Pteridines. 41. Synthesis and dihydrofolate reductase inhibitory activity of some cycloalka[g]pteridines.

A number of homologous 2,4-diaminocycloalka[g]pteridines varying in ring size from 5 to 15 were prepared by (a) condensation of aminomalononitrile tosylate with alpha-oximinocycloalkanones, deoxygenation of the resulting 2-amino-3-cyanocycloalka[b]pyrazine 1-oxides, and guanidine cyclization; (b) guanidine cyclization of the above pyrazine 1-oxides to give 2,4-diaminocycloalka[g]pteridine 8-oxides, followed by deoxygenation; or (c) condensation of 2,4,5,6-tetraaminopyrimidine with a cycloalka-1,2-dione (for the cyclohepta- and cycloocta[g]pteridines only). These compounds were examined for their activity as dihydrofolate reductase inhibitors against Lactobacillus casei, rat liver, L1210, and Trypanosoma cruzi. Activity was found to depend upon ring size, with the greatest activity exhibited by the cyclododeca derivatives 31.

Common anionic receptor site hypothesis: its relevance to the antagonist action of naloxone.

Appropriate modification of 14 beta-methoxy- and 14 beta-ethoxycodeinone (prepared by alkylation of 14 beta-hydroxycodeinone) has generated four alkoxy analogues (3a-d) of naloxone and naltrexone. These agents were pure narcotic antagonists in contradiction to the predictions of the common anionic receptor site hypothesis, postulated to be of importance in the enhanced antagonism of naloxone. The molecular change from allyl to cyclopropylmethyl on the N atom increased selectivity of these antagonists for the mu receptor to the same extent as found for naloxone. Increase in the length of the C14 O-substituent had no effect on receptor selectivity, and either formation in most cases did not significantly alter oral/parenteral ratios of durations of action.

Biotransformation of amlodipine. Identification and synthesis of metabolites found in rat, dog and human urine/confirmation of structures by gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry.

Metabolism of the dihydropyridine calcium antagonist (R,S)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-3-ethoxycarbony l-5- methoxycarbonyl- 6 -methyl- 1,4-dihydropyridine (amlodipine) has been studied in animals and man using 14C-labelled drug. The metabolite patterns are complex; 18 metabolites have been isolated from rat, dog and human urine. Based on chromatographic and mass-spectral evidence, structures have been proposed for the main metabolites and confirmed by synthesis of unambiguous reference compounds. Comparison of all reference compounds and isolated metabolites was made by gas chromatography-mass spectrometry pressure liquid chromatography on-line thermospray-mass spectrometry of underivatised compounds directly in urine. The metabolites are largely pyridine derivatives. The methods used in structure designation are presented, along with the proposed route of metabolism, which indicates that the metabolic pattern for amlodipine in man has features in common with those of both rat and dog.

Dioxin and fly ash free incineration by ash pelletization and reburning.

Dioxins (DXNs) in municipal waste incinerator fly ash were effectively reduced by pelletizing the mixture of ash, cement, and sodium phosphate and reburning the pellets in a laboratory scale bubbling fluidized bed (BFB) furnace. Three types of pellets--A, B and C, of various sizes and compositions were used in the experiments. The efficiency of DXN reduction in the pellet matrix was proportional to the incineration time, temperature, and degree of pellet incineration. At 700 degrees C and incineration time sufficient for a complete burnout, the efficiency of DXN reduction in the pellets of type A and C was found to be 99.9% and 99.7%, respectively. Correspondingly, the DXN concentration in the pellets decreased from 862 ng TEQ/kg to 0.9 ng TEQ/kg for pellets A and 2.2 ng TEQ/kg for pellets C. The residual concentration of coplanar polychlorinated biphenyls (coplanar PCBs) was below 0.2 ng TEQ/kg and 0.4 ng TEQ/kg, respectively. Assuming a tortuosity factor of tau = 3 and the reaction rate constants of 0.013 m/s (at 700 degrees C) and 0.025 m/s (at 800 degrees C), the experimental pellet incineration times were reasonably predicted by using the shrinking core model. Possible DXN evaporation from the pellets was also studied. The amount of DXNs in the flue gas captured by an impinger trap was less than 3% when the reactor was operated at 700 and 800 degrees C. The described method of fly ash pelletization and reburning seems to be a relatively easy and inexpensive way to reduce both the emission of DXNs and the amount of fly ash.