Synthesis and pharmacological activities of some dibenzopyrazolocinnolines and dibenzopyridazinoquinoxalines

Article abstract of DOI:10.1007/s10593-011-0726-z

Derivatives of three new classes of heterocyclic compounds have been synthesized. The first class comprises the synthesis of pyrimidino- and imidazolopyrazolopyridazine using 11 H-dibenzo[f,h]pyrazolo[3,4-c]-cinnoline-13- amine. The second class involves

Full text of DOI:10.1007/s10593-011-0726-z

Chemistry of Heterocyclic Compounds, Vol. 47, No. 1, April, 2011 (Russian Original Vol. 47, No. 1, January, 2011)
SYNTHESIS AND PHARMACOLOGICAL ACTIVITIES
OF SOME DIBENZOPYRAZOLOCINNOLINES AND
DIBENZOPYRIDAZINOQUINOXALINES
A. M. Amer1*, A. F. El-Farargy1, N. M. Yousif 2, and A. A. Fayed2
Derivatives of three new classes of heterocyclic compounds have been synthesized. The first class comprises
the synthesis of pyrimidino- and imidazolopyrazolopyridazine using 11H-dibenzo[f,h]pyrazolo[3,4-c]-
cinnoline-13-amine. The second class involves the synthesis of triazine derivatives using 11H-dibenzo-
[f,h]pyrazolo[3,4-c]cinnoline-13-diazonium chloride. The third class deals with the synthesis of polycyclic
compounds using dibenzo[f,h]pyridazino[4,5-b]quinoxaline-10,13-diamine. The pharmacological screening
has shown that several of these compounds have good antiparkinsonian activities comparable to
Benzatropine. The detailed synthesis, spectroscopic data, and pharmacological properties are reported.
Keywords: pyridazine, pyrimidine, triazine, antiparkinsonian activity.
Pyrimidines, pyridazines, pyrazoles, and triazines play an essential role in several biological processes
and have considerable chemical and pharmacological importance. In particular, these compounds can be found
in nucleoside antibiotics and in antibacterial, cardiovascular, as well as agrochemical and veterinarian products
[1–9]. In view of these observations and in continuation of our interest in developing efficient synthesis of
polyfunctionally substituted heterocycles we used the readily obtainable pyrazoles as starting materials [10–13].
We have previously described the synthesis of 11H-dibenzo[f,h]pyrazolo[3,4-c]cinnoline-13-amine (2)
from phenanthraquinone 1 [14]. Therefore, in the present work we have focused on the reactions of compound
2. The compound 2 reacted with oxalyl chloride to afford imidazolo derivative 3. The reactions of compound 2
with acrylonitrile and cinnamaldehyde yielded compounds 4 and 5, respectively (Scheme 1).
Reaction of diazonium salt 6 with dimedone, resorcinol, and β-naphthol afforded triazine derivatives
7-9, respectively. The reaction occurred by azocoupling followed by cyclization to form the new polycyclic
compounds (Scheme 2).
Similarly, the reaction of diazonium salt 6 with appropriate active hydrogen reagents, namely, ethyl
acetoacetate, acetylacetone, ethyl cyanoacetate, benzoylacetonitrile, benzoylacetone, and malononitrile yielded
compounds 10–15 (Scheme 3).
_______
* To whom correspondence should be addressed, e-mail: nada_5eg@yahoo.com.
1Chemistry Department, Faculty of Science, Zagazig University, Zagazig, Egypt.
2National Research Center, Photochemistry Department, Cairo, Dokki, Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 129-135, January, 2011. Original
article received March 20, 2009, revised version submitted October 8, 2010.
0009-3122/11/4701-0101©2011 Springer Science+Business Media, Inc.
101

Scheme 1
CH2CN
NH2
O
N
O
O
N
N
N
N
N
(COCl)2
H
NH
N
N
HN
O
H2N
1
O
2
3
H2C CHCN
Ph
C C CHO
H
H
N
N
N
N
N
N
N
HN
N
N
NH2
Ph
4
5
Scheme 2
N
N
N
N
Dimedone
2
N
NH
+
N
N
N
N
–
N
Cl
-Naphthol
N
Me
Me
6
O
N
7
Resorcinol
N
N
N
N
N
N
N
N
N
N
N
OH
9
8
102

Scheme 3
N
N
N
6
N
R
N
N
R1
10–15
Compound
Reagent
R
R1
10
11
12
13
14
15
Ethyl acetoacetate
Acetylacetone
Me
Me
OH
Ph
COOEt
COMe
CN
Ethyl cyanoacetate
Benzoylacetonitrile
Benzoylacetone
Malononitrile
CN
Me
NH2
COPh
CN
We have also focused on the preparation and reactions of quinoxalinedicarbonitrile 16. Compound 16
reacted with hydrazine hydrate to afford pyrazine derivative 17 which reacted with acetic anhydride to afford
diamide 18. Reaction of compound 17 with oxalyl chloride or diethyl malonate afforded imidazole and
pyrimidine derivatives 19 and 20, respectively (Scheme 4).
Scheme 4
NH2
NHCOMe
Ac2O
CN
CN
N
N
N
N
N
N
NH2NH2
N
N
N
1
N
NH2
NHCOMe
16
17
18
(COCl)2
CH2(COOEt)2
O
N
O
N
O
O
N
N
N
N
N
N
N
OH
OH
N
N
N
O
O
19
20
103

TABLE 1. Antiparkinsonian Activity of the Tested Compounds
% decrease
of Oxotremorine-
induced effects
Salivation and
lacrimation score
Potency relative
to Benzatropine
Compound
Tremor score
0
Control
0
1
2
1
2
1
2
3
3
0
1
2
1
2
1
2
3
3
0
26
12
19
16
21
11
5
Benzatropine
1
3
0.45
0.81
0.61
0.82
0.43
0.17
0.14
4
8
10
15
18
19
4
Compounds 4 and 10 were the most potent antiparkinsonian agents of those tested (Table 1), while
compounds 3, 8, and 15 showed moderate antiparkinsonian activity.
EXPERIMENTAL
All melting points were taken on an Electrothermal IA 9000 series digital melting point apparatus.
Elemental analysis data were obtained from the Microanalytical Unit, Cairo University, Cairo, Egypt. The IR
1
spectra (KBr) were recorded on a Perkin-Elmer model 1430 spectrophotometer. The H NMR spectra were
recorded at 270 MHz on a Perkin-Elmer R12B spectrometer using TMS as an internal standard. The mass
spectra were recorded using VG 2AB-3F spectrometer (EI, 70 eV). All reactions were followed by TLC (silica
gel, aluminum sheets 60 F254, Merck).
15H-Dibenzo[f,h]imidazo[1',2':1,5]pyrazolo[3,4-c]cinnoline-13,14-dione (3). A mixture of amine 2
(0.28 g, 1 mmol) and oxalyl chloride (0.13 g, 1 mmol) in DMF (20 ml) and a few drops of piperidine was
refluxed for 6 h and, after cooling, poured into ice water. The solid product was collected and recrystallized
from DMF/ethanol to give compound 3 as a reddish-brown solid. Yield 58%; mp 267°C. IR spectrum, , cm-1:
1
1682 (C=O), 1657 (C=O amide). H NMR spectrum, , ppm: 7.42-7.85 (8H, m, H Ar); 11.12 (1H, br. s, NH).
Mass spectrum, m/z (Irel, %): 339 [M]+ (18), 268 (100), 104 (60). Found, %: C 67.20; H 2.69; N 20.58.
C19H9N5O2. Calculated, %: C 67.25; H 2.67; N 20.64.
15,16-Dihydrodibenzo[f,h]pyrimido[1',2':1,5]pyrazolo[3,4-c]cinnoline-13-amine (4). A mixture of amine
2 (0.28 g, 1 mmol) and acrylonitrile (0.05 g, 1 mmol) in DMF (20 ml) and a few drops of piperidine was refluxed for
8 h and, after cooling, the solid product was collected and recrystallized from DMF/ethanol to give compound 4 as a
1
brown powder. Yield 64%; mp >300°C. IR spectrum, , cm-1: 3250–3120 (NH, NH2), 1620 (C=N). H NMR
spectrum, , ppm (J, Hz): 3.21 (2H, d, J = 6.6, CH2); 6.40 (1H, t, J = 6.6, H-14); 7.59 (9H, m, H Ar + NH); 10.24
(2H, s, NH2). Mass spectrum, m/z (Irel, %): 338 [M]+ (20), 322 (10), 297 (26). Found, %: C 70.92; H 4.21; N 24.81.
C20H14N6. Calculated, %: C 70.99; H 4.17; N 24.83.
13-Phenyldibenzo[f,h]pyrimido[1',2':1,5]pyrazolo[3,4-c]cinnoline (5). To a solution of amine 2
(0.28 g, 1 mmol) in pyridine (30 ml), cinnamaldehyde ( 0.13 g, 1 mmol) was added. The reaction mixture was
refluxed for 4 h and poured into ice water containing HCl. The solid product was collected by filtration and
recrystallized from a DMF/ethanol mixture to give compound 5 as a brown powder. Yield 58%; mp 257°C. IR
spectrum, , cm-1: 1610 (C=N), 1540 (C=C). 1H NMR spectrum, , ppm (J, Hz): 7.58 (13H, m, H Ar); 8.48 (1H,
d, J = 5.5, H-14); 8.69 (1H, d, J = 5.5, H-15). Mass spectrum, m/z (Irel, %): 397 [M]+ (32); 371 (17); 296 (43).
Found, %: C 78.51; H 3.82; N 17.60. C26H15N5. Calculated, %: C 78.57; H 3.80; N 17.62.
104

14,14-Dimethyl-14,15-dihydro[1,2,4]benzotriazino[4',3':1,5]pyrazolo[3,4-c]dibenzo[f,h]cinnolin-
16(13H)-one (7). A stirred solution of amine 2 (0.28 g, 1 mmol) in 35% HCl (7 ml) was diazotized at 0-5°C by a
solution of 30% aq. NaNO2 (7 ml) to yield the diazonium salt 6. A cooled solution of diazonium salt 6 was
added to a solution of dimedone (1 mmol) and sodium acetate (5 g) in ethanol (30 ml). The reaction mixture was
stirred at room temperature for 2 h, and the solid product was collected by filtration and recrystallized from ethanol
to give compound 7 as a green powder. Yield 68%; mp >300°C. IR spectrum, , cm-1: 1715 (C=O), 1615 (C=N).
1H NMR spectrum, , ppm: 1.20 (6H, s, 2CH3); 2.12 (2H, s, CH2); 2.30 (2H, s, CH2); 7.21–7.63 (8H, m, H Ar).
Mass spectrum, m/z (Irel, %): 418 [M]+ (18), 392 (9), 297 (100). Found, %: C 71.71; H 4.36; N 20.12. C25H18N6O.
Calculated, %: C 71.75; H 4.33; N 20.08.
Synthesis of Compounds 8 and 9. The cooled solution of diazonium salt 6 (1 mmol) was added dropwise
while stirring at 0-5°C to a solution of resorcinol or β-naphthol (1 mmol) and sodium acetate (5 g) in ethanol (30 ml)
to give compounds 8 and 9, respectively.
1,2,4-Benzotriazino[4',3':1,5]pyrazolo[3,4-c]dibenzo[f,h]cinnolin-14-ol (8) was crystallized from
DMF. Red powder; yield 77%; mp >300°C. IR spectrum, , cm-1: 3450 (OH), 1612 (C=N). 1H NMR spectrum,
, ppm: 7.18 (7H, m, H Ar); 8.10 (4H, m, H Ar); 13.21 (1H, br. s, OH). Mass spectrum, m/z (Irel, %): 388 [M]+
(22), 268 (100), 108 (24). Found, %: C 71.15; H 3.13; N 21.61. C23H12N6O. Calculated, %: C 71.12; H 3.11;
N 21.64.
Dibenzo[f,h]naphtho[2",1":5',6'][1,2,4]triazino[4',3':1,5]pyrazolo[3,4-c]cinnoline (9) was crystallized
1
from DMF. Brown powder; yield 84%; mp 185°C. IR spectrum, , cm-1: 1618 (C=N), 1520 (C=C). H NMR
spectrum, , ppm: 7.24–7.68 (8H, m, H Ar); 8.41–9.40 (6H, m, H Ar). Mass spectrum, m/z (Irel, %): 422 [M]+
(50), 394 (32), 270 (27), 62 (100). Found, %: C 76.78; H 3.38; N 19.92. C27H14N6. Calculated, %: C 76.77;
H 3.34; N 19.89.
Synthesis of Compounds 10–15. The cooled solution of diazonium salt 6 (1 mmol) was added
dropwise while stirring to a solution of active methylene reagents (0.13 g ethyl acetoacetate, 0.10 g acetyl
acetone, 0.11 g ethyl cyanoacetate, 0.15 g benzoylacetonitrile, 0.16 g benzoylacetone, or 0.07 g malononitrile)
and sodium acetate (5 g) in ethanol (30 ml) to give compounds 10–15, respectively.
Ethyl 13-Methyldibenzo[f,h][1,2,4]triazino[4',3':1,5]pyrazolo[3,4-c]cinnoline-14-carboxylate (10)
was crystallized from ethanol. Yellow powder; yield 69%; mp 298°C. IR spectrum, , cm-1: 1715 (C=O), 1625
1
(C=N). H NMR spectrum, , ppm (J, Hz): 1.23 (3H, s, CH3); 2.15 (3H, t, J = 7.5, CH3); 2.92 (2H, q, J = 7.5,
CH2); 7.14 (8H, m, H Ar). Mass spectrum, m/z (Irel, %): 408 [M]+ (45), 379 (40), 335 (100). Found, %: C 67.67;
H 3.91; N 20.52. C23H16N6O2. Calculated, %: C 67.63; H 3.94; N 20.57.
14-Acetyl-13-methyldibenzo[f,h][1,2,4]triazino[4',3':1,5]pyrazolo[3,4-c]cinnoline (11) was crystallized
from ethanol. Green powder; yield 72%; mp >300°C. IR spectrum, , cm-1: 1710 (C=O), 1644 (C=N). 1H NMR
spectrum, , ppm: 1.90 (3H, s, CH3); 3.01 (3H, s, COCH3); 7.68-7.92 (8H, m, H Ar). Mass spectrum, m/z (Irel,
%): 378 [M]+ (14), 350 (30), 363 (22), 335 (100). Found, %: C 69.80; H 3.78; N 22.25. C22H14N6O. Calculated,
%: C 69.83; H 3.73; N 22.21.
13-Hydroxydibenzo[f,h][1,2,4]triazino[4′,3′:1,5]pyrazolo[3,4-c]cinnoline-14-carbonitrile (12) was
crystallized from methanol. Yellow crystals; yield 71%; mp >300°C. IR spectrum, , cm-1: 3210 (OH), 2210 (C≡N).
1H NMR spectrum, , ppm: 7.24–7.86 (8H, m, H Ar ); 13.12 (1H, br. s, OH). Mass spectrum, m/z (Irel, %): 363 [M]+
(31), 240 (100). Found, %: C 66.15; H 2.41; N 26.95. C20H9N7O. Calculated, %: C 66.11; H 2.49; N 26.98.
13-Phenyldibenzo[f,h][1,2,4]triazino[4',3':1,5]pyrazolo[3,4-c]cinnoline-14-carbonitrile (13) was
crystallized from ethanol. Brown crystals; yield 66%; mp 295°C. IR spectrum, , cm-1: 2210 (C≡N), 1605
1
(C=N), 1470 (C=C). H NMR spectrum, , ppm: 6.89–7.92 (13H, m, H Ar). Mass spectrum, m/z (Irel, %): 423
[M]+ (46), 395 (7), 397 (25), 346 (10), 297 (100). Found, %: C 73.70; H 3.14; N 23.14. C26H13N7. Calculated, %:
C 73.74; H 3.09; N 23.15.
105

14-Benzoyl-13-methyldibenzo[f,h][1,2,4]triazino[4',3':1,5]pyrazolo[3,4-c]cinnoline
(14)
was
crystallized from ethanol. Brown crystals; yield 67%; mp >300°C. IR spectrum, , cm-1: 1716 (CO), 1600
(C=N), 1470 (C=C). 1H NMR spectrum, , ppm: 2.49 (3H, s, CH3), 7.61–7.96 (13H, m, H Ar). Mass spectrum,
m/z (Irel, %): 440 [M]+ (31), 268 (100). Found, %: C 73.65; H 3.68; N 19.22. C27H16N6O. Calculated, %:
C 73.62; H 3.66; N 19.18.
13-Aminodibenzo[f,h][1,2,4]triazino[4',3':1,5]pyrazolo[3,4-c]cinnoline-14-carbonitrile (15) was
crystallized from ethanol. Yellow crystals; yield 78%; mp >300°C. IR spectrum, , cm1: 3380 (NH2), 2229
1
(C≡N), 1614 (C=N), 1512 (C=C). H NMR spectrum, , ppm: 7.85 (4H, m, H Ar); 8.10 (4H, m, H Ar); 11.24
(2H, br. s, NH2). Mass spectrum, m/z (Irel, %): 362 [M]+ (40), 334 (100). Found, %: C 66.34; H 2.76; N 30.97.
C20H10N8. Calculated, %: C 66.29; H 2.78; N 30.92.
Dibenzo[f,h]quinoxaline-2,3-dicarbonitrile (16). A mixture of 9,10-phenanthrenequinone 1 (0. 21g,
1 mmol), diaminodicyanoethane (0.11 g, 1 mmol), ethanol (30 ml), and acetic acid (3 drops) was refluxed with
stirring for 2 h. The resulting solid product was collected and recrystallized from ethanol to give compound 16
as red crystals. Yield 75%; mp 220-222°C. IR spectrum, , cm1: 3079 (CH aromatic), 2220 (2CN), 1617
(C=N). Found, %: C 77.04; H 2.92; N 19.71. C18H8N4. Calculated, %: C 77.10; H 2.87; N 19.71.
Dibenzo[f,h]pyridazino[4,5-b]quinoxaline-10,13-diamine (17). A mixture of compound 16 (0.22 g,
1 mmol), hydrazine hydrate (0.10 g, 1.5 mmol), and n-butanol (40 ml) was refluxed for 3 h. The resulting solid
product was collected and recrystallized from ethanol to give compound 17 as a brown powder. Yield 68%; mp
1
>300°C. IR spectrum, , cm-1: 3620, 3536 (2NH2), 3289 (CH aromatic), 1616 (C=N). H NMR spectrum, ,
ppm: 7.74–7.96 (8H, m, H Ar); 10.31 (4H, s, 2NH2). Mass spectrum, m/z (Irel, %): 312 [M]+ (36), 296 (27), 270
(100). Found, %: C 69.43; H 3.91; N 26.71. C18H12N6. Calculated, %: C 69.23; H 3.87; N 26.90.
N,N'-(Dibenzo[f,h]pyridazino[4,5-b]quinoxaline-10,13-diyl)diacetamide (18).
A
mixture of
compound 17 (0.31 g, 1 mmol) and acetic anhydride (20 ml) was refluxed for 2 h. The resulting solid product
was collected and recrystallized from petroleum ether to give compound 18 as a reddish-brown solid. Yield
1
65%; mp >300°C. IR spectrum, , cm-1: 3380 (NH), 1675 (C=O amide), 1618 (C=N). H NMR spectrum, ,
ppm: 1.32 (6H, s, 2CH3); 7.20-7.61 (8H, m, H Ar); 11.21 (2H, br. s, 2NH). Mass spectrum m/z (Irel, %): 396
[M]+ (15); 312 (100). Found, %: C 66.52; H 4.11; N 21.22. C22H16N6O2. Calculated, %: C 66.66; H 4.06;
N 21.20.
Dibenzo[f,h]diimidazo[1',2':1,6;1",2":2,3]pyridazino[4,5-b]quinoxaline-2,3,6,7-tetrone (19).
A
mixture of compound 17 (0.31 g, 1 mmol) and oxalyl chloride (0.13 g, 1 mmol) in DMF (20 ml) and a few drops
of piperidine was refluxed for 8 h. After cooling and pourring into ice water, the solid product was collected and
recrystallized from DMF/ethanol to give compound 19 as brown crystals. Yield 62%; mp >300°C. IR spectrum,
1
, cm-1: 1730 (C=O), 1590 (C=N). H NMR spectrum, , ppm: 7.15-7.73 (8H, m, H Ar). Mass spectrum, m/z
(Irel, %): 420 [M]+ (23), 228 (100). Found, %: C 62.84; H 1.95; N 19.92. C22H8N6O4. Calculated, %: C 62.86;
H 1.91; N 19.98.
4,7-Dihydroxydibenzo[f,h]dipyrimido[1',2':1,6;1",2":2,3]pyridazino[4,5-b]quinoxaline-2,9-dione
(20). A solution of compound 17 (0.31 g, 1 mmol), 0.16 g diethyl malonate (1 mmol), and polyphosphoric acid
(30 ml) was refluxed for 6 h. The solid product was collected and recrystallized from methanol to give
compound 20 as yellow crystals. Yield 61%; mp >300 °C. IR spectrum, , cm-1: 3280 (OH), 1720 (C=O), 1610
1
(C=N). H NMR spectrum, , ppm: 7.85 (4H, m, H Ar); 8.10 (4H, m, H Ar); 13.41 (2H, br. s, 2OH). Mass
spectrum, m/z (Irel, %): 448 [M]+ (25), 228 (100). Found, %: C 64.23; H 2.66; N 18.79. C24H12N6O4. Calculated,
%: C 64.28; H 2.69; N 18.74.
Antiparkinsonian Activity. The muscarinic agonists Tremorine and Oxotremorine induce
parkinsonism-like signs such as tremor, ataxia, spasticity, salivation, lacrimation, and hypothermia. These signs
are antagonized by antiparkinsonian agents.
Groups of eight male mice (18–20 g) were used. They were dosed orally with the tested compounds
(5 mg/kg) or the standard (Benzatropine mesilate, 5 mg/kg) [15], 1 h prior to the administration of 0.5 mg/kg of
106

Oxotremorine. Rectal temperature was measured before administration of the compounds and 1 h after
Oxotremorine dosage. The scores for the recorded signs are zero (absent), one (slight), two (medium), and three
(high) (Table 1).
The authors thank Dr. A. Attia, Pharmacology Department, Faculty of Pharmacy, Zagazig University,
Egypt, for pharmacology screening.
This work was supported by the Deutsche Forschungsgemeinschaft. We thank Prof. Dr. Norbert Krause
(Organic Chemistry II, Dortmund University, Dortmund, Germany) for his useful advices and scientific support.
REFERENCES
1.
2.
J. Clark, M. S. Shahhet, D. Korakas, and G. J. Varvounis, J. Heterocycl. Chem., 30, 1065 (1993).
K. Ogawa, I. Yamawaki, Y.-I. Matsusita, N. Nomura, P. F. Kador, and J. H. Kinoshita, Eur. J. Med.
Chem., 28, 769 (1993).
3.
4.
B. Tozkoparan, M. Ertan, P. Kelicen, and R. Demirdamar, Farmaco, 54, 588 (1999).
J. Quiroga, B. Insuasty, S. Cruz, P. Hernandez, A. Bolanos, R. Moreno, A. Hormaza, and R. H. S. de
Almeida, J. Heterocycl. Chem., 35, 333 (1998).
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
M. Santagati, M. Modica, A. Santagati, F. Russo, and S. Spampinato, Pharmazie, 51, 7 (1996).
V. K. Ahluwalia, M. Chopra, and R. Chandra, J. Chem. Res. (S), 162 (2000).
L. V. G. Nargund, V. V. Badiger, and S. M. Yarnal, Eur. J. Med. Chem., 29, 245 (1994).
M. van Laar, E. B. Volkerts, and M. Verbaten, Psychopharmacology, 154, 189 (2001).
K. Danel, E. B. Pedersen, and C. Nielsen, J. Med. Chem., 41, 191 (1998).
Y. A. Issac and A. A. Aly, Z. Naturforsch., 58b, 1227 (2003).
A. A. Aly and S. A. Nassar, Heteroatom Chem., 15, 2 (2004).
A. A. Aly, Phosphorus, Sulfur, Silicon, Relat. Elem., 178, 2415 (2003).
A. A. Aly, J. Chin. Chem. Soc. (Taipei), 51, 1381 (2004).
A. A. Aly, Ph.D. Thesis, Zagazig University, 2008.
H. Vieweg, S. Leistner, and G. Wagner, Pharmazie, 43, 358 (1988).
107