Synthesis of biologically active N-methyl derivatives of amidines and cyclized five-membered products of amidines with oxalyl chloride

Article abstract of DOI:10.1016/j.ejmech.2007.10.005

A series of substituted N-methylisonicotinamidine (2a-f), N-methylpyrazine-2-carboxamidine (2g-i) derivatives were synthesized by reaction of amidine derivatives (1a-i) with methyl iodide in presence of triethylamine. Five-membered condensed dihydroimidazolylbenzenesulfonamide derivatives (3a-i) were obtained by the reaction of amidine derivatives (1a-i) with acylating agent oxalyl chloride. All the compounds, i.e. 2a-i and 3a-i were purified by crystallization. Structures of all the synthesized compounds are supported by correct IR, ¹H NMR, mass spectral and analytical data. Anti-inflammatory activity evaluation was carried out using carrageenan-induced paw oedema assay and compounds 2e, 3a and 3d exhibited good anti-inflammatory activity (44%, 31% and 37% activity at 50 mg/kg p.o., respectively). Analgesic activity evaluation was carried out using acetic acid writhing assay and compounds 2a and 3f gave 75% activity each at 100 mg/kg p.o.; on the other hand compounds 3a and 3d exhibited 60% analgesic activity each at 50 mg/kg p.o. Compounds 3a and 3d exhibited good anti-inflammatory and analgesic activities.

Full text of DOI:10.1016/j.ejmech.2007.10.005

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 43 (2008) 2824e2830
http://www.elsevier.com/locate/ejmech
Original article
Synthesis of biologically active N-methyl derivatives of
amidines and cyclized five-membered products of amidines
with oxalyl chloride
a
a
b
Sham M. Sondhi a, , Monica Dinodia , Shubhi Jain , Ashok Kumar
*
a Department of Chemistry, Indian Institute of Technology Roorkee (IIT R), Roorkee-247667, Uttarakhand, India
b Department of Pharmacology, LLRM Medical College, Meerut, UP, India
Received 16 April 2007; received in revised form 3 October 2007; accepted 4 October 2007
Available online 7 October 2007
Abstract
A series of substituted N-methylisonicotinamidine (2aef), N-methylpyrazine-2-carboxamidine (2gei) derivatives were synthesized by re-
action of amidine derivatives (1aei) with methyl iodide in presence of triethylamine. Five-membered condensed dihydroimidazolylbenzene-
sulfonamide derivatives (3aei) were obtained by the reaction of amidine derivatives (1aei) with acylating agent oxalyl chloride. All the
compounds, i.e. 2aei and 3aei were purified by crystallization. Structures of all the synthesized compounds are supported by correct IR,
1H NMR, mass spectral and analytical data. Anti-inflammatory activity evaluation was carried out using carrageenan-induced paw oedema
assay and compounds 2e, 3a and 3d exhibited good anti-inflammatory activity (44%, 31% and 37% activity at 50 mg/kg p.o., respectively).
Analgesic activity evaluation was carried out using acetic acid writhing assay and compounds 2a and 3f gave 75% activity each at
100 mg/kg p.o.; on the other hand compounds 3a and 3d exhibited 60% analgesic activity each at 50 mg/kg p.o. Compounds 3a and 3d ex-
hibited good anti-inflammatory and analgesic activities.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Methyl iodide; Oxalyl chloride; Acylating agent; Anti-inflammatory; Analgesic
1. Introduction
and congestive heart failure [3]. These observations raised
a cautionary flag in this research. There is a demand for
more efficacious and safer anti-inflammatory drugs with
higher patient acceptability to completely abandon the use
of steroidal and narcotic drugs. Derivatives comprising the
sulfonamide functionalities act as anticancer agents [4], in-
hibitors of the serine protease human leukocyte elastase
(HLE), proteinase 3 (PR 3) and cathepsin G (Cat G) [5].
Their use as anti-inflammatory analgesic agents [6], inhibitors
of metallo-b-lactamases [7] is also reported in the literature.
In continuation of our efforts in this direction to explore safer
non-steroidal anti-inflammatory drugs [8e14] we have syn-
thesized various compounds, i.e imidazoline diones [15e
21], N-methylpicolinamidine and N-methylisonicotinamidine
derivatives [22,23]. These were then screened for anti-
inflamamtory and analgesic activities which we wish to report
in this paper.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the
most commonly prescribed medications for the treatment of
pain, management of oedema and tissue damage resulting
from inflammatory joint disease (arthritis). The major limit-
ing side effects of chronic use of NSAIDs are gastrointestinal
(GI) symptoms and bleeding ulceration [1,2]. The identifica-
tion of cyclooxygenase-2 (COX-2) and the subsequent intro-
duction of the COX-2 selective inhibitor NSAID drugs were
thought to be a major breakthrough, with the expectation of
a significant reduction in GI side effects. It has now been
proved that COX-2 inhibitors cause oedema, hypertension
* Corresponding author. Tel.: þ91 1332 285811; fax: þ91 1332 273650.
E-mail address: sondifcy@iitr.ernet.in (S.M. Sondhi).
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2007.10.005

S.M. Sondhi et al. / European Journal of Medicinal Chemistry 43 (2008) 2824e2830
2825
3
2
2. Results and discussion
NHSO2
HN
to N1 and N2 of
moiety of 1a. Compound 1a was
1
NH
2.1. Chemistry
treated with methyl iodide in the presence of triethylamine at
room temperature for 2 h using methanol as a solvent of the re-
action. After 2 h the solvent was removed under reduced pres-
sure and the crude mass so obtained was taken in ethylacetate;
this ethylacetate solution was washed with water. Organic
layer so obtained was dried on sodium sulphate and solvent
was removed under reduced pressure. The crude product so ob-
tained was crystallized from methanol/ethylacetate to give
Amidine derivatives 1aei (Scheme 1) were synthesized by
following the reaction procedure reported earlier [24]. A look
at amidine molecule 1 (Scheme 1) indicates that there are three
nitrogens i.e. N1, N2 and N3 present in the molecule. Since e
SO2e present in the molecule is electron withdrawing in
nature, its electron withdrawing inductive effect (ꢀI) will in-
crease when we move from N1 / N2 / N3 thus nucleophilic
character of these three nitrogens will be N1 > N2 > N3. Sim-
ilar observation is also mentioned in literature [25,26]. From
this observation it is expected that mono-alkylation will occur
on N1 and if we have bifunctional acylating agent such as ox-
alyl chloride [15e17], attack will occur on N1 and N2, thus
forming a five-membered ring structure. With these observa-
tions in mind we alkylated amidine derivatives with methyl
iodide/Et3N and acylated with oxalyl chloride, which is de-
1
pure product 2a (Scheme 1). H NMR (500 MHz; DMSO-
d6) of 2a shows a singlet at d 6.47 (s, 1H, NH, exch) account-
ing for one proton which indicates that methylation has taken
place on N1 of 1a to give product 2a.The structure of product
1
2a is fully supported by IR, H NMR and FAB-MS spectral
data reported in Table 1. Similarly other N-methyl derivatives
of amidines (2bei, Scheme 1) were synthesized. Physical con-
stants and spectral data of 2bei are reported in Table 1.
Again when compound 1a was treated with oxalyl chloride
using dry THF as a solvent of the reaction, after usual work up
of the reaction compound 3a (Scheme 1) was obtained in good
1
scribed here. H NMR (500 MHz; DMSO-d6) of 1a shows
a broad singlet at d 6.47 accounting for two protons which
are exchangeable with D2O. Evidently these protons belong
1
yield. H NMR (500 MHz; DMSO-d6) of 3a does not show
O2
NH S
3
H
R1
R
N
2
HN
1
1a-i
Cl
Cl
O
O
MeI
Et3N
THF
K2CO3
R1
H
N
R
N
O2
NH S
H
N
N
S
R
R1
O2
O
N
H3C
2a-i
O
3a-i
R and R1 are same for compounds1, 2 and 3
R1
R
R1
R
2a, 3a
CH3
N
N
N
OCH3
H
2f, 3f
OCH3
2b, 3b
2c, 3c
2d, 3d
N
N
2g, 3g
N
N
H
2h, 3h
2i, 3i
CH3
N
N
N
N
H
OCH3
2e, 3e
CH3
N
Scheme 1. Synthesis of N-methylpicolinamidine (2aef), N-methylpyrazine-2-carboxamidine (2gei) and dihydroimidazol-1-yl benzenesulfonamide (3aei)
derivatives.

2826
S.M. Sondhi et al. / European Journal of Medicinal Chemistry 43 (2008) 2824e2830
Table 1
Physical, spectral and analytical data of 2aei and 3aei
Compund Solvent of
m.p. Yield% Spectral and analytical data: IR (KBr) cmꢀ1
crystallization/ (ꢁC)
ESI-MS, GCeMS (m/z; relt int%)
.
1H NMR, FAB-MS, EI-MS,
no.
elution
2a
EtOAc/CHCl3
100
33
IR (KBr) nmax: 3495 and 3368 (eNHeNHe), 1641 (C]N), 1590 (Ar) cmꢀ1 1H NMR (500 MHz,
.
DMSO-d6) d: 2.36 (s, 3H, eCH3), 2.65 (s, 3H, CH3), 6.47 (s, 1H, NH, exch), 7.13 (s, 1H, NH, exch),
7.39e7.54 (m, 3H, Ar), 7.75e7.94 (m, 4H, Ar), 8.54e8.63 (d, 1H, Ar). FAB-MS m/z 305 (MHþ, 5%).
Anal. Calcd for C14H16SN4O2: C, 55.26; H, 5.26; N, 18.42; S, 10.52. Found: C, 55.33; H, 4.89; N,
18.11; S, 10.82
2b
EtOAc/CHCl3
140
49
IR (KBr) nmax: 3495 and 3369 (eNHeNHe), 1637 (C]N), 1594 (Ar) cmꢀ1 1H NMR (500 MHz,
.
DMSO-d6) d: 2.64 (s, 3H, eCH3), 3.88 (s, 3H, OCH3), 6.44 (br s, 1H, NH), 7.10e7.12 (br d, 1H, NH),
7.19e7.20 (d, 2H, Ar), 7.53e7.56 (t, 1H, Ar), 7.80e7.84 (t, 2H, Ar), 7.87e7.91 (q, 1H, Ar), 7.95e7.97
(d, 1H, Ar), 8.63e8.64 (d, 1H, Ar). GCeMS molecular ion peak was not observed but some other
+
H
+
2
N
fragment peaks were present, i.e. m/z 171 (O S
CH , 25%), 149 (
NH, 4%),
N
3
N
H C
3
+
N
N
+
OCH
147 (
, 8%), 107 (
3, 18%), 78 (
+, 18%). Anal. Calcd for C14H16SN4O3:
N
N
N
H C
3
C, 52.50; H, 5.00; N, 17.50; S, 10.00. Found: C, 52.82; H, 4.68; N, 17.27; S, 9.87
IR (KBr) nmax: 3473 and 3356 (eNHeNHe), 1635 (C]N), 1577 (Ar) cmꢀ1 1H NMR (300 MHz,
2c
EtOAc/CHCl3
EtOAc/CHCl3
100
160
49
47
.
DMSO-d6 þ CDCl3) d: 2.81 (s, 3H, eCH3), 6.50 (br s, 2H, eNHeNHe, exch), 7.45 (m, 1H, Ar), 7.65
(m, 3H, Ar), 7.75 (m, 1H, Ar), 7.90e8.20 (m, 3H, Ar), 8.54 (m, 1H, Ar). FAB-MS m/z 291
(MHþ, 100%). Anal. Calcd for C13H14SN4O2: C, 53.79; H, 4.82; N, 19.31; S, 11.03. Found: C, 53.91;
H, 4.70; N, 19.58; S, 10.69
2d
IR (KBr) nmax: 3434 and 3356 (eNHeNHe), 1652 (C]N), 1598 and 1540 (Ar) cmꢀ1 1H NMR
.
(500 MHz, DMSO-d6) d: 2.65 (s, 3H, eCH3), 6.61 (s, 1H, NH, exch), 7.33 (br s, 1H, NH), 7.58e7.70
(m, 4H, Ar), 7.73e7.76 (t, 1H, Ar), 7.86e7.91 (m, 2H, Ar), 8.58e8.59 (d, 1H, Ar), 8.65e8.66
+
2
(d, 1H, Ar). GCeMS does not give Mþ ion peak but gave m/z 141 (O S
, 55%), 78 (
,
N
+
33%), 77 (
Found: C, 53.59; H, 4.72; N, 19.50; S, 11.40
IR (KBr) nmax: 3447 and 3364 (eNHeNHe), 1642 (C]N), 1600 and 1547 (Ar) cmꢀ1 1H NMR
.
+, 100%). Anal. Calcd for C13H14SN4O2: C, 53.79; H, 4.82; N, 19.31; S, 11.03.
2e
EtOAc/CHCl3
180
33
(500 MHz, DMSO-d6) d: 2.07 (s, 3H, eCH3), 2.27 (s, 3H, eCH3), 6.58 (s, 1H, NH, exch), 7.09e7e11
(d, 2H, Ar), 7.38e7.40 (d, 2H, Ar), 7.78e7.80 (d, 2H, Ar), 8.57e8.58 (d, 2H, Ar), 9.42 (s, 1H,
+
.
NH, exch). GCeMS does not give molecular ion peak but gave m/z 184 (HN
, 4%),
N
O S
2
H
H
N
+
2
CH
N
C
+
155 (O S
CH , 25%), 121 (
, 8%), 91 (
3
CH
3, 85%), 78 (
N, 8%).
+
3
+
Anal. Calcd for C14H16SN4O2: C, 55.26; H, 5.26; N, 18.42;
S, 10.52. Found: C, 54.80; H, 5.24; N, 18.11; S, 10.35
IR (KBr) nmax: 3432 and 3350 (eNHeNHe), 1654 (C]N), 1596 and 1544 (Ar) cmꢀ1 1H NMR
.
2f
EtOAc/CHCl3
195
46
(500 MHz, DMSO-d6) d: 2.62 (s, 3H, eNCH3), 3.87 (s, 3H, OCH3), 6.55 (s, 1H, NH), 7.11e7.13
(d, 1H, Ar), 7.17e7.19 (d, 1H, Ar), 7.28 (br s, 1H, NH), 7.59e7.60 (d, 1H, Ar), 7.69e7.71 (d, 1H, Ar),
7.78e7.83 (q, 2H, Ar), 8.60 (d, 1H, Ar), 8.68 (d, 1H, Ar). GCeMS does not give molecular ion peak
+
3, 2%), 171 (O S
but gave m/z 199 (+HN NSO2
, 35%), 107 (+
OCH3
OCH3, 38%),
OCH
2
+
78 (
N, 13%). Anal. Calcd for C14H16SN4O3: C, 52.50; H, 5.00; N, 17.50; S, 10.00. Found: C,
52.93; H, 5.15; N, 17.50; S, 9.83
IR (KBr) nmax: 3442 and 3316 (eNHeNHe), 1662 (C]N), 1593 (Ar) cmꢀ1 1H NMR (500 MHz,
.
2g
EtOAc/CHCl3
160
72
DMSO-d6) d: 2.68 (s, 3H, eCH3), 7.30 (s, 2H, NHeNH, exch), 7.61e7.77 (m, 3H, Ar), 7.89e7.93
(t, 2H, Ar), 8.71 (s, 1H, Ar), 8.79 (s, 1H, Ar), 9.08 (s, 1H, Ar). FAB-MS m/z 292 (MHþ, 100%),
N
261 (
, 13%). Anal. Calcd for C12H13SN5O2: C, 49.48; H, 4.46; N, 24.05;
N NHSO
2
N
S, 10.99. Found: C, 49.81; H, 4.05; N, 24.08; S, 10.60

S.M. Sondhi et al. / European Journal of Medicinal Chemistry 43 (2008) 2824e2830
2827
Table 1 (continued)
Compund Solvent of
no.
m.p. Yield% Spectral and analytical data: IR (KBr) cmꢀ1 1H NMR, FAB-MS, EI-MS,
.
crystallization/ (ꢁC)
elution
ESI-MS, GCeMS (m/z; relt int%)
2h
MeOH/EtOAc
240
48
IR (KBr) nmax: 3430 (eNHeNHe), 1658 (C]N) and 1560 (Ar) cmꢀ1 1H NMR (500 MHz,
.
DMSO-d6) d: 2.35 (s, 3H, eCH3), 2.55 (s, 3H, NeCH3), 6.55 (br s, 1H, NH, exch,), 7.40 (d, 2H, Ar),
7.85 (d, 2H, Ar), 8.65 (d, 1H, Ar), 8.78 (d, 1H, Ar). 9.02 (s, 1H, Ar), 9.69 (s, 1H, NH, exch). GCeMS
+
N
N
.
+
H
N
does not give Mþ ion peak but gave m/z 150 (
NH, 1.78%), 149 (
NH , 25.86%),
N
N
N
N
N
H C
3
H C
3
N
+
+
.
N
N
N
N
C
N
N
CH
3, 2.75%),
148 (
80 (
N, 74.31%), 120 (
N CH , 5.00%), 105 (
, 3.59%), 91 (+
N
3
+
N
H C
3
+
N
N
. , 100%), 79 (
, 24.04%). Anal. Calcd for C13H15SN5O2: C, 51.14; H, 4.91; N, 24.05;
+
N
N
S, 10.49. Found: C, 51.02; H, 4.51; N, 24.51; S, 10.19
IR (KBr) nmax: 3419 and 3303 (eNHeNHe), 1638 (C]N), 1589 (Ar) cmꢀ1 1H NMR (500 MHz,
.
2i
EtOAc/CHCl3
205
62
DMSO-d6) d: 2.66 (s, 3H, eNCH3), 3.82 (s, 3H, OCH3), 7.14e7.24 (t, 4H, 2H exch, 2H Ar), 7.82e7.86
(t, 2H, Ar), 8.71e8.72 (q, 1H, piperazine), 8.79e8.80 (d, 1H, piperazine), 9.10e9.11 (d, 1H, piperazine).
+
N
.
GCeMS does not give Mþ ion peak but gave other peaks, i.e. m/z 149 (
NH , 10%),
N
N
N
H
C
3
N
+
N
N
148 (
N, 50%), 79 (
, 15%). Anal. Calcd for C13H15SN5O3: C, 48.59; H, 4.67; N, 21.80;
N
+
N
N
H
C
3
S, 9.96. Found: C, 48.81; H, 4.34; N, 21.95; S, 9.84
IR (KBr) nmax: 3260 (eNHe), 1701 (pC]O), 1637 (C]N), 1598 and 1555 (Ar) cmꢀ1 1H NMR
.
3a
3b
MeOH/EtOAc
MeOH/EtOAc
200
200
48
42
(300 MHz, DMSO-d6) d: 2.41 (s, 3H, CH3), 7.44e7.46 (d, 2H, Ar), 7.72e7.73 (d, 1H, Ar), 7.81e7.83
(d, 2H, Ar), 8.07 (s, 2H, Ar), 8.75e8.76 (d, 1H, Ar), 10.84 (br s, 1H, NH, exch). FAB-MS m/z 345.0
ꢂ
(MHþ, 70%), 329 (Mþ ꢀ CH3, 5%), 287.3 (MHþ ꢀ O]C]C]OSþ , 14%). Anal. Calcd for
C15H12SN4O4: C, 52.32; H, 3.48; N, 16.27; S, 8.30. Found: C, 52.01; H, 3.75; N, 16.07; S, 8.00
IR (KBr) nmax: 3505 (eNHe), 1689 (pC]O) and 1595 (Ar) cmꢀ1 1H NMR (500 MHz, DMSO-d6)
.
d: 3.87 (s, 3H, OCH3), 7.20e7.22 (d, 2H, Ar), 7.60e7.62 (m, 1H, Ar), 8.01e8.09 (m, 4H, Ar), 8.60e8.69
(d, 1H, Ar), 12.27 (br s, 1H, NH, exch). FAB-MS m/z 361 (MHþ, 1%), 345 (Mþ ꢀ CH3, 70%), 329
ꢂ
(Mþ ꢀ OCH3, 5%). Anal. Calcd for C15H12SN4O5: C, 50.00; H, 3.33; N, 15.55; S, 8.88. Found:
C, 50.43; H, 3.68; N, 15.95; S, 8.70
IR (KBr) nmax: 3465 (eNHe), 1698 (pC]O), 1625 (C]N) and 1582 (Ar) cmꢀ1 1H NMR (300 MHz,
.
3c
3d
3e
3f
MeOH/EtOAc
MeOH/EtOAc
MeOH/EtOAc
MeOH/EtOAc
140
220
255
140
58
41
49
64
DMSO-d6 þ CDCl3) d: 7.56e7.71 (m, 4H, Ar), 7.92e8.06 (m, 3H, Ar), 8.64e8.70 (q, 2H, Ar), 9.98 (br s,
1H, NH, exch). Anal. Calcd for C14H10SN4O4: C, 50.90; H, 3.03; N, 16.96; S, 9.69. Found: C, 50.45;
H, 3.00; N, 16.86; S, 9.93
.
IR (KBr) nmax: 3426 (eNHe), 1665 (pC]O), 1634 (C]N) and 1603 (Ar) cmꢀ1 1H NMR (300 MHz,
DMSO-d6 þ CDCl3) d: 7.54e7.67 (m, 3H, Ar), 7.98e7.99 (t, 2H, Ar), 8.18e8.21 (d, 2H, Ar), 8.82e8.84
(d, 2H, Ar), 10.5e11.0 (br s, 1H, NH, exch). FAB-MS m/z 331 (MHþ, 4%). Anal. Calcd for C14H10SN4O4:
C, 50.90; H, 3.03; N, 16.96; S, 9.69. Found: C, 51.22; H, 2.87; N, 17.05; S, 9.25
.
IR (KBr) nmax: 3437 (eNHe), 1688 (pC]O), 1632 (C]N) and 1488 (Ar) cmꢀ1 1H NMR (300 MHz,
DMSO-d6 þ CDCl3) d: 2.41 (s, 3H, CH3), 7.34e7.37 (d, 2H, Ar), 7.80e7.83 (d, 2H, Ar), 8.43 (s, 2H, Ar),
9.09 (s, 2H, Ar). 9.90 (br s, 1H, NH, exch). FAB-MS m/z 345.0 (MHþ, 1%). Anal. Calcd for C15H12SN4O4:
C, 52.32; H, 3.48; N, 16.27; S, 9.30. Found: C, 52.05; H, 3.30; N, 16.15; S, 9.36
.
IR (KBr) nmax: 3443 (eNHe), 1681 (pC]O) and 1595 (Ar) cmꢀ1 1H NMR (500 MHz, DMSO-d6)
d: 3.88 (s, 3H, OCH3), 7.13e7.14 (d, 2H, Ar), 7.88e7.89 (d, 2H, Ar), 7.94 (s, 2H, Ar), 8.89e8.90
(d, 2H, Ar), 10.61 (br s, 1H, NH, exch). GCeMS does not give ion peak, but gave m/z 189
N
+
, 3%), 171 (O S
+
NH
OCH
3, 27%). Anal. Calcd for C15H12SN4O5:
(
N
OCH , 30%), 107 (+
3
2
N
O
O
C, 50.00; H, 3.33; N, 15.55; S, 8.88. Found: C, 50.30; H, 3.70; N, 15.20; S, 8.80
IR (KBr) nmax: 3399 (eNHe), 1695 (pC]O) and 1622, 1470 (Ar) cmꢀ1 1H NMR (300 MHz,
3g
MeOH/EtOAc
200
81
.
DMSO-d6 þ CDCl3) d: 7.56e7.67 (m, 2H, Ar), 7.99e8.00 (dd, 1H, Ar), 8.66e8.76 (m, 2H, Ar),
8.83e8.84 (d, 1H, Ar), 9.36e9.37 (d, 1H, Ar), 9.51e9.52 (d, 1H, Ar). FAB-MS m/z 332 (MHþ, 20%),
+
2
304 (MHþ ꢀ CO, 5%), 141 (
21.14; S, 9.66. Found: C, 47.31; H, 3.04; N, 21.04; S, 9.86
, 8%). Anal. Calcd for C13H9SN5O4: C, 47.12; H, 2.71; N,
O S
(continued on next page)

2828
S.M. Sondhi et al. / European Journal of Medicinal Chemistry 43 (2008) 2824e2830
Table 1 (continued)
Compund Solvent of
no.
m.p. Yield% Spectral and analytical data: IR (KBr) cmꢀ1 1H NMR, FAB-MS, EI-MS,
.
crystallization/ (ꢁC)
elution
ESI-MS, GCeMS (m/z; relt int%)
3h
MeOH/EtOAc
145
38
IR (KBr) nmax: 3469 (eNHe), 1697 (pC]O), 1632 (C]N) and 1538 (Ar) cmꢀ1 1H NMR
.
(300 MHz, DMSO-d6 þ CDCl3) d: 2.44 (s, 3H, CH3), 7.33e7.36 (d, 2H, Ar), 7.92e7.95 (d, 2H, Ar),
8.66 (s, 1H, Ar), 8.82e8.83 (d, 1H, Ar), 9.54 (s, 1H, Ar), 10.90 (br s, 1H, NH, exch). FAB-MS does not
+
.
N
N
C
N
+
O S
2
give MHþ ion peak but gave m/z 155 (
CH3, 30%), 105 (
, 9%), 91 (
CH3,
+
15%). Anal. Calcd for C14H11SN5O4: C, 48.69; H, 3.18; N, 20.28; S, 9.27. Found: C, 48.31; H, 3.17;
N, 19.87; S, 9.63
3i
MeOH/EtOAc
260
55
IR (KBr) nmax: 3468 (eNHe), 1697 (pC]O), 1630 (C]N) and 1600 (Ar) cmꢀ1 1H NMR (500 MHz,
.
CDCl3) d: 3.65 (s, 3H, OCH3), 6.86e6.87 (d, 2H, Ar), 7.67e7.68 (d, 2H, Ar), 8.59e8.60 (d, 1H, Ar),
8.72e8.73 (d, 1H, Ar), 8.99 (s, 1H, Ar), NH was not observed. EI-MS does not give Hþ ion peak but
+
+
gave m/z 228 (OCNHNO S
., 2%), 227 (228 ꢀ H, 11%), 171 (O S
OCH , 4%), 121
OCH3
2
3
2
+
.
N
N
N
C
N
+
OCH
3, 9%), 105 (
OCH
(228 ꢀ
, 13%), 107 (
, 8%), 79 (
, 34%). Anal. Calcd
+
3
+
N
for C14H11SN5O5: C, 46.53; H, 3.04; N, 19.39; S, 8.86. Found: C, 46.91; H, 2.94; N, 19.70; S, 8.68
any peak at d 6.47 (which was present in the starting material
1a). This observation indicates that oxalyl chloride reacted
with N1 and N2 of 1a to give product 3a, i.e. N-(4,5-dioxo-
2-(pyridin-2-yl)-4,5-dihydroimidazol-1-yl)-4-methylbenzene-
sulfonamide. Structure of compound 3a is further supported
by correct IR, 1H NMR, FAB-MS and elemental analysis
reported in Table 1. Similarly were synthesized other dioxo-
imidazol derivatives (3bei; Scheme 1). Physical constants
and spectral data of 3bei are reported in Table 1.
In literature there are several examples available where pyr-
idine and pyrazine derivatives [27e33] have shown potent
anti-inflammatory activity. Hence it is considered worthwhile
to screen these compounds for anti-inflammatory and analge-
sic activities.
2.2.1. Structureeactivity relationship
A look at Table 2 indicates that in case of N-methyl deriva-
tives of amidines replacement of 2-pyridyl or 2-pyrazinyl group
by 4-pyridyl was found to be beneficial for anti-inflammatory
activity and similarly a substitution by eCH3 on phenyl ring
increased the electron richness of the phenyl ring and hence
was found useful for increasing anti-inflammatory activity, i.e
compound 2e. When CH3 group on phenyl ring was replaced
by eOCH3 there is decrease in anti-inflammatory and analgesic
activities. This could be due to change in electron richness of
phenyl ring and steric crowding. Compound 2a exhibited
good analgesic activity and any change in phenyl ring or of
2-pyridyl to 4 pyridyl or 2-pyrazinyl decreased the analgesic ac-
tivity. Again in case of cyclized compounds, i.e 3aei, 4-pyridyl
derivatives exhibited better anti-inflammatory activity as com-
pared to 2-pyridyl or 2-pyrazinyl derivatives. In short 4-pyridyl
derivatives exhibit better anti-inflammatory activity as com-
pared to 2-pyridyl or 2-pyrazinyl derivatives.
2.2. Biological results
Anti-inflamamtory activity screening [34] of compounds 2a,
3f at 100 mg/kg p.o. and 2b, 2deg, 2i, 3a, 3b, 3d, 3g, 3i at
50 mg/kg p.o. was carried out using carrageenan-induced paw
oedema model and results are summarized in Table 2. Com-
pounds 2a, 3f (at 100 mg/kg p.o.) and 2b, 2deg, 2i, 3a, 3b,
3d, 3g, 3i (at 50 mg/kg p.o.) showed 20%, 12%, 34%, 16%,
44%, 21%, 11%, 20%, 31%, 20%, 37%, 25% and 13% activity
whereas the standard drug phenylbutazone exhibited 58% (at
100 mg/kg p.o.) and 37% (at 50 mg/kg p.o.) anti-inflammatory
activity. Compound 2e exhibited anti-inflammatory activity bet-
ter than the standard drug. Compounds 2a, 3f (at 100 mg/kg p.o.)
and 2b, 2deg, 2i, 3a, 3b, 3d, 3g, 3i (at 50 mg/kg p.o.) on anal-
gesic activity [35] evaluation using acetic acid writhing assay ex-
hibited 75%, 75%, 20%, 7%, 17%, 13%, 11%, 16%, 60%, 18%,
60%, 30% and 12% activity whereas the standard drug phenyl-
butazone showed 58% (at 100 mg/kg p.o.) and 40% (at 50 mg/
kg p.o.) analgesic activity (Table 2) .Compounds 2a, 3a, 3d
and 3f exhibited analgesic activity better than phenylbutazone.
Compound 3d exhibited anti-inflammatory activity comparable
to and analgesic activity better than phenylbutazone.
3. Conclusion
A series of substituted N-methylisonicotinamidine (2aef),
N-methylpyrazine-2-carboxamidine (2gei) derivatives and di-
hydroimidazolylbenzenesulfonamide derivatives (3aei) have
been synthesized and screened for anti-inflammatory and anal-
gesic activities. Compound 3d exhibited anti-inflammatory
activity comparable to and analgesic activity better than
phenylbutazone.
4. Experimental
4.1. General
Melting points (m.p) were determined on a JSGW appara-
tus and are uncorrected. IR spectra were recorded using
a Perkin Elmer 1600FT Spectrometer. 1H NMR were recorded
on a Bruker WH-300/Bruker AV-500 Spectrometer in a ca.

S.M. Sondhi et al. / European Journal of Medicinal Chemistry 43 (2008) 2824e2830
2829
5e15% (w/v) solution in appropriate deuterated solvent.
FAB-MS was recorded on a Jeol SX-120 (FAB) Spectrometer.
GCeMS was recorded on Perkin Elmer Clarus 500 Mass
Spectometer. Thin-layer chromatography (TLC) was perfor-
med by using silica gel G for TLC (Merck) and spots were
visualized by iodine vapours or by irradiation with UV light
(254 nm). Column chromatography was performed by using
Qualigen’s silica gel for column chromatography (60e120
mesh). Elemental analysis was performed using a Vario EL
III elemental analyzer. Physical constants, spectral and analyt-
ical data of all the compounds 2aei and 3aei synthesized are
reported in Table 1.
give crude product which was further purified by crystalliza-
tion from MeOH/EtOAc to give pure product 3a.
Similarly were synthesized compounds N-(4,5-dioxo-2-
(pyridin-2-yl)-4,5-dihydroimidazol-1-yl)-4-methoxybenzene-
sulfonamide (3b), N-(4,5-dioxo-2-(pyridin-2-yl)-4,5-dihydroi-
midazol-1-yl)benzenesulfonamide (3c), N-(4,5-dioxo-2-(pyridin-
4-yl)-4,5-dihydroimidazol-1-yl)benzenesulfonamide (3d), N-
(4,5-dioxo-2-(pyridin-4-yl)-4,5-dihydroimidazol-1-yl)-4-methyl
benzenesulfonamide (3e), N-(4,5-dioxo-2-(pyridin-4-yl)-4,5-
dihydroimidazol-1-yl)-4-methoxybenzenesulfonamide (3f), N-
(4,5-dioxo-2-(pyrazin-2-yl)-4,5-dihydroimidazol-1-yl)benzene
sulfonamide (3g), N-(4,5-dioxo-2-(pyrazin-2-yl)-4,5-dihydroi-
midazol-1-yl)-4-methylbenzenesulfonamide (3h) and N-(4,
5-dioxo-2-(pyrazin-2-yl)-4,5-dihydroimidazol-1-yl)-4-methoxy-
benzenesulfonamide (3i).
4.2. General procedure for the synthesis of
N-methylpicolinamidine (2aef) and N-methylpyrazine-2-
carboxamidine (2gei) derivatives
4.2.1. Synthesis of N1-methyl-N-(4-
4.4. Anti-inflammatory activity
methylphenylsulfonamido)picolinamidine (2a)
Paw oedema inhibition test was performed on albino rats of
Charles Foster strain by adopting the method of Winter et al.
[34]. Groups of five animals of both sexes (body weight 120e
160 g), excluding pregnant females, were given a dose of a test
compound. After 30 min, 0.20 ml of 1% freshly prepared car-
rageenan suspension in 0.9% NaCl solution was injected sub-
cutaneously into the plantar aponeurosis of the hind paw and
the volume was measured by a water plethysmometer appara-
tus and then measured again 1e3 h later. The mean increase of
paw volume at each time interval was compared with that of
control group (five rats treated with carrageenan, but not
with test compounds) at the same time intervals and percent
inhibition values were calculated by the formula given below.
Amidine derivative [24] 1a (0.290 g; 1 mmol) was dis-
solved in methanol (5 ml), to it were added triethylamine
(0.1 ml; 1 mmol) and methyl iodide (0.1 ml; 1.5 mmol). The
reaction contents were stirred at room temperature for 2 h.
Solvent was removed under reduced pressure and to the resi-
due left behind was added distilled water (5 ml) and the prod-
uct was extracted with ethylacetate. Ethylacetate extract was
dried over sodium sulphate (5 g). The organic solvent was re-
moved under reduced pressure to give an oily mass. This oily
mass was washed with diethyl ether (3 ꢃ 5 ml) to give crude
product, which was purified by crystallization from EtOAc/
CHCl3 to give pure product 2a.
Similarly were synthesized compounds N-(4-methoxyphe-
nylsulfonamido)-N1 methylpicolinamidine (2b), N1-methyl-
N-(phenylsulfonamido)picolinamidine (2c), N1-methyl-N-
(phenylsulfonamido)isonicotinamidine (2d), N1-methyl-N-
(methylphenylsulfonamido)isonicotinamidine (2e), N-(4-me-
thoxyphenylsulfonamido)-N1-methylisonicotinamidine (2f),
N1-methyl-N-(phenylsulfonamido)pyrazine-2-carboxamidine
(2g), N1-methyl-N-(4-methylphenylsulfonamido)pyrazine-2-
carboxamidine (2h) and N-(4-methoxyphenylsulfonamido)-
N1-methylpyrazine-2-carboxamidine (2i).
% Anti-inflammatory activity ¼ ½1 ꢀ Dt=Dcꢄ ꢃ 100
Dt and Dc are paw volumes of oedema in tested and control
groups, respectively.
Anti-inflammatory activity of compounds 2a, 2b, 2deg, 2i,
3a, 3b, 3d, 3f, 3g and 3i screened is reported in Table 2.
4.3. General procedure for synthesis of dihydroimidazol-
1-yl benzenesulfonamide derivatives (3aei)
4.5. Analgesic activity
4.3.1. N-(4,5-Dioxo-2-(pyridin-2-yl)-4,5-
Acetic acid writhing test was performed on mice by follow-
ing the method of Davis et al. [35]. Groups of five mice (body
weight 20e30 g) of both sexes, excluding pregnant females,
were given a dose of a test compound. After 30 min, the ani-
mals were injected intraperitoneally with 0.25 ml/mouse of
0.5% acetic acid solution and writhes were counted during
the following 60 min. The mean number of writhes for each
experimental group and percent decrease compared with con-
trol group (five mice not treated with test compounds) were
calculated. Compounds 2a, 2b, 2deg, 2i, 3a, 3b, 3d, 3f, 3g
and 3i were screened for analgesic activity and results are
reported in Table 2.
dihydroimidazol-1-yl)-4-methylbenzene sulfonamide (3a)
Amidine derivative [24] 1a (0.290 g; 1 mmol) was dis-
solved in dry THF (10 ml) and to it was added potassium car-
bonate (0.414 g; 3 mmol). The reaction mixture was cooled in
an ice bath and then oxalyl chloride (0.1 ml; 1.2 mmol) was
added dropwise while the reaction contents were stirred con-
tinuously. After complete addition of oxalyl chloride it was
further stirred at room temperature for 1 h. The solid product
that separated out was filtered and then dissolved in methanol
to remove insoluble potassium salts. Solvent from the clear
methanol solution was removed under reduced pressure to

2830
S.M. Sondhi et al. / European Journal of Medicinal Chemistry 43 (2008) 2824e2830
Table 2
Anti-inflammatory activity and analgesic activity evaluation of compounds 2a,
2b, 2deg, 2i, 3a, 3b, 3d, 3f, 3g and 3i
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Compounds
tested
Anti-inflammatory activity
Analgesic activity
Dose
(mg/kg p.o.)
Activity
(%)
Dose
(mg/kg p.o.)
Activity
(%)
2a
2b
2d
2e
100
50
12
20
16
27
44
56
21
11
20
31
20
37
34
25
13
19
37
58
100
50
75
20
7.0
9.0
17
33
13
11
16
60
18
60
75
30
12
24
40
58
[13] S.M. Sondhi, R.P. Verma, N. Singhal, R. Shukla, R. Raghubir,
M.P. Dubey, Indian Drugs 36 (1999) 50e54.
50
25
50
25
[14] S.M. Sondhi, N. Singhal, R.P. Verma, S.K. Arora, R. Shukla,
R. Raghubir, S.G. Dastidar, Monatsh. Chem. 131 (2000) 501e509.
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[16] H. Schaefer, B. Bartho, K. Gewald, J. Prakt. Chem. (Leipzig) 319 (1977)
149e158.
50
50
100
50
100
50
2f
2g
50
50
50
50
2i
3a
[17] M. Arca, F. Demartin, F.A. Devillanova, F. Isaia, F. Lelj, V. Lippolis,
G. Verani, Can. J. Chem. 78 (2000) 1147e1157.
50
50
50
50
3b
3d
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(1968) 1099e1101.
50
50
3f
3g
100
50
100
50
[19] B. Eistert, G.W. Mueller, T.J. Arackai, Justus Liebigs Ann. Chem. 6
(1976) 1023e1030.
3i
Phenylbutazone
50
25
50
25
[20] R. Neidlein, P. Leinberger, A. Gieren, B. Dederer, Chem. Ber. 110 (1977)
3149e3160.
50
100
50
100
[21] G. Kollenz, C. Labes, Justus Liebigs Ann. Chem. 11 (1975) 1979e1983.
[22] S. Massip, J. Guillon, D. Bertarelli, J.J. Bosc, J.M. Leger, S. Lacher,
C. Bontemps, T. Dupont, C.E. Muller, C. Jarry, Bioorg. Med. Chem.
14 (2006) 2697e2719.
Acknowledgements
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One of the authors, Ms. Monica Dinodia (SRF NET) is
thankful to UGC, New Delhi and another author Ms. Shubhi
Jain is thankful to MHRD, Govt. of India for financial assis-
tance. We are thankful to technical staff of the Chemistry
Department, IIT Roorkee, Roorkee, for the spectroscopic
and elemental analysis.
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