Design and synthesis of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives as selective cyclooxygenase (COX-2) inhibitors

Article abstract of DOI:10.1016/j.bmcl.2009.04.125

A new group of 3-alkyl-2-aryl-1,3-thiazinan-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activity. In vitro COX-1/COX-2 inhibition studies identi

Full text of DOI:10.1016/j.bmcl.2009.04.125

Bioorganic & Medicinal Chemistry Letters 19 (2009) 3162–3165
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives
as selective cyclooxygenase (COX-2) inhibitors
c
d
e
Tannaz Zebardast a, Afshin Zarghi a,b, , Bahram Daraie , Mehdi Hedayati , Orkideh G. Dadrass
*
a Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University (M.C), Tehran, Iran
b Pharmaceutical Research Center, School of Pharmacy, Shahid Beheshti University (M.C), Tehran, Iran
c Department of Toxicology, Tarbiat Modarres University, Tehran, Iran
d Endocrine Research Center, Shahid Beheshti University (M.C), Tehran, Iran
e Department of Pharmaceutical Chemistry, School of Pharmacy, Azad University, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 December 2008
Revised 8 April 2009
Accepted 27 April 2009
Available online 3 May 2009
A new group of 3-alkyl-2-aryl-1,3-thiazinan-4-ones, possessing a methylsulfonyl pharmacophore, were
synthesized and their biological activities were evaluated for cyclooxygenase-2 (COX-2) inhibitory activ-
ity. In vitro COX-1/COX-2 inhibition studies identified 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-thiaz-
inan-4-one (11a) as a potent (IC50 = 0.06
l
M) and selective (selectivity index >285) COX-2 inhibitor.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1,3-Thiazinan-4-ones
COX-2 inhibition, SAR
The non-steroidal anti-inflammatory drugs (NSAIDs) such as
aspirin and indomethacin that act via inhibition of the cyclooxy-
genase (COX) enzyme, are widely used as analgesic, anti-pyretic
and anti-inflammatory agents. The success of NSAIDs in treatment
of various inflammatory disorders validated inhibition of COX en-
zyme as a highly suitable target in anti-inflammatory therapies.1
However, the gastrointestinal toxicities associated with wide-
spread use of NSAIDs proved to be a major problem during long
term therapy. COX enzyme catalyzes the first step of the biosyn-
thesis of PGG2 from arachidonic acid which serves as a precursor
for the synthesis of PGs, prostacyclines and thromboxanes such
as TXA2 that are collectively termed as prostanoides.2 Nowadays,
it is well established that there are at least two COX isozymes,
COX-1 and COX-2.3 The COX isoforms are heme containing
enzymes that inhibit distinct expression roles in several physiolog-
ical processes. The constitutive COX-1 isozyme is expressed in
many tissues and appears to be important to the maintenance of
physiological functions such as gastro protection and vascular
homeostasis.4 In contrast, the COX-2 isozyme is induced by stimuli
such as mitogenes and oncogenes, growth factors, hormones and
disorders of water-electrolyte homeostasis linking its involvement
to pathological processes such as inflammation and various cancer
types.5–7 The gastrointestinal side effects associated with NSAIDs
are due to the inhibition of gastroprotective PGs synthesized
through the COX-1 pathway.8,9 Thus, selective inhibition of COX-
2 over COX-1 is useful for the treatment of inflammation and
inflammation-associated disorders with reduced gastrointestinal
toxicities when compared with NSAIDs. Recent studies have shown
that the progression of Alzheimer’s disease is reduced among some
users of NSAIDs. Chronic treatment with selective COX-2 inhibitors
may therefore slow the progress of Alzheimer’s disease without
causing gastrointestinal damage.10 The majority of selective
COX-2 inhibitors belong to a class of diarylheterocycles that pos-
sess vicinal diaryl substitution attached to a five- or six-membered
central hetero or carbocyclic ring system (see structures 1–6 in
Chart 1).11–17 The recent termination of clinical use of some diaryl-
heterocyclic selective COX-2 inhibitors such as rofecoxib, and
valdecoxib due to their adverse cardiovascular side effects18 clearly
delineates the need to explore and evaluate new structural ring
templates (scaffolds) possessing COX inhibitory activity. In addi-
tion, some studies have suggested that rofecoxib’s adverse cardiac
events may not be a class effect but rather an intrinsic chemical
property related to its metabolism.19 For this reason novel scaf-
folds with high selectivity for COX-2 inhibition need to be found
and evaluated for their anti-inflammatory effects. Recently, we re-
ported a group of 2,3-diaryl-1,3-thiazolidine-4-ones possessing a
COX-2 SO2Me pharmacophore at the para-position of C-2 phenyl
ring in conjunction with different substituents at the para-position
of the N-3 phenyl ring.17 For example, 3-(4-fluorophenyl)-2-
(4-methylsulfonylphenyl)-1,3-thiazolidine-4-one (see structure 6)
exhibited highly selectivity for COX-2 inhibition. As part of our
ongoing program to design new types of selective COX-2
inhibitors, we now report the design, synthesis, cyclooxygenase
inhibitory and some molecular modeling studies of a new group
of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives having a six-membered
* Corresponding author. Tel.: +98 21 88665341.
E-mail address: azarghi@yahoo.com (A. Zarghi).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.04.125

T. Zebardast et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3162–3165
3163
The target 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives (11a–
f) were synthesized via the route outlined in Scheme 1. Accordingly,
an appropriate amine (7a–c) was treated with 4-methylthiobenzal-
dehyde (8) and thioglycolic acid (9) in dry toluene in presence of
p-toluenesulfonic acid under reflux to give 3-alkyl-2-(4-methylthi-
ophenyl)-1,3-thiazinan-4-one (10, 10–12%).20 Oxidation of 10 using
30% H2O2 in hydromethanol in the presence of a trace amount of
WO3 afforded the 3-alkyl-2-(4-methylsulfonylphenyl)-1,3-thiaz-
inan-4-one (11a–c, 35–75%).24 For low boiling point amines (7d–
f), the intermediate imine products (12) were obtained by the reac-
tion with 4-metylthiobenzaldehyde in anhydrous DMF. Subsequent
oxidation 12 with hydrogen peroxide and WO3 in hydromethanol
solution afforded the (E)-N-(4-(methylsulfonylbenzylidene) alkan-
1-amine (13).25 Reaction of 13 and mercaptopropionicacid under
refluxing in dry toluene according as described previously gave
11d–f (12–45%).24
SO2NH2
SO2Me
N
F3C
N
Me
Celecoxib (1)
F
SC57666 (2)
SO2Me
SO2NH2
Me
Cl
O
N
N
N
Me
A group of 3-alkyl-2-aryl-1,3-thiazinan-4-one derivatives hav-
ing different substituents at the N-3 central ring (11a–f) were pre-
pared to investigate the effect of different substituents on COX-2
selectivity and potency. The ability of the 1,3-thiazinan-4-ones
11a–f to inhibit the COX-1 and COX-2 isozymes was determined
using chemiluminescent enzyme assays21 (see enzyme inhibition
data in Table 1) according to our previously reported method.17
In vitro COX-1/COX-2 inhibition studies showed that all com-
pounds 11a–f were selective inhibitors of the COX-2 isozyme with
Valdecoxib (3)
Etoricoxib (4)
NHSO2Me
SO2Me
S
O
N
O
O
F
F
IC50 values in the highly potent 0.06–0.11 lM range, and COX-2
6
5
selectivity indexes (S.I.) in the 128.4–285.8 range. The relative
COX-2 potency, and COX-2 selectivity profiles for the 1,3-thiaz-
inan-4-one derivatives 11a–f, with respect to the N-3 substituent
(R) was benzyl > phenethyl > pentyl > butyl > propyl. These data
showed that increasing of lipophilicity of substituent attached to
N-3 of 1,3-thiazinan-4-one ring increased both selectivity and
Chart 1. Representative examples of selective COX-2 inhibitors.
central ring scaffold and different alkyl or arylalkyl groups at the
N-3, in order to find the effect of alkyl and arylalkyl groups on
the inhibition of COX-2 activity.
SMe
R
COOH
N
+
+
R
NH2 OHC
SMe
a
HS
S
O
7a, R=Benzyl
7b, R=Phenethyl
7c, R=Cyclohexyl
8
9
10 a-c
SO2Me
R
b
N
11a, R=Benzyl
11b, R=Phenethyl
11c, R=Cyclohexyl
O
S
R
R
c
N
N
d
NH2
+
8
R
7d, R=Propyl
7e, R=Butyl
7f, R=Pentyl
SO2Me
SMe
12a-c
13a-c
SO2Me
R
N
e
11d, R=Propyl
11e, R=Butyl
11f, R=Pentyl
13
+
9
O
S
Scheme 1. Reagents and conditions: (a) toluene, reflux, 72 h; (b) H2O2 30%, WO3, 25 °C, 6 h; (c) DMF, 25 °C, 24 h; (d) H2O2 30%, WO3, 25 °C, 4 h; (e) toluene, reflux, 24 h.

3164
T. Zebardast et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3162–3165
ment (Fig. 1).22,23 This molecular modeling shows that it binds in
Table 1
In vitro COX-1 and COX-2 enzyme inhibition data
the primary binding site such that the C-2 para-SO2Me substituent
inserts into the secondary pocket present in COX-2 isozyme. One of
the O-atoms of p-SO2Me forms a hydrogen bonding interaction
with amino group of Arg513 (distance = 4.0 Å) whereas the other
O-atom is close to other hydrogen of this amino acid (dis-
tance = 5.4 Å). The C@O of the central thiazinan-4-one is almost
close to (distance = 5.9 Å) OH of Ser530. In addition, the phenyl ring
of benzyl substituent is very close to phenyl ring of Tyr348 which
may involve with hydrophobic interaction. These observations to-
gether with experimental results provide a good explanation for
the potent and selective inhibitory activity of 11a.
SO2Me
R
N
O
S
Compound
R
IC50
COX-1
(lM)
COX-2 S.I.b
a
COX-2
11a
11b
11c
11d
11e
11f
Celecoxib
Benzyl
17.15
15.98
ND
14.12
14.8
0.06
0.07
ND
0.11
0.08
0.08
0.06
285.8
228.3
NDc
128.4
185
Phenethyl
Cyclohexyl
Propyl
Acknowledgement
Butyl
Pentyl
We are grateful to the research deputy of Shahid Beheshti Uni-
versity of Medical Sciences for financial support of this research.
14.91
24.3
186.4
405
a
Values are mean values of two determinations acquired using an ovine COX-1/
COX-2 assay kit, where the deviation from the mean is <10% of the mean value.
References and notes
b
In vitro COX-2 selectivity index (COX-1 IC50/COX-2 IC50).
c
1. Smith, W. L.; DeWitt, D. L.; Garavito, R. M.; Raz, A. Ann. Rev. Biochem. 2000, 69,
145.
Not determined.
2. Vane, J. R.; Bakhle, Y. S.; Botting, R. M. Ann. Rev. Pharmacol. Toxicol. 1998, 38,
97.04.
3. Xie, W. L.; Chipman, J. G.; Robertson, D. L.; Erikson, R. L.; Simmons, D. L. Proc.
Natl. Acad. Sci. U.S.A. 1991, 88, 2692.
4. Smith, W. L.; DeWitt, D. L. Adv. Immunol. 1996, 62, 167.
5. Herschman, H. R. Biochem. Biophys. Acta 1996, 1299, 125.
potency for COX-2 inhibitory activity. However, compound 11b
showed less selectivity and potency for COX-2 isozyme compared
with compound 11a that may be explained by steric parameter.
According to these results, 3-benzyl-2-(4-methyl sulfonyl
phenyl)-1,3-thiazinan-4-one 11a was the most potent
6. Kawamori, T.; Rao, C. V.; Seibert, K.; Reddy, B. S. Cancer Res. 1998, 58, 409.
7. Kanaoka, S.; Takai, T.; Yoshida, K. Adv. Clin. Chem. 2007, 43, 59.
8. Allison, C. E.; Howatson, A. G.; Torrance, C. J.; Lee, F. D.; Russel, R. L. N. Eng. J.
Med. 1992, 327, 749.
9. Eberhart, C. E.; DuBois, R. N. Gasteroenterology 1995, 109, 285.
10. Vane, J. R.; Botting, R. M. Inflamm. Res. 1998, 47, S78.
11. Penning, T. D.; Tally, J. J.; Bertenshaw, S. R.; Carter, J. S.; Collins, P. W.; Docter,
S.; Graneto, M. J.; Lee, L. F.; Malecha, J. W.; Miyashiro, J. M.; Rogers, R. S.; Rogier,
D. J.; Yu, S. S.; Anderson, G. D.; Burton, E. G.; Cogburn, J. N.; Gregory, S. A.;
Koboldt, C. M.; Perkins, W. E.; Seibert, K.; Veenhuizen, A. W.; Zhang, Y. Y.;
Isakson, P. C. J. Med. Chem. 1997, 40, 1347.
12. Riendeau, D.; Percival, M. D.; Brideau, C.; Dube, C. S.; Ethier, D.; Falgueyret, J. P.;
Friesen, R. W.; Gordon, R.; Greig, G.; Guay, J.; Girard, Y.; Prasit, P.; Zamboni, R.;
Rodger, I. W.; Gresser, M.; Ford-Hutchinson, A. W.; Young, R. N.; Chan, C. C. J.
Pharmacol. Exp. Ther. 2002, 296, 558.
13. Prasit, P.; Wang, Z.; Brideau, C.; Chan, C.-C.; Charlson, S.; Cromlish, W.; Ethier,
D.; Evans, J. F.; Ford-Hutchinson, A. W.; Gauthier, J. Y.; Gordon, R.; Guay, J.;
Gresser, M.; Kargman, S.; Kennedy, B.; Leblanc, Y.; Leger, S.; Mancini, J.; O_Neil,
G. P.; Quellet, M.; Percival, M. D.; Perrier, H.; Riendeau, D.; Rodger, I.; Tagari, P.;
Therien, M.; Vikers, P.; Wong, E.; Xu, L.-J.; Young, R. N.; Zamboni, R.; Boyce, S.;
Rupniak, N.; Forrest, M.; Visco, D.; Patrick, D. Bioorg. Med. Chem. Lett. 1999, 9,
1773.
(IC50 = 0.06
among the synthesized compounds. It was as potent as celecoxib
(IC50 = 0.06 M; S.I. = 405) in terms of COX-2 inhibitory activity
lM), and selective (S.I. = 285.8), COX-2 inhibitor
l
but showed less selectivity. These data suggest that the compound
11a should inhibit the biosynthesis of prostaglandins via the cyc-
looxgenase pathway at sites of inflammation and be devoid of ulc-
erogenicity due to the absence of COX-1 inhibition.
The orientation of the highly potent and selective COX-2 inhib-
itor,
3-benzyl-2-(4-methylsulfonylphenyl)-1,3-thiazinan-4-one
11a in the COX-2 active site was examined by a docking experi-
14. Friesen, R. W.; Dube, D.; Fortin, R.; Frenette, R.; Prescott, S.; Cromlish, W.;
Greig, G. M.; Kargman, S.; Wong, E.; Chan, C. C.; Gordon, R.; Xu, L. J. Bioorg. Med.
Chem. Lett. 1996, 6, 2677.
15. Talley, J. J.; Brown, D. L.; Carter, J. S.; Graneto, M. J.; Koboldt, C. M.; Masferrer, J.
L.; Perkins, W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert,
K. J. Med. Chem. 2000, 43, 775.
16. Zarghi, A.; Rao, P. N. P.; Knaus, E. E. Bioorg. Med. Chem. 2007, 15, 1056.
17. Zarghi, A.; Najafnia, L.; Daraee, B.; Dadrass, O. G.; Hedayati, M. Bioorg. Med.
Chem. Lett. 2007, 17, 5634.
18. Dogné, J. M.; Supuran, C. T.; Pratico, D. J. Med. Chem. 2005, 48, 2251.
19. Mason, R. P.; Walter, M. F.; McNulty, H. P.; Lockwood, S. F.; Byun, J.; Day, C. A.;
Jacob, R. F. J. Cardivasc. Pharmacol. 2006, 47, S7.
20. Surrey, A. R.; Webb, W. G.; Gesler, R. M. J. Am. Chem. Soc. 1957, 80, 3469.
21. COX-1 and COX-2 assays: The assay was performed using an enzyme
chemiluminescent kit (catalog number 760101, Cayman chemical, MI, USA).
The Cayman chemical chemiluminescent COX (ovine) inhibitor screening assay
utilizes the heme-catalyzed hydroperoxidase activity of ovine cyclooxygenases
to generate luminescence in the presence of a cyclic naphthalene hydrazide
and the substrate arachidonic acid. Arachidonate-induced luminescence was
shown to be an index of real-time catalytic activity and demonstrated the
turnover inactivation of the enzyme. Inhibition of COX activity, measured by
luminescence, by a variety of selective and nonselective inhibitors showed
potencies similar to those observed with other in vitro and whole cell
methods.7
22. Docking studies were performed using Autodock software Version 3.0. The
coordinates of the X-ray crystal structure of the selective COX-2 inhibitor SC-
558 bound to the murine COX-2 enzyme was obtained from the RCSB Protein
Data Bank (1cx2) and hydrogens were added. The ligand molecules were
constructed using the Builder module and were energy minimized for 1000
iterations reaching a convergence of 0.01 kcal/mol Å. The energy minimized
Figure 1. Compound 5b 3-benzyl-2-(4-methylsulfonylphenyl)-1,3-thiazinane-4-
one docked in the active site of murine COX-2 isozyme.

T. Zebardast et al. / Bioorg. Med. Chem. Lett. 19 (2009) 3162–3165
3165
ligands were superimposed on SC-558 in the PDB file 1cx2 after which SC-558
was deleted. The purpose of docking is to search for favourable binding
configuration between the small flexible ligands and the rigid protein. Protein
residues with atoms greater than 7.5 Å from the docking box were removed for
efficiency. Searching is conducted within a specified 3D docking box using
annealing based on the Monte Carlo method and MMFF94 molecular
mechanics force field for 8000 iterations. These docked structures were very
similar to the minimized structures obtained initially. The quality of the
docked structures was evaluated by measuring the intermolecular energy of
the ligand–enzyme assembly.
73.1 (34); 1H NMR(CDCl3): d ppm 1.14–1.88 (m, 10H, cyclohexyl), 2.52 (m, 2H,
CH2S), 2.90 (s, 1H, SO2Me), 2.96 (m, 2H, CH2CO), 3.76 (m, 1H, CHN), 7.72 (d, 2H,
4-methylsulfonylphenyl H2 and H6, J = 8.3 Hz), 8.08 (d, 2H, 4-methylsulfonyl
phenyl H3 and H5, J = 8.3 Hz). Anal. Calcd for C17H23NO3S2: C, 57.76; H, 6.56; N,
3.96. Found: C, 57.42; H, 6.80; N, 4.02. Compound 11d. Yield, 12%, yellow
crystalline powder, mp 152–153 °C; IR (KBr):
m
cmÀ1 1670 (C@O), 1300, 1150
(SO2); MS: m/z (%) 313.2 (M+, 55), 233.1 (25), 206.1 (30), 179.1 (15), 91.0 (100),
77.0 (40); 1H NMR(CDCl3): d ppm 0.99 (t, 3H, CH3), 1.68 (m, 2H, CH2), 2.55–2.90
(m, 4H, COCH2CH2), 3.05 (s, 3H, SO2Me), 3.94 (t, 2H, CH2N), 5.53 (s, 1H, CH),
7.93 (d, 2H, 4-methylsulfonylphenyl H2 and H6, J = 8.5 Hz), 8.40 (d, 2H, 4-
methylsulfonylphenyl H3 and H5, J = 8.5 Hz). Anal. Calcd for C14H19NO3S2: C,
53.65; H, 6.11; N, 4.47. Found: C, 53.42; H, 5.90; N, 4.38. Compound 11e. Yield,
23. Kurumbail, R. G.; Stevens, A. M.; Gierse, J. K.; McDonald, J. J.; Stegeman, R. A.;
Pak, J. Y.; Gildehaus, D.; Miyashiro, J. M.; Penning, T. D.; Seibert, K.; Isakson, P.
C.; Stallings, W. C. Nature 1996, 384, 644.
45%, yellow crystalline powder, mp 159–160 °C; IR (KBr):
m
cmÀ1 1670 (C@O),
24. Analytical data for 10a. Yield, 11%; yellow oil; IR (neat):
m
cmÀ1 1650 (C@O)
1310, 1150 (SO2); MS: m/z (%) 327.2 (M+, 15), 240.2 (40), 196.1 (40), 159.1 (15),
117.1 (100), 91.0 (60), 77.0 (50); 1H NMR(CDCl3): d ppm 0.96 (t, 3H, CH3), 1.35
(m, 2H, CH2), 1.63 (m, 2H, CH2), 2.74–2.89 (m, 4H, COCH2CH2), 3.12 (s, 3H,
SO2Me), 4.20 (t, 2H, CH2N), 5.59 (s, 1H, CH), 7.49 (d, 2H, 4-methyl
sulfonylphenyl H2 and H6, J = 8.3 Hz), 8.01 (d, 2H, 4-methylsulfonylphenyl H3
and H5, J = 8.3 Hz). Anal. Calcd for C15H21NO3S2: C, 55.02; H, 6.46; N, 4.28.
Found: C, 55.32; H, 6.65; N, 4.40. Compound 11f. Yield, 44%, yellow crystalline
cmÀ1; MS: m/z (%) 329.3 (M+, 35), 241.1 (45), 224.2 (60), 192.1 (70), 178.1 (40),
137.0 (70), 91.0 (100), 77.2 (40); 1H NMR (CDCl3): d ppm 2.55 (S, 3H, SCH3),
2.71–3.01 (m, 4H, CH2–CH2), 3.60 (d, 1H, CH2N, J = 15.2 Hz), 4.40 (d, 1H, CH2N,
J = 15.2 Hz), 5.41 (S, 1H, CH), 7.18 (d, 2H, 4-methylthiophenyl H3 and H5,
J = 8.3 Hz), 7.24–7.43 (m, 5H, phenyl), 7.36 (d, 2H, 4-methylthiophenyl H2 and
H6, J = 8.3 Hz). Anal. Calcd for C18H19NOS2: C, 65.62; H, 5.81; N, 4.25. Found: C,
65.32; H, 5.60; N, 4.08. Compound 10b. Yield, 12%; yellow oil; IR (neat):
m
cmÀ1
powder, mp 167–168 °C; IR (KBr): m
cmÀ1 1670 (C@O), 1310, 1160 (SO2); MS:
1650 (C@O); MS: m/z (%) 343.1 (M+, 40), 254.2 (50), 238.9 (90), 163.8 (100),
137.0 (85), 116.9 (85), 105.1 (60), 77.1 (65); 1H NMR (CDCl3): d ppm 2.41 (s, 3H,
SMe), 2.52–2.86 (m, 6H, COCH2CH2 and Phenyl CH2), 2.90 (m, 1H, CH2N), 4.26
(m, 1H, CH2N), 5.06 (s, 1H, CH), 7.02 (d, 2H, 4-methylthiophenyl H3 and H5,
J = 8.1 Hz), 7.10–7.17 (m, 5H, phenyl), 7.22 (d, 2H, 4-methylthiophenyl H2 and
H6, J = 8.1 Hz). Anal. Calcd for C19H21NOS2: C, 66.43; H, 6.16; N, 4.08. Found: C,
m/z (%) 341.1 (M+, 30), 254.2 (60), 238.1 (65), 196.1 (50), 131.1 (25), 117.1
(100), 91.0 (50), 77.0 (30); 1H NMR (CDCl3): d ppm 0.93 (t, 3H, CH3), 1.30 (m,
2H, CH2), 1.62 (m, 2H, CH2), 2.73–2.87 (m, 4H, COCH2CH2), 2.76 (m, 2H, CH2),
3.11 (s, 3H, SO2Me), 4.21 (t, 2H, CH2N), 5.59 (s, 1H, CH), 7.50 (d, 2H, 4-
methylsulfonylphenyl H2 and H6, J = 8.3 Hz), 8.00 (d, 2H, 4-methylsulfonyl
phenyl H3 and H5, J = 8.3 Hz). Anal. Calcd for C16H23NO3S2: C, 56.27; H, 6.79; N,
4.10. Found: C, 56.52; H, 6.99; N, 4.12.
66.79; H, 6.40; N, 4.21. Compound 10c. Yield, 10%; yellow oil; IR (neat):
m
cmÀ1
1650 (C@O); MS: m/z (%) 321.2 (M+, 30), 233.2 (100), 218.2 (30), 190.1 (40),
178.1 (45), 150.0 (90), 137.0 (100), 109.1 (30), 83.1 (30). Anal. Calcd for
C17H23NOS2: C, 63.51; H, 7.21; N, 4.36. Found: C, 63.22; H, 7.60; N, 4.18.
Compound 11a. Yield, 35%; yellow crystalline powder, mp 193–194 °C; IR
25. Analytical data for 12a. Yield, 20%, yellow oil; IR (neat):
m
cmÀ1 1650 (C@N);
m
cmÀ1 1650 (C@N); MS:
MS: m/z (%) 193.1 (M+, 30), 178.1 (15), 136.1 (50), 120.0 (100), 91.1 (30), 77.1
(20). Compound 12b. Yield, 22%, yellow oil; IR (neat):
m/z (%) 207.3 (M+, 25), 192.2 (45), 178.2 (35), 164.0 (45), 150.1 (40), 136.9 (55),
117.2 (100), 91.1 (30). Compound 12c. Yield, 16%, pale yellow powder; IR (KBr):
(KBr):
m
cmÀ1 1670 (C@O), 1320, 1170 (SO2); MS: m/z (%) 361.3 (M+, 10), 289.4
(10), 251.1 (20), 212.3 (10), 165.9 (100), 140.4 (20), 109.1 (100), 83.1 (100); 1H
NMR(DMSO-d6) d ppm 3.27 (s, 3H, SO2Me), 3.05–3.39 (m, 4H, CH2–CH2), 3.91
(d, 1H, CH2N, J = 15.4 Hz), 4.97 (d, 1H, CH2N, J = 15.4 Hz), 6.13 (s, 1H, CH), 7.20–
7.27 (m, 5H, phenyl), 7.71 (d, 2H, 4-methylsulfonylphenyl H2 and H6,
m
cmÀ1 1650 (C@N); MS: m/z (%) 253.2 (M+, 15), 238.1 (90), 224.1 (20), 210.1
(60), 196.0 (50), 182.0 (50), 132.1 (30), 117.0 (100), 91.1 (20), 77.1 (25).
Compound 13a. Yield, 18%, pale yellow powder; IR (KBr):
m
cmÀ1 1300, 1150
(SO2); MS m/z (%): 225.0 (M+, 20), 196.0 (85), 146.1 (40), 117.0 (100), 91.0 (50),
77.0 (25); 1H NMR (CDCl3): d ppm 0.99 (t, 3H, CH3), 1.63 (m, 2H, CH2), 3.05 (s,
3H, SO2Me), 3.42 (t, 2H, CH2N), 7.92 (d, 2H, 4-methylsulfonylphenyl H2 and H6,
J = 8.4 Hz) 7.99 (d, 2H, 4-methylsulfonyl phenyl H3 and H5, J = 8.4 Hz); Anal.
Calcd for C11H15NO2S: C, 58.64; H, 6.71; N, 6.22. Found: C, 58.34; H, 6.91; N,
J = 8.4 Hz), 7.96 (d, 4-methylsulfonylphenyl H3 and H5,
Calcd for C18H19NO3S2: C, 59.81; H, 5.30; N, 3.87. Found: C, 59.62; H, 5.41; N,
4.02. Compound 11b. Yield, 40%; yellow semisolid; IR (KBr):
cmÀ1 1670
J = 8.4 Hz). Anal.
m
(C@O), 1330, 1150 (SO2); MS: m/z (%) 375.1 (M+, 5), 286.2 (15), 196.1 (45),
117.2 (95), 90.0 (100), 77.1 (30); 1H NMR (CDCl3): d ppm 2.68–2.87 (m, 4H,
COCH2CH2), 3.05 (s, 1H, SO2Me), 3.07–3.10 (m, 2H, CH2 Phenyl), 3.17 (m, 1H,
CH2N), 4.23 (m, 1H, CH2N), 5.01 (s, 1H, CH), 7.09 (d, Phenyl H2 and H6,
J = 7.1 Hz), 7.15–7.24 (m, 3H, Phenyl H3–H5), 7.48 (d, 2H, 4-
methylsulfonylphenyl H2 and H6, J = 8.4 Hz) 7.96 (d, 2H, 4-
methylsulfonylphenyl H3 and H5, J = 8.4 Hz). Anal. Calcd for C19H21NO3S2: C,
60.77; H, 5.64; N, 3.73. Found: C, 60.52; H, 5.50; N, 3.88. Compound 11c.Yield,
6.30. Compound 13b. Yield, 17%, pale yellow powder; IR (KBr):
m
cmÀ1 1310,
1150 (SO2); MS m/z (%): 239.1 (M+, 10), 210. 0 (15), 196.0 (35), 137.1 (25),
117.0 (100), 91.0 (60), 77.0 (70). Anal. Calcd for C12H17NO2S: C, 60.22; H, 7.16;
N, 5.85. Found: C, 60.39; H, 7.44; N, 5.98. Compound 13c. Yield, 15%, pale yellow
powder; IR (KBr):
m
cmÀ1 1310, 1150 (SO2); MS m/z (%): 253.1 (M+, 10), 238.1
(85), 210.1 (60), 196.0 (50), 182.0 (50), 132.1 (30), 117.0 (100), 90.1 (75), 77.1
(25); Anal. Calcd for C13H19NO2S: C, 61.63; H, 7.56; N, 5.53. Found: C, 61.88; H,
75%, yellow powder, mp 138–140 °C; IR (KBr):
m
cmÀ1 1660 (C@O), 1300, 1150
7.77; N, 5.60. Satisfactory analysis for C, H,
N was obtained for all the
(SO2); MS: m/z (%) 353.1 (M+, 5), 265.0 (48), 202.0 (25), 155.0 (100), 139.1 (35),
compounds within 0.4% of the theoretical values.