Novel benzopyranopyridone carboxylic acids and processes for the preparation thereof

Abstract: The present invention relates to novel coumarin quinolone carboxylic acids wherein the pyridone system is fused in 3,4-, 6,7- and 7,8-positions of the coumarin system, of the general formula I wherein R 1 R 2 = -NHCH=C(CO 2 R 6 )CO-, R 3 = NO 2 or NH 2 , R 4 = R 5 = H, R 6 = H or C 2 H 5 ; R 1 R 2 = -NHCH=C(CO 2 R 6 )CO-, R 3 = R 4 = H, R 5 = F, R 6 = H or C 2 H 5 ; R 1 R 2 = -CO(CO 2 R 6 )C=CHNH-, R 3 = R 4 = R 5 = H, R 6 = H or C 2 H 5 ; R 1 R 2 = R 3 R 4 = -NHCH=C(CO 2 R 6 )CO-, R 5 = H, R 6 = H or C 2 H 5 ; R 1 = H or OH, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 R 6 )CO-, R 6 = H or C 2 H 5 ; R 1 = OH, R 2 = R 3 = H, R 4 R 5 =-CO(CO 2 R 6 )C=CHNH-, R 6 = H or C 2 H 5 ; R 1 = R 5 = H, R 2 = CH 3 or CF 3 , R 3 R 4 = -CO(CO 2 R 6 )C=CHNH-, R 6 = H or C 2 H 5 , as well as pharmaceutically acceptable salts thereof. The object of the invention are also processes for the preparation of novel coumarin quinolone carboxylic acids with anti tumour and bactericide activity.

Description: The present invention relates to novel benzopyranopyridone carboxylic acids, wherein the pyridone system is fused in 3,4-, 6,7- and 7,8-positions of the benzopyrano system, of the general formula I wherein R 1 R 2 = =NHCH=C(CO 2 R 6 )CO-,R 3 = NO 2 or NH 2 , R 4 = R 5 = H, R 6 = H or C 2 H 5 ; R 1 R 2 = = -NHCH=C(CO 2 R 6 )CO-,R 3 = R 4 = H, R 5 = F, R 6 = H or C 2 H 5 ; R 1 R 2 = -CO(CO 2 R 6 )C=CHNH-,R 3 = R 4 = R 5 = H, R 6 = H or C 2 H 5 ; R 1 R 2 = R 3 R 4 =-NHCH=C(CO 2 R 6 )CO-, R 5 = H, R 6 = H or C 2 H 5 ; R 1 = H or OH, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 R 6 )CO, R 6 = H or C 2 H 5 ; R 1 = OH, R 2 = R 3 = H, R 4 R 5 =-CO(CO 2 R 6 )C=CHNH-, R 6 = H or C 2 H 5 ; R 1 = R 5 = H, R 2 = CH 3 or CF 3 , R 3 R 4 = CO(CO 2 R 6 ) C=CHNH-, R 6 = H or C 2 H 5 , as well as pharmaceutically acceptable salts thereof. As used in the specification, for example the definition "R 1 R 2 = -NHCH = C(CO 2 R 6 )CO-" means that the ring closes in the direction from R 1 to R 2 positions, i.e. a 6-membered ring is formed wherein NH is attached to the R 1 -position and C=O is attached to the R 2 -position. A further subject matter of the invention are processes for the preparation of the novel benzopyranopyridone carboxylic acids. A further subject matter of the invention is the use of the novel benzopyranopyridone carboxylic acids for the preparation of antibacterial and antitumour agents. According to the present invention, novel benzopyranopyridone carboxylic acids of the general formula I are prepared starting from coumarin malonate esters of the formula II disclosed in Croatian patent application P-960308A (EP-A-0 816 353) of 2 July 1996 wherein R 1 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = H, R 3 = H or NO 2 , R 5 = H or F; R 2 = -NHCH = C(CO 2 C 2 H 5 ) 2 , R 1 = R 3 = R 4 = R 5 = H; R 1 = R 3 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = R 5 = H; R 1 = H or OH, R 3 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = R 5 = H; R 1 = OH, R 2 = R 3 = R 4 = H, R 5 = -NHCH=C(CO 2 C 2 H 5 ) 2 ; R 1 = R 3 = R 5 = H, R 2 = CH 3 or CF 3 , R 4 = -NHCH=C(CO 2 C 2 H 5 ) 2 , which are heated in Dowtherm A® at 250-260°C for 10 minutes to 13 hours to obtain cyclized esters of the general formula III wherein R 1 R 2 =-NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = R 4 = H, R 5 = F; R 1 R 2 =-NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = NO 2 , R 4 = R 5 = H; R 1 R 2 =-CO(CO 2 C 2 H 5 )C=CHNH-, R 3 = R 4 = H, R 5 = H or F; R 1 R 2 = R 3 R 4 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 5 = H; R 1 = H or OH, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 C 2 H 5 )CO-; R 1 = OH, R 2 = R 3 = H, R 4 R 5 = -CO(CO 2 C 2 H 5 )C=CHNH-; R 1 = R 5 = H, R 2 = CH 3 or CF 3 , R 3 R 4 =-CO(CO 2 C 2 H 5 )C=CHNH. For the compound of the formula III wherein R 1 R 2 = -CO(CO 2 C 2 H 5 )C=CHNH-, R 3 = R 4 = H, R 5 = H, it is expressly stated in D.T. Connor, P.A. Young, M. von Strandtman, J. Heterocyclic Chem. 18 (1981) 697-702 that an attempt to cyclize the corresponding coumarin malonate ester to an ester of the formula III having the above mentioned substituents was unsuccessful and thus no corresponding acid was obtained either, said acid being, beside the ester of the formula III, also a subject matter of the present invention and having the general formula I with the meaning R 1 R 2 = -CO(CO 2 H)C=CHNH-, R 3 = R 4 = H, R 5 = H. The compound of the formula III wherein R 1 R 2 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = R 4 = H, R 5 = H (disclosed earlier in US patent No. 4,210,758 to D. T. Connor (Warner-Lambert Company)) is at first nitrated and then reduced to obtain a compound of the formula IV wherein R = NO 2 or NH 2 . For obtaining the compounds of the general formula I wherein R 1 R 2 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = NH 2 , R 4 = R 5 = H, the compounds of the general formula III wherein R 1 R 2 =-NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = NO 2 , R 4 = R 5 = H are reduced in glacial acetic acid under the catalyst palladium on active carbon and in a nitrogen stream of 3 bar for a time period of 6 hours. By the hydrolysis of the compounds of the formula III, coumarin quinolone carboxylic acids of the formula I are obtained, wherein R 1 , R 2 , R 3 , R 4 and R 5 have the earlier disclosed meanings and R 6 = H. US-A-4060619 relates to 1,4-dihydro-4-oxo-benzopyrano[4,3-b]pynoline-2-carboxylates as being useful for treating allergic conditions and microbial infections. Benzopyranopyridone carboxylic acids, which are the subject matter of the present invention, as well as pharmaceutically acceptable salts thereof are inhibitors of bacteria strains tested. In these tests a microdilution test for investigation of bacterial susceptibility according to the method NCCLS (M7-A2, Vol. 10, No. 8, 1990; M100-S4, Vol. 12, No. 20, 1992) was used. Control test microorganisms employed in these experiments were S . aureus ATCC 29213, E. faecalis ATCC 29212 and P. aeruginosa ATCC 29213 with norfloxacin and enorfloxacin as working standards of antibiotics for comparison. The following strains were tested: Staphiloc. aureus ATCC 6538P, Bacillus subtilis NCTC 8236, Micrococcus flavus ATCC 10240, Pseudomonas aerug. NCTC 10490, Salmonela Panama 6117, E. coli Lac+ 6131, E. coli Lac- 6130, b-Haemol. streptococc. - B J-22, b-Haemol. streptococc. - A J-21 , Streptococcus pyogenes 20F, Streptococcus faecalis ATCC 8043, E. coli ATCC 10536, Staphyloc. epidermis ATCC 12228, B. cereus AYCC 11778, B. pumilus ATCC 8241 and B. subtilis ATCC 6633. 4,5-dihydro-4,5-dioxo-1 H -[1]benzopyrano[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-4 H -[1]benzopyrano[3,4-b]pyridine-2 -carboxylic acid inhibited the strains tested. 4,7-dihydro-4,7-dioxo-1 H -[1]benzopyrano[6,7-b]pyridine-3-carboxylic acid inhibited Bacillus subtilis NCTC 8236, Streptococcus pyogenes 20F and Streptococcus faecalis ATCC 8043. Benzopyranopyridone carboxylic acids according to the present invention and pharmaceutically acceptable salts thereof were also investigated for an in vitro antitumour action. The antitumour action was tested on the growth of cell lines of mammary cancer (MCF7), cancer of cervix uteri (HeLa), pancreas cancer (MiaPaCa2), larinx cancer (Hep2) and on normal human fibroblasts (Hef522). 1,7-dihydro-1,7-dioxo-9-(trifluoromethyl)-4 H -[1]benzopyrano[7,6-b]pyridine-2-carboxylic acid inhibited the growth of the cells of mammary cancer (MCF7), pancreas cancer (MiaPaCa2) and larinx cancer (Hep2) and slightly stimulated the growth of cells of cancer of cervix uteri (HeLa) in higher concentrations. It had no significant action on the growth of fibroblasts (Hef522). The MCF7 growth was inhibited depending on the concentration and the best inhibition was achieved at 10 -5 and 10 -8 M. It had no effect on the growth of HeLa cells in the concentration range from 10 -8 to 10 -6 M, whereas at higher concentrations (10 -5 and 10 -4 M) it stimulated their growth. The growth of MiaPaCa2 cells was inhibited depending on the concentration. At the concentration of 10 -4 M the attained inhibition was 35%. The tested substance inhibited the growth of Hep2 cells, with increased concentration the inhibitory action was decreased and the best results were achieved in the concentration ranges of 10 -7 and 10 -5 M. The tested substance exhibited no effect on the growth of normal fibroblasts (Hef522). The invention is illustrated by the following Examples. Example 1 Ethyl-1,5-dihydro-1,5-dioxo-7-fluoro-4 H -[1]benzopyrano[3,4-b]pyridine-2-carboxylate A solution of diethyl-{[(8-fluoro-2-oxo-2 H -[1]-benzopyrano-3-yl)amino]-methylene} malonate (2.40 g; 0.871 mmole) in Dowtherm A® (55 ml) was heated for 40 minutes at the boiling temperature. Into the cooled solution a petroleum ether having a low boiling point was added to assist with a complete precipitation of the obtained ester. The obtained precipitate of ethyl-1,5-dihydro-1,5-dioxo-7-fluoro-4 H -[1]-benzopyrano[3,4-b]pyridine-2-carboxylate of a gray brown colour was washed first with petroleum ether and then with diethyl ether (1.85 g; 89%). M.p.: 288-290°C. Analysis calculated for C 15 H 10 FNO 5 : C 59.41; H 3.32; N 4.62. found C 59.74; H 2.97; N 4.72. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.3 (t, CH 3 ); 4.3 (q, CH 2 ); 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-1 H -[1]-benzopyrano[4,3-b]pyridine-3-carboxylate It was prepared according to the method disclosed in Example 1 starting from diethyl-{[(2-oxo-4 H -[1]-benzopyrano-4-yl)amino]methylene} malonate (3.96 g; 0.012 mole). Duration of the reaction: 13 hours. Ethyl-4,5-dihydro-4,5-dioxo-1 H -[1]-benzopyrano[4,3-b]pyridine-3-carboxylate (1.90 g; 56%) was obtained. Analysis calculated for C 11 H 15 NO 5 : C 63.16; H 3.89; N 4.91. found C 62.98; H 3.92; N 5.07. 1 H-NMR (TFA) δ/ppm: 1.2 (t, CH 3 ); 4.3 (q, CH 2 ); 7.3-8.0 (m, Ar H); 8.4 (s, Py H); 11.3 (s, NH). Example 3 Diethyl-1,5,8-trihydro-1,5,8-trioxo-4,11 H -[1]-benzopyrano[3,4-b]-[6,7-b]dipyridine-2,9-dicarboxylate It was prepared according to the method disclosed in Example 1 starting from tetraethyl-{[(2-oxo-2 H -[1]-benzopyrano-3,6-diyl)diamino]dimethylene} malonate (2.00 g; 3.872 mole). Duration of the reaction: 50 minutes. The obtained diethyl-1,5,8-trihydro-1,5,8-trioxo-4,11 H -[1]-benzopyrano[3,4-b][6, 7-b]dipyridine-2, 9-dicarboxylate of brown colour was recrystallized from absolute ethanol (1.43 g; 87%). M.p.: 175-177°C. Analysis calculated for C 21 H 16 N 2 O 5 C 59.43; H 3.80; N 6.60. found C 59.72; H 3.89; N 6.89. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.3 (2 t, 2 CH 3 ); 4.2 (2 q, 2 CH 2 ); 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-1 H -[1]-benzopyrano[6,7-b]pyridine-3-carboxylate It was prepared according to the method disclosed in Example 1 starting from diethyl-{[(2-oxo-2 H -[1]-benzopyrano-6-yl)amino]methylene} malonate (3.10 g; 9.357 mmole). Duration of the reaction: 45 minutes. The obtained yellow brown precipitate of ethyl-4,7-dihydro-4,7-dioxo-1 H -[1]-benzopyrano[6,7-b]pyridine-3-carboxylate was recrystallized from N,N-dimethylformamide (2.23 g; 84%). M.p. >300°C. Analysis calculated for C 15 H 11 NO 5 C 63.16; H 3.89; N 4.91. found C 63.05; H 3.92; N 4.88. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.3 (t, CH 3 ); 4.2 (q, CH 2 ); 6.5 (d, H8), 7.4-8.0 (m, Ar H, Py H); 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-8-hydroxy-1 H -[1]-benzopyrano[6,7-b]pyridine-3-carboxylate It was prepared according to the method disclosed in Example 1 starting from diethyl-{[(3-hydroxy-2-oxo-2 H -[1]-benzopyrano-6-yl)amino]methylene} malonate (3.63 g; 0.011 mole). Duration of the reaction: 15 minutes. A light yellow brown precipitate of ethyl-4,7-dihydro-4,7-dioxo-8 -hydroxy-1 H -[1]-benzopyrano[6,7-b] pyridine-3-carboxylate (3.63 g; 95%) was obtained. M.p. >300°C Analysis calculated for C 15 H 11 NO 6 C 59.80; H 3.68; N 4.65. found C 59.66; H 3.61; N 4.27. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.3 (t, CH 3 ); 4.2 (q, CH 2 ); 7.2-9.3 (m, Ar H, Py H); 10.7 (s, OH); 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-4 H -[1]-benzopyrano[7,6 -b]pyridine-2-carboxylate It was prepared according to the method disclosed in Example 1 starting from diethyl-{[(4-methyl-2-oxo-2 H -[1]-benzopyrano-7-yl)amino]methylene}malonate (5.70 g; 0.017 mole). Duration of the reaction: 10 minutes. A gray brown precipitate of ethyl-1,7-dihydro-1,7-dioxo-9-methyl-4 H -[1]-benzopyrano[7,6 -b]pyridine-2-carboxylate (3.43 g; 69%) was obtained. M.p. >300°C. Analysis calculated for C 16 H 13 NO 5 C 64.21; H 4.38; N 4.68. found C 64.36; H 4.14; N 4.50. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.3 (s, CH 3 ); 2.1 (t, CH 3 ); 4.1 (q, CH 2 ); 6.2 (d, H8); 7.4 (d, H5); 7.7 (t, H10); 10.3 (s, Py H); 12.4 (bs, NH). Example 7 Ethyl-1,7-dihydro-1,7-dioxo-9-(trifluoromethyl)-1H-[1]-benzopyrano[7,6-b]pyridine-2-carboxylate It was prepared according to the method disclosed in Example 1 starting from diethyl-{[(4-(trifluoromethyl)-2-oxo-2 H -[1]-benzopyrano-7-yl)amino]methylene} malonate (2.00 g; 0.005 mole). Duration of the reaction: 15 minutes. A light yellow precipitate of the ester (1.67 g; 94%) was obtained. M.p. >300°C. Analysis calculated for C 16 H 10 F 3 NO 5 C 54.40; H 2.85; N 3.97. found C 54.41; H 2.97; N 3.86. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.3 (t, CH 3 ); 4.2 (q, CH 2 ); 7.0 (d, H8); 7.4 (s, H5); 7.9 (d, H10); 8.5 (d, Py H); 12.4 (bs, NH). Example 8 Ethyl-1,6-dihydro-1,6-dioxo-7-hydroxy-4 H -[1]-benzopyrano[8,7-b]pyridine-2-carboxylate It was prepared according to the method disclosed in Example 1 starting from diethyl-{[(3-hydroxy-2-oxo-2 H -[1]-benzopyrano-8-yl)amino]methylene} malonate (3.15 g; 9.070 mole). Duration of the reaction: 40 minutes. Ethyl-1,6-dihydro-1,6-dioxo-7-hydroxy-4 H -[1]-benzopyrano[8,7-b]pyridine-2-carboxylate of orange brown colour (2.35 g; 86%) was obtained. M.p. >300°C. Analysis calculated for C 15 H 11 NO 6 C 59.80; H 3.68; N 4.65. found C 59.45; H 3.29; N 4.28. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.3 (t, CH 3 ); 4.2 (q, CH 2 ); 7.1-8.3 (m, Ar H, Py H); 10.4 (s, OH); 11.8 (s, NH). m/z: 302 (M + ), 171, 155, 141. Example 9 Ethyl-1,5-dihydro-1,5-dioxo-9-nitro-4 H -[1]-benzopyrano[3,4-b]pyridine-2-carboxylate To a solution of ethyl-1,5-dihydro-1,5-dioxo-4 H -[1]-benzopyrano[3,4-b]pyridine-2-carboxylate (0.81g; 2.840 mmole) in concentrated sulfuric acid (3.73 g; 0.038 mole) which was cooled to 0-5°C, a mixture of nitric acid (d=1.4; 1.01 g; 0.016 mole) and concentrated sulfuric acid (1.96 g; 0.020 mole) was added drop by drop under stirring. The reaction mixture was stirred for another 10 minutes after attaining room temperature and then it was poured to a water-ice mixture. The obtained ethyl-1,5-dihydro-1,5-dioxo-9-nitro-4 H -[1]-benzopyrano[3,4-b]pyridine-2-carboxylate was recrystallized from ethanol (0.89 g; 95%). M.p.: 246-247°C. Analysis calculated for C 15 H 10 N 2 O 7 C 54.55; H 3.05; N 8.48. found C 54.50; H 2.87; N 8.65. 1 H-NMR (TFA) δ/ppm: 1.2 (t, CH 3 ); 4.3 (q, CH 2 ); 7.4 (d, H7); 8.3 (d, H8); 9.1 (s, H10); 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-dioxo-9-amino-4 H -[1]-benzopyrano[3,4-b]pyridine-2-carboxylate To a solution of ethyl-1,5-dihydro-1,5-dioxo-9-nitro-4 H -[1]-benzopyrano[3,4-b]-pyridine-2-carboxylate (0.50 g; 1.514 mmole) in glacial acetic acid (150 ml) a catalyst (4.92% Pd/C; 0.15 g) was added and the reduction took place for 6 hours under hydrogen stream of 3 bar. After the completion of the reaction acetic acid was evaporated from the filtered reaction mixture. The obtained amine (0.59 g; 100%) was recrystallized from glacial acetic acid. M.p.: 270-272°C. Analysis calculated for C 15 H 22 N 2 O 5 xC 2 H 4 O 2 C 58.18; H 4.28; N 8.48. found C 57.94; H 4.14; N 8.24. 1 H-NMR (TFA) δ/ppm: 1.3 (t, CH 3 ); 4.4 (q, CH 2 ); 7.4-7.8 (m, Ar H); 9.2 (m, Py H); 11.3 (s, NH). Example 11 1,5-dihydro-1,5-dioxo-7-fluoro-4 H -[1]-benzopyrano[3,4-b]pyridine-2-carboxylic acid A solution of ethyl-1,5-dihydro-1,5-dioxo-7-fluoro-4 H -[1]-benzopyrano[3,4-b]-pyridine-2-carboxylate (1.70 g; 5.606 mmole) in a 10% aqueous sodium hydroxide solution (22 ml) was heated for 90 minutes at the boiling temperature and then it was boiled for about 5 minutes with active carbon. In the filtrate the acid was precipitated with a 10% aqueous hydrochloric acid solution (up to pH 2-3) and the cooled solution was left to stand for a few hours at +4°C. The obtained light yellow precipitate of the acid (1.50 g; 97%) was recrystallized from an ethyl acetate/ethanol mixture (1:1) or from N,N-dimethylformamide. M.p. >300°C. Analysis calculated for C 13 H 6 FNO 5 C 56.74; H 2.20; N 5.09. found C 56.52; H 1.84; N 5.11. 1 H-NMR (TFA) δ/ppm: 7.3-7.4 (m, 3 Ar H); 8.7 (m, Py H); 9.2 (s, NH); 11.3 (s, COOH). Example 12 4,5-dihydro-4,5-dioxo-1 H -[1]-benzopyrano[4,3-b]pyridine-3-carboxylic acid A solution of ethyl-4,5-dihydro-4,5-clioxo-1 H -[1]-benzopyrano[4,3-b]pyridine-3-carboxylate (1.90 g; 6.661 mmole) in 1 M sodium hydroxide (50 ml) was heated for 90 minutes at boiling temperature and then shortly boiled with active carbon, it was filtered and the filtrate was acidified with a 10% aqueous hydrochloric acid solution (up to pH 2-3) and the acid was precipitated (1.54 g; 95%). M.p.>300°C. Analysis calculated for C 13 H 7 NO 5 C 60.70; H 2.74; N 5.45. found C 60.37; H 2.43; N 5.51. 1 H-NMR (DMSO-d 6 ) δ/ppm: 7.5 (d, H7); 7.8 (t, H9); 8.4 (d, H10); 8.7 (m, H8, Py H); 9.2 (s, NH); 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][6,7-b]dipyridine-2,9-dicarboxylic diacid It was prepared according to the method disclosed in Example 12 starting from diethyl-1,5,8-trihydro-1,5,8-trioxo-4,11 H -[1]-benzopyrano[3,4-b][6,7-b]dipyridine-2,9-dicarboxylate (0.90 g; 121 mmole). Duration of the reaction: 45 minutes. The obtained acid was of yellow brown colour (0.45 g; 58%). M.p. >300°C. Analysis calculated for C 17 H 8 N 2 O 8 C 55.44; H 2.19; N 7.61. found C 55.22; H 2.58; N 7.50. 1 H-NMR (DMSO-d 6 ) δ/ppm: 7.1-9.5 (m, Ar H, Py H); 12.3 (d, 2 NH); 14.8 (s, COOH); 15.4 (s, COOH). m/z: 368 (M + ), 341, 264, 256, 213, 198, 188, 156, 137, 129, 91, 81, 69. Example 14 4,7-dihydro-4,7-dioxo-1 H -[1]-benzopyrano[6,7-b]pyridine-3-carboxylic acid It was prepared according to the method disclosed in Example 11 starting from ethyl-4,7-dihydro-4,7-dioxo-1 H -[1]-benzopyrano[6,7-b]pyridine-3-carboxylate (1.10 g; 3.856 mmole). Duration of the reaction: 3 hours. A light yellow precipitate of the acid (0.84 g; 85%) was obtained. M.p. >300°C. Analysis calculated for C 13 H 7 NO 5 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-1 H -[1]-benzopyrano[6,7-b]pyridine-3-carboxylic acid It was prepared according to the method disclosed in Example 12 starting from ethyl-4,7-dihydro-4,7-dioxo-8-hydroxy-1 H -[1]-benzopyrano[6,7-b]pyridine-3-carboxylate (2.83 g; 9.394 mmole). Duration of the reaction: 3 hours. A yellow precipitate of the acid (2.13 g; 83%) was obtained. M.p. >300°C. 1 H-NMR (DMSO-d 6 ) δ/ppm: 7.6-8.7 (m, Ar H); 9.4 (s, Py H); 13.4 (s, NH); 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-4 H -[1]-benzopyrano[7,6-b]pyridine-2-carboxylic acid It was prepared according to the method disclosed in Example 11 starting from ethyl-1,7-dihydro-1,7-dioxo-9-methyl-4 H -[1]-benzopyrano[7,6-b]pyridine-2-carboxylate (3.40 g; 0.011 mole). Duration of the reaction: 20 minutes. The obtained precipitate of gray white colour was recrystallized from N,N-dimethylformamide (2.32 g; 75%). Analysis calculated for C 14 H 9 NO 5 xC 3 H 7 NO C 59.30; H 4.68; N 8.14. found C 59.50; H 4.61; N 7.81. 1 H-NMR (DMSO-d 6 ) δ/ppm: 1.9 (s, CH 3 ); 6.3 (s, H8); 7.6 (d, H5); 8.0 (s, H10); 9.0 (s, Py H); 13.2 (bs, NH); 14.9 (s, COOH). Example 17 1,7-dihydro-1,7-dioxo-9-(trifluoromethyl)-4H-[1]-benzopyrano[7,6-b]pyridine-2-carboxylic acid It was prepared according to the method disclosed in Example 12 starting from ethyl-1,7-dihydro-1,7-dioxo-9-(trifluromethyl)-4 H -[1]-benzopyrano[7,6-b]pyridine-2-carboxylate (1.40 g; 3.963 mmole). Duration of the reaction: 2 hours. The obtained acid was recrystallized from the N,N-dimethylformamide/ethanol mixture (1.28 g; 99%). M.p. >300°C. Analysis calculated for C 14 H 6 F 3 NO 5 C 51.70; H 1.86; N 4.31. found C 51.48; H 1.82; N 4.27. 1 H-NMR (DMSO-d 6 ) δ/ppm: 7.2 (s, H8); 7.8 (s, H5); 8.6 (s, H10); 9.0 (s, Py H); 13.4 (bs, NH); 14.5 (bs, COOH). Example 18 1,6-dihydro-1,6-dioxo-7-hydroxy-4 H -[1]-benzopyrano[8,7-b]pyridine-2-carboxylic acid It was prepared according to the method disclosed in Example 13 starting from ethyl-1,5-dihydro-1,5-dioxo-7-hydroxy-4 H -[1]-benzopyrano[8,7-b]pyridine-2-carboxylate (2.12 g; 7.037 mmole). Duration of the reaction: 3 hours. A green brown acid (1.27 g; 66%) was obtained. M.p. >300°C. 1 H-NMR (DMSO-d 6 ) δ/ppm: 7.1-7.8 (m, Ar H, Py H); 8.6 (s, OH); 10.6 (s, NH); 15.2 (s, COOH). m/z: 273 (M + ), 212, 179, 81, 79, 61, 59, 45, 43.

Claims: Benzopyranopyridone carboxylic acids wherein the pyridone system is fused in 3,4-, 6,7- and 7,8-positions of the benzopyrano system, of the general formula I wherein R 1 R 2 = -NHCH=C(CO 2 R 6 )CO-, R 3 = NO 2 or NH 2 , R 4 = R 5 = H, R 6 = H or C 2 H 5 ; R 1 R 2 =-NHCH=C(CO 2 R 6 )CO-, R 3 = R 4 = H, R 5 = F, R 6 = H or C 2 H 5 ; R 1 R 2 =-CO(CO 2 R 6 )C=CHNH-, R 3 = R 4 = R 5 = H, R 6 = H or C 2 H 5 ; R 1 R 2 = R 3 R 4 = -NHCH=C(CO 2 R 6 )CO-, R 5 = H, R 6 = H or C 2 H 5 ; R 1 = H or OH, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 R 6 )CO-, R 6 = H or C 2 H 5 ; R 1 = OH, R 2 = R 3 = H, R 4 R 5 = -CO(CO 2 R 6 )C=CHNH-, R 6 = H or C 2 H 5 ; R 1 = R 5 = H, R 2 = CH 3 or CF 3 , R 3 R 4 =-CO(CO 2 R 6 )C=CHNH-, R 6 = H or C 2 H 5 , as well as pharmaceutically acceptable salts thereof. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 =-NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = R 4 = H, R 5 = F. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 =-CO(CO 2 C 2 H 5 )C=CHNH-, R 3 = R 4 = R 5 = H. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 = R 3 R 4 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 5 = H. The compound of the general formula I according to claim 1, characterized in that R 1 = H, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 C 2 H 5 )CO. The compound of the general formula I according to claim 1, characterized in that R 1 = OH, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 C 2 H 5 )CO-. The compound of the general formula I according to claim 1, characterized in that R 1 = R 5 = H, R 2 = CH 3 , R 3 R 4 = -CO(CO 2 C 2 H 5 )C=CHNH-. The compound of the general formula I according to claim 1, characterized in that R 1 = R 5 = H, R 2 = CF 3 , R 3 R 4 = -CO(CO 2 C 2 H 5 ) C=CHNH-. The compound of the general formula I according to claim 1, characterized in that R 1 = OH, R 2 = R 3 = H, R 4 R 5 = -CO(CO 2 C 2 H 5 )C=CHNH-. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 =-NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = NO 2 , R 4 = R 5 = H. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 =-NHCH=C(CO 2 C 2 H 5 ) CO-, R 3 = NH 2 , R 4 = R 5 = H. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 = -NHCH=C(CO 2 H)CO-, R 3 = R 4 = H, R 5 = F. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 = -CO(CO 2 H) C=CHNH-, R 3 = R 4 = R 5 = H. The compound of the general formula I according to claim 1, characterized in that R 1 R 2 = R 3 R 4 = -NHCH=C(CO 2 H) CO-, R 5 = H. The compound of the general formula I according to claim 1, characterized in that R 1 = H, R 2 = R 5 = H, R 3 R 4 =-NHCH=C(CO 2 H)CO-. The compound of the general formula I according to claim 1, characterized in that R 1 = OH, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 H)CO-. The compound of the general formula I according to claim 1, characterized in that R 1 = R 5 = H, R 2 = CH 3 , R 3 R 4 = -CO(CO 2 H)C=CHNH-. The compound of the general formula I according to claim 1, characterized in that R 1 = R 5 = H, R 2 = CF 3 , R 3 R 4 = -CO(CO 2 H)C=CHNH-. The compound of the general formula I according to claim 1, characterized in that R 1 = OH, R 2 = R 3 = H, R 4 R 5 = -CO(CO 2 H)C=CHNH-. Process for the preparation of the compounds of the general formula I according to claim 1, characterized in that the compounds of the general formula II wherein R 1 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = H, R 3 = H or NO 2 , R 5 = H or F; R 2 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 1 = R 3 = R 4 = R 5 = H; R 1 = R 3 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = R 5 = H; R 1 = H or OH, R 3 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = R 5 = H; R 1 = OH, R 2 = R 3 = R 4 = H, R 5 = -NHCH =C(CO 2 C 2 H 5 ) 2 ; R 1 = R 3 = R 5 = H, R 2 = CH 3 or CF 3 , R 4 = -NHCH = C(CO 2 C 2 H 5 ) 2 . are heated at 250-260°C for 10 minutes to 13 hours to obtain cyclized benzopyranopyridone carboxylic acid esters of the formula III wherein R 1 R 2 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = R 4 = H, R 5 = F; R 1 R 2 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = NO 2 , R 4 = R 5 = H; R 1 R 2 = -CO(CO 2 C 2 H 5 )C=CHNH-, R 3 = R 4 = R 5 = H; R 1 R 2 = R 3 R 4 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 5 = H; R 1 = H or OH, R 2 = R 5 = H, R 3 R 4 = -NHCH=C(CO 2 C 2 H 5 )CO-; R 1 = OH, R 2 = R 3 = H, R 4 R 5 = -CO(CO 2 C 2 H 5 )C=CHNH-; R 1 = R 5 = H, R 2 = CH 3 or CF 3 , R 3 R 4 = -CO(CO 2 C 2 H 5 )C=CHNH, which are compounds of the formula I wherein R 6 = C 2 H 5 , and for obtaining the compounds of the general formula I wherein R 1 R 2 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = NH 2 , R 4 = R 5 = H, the compounds of the general formula III wherein R 1 R 2 = -NHCH=C(CO 2 C 2 H 5 )CO-, R 3 = NO 2 , R 4 = R 5 = H, are reduced, and for obtaining the compounds of the general formula I, wherein R 1 , R 2 , R 3 , R 4 and R 5 have the meanings defined in claim 1 and R 6 = H, the compounds of the general formula III wherein R 6 = C 2 H 5 , are hydrolysed. Compounds of the formula I according to claim 1 for the preparation of antibacterial and antitumour agents. Use of the compounds of the formula I according to claim 1 for the preparation of antibacterial and antitumour agents.

Inventors: IVEZIC ZRINKA, KELNERIC ZELJKO, POLAK LJERKA, TRKOVNIK MLADEN, IVEZIC, ZRINKA, KELNERIC, ZELJKO, POLAK, LJERKA, TRKOVNIK, MLADEN
Applicants: PLIVA PHARM & CHEM WORKS, PLIVA, FARMACEUTSKA, KEMIJSKA, PREHRAMBENA
Application year: 1997
Main classification: C07D491
IPC codes: C07D491, A61K31, A61P35, C07D411, A61P31