Characterization of polymorphs of a novel quinolinone derivative, TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone).

The polymorphic forms and amorphous form of TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)-quinolinone), a newly developed antiallergenic compound, were characterized by powder X-ray diffractometry, thermal analysis, infrared spectroscopy and solid state 13C-NMR. The intrinsic dissolution rates of polymorphic forms were measured using the rotating disk method at 37 degrees C. The dissolution rates correlated well with the thermodynamic stability of each polymorphic form. These dissolution properties were clearly reflected in the oral bioavailability of TA-270 in rats. The transition behavior for each polymorph and for the amorphous form was studied under the high temperature and humidity conditions. The beta- and delta-forms were transformed into the alpha-form by heating. The amorphous form was also easily crystallized into alpha-form by heating, however it was relatively stable under humidified conditions. The internal molecular packing of each polymorph was estimated from IR and solid state NMR spectral analysis.

Inhibitory effect of a novel quinolinone derivative, TA-270, on asthmatic inflammatory responses in sensitized guinea pigs.

TA-270 (4-hydroxy-1-methyl-3-octyloxy-7-sinapinoylamino-2(1H)- quinolinone), a novel quinolinone derivative, was designed as an antioxidant to scavenge reactive oxygen species. Here, we investigated the effects of TA-270, in comparison with several antiasthmatic drugs, on asthmatic responses as induced by ovalbumin in sensitized guinea pigs. When orally administered 1 h before and 3 h after the antigen challenge, TA-270 at 10 mg/kg and higher doses significantly inhibited both immediate and late responses in airway resistance induced by the antigen. The inhibitory effects were comparable to or superior, at least under the present experimental conditions, to those of several clinically used antiasthmatic drugs. Furthermore, TA-270, in a dose-dependent manner, reduced accumulation of pulmonary inflammatory cells, especially eosinophils, and significantly reversed the airway hyperresponsiveness to acetylcholine 24 h after the antigen challenge. These results suggest that TA-270 may be of therapeutic use for bronchial asthma.

Radical scavenging properties of novel benzopyran derivatives, TA248 and TA276, and effects of the compounds on ischemic/reperfused myocardium in dogs.

Characteristics of novel benzopyran derivatives, TA248 and TA276, and their effects on myocardial contraction in ischemic/reperfused hearts in dogs were examined. TA248 and TA276 inhibited NADPH-dependent lipid peroxidation induced by Fe(3+) in the rat brain homogenate. Both compounds reduced *O(2-) produced by xanthine-xanthine oxidase system in a dose-dependent manner. TA276 scavenged.OH generated by Fenton reaction in a dose-dependent manner. TA248 also inhibited the.OH production, but the effect was neither complete nor dose dependent. Myocardial contraction was assessed as segment shortening of the left ventricular wall in pentobarbital-anesthetized open-chest dogs. The segment shortening was decreased by the left anterior descending coronary artery ligation (ischemia) and returned by release of the ligated artery (reperfusion). The segment shortening did not recover fully during reperfusion. Either TA248 or TA276 injected 10 min before ischemia improved the recovery of myocardial contraction during reperfusion. Both compounds preserved the level of ATP in the 60-min reperfused myocardium. However, the level of lipid peroxides was not changed by TA248 and TA276. TA248 and TA276 may protect myocardium against ischemic/reperfusion insult, partly because of their free radical scavenging activity, but no significant change in myocardial lipid peroxide level was observed.