Novel coumarin derivatives with expected biological activity

A number of novel 3-bromo-4-methyl-7-methoxy-8-amino substituted coumarins and 2-substituted 7-bromo-6-methyl-8H-pyrano-benzimidazoles, benzoxazoles and/or benzoxazine-8-ones were synthesized for the purpose of pharmacological evaluation. Some representative compounds showed antitumor activity in vitro on Ehrlich ascites carcinoma in the preliminary testing.


Introduction
A review article dealing with the varied physiological activities of coumarin derivatives has been published, describing their anticoagulant, antibacterial, antihelminitic, hypothermal properties and vasodilatatory action [1].During the last twenty years, the study of the biological activities of coumarin derivatives has been the aim of many researchers [2][3][4][5].Also, the structure activity relationships of coumarins have revealed that the presence of substituted thiocarbonylmercaptoacetylamino derivatives is an essential feature of their pharmacological action.Based on these findings, we describe the synthesis of some compounds featuring different heterocyclic rings fused onto the coumarin moiety with the aim of obtaining more potent pharmacologically active compounds.
In contrast with the condensation of isothiocyanates, the amino derivative 10 condensed with phenyl isocyanate and propyl isocyanate without cyclization to give disubstituted ureas, namely Nphenyl (or propyl) -N`-[3-bromo-7-hydroxy-4-methyl coumarin-8-yl] urea (15a,b) respectively.The structure of 15a was confirmed by its mass spectrum that showed a molecular ion peak (M + ) at m/z 388 and 390.The structure of 15b was confirmed by its mass spectrum that showed the molecular ion peak (M + ) at m/z 354 and 356.Also, the .55ppm (2H, dd, aromatic protons, J = 10 Hz).The mass spectrum 17c showed the expected molecular ion peak (M + ) which is the base peak, at m/z 397 and 399.Also, the mass spectrum of 17d showed the expected molecular ion peak (M + ) at m/z 451 and 453.

Biological Screening
Some of the prepared compounds 1a,  It is clear from the tabulated results that compound 15a is the most active promising compound, while compounds 4, 6, 14a, 15a, 17a, and 20b showed no activity.

Experimental
Melting points were taken on Electrothermal capillary melting point apparatus and are uncorrected.The microanalyses were done at Faculty of Science, Cairo University.Infrared spectra were recorded on a Beckmann FT/IR3303, using KBr disks. 1 H-NMR spectra were recorded on JEOL EX-270 MHz NMR Spectrometer.Mass spectra were recorded on a Finnigan Mat SSQ-7000 mass spectrometer.

3-Bromo-7-hydroxy-4-methyl-8-nitrocoumarin (1a)
A mixture of 3-bromo-7-hydroxy-4-methyl coumarin [5] (5.1 gm, 0.02 mole) and concentrated sulphuric acid (30 ml) was stirred at 0 o C for 15 minutes.Then a mixture of concentrated nitric acid (1.5 ml, d 1.4) and sulphuric acid (5 ml, 98%) was added.The temperature was kept at 0-5 o C during the period of addition, and the mixture was then continuously stirred for 2 hours at 5 o C. The reaction mixture was poured into ice/cold water, the precipitate formed was filtered and dried, then purified by column chromatography using silica gel eluting with petroleum ether/benzene (1:1) to isolate the 6nitro isomer, then using methanol to isolate 8-nitro isomer (cf.Table 2).

3-Bromo-7-methoxy-4-methyl-8[substituted thiocarbonylmercaptoacetyl amino]coumarins (5a-d)
A solution of the ammonium salt of the appropriate substituted dithiocarbamic acid [7] (0.001 mole) in dry acetone was added while stirring to a suspended of 4 (0.36 gm, 0.001 mole) in dry acetone.Stirring was continued for 30 minutes at room temperature.The reaction mixture was then refluxed for 15 hours, cooled, the precipitate formed was filtered off and recrystallized (cf.Table 2).