61014-91-3

We developed new intravenous sedative-hypnotic compounds with the isoindolin-1-one skeleton focusing on the water-soluble property and in vivo safety. We synthesized approximately 170 derivatives and evaluated their hypnotic effects by intravenous administration of the compounds to mice. A series of the 2-phenyl-3-[2-(4-methyl-1-piperazinyl)-2-oxoethyl]isoindolin-1-one analogs, 3(-), 5(-), 27(-), and 47(-) [JM-1232(-)], showed potent sedative-hypnotic activity with good water solubility and a wide safety margin. The hypnotic doses (HD50s) of these 4 compounds when administered to mice were 2.35, 1.90, 2.17, and 3.12 mg/kg, respectively, and the lethal doses (LD50s) were 88.67, 64.69, >120, and >120 mg/kg, respectively. The therapeutic indexes (LD50/HD50) were 37.73, 34.05, >55.30, and >38.46, respectively. Among these compound, 47(-) [JM-1232(-)] is being considered as the most potential candidate for clinical trials in humans.

A series of 2,3-dihydro-2-oxo-1H-benzimidazole-l-carboxamide derivatives bearing a piperazine moiety was synthesized. Their in vitro 5-HT4, 5-HT3, and D2 receptors affinities were evaluated by radioligand binding assay. For selected compounds functional studies at the 5-HT4 receptor were made by using precontracted (by carbachol) preparations of rat esophageal tunica muscularis mucosae (TMM). The influence of the 3-substituent of the benzimidazole ring, the 4-substituent of the piperazine moiety, and the alkylene spacer was studied. Compounds with an ethyl or a cyclopropyl substituent in the 3-position of the benzimidazole ring showed moderate to high affinity (K(i) = 6.7-75.4 nM) for the 5-HT4 receptor with selectivity over 5-HT3 and D2 receptors and moderate antagonist activity (pK(b) = 6.19- 7.73). Compounds with an isopropyl substituent in the 3-benzimidazole position exhibited moderate and selective 5-HT4 affinity (K(i) ≥ 38.9 nM) and a partial agonist activity (5a, i.a. = 0.94) higher than that of the reference compound BIMU 8 (i.a. = 0.70). This reversal of the pharmacological activity due only to a small structural difference might confirm the existence of two binding sites on the 5-HT4 receptor. In the alkylene spacer, a two-methylene chain is favorable to optimize the affinity and the antagonist or the partial agonist activity. In the ethyl and cyclopropyl series, 5-HT4 antagonist activity seems to be unrelated to the size of the 4-substituent of the piperazine moiety, whereas a methyl group is optimal for high partial agonist activity in the isopropyl series; however, the presence of a butyl substituent is a favorable pattern for 5-HT4 antagonism and even causes a reversal of the pharmacological profile in the isopropyl series (5h, pK(b) = 7.94). N-Butyl quaternization of 5a led to an improvement in affinity for the 5-HT4 receptor and maintained the high partial agonist activity (5r, K(i) = 66.3 nM, i.a. = 0.93).

This invention relates to tri- and tetra-substituted-oxetanes, e.g. (±)-cis- and (±)-trans-2-[(4-(4-isopropylpiperazin-1-yl)phenoxy)methyl]-4-(2,4-dihalophenyl)-4-[1H-1,2,4-triazol-1-yl)-methyl]oxetane and tri- and tetra-substituted-tetrahydrofurans, e.g. (±)-cis- and (±)-trans-1-[4-[[2-(2,4-dihalophenyl)tetrahydro-2-[(1H-azol-1-yl)methyl]-5-furanylmethoxy]phenyl]-4-yl-1-substituted piperazine-3-one and related derivatives which exhibit antifungal and antiallergy activities, pharmaceutical composition thereof, methods of their use in treating or preventing susceptible fungal infections and allergic reactions in a host including warm-blooded animals such as humans.

This invention relates to tri- and tetra--substituted-oxetanes of the formula,e.g. (±)-cis- and (±)-trans-2-[(4--(4-isopropylpiperazin-1-yl)phenoxy)methyl]-4-(2,4--dihalophenyl)-4-[1H-1,2,4-triazol-1-yl)methyl]oxetane and tri- and tetra- substituted-tetrahydrofurans, e.g. (±)--cis- and (±)-trans-1-[4-[[2-(2,4-dihalophenyl)tetrahydro--2-[(1H-azol-1-yl)methyl]-5-furanyl]methoxy]phenyl]-4-yl--1-substituted piperazine-3-one and related derivatives which exhibit antifungal and antiallergy activities, pharmaceutical composition thereof, methods of their use in treating or preventing susceptible fungal infections and allergic reactions in a host including warm-blooded animals such as humans.