Synthesis and antihistamine evaluations of novel loratadine analogues

Article abstract of DOI:10.1016/j.bmcl.2011.06.012

A series of loratadine analogues containing hydroxyl group and chiral center were synthesized. The effect of the synthesized compounds on the histamine-induced contractions of guinea-pig ileum muscles was studied. In addition, the in vivo asthma-relieving effect of the analogues in the histamine induced asthmatic reaction in guinea-pigs was determined. Most of the compounds exhibited definite H₁ antihistamine activity. The S-enantiomers, compounds 2, 4 and 8, are more potent than the R-enantiomers, compounds 1, 3 and 7. Compound 6 was the most active one among the eight synthesized compounds.

Full text of DOI:10.1016/j.bmcl.2011.06.012

Bioorganic & Medicinal Chemistry Letters 21 (2011) 4454–4456
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and antihistamine evaluations of novel loratadine analogues
Yue Wang a, Juan Wang b, Yan Lin a, Li-Feng Si-Ma a, Dong-hua Wang c, Li-Gong Chen a, , Deng-Ke Liu d
⇑
a School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, PR China
b School of Chemical Engineering, Shijiazhuang University, Shijiazhuang, Hebei 050035, PR China
c School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, PR China
d Tianjin Institute of Pharmaceutical Research, Tianjin 300072, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of loratadine analogues containing hydroxyl group and chiral center were synthesized. The effect
of the synthesized compounds on the histamine-induced contractions of guinea-pig ileum muscles was
studied. In addition, the in vivo asthma-relieving effect of the analogues in the histamine induced asth-
matic reaction in guinea-pigs was determined. Most of the compounds exhibited definite H1 antihista-
mine activity. The S-enantiomers, compounds 2, 4 and 8, are more potent than the R-enantiomers,
compounds 1, 3 and 7. Compound 6 was the most active one among the eight synthesized compounds.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 15 March 2011
Revised 11 May 2011
Accepted 3 June 2011
Available online 16 June 2011
Keywords:
Synthesis
Antihistamine
Loratadine
Allergy disorders, such as asthma, urticaria and allergic rhinitis,
are common human diseases. Although pathogenic factors are
complicated, investigations have indicated that these diseases are
mainly caused by histamine.1,2 Histamine can activate H1 receptors
which are present in nerve endings, smooth muscles, and glandular
cells. Activation is followed by vasodilation and increased capillary
permeability which leads to plasma exudation, local tissue swell-
ing, and bronchial and gastrointestinal smooth muscle contrac-
tions.3,4 Antihistamine compounds competitively bind to H1
receptors to prevent them from attacking and being activated by
histamine, which inhibits the biological effects of histamine.5 Anti-
histamines are a class of commonly prescribed drugs, and numer-
ous reviews are available6–12 Loratadine, cetirizine and astemizole
are second-generation antihistamines which have replaced first-
generation antihistamines such as diphenhydramine and ketotifen
because of they have fewer CNS (central nervous system) and anti-
cholinergic side effects.13–17 Loratadine has a potent therapeutic
effect by reason of its semi-rigid conformation.18,19 The chair con-
formation of the piperidine ring seems to be important in allowing
the basic nitrogen to interact with the H1 receptor.20 Lewis et al. re-
ported a series of loratadine-based compounds that exhibited both
H1 histamine receptor antagonist activity and 5-lipoxygenase
(5-LO) inhibitory activity.21 Liu et al. successfully synthesized a
series of loratadine derivatives using c-alkylidene butenolide and
found that several of them displayed potent activity for inhibiting
histamine-induced effects.22
Cl
Cl
N
N
N
N
CO2Et
Loratadine
Chlorpheniramine
Figure 1.
In this paper, hydroxyl group and chiral center were introduced
into the molecules in order to enhance its affinity for the H1 recep-
tor. The effect of different stereoisomers on the antihistamine
effects was also investigated. Eight loratadine analogues 1–8 were
synthesized and their antihistamine activities were evaluated
against chlorpheniramine. Chlorpheniramine (Fig. 1) has better
antihistamine activities than loratadine23,24, although it is a kind
of first-generation type H1 antihistamine with CNS side-effects.
Compounds synthesized based on the structure of loratadine can
avoid such side-effects and are expected to exhibit good antihista-
mine activities.
A series of chiral hydroxyl group containing N-substituted-
4-piperidones were obtained from chiral or achiral amino alcohols
and methyl acrylate via a Michael addition, a Dieckmann cycliza-
tion and decarboxylation in about 35% yield. The various carbonyls
obtained from the above piperidones were coupled with a tricyclic
ketone using a low valent titanium catalyst to afford a series of
target compounds in about 25% yield25–29 (Scheme 1).
⇑
Corresponding author. Tel./fax: +86 022 27406314.
E-mail address: lgchen@tju.edu.cn (L.-G. Chen).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.06.012

Y. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4454–4456
4455
O
O
O
a)
b)
c)
O
RN
RNH2
+
N
R
O
O
O
1b~8b
1a~8a
O
Cl
Cl
d)
+
N
N
N
R
O
N
R
1~8
HO
HO
HO
HO
R=
1
2
3
4
OH
OH
5
6
7
8
Scheme 1. Loratidine Analogues Synthesis. Reagents and conditions: (a) MeOH, 40 °C, 12 h; (b) MeONa/MeOH 30%aq, toluene, 110 °C, 5 h; (c) conc. HCl, 100 °C, 5 h; (d) TiCl4/
Zn, THF dry, 70 °C, 17 h; See Supplementary data for experimental details.
Table 1
The effects of eight synthesized compounds on the inhibition of histamine
a
b
Groups
Large dose groups
Small dose groups
The incubation period before
drug (s)
The incubation period after drug The incubation period before
The incubation period after drug
(s)
(s)
drug (s)
Negative control group
Chlorphenira-mine
98.70 46.88
98.10 17.05
99.30 30.06
97.00 43.29
94.20 16.80
95.50 18.98
105.70 17.27
214.70 29.20⁄⁄
group
1
2
3
4
5
6
7
8
101.50 34.31
95.10 16.02
95.50 19.85
92.00 22.35
95.90 17.16
94.50 16.96
93.80 27.48
103.40 33.79
215.60 7.40⁄⁄
209.70 9.56⁄⁄
229.20 24.39⁄⁄
216.00 12.49⁄⁄
248.50 22.27⁄⁄
360.00 0.00⁄⁄
309.60 31.01⁄⁄
273.20 37.62⁄⁄
99.20 31.48
93.50 16.37
94.10 16.30
92.90 19.28
93.10 15.93
91.90 15.79
93.10 23.27
100.50 32.49
111.10 26.42
112.80 40.76
125.30 40.33⁄
123.10 23.20⁄⁄
133.30 27.79⁄⁄
360.00 0.00⁄⁄
210.60 51.82⁄⁄
170.20 57.45⁄⁄
Compared to the negative control group: ⁄P < 0.05, ⁄⁄P < 0.01.
a
The large dose chlopheniramine group (0.5 mg/kg) and the eight large dose compounds groups (0.5 mg/kg) were pretreated with intragastric administration in 4 mL/kg
bw.
b
The small dose chlopheniramine group (0.2 mg/kg) and eight little dose compounds groups (0.2 mg/kg) were pretreated with intragastric administration in 4 mL/kg bw.
See Supplementary data for assay details.
Compounds 1–8 were tested for their asthma-relieving effects
by using the asthmatic reaction caused by histamine in guinea-
pigs. (Table 1) Chlorpheniramine was used as the positive control.
The guinea pigs were pretreated with intragastric administration
of the chlorpheniramine and eight synthesized compounds and
then sprayed with a histamine phosphate solution to induce the
guinea pigs model of experimental asthma. The asthmogenic latent
periods were determined in order to determine the anti-histamine
activity of tested compounds. The untreated groups served as the
negative control groups (blank control groups).
As shown in Table 1, it is apparent that the asthmogenic latency
periods of the guinea pigs were prolonged by the eight compounds
and chlopheniramine in both dose groups. The advantage is also
significant compared to the negative control group (P < 0.01). In
the large dosage groups, compounds 1–6, which all contain a hy-
droxyl group, all prolonged the asthmogenic latent periods in the
guinea pigs, compound 6 had the strongest effect with a period
of over 360s. This indicates that the introduction of a hydroxyl
group into the molecule can significantly enhance the antihista-
mine potency. Moreover, different positions of the hydroxyl group

4456
Y. Wang et al. / Bioorg. Med. Chem. Lett. 21 (2011) 4454–4456
Table 2
more potent than the R-isomers. Among the tested compounds,
compound 6 would be the best compound for the development
of new drugs as anti-allergy medications.
The effects of the eight compounds on the inhibition of histamine induced smooth
muscle spasms in guinea pigs
Groups
Antispasmodic
percentage (%)
Groups
Antispasmodic
percentage (%)
Acknowledgment
Negative control group
Chlorpheniramine group
1
2
3
0.31 6.83⁄⁄
4
5
6
7
8
53.52 7.54⁄⁄
50.63 13.99⁄⁄
53.73 9.86⁄⁄
31.45 8.56⁄⁄
32.06 5.59⁄⁄
41.31 3.65
The authors thank professor Ren-bin Huang of GuangXi Medical
University for the in vivo and in vitro antihistamine assays.
32.37 5.67⁄⁄
49.73 7.77⁄⁄
29.37 1.50⁄⁄
Supplementary data
Compared to the control group: ⁄P < 0.05, ⁄⁄P < 0.01. The concentration of Chlor-
pheniramine and the 8 compounds was 2 Â 10À3 mg/mL. See Supplementary data
for assay details.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.bmcl.2011.06.012.
References and notes
in the molecule led to different results. The effects of a 3-carbon
linker are more obvious than a 2-carbon linker. For example, com-
pound 6 led to a longer asthmogenic latent period than 5. The lin-
ear hydroxyl side chain containing compound 5 is more potent
than compounds 1, 2, 3 and 4 which have a hydroxyl side chain
with an alkyl substituent group. The R and S enantiomers of com-
pounds 1 and 3 and compounds 2 and 4 contributed no evident
diversity. However, the R enantiomer of compound 7 with a ben-
zene ring instead of a hydroxyl group was more active than its S
enantiomer. The same trends were in the small dosage group.
Compound 6 with a straight hydroxyl containing was the most ac-
tive among the eight synthesized compounds with a latent period
of over 360s.
The next area of focus was to investigate the effects of the eight
compounds on the inhibition of in vitro histamine induced muscle
spasms using isolated ileum smooth muscle from guinea pigs.
Chlorpheniramine was again used as the positive control. The con-
traction intensity of guinea pig ileum was treated as index in order
to preliminarily judge the anti-histamine activity of target com-
pounds in vitro. The effects of eight compounds on the inhibition
of guinea pigs smooth muscle spasms induced by histamine are
shown in Table 2.
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