Regiospecific one-pot, combinatorial synthesis of new substituted pyrimido[4,5-c]pyridazines as potential monoamine oxidase inhibitors

Article abstract of DOI:10.3906/kim-1408-32

New 3-aryl-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H)-diones and 3-aryl-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5- c]pyridazin-5(6H)-ones were efficiently synthesized via a regiospecific one-pot reaction of N -methylbarbituric acid and N -ethyl-2-thiobarbituric acid with various arylglyoxal monohydrates in the presence of hydrazine dihydrochloride in ethanol at 50°C. The target compounds were obtained in high yields and were regioisomerically pure after recrystallization. These new heterocycles may act as potential MAO_B inhibitors.

Full text of DOI:10.3906/kim-1408-32

Turk J Chem
Turkish Journal of Chemistry
(2015) 39: 244 – 254
¨
http://journals.tubitak.gov.tr/chem/
˙
c
⃝ TUBITAK
doi:10.3906/kim-1408-32
Research Article
Regiospecific one-pot, combinatorial synthesis of new substituted
pyrimido[4,5-c]pyridazines as potential monoamine oxidase inhibitors
Mehdi RIMAZ1,∗, Paria POURHOSSEIN1, Behzad KHALILI2
1Department of Chemistry, Payame Noor University, Tehran, Iran
2Department of Chemistry, Faculty of Sciences, University of Guilan, Rasht, Iran
Received: 13.08.2014
•
Accepted/Published Online: 04.11.2014
•
Printed: 30.04.2015
Abstract:New 3-aryl-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H)-diones and 3-aryl-6-ethyl-7-thioxo-7,8-dihydropy-
rimido[4,5-c]pyridazin-5(6H)-ones were efficiently synthesized via a regiospecific one-pot reaction of N -methylbarbituric
acid and N -ethyl-2-thiobarbituric acid with various arylglyoxal monohydrates in the presence of hydrazine dihydrochlo-
ride in ethanol at 50 ◦ C. The target compounds were obtained in high yields and were regioisomerically pure after
recrystallization. These new heterocycles may act as potential MAOB inhibitors.
Key words: Pyrimido[4,5-c]pyridazine, regiospecific, arylglyoxal, N -methylbarbituric acid, N -ethyl-2-thiobarbituric
acid
1. Introduction
Multicomponent reactions (MCRs) are one-pot processes in which three or more reactants come together in a
single reaction vessel to form a product containing substantial elements of all the reactants.1−4 MCRs, leading
to interesting heterocyclic scaffolds, are particularly useful for combinatorial chemistry as powerful tools,5−9
because of their valuable features such as atom economy, environmental friendliness, straightforward reaction
design, and the opportunity to construct target compounds by the introduction of several diverse elements in
a single chemical operation.10−14 Therefore, a great deal of current interest is focused on the development of
novel MCRs.15
Substituted pyridazines are valuable therapeutic agents and are the subunits of multiple classes of nat-
ural products.16,17 The synthesis and utility of many pyridazine derivatives as analgesics, insecticidals,18
fungicidals,19 cardiotonics,20 and bacteriocides21 have been reported. Moreover, fused pyridazines and their
derivatives are known to exhibit pharmacological properties, for example, as anti-inflammatory22 and antibac-
terial agents,23 protein tyrosine phosphatase inhibitors,24 and anticancer agents.25 In particular, pyrimido[4,
5-c]pyridazine-5, 7(6H , 8H)-diones are common sources for the development of new potential therapeutic
agents.26−28 Carotti et al. have reported that the 3-arylpyrimido[4,5-c]pyridazine-5,7(6H ,8H)-diones have
MAO inhibitory activity, and substituents on the diazine nucleus modulate the inhibitory activity.29
Monoamine oxidase (MAO) is a ubiquitous membrane-bound, flavin-containing enzyme particularly
abundant in the liver and brain.30 In mammals, two distinct isoforms of MAO are present in most tissues,
∗Correspondence: rimaz.mehdi@gmail.com
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namely, MAOA and MAOB , which were defined in 1968, based on their differential substrate and inhibitor
specificity,31−33 tissue and cell distribution,34 and gene expression35,36 characteristics.
As such, the development of synthetic methodologies that combine high levels of regiocontrol and flexi-
bility continues to be intensively researched within organic chemistry.
Recently, we have been interested in regioselective one-pot synthesis of various heterocyclic compounds.37−45
Following our previous reports about the synthesis of 3- or 4-aryl substituted pyrimido[4,5-c]pyridazines,40,43,45
herein we wish to report the synthesis of new substituted pyrimidopyridazines as 3-aryl-6-methylpyrimido[4,5-
c]pyridazine-5,7(6H ,8H)-diones and 3-aryl-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H)-ones,
which were efficiently prepared via a regiospecific one-pot reaction of N -methylbarbituric acid and N -ethyl-
2-thiobarbituric acid with various arylglyoxal monohydrates in the presence of hydrazine dihydrochloride in
ethanol.
2. Results and discussion
Recently, glyoxals have attracted much attention in heterocyclic synthetic chemistry.46 They can be prepared
from the corresponding acetophenones via oxidation by SeO2 in dioxane in reflux conditions.47 In order
to protect the arylglyoxals from oxidation and polymerization, these compounds were converted to their
monohydrate isomers. The synthesis of the utilized arylglyoxal monohydrates is shown in Scheme 1.
Scheme 1. Synthesis of arylglyoxal monohydrates.
As shown in Scheme 2, arylglyoxal monohydrates 3a–k were reacted with N -methylbarbituric acid 4a or
N -ethyl-2-thiobarbituric acid 4b in the presence of hydrazine dihydrochloride salt in ethanol at 50 ◦ C, leading
to the formation of pyrimidopyridazines 5a–v in moderate to good yields.
Scheme 2. Synthesis of 3-aryl-6-alkylpyrimido[4,5-c]pyridazine derivatives.
The structures of all twenty-two new examples of these substituted pyrimido[4,5-c]pyridazines are shown
in the Table.
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Table. List of synthesized substituted pyrimido[4,5-c]pyridazines.
Arylglyoxal
monohydrate
Entry
3-Aryl-6-methylpyrimidopyridazine 3-Aryl-6-ethylpyrimidopyridazine
1
2
3
4
5
6
7
8
9
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Table. Continued
Arylglyoxal
monohydrate
Entry
3-Aryl-6-methylpyrimidopyridazine 3-Aryl-6-ethylpyrimidopyridazine
9
10
11
Attempts to synthesize the desired pyrimidopyridazines by using hydrazinium hydroxide instead of
hydrazine dihydrochloride failed. All new products were characterized as 3-aryl substituted pyrimidopyridazines
and there was no evidence of the formation of 4-aryl substituted isomers. This is due to initial regioselective
Knoevenageal condensation between hydrated carbonyl of the arylglyoxal monohydrates and barbituric acids
(path A). Furthermore, because of regiospecific condensation of the hydrazone intermediate 7 and the carbonyl
located in position 4 of the barbituric acids, both CH3 and CH3 CH2 groups were located in position 6 of the
pyrimidopyridazine rings (path C). The suggested mechanism for these reactions is shown in Scheme 3.
Scheme 3. Proposed mechanism for regiospecific synthesis of 3-aryl-6-alkylpyrimidopyridazine derivatives.
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We have previously reported that 3-arylpyrimido[4, 5-c]pyridazine-5, 7(6H , 8H)-diones and 3-aryl-7-
thioxo-7, 8-dihydropyrimido[4, 5-c]pyridazin-5(6H)-ones can have one cluster water in their molecular structure.48
As outlined from the 1 H NMR spectra of 3-aryl-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H)-diones and 3-
aryl-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H)-ones, there is no evidence of the existence of
cluster water in the molecular structure of these compounds. This phenomenon may be because of the presence
of methyl or ethyl groups, which prevent the formation of hydrogen bonding between water and the amide
group.
According to Carotti and coworkers’ report about the MAOB inhibitory property of 3-arylsubstituted
pyrimido[4,5-c]pyridazines,29 we speculated that the synthesis of various aryl and alkyl substituted pyrimi-
dopyridazines as potential MAOB inhibitors may change the MAO inhibitory effect of these derivatives. The
corresponding biological activity of all the new substituted 3-arylpyrimido[4,5-c]pyridazine-5, 7(6H , 8H)-diones
and 3-aryl-7-thioxo-7, 8-dihydropyrimido[4,5-c]pyridazin-5(6H)-ones is under assessment.
3. Experimental
3.1. General procedures
All chemicals were purchased from Merck, Aldrich, and Acros. Melting points were determined on an Elec-
trothermal 9200 apparatus. Infrared spectra were recorded on a PerkinElmer Spectrum Two 10.4 spectrometer,
using KBr discs. The 1 H NMR and 13 C NMR spectra were recorded on a Bruker AVANCE (300 MHz)
spectrometer using d6 -DMSO as solvent. Microanalyses were performed on a Leco Analyzer 932.
3.2. General procedure for the synthesis of 3-aryl-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-
diones
A mixture of N -methylbarbituric acid (1 mmol) and arylglyoxal monohydrate (1 mmol) in the presence of
hydrazine dihydrochloride (1 mmol) in absolute ethanol (10 mL) was heated at 50 ◦ C for 60 min. The
obtained precipitate was separated by filtration and washed with excess rectified spirit. The crude products
were recrystallized from methanol to give the title compounds in good yields.
3.2.1. 3-Phenyl-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5a)
A white powder, 78%, mp 271 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.59 (s, 1H, NH), 8.47 (s,
1H, Ar), 8.18 (d, J = 8.0 Hz, 2H, Ar), 7.60–7.49 (m, 3H, Ar), 3.26 (s, 3H, NCH3). 13 C NMR (d6 -DMSO, 75
MHz) δ (ppm) 161.3, 155.4, 151.1, 135.3, 130.3, 129.8, 129.1, 127.9, 126.4, 121.5, 27.4. FT-IR (KBr) νmax 3190,
1727, 1663, 1483, 1368, 1296, 1049, 762, 693 cm−1 . Anal. found, C, 61.47; H, 3.98; N, 22.11. C13 H10 N4 O2
requires C, 61.41; H, 3.96; N, 22.04.
3.2.2. 3-(4-Bromophenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5b)
A gray powder, 82%, mp 275 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.61 (s, 1H, NH), 8.52
(s, 1H, Ar), 8.15 (d, J = 7.8 Hz, 1H, Ar), 7.73 (d, J = 7.8 Hz, 1H, Ar), 3.27 (s, 3H, NCH3). 13 C NMR
(d6 -DMSO, 75 MHz) δ (ppm) 161.2, 154.4, 151.2, 150.0, 134.5, 132.0, 123.5, 123.4, 121.5, 113.3, 27.4. FT-IR
(KBr) νmax 3175, 1736, 1662, 1615, 1481, 1447, 1364, 1297, 1047, 828 cm−1 . Anal. found, C, 46.80; H, 2.62;
N, 16.91. C13 H9 BrN4 O2 requires C, 46.87; H, 2.72; N, 16.82.
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3.2.3. 3-(4-Chlorophenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5c)
A gray powder, 86%, mp 279 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.63 (s, 1H, NH), 8.83 (s,
1H, Ar), 8.23 (d, J = 8.6 Hz, 2H, Ar), 7.61 (d, J = 8.5 Hz, 2H, Ar), 3.27 (s, 3H, NCH3). 13 C NMR (d6 -DMSO,
75 MHz) δ (ppm) 161.2, 154.3, 151.2, 150.1, 134.7, 134.2, 129.1, 128.3, 121.6, 113.3, 27.5. FT-IR (KBr) νmax
3178, 1739, 1661, 1615, 1482, 1447, 1365, 1297, 1093, 831 cm−1 . Anal. found, C, 54.01; H, 3.10; N, 19.61.
C13 H9 ClN4 O2 requires C, 54.09; H, 3.14; N, 19.41.
3.2.4. 3-(4-Fluorophenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5d)
A white powder, 80%, mp 257 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.59 (s, 1H, NH), 8.50 (s,
1H, Ar), 8.26–8.23 (m, 2H, Ar), 7.39–7.35 (m, 2H, Ar), 3.27 (s, 3H, NCH3). 13 C NMR (d6 -DMSO, 75 MHz)
δ (ppm) 164.4, 162.0, 161.2, 154.5, 151.0, 150.0, 131.8, 128.8, 128.7, 121.4, 116.1, 115.8, 113.3, 27.4. FT-IR
(KBr) νmax 3195, 3053, 1722, 1671, 1604, 1489, 1366, 1230, 836 cm−1 . Anal. found, C, 57.40; H, 3.38; N,
20.68. C13 H9 FN4 O2 requires C, 57.35; H, 3.33; N, 20.58.
3.2.5. 3-(4-Methoxyphenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5e)
A yellow powder, 85%, mp 253 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.52 (s, 1H, NH), 8.81
(s, 1H, Ar), 8.13 (d, J = 8.6 Hz, 2H, Ar), 7.08 (d, J = 8.6 Hz, 2H, Ar), 3.83 (s, 3H, OCH3), 3.26 (s, 3H,
NCH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 161.4, 155.2, 150.6, 132.0, 129.3, 128.0, 127.9, 127.7, 120.7,
114.5, 55.3, 27.5. FT-IR (KBr) νmax 3198, 2931, 1729, 1666, 1609, 1490, 1296, 1252, 1176, 1176, 1032, 839, 747
cm−1 . Anal. found, C, 59.18; H, 4.24; N, 19.80. C14 H12 N4 O3 requires C, 59.15; H, 4.25; N, 19.71.
3.2.6. 3-(4-Nitrophenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5f)
A yellow powder, 79%, mp 281 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.84 (s, 1H, NH), 8.93
(s, 1H, Ar), 8.45 (d, J = 8.5 Hz, 2H, Ar), 7.89 (d, J = 8.5 Hz, 2H, Ar), 3.45 (s, 3H, NCH3). 13 C NMR (d6 -
DMSO, 75 MHz) δ (ppm) 161.4, 155.2, 150.6, 132.0, 129.3, 128.0, 127.9, 127.7, 120.7, 114.5, 55.3, 27.5. FT-IR
(KBr) νmax 3203, 2954, 1754, 1675, 1567, 1358, 839, 747 cm−1 . Anal. found, C, 52.25; H, 3.06; N, 23.55.
C13 H9 N5 O4 requires C, 52.18; H, 3.03; N, 23.40.
3.2.7. 3-(3-Bromophenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5g)
A cream powder, 75%, mp 254 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.65 (bs, 1H, NH), 8.59
(s, 1H, Ar), 8.40 (s, 1H Ar), 8.21 (d, J = 7.9 Hz, 1H, Ar), 7.72 (d, J = 7.9 Hz, 1H, Ar), 7.51 (t, J = 7.9
Hz, 1H, Ar), 3.27 (s, 3H, NCH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 161.2, 153.9, 151.5, 150.1, 137.6,
132.4, 131.2, 129.1, 129.0, 122.5, 122.0, 113.3, 27.5. FT-IR (KBr) νmax 3183, 1737, 1661, 1564, 1500, 1450,
1367, 1295, 1193, 1050, 790 cm−1 . Anal. found, C, 46.89; H, 2.67; N, 16.99. C13 H9 BrN4 O2 requires C, 46.87;
H, 2.72; N, 16.82.
3.2.8. 3-(3-Methoxyphenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5h)
A yellow powder, 90%, mp 258 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.70 (s, 1H, NH), 8.47 (s,
1H, Ar), 7.94–7.84 (m, 4H, Ar), 3.85 (s, 3H, OCH3), 3.26 (s, 3H, NCH3). 13 C NMR (d6 -DMSO, 75 MHz) δ
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(ppm) 159.8, 159.2, 158.1, 156.2, 146.7, 138.6, 137.0, 135.2, 130.1, 129.6, 120.2, 113.6, 55.1, 27.6. FT-IR (KBr)
νmax 3091, 2933, 1659, 1583, 1482, 1359, 1273, 1230, 1047, 781 cm−1 . Anal. found, C, 59.18; H, 4.24; N, 19.80.
C14 H12 N4 O3 requires C, 59.15; H, 4.25; N, 19.71.
3.2.9. 3-(3,4-Dimethoxyphenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5i)
A yellow powder, 88%, mp 251 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.51 (s, 1H, NH), 8.45
(s, 1H, Ar), 7.73 (s, 1H, Ar), 7.71 (d, J = 8.2 Hz, 1H, Ar), 7.08 (d, J = 8.0 Hz, 1H, Ar), 3.87 (s, 3H, OCH3),
3.82 (s, 3H, OCH3), 3.26 (s, 3H, NCH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 161.3, 155.2, 150.6, 149.1,
129.9, 127.8, 127.5, 120.9, 119.3, 113.2, 111.8, 109.4, 55.6, 55.5, 27.4. FT-IR (KBr) νmax 3108, 3088, 2933,
1734, 1679, 1595, 1501, 1457, 1386, 1263, 1148, 1023, 794 cm−1 . Anal. found, C, 57.27; H, 4.45; N, 17.98.
C15 H14 N4 O4 requires C, 57.32; H, 4.49; N, 17.83.
3.2.10. 3-(4-Hydroxy-3-methoxyphenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5j)
An orange powder, 92%, mp 249 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.52 (bs, 1H, NH), 9.48
(bs, 1H, OH), 8.41 (s, 1H, Ar), 7.82 (s, 1H, Ar), 7.80 (d, J = 7.6 Hz, 1H, Ar), 6.91 (dd, J1 = 8.4 Hz, J2
=
2.9 Hz, 1H, Ar), 3.88 (s, 3H, OCH3), 3.25 (s, 3H, NCH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 161.4,
156.3, 155.5, 153.2, 150.4, 148.5, 128.7, 126.5, 119.6, 115.8, 113.2, 110.0, 55.7, 27.4. FT-IR (KBr) νmax 3430,
1728, 1674, 1567, 1451, 1383, 1275, 1217, 1124, 1033, 791 cm−1 . Anal. found, C, 56.09; H, 4.10; N, 18.77.
C14 H12 N4 O4 requires C, 56.00; H, 4.03; N, 18.66.
3.2.11. 3-(3,4-Methylenedioxyphenyl)-6-methylpyrimido[4,5-c]pyridazine-5,7(6H ,8H )-dione (5k)
A beige powder, 83%, mp 268 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.57 (s, 1H, NH), 8.47 (s,
1H, Ar), 7.86 (d, J = 8.4 Hz, 1H, Ar), 7.83 (s, 1H, Ar), 7.03 (dd, J1 = 7.6 Hz, J2 = 3.2 Hz, 1H, Ar), 6.12
(s, 2H, CH2), 3.25 (s, 3H, NCH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 161.4, 156.1, 152.8, 148.7, 148.1,
129.0, 128.8, 125.1, 122.2, 116.2, 110.5, 101.3, 27.4. FT-IR (KBr) νmax 3100, 2902, 1673, 1580, 1482, 1448,
1237, 1037, 930, 810 cm−1 . Anal. found, C, 56.43; H, 3.33; N, 18.92. C14 H10 N4 O4 requires C, 56.38; H, 3.38;
N, 18.78.
3.3. General procedure for the synthesis of 3-aryl-6-ethyl-7-thioxo-7, 8-dihydropyrimido[4,5-c]pyri-
dazine-5(6H )-ones
A mixture of N -ethyl-2-thiobarbituric acid (1 mmol) and arylglyoxal monohydrate (1 mmol) in the presence of
hydrazine dihydrochloride (1 mmol) in absolute ethanol (10 mL) was heated at 50 ◦ C for 90 min. The obtained
precipitate was separated by filtration and washed with excess rectified spirit. The crude products were purified
via recrystallization from methanol.
3.3.1. 3-Phenyl-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5l)
An orange powder, 80%, mp 218 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 12.15 (s, 1H, NH), 8.50
(s, 1H, Ar), 8.01 (d, J = 7.8 Hz, 2H, Ar), 7.80 (t, J = 7.2 Hz, 1H, Ar), 7.55 (t, J = 7.2 Hz, 2H, Ar), 4.43
(q, J = 7.2 Hz, 2H, CH2), 1.23 (t, J = 6.9 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 176.4,
159.1, 145.1, 142.5, 135.1, 130.2, 129.6, 127.0, 121.2, 114.8, 41.3, 11.6. FT-IR (KBr) νmax 3191, 3059, 2931,
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2829, 1679, 1620, 1559, 1454, 1346, 1205, 1112, 1087, 688 cm−1 . Anal. found, C, 59.16; H, 4.21; N, 19.84; S,
11.34. C14 H12 N4 OS requires C, 59.14; H, 4.25; N, 19.70; S, 11.28.
3.3.2. 3-(4-Bromophenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5m)
A brown powder, 72%, mp 221 ◦ C (dec.). 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.65 (s, 1H, NH), 8.65
(s, 1H, Ar), 8.47 (d, J = 8.7 Hz, 2H, Ar), 7.78 (d, J = 8.7 Hz, 2H, Ar), 4.38 (q, J = 6.9 Hz, 2H, CH2), 1.19
(t, J = 6.9 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 161.7, 154.0, 148.2, 143.9, 141.1, 128.3,
127.8, 124.2, 121.5, 113.9, 71.4, 11.5. FT-IR (KBr) υmax 3179, 3048, 2979, 2932, 1681, 1605, 1591, 1568, 1523,
1489, 1443, 1343, 1236, 1108, 829 cm−1 . Anal. found, C, 46.30; H, 3.01; N, 15.57; S, 8.91. C14 H11 BrN4 OS
requires C, 46.29; H, 3.05; N, 15.42; S, 8.83.
3.3.3. 3-(4-Chlorophenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5n)
A brown powder, 79%, mp 232 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.95 (s, 1H, NH), 8.55
(s, 1H, Ar), 8.25 (d, J = 8.5 Hz, 2H, Ar), 7.61 (d, J = 8.5 Hz, 2H, Ar), 4.43 (q, J = 6.6 Hz, 2H, CH2), 1.23
(t, J = 6.9 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 176.6, 158.8, 135.0, 134.1, 129.2, 128.6,
128.5, 127.3, 121.5, 114.9, 41.4, 11.7. FT-IR (KBr) υmax 3180, 3068, 2980, 2896, 1680, 1569, 1524, 1492, 1444,
1344, 1236, 1109, 1096, 832 cm−1 . Anal. found, C, 52.81; H, 3.44; N, 17.69; S, 10.10. C14 H11 ClN4 OS requires
C, 52.75; H, 3.48; N, 17.58; S, 10.06.
3.3.4. 3-(4-Fluorophenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5o)
A yellow powder, 71%, mp 225 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.93 (s, 1H, NH), 8.53
(s, 1H, Ar), 8.30–8.25 (m, 2H, Ar), 7.40–7.35 (m, 2H, Ar), 4.41 (q, J = 6.9 Hz, 2H, CH2), 1.23 (t, J = 6.9
Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 173.2, 158.7, 155.6, 131.6, 130.0, 129.0, 128.9, 121.2,
116.2, 115.9, 114.8, 92.9, 12.2. FT-IR (KBr) υmax 3185, 3081, 2981, 2895, 1709, 1675, 1634, 1597, 1555, 1507,
1443, 1344, 1236, 1111, 839 cm−1 . Anal. found, C, 55.68; H, 3.61; N, 18.68; S, 10.69. C14 H11 FN4 OS requires
C, 55.62; H, 3.67; N, 18.53; S, 10.61.
3.3.5. 3-(4-Methoxyphenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5p)
A yellow powder, 75%, mp 268 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.88 (s, 1H, NH), 8.41
(s, 1H, Ar), 8.15 (d, J = 8.7 Hz, 2H, Ar), 7.10 (d, J = 7.2 Hz, 2H, Ar), 4.42 (q, J = 6.9 Hz, 2H, CH2), 3.84
(s, 3H, OCH3), 1.22 (t, J = 6.9 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 160.4, 158.8, 144.8,
132.0, 128.6, 127.5, 126.9, 120.3, 114.7, 112.4, 81.7, 55.2, 11.6. FT-IR (KBr) υmax 3185, 3071, 2984, 2888, 1678,
1609, 1570, 1502, 1452, 1363, 1250, 1178, 1106, 1031, 831 cm−1 . Anal. found, C, 57.33; H, 4.46; N, 17.99; S,
10.27. C15 H14 N4 O2 S requires C, 57.31; H, 4.49; N, 17.82; S, 10.20.
3.3.6. 3-(4-Nitrophenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5q)
A brown powder, 73%, mp 181 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 14.05 (s, 1H, NH), 8.71 (s,
1H, Ar), 8.52 (d, J = 9.0 Hz, 2H, Ar), 8.38 (d, J = 9.0 Hz, 2H, Ar), 4.44 (q, J = 7.2 Hz, 2H, CH2), 1.23 (t, J
= 6.6 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 158.6, 154.0, 148.2, 144.5, 141.1, 128.3, 127.8,
124.2, 122.5, 114.8, 72.8, 11.5. FT-IR (KBr) υmax 3182, 3062, 2985, 2898, 1678, 1605, 1518, 1494, 1445, 1343,
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1235, 1106, 856 cm−1 . Anal. found, C, 51.08; H, 3.40; N, 21.39; S, 9.80. C14 H11 N5 O3 S requires C, 51.06; H,
3.37; N, 21.27; S, 9.74.
3.3.7. 3-(3-Bromophenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5r)
A beige powder, 75%, mp 188 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.96 (s, 1H, NH), 8.55
(s, 1H, Ar), 8.40 (s, 1H, Ar), 8.21 (d, J = 7.8 Hz, 1H, Ar), 7.71–7.65 (m, 2H, Ar), 4.41 (q, J = 6.9 Hz, 2H,
CH2), 1.22 (t, J = 6.9 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ (ppm) 158.7, 154.6, 137.5, 136.1,
132.7, 132.6, 131.3, 129.2, 128.5, 125.7, 122.6, 121.9, 41.4, 11.9. FT-IR (KBr) υmax 3184, 3095, 2988, 2887,
1681, 1651, 1669, 1564, 1518, 1452, 1343, 1239, 1110, 1087, 793, 737 cm−1 . Anal. found, C, 46.23; H, 3.09; N,
15.59; S, 8.90. C14 H11 BrN4 OS requires C, 46.29; H, 3.05; N, 15.42; S, 8.83.
3.3.8. 3-(3-Methoxyphenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one (5s)
A yellow powder, 73%, mp 251 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.93 (s, 1H, NH), 8.51 (s,
1H, Ar), 7.76–7.72 (m, 2H, Ar), 7.44 (t, J = 8.1 Hz, 1H, Ar), 7.06 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1 H, Ar),
4.42 (q, J = 6.9 Hz, 2H, CH2), 3.85 (s, 3H, OCH3), 1.22 (t, J = 6.9 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75
MHz) δ (ppm) 176.5, 160.0, 158.8, 155.9, 150.5, 136.6, 130.3, 121.5, 119.0, 116.1, 114.8, 111.5, 55.4, 41.4, 11.7.
FT-IR (KBr) υmax 3196, 3092, 2988, 1680, 1609, 1495, 1452, 1342, 1238, 1129, 1104, 1032, 793, 741 cm−1
.
Anal. found, C, 57.36; H, 4.41; N, 17.91; S, 10.24. C15 H14 N4 O2 S requires C, 57.31; H, 4.49; N, 17.82; S,
10.20.
3.3.9. 3-(3,4-Dimethoxyphenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5(6H )-one
(5t)
A gray powder, 79%, mp 228 ◦ C (dec.). 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 3.54 (s, 3H), 3.94 (s, 3H),
3.97 (s, 3H), 4.02 (s, 3H), 7.01 (d, J = 8.4 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.88 (s, 1H), 8.46 (s, 1H). 13 C
NMR (d6 -DMSO, 75 MHz) δ (ppm) 160.6, 156.1, 151.3, 150.3, 149.9, 127.4, 121.6, 119.5, 113.8, 111.3, 109.3,
56.1, 56.0, 29.9, 28.9. FT-IR (KBr) υmax 3151, 3082, 2996, 2834, 1701, 1656, 1601, 1585, 1521, 1513, 1437,
1347, 1234, 1148, 1108, 1022, 885, 793 cm−1 . Anal. found, C, 55.85; H, 4.72; N, 16.36; S, 9.37. C16 H16 N4 O3 S
requires C, 55.80; H, 4.68; N, 16.27; S, 9.31.
3.3.10. 3-(4-Hydroxy-3-methoxyphenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5
(6H )-one (5u)
An orange powder, 70%, mp 269 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.85 (s, 1H, NH), 9.53
(s, 1H, OH), 8.44 (s, 1H, Ar), 7.75 (s, 1H, Ar), 7.65 (dd, J1 = 8.3 Hz, J2 = 1.8 Hz, 1H, Ar), 6.91 (d, J = 8.3
Hz, 1H, Ar), 4.43 (q, J = 6.9 Hz, 2H, CH2), 3.88 (s, 3H, OCH3), 1.22 (t, J = 6.9 Hz, 3H, CH3). 13 C NMR
(d6 -DMSO, 75 MHz) δ (ppm) 176.0, 158.8, 156.1, 149.8, 148.7, 148.1, 126.3, 120.3, 119.8, 115.9, 114.7, 110.1,
55.7, 41.3, 11.6. FT-IR (KBr) υmax 3294, 3082, 1673, 1615, 1600, 1518, 1432, 1347, 1285, 1262, 1222, 1110,
1090 cm−1 . Anal. found, C, 54.61; H, 4.29; N, 17.11; S, 9.79. C15 H14 N4 O3 S requires C, 54.53; H, 4.27; N,
16.96; S, 9.71.
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3.3.11. 3-(3,4-Methylenedioxyphenyl)-6-ethyl-7-thioxo-7,8-dihydropyrimido[4,5-c]pyridazin-5
(6H )-one (5v)
A beige powder, 77%, mp 262 ◦ C (dec.), 1 H NMR (d6 -DMSO, 300 MHz) δ (ppm) 13.53 (s, 1H, NH), 8.42 (s,
1H, Ar), 7.79 (d, J = 8.7 Hz, 1H, Ar), 7.74 (s, 1H, Ar), 7.01 (dd, J1 = 7.8 Hz, J2 = 1.8 Hz, 1H, Ar), 6.09 (s,
2H, CH2), 3.28 (q, J = 6.9 Hz, 2H, CH2), 1.43 (t, J = 6.9 Hz, 3H, CH3). 13 C NMR (d6 -DMSO, 75 MHz) δ
(ppm) 171.4, 166.1, 153.8, 148.7, 148.1, 129.0, 127.8, 124.9, 121.8, 117.1, 111.3, 101.1, 49.4, 11.8. FT-IR (KBr)
υmax 3106, 2987, 1675, 1585, 1488, 1473, 1239, 1043, 850 cm−1 . Anal. found, C, 54.90; H, 3.69; N, 17.21; S,
9.85. C15 H12 N4 O3 S requires C, 54.87; H, 3.68; N, 17.06; S, 9.77.
4. Conclusions
In summary, we have reported a one-pot reaction for the efficient synthesis of new substituted pyrimido[4,5-
c]pyridazine derivatives as potential MAOB inhibitors. By using different types of arylglyoxal monohydrates
and barbituric acid derivatives, we obtained novel libraries of pyrimido[4,5-c]pyridazine derivatives, which make
this methodology suitable for combinatorial and parallel synthesis. The proposed reactions proceed in mild
conditions and give the products in good yields with high regiospecificity. The separation and purification
processes are very simple and convenient, only needing recrystallization. The starting materials are inexpensive
and commercially available.
Acknowledgments
The authors express their thanks to Payame Noor University for partial financial support of this work.
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