Synthesis and biological evaluation of novel derivatives of desloratadine

Article abstract of DOI:10.1016/j.cclet.2013.03.041

Series of novel derivatives of desloratadine designed as arginine vasopressin receptor antagonists were synthesized and structurally characterized by melting points, ¹H NMR and HRMS. Their in vivo diuretic activities were evaluated on rats, and

Full text of DOI:10.1016/j.cclet.2013.03.041

Chinese Chemical Letters 24 (2013) 531–534
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Chinese Chemical Letters
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Original article
Synthesis and biological evaluation of novel derivatives of desloratadine
Shuai Mu a,b, Xiao-Shuai Xie c, Duan Niu c, Da-Shuai Zhang c, Deng-Ke Liu d, Chang-Xiao Liu b,
*
a School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China
b State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
c Graduate School of Tianjin Medical University, Tianjin 300070, China
d Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Series of novel derivatives of desloratadine designed as arginine vasopressin receptor antagonists were
synthesized and structurally characterized by melting points, 1H NMR and HRMS. Their in vivo diuretic
activities were evaluated on rats, and several target compounds showed promising diuretic results,
especially compounds 8, 18, 27 and 31. Further in vitro bonding assay and cAMP assay showed that these
compounds had a higher affinity to vasopressin V2 receptor than V1a receptor. Our studies indicated that
desloratadine may be an active substructure for novel arginine vasopressin receptor antagonist
development.
Received 2 February 2013
Received in revised form 4 March 2013
Accepted 11 March 2013
Available online 23 April 2013
Keywords:
Derivatives of desloratadine
Arginine vasopressin receptor antagonists
Diuretic activity
ß 2013 Chang-Xiao Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
1. Introduction
another two benzene rings, which are linked through two amide
bonds. The benzazepine group and the middle benzene ring were
Arginine vasopressin (AVP),
a
neurohypophysial peptide
replaced with desloratadine, which has a similar structure, to
reveal the significance of the benzazepine group and amide bond in
AVP receptor antagonist activity. Then, straight-chain or branched-
chain alkanes (compounds 3–10) and bezene rings (compounds
11–31), whether substituted or not, were bonded to the
desloratadine group through amide or sulfonamide bonds to give
total twenty-nine target compounds. These compounds were
synthesized by a one-step acylation reaction and evaluated to
show the necessary functional groups and find better lead
compounds.
hormone produced in the hypothalamus in response to low blood
volume or high serum osmolality, plays an important role in
circulatory and water homeostasis. The biological effects of AVP
are mediated via three receptor subtypes (V1a, V1b and V2) which
belong to the GTP-binding G-protein-coupled receptor family [1–
3]. Inhibition of AVP may have benefits to patients with diseases
related to the inappropriate secretion of serum AVP. The AVP V2
receptor antagonists seem to have no harmful hemodynamic
consequences and show promising results in the treatment of
patients with hyponatremia, hypertension, congestive heart
failure, liver cirrhosis, and any state of excessive retention of
water [4–6].
2. Experimental
Our research was refocused to design and synthesize com-
pounds with a new parent nucleus in order to find novel V2
receptor antagonists. The chemical structures of the extant V2
receptor antagonists including tolvaptan, conivaptan and lixivap-
tan were analyzed and desloratadine was introduced as an active
substructure of novel V2 receptor antagonists (Fig. 1). Then
numerous of derivatives of desloratadine were designed, synthe-
sized and evaluated based on the following considerations: Most
V2 receptor antagonists consist of one benzazepine group and
The desloratadine was purchased from Beijing Datian Fengtuo
Chemistry Co., Ltd. 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. The cells, in DMEM containing 10%
fetal calf serum and penicillin/streptomycin, were grown in 5% CO2
at 37 8C and then plated in 24-well plates with a density of 2 Â 105
cells/100
mL/well.
The syntheses of the compounds are illustrated in Schemes 1
and 2. To a solution of desloratadine in CH2Cl2, Et3N was added and
was then stirred at 0 8C for 10 min. Then 1 or 2 (or their solutions in
CH2Cl2) was added dropwise into the mixture and stirred for
another 2 h. The reaction solution was concentrated under reduced
pressure to get yellow powder as a crude product. The crude
* Corresponding author.
E-mail address: liuchangxiao@163.com (C.-X. Liu).
1001-8417/$ – see front matter ß 2013 Chang-Xiao Liu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.03.041

[
S. Mu et al. / Chinese Chemical Letters 24 (2013) 531–534
Fig. 1. Chemical structures of tolvaptan, conivaptan, lixivaptan and desloratadine.
[(cShem_)2DT$FI]G
[(Scheme_1)TD$FIG]
Cl
Cl
Cl
Cl
XCl
N
a
b
N
N
R XCl
1
+
R
2
N
+
N
X
N
X
N
H
N
H
R
2
1
2
R
1
3-10
11-31
Scheme 1. Synthetic route of compounds 3–10: (a) CH2Cl2, Et3N, 0 8C, 2 h.
Scheme 2. Synthetic route of compounds 11–31: (b) CH2Cl2, Et3N, 0 8C, 2 h.
product was then purified by silica gel column chromatography
(methanol/dichloromethane = 1/10) to give object compounds.
In the early in vivo diuretic activity study, male Sprague-Dawley
rats at 6 or 7 weeks of age were purchased and fed in an air-
conditioned animal room, which has relatively constant tempera-
ture, humidity and light-control, with free access to food and
water. Desloratadine, tolvaptan and the synthesized compounds
suspended in 1% hydroxymethyl cellulose were administered
orally at doses of 10 mg/kg to rats at 8 weeks of age (body weight:
(260 Æ 20) g) by a gastric tube. Seven animals in each group were
then placed individually in metabolic cages and spontaneously
voided urine was collected and measured for the periods of 0–2, 2–4,
4–8, 8–20 h.
The functional activity was then subsequently determined by
measuring the activation or inhibition of vasopressin induced
cAMP accumulation in V2 receptor expressing cells. Cells
(3.0 Â 104, 5
m
L) were seeded and plated in each well of a 384-
g) were
well white solid plate. After 24 h, compounds 3–31 (10
m
titrated respectively and then incubated with cells for 30 min and
then the treated cells were sonicated for cAMP extraction. The
cAMP levels induced by compounds (3–31) were analyzed by
cAMP femto kit (Cisbio). Homogeneous time resolved fluorescence
(HTRF) signal was read on SpectraMax M5 (Molecular Device)
microplate reader.
3. Results and discussion
In order to determine the binding affinity of candidates to
human vasopressin receptor, the radioligand binding assay was
performed. The cells in 24-wells plate were incubated with [3H]-
AVP for 2 h at 4 8C after washing with ice-cold PBS. Aqueous
solutions of compounds 3–31 were dissolved in culture medium at
variant final concentrations. After 4 h of incubation, the cells were
lysed in 250 mL of 0.1 mol/L NaOH containing 0.1% sodium dodecyl
sulfate followed rinsing twice with ice-cold PBS. The lysated were
transferred into scintillation vials, combined with 5 mL of Aquazol
II (NEN, Boston, MA) and detected using a liquid scintillation
counter (Hidex 300 SL, Finland).
The structures of compounds 3–31 and the total volume of
urine from 0 to 20 h in each group were shown in Tables 1 and 2.
Their structures were characterized by HRMS (Tables 1 and 2) and
1H NMR [7]. Table 3 summarized the results of the binding assay
and cAMP assay.
As shown in Table 1, several target compounds showed
promising diuretic results, especially compounds 8, 18, 27 and
31. The diuretic activity increased with the extension of the carbon
chain, and halogen substituents made the activity even higher.
Table 2 indicated that when the benzene ring was di-substituted,
Table 1
The substituents, melting points, HRMS, purity and diuretic activity of compounds 3–10.
Compound
X
R1
Melting point (8C)
ESI-HRMS ([M+H]+)
Purity (HPLC, %)
Total volume of urine (0–20 h, mL)
Control
4.5 Æ 0.8
4.8 Æ 1.1
Desloratadine
Tolvaptan
26.8 Æ 4.3
5.9 Æ 1.3
3
CO
CO
CO
CO
CO
CO
SO2
SO2
CH3
154.1–156.1
126.6–127.5
136.3–137.1
123.5–125.0
170.7–172.5
117.2–119.1
214.7–216.1
183.5–185.3
353.1414
367.1573
381.1733
381.1723
401.1182
415.1341
403.1238
401.1085
99.3
98.8
99.1
98.2
98.8
96.9
99.6
98.2
4
CH2CH3
6.0 Æ 1.3
5
CH2CH2CH3
CH(CH3)2
CHClCH3
CH2CH2CH2Cl
CH2CH3
13.7 Æ 3.1
15.7 Æ 3.6
13.9 Æ 2.0
18.4 Æ 4.0
13.8 Æ 2.1
13.6 Æ 3.2
6
7
8
9
10
CH2CH2Cl

S. Mu et al. / Chinese Chemical Letters 24 (2013) 531–534
533
Table 2
The substituents, melting points, HRMS, purity and diuretic activity of compounds 11–31.
Compound
X
R2
Melting point (8C)
ESI-HRMS [M+H]+
Purity (HPLC, %)
Total volume of urine (0–20 h, mL)
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
CO
H
91.3–92.6
80.5–81.3
415.1572
429.1726
429.1724
429.1732
449.1190
449.1185
433.1481
451.1385
445.1676
445.1676
460.1427
460.1427
465.1395
465.1395
485.0857
496.1097
496.1088
496.1087
519.0463
511.1452
510.1241
98.3
99.1
98.2
98.3
99.9
96.8
97.2
97.4
99.3
99.9
99.9
98.9
99.6
99.9
96.6
98.3
98.5
98.9
98.5
99.9
99.5
6.6 Æ 3.7
5.8 Æ 3.2
9.6 Æ 2.1
8.0 Æ 4.4
5.8 Æ 3.1
5.9 Æ 4.5
6.0 Æ 2.4
21.1 Æ 5.6
16.8 Æ 4.8
11.5 Æ 1.9
9.6 Æ 4.1
9.5 Æ 0.7
14.9 Æ 4.0
5.4 Æ 2.4
10.3 Æ 4.8
9.4 Æ 3.6
26.5 Æ 4.3
17.7 Æ 5.5
13.0 Æ 3.0
21.4 Æ 5.5
24.0 Æ 5.1
CO
2-CH3
4-CH3
3-CH3
2-Cl
CO
165.2–165.8
93.6–94.8
CO
CO
109.5–110.8
96.0–96.8
CO
3-Cl
CO
2-F
129.8–131.5
159.5–161.0
105.2–107.9
71.2–72.8
CO
2,5-DiF
2-OCH3
3-OCH3
3-NO2
4-NO2
2-CH3
4-CH3
2-Cl
CO
CO
CO
193.8–194.6
188.2–189.0
92.8–94.9
CO
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
SO2
209.2–209.7
169.8–170.4
176.9–177.6
221.7–222.8
>230
2-NO2
3-NO2
4-NO2
2,5-DiCl
2,5-DiOCH3
2-CH3-5-NO2
95.8–96.0
182.9–184.3
178.1–179.2
Table 3
In vitro binding and cAMP assay data.
Acknowledgments
Compound
Radioligand binding assay
cAMP assay
This project was supported by National 973 Plan (Nos.
2010CB735602 and 2012CB724002) and National Major Scientific
and Technological Special Project for ‘‘Significant New Drugs
Development’’ (No. 2011ZX09401-009).
(V2, IC50, nmol/L)
V2 (IC50
nmol/L)
,
V1a (IC50
nmol/L)
,
V1a/V2
5
8
20
11
35
9
440
160
930
540
820
490
380
91
22
15
27
60
63
31
48
10
130
260
93
References
11
12
15
18
23
27
30
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[3] R. Lemmens-Gruber, M. Kamyar, Vasopressin antagonists, Cell. Mol. Life Sci. 63
(2006) 1766–1779.
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[4] F. Ali, M.A. Raufi, B. Washington, Conivaptan: a dual receptor vasopressin V-1a/V-2
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(2007) 1–13.
the activity was much stronger than when it was mono-
substituted. The diuretic activity of the sulfonamide derivatives
was higher than that of the amide derivatives.
[7] 3: 1H NMR (400 MHz, CDCl3): d 2.08 (s, 3H), 2.29–2.53 (m, 4H), 2.76–2.88 (m, 2H),
3.12–3.40 (m, 4H), 3.61–3.67 (m, 1H), 3.99–4.07 (m, 1H), 7.07–7.16 (m, 4H), 7.42
(d, 1H, J = 7.6 Hz), 8.38 (d, 1H, J = 3.2 Hz). 4: 1H NMR (400 MHz, CDCl3): d 1.14 (t,
3H, J = 7.4 Hz), 2.34–2.72 (m, 6H), 2.76–2.89 (m, 2H), 3.12–3.43 (m, 4H), 3.64–3.70
(m, 1H), 4.03–4.11 (m, 1H), 7.08–7.17 (m, 4H), 7.43–7.45 (d, 1H, J = 7.6 Hz), 8.40 (d,
1H, J = 3.6 Hz). 5: 1H NMR (400 MHz, CDCl3): d 1.13 (dd, 6H, J1 = 8.0 Hz,
J2 = 16.0 Hz), 2.32–2.58 (m, 4H), 2.76–2.89 (m, 3H), 3.10–3.43 (m, 4H), 3.71–
3.77 (m, 1H), 4.05–4.12 (m, 1H), 7.08–7.17 (m, 4H), 7.44 (d, 1H, J = 7.2 Hz), 8.40
(d, 1H, J = 3.6 Hz). 6: 1H NMR (400 MHz, CDCl3): d 0.96 (t, 3H, J = 9.2 Hz), 1.63–1.78
(m, 2H), 2.33–2.40 (m, 5H), 2.45–2.56 (m, 1H), 2.57–2.89 (m, 2H), 3.10–3.43 (m,
4H), 3.64–3.72 (m, 1H), 7.08–7.17 (m, 4H), 7.43 (d, 1H, J = 7.6 Hz), 8.39–8.41 (t, 1H,
J = 2.2 Hz). 7: 1H NMR (400 MHz, CDCl3): d 1.62–1.75 (m, 3H), 2.39–2.48 (m, 3H),
2.49–2.66 (m, 1H), 2.68–2.88 (m, 2H), 2.99–3.29 (m, 1H), 3.31–3.49 (m, 3H), 3.65–
4.23 (m, 2H), 4.54–4.62 (m, 1H), 7.08–7.17 (m, 4H), 7.43 (d, 1H, J = 7.6 Hz), 8.40 (d,
1H, J = 3.6 Hz). 8: 1H NMR (400 MHz, CDCl3): d 2.09–2.19 (m, 2H), 2.30–2.43 (m,
3H), 2.46–2.59 (m, 3H), 2.76–2.89 (m, 2H), 3.08–3.42 (m, 4H), 3.62–4.10 (m, 4H),
7.08–7.17 (m, 4H), 7.44 (d, 1H, J = 7.6 Hz), 8.40 (d, 1H, J = 4.8 Hz). 9: 1H NMR
(400 MHz, CDCl3): d 1.37 (t, 3H, J = 14.2 Hz), 2.37–2.45 (m, 2H), 2.47–2.51 (m, 1H),
2.52–2.65 (m, 1H), 2.76–2.90 (m, 2H), 2.96 (q, 2H, J = 7.5 Hz), 3.13–3.20 (m, 2H),
3.30–3.42 (m, 2H), 3.47–3.66 (m, 2H), 7.09–7.18 (m, 4H), 7.44 (dd, 1H, J1 = 1.2 Hz,
J2 = 8.8 Hz), 8.40 (dd, 1H, J1 = 1.2 Hz, J2 = 5.6 Hz). 10: 1H NMR (400 MHz, CDCl3): d
2.49–2.54 (m, 3H), 2.60–2.66 (m, 1H), 2.75–2.89 (m, 2H), 3.00–3.06 (m, 2H), 3.28–
3.47 (m, 4H), 6.01 (d, 1H, J = 10.0 Hz), 6.22 (d, 1H, J = 16.4 Hz), 6.43 (dd, 1H,
J1 = 6.0 Hz, J2 = 16.8 Hz), 7.07–7.17 (m, 4H), 7.43 (d, 1H, J = 8.8 Hz), 8.39 (d, 1H,
J = 6.0 Hz). 11: 1H NMR (400 MHz, CDCl3): d 2.31–2.58 (m, 4H), 2.76–2.89 (m, 2H),
3.22–3.43 (m, 4H), 3.62 (br s, 1H), 4.14 (br s, 1H), 7.11–7.46 (m, 10H), 8.38 (br s,
1H). 12: 1H NMR (400 MHz, CDCl3): d 2.28–2.64 (m, 6H), 2.75–2.95 (m, 2H), 3.078
(br s, 1H), 3.29–3.44 (m, 4H), 4.26 (br s, 1H), 7.04–7.46 (m, 9H), 8.33 (d, 0.5H,
J = 3.6 Hz), 8.43 (d, 0.5H, J = 3.6 Hz). 13: 1H NMR (400 MHz, CDCl3): d 2.35–2.50 (m,
7H), 2.77–2.89 (m, 2H), 3.27–3.42 (m, 4H), 3.66 (br s, 1H), 4.16 (br s, 1H), 7.12–7.44
(m, 9H), 8.38 (br s, 1H). 14: 1H NMR (400 MHz, CDCl3): d 2.33–2.48 (m, 7H),
Table 3 indicated that these compounds had a strong affinity to
human AVP receptors. Furthermore, they were more selective to
V2 receptors. Unfortunately, no clear relationship between diuretic
activity and bonding affinity was observed. 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
bonding assay in cells expressing the human receptor, especially
with the limited number of compounds involved. At the same time,
absorption and metabolism also affect the diuretic activity.
4. Conclusion
Twenty-nine derivatives of desloratadine, which can be
potentially used as antagonists of AVP receptors, were synthesized
and evaluated. Several target compounds showed promising
diuretic results in rats. The radioligand binding assay and cAMP
assay further proved the AVP receptor antagonism of these
compounds. Although most of the target compounds had lower
diuretic activity than tolvaptan, which proved the importance of
benzazepine group, our studies still indicated that desloratadine
may be an active substructure for novel AVP V2 receptor
antagonist development.

534
S. Mu et al. / Chinese Chemical Letters 24 (2013) 531–534
2.75–2.88 (m, 2H), 3.22–3.42 (m, 4H), 3.62 (br s, 1H), 4.16 (br s, 1H), 7.10–7.24 (m,
2.70–2.83 (m, 2H), 2.93–3.00 (m, 2H), 3.17–3.32 (m, 4H), 6.99–7.13 (m, 4H),
7.31 (d, 2H, J = 8.0 Hz), 7.38–7.41 (m, 1H), 7.63 (d, 2H, J = 9.6 Hz), 8.35–8.36
(dd, 1H, J1 = 1.6 Hz, J2 = 4.8 Hz). 25: 1H NMR (400 MHZ, DMSO-d6): d 2.21–2.43
(m, 4H), 2.75–2.81 (m, 2H), 3.07–3.12 (m, 2H), 3.22–3.44 (m, 4H), 7.06 (d, 1H,
J = 8.4 Hz), 7.16–7.19 (m, 2H), 7.28 (s, 1H), 7.53 (t, 2H, J = 6.4 Hz), 7.67 (q, 2H,
J = 8.1 Hz), 7.96 (d, 1H, J = 7.6 Hz), 8.31 (d, 1H, J = 4.0 Hz). 26: 1H NMR (400 MHz,
CDCl3): d 2.39–2.43 (m, 2H), 2.46–2.64 (m, 2H), 2.73–2.87 (m, 2H), 3.16–3.39 (m,
4H), 3.50–3.59 (m, 2H), 7.05–7.16 (m, 4H), 7.42 (dd, 1H, J1 = 1.6 Hz, J2 = 7.6 Hz),
7.59–7.72 (m, 3H), 7.96–7.98 (m, 1H), 8.37 (t, 1H, J = 2.4 Hz). 27: 1H NMR
(400 MHz, CDCl3): d 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, 2H, J = 8.0 Hz),
7.11–7.15 (m, 3H), 7.45 (d, 1H, J = 7.6 Hz), 7.76 (t, 1H, J = 8.0 Hz), 8.07–8.10 (m, 1H),
8.37 (d, 1H, J = 6.4 Hz), 8.44–8.59 (m, 1H), 8.59 (d, 1H, J = 2.0 Hz). 28: 1H NMR
(400 MHz, CDCl3): d 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, 1H, J = 8.4 Hz), 7.05–
8H), 7.43 (d, 1H, J = 7.2 Hz), 8.36 (br s, 1H). 15: 1H NMR (400 MHz, CDCl3):d 2.17–
2.66 (m, 4H), 2.75–2.88 (m, 2H), 3.01–3.67 (m, 1H), 3.28–3.44 (m, 4H), 4.14–4.28
(m, 1H), 7.02–7.44 (m, 9H), 8.29–8.41 (m, 1H). 16: 1H NMR (400 MHz, CDCl3): d
2.28–2.68 (m, 4H), 2.77–2.89 (m, 2H), 3.22–3.42 (m, 4H), 3.59 (br s, 1H), 4.11 (br s,
1H), 7.12–7.26 (m, 4H), 7.27–7.39 (m, 3H), 7.41–7.46 (m, 2H), 8.38 (br s, 1H). 17:
1H NMR (400 MHz, CDCl3): d 2.24–2.27 (m, 4H), 2.75–2.96 (m, 2H), 3.19 (br s, 1H),
3.31–3.55 (m, 4H), 4.13–4.40 (m, 1H), 7.02–7.24 (m, 6H), 7.32–7.38 (m, 2H),
7.45–7.51 (m, 1H), 8.34–8.48 (m, 1H). 18: 1H NMR (400 MHz, CDCl3): d 2.28–
2.64 (m, 4H), 2.74–2.89 (m, 2H), 3.17–3.28 (m, 1H), 3.30–3.51 (m, 4H), 4.11–4.21
(m, 1H), 7.02–7.17 (m, 7H), 7.42 (dd, 1H, J1 = 8.0 Hz, J2 = 11.2 Hz), 8.38 (dd, 1H,
J1 = 4.0 Hz, J2 = 30.8 Hz). 19: 1H NMR (400 MHz, CDCl3): d 2.20–2.49 (m, 4H), 2.52–
2.88 (m, 2H), 3.00–3.12 (m, 1H), 3.23–3.46 (m, 4H), 3.756–3.84 (m, 3H), 4.19–4.31
(m, 1H), 6.83–6.98 (m, 2H), 7.03–7.16 (m, 5H), 7.27–7.44 (m, 2H), 8.32–8.42
(m, 1H). 20: 1H NMR (400 MHz, CDCl3): d 2.02–2.68 (m, 4H), 2.75–2.89 (m, 2H),
3.22–3.43 (m, 4H), 3.60–3.86 (m, 4H), 4.07–4.37 (m, 1H), 6.89–6.94 (m, 3H), 7.12–
7.15 (m, 4H), 7.26–7.59 (m, 2H), 8.39 (br s, 1H). 21: 1H NMR (400 MHz, CDCl3): d
2.18–2.45 (m, 4H), 2.81–2.82 (m, 2H), 3.42–3.44 (m, 5H), 3.96 (br s, 1H), 7.11–7.30
(m, 4H), 7.56–7.87 (m, 3H), 8.21–8.36 (m, 3H). 22: 1H NMR (400 MHz, DMSO-d6): d
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, 2H, J = 8.4 Hz), 8.25–8.36 (m,
3H). 23: 1H NMR (400 MHz, CDCl3): d 2.33–2.44 (m, 3H), 2.54–2.60 (m, 4H), 2.63–
2.83 (m, 2H), 3.01–3.07 (m, 2H), 3.29–3.48 (m, 4H), 7.05–7.14 (m, 4H), 7.26–7.30
(m, 2H), 7.41–7.45 (m, 2H), 7.86 (t, 1H, J = 4.0 Hz), 8.39 (d, 1H, J = 3.2 Hz).
24: 1H NMR (400 MHz, CDCl3): d 2.36–2.37 (m, 2H), 2.44–2.63 (m, 5H),
7.13 (m, 3H), 7.39 (d, 1H, J = 7.6 Hz), 7.91–7.94 (m, 2H), 8.33–8.37 (m, 3H). 29: 1
H
NMR (400 MHz, CDCl3): d 2.33–2.49 (m, 3H), 2.54–2.60 (m, 1H), 2.72–2.86 (m, 2H),
3.14–3.38 (m, 4H), 3.49–3.57 (m, 2H), 7.03–7.15 (m, 4H), 7.40–7.43 (m, 3H), 8.01 (t,
1H, J = 0.6 Hz), 8.36 (d, 1H, J = 4.8 Hz). 30: 1H NMR (400 MHz, CDCl3): d 2.29–2.57
(m, 4H), 2.71–2.84 (m, 2H), 3.04–3.13 (m, 2H), 3.24–3.37 (m, 2H), 3.44–3.77
(m, 2H), 3.77 (s, 3H), 3.83 (s, 3H), 6.92–7.13 (m, 6H), 7.39–7.41 (m, 2H), 8.36
(dd, 1H, J1 = 1.6 Hz, J2 = 4.8 Hz). 31: 1H NMR (400 MHz, CDCl3): d 2.38–2.62 (m, 4H),
2.73–2.88 (m, 5H), 3.12–3.52 (m, 6H), 7.03–7.15 (m, 4H), 7.43–7.51 (m, 2H),
8.25–8.37(m, 2H), 8.70 (d, 1H, J = 2.4 Hz).