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|a In this study, a number of prodrugs have been synthesized starting from Non-steroidal anti inflammatory drugs such as Ibuprofen, Indomethacin, Naproxen, Aspirin, Captopril and Isoniazid. The modification process started from the conversion of carboxyl group which is existing in these drugs (except in Isoniazid) into esters, chlorides and acid hydrazide. The drugs have been linked to each other and to itself via amide linkage through the reaction of their acid chlorides and acid hydrazides to afford 1,2-diacyl hydrazine derivatives(M17-M27). Some acid hydrazides have been treated with isophthaloyl chloride to Benzene-1,3-dicarbo hydrazide-1,3-Bis substituent(M28-M30). The same hydrazides have been treated with Benzen-1,3,5-tri carbonyl tri chloride to afford Benzen-1,3,5-tricarbhydrazide-1,3-Tris substituent (M31-M33). Compounds M28 and M29 have been treated with POCl3 to afford Bis-substituent-5-phenyl-1,3,4-Oxadizole(M34-M35). Another modification onto drugs has been done through the linking of these drugs with quinazoline nucleus through amide linkage to afford N-(4-oxo-2-phenylquinazolin-3(4H)-yl)amide-substit derivatives (M38-M42). Another modification has been carried out through the reaction of hydrazides with Aromatic aldehydes to afford the mono hydrazide-hydrazones derivatives or Schiff's bases (M43-M65) and di hydrazide-hydrazones derivatives in which two moles from hydrazide have been treated with one mole of dialdehyde(M66-M73). In addition, new hydrazones have been synthesized through the reaction of hydrazides with Isatin nucleus which is well known as biological active center to afford the compounds (M74-M77) with good biological activity. Benzodiazepines have been obtained through the reaction of Isoniazid hydrazones with glycene phthalimide and p-aminobenzoic acid(M82-M92). Indomethacin hydrazones have been treated with acetic anhydride to afford 1-[2-(substituent)-5-(5-methoxy-2-methyl-1H-indol-3-ylmethyl)-[1,3,4]oxadiazol-3-yl]-ethanone derivatives (93-M97).
|a The Derivatives of 5-substit-2-Mercapto-1,3,4-Oxadiazole(M98-M103) have been obtained through the reaction of the drug hydrazides with CS2 in the presence of KOH . The oxadizoles have been treated with hydrazine hydrate to afford 4-amino-5-sub-4H-1,2,4-triazole-3-thiol derivatives for the Non-steroidal anti-inflammatory drugs(M104-M107). In addition, 5-sub-1,3,4-Oxadiazole-2-amine derivatives have been obtained through the reaction of drug hydrazides with BrCN(M108-M111). The compound 5-{1-[4-(2-methylpropyl)phenyl]ethyl}-N3-phenyl-4H-1,2,4-triazole-3,4-diamine (M113) has been synthesized through the reaction of the compound 2-{2-[4-(2-methylpropyl)phenyl]propanoyl}-N-phenylhydrazinecarbothioamide (M112) with hydrazine hydrate. The ester compound 2-hydroxyphenyl 2-[4-(2-methylpropyl)phenyl]propanoate (M114) have been obtained through the reaction of Ibuprofen chloride with salicylic acid. The two compounds, 2-(4-Isobutyl-phenyl)-propionic acid [1-(4-methyl-piperazin-1-ylmethyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazide (M115) and 2-(4-Isobutyl-phenyl)-propionic acid [5-fluoro-1-(4-methyl-piperazin-1-ylmethyl)-2-oxo-1,2-dihydro-indol-3-ylidene]-hydrazide (M116) have been obtained through the reaction of M74, M77 with excess of formaldehyde and equimolar of N-methyl piperazine. The synthesized compounds have been identified using Infra-red spectroscopy FTIR, Nuclear Magnetic resonance (1H,13C), Mass spectroscopy and X-Ray. In addition , the changes in physical properties such as melting points, boiling points and color have been considered. Finally, the biological activity of some synthesized compounds has been evaluated and some of them have shown good biological activity especially those containing Isatin nucleus (M74-M77) and (M115-M116).
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