1024
A. Foroumadi et al. / Il Farmaco 58 (2003) 1023Á1028
/
was recorded on a Bruker DRX-500 Avance instrument.
Chemical shifts are reported in parts per million (d)
relative to tetramethyl silane as an internal standard.
Hz), 8.24 (s, 1H, H4-imidazole), 4.55 (q, 2H, CH2, Jꢀ
7.1 Hz), 4.35 (s, 3H, CH3), 4.07Á4.05 (m, 4H, CH2,
piperazine), 3.85Á3.83 (m, 4H, CH2, piperazine), 1.43
ppm (t, 3H, CH3, Jꢀ7.1 Hz).
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2.2. Synthesis of compounds 5aÁl
/
2.2.4. 1-Cyclopropyl-6-fluoro-7-{4-[5-(2-nitrophenyl)-
1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-
3-quinoline carboxylic acid (5d)
This compound was prepared as described for 5a in
69% yield. Reaction time: 8 h, temperature: 120 8C, m.p.
2.2.1. 1-Cyclopropyl-6-fluoro-7-{4-[5-(1-methyl-5-nitro-
2-imidazolyl)-1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-
oxo-1,4-dihydro-3-quinoline carboxylic acid (5a)
A mixture of compound 3a (246 mg, 1 mmol),
ciprofloxacin (331 mg, 1 mmol) and sodium bicarbonate
(84 mg, 1 mmol) in dimethylformamide (DMF) (5 ml)
was heated under reflux at 90 8C for 6 h. The solvent
was removed under reduced pressure. Water was added
to the residue, the solids were filtered, washed with H2O
and crystallized from DMF giving 448 mg of 5a in 83%
289Á
(CÄ
O) and 1591, 1337/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.68 (s, 1H, H2-quinoline), 8.01 (d, 1H,
phenyl, Jꢀ8 Hz) 7.96 (d, 1H, H5-quinoline, Jꢀ13.0
Hz), 7.85Á7.79 (m, 2H, phenyl), 7.78Á7.74 (m, 1H,
phenyl), 7.65 (d, 1H, H8-quinoline, Jꢀ7.2 Hz), 3.87Á
3.78 (m, 5H, 4H, piperazine and 1H, CH), 3.57Á3.53 (m,
4H, piperazine), 1.36Á1.20 ppm (m, 4H, cyclopropyl).
/
290 8C (dec.) (DMF). IR (KBr) nmax: 1728, 1628
/
/
/
/
/
/
/
yield, m.p. 307Á
(CÄ
O) and 1523, 1366/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.70 (s, 1H, H2-quinoline), 8.2 (s, 1H, H4-
imidazole), 7.97 (d, 1H, H5-quinoline, Jꢀ13 Hz), 7.66
(d, 1H, H8-quinoline, Jꢀ7 Hz), 4.35 (s, 3H, CH3),
3.88Á3.84 (m, 4H, piperazine), 3.60Á3.53 (m, 5H, 4H,
piperazine and 1H, CH), 1.34Á1.20 ppm (m, 4H,
cyclopropyl).
/
310 8C (dec.). IR (KBr) nmax: 1715, 1619
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/
2.2.5. 1-Ethyl-6-fluoro-7-{4-[5-(2-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-
quinoline carboxylic acid (5e)
This compound was prepared as described for 5b in
73% yield, reaction time: 12 h, temperature: 90 8C, m.p.
/
/
/
/
284Á
(CÄ
O) and 1532, 1352/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.98 (s, 1H, H2-quinoline), 8.03 (d, 1H,
phenyl, Jꢀ7.9 Hz), 7.99 (d, 1H, H5-quinoline, Jꢀ13.0
Hz), 7.84Á7.75 (m, 3H, phenyl), 7.29 (d, 1H, H8-
quinoline, Jꢀ7.0 Hz), 4.64Á4.60 (m, 2H, CH2), 3.80Á
3.76 (m, 4H, piperazine), 3.58Á3.53 (m, 4H, piperazine),
1.45 ppm (t, 3H, CH3, Jꢀ7.0 Hz).
/
286 8C (dec.) (DMF). IR (KBr) nmax: 1712, 1628
2.2.2. 1-Ethyl-6-fluoro-7-{4-[5-(1-methyl-5-nitro-2-
imidazolyl)-1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-
1,4-dihydro-3-quinoline carboxylic acid (5b)
A mixture of compound 3a (246 mg, 1 mmol),
norfloxacin (319 mg, 1 mmol) and sodium bicarbonate
(84 mg, 1 mmol) in DMF (5 ml) was heated under reflux
at 90 8C for 6 h. The solvent was removed under reduced
pressure. Water was added to the residue, the solids were
filtered, washed with H2O and crystallized from DMF
/
/
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2.2.6. 1-Ethyl-6-fluoro-7-{4-[5-(2-nitrophenyl)-1,3,4-
thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-1,8-
naphthyridine-3-carboxylic acid (5f)
This compound was prepared as described for 5c in
80% yield, reaction time: 12 h, temperature: 120 8C, m.p.
giving 370 mg of 5b in 70% yield, m.p. 302Á
/
304 8C
(dec.). IR (KBr) nmax: 1720, 1625 (CÄ
/
O) and 1520, 1330/
1
cm (NO2). H NMR (DMSO-d6, 500 MHz) d: 8.98 (s,
1H, H2-quinoline), 8.2 (s, 1H, H4-imidazole), 8.16 (d,
1H, H5-quinoline, Jꢀ
line, Jꢀ7 Hz), 4.64Á4.59 (m, 2H, CH2), 4.35 (s, 3H,
CH3), 3.85Á3.81 (m, 4H, piperazine), 3.61Á3.56 (m, 4H,
piperazine), 1.44 ppm (t, 3H, CH3, Jꢀ7 Hz).
/
13 Hz), 7.27 (d, 1H, H8-quino-
285Á
(CÄ
O), 1523, 1372/cm (NO2). 1H NMR (DMSO-d6, 500
MHz) d: 9.01 (s, 1H, H2-quinoline), 8.16 (d, 1H, H5-
quinoline, Jꢀ13.2 Hz), 8.02 (d, 1H, phenyl, Jꢀ7.9 Hz),
7.88Á7.84 (m, 1H, phenyl), 7.83Á7.81 (m, 2H, phenyl),
4.55 (q, 2H, CH2, Jꢀ7.0 Hz), 4.07Á4.05 (m, 4H,
piperazine), 3.79Á3.77 (m, 4H, piperazine), 1.42 ppm
(t, 3H, CH3, Jꢀ7.0 Hz).
/
287 8C (dec.) (DMF). IR (KBr) nmax: 1715, 1628
/
/
/
/
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/
2.2.3. 1-Ethyl-6-fluoro-7-{4-[5-(1-methyl-5-nitro-2-
imidazolyl)-1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-
1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (5c)
A mixture of compound 3a (246 mg, 1 mmol),
enoxacin (320 mg, 1 mmol) and sodium bicarbonate
(84 mg, 1 mmol) in DMF (5 ml) was heated under reflux
at 90 8C for 6 h. The solvent was removed under reduced
pressure. Water was added to the residue, the solids were
filtered, washed with H2O and crystallized from DMF
/
/
/
/
2.2.7. 1-Cyclopropyl-6-fluoro-7-{4-[5-(3-nitrophenyl)-
1,3,4-thiadiazole-2-yl]-1-piperazinyl}-4-oxo-1,4-dihydro-
3-quinoline carboxylic acid (5g)
This compound was prepared as described for 5a in
69% yield, reaction time: 10 h, temperature: 120 8C, m.p.
giving 444 mg of 5c in 84% yield, m.p. 315Á
(dec.). IR (KBr) nmax: 1715, 1625 (CÄO) and 1523, 1363/
cm (NO2). H NMR (DMSO-d6, 500 MHz) d: 9.01 (s,
1H, H2-quinolone), 8.17 (d, 1H, H5-quinolone, Jꢀ13.3
/
316 8C
303Á
(CÄ
O) and 1523, 1372/cm (NO2). 1H NMR (DMSO-d6,
500 MHz) d: 8.70 (s, 1H, H2-quinoline), 8.58Á8.55 (m,
1H, phenyl), 8.33Á8.30 (m, 1H, phenyl), 8.25Á8.23 (m,
/
305 8C (dec.) (DMF). IR (KBr) nmax: 1712, 1628
/
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1
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