Bicyclic complexes of beta-lactam/ hydroxybenzoic acid, methods of obtaining beta-lactams

 

(57) Abstract:

The invention relates to new cephalosporins and complexes arbocatalogi/para-aminobenzoic acid, methods of their production and in particular the isolation and purification of antibiotics containing the beta-lactam ring. Describes complexes of the formula (V), where X is chlorine, hydrogen, vinyl, or-CH3; Z - CH2,S or O; n = 0-5; Y is phenyl or 1,4-cyclohexadiene-1-yl; R1and R2is hydrogen or a hydroxy-group, provided that both (R1and R2are not hydrogen; R3- -COOH, -COO(C1-C4-alkyl), or

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where R4- C1-C4-alkyl. 3 S. and 3 C.p. f-crystals, 1 PL.

The invention relates to new cephalosporins and complexes arbocatalogi/4-hydroxybenzoic acid, and methods of their application and in particular the isolation and purification of antibiotics containing the beta-lactam ring.

Cefaclor, cephalexin, cefradine, loracarbef have the structure shown below:

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Four-lactam compounds, in which the asymmetric centers at C-2'-position have an absolute R-configuration, are commercially important oral antibiotics.

In different the ke patent 0341991, published November 15, 1989.

In the specified EPO application demonstrates the use of anthraquinone-1,5-disulfonic acid to obtain pharmaceutically acceptable salts, in particular of a cephalosporin or carbazepine, which allows regeneration-lactam from the mother solution after crystallization.

Since the production of these antibiotics is expensive, constantly are searching for new more sophisticated methods such regeneration to maximize the total yield of product.

Found that commercially important antibiotics cephalexin, cefaclor, cefradine, loracarbef form crystalline complexes with 4-hydroxybenzoic acid and related compounds. The present invention relates to complexes with the following formula:

< / BR>
where X is chlorine, vinyl or-CH3;

Z - CH2, S, or O;

n = 0 - 5;

Y is phenyl or 1,4-cyclohexadiene-1-yl;

R1and R2is hydrogen or a hydroxyl group provided that both R1and R2are not hydrogen;

R3- CO2H, -COO(C1-C4-alkyl), or

< / BR>
where R4- C1-C4-alkyl.

Further, the invention describes the receipt of the criminal code of the Xia to describe only the solid phase, the resulting combination of antibiotic and 4-hydroxybenzoic acid or related compounds.

The preferred complexes of the present invention are cefradine methylparaben H2Oh, cefaclor methylparaben 3H2O, cefaclor of ethylparaben, 2 cefaclor 4-hydroxybenzoic acid 4H2O, cefaclor methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O, cefaclor 4-hydroxyacetophenone, cefaclor 3 - hydroxyacetophenone, cephalexin methylparaben H2O, cephalexin of ethylparaben 2H2O, cephalexin methyl ester of 3-hydroxybenzoic acid (0.1 or 5) H2O, cephalexin 3-hydroxyacetophenone; loracarbef methylparaben, loracarbef ethylparaben, loracarbef propylparaben; loracarbef methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O, loracarbef 4-hydroxyacetophenone or loracarbef 3-hydroxyacetophenone.

Method of acquisition and allocation of complexes cefalexina, cefaclor, cefradine and loracarbef with 4-hydroxybenzoic acid or related compounds is quite simple. Aqueous or substantially aqueous solutions or suspensions-lactam and antibiotic or related compounds are mixed, and further components leave for education Krista acid or related compound in an amount of from 1 to 3 parts, 1 part used-lactam.

In each case, the formation of complexes is confirmed by their characteristic powder x-ray, which differs from previously published powder x-ray cephalexin (L. P. Marelli, Analytical Profiles of Drug Substances, 4, pp. 21-46 (1975)); cefradine (K. Florey, Analytical Profiles of Drug Substances, 5, pp. 21-59 (1976)); cefaclor (L. S. Lorens, Analytical Profiles of Drug Subctances, 9, pp. 107-123 (1980)); monohydrate loracarbef (Pasini, European patent application EP 0311366 A1, published 12 April 1989) and dihydrate loracarbef (Eckrich et A1. European patent application 0369686 A1, published may 23, 1990); and methyl-, ethyl - and propylphosphonic 4-hydroxybenzoic acid, methyl-3-oxybenzoates and acetophenone.

In our studies, neither the cephalo-Smoking, no arilpirolului penicillins, amoxicillin and ampicillin did not form appreciable amounts of sekretarev with methyl - or preprocessing acid.

Crystalline complexes-lactams 4-hydroxybenzoic acid and related compounds can be used in the processes of regeneration, separation and/or purification of the lactam. The complexes can be used for deposition-lactam from dilute solutions (e.g., from mother solutions or reaction solutions). The complexes can be widely in the system, comprising an organic solvent, acid or water.

Suitable for this purpose, the acid can be, for example, hydrochloric, sulphuric and Hydrobromic acid.

Suitable solvents include ethanol, n-butanol, methylisobutylketone, diethyl ether, diisopropyl ether, ethyl acetate, methylene chloride, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and aqueous solutions.

-lactam stands out from the resulting solution by raising the pH by adding a base to precipitate-lactam, whereas 4-hydroxybenzoic acid and related compounds remain in solution. Suitable for this reason are also known and include ammonium hydroxide, sodium hydroxide and triethylamine.

Selection-lactam can be carried out in the temperature range from 0 to 50oC. alternatively, the complexes can be dissolved in a predominantly organic solvent or in a system containing an organic solvent, alkali and water, and-lactam in this case precipitated at lower pH by adding acid.

In any case-lactam can be separated by filtering and then be used in the form in which it received or may be converted to another over the

The table presents data on powder x-ray (x ray powder patterns) products described in examples 1-5, where d is the interplanar distance, measured in angstroms, and "I/I0" indicates the relative intensity.

Example 1. Cephalexin methylparaben H2O.

Methylparaben (375 mg, 2.5 mmol) in 150 ml of water is added to the monohydrate cephalexin (2.4 g, 6 mmol) to obtain a suspension. After keeping the suspension at a temperature of 5oC for 5 days, the crystals are separated by filtration and washed with water, forming 1.06 g of the complex (2.0 mmol) with a melting point 168-169oC.

Calculated (%) C24H25N3O7S H2O: 55,70; H - 5,26; N - 8,12.

Found: 55,65; H Is 5.28; N - 8,13.

HPLC (calculation) found: (67,1), 67.1 per cent for cephalexin, (29,4), or 28.7% of methylparaben.

KF (calculation) found: (3,5) 4,0% water.

Example 2. Cefradine methylparaben H2O.

Methylparaben (250 mg, 1.6 mmol) in 100 ml of water is added to the monohydrate cefradine (1.6 g, 4.4 mmol) to obtain a suspension. After keeping the suspension for 3 days at a temperature of 25oC crystals are separated by filtration and washed with water to obtain Chicano % for C24H27N3O7S H2O: 55,48; H - 5,63; N - 8,09.

Found: C - 55,58; H - To 5.57; N - 8,08.

HPLC (calculation) found: (67,2), 67,7% for cefradine, (29,3), 28.9 percent for methylparaben.

KF (calculation) found: (3,5), 3.7% of water.

Example 3. Cefaclor methylparaben 3H2O.

Methylparaben (250 mg, 1.6 mmol) in 100 ml of water is added to the monohydrate cefaclor (1.3 g, 3.4 mmol) to form a suspension. After keeping the suspension for 5 days at a temperature of 5oC crystals are separated by filtration and washed with water with the formation of a complex containing 3 mol of water of crystallization, the melting temperature of the complex: 142oC (Razlog).

Calculated (%) C23H22ClN3O7S 3H3O: 48,13; H TO 4.92; N - 7,32.

Found: 48,01; H To 4.92; N - 6,99.

HPLC (calculation) found: (64,1), 65,0% for cefaclor, (26,5), and 25.4% for methylparaben.

KF (calculation) found: (9,4), 9.9% of water.

Example 4. Loracarbef methylparaben.

Methylparaben (460 mg, 3.0 mmol) in 230 ml of water is added to the monohydrate cefaclor (3.0 g, 8.2 mmol) to form a suspension. After keeping the suspension at a temperature of 25oC for 25 days, the crystals are separated by filtration, about the LASS="ptx2">

Calculated for C24H24ClN3O7(in %): 57,44; H - 4,82; N - of 8.37.

Found: 57,16; H To 4.92; N - 8,59.

HPLC (calculation) found: (69,7), 70,6% for loracarbef, (30,3), and 30.0% for methylparaben.

Example 5. Loracarbef propylparaben.

Propylparaben (500 mg, 2.8 mmol) in 500 ml of water is added to the monohydrate loracarbef (5.5 g, 14.9 mmol) to form a suspension. After keeping the suspension for 20 days at 5oC crystals are separated by filtration and washed with water; the results of 1.31 g (2.5 mmol) of the complex, melting point 178oC (decomposition).

Calculated (%) C26H28ClN3O7: TO 58.9; H - 5,32; N - 7,93.

Found; C - 58,69; H - 5,31; N - Of 7.90.

HPLC (calculation) found: (66,0), 64,31% for loracarbef, (34,0), 33,3% of propyl paraben.

Example 6. Loracarbef ethylparaben.

the pH of the aqueous mother liquor monohydrate loracarbef (1000 ml containing 9,23 mg/ml monohydrate loracarbef) was adjusted with HCl to 3.6. Ethyl-p-hydroxybenzoate (ethylparaben) (4.52 g) in ethanol (36 ml) is added dropwise within 15 minutes. After about 5 minutes of beginning the process of deposition, leading eventually to the formation of white crystals. Mix peremesite at 40oC. Obtained 11,72 g of product containing 73,5% loracarbef, theoretical output loracarbef - 8,78 g, output, therefore, is to 98.2%. The following characteristics of the powder x-ray complex loracarbef : ethylparaben:

d - I/I0< / BR>
12.03778 - 100.0

10.51978 - 2.7

8.87879 - 28.6

7.24748 - 4.0

6.04328 - 1.6

5.77434 - 39.3

5.27012 - 2.9

4.95456 - 3.6

4.80014 - 0.6

4.60833 - 2.7

4.50920 - 2.6

4.03255 - 38.1

3.57845 - 38.9

3.54171 - 4.3

3.35279 - 22.4

3.20988 - 1.4

3.16843 - 0.7

3.02715 - 4.6

2.89099 - 3.9

2.83791 - 0.5

2.80444 - 1.0

2.76760 - 1.9

2.69465 - 1.5

2.62614 - 1.6

Example 7. Loracarbef methyl-3-hydroxybenzoate 5H2O.

Methyl-3-hydroxybenzoate (496 mg, 3.3 mmol) in 3 ml of 95% EtOH is added to the monohydrate loracarbef (1.2 g, 3.3 mmol) in 200 ml of water. After keeping the mixture at 25oC for 19 days, the crystals are separated by filtration, washed with water, thus receive 576 mg (0.97 mmol) of the complex.

Calculated (%) C24H24ClN3O75 H2O: 48,69; H - 5,79; N - 7,10.

Found: 48,84; H - 5,56; N - 7.23 Percent.

Example 8. Loracarbef methylparaben.

The ethylate loracarbef (2.55 g, 74.7 per cent of the contents loracarbef) are suspended in 100 ml of water. NaOH (1N, 1.08 ml) dobut methyl-p-hydroxybenzoate (methylparaben) (0,83 g) in 7 ml of ethanol, in several minutes the pH falls to a value of 8.1.

The mixture becomes cloudy due to the beginning of the deposition process. The mixture is stirred at room temperature for 2 hours, filtered, washed with water and dried in vacuum at 40oC during the night.

The estimated output is complex 2.83 g, obtained 1.92 g, representing 67.8% of theoretically expected.

Example 9. Loracarbef butylparaben.

The ethylate loracarbef (2.55 g, 74.6% of the content loracarbef) is added to 100 ml of water. the pH is brought to 8.4 with NaOH (1N, 1.08 ml). After stirring for 30 minutes at room temperature the solution becomes almost transparent. Butyl-p-hydroxybenzoate (butylparaben) (1.06 g) in 7 ml of ethanol is added to the mixture. The mixture is stirred for several hours at room temperature, filtered, washed with water and dried in vacuum at 40oC. Target product is white.

The estimated output of the complex is a 3.06 g, obtained 1,78, which is 58.2% from theoretically expected output.

Example 10. Loracarbef ethylparaben.

The ethylate loracarbef (2.55 g, 74.7 per cent of the contents loracarbef) are suspended in 100 ml of water. It is oxybenzoic (0,90 g, 5,44 mmol) in 7 ml of ethanol is added to the mixture, and in a few minutes formed a thick precipitate. pH is 9,95. The mixture is stirred for several hours at room temperature, filtered, washed with water and dried in vacuum at 40oC.

The estimated output of the complex is 2.90 g, obtained 2,08 g, output is 71,7%.

Example 11. Loracarbef propylparaben.

The ethylate loracarbef (2.55 g, 74.7 per cent of the contents loracarbef) are suspended in 100 ml of water. Add NaOH (1N, 1.08 ml), and pH becomes of 7.2. Next, add 1N NaOH to raise the pH to 8.2.

Propyl-p-hydroxybenzoate (0,90 g, 5,44 mmol) in 7 ml of ethanol is added to the mixture, and then immediately starts to fall a white solid precipitate. The mixture is stirred at room temperature for several hours. The mixture is then filtered, washed with water and dried in vacuum at 40oC.

the pH of the filtrate is lowered to 4.9, but the additional sediment is not observed.

The estimated output of the complex is 2,98 g, obtained from 0.90 g, and the output is 30.2%.

Example 12. Loracarbef ethylparaben.

The acylation reaction is carried out in accordance with U.S. patent 4,dnow phase is then filtered. Ethylparaben (3,82 g) dissolved in 3 ml of ethanol and added to aqueous solution containing to 4.23 g loracarbef in the form of a monohydrate.

The solution starts the crystallization process, reduce pH to 4.3 with hydrochloric acid. The mixture is stirred for several hours at room temperature. The mixture is cooled overnight in the refrigerator, filtered, washed with water and dried in vacuum at 45oC. the Estimated output for loracarbef is 3,99 g obtained of 8.37 g of the product with the content loracarbef 39%, so the output is 81,2%.

Example 13. Loracarbef ethylparaben.

Ethylparaben dissolved in 30 ml of ethanol and added to aqueous solution of the monohydrate loracarbef (3.88 g, 10,55 mm). the pH of the suspension is reduced to 3.5 with hydrochloric acid and leave it for stirring for several hours at room temperature. The suspension is cooled at 5oC for several hours, filtered and dried in vacuum at 55oC.

The calculated output is at 3.69 g, obtained 6,35 g of the product with the content loracarbef equal to 55.3 per cent, while the output is 95,1%.

Example 14. Desolat loracarbef DMF.

To the mixture laragy acid to obtain a clear solution. the pH of the solution is slowly increased to a value of 6.9 using triethylamine, with the rapid crystallization of the desired product. The mixture is stirred for 1 hour at room temperature, filtered, washed with a solution containing DMF: H2O/10:1, and dried in vacuum at 40oC.

HPLC shows no ethylparaben.

The estimated output in relation loracarbef is 0.87 g, obtained 1.01 g of product with content loracarbef equal to 73,9%, output is 85,3%.

Example 15. Desolat loracarbef DMF.

To a mixture of loracarbef ethylparaben (15.0 g, 49.1% of the content loracarbef) in a solvent containing 150 ml of DMF and 15 ml of water is added dropwise concentrated hydrochloric acid (2,53 ml). The solution is heated to 45oC and then with triethylamine raise the pH of 1.84 to 4.0 within 45 minutes.

After you begin the process of crystallization, slowly add triethylamine to increase the pH to 6.7. The mixture is stirred for 1 hour, filtered, washed with DMF and ethanol and dried in vacuum at 40oC.

HPLC shows no ethylparaben. Theoretical output in relation loracarbef is 7,37 g obtained 10,07 2">

Loracarbef ethylparaben (3.0 g, 49.1% of the content loracarbef) are suspended in 30 ml of a mixture acetonitrile: water (1:1). Using concentrated hydrochloric acid the pH of the solution reduces to 1.9, and the solution becomes transparent. Next, using triethylamine pH of the mixture is brought to a value of 4.9, which quickly formed a white precipitate. The mixture is stirred at room temperature for 1 hour, filtered, washed with a mixture of acetonitrile: water/1:1 and dried in vacuum at 45oC. the Estimated output is 1.47 g, obtained of 1.36 g of the product with the content loracarbef 98,1%, output is 90.3 per cent.

Example 17. The ethylate loracarbef.

Loracarbef ethylparaben (of 11.26 g, 72,9% content loracarbef) suspended in a solution consisting of 90 ml of ethanol and 9 ml of water. Add hydrochloric acid (3.5 ml) to obtain a clear solution at about pH 0,80. To the mixture add triethylamine (5 ml) in 30 ml of ethanol. The mixture is stirred for 2 hours, filtered, washed with ethanol and dried in vacuum at 40oC. the Estimated output is 8,21 g, obtained by 8.22 g of the product with the content loracarbef equal to 94.8%, output is 95,0%.

Example 18. Monohydrate loracarbef.

Loracarbef ethylparaben (30,th mixture is added 9 ml of concentrated hydrochloric acid to obtain a clear solution. To the mixture then add 15 ml of triethylamine and 84 ml of ethanol. The mixture is stirred for 1 hour at room temperature, filtered, washed with ethanol and dried in vacuum at 40oC, resulting in the ethylate loracarbef. The estimated output in terms of content loracarbef is 21,81 g obtained 22,59 g ethylate loracarbef content loracarbef equal to 86.2 per cent, interest, the output is 89.3 per cent.

The above ethylate loracarbef (5.0 g, 86.2% of the content loracarbef) are suspended in 70 ml of H2O, and the resulting suspension heated to 50oC. the Slurry becomes too thick, which indicates the formation of the monohydrate. The suspension is stirred for 1 hour at a temperature of 50oC, filtered, washed with water and dried in vacuum at 40oC. the Estimated output is 4.53 g, obtained a 3.06 g of monohydrate loracarbef content monohydrate loracarbef equal 102,8%, the output is 69.3%.

Example 19. Cefaclor 4-hydroxyacetophenone.

A solution of 265 mg (1.94 mmol) of 4-hydroxyacetophenone in 1 ml of ethanol is added to 750 mg (1.94 mmol) of monohydrate cefaclor dissolved in 81 ml of water. The obtained turbid solution is closed and incubated over night at km.

Melting point 198-203oC (decomposition).

Designed CHN (%) C23H22ClN3O6S: 54,81; H IS 4.36; N - 8.34 PER.

Found: 54,95; H - 4,51; N - 8,63.

Below are the characteristics of the powder x-ray complex cefaclor 4-hydroxyacetophenone:

d - I/I0< / BR>
11.4958 - 100.00

10.1960 - 10.80

8.7598 - 16.87

7.3321 - 10.70

6.9139 - 8.61

6.8571 - 6.32

6.4493 - 7.76

5.6711 - 89.55

5.5743 - 30.10

5.1132 - 10.55

4.9524 - 11.19

4.8824 - 13.13

4.7479 - 63.18

4.5850 - 26.57

4.5361 - 45.42

4.3973 - 27.41

4.3076 - 17.56

4.1818 - 5.97

4.1310 - 7.86

4.0050 - 41.00

3.9243 - 30.40

3.8845 - 37.66

3.6794 - at 14.88

3.5963 - 22.29

3.5070 - 42.29

3.4101 - 11.74

3.3658 - 14.28

3.3072 - 46.17

3.2420 - 49.50

3.1725 - 13.58

3.1421 - 14.48

3.0758 - 10.95

3.0452 - 11.29

2.9962 - 13.28

2.9223 - 59.60

2.8845 - 15.67

2.8232 - 14.38

2.7527 - 14.63

2.7286 - 7.46

2.6418 - 21.14

2.5815 - 14.73 l

1. The complex of General formula V

< / BR>
where X is chlorine, vinyl or-CH3;

Z - CH2, S, or O;

n = 0 - 5;

Y is phenyl or 1,4-cyclohexadiene-1-yl;

R1and R2is hydrogen or a hydroxy-group, provided that R1and R2are not both hydrogen;

R3- CO2H, -COO(C12O; cefaclor methylparaben 3H2O, cefaclor of ethylparaben; 2 cefaclor 4-hydroxybenzoic acid 4H2O; cefaclor methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O; cefaclor 4-hydroxyacetophenone; cefaclor 3-hydroxyacetophenone; cephalexin methylparaben H2O, cephalexin of ethylparaben 2H2O; cephalexin methyl ester of 3-hydroxybenzoic acid (0.1 or 5) H2O; cephalexin 3-hydroxyacetophenone; loracarbef methylparaben, loracarbef ethylparaben; loracarbef propylparaben, loracarbef methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O; loracarbef 4-hydroxyacetophenone or loracarbef 3-hydroxyacetophenone.

3. The method of obtaining the compounds of formula VI

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characterized in that it includes a step of dissolution of the complex formulas

< / BR>
where X is chlorine, vinyl or-CH3;

Z - CH2, S, or O;

n = 0 - 5;

Y is phenyl or 1,4-cyclohexadiene-1-yl;

R1and R2is hydrogen or a hydroxy-group, provided that R1and R2are not both hydrogen;

R3is CO2H, -COO(C1- C4-alkyl) or

< / BR>
where R4- C1- C4-alkyl;

in acidic org is sufficient amount of base to precipitate the compounds of formula (VI).

4. The method according to p. 3, characterized in that the complex is cefradine methylparaben H2O; cefaclor methylparaben 3H2O, cefaclor of ethylparaben; 2 cefaclor 4-hydroxybenzoic acid 4H2O; cefaclor methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O; cefaclor 4-hydroxyacetophenone; cefaclor 3-hydroxyacetophenone; cephalexin methylparaben H2O, cephalexin of ethylparaben 2H2O; cephalexin methyl ester of 3-hydroxybenzoic acid (0.1 or 5) H2O; cephalexin 3-hydroxyacetophenone; loracarbef methylparaben, loracarbef ethylparaben; loracarbef propylparaben, loracarbef methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O; loracarbef 4-hydroxyacetophenone or loracarbef 3-hydroxyacetophenone.

5. The method of obtaining the compounds of formula VI

< / BR>
characterized in that it includes a step of dissolution of the complex of formula V

< / BR>
where R1, R2, R3X, Y, Z and n are defined in paragraph 1,

in the system of basic organic solvent or mixture of organic solvent with water and then adding sufficient acid to precipitate the compounds of formula (VI).

6. The method according to p. 5 different t 2O, cefaclor of ethylparaben; 2 cefaclor 4-hydroxybenzoic acid 4H2O; cefaclor methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O; cefaclor 4-hydroxyacetophenone; cefaclor 3-hydroxyacetophenone; cephalexin methylparaben H2O, cephalexin of ethylparaben 2H2O; cephalexin methyl ester of 3-hydroxybenzoic acid (0.1 or 5) H2O; cephalexin 3-hydroxyacetophenone; loracarbef methylparaben, loracarbef ethylparaben; loracarbef propylparaben, loracarbef methyl ester of 3-hydroxybenzoic acid (1 or 5) H2O; loracarbef 4-hydroxyacetophenone or loracarbef 3-hydroxyacetophenone.

 

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< / BR>
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23 cl, 10 tbl, 231 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes compound of the formula (I): wherein cycle A represents imidazo[1,2-a]pyrid-3-yl or pyrazole[2,3-a]pyrid-3-yl; R2 is joined to cyclic carbon atom and taken among halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkyl-S(O)a wherein a = 0, phenyl, phenylthio- or (heterocyclic group)-thio-group wherein any (C1-C6)-alkyl, phenyl or heterocyclic group can be substituted optionally by carbon atom with one or some G wherein heterocyclic group represents saturated, partially saturate or unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least atom is taken among nitrogen, sulfur or oxygen atom that can be bound if another variants are not specified with unsaturated, mono- or bicyclic structure comprising 4-12 atoms among them at least one atom is taken among nitrogen, sulfur or oxygen atoms that can be bound if another variants are not specified with carbon or nitrogen atom wherein group -CH2- can be substituted optionally with -C(O)- and cyclic atom can carry optionally (C1-C6)-alkyl group and to form quaternary compound, or cyclic atom of nitrogen and/or sulfur can be oxidized to form N-oxide and/or S-oxides; m = 0-2 and R2 values can be similar or different; R1 means halogen atom, (C1-C3)-alkyl-S(O)a wherein a = 0 wherein any (C1-C3)-alkyl can be substituted optionally by carbon atom with one or some J; n = 0-1; cycle B represents phenyl or phenyl condensed with (C5-C7)-cycloalkyl cycle; R3 means halogen atom or sulfamoyl; p = 0-2 and R3 values can be similar or different; R4 means group A-E- wherein A is taken among (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heterocyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl wherein (C1-C6)-alkyl, phenyl, heterocyclic group, (C3-C8)-cycloalkyl, phenyl-(C1-C6)-alkyl, (heteroccyclic group)-(C1-C6)-alkyl or (C3-C8)-cycloalkyl-(C1-C6)-alkyl can be substituted optionally by carbon atom with one or some D and wherein above mentioned heterocyclic group comprises fragment -NH- then nitrogen atom can be substituted optionally with group taken among R; E means a simple bond or -O-, -C(O)-, -N(Ra)C(O)- or -N(Ra)SO2-, -S(O)r wherein Ra means hydrogen atom or (C1-C6)-alkyl and r = 0-2; D is taken independently among hydroxy-, amino- (C1-C6)-alkoxy-, N-(C1-C6-alkyl)-amino-, N,N-(C1-C6-alkyl)-amino-, (C1-C6)-alkoxycarbonylamino- and benzyloxycarbonylamino-group wherein any (C1-C6)-alkyl or phenyl can be substituted optionally by carbon atom with one or some K; q = 0-1; G, J and K are taken independently among hydroxy-, dimethylamino-, diethylamino-group; R is taken among (C1-C4)-alkyl; or its pharmaceutically acceptable salt. Invention proposes applying pyrimidine compounds for inhibition of activity of kinases CDK2, CDK4 and CDK6 in cellular cycle eliciting anti-proliferative properties. Indicated properties have value in treatment of cancer diseases (solid tumors and leukemia), fibroproliferative and differential disorders, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic nephropathy, atheroma, atherosclerosis, arterial repeated stenosis, osseous and ophthalmic diseases with proliferation of cellular tissue in vessels.

EFFECT: valuable medicinal properties of compounds.

22 cl, 99 ex

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