Synthesis and biological evaluation of substituted desloratadines as potent arginine vasopressin V2 receptor antagonists

Article abstract of DOI:10.3390/molecules19022694

Twenty-one non-peptide substituted desloratadine class compounds were synthesized as novel arginine vasopressin receptor antagonists from desloratadine via successive acylation, reduction and acylation reactions. Their structures were characterized by ¹H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo studies. The in vitro binding assay and cAMP accumulation assay indicated that these compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t is a potent novel AVP V2 receptor antagonist candidate.

Full text of DOI:10.3390/molecules19022694

Molecules 2014, 19, 2694-2706; doi:10.3390/molecules19022694
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Synthesis and Biological Evaluation of Substituted
Desloratadines as Potent Arginine Vasopressin V2
Receptor Antagonists
Shuai Mu 1,2, Ying Liu 2, Min Gong 2, Deng-Ke Liu 2 and Chang-Xiao Liu 3,*
1
School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China;
E-Mail: mushuai2005@163.com
2
Tianjin Key Laboratory of Molecular Design and Drug Discovery,
Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China;
E-Mails: liuy6@tjipr.com (Y.L.); gongm@tjipr.com (M.G.); liudk@tianjinipr.com (D.-K.L.)
3
State Key Laboratory of Drug Delivery Technology and Pharmacokinetics,
Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
* Author to whom correspondence should be addressed; E-Mail: liuchangxiao@163.com;
Tel./Fax: +86-22-2300-6856.
Received: 2 December 2013; in revised form: 14 January 2014 / Accepted: 26 January 2014 /
Published: 24 February 2014
Abstract: Twenty-one non-peptide substituted desloratadine class compounds were
synthesized as novel arginine vasopressin receptor antagonists from desloratadine via
successive acylation, reduction and acylation reactions. Their structures were characterized
1
by H-NMR and HRMS, their biological activity was evaluated by in vitro and in vivo
studies. The in vitro binding assay and cAMP accumulation assay indicated that these
compounds are potent selective V2 receptor antagonists. Among them compounds 1n, 1t
and 1v exhibited both high affinity and promising selectivity for V2 receptors. The in vivo
diuretic assay demonstrated that 1t presented remarkable diuretic activity. In conclusion, 1t
is a potent novel AVP V2 receptor antagonist candidate.
Keywords: substituted desloratadine; synthesis; arginine vasopressin receptor antagonists;
biological activity

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1. Introduction
Arginine vasopressin (AVP), a neurohypophysial peptide hormone that is secreted mainly from the
posterior pituitary gland in response to low blood volume or high serum osmolality exerts its biological
action through three major G-protein-coupled receptors, V1a, V1b and V2 [1–3]. The V2 receptors,
which are localized predominately in the kidney collecting tubules, are responsible for controlling
water reabsorption and salt (NaCl) balance [4]. The receptor stimulates adenylate cyclase, which
results in the production of cyclic AMP [5]. Thus, there is potential to develop a vasopressin V2 receptor
antagonist for the treatment of disorders such as congestive heart failure [6–9], hypertension [10,11], renal
disease [12,13], edema [14,15], liver cirrhosis [16,17], hyponatremia [18–22], inappropriate antidiuretic
hormone secretion (SIADH) syndrome [23] and any state involving excessive retention of water.
Numerous AVP receptor antagonists were developed and evaluated in recent decades [24–30].
A few of them have undergone sufficient clinical trials to be on the market, such as the dual V1a/V2
receptor antagonist conivaptan and the selective V2 receptor antagonist tolvaptan approved for the
treatment of hyponatremia in the USA. Another promising selective AVP V2 receptor antagonist,
lixivaptan, is still undergoing phase 3 clinical trials at this moment. The structures of most extant AVP
receptor antagonists include a benzene-fused seven membered ring system (ring A) and two aromatic
rings (ring B and ring C) linked through amide bonds. Recently, we reported some amide and
sulfamide derivatives of desloratadine, which are potent AVP V2 receptor antagonists [31].
Desloratadine is a selective, H1-receptor antagonist, and also has anti-inflammatory activity [32]. In the
previous study, ring A and ring B of classic V2 receptor antagonists were replaced by desloratadine
(Figure 1). In a continuous study, we synthesized several compounds centered on a desloratadine
scaffold as ring A (compounds 1a, 1b, 1h and 1i, see Table 1) and found that they exhibited potent
diuretic activity [33]. Therefore, additional compounds with a desloratadine scaffold as ring A were
designed, synthesized and evaluated. Herein, we report the synthesis and biological evaluation of this
series of substituted desloratadine designed as potent AVP V2 receptor agonists.
Figure 1. Chemical structures of tolvaptan, lixivaptan and desloratadine (black: previous
study; red: reported here in this article).

Molecules 2014, 19
Table 1. The structures of the target compounds and their biological activity evaluation.
2696
Bingding Assy
cAMP
Assay
Structures of Target Compound
Position
Volume of
Urine
(IC50; nmol/mL)
Compound
(V2, IC50;
nmol/mL)
26
(mL, 0–20 h)
X1
X2
R
V2
V1a
Of -NH2
p-NH2
p-NH2
p-NH2
p-NH2
m-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
p-NH2
m-NH2
m-NH2
m-NH2
m-NH2
p-NH2
p-NH2
1a
1b
CO CO
CO CO
CO CO
CO SO2
SO2 CO
SO2 CO
CO CO
CO CO
CO CO
CO CO
CO CO
CO CO
CO CO
CO CO
CO CO
CO CO
CO SO2
CO SO2
CO SO2
SO2 CO
SO2 CO
SO2 CO
SO2 SO2
SO2 CO
SO2 SO2
-CH2CH3
-CH2CH2CH3
-CH2CH2CH2Cl
-CH2CH3
-CH2CH2CH3
-CH2CH2CH3
H
6.3
47
25
11
26
40
19
23
18
15
27
16
20
8.5
18
52
24
11
9.2
7.7
19
5.5
30
310
170
130
>1000
>1000
92
27.5±5.7
21.4±4.1
1c
1d
160
1e
176
1f
480
1g
330
1h
2-Me
210
1i
4-Me
220
1j
3-Me
370
53
19.3 ± 5.5
19.9 ± 6.7
1k
2-Cl
490
1l
3-Cl
560
1m
1n
2-F
170
3-OMe
3-NO2
4-NO2
4-Me
390
380
1o
550
1p
>1000
720
1q
1r
2-Cl
830
220
37
16.1 ± 3.2
18.3 ± 4.3
28.1 ± 5.0
1s
2,5-DiCl
H
320
1t
>1000
840
98
1u
3-Cl
1v
3- NO2
4-Me
630
110
11.9 ± 2.7
1w
1x
860
3-Cl
>1000
920
1y
4-Me
Control
tolvaptan
6.5 ± 0.5
28.0 ± 6.5
2. Results and Discussion
The synthetic routes used in this study are illustrated in Schemes 1 and 2, respectively. As shown in
Scheme 1, the acylation of 2 with a p-nitrobenzoyl chloride, p-nitrobenzene sulfonyl chloride or
m-nitrobenzene sulfonyl chloride provided 4a–c, which were subsequently reduced with SnCl2 to
provide the corresponding anilines 5a–c in satisfied yields. Acylation of 5a–c with alkyl chloride or

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alkylsulfonyl chloride yielded the target compounds 1a–f. Similarly, as shown in Scheme 2, acylation
of 5a–c with substituted benzoyl chlorides or benzenesulfonyl chlorides gave target product 1g–y.
Scheme 1. Synthetic route to 1a–f.
Reagents and Conditions: i: DCM, TEA, 0 °C. ii: SnCl2 and concentrated hydrochloric acid in refluxing
ethanol; iii: Alkyl chloride or alkylsulfonyl chloride; DCM, TEA, 0 °C.
Scheme 2. Synthetic route to 1g–y.
Reagents and Conditions: iv. Substituted benzoyl chloride or benzenesulfonyl chloride, DCM, TEA, 0 °C.
1
Twenty-one compounds 1c–g, 1j–y were synthesized and characterized by H-NMR and HRMS. In
order to provide a comprehensive understanding of the structure-activity relationships, compounds 1a,
1b, 1h and 1i were included in this research as well. The structures of the target compounds 1a–y and
evaluation of the biological features were summarized in Table 1. The binding affinity was determined
by a radioligand binding assay and cAMP assay on V1a and V2 over-expressing cells. These compounds
had specific affinity to human AVP receptors. Furthermore, they showed high selectivity to V2
receptors. When ring C was replaced by an alkyl group with straight chain, their binding constants to
V2 receptor were reduced significantly along the length increase of the carbon chain.
Halogen-substituted alkyl group slightly increased their binding affinity to V2 receptors. When ring C
was a substituted benzene ring, the different substituted positions of methyl or halogen did not
significantly affect the binding affinity to V2 receptors or V1a/V2 selectivity of the compounds.

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Moreover, meta-substituted compounds had a relatively higher binding affinity to V2 receptors than
ortho-substituted or para-substituted compounds. Compounds 1x and 1y showed poor binding activity
to both V1a and V2 receptors. Compounds 1a, 1n, 1t and 1v presented encouraging binding affinity,
with both remarkable binding affinity and selectivity for the V2 receptor.
Several compounds with satisfactory binding affinity were selected to conduct the in vivo diuretic
assay, with 1a as the reference compound [33]. As shown in Table 1, it is evident that the selected
compounds have significant diuretic activity, as they strongly increased urine volume compared with
the control group. Compound 1t exhibited an excellent diuretic activity which was equivalent to
tolvaptan. It is very difficult to declare the relationship between diuretic activity and binding affinity.
Because of specific differences in the vasopressin receptors, it may be difficult to draw a direct
comparison between the diuretic assay in rats and the binding assay in cells expressing the human receptor.
3. Experimental
3.1. General Information
Desloratadine was purchased from Beijing Datian Fengtuo Chemistry Co., Ltd (Beijing, China).
Other reagents and solvents were obtained from commercial suppliers. The human recombinant
vasopressin V1a (Cat. ES-361-C) and V2 (ES-363-C) receptors in 1321N1 host cell were obtained
from Perkin Elmer Inc (Waltham, MA, USA). The Sprague-Dawley rats were purchased from Tianjin
Shanchuanhong Experimental Animals Co., Ltd (Tianjin, China). All reactions were monitored by thin
layer chromatography. Silica gel chromatography was conducted on a Teledyne Isco COMBIFLASH
Rf200 Purification System (Teledyne Isco, Inc., Lincoln, NE, USA) (petroleum ether and ethyl acetate,
gradient elution). HPLC data was obtained with an Agilent 1260 (Agilent Technologies, Inc., Santa
Clara, CA, USA) equipped with a Grace C18 column (5 μm, 250 mm × 4.6 mm, Lot No. 55/182).
1H-NMR spectra were recorded on a Bruker AV400 NMR (Bruker, Billerica, MA, USA) and HRMS
were measured on a VG ZAB-HS instrument (VG Instruments, London, UK). Melting points
(uncorrected) were determined on a YRT-3 Melting Point Tester (Precision Instrument of Tianjin
University, Tianjin, China).
3.2. Synthesis
(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)(4-nitrophenyl)
methanone (4a) [33]. To a solution of desloratadine (100 g, 322 mmol) in CH2Cl2 (500 mL), Et3N
(48 g, 480 mmol) was added and the mixture was stirred at 0 °C for 10 min. Then 2a (59.8 g,
322 mmol) dissolved in CH2Cl2 (200 mL) was added dropwise into the mixture and stirring was continued
for another 2 h. The reaction misxture was washed successively with 1 mol/L hydrochloric acid and
water. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give the
crude product as a yellow powder, which was recrystallized from ethanol affording 4a as a white powder.
Yield: 95%; m.p.: 188.2–189.0 °C; 1H-NMR (400 MHz, DMSO-d6): δ 2.18–2.32 (m, 2H), 2.41 (br s, 1H),
2.79–2.84 (m, 2H), 3.17–3.36 (m, 6H), 3.97 (br s, 1H), 7.05–7.32 (m, 4H), 7.54–7.57 (m, 1H), 7.68 (d,
J = 8.4 Hz, 2H), 8.25–8.36 (m, 3H).

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8-Chloro-11-(1-((3-nitrophenyl)sulfonyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridine (4b). Compound 4b was prepared using a similar method as for 4a. Yield: 97%, m.p.:
1
221.7–222.8 °C; H-NMR (CDCl3): δ 2.40–2.41 (m, 2H), 2.50–2.57 (m, 1H), 2.62–2.68 (m, 1H),
2.71–2.86 (m, 2H), 3.09–3.15 (m, 2H), 3.22–3.36 (m, 4H), 7.01 (d, J = 8.0 Hz, 2H), 7.11–7.15 (m, 3H),
7.45 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 8.0 Hz, 1H), 8.07–8.10 (m, 1H), 8.37 (d, J = 6.4 Hz, 1H),
8.44–8.59 (m, 1H), 8.59 (d, J = 2.0 Hz, 1H).
8-Chloro-11-(1-((4-nitrophenyl)sulfonyl)piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta-
[1,2-b]pyridine (4c). Compound 4c was prepared using a similar method as for 4a. Yield: 88%,
1
m.p.: >230 °C; H-NMR (CDCl3): δ 2.34–2.39 (m, 2H), 2.46–2.49 (m, 1H), 2.60–2.62 (m, 1H),
2.72–2.81 (m, 2H), 2.99–3.03 (m, 2H), 3.20–3.33 (m, 4H), 6.98 (d, J = 8.4 Hz, 1H), 7.05–7.13 (m, 3H),
7.39 (d, J = 7.6 Hz, 1H), 7.91–7.94 (m, 2H), 8.33–8.37 (m, 3H).
(4-Aminophenyl)(4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)-
methanone (5a) [33]. To a mixture of 4a (100 g, 217 mmol) dissolved in ethanol (600 mL) and
concentrated hydrochloric acid (150 mL), SnCl2 (171 g, 760 mmol) dissolved in ethanol (400 mL) was
added. After the addition was completed, the mixture was heated to reflux and stirred for 4–6 h. Then
the mixture was poured into ice water and extracted with dichloromethane. The organic layer was
collected and concentrated under reduced pressure to give the crude product as a brown powder.
1
Compound 5a was obtained by recrystallization from ethyl acetate. Yield: 82%, H-NMR (CDCl3): δ
2.38–2.56 (m, 4H), 2.75–2.87 (m, 2H), 3.20–3.42 (m, 4H), 3.82 (s, 2H), 3.94 (br s, 2H), 6.59–6.62 (m,
2H), 7.06–7.15 (m, 4H), 7.22–7.26 (m, 2H), 7.40–7.43 (dd, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H), 8.37 (d,
J = 3.6 Hz, 1H).
3-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
aniline (5b). Compound 5b was prepared using a similar method as used for 5a. Yield: 78%, m.p.:
1
227.9–228.8 °C; H-NMR (CDCl3): δ 2.34–2.37 (m, 2H), 2.44–2.50 (m, 1H), 2.56–2.63 (m, 1H),
2.68–2.81 (m, 2H), 2.88–2.94 (m, 2H), 3.20–3.39 (m, 4H), 3.89 (s, 1H), 6.83 (dd, J1 = 2.0 Hz, J2 = 8.0
Hz, 1H), 6.99–7.01 (m, 2H), 7.04–7.12 (m, 4H), 7.23–7.27 (m, 1H), 7.38 (dd, J1 = 1.2 Hz, J2 = 7.6 Hz,
1H), 8.34 (dd, J1 = 2.0 Hz, J2 = 4.8 Hz, 1H).
4-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
aniline (5c). Compound 5c was prepared using a similar method as used for 5a. Yield: 88%, m.p.:
1
110.1–111.6 °C; H-NMR (CDCl3): δ 2.30–2.36 (m, 2H), 2.43–2.46 (m, 1H), 2.56–2.60 (m, 1H),
2.70–2.90 (m, 4H), 3.17–3.30 (m, 4H), 6.65–6.67 (m, 2H), 6.99–7.11 (m, 4H), 7.38 (dd, J1 = 1.6 Hz, J2
= 8.0 Hz, 1H), 7.50 (dd, J1 = 1.8 Hz, J2 = 6.6 Hz, 2H), 8.35 (dd, J1 = 1.6 Hz, J2 = 4.8 Hz, 1H).
4-Chloro-N-(4-(4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-
carbonyl)phenyl)butanamide (1c). The syntheses of 1a, 1b, 1h and 1i have been reported in our
previous study [33]. Other target compounds were prepared using similar methods. Taking 1c as an
example, to a solution of 5a (5.0 g, 12 mmol) in CH2Cl2 (40 mL), Et3N (1.8 g, 18 mmol)was added and
the resulting mixture was then stirred at 0 °C for 10 min. Then 4-chlorobutanoyl chloride (1.7 g, 12 mmol)
dissolved in CH2Cl2 (20 mL) was added dropwise into the mixture that was stirred for another 3 h. The

Molecules 2014, 19
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reaction solution was washed successively with 1 mol/L hydrochloric acid and water. The organic
layer was dried over anhydrous magnesium sulfate and concentrated to give the crude product as a
yellow solid that was purified by silica gel chromatography to give compound 1c. Yield: 85%, m.p.:
1
204.8–207.6 °C; H-NMR (CDCl3): δ 2.15–2.20 (m, 2H), 2.29–2.64 (m, 6H), 2.77–2.90 (m, 2H),
3.25–3.44 (m, 4H), 3.61–3.69 (m, 3H), 4.15 (br s, 1H), 7.10–7.17 (m, 4H), 7.33 (d, J = 8.4 Hz, 2H),
7.43–7.49 (m, 3H), 7.95 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H); HRMS (ESI): calcd for C30H29Cl2N3O2 [M + H]+
m/z: 534.1710, found: 534.1705.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
1
phenyl)ethanesulfonamide (1d). Yield: 44%, m.p.: 210.0–211.1 °C; H-NMR (CDCl3): δ 2.32–2.46
(m, 4H), 2.75–2.89 (m, 2H), 3.21–3.40 (m, 4H), 3.57 (br s, 1H), 4.13 (br s, 1H), 6.11–6.14 (m, 2H),
6.24–6.28 (d, J = 16.8 Hz, 2H), 6.98–7.16 (m, 5H), 7.24–7.28 (m, 2H), 7.41–7.45 (m, 3H), 8.37 (s, 1H);
HRMS (ESI): calcd for C28H28ClN3O3S [M + H]+ m/z: 522.1613, found: 522.1609.
N-(3-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
1
phenyl)butyramide (1e). Yield: 50%, m.p.: 174.1–174.9 °C; H-NMR (CDCl3): δ 1.00 (t, J = 7.4 Hz,
3H), 1.75 (d, J = 7.6 Hz, 2H), 2.32–2.37 (m, 4H), 2.44–2.50 (m, 1H), 2.57–2.62 (m, 1H), 2.70–2.81
(m, 2H), 2.90 (t, J = 3.8 Hz, 2H), 3.22–3.31 (m, 4H), 7.00 (d, J = 8.0 Hz, 1H), 7.08–7.12 (m, 3H),
7.40–7.47 (m, 3h), 7.78 (s, 1H), 7.92 (d, J = 4.0 Hz, 1H), 8.35 (dd, J1 = 1.2 Hz, J2 = 4.8 Hz, 1H);
HRMS (ESI): calcd for C29H30ClN3O3S [M + H]+ m/z: 536.1769, found: 536.1770.
N-(4-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
1
phenyl)butyramide (1f). Yield: 60%, mp: 210.0–211.1 °C; H-NMR (CDCl3): δ 1.01 (t, J = 7.4 Hz,
3H), 1.77 (q, J = 7.5 Hz, 1H), 2.31–2.39 (m, 4H), 2.44–2.47 (m, 1H), 2.57–2.59 (m, 1H), 2.70–2.89
(m, 4H), 3.23–3.30 (m, 4H), 7.00 (d, J = 8.0 Hz, 1H), 7.08–7.12 (m, 3H), 7.33 (s, 1H), 7.41 (d, J = 7.6 Hz,
1H), 7.67 (s, 4H), 8.35 (dd, J1 = 1.6 Hz, J2 = 4.8 Hz, 1H); HRMS (ESI): calcd for C29H30ClN3O3S
[M + H]+ m/z: 536.1769, found: 536.1771.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
1
phenyl)benzamide (1g). Yield: 85%, m.p.: 128.5–131.6 °C; H-NMR (CDCl3): δ 2.41–2.53 (m, 4H),
2.78–2.88 (m, 2H), 3.31–3.42 (m, 4H), 3.68 (s, 1H), 4.14 (s, 1H), 7.12–7.17 (m, 4H), 7.36 (d, J = 8.8Hz,
2H), 7.43–7.55 (m, 4H), 7.64 (d, J = 8.8 Hz, 2H), 7.88 (dd, J1 = 1.2 Hz, J2 = 7.2 Hz, 2H), 8.34 (s, 1H),
8.40 (s, 1H); HRMS (ESI): calcd for C33H28ClN3O2 [M + H]+ m/z: 534.1943, found: 534.1939.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
1
phenyl)-3-methylbenzamide (1j). Yield: 79%; m.p.: 154.9–156.0 °C; H-NMR (CDCl3): δ 2.40–2.56
(m, 7H), 2.76–2.89 (m, 2H), 3.28–3.43 (m, 4H), 3.68–3.71 (m, 1H), 4.14 (s, 1H), 7.09–7.17 (m, 4H),
7.31–7.45 (m, 5H), 7.63–7.70 (m, 4H), 8.28 (s, 1H), 8.34 (s, 1H); HRMS (ESI): calcd for
C34H30ClN3O2 [M + H]+ m/z: 548.2099, found: 548.2108.
2-Chloro-N-(4-(4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-
1
carbonyl)phenyl)benzamide (1k). Yield: 96%, mp: 120.4–123.1 °C; H-NMR (CDCl3): δ 2.42–2.58
(m, 4H), 2.79–2.89 (m, 2H), 3.29–3.43 (m, 4H), 3.70 (br s, 1H), 4.14 (br s, 1H), 7.10–7.17 (m, 4H),

Molecules 2014, 19
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7.35–7.46 (m, 7H), 7.65–7.75 (m, 3H), 8.14 (s, 1H), 8.41 (s, 1H); HRMS (ESI): calcd for
C33H27Cl2N3O2 [M + H]+ m/z: 568.1553, found: 568.1547.
3-Chloro-N-(4-(4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-
1
carbonyl)phenyl)benzamide (1l). Yield: 70%, m.p.: 241.8–243.7 °C; H-NMR (CDCl3): δ 2.43–2.54
(m, 4H), 2.77–2.90 (m, 2H), 3.31–3.44 (m, 4H), 3.69–3.73 (m, 1H), 4.11–4.14 (m, 1H), 7.01–7.18
(m, 4H), 7.39–7.58 (m, 7H), 7.79 (d, J = 8.0 Hz, 1H), 7.92 (t, J = 2.0 Hz, 1H), 8.39 (s, 1H); HRMS
(ESI): calcd for C33H27Cl2N3O2 [M + H]+ m/z: 568.1553, found: 568.1556.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
1
phenyl)-2-fluorobenzamide (1m). Yield: 94%, m.p.: 166.9–167.8 °C; H-NMR (CDCl3): δ 2.41–2.56
(m, 4H), 2.77–2.90 (m, 2H), 3.32–3.44 (m, 4H), 3.71 (br s, 1H), 4.16 (br s, 1H), 7.09–7.23 (m, 5H),
7.30–7.32 (m, 1H), 7.44–7.46 (m, 3H), 7.51–7.57 (m, 1H), 7.70 (d, J = 8.4 Hz, 2H), 8.14–8.19 (m, 1H),
8.40 (s, 1H), 8.54 (d, J = 15.6 Hz, 1H); HRMS (ESI): calcd for C33H27ClFN3O2 [M + H]+ m/z:
552.1849, found: 552.1841.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
phenyl)-3-methoxybenzamide (1n). Yield: 52%, m.p.: 148.3–151.0 °C; 1H-NMR (CDCl3): δ 2.39–2.59
(m, 4H), 2.77–2.89 (m, 2H), 3.28–3.43 (m, 4H), 3.71 (br s,1H), 3.84 (s, 3H), 4.17 (br s, 1H), 7.05–7.20
(m, 5H), 7.33–7.45 (m, 6H), 7.63 (d, J = 8.8 Hz, 2H), 8.31 (s, 1H), 8.39 (s, 1H); HRMS (ESI): calcd
for C34H30ClN3O3 [M + H]+ m/z: 564.2048, found: 564.2049.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
1
phenyl)-3-nitrobenzamide (1o). Yield: 53%, m.p.: >250 °C; H-NMR (CDCl3): δ 2.32–2.45 (m, 4H),
2.75–2.89 (m, 2H), 3.25–3.42 (m, 4H), 3.62 (br s, 1H), 4.16 (br s, 1H), 7.09–7.24 (m, 6H), 7.43 (d,
J = 8.4 Hz, 3H), 7.61–7.65 (m, 1H), 8.32–8.41 (m, 3H), 8.86 (t, J = 2.0 Hz,1H), 9.37 (s, 1H); HRMS
(ESI): calcd for C33H27ClN4O4 [M + H]+ m/z: 579.1794, found: 579.1786.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
1
phenyl)-4-nitrobenzamide (1p). Yield: 68%, m.p.: >250 °C; H-NMR (CDCl3): δ 2.27–2.56 (m, 4H),
2.79–2.91 (m, 2H), 3.32–3.43 (m, 4H), 3.66 (br s, 1H), 4.16 (br s, 1H), 7.12–7.18 (m, 4H), 7.37–7.46
(m, 3H), 7.60 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.4 Hz, 2H), 8.32–8.37 (m, 4H); HRMS (ESI): calcd for
C33H27ClN4O4 [M + H]+ m/z: 579.1794, found: 579.1792.
N-(4-(4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-carbonyl)
1
phenyl)-4-methylbenzenesulfonamide (1q). Yield: 92%, m.p.: 161.5–162.9 °C; H-NMR (CDCl3):
δ 2.33–2.50 (m, 7H), 2.78–2.86 (m, 2H), 3.28–3.39 (m, 4H), 3.58 (br s, 1H), 4.13 (br s, 1H), 7.04–7.25
(m, 10 H), 7.42 (d, J = 6.4 Hz, 1H), 7.59–7.65 (m, 3H), 8.36 (s, 1H); HRMS (ESI): calcd for
C33H30ClN3O3S [M + H]+ m/z: 584.1769, found: 584.1777.
2-Chloro-N-(4-(4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-
1
carbonyl)phenyl)benzenesulfonamide (1r). Yield: 80%, m.p.: 153.9–155.5 °C; H-NMR (CDCl3):
δ 2.39–2.46 (m, 4H), 2.73–2.87 (m, 2H), 3.17–3.39 (m, 4H), 3.57 (br s, 1H), 4.09 (br s, 1H), 7.06–7.14

Molecules 2014, 19
2702
(m, 6H), 7.23–7.34 (m, 3H), 7.40–7.45 (m, 3H), 7.630 (s, 1H), 8.01 (d, J =8.4 Hz, 1H), 8.36 (s, 1H);
HRMS (ESI): calcd for C32H27Cl2N3O3S [M + H]+ m/z: 604.1223, found: 604.1224.
2,5-Dichloro-N-(4-(4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidine-1-
1
carbonyl)phenyl)benzenesulfonamide (1s). Yield: 96%, m.p.: 147.8–149.5 °C; H-NMR (CDCl3):
δ 2.15–2.40 (m, 4H), 2.74–2.87 (m, 2H), 3.20–3.52 (m, 5H), 4.11 (br s, 1H), 7.08–7.11 (m, 6H),
7.24–7.28 (m, 2H), 7.34–7.43 (m, 3H), 7.51–7.53 (m, 1H), 7.98 (d, J =2.0 Hz, 1H), 8.38 (s, 1H);
HRMS (ESI): calcd for C32H26Cl3N3O3S [M + H]+ m/z: 640.0833, found: 640.0824.
N-(3-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
1
phenyl)benzamide (1t). Yield: 78%, m.p.: 119.8–122.4 °C; H-NMR (CDCl3): δ 2.34–2.37 (m, 2H),
2.44–2.50 (m, 1H), 2.56–2.63 (m, 1H), 2.68–2.81 (m, 2H), 2.88–2.94 (m, 2H), 3.20–3.39 (m, 4H), 3.89
(s, 1H), 6.83 (dd, J1 = 2.0 Hz, J2 = 8.0 Hz, 1H), 6.99–7.01 (m, 2H), 7.04–7.12 (m, 4H), 7.23–7.27 (m, 1H),
7.38 (dd, J1 = 1.2 Hz, J2 = 7.6 Hz, 1H), 8.34 (dd, J1 = 2.0 Hz, J2 = 4.8 Hz, 1H); HRMS (ESI): calcd for
C32H28ClN3O3S [M + H]+ m/z: 570.1613, found: 570.1612.
3-Chloro-N-(3-((4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)-
1
sulfonyl)phenyl)benzamide (1u). Yield: 70%, m.p.: 131.2–133.5 °C; H-NMR (CDCl3): δ 2.31–2.36
(m, 2H), 2.42–2.49 (m, 1H), 2.55–2.62 (m, 1H), 2.67–2.81 (m, 2H), 2.85–2.91 (m, 2H), 3.19–3.38 (m, 4H),
6.98 (d, J = 8.0 Hz, 1H), 7.04–7.11 (m, 3H), 7.37–7.54 (m, 5H), 7.77 (d, J = 7.6 Hz, 1H), 7.90 (dd,
J1 = 1.6 Hz, J2 = 10.0 Hz, 1H), 8.10 (dd, J1 = 2.0 Hz, J2 = 7.2 Hz, 1H), 8.19 (s, 1H), 8.33 (d, J = 3.6 Hz,
1H); HRMS (ESI): calcd for C32H27Cl2N3O3S [M + H]+ m/z: 604.1223, found: 604.1218.
N-(3-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
phenyl)-3-nitrobenzamide (1v). Yield: 87%, m.p.: 206.1–208.2 °C; 1H-NMR (CDCl3): δ 2.34–2.43 (m,
2H), 2.56–2.62 (m, 1H), 2.80–2.84 (m, 2H), 2.94–3.07 (m, 2H), 3.29–3.53 (m, 4H), 4.19 (s, 1H),
7.16–7.23 (m, 3H), 7.54–7.57 (m, 2H), 7.66–7.70 (m, 2H), 8.07 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 8.35
(dd, J1 = 2.0 Hz, J2 = 8.0 Hz, 1H), 8.51–8.65 (m, 3H), 9.17 (s, 1H); HRMS (ESI): calcd for
C32H27ClN4O5S [M + H]+ m/z: 615.1464, found: 615.1461.
N-(3-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
1
phenyl)-4-methylbenzenesulfonamide (1w). Yield: 98.4%; m.p.: 192.7–194.9 °C; H-NMR (CDCl3):
δ 2.26–2.28 (m, 2H), 2.31 (s, 3H), 2.50–2.54 (m, 1H), 2.77–2.83 (m, 2H), 2.94–3.03 (m, 2H), 3.10 (s,
1H), 3.22–3.25 (m, 1H), 3.32–3.36 (m, 1H), 3.46–3.50 (m, 1H), 3.88 (s, 1H), 7.14–7.22 (m, 4H),
7.33–7.43 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.66 (t, J = 6.4 Hz, 1H), 7.75 (d, J = 8.0 Hz,
2H), 8.04 (d, J = 8.0 Hz, 1H), 8.61 (d, J = 4.8 Hz, 1H), 9.14 (s, 1H); HRMS (ESI): calcd for
C32H30ClN3O4S2 [M + H]+ m/z: 620.1439, found: 620.1439.
3-Chloro-N-(4-((4-(8-chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)-
sulfonyl)phenyl)benzamide (1x). Yield: 96%; m.p.: 130.5–133.0 °C; 1H-NMR (CDCl3): δ 2.32–2.38 (m,
2H), 2.45–2.47 (m, 1H), 2.58–2.59 (m, 1H), 2.71–2.89 (m, 4H), 3.22–3.33 (m, 4H), 6.99 (d, J = 8.4 Hz,
1H), 7.06–7.11 (m, 3H), 7.39–7.45 (m, 2H), 7.52–7.55 (m, 1H), 7.70–7.87 (m, 6H), 8.13 (s, 1H), 8.34

Molecules 2014, 19
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(dd, J1 = 1.6 Hz, J2 = 4.8 Hz, 1H); HRMS (ESI): calcd for C32H27Cl2N3O3S [M + H]+ m/z: 604.1223,
found: 604.1219.
N-(4-((4-(8-Chloro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11(6H)-ylidene)piperidin-1-yl)sulfonyl)
1
phenyl)-4-methylbenzenesulfonamide (1y). Yield: 78%; m.p.: 126.1–129.1 °C; H-NMR (CDCl3): δ
2.29–2.35 (m, 2H), 2.38 (s, 3H), 2.43–2.46 (m, 1H), 2.57–2.59 (m, 1H), 2.70–2.82 (m, 2H), 2.89–2.93
(m, 2H), 3.14–3.30 (m, 4H), 6.98 (d, J = 8.0 Hz, 1H), 7.07–7.12 (m, 3H), 7.16–7.19 (m, 2H), 7.26–7.30
(m, 3H), 7.42 (d, J = 6.4 Hz, 1H), 7.57–7.60 (m, 2H), 7.73 (d, J = 8.4 Hz, 2H), 8.35 (d, J = 4.0 Hz, 1H);
HRMS (ESI): calcd for C32H30ClN3O4S2 [M + H]+ m/z: 620.1439, found: 620.1437.
3.3. Biological Evaluation
The in vitro evaluation was done by a slightly modified method we reported previously [31]. An
in vitro radioligand binding assay was performed to determine the binding affinity of the candidates to
human V2 and V1a receptors. The functional activity was then subsequently determined by measuring
the activation or inhibition of vasopressin induced cAMP accumulation in V2 receptor expressing
cells. We investigated some potent derivatives for in vivo diuretic activity in conscious hydrated male
Sprague-Dawley rats at 8 weeks of age (body weight: (260 ± 20) g). Urine volume was measured 20 h
after oral administration of the test compounds.
4. Conclusions
Twenty-one derivatives of desloratadine designed as AVP V2 receptor antagonists were synthesized
1
and characterized by H-NMR, HRMS and HPLC. Their biological activity was evaluated by in vitro
radioligand binding assay, cAMP assay and in vivo diuretic assay. Compounds 1n, 1t and 1v exhibited
both high affinity and promising selectivity for V2 receptors. The selected compounds showed
promising diuretic results in rats, especially compound 1t, which produced a total urine volume
equivalent to tolvaptan during the experimental period. Through the present studies, compound 1t,
which has good efficacy both in vitro and in vivo, could be a novel AVP V2 receptor antagonist
candidate. Further preclinical studies are however still required.
Acknowledgments
This project was supported by the National Basic Research Program of China (973 Program,
granted Nos. 2010CB735602 and 2012CB724002) and National Major Scientific and Technological
Special Project for “Significant New Drugs Development” (No. 2013ZX09102014).
Conflicts of Interest
The authors declare no conflict of interest.
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distributed under the terms and conditions of the Creative Commons Attribution license
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