Synthesis and biological evaluation of novel laropiprant derivatives as potential anti-allergic agents

Article abstract of DOI:10.1007/s00044-015-1431-8

DP antagonists are claimed to be useful in the treatment of allergic disorders. Laropiprant is a potent and selective DP antagonist to reduce the allergic disorders, especially niacin-induced flushing. In our study, a series of novel laropiprant derivativ

Full text of DOI:10.1007/s00044-015-1431-8

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2015) 24:3920–3931
DOI 10.1007/s00044-015-1431-8
ORIGINAL RESEARCH
Synthesis and biological evaluation of novel laropiprant
derivatives as potential anti-allergic agents
Haiping Zhou1 Qihua Zhu1 Zongjie Gan2 Guangping Dong2
Yungen Xu1,2
•
•
•
•
Received: 16 June 2014 / Accepted: 17 August 2015 / Published online: 29 August 2015
Ó Springer Science+Business Media New York 2015
Abstract DP antagonists are claimed to be useful in the
treatment of allergic disorders. Laropiprant is a potent and
selective DP antagonist to reduce the allergic disorders,
especially niacin-induced flushing. In our study, a series of
novel laropiprant derivatives (I-1–I-18) were synthesized
Maicas et al., 2012; Van Hecken et al., 2007). Recent
studies have shown PGD2 binds to two types of specific
receptor. One is DP (the PGD receptor) and the other is
CRTH2 (chemoattractant receptor-homologous molecule
expressed on Th2) (Pettipher et al., 2007). The DP receptor
has already been cloned (Boie et al., 1995; Hirata et al.,
1994; Wright et al., 1999). Since then, its ligand-binding
property has been well characterized, and novel specific
antagonists have been or are being developed. Laropiprant,
discovered by Merck & Co., is a potent and selective DP
antagonist to treat allergic disorders (Fig. 1) (Ballantyne
et al., 2012; Maccubbin et al., 2012; McKenney et al.,
2010; Sturino et al., 2007). It was formerly used in com-
bination with niacin to treat dyslipidemia. Niacin induces
flushing through dermal Langerhans cells where the acti-
vation of G protein-coupled receptor 109A (GPR109A)
increases arachidonic acid and PGD2. PGD2 acts as a
vasodilator via DP receptor, increasing blood flow and thus
leading to flushes (Cheng et al., 2006; Maciejewski-Lenoir
et al., 2006). Laropiprant acts as a DP antagonist, reducing
the vasodilation. In order to find new active DP antago-
nists, several compounds (I-1–I-18) were synthesized and
the bioactivity was evaluated in a murine model of niacin-
induced flushing (Perry, 2009; Sanyal et al., 2010).
1
and characterized by IR, H-NMR, 13C-NMR and HRMS
spectrum. The potency of these compounds was evaluated
in a murine model of niacin-induced flushing. The results
indicated that most compounds exhibited faster-acting
effect of suppressing vasodilation than laropiprant. Among
them, I-1, I-2, I-3, I-9, I-13, I-15 and I-16 exhibited sub-
stantial flushing inhibitory effect. Especially, I-1 and I-2
showed higher potency than laropiprant and would be
valuable for further investigation.
Keywords Anti-allergic agents Á
Laropiprant derivatives Á Synthesis Á Flushing Á
Biological evaluation
Introduction
Prostaglandin (PG) D2 is the major cyclooxygenase
metabolite of arachidonic acid produced by mast cells in
response to allergen in diseases, such as asthma, atopic
dermatitis, allergic rhinitis and allergic conjunctivitis
(Kabashima and Narumiya, 2003; Matsuoka et al., 2000;
Results and discussion
Chemistry
& Yungen Xu
xyg@cpu.edu.cn
We selected laropiprant as the leading compound and
replaced the acetate acid moiety with an aromatic acid
group. Besides, several substituents were introduced on the
benzyl group. In order to improve the solubility, title com-
pounds (I-1–I-18) were converted into a form of sodium
1
Jiangsu Key Laboratory of Drug Design and Optimization,
China Pharmaceutical University, Nanjing 210009, China
2
Department of Medicinal Chemistry, China Pharmaceutical
University, Nanjing 210009, China
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Med Chem Res (2015) 24:3920–3931
3921
Fig. 1 The structure of
laropiprant
F
followed by corresponding substituted benzyl chloride to
cleanly generate 4A–4I. And then 4A–4I were reduced by
sodium borohydride (NaBH4) to afford 5A–5I (4A–4I and
5A–5I were used without further purification). Secondly,
5A–5I were treated with methyl 4-hydroxybenzoate at 0 °C
by Mitsunobu reaction to give 6A–6I (methyl 2-(4-hy-
droxyphenyl) acetate was also used to afford corresponding
6J–6R). And 6A–6R were further treated with methane-
sulfinic acid sodium salt (CH3SO2Na) and copper (I) iodide
(CuI) to afford 7A–7R. Finally, 7A–7R were directly
hydrolyzed to sodium salts as title compounds I-1–I-18.
H
O
N
O
S
O
O
H
3C
l
C
salts (Fig. 2). The structures of title compounds are outlined
in Table 1. All the synthesized compounds are racemic
mixtures; the resolution process and further biological
evaluation are being studied and will be reported in future.
The synthesis route for the title compounds (I-1–I-18) is
outlined in Scheme 1 (the structures of the intermediates are
outlined in Table 2). Firstly, the ketone 3 was synthesized
by performing a Fischer indole reaction with 2-bromo-4-
fluoroaniline (1) and 2-oxocyclopentane-1-carbaldehyde (2).
Secondly, 3 was treated with sodium hydroxide (NaOH)
Pharmacology
The potency of the title compounds was evaluated by
suppression of niacin-induced vasodilation assay. A murine
model was used, and blood flow velocity in the mouse ear
(a measure of vasodilation, a prominent component of
Fig. 2 Design of title
compounds (I-1–I-18)
F
CO2Na
O
I-1~I-9
N
SO2CH3
R1
F
H
O
N
R3
O
S
O
O
R2
O
H3C
F
l
C
a
N
CO2
N
SO2CH3
R1
I-10~I-18
Laropiprant
R3
R2
Table 1 The structure of title compounds (I-1–I-18)
Compound
I-1, I-10
I-2, I-11
I-3, I-12
I-4, I-13
I-5, I-14
I-6, I-15
I-7, I-16
I-8, I-17
I-9, I-18
R1
R2
R3
H
H
H
H
Cl
H
H
H
H
F
F
H
F
H
Cl
H
H
Cl
H
H
H
H
Cl
H
H
OCH3
Cl
123

3922
Med Chem Res (2015) 24:3920–3931
F
l
C
NH2
F
R1
R3
F
Br
R2
O
(a)
O
N
R1
1
N
H
O
R2
R3
Br
Br
(b)
CHO
3
4A~4I
2
CO2CH3
n
CO2CH3
F
F
n
HO
H
O
O
(c)
N
R1
N
R1
R2
R3
n=0 or 1
R2
R3
(d)
Br
Br
n=0, 6A~6I
n=1, 6J~6R
5A~5I
CO2CH3
F
CO2Na
n
F
n
(e)
(f)
O
R1
O
R1
N
N
R2
R3
R2
R3
SO2CH3
SO2CH3
n=0, 7A~7I
n=1, 7J~7R
n=0, I-1~I-9
n=1, I-10~I-18
Scheme 1 The synthesis route of title compound I-1–I-18.
(a) (i) Sodium nitrite, hydrochloric acid, 0 °C; (ii) sodium acetate,
MeOH, 0 °C; (iii) 3M sulfuric acid, acetonitrile, reflux; (b) NaOH,
tetrabutylammonium bromide, THF, H2O, reflux; (c) NaBH4, CH2Cl2,
MeOH, r.t.; (d) diethyl diazodicarboxylate, tributylphosphane, THF,
0 °C; (e) CH3SO2Na, CuI, NMP, 130 °C; (f) NaOH, THF, MeOH,
H2O, r.t.
Table 2 The substituents of the intermediates
Intermediate
4A
5A
6A
6J
7A
7J
R1
H
4B
5B
6B
6K
7B
7K
4C
5C
6C
6L
7C
7L
4D
5D
6D
6M
7D
7M
4E
4F
5F
6F
6O
7F
7O
4G
5G
6G
6P
7G
7P
4H
5H
6H
6Q
7H
7Q
4I
5E
6E
6N
7E
7N
5I
6I
6R
7I
7R
H
H
H
Cl
H
H
H
H
F
F
H
F
H
Cl
H
R2
H
Cl
H
H
H
H
R3
Cl
H
H
OCH3
Cl
flushing) was measured after administration of niacin to
mice that had been pretreated with vehicle (as a control),
laropiprant or the test compounds I-1–I-18.
As was shown in Tables 3 and 4, most of the test
compounds were found to exhibit good inhibitive activity
against niacin-induced vasodilation (the percentage of
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Med Chem Res (2015) 24:3920–3931
3923
Table 3 Suppression of niacin-induced vasodilation assay of the compounds (effect on blood flow velocity in the mouse ear)a
Group
Initial velocity (lm/s)
Velocity after administration of niacinb (lm/s)
2 min
4 min
6 min
8 min
10 min
Controlc
Positived
I-1
684 34
589 88
709 92
677 77
699 53
691 53
614 41
635 56
667 35
649 38
685 53
633 63
606 47
689 61
612 59
691 48
629 33
733 70
703 24
683 20
867 190
724 112
795 55
746 64
749 39
782 46
673 76
729 55
770 50
749 34
765 65
776 26
734 39
803 22
663 60
769 17
736 45
847 52
812 49
655 15
943 177
744 134
859 45
788 68
836 37
853 25
715 68
803 52
837 40
847 28
830 33
829 22
786 30
916 27
685 66
841 22
773 76
895 81
895 54
800 43
1071 195
715 130
902 70
839 46
866 68
930 23
753 72
847 46
920 66
935 53
906 44
898 20
857 40
1000 42
707 61
926 24
779 94
950 65
1031 92
844 41
1149 205
688 147
855 85
834 71
849 55
883 34
753 47
813 45
954 84
897 60
880 22
896 58
906 54
939 25
711 50
905 36
749 72
956 50
1186 83
889 23
1172 230
672 122
811 77
765 46
803 46
840 52
741 74
769 34
915 641
823 32
823 46
835 342
934 52
908 23
689 49
845 14
726 72
880 66
1053 518
829 23
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-17
I-18
a
Number of animals in each group n = 6; laropiprant and test compounds were injected at the dose of 10 mg/kg; niacin was injected at the dose
of 100 mg/kg
b
The blood flow velocity was measured every 2 min, and the results were expressed as mean SEM
c
Mice in control group were pretreated with vehicle before administration of niacin
d
Mice in positive/control group were pretreated with laropiprant before administration of niacin
inhibition of 12 compounds [30 % at 10 min). Among
them, compounds I-1, I-2, I-3, I-9, I-13, I-15 and I-16
exhibited substantial effect against vasodilation. Espe-
cially, I-1 and I-2 showed higher potency than laropiprant
(the inhibition (%) of I-1 and I-2 totally exceeded the
positive from 2 to 10 min) and would be valuable for
further investigation. The biological studies also revealed
that compounds with benzoic acid group (I-1–I-9) mostly
exhibited better inhibitive effect than compounds with
phenyl acetic acid group (I-10–I-18). We found that I-1–I-
9 had better solubility than I-10–I-18 and attributed it to
the stronger acidity of the benzoic acid group. Besides, it
was observed that the inhibition (%) of all the test com-
pounds exceeded laropiprant at 2 min (most of the com-
pounds exceeded laropiprant at 4 min). It indicated that the
test compounds showed faster-acting inhibitory effect
against niacin-induced flushing than laropiprant. To illus-
trate this, the pharmacokinetic profiles of the test com-
pounds (especially I-1 and I-2) have been studied and the
results will be reported in due course.
Experimental section
Chemistry
General information
Melting points (uncorrected) were determined on an XT-5
1
microscopic melting point spectrometer. H and 13C NMR
spectra were recorded on an ACF* 300Q or ACF* 500Q
Bruker spectrometer in CDCl3, DMSO-d6 or CD3OD, with
Me4Si as the internal reference. The IR spectra were
recorded in film or in potassium bromide disks on a Perkin-
Elmer 398 spectrometer. High-resolution mass spectra
(HRMS) were recorded in electron impact mode. The
procedure for synthesis of I-1 was described as an example
as follows (I-2–I-18 were prepared similarly):
5-Bromo-7-fluoro-1, 2-dihydrocyclopenta[b]indol-3(4H)-
one (3) Firstly, a diazonium salt of 2-bromo-4-fluo-
roaniline was prepared as follows: To a mixture of 1
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Med Chem Res (2015) 24:3920–3931
0.007 mol), 4-chlorobenzyl chloride (1.13 g, 0.007 mol)
and tetrabutylammonium bromide (0.05 g), and the mix-
ture was stirred and refluxed for 6 h. After concentration,
the residual precipitate was filtered and dried to give 4A as
a brown solid. Secondly, 5A was prepared by reduction of
4A using sodium borohydride (0.53 g, 0.014 mol) in
methanol (15 mL) cleanly. Thirdly, 6A was prepared from
5A by Mitsunobu reaction. 5A (crude but dried) and methyl
4-hydroxybenzoate (1.06 g, 0.007 mol), anhydrous THF
(20 mL) and tributylphosphane (3.5 mL, 0.014 mol) were
added to a 50-mL three-necked flask subsequently. A
solution of diethyl diazodicarboxylate (2.2 mL, 0.014 mol)
in THF (10 mL) was added dropwise at 0 °C to the mixture
that was predegassed by N2 gas. It was stirred at 0 °C for
3 h, concentrated and purified by flash chromatography to
give 2.65 g of 6A as a white solid. Yield in 3 steps: 71.7 %.
Table 4 Percentage of inhibition of niacin-induced vasodilation
Group
Inhibition (%)
2 min
4 min
6 min
8 min
10 min
Control
Laropiprant
I-1
–
–
–
–
–
3.15
8.63
22.78
23.99
25.61
23.23
19.99
22.49
20.71
18.34
14.68
21.46
15.39
10.21
13.47
26.74
20.38
21.75
22.47
13.25
26.80
31.36
36.12
34.04
33.08
32.40
27.38
32.35
24.71
27.06
32.07
25.18
11.36
27.72
30.99
30.89
29.60
30.95
11.18
31.46
34.10
36.40
36.58
33.57
32.50
30.38
32.76
24.19
29.69
33.18
26.66
10.72
26.60
34.72
32.16
33.35
33.15
17.23
32.83
13.71
15.52
14.38
13.31
13.87
12.12
11.73
11.76
14.47
5.55
15.69
19.31
13.40
14.42
16.24
12.48
13.32
9.80
I-2
I-3
I-4
I-5
I-6
I-7
I-8
I-9
16.13
8.87
I-10
I-11
I-12
I-13
I-14
I-15
I-16
I-17
I-18
4.04
6.16
Methyl 4-((5-bromo-4-(4-chlorobenzyl)-7-fluoro-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate (6A)
White solid. mp 116–118 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.94–7.98 (2H, m, H-6; H-8), 7.16–7.21
(4H, m, H-300, benzyl; H-500; H-200; H-600), 6.83–6.87 (2H,
m, H-20, methyl benzoate; H-60), 6.77–6.79 (2H, m, H-30;
H-50), 5.88 (1H, d, J = 17.0 Hz, ArCH2), 5.65 (1H, m,
OCH), 5.53 (1H, d, J = 17.0 Hz, ArCH2), 3.89 (3H, s,
CO2CH3), 3.02–3.09 (2H, m, CH2), 2.84–2.89 (1H, m,
CH2), 2.53–2.56 (1H, m, CH2); 13C NMR (CDCl3,
300 MHz,): d = 160.6 (C=O, CO2CH3), 159.6 (C-7),
144.8 (C-10, methyl benzoate), 138.2 (C-4a), 137.5 (C-3a),
137.0 (C-100, benzyl), 133.8 (C-8a), 132.5 (C-400), 131.4 (C-
200), 128.2 (C-600), 126.9 (C-300), 126.8 (C-500), 122.5 (C-30),
121.1 (C-50), 115.9 (C-40), 115.5 (C-20), 115.2 (C-60), 114.7
(C-6), 114.4 (C-8), 104.2 (C-8b), 103.9 (C-5), 103.6 (C-3),
54.4 (CH3, CO2CH3), 51.5 (CH2, benzyl), 35.7 (C-2), 22.2
(C-1); EIMS m/z 552.1 [M ? Na]?.
10.61
14.63
14.79
7.72
7.55
19.46
15.74
11.70
14.80
12.25
19.10
11.22
11.81
15.84
(6.00 g, 0.032 mol) in 4N hydrochloric acid (30 mL), a
solution of sodium nitrite (2.42 g, 0.035 mol) in water
(10 mL) was added dropwise at 0 °C and was aged for
another hour. Secondly, a mixture of 2-oxocyclopentane-1-
carbaldehyde (2) (3.58 g, 0.032 mol) and sodium acetate
(5.25 g, 0.064 mol) in methanol (30 mL) was added slowly
at 0 °C. Upon complete addition, the mixture was aged for
2 h. The resulting precipitate was filtered and dissolved in
acetonitrile (50 mL). After addition of 3 M sulfuric acid
(35 mL), the mixture was refluxed for 6 h under N2
atmosphere. Acetonitrile was removed by concentration,
and the resulting precipitate was filtered and dried to give
5.60 g of 3 as a brown solid. Yield: 65.3 %. mp 202–
204 °C; 1H NMR (DMSO-d6, 300 MHz,): d = 7.58–7.64
(2H, m, H-6, H-8), 3.00–3.02 (2H, m, CH2), 2.91–2.93 (2H,
m, CH2); 13C NMR (CDCl3, 300 MHz,): d = 194.0
(C=O), 158.4 (C-7), 155.2 (C-4a), 146.2 (C-3a), 140.0 (C-
8a), 138.5 (C-8b), 118.2 (C-8), 117.8 (C-6), 105.2 (C-5),
40.4 (C-2), 19.6 (C-1); EIMS m/z 290.0, 292.0 [M ? Na]?.
Methyl 4-((4-benzyl-5-bromo-7-fluoro-1, 2, 3, 4-tetrahy-
drocyclopenta[b]indol-3-yl) oxy) benzoate (6B) White
solid. mp 160–164 °C; 1H NMR (CDCl3, 300 MHz,):
d = 7.95 (2H, m, H-6; H-8), 7.22–7.25 (4H, m, H-300,
benzyl; H-500; H-200; H-600), 6.65–7.01 (5H, m, H-400; H-20,
methyl benzoate; H-60; H-30; H-50), 6.01 (1H, d,
J = 16.7 Hz, ArCH2), 5.63 (1H, s, OCH), 5.50 (1H, d,
J = 16.4 Hz, ArCH2), 3.89 (3H, s, CO2CH3), 3.02 (2H, m,
CH2), 2.85–2.88 (1H, m, CH2), 2.17 (1H, m, CH2).
Methyl 4-((5-bromo-4-(2-chlorobenzyl)-7-fluoro-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate (6C)
White solid. mp 161–163 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.92–7.95 (2H, m, H-6; H-8), 7.31–7.39
(2H, m, H-300, benzyl; H-500), 7.06–7.21 (3H, m, H-400;
H-20, methyl benzoate; H-60), 6.66–6.72 (2H, m, H-30,
H-50), 6.41 (1H, d, J = 7.6 Hz, H-600), 5.71–5.76 (2H, m,
ArCH2), 5.69 (1H, s, OCH), 3.88 (3H, s, CO2CH3),
General procedure for the synthesis of intermediates 6A–
6R (6A as an example)
Firstly, to a solution of NaOH (1.30 g, 0.033 mol) in water
(15 mL) and THF (30 mL) were added 3 (1.88 g,
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Med Chem Res (2015) 24:3920–3931
3925
3.02–3.12 (2H, m, CH2), 2.87–2.92 (1H, m, CH2),
2.55–2.59 (1H, m, CH2).
(2H, m, H-200, benzyl; H-600), 6.80–6.91 (4H, m, H-300;
H-500; H-20, methyl benzoate; H-60), 6.75 (2H, d,
J = 8.7 Hz, H-30; H-50), 5.99 (1H, d, J = 16.5 Hz,
ArCH2), 5.61 (1H, d, J = 6.5 Hz, OCH), 5.40 (1H, d,
J = 16.5 Hz, ArCH2), 3.89 (3H, s, OCH3), 3.75 (3H, s,
CO2CH3), 2.95–3.08 (2H, m, CH2), 2.80–2.87 (1H, m,
CH2), 2.48–2.56 (1H, m, CH2).
Methyl 4-((5-bromo-4-(3-chlorobenzyl)-7-fluoro-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate (6D)
White solid. mp 162–166 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.94–7.98 (2H, m, H-6; H-8), 7.12–7.25
(3H, m, H-200, benzyl; H-400; H-600), 6.85–6.95 (1H, m,
H-500), 6.72–6.79 (3H, m, H-20, methyl benzoate; H-60;
H-30), 6.58–6.62 (1H, m, H-50), 5.88 (1H, dd, J = 9.8 and
17.1 Hz, ArCH2), 5.68 (1H, d, J = 2.7 Hz, OCH), 5.55
(1H, d, J = 17.1 Hz, ArCH2), 3.88 (3H, s, CO2CH3),
3.03–3.10 (2H, m, CH2), 2.81–2.87 (1H, m, CH2),
2.50–2.59 (1H, m, CH2).
Methyl 4-((5-bromo-4-(2,4-dichlorobenzyl)-7-fluoro-1, 2,
3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate
(6I) White solid. mp 180–182 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.93–7.98 (2H, m, H-6; H-8), 7.35 (1H, d,
J = 1.8 Hz, H-300, benzyl), 7.17–7.21 (2H, m, H-500; H-600),
7.13 (1H, d, J = 9.8 Hz, H-20, methyl benzoate), 6.72 (2H,
d, J = 8.8 Hz, H-30; H-50), 6.35 (1H, d, J = 8.4 Hz, H-60),
5.70–5.79 (3H, m, ArCH2, OCH), 3.88 (3H, s, CO2CH3),
3.01–3.11 (2H, m, CH2), 2.86–2.92 (1H, m, CH2),
2.52–2.59 (1H, m, CH2).
Methyl 4-((5-bromo-7-fluoro-4-(4-fluorobenzyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate (6E)
White solid. mp 124–126 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.94–7.98 (2H, m, H-6; H-8), 7.17 (2H, d,
J = 8.6 Hz, H-200, benzyl; H-600), 6.85–6.90 (4H, m, H-300;
H-500; H-20, methyl benzoate; H-60), 6.78 (2H, d,
J = 8.9 Hz, H-30; H-50), 5.91 (1H, d, J = 16.7 Hz,
ArCH2), 5.64 (1H, d, J = 6.5 Hz, OCH), 5.51 (1H, d,
J = 16.7 Hz, ArCH2), 3.89 (3H, s, CO2CH3), 2.99–3.09
(2H, m, CH2), 2.83–2.88 (1H, m, CH2), 2.50–2.57 (1H, m,
CH2).
Methyl 2-(4-((5-bromo-4-(4-chlorobenzyl)-7-fluoro-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acetate
(6J) White solid. mp 136–138 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.12–7.20 (6H, m, H-6; H-8; H-300, ben-
zyl; H-500; H-200; H-600), 6.85 (2H, d, J = 8.4 Hz, H-20,
methyl phenyl acetate; H-60), 6.73 (2H, d, J = 8.6 Hz,
H-30; H-50), 5.88 (1H, d, J = 17.0 Hz, ArCH2), 5.58–5.60
(1H, m, OCH), 5.51 (1H, d, J = 17.0 Hz, ArCH2), 3.69
(3H, s, CH2CO2CH3), 3.57 (2H, s, CH2CO2CH3),
2.94–3.08 (2H, m, CH2), 2.79–2.87 (1H, m, CH2),
2.52–2.60 (1H, m, CH2).
Methyl 4-((5-bromo-7-fluoro-4-(2-fluorobenzyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate (6F)
White solid. mp 154–156 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.95 (2H, d, J = 9.0 Hz, H-6; H-8),
7.34–7.37 (1H, m, H-300, benzyl), 7.16–7.23 (3H, m, H-400;
H-500; H-600), 7.09–7.14 (1H, m, H-20, methyl benzoate),
6.73 (2H, d, J = 9.0 Hz, H-30; H-50), 6.41–6.44 (1H, m,
H-60), 5.78 (2H, d, J = 1.8 Hz, ArCH2), 5.71–5.73 (1H, m,
OCH), 3.90 (3H, s, CO2CH3), 3.07–3.14 (2H, m, CH2),
2.87–2.94 (1H, m, CH2), 2.54–2.64 (1H, m, CH2).
Methyl 2-(4-((4-benzyl-5-bromo-7-fluoro-1, 2, 3, 4-te-
trahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acetate
(6K) White solid. mp 136–138 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.15–7.18 (2H, m, H-6; H-8), 7.12–7.14
(4H, m, H-300, benzyl; H-500; H-200; H-600), 6.90–6.92 (3H,
m, H-400; H-20, methyl phenyl acetate; H-60), 6.74 (2H, d,
J = 8.5 Hz, H-30; H-50), 6.01 (1H, d, J = 17.0 Hz,
ArCH2), 5.58 (1H, m, OCH), 5.49 (1H, d, J = 17.0 Hz,
ArCH2), 3.69 (3H, s, CH2CO2CH3), 3.56 (2H, s, CH2-
CO2CH3), 2.92–3.04 (2H, m, CH2), 2.80–2.83 (1H, m,
CH2), 2.53–2.57 (1H, m, CH2).
Methyl 4-((5-bromo-7-fluoro-4-(3-fluorobenzyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate (6G)
White solid. mp 158–160 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.96 (2H, d, J = 8.8 Hz, H-6; H-8),
7.16–7.20 (3H, m, H-200, benzyl; H-400; H-500), 6.88–6.93
(1H, m, H-600), 6.78 (1H, d, J = 8.8 Hz, H-20, methyl
benzoate), 6.70 (1H, d, J = 7.5 Hz, H-60), 6.60 (2H, d,
J = 9.6 Hz, H-30; H-50), 5.90 (1H, d, J = 17.1 Hz,
ArCH2), 5.67 (1H, d, J = 4.7 Hz, OCH), 5.56 (1H, d,
J = 17.1 Hz, ArCH2), 3.88 (3H, s, CO2CH3), 2.99–3.06
(2H, m, CH2), 2.81–2.89 (1H, m, CH2), 2.50–2.57 (1H, m,
CH2).
Methyl 2-(4-((5-bromo-4-(2-chlorobenzyl)-7-fluoro-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acetate
(6L) White solid. mp 144–146 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.32–7.36 (1H, m, H-6), 7.09–7.19 (5H,
m, H-8; H-300, benzyl; H-400; H-500; H-600), 7.05–7.07 (1H,
m, H-20, methyl phenyl acetate), 6.65–6.70 (2H, m, H-30;
H-50), 6.37 (1H, d, J = 7.6 Hz, H-60), 5.75 (2H, d,
J = 11.1 Hz, ArCH2), 5.62–5.67 (1H, m, OCH), 3.68 (3H,
s, CH2CO2CH3), 3.55 (2H, s, CH2CO2CH3), 2.96–3.10
(2H, m, CH2), 2.84–2.90 (1H, m, CH2), 2.56–2.62 (1H, m,
CH2).
Methyl 4-((5-bromo-7-fluoro-4-(4-methoxybenzyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate (6H)
White solid. mp 168–172 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.96–8.02 (2H, m, H-6; H-8), 7.14–7.20
123

3926
Med Chem Res (2015) 24:3920–3931
Methyl 2-(4-((5-bromo-4-(3-chlorobenzyl)-7-fluoro-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acetate
(6M) White solid. mp 130–132 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.14–7.24 (5H, m, H-6; H-8; H-200, ben-
zyl; H-400; H-600), 6.95 (1H, s, H-500), 6.75–6.80 (3H, m,
H-20, methyl phenyl acetate; H-30; H-50), 6.66–6.73 (1H, m,
H-60), 5.85–5.94 (1H, m, ArCH2), 5.56–5.61 (1H, m,
ArCH2), 5.50 (1H, s, OCH), 3.69 (3H, s, CH2CO2CH3),
3.56 (2H, s, CH2CO2CH3), 2.96–3.08 (2H, m, CH2),
2.82–2.87 (1H, m, CH2), 2.54–2.59 (1H, m, CH2).
Methyl 2-(4-((5-bromo-4-(2,4-dichlorobenzyl)-7-fluoro-1,
2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl)
acetate (6R) White solid. mp 134–136 °C; 1H NMR
(CDCl3, 300 MHz,): d = 7.36 (1H, m, H-6), 7.18–7.21
(1H, m, H-8), 7.14–7.17 (2H, m, H-300, benzyl; H-600),
7.11–7.13 (1H, m, H-500), 7.04–7.08 (1H, m, H-20, methyl
phenyl acetate), 6.73 (2H, d, J = 21.2 Hz, H-30; H-50),
6.32 (1H, d, J = 8.4 Hz, H-60), 5.62–5.71 (3H, m, ArCH2,
OCH), 3.69 (3H, s, CH2CO2CH3), 3.57 (2H, s, CH2CO2
CH3), 2.99–3.07 (2H, m, CH2), 2.84–2.89 (1H, m, CH2),
2.57–2.58 (1H, m, CH2).
Methyl 2-(4-((5-bromo-7-fluoro-4-(4-fluorobenzyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acetate
(6N) White solid. mp 114–116 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.14–7.19 (4H, m, H-6; H-8; H-200, ben-
zyl; H-600), 6.86–6.95 (4H, m, H-300; H-500; H-20, methyl
phenyl acetate; H-60), 6.74 (2H, d, J = 8.6 Hz, H-30; H-50),
5.90 (1H, d, J = 16.7 Hz, ArCH2), 5.58–5.60 (1H, m,
OCH), 5.51 (1H, d, J = 16.7 Hz, ArCH2), 3.69 (3H, s,
CH2CO2CH3), 3.57 (2H, s, CH2CO2CH3), 2.93––3.08 (2H,
m, CH2), 2.79–2.86 (1H, m, CH2), 2.51–2.60 (1H, m, CH2).
General procedure for the synthesis of compound I-1–I-16
(I-1 as an example)
The sulfonylation was accomplished by
6 (0.60 g,
1.1 mmol) and thus formed with methanesulfinic acid
sodium salt (0.34 g, 3.3 mmol) and copper(I) iodide (1.05 g,
5.5 mmol) in N-methylpyrrolidinone (10 mL). The resulting
suspension was degassed under N2, heated to 130 °C, stirred
for 3 h and then cooled to r.t. The reaction was quenched by
the addition of ethyl acetate (EtOAc) (20 mL) and hexane
(20 mL), filtered through a pad of silica gel, eluting with
EtOAc, concentrated and further purified by flash chro-
matography to give 7 as a white solid. I-1 was prepared by
the treatment of the ester 7 in methanol (10 mL) with 1 N
NaOH (0.48 g, 1.2 mmol) and purified by recrystallization
in isopropyl alcohol (IPA). Yield in 2 steps: 55.3 %.
Methyl 2-(4-((5-bromo-7-fluoro-4-(2-fluorobenzyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acetate
(6O) White solid. mp 132–134 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.33––7.35 (2H, m, H-6; H-8), 7.07–7.16
(5H, m, H-300, benzyl; H-400; H-500; H-600; H-20, methyl
phenyl acetate), 6.67–6.70 (2H, m, H-30; H-50), 6.35––6.38
(1H, m, H-60), 5.73–5.83 (2H, m, ArCH2), 5.64 (1H, m,
OCH), 3.68 (3H, s, CH2CO2CH3), 3.55 (2H, s, CH2CO2
CH3), 3.04 (2H, m, CH2), 2.86–2.90 (1H, m, CH2), 2.58
(1H, s, CH2).
Sodium 4-((4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-
1, 2, 3, 4-tetrahydrocyclopenta[b] indol-3-yl) oxy) ben-
zoate (I-1) White solid (IPA), mp: 250–252 °C; IR (KBr)
mmax 3430, 1594, 1547, 1492, 1409, 1310, 1235, 1146,
1123, 1014, 963, 791, 540 cm-1; 1H NMR (DMSO-d6 and
D2O, 500 MHz,): d = 7.72–7.74 (3H, m, H-6; H-30,
sodium benzoate; H-50), 7.60 (1H, m, H-8), 7.19 (2H, m,
H-20; H-60), 6.75 (2H, m, H-200, benzyl; H-600), 6.61 (2H, m,
H-300; H-500), 5.84 (1H, d, J = 17.5 Hz, ArCH2), 5.68 (1H,
d, J = 17.3 Hz, ArCH2), 5.55 (1H, m, OCH), 2.93–2.99
(2H, m, CH2), 2.79–2.82 (1H, m, CH2), 2.52 (3H, s, SO2
CH3), 2.30–2.31 (1H, m, CH2); 13C NMR (DMSO-d6 and
D2O, 500 MHz,): d = 178.0 (CO2Na, sodium benzoate),
171.8 (C-7), 159.1 (C-10, sodium benzoate), 156.7 (C-3a),
154.8 (C-4a), 148.6 (C-100, benzyl), 138.3 (C-30), 133.5 (C-
50), 132.7 (C-400), 132.4 (C-8a, C-40), 131.7 (C-200), 129.2
(C-600), 128.6 (C-300), 126.9 (C-500), 124.9 (C-5), 114.7 (C-
20), 113.5 (C-60), 113.3 (C-8), 112.7 (C-8b), 112.5 (C-6),
75.9 (C-3), 50.1 (CH2, benzyl), 44.8 (CH3, SO2CH3), 36.7
(C-2), 23.0 (C-1). HRESIMS m/z (pos): 536.0692 C26H20
ClFNNaO5S (calcd. 536.0632).
Methyl 2-(4-((5-bromo-7-fluoro-4-(3-fluorobenzyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acetate
(6P) White solid. mp 116–118 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.20–7.24 (2H, m, H-6; H-8), 7.15–7.18
(2H, m, H-200, benzyl; H-400), 6.91–6.96 (1H, m, H-500),
6.79–6.83 (2H, m, H-600; H-20, methyl phenyl acetate),
6.69–6.78 (2H, m, H-30; H-50), 6.61–6.65 (1H, m, H-60),
3.72 (3H, s, CH2CO2CH3), 3.59 (2H, s, CH2CO2CH3),
2.90–3.09 (2H, m, CH2), 2.82–2.87 (1H, m, CH2),
2.56–2.63 (1H, m, CH2).
Methyl 2-(4-((5-bromo-7-fluoro-4-(4-methoxybenzyl)-1, 2,
3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl) acet-
ate (6Q) White solid. mp 123–125 °C; 1H NMR (CDCl3,
300 MHz,): d = 7.12–7.19 (4H, m, H-6; H-8; H-200, ben-
zyl; H-600), 6.85–6.90 (2H, m, H-300, H-500), 6.74–6.81 (4H,
m, H-20, methyl phenyl acetate; H-60; H-30; H-50), 5.98 (1H,
d, J = 16.6 Hz, ArCH2), 5.57 (1H, d, J = 4.8 Hz, OCH),
5.40 (1H, d, J = 16.6 Hz, ArCH2), 3.80 (3H, s, OCH3),
3.75 (3H, s, CH2CO2CH3), 3.57 (2H, s, CH2CO2CH3),
2.90–3.06 (2H, m, CH2), 2.77–2.85 (1H, m, CH2),
2.50–2.56 (1H, m, CH2).
Sodium 4-((4-benzyl-7-fluoro-5-(methylsulfonyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl)
oxy)
benzoate
(I-2) White solid (IPA), mp: 234–236 °C; IR (KBr) mmax
123

Med Chem Res (2015) 24:3920–3931
3927
3406, 2925, 1603, 1549, 1493, 1453, 1397, 1301, 1236, 1196,
1143, 1121, 1036, 958, 860, 788, 756, 701, 619, 539 cm-1
ArCH2), 5.67 (1H, m, OCH), 3.06–3.12 (2H, m, CH2),
2.93–2.96 (1H, m, CH2), 2.89 (3H, s, SO2CH3), 2.46–2.54
(1H, m, CH2); 13C NMR (MeOD, 300 MHz,): d = 173.3
(CO2Na, sodium benzoate), 164.2 (C-7), 161.0 (C-10,
sodium benzoate), 158.7 (C-3a), 153.6 (C-4a), 147.4 (C-100,
benzyl), 141.4 (C-30), 141.3 (C-50), 132.7 (C-40), 130.3 (C-
8a), 130.1 (C-300), 129.6 (C-600), 129.5 (C-200), 128.0 (C-
400), 123.2 (C-500,C-5), 121.1 (C-20), 113.3 (C-60), 112.3 (C-
8), 110.8 (C-8b), 110.5 (C-6), 74.8 (C-3), 49.6 (CH2,
benzyl), 43.0 (CH3, SO2CH3), 35.5 (C-2), 21.4 (C-1);
HRESIMS m/z (pos): 536.0730 C26H20ClFNNaO5S (calcd.
536.0632).
;
1H NMR (MeOD, 300 MHz,): d = 7.87 (2H, d, J = 8.7 Hz,
H-6; H-8), 7.71 (1H, m, H-30, sodium benzoate), 7.65 (1H, m,
H-50), 7.21–7.23 (3H, m, H-200, benzyl; H-600; H-400),
6.81–6.83 (2H, m, H-20; H-60), 6.72 (2H, d, J = 9.0 Hz,
H-300; H-500), 6.15 (1H, d, J = 17.1 Hz, ArCH2), 5.80 (1H, d,
J = 17.4 Hz, ArCH2), 5.61–5.65 (1H, m, OCH), 3.05–3.13
(2H, m, CH2), 2.90–2.95 (1H, m, CH2), 2.72 (3H, s, SO2
CH3), 2.46–2.55 (1H, m, CH2); 13C NMR (MeOD,
300 MHz,): d = 173.3 (CO2Na, sodium benzoate), 158.7
(C-7), 156.6 (C-10, sodium benzoate), 153.5 (C-3a), 147.6
(C-4a), 138.4 (C-100, benzyl), 132.7 (C-30), 130.2 (C-50),
130.1 (C-40), 127.9 (C-8a), 127.8 (C-400), 127.5 (C-200), 126.5
(C-600), 125.2 (C-300), 122.9 (C-500), 122.8 (C-5), 113.4 (C-
20), 112.8 (C-60), 112.4 (C-8), 110.7 (C-8b), 110.4(C-6), 74.9
(C-3), 49.9 (CH2, benzyl), 42.9 (CH3, SO2CH3), 35.4 (C-2),
21.4 (C-1); HRESIMS m/z (pos): 501.9683 C26H21
FNNaO5S (calcd. 502.1022).
Sodium 4-((7-fluoro-4-(4-fluorobenzyl)-5-(methylsulfonyl)-
1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate
(I-5) White solid (IPA), mp:238–240 °C; IR (KBr) mmax
3433, 1639, 1559, 1510, 1412, 1302, 1235, 1145, 1121,
791, 647, 539 cm-1; 1H NMR (MeOD, 300 MHz,):
d = 7.89 (2H, d, J = 9.0 Hz, H-6; H-8), 7.72 (1H, m, H-30,
sodium benzoate), 7.63–7.67 (1H, m, H-50), 6.92–6.98 (2H,
m, H-20; H-60), 6.83–6.88 (2H, m, H-200, benzyl; H-600),
6.73–6.75 (2H, m, H-300; H-500), 6.10(1H, d, J = 17.1 Hz,
ArCH2), 5.78 (1H, d, J = 16.8 Hz, ArCH2), 5.60–5.64
(1H, m, OCH), 3.03–3.13 (2H, m, CH2), 2.91–2.96 (1H, m,
CH2), 2.92(3H, s, SO2CH3), 2.46–2.55 (1H, m, CH2); 13C
NMR (MeOD, 300 MHz,): d = 178.5 (CO2Na, sodium
benzoate), 173.3 (C-7), 163.2 (C-400, benzyl), 159.9 (C-10,
sodium benzoate), 158.7 (C-3a), 147.4 (C-4a), 134.3 (C-
100), 134.2 (C-40), 132.7 (C-30), 130.3 (C-50), 130.1 (C-8a),
127.3 (C-200), 127.2 (C-600), 123.2 (C-300), 114.6 (C-500),
114.3 (C-5), 113.4 (C-20), 112.8 (C-60), 112.4 (C-8), 110.7
(C-8b), 110.4 (C-6), 74.9 (C-3), 43.0 (CH2, benzyl), 35.5
(CH3, SO2CH3), 22.3 (C-2), 21.4 (C-1); HRESIMS m/
z (pos): 520.1017 C26H20F2NNaO5S (calcd. 520.0928).
Sodium 4-((4-(2-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-
1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate
(I-3) White solid (IPA), mp: 242–246 °C; IR (KBr) mmax
3386, 1601, 1549, 1446, 1393, 1307, 1234, 1171, 1121,
1039, 957, 861, 788, 755, 617, 567, 540, 467 cm-1; 1H
NMR (MeOD, 300 MHz,): d = 7.84 (2H, d, J = 8.7 Hz,
H-6; H-8), 7.67–7.74 (2H, m, H-30, sodium benzoate;
H-50), 7.38 (1H, m, H-20), 7.21–7.26 (1H, m, H-60),
7.08–7.13 (1H, m, H-300, benzyl), 6.62 (2H, d, J = 8.7 Hz,
H-400; H-600), 6.47 (1H, d, J = 7.8 Hz, H-500), 6.17 (1H, d,
J = 18.3 Hz, ArCH2), 5.97 (1H, d, J = 18.3 Hz, ArCH2),
5.72 (1H, m, OCH), 3.08–3.18 (2H, m, CH2), 2.90–2.98
(1H, m, CH2), 2.75 (3H, s, SO2CH3), 2.48–2.56 (1H, m,
CH2); 13C NMR (MeOD, 300 MHz,): d = 173.3 (CO2Na,
sodium benzoate), 158.7 (C-7), 156.8 (C-10, sodium ben-
zoate), 155.3 (C-3a), 153.7 (C-4a), 147.4 (C-100, benzyl),
136.0 (C-30), 130.9 (C-50), 130.2 (C-40), 130.1 (C-8a),
128.6 (C-200), 128.0 (C-600), 127.9 (C-300), 126.3 (C-500),
126.0 (C-400), 123.2 (C-5), 113.3 (C-20), 112.9 (C-60), 112.5
(C-8), 110.9 (C-8b), 110.6 (C-6), 74.9 (C-3), 49.9 (CH3,
SO2CH3; CH2, benzyl), 35.6 (C-2), 21.5 (C-1); HRESIMS
m/z (pos): 536.0713 C26H20ClFNNaO5S (calcd. 536.0632).
Sodium 4-((7-fluoro-4-(2-fluorobenzyl)-5-(methylsulfonyl)-
1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate
(I-6) White solid (IPA), mp:230–232 °C; IR (KBr) mmax
3385, 1601, 1552, 1491, 1396, 1303, 1235, 1198, 1121,
1039, 958, 860, 788, 755, 617, 539, 468 cm-1; 1H NMR
(MeOD, 300 MHz,): d = 7.84 (2H, d, J = 8.7 Hz, H-6;
H-8), 7.67–7.74 (2H, m, H-30, sodium benzoate; H-50), 7.37
(1H, m, H-300, benzyl), 7.20–7.26 (1H, m, H-400), 7.07–7.13
(1H, m, H-500), 6.60–6.63 (2H, m, H-20; H-60), 6.16–6.19
(1H, m, H-600), 6.07 (1H, d, J = 18.0 Hz, ArCH2), 5.96
(1H, d, J = 18.3 Hz, ArCH2), 5.69–5.73 (1H, m, OCH),
3.07–3.16 (2H, m, CH2), 2.92–2.99 (1H, m, CH2), 2.87
(3H, s, SO2CH3), 2.47–2.56 (1H, m, CH2); 13C NMR
(MeOD, 300 MHz,): d = 173.3 (CO2Na, sodium ben-
zoate), 158.7 (C-7), 156.8 (C-200, benzyl), 153.7 (C-10,
sodium benzoate), 147.4 (C-3a), 136.0 (C-4a), 130.9 (C-
100), 130.2 (C-30), 130.1 (C-50), 128.6 (C-40), 128.0 (C-8a),
127.9 (C-300), 126.3 (C-400), 126.0 (C-600), 123.3 (C-500),
123.2 (C-5), 113.3 (C-20), 112.9 (C-60), 112.5 (C-8), 110.9
Sodium 4-((4-(3-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-
1, 2, 3, 4-tetrahydrocyclopenta[b] indol-3-yl) oxy) ben-
zoate (I-4) White solid (IPA), mp: 208–210 °C; IR (KBr)
mmax 3404, 1601, 1553, 1489, 1412, 1302, 1237, 1145,
1120, 1036, 957, 861, 787, 567, 539, 466 cm-1; 1H NMR
(MeOD, 300 MHz,): d = 7.88 (2H, d, J = 9.0 Hz, H-6;
H-8), 7.72 (1H, m, H-30, sodium benzoate), 7.65 (1H, m,
H-50), 7.19–7.27 (1H, m, H-200, benzyl), 6.91–6.97 (1H, m,
H-400), 6.71 (2H, d, J = 8.7 Hz, H-20; H-60), 6.66 (1H, d,
J = 8.1 Hz, H-500), 6.54 (1H, d, J = 9.9 Hz, H-600), 6.07
(1H, d, J = 17.4 Hz, ArCH2), 5.86 (1H, d, J = 17.7 Hz,
123

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Med Chem Res (2015) 24:3920–3931
(C-8b), 110.6 (C-6), 74.9 (C-3), 48.4 (CH2, benzyl; CH3,
SO2CH3), 35.6 (C-2), 21.5 (C-1); HRESIMS m/z (neg):
496.1050 C26H20F2NNaO5S (calcd. 496.1036).
1234, 1171, 1146, 1122, 1307, 959, 863, 834, 788,
539 cm-1; 1H NMR (MeOD, 300 MHz,): d = 7.86 (2H, d,
J = 9.0 Hz, H-6; H-8), 7.67–7.74 (2H, m, H-30, sodium
benzoate; H-50), 7.42 (1H, d, J = 2.1 Hz, H-300, benzyl),
7.15 (1H, m, H-500), 6.61–6.66 (2H, m, H-20; H-60), 6.20
(1H, d, J = 8.4 Hz, H-600), 6.04 (1H, d, J = 18.3 Hz,
ArCH2), 5.89 (1H, d, J = 18.0 Hz, ArCH2), 5.75 (1H, m,
OCH), 3.08–3.17 (2H, m, CH2), 2.90–2.99 (1H, m, CH2),
2.87 (3H, s, SO2CH3), 2.48–2.55 (1H, m, CH2); 13C NMR
(MeOD, 300 MHz,): d = 173.3 (CO2Na, sodium ben-
zoate), 158.6 (C-10, sodium benzoate), 156.9 (C-7), 153.7
(C-100, benzyl), 147.3 (C-200), 135.0 (C-400), 132.7 (C-3a),
132.6 (C-4a), 131.6 (C-600), 130.2 (C-500), 128.1 (C-300),
127.4 (C-30), 126.5 (C-50), 126.0 (C-8a), 123.5 (C-40),
123.4 (C-5), 113.2 (C-8), 112.7 (C-20), 112.3 (C-60), 110.9
(C-6), 110.6 (C-8b), 74.7 (C-3), 49.8 (CH2, benzyl; CH3,
SO2CH3), 35.6 (C-2), 21.5 (C-1); HRMS (ESI) calcd.
HRESIMS m/z (pos): 570.0343 C26H19Cl2FNNaO5S
(calcd. 570.0243).
Sodium 4-((7-fluoro-4-(3-fluorobenzyl)-5-(methylsulfonyl)-
1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy) benzoate
(I-7) White solid (IPA), mp: 220–224 °C; IR (KBr) mmax
3411, 2926, 1601, 1553, 1489, 1403, 1302, 1268, 1197,
1147, 1120, 1037, 958, 860, 787, 567, 540, 467 cm-1; 1H
NMR (MeOD, 300 MHz,): d = 7.86–7.92 (2H, m, H-6;
H-8), 7.73 (1H, m, H-30, sodium benzoate), 7.66 (1H, m,
H-50), 7.17–7.27 (2H, m, H-400, benzyl; H-500), 6.86–6.98
(2H, m, H-20; H-60), 6.72 (1H, m, H-600), 6.52–6.70 (1H, m,
H-200), 6.02–6.12 (1H, m, ArCH2), 5.86 (1H, d,
J = 14.5 Hz, ArCH2), 5.66–5.68 (1H, m, OCH), 3.05–3.14
(2H, m, CH2), 2.89–2.98 (1H, m, CH2), 2.94 (3H, s, SO2
CH3), 2.47–2.55 (1H, m, CH2); 13C NMR (MeOD,
300 MHz,): d = 173.3 (CO2Na, sodium benzoate), 158.7
(C-7), 158.6 (C-300, benzyl), 147.4 (C-10, sodium benzoate),
147.3 (C-3a), 140.8 (C-4a), 133.8 (C-100), 130.3 (C-30),
129.5 (C-50), 129.3 (C-40), 126.6 (C-8a), 125.5 (C-200),
123.8 (C-400), 121.1 (C-500), 113.3 (C-600), 113.0 (C-5),
112.0 (C-20, C-6), 110.8 (C-60, C-8), 110.5 (C-8b), 74.8 (C-
3), 49.6 (CH2, benzyl; CH3, SO2CH3), 35.4 (C-2), 21.4 (C-
1); HRESIMS m/z (pos): 520.1024 C26H20F2NNaO5S
(calcd. 520.0928).
Sodium 2-(4-((4-(4-chlorobenzyl)-7-fluoro-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy)
phenyl) acetate (I-10) White solid (IPA), mp:
242–246 °C; IR (KBr) mmax 3426, 1570, 1509, 1404,
1312, 1233, 1145, 1123, 1039, 1014, 959, 810, 757, 568,
540, 468 cm-1; 1H NMR (MeOD, 300 MHz,): d = 7.83
(1H, m, H-6), 7.64 (1H, m, H-8), 7.30 (2H, d, J = 8.5 Hz,
H-30, sodium phenyl acetate; H-50), 7.10 (2H, d,
J = 8.5 Hz, H-300, benzyl; H-500), 6.79 (2H, d, J = 8.5 Hz,
H-20; H-60), 6.61 (2H, d, J = 8.5 Hz, H-200; H-600), 6.00
(1H, d, J = 17.5 Hz, ArCH2), 5.71 (1H, d, J = 17.5 Hz,
ArCH2), 5.54 (1H, m, OCH), 3.14 (2H, s, CH2CO2Na),
3.12 (3H, s, SO2CH3), 2.98–3.02 (2H, m, CH2), 2.81–2.86
(1H, m, CH2), 2.35–2.38 (1H, m, CH2); 13C NMR (MeOD,
300 MHz,): d = 174.8 (C=O, CH2CO2Na), 155.7 (C-7),
154.7 (C-10, sodium phenyl acetate), 153.9 (C-100, benzyl),
148.0 (C-3a), 137.7 (C-4a), 132.7 (C-400), 132.5 (C-30),
131.5 (C-50), 130.1 (C-8a), 128.4 (C-200), 127.7 (C-600),
127.5 (C-300), 126.6 (C-500), 123.4 (C-40), 114.4 (C-5),
112.5 (C-8), 111.5 (C-8b, C-20), 111.3 (C-6; C-60), 74.9 (C-
3), 49.9 (CH2, benzyl), 45.1 (CH3, SO2CH3), 40.0 (CH2,
CH2CO2Na), 35.3 (C-2), 22.2 (C-1); HRESIMS m/z (pos):
550.0858 C27H22ClFNNaO5S (calcd. 550.0789).
Sodium
4-((7-fluoro-4-(4-methoxybenzyl)-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy)
benzoate (I-8) White solid (IPA), mp: 220–224 °C; IR
(KBr) mmax 3423, 1594, 1510, 1414, 1385, 1299, 1231,
1178, 1143, 1122, 1036, 960, 818, 757, 541 cm-1; 1H
NMR (MeOD, 300 MHz,): d = 7.89–7.92 (2H, m, H-6;
H-8), 7.71–7.76 (1H, m, H-30, sodium benzoate), 7.63–7.68
(1H, m, H-50), 6.76–6.81 (4H, m, H-20; H-60; H-300, benzyl;
H-500), 6.70–6.73 (2H, m, H-200; H-600), 6.10–6.16 (1H, m,
ArCH2), 5.66–5.73 (1H, m, ArCH2), 5.60–5.62 (1H, m,
OCH), 3.73 (3H, s, OCH3), 3.05–3.13 (2H, m, CH2), 2.97
(3H, s, SO2CH3), 2.87–2.95 (1H, m, CH2), 2.47–2.55 (1H,
m, CH2); 13C NMR (MeOD, 300 MHz,): d = 178.7
(CO2Na, sodium benzoate), 158.6 (C-7), 155.3 (C-400,
benzyl), 148.0 (C-10, sodium benzoate), 130.4 (C-3a),
130.2 (C-4a), 128.2 (C-8a, C-200), 129.3 (C-600), 126.5 (C-
300), 126.3 (C-500), 114.4 (C-100, C-40), 113.2 (C-8), 112.6
(C-5), 112.2 (C-30), 110.6 (C-50), 110.3 (C-20), 109.8 (C-
60), 108.4 (C-6), 107.6 (C-8b), 75.0 (C-3), 53.8 (OCH3),
49.3 (CH2, benzyl), 43.6 (CH3, SO2CH3), 35.5 (C-2), 21.3
(C-1);HRESIMS m/z (pos): 532.1241 C27H23FNNaO6S
(calcd. 532.1128).
Sodium 2-(4-((4-benzyl-7-fluoro-5-(methylsulfonyl)-1, 2, 3,
4-tetrahydrocyclopenta[b]indol-3-yl) oxy) phenyl)acetate
(I-11) White solid (IPA), mp: 242–244 °C; IR (KBr)
mmax 3423, 1578, 1509, 1491, 1416, 1400, 1359, 1315,
1301, 1234, 1175, 1146, 1122, 1039, 960, 769, 542 cm-1
;
1H NMR (MeOD, 300 MHz,): d = 7.70 (1H, m, H-6),
7.62 (1H, m, H-8), 7.20–7.24 (4H, m, H-30, sodium phenyl
acetate; H-50; H-300, benzyl; H-500), 7.18 (1H, s, H-400),
6.80–6.82 (2H, m, H-200; H-600), 6.67 (2H, d, J = 6.6 Hz,
Sodium 4-((4-(2, 4-dichlorobenzyl)-7-fluoro-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydro cyclopenta[b]indol-3-yl) oxy)
benzoate (I-9) White solid (IPA), mp: 248–250 °C; IR
(KBr) mmax 3406, 1600, 1552, 1451, 1389, 1352, 1315,
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Med Chem Res (2015) 24:3920–3931
3929
H-20; H-60), 6.17 (1H, d, J = 17.4 Hz, ArCH2), 5.77 (1H, d,
J = 17.4 Hz, ArCH2), 5.55–5.57 (1H, m, OCH), 3.40 (2H,
s, CH2CO2Na), 3.18 (3H, s, SO2CH3), 2.99–3.12 (2H, m,
CH2), 2.89–2.93 (1H, m, CH2), 2.47–2.55 (1H, m, CH2);
13C NMR (MeOD, 300 MHz,): d = 178.7 (C=O, CH2
CO2Na), 156.6 (C-7), 155.3 (C-10, sodium phenyl acetate),
153.5 (C-100, benzyl), 148.0 (C-3a), 138.5 (C-4a), 132.7 (C-
8a), 130.4 (C-30), 129.3 (C-50), 128.3 (C-300), 127.9 (C-500),
126.5 (C-200), 125.2 (C-600), 123.4 (C-400), 122.7 (C-40, C-5),
114.4 (C-8), 112.7 (C-20), 112.3 (C-60), 110.7 (C-8b), 110.4
(C-6), 75.0 (C-3), 49.8 (CH2, benzyl), 43.6 (CH3, SO2CH3;
CH2, CH2CO2Na), 35.5 (C-2), 21.4 (C-1); HRESIMS m/
z (pos): 515.9829 C27H23FNNaO5S (calcd. 516.1179).
130.4 (C-30), 129.6 (C-50), 129.3 (C-200), 129.2 (C-600),
126.5 (C-400), 125.4 (C-500), 123.7 (C-300), 121.0 (C-40),
114.3 (C-5), 113.2 (C-8), 112.7 (C-20), 112.2 (C-60), 111.9
(C-8b), 110.7 (C-6), 74.9 (C-3), 49.5 (CH2, benzyl), 43.5
(CH3, SO2CH3; CH2, CH2CO2Na), 35.4 (C-2), 21.3 (C-1);
HRMS (ESI) calcd. HRESIMS m/z (pos): 550.0890 C27
H22ClFNNaO5S (calcd. 550.0789).
Sodium
2-(4-((7-fluoro-4-(4-fluorobenzyl)-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy)
phenyl) acetate (I-14) White solid (IPA), mp:
244–248 °C; IR (KBr) mmax 3408, 1575, 1509, 1411,
1314, 1232, 1159, 1146, 1122, 958, 821, 757, 541 cm-1
;
1H NMR (MeOD, 300 MHz,): d = 7.71 (1H, m, H-6),
7.65 (1H, m, H-8), 7.26–7.28 (1H, m, H-30, sodium phenyl
acetate), 7.20 (2H, d, J = 7.3 Hz, H-20; H-60), 6.92–6.97
(1H, m, H-50), 6.64–6.70 (3H, m, H-200, benzyl; H-600;
H-300), 6.52–6.55 (1H, m, H-500), 6.10 (1H, d, J = 14.5 Hz,
ArCH2), 5.83 (1H, d, J = 14.8 Hz, ArCH2), 5.59–5.62
(1H, m, OCH), 3.41 (2H, s, CH2CO2Na), 2.99–3.13 (2H,
m, CH2), 2.94 (3H, s, SO2CH3), 2.86–2.91 (1H, m, CH2),
2.47–2.56 (1H, m, CH2); 13C NMR (MeOD, 300 MHz,):
d = 178.4 (C=O, CH2CO2Na), 164.2 (C-400, benzyl), 161.0
(C-10, sodium phenyl acetate), 156.7 (C-7), 155.2 (C-100),
153.6 (C-3a), 147.8 (C-4a), 141.5 (C-8a), 141.4 (C-30),
130.5 (C-50), 129.7 (C-200), 129.6 (C-600), 129.4 (C-300),
121.0 (C-500), 114.3 (C-40), 113.3 (C-5), 113.0 (C-8), 112.4
(C-20), 112.2 (C-60), 111.9 (C-8b), 110.8 (C-6), 74.9 (C-3),
49.5 (CH2, benzyl), 43.6 (CH3, SO2CH3; CH2, CH2CO2
Na), 35.5 (C-2), 21.4 (C-1); HRESIMS m/z (pos): 534.1168
C27H22F2NNaO5S (calcd. 534.1084).
Sodium 2-(4-((4-(2-chlorobenzyl)-7-fluoro-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta [b]indol-3-yl) oxy)
phenyl) acetate (I-12) White solid (IPA), mp:
200–202 °C; IR (KBr) mmax 3425, 1574, 1574, 1509,
1490, 1444, 1417, 1393, 1301, 1231, 1146, 1122, 1040,
959, 761, 540 cm-1;1H NMR (MeOD, 300 MHz,):
d = 7.71 (1H, m, H-6), 7.65 (1H, m, H-8), 7.21 (2H, d,
J = 8.7 Hz, H-30, sodium phenyl acetate; H-50), 6.94–7.00
(2H, m, H-300, benzyl; H-600), 6.83–6.88 (2H, m, H-20;
H-60), 6.70 (2H, d, J = 8.7 Hz, H-400; H-500), 6.12 (1H, d,
J = 17.1 Hz, ArCH2), 5.75 (1H, d, J = 17.1 Hz, ArCH2),
5.54–5.57 (1H, m, OCH), 3.41 (2H, s, CH2CO2Na),
3.02–3.11 (2H, m, CH2), 2.90 (3H, s, SO2CH3), 2.85–2.93
(1H, m, CH2), 2.46–2.52 (1H, m, CH2); 13C NMR (MeOD,
300 MHz,): d = 178.7 (C=O, CH2CO2Na), 163.2 (C-7),
159.9 (C-10, sodium phenyl acetate), 156.7 (C-100, benzyl),
155.3 (C-3a), 147.8 (C-4a), 134.3 (C-8a), 130.5 (C-30),
129.4 (C-50), 127.9 (C-600), 127.3 (C-400), 127.2 (C-300),
123.0 (C-500, C-40), 122.9 (C-200), 114.6 (C-5), 114.3 (C-8),
112.7 (C-20), 112.3 (C-60), 110.7 (C-8b), 110.4 (C-6), 75.0
(C-3), 49.3 (CH2, benzyl), 43.6 (CH3, SO2CH3), 43.0 (CH2,
CH2CO2Na), 35.5 (C-2), 21.3 (C-1); HRESIMS m/z (pos):
550.0893 C27H22ClFNNaO5S (calcd. 550.0789).
Sodium
2-(4-((7-fluoro-4-(2-fluorobenzyl)-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy)
phenyl) acetate (I-15) White solid (IPA), mp:
184–186 °C; IR (KBr) mmax 3397, 1574, 1509, 1490,
1457, 1417, 1393, 1350, 1301, 1231, 1146, 1121, 1152,
959, 762, 540, 468 cm-1; 1H NMR (MeOD, 300 MHz,):
d = 7.64–7.72 (2H, m, H-6; H-8), 7.38 (1H, m, H-30,
sodium phenyl acetate), 7.22–7.25 (1H, m, H-50),
7.15–7.20 (2H, m, H-300, benzyl; H-500), 7.06–7.12 (1H, m,
H-400), 5.58 (2H, d, J = 9.0 Hz, H-20; H-60), 6.12–6.15
(1H, m, H-600), 5.94–6.07 (2H, m, ArCH2), 5.60–5.63 (1H,
m, OCH), 3.39 (2H, s, CH2CO2Na), 3.01–3.13 (2H, m,
CH2), 2.90–2.95 (1H, m, CH2), 2.87 (3H, s, SO2CH3),
2.45–2.54 (1H, m, CH2); 13C NMR (MeOD, 300 MHz,):
d = 178.8 (C=O, CH2CO2Na), 156.8 (C-200, benzyl), 155.2
(C-10, sodium phenyl acetate), 153.6 (C-7), 147.7 (C-100),
136.1 (C-3a), 132.7 (C-4a), 130.8 (C-8a), 130.4 (C-30),
129.3 (C-50), 128.6 (C-300), 127.8 (C-600), 126.4 (C-400),
125.9 (C-500), 123.1 (C-40), 123.0 (C-5), 114.3 (C-8), 112.8
(C-20), 112.4 (C-60), 110.9 (C-8b), 110.6 (C-6), 75.0 (C-3),
43.6 (CH3, SO2CH3; CH2, benzyl), 42.8 (CH2,
Sodium 2-(4-((4-(3-chlorobenzyl)-7-fluoro-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy)
phenyl) acetate (I-13) White solid (IPA), mp:
140–142 °C; IR (KBr) mmax 3462, 1589, 1509, 1489,
1452, 1413, 1311, 1231, 1197, 1146, 1121, 958, 541 cm-1
;
1H NMR (MeOD, 300 MHz,): d = 7.71 (1H, m, H-6),
7.64 (1H, m, H-8), 7.18–7.22 (4H, m, H-30, sodium phenyl
acetate; H-50; H-200, benzyl; H-400), 6.85–6.98 (1H, m,
H-500), 6.51–6.69 (3H, m, H-20; H-60; H-600), 6.02–6.08
(1H, m, ArCH2), 5.82 (1H, d, J = 8.6 Hz, ArCH2),
5.57–5.60 (1H, m, OCH), 3.41 (2H, s, CH2CO2Na),
3.00–3.11(2H, m, CH2), 2.96 (3H, s, SO2CH3),
2.85–2.93(1H, m, CH2), 2.47–2.55(1H, m, CH2); 13C
NMR (MeOD, 300 MHz,): d = 178.7 (C=O, CH2CO2Na),
156.7 (C-7), 155.1 (C-10, sodium phenyl acetate), 153.5 (C-
100, benzyl), 147.7 (C-3a), 140.8 (C-4a), 133.7 (C-8a),
123

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Med Chem Res (2015) 24:3920–3931
CH2CO2Na), 35.6 (C-2), 21.5 (C-1); HRESIMS m/z (neg):
1231, 1145, 1123, 1039, 958, 832, 540 cm-1; 1H NMR
(MeOD, 300 MHz,): d = 7.66–7.73 (2H, m, H-6; H-8),
7.44 (1H, d, J = 2.1 Hz, H-30, sodium phenyl acetate),
7.16–7.19 (1H, m, H-50), 7.12–7.16 (2H, m, H-500, benzyl;
H-600), 6.57–6.61 (2H, m, H-20; H-60), 6.16 (1H, d,
J = 8.4 Hz, H-300), 6.01 (1H, d, J = 15.3 Hz, ArCH2),
5.90 (1H, d, J = 15.3 Hz, ArCH2), 5.64–5.66 (1H, m,
OCH), 3.40 (2H, s, CH2CO2Na), 3.05–3.13 (2H, m, CH2),
2.98 (3H, s, SO2CH3), 2.90–2.96 (1H, m, CH2), 2.46–2.55
(1H, m, CH2); 13C NMR (MeOD, 300 MHz,): d = 178.7
(C=O, CH2CO2Na), 156.9 (C-10, sodium phenyl acetate),
155.2 (C-7), 153.7 (C-100, benzyl), 147.6 (C-3a), 135.1 (C-
4a), 132.7 (C-8a), 131.5 (C-30), 130.5 (C-50), 129.3 (C-200),
128.1 (C-400), 127.3 (C-300), 126.5 (C-600), 123.3 (C-500),
123.6 (C-40), 114.2 (C-5), 112.6 (C-8), 112.3 (C-20; C-8b),
110.5 (C-60; C-6), 74.9 (C-3), 61.4 (CH2, benzyl), 43.6
(CH3, SO2CH3; CH2, CH2CO2Na), 35.6 (C-2), 21.4 (C-1);
HRESIMS m/z (pos): 584.0501 C27H21Cl2FNNaO5S
(calcd. 584.0399).
510.1203 C27H22F2NNaO5 (calcd. 510.1192).
Sodium
2-(4-((7-fluoro-4-(3-fluorobenzyl)-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy)
phenyl) acetate (I-16) White solid (IPA), mp:
226–228 °C; IR (KBr) mmax 3415, 1589, 1509, 1489,
1460, 1316, 1227, 1185, 1137, 1121, 1037, 955, 788, 765,
680, 539 cm-1
;
1H NMR (MeOD, 300 MHz,):
d = 7.67–7.73 (2H, m, H-6; H-8), 7.39 (1H, d, J = 4.1 Hz,
H-30, sodium phenyl acetate), 7.07–7.25 (4H, m, H-50;
H-400, benzyl; H-500; H-600), 6.59 (2H, d, J = 4.2 Hz, H-20;
H-60), 6.13 (1H, d, J = 3.8 Hz, H-200), 6.02 (2H, s, ArCH2),
5.62 (1H, m, OCH), 3.39 (2H, s, CH2CO2Na), 3.06–3.13
(2H, m, CH2), 2.97 (3H, s, SO2CH3), 2.92–2.96 (1H, m,
CH2), 2.47–2.55 (1H, m, CH2); 13C NMR (MeOD,
300 MHz,): d = 178.7 (C=O, CH2CO2Na), 155.2 (C-300,
benzyl), 147.8 (C-10, sodium phenyl acetate; C-7), 136.1
(C-100), 130.5 (C-3a), 129.3 (C-4a), 128.6 (C-8a), 128.1 (C-
30), 128.0 (C-50), 127.8 (C-200), 126.3 (C-400), 125.9 (C-500),
125.8 (C-600), 123.1 (C-40), 123.0 (C-5), 114.3 (C-8), 112.8
(C-20), 112.4 (C-60), 110.8 (C-8b), 110.5 (C-6), 75.0 (C-3),
43.6 (CH2, CH2CO2Na; CH3, SO2CH3; CH2, benzyl), 35.6
(C-2), 21.5 (C-1); HRESIMS m/z (pos): 534.1164 C27
H22F2NNaO5S (calcd. 534.1084).
Pharmacology
The biological activity test was based on the method of
Paolini (Paolini et al., 2008). Briefly, male SPF C57BL/6
mice (* 25 g) were purchased from Shanghai SLAC Lab-
oratory Animal Co. (Shanghai, China) and were acclima-
tized for 2 days. Six mice were evaluated in each test group.
Nembutal (3 % w/v) was injected (40 mg/kg) intraperi-
toneally to anesthetize the mice, and the initial velocity of
blood flow in mouse ear was monitored by ZL104 micro-
circulatory detector (Xuzhou Public Medical Devices Co.,
China). Laropiprant and the compounds were dissolved in
5 % hydroxypropyl-b-cyclodextrin at 5 mg/mL and
administered intraperitoneally (10 mg/kg). After 30 min-
utes, niacin (dissolved in 5 % hydroxypropyl-b-cyclodex-
trin at 12.5 mg/mL and adjusted to pH = 7.4) was injected
subcutaneously. And the velocity of blood flow in mouse ear
was measured every 2 min out of 10. The percentage of
inhibition compared with vehicle was calculated as follows:
Percentage of inhibition (%) = (R2 - R1)/R2 9 100 %
Increased rate of blood flow velocity (R) = V1/V0
Sodium 2-(4-((7-fluoro-4-(4-methoxybenzyl)-5-(methylsul-
fonyl)-1, 2, 3, 4-tetrahydrocyclopenta[b]indol-3-yl) oxy)
phenyl) acetate (I-17) White solid (IPA), mp:
238–240 °C; IR (KBr) mmax 3395, 1602, 1549, 1514,
1455, 1390, 1303, 1250, 1201, 1174, 1142, 1118, 1031,
964, 791, 538, 470 cm-1;1H NMR (MeOD, 300 MHz,):
d = 7.71 (1H, m, H-6), 7.64 (1H, m, H-8), 7.21 (2H, d,
J = 4.4 Hz, H-30, sodium phenyl acetate; H-50), 6.77–6.81
(4H, m, H-300, benzyl; H-500; H-200; H-600), 6.72 (2H, d,
J = 4.4 Hz, H-20; H-60), 6.13 (1H, d, J = 8.4 Hz, ArCH2),
5.66 (1H, d, J = 8.4 Hz, ArCH2), 5.53–5.55 (1H, m,
OCH), 3.73 (3H, s, OCH3), 3.41 (2H, s, CH2CO2Na),
3.03–3.10 (2H, m, CH2), 2.96 (3H, s, SO2CH3), 2.84–2.93
(1H, m, CH2), 2.46–2.55 (1H, m, CH2); 13C NMR (MeOD,
300 MHz,): d = 173.3 (C=O, CH2CO2Na), 158.8 (C-10,
sodium phenyl acetate), 158.7 (C-7; C-400, benzyl), 156.6
(C-100), 153.5 (C-3a), 147.6 (C-4a), 132.7 (C-8a), 130.3 (C-
30), 130.1 (C-50), 128.3 (C-200), 126.6 (C-600), 125.8 (C-300),
125.7 (C-500), 122.9 (C-40), 113.5 (C-5), 113.2 (C-8), 112.7
(C-20), 112.3 (C-60), 110.7 (C-8b), 110.4 (C-6), 75.0 (C-3),
53.8 (CH2, benzyl; CH3, PhOCH3), 49.4 (CH3, SO2CH3;
CH2, CH2CO2Na), 35.4 (C-2), 21.3 (C-1); HRESIMS m/
z (pos): 546.1390 C28H25FNNaO6S (calcd. 546.1284).
V1 blood flow velocity after administration of niacin (mea-
sured in every 2 of 10 min); V0 initial blood flow velocity; R1
increased rate of control group; R2 increased rate of positive
group (laropiprant) or experimental group (I-1–I-18).
Conclusions
Sodium 2-(4-((4-(2,4-dichlorobenzyl)-7-fluoro-5-(methylsul-
fonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)oxy) phe-
nyl) acetate(I-18) White solid (IPA), mp: 216–218 °C; IR
(KBr) mmax 3404, 1587, 1509, 1490, 1473, 1388, 1301,
In our present work, a series of novel laropiprant deriva-
tives (I-1–I-18) have been synthesized and evaluated. Most
compounds exhibited potent and fast-acting inhibitory
123

Med Chem Res (2015) 24:3920–3931
3931
´
´
´
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2, I-3, I-9, I-13, I-15 and I-16 exhibited substantial flush-
ing inhibitory effect. Especially, compounds I-1 and I-2
showed higher percentage of inhibition than laropiprant
and would be valuable for further investigation. The res-
olution work and further biological evaluation of I-1 and I-
2 are being studied and will be reported in future.
McKenney J, Bays H, Koren M, Ballantyne CM, Paolini JF, Mitchel
Y, Betteridge A, Kuznetsova O, Sapre A, Sisk CM, Maccubbin
Acknowledgments This work was supported by the enterprise
innovation drug incubation base of the Ministry of Science and
Technology, China (No.2012ZX09401-006).
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