Coumadinhydrochloride acid and method of production thereof

 

(57) Abstract:

The invention relates to new coumadinhydrochloride acids, in which the system of pyridone condensed in the 3,4-, 6,7 - and 7,8-positions coumarin system, the General formula I

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where R1R2= NHCH=C(CO2R6)CO., R3= NO2or NH2, R4= R5= H, R6= H or C2H5; R1R2= NHCH=C(CO2R6)CO., R3= R4= H, R5= F, R6= H or C2H5; R1R2= CO(CO2R6) = NH, R3= R4= R5= H, R6= H or C2H5; R1R2= R3R4= NHCH= C(CO2R6)CO., R5= H, R6= H or C2H5; R1= H or HE, R2= R5= N, R3R4= -NHCH=C(CO2R6)CO., R6= H or C2H5; R1= HE, R2= R3= N, R4R5= -CO(CO2R6) = NH, R6= H or C2H5; R1= R5= N, R2- CH3or CF3, R3R4= CO(CO2R6)C = CHNH, R6= H or C2H5and their pharmaceutically acceptable salts. New compounds are inhibitors of the tested strains of bacteria, inhibit the growth of cells ginini. 3 S. and 18 C.p. f-crystals, 10 PL.

The invention relates to new coumadinhydrochloride acids, in which the system of pyridone condensed 3.4-; 6,7 - and 7,8-positions coumarin system General formula I

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where R1R2= -NHCH=C(CO2R6)CO-, R3= NO2or NH2, R4= R5= H, R6= H or C2H5;

R1R2= -NHCH=C(CO2R6)CO-, R3= R4= H, R5= F, R6= H or C2H5;

R1R2= -CO(CO2R6)C=CHNH, R3= R4= R5= H, R6= H or C2H5;

R1R2= R3R4= -NHCH = C(CO2R6)CO-, R5= H, R6= H or C2H5;

R1= H or HE, R2= R5= H, R3R4= -NHCH-C(CO2R6)CO-, R6= H or C2H5;

R1= HE, R2= R3= H, R4R5= -CO(CO2R6)C=CHNH, R6= H or C2H5;

R1= R5= H, R2= CH3or CF3, R3R4= -CO(CO2R6)C = CHNH, R6= H or C2H5,

and their pharmaceutically acceptable salts.

The object of the invention also include methods of obtaining new kumaranayake coumadinhydrochloride acid of General formula I is obtained from the complex Komorimatic esters of the formula II, described in the patent application Croatia P-960308A (European patent application N...) from July 2, 1996

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where R1= -NHCH = C(CO2C2H5)2, R2= R4= H or NO2, R5= H or F;

R1= R3= -NHCH-C(CO2C2H5)2, R2= R4= R5= H;

R1= H or HE, R3= -NHCH = C(CO2C2H5)2, R2= R4= R5= H;

R1= HE, R2= R3= R4= H, R5= -NHCH-C(CO2C2H5)2;

R1= R3= R5= H, R2= CH3or CF3, R4= -NHCH=C(CO2C2H5)2that heat in Dowtherm A at 250-260oC for 10 minutes to 13 hours to get cyklinowanie esters of General formula III

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where R1R2= -NHCH=C(CO2C2H5)CO-, R3= R4= H, R5= F;

R1R2= -NHCH-C(CO2C2H5)CO-, R3= NO2, R4= R5= H;

R1R2= -CO(CO2C2H5)C = CHNH, R3= R4= H, R5= H or F;

R1R2= R3R4= -NHCH-C(CO2C2H5)CO-, R5= H;

R1= H or HE, R2= R5= H, R3R4UB>H5)C=CHNH-,

R1= R5= H, R2= CH3or CF3, R3R4= -CO(CO2C2H5)C=CHNH-.

For the compounds of formula III, where R1R2= -CO(CO2C2H5)C=CHNH, R3= R4= H, R5= H, D. T. Connor, P. A. Young, M. von Strandtman, J. Heterocyclic Chem. , 18, (1981) 697-702 emphasized that the attempt to cilitate corresponding complex kumarihamy the ether in the ether of formula III having the above-mentioned substituents, was unsuccessful, and thus was not collected acid; this acid, in addition to the complex ester of the formula III, is also the subject of the present invention and it has the General formula I with values of R1R2= -CO(CO2H)C = CHNH, R3= R4= H, R5= H.

The compound of formula III, where R1R2= -NHCH=C(CO2C2H5)CO-, R3= R4= H, R5= H (described previously in U.S. patent N 4210758 D. T. Connor (Warner-Lambert Company), first nitrous, then restore and finally condensed with diethyl-ethoxymethylenemalonic with the formation of the compounds of formula IV

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where R = NO2or NH2.

To obtain the compounds of General formula I, where R2R2= -NHCH-C(CO2C2H5SUB>2H5)CO-, R3= NO2, R4= R5= H, restore in glacial acetic acid in the presence of palladium on charcoal as catalyst and in the stream of nitrogen at 3 bar for 6 hours.

By hydrolysis of compounds of formula III get coumadinhydrochloride acid of the formula I, where R1, R2, R3, R4and R5have the previously described meanings and R6= N.

Coumadinhydrochloride acids, which are the subject of the present invention and their pharmaceutically acceptable salts, are inhibitors of the tested bacterial strains. In these tests we used the test microrasbora to study the sensitivity of bacteria according to NCCLS (M7-A2, vol 10, No. 8, 1990; M100-S4, volume 12, No. 20, 1992). Control subjects microorganisms used in these experiments were S. aureus was ATSS 29213, E. faecalis was ATSS 29212 and P. aeruginosa was ATSS 29213 with norfloxacin and norfloksacinom as working standards of antibiotics for comparison. Tested the following strains: Skaphiloc. aureus ATCC 6538P, Bacillus subtilis NCTC 8236, Micrococcus flavus ATCC 10240, Pseudomonas aerug. NCTC 10490, Salmonella Panama 6117, E. coli Lac.+ 6131, E. coli Lac - 6130, b-Haemol. streptococc. - B J22, b-Haemol. streptococc. -A J-21, Streptococcus pyogenes 20F, Streptococcus faecalis ATCC 8043, E. coli AT the[4,3-b] pyridine-3 - carboxylic acid inhibited E. coli Lac+ 6131 and b-Haemol. streptococc.- A J-21.

1,5-Dihydro-1,5-dioxo-7-fluoro-4H-[1] benzopyrano[3,4-b] pyridine-3-carboxylic acid inhibited the investigated strains.

4,7-Dihydro-4,7-dioxo-1H-[1] benzopyrano[6,7-b] pyridine - 3-carboxylic acid inhibited Bacillus subtilis NCTC 8236, Streptococcus pyogenes 20F and Streptococcus faecalis ATCC 8043.

Coumadincirrhosis acid according to the present invention and their pharmaceutically acceptable salts are also investigated for antitumor activity in vitro. Antitumor activity was studied on the growth of cell lines of breast cancer (MCF7), cervical cancer (HeLa), pancreatic cancer (MiaPaCa2), larynx cancer (Hep2) and normal human fibroblasts (Hef522).

1,7-dihydro-1,7-dioxo-9-(trifluoromethyl)-4H-[1] benzopyrano[6,7-b]pyridine-3-carboxylic acid inhibited growth of breast cancer cells (MCF7), pancreatic cancer (MiaPaCa2) and laryngeal cancer (Hep2) and slightly stimulated the growth of cancer cells of the cervix (HeLa) at high concentrations. She had no significant impact on the growth of fibroblasts (Hef522).

The growth of MCF7 inhibited depending on the concentration, and the best inhibition was achieved at 10-5and 10-8M

It had no effect on the growth of HeLa cells in diapason (10-5and 10-4M).

Cell growth UiaPaCa2 inhibited depending on the concentration. At a concentration of 10-4M was achieved inhibition of 35%.

The test compound inhibited the growth of Hep2 cells with increasing concentrations of the inhibitory effect decreased, and the best results were achieved in the concentration ranges of 10-7and 10-5M

The test compound did not affect the growth of normal fibroblasts (f522).

The invention is illustrated by the following examples, which in no case should not be considered as limiting. The results of studies on the antitumor activity are presented in table. 1-10.

Example 1

Ethyl-1,5-dihydro-1,5-dioxo-7-fluoro-4H-[1] benzopyrano[3,4-b] pyridine-2-carboxylate

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A solution of diethyl-{[(8-fluoro-2-oxo-2H-[1]-benzopyran-3 - yl)amino]methylene} malonate (2.40 g, 0.871 mmol) in Dowtherm A (55 ml) was heated for 40 minutes at boiling temperature. The cooled solution was added petroleum ether with a low boiling point to facilitate complete precipitation of the derived complex ester. The precipitate ethyl-1,5-dihydro-1,5-dioxo-7-fluoro-4H-[1] benzopyrano[3,4-b]-pyridine-2-carboxylate gray-brown">

Analysis: calculated for C15H10FNO5: C, 59.41; H, 3.32; N, 4.62;

found: C, 59.74; H, 2.97; N, 4.72.

1H-NMR (DMSO-d6) M. D. 1.3 (t, CH3); 4.3 (square, CH2); 6.8-7.6 (m, Ar H), 8.3 (s, Py H), 9.3 (d, NH).

Example 2

Ethyl-4,5-dihydro-4,5-dioxo-1H-[1] benzopyrano[3,4-b] pyridine-3-carboxylate

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It was obtained by the method described in example 1, from diethyl{ [(2-oxo-4H-[1] -benzopyran-3-yl)amino] methylene} -malonate (3.96 g, 0.012 mol). Duration of response: 13 hours. The obtained ethyl-4,5-dihydro-4,5-dioxo-1H-[1]benzopyrano[3,4-b]pyridine-3-carboxylate (1.90 g, 56%).

Analysis: calculated for C11H15NO5: C, 63.16; H, 3.89; N, 4.91;

found: C, 62.98; H, 3.92; N, 5.07.

1H-NMR (TFA) M. D. 1.2 (t, CH2); 4.3 (square, CH3); 7.3-8.0 (m, Ar H), 8.4 (s, Py H), 11.3 (d, NH).

Example 3

Diethyl-1,5,8-trihydro-1,5,8-trioxo-4,11 H-[1] benzopyrano[3,4-b] [7,6 -] piperidin-2,9, in primary forms

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It was obtained by the method described in example 1, based on tetraethyl-[[(2-oxo-2H-[1] -benzopyrano-3,6-diyl) diamino]dimethylene]malonate (2.00 g, 3,872 mol). Duration of response: 50 minutes. The resulting diethyl-1,5,8-trihydro-1,5,8-trioxo - 4,11 H-[1] -benzopyrano[3,4-b] [7,6-c]piperidin-2,9, in primary forms brown recrystallized from abs/SUB>O5: C, 59.43; H, 3.80; N, 6.60;

found: C, 59.72; H, 3.89; N, 6.89.

1H-NMR (DMSO-d6) M. D. 1.3 (2T, 2 CH3); 4.2 (2 square, 2 CH2); 7-10 (m, C, H, Ar H, Py H); 10.6 and 12.3 (2 d, 2 NH).

Example 4

Ethyl-4,7-dihydro-4,7-dioxo - 1H-[1] -benzopyrano [6,7-b]pyridine-3-carboxylate

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It was obtained by the method described in example 1, from diethyl-[[(2-oxo-2H-[1]-benzopyran-3-yl)amino]methylene]malonate (3,10 g 9,357 mmol). Duration of response: 45 minutes. The yellow-brown precipitate ethyl-4,7 - dihydro-4,7-dioxo-1H-[1] -benzopyrano[6,7-b]pyridine - 3-carboxylate was recrystallized from N,N-dimethylformamide (2,23 g, 84%). So pl. > 300oC.

Analysis: calculated for C15H11NO5: C, 63.16; H, 3.89; N, 4.91;

found: C, 63.05; H, 3.92; N, 4.88.

1H-NMR (DMSO-d6) M. D. 1.3 (t, CH3); 4.2 (2 kV, CH2); and 6.5 (d, H8), 7,4-8,0 (m, Ar H, Py H); and 8.4 (d, H9); 10,7 (d, NH).

m/z: 284 (M-), 258, 256, 239, 212, 183, 127, 79.

Example 5

Ethyl-4,7-dihydro-4,7-dioxo-3-hydroxy-1H-[1]- benzopyrano[6,7-b]pyridine-3-carboxylate

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It was obtained by the method described in example 1, from diethyl-[[(3-hydroxy-2-oxo-2H-[1] -benzopyran-6-yl) amino]methylene]malonate (3,63 g to 0.011 mol). Duration of response: 15 minutes. The obtained light-yellow-maxoC.

Analysis: calculated for C15H11NO6: C, 59.80; H, 3.68; N, 4.65;

found: C, 59.66; H, 3.61; N, 4.27.

1H-NMR (DMSO-d6) M. D. 1.3 (t, CH3); 4.2 (square, CH2); to 7.2 and 9.3 (m, Ar H, Py H); 10,7 (s, OH); and 12.4 (s, NH).

m/z: 300 (M-), 273, 272, 255, 227, 178, 136, 91, 68, 54.

Example 6

Ethyl-1,7-dihydro-1,7-dioxo-9-methyl-4H- [1] -benzopyrano [6,7-b] pyridine-2-carboxylate

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It was obtained by the method described in example 1, from diethyl-[[(4-methyl-2-oxo-2H-[1] -benzopyran-7-yl)amino] methylene]malonate (5,70 g of 0.017 mol). Duration of response: 10 minutes. The obtained gray-brown precipitate ethyl-1,7-dihydro-1,7-dioxo-9-methyl-4H-[1] -benzopyrano[6,7-b] pyridine-2-carboxylate (3,43 g, 69%). So pl. > 300oC.

Analysis: calculated for C16H13NO5: C, 64.21; H, 4.38; N, 4.68;

found: C, 64.36; H, 4.14; N, 4.50.

1H-NMR (DMSO-d6) M. D. 1.3 (s, CH3); 2.1 (m, CH2); 4,1 (square, CH2); 6,2 (d, H8); and 7.4 (d, H5), and 7.7 (t, H10); or 10.3 (s, Py H); 12,4 (CL, NH).

Example 7

Ethyl-4,7-dihydro-4,7-dioxo-9-(trifluoromethyl)-1H- [1]-benzopyrano[6,7-b] pyridine-2-carboxylate

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It was obtained by the method described in example 1, from diethyl-[[(4-trifluoromethyl)-2-oxo-2H-[1] -benzopyran-7-yl) amino] methylene]malonate (2.00 g, of 0.005 mol). About the ptx2">

Analysis: calculated for C16H10F3NO5: C, 54.40; H, 2.85; N, 3.97;

found: C, 54.41; H, 2.97; N, 3.86.

1H-NMR (DMSO-d6) M. D. 1.3 (t, CH3); 4,2 (square, CH2); 7,0 (d, H8); 7,4 (C, H5); 7,9 (d, H10); and 8.5 (d, Py H); 12,4 (CL, NH).

Example 8

Ethyl-1,6-dihydro-1,6-dioxo-7-hydroxy-4H-[1] - benzopyrano[7,8-b]pyridine-2-carboxylate

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It was obtained by the method described in example 1, from diethyl-[[(3-hydroxy-2-oxo-2H-[1] -benzopyran-8-yl) amino]methylene]malonate (3,15 g 9,070 mol). Duration of response: 40 minutes. The obtained ethyl-1,6-dihydro-1,6-dioxo-7 - hydroxy-4H-[1]-benzopyrano[7,8-b]pyridine-2-carboxylate orange-brown (2.35 g, 86%). So pl. > 300oC.

Analysis: calculated for C15H11NO6: C, 59.80; H, 3.68; N, 4.65;

found: C, 59.45; H, 3.29; N, 4.28.

1H-NMR (DMSO-d6) M. D. 1.3 (t, CH3); 4,2 (square, CH2); and 7.1 to 8.3 (m, Ar H Py H); 10,4 (s, OH); 11.8 in (s, NH).

m/z: 302 (M+), 171, 155, 141.

Example 9

Ethyl-1,5-dihydro-1,5-dioxa-9-nitro-4H-[1] -benzopyrano-[3,4-b] pyridine-2-carboxylate

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To a solution of ethyl-1,5-dihydro-1,5-dioxo-4H-[1]-benzopyrano[3,4-b] pyridine-2-carboxylate (0,81 g, 2,840 mmol) in concentrated sulfuric acid (of 3.73 g of 0.038 mol), which was cooled to 0-5oC, when s is s (1.96 g, 0.020 mol). The reaction mixture was stirred for another 10 minutes after reaching room temperature and then poured into a mixture of water and ice. The obtained ethyl-1,5-dihydro-1,5-dioxa-9-nitro-4H-[1] -benzopyrano[3,4-b]pyridine - 2-carboxylate was recrystallized from ethanol (0.89 g, 95%). So pl.: 246-247oC.

Analysis: calculated for C15H10N2O7: C, 54.55; H, 3.05; N, 8.48;

found: C, 54.50; H, 2.87; N, 8.65.

1H-NMR (TFA) M. D. 1.2 (t, CH3); 4.3 (square, CH2); to 7.4 (d, H7); 8.3 (d, H8); and 9.1 (s, H10); and 9.6 (s, Py H); 11.3 (s, NH).

m/z: 329 (M-), 313, 301, 284, 269, 257, 256, 241, 228, 151.

Example 10

Ethyl-1,5-dihydro-1,5-dioxa-9-amino-4H-[1] -benzopyrano[3,4-b] pyridine-2-carboxylate

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To a solution of ethyl-1,5-dihydro-1,5-dioxa-9-nitro-4H-[1] - benzopyrano[3,4-b] pyridine-2-carboxylate (0.50 g, 1,514 mmol) in glacial acetic acid (150 ml) was added the catalyst (4,92% Pd/C (0.15 g), and recovery was 6 hours in a stream of nitrogen at 3 bar. After completion of the reaction, acetic acid is evaporated from the filtered reaction mixture. The obtained amine (0.59 g, 100%) was recrystallized from glacial acetic acid. So pl.: 270-272oC.

Analysis: calculated for C15H22N2O5C2H4O2: C, 58.18; H, 4.28; N, 8.48;

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Example 11

1,5-dihydro-1,5-dioxo-7-fluoro-4H- [1]-benzopyrano[3,4-b]pyridine - 2-carboxylic acid

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A solution of ethyl-1,5-dihydro-1,5-dioxo - 7-fluoro-4H-[1]-benzopyrano [3,4-b] pyridine-2-carboxylate (1.70 g, 5.606 mmol) in 10% aqueous sodium hydroxide solution (22 ml) was heated for 90 minutes at boiling temperature, then boiled for about 5 minutes with activated carbon. The acid filtrate was besieged by a 10% aqueous solution of hydrochloric acid (pH 2-3) and the cooled solution was left to stand for several hours at +4oC. the Obtained light-yellow precipitate acid (1.50 g; 97%) was recrystallized from a mixture of ethyl acetate/ethanol (1:1) or N,N-dimethylformamide. So pl. > 300oC.

Analysis: calculated for C13H6FNO5: C 56.74 LAST; H, 2.20; N, 5.09;

found: C, 56.52; H, 1.84; N, 5.11.

1H-NMR (TFA) M. D. 7.3 to 7.4 (m, 3, Ar H); to 8.7 (m, Py H); and 9.2 (s, NH) and 11.3 (s, COOH).

Example 12

4,5-dihydro-4,5-dioxo-4H-[1] -benzopyrano[4,3-b] pyridine-3-carboxylic acid

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A solution of ethyl-4,5-dihydro-4,5-dioxo-4H-[1] -benzopyrano [4,3-b]pyridine-3-carboxylate (1.90 g, 6.661 mmol) in 1 M sodium hydroxide (50 ml) was heated for 90 minutes at boiling temperature, and then a short time was boiled with activated charcoal, filtered and the filtrate tx2">

Analysis: calculated for C13H7NO5: C, 60.70; H, 2.74; N, 5.45;

found: C, 60.37; H, 2.43; N, 5.51.

1H-NMR (DMSO-d6) memorial plaques 7.5 (l, H7): 7,8 (t, H9); and 8.4 (d, H10); to 8.7 (m, H8, Py H); and 9.2 (s, NH) and 11.3 (s, COOH).

m/z: 256 (M-), 240, 239, 223, 212, 211, 183, 120, 82.

Example 13

1,5,8-trihydro-1,5,8-trioxo - 4,11 H-[1]-benzopyrano [3,4-b][7,6 -] piperidin - 2,9-dicarboxylic acid

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It was obtained by the method described in example 12, on the basis of diethyl-1,5,8-trihydro-1,5,8-trioxo-4,11 H-[1] -benzopyrano [3,4-b][7,6 -] piperidin-2,9-in primary forms (0.90 g, 121 mmol). Duration of response: 45 minutes. The resulting acid had a yellow-brown color (0.45 g, 58%). So pl. > 300oC.

Analysis: calculated for C17H8N2O8: C, 55.44; H, 2.19; N, 7.61;

found: C, 55.22; H, 2.58; N, 7.50.

1H-NMR (DMSO-d6) memorial plaques of 7.1 to 9.5 (m, Ar H, Py H); 12,3 (d, 2 NH); 14,8 (s, COOH); 15,4 (s, COOH).

m/z: 368 (M+), 314, 264, 256, 213, 198, 188, 156, 137, 129, 91, 81, 69.

Example 14

4,7-dihydro-4,7-dioxo-1H-[1] -benzopyrano[6,7-b] pyridine-3-carboxylic acid

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It was obtained by the method described in example 11, on the basis of ethyl-4,7-dihydro-4,7-dioxo-1H-[1] -benzopyrano[6,7-b] pyridine-3 - carboxylate (1.10 g, 3.856 mmol). Duration of response: 3 hours. Received light W is C, 60.70; H, 2.74; N, 5.45;

found: C, 60.37; H, 2.80; N, 5.76.

m/z: 258 (M+), 254, 249, 213, 151, 138, 125, 109, 98, 74, 62.

Example 15

4,7-dihydro-4,7-dioxo-8-hydroxy-1H-[1] -benzopyrano[6,7-b] pyridine-3-carboxylic acid

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It was obtained by the method described in example 12, on the basis of ethyl-4,7-dihydro-4,7-dioxo-8-hydroxy-1H-[1] -benzopyrano [6,7-b]pyridine-3-carboxylate (2.83 g, 9.394 mmol). Duration of response: 3 hours. The obtained yellow precipitate acid (2.13 g, 83%). So pl. > 300oC.

1H-NMR (DMSO-d6) memorial plaques of 7.6 to 8.7 (m, Ar H); and 9.4 (s, Py H); 13,4 (s, NH), and 15.2 (s, COOH).

m/z: 273 (M+), 256, 239, 229, 181, 125, 114, 95, 73.

Example 16

1,7-dihydro-1,7-dioxo-9-methyl-4H-[1] -benzopyrano[6,7-b] pyridine-2-carboxylic acid

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It was obtained by the method described in example 11, on the basis of ethyl-1,7-dihydro-1,7-dioxo-9-methyl-4H-[1] -benzopyrano [6,7-b] pyridine-2-carboxylate (3.40 g, 0.011 mol). Duration of response: 20 minutes. The precipitate gray-white recrystallized from N,N-dimethylformamide (2.32 g, 75%).

Analysis: calculated for C14H9NO5C3H7NO: C, 59.30; H, 4.68; N, 8.14;

found: C, 59.50; H, 4.61; N, 7.81.

1H-NMR (DMSO-d6) memorial plaques 1.9 (s, CH3); 6,3 (s, H8); and 7.6 (d, H5); 8.0 a (s, H10); 9,0 (s, Py H); 13,2 (shebanova acid

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It was obtained by the method described in example 12, on the basis of ethyl-1,7-dihydro-1,7 - dioxo-9-(trifluoromethyl-4H-[1]- benzopyrano[6,7-b]pyridine-2-carboxylate (1.40 g, 3.963 mmol). Duration of response: 2 hours. The resulting acid was recrystallized from a mixture of N,N-dimethylformamide/ethanol (1.28 g, 99%). So pl. > 300oC.

Analysis: calculated for C14H6F3NO5: C, 51.70; H, 1.86; N, 4.31;

found: C, 51.48; H, 1.82; N, 4.27.

1H-NMR (DMSO-d6) memorial plaques to 7.2 (s, H8); 7,8 (C, H5); and 8.6 (s, H10); 9,0 (s, Py H); 13,4 (CL, NH); 14,5 (CL, COOH).

Example 18

1,5-dihydro-1,5-dioxo-7-hydroxy-4H-[1] -benzopyrano[7,8-b] pyridine - 2-carboxylic acid

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It was obtained by the method described in example 13, on the basis of ethyl-1,5-dihydro-1,5-dioxo-7-hydroxy-4H-[1] -benzopyrano [7,8-b] pyridine-2-carboxylate (2.12 g, 7.037 mmol). Duration of response: 3 hours. The resulting acid green-brown (1.27 g, 66%). So pl. > 300oC.

1H-NMR (DMSO-d6) memorial plaques a 7.1 to 7.8 (m, Ar H, Py H); and 8.6 (s, OH); 10,6 (s, NH), and 15.2 (s, COOH).

m/z: 273 (M+), 212, 179, 81, 79, 61, 59, 45, 43.

1. Coumadinhydrochloride acid, in which the system of pyridone condensed 3.4-; 6,7 - and 7,8 - positions coumarin system, the General formula I

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where R2H5;

R1R2= -NHCH=C(CO2R6)CO-, R3= R4= H, R5= F, R6= H or C2H5;

R1R2= -CO(CO2R6)C=CHNH, R3= R4= R5= H, R6= H or C2H5;

R1R2= R3R4= -NHCH=C(CO2R6)CO-, R5= H, R6= H or C2H5;

R1= H or OH, R2= R5= H, R3R4= -NHCH=C(CO2R6)CO-, R6= H, or C2H5;

R1= OH, R2= R3= H, R4R5= -CO(CO2R6)C=CHNH, R6= H or C2H5;

R1= R5= H, R2= CH3or CF3, R3R4= CO(CO2R6)C=CHNH, R6= H or C2H5,

and their pharmaceutically acceptable salts.

2. The compound of General formula I on p. 1, wherein R1R2= -NHCH=C(CO2C2H5)CO-, R3= R4= H, R5= F.

3. The compound of General formula I on p. 1, wherein R1R2= -CO(CO2C2H5)C=CHNH, R3= R4= R5= H.

4. The compound of General formula I on p. 1, wherein R1R2= R3R4= -NHCH=C(CO2C2H5= H, R3R4= -NHCH=C(CO2C2H5)CO-.

6. The compound of General formula I on p. 1, wherein R1= OH, R2= R5= H, R3R4= -NHCH=C(CO2C2H5)CO-.

7. The compound of General formula I on p. 1, wherein R1= R5= H, R2= CH3, R3R4= -CO(CO2C2H5)C=CHNH-.

8. The compound of General formula I on p. 1, wherein R1= R5= H, R2= CF3, R3R4= -CO(CO2C2H5)C=CHNH-.

9. The compound of General formula I on p. 1, wherein R1= OH, R2= R3= H, R4R5= -CO(CO2C2H5)C=CHNH-.

10. The compound of General formula I on p. 1, wherein R1R2= -NHCH=C(CO2C2H5)CO-, R3= NO2, R4= R5= H.

11. The compound of General formula I on p. 1, wherein R1R2= -NHCH=C(CO2C2H5)CO-, R3= NH2, R4= R5= H.

12. The compound of General formula I on p. 1, wherein R1R2= -NHCH=C(CO2H)CO-, R3= R4= H, R5= F.

13. The compound of General formula I on p. 1, wherein Uly I on p. 1, wherein R1R2= R3R4= -NHCH=C(CO2H)CO-, R5= H.

15. The compound of General formula I on p. 1, wherein R1= H, R2= R5= H, R3R4= -NHCH=C(CO2H)CO-.

16. The compound of General formula I on p. 1, wherein R1= OH, R2= R5= H, R3R4= -NHCH=C(CO2H)CO-.

17. The compound of General formula I on p. 1, wherein R1= R5= H, R2= CH3, R3R4= -CO(CO2H)C=CHNH-.

18. The compound of General formula I on p. 1, wherein R1= R5= H, R2= CF3, R3R4= -CO(CO2H)C=CHNH-.

19. The compound of General formula I on p. 1, wherein R1= OH, R2= R3= H, R4R5= -CO(CO2H)C=CHNH-.

20. The method of obtaining compounds of General formula I on p. 1, characterized in that compounds of General formula II

< / BR>
where R1= -NHCH=C(CO2C2H5)2, R2= R4= H, R3= NO2, R5= H or F;

R1= R3= -NHCH=C(CO2C2H5)2, R2= R4= R5= H;

R1= H or OH, R3= -NHCH=C(CO2C2H5)2, R2= R2
;

R1= R3= R5= H, R2= CH3or CF3, R4= -NHCH=C(CO2C2H5)2,

heated Dowtherm A at 250 - 260oC for 10 min 13 h to obtain cyklinowanie complex coumadinimuranwh esters of General formula III

< / BR>
where R1R2= -NHCH=C(CO2C2H5)CO-, R3= R4= H, R5= F;

R1R2= -NHCH=C(CO2C2H5)CO-, R3= NO2, R4= R5= H;

R1R2= -CO(CO2C2H5)C=CHNH, R3= R4= R5= H;

R1R2= R3R4= -NHCH=C(CO2C2H5)CO-, R5= H;

R1= H or OH, R2= R5= H, R3R4= -NHCH=C(CO2C2H5)CO-,

R1= OH, R2= R3= H, R4R5= - CO(CO2C2H5)C=CHNH-,

R1= R5= H, R2= CH3or CF3, R3R4= -CO(CO2C2H5)C=CHNH-,

which are the compounds of formula I, where R6= C2H5and to obtain the compounds of General formula I, where R1R2= -NHCH=C(CO2C2H5)CO-, R3= NH2, R4= R5= H, restore compounds of General formula III, where R1, R2, R3, R4and R5have the meanings given in paragraph 1, and R6= H, hydrolyzing compounds of General formula III, where R6= C2H5.

21. The compounds of formula I, having antimicrobial and antitumor activity.

 

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