Synthesis and biological evaluation of amide derivatives of diflunisal as potential anti-inflammatory agents

Article abstract of DOI:10.1016/j.bmcl.2008.11.035

To improve the medicinal activity, the structure of diflunisal has been modified. Twenty-one amide derivatives of diflunisal were synthesized starting from diflunisal in three steps with total yields from 72% to 89%. All compounds were identified by ¹H NMR, MS, and elemental analysis. The anti-inflammatory and analgesic activities for 19 compounds were evaluated. It was found that 5m possesses an excellent anti-inflammatory activity and a good analgesic activity, maybe a potential anti-inflammatory agent.

Full text of DOI:10.1016/j.bmcl.2008.11.035

Bioorganic & Medicinal Chemistry Letters 19 (2009) 516–519
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and biological evaluation of amide derivatives of diflunisal
as potential anti-inflammatory agents
*
Guang-Xiang Zhong , Jin-Qing Hu, Kun Zhao, Lu-Lu Chen, Wei-Xiao Hu, Ming-You Qiu
College of Pharmaceutical Science, Zhejiang University of Technology, 18, Chaowang Road, Hangzhou, Zhejiang 310032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 July 2008
Revised 2 November 2008
Accepted 11 November 2008
Available online 14 November 2008
To improve the medicinal activity, the structure of diflunisal has been modified. Twenty-one amide deriv-
atives of diflunisal were synthesized starting from diflunisal in three steps with total yields from 72% to
89%. All compounds were identified by 1H NMR, MS, and elemental analysis. The anti-inflammatory and
analgesic activities for 19 compounds were evaluated. It was found that 5m possesses an excellent anti-
inflammatory activity and a good analgesic activity, maybe a potential anti-inflammatory agent.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Diflunisal
Amide derivative
Anti-inflammatory and analgesic activity
Fluorine-containing non-steroid anti-inflammatory drugs have
been attractive for their special properties.1–3 Diflunisal (1, CAS
22494-42-4), 20,40-difluoro-4-hydroxybiphenyl-3-carboxylic acid,
has been approved worldwide as therapeutics for the treatment
of inflammation and pain.4,5 Recently, the modifications of the
chemical structure of 1 were studied. For example, 3-(1,3-dihy-
same way when 3a (R = CH3) was reacted with a secondary amine
in amidation, such as dimethylamine, diethylamine, N-methylpi-
perazine or N-ethylpiperazine, because the four secondary amines
are stronger alkaline and promoted the hydrolyzation of acetates.
The 21 amides were synthesized from 72% to 89% in total yield.
The synthetic route is shown in Scheme 1. Starting from 1, esteri-
fication of phenolic hydroxy group and amidation of carboxylic
acid gave desired product 5. The preparations are summarized in
Table 1. The structures of all compounds were identified by IR,
1H NMR, MS, and elemental analysis (Table 2).12,13 The crystal
structure of 5a was determined by X-ray.14
dro-2H-isoindol-2-ylcarbonyl)-20,40-difluorobiphenyl-4-ol
was
synthesized and reported to have the H3P-90 inhibition, and
H3P-90 in abnormal cells, such as in cancer cells would damage
the regulation of signal transduction network.6 Yu reported that
esterification or amidation of 1 could increase their solubility and
absorption in vivo, and some of them have even better analgesic
activity than that of dilunisal.7 Some changes in the carboxyl group
of 1 also showed good antimycobacterial, antiviral and antimicro-
bial activities.8 Roberts found that O-aryl esters of 1, especially
lipophilic esters, possess large permeability surface area and tissue
distribution value.9
Our group have studied the synthesis and the SAR of fluorine-
containing non-steroid anti-inflammatory drugs, and patented that
some amides of fluorine-containing benzoic acid possessed good
anti-inflammatory activity.10,11
In continuation of our research, the modification of diflunisal
was studied by esterification of the hydroxyl group and amidation
of the carboxylic group. We designed and synthesized 17 amide
derivatives of O-acetyldiflunisal or O-benzoyldiflunisal, 5a–5q,
and evaluated their anti-inflammatory and analgesic activity. Acci-
dentally, four amide derivatives of 1, 5r–5u, were obtained in the
The anti-inflammatory and analgesic activities for these com-
pounds (2, 5a–5q) were evaluated by xylene induced mice ear ede-
ma and acetic acid induced mice writhing models for male and
female Kunming mice (weight 20–26 g). The substances were
administrated via the oral route at the dose of 40 mg kgꢀ1. The diflu-
nisal, a registered anti-inflammatory drug, ED50 59.6 mg kgꢀ1 on
carragegenin-induced paw edema in rats,15,16 was used as a positive
control. The results of the evaluation of anti-inflammatory and anal-
gesic activity are summarized on Table 3. The ED50 on active com-
pounds was determined and the results were listed in Table 4. The
ED50 for 5m and 5p on xylene induced mice ear edema model is
24.24 and 25.69 mg kgꢀ1 and for 5m and 5q on acetic acid induced
mice writhing model is 43.79 and 11.58 mg kgꢀ1
.
From Table 3, it could be found that the inhibition on xylene in-
duced mice ear edema model of 5m, 5p, 5a, and 5i is 68.86%,
65.20%, 48.83%, and 41.37% relatively, superior to diflunisal
39.85% at the dose of 40 mg kgꢀ1. Comparing 2b, 5m, 5n, and 5o
with 2a, 5a, 5e, and 5f relatively, the biological activity of 5m is
superior to 5a in both anti-inflammatory and analgesic activity
* Corresponding author. Tel.: +86 571 88320722; fax: +86 571 88320557.
E-mail address: drzhonggx@sohu.com (G.-X. Zhong).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.11.035

G.-X. Zhong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 516–519
517
O
O
F
OH
O
F
OH
OH
RCOCl
SOCl2
F
F
pyridine
R
CH2Cl2
O
2
1
R2
R3
O
O
F
N
O
F
Cl
O
CH2Cl2
F
F
R1
R2 R3
N
R
O
H
5
3
4
Scheme 1. Route of synthesis.
and others are nearly equal to each partner. Therefore, the com-
pound containing O-benzoyl group may have a good biological
activity.
Table 1
Synthesis of compounds (5)
Compound R1
R2
R3
Yield (%) Mp (°C)
Additionally, it indicates that the substituted groups on amide
could affect the anti-inflammatory activity. It was found that the
alkyl group benefits as increase as following: CH3 > CH2C6H5 >
CH2CH3, and the aryl group are more complex. It was discovered
that the compounds with such electron-donating group (CH3
group) seems to benefit as increase as following: para > ortho > me-
ta, and the compounds with electro-withdrawing group (Cl group)
is ortho > para. But it needs more data to find the relationship.
From Table 3, it could also be found that the inhibition on acetic
acid induced mice writhing model of 5q and 5m is 88.33% and
47.50% at the dose of 40 mg kgꢀ1. Additionally, it indicates that
the substituted groups on amide could also affect the analgesic
activity and the compound with hetero-atom on amide group is
better than others in analgesic activity. The effect of substituted
group on the analgesic activity seems more complex than on the
anti-inflammatory activity.
5a
5b
5c
5d
5e
5f
5g
5h
5i
COCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH2CH3
81
77
73
81
87
85
81
89
84
84
81
76
75
84
86
72
157–160
110–112
159–162
134–136
152–155
166–169
123–125
164–167
159–163
183–186
109–112
124–126
147–150
139–140
165–168
125–128
154–157
123–125
139–141
95–97
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COCH3
COC6H5
COC6H5
COC6H5
COC6H5 CH2CH3 CH2CH3
COC6H5
H
H
H
H
Cyclohexyl
CH2C6H5
C6H5
o-C6H4CH3
m-C6H4CH3
p-C6H4CH3
o-C6H4Cl
p-C6H4Cl
2,5-(CH3)2C6H3
Morpholine-4-yl
CH3
C6H5
o-C6H4CH3
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
4-Methylpiperazin-1-yl 83
CH3
CH3
76
73
CH2CH3 CH2CH3
On the whole, it seems a trend that the substituted groups on
the either amide or ester could affect on the inflammatory activity
4-Methylpiperazin-1-yl 74
4-Ethylpiperazin-1-yl 77
5u
142–143
Table 2
Elemental analysis (calcd data in parentheses) and 1H NMR data (in CDCl3) of new compounds
Compound
Elemental analysis (%)
1H NMR (d, ppm)
C
H
N
5a
5b
5c
62.86
4.36
4.49
2.36 (s, 3H, COCH3), 2.99 (d, 3H, J = 4.8 Hz, N-CH3), 6.25 (s, 1H, –NH), 6.94 (m, 2H, 30,50-CH), 7.18 (d, 1H, J = 8.4 Hz, 5-CH), 7.40 (q, 1H,
(62.95) (4.29) (4.59) J = 7.6 Hz, 60-CH), 7.59 (d, 1H, J = 8.4 Hz, 6-CH), 7.84 (s, 1H, 2-CH)
63.83
4.82
4.31
1.24 (t, 3H, J = 7.2 Hz, –CH3), 2.34 (s, 3H, –COCH3), 3.47 (m, 2H, –CH2), 6.25 (s, 1H, –NH), 6.94 (m, 2H, 30,50-CH), 7.17 (d, 1H, J = 8.4 Hz,
(63.95) (4.74) (4.39) 5-CH), 7.40 (q, 1H, J = 7.6 Hz, 60-CH), 7.59 (d, 1H, J = 8.4 Hz, 6-CH), 7.84 (s, 1H, 2-CH)
67.43
5.73
3.67
1.24 (m, 3H, 300,400,500-CH), 1.44 (q, 2H, J = 5.0 Hz, 300,500-CH), 1.66 (m, 1H, 400-CH), 1.74 (m, 2H, 200,600-CH), 2.02 (m, 2H, 200,600-CH), 2.36
(67.55) (5.67) (3.75) (s, 3H, ꢀCH3), 3.96 (m, 1H, 100-CH), 6.13 (d, 1H, J = 7.5 Hz, –NH), 6.92 (t, 1H, J = 8.5 Hz, 30-CH), 6.96 (d, 1H, J = 8.0 Hz, 50-CH), 7.16 (d,
1H, J = 8.5 Hz, 5-CH), 7.41 (q, 1H, J = 8.0 Hz, 60-CH), 7.58 (d, 1H, J = 8.5 Hz, 6-CH), 7.84 (s, 1H, 2-CH)
2.08 (s, 3H, –CH3), 4.61 (d, 2H, J = 5.5 Hz, –CH2), 6.63 (s, 1H, N-H), 6.92 (t, 1H, J = 8.5 Hz, 30-CH), 6.97 (d, 1H, J = 8.0 Hz, 50-CH), 7.16 (d,
5d
5e
5f
69.22
(69.29) (4.49) (3.67) 1H, J = 8.5 Hz, 5-CH), 7.35 (q, 1H, J = 8.5 Hz, 60-CH), 7.38 (m, 5H, –C6H5), 7.59 (s, 1H, 2-CH), 7.94 (d, 1H, J = 8.4 Hz, 6-CH)
68.60 4.19 3.75
2.37 (s, 3H, –CH3), 6.94 (m, 2H, 30,50-CH), 7.17 (d, 1H, J = 8.0 Hz, 5-CH), 7.25 (q, 1H, J = 8.0 Hz, 400-CH), 7.40 (m, 3H, 60,300,500-CH), 7.64
(68.66) (4.12) (3.81) (m, 3H, 6, 200,600-CH), 7.98 (s, 1H, 2-CH), 8.07 (s, 1H, –NH)
69.23 4.54 3.60
4.55
3.56
2.34 (s, 3H, –CH3), 2.37 (s, 3H, –CH3), 6.95 (t, 1H, J = 8.5 Hz, 30-CH), 7.00 (d, 1H, J = 8.0 Hz, 50-CH), 7.15 (t, 1H, J = 7.5 Hz, 400-CH), 7.25
(69.29) (4.49) (3.67) (d, 1H, J = 7.5 Hz, 5-CH), 7.27 (d, 1H, J = 8.5 Hz, 600-CH), 7.28 (t, 1H, J = 8.5 Hz, 500-CH), 7.46 (q, 1H, J = 8.0 Hz, 60-CH), 7.67 (d, 1H,
J = 8.5 Hz, 300-CH), 7.83 (s, 1H, 2-CH), 7.95 (d, 1H, J = 7.5 Hz, 6-CH), 8.00 (s, 1H, –NH)
2.36 (s, 3H, –CH3), 2.37 (s, 3H, –CH3), 6.95 (m, 2H, 30,50-CH), 6.99 (d, 1H, J = 7.6 Hz, 400-CH), 7.24 (d, 1H, J = 8.0 Hz, 5-CH), 7.27 (t, 1H,
5g
5h
69.23
4.55
3.58
(69.29) (4.49) (3.67) J = 7.6 Hz, 400-CH), 7.36 (d, 1H, J = 7.6 Hz, 600-CH), 7.43 (q, 1H, J = 7.6 Hz, 60-CH), 7.51 (s, 1H, 200-CH), 7.65 (d, 1H, J = 8.4 Hz, 6-CH), 7.97
(s, 1H, 2-CH), 8.01 (s, 1H, –NH)
69.21
(69.29) (4.49) (3.67) 1H, J = 7.6 Hz, 60-CH), 7.51 (d, 2H, J = 8.0 Hz, 200,600-CH), 7.65 (d, 1H, J = 8.4 Hz, 6-CH), 7.99 (s, 1H, 2-CH), 8.01 (s, 1H, –NH)
(continued on next page)
4.54
3.61
2.36 (s, 3H, –CH3), 2.38 (s, 3H, –CH3), 6.95 (m, 2H, 30,50-CH), 7.19 (d, 2H, J = 7.6 Hz, 300,500-CH), 7.25 (d, 1H, J = 8.0 Hz, 5-CH), 7.43 (q,

518
G.-X. Zhong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 516–519
Table 2 (continued)
Compound
Elemental analysis (%)
1H NMR (d, ppm)
C
H
N
5i
62.70
3.56
3.43
2.41 (s, 3H, –CH3), 6.96 (m, 2H, 30,50-CH), 7.10 (t, 1H, J = 7.6 Hz, 400-CH), 7.28 (d, 1H, J = 8.0 Hz, 5-CH), 7.34 (t, 1H, J = 8.0 Hz, 500-CH),
(62.78) (3.51) (3.49) 7.44 (m, 2H, J = 8.0 Hz, 60,300-CH), 7.68 (d, 1H, J = 8.4 Hz, 6-CH), 8.10 (s, 1H, 2-CH), 8.58 (d, 1H, J = 8.4 Hz, 600-CH), 8.78 (s, 1H, –NH)
5j
62.71
3.57
3.42
2.36 (s, 3H, –CH3), 6.95 (m, 2H, 30,50-CH), 7.25 (d, 1H, J = 8.0 Hz, 5-CH), 7.34 (d, 2H, J = 8.4 Hz, 300,500-CH), 7.43 (q, 1H, J = 8.0 Hz, 60-
(62.78) (3.51) (3.49) CH), 7.57 (d, 2H, J = 8.4 Hz, 200,600-CH), 7.66 (d, 1H, J = 8.0 Hz, 6-CH), 7.97 (s, 1H, 2-CH), 8.06 (s, 1H, –NH)
5k
69.78
4.92
3.43
2.29 (s, 3H, CO-CH3), 2.37 (s, 6H, Ph-CH3), 6.94 (d, 1H, J = 8.5 Hz, 30-CH), 6.96 (d, 1H, J = 8.0 Hz, 400-CH), 7.00 (d, 1H, J = 8.0 Hz, 50-CH),
(69.87) (4.84) (3.54) 7.13 (d, 1H, J = 8.0 Hz, 300 –CH), 7.26 (d, 1H, J = 8.5 Hz, 5-CH), 7.46 (q, 1H, J = 8.0 Hz, 60-CH), 7.67 (d, 1H, J = 8.0 Hz, 6-CH), 7.79 (s, 2H,
2,600-CH), 8.00 (s, 1H, –NH)
5l
63.04
4.83
3.79
2.32 (s, 3H, –CH3), 3.40 (t, 2H, J = 5.0 Hz, 200,600-CH), 3.63 (t, 2H, J = 5.0 Hz, 200,600-CH), 3.75 (m, 4H, 300,500-CH2), 6.92 (t, 1H, J = 8.5 Hz,
(63.15) (4.74) (3.88) 30-CH), 6.97 (d, 1H, J = 8.0 Hz, 50-CH), 7.26 (d, 1H, J = 8.5 Hz, 5-CH), 7.36 (q, 1H, J = 8.0 Hz, 60-CH), 7.43 (s, 1H, 2-CH), 7.55 (d, 1H,
J = 8.5 Hz, 6-CH)
5m
5n
5o
68.49
4.14
3.70
2.89 (d, 3H, J = 4.8 Hz, CH3), 6.36 (s, 1H, NH), 6.94 (t, 1H, J = 8.4 Hz, 30-H), 7.00 (t, 1H, J = 8.2 Hz, 50-H), 7.31 (d, 1H, J = 8.4 Hz, 5-H),
(68.66) (4.12) (3.81) 7.45 (q, 1H, J = 7.6 Hz, 7.56 (t, 2H, J = 7.6 Hz, 300,500-H), 7.65 (d, 1H, J = 8.4 Hz, 6-H), 7.69 (t, 1H, J = 7.6 Hz, 400-H), 7.94 (s, 1H, 2-H), 8.27
(d, 2H, J = 6.8 Hz, 200,600-H)
72.59
4.01
3.19
6.96 (t, 1H, J = 8.4 Hz, 30-H), 7.00 (t, 1H, J = 8.4 Hz, 50-H), 7.08 (t, 1H, J = 7.6 Hz, 4000-H), 7.26 (t, 2H, J = 8.0 Hz, 3000,5000-H), 7.37 (d, 1H,
(72.72) (3.99) (3.26) J = 8.0 Hz, 5-H), 7.45 (d, 2H, J = 7.6 Hz, 2000,6000-H), 7.47 (q, 1H, J = 8.0 Hz, 60-CH), 7.55 (t, 2H, J = 7.6 Hz, 300,500-H), 7.69 (t, 1H, J = 7.6 Hz,
400-H), 7.72 (d, 1H, J = 8.0 Hz, 6-H), 8.10 (s, 1H, 2-H), 8.23 (s, 1H, NH), 8.24 (d, 2H, J = 7.2 Hz, 200,600-H)
73.27
4.40
3.13
2.18 (s, 3H, CH3), 6.96 (t, J = 8.4 Hz, 1H, 30-H), 7.00 (t, 1H, J = 8.0 Hz, 50-H), 7.07 (t, 1H, J = 7.2 Hz, 4000-H), 7.14 (d, 1H, J = 7.6 Hz, 3000-H),
(73.13) (4.32) (3.16) 7.20 (t, 1H, J = 6.8 Hz, 5000-H), 7.36 (d, 1H, J = 8.4 Hz, 5-H), 7.48 (q, 1H, J = 8.0 Hz, 60-CH), 7.53 (t, 2H, J = 7.6 Hz, 300,500-H), 7.68 (t, 1H,
J = 7.6 Hz, 400-H), 7.72 (d, 1H, J = 8.4 Hz, 6-H), 7.85 (d, 1H, J = 8.4 Hz, 6000-H), 7.90 (s, 1H, –NH), 8.09 (s, 1H, 2-H), 8.22 (d, 2H, J = 7.2 Hz,
200,600-H)
5p
5q
70.48
5.08
3.30
1.02, 1.08 (t, t, 6H, J = 7.2 Hz, CH3), 3.24 (m, 4H, CH2), 6.94 (t, 1H, J = 8.4 Hz, 30-H), 6.98 (t, 1H, J = 8.4 Hz, 50-H), 7.43 (d, 1H, J = 8.4 Hz,
(70.41) (5.17) (3.42) 5-H), 7.43 (q, 1H, J = 8.0 Hz, 60-CH), 7.50 (t, 3H, J = 7.6 Hz, 2,300,500-H), 7.58 (d, 1H, J = 8.0 Hz, 6-H), 7.64 (t, 1H, J = 8.0 Hz, 400-H), 8.18 (d,
2H, J = 7.2 Hz, 200,600-H)
66.37
5.30
9.16
2.20 (s, 3H, –CH3), 2.28 (t, 4H, J = 4.2 Hz, 3000-CH2), 3.38, 3.720 (t, t, 4H, J = 4.8 Hz, 2000-CH2), 6.94 (t, 1H, J = 8.0 Hz, 30-H), 6.97 (t, 1H,
(66.51) (5.13) (9.31) J = 8.0 Hz, 50-H), 7.42 (d, 1H, J = 8.4 Hz, 5-H), 7.42 (q, 1H, J = 8.0 Hz, 60-H), 7.49 (s, 1H, 2-H), 7.51 (t, 2H, J = 8.0 Hz, 300,500-H), 7.60 (d,
1H, J = 8.0 Hz, 6-H), 7.65 (t, 1H, J = 7.6 Hz, 400-H), 8.18 (d, 2H, J = 8.0, 200-H);
3.21 (s, 6H, N-CH3), 6.93 (t, 1H, J = 8.5 Hz, 30-CH), 6.95 (d, 1H, J = 8.5 Hz, 50-CH), 7.10 (d, 1H, J = 8.5 Hz, 5-CH), 7.36 (q, 1H, J = 8.0 Hz,
5r
5s
5t
64.92
(64.98) (4.73) (5.05) 60-CH), 7.46 (d, 1H, J = 8.5 Hz, 6-CH), 7.50 (s, 1H, 2-CH), 10.08 (s, 1H, OH)
66.80 5.69 4.52
1.31 (t, 6H, J = 7.0 Hz, –CH3), 3.59 (q, 4H, J = 7.0 Hz, N-CH2), 6.92 (t, 1H, J = 8.5 Hz, 30-CH), 6.96 (d, 1H, J = 8.0 Hz, 50-CH), 7.10 (d, 1H,
(66.87) (5.61) (4.59) J = 8.5 Hz, 5-CH), 7.36 (q, 1H, J = 8.0 Hz, 60-CH), 7.45 (d, 1H, J = 8.5 Hz, 6-CH), 7.49 (s, 1H, 2-CH), 10.08 (s, 1H, OH)
4.78
4.97
64.98
5.56
8.38
2.35 (s, 3H, –CH3), 2.50 (t, 4H, J = 5.0 Hz, 300,500-CH2), 3.80 (t, 4H, J = 5.0 Hz, 200,600-CH2), 6.92 (t, 1H, J = 8.5 Hz, 30-CH), 6.96 (d, 1H,
(65.05) (5.46) (8.43) J = 8.0 Hz, 50-CH), 7.09 (d, 1H, J = 8.5 Hz, 5-CH), 7.36 (q, 1H, J = 8.5 Hz, 60-CH), 7.43 (s, 1H, 2-CH), 7.47 (d, 1H, J = 8.5 Hz, 6-CH), 9.74 (s,
1H, OH)
5u
65.81
5.91
8.02
1.12 (t, 3H, J = 7.0 Hz, –CH3), 2.48 (q, 2H, J = 7.0 Hz, –CH2), 2.53 (t, 4H, J = 5.0 Hz, 300,500-CH2), 3.81 (t, 4H, J = 5.0 Hz, 200,600-CH2), 6.92 (t,
(65.88) (5.82) (8.09) 1H, J = 8.5 Hz, 30-CH), 6.96 (d, 1H, J = 8.0 Hz, 50-CH), 7.09 (d, 1H, J = 8.5 Hz, 5-CH), 7.35 (q, 1H, J = 8.5 Hz, 60-CH), 7.44 (s, 1H, 2-CH),
7.45 (d, 1H, J = 8.5 Hz, 6-CH), 9.79 (s, 1H, OH)
Table 4
Table 3
The ED50 of compound 5m, 5p, and 5q
The anti-inflammatory and analgesic activities of compounds
Compound
Test model
ED50/(mg kgꢀ1
)
Compound
The inhibitory effect on xylene
induced mice ear edema
The inhibitory effect on acetic
acid induced mice writhing
5m
5p
5m
5q
On xylene induced mice ear edema
On xylene induced mice ear edema
On acetic acid induced mice writhing
On acetic acid induced mice writhing
24.24
25.69
43.79
11.58
Dose/(mg kgꢀ1
)
Inhibition/%
Dose/(mg kgꢀ1
)
Inhibition/%
2a
2b
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
1
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
13.65
16.06
48.83
5.38
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
0
7.97
29.87
23.86
15.63
16.58
8.90
12.30
18.96
30.96
11.74
29.87
13.20
28.52
47.50
5.57
0
Acknowledgments
34.12
23.16
19.58
12.78
36.40
41.37
0
The authors thank the Opening Foundation of the Biochemical
Engineering Key Discipline (20050105), Zhejiang, China, for finan-
cial support and the National Center for Drug Screening, Shanghai,
China, for evaluation of anti-inflammatory and analgesic activity.
22.03
0
References and notes
68.86
19.79
21.40
65.20
27.47
39.85
1. Fujisawa, H.; Fujiwara, T.; Takeuchi, Y.; Omata, K. Chem. Pharm. Bull. 2005, 53,
524.
2. Bilecen, D.; Schulte, A. C.; Kaspar, A.; Kustermann, E.; Seelig, J.; Elverfeldt, D. V.;
Scheffler, K. NMR Biomed. 2003, 16, 144.
3. Betageri, G. V.; Nayernama, A.; Habib, M. J. Int. J. Pharm. Adv. 1996, 1, 310;
Betageri, G. V.; Nayernama, A.; Habib, M. J. Chem. Abstr. 1995, 124, 193178.
4. Green, N. S.; Palaninathan, S. K.; Sacchettini, J. C.; Kelly, J. W. J. Am. Chem. Soc.
2003, 125, 13404.
20.79
0
88.33
8.33
5. Adamski-werner, S. L.; Palaninathan, S. K.; Sacchettini, J. C.; Kelly, J. W. J. Med.
Chem. 2004, 47, 355.
6. Funk, L. A.; Mary, M. C.; Kung, P. P.; Meng, J. J.; Zhou, J. Z. WO Patent
2006,117,669, 2006.
7. Yu, C. X.; Xu, L. WO Patent 2008,012,603, 2008.
8. Kucukguzel, G.; Kocatepe, A.; Clercq, E. D.; Sahin, F.; Gulluce, M. Eur. J. Med.
Chem. 2006, 41, 353.
and analgesic activity. So these results will provide a good idea to
design and research the SAR in the future.
Fortunately, because of possessing an excellent anti-inflamma-
tory activity and a good analgesic activity, 5m may be a potential
anti-inflammatory agent.

G.-X. Zhong et al. / Bioorg. Med. Chem. Lett. 19 (2009) 516–519
519
9. Hung, D. Y.; Mellick, G. D.; Anissimov, Y. G.; Weiss, M.; Roberts, M. S. J. Pharm.
Sci. 1998, 87, 943.
10. Zhong, G. X.; Zhao, K. CN Patent 101,029,010A, 2007.
(17). Compound 5d: IR (KBr, cmꢀ1): 3069, 2863, 1765, 1634, 865, 833; MS m/z:
381 [M]+ (3), 339 (77), 232 (18), 204 (10), 175 (11), 151 (5), 106 (18), 91 (100).
Compound 5e: MS m/z: 367 [M]+ (4), 325 (32), 233 (39), 232 (12), 204 (8), 175
(16), 151 (10), 93 (100). Compound 5f: IR (KBr, cmꢀ1): 3204, 2860, 1760, 1640,
875, 846; MS m/z: 381 [M]+ (2), 339 (27), 233 (28), 204 (4), 177 (10), 175 (7),
151 (7), 107 (100). Compound 5g: MS m/z: 381 [M]+ (3), 339 (16), 233 (21), 204
(5), 177 (6), 175 (6), 151 (5), 107 (100). Compound 5h: MS m/z: 381 [M]+ (4),
339 (15), 233 (25), 204 (4), 177 (6), 175 (5), 151 (5), 107 (100). Compound 5i:
MS m/z: 401 [M]+ (2), 359 (35), 233 (66), 232 (39), 204 (16), 175 (26), 151 (18),
127 (100). Compound 5j: MS m/z: 401 [M]+ (2), 359 (22), 233 (63), 232 (14),
204 (8), 175 (16), 151 (10), 127 (100). Compound 5k: IR (KBr, cmꢀ1): 3199,
2860, 1763, 1641, 864, 857; MS m/z: 395 [M]+ (4), 353 (29), 233 (34), 204 (4),
177 (11), 175 (8), 151 (8), 121 (100). Compound 5l: IR (KBr, cmꢀ1): 2858, 1762,
1639, 1613, 1255, 847, 807; MS m/z: 361 [M]+ (3), 319 (98), 275 (35), 233
(100), 204 (18), 175 (29), 151 (23), 86 (81). Compound 5m: IR (KBr, cmꢀ1):
3392, 1719, 1665, 1611, 1481, 1272, 1213, 709; MS m/z: 367 [M]+ (2), 245
(123), 232 (2), 204 (2), 175 (4), 151 (2), 105 (100), 77 (24). Compound 5n: IR
(KBr, cmꢀ1): 3335, 1745, 1647,1597, 1442, 1265, 1200, 707; MS m/z: 429 [M]+
(1), 337 (4), 307 (5), 232 (2), 180 (5), 106 (8), 105 (100), 77 (23). Compound 5o:
IR (KBr, cmꢀ1): 3445, 1736, 1644), 1602, 1487, 1272, 1213, 706; MS m/z: 443
[M]+ (1), 337 (3), 321 (5), 194 (3), 175 (3), 106 (10), 105 (100), 77 (40).
Compound 5p: IR (KBr, cmꢀ1): 1739, 1633, 1471, 1266, 1211, 710; MS m/z: 409
[M]+ (5), 337 (2), 175 (4), 151 (2), 106 (8), 105 (100), 77 (20), 72 (18).
Compound 5q: IR (KBr, cmꢀ1): 1735, 1634, 1462, 1260, 1208, 708; MS m/z: 436
[M]+ (7), 379 (54), 337 (7), 233 (8), 175 (6), 106 (8), 105 (100), 77 (39).
Compound 5r: MS m/z: 277 [M]+ (100), 276 (30), 233 (56), 232 (82), 204 (27),
175 (30), 151 (23), 44 (37). Compound 5s: MS m/z: 305 [M]+ (65), 304 (43), 232
(57), 204 (21), 175 (23), 151 (33), 72 (100), 58 (76). Compound 5t: MS m/z: 332
[M]+ (33), 275 (7), 233 (18), 204 (5), 151 (11), 99 (22), 83 (18), 70 (100).
Compound 5u: MS m/z: 346 [M]+ (39), 275 (9), 233 (33), 204 (6), 175 (8), 151
(15), 99 (19), 84 (100).
11. Zhong, G. X.; Zhao, K. CN Patent 101,033,198A, 2007.
12. All the chemicals and solvents were analytical reagent and used as received,
unless otherwise stated. Melting points were taken on XRC-1 apparatus and
are uncorrected. IR spectra were measured on a Bio-Rad FTS-40 spectrometer
(KBr); 1H NMR spectra were recorded on
a Brucker AC-80 spectrometer
(400 MHz) or a Brucker AC-100 spectrometer (500 MHz) using TMS as the
internal standard in CDCl3. MS spectra were run on an HP5989B instrument.
13. General procedure for the synthesis of compound 5.A solution of diflunisal 1 (1
equiv) and pyridine (2 equiv) in CHCl3 was stirred for 30 min to protect the
carboxyl group by forming a salt (mp 126–129 °C after being separated). To
this reaction mixture was added dropwise a solution of RCOCl (1 equiv) in
chloroform at room temperature, and the reaction was allowed to processed
with stirring for an additional about 3 h (monitored by TLC). After that 1 M HCl
was used to precipitate, filtrate, wash and dry to afford compound 2. It was
observed that insufficient amount of pyridine would decrease the yield.
Compound 2a (R = CH3): yield 98%, white crystalline solid, mp 161–165 °C; MS
m/z: 292 [M]+ (2), 250 (49), 232 (100), 204 (27), 175 (23), 156 (7). Compounds
2b (R = C6H5): yield 95%, white crystalline solid, mp 167–172 °C; IR (KBr,
cmꢀ1): 3444, 1738, 1689, 1267, 1210, 706; 1H NMR (500 MHz, CDCl3): d (ppm):
6.96 (t, 1H, J = 8.0 Hz, 30-H), 7.00 (t, 1H, J = 8.0 Hz, 50-H), 7.35 (d, 1H, J = 7.5 Hz,
5-H), 7.46 (q, 1H, J = 8.0 Hz, 60-H), 7.50 (t, 2H, J = 8.0 Hz, 300,500-H), 7.65 (t, 1H,
J = 7.6 Hz, 400-H), 7.80 (d, 1H, J = 8.0 Hz, 6-H), 8.21 (d, 2H, J = 7.5 Hz, 200,600-H),
8.25 (s, 1H, 2-H), 11.24 (s, 1H, –COOH); MS m/z: 354 [M]+ (2), 232 (20), 175 (4),
151 (2), 122 (4), 105 (100), 77 (29), 51 (5).A mixture of compound 2 and SOCl2
(2 equiv) in CH2Cl2 was refluxed for 4 h prior to work up to give compound 3.
The compounds 5 were prepared by reaction of 3 (1 equiv) with substituted
amines 4 (2 equiv) in CH2Cl2 at room temperature for 3 h, in 72–89% total
yields based on the diflunisal. Compound 5a: MS m/z: 305 [M]+ (2), 263 (77),
245 (22), 233 (23), 232 (100), 204 (24), 175 (21), 151 (9). Compound 5b: MS m/
z: 319 [M]+ (3), 277 (73), 259 (20), 233 (28), 232 (100), 204 (17), 175 (17), 151
(6). Compound 5c: IR (KBr, cmꢀ1): 3069, 2937, 2852, 1767, 1633, 846, 818; MS
m/z: 373 [M]+ (5), 332 (15), 249 (28), 232 (100), 204 (16), 175 (18), 151 (12), 98
14. Zhong, G. X.; Li, J.; Zheng, R. H.; Zhao, K. Acta Crystallogr. E 2007, 63, o4583.
15. Brooks, R. R.; Bonk, K. R.; Decker, G. E.; Miller, K. E. Agents Actions 1985, 16, 369.
16. Graziella, B. EP Patent 0,126,287, 1984.