Design, synthesis, and anti-allergic activities of novel (R)(-)-1-[(4-chlorophenyl)phenyl methyl]piperazine derivatives

Article abstract of DOI:10.1007/s00044-010-9512-1

A series of novel (R)(-)-1-[(4-chlorophenyl) phenylmethyl]piperazine derivatives were designed, synthesized, and tested for in vivo anti-allergic activities. Most of these derivatives exhibited significant effects on both allergic asthma and allergic itching. Three of the 19 piperazine derivatives (namely, 3d, 3i, and 3r) have stronger potency against allergic asthma than levocetirizine, the positive control drug. Meanwhile, in the test of allergic itching, five of the 19 compounds (namely, 3b, 3g, 3k, 3o, and 3s) have more potent activities than levocetirizine. Springer Science+Business Media, LLC 2010.

Full text of DOI:10.1007/s00044-010-9512-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:124–132
DOI 10.1007/s00044-010-9512-1
ORIGINAL RESEARCH
Design, synthesis, and anti-allergic activities of novel
(R)(-)-1-[(4-chlorophenyl)phenyl methyl]piperazine derivatives
•
Lisheng Wang Tianwen Wang Bin Yang
•
•
•
Zhigang Chen Hua Yang
Received: 3 June 2010 / Accepted: 12 November 2010 / Published online: 1 December 2010
Ó Springer Science+Business Media, LLC 2010
Abstract A series of novel (R)(-)-1-[(4-chlorophenyl)
phenylmethyl]piperazine derivatives were designed, syn-
thesized, and tested for in vivo anti-allergic activities. Most
of these derivatives exhibited significant effects on both
allergic asthma and allergic itching. Three of the 19 piper-
azine derivatives (namely, 3d, 3i, and 3r) have stronger
potency against allergic asthma than levocetirizine, the
positive control drug. Meanwhile, in the test of allergic
itching, five of the 19 compounds (namely, 3b, 3g, 3k, 3o,
and 3s) have more potent activities than levocetirizine.
drugs share the same pharmacophore diphenylmethylpip-
erazine. Among these drugs, levocetirizine has more potent
activities and fewer side effects than classic antihistamines,
such as diphenhydramine (Hancock, 2006) and prometha-
zine (Wang et al., 2001; Devalia et al., 2001; Day et al.,
2004; Gandon and Allain, 2002). Therefore, we chose lev-
ocetirizine as the leading compound in the treatment of
allergies and designed a series of derivatives to screen
potential anti-allergy drugs.
The target compounds (3a–3q) were designed and syn-
thesized. Part C of levocetirizine (Scheme 1) was replaced
with sulfonamides, Part A was unchanged, and Part B was
kept either two or three carbons long (Scheme 2). Allergies
are associated with subsequent inflammation. Some
derivatives of sulfonamides reported showed good anti-
inflammatory activities (Husain, 2009; Lloret et al., 2009);
hence, sulfonamides may produce synergistic action with
the pharmacophore of levocetirizine. The new combined
compounds are anticipated to be more potent than levoce-
tirizine and were therefore systemically studied. Glycine
and alanine, as kinetophores, were attached to the phar-
macophore in an attempt to generate suitable bioavailability
(3r and 3s in Scheme 2). To the best of our knowledge,
these compounds have not been reported in literatures.
Keywords Diphenylmethylpiperazine Á Levocetirizine Á
Anti-allergy Á Allergic asthma Á Allergic itching
Introduction
Allergies are the most common serious disorders of the
immune system (Akdis, 2009; Sicherer and Leung, 2009).
Allergic reactions occur in response to environmental sub-
stances known as allergens, which vary largely. The number
of patients suffering from allergies is gradually increasing
with morbidity rate likewise growing (Li and Brown, 2009;
Smith et al., 2009; Mullins et al., 2009). Histamine interacts
with H1 receptors and causes allergies with exposure to
excessive amounts of an allergen. Currently, piperazine H1
receptor antagonists (Slater et al., 1999; Ishiwata et al.,
2004), having higher affinity to H1 receptors than histamine
(Banu and Watanabe, 1999; De Bruin et al., 2002), are often
clinically used in the treatment of allergies. Most piperazine
Results and discussion
Chemistry
The (R)(-)-1-[(4-chlorophenyl)benzyl]piperazine deriva-
tives (3a–3s) (Table 1) were prepared according to the
synthetic routes shown in Scheme 2. The derivatives
were obtained by the reaction of compound 1 with
1-bromo-2-chloroethane or 1-bromo-3-chloropropane, and
L. Wang (&) Á T. Wang Á B. Yang Á Z. Chen Á H. Yang
School of Chemistry and Chemical Engineering,
Guangxi University, 530004 Nanning, China
e-mail: lswang@gxu.edu.cn
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Med Chem Res (2012) 21:124–132
125
procellus) as model animals; their asthma was caused by
histamine phosphate (Kayasuga et al., 2002; Mavrova et al.
2006). Compounds 3b, 3d, 3f–3j, 3l, 3m, 3o, and 3q–3s
showed significantly more potent anti-asthmatic activities
than that of the control group (Table 2). Compounds 3d, 3i,
and 3r exhibited significantly more potent anti-asthmatic
activities than levocetirizine. Compounds 3h, 3j, 3m, 3q,
and 3s showed activities similar to levocetirizine.
2HCl
N CH2CH2 OCH2COOH
N
H
Cl
part A
part B
part C
The structure–activity relationships of compounds 3a–3s
were analyzed. Target compounds 3d and 3m (with inter-
mediates 2a and 2b, respectively) connected to the N
position of the phenylamino group (Scheme 2), were more
active than 3c and 3l (with respective intermediates 2a and
2b) connected to the N position of the sulfonylamino
group. Their activities might be closely related to R group
configurations in the foregoing compounds. When there
was a methoxypyridazine ring in the R group, the anti-
asthmatic activities of compounds 3h, 3i, and 3q were
clearly more effective than that of levocetirizine. Results
indicate that the methoxypyridazine ring of compounds 3h,
3i, and 3q play an important role in the anti-asthmatic
activities. 3q was significantly more active than 3k, in
which the electron-withdrawing chlorine atom on the pyr-
idazine ring was replaced with an electron-donating
methoxy group. Both compounds 3r and 3s, having an
amino acid group as Part C, showed very strong activities,
particularly 3s. As kinetophores, these amino acid groups
can enhance efficacies in the treatment of allergies by
increasing pharmacological bioavailability. Compounds 3e,
3g, 3n, and 3p, having pyrimidine or dimethylpyrimidine
rings, showed weak activities, which may cause a weak
interaction with the H1 receptor.
Scheme 1 Structure of levocetirizine
subsequently with appropriate sulfonamides or amino acids
to produce 3a–3s in yields ranging from 40 to 71%. Inter-
mediate 2b was prepared by the reaction of excessive
1-bromo-3-chloropropane with 1. 1-Bromo-3-chloropro-
pane has a high boiling point, making its removal by distil-
lation difficult. After the reaction was completed, the dilute
solution of hydrogen chloride was added into the reaction
mixture to convert 5 into its hydrochloride salt, which dis-
solves in water. The acidic aqueous layer of the salt of 2b was
separated from the organic layer, and unreacted 1-bromo-3-
chloropropane was left in the organic layer. The dilute
solution of sodium hydroxide was then used to adjust the pH
value to 8 to give 2b. The R groups of 3r and 3s are glycine
and alanine, respectively. The methyl esters of glycine and
alanine are not soluble in most organic solvents. After many
solvents were tested, the synthesis of 3r and 3s from the
methyl esters of glycine and alanine was carried out in ace-
tonitrile of a homogeneous phase to generate a high yield.
The synthesized compounds were characterized through
infrared (IR), proton nuclear magnetic resonance (1HNMR),
mass spectrometry (MS), and elemental analyses.
Based on the R configuration of levocetirizine, all
designed compounds have configurations identical to
levocetirizine.
Anti-pruritic activity
The anti-pruritic activities of compounds 3a–3s were also
determined using cavies as model animals; their skin
itching was caused by histamine phosphate. Results indi-
cate that compounds 3b–3d, 3f–3h, and 3j–3s had stronger
anti-pruritic activities compared with the control group
Anti-asthmatic activity
The anti-asthmatic activities of the target compounds
(3a–3s) were determined using asthmatic cavies (Cavia
a, b
c
N
H
N
(CH2)nCl
N
H
NH
N
H
N
(CH2)n
R
Cl
Cl
Cl
3a-3i n=2, R=sulfanilamides
3j-3q n=3, R=sulfanilamides
3r, 3s n=3, R=amino acids
2a n=2
2b n=3
1
Scheme 2 Synthetic route of the target compounds. (Reagents and conditions: a Br(CH2)2Cl, TEA, toluene, 55°C; b Br(CH2)3Cl, TEA, toluene,
55°C; c 3a–3q: HR, K2CO3, acetone, ref.; 3r, 3s: HR, TEA, CH3CN, ref)
123

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Med Chem Res (2012) 21:124–132
Table 1 Structures of compounds 3a–3s
N
N
(CH2)n R
H
Cl
Compd.
3a
n
2
R
Compd.
3k
n
3
R
O
S
O
NH2
NH
N
Cl
NH
NH2
NH
S
N
H
Cl
N
N
N
N
O
O
O
O
3b
3c
3d
2
2
2
3l
3
3
3
S
S
N
Cl
S
N
H
N
N
O
N
O
O
O
3m
3n
S
S
H
NH2
NH
S
N
S
N
N
N
O
O
O
CH3
CH3
S
H
S
N
O
S
N
N
O
NH
N
H
N
O
O
3e
2
CH3
3o
3
NH
S
NH2
O
S
N
O
NH
N
H
N
O
CH3
O
S
O
S
N
N
3f
3g
3h
3i
2
2
2
2
3
3p
3q
3r
3s
3
3
3
3
H
N
NH
NH
NH2
NH
NH2
NH
NH
O
O
O
S
N
N
O
S
H
N
N
H
OCH3
N
N
O
O
NH CH2COOH
O
S
N
OCH3
OCH3
Cl
N
N
O
CH3
O
NH CHCOOH
S
N
H
N
N
O
O
S
3j
NH2
N
N
N
O
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Med Chem Res (2012) 21:124–132
127
Table 2 Comparison of anti-asthmatic activities of compounds 3a–
3s at a dose of 50 mg/kg with that of levocetirizine of the same dose
Table 3 Anti-pruritic activity data of target compounds 3a–3s at a
dose of 50 mg/kg
Compounds
Latency before
administration (/s)
Latency after
administration (/s)
Chemicals
Concentration of
histamine (mg/g)
Percent increase
relative to (%)
Control
Levocetirizine
Control
113.0 123.4
99.2 17.2
103.50 32.4
95.0 27.4
95.5 53.5
98.6 30.9
100.7 13.9
100.5 17.2
97.3 17.6
103.4 48.9
95.0 17.8
102.5 34.6
110.4 37.5
94.4 17.0
93.3 17.6
115.3 53.5
103.9 32.7
97.9 17.8
92.2 27.7
97.8 16.0
105.8 48.0
a
115.4 126.2
274.0 99.4c
151.2 110.0
255.5 109.2a
184.8 100.4
360.0 0.0cd
167.4 103.4
266.2 125.7a
246.4 117.5a
288.0 112.5c
360.0 0.0cd
301.8 120.1c
184.1 149.7
240.3 112.8a
324.8 71.9c
136.8 115.8
269.4 118.5a
229.2 119.3
295.6 103.8c
360.0 0.0cd
307.6 107.9c
Levocetirizine
Control
0.09 0.03
0.42 0.35b
0.09 0.07
0.85 0.78c
0.46 0.47b
0.34 0.29a
0.17 0.13
0.43 0.42b
1.33 0.31c
0.68 0.56b
0.33 0.38
0.46 0.57b
0.76 0.50c
0.43 0.45b
0.34 0.32a
0.42 0.45b
0.87 0.58c
0.59 0.48b
0.60 0.52b
0.51 0.30b
0.89 0.37c
a
–
–
3a
3b
3c
3d
3e
3f
Levocetirizine
383.54
6.40
–
3a
3b
3c
3d
3e
3f
-78.00
103.46d
9.40
883.81
429.01
292.61
92.07
-18.80
-60.28
2.55
217.80f
62.62
-21.49
10.10
82.74d
2.44
3g
3h
3i
395.87
1436.72
686.34
279.65
432.37
783.62
395.34
296.34
382.83
901.67
576.61
593.50
493.36
933.80
b
3g
3h
3i
3j
3k
3l
3j
3k
3l
3m
3n
3o
3p
3q
3r
3s
3m
3n
3o
3p
3q
3r
3s
-18.04
-0.15
107.15d
39.93
43.42
22.71
113.80e
c
Comparison with control group: P \ 0.05; P \ 0.01; c P \ 0.001
b
d
Comparison with levocetirizine group: P \ 0.05
Comparison with control group: P \ 0.05, P \ 0.01, P \ 0.001
d
e
Comparison with levocetirizine group:
f
P \ 0.05, P \ 0.01,
(Table 3). Compounds 3b, 3g, 3k, 3o, and 3s were more
active than levocetirizine, and compounds 3c, 3f, 3h, 3j, 3l,
3n, 3p, 3q, and 3r showed anti-pruritic activities similar to
levocetirizine.
P \ 0.001
elemental analyses. Results of in vivo biological tests show
that compounds 3d, 3i, and 3r had significantly more
potent anti-allergic asthma activities than levocetirizine,
whereas compounds 3b, 3g, 3k, 3o, and 3s exhibited
stronger anti-pruritic activities than levocetirizine. Com-
pounds 3r and 3s, having amino acid groups as Part C
moiety, showed very strong anti-pruritic and anti-asthmatic
activities, which warrants the synthesis of more amino acid
analogs and the further study of their biological activities.
These suggest that the given target compounds with more
potent activities than levocetirizine are worthy of further
evaluation by more biological tests.
The activities of 3b and 3k were significantly superior to
those of 3a and 3j. Intermediates 2a and 2b were linked to
the amino N position of the sulfonamide, generating 3b and
3k, respectively, whereas intermediates 2a and 2b were
linked to the sulfonylamino N position of the sulfonamide,
yielding 3a and 3j, respectively. The different linking
methods generate different configurations of Part C moiety,
which plays an important role in enhancing anti-pruritic
activities. The type of Part C moiety also plays a significant
role in anti-pruritic and anti-asthmatic activities
(Scheme 2; Tables 2, 3). For example, both compounds 3r
and 3s, with amino acid groups, showed very strong anti-
pruritic (Table 3), as well as anti-asthmatic activities
(Table 2).
Experimental protocols
Chemistry
Conclusion
IR spectra were recorded on a JASCO IR Report 100
1
(KBr), and H NMR spectra were recorded on a Brucker
A series of levocetirizine analogs were successfully syn-
1
thesized and characterized through IR, H NMR, MS, and
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Med Chem Res (2012) 21:124–132
Avance (500 MHz) instrument. Chemical shifts were
reported in parts per million (ppm) using tetramethyl
silane as internal standard. All protons were confirmed by
the addition of DCCl3, except in compounds 3f, 3h, and
3s, in which protons were confirmed by the addition of
CD3OD. Elemental analyses (C, H, and N) were con-
ducted with a Perkin–Elmer model 240C analyzer, and all
analyses results were consistent with theoretical values
(within 0.3%), unless otherwise indicated. The homo-
geneity of the compounds was monitored by ascending
thin layer chromatography (TLC) on silica gel GF254-
coated glass plates, visualized by UV light. Mass spectra
were obtained with an Agilent 1100 series ion trap mass
spectrometer. For all compounds, the mass spectrometer
was operated under electron spray ionization mode.
Melting points were determined in open capillary tubes on
a Buchi 530 melting point apparatus and are uncorrected.
All chemical reagents used in the experiment were of
analytical grade and were obtained from Sinopharm
Chemical Reagent Co., Ltd.
intermediate 2a (instead of 2b used for 3j–3q) with
potassium carbonate (0.03 mol) as a catalyst in acetone
(50 ml), followed by an overnight reflux period. The
mixture was cooled to ambient temperature and was fil-
tered to remove potassium carbonate. After removing the
solvent, the residue was purified on a silica gel column
eluted with ethyl acetate and petroleum ether (1:1, v/v),
yielding products 3a–3i and 3j–3q.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[N-(6-
chloropyrida zine-3-yl)-N-(4-amino
benzenesulfonylamino)]amino]ethylpiperazine (3a)
Yield: 45%. m.p.: 109–112°C. [a]3D0: 26.46 (c = 1, EtOH).
IR (KBr) cm-1: 3462, 3384, 3219 (N–H), 3057, 3025 (Ar–
H), 2944, 2877, 2804 (–CH2–) 1625, 1597, 1481, 1449
1
(aromatic ring); H-NMR (CDCl3) d: 2.20–2.42 (m, 6H),
2.59 (t, J = 6.4, 2H), 4.05 (t, J = 6.7, 2H), 4.14 (s, 1H),
4.22 (t, 2H), 6.61 (d, J = 8.7, 2H), 7.41 (d, J = 8.7, 2H),
7.46 (d, J = 9.2, 1H), 7.86 (d, J = 9.2, 1H), 7.20–7.84 (m,
9H), 7.28(s, CDCl3). MS m/z: 597.4 (M?). Anal. Calcd for
C29H30Cl2N6O2S: C, 58.29; H, 5.30; N, 14.07; Found: C,
58.60; H, 5.21; N, 14.12.
Synthesis of intermediate 1
The preparation of 1 is in accordance with literature (Wang
et al., 2007).
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[4-[N-(6-
chloropyridazine-3-yl amino] sulfonyl]
phenylamino]ethylpiperazine (3b)
Synthesis of 2a and 2b
A 250 ml round-bottomed flask connected to a reflux
condenser was charged with 1 (16 g, 0.056 mol), 1-bromo-
3-chloropropane (11 ml, 0.112 mol) (instead of 1-bromo-
2-chloroethane used for 2a), and toluene (120 ml). The
mixture was stirred and heated at 55°C until TLC indicated
the absence of any starting material. The mixture was
cooled to ambient temperature and then filtered. Diluted
hydrochloric acid (250 ml) was added to the filtrate while
shaking, and the yellow solid was precipitated. The mixture
was filtered to remove the yellow solid. The solid was then
washed with toluene (60 ml). Subsequently, the yellow
solid was transferred to a 1000 ml beaker containing
250 ml of distilled water. The mixture was adjusted to pH
12–13 by sodium hydroxide and extracted with chloroform
(3 9 50 ml). The combined organic phases were concen-
trated using a rotary evaporator (45°C, 40 mmHg), pro-
ducing 14.2 g (70%) of product 2b in the form of yellow
oil.
Yield: 51%. m.p.: 120–1228 C. [a]3D0: -7.13 (c = 1,
EtOH). IR (KBr) cm-1: 3452, 3364, 3229 (N–H), 3058,
3025 (Ar–H), 2955, 2879, 2809 (–CH2–), 1616, 1594,
1529, 1492 (aromatic ring). 1H-NMR (CDCl3) d: 2.20–2.75
(m, 8H), 3.95 (s, 2H), 4.15 (s, 1H), 4.34 (t, J = 6.7, 2H),
6.55 (d, J = 8.6, 2H), 7.68 (d, J = 8.6, 2H), 8.24 (d,
J = 9.5, 1H), 7.22–7.39 (m, 10H), 7.28 (s, CDCl3). MS m/z:
597.2 (M?). Anal. Calcd for C29H30Cl2N6O2S: C, 58.29; H,
5.30; N, 14.07; Found: C, 58.37; H, 5.32; N, 13.89.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[N-
(thiazole-2-yl)-N-(4-aminophenylsulfonyl)]
amino]ethylpiperazine (3c)
Yield: 42%. m.p.: 96–98°C. [a]3D0: -4.33 (c = 1, EtOH).
IR (KBr) cm-1: 3448, 3383, 3219 (N–H), 3057, 3025 (Ar–
H), 2959, 2877, 2809 (–CH2–), 1631, 1594, 1488, 1448
1
(aromatic ring). H-NMR (CDCl3) d: 2.37–2.55(m, 6H),
2.70 (t, J = 7.0, 2H), 4.03(t, J = 7.5, 2H), 4.21 (d, 3H),
6.60 (d, J = 8.7, 2H), 7.60 (d, J = 8.7, 2H), 6.97 (d,
J = 3.6, 1H), 7.19–7.38 (m, 10H), 7.28 (s, CDCl3). MS m/z:
582.1 (M?). Anal. Calcd for C28H30ClN5O2S2: C, 57.75;
H, 5.50; N, 12.03; Found: C, 57.58; H, 5.35; N, 11.86.
General procedure for the preparation of 3a–3i and 3j–3q
(Fan et al., 2007; Boos et al., 2006; Girisha et al., 2009)
Piperazine derivatives 3a–3i were prepared by the reaction
of appropriate substituted sulfonamides (0.01 mol) and
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Med Chem Res (2012) 21:124–132
129
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[4-[N-
(thiazole-2-yl)amino]sulfonyl]phenyl
amino]ethylpiperazine (3d)
J = 7.2, 6H), 2.82 (m, 2H), 4.13 (s, 2H), 4.24 (s, 1H), 4.35
(t, 2H), 6.61 (d, J = 8.7, 2H), 7.94 (d, J = 8.7, 2H), 6.83
(t, J = 4.8, 1H), 8.42 (d, J = 4.8, 2H), 7.20–7.43 (m, 9H),
7.28 (s, CDCl3). MS m/z: 563.2 (M?). Anal. Calcd for
C29H31ClN6O2S: C, 61.87; H, 5.51; N, 14.93; Found: C,
61.70; H, 5.42; N, 15.12.
Yield: 64%. m.p.: 110–112°C. [a]3D0: 25.76 (c = 1, EtOH).
IR (KBr) cm-1: 3451, 3369, 3237 (N–H), 3058, 3025 (Ar–
H), 2956, 2879, 2809 (–CH2–), 1625, 1594, 1501, 1435
1
(aromatic ring). H-NMR (CDCl3) d: 2.32–2.44(m, 8H),
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[N-(6-
methoxypyridazine-3-yl)-N-(4-amino
benzenesulfonyl)]amino]ethylpiperazine (3h)
2.62 (t, J = 6.0, 2H), 4.01 (m, 4H), 4.15(s, 1H), 6.38 (d,
J = 4.7, 1H), 6.91 (d, J = 4.7, 1H), 6.60 (d, J = 8.7, 2H),
7.72 (d, J = 8.7, 2H), 7.20–7.37 (m, 9H), 7.28 (s, CDCl3).
MS m/z: 582.1 (M?). Anal. Calcd for C28H30ClN5O2S2: C,
57.75; H, 5.50; N, 12.03; Found: C, 57.25; H, 5.41; N,
12.12.
Yield: 40%. m.p.: 95–97°C. [a]3D0: -6.20 (c = 1, EtOH).
IR (KBr) cm-1: 3437 (N–H), 3062, 3024 (Ar–H), 2927,
2812 (–CH2–, –CH3), 1632, 1598, 1459, 1452 (aromatic
ring). 1H-NMR (CDCl3) d: 2.20–2.42 (m, 6H), 2.53 (t,
J = 6.4, 2H), 2.93 (t, J = 6.6, 2H), 4.11 (s, 3H), 4.13 (s,
2H), 4.14 (s, 1H), 6.61 (t, J = 8.7, 2H), 6.99 (d, J = 8.7,
1H), 7.70 (d, J = 8.7, 2H), 7.72 (d, J = 8.2, 1H),
7.23–7.39 (m, 9H), 7.27 (s, CDCl3). MS m/z: 593.3 (M?).
Anal. Calcd for C30H33ClN6O3S: C, 60.76; H, 5.57; N,
14.18; Found: C, 60.94; H, 5.56; N, 14.01.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[4-[N-(4,6-
dimethylpyrimidine-2-yl)amino]
sulfonyl]phenylamino]ethylpiperazine (3e)
Yield: 61%. m.p.: 115–117°C. [a]3D0: -6.23 (c = 1, EtOH).
IR (KBr) cm-1: 3443, 3382 (N–H), 3059, 3024 (Ar–H),
2953, 2883, 2809 (-CH2-, -CH3), 1625, 1594, 1555, 1493
(aromatic ring). 1H-NMR (CDCl3) d: 2.30 (s, 6H),
2.38–2.75 (m, 6H), 2.81 (t, J = 7.2, 2H), 4.10 (s, 2H), 4.24
(s, 1H), 4.35 (t, J = 7.2, 2H), 6.55 (s, 1H), 6.62 (d,
J = 8.6, 2H), 7.96 (d, J = 8.6, 2H), 7.20–7.94 (m, 9H),
7.28 (s, CDCl3). MS m/z: 591.2 (M?). Anal. Calcd for
C31H35N6O2S: C, 62.97; H, 5.92; N, 14.22; Found: C,
62.74; H, 5.85; N, 14.50.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[4-[N-(6-
methoxypyridazine-3-yl)amino]
sulfonyl]phenylamino]ethylpiperazine (3i)
Yield: 42%. m.p.: 102–104°C. [a]3D0: -5.63 (c = 1, EtOH).
IR (KBr) cm-1: 3447, 3368, 3240 (N–H), 3055, 3031(Ar–
H), 2941, 2870, 2809 (–CH2–, –CH3), 1636, 1594, 1501,
1
1452 (aromatic ring) H-NMR (CDCl3) d: 2.30–2.48 (m,
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[(4-
amino)sulfonyl]phenylamino]ethyl piperazine (3f)
6H), 2.75 (t, J = 6.2, 2H), 3.83 (s, 3H), 3.90 (s, 2H), 4.16
(s, 1H), 4.31 (t, J = 6.2, 2H), 6.54 (d, J = 8.3, 2H), 6.97
(d, J = 10.0, 2H), 7.70 (d, J = 8.3, 2H), 8.20 (d, J = 10.0,
1H), 7.21–7.60 (m, 9H), 7.28 (s, CDCl3). MS m/z: 593.2
(M?). Anal. Calcd for C30H33ClN6O3S: C, 60.76; H, 5.57;
N, 14.18; Found: C, 60.85; H, 5.48; N, 14.25.
Yield: 71%. m.p.: 72–75°C. [a]3D0: 25.02 (c = 1, EtOH).
IR (KBr) cm-1: 3461, 3382, 3243 (N–H), 3059, 3024 (Ar–
H), 2938, 2875, 2815 (–CH2–), 1627, 1596, 1503, and 1452
1
(atomatic ring). H-NMR (CD3OD) d: 2.43 (m, 8H), 2.92
(t, J = 7.0, 2H), 3.32 (t, J = 1.4, 2H), 4.24 (s, 1H), 6.67 (d,
J = 8.2, 2H), 7.52 (d, J = 8.2, 2H), 7.20–7.39 (m, 9H),
4.88 (s, CD3OD). MS m/z: 485.2 (M?). Anal. Calcd for
C25H29ClN4O2S: C, 61.92; H, 5.99; N, 11.56; Found: C,
61.91; H, 6.12; N, 11.36.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[N-(6-
chloropyrida zine-3-yl)-N-(4-amino
benzenesulfonyl)]amino]propylpiperazine (3j)
Yield: 43%. m.p.: 91–92°C. [a]3D0: -6.88 (c = 1, EtOH).
IR (KBr) cm-1: 3440 (N–H), 3051, 3023 (Ar–H), 2948,
2882, 2813 (–CH2–), 1630, 1597, 1503, 1484 (aromatic
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[2-[4-[N-
(pyrimidine-2-yl)amino]sulfonyl]phenyl
amino]ethylpiperazine (3g)
1
ring). H-NMR (CDCl3) d: 1.76 (m, 2H), 2.23 (m, 8H),
3.97 (d, J = 9.4, 2H), 4.19 (s, 1H), 4.22 (t, J = 9.4, 2H),
6.61 (d, J = 8.7, 2H),7.47 (d, J = 9.4, 1H), 7.89 (d,
J = 9.4, 1H), 7.20–7.38 (m, 11H), 7.27 (s, CDCl3). MS m/z:
611.3 (M?). Anal. Calcd for C30H32Cl2N6O2S: Calculated:
C, 58.91; H, 5.24; N, 13.75; Found: C, 58.97; H, 5.63; N,
13.86.
Yield: 60%. m.p.: 110–112°C. [a]3D0: -8.13 (c = 1, EtOH).
IR (KBr) cm-1: 3465, 3378, 3222 (N–H), 3059, 3038
(Ar–H), 2958, 2875, 2809 (–CH2–), 1625, 1601, 1487,
1
1438 (atomatic ring). H-NMR (CDCl3) d: 2.20–2.65 (m,
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Med Chem Res (2012) 21:124–132
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[4-[N-(6-
chloropyridazine-3-yl)amino]sulfonyl]
phenylamino]propylpiperazine (3k)
J = 8.7, 2H), 7.19–7.39 (m, 9H), 7.28 (s, CDCl3). MS m/z:
605.1 (M?). Anal. Calcd for C32H37ClN6O2S: C, 63.49; H,
6.12; N, 13.89; Found: C, 63.47; H, 6.35; N, 13.75.
Yield: 42%. m.p.: 106–107°C. [a]3D0: -7.17 (c = 1, EtOH).
IR (KBr) cm-1: 3441, 3368, 3233 (N–H), 3061, 3024 (Ar–
H), 2952, 2882, 2806 (–CH2–), 1619, 1597, 1528, 1488
(aromatic ring). 1H-NMR (CDCl3) d: 1.95 (m, 2H),
2.30–2.40 (m, 8H), 3.86 (s, 2H), 4.18 (s, 1H), 4.30 (ddd,
J = 7.7, J = 3.9, 2H), 6.53 (d, J = 8.6, 2H),7.68 (d,
J = 8.6, 2H), 7.20 (d, J = 9.8, 1H), 8.25 (d, J = 9.8, 1H),
7.23–7.38 (m, 9H), 7.27 (s, CDCl3). MS m/z: 611.3 (M?).
Anal. Calcd for C30H32Cl2N6O2S: C, 58.91; H, 5.24; N,
13.75; Found: C, 58.85; H, 5.23; N, 14.02.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[(4-
amino)sulfonyl]phenylamino]propyl piperazine (3o)
Yield: 59%. m.p.: 73–75°C. [a]3D0: -6.41 (c = 1, EtOH).
IR (KBr) cm-1: 3465, 3371, 3243 (N–H), 3062, 3027(Ar–
H), 2955, 2878, 2812(–CH2–), 1625, 1598, 1487, 1448
1
(aromatic ring). H-NMR (CD3OD) d: 1.61 (m, 2H), 2.43
(m, 8H), 2.92 (t, J = 7.0, 2H), 3.32 (t, J = 1.4, 2H), 4.24
(s, 1H), 6.67 (d, J = 8.2, 2H), 7.52 (d, J = 8.2, 2H),
7.20–7.39 (m, 9H), 4.88 (s, CD3OD). MS m/z: 499.2 (M?).
Anal. Calcd for C26H31ClN4O2S: C, 65.59; H, 6.22; N,
11.23; Found: C, 62.32; H, 6.31; N, 11.33.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[N-
(thiazole-2-yl)-N-(4-aminobenzene
sulfonyl)]amino]propylpiperazine (3l)
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[4-[N-
(pyrimidine-2-yl)amino] sulfonyl]
phenylamino]propylpiperazine (3p)
Yield: 40%. m.p.: 97–99°C. [a]3D0: -8.80 (c = 1, EtOH).
IR (KBr) cm-1: 3447, 3385, 3213 (N–H), 3069, 3022 (Ar–
H), 2956, 2875, 2805 (–CH2–), 1625, 1594, 1497, 1458
Yield: 50%. m.p.: 109–111°C. [a]3D0: -6.23 (c = 1, EtOH).
IR (KBr) cm-1: 3468, 3375, 3243 (N–H), 3062, 3027
(Ar–H), 2955, 2882, 2816 (–CH2–), 1625, 1598, 1483,
1448 (aromatic ring). 1H-NMR (CDCl3) d: 1.27 (t, J = 7.0,
2H), 2.05 (t, J = 7.0, 2H), 2.45–2.51 (m, 6H), 3.75 (q,
J = 7.0, 1H), 4.14 (s, 1H), 4.25 (t, J = 7.0, J = 9.4, 3H),
6.62 (t, J = 7.5, 2H), 6.82 (d, 1H), 7.86 (t, J = 7.5, 1H),
8.41 (d, J = 4.6, 2H), 7.19–7.39 (m, 9H), 7.28 (s, CDCl3).
MS m/z: 577.2 (M?). Anal. Calcd for C30H33ClN6O3S: C,
62.45; H, 5.72; N, 14.57; Found: C, 62.60; H, 5.79; N,
14.78.
1
(aromatic ring). H-NMR (CDCl3) d: 1.88 (m, 2H), 2.44
(m, 8H), 3.93 (t, J = 7.0, 2H), 4.20 (s, 3H), 6.61 (d,
J = 7.1, 2H), 6.98 (d, J = 3.4, 1H), 7.20–7.39 (m, 10H),
7.56 (d, J = 8.1, 2H), 7.27 (s, CDCl3). MS m/z: 597.2
(M?). Anal. Calcd for C29H32ClN5O2S2: C, 58.41; H, 5.71;
N, 11.75; Found: C, 58.56; H, 5.62; N, 11.69.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[4-[N-
(thiazole-2-yl)amino]sulfonyl]
phenylamino]propylpiperazine (3m)
Yield: 63%. m.p.: 107–109°C. [a]3D0: -3.63 (c = 1, EtOH).
IR (KBr) cm-1: 3455, 3369, 3237 (N–H), 3059, 3024 (Ar–
H), 2953, 2879, 2809 (–CH2–), 1629, 1598, 1505, 1431
(aromatic ring). 1H-NMR (CDCl3) d: 1.84 (m, 2H), 2.26 (t,
J = 7.4, 2H), 2.33 (m, 6H), 3.98 (m, 4H), 4.19 (s, 1H), 6.38
(d, J = 4.7, 1H), 6.56 (d, J = 8.5, 2H), 6.83 (d, J = 4.7, 1H),
7.71 (d, J = 8.5, 2H), 7.19–7.38 (m, 9H), 7.27 (s, CDCl3).
MS m/z: 597.2 (M?). Anal. Calcd for C29H32ClN5O2S2: C,
58.41; H, 5.71; N, 11.75; Found: C, 58.47; H, 5.82; N, 11.81.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[4-[N-(6-
methoxypyridazine-3-yl)amno]
sulfonyl]phenylamino]propylpiperazine (3q)
Yield: 53%. m.p.: 101–103°C. [a]3D0: -5.12 (c = 1, EtOH).
IR (KBr) cm-1: 3450, 3361, 3222 (N–H), 3055, 3024 (Ar–
H), 2939, 2875, 2810 (–CH2–, –CH3), 1631, 1596, 1501,
1
1452 (aromatic ring). H-NMR (CDCl3) d: 1.99 (m, 2H),
2.43 (m, 8H), 3.83 (s, 3H), 3.85 (s, 2H), 4.19 (s, 1H), 4.25
(t, J = 6.2, 2H), 6.55 (d, J = 8.6, 2H), 7.70 (d, J = 8.6,
2H), 6.97 (d, J = 9.4, 1H), 8.21 (d, J = 9.4, 1H),
7.20–7.39 (m, 9H), 7.28 (s, CDCl3). MS m/z: 607.2 (M?).
Anal. Calcd for C31H35ClN6O3S: C, 61.34; H, 5.77; N,
13.85; Found: C, 61.12; H, 5.86; N, 13.69.
(R)(-)-1-[(4-chlorophenyl)phenyl]methyl-4-[3-[4-[N-(4,6-
dimethylpyrimidine-2-yl)amino]
sulfonyl]phenylamino]propylpiperazine (3n)
Yield: 65%. m.p.: 213–215°C. [a]3D0: -4.50 (c = 1, EtOH).
IR (KBr) cm-1: 3465, 3364, 3250 (N–H), 3062, 3024 (Ar–
H), 2958, 2875, 2816 (–CH2–, –CH3), 1636, 1598, 1560,
General procedure for the preparation of 3r and 3s
1
1445 (aromatic ring). H-NMR (CDCl3) d: 2.05 (m, 2H),
2.29 (s, 6H), 2.30–2.62 (m, 8H), 4.11 (s, 2H), 4.22 (s, 1H),
Glycine methyl ester (0.89 g, 0.01 mol) (instead of L-ala-
nine methyl ester used for 3s) was added to a stirring
solution of TEA (4 ml, 0.028 mol) and 2b (3.63 g,
4.25 (s, 2H), 6.53 (s, 1H), 6.61 (d, J = 8.7, 2H), 7.88 (d,
123

Med Chem Res (2012) 21:124–132
131
Anti-asthmatic activity
0.01 mol) in acetonitrile (30 ml). When TLC analysis
showed no remaining starting material, the mixture was
filtered to remove the triethylamine hydrochloride. The
filtrate was concentrated using a rotary evaporator (40°C,
40 mmHg). The residue was dissolved in chloroform
(30 ml) and then washed with water (3 9 20 ml). After
chloroform was removed, methanol (20 ml) and 2N
sodium hydroxide (10 ml) were added to the residue, stir-
red at room temperature for 6 h, and evaporated to remove
methanol under reduced pressure. The pH value was
adjusted to 5 with dilute hydrogen chloride, extracted with
chloroform (3 9 20 ml). The organic layer was washed
with brine (3 9 20 ml), dried overnight with magnesium
sulfate, filtered, and evaporated under reduced pressure.
The residue was purified on a silica gel column eluted with
ethanol and chloroform (1:2, v/v), producing product 3r
(3s).
Cavies were divided into 23 groups (n = 10/group). The
administration group was fed with 5 ml/kg (10 mg/ml, i.e.,
50 mg/kg) of the target compounds, while the positive
control group was orally administered with levocetirizine
(50 mg/kg). Meanwhile, the blank control group was given
distilled water of equal volumes. One hour after adminis-
tration, all the cavies were treated with histamine phos-
phate (0.2%) in the state of ultrasonic pulverization for
20 s. The latent period of asthma was recorded, and final
data were statistically analyzed (Table 2).
Anti-pruritic activity
The experimental animals were divided into 23 groups
(n = 10/group). The administration group was fed with
5 ml/kg (10 mg/mL, i.e., 50 mg/kg) of the target com-
pounds, while the positive control group was orally
administered with levocetirizine (50 mg/kg). Meanwhile,
the blank control group was given distilled water of equal
volumes. One hour after administration, histamine phos-
phate (0.05 ml, 0.01%) was dropped on the scraped right
hind feet of the cavies; the amount of histamine phosphate
was increased by 0.01, 0.02, 0.03, 0.04, and 0.05% every
3 min until the cavies began licking their right hind foot.
The total amount of histamine phosphate was recorded, and
final data were statistically analyzed (Table 3).
(R)(-)-2-[3-[4-(4-chlorophenyl)phenylmethyl]piperazine-1-
yl]propylamino acetic acid (3r)
Yield: 54%. m.p.: 111–113°C. [a]3D0: -5.58 (c = 1, EtOH).
IR (KBr) cm-1: 3430 (N–H), 3180–2521 (COO–H), 3059,
3024 (Ph–H), 2962, 2817 (–CH2–), 1624, 1486, 1449
1
(benzene ring). H-NMR (CD3OD) d: 1.79–1.88 (m, 2H),
2.52–2.70 (m, 10H), 3.08 (d, J = 8.4, 2H), 3.14 (d,
J = 5.8, 1H), 3.48 (d, J = 7.2, 1H), 4.32 (s, 1H), 7.18–7.46
(m, 9H), 7.29 (t, J = 4.8, 4H), 7.40–7.45 (m, 4H), 4.88 (s,
CD3OD). MS m/z: 402.2 (M?). Anal. Calcd for
C22H28ClN3O2: C, 65.75; H, 6.97; N, 10.46; Found: C,
65.45; H, 6.88; N, 10.52.
Acknowledgments The work was supported by the Scientific
Research Startup Foundation of Chinese Ministry of Education for
Returnee (jiaowaisiliu-2007-1108) and the Scientific Research
Startup Foundation of Guangxi University (X071038).
(R)(-)-2-[3-[4-(4-chlorophenyl)phenylmethyl]piperazine-1-
yl]propylamino propanoic acid (3s)
References
Yield: 52%. m.p.: 125–126°C. [a]3D0: -6.00 (c = 1, EtOH).
IR (KBr) cm-1: 3420 (N–H), 3199–2500 (COO–H), 3059,
3027 (Ph–H), 2953, 2875, 2809 (–CH2–, –CH3), 1622,
Akdis M (2009) Immune tolerance in allergy. Curr Opin Immunol
21:1–8
Banu Y, Watanabe T (1999) Augmentation of antigen receptor–
mediated responses by histamine H1 receptor signaling. J Exp
Med 189:673–682
1
1489, 1454 (benzene ring). H-NMR (CD3OD) d: 1.46 (d,
J = 7.2, 3H), 1.79–1.88 (m, 2H), 2.52–2.70 (m, 10H), 3.08
(d, J = 8.4, 2H), 3.13 (d, J = 5.8, 1H), 3.49 (d, J = 7.2,
1H), 4.32 (s, 1H), 7.19–7.46 (m, 9H), 4.88 (s, CD3OD). MS
m/z: 416.2 (M?). Anal. Calcd for C23H30ClN3O2: C, 66.43;
H, 7.22; N, 10.11; Found: C, 66.67; H, 7.35; N, 10.24.
Boos TL, Greiner E, Jason Calhoun W et al (2006) Structure–activity
relationships of substituted N-benzyl piperidines in the GBR
series: synthesis of 4-(2-(bis(4-fluorophenyl)methoxy)ethyl)-1-
(2-trifluoromethylbenzyl) piperidine, an allosteric modulator of
the serotonin transporter. Bioorg Med Chem 14:3967–3973
Day JH, Ellis AK, Rafeiro E (2004) Levocetirizine: a new selective
H1 receptor antagonist for use in allergic disorders. Drugs Today
40:415–423
De Bruin ML, van Puijenbroek EP, Egberts ACG et al (2002) Non-
sedating antihistamine drugs and cardiac arrhythmias-biased risk
estimates from spontaneous reporting systems? Br J Clin
Phamcol 53:370–374
Anti-allergic activity
All synthesized compounds were tested for anti-allergic
activities using cavies, purchased from Center of Animal
Research in Guangxi Medical University. The cavies had a
weight range of 200 20 g. The tested compounds were
dispersed in distilled water at a concentration of 10 mg/ml.
Devalia JL, De Vos C, Hanotte F et al (2001) A randomized, double-
blind, crossover comparison among cetirizine, levocetirizine,
and ucb 28557 on histamine-induced cutaneous responses in
healthy adult volunteers. Allergy 56:50–57
123

132
Med Chem Res (2012) 21:124–132
´
Fan H, Xu G, Chen Y et al (2007) Synthesis and antibacterial activity
of oxazolidinones containing triazolyl group. Eur J Med Chem
42:1137–1143
Gandon JM, Allain H (2002) Lack of effect of single and repeated
doses of levocetirizine, a new antihistamine drug, on cognitive
and psychomotor functions in healthy volunteers. Br J Clin
Pharmacol 54:51–58
Lloret GR, Neto AC, Rittner R et al (2009) Synthesis and rational
design of anti-inflammatory compounds: N-phenyl-cyclohexenyl
sulfonamide derivatives. J Phys Org Chem 22:1188–1192
Mavrova ATs, Anichina KK, Vuchev DI et al (2006) Antihelminthic
activity of some newly synthesized 5(6)-(un)substituted-1H-
benzimidazol-2-ylthioacetylpiperazine derivatives. Eur J Med
Chem 41:1412–1420
Girisha HR, Narendra Sharath Chandra JN, Boppana S et al (2009)
Active site directed docking studies: synthesis and pharmacolog-
ical evaluation of cis-2,6-dimethyl piperidine sulfonamides as
inhibitors of acetylcholinesterase. Eur J Med Chem 44:4057–4062
Hancock AA (2006) The challenge of drug discovery of a GPCR
target: analysis of preclinical pharmacology of histamine H3
antagonists/inverse agonists. Biochem Pharmacol 71:1103–1113
Husain A (2009) Amide derivatives of sulfonamides and isoniazid:
synthesis and biological evaluation. Acta Pol Pharm 66:513–521
Ishiwata K, Kawamura K, Wang W-F et al (2004) Evaluation of in
vivo selective binding of [11C] doxepin to histamine H1 receptors
in five animal species. Nucl Med Biol 31:493–502
Mullins RJ, Dear KBG, Tang MLK (2009) Characteristics of
childhood peanut allergy in the Australian Capital Territory,
1995 to 2007. J Allergy Clin Immunol 123:689–693
Sicherer SH, Leung DYM (2009) Advances in allergic skin disease,
anaphylaxis, and hypersensitivity reactions to foods, drugs, and
insects in 2008. J Allergy Clin Immunol 123:319–327
Slater JW, Zechnich AD, Haxby DG (1999) Second-generation
antihistamines: a comparative review. Drugs 57(1):31–47
Smith HE, Hogger C, Lallemant C et al (2009) Is structured allergy
history sufficient when assessing patients with asthma and rhinitis
in general practice? J Allergy Clin Immunol 123:646–650
Wang DY, Hanotte F, De Vos C et al (2001) Effect of cetirizine,
levocetirizine, and dextrocetirizine on histamine-induced nasal
response in healthy adult volunteers. Allergy 56:339–343
Wang L-S, Wand T-W, Zhu H-Y (2007) Synthesis of levocetirizine.
J Guangxi Univ (Nat Sci Ed) 32:384–386
Kayasuga R, Sugimoto Y, Watanabe T et al (2002) Histamine H1
receptors are involved in mouse nasal allergic responses: a
demonstration with H1 receptor-deficient mice. Int Immuno-
pharmacol 2:745–750
Li X-M, Brown L (2009) Efficacy and mechanisms of action of
traditional Chinese medicines for treating asthma and allergy.
J Allergy Clin Immunol 123:297–306
123