Novel method of derivatization of an amidinourea (lidamidine) for GLC analysis.

A new quantitative GLC method for analysis of lidamidine hydrochloride (I) was developed. The method was based on derivatization of I to 1-(2,6-dimethylphenyl)-4-methylamino-dihydro-1,3,5-triazin-2-one (II) using dimethylformamide dimethylacetal reagent. Compound II was synthesized and characterized by IR, NMR, mass spectrometry, and elemental analysis. The assigned structure was in agreement with characterization analyses. Cyclization of I to a triazinone using dimethylformamide dimethylacetal reagent presented a new route for the preparation of II.

Characterization of impurities in sulfasalazine.

The chemical structures of four impurities isolated from sulfasalazine were determined. Three impurities are the by-products of the reaction process in drug synthesis, i.e., during diazotization of sulfapyridine and during coupling with salicylic acid. Only one contaminant was identified as a starting material, sulfapyridine, in the drug synthesis. The four impurities were characterized as 2-[[p-(2-pyridylsulfamoyl)-phenyl]azo]hydroxybenzene (I), 3-[[P-(2-pyridylsulfamoyl) phenyl]-azo]salicylic acid (II), 5-[[p-[4-(2-pyridylanilino)]-N-phenyl]azo]salicylic acid (III), and sulfapyridine (IV). Compounds I-III are novel molecules, and IV is the precursor of sulfasalazine. The isolation of the impurities was accomplished by TLC and liquid extraction procedures. The methods used to characterize the impurities were a combination of IR, UV, and NMR spectroscopy, mass spectrometry, and TLC. For I and III, comparisons also were made with the synthesized materials to supplement the evaluation.

Hydrolytic degradation of 2,6-dichlorobenzylthiopseudourea hydrochloride.

Degradation of 2,6-dichlorobenzylthiopseudourea hydrochloride was followed in basic medium (pH 7.5) to isolate and characterize all possible degradation products. IR, Raman, and NMR spectroscopy, TLC, and elemental analysis were used to identify the products. Degradation of base-hydrolyzed 2,6-dichlorobenzylthiopseudourea hydrochloride produced 2,6-dichlorobenzylthiol and cyanamide and was followed by oxidation (air) to produce bis(2,6-dichlorobenzyl) disulfide, dimerization to give cyanoguanidine, and hydrolysis to yield urea. The kinetics of hydrolysis at 22.5 degrees (pH 7.0 and 7.5) and at 37 degrees (pH 7.0) revealed a pseudo-first-order reaction with respect to the substrate. Apparent first-order rate constants and energy of activation, entropy of activation, and half-life values were determined.

Analytical-physical profile of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent.

The structure elucidation, physical and chemical parameters and hydrolysis kinetics of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride (WHR-1142 A, lidamidine hydrochloride), a novel antidiarrheal agent, were determined. The stability of the substance in aqueous solution (pH 1-13) was studied at 50 degrees, 65 degrees and 80 degrees C.

Antimotility and antisecretory activity of some aryl substituted amidinoureas.

A number of aryl substituted amidinoureas have been prepared and examined for their gastrointestinal spasmolytic, antimotility, antidiarrheal and antisecretory effects. In general, antisecretory and antimotility effects have been found to be associated with each other in these compounds. The structure-activity relationships found show that substitution of the aromatic ring in positions other than 2 and 6 correlates poorly with potency, and potency of such compounds is low. In contrast to this, 2,6-disubstitution confers high potency. The potency of 2,6-disubstituted compounds declines sharply with increasing weight of substitution of the amidinourea chain, with the important exception of the N-alkoxyamidinoureas. Increasing the molecular weight of an N-alkoxy substituent has a much less profound effect than the corresponding increase has in an N-alkyl substituent. High potency in an amidinourea may well be related to low basicity (or a high pKa value for its conjugate salt) but there is insufficient data to support this hypothesis fully. The actual tautomeric structure of an amidinourea probably affects its potency and this is discussed briefly.

Kinetics of hydrolysis of fenclorac.

The kinetics of hydrolysis of fenclorac were studied to determine its stability in aqueous solution at different pH's and temperatures. For this study, a stability-specific liquid chromatographic assay method was developed to separate fenclorac from its hydrolysis product, alpha-hydroxy-3-chloro-4-cyclohexylbenzeneacetic acid. The k-pH profile in the 0-12 pH range in various buffer solutions shows that fenclorac is stable in its undissociated form in strongly acidic media and is unstable in neutral and alkaline media. The instability of fenclorac in aqueous solution is proportional to the degree of ionization of the carboxyl group in the 1-4 pH range and is independent of pH above 4. The rate-determining step in the mechanism of hydrolysis of fenclorac involves ionization of the carbon-chlorine bond. The ionization is catalyzed by an intramolecular necleophilic attack on the alpha-carbon by the dissociated carboxyl group, resulting in the formation of an unstable intermediate, a three-membered ring lactone. This unstable intermediate rapidly hydrolyzes to the final hydrolysis product. This mechanism is supported by experimental evidence such as the medium effect, positive salt effect, common ion effect, and substituent effect. Arrhenius parameters for the hydrolysis of fenclorac and its 3-nitro substituted analog were obtained.