene derived 3-iodine-rifamycin S, obtained according to the method similar to that described in Belgium patent No. 893873, and then poured a solution of 9.7 g (0.15 mol) of sodium azide in 30 ml of water. Carrying out the reaction and isolation of the product is carried out as in example 1.

Output 21,23-benzylidene derived 3-azido-rifamycin S 73,4 g (89%).

Data CHN analysis: 14,15, N 5,94, N of 6.71, C44 H48N4O12.

IR-spectrum: 2168 cm-1that confirms the presence of azido group.

range PMR: there is no signal for the proton at C(3).

High-performance liquid chromatography (HPLC): homogeneous.

Example 4

Carry out the reaction as in example 1, with 85,5 g (0.1 mol) 21,23-cyclohexylidene derivative of 3-bromo-rifamycin S.

Output 21,23-cyclohexylidene derived 3-azido-rifamycin S 77 g (90%).

Data N analysis: From 63.1, N 6,47, N 6,79, C43H52N4O12.

IR-spectrum: 2172 cm-1that confirms the presence of azido group.

range PMR: there is no signal for the proton at C(3).

High-performance liquid chromatography (HPLC): homogeneous.

Similar to the preceding examples 1-4 were carried out in examples 5-7.

The process of obtaining derivatives of 3-azido-rifamycin S in examples 5-7 carried out analogously to example 1 and in examples 8-13 analogously to example 2. Reagents and process parameters listed in the table.

As can be seen from the table, the inventive method allows approximately 65% to increase the yield of the target product as compared with the method of the prototype. In addition, as shown by the results obtained by the reaction between 3-halogenated derivatives of rifamycin S sodium azide or potassium azide in a homogeneous or heterogeneous conditions, the target product is formed quickly in soft conditions is x and with high yield, that will allow you to minimize the formation of by-products and to obtain the target product of high quality.

Table
# exampleX*Y, Y*azideTemperature,Csolventthe product yield, %
1VG(CH3)2With<NaN320ethanol92
2CLNKP320the ethyl acetate86
3IWith6H5CH-NaN320ethanol89
4VGWith6H10<NaN320ethanol90
5VG(CH3)2With<NaN30methanol88
6VGWith6H5CH-NaN320propanol-187
7VG(CH3)2With< NaN360acetonitrile85
8VG(CH3)2With<NaN320chloroform89
9VG(CH3)2With<NaN320methylene chloride90
10VG(CH3)2With<NaN330the acetate92
11VG(CH3)2With<NaN320benzene85
12VG(CH3)2With<NaN330toluene87
13VG(CH3)2With<NaN360m-xylene84
the placeholderNNNaN30-100aprotic dipolar21
* General formula 3-halogen derivatives of rifamycin S

The method of obtaining 3-Isidorovich ri is amicin S formula I

where X=N3Y=Z=H or (CH3)2With< or (C6H5CH< or (C6H10<,

including the interaction of 3-halogenated derivatives of rifamycin S in the medium of the solvent, which is used as a simple aliphatic alcohols with carbon atoms of 1 to 5 or acetonitrile or a mixture of water and water-immiscible organic solvent selected from the range: ethyl acetate, methyl acetate, benzene or mono - or dimethyl analogues, chlorinated hydrocarbons with carbon atoms of 1 to 3, with salt, attestations acid, which use sodium azide or potassium azide, at a temperature of from 0 to 100C for 0.5 to 2 hours, and the extraction of the target product extraction of water-immiscible organic solvent or by dilution of the reaction mixture with water followed by filtering.



 

Same patents:

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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