Arch. Pharm. Pharm. Med. Chem. 2003, 336, 18–30
4-Imino- and 4-Oxo-1,4-dihydrocinnoline-3-carboxylic 29
Physical and analytical data for 9 are shown inTable 5.Example
of spectral data for 9 b: IR (KBr): νmax cm–1 = 3950–3780 (NH),
1690 (C=O). 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 2.7 (s,
3 H, CH3-Ar), 3,8 (d, 3 H, N-CH3), 4.9 (bs, 1 H, NH-CH3), 5.9 (s,
2 H, CH2), 7.2–7.4 (m, 5 H, Ar-H), 7.8–7.9 (m, 2 H, Ar-H),
8.1–8.3 (m, 2 H, Ar-H + NH2), 10.8 (bs, 1 H, CO-NH).
Synthesis of ethyl 1-alkyl-1,4-dihydro-4-iminocinnoline-3-car-
boxylates 6 and ethyl 1-alkyl-1,4-dihydro-4-oxocinnoline-3-
carboxylates 6
To a stirred suspension of the appropriate esters 4 (10 mmol) in
CH3CN or DMF was added 15 mmol DBU or K2CO3 (for benzyl
derivatives) and the mixtures were refluxed for 0.5 h. After that
the alkylating agents (25 mmol) were added dropwise and the
mixtures were refluxed for 2 h before being evaporated down to
1/3 volume. The remaining solutions were rendered alkaline
with 10 % ammonia. The crude products were filtered off and
crystallized from a mixture of DMF and water.
Synthesis of 1-alkyl-1,4-dihydro-4-iminocinnoline-3-carboxylic
acid amides and 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carb-
oxylic acid amides 7
Compounds 7 were synthesized as described above for com-
pound 6.
Physical and analytical data for 7 are shown inTable 6.Example
of spectral data for 7 b: IR (KBr): νmax cm–1 = 3250–31250 (NH),
1680 (C=O). 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 1.4–1.5
(t, 3 H, CH3), 4.7–4.9 (q, 2 H, CH2), 8.0 (s, 1 H, Ar-H), 8.1 (s, 1 H,
Ar-H), 8.2–8.4 (bs, 2 H, CONH2), 10.3 (s, 1 H, NH).
Physical and analytical data for 6 are shown inTable 2.Example
of spectral data for 6 g: IR (KBr): νmax cm–1 = 3270–3000 (NH),
1700 (C=O). 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 1.2–1.5
(dt, 6 H, CH3), 3.7–3.8 (q, 2 H, N-CH2), 4.3–4.4 (q, 2 H, –OCH2),
7.2–7.6 (m, 2 H, Ar-H), 8.0–8.2 (d, 1 H, Ar-H), 9.6 (s, 1 H, NH);
6 r: IR (KBr):νmax cm–1 = 1700, 1680 (C=O). 1H NMR (300 MHz,
DMSO-d6): δ (ppm) = 1.3–1.6 (t, 3 H, CH3), 4.2–4.5 (q, 2 H,
CH2), 5.9 (s, 2 H, CH2-Ar), 7.5–8.0 (m, 6 H, Ar-H), 8.3 (d, 2 H,
Ar-H).
Synthesis of 1-alkyl-1,4-dihydro-4-iminocinnoline-3-hydrox-
amic
acids
and
1-alkyl-1,4-dihydro-4-oxocinnoline-3-
hydroxamic acids 8
To a stirred solution of the appropriate esters 4 (10 mmol) in
DMF was added DBU (15 mmol) and the mixtures were reflux-
ed for 0.5 h.After that the hydroxylamine hydrochloride solution
25 mmol was added dropwise and mixtures were stirred for
20 h.The solvents were evaporated to 1/2 volume and acidified
with 30 % CH3COOH and filtered. The products were purified
by crystallization from mixture DMF and water with charcoal.
Synthesis of 1-alkyl-1,4-dihydro-4-iminocinnoline-3-carboxylic
acids 10
Compounds 10 a–k were synthesized as described in [13].
Physical and analytical data for 10 a–k are shown in Table 3.
Example of spectral data for 10 h: IR (KBr): νmax cm–1 = 3200–
3050 (OH, NH), 1670 (C=O). 1H NMR (300 MHz, DMSO-d6): δ
(ppm) = 1.4–1.5 (t, 3 H, CH3), 4.6–4.8 (q.2 H, CH2), 7.9–8.1 (m,
2 H, Ar-H), 8.3–8.4 (d, 1 H, Ar-H), 10.6 (s, 1 H, NH).
Physical and analytical data for 8 are shown inTable 6.Example
of spectral data for 8c: IR (KBr): νmax cm–1 = 3050–2860 (NH,
OH), 1660 (C=O). 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 6.0
(s, 2 H, CH2), 7.2–7.4 (m, 5 H, Ar-H), 8.4-8.5 (d, 2 H, Ar-H),
8.9–9.0 (s, 1 H, NH), 10.5 (s, 1 H, NH).
Synthesis of 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic
acids 10
X-ray structure determination
A stirred suspension of 5 mmol esters 6 and 2 M solution
(20 cm3) NaOH was refluxed for 2 h. After cooling the mixtures
were acidified with 30 % CH3COOH and filtered. The products
were purified by crystallization from CH3COOH with charcoal.
Physical and analytical data for 10 l–m are shown in Table 3.
X-ray data were collected on four-circle diffractometer KM-4 at
room temperature with Cu Kα. The structure was solved by di-
rect method and refined with SHELXL [19].
Crystal data and structure refinement details for 10 b.
Example of spectral data for 10 l: IR (KBr): νmax cm–1
=
2900–2400 (OH), 1675 (C=O). 1H NMR (300 MHz, DMSO-d6):
δ (ppm) = 1.4–1.5 (t, 3 H, CH3), 4.6–4.8 (q, 2 H, CH2), 7.9–8.0
(m, 1 H, Ar-H), 8.4–8.5 (dd, 1 H, Ar-H), 8.9–9.0 (m, 1 H, Ar-H).
Empirical formula
Crystal system and space group
Unit cell dimensions (A and °)
C17H15N3O2
monoclinic, P21/c
7.579(2)
14.808(3)
12.679(3)
90.10(3)
1456.8(6); 4
616
3–80
a
b
c
β
Synthesis of 4-aminocinnoline-3-carboxylic acid hydrazides 5
and 4-hydroxycinnoline-3-carboxylic acid hydrazides 5
Volume [A] and Z
F(000)
Theta range in data collection [°]
No. of reflections:
A solution of esters 4 or 6 (10 mmol) and DBU (15 mmol) in
DMF (50 cm3) was refluxed for 0.5 h. To the reaction mixtures
the corresponding hydrazines (10 mmol) were added and the
mixtures were heated under reflux for 2 h. After cooling water
(50 cm3) was added and the mixtures were left for 24 h.The sol-
ids were filtered off, washed with hot ethanol, and crystallized
from mixture DMF and water.
– collected 4019
– unique 2857
– observed 2254
Data/parameter ratio
Goodness of fit (on F2)
Final R (Rw)
10
1.017
0.048
Physical and analytical data for 5 are shown inTable 4.Example
of spectral data for 5 a: IR (KBr): νmax cm–1 = 3900–3550 (NH),
1690 (C=O). 1H NMR (300 MHz, DMSO-d6): δ (ppm) = 2.7 (s,
3 H, CH3-Ar), 4.5 (bs, 2 H, NH2), 7.8–7.9 (m, 2 H, Ar-H), 8.1–8.3
(m, 2 H, Ar-H + NH2), 10.5 (bs, 1 H, CONH).
Largest difference peak (e/Å3)
0.19
In vitro antibacterial activity
Synthesis of 1-alkyl-1,4-dihydro-4-iminocinnoline-3-carboxylic
acids hydrazides and 1-alkyl-1,4-dihydro-4-oxocinnoline-3-
carboxylic acid hydrazides 9
The minimal inhibitory concentrations (MICs) of the
studied compounds were determined according to the
method of serial twofold dilutions in agar, recommended
by NCCLS (National Committee for Clinical Laboratory
Compounds 9 were synthesized as described above for com-
pounds 5.