piperidines and dicyandiamido

A rapid, simple, and precise RPLC method was developed for the simultaneous determination of the widely used oral antidiabetic, metformin hydrochloride (MTF), with some commonly coadministered oral antidiabetics from different pharmacological classes-glipizide (GPZ), pioglitazone hydrochloride (PGZ), glimepiride (GLM), and repaglinide (RPG)-in bulk, laboratory-prepared mixtures and pharmaceutical formulations in the presence of metformin-reported impurity [1-cyanoguanidine (CNG)]. Chromatographic separation was achieved using isocratic elution mode with a mobile phase of acetonitrile: 0.02 M potassium dihydrogen phosphate (pH 3.17; 50-50, v/v) flowing through a CN Phenomenex column (Phenosphere Next, 250 × 4.6 mm, 5 μm) at a rate of 1.5 mL/min at ambient temperature. UV detection was carried out at 220 nm. The method was validated according to International Conference on Harmonization guidelines. Linearity, accuracy, and precision were satisfactory for concentration ranges: 0.175-350 μg/mL for MTF, 0.0525-105 μg/mL for GPZ, 0.125-250 μg/mL for PGZ, and 0.05-100 μg/mL for GLM and RPG. Correlation coefficients were >0.99 for all analytes. LOQs were 0.009 μg/mL for MTF, 0.009 μg/mL for GPZ, 0.04 μg/mL for GLM, 0.124 μg/mL for PGZ, and 0.044 μg/mL for RPG. The developed method is specific, accurate, and suitable for the QC and routine analysis of the cited drugs in their pharmaceutical products.

Topics: Carbamates; Chromatography, High Pressure Liquid; Drug Contamination; Glipizide; Guanidines; Hypoglycemic Agents; Metformin; Pioglitazone; Piperidines; Sulfonylurea Compounds; Thiazolidinediones

Premedication with a combination of histamine H₁ receptor (H₁R) and H₂ receptor (H₂R) antagonists has been suggested as a prophylactic principle, for instance, in anaesthesia and surgery. Aiming at pharmacological hybrids combining H₁R and H₂R antagonistic activity, a series of cyanoguanidines 14-35 was synthesized by linking mepyramine-type H₁R antagonist substructures with roxatidine-, tiotidine-, or ranitidine-type H₂R antagonist moieties. N-desmethylmepyramine was connected via a poly-methylene spacer to a cyanoguanidine group as the "urea equivalent" of the H₂R antagonist moiety. The title compounds were screened for histamine antagonistic activity at the isolated ileum (H₁R) and the isolated spontaneously beating right atrium (H₂R) of the guinea pig. The results indicate that, depending on the nature of the H₂R antagonist partial structure, the highest H₁R antagonist potency resided in roxatidine-type compounds with spacers of six methylene groups in length (compound 21), and tiotidine-type compounds irrespective of the alkyl chain length (compounds 28, 32, 33), N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-N″-[2-[N-[2-[N-(4-methoxybenzyl)-N-(pyridyl)-amino] ethyl]-N-methylamino]ethyl] guanidine (25, pKB values: 8.05 (H₁R, ileum) and 7.73 (H₂R, atrium) and the homologue with the mepyramine moiety connected by a six-membered chain to the tiotidine-like partial structure (compound 32, pKB values: 8.61 (H₁R) and 6.61 (H₂R) were among the most potent hybrid compounds. With respect to the development of a potential pharmacotherapeutic agent, structural optimization seems possible through selection of other H₁R and H₂R pharmacophoric moieties with mutually affinity-enhancing properties.

Topics: Animals; Cimetidine; Guanidines; Guinea Pigs; Histamine H1 Antagonists; Histamine H2 Antagonists; Magnetic Resonance Spectroscopy; Male; Molecular Structure; Piperidines; Pyrilamine

A series of novel N-cyanoguanidine tricyclic farnesyl protein transferase (FPT) inhibitors was prepared. Replacement of a piperidine amide-group with a N-cyanoguanidine functionality increased FPT activity. X-ray crystal structure determination of 42 complexed with FPT revealed differences in the interactions of the amide and N-cyanoguanidine groups with the protein.

Topics: Alkyl and Aryl Transferases; Crystallography, X-Ray; Enzyme Inhibitors; Guanidines; Heterocyclic Compounds, 4 or More Rings; Humans; Inhibitory Concentration 50; Molecular Structure; Piperidines; Structure-Activity Relationship

Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.

Topics: Alkyl and Aryl Transferases; Amides; Benzazepines; Benzoxepins; Enzyme Inhibitors; Guanidines; Models, Chemical; Piperazines; Piperidines; Protein Prenylation; Pyridines; Structure-Activity Relationship