Benzophenone-N-ethyl piperidine ether analogues-Synthesis and efficacy as anti-inflammatory agent

Article abstract of DOI:10.1016/j.bmcl.2009.02.070

A sequence of substituted benzophenone-N-ethyl piperidine ether analogues has been synthesized and evaluated as orally active anti-inflammatory agents with reduced side effects. The anti-inflammatory and ulcerogenic activities of the compounds were compared with naproxen, indomethacin, and phenylbutazone. These analogues showed an interesting anti-inflammatory activity in carrageenan-induced foot pad edema assay. In the air-pouch test, some of the analogues reduced the total number of leukocytes of the exudate, which indicates inhibition of prostaglandin production. Side effects of the compounds were examined on gastric mucosa, in the liver and stomach. None of the compounds illustrated significant side effects compared with standard drugs like indomethacin and naproxen.

Full text of DOI:10.1016/j.bmcl.2009.02.070

Bioorganic & Medicinal Chemistry Letters 19 (2009) 1887–1891
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Benzophenone-N-ethyl piperidine ether analogues—Synthesis and efficacy
as anti-inflammatory agent
b
c
d
Shaukath A. Khanum a, , V. Girish , S. S. Suparshwa , Noor Fatima Khanum
*
a Department of Chemistry, Yuvaraja College, University of Mysore, Mysore 570 005, India
b Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India
c Sri Lakshmi Hayagreeva College, Mysore 570005, India
d Department of Food Science and Nutrition, Maharani’s Science College for Women, Mysore 570 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A sequence of substituted benzophenone-N-ethyl piperidine ether analogues has been synthesized and
evaluated as orally active anti-inflammatory agents with reduced side effects. The anti-inflammatory
and ulcerogenic activities of the compounds were compared with naproxen, indomethacin, and phenyl-
butazone. These analogues showed an interesting anti-inflammatory activity in carrageenan-induced foot
pad edema assay. In the air-pouch test, some of the analogues reduced the total number of leukocytes of
the exudate, which indicates inhibition of prostaglandin production. Side effects of the compounds were
examined on gastric mucosa, in the liver and stomach. None of the compounds illustrated significant side
effects compared with standard drugs like indomethacin and naproxen.
Received 12 October 2008
Revised 26 January 2009
Accepted 18 February 2009
Available online 21 February 2009
Keywords:
Benzophenone-N-ethyl piperidine ethers
Anti-inflammatory activity
Ó 2009 Elsevier Ltd. All rights reserved.
Inflammation is the complex biological response of vascular tis-
sues to harmful stimuli, such as pathogens, damaged cells, or irri-
tants.1,2 Symptoms of inflammation include pain, swelling, red
coloration to the area, and sometimes loss of movement or func-
tion.3 The potent mediators of inflammation are derivatives of ara-
chidonic acid a 20-carbon unsaturated fatty acid produced from
membrane phospholipids.4 The principal pathways of arachidonic
acid metabolism are the 5-lipoxygenase pathway, which produce
a collection of leukotrienes and cyclooxygenase (COX), the key en-
zyme required for the conversion of arachidonic acid to prostaglan-
dins.5 COX was first identified over 20 years ago and drugs that
inhibit COX activity have been available to the public for about
100 years.6 In the past decade, however, more progress has been
made in understanding the role of COX enzymes in biology and dis-
ease than at any other time in history.7,8 Pharmacological inhibi-
tion of COX can provide relief from the symptoms of
inflammation and pain.9 Two COX isoforms have been identified
and are referred to as COX-1 and COX-2.5 Both COX are constitu-
tively expressed in most tissues, but COX-2, in contrast to COX-1,
is the mitogen inducible isoform.10,11 COX isoforms are almost
identical in structure but have important differences in substrate
and inhibitor selectivity and in their intracellular locations.12
COX is the principal target of nonsteroidal anti-inflammatory drugs
(NSAIDs) and metabolites of the COX pathway are widely accepted
as mediators of the inflammatory response. NSAIDs blocks the for-
mation of prostaglandins and have anti-inflammatory, analgesic,
and antipyretic activity.8
The proficiency of piperidine analogues as chemotherapeutic
agents, in particular anti-inflammatory agents are well docu-
mented.13,14 Scientist has explored anti-proliferative and anti-
inflammatory activities of phenylpiperidine analogues which is
comparable or slightly inferior to that of standard drug.15 For in-
stance, piperidine ureas display an unprecedented combination
of potency and selectivity for use as potential analgesic and anxio-
lytic agents.16 Recently synthesis, anti-inflammatory activity and
structure–activity relationship of a series of trialkyl-piperidine
analogues were performed.17
Benzophenones, the precursor for the synthesis of the title com-
pounds are essential due to their diverse biological and chemical
properties. For instance, these analogues possess a high analge-
sic.18 efficacy and also endowed with anti-inflammatory property.7
Several attempts to derive COX-2 selective inhibitors from NSAIDs
like benzophenone analogue8 have been published and are indi-
cated in the treatment of rheumatoid arthritis, ankylosing spondy-
litis, and osteoarthritis. The literature investigation reveals that no
endeavor was proposed toward the designing of benzophenone-N-
ethyl piperidine ether analogues to verify the importance of title
compounds on the pharmacological activity. Based on this infor-
mation and in our search for new molecules with anti-inflamma-
tory activity,19,20 it was considered valuable to synthesize
benzophenone-N-ethyl piperidine ether analogues (5a–j) as anti-
inflammatory agents as explained below, for a rational study of
the structure–activity relationships.
* Corresponding author. Tel.: +91 9901888755.
E-mail address: shaukathara@yahoo.co.in (S.A. Khanum).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.02.070

1888
S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1887–1891
Chemicals were purchased from Aldrich Chemical Co. TLC
A mixture of 4a–j (2.06 mmol) and 1-(2-chloroethyl) piperidine
hydrochloride (2.06 mmol) in presence of anhydrous potassium
carbonate (5.15 mmol) and dimethyl sulfoxide (10 ml) was re-
fluxed for 9 h then cooled. The residual mass was triturated with
ice water to remove potassium carbonate and dimethyl sulfoxide
and extracted with ethyl acetate (3 ꢀ 20 ml). The ethyl acetate
layer was washed with saturated sodium chloride solution
(3 ꢀ 20 ml), 10% sodium hydroxide solution (3 ꢀ 20 ml) followed
by distilled water (3 ꢀ 30 ml) and then dried over anhydrous so-
dium sulfate. Finally the ether layer was evaporated to dryness
to get crude product, which on recrystallization with ethanol gave
pasty mass of the title compounds 5b–j. The compounds 3a–j,21
4a–j,22 and 5a–j23 were characterized by IR, 1H NMR, and mass
spectrophotometer.
Biological evaluation of compounds: All the animal experiments
with Albino mice were carried out at Farooqia College of Pharmacy,
Mysore and permission for conducting these animal experiments
was obtained from institutional Animals Ethics Committee
(1848/06-07). The animals were housed in groups of six and accli-
matized to room conditions for at least 2 days before the experi-
ments, with food and water at libitum. The food was withdrawn
on the day before the experiment, but free access to water was al-
lowed. The compounds (100 mg/kg) and the reference NSAIDs,
phenylbutazone (100 mg/kg), indomethacin (10 mg/kg), and na-
proxen (30 mg/kg), were suspended in 0.5% carboxymethylcellu-
lose (CMC) and administered orally by animal feeding needle.
The control groups received appropriate volumes of the vehicle
(0.5% CMC, oral) only.
was performed on aluminium-backed silica plated with visuali-
zation by UV-light. Melting points were determined on a Tho-
mas Hoover capillary melting point apparatus with a digital
thermometer. IR spectra were recorded in Nujol on FT-IR Shima-
dzu 8300 spectrometer and 1H NMR spectra were recorded on a
Bruker 300 MHz spectrometer in CDCl3. Chemical shifts were
recorded in parts per million downfield from tetramethylsilane.
Mass spectra were obtained with a VG70-70H mass spectrome-
ter and elemental analysis results are within 0.4% of the calcu-
lated value.
The synthetic sequence is outlined in Scheme 1. To 2-methyl-
phenol (1, 13.9 mmol), corresponding benzoyl chlorides (2a–j,
13.9 mmol) were added with constant stirring. The reaction mix-
ture was cooled to 0 °C, made alkaline by adding 10% sodium
hydroxide solution and stirring was continued for about 1 h. The
separated oil was extracted with ether (3 ꢀ 20 ml), the organic
layer was washed with 10% sodium hydroxide solution
(3 ꢀ 15 ml) and with distilled water (3 ꢀ 30 ml). Finally, the organ-
ic layer was dried over anhydrous sodium sulfate and ether was re-
moved to afford substituted 2-methylphenyl benzoates (3a–j).
Substituted hydroxy benzophenones (4a–j) were synthesized
by Fries rearrangement of 3a–j. A mixture of anhydrous aluminum
chloride (6.1 mmol) and 3a–j (4.1 mmol) was heated over oil bath
at 80–90 °C for 45 min. At the end of this period the solution was
cooled and decomposed by ice-cold water. The residual solid was
crushed into powder, dissolved in ether (40 ml) and extracted with
10% sodium hydroxide (3 ꢀ 30 ml). The basic aqueous solution was
neutralized with 10% hydrochloric acid. The filtered solid was
washed with distilled water (3 ꢀ 30 ml) and recrystallized from
ethanol to afford 4a–j.
Anti-inflammatory activity–carrageenan paw edema test
(CPE):24,25 One hour after oral administration of the compounds,
the thickness of right hind paw was measured by a peacok dial
R3
R2
COCl
OH
R1
R2
R1
H3C
Anhy AlCl3
10% NaOH
Stirring
+
80-90oC
O
O
R3
2a-j
H3C
1
3a-j
R2
R2
R3
R1
R3
R1
N
O
O
Cl
Anhy. K2CO3
DMSO
H3C
H3C
O
OH
N
4a-j
5a-j
a: R1=R2=H, R3=Br
c: R1=CH3, R2=R3=H
e: R1=R2=H, R3=CH3
g: R1=R2=H, R3=OCH3
i: R1=Br, R2=R3=H
b: R1=R3=H, R2=Cl
d: R1=R2=H, R3=F
f: R1=R3=Cl. R2=H
h: R1=R3=H, R2=CH3
j: R1=R2=R3=H
Scheme 1.

S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1887–1891
1889
thickness gauge and 0.1 ml 2% carrageenan was injected subcuta-
neously into the plantar surface of the right hind paw. After 2 h,
the volume of the edema was measured again and the anti-ede-
matic effects of the drugs were estimated in terms of percent inhi-
bition using following equation:
new anti-inflammatory compounds, it is desirable to search for a
new series of compounds with low ulceration potential. Our results
show that the newly synthesized compounds reduce leukocytes,
which suggests inhibition of PG synthesis. COX-1, is constitutively
expressed in most tissues and appears to be relevant for tissue
homeostatic functions of PGs, whereas COX-2 is an inducible iso-
zyme and plays a role in many inflammatory reactions.11 The en-
zymes are the primary targets of aspirin and other NSAIDs and
thus are of major interest in pharmacology, pharmacogenetics,
and epidemiology. NSAIDs have several potential pharmacologic
effects. However, their anti-inflammatory action depends primar-
ily on their ability to inhibit the COX enzymes.29 This results in
the decreased production of pro-inflammatory PGs. Macrophages
is known to produce PGE2 via the COX-2 dependent pathway in re-
sponse to pro-inflammatory cytokines. Furthermore, rat peritoneal
macrophages have been recently found to have the capacity to
metabolize exogenous arachidonic acid to thromboxane via COX-
1 and to PGE2 via COX-2.30 This observation suggested that there
is a preferential, phase-specific correlation between the two COX
isoforms and the downstream respective terminal PG synthases.
Previous work has shown that the inflammatory effect of carra-
geenan is due to an influx of predominantly neutrophilic leuko-
cytes (predominantly PMNL) from blood circulation into the
cavity. In addition, leukocyte migration is induced locally in the
inflammatory process and leukocytes also intensify inflammation
by releasing several inflammatory mediators. The method is used
for measuring the edema induced by injection of carrageenan into
the pouches in mice back. Air-pouches were highly reactive to
inflammatory stimulus. The enhanced inflammatory reactions in
the sites correlated with formation of lining tissue, the type of cells,
and/or the reactivity of newly formed blood cells.26,27,31,32 Mean
leukocyte numbers per milliliter of exudates for each drug com-
pared with control values obtained from similar group of animals
receiving vehicle alone and the degree of inflammatory response
produced in the air pouch cavity was assessed by measuring total
cell number of the exudates. Compounds 5a, 5d, and 5f reduced to-
tal number of leukocytes of the exudates. The reduction of leuko-
cytes suggests inhibition of PG production. Compounds 5a, 5d,
and 5f were inhibited PMNL production compared with control
and reference compounds 4–4.5 and 1–1.4-fold greater, respec-
tively (Table 1).
The ulcerogenic potential of anti-inflammatory compounds can
be demonstrated in animal models using positive (naproxen, ido-
methacin) and negative (phenylbutazone) controls. Upon micro-
scopic examination, lesions seen in the stomach, kidney and liver
tissues are graded according to their severity. The grade of the
scale is designed as (+) for mild (++) for moderate and (+++) for se-
vere changes. Stomachs of the mice are thoroughly sectioned and
both corpus and antrum are evaluated. Surface epithelium and
the lamina propria of the gastric mucosa are all examined. Acute
gastritis may exist in an earlier or milder non-erosive form with
merely mucosal congestion, edema and histological evidence of
inflammation. These earlier changes are known to be transient
and completely reversible within few days, but the development
of erosions and hemorrhages is more serious and related to an in-
creased risk of major upper gastrointestinal bleeding. In our study,
the animals were sacrificed 4 h after ingestion of the drugs. None of
the sections displayed the morphology of the ulceration, but the
non-erosive form of acute gastritis was observed in various degrees
of severity with compounds 5b, 5c, 5e, 5h, and 5j (Table 2). Upon
microscopic examination of the kidney sections, the morphologic
mononuclear cell infiltrations were characteristic for tubulointer-
stitial nephritis. The presence of some scattered eosinophil leuko-
cytes also provided evidence for the drug effect. Focal areas
displaying variable but generally mild degree of tubular regenera-
tion were also present. Acute pyelonephritis should be considered
ꢀ
ꢁ
ðm ꢁ m0Þ
Anti-inflammatory activity ð%Þ ¼
ꢀ 100
m
where m and m0 indicate the difference in thickness between the
first and second measurements of hind paws in control and test
groups, respectively.
Air-pouch test:26–28 The carrageenan powder was dissolved in
saline to a concentration of 10 mg/ml. The solution was sterilized
and homogenized by placing it in an oven at 90 °C for about 1 h.
It was then maintained at 37 °C. Air pouches were formed by sub-
cutaneous (sc) injection of 1 ml of air for 3 days. On the third day,
after the initial injection of air, carrageenan solution (1 ml) was in-
jected into the air-pouch to induce inflammation. Compounds
were administered orally 1 h before injection of the carrageenan
into the pouch. After 4 h, mice were killed by ether exposure and
pouches washed thoroughly with 3 ml of phosphate buffer solu-
tion (PBS) containing 50 l/ml heparin. Lavage fluids were centri-
fuged at 2000 rpm for 15 min at 4 °C and the pellet was
resuspended in 1 ml of PBS-heparin. The total number of polymor-
phonuclear leukocytes (PMNL) infiltration was measured using a
Coulter Counter.
Histopathological examination: Mice were sacrificed 4 h after the
paw edema experiments and their liver, stomach, and kidneys
were removed and put into 10% formalin solution. The sections ta-
ken from these specimens were stained with hematoxilen eosine
and examined under the light microscope.
The pharmacological results (Table 1) indicate that some of the
compounds possess anti-inflammatory properties. In the CPE as-
say, compounds 5a, 5b, 5d, 5f, 5g, and 5i showed anti-inflamma-
tory activity. The most effective compounds were 5a, 5d, and 5f
which have a bromo, chloro, and fluoro, respectively, group at para
position in benzoyl moiety. Compound 5b with chloro groups at
meta position, 5g with a methoxy group at para position and 5i
with a bromo group at ortho position, in benzoyl moiety, showed
promising activity whereas compounds 5c with a methyl group
at ortho position, 5h with a methyl group meta position and 5j with
no substituent in benzoyl moiety showed only weak activity com-
pared to standard. In addition to the synthesis and identification of
Table 1
Anti-inflammatory activity of compounds 5a–j
Compd 100 mg/kg
CPE (% inhibition SE)a
PMNL (105/cm3)
(n = 6, after 4 h)b
Control
5a
5b
5c
5d
5e
—
122.40 4.06
31.75 0.75
56.26 0.37
69.51 0.96
32.41 3.14
n.t
67.51 9.26c
51.42 3.97c
35.62 1.21d
60.60 8.54c
n.a
5f
5g
5h
5i
68.70 9.55c
51.42 3.97c
15.45 1.67d
51.41 3.98c
22.44 3.08d
66.90 1.70c
53.28 1.84c
32.11 1.39c
30.15 0.77
56.26 0.37
104.76 1.56
56.25 0.38
95.25 0.80
49.20 1.30
53.28 1.71
68.81 1.80
5j
Naproxen (30 mg/kg)
Phenylbutazone (100 mg/kg)
Indomethacin (10 mg/kg)
PMNL, polymorphonuclear leucocytes; n.a.: no activity; n.t: not tested.
a
Results are expressed as their mean values (n = 6).
Mean SEM (n = 6).
p < 0.01.
p < 0.05.
b
c
d

1890
S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1887–1891
Table 2
Histopathological examination results of compounds 5a–j
Compd (100 mg/kg) p.o.
Kidney
Stomach
Gastritis
Liver
Edema
Infected cell (MNL)
Fatty change
Acute hepatitis/spotty necrosis
Cholestasis
5a
5b
5c
5d
5e
5f
5g
5h
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++
+
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
++
+
++
+++
+
ꢁ
++
++
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
++
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
+
+
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
++
ꢁ
ꢁ
+
++
ꢁ
++
+
+
ꢁ
5i
5j
ꢁ
ꢁ
+
+
Indomethacin (10 mg/kg)
Naproxen (30 mg/kg)
Phenylbutazone (100 mg/kg)
++
+
ꢁ
++
+++
ꢁ
ꢁ
ꢁ
ꢁ
+
ꢁ
ꢁ
ꢁ
ꢁ, no; +, mild; ++, moderate; +++, severe side effects.
Corcoran, T. W.; Derian, C. K.; Eckardt, A. J.; Damiano, B. P.; Andrade-Gordon, P.;
Maryanoff, B. E. J. Biol. Chem. 2005, 280, 18001.
14. Mosnaim, A. D.; Ranade, V. V.; Wolf, M. E.; Puente, J.; Antonieta Valenzuela, M.
Am. J. Ther. 2006, 13, 261.
15. Ranise, A.; Schenone, S.; Bruno, O.; Bondavalli, F.; Filippelli, W.; Falcone, G.;
Rivaldi, B. Farmaco 2001, 56, 647.
16. Ahn, K.; Johnson, D. S.; Fitzgerald, L. R.; Liimatta, M.; Arendse, A.; Stevenson, T.;
Lund, E. T.; Nugent, R. A.; Nomanbhoy, T. K.; Alexander, J. P.; Cravatt, B. F.
in the differential diagnosis of the tubulointerstitial nephritis, but
none of our samples showed interstitial suppurative (inflammation
with polymorphonuclear leukocytes) inflammation with microab-
scesses. Therefore, the renal morphologic findings reflect the ef-
fects of the compounds. Liver tissues were also examined
thoroughly and the integrity of the basic structure, degree of lobu-
lar and portal inflammation and the presence or absence of necro-
sis, fatty change or cholestasis were evaluated. NSAIDs such as
phenylbutazone33 and naproxen34 are known to cause acute or
chronic hepatitis, confluent or spotty necrosis, cholestatic hepatitis
and/or fatty change. This shows the importance of examining the
liver tissues to better assess the safety of NSAIDs. In compounds
5b, 5c, 5h, and 5j (moderate, ++) showed macro and microvesicular
fatty change and several scattered mild (+) focal spotty necrosis.
Multiple foci of spotty necrosis (moderate ++) was seen with com-
pounds 5c and 5e. Cholestatic hepatitis was observed for com-
pounds 5c and 5j (Table 2).
Biochemistry 2007,
13019.
17. Viegas, C., Jr.; Alexandre-Moreira, M. S.; Fraga, C. A.; Barreiro, E. J.; Bolzani Vda,
S.; de Miranda, A. L. Chem. Pharm. Bull. (Tokyo) 2008, 56, 407.
18. Jiri, J.; Miroslav, P.; Josef, P.; Stanislav, W.; Csech C. S., 1991, 271, 185; Chem.
Abstr. 1992, 117, 170994d.
19. Khanum, S. A.; Shashikanth, S.; Deepak, A. V. Bioorganic Chem. 2004, 32, 211.
20. Venu, T. D.; Shashikanth, S.; Khanum, S. A.; Naveen, S.; Firdouse, A.; Sridhar, M.
A.; Shashidhara Prasad, J. Bioorg. Med. Chem. 2007, 15, 3505.
21. Compound 3a: IR (Nujol): 1725 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.0 (s, 3H,
CH3), 6.9–7.3 (m, 8H, Ar-H). Anal. Calcd for C14H11BrO2 (291): C, 57.76; H, 3.81;
Br, 27.45. Found: C, 57.61; H, 3.89; Br, 27.32. Compound 3b: IR (Nujol):
1718 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.1 (s, 3H, CH3), 6.5–7.3 (m, 8H, Ar-
H). Anal. Calcd for C14H11ClO2 (246.5): C, 68.16; H, 4.49; Cl, 14.37. Found: C,
68.22; H, 4.58; Cl, 14.45. Compound 3c: IR (Nujol): 1760 cmꢁ1 (ester, C@O); 1
H
NMR (CDCl3): d 2.25 (s, 6H, 2CH3), 6.9–7.4 (m, 8H, Ar-H). Anal. Calcd for
C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.49; H, 6.15. Compound 3d: Yield
27.74 g (92%). IR (Nujol): 1770 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.3 (s, 3H,
CH3), 6.95–7.45 (m, 8H, Ar-H). Anal. Calcd for C14H11FO2 (230): C, 73.03; H,
4.82; F, 8.25. Found: C, 73.13; H, 4.75; F, 8.12. Compound 3e: IR (Nujol):
1760 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.2–2.5 (d, 6H, 2CH3), 6.95–7.43
(m, 8H, Ar-H). Anal. Calcd for C15H14O2 (226): C, 79.62; H, 6.24. Found: C,
79.51; H, 6.16. Compound 3f: IR (Nujol): 1735 cmꢁ1 (ester, C@O); 1H NMR
(CDCl3): d 2.15 (s, 3H, CH3), 6.9–7.5 (m, 7H, Ar-H). Anal. Calcd for C14H10Cl2O2
(281): C, 59.81; H, 3.59; Cl, 25.22. Found: C, 59.72; H, 3.66; Cl, 25.15. Compound
3g: IR (Nujol): 1750 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3), 3.75
(s, 3H, OCH3), 6.8–7.65 (m, 8H, Ar-H). Anal. Calcd for C15H14O3 (242): C, 74.38;
H, 5.78. Found: C, 74.34; H, 5.75. Compound 3h: IR (Nujol): 1720 cmꢁ1 (ester,
C@O); 1H NMR (CDCl3): d 2.2–2.4 (d, 6H, 2CH3), 6.85–7.5 (m, 8H, Ar-H). Anal.
Calcd for C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.44; H, 6.10. Compound
3i: IR (Nujol): 1710 cmꢁ1 (ester, C@O); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3),
6.95–7.4 (m, 8H, Ar-H). Anal. Calcd for C14H11BrO2 (291): C, 57.76; H, 3.81; Br,
27.45. Found: C, 57.59; H, 3.81; Br, 27.29. Compound 3j: IR (Nujol): 1765 cmꢁ1
(ester, C@O); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3), 6.75–7.55 (m, 9H, Ar-H). Anal.
Calcd for C14H12O2 (212): C, 79.22; H, 5.70. Found: C, 79.05; H, 5.79.
In conclusion, a new sequence of benzophenone N-ethyl piper-
idine ether analogues exhibiting anti-inflammatory activity was
synthesized. Halo compounds, with a bromo group (5a), fluoro
group (5d), and chloro group (5f), at para position showed signifi-
cant anti-inflammatory profile with low gastric ulceration inci-
dence as compared with similar toxic profiles for reference non
NSAIDs in the liver.
Acknowledgments
The authors express their sincere gratitude to the University of
Mysore, Mysore for providing laboratory facilities.
References and notes
22. Compound 4a: mp 166–168 °C; IR (Nujol): 1640 (C@O), 3515–3630 cmꢁ1 (OH);
1H NMR (CDCl3): d 2.1 (s, 3H, CH3), 6.9–7.4 (m, 7H, Ar-H), 9.0 (br s, 1H, OH); EI-
MS: m/z 290 (M+, 84), 292 (M+, 81), 289 (100), 291 (94), 135 (56), 107 (51).
Anal. Calcd for C14H11BrO2 (291): C, 57.73; H, 3.78; Br, 27.49. Found: C, 57.67;
H, 3.88; Br, 27.39. Compound 4b: mp 158–160 °C; IR (Nujol): 1660 (C@O),
3515–3625 cmꢁ1 (OH); 1H NMR (CDCl3): d 2.2 (s, 3H, CH3), 6.9–7.35 (m, 7H, Ar-
H), 9.3 (br s, 1H, OH); EI-MS: m/z 246.5 (M+, 86), 245.5 (100), 135 (57), 107
(52). Anal. Calcd for C14H11ClO2 (246.5): C, 68.15; H, 4.46; Cl, 14.40. Found: C,
68.11; H, 4.42; Cl, 14.36. Compound 4c: mp 156–158 °C; IR (Nujol): 1660
(C@O), 3520–3610 cmꢁ1 (OH); 1H NMR (CDCl3): d 2.3 (s, 6H, 2CH3), 6.95–7.65
(m, 7H, Ar-H), 9.25 (br s, 1H, OH); EI-MS: m/z 226 (M+, 87), 225 (100), 135 (56),
107 (51). Anal. Calcd for C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.75; H,
6.38. Compound 4d: mp 130–132 °C; IR (Nujol): 1670 (C@O), 3570–3665 cmꢁ1
(OH); 1H NMR (CDCl3): d 2.0 (s, 3H, CH3), 6.8–7.55 (m, 7H, Ar-H), 9.3 (br s, 1H,
OH); EI-MS: m/z 230 (M+, 79), 229 (100), 135 (60), 107 (47). Anal. Calcd for
C14H11FO2 (230): C, 73.03; H, 4.82; F, 8.25. Found: C, 73.13; H, 4.75; F, 8.32.
Compound 4e: mp 160–162 °C; IR (Nujol): 1673 (C@O), 3550–3640 cmꢁ1
(OH);1H NMR (CDCl3): d 2.2–2.45 (d, 6H, 2CH3), 6.95–7.65 (m, 7H, Ar-H), 9.1 (br
s, 1H, OH); EI-MS: m/z 226 (M+, 88), 225 (100), 135 (55), 107 (50). Anal. Calcd
for C15H14O2 (226): C, 79.62; H, 6.24. Found: C, 79.70; H, 6.35. Compound 4f:
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S. A. Khanum et al. / Bioorg. Med. Chem. Lett. 19 (2009) 1887–1891
1891
mp 128–130 °C; IR (Nujol): 1675 (C@O), 3515–3655 cmꢁ1 (OH); 1H NMR
(CDCl3): d 2.2 (s, 3H, CH3), 6.9–7.5 (m, 7H, Ar-H), 9.1 (br s, 1H, OH); EI-MS: m/z
281 (M+, 80), 280 (100), 135 (57), 107 (51). Anal. Calcd for C14H10Cl2O2 (281): C,
59.81; H, 3.59; Cl, 25.22. Found: C, 59.73; H, 3.45; Cl, 25.12. Compound 4g: mp
150–152 °C; IR (Nujol): 1665 (C@O), 3520–3640 cmꢁ1 (OH); 1H NMR (CDCl3): d
2.3 (s, 3H, CH3), 3.7 (s, 3H, OCH3), 6.8–7.5 (m, 7H, Ar-H), 9.5 (br s, 1H, OH); EI-
MS: m/z 242 (M+, 83), 241 (100), 135 (56), 107 (52). Anal. Calcd for C15H14O3
(242): C, 74.38; H, 5.78. Found: C, 74.31; H, 5.71. Compound 4h: mp 168–
170 °C; IR (Nujol): 1620 (C@O), 3560–3650 cmꢁ1 (OH); 1H NMR (CDCl3): d 2.1–
2.4 (d, 6H, 2CH3), 6.9–7.6 (m, 7H, Ar-H), 9.0 (br s, 1H, OH); EI-MS: m/z 226 (M+,
85), 225 (100), 135 (53), 107 (50). Anal. Calcd for C15H14O2 (226): C, 79.62; H,
6.24. Found: C, 79.61; H, 6.28. Compound 4i: mp 164–166 °C; IR (Nujol): 1650
(C@O), 3510–3610 cmꢁ1 (OH); 1H NMR (CDCl3): d 2.3 (s, 3H, CH3), 6.8–7.75 (m,
7H, Ar-H), 12.0 (br s, 1H, OH); EI-MS: m/z 290 (M+, 85), 292 (M+, 80), 289 (100),
291 (95), 135 (55), 107 (50). Anal. Calcd for C14H11BrO2 (291): C, 57.73; H, 3.78;
Br, 27.49. Found: C, 57.80; H, 3.69; Br, 27.41. Compound 4j: mp 138–140 °C; IR
(Nujol): 1670 (C@O), 3545–3649 cmꢁ1 (OH); 1H NMR (CDCl3): d 2.3 (s, 3H,
CH3), 6.85–7.75 (m, 8H, Ar-H), 9.05 (br s, 1H, OH); MS: m/z 212 (M+, 87), 211
(100), 135 (60), 107 (55). Anal. Calcd for C14H12O2 (212): C, 79.24; H, 5.66.
Found: C, 79.33; H, 5.58.
8.18; N, 4.26. Compound 5f: IR (Nujol): 1675 cmꢁ1 (C@O); 1H NMR (CDCl3): d
1.24–1.53 (m, 6H, ring-3CH2), 2.1 (s, 3H, CH3), 2.42 (t, 4H, ring-2NCH2), 2.85 (t,
2H, NCH2), 4.2 (t, 2H, OCH2), 6.9–7.8 (m, 6H, Ar-H); EI-MS: m/z 392 (M+, 63).
Anal. Calcd for C21H23Cl2NO2 (392): C, 64.29; H, 5.91; Cl, 18.07; N, 3.57. Found:
C, 64.15; H, 5.62; Cl, 18.16; N, 3.44. Compound 5g: IR (Nujol): 1605 cmꢁ1
(C@O); 1H NMR (CDCl3): d 1.21–1.52 (m, 6H, ring-3CH2), 2.1 (d, 6H, 2CH3), 2.45
(t, 4H, ring-2NCH2), 2.75 (t, 2H, NCH2), 3.8 (s, 3H, OCH3), 4.2 (t, 2H, OCH2),
6.95–7.75 (m, 7H, Ar-H); EI-MS: m/z 353 (M+, 59). Anal. Calcd for C22H27NO3
(353): C, 74.76; H, 7.70; N, 3.96. Found: C, 74.82; H, 7.61; N, 3.83. Compound
5h: IR (Nujol): 1610 cmꢁ1 (C@O); 1H NMR (CDCl3): d 1.24–1.54 (m, 6H, ring-
3CH2), 2.1–2.25 (d, 6H, 2CH3), 2.6 (t, 4H, ring-2NCH2), 2.85 (t, 2H, NCH2), 4.2 (t,
2H, OCH2), 6.9–7.65 (m, 7H, Ar-H); EI-MS: m/z 337 (M+, 60). Anal. Calcd for
C22H27NO2 (337): C, 78.30; H, 8.06; N, 4.15. Found: C, 78.35; H, 8.11; N, 4.21.
Compound 5i: IR (Nujol): 1620 cmꢁ1 (C@O); 1H NMR (CDCl3): d 1.25–1.55 (m,
6H, ring-3CH2), 2.1 (s, 3H, CH3), 2.36 (t, 4H, ring-2NCH2), 2.8 (t, 2H, NCH2), 4.2
(t, 2H, OCH2), 6.9–7.3 (m, 7H, Ar-H); EI-MS: m/z 403 (M+, 64) and 401 (M+, 60).
Anal. Calcd for C21H24BrNO2 (402): C, 62.69; H, 6.01; Br, 19.86; N, 3.48. Found:
C, 62.76; H, 6.15; Br, 19.63; N, 3.58. Compound 5j: IR (Nujol): 1620 cmꢁ1 (C@O);
1H NMR (CDCl3): d 1.21–1.5 (m, 6H, ring-3CH2), 2.1 (s, 3H, CH3), 2.55 (t, 4H,
ring-2NCH2), 2.8 (t, 2H, NCH2), 4.2 (t, 2H, OCH2), 6.9–7.7 (m, 8H, Ar-H); EI-MS:
m/z 337 (M+, 60). Anal. Calcd for C21H25NO2 (323): C, 77.98; H, 7.79; N, 4.33.
Found: C, 77.82; H, 7.64; N, 4.26.
23. Compound 5a: IR (Nujol): 1650 cmꢁ1 (C@O); 1H NMR (CDCl3): d 1.2–1.5 (m, 6H,
ring-3CH2), 2.0 (s, 3H, CH3), 2.35 (t, 4H, ring-2NCH2), 2.78 (t, 2H, NCH2), 4.1 (t,
2H, OCH2), 6.8–7.4 (m, 7H, Ar-H); EI-MS: m/z 403 (M+, 65) and 401 (M+, 62).
Anal. Calcd for C21H24BrNO2 (402): C, 62.69; H, 6.01; Br, 19.86; N, 3.48. Found:
C, 62.54; H, 6.21; Br, 19.69; N, 3.32. Compound 5b: IR (Nujol): 1655 cmꢁ1
(C@O); 1H NMR (CDCl3): d 1.25–1.52 (m, 6H, ring-3CH2), 2.2 (s, 3H, CH3), 2.4 (t,
4H, ring-2NCH2), 2.8 (t, 2H, NCH2), 4.15 (t, 2H, OCH2), 6.8–7.55 (m, 7H, Ar-H);
EI-MS: m/z 357.5 (M+, 63). Anal. Calcd for C21H24ClNO2 (357.5): C, 70.48; H,
6.76; Cl, 9.91; N, 3.91. Found: C, 70.37; H, 6.65; Cl, 9.82; N, 3.81. Compound 5c:
IR (Nujol): 1605 cmꢁ1 (C@O); 1H NMR (CDCl3): d 1.22–1.51 (m, 6H, ring-3CH2),
2.3 (s, 6H, 2CH3), 2.55 (t, 4H, ring-2NCH2), 2.81 (t, 2H, NCH2), 4.15 (t, 2H, OCH2),
6.8–7.65 (m, 7H, Ar-H); EI-MS: m/z 337 (M+, 60). Anal. Calcd for C22H27NO2
(337): C, 78.30; H, 8.06; N, 4.15. Found: C, 78.39; H, 8.16; N, 4.25. Compound
5d:IR (Nujol): 1655 cmꢁ1 (C@O); 1H NMR (CDCl3): d 1.2–1.5 (m, 6H, ring-
3CH2), 2.0–2.3 (d, 6H, 2CH3), 2.56 (t, 4H, ring-2NCH2), 2.85 (t, 2H, NCH2), 4.2 (t,
2H, OCH2), 6.9–7.7 (m, 7H, Ar-H); EI-MS: m/z 230 (M+, 61). Anal. Calcd for
C21H24FNO2 (341): C, 73.88; H, 7.09; F, 5.56; N, 4.10. Found: C, 73.77; H, 7.18; F,
5.42; N, 4.22. Compound 5e: IR (Nujol): 1615 cmꢁ1 (C@O); 1H NMR (CDCl3): d
1.23–1.53 (m, 6H, ring-3CH2), 2.0–2.2 (d, 6H, 2CH3), 2.5 (t, 4H, ring-2NCH2), 2.8
(t, 2H, NCH2), 4.1 (t, 2H, OCH2), 6.9–7.6 (m, 7H, Ar-H); EI-MS: m/z 337 (M+, 61).
Anal. Calcd for C22H27NO2 (337): C, 78.30; H, 8.06; N, 4.15. Found: C, 78.38; H,
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