Synthesis and anti-inflammatory activity of resveratrol analogs

Article abstract of DOI:10.1248/cpb.53.1587

Seventeen novel resveratrol derivatives were synthesized. Their anti-inflammatory activities were tested on xylene-induced mouse ear edema. The pharmacological results showed that some compounds have potent anti-inflammatory activities.

Full text of DOI:10.1248/cpb.53.1587

December 2005
Notes
Chem. Pharm. Bull. 53(12) 1587—1590 (2005)
1587
Synthesis and Anti-inflammatory Activity of Resveratrol Analogs
a
Guoliang CHEN, ,a Wei SHAN,a Yingliang WU,b Lixiang REN,b Jinhua DONG,a and Zhizhong JI
*
a Pharmaceutical Engineering Department, Shenyang Pharmaceutical University; and b School of Pharmacy, Shenyang
Pharmaceutical University; No103, Wenhua Road, Shenyang, 110016, P.R. China.
Received June 8, 2005; accepted September 14, 2005
Seventeen novel resveratrol derivatives were synthesized. Their anti-inflammatory activities were tested on
xylene-induced mouse ear edema. The pharmacological results showed that some compounds have potent anti-
inflammatory activities.
Key words resveratrol; analogue; synthesis; anti-inflammatory activity
Resveratrol (3,4ꢀ,5-trihydroxystilbene) is a phytoalexin maic mice according to the method described by Xu
found in grapes and certain other plants. In recent years, Shuyun.9) The results were summarized in Table 2.
there have been a large of reports about resveratrol and it ex-
At the tested doses, resveratrol was the most active com-
hibits a variety of useful bioactivities including anti-inflam- pounds inhibiting the edematous response by 38.9%. Target
matory, cancer chempreventive, antiplatelet aggregation, an- compound 9c showed almost the same inhibition rate as
tioxidative and antibacterial activities.1—4)
resveratrol by 37.0%. The other compounds (9d, 11b, 12c)
In past years, resveratrol and some its analogs were syn- showed an edema reduction ranging from 30 to 35%. As ex-
thesized.5—8) This intrigued us to prepare its analoges and pected, the reference NSAID Ibuprofen provoked 42.2%
their derivatives and investigate their bioactivities. In order to edema reduction. The pharmacological tests showed that
increase its stability and water-solubility, we designed and resveratrol pyridyl-substituted analogs and the Mannich base
synthesized some analogues of resveratrol by substituting have potent anti-inflammatory activity.
one of two benzenes with pyridyl and their Mannich base and
Experimental
phenoxy acetic acid derivatives of phenol, and tested their
anti-inflammatory activity in mice in order to find new potent
anti-inflammatory agents.
General Except where indicated, materials and reagents were used as
supplied by the manufacturer. Melting points were determined with Yanaco
micro melting point apparatus and were not corrected. NMR spectra were
recorded at 300 MHz using Bruker ARX-300 instrument with TMS as inter-
nal reference. Mass spectra (ESI-MS) were measured on Agilent 1100 Se-
ries MSD Trap (SL). Element analysis was performed using a Vario EL ap-
paratus.
Methyl 3,5-Dimethoxybenzoate (2a) To a well-stirred suspension of
3,5-dihydroxybenzoic acid (7.70 g, 0.05 mol) and freshly powered anhydrous
K2CO3 (20 g, 0.15 mol) in 100 ml of acetone was added dimethyl sulfate
(15 ml, 0.15 mol) at room temperature. After the mixture was refluxed for
3 h, the acetone was removed under reduced pressure and water (100 ml)
was added to the residue. The resulted mixture was extracted with
dichloromethane (50 mlꢁ3) and the organic layer was dried over MgSO4
and concentrated in vacuum to afford 9.53 g of white solid (93.6%), mp
42—43 °C.
Results and Discussion
Resveratrol and its analogues were synthesized according
to Chart 1. Starting from 3,5-dihydroxybenzoic acid or 4-hy-
droxybenzoic acid, the compounds 2a, b were prepared in
good yield, followed by reduction with LiAlH4. Subsequent
treatment of 3a, b with SOCl2 afforded 4a, b in about 94%.
Using Wittig-Horner reaction, the compounds 5a, b were ob-
tained by refluxing 4a, b with P(OEt)3, which were con-
densed with ArCHO in NaOEt/DMF to give 6a—f, only the
trans isomer was obtained. BBr3 was used for deprotection of
methyl groups in CH2Cl2 to afforded 7a—f.
Methyl 4-Methoxybenzoate (2b) Compound 2b was prepared in the
same way as white solid (yield 95.3%), mp 47—49 °C.
3,5-Dimethoxybenzyl Alcohol (3a) To a well-stirred suspension of
LiAlH4 (4.0 g, 0.04 mol) in anhydrous ether (30 ml) was added a solution of
The derivatives were prepared according to Scheme I or II.
The ethyl aryloxyacetates 8a—f were synthesized by the re-
action of compounds 7a—f with ethyl chloroacetate in the methyl 3,5-dimethoxybenzoate (4.0 g, 0.02 mol) in anhydrous ether (30 ml).
After the addition was finished, the mixture was refluxed for 4 h, then mois-
ture ether (10 ml) and water (60 ml) were added to the mixture respectively.
The water layer was extracted with ether (30 mlꢁ3). The organic layer was
dried over MgSO4 and concentrated to provide 3.15 g of white solid (92.3%),
presence of KOH in ethanol–DMF and hydrolyzed to afford
aryloxyacetic acids 9a—e. Some Mannich base derivatives
were prepared by the Mannich reaction of compounds 7 with
morpholine and 36% HCHO in boiling ethanol or 1,4-diox-
ane (Scheme II).
The structures and physical data of these new compounds
were listed in Table 1.
Ten target compounds, three intermediates and resveratrol
with ibuprofen were tested for anti-inflammatory activity at
doses of 200 mg/kg body weight by xylene-induced ear-ede-
mp 47—49 °C.
4-Methoxybenzyl Alcohol (3b) Compound 3b was prepared in the
above method as colorless oil (94.4%).
3,5-Dimethoxybenzyl Chloride (4a) To a well-stirred solution of 3,5-
dimethoxy benzyl alcohol (16.8 g, 0.1 mol) in anhydrous ether (150 ml) was
added SOCl2 (15 ml, 0.2 mol) and the mixture was stirred for 3 h at room
temperature, then poured into water, and extracted with ether (50 mlꢁ3) and
the organic layer was dried over MgSO4 and concentrated to afford 18.9 g of
white solid (94.4%), mp 46—47 °C (lit. 10) 46 °C).
4-Methoxybenzyl Chloride (4b) Compound 4b was prepared in the
same way as a yellowish oil (93.8%).
General Procedure for Wittig-Horner Reaction. A. Diethyl (3,5-
Dimethoxybenzyl) Phosphonate (5a) A mixture of 3,5-dimethoxybenzyl
chloride (3.7 g, 0.02 mol) and triethyl phosphate (7 ml, 0.04 mol) was re-
fluxed for 4 h, then the excess triethyl phosphate was removed in vacuo and
Fig. 1. The Chemical Structure of Resveratrol
∗ To whom correspondence should be addressed. e-mail: guoliang222@yahoo.com.cn
© 2005 Pharmaceutical Society of Japan

1588
Vol. 53, No. 12
Chart 1. The Synthetic Route of Target Compounds
Table 1. The Structures and Physical Data of Target Compounds
Compd.
Structure
mp (°C)
89—91
92—94
65—67
Compd.
9a
Structure
mp (°C)
135—137
150—153
235—238
8a
8b
9b
8c
9c
8d
8e
91—93
82—83
9d
9e
258—260
225—228
8f
106—108
154—156
11a
11b
150—151
136—137
10a
10c
12c
93—95
75—78
11c
90—93

December 2005
1589
Table 2. Inhibitory Effects of Some Target Compounds and Intermediates
on Xylene-Induced Mouse Ear Edema
(300 MHz, CDCl3) d: 1.30 (6H, t, Jꢂ7.1 Hz, CH3), 4.28 (4H, m, –OCH2–),
4.64 (4H, s, –OCH2Ph), 6.46 (1H, s), 6.72 (2H, s), 6.98 (1H, d, Jꢂ16.7 Hz,
–CHꢂCH–), 7.15 (1H, d, Jꢂ16.7 Hz, –CHꢂCH–), 7.35 (1H, s), 7.87 (1H,
d, Jꢂ7.1 Hz), 8.51 (1H, s), 8.73 (1H, s). ESI-MS m/z: 386.2 [MꢄH]ꢄ. Anal.
Calcd for C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.10; H, 5.86;
N, 3.49.
Ethyl [3-Ethoxycarbonylmethoxy-5-[(E)-2-pyridin-2-ylvinyl]phenoxy]ac-
etate (8c): Yield 61.5%, white solid, mp 65—67 °C. 1H-NMR (300 MHz,
CDCl3) d: 1.29 (6H, t, Jꢂ7.1 Hz, CH3), 4.27 (4H, q, Jꢂ7.1 Hz, –OCH2–),
4.63 (4H, s, –OCH2Ph), 6.47 (1H, s), 6.79 (2H, d, Jꢂ2.0 Hz), 7.15 (1H, d,
Jꢂ16.0 Hz, –CHꢂCH–), 7.21 (1H, m), 7.42 (1H, d, Jꢂ7.7 Hz), 7.58 (1H, d,
Jꢂ16.0 Hz, –CHꢂCH–), 7.73 (1H, t, Jꢂ7.2 Hz), 8.61 (1H, d, Jꢂ4.1 Hz).
ESI-MS m/z: 386.2 [MꢄH]ꢄ. Anal. Calcd for C21H23NO6: C, 65.44; H, 6.02;
N, 3.63. Found: C, 65.63; H, 5.78; N, 3.78.
Ethyl [4-[(E)-2-Pyridin-4-ylvinyl]phenoxy]acetate (8d): Yield 75.2%, yel-
low solid, mp 91—93 °C. 1H-NMR (300 MHz, CDCl3) d: 1.32 (3H, t,
Jꢂ7.1 Hz, CH3), 4.30 (2H, q, Jꢂ7.1 Hz, –OCH2–), 4.67 (2H, s, –OCH2Ph),
6.92 (1H, d, Jꢂ16.2 Hz, –CHꢂCH–), 6.95 (2H, d, Jꢂ8.7 Hz), 7.27 (1H, d,
Jꢂ16.2 Hz, –CHꢂCH–), 7.37 (2H, d, Jꢂ5.2 Hz), 7.51 (2H, d, Jꢂ8.6 Hz),
8.57 (2H, br s). ESI-MS m/z: 284.1 [MꢄH]ꢄ, 567.3 [2MꢄH]ꢄ. Anal. Calcd
for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 72.13; H, 6.01; N,
4.83.
Dose
(mg/kg)
Number of
mice
Edema
meanꢅS.D. (mg)
Inhb. rate
(%)
Compoud
CMC-Na
Ibupr.
Resveratrol
—
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
15.8ꢅ5.0
—
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
9.1ꢅ3.2**
9.7ꢅ4.0**
13.2ꢅ2.8
12.0ꢅ4.2*
13.2ꢅ4.6
10.0ꢅ2.5**
11.0ꢅ2.7**
12.7ꢅ3.7
42.2
38.9
16.4
24.0
16.4
37.0
30.4
19.6
14.6
22.8
34.2
34.2
27.2
25.3
21.5
8c
8d
9b
9c
9d
9e
10c
11a
11b
12c
6a
13.5ꢅ4.2
12.2ꢅ2.2*
10.4ꢅ4.6**
10.4ꢅ4.0**
11.5ꢅ3.7*
11.8ꢅ3.3*
12.4ꢅ4.1*
7a
7b
Ethyl [4-[(E)-2-Pyridin-3-ylvinyl]phenoxy]acetate (8e): Yield 77.3%,
white solid, mp 82—83 °C. 1H-NMR (300 MHz, CDCl3) d: 1.31 (3H, t,
Jꢂ7.1 Hz, CH3), 4.29 (2H, q, Jꢂ7.1 Hz, –OCH2–), 4.65 (2H, s, –OCH2Ph),
6.92 (2H, d, Jꢂ8.8 Hz), 6.94 (1H, d, Jꢂ16.8 Hz, –CHꢂCH–), 7.11 (1H, d,
Jꢂ16.4 Hz, –CHꢂCH–), 7.29 (1H, m), 7.46 (2H, d, Jꢂ8.7 Hz), 7.82 (1H, d,
Jꢂ8.0 Hz), 8.47 (1H, d), 8.70 (1H, s). ESI-MS m/z: 284.1 [MꢄH]ꢄ. Anal.
Calcd for C17H17NO3: C, 72.07; H, 6.05; N, 4.94. Found: C, 71.95; H, 5.90;
N, 4.75.
∗ pꢆ0.05, ∗∗ pꢆ0.01 compared with CMC-Na group.
the orange oil was dissolved in DMF (15 ml) and used without further purifi-
cation.
B. Diethyl (4-Methoxybenzyl) Phosphonate (5b) Compound 5b was
prepared in the same way.
The Preparation of (E)-Stilbenes (6) To a well-stirred above solution
of phosphonate (5a, b) was added sodium ethoxide (made of 0.54 g sodium
and 10 ml absolute alcohol), 5 min later, was added appropriate aldehyde at
room temperature. The mixture was stirred for 3 h at the same temperature
and poured to water to provide the desired E-stilbenes 6.
(E)-4-[2-(3,5-Dimethoxyphenyl)vinyl]pyridine (6a): Yield 68.5%, white
needle solid, mp 139—141 °C. 1H-NMR (300 MHz, CDCl3) d: 3.84 (6H, s),
6.45 (1H, s), 6.69 (2H, d), 7.01 (1H, d, Jꢂ18.6 Hz), 7.23 (1H, d, Jꢂ
18.6 Hz), 7.36 (2H, d, Jꢂ6.2 Hz), 8.58 (2H, d, Jꢂ5.9 Hz).
General Procedure for Demethylation. The Preparation of Com-
pounds 7 To a well-stirred solution of compounds 6 in CH2Cl2 was added
BBr3 (1.3 mol for 1 mol methoxy) in CH2Cl2 at ꢃ10 °C. After the mixture
was stirred for 4 h at ꢃ5—0 °C, the reaction mixture was poured into ice-
water. The precipitate was collected and recrystallized in alcohol or
methanol.
(E)-5-[2-(Pyridin-4-yl)vinyl]benzene-1,3-diol (7a): Yield 78.5%, yellow
powder, mp 260—263 °C (dec). 1H-NMR (300 MHz, DMSO-d6) d: 6.24
(1H, s), 6.51 (2H, br s), 7.12 (1H, d, Jꢂ16.4 Hz), 7.49 (1H, d, Jꢂ16.4 Hz),
7.74 (2H, d, Jꢂ5.6 Hz), 8.60 (2H, d, Jꢂ5.6 Hz), 9.41 (2H, s).
Ethyl [4-[(E)-2-Pyridin-2-ylvinyl]phenoxy]acetate (8f): Yield 74.5%,
white solid, mp 106—108 °C. H-NMR (300 MHz, CDCl3) d: 1.31 (3H, t,
1
Jꢂ7.1 Hz, CH3), 4.29 (2H, q, Jꢂ7.1 Hz, –OCH2–), 4.64 (2H, s, –OCH2Ph),
6.92 (2H, d, Jꢂ8.7 Hz), 7.06 (1H, d, Jꢂ16.1 Hz, –CHꢂCH–), 7.13 (1H, dd,
Jꢂ4.9, 7.4 Hz), 7.37 (1H, d, Jꢂ7.8 Hz), 7.53 (1H, d, Jꢂ16.1 Hz,
–CHꢂCH–), 7.54 (1H, d), 7.60 (1H, m), 7.66 (1H, m), 8.59 (1H, d,
Jꢂ4.7 Hz). ESI-MS m/z: 284.2 [MꢄH]ꢄ. Anal. Calcd for C17H17NO3: C,
72.07; H, 6.05; N, 4.94. Found: C, 71.83; H, 5.88; N, 4.68.
General Procedure for Preparation of Compounds 9 Compounds 8
(1 mmol) were added to 4 M NaOH solution (10 ml). The resulting mixture
was stirred for 1 h to afford a solution at room temperature. The solution was
acidified and the precipitate was filtered off to provide compounds 9.
[3-Carboxymethoxy-5-[(E)-2-pyridin-4-ylvinyl]phenoxy]acetic Acid (9a):
Yield 68.5%, light-yellow powder, mp 135—137 °C. 1H-NMR (300 MHz,
DMSO-d6) d: 4.73 (4H, s, –OCH2Ph), 6.48 (1H, s), 6.86 (2H, d, Jꢂ2.0 Hz),
7.32 (1H, d, Jꢂ16.4 Hz, –CHꢂCH–), 7.53 (1H, d, Jꢂ16.3 Hz, –CHꢂCH–),
7.62 (2H, d, Jꢂ5.6 Hz), 8.58 (2H, d, Jꢂ4.9 Hz), 13.20 (2H, s, COOH). ESI-
MS m/z: 328.0 [MꢃH]ꢃ. Anal. Calcd for C17H15NO6: C, 62.00; H, 4.59; N,
4.25. Found: C, 61.95; H, 4.43; N, 4.09.
(E)-5-[2-(Pyridin-3-yl)vinyl]benzene-1,3-diol (7b): Yield 74.8%, yellow
powder, mp 230—233 °C (dec). 1H-NMR (300 MHz, DMSO-d6) d: 6.18
(1H, s), 6.46 (2H, d), 7.07 (1H, d, Jꢂ16.5 Hz), 7.23 (1H, d, Jꢂ16.5 Hz),
7.38 (1H, m), 8.03 (1H, d, Jꢂ7.7 Hz), 8.43 (1H, br s), 8.75 (1H, s), 9.32 (2H,
s).
General Procedure for Preparation of Compounds 8 A solution of
KOH (1 mol for 1 mol hydroxyl) in methanol was added to a well-stirred so-
lution of compounds 7 in methanol at room temperature. The resulting mix-
ture was stirred for 30 min and removal of the solvent in vacuo to afford a
solid. DMF was added to dissolve the residue and ethyl chloroacetate
(1.3 mol for 1 mol hydroxyl) was added to the resulting solution at 40 °C.
The reaction mixture was stirred for 1 h at the same temperature and poured
into water and extracted with ethyl acetate. The organic phase was dried over
MgSO4. Removal of ethyl acetate in reduced pressure provide the crude
product. The crude product was separated by silica gel column chromatogra-
phy (hexane/ethyl acetate 20 : 1) to afford the compounds 8.
[3-Carboxymethoxy-5-[(E)-2-pyridin-3-ylvinyl]phenoxy]acetic Acid (9b):
Yield 70.6%, light-yellow powder, mp 150—153 °C. 1H-NMR (300 MHz,
DMSO-d6) d: 4.72 (4H, s, –OCH2Ph), 6.48 (1H, s), 6.83 (2H, d, Jꢂ2.1 Hz),
7.40 (1H, d, Jꢂ16.6 Hz, –CHꢂCH–), 7.50 (1H, d, Jꢂ16.6 Hz, –CHꢂCH–),
7.77 (1H, dd, Jꢂ7.9, 5.4 Hz), 8.45 (1H, d, Jꢂ8.2 Hz), 8.65 (1H, d,
Jꢂ5.1 Hz), 8.94 (1H, s), 13.10 (2H, s, COOH). ESI-MS m/z: 327.9
[MꢃH]ꢃ, 657.0 [2MꢃH]ꢃ. Anal. Calcd for C17H15NO6: C, 62.00; H, 4.59;
N, 4.25. Found: C, 61.90; H, 4.31; N, 4.15.
[3-Carboxymethoxy-5-[(E)-2-pyridin-2-ylvinyl]phenoxy]acetic Acid (9c):
Yield 69.2%, light-yellow powder, mp 235—238 °C. 1H-NMR (300 MHz,
DMSO-d6) d: 4.72 (4H, s, –OCH2Ph), 6.47 (1H, s), 6.85 (2H, d, Jꢂ2.1 Hz),
7.36 (1H, d, Jꢂ15.9 Hz, –CHꢂCH–), 7.37 (1H, m), 7.65 (1H, d, Jꢂ15.9 Hz,
–CHꢂCH–), 7.66 (1H, m), 7.92 (1H, m), 8.61 (1H, d, Jꢂ4.2 Hz), 13.05
(2H, br s, COOH). ESI-MS m/z: 327.9 [MꢃH]ꢃ, 657.0 [2MꢃH]ꢃ. Anal.
Calcd for C17H15NO6: C, 62.00; H, 4.59; N, 4.25. Found: C, 61.85; H, 4.35;
N, 4.11.
Ethyl [3-Ethoxycarbonylmethoxy-5-[(E)-2-pyridin-4-ylvinyl]phenoxy]ac-
etate (8a): Yield 63.5%, white solid, mp 89—91 °C. 1H-NMR (300 MHz,
CDCl3) d: 1.33 (6H, t, Jꢂ7.1 Hz, CH3), 4.30 (4H, q, Jꢂ7.1 Hz, –OCH2–),
4.65 (4H, s), 6.48 (1H, s), 6.72 (2H, d, Jꢂ2.1 Hz), 6.95 (1H, d, Jꢂ16.2 Hz,
–CHꢂCH–), 7.18 (1H, d, Jꢂ16.2 Hz, –CHꢂCH–), 7.34 (2H, d, Jꢂ5.9 Hz),
8.58 (2H, d, Jꢂ5.9 Hz). ESI-MS m/z: 386.1 [MꢄH]ꢄ. Anal. Calcd for
C21H23NO6: C, 65.44; H, 6.02; N, 3.63. Found: C, 65.14; H, 5.98; N, 3.40.
Ethyl [3-Ethoxycarbonylmethoxy-5-[(E)-2-pyridin-3-ylvinyl]phenoxy]ac-
etate (8b): Yield 62.3%, light-yellow powder, mp 92—94 °C. 1H-NMR
[4-[(E)-2-Pyridin-4-ylvinyl]phenoxy]acetic Acid (9d): Yield 80.0%, yel-
low solid, mp 225—228 °C. 1H-NMR (300 MHz, DMSO-d6) d: 4.74 (2H, s,
–OCH2Ph), 7.00 (2H, d, Jꢂ8.8 Hz), 7.26 (1H, d, Jꢂ16.3 Hz, –CHꢂCH–),
7.57 (2H, d, Jꢂ8.8 Hz), 7.58 (1H, d, Jꢂ16.3 Hz, –CHꢂCH–), 7.90 (1H, m),
8.60 (1H, m), 8.68 (1H, d, Jꢂ5.2 Hz), 9.00 (1H, s), 13.00 (1H, br s, COOH).
ESI-MS m/z: 256.0 [MꢄH]ꢄ, 253.9 [MꢃH]ꢃ. Anal. Calcd for C15H13NO3:
C, 70.58; H, 5.13; N, 5.49. Found: C, 70.29; H, 5.11; N, 5.30.
[4-[(E)-2-Pyridin-3-ylvinyl]phenoxy]acetic Acid (9e): Yield 81.5%, yel-
low solid, mp 258—260 °C. 1H-NMR (300 MHz, DMSO-d6) d: 4.77 (2H, s,

1590
Vol. 53, No. 12
–OCH2Ph), 7.02 (2H, d, Jꢂ8.8 Hz), 7.37 (1H, d, Jꢂ16.3 Hz, –CHꢂCH–), m/z: 396.2 [MꢄH]ꢄ, 394.0 [MꢃH]ꢃ. Anal. Calcd for C23H29N3O3: C, 69.85;
7.70 (2H, d, Jꢂ8.7 Hz), 7.94 (1H, d, Jꢂ16.3 Hz, –CHꢂCH–), 8.11 (2H, H, 7.39; N, 10.62. Found: C, 69.95; H, 7.49; N, 10.88.
d, Jꢂ6.4 Hz), 8.78 (2H, d, Jꢂ6.3 Hz), 13.10 (1H, br s, COOH). ESI-MS
2,4,6-Tri(morpholin-4-ylmethyl)-5-[(E)-2-pyridin-2-ylvinyl]benzene-1,3-
m/z: 256.0 [MꢄH]ꢄ, 253.8 [MꢃH]ꢃ, 508.9 [2MꢃH]ꢃ. Anal. Calcd for diol (12c): Yield 50.2%, light-yellow solid, mp 75—78 °C. 1H-NMR
C15H13NO3: C, 70.58; H, 5.13; N, 5.49. Found: C, 70.35; H, 5.07; N, 5.15.
General Procedure for the Mannich Reaction To a well-stirred solu-
tion of 7 (4—20 mmol) in 1,4-dioxane (10—50 ml) was added amine (mor-
pholine 5—50 mmol) and 37% formaldehyde (6—60 mmol). The resulting
mixture was refluxed for 24 h and then concentrated to give a viscous solid
in vacuo. The viscous solid was dissolved in 5% HCl (20—100 ml) and ex-
tracted with dichloromethane (10—30 ml, two times). The water phase was
basified to pH 11 and extracted with dichloromethane (30—50 ml, 4 times).
(300 MHz, CDCl3) d: 2.53 (8H, m), 2.60 (4H, m), 3.68 (6H, s, PhCH2-N),
3.76 (12H, m), 6.59 (1H, d, Jꢂ16.3 Hz, –CHꢂCH–), 7.20 (1H, m), 7.32
(1H, d, Jꢂ7.9 Hz), 7.69 (1H, d, Jꢂ16.4 Hz, –CHꢂCH–), 7.62 (1H, m), 8.63
(1H, d, Jꢂ4.0 Hz). ESI-MS m/z: 511.3 [MꢄH]ꢄ, 509.1 [MꢃH]ꢃ. Anal.
Calcd for C28H38N4O5: C, 65.86; H, 7.50; N, 10.97. Found: C, 65.68; H,
7.22; N, 10.68.
Evaluation of Anti-inflammatory Effect in Vivo All tested compounds
were homogenized with 0.5% sodium carboxymethylcellulose and adminis-
The combined organic phase was washed with water and dried over anhy- tered orally to Swiss male mice (22—26 g body weight, 10 animals per
drous MgSO4 and removal of dichloromethane provided the crude products.
The crude product was recrystallized from alcohol or separated by silica gel
column chromatography (CH2Cl2/ethyl acetate 10 : 1).
group) at a dose of 200 mg/kg. Control mice received the vehicle only (0.5%
sodium carboxymethylcellulose, 0.2 ml/10 g). One hour later, the mice were
anaesthetized and 30 ml xylene was applied to the surface of the right ear by
2-Morpholin-4-ylmethyl-4-[(E)-2-pyridin-4-ylvinyl]phenol (10a): Yield a micropipette. After 20 min, mice were sacrificed and a plug (7 mm diame-
1
28.7%, white needle solid, mp 154—156 °C. H-NMR (300 MHz, DMSO-
ter) was excised from both the treated and untreated ears: edema was quanti-
fied by the difference in weight between the two plugs. The anti-inflamma-
d6) d: 2.60 (4H, m), 3.75 (2H, s, PhCH2-N), 3.77 (4H, m), 6.84 (1H, d,
Jꢂ16.1 Hz, –CHꢂCH–), 6.83 (1H, s), 7.20 (1H, d), 7.21 (1H, d, Jꢂ16.2 Hz, tory activity was expressed as percent reduction of the control mice using as
–CHꢂCH–), 7.31 (2H, d, Jꢂ5.9 Hz), 7.38 (1H, dd, Jꢂ8.4, 2.0 Hz), 8.54
reference, the NSAID Ibuprofen. Edema values, expressed as meanꢅstan-
dard deviation, were evaluated statistically using Student’s t-test. A level of
(2H, d, Jꢂ5.7 Hz). ESI-MS m/z: 297.2 [MꢄH]ꢄ, 294.9 [MꢃH]ꢃ. Anal.
Calcd for C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C, 73.04; H, 6.70; pꢆ0.05 was adopted as the test of significance.
N, 9.31.
2-Morpholin-4-ylmethyl-4-[(E)-2-pyridin-2-ylvinyl]phenol (10c): Yield
Acknowledgements We are grateful to the National Natural Science
25.8%, white solid, mp 93—95 °C. 1H-NMR (300 MHz, CDCl3) d: 2.61 Foundation of China for the financial support (No. 39800185).
(4H, s), 3.74 (2H, s, PhCH2-N), 3.76 (4H, s), 6.84 (1H, d, Jꢂ8.4 Hz), 7.02
(1H, d, Jꢂ16.1 Hz, –CHꢂCH–), 7.14 (2H, m), 7.37 (1H, d, Jꢂ7.9 Hz), 7.44
(1H, m), 7.56 (1H, d, Jꢂ16.1 Hz, –CHꢂCH–), 7.67 (1H, m), 8.58 (1H, d,
Jꢂ3.9 Hz). ESI-MS m/z: 297.1 [MꢄH]ꢄ, 294.9 [MꢃH]ꢃ. Anal. Calcd for
C18H20N2O2: C, 72.95; H, 6.80; N, 9.45. Found: C, 73.10; H, 6.47; N, 9.20.
2,6-Bis(morpholin-4-ylmethyl)-4-[(E)-2-pyridin-4-ylvinyl]phenol (11a):
Yield 42.3%, light-green solid, mp 150—151 °C. 1H-NMR (300 MHz,
CDCl3) d: 2.58 (8H, m), 3.68 (4H, s, PhCH2-N), 3.76 (8H, m), 6.86 (1H, d,
Jꢂ16.3 Hz, –CHꢂCH–), 7.20 (1H, d, Jꢂ16.3 Hz, –CHꢂCH–), 7.29 (2H, s),
7.32 (2H, d, Jꢂ6.1 Hz), 8.54 (2H, d, Jꢂ6.0 Hz). ESI-MS m/z: 396.2
[MꢄH]ꢄ, 394.0 [MꢃH]ꢃ. Anal. Calcd for C23H29N3O3: C, 69.85; H, 7.39;
N, 10.62. Found: C, 70.10; H, 7.34; N, 10.90.
References
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2,6-Bis(morpholin-4-ylmethyl)-4-[(E)-2-pyridin-3-ylvinyl]phenol (11b):
1
Yield 38.5%,white solid, mp 136—137 °C. H-NMR (300 MHz, CDCl3) d:
2.58 (m, 8H), 3.55 (4H, s, PhCH2-N), 3.79 (8H, m), 6.93 (1H, d, Jꢂ16.4 Hz,
–CHꢂCH–), 7.08 (1H, d, Jꢂ16.4 Hz, –CHꢂCH–), 7.25 (1H, m), 7.30 (2H,
d, Jꢂ3.4 Hz), 7.80 (1H, m), 8.46 (1H, m), 8.71 (1H, d, Jꢂ2.0 Hz). ESI-MS
m/z: 396.2 [MꢄH]ꢄ, 394.0 [MꢃH]ꢃ. Anal. Calcd for C23H29N3O3: C, 69.85;
H, 7.39; N, 10.62. Found: C, 70.15; H, 7.56; N, 10.85.
2,6-Bis(morpholin-4-ylmethyl)-4-[(E)-2-pyridin-2-ylvinyl]phenol (11c):
Yield 40.5%, light-yellow solid, mp 90—93 °C. 1H-NMR (300 MHz, CDCl3)
d: 2.59 (8H, m), 3.68 (4H, s, PhCH2-N), 3.77 (8H, m), 7.03 (1H, d,
Jꢂ16.1 Hz, –CHꢂCH–), 7.11 (1H, m), 7.36 (3H, m), 7.53 (1H, d,
Jꢂ16.1 Hz, –CHꢂCH–), 7.65 (1H, m), 8.58 (1H, d, Jꢂ4.3 Hz). ESI-MS