The safety, tolerability and pharmacokinetics of DW-116, a new fluoroquinolone with a broad antibacterial spectrum, were evaluated in healthy male subjects after administration of single oral doses of 100, 200, 300 and 800 mg and after administration of multiple oral doses of 300 or 400 mg, respectively, for 7 days. DW-116 was well tolerated. Gastrointestinal symptoms and skin reactions were noted and considered to be possibly related to DW-116. The geometric means of the maximum plasma concentrations (Cmax) linearly increased with the dose administered from 1.19 mg/L to 8.73 mg/L after single dose administration. At steady state, the geometric mean minimum and maximum plasma concentrations were 2.14 and 5.65 mg/L, respectively, after the multiple 300 mg dose and 2.73 and 8.00 mg/L, respectively, for the multiple 400 mg dose. Tmax varied between 1 and 5 h. The terminal half-life ranged from 11.37 to 24.89 h. The geometric mean renal clearance was approximately 30 mL/min. Approximately 45% of the dose was excreted unchanged in urine within 60 h. There was no clinically relevant deviation from dose proportionality. The changes in steady-state pharmacokinetic parameters when DW-116 was taken before a high-fat breakfast were not clinically relevant. In conclusion, DW-116 was safe in this study, the first administration to human subjects. Its pharmacokinetics indicate that once-daily dosing may be possible.
Benzotriazol-1-yl akyl carbonate 1 has been found to be a new convenient and inexpensive coupling agent to prepare an active ester 2 for the synthesis of an amide 3 in good yield and with high purity.During the process of o w research for the preparation of a peristaltic stimulant, Cisapride' (3a) wluch contains an amide bond in its structure, we felt the need of more convenient and inexpensive method to prepare an amide bond in more yield and with higher purity than the conventional method.The representative one of conventional methods to form an amide bond is to react a primary or secondary amine with a suitable active este?. This reaction is generally carried out in the same vessel like one reaction from a carboxylic acid through an active ester to an amide which is a goal. 2547 LEE ET AL.The most popular and useful active ester is the one which is easily prepared by reacting a carboxylic acid with 1-HOBT (I-hydroxybenzotriazole) through the intercession of DCC ( NJ" dicyclohexylcarbodiimide)a. But this method has an defect in that DCC used as a coupling agent to prepare an active ester is transformed into DCU (N,N'-dicyclohexylu) atter the reaction preparing an active ester and this DCU is not easily removed but very often remains in a product, an amide which is usually solid'.In order to remove a problem provoked by DCC and prepare an amide economically in good yield, we have developed a new coupling agent, benzotriazol-1-yl alkyl carbonate (BAC) which can afford an active ester derived from 1-HOBT. BAC which is called a new coupling agent by us has been used as an agent carbethoxylating an alcohol, a thiol, and an a~n i n e~~~. According to our search, we have firstly used BAC as a coupling agent to afford an active ester by being treated with a carboxylic acid.On the one hand, in 1983, Mitsuru UEDA, et al, reported6 that 1,l'- [carbonyldioxy] dibenzotriazole is a new reactive condensing agent to prepare an active ester for the synthesis of amide. In the literature, 1,l'-[carbonyldioxy] dibenzotriazole was prepared from 1-HOBT and trichloromethyl carbonochloridate. But this reaction has a problem using trichloromethyl carbonochloridate which is more expensive than ethylchloroformate used for BAC preparation and after reaction to give an active ester, generates phosgene(C0Cl2) as a highly toxic agent.Herein, we report the new method preparing an active ester derived from a wboxylic acid using BAC, the mechanism involved in preparing such an active ester, and the amide bond formation using the resulting active ester. BAC (1) was conveniently prepared by reacting 1-HOBT (4)with alkylchlorofonnate under triethylamine in dimethylformamide at O°C (eq.2). The lH-1,2,3-benzotriazol-1-yl ethyl carbonate among BAC, a general formula, was isolated and identified' by comparing its melting point and J R spectrum with those reported in literature'. The results are summarized in the Table 1. These results are the case that all the processes from the preparation of BAC through an active ester (2) to an amide (J), being ...
The 1‐(5‐fluoro‐2‐pyridyl) or 1‐(3‐fluoro‐4‐pyridyl) group was introduced in the syntheses of new pyridonecarboxylic acid antibacterial agents. 1‐(5‐Fluoro‐2‐pyridyl)‐6‐fluoro‐1,4‐dihydro‐7‐(4‐methyl‐1‐piperazinyl)‐4‐oxoquinolone‐3‐carboxylic acid 7b (DW‐116) showed a moderate in vitro antibacterial activity but it was found to have very excellent pharmacokinetic profiles so that 7b (DW‐116) showed dramatic increased in vivo efficacy.
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DW-116, (1-(5-fluoro-2-pyridyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride), is a new quinolone antibiotic with a broad antibacterial spectrum against G(+) and G(-) bacteria. DW-116 was evaluated for the immunomodulating activities, which is one of the efforts to investigate the mechanism of action related to the good in vivo antibacterial efficacy. The results of in vitro studies revealed there was no statistically significant increase in B and T lymphocyte proliferation. But the results of in vivo studies showed that the number of plaque forming cells (PFC), the amount of polyclonal antibodies and delayed-type hypersensitivity (DTH) were significantly increased after the repeat administration with 12 and 60 mg/kg of DW-116. Taken together, these results proposed that immunostimulating effect of DW-116 could be one of the action mechanisms for demonstrating in vivo antibacterial activities under these experimental conditions.
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