New potential calcium channel modulators: Design and synthesis of compounds containing two pyridine, pyrimidine, pyridone, quinoline and acridine units under microwave irradiation

Article abstract of DOI:10.1016/j.bmcl.2003.12.092

The synthesis of bifunctional pyridine, pyrimidine, pyridone, quinoline and acridine derivatives was investigated using dialdehyde as a precursor. A rapid and efficient method was developed for the synthesis of a range of bifunctional monocyclic, bicyclic

Full text of DOI:10.1016/j.bmcl.2003.12.092

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1533–1536
New potential calcium channel modulators: design and synthesis of
compounds containing two pyridine, pyrimidine, pyridone,
quinoline and acridine units under microwave irradiation
Shujiang Tu,* Chunbao Miao, Fang Fang, Feng Youjian, Tuanjie Li, Qiya Zhuang,
Xiaojing Zhang, Songlei Zhu and Daqing Shi
Department of Chemistry, Xuzhou Normal University, Key Laboratory of Biotechnology on Medical Plant,
Jiangsu, Xuzhou, Jiangsu 221009, People’s Republic of China
Received 31July 2003; accepted 26 December 2003
Abstract—The synthesis of bifunctional pyridine, pyrimidine, pyridone, quinoline and acridine derivatives was investigated using
dialdehyde as a precursor. A rapid and efficient method was developed for the synthesis of a range of bifunctional monocyclic,
bicyclic and tricycilc products related to 1,4-DHPs with the aim of finding new classes of biologically active compounds.
# 2004 Elsevier Ltd. All rights reserved.
1,4-Dihydropyridines (1,4-DHPs) are well-known com-
pounds as a consequence of their pharmacological pro-
file as the most important calcium channel modulators.1
Extensive efforts have been exerted on developing
methodology for the modification of the 1,4-DHPs
ring.2
drugs, antimalarial and antitumor agents has attracted
the attention of organic chemists and thus led to inten-
sive interest in the synthesis of several drugs based on
acridine.8 It is well established that slight structural
modification on the DHP ring may bring remarkable
changes of pharmacological effect.9
4-Aryl-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxyl-
ate (1,4-DHP) derivatives are widely used for the treatment
of cardiovascular diseases (hypertension, angina pectoris,
infarction).3 1,4-DHPs having different ester groups on the
3- and 5-positions possess a stereogenic carbon on the
4-position in the 1,4-DHP nucleus, and their two enan-
tiomers often show different biological activities.4 Many
heterocyclic compounds having a 1,4-dihydropyridine
nucleus are also known to have a wide range of biological
activities. Quinoline derivatives have good amoebici-dal,
bactericidal, fungicidal and antimalarial activities.5 Di-
hyropyridone are potential calcium channel modulators.6
Dihydropyrimidinone derivatives have exhibited attractive
pharmacological profiles, serving as the integral back-
bones of several calcium channel blocks, antihypertensive
agents, alpha-la-antagonists and neuropeptide Y (NPY)
antagonists.7 The discovery of acridines as anticancer
However, so far attention has mainly been paid to the
synthesis of monofunctional 1,4-DHPs derivatives and
the bifunctional ones are seldom investigated. Further-
more, introduction of substituents to pyridine ring often
require prolonged reaction time to achieve acceptable
yields under conventional or photolysis conditions.10
The efficiency of microwave irradiation (MWI) in
promoting organic synthesis11,12 and the success of their
application in these heterocyclic syntheses prompted us
to extend those procedures to the synthesis of two
bifunctional compounds containing two 1,4-DHPs
nuclei.
Herein, we wish to report that microwave irradiation
provides a convenient and efficient approach to a range of
bifunctional monocyclic, bicyclic and tricycilc precursors
to 1,4-DHPs with dialdehyde 1 as starting material.
When a mixture of p-phenylenedialdehyde or m-phenyl-
enedialdehyde 1 and active methylene compounds 2 (in
* Corresponding author. Tel.: +86-516-3403163; fax: +86-516-
3403164; e-mail: laotu2001@263.net
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.12.092

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S. Tu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1533–1536
proper ratio) was radiated with microwave (300W)
irradiation using small amount of glycol as energy
transfer reagent (Scheme 1), the reactions were com-
pleted in 5–9 min. The reaction mixture was then cooled
and poured into cold water and filtered. The solid was
washed with a small amount of ethanol. The crude
products were purified by recrystallization from 95%
ethanol or acetone to afford products with good yields
Scheme 1. Synthetic route of bifunctional 1,4-DHPs derivatives.
Table 1. Synthesis of bifunctional 1,4-DHPs derivatives
Entry
Product
Starting material
Ratio
Time (min)
Yield (%)
1
2
3
1
2
4a
4b
—
NH4OAc
1:4:3
1:4:3
7
8
75
78
—
—
NH4OAc
NH4OAc
3
4
4c
5
1:4:3
7
8
70
83
NH4OAc
1:2:2:3
5
6
7
6a
6b
7a
1:2:2.4
1:2:2.4
1:2:2:3
7
8
9
91
88
92
NH4OAc
NH4OAc
8
7b
7c
8
1:2:2:3
1:2:2:3
1:2:2:3
1:4:3
8
8
8
5
8
90
89
85
93
90
9
NH4OAc
NH4OAc
NH4OAc
NH4OAc
10
11
12
9a
9b
—
—
1:4:3
.
NH2OH HCl NaOAc
13
9c
—
1:4:2
8
92

S. Tu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1533–1536
1535
(70–93%). All the reactions were followed by TLC and
References and notes
the experiments were replicated in order to ensure the
reproducibility. The main results for the synthesis of
these compounds are listed in Table 1. Therefore, these
reactions have the advantage of short reaction time,
good yields, convenient work up procedures and being
environmentally friendly.13 The mechanisms are similar
to that reported in earlier work.14
1. (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem.,
Int. Ed. 1981, 93, 755. (b) Stout, D. M.; Meyers, A. I.
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Chudik, M.; Mastihuba, V.; Decroix, B. Heterocycles
1998, 48, 1943. (g) Achiwa, K.; Kato, T. Curr. Org. Chem.
1999, 3, 77.
These new classes of compounds are interesting new
lead compounds for biological activity evaluation. This
work is in progress in our laboratories.
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Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223. (c)
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nieks, E. A.; Makarova, N. R.; Kimenis, A. A.; Uldrikis,
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& Therapeutics 1998, 77, 1. (c) Sharad, S. D.; Robert,
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Tonglan, N.; Laychoo, T. A.; Kunnika, K.; Prapon, W.
European Journal of Pharmaceutical Sciences 1998, 6, 1 9.
6. Ochoa, E.; Suarez, M.; Verdecia, Y.; Pita, B.; Martın, N.;
Quinteiro, M.; Seoane, C.; Soto, J. L.; Duque, J.; Pomes,
R. Tetrahedron 1998, 54, 12409.
7. (a) Atwal, K. S.; Swanson, B. N.; Unger, S. E.; Floyd,
D. M.; Moreland, S.; Hedberg, A.; O’Reilly, B. C. J. Med.
Chem. 1991, 34, 806. (b) Rovnyak, G. C.; Atwal, K. S.;
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J. Z.; O’Reilly, B. C.; Schwartz, J.; Malley, M. F. J. Med.
Chem. 1992, 35, 3254. (c) Grover, G. J.; Dzwonczyk, S.;
Mcmullen, D. M.; Normadin, A. M.; Parham, C. S.;
Slenph, P. G.; Moreland, S. J. J. Cardiovasc. Pharmacol.
1995, 26, 289.
8. (a) Khurana, J. M.; Maikap, G. C.; Mehta, S. Synthesis
1990, 731. (b) Matsumoto, H.; Arai, T.; Takahashi, M.;
Ashizawa, T.; Nakano, T.; Nagai, Y. Bull. Chem. Soc.
Jpn. 1983, 56, 3009. (c) Nakano, T.; Takahashi, M.; Arai,
T.; Seki, S.; Matsumoto, H.; Nagai, Y. Chem. Lett 1982,
613.
9. (a) Chorvat, R. J.; Rorig, K. J. J. Org. Chem. 1988, 53,
5779. (b) Kappe, C. O.; Fabian, W. M. F. Tetrahedron
1997, 53, 2803. (c) Kappe, C. O. Tetrahedron 1993, 49,
6937.
10. (a) Loupy, A.; Philippon, N.; Pigeon, P.; Galond, H.
Heterocycles 1991, 32, 1947. (b) Shuj, K.; Minoru, N.;
Kazuichi, T. J. Heterocycl. Chem. 1984, 24, 1243. (c)
Rodrıguez, H.; Suarez, M.; Rolando, P.; Petıt, A.; Loupy,
A. Tetrahedron Lett. 2003, 44, 3709.
11. (a) Tu, S. J.; Wei, Q. H.; Ma, H. R.; Shi, D. Q.; Gao, Y.;
Cui, G. Y. Synth. Commun. 2001, 17, 2657. (b) Tu, S. J.;
Deng, X.; Shi, D. Q.; Gao, Y.; Feng, J. C. Chinese Journal
of Chemistry 2001, 19, 714. (c) Tu, S. J.; Zhou, J. F.; Cai,
P. J.; Wang, H.; Feng, J. C. Synth. Commun. 2001, 24,
3729. (d) Tu, S. J.; Lu, Z. S.; Shi, D. Q.; Yao, C. S.; Gao,
Y.; Guo, C. Synth. Commun. 2002, 14, 2181.
The structures of these compounds are established by
spectroscopic and analytical data. The IR spectra of
compound 5 show the NH stretching at 3200 and 3100
cmꢀ1 region. The 1H NMR spectra of compound 5
show the NH proton absorption at 9.84 ppm. The two
protons at C-3 appear at 2.39–2.93 ppm and form a
part of an ABX system which was confirmed by the
appearance of a doublet of doublets at 4.01–4.08 ppm
corresponding to the proton at C-4 split by coupling
0
with the protons on C-3 (J3,4=1.9 and J3 ,4=7.9 Hz).
1
The H NMR spectra of compound 8 show the NH
proton at 10.05 ppm. The two protons on C-3
appear at 2.18–2.89 ppm and form a part of an
ABX system which was confirmed by a doublet of
doublets at 4.06–4.08 ppm corresponding to the proton
on C-4 split by coupling with the protons on C-3
0
(J3,4=1.1 and J3 ,4=8.4 Hz). The two protons on C-6
appear as an AB system, with a couping constant
ꢁ15.6 Hz, indicating that these two protons are not
equivalent.
The IR of 9 shows the OH group at around 3225 cmꢀ1
and the two carbonyl groups at 1667 and 1660 cmꢀ1
.
Meanwhile, the 1H NMR spectrum of 9c shows the OH
proton at 10.73 ppm.
1
The IR and H NMR of compounds 3, 4, 6 and 7 are
consistent with the respective structures, and these
compounds showed good elemental analysis results.
In summary, keeping in view the utility of MWI and the
pharmacological importance of the above-mentioned
heterocycles, we have synthesized a series of new
bifunctional 1,4-DHPs derivatives using MWI in order
to provide a facile, rapid, efficient, and environmentally
friendly method. These compounds may show interesting
and unique properties.
Acknowledgements
We thank the National Natural Science Foundation
of China (No. 20372057), Natural Science Foundation of
the Jiangsu Province (No. BK2001142), the Natural
Science Foundation of Jiangsu Education Department
(No. 01KJB150008) and the Key Laboratory of
Chemical Engineering & Technology of the Jiangsu
Province Open Foundation (No. KJS02060) for financial
support.
12. Pelle, L.; Jason, T.; Bernard, W.; Jacob, W. Tetrahedron
2001, 57, 9225.
13. The general procedure is represented as bellow: A dry
flask (25 mL) was charged with m-phenylenedialdehyde
(2 mmol) or p-phenylenedialdehyde (2 mmol), corres-
ponding 2 and 3 (except 6) in proper ratio, glycol (2 mL),
proper catalyst (for 6, potassium hydrogen sulfate (2

1536
S. Tu et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1533–1536
mmol)) in a microwave oven. The flask was then con-
1281, 1213, 1187, 1168, 1142, 1110, 1078, 1016, 800, 739,
609, 592, 533; 1H NMR (DMSO-d6) (d, ppm): 0.79 (6H, s,
2ꢃCH3), 0.97 (6H, s, 2ꢃCH3), 1.94–2.49 (8H, m,
4ꢃCH2), 2.25 (6H, s, 2ꢃCH3), 3.50 (6H, s, 2ꢃCH3), 4.77
(2H, s, 2ꢃCH), 6.90 (4H, s, ArH), 9.00 (2H, s, 2ꢃNH);
CHN analysis: %C (calcd 71.31, found 71.05), %H (calcd
7.04, found 6.79), %N (calcd 4.89, found 4.62); 8.
mp>300 ꢂC; IR (KBr, n, cmꢀ1): 3379, 3149, 2956, 1713,
1605, 1494, 1378, 1282, 1216, 1149; 1H NMR (DMSO-d6)
(d, ppm): 0.98 (6H, s, 2ꢃCH3), 1.04 (6H, s, 2ꢃCH3), 2.31
(2H, dd, J=15.6 Hz, 2ꢃ6-H), 2.24 (2H, dd, J=15.6 Hz,
2ꢃ60-H), 2.31(2H, dd, J=15.2 Hz, J=1.1 Hz, B part of
ABX, 2ꢃ3-H), 2.88 (2H, dd, J=8.4 Hz, J=15.2 Hz, A
part of ABX, 2ꢃ30-H), 4.07 (2H, dd, J=8.4 Hz, J=1.1
Hz, X part of ABX, 2ꢃ4-H), 7.00 (4H, s, ArH), 10.05
(2H, s, 2ꢃNH); CHN analysis: %C (calcd 73.02, found
72.93), %H (calcd 7.00, found 6.77), %N (calcd 6.08,
found 5.87); 9c. mp>300 ꢂC; IR (KBr, n, cmꢀ1): 3225,
2954, 2871, 1667, 1660, 1504, 1462, 1504, 1462, 1369,
nected with refluxing equipment. After irradiation for 5–9
min. (irradiation sequences were interrupted with a cooling
period in between), the reaction mixture was cooled and
poured into cold water, then filtered and washed with
ethanol (3 mL). The crude products were purified by
recrystallization from 95% ethanol or acetone to afford
products. Spectra of six compounds are summarized as
follows: 4a. mp>300 ꢂC; IR (KBr, n, cmꢀ1): 3354, 2954,
2864, 1652, 1483, 1220, 1122, 1017; 1H NMR (DMSO-d6)
(d, ppm): 2.24 (6H, s, 2ꢃCH3), 2.50 (6H, s, 2ꢃCH3), 3.55
(12H, s, 4ꢃCH3), 4.46 (2H, s, 2ꢃCH), 6.97 (4H, s, ArH),
8.60 (2H, s, 2ꢃNH); CHN analysis: %C (calcd 64.11,
found 63.92), %H (calcd 6.15, found 5.88), %N (calcd
5.34, found 5.10); 5. mp>300 ꢂC; IR (KBr, n, cmꢀ1):
3200, 3100, 2950, 1702, 1645, 1490, 1431, 1420, 1285,
1225, 1175, 1103, 962, 845, 800, 676, 565; 1H NMR
(DMSO-d6) (d, ppm): 1.09 (6H, t, J=7.0 Hz, 2ꢃCH3),
2.29 (6H, s, 2ꢃCH3), 2.41(2H, dd, J=16.3 Hz, J=1.9
Hz, B part of ABX, 2ꢃ3-H), 2.89 (2H, dd, J=16.3 Hz,
J=7.9 Hz, A part of ABX, 2ꢃ30-H), 3.96 (4H, q, J=6.9
Hz, 2ꢃOCH2), 4.06 (2H, dd, J=7.6 Hz, J=1.9 Hz, X part
of ABX, 2ꢃ4-H), 7.05 (4H, s, ArH), 9.84 (2H, s, 2ꢃNH);
CHN analysis: %C (calcd 65.14, found 64.88), %H (calcd
6.83, found 6.62), %N (calcd 6.33, found 6.14); 6a.
1
1229, 1154, 1010, 808, 661, 582; H NMR (DMSO-d6) (d,
ppm): 0.82 (12H, s, 4ꢃCH3), 1.02 (12H, s, 4ꢃCH3), 2.00–
2.65 (16H, m, 8ꢃCH2), 4.47 (2H, s, 2ꢃCH), 6.95 (4H, s,
ArH), 10.73 (2H, s, 2ꢃOH). CHN analysis: %C (calcd
77.59, found 77.34), %H (calcd 7.41, found 7.28), %N
(calcd 4.29, found 4.10).
ꢂ
mp>300 C; IR (KBr, n, cmꢀ1): 3231, 3112, 2973, 1700,
14. (a) Oliver Kappe, C. J. Org. Chem. 1997, 62, 720 1. (b)
Suarez, M.; Verdecia, Y.; Ochoa, E.; Salfran, E.; Moran,
L.; Martın, N.; Martınez, R.; Quinteiro, M.; Seoane, C.;
Soto, J. L.; Novoa, H.; Blaton, N.; Peeters, O. M.; Ranter,
C. D. J. Eur. J. Org. Chem. 2000, 2079. (c) Suarez, M.;
Ochoa, E.; Verdecia, Y.; Martin, M.; Quinteiro, C.;
Seoane, J.; Soto, J. L.; Novoa, N.; Blaton, N.; Peeters,
O. M. Tetrahedron 1999, 55, 875. (d) Ahluwalia, V. K.;
Goyal, B.; Das, U. J. Chem. Research (S) 1997, 266.
1458, 1374, 1321, 1227, 1171, 1094, 808, 663 cmꢀ1 1H
;
NMR (DMSO-d6) (d, ppm): 1.09 (6H, t, J=7.2 Hz,
2ꢃCH3), 2.22 (6H, s, 2ꢃCH3), 3.97 (4H, q, J=7.2 Hz,
2ꢃOCH2), 5.10 (2H, s, 2ꢃCH), 7.17 (4H, s, ArH), 7.70
(2H, s, 2ꢃNH), 9.18 (2H, s, 2ꢃNH); CHN analysis: %C
(calcd 60.74, found 60.56), %H (calcd 7.22, found 6.97),
%N (calcd 11.81, found 11.59); 7a. mp>300 ꢂC; IR (KBr,
n, cmꢀ1): 3291, 3082, 2955, 1698, 1604, 1488, 1381, 1310,