New coumarin derivatives, processes for the preparation thereof and their use

Abstract: The present invention relates to new coumarin derivatives represented by the general formula I wherein R 1 = NH 2 or -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 3 = R 4 = H, R 5 = F, 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 , processes for the preparation thereof and their use as intermediates for the synthesis of new coumarin derivatives with potential biological action.

Description: The present invention relates to novel coumarin derivatives represented by the general formula I wherein R 1 = NH 2 or -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 3 = R 4 = H, R 5 = F, R 1 = R 3 = NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = R 5 = H, R 1 = 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 . According to the present invention the novel coumarin derivatives of the general formula I are prepared by reacting substituted coumarins of the formula II wherein R 1 = R 3 = NH 2 , R 2 = R 4 = R 5 = H, R 1 = OH, R 2 = R 4 = R 5 = H, R 3 = NH 2 , R 1 = OH, R 2 = R 3 = R 4 = H, R 5 = NH 2 , R 1 = NH 2 , R 2 = R 3 = R 4 = H, R 5 = F, R 1 = R 3 = R 5 = H, R 2 = CH 3 or CF 3 , R 4 = NH 2 , with diethyl-ethoxymethylene malonate of the formula III C 2 H 5 OCH=C(CO 2 C 2 H 5 ) 2 at the temperature of 120°C within a period from 10 minutes to 27 hours, whereat coumarin malonate esters of the general formula I with the above defined substituents are obtained. The starting substituted aminocoumarins of the general formula II, with the exception of the compound with R 1 = NH 2 , R 2 = R 3 = R 4 = H, R 5 = F, have already been described in the literature: F. W. Linch, J. Chem. Soc. 101 (1912) 1758; G. T. Morgan, F. M. G. Micklethwait, J. Chem. Soc. 85 (1904) 1230; G. Kokotos, C. Tzougraki, J. Heterocyclic Chem. 23 (1986) 87; I. C. Ivanov, S. K. Karagiosov, I. Manolov, Arch. Pharm. (Weinheim) 324 (1991) 61. Novel coumarin derivatives of the general formula I are useful intermediates for the synthesis of new coumarin derivatives with a potential biological action such as antimicrobial, antitumour and antiviral action. The present process is illustrated by the following examples. Example 1 3-amino-8-fluorocoumarin A solution of 3-acetylamino-8-fluorocoumarin (3.00 g, 0.014 mole) in concentrated sulfuric acid (2.65 g, 0.027 mole) was heated at 75-80°C for 1 hour. The cooled solution was poured onto an ice-water mixture and it was alkalized with a saturated NaHCO 3 water solution up to pH = 6 and subsequently left to precipitate at +4°C. The obtained 3-amino-8-fluorocoumarin was recrystallized from 50% ethanol (1.63 g, 67%). M.p.: 173-174°C. Analysis: calculated for C 9 H 6 F 3 NO 2 C = 60.34; H = 3.38; N=7.82. found C = 59.97; H = 3.22; N = 7.72. 1 H-NMR (DMSO-d 6 ). δ/ppm: 5.9 (s, NH 2 ), 6.7 (s, H4); 7.1-7.2 (m, H5 - H7). m/z: 178 (M - ), 151, 141, 134, 127. Comparative Example Diethyl-{[(2-oxo-2 H [1]-benzopyrano-6-yl)amino]methylene} malonate A solution of 6-aminocoumarin (2.00 g, 0.012 mole) in diethyl-ethoxymethylene malonate (3.03 g, 0.014 mole) was heated for 10 minutes at 120°C, whereat a solidification of the reaction mixture occurred. The obtained light brown precipitate of diethyl-{[(2-oxo-2 H [1]-benzopyrano-6-yl)amino]methylene} malonate (3.95 g, 96%) was recrystallized from ethanol. M.p.: 141-142°C. Analysis: calculated for C 17 H 17 NO 6 C = 61.62; H = 5.17; N = 4.23. found C = 61.87; H = 4.99; N = 4.17. 1 H-NMR (DMSO-d 6 ). δ/ppm: 1.3 (t, CH 3 ), 4.3 (q, CH 2 ); 6.6 (d; H3); 7.7 (d, H8); 7.9 (d, H7), 8.5 (d; H5); 10.0 (d; H4); 12.4 (bs, NH). Example 2 Tetraethyl-{[(2-oxo-2 H [1]-benzopyrano-3,6-di-yl)diamino]dimethylene} malonate It was prepared according to the method described in the Comparative Example starting from 3,6-diaminocoumarin (1.00 g, 5.676 mmole) and diethyl-ethoxymethylene malonate (2.81 g, 0.013 mole). Reaction duration: 6 hours. Recrystallization from ethanol gave yellow-green crystals of tetraethyl-{[(2-oxo-2 H [1]-benzopyrano-3,6-di-yl)diamino]- dimethylene} malonate (2.55 g, 87%). M.p.: 131-134°C. Analysis: calculated for C 25 H 28 N 2 O 10 C = 58.13; H = 5.46; N = 5.43. found C = 57.74; H = 5.19; N = 5.40. 1 H-NMR (DMSO-d 6 ). δ/ppm: 1.2 (t, CH 3 ), 4.2 (q, CH 2 ); 7.4 (m, C H), 7.6 (s, H5); 7.9 (s, H4); 8.2-8.5 (m; H7-H8); 10.6-10.8 (m; 2NH). Example 3 Diethyl-{[(3-hydroxy-2-oxo-2 H [1]-benzopyrano-6-yl)amino]methylene} malonate It was prepared according to the method described in the Comparative Example starting from 6-amino-3-hydroxycoumarin (0.88 g, 4.967 mmole). Reaction duration: 1 hour. The yellow-brown precipitate of diethyl-{[(3-hydroxy-2-oxo-2 H [1]-benzopyrano-6-yl)-amino]methylene}malonate obtained by cooling the solution was recrystallized from glacial acetic acid (1.52 g, 88%). Analysis: calculated for C 17 H 17 NO 7 C = 58.79; H = 4.93; N = 4.03. found C = 58.64; H = 4.64; N = 4.25. 1 H-NMR (DMSO-d 6 ). δ/ppm: 1.3 (t, CH 3 ), 4.2 (q, CH 2 ); 7.1-8.4 (m; Ar H); 10.5 (s; NH); 10.8 (d; OH). m/z: 347 (M + ), 302, 149, 79, 61, 45, 43. Example 4 Diethyl-{[(3-hydroxy-2-Oxo-2 H [1]-benzopyrano-8-yl)amino]methylene} malonate It was prepared according to the method described in the Comparative Example starting from 8-amino-3-hydroxycoumarin (1.93 g, 0.011 mole). Reaction duration: 4 hours. Recrystallization from glacial acetic acid gave a precipitate of diethyl-{[(3-hydroxy-2-oxo-2 H [1]-benzopyrano-8-yl)amino]methylene} malonate in the form of brown shiny plate crystals (3.37 g, 89%). Analysis: calculated for C 17 H 17 NO 7 C = 58.79; H = 4.93; N = 4.03. found C = 58.98; H = 4.89; N = 3.91. 1 H-NMR (DMSO-d 6 ). δ/ppm: 1.3 (t, CH 3 ), 4.2 (q, CH 2 ); 7.1-8.5 (m; Ar H); 10.7 (s; NH); 11.1 (d; OH). m/z: 347 (M + ), 302, 273, 199, 177, 70, 61, 47. Example 5 Diethyl-{[(8-fluoro-2-oxo-2 H [1]-benzopyrano-3-yl)amino]methylene} malonate It was prepared according to the method described in the Comparative Example starting from 3-amino-8-fluorocoumarin (2.00 g, 9.250 mmole). Reaction duration: 5 hours. Cooling of the solution gave the precipitate of light yellow diethyl-{[(8-fluoro-2-oxo-2 H [1]-benzo-pyrano-3-yl)amino]methylene} malonate, which was recrystallized from ethanol (2.76 g, 95%). M.p.: 175-177°C. Analysis: calculated for C 17 H 16 FNO 6 C = 58.45; H = 4.62; N = 4.01. found C = 58.38 H = 4.46; N = 3.98. Example 6 Diethyl-{[(4-methyl-2-oxo-2 H [1]-benzopyrano-7-yl)amino]methylene} malonate It was prepared according to the method described in the Comparative Example starting from 7-amino-4-methylcoumarin (5.00 g, 0.029 mole). Reaction duration: 30 minutes. The precipitated diethyl-{[(4-methyl-2-oxo-2 H [1]-benzopyrano-7-yl)amino] methylene} malonate was recrystallized from ethanol (9.70 g, 98%). M.p.: 139-140°C. Analysis: calculated for C 18 H 19 NO 6 C = 62.60; H = 5.55; N = 4.06. found C = 61.97 H = 5.05; N = 4.25. Example 7 Diethyl-{[(4(trifluoromethyl)-2-oxo-2 H [1]-benzopyrano-7-yl)amino]methylene} malonate It was prepared according to the method described in the Comparative Example starting from 7-amino-4-trifluoromethyl)coumarin (3.00 g, 0.015 mole). Reaction duration: 27 hours. By cooling yellow diethyl-{[(4-trifluoromethyl-2-oxo-2 H [1]-benzopyrano-7-yl)-amino]methylene} malonate was precipitated, which was recrystallized from ethanol (4.83 g, 92%). M.p.: 125-126°C. Analysis: calculated for C 18 H 16 F 3 NO 6 C = 54.14; H = 4.04; N = 3.51. found C = 54.12 H = 4.17; N = 3.46. 1 H-NMR (DMSO-d 6 ). δ/ppm: 1.3 (t; CH 3 ); 4.2 (q; CH 2 ); 6.8 (s, H3), 7.4-7.6 (m; H6, H8, CH); 8.4 (d, H5); 10.7 (d; NH).

Claims: Coumarin derivatives of the general formula I wherein R 1 = NH 2 or -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 3 = R 4 = H, R 5 = F, R 1 = R 3 = NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = R 5 = H, R 1 = 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 . Coumarin derivative of the formula I of claim 1, characterized in that R 1 = NH 2 , R 2 = R 3 = R 4 = H, R 5 = F. Coumarin derivative of the formula I of claim 1, characterized in that R 2 = R 4 = R 5 = H, R 1 = R 3 = -NHCH=C(CO 2 C 2 H 5 ) 2 . Coumarin derivative of the formula I of claim 1, characterized in that R 1 = OH, R 3 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 4 = R 5 = H. Coumarin derivative of the formula I of claim 1, characterized in that R 1 = OH, R 2 = R 3 = R 4 = H, R 5 = -NHCH=C(CO 2 C 2 H 5 ) 2 . Coumarin derivative of the formula I of claim 1, characterized in that R 1 = -NHCH=C(CO 2 C 2 H 5 ) 2 , R 2 = R 3 = R 4 = H, R 5 = F. Coumarin derivative of the formula I of claim 1, characterized in that R 1 = R 3 = R 5 = H, R 2 = CH 3 , R 4 = -NHCH=C(CO 2 C 2 H 5 ) 2 . Coumarin derivative of the formula I of claim 1, characterized in that R 1 = R 3 = R 5 = H, R 2 = CF 3 , R 4 = -NHCH=C(CO 2 C 2 H 5 ) 2 . A process for the preparation of compounds of the general formula I of claim 1, characterized in that the compounds of the general formula II wherein R 1 = R 3 = NH 2 , R 2 = R 4 = R 5 = H, R 1 = OH, R 2 = R 4 = R 5 = H, R 3 = NH 2 , R 1 = OH, R 2 = R 3 = R 4 = H, R 5 = NH 2 , R 1 = NH 2 , R 2 = R 3 = R 4 = H, R 5 = F, R 1 = R 3 = R 5 = H, R 2 = CH 3 or CF 3 , R 4 = NH 2 , and diethyl-ethoxymethylene malonate of the formula III C 2 H 5 OCH=C(CO 2 C 2 H 5 ) 2 are heated at the temperature of 120°C within a period from 10 minutes to 27 hours, followed by cooling, whereat coumarin malonate esters are precipitated.

Inventors: IVEZIC ZRINKA, POLAK LJERKA, TRKOVNIK MLADEN, IVEZIC, ZRINKA, POLAK, LJERKA, TRKOVNIK, MLADEN
Applicants: PLIVA PHARM & CHEM WORKS, PLIVA FARMACEUTSKA, KEMIJSKA, PREHRAMBENA I KOZMETICKA INDUSTRIJA, DIONICKO DRUSTVO
Application year: 1997
Main classification: C07D311
IPC codes: A61K31, C07D311