Discovery of novel S1P2 antagonists, part 3: Improving the oral bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives

Article abstract of DOI:10.1016/j.bmcl.2016.01.031

The structure of the S1P₂ antagonist 1 has been modified with the aim of improving its oral bioavailability. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant improvements in the oral exposure of compounds belonging to this series. The optimization of the ring size of the urea portion of these molecules also led to remarkable improvements in the oral exposure. Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency and selective antagonistic activity toward S1P₂.

Full text of DOI:10.1016/j.bmcl.2016.01.031

Bioorganic & Medicinal Chemistry Letters 26 (2016) 1209–1213
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel S1P2 antagonists, part 3: Improving the oral
bioavailability of a series of 1,3-bis(aryloxy)benzene derivatives
b
a
a
a
Kensuke Kusumi a, , Koji Shinozaki , Yoshiyuki Yamaura , Ai Hashimoto , Haruto Kurata ,
Atsushi Naganawa a, Kazuhiro Otsuki a, Takeshi Matsushita a, Tetsuya Sekiguchi a, Akito Kakuuchi a,
Hiroshi Yamamoto a, Takuya Seko c
⇑
a Minase Research Institute, Ono Pharmaceutical Co., Ltd, 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan
b Ono Pharma UK Ltd, MidCity Place, 71 High Holborn, London WC1V 6EA, United Kingdom
c Head Office, Ono Pharmaceutical Co., Ltd, 8-2, Kyutaromachi 1-chome, Chuo-ku, Osaka 541-8564, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The structure of the S1P2 antagonist 1 has been modified with the aim of improving its oral bioavailabil-
ity. The chemical modification of the alkyl chain and carboxylic acid moieties of 1 led to significant
improvements in the oral exposure of compounds belonging to this series. The optimization of the ring
size of the urea portion of these molecules also led to remarkable improvements in the oral exposure.
Based on these changes, the pyrrolidine derivative 16 was identified as a suitable candidate compound
and showed excellent pharmacokinetic profiles in rat and dog, while maintaining high levels of potency
and selective antagonistic activity toward S1P2.
Received 12 November 2015
Revised 7 January 2016
Accepted 12 January 2016
Available online 12 January 2016
Keywords:
Sphingosine-1-phosphate receptor 2
Antagonist
Ó 2016 Elsevier Ltd. All rights reserved.
G protein-coupled receptors
Sphingosine-1-phosphate (S1P) is a membrane-derived bioac-
tive sphingolipid that plays an important role in homeostasis.
S1P is present in low micromolar concentrations in plasma, and
elicits most of its biological effects through five different G pro-
tein-coupled receptors (GPCRs), including S1P1, S1P2, S1P3, S1P4
and S1P5. S1P2 is mainly expressed in the heart, thyroid gland,
lung, trachea and liver, and it has been suggested that this receptor
is involved in a broad range of important biological functions.1–4
Based on the results of numerous studies involving the well-
known S1P2 antagonist JTE-013, it was envisaged that selective
S1P2 antagonists could be developed as useful drugs for the treat-
ment of various diseases.5–8 However, there have been very few
reports pertaining to the development of S1P2 antagonists in the
literature, least of all selective antagonists.
We recently reported the development of a novel series of 1,3-
bis(aryloxy)benzene derivatives as highly potent S1P2 antagonists,
together with some limited exploration of their structure–activity
relationships (SARs).9 Compound 1 (Fig. 1) is a representative
example from this previous series, and the results of an SAR study
revealed that the carboxylic acid moiety was critical to the antag-
onistic activity of these compounds, as well as their physicochem-
ical properties.10 Although 1 showed potent antagonistic activity
against S1P2 (IC50 = 12 nM), the pharmacokinetic (PK) profile of
this compound in rat was poor because of its low bioavailability
(F = 12%) and moderate clearance (Cl = 10.2 ml/min/kg). To address
these issues, we initiated a lead optimization campaign with the
aim of identifying improved S1P2 antagonists with potent antago-
nist activity and good PK profiles.
As reported in our previous study, it was possible to improve
the metabolic stability of these compounds by changing the alkyl
chain in the piperidine moiety. Compound 2 (in Table 1) is another
representative compound from our previous report,10 and the
remaining ratio of this compound in rat liver microsomes was
much greater than that of compound 1 under both testing condi-
tions (i.e., 94% with NADPH resulting from oxidative phase I meta-
bolism and 74% with UDPGA resulting from glucuronic acid
conjugation phase II metabolism). Although improvements in the
metabolic stability can sometimes lead to improvements in the
oral exposure, a variety of different factors can influence the oral
exposure of a drug molecule, with improved metabolic stability
being only one of these factors. Thus, we thought that the oral
exposure of the compounds might be improved more by modifica-
tion of the other factors. However, it can be difficult to predict the
most important characteristics of a small molecule for improving
its oral exposure. With this in mind, we decided to focus exclu-
sively on the relationship between the structure of the compounds
belonging to this series and their oral exposure. Given that the
⇑
Corresponding author. Tel.: +81 75 961 1151; fax: +81 75 962 9314.
E-mail address: kusumi@ono.co.jp (K. Kusumi).
http://dx.doi.org/10.1016/j.bmcl.2016.01.031
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

1210
K. Kusumi et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1209–1213
S1P2 Ca2+ IC50 = 12 nM
To evaluate this idea, we also synthesized the 4-chloro and 4-meth-
H3C
H3C
OH
oxy derivatives (i.e., compounds 8 and 9, respectively). Compounds
7 and 8 were predicted to be more acidic than compound 3 (pKa val-
ues of 3.57, 3.42 and 3.85, respectively), while compound 9 was
predicted to be less acidic (pKa = 4.27). We supposed that the low
acidity could be advantageous for the preparation of drugs with
good exposure because ionic compound shows less permeability.
In this case, the least acidic compound 9 had a higher AUC and Cmax
than compounds 3, 7 and 8 (155 ngÁh/ml, 29 ng/ml, respectively),
although this difference was too small to allow for this compound
to be taken any further. Based on these results, it seemed that
reducing the acidity of these compounds would provide better
exposure. With this in mind, we synthesized the less acidic phenyl
acetic acid derivative 10 (pKa = 4.41). Although 10 showed low
potency (IC50 = 21 nM), it gave a large AUC value (787 ngÁh/ml)
and Cmax value (127 ng/ml), as we predicted. This increase in the
AUC was not only attributed to the lower acidity of 10 but was also
attributed to the higher lipophilicity of the phenyl acetic acid moi-
ety, which would improve the absorption of the molecule. Based on
this result, we shifted our focus toward the phenyl acetic acid
H
N
N
O
Rat PK profile
F = 12%
Cl = 10 ml/min/kg
O
F
O
1
CO2H
Figure 1. Representative compound from our previous report.10
modification of the western substructure of 1 appeared to be an
effective strategy for improving the oral exposure of the com-
pounds, we also synthesized compound 3, which has a shorter
alkyl chain at the 4-position of the piperidine moiety. Pleasingly,
this compound showed better oral exposure than
1
(AUC = 70 ngÁh/ml, Cmax = 18 ng/ml), while maintaining strong
antagonistic activity (IC50 = 4.0 nM). The improved oral exposure
of this compound compared with 1 was attributed to the reduced
flexibility of its alkyl group, as well as its improved metabolic sta-
bility (99% with NADPH and 86% with UDPGA). Although com-
pounds 2 and 3 both showed better oral exposure than 1,
compound 3 was selected as the best starting point for the opti-
mization of this series. Compound 3 had lower lipophilicity than
compound 2 (clogD = 1.63 and 1.70, respectively), as well as a
lower molecular weight (522.6 and 560.5, respectively). We then
proceeded with a SAR study using 3 as a lead compound, and the
results are shown in Table 2.
We initially walked a fluorine substituent around the phenyl
ring on the eastern portion of the molecule to develop a better
understanding of whether these positions could accommodate an
additional substituent. The 1- and 2-fluoro derivative of 3 (i.e.,
compounds 4 and 5, respectively) showed weaker potency than 3
(IC50 values of 20 and 25 nM, respectively). Furthermore, the intro-
duction of a fluoro group at the 1- or 2-position did not lead to an
increase in the AUC (65 and 62 ngÁh/ml, respectively) and Cmax
(10 and 12 ngÁh/ml, respectively). The 3- and 4-fluoro derivative
of 3 (i.e., compounds 6 and 7, respectively) also showed weaker
potency than 3 (IC50 values of 17 and 34 nM, respectively).
Although the AUC and Cmax value for 7 was almost same as that
of 3, we supposed that the introduction of substituents at the 4-
position of the phenyl ring could affect the acidity of the carboxylic
acid moiety, which might have an impact on the oral bioavailability.
moiety and conducted an SAR study using a variety of
-substituted carboxylic acid groups. The results of this study
are shown in Table 3.
a- and
a,a
At the start of this SAR study, we searched for the metabolites of
the phenyl acetic acid derivatives in vivo (i.e., in the blood, urine
and feces of the rat), and found that one of the main metabolites
was an acyl glucuronide. It is well known that the acyl glucuronide
conjugates of phenyl acetic acid derivatives may represent a seri-
ous idiosyncratic drug toxicity risk. As exemplified for Ibuprofen
and Ibufenac,11 the introduction of a suitable substituent at the
a
-position of the carboxylic acid moiety can mitigate these issues.
With this in mind, we investigated the introduction of different
substituents at the -position of these compounds. The mono-
a
methylated derivative 11 exhibited greater antagonistic activity
than the unmethylated compound 10 (IC50 = 9.3 nM). Moreover,
the di-methylated derivative 12 showed even greater antagonist
activity (IC50 = 2.3 nM). We subsequently compared the stabilities
of the acyl glucuronides of 12 and 10, and found that the acyl glu-
curonide of 12 was more stable than that of 10 (remaining ratios of
97% and 77%, respectively, in human blood plasma after 2 h). This
result indicated that 12 would pose a lower idiosyncratic drug tox-
icity risk than 10.11 The cyclopropane derivative 13 also showed
Table 1
Effect of structural modifications on the AUCa
H3C
H3C
OH
CH3
OH
OH
H
N
H
N
H3C
F
H
N
N
O
N
O
N
O
F
O
O
O
F
F
O
O
O
CO2H
CO2H
CO2H
1
2
3
Compd
1
2
3
S1P2 Ca2+ IC50 (nM)
12
12
3.3
64
6.2
40
11
94
74
1.70
3.76
560.5
4.0
70
18
99
AUCa (ngÁh/ml)
b
Cmax (ng/ml)
rLMSc (NADPH,%)
rLMSc (UDPGA, %)
LogDd
61
86
2.24
3.90
550.6
1.63
3.85
522.6
d
pKa
M.W.e
a
b
c
Area under the blood concentration–time curve, Rat, p.o. 1 mg/kg, calculated within 0–24 h. n = 2 (compounds 1 & 3), n = 3 (compound 2).
Rat, p.o. 1 mg/kg, n = 2 (compounds 1 & 3), n = 3 (compound 2).
Remaining ratio (%) in rat liver microsomes at 15 min with NADPH or UDPGA.
Predicted using ADMET predictor (SimulationsPlus, Lancaster, CA, USA).
Molecular weight.
d
e

K. Kusumi et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1209–1213
1211
Table 2
Introduction of different substituents to compound 3
CH3 OH
1
H
N
H3C
N
O
4
2
O
F
O
3
R
Ca2+ IC50 (nM)
AUCa (ngÁh/ml)
Cmax (ng/ml)
pKa
clogDc
b
c
Compd
Substituent
1
2
3
4
R
3
4
5
6
7
8
9
10
—
F
—
—
F
—
—
—
—
—
—
—
F
—
—
—
—
—
—
—
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
CO2H
4.0
20
25
17
34
3.6
11
21
70
65
62
83
92
60
155
787
18
10
12
15
22
15
29
127
3.85
3.80
3.80
3.68
3.57
3.42
4.27
4.41
1.63
1.67
1.71
1.62
1.59
2.20
1.95
1.90
—
—
—
—
—
F
Cl
OMe
CH2CO2H
a
b
c
Rat, p.o., 1 mg/kg, calculated within 0–24 h, n = 2.
Rat, p.o., 1 mg/kg, n = 2.
Predicted using ADMET predictor (SimulationsPlus, Lancaster, CA, USA).
Table 3
Table 4
Effect on different substituents on compound 4
Modification the urea substituent of compound 12
CH3 OH
H
H
N
H3C
R
N
O
N
O
O
O
F
F
O
O
R
CO2H
H3C CH3
Ca2+ IC50
(nM)
AUCa
(ngÁh/ml)
Cmax
pKa
LogDc
b
c
Compd
R
(ng/ml)
b
c
Compd
R
Ca2+ IC50
(nM)
AUCa
(ngÁh/ml) (ng/ml)
Cmax
pKa
LogDc
*
*
10
21.3
9.3
787
127
4.41 1.9
4.53 2.2
CO2H
CO2H
CH3 OH
OH
12
H3C
2.3
5.2
8.2
29
390
88
4.65 2.55
4.57 2.11
4.62 2.27
4.62 2.27
11e
N.T.d
390
N.T.
88
N
*
CH3
H3C
*
*
15
1058
3232
N.T.d
396
1310
N.T.
N
CO2H
H3C CH3
H3C
12
2.5
4.34 1.98
*
HO
H3C
H3C
N
16e
17e
*
13
14
6.4
8.8
320
N.T.
62
4.33 2.42
4.72 2.55
CO2H
HO
H3C CH3
CO2H
N
H3C
*
*
N.T.
CH3
HO
a
N
18e
19e
17
N.T.
N.T.
484
4.64 2.74
4.61 2.40
Rat, p.o., 1 mg/kg, calculated within 0–24 h, n = 3 (compound 12), n = 2 (the
*
other compounds).
b
Rat, p.o., 1 mg/kg, n = 3 (compound 12), n = 2 (the other compounds).
Predicted using ADMET predictor (SimulationsPlus, Lancaster, CA, USA).
Not tested.
Racemate.
HO
c
N
d
8.8
1988
*
e
a
Rat, p.o., 1 mg/kg, calculated within 0–24 h, n = 3 (compound 16), n = 2 (the
other compounds).
b
good antagonistic activity (IC50 = 6.4 nM) and good oral exposure
(AUC = 320 ngÁh/ml, Cmax = 62 ng/ml). We also synthesized the
meta-substituted phenyl acetic acid derivative 14 to investigate
the tolerance of this position for the acid moiety. Compound 14
also showed good potency (IC50 = 8.8 nM). These results suggested
that the position of the carboxylic acid was not critical to the
antagonistic activity.10 Although 12 showed the most potent
antagonistic activity toward S1P2, it only showed limited oral
exposure (AUC = 390 ngÁh/ml, Cmax = 88 ng/ml). Given that the
modification of the western part of these compounds could be used
as an effective strategy for improving their PK profile, we
conducted further SAR studies of 12 by varying the piperidine
substructure. The results of these studies are shown in Table 4.
Rat, p.o., 1 mg/kg, n = 3 (compound 16), n = 2 (the other compounds).
Predicted using ADMET predictor (SimulationsPlus, Lancaster, CA, USA).
Not tested.
Racemates.
c
d
e
Further optimization studies were conducted to investigate the
optimal ring size of the saturated heterocycle moiety on the left
portion of 12. The results revealed that the azetidine derivative
15 showed potent antagonist activity (IC50 = 5.2 nM) and improved
oral exposure (AUC = 1058 ngÁh/ml, Cmax = 396 mg/ml). Moreover,
the pyrrolidine derivative 16 showed potent antagonist activity
(IC50 = 8.2 nM) and large AUC value (3232 ngÁh/ml) and Cmax value

1212
K. Kusumi et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1209–1213
Table 5
Based on these results, compound 16 was selected as the best of
Additional PK profiles of compounds 16 and 19
all of the compounds prepared in the current study, and taken for-
ward for detailed PK studies in rat, dog and monkey. The results of
these PK experiments are shown in Table 6.
Parameters
16
19
F (%)
64.4
3232
1310
3.04
205
32.0
1988
484
2.98
297
AUCa (ngÁh/ml)
Compound 16 showed much better PK profiles than compound
in rat (F = 64.4%, Cl = 3.40 ml/min/kg). Also, compound 16
b
Cmax (ng/ml)
1
CLc (ml/min/kg)
Vdc (ml/kg)
showed similar profile in dog (F = 54.8%, Cl = 6.76 ml/min/kg) to
that in rat, as well as a moderate profile in monkey (F = 12.5%,
Cl = 9.91 ml/min/kg).
Information pertaining to the receptor selectivity of 16 is shown
in Table 7.
a
b
c
Rat, p.o., 1 mg/kg, AUC was calculated within 0–24 h, n = 2.
Rat, p.o., 1 mg/kg, n = 2.
Rat, i.v., 0.1 mg/kg, n = 2.
Compound 16 exhibited excellent selectivity toward all of the
other S1PR subtypes (IC50 > 10,000 nM against S1P1, S1P3, S1P4
and S1P5). Because 16 was prepared as a racemic mixture, we con-
ducted a chiral SFC separation process to obtain the individual
enantiomers.12 These enantiomers are currently being evaluated
in more detail in our laboratory and the results of these experi-
ments will be published as part of a separate study.
All of the derivatives described in this report were synthesized
in a similar manner. Representative examples of the synthetic
routes used for the construction of these compounds are shown
in Schemes 1 and 2. The synthesis of the key activated carbamate
intermediate 25 is shown in Scheme 1.
Table 6
PK profiles of compound 16
HO
H
N
H3C
H3C
N
O
O
F
O
CO2H
H3C CH3
Species
Fa (%)
Cla (ml/min/kg)
Commercially available methyl 4-hydroxyphenylacetate (20)
was converted to the corresponding benzyl ether, which was trea-
Rat
Dog
Monkey
64.4
54.8
12.5
3.40
6.76
9.91
ted with methyl iodide under basic conditions to give the
a,a-
dimethylated phenyl acetate. The reductive cleavage of the benzyl
ether under hydrogenation conditions gave phenol 21, which was
treated with 3,5-difluoronitrobenzene (22) and K3PO4 to yield the
corresponding phenylether 23. The SNAr reaction of 4-fluorophenol
(24) with 23, followed by the palladium-catalyzed reduction of the
nitro group and the condensation of the resulting aniline with
2,2,2-trichloroethyl chlorocarbamate gave the activated carbamate
25. Compound 25 was then used as a common intermediate for the
preparation of the ureas shown in Table 4, which were synthesized
as shown in Scheme 2.
Commercially available carbobenzyloxy-3-pyrrolidinone (26)
was treated with isobutyl magnesium chloride in the presence of
a lanthanum trichloride–lithium chloride complex to give an alco-
hol intermediate,13 which was converted to 3-isobutyl-3-pyrrolidi-
nol (27) under palladium-catalyzed hydrogenation conditions. The
subsequent condensation reaction of intermediate 25 with 27,
followed by the hydroxylation of the methyl ester gave the
corresponding urea 16.
The compounds listed in Tables 2 and 3 were synthesized
according to the strategy shown in Scheme 1 using the correspond-
ing phenols instead of 20 or 21. The compounds listed in Tables 1
and 4 were synthesized according to the strategy described in
Scheme 2 using the corresponding amines instead of 27 or 28.
In summary, we have succeeded in improving the PK profile of
the S1P2 antagonist 1 while maintaining a high level of potency
and selectivity toward the desired target. The chemical modifica-
tion of compound 1 provided the phenyl acetic acid derivative 10
a
n = 3.
Table 7
Selectivity of compound 16
S1P1
>10
S1P2
0.5
S1P3
>10
S1P4
>10
S1P5
>10
Binding IC50 (lM)
(1310 ng/ml). Given that compound 16 showed large oral exposure
and strong potency, we focused our attention on this pyrrolidine
derivative, and conducted further modifications to the isobutyl
moiety. The conversion of the isobutyl moiety to an isopropyl
group resulted in a decrease in the antagonistic activity (com-
pound 17, IC50 = 29 nM). The replacement of the isobutyl group
with a cyclohexyl group also led to a decrease in the activity (com-
pound 18, IC50 = 17 nM). In contrast, the cyclopentyl derivative 19
showed similar antagonist activity (IC50 = 8.8 nM) to 16. However,
compound 19 showed much lower oral exposure than 16
(AUC = 1988 ngÁh/ml, Cmax = 484 ng/ml). We were interested in this
point, and checked their PK parameter in detail. The results are
shown in Table 5.
Compound 16 and 19 show close clearance value (3.04 and 2.98,
respectively). Compound 19 shows larger Vd value than 16 (297
and 205, respectively), but the differences thought to be not
significant. The reason of the difference between these compounds
currently remains unclear.
HO
O2N
+
F
HO
(C)
(A)
(B)
(D)
CO2Me
H3C CH3
CO2Me
F
22
20
21
Cl
H
HO
O2N
F
+
(E)
(F)
O
N
O
(G)
Cl
Cl
O
F
F
23
24
25
O
O
CO2Me
H3C CH3
CO2Me
H3C CH3
Scheme 1. Synthesis of common intermediate 25. Reagents and conditions: (A) BnCl, K2CO3, DMA, 60 °C, 82% (B) MeI, tBuOK, THF, rt, 68% (C) H2, 5% Pd/C, MeOH, rt, 66% (D)
K3PO4, DMA, 70 °C, 83% (E) K3PO4, DMA, 100 °C, 83% (F) H2, 5% Pd/C, MeOH, rt, 66% (G) 2,2,2-trichloroethyl chlorocarbamate, K2CO3, EtOAc, rt 92%.

K. Kusumi et al. / Bioorg. Med. Chem. Lett. 26 (2016) 1209–1213
1213
O
031. These data include MOL files and InChiKeys of the most
important compounds described in this article.
HO
H3C
H3C
(B)
(A)
O
N
NH
O
26
27
References and notes
HO
H
H3C
H3C
N
N
O
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(C)
(D)
O
+
25
27
F
O
16
CO2H
H3C CH3
Scheme 2. Synthesis of compound 16.14 Reagents and conditions: (A) iBuMgCl,
LaCl3–2LiCl, THF, 0 °C, 79% (B) H2, 5% Pd/C, MeOH, rt, quant. (C) DMA, 90 °C, 83% (D)
2 N NaOH aq, THF, MeOH, 40 °C, quant.
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which showed improved plasma exposure with moderate activity.
The subsequent modification of 10 afforded the highly potent com-
pound 16, which exhibited similar PK profiles in rat to dog, as well
as pronounced selectivity for S1P2 over the other S1PRs. Further
investigations toward the properties of 16, including the character-
ization of its individual enantiomers, will be reported in due course.
Acknowledgements
12. 16 was separated by following condition; Column: DAICEL CHIRALPAK IB/SFC,
MeOH 20%–CO2 80%, flow rate: 30 ml/min.
The authors are deeply grateful to Dr. T. Maruyama for his many
kind and helpful suggestions during the preparation of this article.
The authors would also like to thank Dr. Y. Inagaki for his kind
contribution, and Mr. Y. Ochi for his many useful comments on this
article.
13. Metzger, A.; Gavryushin, A.; Knochel, P. Synlett 2009, 1433.
14. Spectra parameters of 16 were shown below:
1H NMR (300 MHz, CDCl3) d ppm 0.98 (d, J = 6.59 Hz, 3 H), 0.99 (d, J = 6.59 Hz, 3
H), 1.50–1.66 (m, 8 H), 1.80–2.04 (m, 3 H), 3.28 (d, J = 10.80 Hz, 1 H), 3.43–3.62
(m, 3 H), 6.21 (s, 1 H), 6.31 (t, J = 2.20 Hz, 1 H), 6.73 (t, J = 2.01 Hz, 1 H), 6.85 (t,
J = 2.11 Hz, 1 H), 6.93–7.05 (m, 5 H), 7.25–7.36 (m, 3 H); 13C NMR (125 MHz,
CDCl3)
d ppm 179.603, 159.339, 159.0535 (d, J = 240.875 Hz), 158.610,
155.526, 153.650, 152.262 (d, J = 2.75 Hz), 141.226, 139.112, 127.281,
120.944 (d, J = 8.25 Hz), 118.878, 116.356 (d, J = 23.25 Hz), 104.420, 104.105,
103.504, 58.432, 47.369, 45.663, 44.399, 38.721, 26.425, 24.754, 24.366,
24.220; MASS (ESI, Pos. 20 V) 551 (M+H)+.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2016.01.