Microwave assisted synthesis of 2-(4-substituted piperazin-1-yl)-1,8- naphthyridine-3-carbonitrile as a new class of serotonin 5-HT3 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.07.060

A series of novel 2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3- carbonitrile were prepared and evaluated for serotonin 5-HT₃ receptor antagonist activities in the isolated Guinea pig ileum.

Full text of DOI:10.1016/j.bmcl.2004.07.060

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5179–5181
Microwave assisted synthesis of 2-(4-substituted
piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile as a
new class of serotonin 5-HT3 receptor antagonists
Radhakrishnan Mahesh,* Ramachandran Venkatesha Perumal and Pandi Vijaya Pandi
Pharmacy Group, Birla Institute of Technology and Science, Pilani 333 031, Rajasthan, India
Received 19 June 2004; revised 24 July 2004; accepted 26July 2004
Available online 1 September 2004
Abstract—A series of novel 2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-carbonitrile 6 were prepared by microwave irradi-
ation and conventional heating. The intermediate, 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbonitrile 3, was prepared from 2-ami-
nonicotinaldehyde 1 and ethyl cyanoacetate 2 in the presence of piperidine under solvent free condition. The synthesized compounds
were evaluated for 5-HT3 antagonisms in longitudinal muscle-myenteric plexus (LMMP) preparation from Guinea pig ileum against
5-HT3 agonist, 2-methyl-5-HT. Among the compounds tested, 2-(4-allylpiperazin-1-yl)-1,8-naphthyridine-3-carbonitrile 6d showed
most favorable 5-HT3 receptor antagonism in the Guinea pig ileum.
Ó 2004 Elsevier Ltd. All rights reserved.
Among the serotonin (5-Hydroxytryptamine, 5-HT)
family, 5-HT3 receptor subtype has gained much
attention because of the clinical use of 5-HT3 receptor
antagonists (RAs) in the treatment of cancer chemother-
apy-induced nausea and vomiting (CNIV)1 and also in
postoperative nausea and vomiting (PONV).2 Moreo-
ver, a number of preclinical studies suggest that 5-HT3
RAs can be used in the treatment of various CNS disor-
ders.3 Hibert et al.4 proposed the pharmacophore of
5-HT3 RAs, which consists of three components: an aro-
matic ring, a carbonyl-containing linking moiety and a
basic center in a specific spatial arrangement. Based on
this pharmacophore, a number of molecules have been
reported so far.5,6 Rosen et al.7 hypothesized that the
carbonyl moiety is not essential for high affinity. This
component could serve as a hydrogen-bonding region.
One of the 5-HT3 ligand that proved this concept is
quipazine (Fig. 1) which exhibits 5-HT3 antagonistic
property8 as well as agonist character in some prepara-
tions.9 Although quipazine lacks a carbonyl group, the
negative electrostatic potential energy field generated
by the quinoline nitrogen may resemble that generated
by a carbonyl group.10 Indeed, Hibert et al.4 anticipated
that the lone pair of the quipazine nitrogen may play a
N
H
N
N
quipazine
Figure 1.
role equivalent to the carbonyl oxygen. Based on this
hypothesis, different heteroaryl piperazines viz., piperaz-
inylquinoxaline,11 piperazinylbenzothiazole,12 piperaz-
inylbenzoxazole,12 and piperazinylbenzimidazole13 have
been reported so far. Among these derivatives piperaz-
inylquinoxaline showed good 5-HT3 antagonistic activi-
ties in the isolated Guinea pig ileum as well as in radio
ligand binding studies.11 Most of the 5-HT3 RAs, which
were prepared on the basis of the pharmacophore pro-
posed by Hibert et al.,4 contains chiral centers, so the
synthetic cost is high. Only limited work has been done
on heteroaryl piperazines as 5-HT3 RAs. As a result, we
undertook a study to prepare the title compounds
(heteroaryl piperazines), which could serve as better
5-HT3 RAs than the currently available ones.
The starting material, 2-aminonicotinaldehyde 1, was
prepared according to the reported method.14 The inter-
mediate, 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carbo-
nitrile 3, was prepared by triturating a mixture of
2-aminonicotinaldehyde 1, ethyl cyanoacetate 2, and
Keywords: 1,8-Naphthyridine; Serotonin 5-HT3 antagonists.
*
Corresponding author. Tel.: +91 1596245073; fax: +91 1596
244183; e-mail: rmahesh@bits-pilani.ac.in
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.07.060

5180
R. Mahesh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5179–5181
N
N
N
CN
CHO
piperidine
+
solid state
N
N
OH
N
N
H
O
N
O
OC2H5
2
N
1
NH2
3
reflux
POCl3 / DMF
N
K2CO3 / DMF
MWI
N
R
N
R
+
H
N
N
N
N
N
Cl
5
4
6
Scheme 1.
piperidine in a mortar and pestle at room temperature
for about 10min. Completion of reaction was marked
by the change of state from solid to semi solid and
reconversion to solid, which was also confirmed by
TLC. The solid thus obtained was treated with water, fil-
tered, and recrystallized from DMF–water mixture to
give 3.15 The compound 3, was refluxed with phospho-
rus oxychloride in the presence of catalytic amount of
DMF for 1h. It was then cooled to room temperature
and treated with ice water. The resulting solution was
basified slowly under cooling with aqueous NaOH
(40%). The separated product was filtered, washed with
water, dried, and recrystallized from DMF–water mix-
ture to give 4.16 Microwave irradiation of 4, with appro-
priate piperazines in the presence of K2CO3 in DMF for
about 5min. gave the corresponding nucleophilic substi-
tuted product 5 (Scheme 1). When this reaction was car-
ried out by conventional heating (oil bath), the reaction
was complete (monitored by TLC) in 8–10h. The prod-
uct obtained by both the methods was identical in all as-
pects (mp, mixed mp, co-TLC and super imposable IR).
Almost similar yields were obtained by both the meth-
ods. It was observed that the reaction was simple and
accelerated greatly when carried out in microwave envi-
ronment. All the synthesized compounds were charac-
terized by spectral (IR, 1H NMR, and mass) and
elemental analysis data. IR spectral analysis of the final
compounds (6a–l) showed strong absorption bands at
ꢀ2200cmÀ1 and ꢀ1600cmÀ1 due to C@N and C@N
1
functions, respectively. In H NMR spectra, methylene
protons (cyclic) adjacent to N1 nitrogen of piperazine
showed triplet at d 3.87–4.13 whereas methylene protons
(cyclic) adjacent to N4 nitrogen of piperazine showed tri-
plet in the range of d 2.62–3.79. The final compounds
1
(6a–l) showed the following H NMR signals for 1,8-
naphthyridinyl moiety; C4–H: d ꢀ 8.4 (s), C5–H:
d ꢀ 8.00 (d), C6–H: d ꢀ 7.3 (dd) C7–H: d ꢀ 9.00 (d). Ele-
mental (CHN) analysis indicated that the calculated and
observed values were within the acceptable limits
( 0.4%). Physical data of the final compounds is repre-
sented in Table 1.
The Institutional Animal Ethics Committee of the Birla
Institute of Technology and Science, Pilani, India, ap-
proved experimentation on animals (Protocol No.
IAEC/RES/6, dated 21.04.03). Male Dunkin Hartley
Guinea pigs (250–300g; Hissar Agricultural University,
Hissar, Haryana, India) were sacrificed by cervical dislo-
cation. The abdomen was cut open and a length of ileum
was excised about 2cm from the ileo–caecal junction.
The longitudinal muscle-myenteric plexus (LMMP), 3–
4cm in length was prepared and mounted as described
Table 1. Physical and pharmacological data of compounds 6a–l
Yield (%) Mp °C (Recryst. solventa) Mol. formulab Mol. wt.c Antagonism to 2-methyl-5-HT pA2
d
Compd no.
R
6a
6b
–H
–CH3
–C2H5
74
82
226–227 (E)
152–154 (E)
C13H13N5
C14H15N5
15H17N5
239
253
267
279
315
329
345
345
345
360
349
3163.9
6.5
7.4
7.1
8.2
5.7
5.1
5.4
6.0
4.9
3.8
2.9
6c
6d
76130–132 (E)
C
–CH2–CH@CH2 75
–C6H5
–CH2C6H5
176–178 (E)
158–160 (E–A)
151–152 (E)
223–225 (E–A)
150–152 (A–W)
142–143 (E)
239–240 (A–C)
C
C16H17N5
C19H17N5
C20H19N5
C20H19N5O
C20H19N5O
C20H19N5O
C19H16N6O2
19H16N5Cl
C18H16N6
6e
75
81
74
82
77
84
6f
6g
o-OCH3–C6H4
m-OCH3–C6H4
p-OCH3–C6H4
p-NO2–C6H4
6h
6i
6j
6k
p-Cl–C6H4 9–17176(E16–A)
2-Pyridyl 80
6l
Ondansetron
172–174 (E)
6.9
a Abbreviations for the solvents used are as follows: A = acetone, C = chloroform, E = ethanol, and W = water.
b Elemental (C, H, and N) analysis indicated that the calculated and observed values were within the acceptable limits ( 0.4%).
c Molecular weight determination by mass spectral analysis.
d Values are the means from three separate experiments. SE was less than 10% of the mean.

R. Mahesh et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5179–5181
5181
by the literature method.17 The tissue was equilibrated
for 30min. under a resting tension of 500mg and con-
stant aeration in a 40mL organ bath containing Tyrode
solution maintained at ca. 37°C. Noncumulative con-
centrations of 2-methyl-5-HT (Tocris, UK) were added
with a 15min. dosing cycle (to prevent desensitization)
and left in contact with the tissue until the maximal con-
traction had developed. To study the antagonist effect of
the test compounds on the response evoked by 2-methyl-
5-HT, the compounds were added to the organ bath and
left in contact with the tissue for at least 10min prior to
the addition of 2-methyl-5-HT. The contractions were
recorded using a T-305 Force transducer coupled to a
StudentÕs physiograph (Bio Devices, Ambala, India).
Antagonism was expressed in the form of pA2 values,
which were graphically determined.18 The pA2 values
of the test compounds were compared with the standard
antagonist Ondansetron (Natco Pharma, Hyderabad,
India). The observed pharmacological data is repre-
sented in the Table 1.
for providing necessary infrastructure to carry out this
research and the RSIC, Punjab University, Chandigarh,
India, for providing spectral and analytical data.
References and notes
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In the present study, we have demonstrated the synthe-
sis and 5-HT3 receptor antagonistic activity of novel
2-(4-substituted piperazin-1-yl)-1,8-naphthyridine-3-car-
bonitrile in the isolated Guinea pig ileum. All the test
compounds showed 5-HT3 receptor antagonistic activi-
ties. Compound 6a (with no substitution at N4 pipera-
zine) showed good antagonism (pA2 6.5); with
increased liphophilicity (i.e., methyl group, 6b) activity
increased (pA2 7.4). Further increase in liphophilicity
(i.e., ethyl group, 6c) decreased the activity (pA2 7.1),
whereas substitution with allyl group (compound 6d)
showed most favorable antagonism (pA2 8.2). Placement
of bulkier groups like aryl/substituted aryl at N4 pipera-
zine (compounds 6e–l) decreased the activity. In addi-
tion, electron withdrawing substituents at aryl group
of N4 piperazine (compounds 6j–l) showed the least
activity among the aryl derivatives. Compounds 6b, 6c,
and 6d showed higher antagonism than Ondansetron
(pA2 6.9) in the isolated Guinea pig ileum. Hence further
studies in these compounds are planned to obtain clini-
cally useful agents.
14. Majewicz, T. G.; Caluwe, P. J. Org. Chem. 1974, 39(5),
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15. 90% Yield; mp > 300°C. IR (KBr) (cmÀ1): 3335 (NH),
2216(C „N), 1671 (C@O), 1593 (C@N). 1H NMR
(300MHz) (DMSO-d6) (d) ppm: 7.29 (dd, 1H, J=7.5,
8.5Hz, C6–H), 7.98 (d, 1H, J = 7.5Hz, C5–H), 8.39 (s, 1H,
C4–H), 8.95 (d, 1H, J = 8.5Hz, C7–H), 12.01 (s, 1H, NH).
Anal. Calcd for C9H5N3O: C, 63.16; H, 2.92; N, 24.56.
Found C, 63.08; H, 2.76; N, 24.68.
16. 79% Yield; mp > 300°C. IR (KBr) (cmÀ1): 2222 (C„N),
Acknowledgements
1
1601 (C@N), 810 (C–Cl). H NMR (300MHz) (DMSO-
d6) (d) ppm: 7.31 (dd, 1H, J = 7.5, 8.5Hz, C6–H), 7.80 (d,
1H, J = 7.5Hz, C5–H), 8.36(s, 1H, C 4–H), 9.01 (d, 1H,
J = 8.5Hz, C7–H). Anal. Calcd for C9H4N3Cl: C, 56.99;
H, 2.11; N, 22.16. Found. C, 56.63; H, 1.91; N, 22.41.
17. Paton, W. D. M.; Zar, A. M. J. Physiol. 1968, 194, 13.
18. Mac Kay, D. J. Pharm. Pharmacol. 1978, 30, 312.
This research was supported by grants from the Univer-
sity Grants Commission, New Delhi, India. We are
thankful to the CSIR, New Delhi, India for awarding
SRF to one of the authors (R.V.P.). We are grateful
to the Birla Institute of Technology and Science, Pilani,