Regioselective reaction: Synthesis, characterization and pharmacological activity of some new Mannich and Schiff bases containing sydnone

Article abstract of DOI:10.1016/j.ejmech.2012.06.011

A novel series of 1-substituted aminomethyl-3-[1-(4-isobutylphenyl)ethyl]- 4-(3-aryl-4-sydnonylidene) amino-1,2,4-triazol-5-thiones (9), was prepared from the 3-[1-(4-isobutylphenyl)ethyl]-4-(3-aryl-4-sydnonylidene) amino 5-mercapto-1,2,4-triazoles (8) by aminomethylation with formaldehyde and secondary amine. The structures of Schiff bases (8) and Mannich bases (9) were characterized on the basis of IR, NMR, mass spectra1 data and elemental analysis. The newly synthesized compounds were screened for their anti-inflammatory and analgesic activities. Mannich bases (9) carrying piperidine and morpholine residues showed promising anti-inflammatory and analgesic activity.

Full text of DOI:10.1016/j.ejmech.2012.06.011

European Journal of Medicinal Chemistry 54 (2012) 597e604
Contents lists available at SciVerse ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Regioselective reaction: Synthesis, characterization and pharmacological activity
of some new Mannich and Schiff bases containing sydnone
,
b
b
Nithinchandra a, B. Kalluraya a , S. Aamir , A.R. Shabaraya
*
a Department of Studies in Chemistry, Mangalore University, Mangalagangotri 574 199, India
b Srinivas College of Pharmacy, Srinivas Campus, Valachil, Farangipete Post, Mangalore 574 143, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel series of 1-substituted aminomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-(3-aryl-4-sydnonylidene)
amino-1,2,4-triazol-5-thiones (9), was prepared from the 3-[1-(4-isobutylphenyl)ethyl]-4-(3-aryl-4-
sydnonylidene) amino 5-mercapto-1,2,4-triazoles (8) by aminomethylation with formaldehyde and
secondary amine. The structures of Schiff bases (8) and Mannich bases (9) were characterized on the
basis of IR, NMR, mass spectra1 data and elemental analysis. The newly synthesized compounds were
screened for their anti-inflammatory and analgesic activities. Mannich bases (9) carrying piperidine and
morpholine residues showed promising anti-inflammatory and analgesic activity.
Received 10 February 2012
Received in revised form
6 June 2012
Accepted 6 June 2012
Available online 15 June 2012
Keywords:
Sydnone
Ó 2012 Elsevier Masson SAS. All rights reserved.
1,2,4-Triazole
Schiff bases
Mannich bases
Anti-inflammatory agents
Analgesic agents
1. Introduction
2. Chemistry
Mesoionic compounds have been studied extensively as
possible medicinal agents. It was shown that the structural features
possessing partial positive charge on the heterocyclic ring and
balanced by a negative charge of an exocyclic atom, they are able to
interact with biomolecules such as proteins and DNA. In addition,
their overall neutral character enables them to cross biological
membranes in vivo [1e3]. Sydnones possessing heterocyclic
moieties at the position-4 are also known for a wide range of bio-
logical properties [4e7].
A number of mesoionic compounds are reported to possess
activities such as anticancer [8e10], anti-inflammatory, analgesic,
antimicrobial etc [11e15]. The 1,2,4-triazole and its derivatives
were reported to exhibit various pharmacological activities such as
antimicrobial, analgesic, anti-inflammatory, antioxidant and anti-
cancer properties [16e20].
3-[1-(4-Isobutylphenyl)ethyl]-4-amino-5-mercapto-1,2,4-
triazole (7) was prepared by the fusion of 2-[4-isobutylphenyl]
propanoic acid (6) with thiocarbohydrazide (TCH) [21]. Substituted
anilines (1) when treated with ethyl chloroacetate in the presence
of sodium acetate in ethanol medium gave the corresponding
anilino acetic ester. This ester on hydrolysis gave the corresponding
anilino acetic acid (2). Diazotization of anilino acetic acid (2) with
sodium nitrite and conc. HCl at 0 ꢀC gave the corresponding
N-nitroso compound (3). Cyclisation of this N-nitroso compound
with acetic anhydride gave 3-arylsydnone (4). Formylation of
3-arylsydnones was carried out using POCl3 and N-methyl-
formanilide to give 3-aryl-4-formylsydnones (5) (Scheme 1).
Condensation of 3-[1-(4-isobutylphenyl)ethyl]-4-amino-5-
mercapto-1,2,4-triazole (7) with 3-aryl-4-formylsydnones (5) in
the presence of catalytic amount of conc. sulphuric acid gave
Schiff bases (8aec) in good yield (Scheme 2).
Reaction of 3-[1-(4-isobutylphenyl)ethyl]-4-(3-aryl-4-sydnonyli
dene) amino 5-mercapto-1,2,4-triazoles (8) with formaldehyde and
secondary amine in ethanol medium gave the N-Mannich bases
rather than the S-Mannich bases (Scheme 3). The reaction proceeds
via the formation of immonium salt which subsequently attacks
the N-1 of triazole giving rise to regioselective N-Mannich base (9).
The structures of the newly synthesized compounds have been
Prompted by these observations and in an attempt to synthesize
a series of mesoionic compounds with improved biological activity,
a new series of Schiff bases (8) and Mannich bases (9) carrying
sydnone moiety were synthesized and evaluated for their anti-
inflammatory and analgesic property.
* Corresponding author. Tel.: þ91 824 2287262; fax: þ91 824 2287367.
E-mail addresses: bkalluraya@gmail.com, kallurayab@yahoo.com (B. Kalluraya).
0223-5234/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2012.06.011

598
Nithinchandra et al. / European Journal of Medicinal Chemistry 54 (2012) 597e604
R
NH2
(1)
COOH
COOH
i) EtOH, NaOAc,
ii) NaOH,
NaNO2/HCl
0 °C
NH
R
N
R
+
COOEt
N
O
(2)
(3)
Cl
AC2O
R
R
O
NMF/POCl3
H
H
+
+
N
N
-
N
-
N
O
O
O
O
(5)
(4)
R = H, CH , OCH
3
3
Scheme 1.
established on the basis of elemental analysis, IR, 1H NMR, mass
spectral and 13C NMR data.
pharmacological data are expressed as mean ꢁ SEM; statistical
analysis was applied to determine the significance of the difference
between the control group and groups of animals tested with the
tested compounds.
3. Pharmacology
Some of the selected compounds from this series were evalu-
ated for analgesic and anti-inflammatory activities. The anti-
inflammatory and analgesic activities of the tested compounds
were measured with respect to the control and compared with the
standard drugs indomethacin and pentazocine respectively. All the
3.1. Anti-inflammatory activity
The anti-inflammatory activity was carried out following the
method of Winter et al. [22]. The wistar albino rats weighing
150e200 g were selected. The animals were weighed and divided
H3C
H3C
CH3
H3C
CO2H
NH
NH
N
N
H2N
NH2
+
Fusion
SH
CH3
S
N
H3C
NH2
(6)
TCH
(7)
H3C
H3C
O
N
N
H
+
R
N
SH
+
N
-
N
H3C
O
NH2
O
(5a-c)
(7)
EtOH , Conc.H SO
2
4
Stirring
H3C
H3C
H3C
H3C
N
NH
N
N
S
N
N
SH
N
N
H3C
H3C
R
R
-
+
O
-
N
+
O
N
O
N
O
N
(8)
R = H, CH , OCH
3
3
Scheme 2.

Nithinchandra et al. / European Journal of Medicinal Chemistry 54 (2012) 597e604
599
H3C
H3C
H3C
X
N
H3C
N
N
N
NH
X
N
HCHO,
H
S
S
N
N
N
N
rt
DMF,
H3C
H3C
R
R
-
-
+
N
O
+
O
N
O
N
O
N
(9)
X = O, CH , NCH , NC H , NC H
5
(8)
R = H, CH , OCH
3
2
3
2
5
6
3
Scheme 3.
into different groups (control, standard and the test groups) of five
rats each. The first group of rats was treated with 1 mL of 1% car-
boxymethyl cellulose suspension orally (control), the second group
was administered with a dose of 20 mg/kg of the indomethacin
(standard) and the third group was treated with 20 mg/kg of the
suspension of the test compounds. After 30 min, the animals were
injected with 0.1 mL of 1% carrageenan in normal saline, subcuta-
neously to the sub-planar region of right hind paw. The paw volume
was measured immediately (0 h), after 30 min, 60 min and 120 min
using plethysmometer. Values are expressed as mean, by one way
ANOVA analysis followed by Dunnett’s-t-test and results are
tabulated in Table 1.
tail (i.e. tail flick). Reaction time is noted at an intervals of 30, 60,
90 min after the administration of drug. Values are expressed as
mean ꢁ SEM, by one way ANOVA analysis followed by Dunnett’s-t-
test and results are tabulated in Table 2.
4. Results and discussion
4.1. Chemistry
The IR spectra of Schiff bases (8aec) the NH absorption band
was observed in the range of 3560e3573 cmꢂ1. The band at
1750e1771 cmꢂ1 is due to carbonyl stretching of the sydnone
moiety and the C]N stretching was observed at 1590e1605 cmꢂ1
.
3.2. Analgesic activity
However in the Mannich bases (9) the absorption band at
3560e3573 cmꢂ1 was not observed there by indicating the
formation of N-Mannich bases. The other prominent bands
observed are 2900e2954 cm_1 for CeH stretching. The sydnone
carbonyl absorption band observed at 1770e1793 cmꢂ1 and C]N
Rats of either sex weighing between 150 and 200 g were used
for the experiment. The animals were weighed and divided into
different groups (control, standard and the test groups) of five rats
each. The first group of rats was treated with control, the second
group was administered with a dose of 20 mg/kg of the pentazocine
(standard) and the third group was treated with 20 mg/kg of the
suspension of the test compounds. In this method heat is used as
a source of pain. Animals were individually placed on an analge-
siometer, so that the tail lies over the nichrome wire of instrument
without touching it (i.e., about 1/8 inch above the nichrome wire)
cut off time is 10 s. The end point of the sensation is when rat lifts its
stretching band was seen in the range of 1588e1600 cmꢂ1
.
In the 1H NMR spectra of (8aec) the NH proton appeared as
singlet at 13.87e13.0 ppm, presumably due to the existence of
thiolethione tautomerism. The N]CH proton appeared as singlet
at 10.16e10.10 ppm, whereas in compounds (9ael) the signal due
to NH proton was absent and the presence of a singlet at
5.07e4.94 due to the NeCH2eN protons confirmed the formation
d
d
d
of Mannich bases (9).
Table 1
Anti-inflammatory activity data of compounds 8aec and 9aek.
Compd.
Edema volume in mL (MeanꢁSEM)
Percentage reduction (%)
0 h
1/2 h
1 h
2 h
0 h
1/2 h
1 h
2 h
Control
Indomethacin
0.11 ꢁ 0.005
0.1 ꢁ 0.003
0.1 ꢁ 0.09
0.74 ꢁ 0.005
0.31 ꢁ 0.01b
0.49 ꢁ 0.01a
0.45 ꢁ 0.010b
0.38 ꢁ 0.010b
0.42 ꢁ 0.003b
0.40 ꢁ 0.005b
0.45 ꢁ 0.003b
0.53 ꢁ 0.02a
0.43 ꢁ 0.017b
0.45 ꢁ 0.011b
0.47 ꢁ 0.011b
0.50 ꢁ 0.017a
0.37 ꢁ 0.008b
0.42 ꢁ 0.008b
0.76 ꢁ 0.005
0.26 ꢁ 0.005b
0.46 ꢁ 0.01b
0.40 ꢁ 0.014b
0.34 ꢁ 0.011b
0.34 ꢁ 0.005b
0.33 ꢁ 0.012b
0.40 ꢁ 0.008b
0.5 ꢁ 0.011a
0.35 ꢁ 0.008b
0.40 ꢁ 0.008b
0.39 ꢁ 0.017b
0.48 ꢁ 0.017b
0.32 ꢁ 0.008b
0.39 ꢁ 0.005b
0.77 ꢁ 0.02
e
e
e
e
0.23 ꢁ 0.01b
0.38 ꢁ 0.003b
0.34 ꢁ 0.014b
0.26 ꢁ 0.008b
0.27 ꢁ 0.003b
0.24 ꢁ 0.008b
0.35 ꢁ 0.008b
0.47 ꢁ 0.008a
0.25 ꢁ 0.008b
0.35 ꢁ 0.006b
0.33 ꢁ 0.006b
0.46 ꢁ 0.005b
0.26 ꢁ 0.008b
0.33 ꢁ 0.012b
6.06
3.03
9.09
9.09
9.09
9.09
9.09
9.09
9.09
9.09
9.09
9.09
9.09
9.09
58.1
32.9
39.2
48.6
43.7
45.0
38.7
27.9
41.9
39.1
36.5
31.5
49.0
42.7
65.8
39.4
46.9
55.2
55.3
56.1
46.9
34.2
53.0
46.9
48.7
35.9
57.0
48.6
70.1
50.2
55.4
64.0
65.3
67.9
54.5
38.5
66.6
54.1
56.2
40.2
65.8
56.2
8a
8b
8c
9a
9b
9d
9e
9f
9g
9h
9i
9j
9k
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.001
0.1 ꢁ 0.005
ANOVA analysis followed by Dunnett’s-t-test, n ¼ 5, values were compared w.r.t. to control.
a
P < 0.01 (significant from the control).
P < 0.001 (significant from the control).
b

600
Nithinchandra et al. / European Journal of Medicinal Chemistry 54 (2012) 597e604
Table 2
Mannich bases 9b, 9a, 9f and 9j showed significant anti-
inflammatory and analgesic activity compared to the standard
drug. The Mannich derivative possessing piperidine and morpho-
line will helps to enhance the biological activity.
Analgesic activity data of compounds 8aec and 9aek.
Compounds
Tail flick latency in secs
0 min 30 min
60 min
90 min
Control
3.35 ꢁ 0.028 3.23 ꢁ 0.005
3.34 ꢁ 0.005
6.95 ꢁ 0.02b
6.24 ꢁ 0.005b
3.25 ꢁ 0.005
7.45 ꢁ 0.02b
6.6 ꢁ 0.057b
Pentazocine 3.23 ꢁ 0.017 6.25 ꢁ 0.02b
6. Experimental protocols
8a
8b
8c
9a
9b
9d
9e
9f
9g
9h
9i
9j
9k
3.21 ꢁ 0.008 5.76 ꢁ 0.005
3.25 ꢁ 0.005 4.99 ꢁ 0.101a
6.11 ꢁ 0.063b 6.92 ꢁ 0.014b
Melting points were determined using open capillary method
and are uncorrected. The IR spectra (in KBr pellets) were recorded
on a Shimadzu FT-IR 157 spectrometer. The 1H NMR spectra were
recorded on a Bruker AMX-400 (400 MHz) NMR spectrometer
using TMS as an internal standard. The chemical shifts are
3.23 ꢁ 0.033 5.41 ꢁ 0.005b 6.30 ꢁ 0.018b 7.23 ꢁ 0.020b
3.25 ꢁ 0.028 4.92 ꢁ 0.005a
3.17 ꢁ 0.017 4.56 ꢁ 0.008a
6.1 ꢁ 0.057b
6.9 ꢁ 0.028b
6.8 ꢁ 0.017b
5.73 ꢁ 0.020b
3.35 ꢁ 0.005
4.4 ꢁ 0.028a
5.39 ꢁ 0.023b 6.41 ꢁ 0.020b
5.03 ꢁ 0.044b 6.05 ꢁ 0.026b
5.91 ꢁ 0.023b 7.12 ꢁ 0.012b
3.27 ꢁ 0.014 4.19 ꢁ 0.025a
3.24 ꢁ 0.003 5.15 ꢁ 0.028
3.25 ꢁ 0.035 3.92 ꢁ 0.014a
3.23 ꢁ 0.035 4.52 ꢁ 0.014a
3.28 ꢁ 0.016 4.15 ꢁ 0.028a
3.22 ꢁ 0.031 4.77 ꢁ 0.014a
3.26 ꢁ 0.020 4.61 ꢁ 0.030a
expressed in
d scale downfield from TMS and proton signals are
4.31 ꢁ 0.012a
5.10 ꢁ 0.008b
indicated as s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet. The mass spectra were recorded either on a Jeol
JMS-D 300 mass spectrometer or API 3000 LCeMS instrument
operating at 70 eV.
5.25 ꢁ 0.028b 6.21 ꢁ 0.030b
4.41 ꢁ 0.018a
5.35 ꢁ 0.017b
5.92 ꢁ 0.005b 6.82 ꢁ 0.012b
5.55 ꢁ 0.028b 6.26 ꢁ 0.008b
ANOVA analysis followed by Dunnett’s-t-test, n ¼ 5, values were compared w.r.t. to
control.
6.1. General procedure for the synthesis of N-substituted glycines
(anilino acetic acid) 2aec
a
P < 0.01 (significant from the control).
b
P < 0.001 (significant from the control).
A mixture of substituted aniline (1) (0.5 mol), ethyl chlor-
oacetate (0.6 mol) and anhydrous sodium acetate (0.6 mol) in
120 mL of ethanol was refluxed in an oil bath for 6 h. The reaction
mixture was left overnight at room temperature and poured into
crushed ice. The precipitate formed was collected by filtration and
dried. The dried product, ethyl ester of N-substituted glycine
without further purification was used for the next step. To ethyl
ester of N-substituted glycine (0.4 mol), sodium hydroxide
(0.45 mol) in 200 mL of water was added and refluxed for 0.5 h.
After cooling, the reaction mixture was acidified to pH ¼ 2 using
hydrochloric acid. The precipitated N-substituted glycine (2) was
filtered and washed thoroughly with cold water. Further purifica-
tion was done by recrystallisation from ethanol. The compounds
prepared by this procedure are, anilino acetic acid 2a: m.p.
127e128 ꢀC, yield 70% (lit. [7] 128e129 ꢀC), p-methylanilino acetic
acid 2b: m.p. 163e164 ꢀC, yield 75% (lit. [7] 163e164 ꢀC),
p-methoxyanilino acetic acid 2c: m.p. 142 ꢀC, yield 75% (lit. [7]
144e145 ꢀC).
In the 13C NMR spectra of (9) the formation of N-alkyl derivative
was indicated by the presence of an NeCH2eN peak around
d
69.02e68.19 ppm, which is absent in 13C spectra of compound (8).
In compound (8) formation of Schiff base was indicated by the
presence of peak in the region of 152.45e152.56 ppm for the
eN¼CHe carbon. In compound (8 and 9) the sydnonyl C-4 signal
appeared in the region of
d 139.78e143.21 ppm and C-5 signal
appeared at 160.50e161.42 ppm.
d
4.2. Pharmacological screening
The tested compounds showed anti-inflammatory activity
ranging from 38.5% to 67.9%, whereas standard drug Indomethacin
showed 70.1% inhibition after 2 h (Table 1). Mannich base 9b dis-
played the highest anti-inflammatory activity among the set of
compounds tested in the present study. Test compounds that
exhibited the most potent anti-inflammatory activity were 8c, 9a,
9b, 9f and 9j.
The anti-inflammatory activity data showed that the
compounds having piperidine 9b and morpholine 9f possess
highest activity 67.9% and 66.6%. Among the Schiff bases tested for
anti-inflammatory activity, 8c showed 64.0% activity.
6.2. General procedure for the preparation of N-nitroso-N-
substituted glycines 3aec
To a stirred suspension of N-substituted glycine (2aec) (0.1 mol)
in 120 mL water at 0 ꢀC, a solution of sodium nitrite (0.1 mol) in
water 24 mL was added drop wise during 30 min. The reaction
mixture was practically clear after 2 h. It was filtered and acidified
with concentrated hydrochloric acid. The precipitated product was
filtered, washed with cold water and dried in air. The nitro-
soglycines (3) prepared by the above method were recrystallised
from aqueous ethanol. Compounds prepared according to this
procedure are, N-nitroso-N-phenylglycine 3a: m.p. 101e102 ꢀC,
yield 80% (lit. [7] 102e103 ꢀC), N-nitroso-N-(p-tolyl)glycine 3b:
m.p. 98e99 ꢀC, yield 83% (lit. [7] 99e100 ꢀC), N-nitroso-N-(p-ani-
syl)glycine 3c: m.p. 120e121 ꢀC, yield 84% (lit. [7] 121 ꢀC).
Among compounds tested for analgesic activity 8b, 8c, 9a, 9b, 9f
and 9j showed activity comparable with that of the standard drug
pentazocine. Compounds showing good anti-inflammatory activity
also exhibited highest analgesic activity.
5. Conclusion
Sydnones are highly versatile and robust members of the mes-
oionic class of heteroaromatic compounds. They possess an array of
interesting chemical and physicochemical properties, as well as
a variety of biological activities. Functionalisation of sydnones in
CeH (4th position) position will enhance their biological activity. In
this regard we synthesized Schiff and Mannich derivatives pos-
sessing sydnone moiety with the objective of developing molecules
possessing better anti-inflammatory and analgesic property. It is
interesting to note that Schiff base 8c show good anti-inflammatory
and analgesic activity compared to that of 8a and 8b, it clearly
concluded that presence of electron releasing group in sydnone will
enhance the anti-inflammatory and analgesic activity. Among the
6.3. General procedure for the preparation of 3-arylsydnone 4aec
N-Nitroso-N-substituted glycine (3aec) (0.1 mol) was heated
with acetic anhydride (0.5 mol) on a water bath for 2e4 h. The
reaction mixture was kept aside at room temperature for overnight.
Then it was poured into ice-cold water, filtered and washed with
water, 5% sodium bicarbonate solution and again with water. The
solid was dried and recrystallised from benzene. Compounds
prepared according to this procedure are, 3-phenylsydnone 4a:

Nithinchandra et al. / European Journal of Medicinal Chemistry 54 (2012) 597e604
601
m.p. 134e135 ꢀC, yield 73% (lit. [7] 134e135 ꢀC), 3-(p-tolyl)sydnone
6.6.2. 3-[1-(4-Isobutylphenyl)ethyl]-4-[3-(p-tolyl)-4-sydnonylidene]
4b: m.p. 143e144 ꢀC, yield 78% (lit. [7] 144e145 ꢀC), 3-(p-anisyl)
sydnone 4c: m.p. 125e126 ꢀC, yield 75% (lit. [7] 125e126 ꢀC).
amino 5-mercapto-1,2,4-triazole 8b
Yield 80%, m.p. 120e124 ꢀC; IR (KBr)
g
/cmꢂ1: 3561.9 (NH
stretching), 2920 (CeH stretching), 1772.2 (sydnone carbonyl),
1592.4 (eN]Ce); 1H NMR (DMSO-d6):
d
0.82 (d, 6H, J ¼ 6.54 Hz,
6.4. Generalprocedurefor thepreparationof3-aryl-4-formylsydnones
5aec
(CH3)2), 1.48 (d, 3H, J ¼ 7.26 Hz, CH3), 2.1e2.3 (m, 1H, CHe(CH3)2),
2.42 (d, 2H, J ¼ 6 Hz, CH2), 2.48 (s, 3H, Syd-Ph-CH3), 4.10 (q, 1H,
CH), 7.04 (d, 2H, J ¼ 8.22 Hz, 30, 50-Ib-Ar-H), 7.15 (d, 2H, J ¼ 8.01 Hz, 20,
60-Ib-Ar-H), 7.49 (d, 2H ortho protons of p-tolyl), 7.71 (d, 2H meta
protons of p-tolyl), 10.16 (s, 1H, N]CH), 13.87 (s, 1H, SH); 13C NMR
N-Methylformanilide (28.4 g, 0.210 mol) and phosphoryl chlo-
ride (31.7 g, 0.205 mol) were mixed and after half an hour,
3-arylsydnone (4aec) (0.186 mol) was added portion wise with
stirring and cooling so that the temperature was below 45 ꢀC.
Hydrogen chloride was evolved vigorously. After standing over-
night the dark brown viscous mixture was dissolved in 150 mL of
acetone and poured into 750 mL ice water with stirring. The solid
obtained was filtered, washed with cold water, dried and recrys-
tallised from ethanol. The compounds prepared according to this
procedure are, 3-phenyl-4-formyl sydnone 5a: m.p. 147e149 ꢀC,
yield 53% (lit. [7] 147e150 ꢀC), 3-(p-tolyl)-4-formylsydnone 5b:
m.p. 102e103 ꢀC, yield 60% (lit. [7] 102e103 ꢀC), 5b further char-
acterized by Single Crystal XRD data [23]. 3-(p-Anisyll)-4-
formylsydnone 5c: m.p. 116e118 ꢀC, yield 59% (lit. [7] 116e119 ꢀC).
(DMSO-d6):
d 19.05 (isobutyl-CH3), 20.84 (CH3), 22.07 (sydnonyl
phenyl CH3), 29.46 (isobutyl CH), 34.61 (isobutyl-CH2), 44.09
(C between triazole and isobutyl phenyl), 125.11 (tolyl C-2 and C-6),
127.22 (isobutyl phenyl C-2 and C-6),129.0 (isobutyl phenyl C-3 and
C-5),130.37 (tolyl C-3 and C-5),130.72 (isobutyl phenyl C-1 and C-4),
137.90 (tolyl C-1), 139.79 (tolyl C-4), 143.19 (sydnonyl C-4), 146.41
(triazole eN]Ce), 152.54 (eN]CHe), 161.49 (sydnonyl C]O),
163.67 (C]S); LCeMS (m/z): 462 (Mþ), (M.F. e C24H26N6O2S); Anal.
Calcd for C24H26N6O2S: C, 62.32; H, 5.67; N, 18.17; S, 6.93. Found: C,
62.34; H, 5.67; N, 18.14; S, 6.90.
6.6.3. 3-[1-(4-Isobutylphenyl)ethyl]-4-[3-(p-anisyl)-4-sydnonylidene]
amino 5-mercapto-1,2,4-triazole 8c
g
/cmꢂ1: 3562.4 (NH
6.5. General procedure for the synthesis of 3-[1-(4-isobutylphenyl)
ethyl]-4-amino-5-mercapto-1,2,4-triazole 7
Yield 76%, m.p. 110e112 ꢀC; IR (KBr)
stretching), 2920.4 (CeH), 1773.0 (sydnone carbonyl), 1592.2 (eN]
Ce); 1H NMR (DMSO-d6):
d
0.92 (d, 6H, J ¼ 6.54 Hz, (CH3)2), 1.52 (d,
An equimolar mixture of thiocarbohydrazide (TCH) and 2-[4-
isobutylphenyl]propanoic acid (6) was mixed and heated gently
on an oil bath until the evolution of H2S ceases. The reaction
mixture was then cooled to room temperature and poured into ice-
cold water and stirred well. It was then filtered, dried and recrys-
tallised from ethanol. Compound prepared according to this
procedure is, 3-[1-(4-isobutylphenyl)ethyl]-4-amino-5-mercapto-
1,2,4-triazole 7: m.p. 147e149 ꢀC, yield 60% (lit. [20] 147e150 ꢀC).
3H, J ¼ 7.26 Hz, CH3), 1.80e1.76 (m, 1H, CHe(CH3)2), 2.36 (d, 2H,
J ¼ 6 Hz, CH2), 3.4 (s, 3H, OCH3), 4.18 (q, 1H, CH), 7.04 (d, 2H,
J ¼ 8.0 Hz, 30, 50-Ib-Ar-H), 7.15 (d, 2H, J ¼ 8.01 Hz, 20, 60-Ib-Ar-H),
7.30e7.80 (m, 4H, Ar-H), 10.12 (s, 1H, N]CH), 13.0 (s, 1H, SH); 13C
NMR (DMSO-d6):
d 19.04 (isobutyl-CH3), 22.40 (CH3), 29.44 (iso-
butyl CH), 34.60 (isobutyl-CH2), 44.08 (C between triazole and
isobutyl phenyl), 69.02 (sydnonyl phenyl OCH3), 125.18 (anisyl C-2
and C-6), 127.28 (isobutyl phenyl C-2 and C-6), 129.18 (isobutyl
phenyl C-3 and C-5), 130.38 (anisyl C-3 and C-5), 130.86 (isobutyl
phenyl C-1 and C-4), 132.70 (anisyl C-1), 142.76 (sydnonyl C-4),
146.12 (triazole eN]Ce), 152.44 (eN]CHe), 156.36 (anisyl C-4),
161.42 (sydnonyl C]O), 163.68 (C]S); LCeMS (m/z): 478 (Mþ),
(M.F. e C24H26N6O3S); Anal. Calcd for C24H26N6O3S: C, 60.23; H,
5.48; N, 17.56; S, 6.70. Found: C, 60.25; H, 5.52; N, 17.56; S, 6.72.
6.6. Generalprocedureforthesynthesis3-[1-(4-isobutylphenyl)ethyl]-
4-(3-aryl-4-sydnonylidene) amino 5-mercapto-1,2,4-triazoles 8
To
a solution of 3-[1-(4-isobutylphenyl)ethyl]-4-amino-5-
mercapto-1,2,4-triazole (7) (0.01 mol) in absolute ethanol
(25 mL), was added 3-aryl-4-formylsydnone (5aec) (0.01 mol).
Concentrated sulphuric acid (0.5 mL) was added to this reaction
mixture. The contents were stirred at room temperature for 1e2 h.
The solid product separated was collected by filtration. It was dried
and recrystallised from ethanol.
6.7. Generalprocedure for the synthesis of 1-substituted aminomethyl-
3-[1-(4-isobutylphenyl)ethyl]-4-(3-aryl-4-sydnonylidene) amino-
1,2,4-triazol-5-thiones (9)
A mixture of Schiff bases (8aec) (0.01 mol) and formaldehyde
40% (1.5 mL) in ethanol (20 mL) was taken and to this solution
secondary amines (0.01 mol) in DMF (10 mL) was added and stirred
at room temperature. The solid product gets separated within half
an hour. The stirring was continued for another 4 h. Finally the
product was collected by filtration, washed with ethanol and dried.
It was further purified by recrystallisation from ethanol.
6.6.1. 3-[1-(4-Isobutylphenyl)ethyl]-4-(3-phenyl-4-sydnonylidene)
amino 5-mercapto-1,2,4-triazole 8a
Yield 78%, m.p. 215e217 ꢀC; IR (KBr)
g : 3562.9
/cmꢂ1
(NH stretching), 2920 (CeH), 1772.7 (sydnone carbonyl), 1592
(eN¼CH); 1H NMR (DMSO-d6):
d
0.84 (d, 6H, J ¼ 6.51 Hz, (CH3)2),
1.50 (d, 3H, J ¼ 7.26 Hz, CH3), 1.82e1.78 (m, 1H, CHe(CH3)2), 2.38
(d, 2H, J ¼ 6 Hz, CH2), 4.26 (q, 1H, CH), 7.04 (d, 2H, J ¼ 8.22 Hz, 30, 50-
Ib-Ar-H), 7.15 (d, 2H, J ¼ 8.01 Hz, 20, 60-Ib-Ar-H), 7.68e7.84 (m, 5H,
Ar-H), 10.10 (s, 1H, N]CH), 13.0 (s, 1H, SH); 13C NMR (DMSO-d6):
6.7.1. 1-Morpholinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-(3-phe
nyl-4-sydnonylidene) amino-1,2,4-triazol-5-thione 9a
d
19.04 (isobutyl-CH3), 22.06 (CH3), 29.47 (isobutyl CH), 34.56
Yield 82%, m.p. 120e122 ꢀC; IR (KBr) /cmꢂ1: 2954.08 (C-H
g
(isobutyl-CH2), 44.09 (C between triazole and isobutyl phenyl),
125.40 (phenyl C-2 and C-6), 127.22 (isobutyl phenyl C-2 and C-6),
128.96 (isobutyl phenyl C-3 and C-5),130.08 (phenyl C-3, C-4 and C-
5), 132.82 (isobutyl phenyl C-1), 133.16 (isobutyl phenyl C-4), 137.95
(phenyl C-1), 139.76 (sydnonyl C-4), 145.78 (triazole eN]Ce),
152.39 (eN]CHe), 161.28 (sydnonyl C]O), 163.66 (C]S); LCeMS
(m/z): 449 (M þ 1), (M.F. e C23H24N6O2S); Anal. Calcd for
C23H24N6O2S: C, 61.59; H, 5.39; N, 18.74; S, 7.15. Found: C, 61.56; H,
5.40; N, 18.76; S, 7.15.
stretching), 1778.39 (sydnone carbonyl C]O), 1588.71 (eN]Ce);
1H NMR (DMSO-d6):
d
0.82 (d, 6H, J ¼ 6 Hz, (CH3)2), 1.52 (d, 3H,
J ¼ 6 Hz, CH3), 1.81e1.76 (m, 1H, CHe(CH3)2), 2.38 (d, 2H, J ¼ 6 Hz,
CH2), 2.50 (t, 4H, CH2NCH2), 3.51 (t, 4H, CH2OCH2), 4.20 (q, 1H, CH),
4.97 (s, 2H, NCH2N), 7.06 (d, 2H, J ¼ 8.0 Hz, 30, 50-Ib-Ar-H), 7.17
(d, 2H, J ¼ 8.0 Hz, 20, 60-Ib-Ar-H), 7.69e7.86 (m, 5H, Ar-H), 10.16 (s,
1H, N]CH); 13C NMR (DMSO-d6):
d 19.02 (isobutyl-CH3), 22.80
(CH3), 29.40 (isobutyl CH), 34.60 (isobutyl-CH2), 44.06 (C between
triazole and isobutyl phenyl), 50.20 (morpholine C-2 and C-6),

602
Nithinchandra et al. / European Journal of Medicinal Chemistry 54 (2012) 597e604
66.00 (morpholine C-3 and C-5), 68.10 (C between morpholine
and triazole), 125.82 (phenyl C-2 and C-6), 128.12 (isobutyl phenyl
C-2 and C-6), 129.52 (isobutyl phenyl C-3 and C-5), 131.24 (phenyl
C-3, C-4 and C-5), 133.96 (isobutyl phenyl C-1), 135.05 (isobutyl
phenyl C-4), 138.56 (phenyl C-1), 143.16 (sydnonyl C-4), 146.50
(triazole eN]Ce), 152.50 (eN]CHe), 161.50 (sydnonyl C]O),
163.60 (C]S); FABMAS (m/z) e 547.5 (Mþ), (M.F. e C28H33N7O3S);
Anal. Calcd for C28H33N7O3S: C, 61.41; H, 6.07; N, 17.90; S, 5.85.
Found: C, 61.39; H, 6.08; N, 17.88; S, 5.84.
NCH2N), 7.10 (d, 2H, J ¼ 8.22 Hz, 30, 50-Ib-Ar-H), 7.22 (d, 2H,
J ¼ 8.01 Hz, 20, 60-Ib-Ar-H), 7.76e7.90 (m, 5H, Ar-H), 10.14 (s, 1H,
N]CH); 13C NMR (DMSO-d6):
d 18.16 (N-ethylpiperazine CH3),
19.08 (isobutyl-CH3), 20.82 (CH3), 29.84 (isobutyl CH), 34.64
(isobutyl-CH2), 44.28 (C between triazole and isobutyl phenyl),
49.20 (N-ethylpiperazine CH2), 49.60 (N-ethylpiperazine C-3 and
C-5), 54.50 (N-methylpiperazine C-2 and C-6), 68.26 (C between
N-methylpiperazine and triazole), 125.86 (phenyl C-2 and C-6),
126.98 (isobutyl phenyl C-2 and C-6), 129.24 (isobutyl phenyl C-3
and C-5), 131.12 (phenyl C-3, C-4 and C-5), 132.96 (isobutyl phenyl
C-1), 134.94 (isobutyl phenyl C-4), 138.28 (phenyl C-1), 142.28
(sydnonyl C-4), 145.74 (triazole eN]Ce), 152.48 (eN]CHe),
160.76 (sydnonyl C]O), 163.60 (C]S); FABMAS (m/z) e 574.1
(Mþ), (M.F. e C30H38N8O2S); Anal. Calcd for C30H38N8O2S: C,
62.69; H, 6.66; N, 19.50; S, 5.58. Found: C, 62.68; H, 6.63; N, 19.52;
S, 5.62.
6.7.2. 1-Piperidinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-(3-phenyl-
4-sydnonylidene) amino-1,2,4-triazol-5-thione 9b
Yield 74%, m.p. 130e132 ꢀC; IR (KBr)
g
/cmꢂ1: 2924 (CeH
stretching), 1781.96 (sydnone carbonyl), 1589.66 (eN]Ce); 1H
NMR (DMSO-d6):
d
0.82 (d, 6H, J ¼ 4 Hz, (CH3)2), 1.28 (m, 2H,
piperidine CH2),1.42 (m, 4H, piperidine (CH2)2),1.51 (d, 3H, J ¼ 6 Hz,
CH3), 1.77 (m, 1H, CHe(CH3)2), 2.38 (d, 2H, J ¼ 4 Hz, CH2), 2.58
(m, 4H, piperidine CH2NCH2), 4.16 (q, 1H, CH), 4.94 (s, 2H, NCH2N),
7.05 (d, 2H, J ¼ 8 Hz, 30, 50-Ib-Ar-H), 7.16 (d, 2H, J ¼ 8 Hz, 20, 60-Ib-Ar-
H), 7.72e7.86 (m, 5H, Ar-H), 10.18 (s, 1H, N]CH); 13C NMR (DMSO-
6.7.5. 1-N-phenyl piperazinomethyl-3-[1-(4-isobutylphenyl)ethyl]-
4-(3-phenyl-4-sydnonylidene) amino-1,2,4-triazol-5-thione 9e
Yield 70%, m.p. 100e102 ꢀC; IR (KBr)
g
/cmꢂ1: 2951.6 (CeH),
d6):
d
19.06 (isobutyl-CH3), 22.08 (CH3), 23.40 (piperidine C-4),
1780.6 (sydnone carbonyl), 1589.8 (eN]Ce); 1H NMR (DMSO-
d6):
25.41 (piperidine C-3 and C-5), 29.49 (isobutyl CH), 34.58 (isobutyl-
CH2), 44.11 (C between triazole and isobutyl phenyl), 51.11 (piperi-
dine C-2 and C-6), 69.02 (C between piperidine and triazole),125.41
(phenyl C-2 and C-6), 127.18 (isobutyl phenyl C-2 and C-6), 128.98
(isobutyl phenyl C-3 and C-5), 130.04 (phenyl C-3, C-4 and C-5),
132.86 (isobutyl phenyl C-1), 133.14 (isobutyl phenyl C-4), 137.93
(phenyl C-1), 139.78 (sydnonyl C-4), 145.80 (triazole eN]Ce),
152.41 (eN]CHe), 161.30 (sydnonyl C]O), 163.68 (C]S); FAB-
MAS (m/z) e 545.3 (Mþ), (M.F. e C29H35N7O2S); Anal. Calcd for
C29H35N7O2S: C, 63.83; H, 6.46; N, 17.97; S, 5.88. Found: C, 63.82; H,
6.48; N, 17.94; S, 5.88.
d
0.84 (d, 6H, J ¼ 6.0 Hz, (CH3)2), 1.54 (d, 3H, J ¼ 7.26 Hz, CH3),
1.76e1.80 (m, 1H, CHe(CH3)2), 2.36 (d, 2H, J ¼ 6 Hz, CH2), 2.52
(t, 4H, N-phenylpiperazine CH2NCH2), 3.16 (t, 4H, N-phenyl-
piperazine CH2NCH2), 4.28 (q, 1H, CH), 5.10 (s, 2H, NCH2N), 6.78
(d, 2H, J ¼ 8 Hz, 30, 50-Ib-Ar-H), 6.92 (d, 2H, J ¼ 8 Hz, 20, 60-Ib-Ar-
H), 7.18e7.77 (m, 10H, N-phenyl and sydnonyl Ar-H), 10.06 (s, 1H,
N]CH); 13C NMR (DMSO-d6):
d 19.08 (isobutyl-CH3), 22.10 (CH3),
29.78 (isobutyl CH), 34.56 (isobutyl-CH2), 44.14 (C between tri-
azole and isobutyl phenyl), 49.70 (N-phenylpiperazine C-3 and
C-5), 50.44 (N-phenylpiperazine C-2 and C-6), 68.48 (C between
N-phenylpiperazine and triazole), 125.88 (phenyl C-2 and C-6),
126.90 (isobutyl phenyl C-2 and C-6), 129.46 (isobutyl phenyl C-3
and C-5), 131.10 (phenyl C-3 and C-5), 131.54 (phenyl C-4), 133.86
(isobutyl phenyl C-1), 135.28 (isobutyl phenyl C-4), 138.92
(phenyl C-1), 142.38 (sydnonyl C-4), 145.76 (triazole eN]Ce),
152.50 (eN]CHe), 161.20 (sydnonyl C]O), 163.60 (C]S); FAB-
MAS (m/z) e 623 (M þ 1), (M.F. e C34H38N8O2S); Anal. Calcd for
C34H38N8O2S: C, 65.57; H, 6.15; N, 17.99; S, 5.15. Found: C, 65.54;
H, 6.15; N, 17.98; S, 5.13.
6.7.3. 1-N-methyl piperazinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-
(3-phenyl-4-sydnonylidene) amino-1,2,4-triazol-5-thione 9c
Yield 63%, m.p. 122e124 ꢀC; IR (KBr)
g
/cmꢂ1: 2954.0 (CeH),
1778.9 (sydnone carbonyl), 1588.6 (eN]Ce); 1H NMR (DMSO-
d6):
d
0.83 (d, 6H, J ¼ 6 Hz, (CH3)2), 1.46 (d, 3H, J ¼ 8 Hz, CH3),
1.75e1.80 (m, 1H, CHe(CH3)2), 2.20 (d, 2H, J ¼ 6 Hz, CH2), 2.38
(t, 4H, CH2NCH2), 2.68 (t, 4H, CH2NCH2), 3.41 (s, 3H, NeCH3), 4.18 (q,
1H, CH), 4.96 (s, 2H, NCH2N), 7.08 (d, 2H, J ¼ 8.10 Hz, 30, 50-Ib-Ar-H),
7.18 (d, 2H, J ¼ 8.01 Hz, 20, 60-Ib-Ar-H), 7.74e7.88 (m, 5H, Ar-H),10.16
6.7.6. 1-Morpholinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-[3-
(s, 1H, N]CH); 13C NMR (DMSO-d6):
d
19.08 (isobutyl-CH3), 22.12
(p-tolyl)-4-sydnonylidene] amino-1,2,4-triazol-5-thione 9f
(CH3), 29.82 (isobutyl CH), 34.68 (isobutyl-CH2), 44.20 (C between
triazole and isobutyl phenyl), 45.75 (NeCH3), 49.48 (N-methyl-
piperazine C-3 and C-5), 54.55 (N-methylpiperazine C-2 and C-6),
68.30 (C between N-methylpiperazine and triazole), 125.82 (phenyl
C-2 and C-6), 128.12 (isobutyl phenyl C-2 and C-6), 128.96 (isobutyl
phenyl C-3 and C-5), 131.10 (phenyl C-3 and C-5), 131.56 (phenyl C-
4),133.86 (isobutyl phenyl C-1),135.10 (isobutyl phenyl C-4),138.46
(phenyl C-1), 141.32 (sydnonyl C-4), 145.72 (triazole eN]Ce),
152.46 (eN]CHe), 160.78 (sydnonyl C]O), 163.64 (C]S); FAB-
MAS (m/z) e 560.2 (Mþ), (M.F. e C29H36N8O2S); Anal. Calcd for
C29H36N8O2S: C, 62.12; H, 6.47; N, 19.98; S, 5.72. Found: C, 62.12; H,
6.43; N, 19.92; S, 5.74.
Yield 80%, m.p. 138e140 ꢀC; IR (KBr) /cmꢂ1: 2952.59 (CeH
g
stretching), 1788.20 (sydnone carbonyl), 1589.45 (eN]CHe); 1H
NMR (DMSO-d6):
d
0.83 (d, 6H, J ¼ 6.6 Hz, (CH3)2), 1.54 (d, 3H,
J ¼ 7.28 Hz, CH3), 1.75e1.82 (m, 1H, CHe(CH3)2), 2.39 (d, 2H,
J ¼ 7.13 Hz, CH2), 2.42 (s, 3H, Syd-Ph-CH3), 2.63 (t, 4H, morpholine
CH2NCH2), 3.53 (t, 4H, morpholine CH2OCH2), 4.19 (q, 1H, CH),
4.99 (s, 2H, NCH2N), 7.07 (d, 2H, J ¼ 8.13 Hz, 30, 50-Ib-Ar-H), 7.19 (d,
2H, J ¼ 8.12 Hz, 20, 60-Ib-Ar-H), 7.52 (d, 2H, J ¼ 8.13 Hz, ortho
protons of p-tolyl), 7.75 (d, 2H, J ¼ 8.13 Hz, meta protons of
p-tolyl), 10.08 (s, 1H, N]CH); 13C NMR (DMSO-d6):
d 19.07 (iso-
butyl-CH3), 20.86 (CH3), 22.09 (sydnonyl phenyl CH3), 29.48
(isobutyl CH), 34.63 (isobutyl-CH2), 44.11 (C between triazole and
isobutyl phenyl), 50.26 (morpholine C-2 and C-6), 66.00 (mor-
pholine C-3 and C-5), 68.19 (C between morpholine and triazole),
125.11 (tolyl C-2 and C-6), 127.19 (isobutyl phenyl C-2 and C-6),
129.0 (isobutyl phenyl C-3 and C-5), 130.37 (tolyl C-3 and C-5),
130.72 (isobutyl phenyl C-1 and C-4), 137.88 (tolyl C-1), 139.79
(tolyl C-4), 143.21 (sydnonyl C-4), 146.43 (triazole eN]Ce),
152.56 (eN]CHe), 161.51 (sydnonyl C]O), 163.69 (C]S); FAB-
MAS (m/z) e 561 (Mþ), (M.F. e C29H35N7O3S); Anal. Calcd for
C29H35N7O3S: C, 62.01; H, 6.28; N, 17.46; S, 5.71. Found: C, 62.00;
H, 6.26; N, 17.42; S, 5.68.
6.7.4. 1-N-ethyl piperazinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-
(3-phenyl-4-sydnonylidene) amino-1,2,4-triazol-5-thione 9d
Yield 66%, m.p. 135e137 ꢀC; IR (KBr)
g
/cmꢂ1: 2952.5 (CeH),
1779.0 (sydnone carbonyl), 1588.2 (eN]Ce); 1H NMR (DMSO-
d6):
d
0.80 (d, 6H, J ¼ 6.2 Hz, (CH3)2), 1.20 (t, 3H, N-ethyl-
piperazine CH3), 1.44 (d, 3H, J ¼ 8 Hz, CH3), 1.74e1.80 (m, 1H,
CHe(CH3)2), 2.20 (d, 2H, J ¼ 6 Hz, CH2), 2.38 (q, 2H, N-ethyl-
piperazine CH2) 2.48 (t, 4H, N-ethypiperazine CH2NCH2), 2.68 (t,
4H, N-ethylpiperazine CH2NCH2), 4.18 (q, 1H, CH), 4.96 (s, 2H,

Nithinchandra et al. / European Journal of Medicinal Chemistry 54 (2012) 597e604
603
6.7.7. 1-Piperidinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-[3-(p-
tolyl)-4-sydnonylidene] amino-1,2,4-triazol-5-thione 9g
(isobutyl phenyl C-1),131.18 (isobutyl phenyl C-4),137.92 (tolyl C-1),
139.86 (tolyl C-4), 142.30 (sydnonyl C-4), 146.18 (triazole eN]Ce),
152.42 (eN]CHe), 161.28 (sydnonyl C]O), 163.56 (C]S); FAB-
MAS (m/z) e 636.3 (Mþ), (M.F. e C35H40N8O2S); Anal. Calcd for
C35H40N8O2S: C, 66.01; H, 6.33; N, 17.60; S, 5.04. Found: C, 66.02; H,
6.35; N, 17.58; S, 5.0.
Yield 65%, m.p. 146e148 ꢀC; IR (KBr)
g
/cmꢂ1: 2950.8 (CeH),
1782.9 (sydnone carbonyl), 1587.6 (eN]CHe); 1H NMR (DMSO-
d6):
d
0.82 (d, 6H, J ¼ 6 Hz, (CH3)2), 1.26 (m, 2H, piperidine CH2), 1.42
(m, 4H, piperidine (CH2)2), 1.50 (d, 3H, J ¼ 6 Hz, CH3), 1.70e1.80
(m, 1H, CHe(CH3)2), 2.30 (d, 2H, J ¼ 6 Hz, CH2), 2.44 (s, 3H, Syd-
Ph-CH3), 2.62 (m, 4H, piperidine CH2NCH2), 4.22 (q, 1H, CH), 4.86
(s, 2H, NCH2N), 7.10 (d, 2H, J ¼ 8 Hz, 30, 50-Ib-Ar-H), 7.22 (d, 2H,
J ¼ 8 Hz, 20, 60-Ib-Ar-H), 7.62 (d, 2H, J ¼ 8 Hz, ortho protons of p-tolyl),
7.85 (d, 2H, J ¼ 8 Hz, meta protons of p-tolyl),10.14 (s,1H, N]CH); 13C
6.7.10. 1-Morpholinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-[3-
(p-anisyl)-4-sydnonylidene] amino-1,2,4-triazol-5-thione 9j
Yield 75%, m.p. 134e136 ꢀC; IR (KBr)
g
/cmꢂ1: 2931.20 (CeH),
1792.9 (sydnone carbonyl), 1585.0 (eN]CH); 1H NMR (DMSO-d6):
NMR (DMSO-d6):
d
19.04 (isobutyl-CH3), 20.16 (CH3), 22.43 (syd-
d
0.88 (d, 6H, J ¼ 6 Hz, (CH3)2), 1.56 (d, 3H, J ¼ 6 Hz, CH3), 1.78e1.84
nonyl phenyl CH3), 23.44 (piperidine C-4), 25.46 (piperidine C-3 and
C-5), 29.50 (isobutyl CH), 34.68 (isobutyl-CH2), 44.10 (C between
triazole and isobutyl phenyl), 50.40 (piperidine C-2 and C-6), 68.90
(C between piperidine and triazole), 125.18 (tolyl C-2 and C-6),
127.24 (isobutyl phenylC-2 and C-6),129.18 (isobutyl phenylC-3 and
C-5),130.38 (tolyl C-3 and C-5),130.86 (isobutyl phenyl C-1 and C-4),
137.84 (tolyl C-1), 139.92 (tolyl C-4), 143.10 (sydnonyl C-4), 145.78
(triazole eN]Ce), 152.46 (eN]CHe), 161.40 (sydnonyl C]O),
163.58 (C]S); FABMAS (m/z) e 559.5 (Mþ), (M.F. e C30H37N7O2S);
Anal. Calcd for C30H37N7O2S: C, 64.37; H, 6.66; N, 17.52; S, 5.73.
Found: C, 64.38; H, 6.64; N, 17.50; S, 5.70.
(m, 1H, CHe(CH3)2), 2.48 (d, 2H, J ¼ 6 Hz, CH2), 2.68 (t, 4H, mor-
pholine CH2NCH2), 3.58 (t, 4H, morpholine CH2OCH2), 3.95 (s, 3H,
OCH3), 4.26 (q, 1H, CH), 4.95 (s, 2H, NCH2N), 7.10 (d, 2H, J ¼ 8 Hz, 30,
50-Ib-Ar-H), 7.30 (d, 2H, J ¼ 8 Hz, 20, 60-Ib-Ar-H), 7.40e7.90 (m, 4H,
Ar-H), 10.16 (s, 1H, N]CH); 13C NMR (DMSO-d6):
d 19.04 (isobutyl-
CH3), 22.44 (CH3), 29.48 (isobutyl CH), 34.60 (isobutyl-CH2), 44.18
(C between triazole and isobutyl phenyl), 50.38 (morpholine C-2
and C-6), 66.12 (morpholine C-3 and C-5), 68.10 (C between mor-
pholine and triazole), 69.08 (sydnonyl phenyl OCH3), 125.24 (anisyl
C-2 and C-6), 127.56 (isobutyl phenyl C-2 and C-6), 129.20 (isobutyl
phenyl C-3 and C-5), 130.38 (anisyl C-3 and C-5), 130.84 (isobutyl
phenyl C-1 and C-4), 132.75 (anisyl C-1), 143.16 (sydnonyl C-4),
146.50 (triazole eN]Ce), 152.50 (eN]CHe), 156.38 (anisyl C-4),
161.52 (sydnonyl C]O), 163.60 (C]S); FABMAS (m/z) e 578.2
(M þ 1), (M.F. e C29H35N7O4S); Anal. Calcd for C29H35N7O4S: C,
60.29; H, 6.11; N, 16.97; S, 5.55. Found: C, 60.28; H, 6.13; N, 16.93; S,
5.50.
6.7.8. 1-N-methyl piperazinomethyl-3-[1-(4-isobutylphenyl)ethyl]-
4-[3-(p-tolyl)-4-sydnonylidene] amino-1,2,4-triazol-5-thione 9h
Yield 60%, m.p. 80e82 ꢀC; IR (KBr)
g
/cmꢂ1: 2951.31 (CeH
stretching), 1783.46 (sydnone carbonyl), 1587.04 (eN]Ce); 1H
NMR (DMSO-d6):
d
0.82 (d, 6H, J ¼ 6 Hz, (CH3)2),1.48 (d, 3H, J ¼ 8 Hz,
CH3), 1.75e1.81 (m, 1H, CHe(CH3)2), 2.13 (d, 2H, J ¼ 6 Hz, CH2), 2.27
(s, 3H, Syd-phenyl-CH3), 2.35 (t, 4H, CH2NCH2), 2.64 (t, 4H,
CH2NCH2), 3.40 (s, 3H, N-CH3), 4.18 (q, 1H, CH), 4.99 (s, 2H, NCH2N),
6.89 (d, 2H, J ¼ 8 Hz, 30, 50-Ib-Ar-H), 7.08 (d, 2H, J ¼ 8 Hz, 20, 60-Ib-Ar-
H), 7.18 (d, 2H, J ¼ 8 Hz, ortho protons of p-tolyl), 7.75 (d, 2H, J ¼ 8 Hz,
meta protons of p-tolyl), 10.07 (s, 1H, N]CH); 13C NMR (DMSO-d6):
6.7.11. 1-Piperidinomethyl-3-[1-(4-isobutylphenyl)ethyl]-4-[3-
(p-anisyl)-4-sydnonylidene] amino-1,2,4-triazol-5-thione 9k
Yield 72%, m.p. 122e125 ꢀC; IR (KBr)
g
/cmꢂ1: 2931.49 (CeH),
1793.16 (sydnone carbonyl), 1585.55 (eN]Ce); 1H NMR (DMSO-
d6):
d
0.94 (d, 6H, J ¼ 4 Hz, (CH3)2), 1.28 (t, 2H, piperidine CH2), 1.45
d
19.06 (isobutyl-CH3), 20.80 (CH3), 22.10 (sydnonyl phenyl CH3),
(m, 4H, piperidine (CH2)2), 1.54 (d, 3H, J ¼ 7.26 Hz, CH3), 1.70e1.80
(m, 1H, CHe(CH3)2), 2.38 (d, 2H, J ¼ 4 Hz, CH2), 2.60 (m, 4H, piperi-
dine CH2NCH2), 3.85 (s, 3H, OCH3), 4.20 (q, 1H, CH), 4.95 (s, 2H,
NCH2N), 7.05 (d, 2H, J ¼ 8 Hz, 30, 50-Ib-Ar-H), 7.25 (d, 2H, J ¼ 8 Hz, 20,
60-Ib-Ar-H), 7.30e7.80 (m, 4H, Ar-H), 10.10 (s, 1H, N]CH); 13C NMR
29.82 (isobutyl CH), 34.64 (isobutyl-CH2), 44.20 (C between triazole
and isobutyl phenyl), 45.78 (NeCH3), 49.50 (N-methylpiperazine
C-3 and C-5), 54.55 (N-methylpiperazine C-2 and C-6), 68.28
(C between N-methylpiperazine and triazole), 125.28 (tolyl C-2 and
C-6),127.53 (isobutyl phenyl C-2 and C-6),129.0 (isobutyl phenyl C-3
and C-5), 130.42 (tolyl C-3 and C-5), 130.72 (isobutyl phenyl C-1),
131.02 (isobutyl phenyl C-4), 137.94 (tolyl C-1), 139.92 (tolyl C-4),
141.32 (sydnonyl C-4),145.70(triazole eN]Ce),152.46 (eN]CHe),
160.76 (sydnonyl C]O),163.62 (C]S); FABMAS (m/z) e 574.2 (Mþ),
(M.F. e C30H38N8O2S); Anal. Calcd for C30H38N8O2S: C, 62.69; H, 6.66;
N, 19.50; S, 5.58. Found: C, 62.69; H, 6.68; N, 19.50; S, 5.54.
(DMSO-d6):
d 19.06 (isobutyl-CH3), 22.42 (CH3), 23.38 (piperidine
C-4), 25.40 (piperidine C-3 and C-5), 29.46 (isobutyl CH), 34.62
(isobutyl-CH2), 44.10 (C between triazole and isobutyl phenyl), 51.10
(piperidine C-2 and C-6), 68.40 (C between piperidine and triazole),
69.02 (sydnonyl phenyl OCH3), 125.11 (anisyl C-2 and C-6), 127.19
(isobutyl phenyl C-2 and C-6), 129.0 (isobutyl phenyl C-3 and C-5),
130.37 (anisyl C-3 and C-5), 130.72 (isobutyl phenyl C-1 and C-4),
132.88 (anisyl C-1),142.78 (sydnonyl C-4),146.12 (triazole eN]Ce),
152.46 (eN]CHe), 156.24 (anisyl C-4), 161.42 (sydnonyl C]O),
163.68 (C]S); FABMAS (m/z) e 575.3 (Mþ), (M.F. e C30H37N7O3S);
Anal. Calcd for C30H37N7O3S: C, 62.59; H, 6.48; N, 17.03; S, 5.57.
Found: C, 62.57; H, 6.50; N, 17.02; S, 5.59.
6.7.9. 1-N-phenyl piperazinomethyl-3-[1-(4-isobutylphenyl)ethyl]-
4-[3-(p-tolyl)-4-sydnonylidene] amino-1,2,4-triazol-5-thione 9i
Yield 62%, m.p. 122e124 ꢀC; IR (KBr)
g
/cmꢂ1: 2949.93 (CeH
stretching), 1784.46 (sydnone carbonyl), 1600.42 (eN]Ce); 1H
NMR (DMSO-d6):
d
0.82(d, 6H, J ¼ 6.2Hz, (CH3)2),1.54(d, 3H, J¼ 8Hz,
CH3), 1.78e1.74 (m, 1H, CHe(CH3)2), 2.38 (d, 2H, J ¼ 8 Hz, CH2), 2.43
(s, 3H, Syd-phenyl-CH3), 2.50 (t, 4H, N-phenylpiperazine CH2NCH2),
3.12 (t, 4H, N-phenylpiperazine CH2NCH2), 4.21 (q, 1H, CH), 5.07
(s, 2H, NCH2N), 6.76 (d, 2H, J ¼ 8 Hz, 30, 50-Ib-Ar-H), 6.90 (d, 2H,
J ¼ 8 Hz, 20, 60-Ib-Ar-H), 7.16e7.75 (m, 9H, N-phenyl and sydnonyl Ar-
6.7.12. 1-N-methyl piperazinomethyl-3-[1-(4-isobutylphenyl)ethyl]-
4-[3-(p-anisyl)-4-sydnonylidene] amino-1,2,4-triazol-5-thione 9l
Yield 70%, m.p. 140e142 ꢀC; IR (KBr)
g
/cmꢂ1: 2932.0 (CeH),
1793.0 (sydnone carbonyl), 1584.9 (eN]CH); 1H NMR (DMSO-d6):
d
0.90 (d, 6H, J ¼ 6 Hz, (CH3)2), 1.62 (d, 3H, J ¼ 8 Hz, CH3), 1.78e1.86
H),10.08 (s,1H, N]CH); 13C NMR (DMSO-d6):
d
19.08 (isobutyl-CH3),
(m, 1H, CHe(CH3)2), 2.40 (d, 2H, J ¼ 6 Hz, CH2), 2.46 (t, 4H,
CH2NCH2), 2.68 (t, 4H, CH2NCH2), 3.38 (s, 3H, NeCH3), 3.54 (s, 3H,
OCH3), 4.28 (q, 1H, CH), 5.10 (s, 2H, NCH2N), 7.12 (d, 2H, J ¼ 8 Hz, 30,
50-Ib-Ar-H), 7.30 (d, 2H, J ¼ 8 Hz, 20, 60-Ib-Ar-H), 7.50e7.60 (m, 4H,
20.40 (CH3), 22.40 (sydnonyl phenyl CH3), 29.44 (isobutyl CH), 34.62
(isobutyl-CH2), 44.10(C betweentriazole and isobutyl phenyl), 49.68
(N-phenylpiperazine C-3 and C-5), 50.46 (N-phenylpiperazine C-2
and C-6), 68.42 (C between N-phenylpiperazine and triazole),125.18
(tolyl C-2 and C-6), 127.19 (isobutyl phenyl C-2 and C-6), 129.24
(isobutyl phenyl C-3 and C-5), 130.34 (tolyl C-3 and C-5), 130.62
Ar-H), 10.12 (s, 1H, N]CH); 13C NMR (DMSO-d6):
d 19.08 (isobutyl-
CH3), 22.12 (CH3), 29.82 (isobutyl CH), 34.60 (isobutyl-CH2), 44.14
(C between triazole and isobutyl phenyl), 45.70 (N-CH3), 49.48

604
Nithinchandra et al. / European Journal of Medicinal Chemistry 54 (2012) 597e604
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(N-methylpiperazine C-3 and C-5), 54.52 (N-methylpiperazine C-2
and C-6), 68.20 (C between N-methylpiperazine and triazole), 69.10
(sydnonyl phenyl OCH3), 125.18 (tolyl C-2 and C-6), 127.28 (isobutyl
phenyl C-2 and C-6), 129.12 (isobutyl phenyl C-3 and C-5), 130.34
(tolyl C-3 and C-5), 130.86 (isobutyl phenyl C-1 and C-4), 132.70
(tolyl C-1), 141.32 (sydnonyl C-4), 145.70 (triazole eN]Ce), 152.46
(eN]CHe), 156.30 (anisyl C-4), 160.68 (sydnonyl C]O), 163.64
(C]S); FABMAS (m/z) e 590 (Mþ), (M.F. e C30H38N8O3S); Anal.
Calcd for C30H38N8O3S: C, 60.99; H, 6.48; N, 18.97; S, 5.43. Found: C,
60.97; H, 6.44; N, 18.95; S, 5.48.
Acknowledgement
The authors are thankful to BRNS-DAE, Mumbai for the financial
assistance and to Head, RSIC, IISC Bangalore and CDRI Lucknow for
providing the spectral analyses.
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