L. V. Anikina

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 Activity of the Products of Interaction of 4-Aroyl-1,2-dihydro-4H-pyrrolo[5,1-c][1,4]benzoxazine-1,2,4-triones with 4-Amino-1,2,4-triazole

Previously we studied the interaction of 4-aroyl-2,4-dihydro-4H-pyrrolo[5,1-c][1,4]benzoxazine-1,2,4-triones and 3-aroyl-1,2,4,5-tetrahydropyrrolo[1,2-a]quinoxaline-1,2,4triones with various nucleophilic reagents [1 – 4] and characterized some of the synthesized compounds with respect to pharmacological activity [3]. To our knowledge, the reactions of hetereno[a]-2,3-dihydro-2,3-pyrrolodiones and their monocyclic analogs with 4-amino-1,2,4-triazole were not studied until now.

Synthesis and Antiinflammatory and Analgesic Activity of N-[2-(p-Hydroxyphenyl)-1,1-dialkylethyl]malonamic Acid Esters and Hydrazides

The group of malonamic acid esters, amides, and hydrazides [1] contains substances possessing anticonvulsant [2], antiinflammatory [3], and tuberculostatic [4] activity. Recently [5], we have found a new synthetic pathway to N-[2-( p-hydroxyphenyl)-1,1-dialkylethyl]malonamic acid ethylates via substituted spiro-(1-pyrroline-3,1 -cyclohexadienes). It was of interest to study the pharmacological properties of both the new malonamic acid derivatives and some of the intermediate spiropyrrolines (IIIa, IIIb). At this stage, we have studied the antiinflammatory and analgesic activity of a series of spiranes (IIIa, IIIb) and amides (IVa – IVg). For comparison, we have also synthesized and characterized some N-substituted amides of benzoic (IVc, IVd), benzylthiocarboxylic (IVe), and phenylacetic (IVf) acids.

Synthesis and biological activity of n-acyl-4-phenyl-1,2-epoxy-2,3,3a,4,5,9b-hexahydro-1h-cyclopenta[c]quinolines

Oxidation of substituted N-acyl-4-phenyl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolines led to the corresponding 1,2-epoxides and 1,2-diols. The synthesized 1,2-epoxides were characterized with respect to acute toxicity, cytotoxicity, analgesic activity, and influence on locomotion and exploration in an open-field test.

Antiinflammatory and Analgesic Activity of N-(3,3-Dimethyl-3,4-dihydroisoquinol-1-yl)amino Acids

As is known, the structural modification of well-known antiinflammatory compounds (ibuprofen, indomethacin, etc.) by reactions with amino acids sometimes leads to an increase in the main pharmacological effect, a decease in toxicity, and a change in the mechanism of antiinflammatory action of the derivatives [1 – 10]. The purpose of this study was to determine the influence of various amino acid residues on the antiinflammatory and analgesic activity of a series of compounds containing the same 3,4-dihydroisoquinoline matrix. Previously [11], we described the synthesis and studied the antiarrhythmic activity of amidinoacids IVa, IVb, IVd – IVh. These stable, water-soluble and low-toxicity substances has proved to be convenient objects for investigation. In this study, we have synthesized and characterized a group of derivatives of nine natural and synthetic amino acids, including amidinoacids IV – VI, in comparison to their synthetic precursors – 3,4-dihydroisoquinolones VII – IX. It was reported that substituted isoquinolones possess antiinflammatory [12] and analgesic [13, 14] activity. Amidinoacids IV – VI were obtained by boiling thiolactim esters I – III in ethanol with the corresponding amino acids A – NH2. Dihydroisoquinolones VII – IX were synthesized using hydrolysis of compounds I – III conducted as described elsewhere [15]. Physicochemical characteristics of the synthesized compounds presented in Tables 1 and 2 are consistent with the proposed structure. Similar to the initial amino acids, amidinoacids IV – VI probably represent intracomplex salts. This is confirmed by their solubility in water and by the spectroscopic characteristics. Indeed, the IR spectra of compounds IV – VI exhibit diffuse absorption in the region of 2400 – 2800 cm corresponding to the vibrations of carboxylate groups and N–H bonds of iminium groups. The iminium groups can be also responsible for the absorption bands at 1640 – 1680 cm – 1 (C=N stretching vibrations). The H NMR spectra (Table 2) indicate that protons of the carboxy and amidino groups participate in the fast exchange: the signals from these protons appear only in the presence of CF3CO2H (spectra of compounds IVc, Vc, Ve, and Vh), that is, under conditions where dissociation of the X–H bonds is suppressed. Another feature of the H NMR spectra is inequivalence of the 3-(CH3)2 groups and 4-CH2 protons in compounds containing asymmetric centers in the amino acid fragments.

Synthesis and Study of the Analgesic and Antiinflammatory Activity of α-Acetoxyphenylacetic Acid Amides

(for R see Table 1) The initial compounds Ia – Ij were obtained using the method described in [1]; the acetylation reaction with acetic anhydride was performed on heating in benzene. The yields and physicochemical characteristics of acetyl derivatives IIa – IIj are presented in Table 1. The target products were obtained with a yield of 50 – 67%. All compounds are readily soluble in DMSO, DMF, acetone, and ethanol; compounds IIa and IIb are moderately soluble in water. The proposed structures of compounds IIa – IIj were confirmed by the H NMR spectroscopic data. The spectra display singlet signals due to protons of the CH groups ( = 6.00 – 6.20 ppm) and CH 3 groups of the acetyl component ( = 2.00 – 2.18 ppm). In the spectra of compounds IIb, IId, and IIg, the signals from protons of the alkyl groups range within = 0.81 – 4.37 ppm. The spectra also contain signals due to the protons of amide groups; the spectrum of unsubstituted amide IIa displays two signals from protons of the NH group, which is evidence of hindered rotation in the amide group. Compounds IIa – IId, IIh, and IIi were characterized with respect to their antiinflammatory and analgesic properties. The results of these tests are summarized in Table 2. It was established that only compound IIi produced a reliable analgesic action comparable with that of a reference drug (analgin). At the same time, all compounds exhibited pro-