Tatyana V. Matveeva

Synthesis and Antiinflammatory and Analgesic Activity of Naproxen Amides with Amino Acid Derivatives

In recent years, there have been attempts to modify the well-known nonsteroidal antiinflammatory drugs by reactions with natural amino acids, aimed at eliminating undesired side effects of the drug action [1]. In particular, the synthesis of naproxen amide with glycine was reported in [2, 3]. The aim of this study was to obtain naproxen amides with some amino acid derivatives and characterize the products with respect to the antiinflammatory and analgesic activity and acute toxicity. The synthesis of naproxen amides (II – V) with methyl esters of (S )-methionine, (S )-phenylalanine, (S )-histidine, and (S )-leucine was based on the condensation of (S )-naproxen chloroanhydride (I) with the corresponding amino acid esters in DMF in the presence of triethanolamine (TEA) [4]:

Synthesis and Antiinflammatory and Analgesic Activity of Amino Acids Acylated with Ibuprofen

As is known, the ulcerogenic properties of nonsteroidal antiinflammatory drugs is a factor limiting their use in clinics. It was established that the side effects can sometimes be reduced by attaching a pharmacophore fragment to a natural amino acid residue. In this context, we have synthesized ibuprofen amides (I – III) by the condensation of ibuprofen chloroanhydride with methyl esters of amino acids (methionine, phenylalanine, histidine) using the method described elsewhere [1] and characterized the products with respect to the antiinflammatory and analgesic activity. The proposed structures of compounds I – III were confirmed by the results of elemental analyses and by H NMR data. According to the H NMR data, the synthesized amides represent diastereomers mixed in a 1 : 1 ratio.

Synthesis and antimycobacterial activity of N-(2-aminopurin-6-yl) and N-(purin-6-yl) amino acids and dipeptides

Synthetic routes to novel N-(purin-6-yl)- and N-(2-aminopurin-6-yl) conjugates with amino acids and glycine-containing dipeptides were developed. In vitro testing of 42 new and known compounds made it possible to reveal a series of N-(purin-6-yl)- and N-(2-aminopurin-6-yl) conjugates exhibiting significant antimycobacterial activity against Mycobacterium tuberculosis H37Rv, Mycobacterium avium, Mycobacterium terrae, and multidrug-resistant M. tuberculosis strain isolated from tuberculosis patients in the Ural region (Russia). N-(2-Aminopurin-6-yl)- and N-(purin-6-yl)-glycyl-(S)-glutamic acids were the most active compounds.

Stereoselective cyclization of alkyl N-phthaloyl-4-bromoglutamates to cyclopropane derivatives

The kinetics of the reactions of alkyl N-phthaloyl-4-bromoglutamates with Et3N and KOH was investigated. The reactions proceed stereospecifically to form alkyl 1-phthalimidocyclopropane-r-1,t-2-dicarboxylates. In alcohols, the reactions are accompanied by transesterification. The concerted mechanism accounting for the stereospecificity of these reactions is proposed.

Determining Technological Impurities in Lysomustin

The optimum ratio of isomers (1)/(2) in lysomustin is 3 : 1 [1]. The industrial drug quality standard [2] restricts the content of technological impurities in drugs. By technological (or specific) impurities are meant foreign compounds appearing in the course of production and/or storage of a given drug. The maximum permissible levels of technological impurities are established and determined using chromatographic analytical techniques. Taking into account the method of synthesis and isolation of the parent substance of lysomustin, the possible technological impurities in this drug are L-lysine (initial compound in the synthesis) and 9-(2-chloroethyl)-L-homocitrulline (CEH, intermediate product). Drugs belonging to the group of nitrosoalkylureas are classified as hydrolytically and thermally unstable and photosensitive compounds. According to the adopted technology, the parent substance of lysomustin is produced in a lyophilic dry form, which is the most stable form of the final product. However, the target compound occurs in solution for a rather long time: the period from the onset of dissolution to the moment of freezing lasts for about 6 h. In addition, the product occurs for 16 – 18 h in the frozen state before all moisture is removed, which is also a period of reduced stability. The HPLC technique used for determining the content of isomers in lysomustin [3] does not provide information on the content of technological impurities in the parent substance ort in the ready-to-use form of this drug. The aim of this study was to develop a method and select conditions for detecting the possible technological impurities and their semiquantitative determination.