600
E. V. Nosova et al.
1
C17H7F2N3O6; H NMR spectrum in DMSO-d6 (d, ppm):
8-H), 7.4 – 7.7 (m, 2H, 2¢-H, 5¢-H), 8.15 (m, 1H, 4¢-H, 6¢–H),
8.32 (m, 1H, 4¢-H, 6¢-H), 8.52 (s, 1H, CH=), 14.5 (bs, 1H,
COOH).
2-(Pyridin-4-yl)-7-oxo-7-H-9-fluoro-10-(pyrrolidin-1-
yl)-[1,3,4]oxadiazino[6,5,4-i,j]quinoline-6-carboxylic acid
3
4
7.76 (m, 1H, 2¢-H), 7.78 (dd, 1H, J 10.4, J 7.6 Hz, 8-H),
7.93 (dd, 1H, 3J 7.9 Hz, 5¢-H), 8.43 (m, 1H, 4¢-H, 6¢–H), 8.53
(m, 1H, 4¢-H, 6¢-H), 8.84 (s, 1H, CH=), 14.1 (bs, 1H,
COOH).
(IIe). To
a
solution of 0.75 g (2.0 mmole) of
2-Aryl-7-oxo-7-H-9-fluoro-10-cycloalkylimino[1,3,4]-
oxadiazino[6,5,4-i,j]quinoline-6-carboxylic acids (IIb – IId).
To a suspension of 0.6 g (1.9 mmole) of acid IIa 15 ml of an-
hydrous acetonitrile was added 0.8 g (8 mmole) of
morpholine and 6 drops of diazabicycloundecene (DBU).
The reaction mixture was boiled for 4 h and cooled. The pre-
cipitate of compound IIc was separated by filtration and
recrystallized from DMSO; yield, 0.48 g (62%); m.p.,
212 – 214°C; C21H16FN3O5; 1H NMR spectrum in DMSO-d6
(d, ppm): 3.38 [m, 4H, N(CH2)2], 3.79 [m, 4H, O(CH2)2],
7.54 (d, 1H, 3J 12.5 Hz, 8-H), 7.67 (m, 3H, 3¢-H, 4¢-H, 5¢-H),
2-(pyridin-4-yl)-7-oxo-7-H-9,10-difluoro[1,3,4]oxadiazino-
[6,5,4-i,j]quinoline-6-carboxylic acid ethyl ester in 12 ml of
acetonitrile was added 0.57 ml (8.0 mmole) of pyrrolidine
and 0.2 ml (1.5 mmole) of triethylamine. The reaction mix-
ture was boiled for 3.5 h and cooled and the precipitate was
separated by filtration. To this product were added 5 ml of
ethanol and 3 ml of 2 N hydrochloric acid and the mixture
was allowed to stand for 15 min. The precipitate of com-
pound IIe was separated by filtration and recrystallized from
DMSO; yield 0.6 g (73%); m.p., > 300°C; C20H15FN4O4; 1H
NMR spectrum in DMSO-d6 (d, ppm): 1.92 [m, 4H, (CH2)2],
2
8.00 (m, H, 2¢-H, 6¢-H), 8.60 (s, 1H, CH=), 14.6 (bs, 1H,
COOH).
3
3.67 [m, 4H, N(CH2)2], 7.28 (d, 1H, J 12.2 Hz, 8-H), 8.03
Compound IIb was obtained by an analogous procedure
using acid IIa and pyrrolidine; yield 57%; m.p., 261 – 263°C;
(d, 2H, 3J 6.0 Hz, 2¢-H, 6¢-H), 8.62 (s, 1H, CH=), 8.86 (d, 2H,
3J 6.0 Hz, 3¢-H, 5¢-H), 14.3 (bs, 1H, COOH).
1
C21H15FN3O4; H NMR spectrum in DMSO-d6 (d, ppm):
1.98 [m, 4H, (CH2)2], 3.78 [m, 4H, N(CH2)2], 7.39 (d, 1H, 3J
14.3 Hz, 8-H), 7.58 (m, 3H, 3¢-H, 4¢-H, 5¢-H), 8.39 (s, 1H,
CH=), 8.89 (m, 2H, 2¢-H, 6¢-H), 14.5 (bs, 1H, COOH).
Compound IId was obtained by an analogous procedure
using acid IIf: yield, 81%; m.p., 168 – 170°C; C21H15FN4O6;
1H NMR spectrum in DMSO-d6 (d, ppm): 2.00 [m, 4H,
EXPERIMENTAL BIOLOGICAL PART
The antibacterial activity of compounds Ia – Ik and
IIa – IIe in vitro was determined by the conventional method
of double serial dilutions in liquid nutrient medium. The ex-
periments were performed with respect to the following mi-
crobes: Bacillus subtilis ATCC 6633, Bacillus pumilus
3
(CH2)2], 3.47 [m, 4H, N(CH2)2], 7.61 (d, 1H, J 12.8 Hz,
TABLE 1. Antibacterial Activity in vitro of the Synthesized 1,3,4-Thia(oxa)diazino[6,5,4-i,j]quinoline-6-Carboxylic Acid Derivatives
MIC, mg/ml
Com-
pound
Y
R
R1
Bacillus subtilis Bacillus pumilus
Staphylococcus
Escherichia coli
ATCC 6633
NCTC 8241
aureus 209 P
157
Ia
H
F
Pyrrolidin-1-yl
F
-“-
2 – 4
2 – 4
8
8
8
32
64
Ib
Ic
Id
-“-
-“-
-“-
4
–
8
H
H
Pyrrolidin-1-yl
2 – 4
8
> 128
8
> 128
16
4-Methylpiperazin-
1-yl
Ie
If
H
H
-“-
-“-
Morpholin-1-yl
1
2
4
> 128
> 32
4-Ethoxycarbonylpi-
perazin-1-yl
> 32
> 32
> 32
Ig
Ih
Ii
H
Cyclohexylamino
Pyrrolidin-1-yl
-“-
Pyrrolidin-1-yl
-“-
> 128
32
–
> 128
16
> 128
16
Pyrrolidin-1-yl
32
4-Ethoxycarbonylpi-
perazin-1-yl
4-Ethoxycarbonylpi-
perazin-1-yl
> 32
> 32
> 32
> 32
Ij
NH(CH2)3N(CH3)2
-“-
Cyclohexylamino
Phenyl
NH(CH2)3N(CH3)2
Pyrrolidin-1-yl
F
16
> 128
4
32
64
64
4
32 – 64
> 128
> 128
> 32
Ik
Pyrrolidin-1-yl
64 – 128
IIa
IIb
IIc
IId
IIe
–
–
–
–
–
–
2
-“-
Pyrrolidin-1-yl
Morpholin-1-yl
Pyrrolidin-1-yl
-“-
1
1
-“-
4
–
4
> 128
> 32
3-Nitrophenyl
Pyridin-4-yl
Pefloxacin
> 32
> 32
2
> 32
> 32
–
> 32
> 32
1
> 128
0.5