Synthesis, structure-activity relationships, and biological profiles of a dihydrobenzoxathiin class of histamine H3 receptor inverse agonists

Article abstract of DOI:10.1016/j.bmcl.2009.05.101

A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human histamine H₃ receptor inverse agonists. After systematic modification of lead 1a, the potent and selective histamine H₃ inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-benzoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacokinetic profiles and brain penetrability in laboratory animals. After 3 mg/kg oral administration of 5k, significant elevation of brain histamine levels was observed in rats where the brain H₃ receptor was fully occupied.

Full text of DOI:10.1016/j.bmcl.2009.05.101

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4232–4236
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis, structure–activity relationships, and biological profiles
of a dihydrobenzoxathiin class of histamine H3 receptor inverse agonists
Takahide Sasaki, Toshiyuki Takahashi, Tsuyoshi Nagase, Takashi Mizutani, Sayaka Ito, Yuko Mitobe,
Yasuhisa Miyamoto, Maki Kanesaka, Ryo Yoshimoto, Takeshi Tanaka, Norihiro Takenaga, Shigeru Tokita,
*
Nagaaki Sato
Tsukuba Research Institute, Merck Research Laboratories, Banyu Pharmaceutical Co., Ltd, Okubo 3, Tsukuba, Ibaraki 300-2611, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel dihydrobenzoxathiin derivatives was synthesized and evaluated as potent human his-
tamine H3 receptor inverse agonists. After systematic modification of lead 1a, the potent and selective
histamine H3 inverse agonist 1-(3-{4-[(2S,3S)-8-methoxy-3-methyl-4,4-dioxido-2,3-dihydro-1,4-ben-
zoxathiin-2-yl]phenoxy}propyl)pyrrolidine (5k) was identified. Compound 5k showed good pharmacoki-
netic profiles and brain penetrability in laboratory animals. After 3 mg/kg oral administration of 5k,
significant elevation of brain histamine levels was observed in rats where the brain H3 receptor was fully
occupied.
Received 7 April 2009
Revised 21 May 2009
Accepted 25 May 2009
Available online 30 May 2009
Keywords:
Histamine H3 receptor inverse agonist
CNS
Ó 2009 Elsevier Ltd. All rights reserved.
Dihydrobenzoxathiin derivative
NC
Despite the pharmacological discovery of the histamine H3
receptor in 1983,1 it was not until 1999, with its genetic identifica-
tion,2 that the H3 receptor gained widespread attention and redi-
rected the detailed pharmacological characterization of the
receptor and drug discovery efforts from academia and pharma-
ceutical industries.3,4 Studies have shown that signaling through
the H3 receptor activates G-proteins that inhibit adenylate cyclase
activity and reduce intracellular cAMP levels.2,5 The H3 receptors,
which are predominantly expressed in the CNS, are localized on
the presynaptic membrane as autoreceptors, and negatively regu-
late the release and synthesis of histamine.1 The H3 receptor is also
known to modulate the release of other neurotransmitters such as
norepinephrine, dopamine, acetylcholine, serotonin, and GABA,6,7
and accordingly, it has been suggested that H3 antagonists/inverse
agonists could serve as effective therapeutics for several CNS-re-
lated disorders.8 In animal models, H3 receptor antagonists/inverse
agonists have been shown to enhance wakefulness, improve atten-
tive and cognitive behaviors, and reduce feeding and body
weight.9,10 It has recently been reported that BF2.649 (Chart 1), a
potent and selective H3 receptor inverse agonist, can suppress
excessive daytime sleep among narcoleptic patients.11
O
N
N
Cl
BF2.649
O
ABT-239
O
H
N
N
N
O
GSK189254
Chart 1. Structures of non-imidazole H3 antagonists and inverse agonists.
have focused on non-imidazole classes of H3 receptor antago-
nists/inverse agonists. Since the identification of the H3 receptor
genes, various classes of non-imidazole H3 receptor antagonists
have been developed to target the CNS H3 receptors.15–17 Among
them, BF2.649,11,18,19 ABT-239,20–22 and GSK189254,23 as shown
in Chart 1, target CNS disorders such as excessive daytime sleepi-
ness, schizophrenia, and cognitive dysfunctions, and have success-
fully entered clinical trials.
We previously reported a series of non-imidazole H3 inverse
agonists, quinazolinone,24,25 regioisomeric quinazolinone26 and
spiro-isobenzofuranone classes.27 In our continuing efforts to iden-
tify structurally diverse H3 antagonists or inverse agonists, high-
throughput screening of Merck sample collections against human
H3 receptor led to the identification of the novel dihydrobenzox-
athiin lead 1a, which has an IC50 value of 6.7 nM (Table 1).
Although 1a is an attractive potent lead, it suffered from potent
hERG K+ channel inhibition with an IC50 value of 5.0 nM. In this pa-
First-generation imidazole-based H3 antagonists, which possess
inhibitory actions on cytochrome P450 activity, may cause drug–
drug interactions against co-administered drugs by inhibiting he-
patic clearance.12–14 Because of these liabilities, current efforts
* Corresponding author. Tel.: +81 29 877 2004; fax: +81 29 877 2029.
E-mail address: nagaaki_sato@merck.com (N. Sato).
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.05.101

T. Sasaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4232–4236
4233
Table 1
was converted to trans-dihydrobenzoxathiin dioxide 5 following
the procedure described for the preparation of 4. Route 3 illus-
trates the preparation of the benzoxathiin derivatives 3 and 6.
Dehydrative cyclization of the ketosulfide 7 in the presence of
p-toluenesulfonic acid gave benzoxathiin 10.28 The Mitsunobu
alkylation of the phenoxy group of 10 gave benzoxathiin 3, which
was oxidized to benzoxathiin dioxide 6. The representative potent
and in vivo active H3 inverse agonist 5k and its enantiomer 5l
were initially prepared by chiral resolution of racemate 5e by
HPLC, using CHIRALCEL AD-H, eluting with diethylamine/isopro-
pyl alcohol/hexane (0.5/45/54.5). The absolute stereochemistry
of 5k was determined to be (2S,3 S) by a single crystal X-ray
crystallography.30
SAR of Dihydrobenzoxathiin Derivatives; Substitution Effect at the C3 positiona
3
R1
S
O
2
N
O
R1
Human H3 (IC50, nM)
hERGc (IC50, nM)
5.0 0.4
b
Compd
1a
1b
1c
Me
Et
Ph
6.7 0.6
5.9 0.8
3.0 0.8
11
12
1
2
a
The values represent the mean SE for n P 3.
b
Inhibition of R-
receptor.
a cS at human H3
-methylhistamine-induced binding of [35S]GTP
The compounds reported herein were first subjected to the
[
35S]GTP
c
S binding assay in membranes isolated from cells transfec-
ted with cloned human H3 receptors. All the derivatives reported
herein reduced basal GTP S binding, indicating that they are inverse
c
Inhibition of [35S]MK-499 binding to hERG in HEK293 cells.
c
agonists. Then, compounds were evaluated for affinity for the hERG
K+ channel using the [35S]N-[(4R)-10-[(2R)-6-cyano-1,2,3,4-tetrahy-
dro-2-naphthalenyl]-3,4-dihydro-4-hydroxyspiro[2H-1-benzopyra
n-2,40-piperidin]-6-yl]methanesulfonamide ([35S]MK-499) binding
assay to assess potential QTc prolongation liability.31
per, our modifications of 1a to enhance H3 activity while minimiz-
ing hERG liabilities will be described. The structure–activity rela-
tionships and biological activities of the dihydrobenzoxathiin
class of histamine H3 inverse agonists are also reported.
Our initial objectives were (i) further enhancement of H3 activ-
ity and (ii) reduction of hERG inhibitory activity of the lead 1a. In
order to achieve these objectives, we initiated SAR investigations
of the lead 1a. At first, the effect of the substitution at C3 of dihy-
drobenzoxathiin was investigated (Table 1). Substitution with
more lipophilic substituents such as ethyl and phenyl groups as
in 1b and 1c led to slight increase in H3 activity; however, no
improvement of hERG inhibitory activity was observed.
Secondly, the C2 and C3 portions of the dihydrobenzoxathiin
ring were investigated (Table 2). trans-Isomer 2a showed a 3.7-fold
increase in H3 activity and a fivefold decrease in hERG inhibitory
activity relative to 1a. The benzoxathiin derivative 3a was slightly
less potent than 1a. Next, replacement of the sulfide moiety of 1a,
2a, and 3a with a sulfone group was attempted. In addition to im-
proved H3 potency, the sulfone derivatives 4a, 5a and 6a displayed
markedly decreased hERG inhibitory activity, more than 50-fold
improvement over the corresponding sulfide derivatives 1a, 2a
and 3a. Of these, the most potent compound 5a was selected as a
benchmark compound for further modification.
The synthesis of dihydrobenzoxathiin derivatives reported
herein is outlined in Scheme 1. The derivatives were prepared
according to the reported procedures with minor modifications,28
and starting ketosulfides 7 were prepared according to the litera-
ture.29 cis-Dihydrobenzoxathiins 1 and 4 were synthesized fol-
lowing Route 1. Ketosulfide
7 was reductively cyclized by
Et3SiH/TFA, followed by desilylation with TBAF in the presence
of acetic acid to result in selective formation of cis-dihydroben-
zoxathiin 8. The phenoxy group of 8 was coupled with the desired
alcohol under the Mitsunobu conditions to provide sulfide 1. Con-
comitant oxidation of the sulfide and pyrrolidine groups of 1 with
excess m-CPBA followed by selective reduction of the resulting
pyrrolidine N-oxide using NaHSO3 furnished cis-dihydrobenzox-
athiin dioxide 4. trans-Dihydrobenzoxathiins 2 and 5 were syn-
thesized following Route 2. Reduction of ketosulfide 7 using
sodium borohydride followed by acid catalyzed cyclization and
subsequent desilylation with TBAF afforded trans-dihydrobenzox-
athiin 9 in 40–49% yield.28 The Mitsunobu alkylation of the phe-
nol 9 with the desired aminoalcohol provided compound 2, which
R2
R2
R2
R2
R2
R2
R2
O
O
O
O
O
O
R1
R1
R1
S
R1
R1
R1
S
R1
R1
R1
S
b
c
Route 1
a
O
O
O
OR3
OR3
OR3
OH
OH
OH
OR3
OR3
OR3
8
4
1
O
R2
OTIPS
S
S
S
b
b
c
c
d
e
S
R1
R2
Route 2
O
O
O
OH
7
9
2
5
R2
S
S
S
Route 3
O
O
O
3
10
6
Scheme 1. Reagents and conditions: (a) (i) Et3SiH, TFA, CH2Cl2, ꢀ20 to 0 °C, 3.5–12 h, (ii) TBAF, AcOH, THF, 0 °C, 2 h, 51–69% from 7; (b) R3OH, ADDP, n-Bu3P, THF, rt, 12–22 h,
58–87%; (c) (i) m-CPBA, CHCl3, rt, 1–15 h, (ii) saturated aq NaHSO3, saturated aq NaHCO3, rt, 3–17 h, 13–58% for two steps; (d) (i) NaBH4, MeOH, rt, 1–2 h; (ii) Amberlyst-15,
toluene, rt–45 °C, 14–19 h; (iii) TBAF, AcOH, THF, 0 °C, 1–2 h; (iv) crystallized from EtOAc/hexane, 40–49% from 7; (e) (i) TsOH, toluene, reflux, 5 h; (ii) TBAF, AcOH, THF, 0 °C,
3 h, 51–69% from 7.

4234
T. Sasaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4232–4236
Table 2
Table 3
SAR of dihydrobenzoxathiin derivatives, modification of the C2 and C3 portions of the
SAR of dihydrobenzoxathiin derivatives; substitution of the dihydrobenzoxathiin ring
dihydrobenzoxathiin ringa
and variation of the amine moietya
O
O
3
5
8
X
3
S
6
7
O
2
O
R2
2
O
N
O
R3
Compd Stereochemistry R2
R3
Human H3
(IC50, nM)
hERGc
(IC50, lM)
b
b
Compd
X
C2,3
Human H3 (IC50, nM)
hERGc (IC50, nM)
5.0 0.4
1a
2a
3a
4a
5a
6a
S
S
S
SO2
SO2
SO2
cis
6.7 0.6
1.8 0.1
trans
Olefin
cis
trans
Olefin
25
5
5a
5b
5c
5d
5e
5f
Racemate
Racemate
Racemate
Racemate
Racemate
Racemate
Racemate
H
0.60 0.10
0.44 0.06
0.40 0.06
0.32 0.04
0.39 0.11
0.34 0.07
0.21 0.03
1.3 0.1
6.3 0.3
1.0 0.1
1.7 0.1
7.0 0.5
4.8 0.3
2.9 0.1
8.6 0.8
3.9 1.1
0.60 0.10
0.84 0.15
4.4 0.5
440 60
1300 100
470 60
N
5-MeO
6-MeO
7-MeO
8-MeO
8-MeO
8-MeO
N
N
N
N
a
The values represent the mean SE for n P 3.
b
Inhibition of R-
receptor.
a cS at human H3
-methylhistamine-induced binding of [35S]GTP
c
Inhibition of [35S]MK-499 binding to hERG in HEK293 cells.
In our previous study on a quinazolinone class of H3 inverse
agonists, introduction of a methoxy group to the core quinazoli-
none ring was found to be effective to reduce hERG activity; hence,
we applied the same strategy to the current dihydrobenzoxathiin
lead (Table 3).24,26 The introduction of a methoxy group was toler-
ated as in the derivatives 5b–e. In this instance, the 5-and 8-meth-
oxy derivatives 5b and 5e were found to exhibit reduced hERG
N
N
5g
inhibitory activities (IC50 = 6.3 and 7.0 lM for 5b and 5e, respec-
5h
5i
Racemate
Racemate
8-MeO
8-MeO
0.82 0.09
0.16 0.03
3.8 0.4
2.5 0.1
tively). Finally, SAR around the 3-(pyrrolidin-1-yl)propoxy portion
was investigated by incorporating appropriate structural modifica-
tions based on knowledge acquired from prior SAR studies.24,25 The
piperidine and 2-(R)-methyl pyrrolidine derivative 5f and 5g were
equipotent to 5e, and the antipode 5h still had appreciable potency
(IC50 = 0.82 nM). The 3-(S)-methyl piperidine derivative 5i was 2.4-
fold more potent than 5e. The structurally rigid cyclobutyl piperi-
dine derivative 5j displayed not only enhanced H3 activity
(IC50 = 0.16 nM) but also significantly improved hERG activity
N
N
5j
Racemate
(2S,3S)
8-MeO
8-MeO
8-MeO
0.16 0.01
0.43 0.03
14
1
N
5k
5l
4.9 0.3
N
N
(IC50 = 14 lM). Compounds 5e and 5j were further evaluated for
rat hepatic clearance using the in vitro serum incubation method
previously reported by our laboratory.32 The predicted hepatic
clearance of 5j (CLh = 43 mL/min/kg) was twice as large as that of
5e (CLh = 21 mL/min/kg). Evaluation of optically active isomers of
the racemate 5e revealed that the 2S,3S-isomer 5k is slightly more
active than the 2R,3R-isomer 5l. 2S,3S-isomer 5k showed potent H3
activity (IC50 = 0.43 nM) and good selectivity over hERG
(2R,3R)
0.607 0.003 6.2 0.3
a
The values represent the mean SE for n P 3.
b
Inhibition of R-
a
-methylhistamine-induced binding of [35S]GTP
cS at human H3
receptor.
c
Inhibition of [35S]MK-499 binding to hERG in HEK293 cells.
(IC50 = 4.9 lM). Given these excellent in vitro profiles, compound
5k was selected for further evaluation.
involving episulfonium ion 18, as reported previously.36 Desilyla-
tion of 19 with TBAF in the presence of acetic acid yielded phenol
20. The Mitsunobu alkylation of the phenol 20 with 3-(pyrrolidin-
1-yl) propan-1-ol followed by oxidation of the sulfide group affor-
ded 5k with high enantiopurity (95.1% ee).
The pharmacokinetic parameters of 5k were evaluated in rats
and dogs. The results are summarized in Table 4. Compound 5k
displayed good pharmacokinetic profiles with excellent oral bio-
availability in rats and dogs. The brain penetrability of 5k was as-
sessed in Sprague-Dawley (SD) rats (Table 5). Compound 5k
showed good brain penetrability 2 h after 10 mg/kg oral dosing
In vitro characterization of 5k was carried out by radioligand
binding assays with [3H]R-
a-methylhistamine using human, rat
and mouse histamine H3 receptors expressed in CHO or HEK293
cell membranes. Compound 5k displayed potent binding affinity
to human, rat and mouse H3 receptors with Ki values of
1.0 0.1 nM, 2.8 0.1 nM, and 5.9 1.2 nM, respectively (n = 3).
Compound 5k is selective against other histamine receptor sub-
types (hH1, hH2, hH4; IC50 >10 lM).
An efficient asymmetric synthesis of 5k was established for
bulk preparation for further in vivo evaluation (Scheme 2). Com-
pound 11 was protected as its triisopropylsilyl ether to give 12. Ke-
tone 12 was converted to (E)-alkene 14 following the literature
procedure.33 The osmium-catalyzed asymmetric dihydroxylation
of alkene 14 gave ( 1R,2R)-1,2-diol 15,34 which was selectively
dehydrated to afford epoxide 16.35 The epoxide ring of 16 was
opened by 2-mercapto-6-methoxyphenol to give sulfide 17. Subse-
quent exposure of 17 to acidic conditions afforded optically active
trans-dihydrobenzoxathiin 19, presumably via a rearrangement
(brain = 1.38 nmol/g, plasma = 0.56 lM, brain-to-plasma ra-
tio = 2.4). With respect to P-glycoprotein (P-gp) transporter sus-
ceptibility, the transcellular transport ratio ((B-to-A)/(A-to-B)) for
5k in human and mouse P-gp were less than 3.0 (Table 5), indicat-
ing that the effects of P-gp mediated efflux in human and mouse
brain is negligible.37,38 Compound 5k displayed no significant com-
petitive inhibitory activity against CYP 3A4, 2D6, and 2C9, (IC50
>10 lM), and no time dependent inhibition of CYP3A4.

T. Sasaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4232–4236
4235
O
O
O
N
i
ii
iii
HO
TIPSO
TIPSO
TIPSO
11
12
13
14
OMe
MeO
HO
OH
HO
O
v
iv
vi
vii
S
S
OH
TIPSO
OH
TIPSO
TIPSO
TIPSO
15
16
17
18
O
O
S
S
S
viii
ix
x
O
OMe
O
OMe
O
OMe
OTIPS
OH
O
N
19
20
5k
Scheme 2. Reagents and conditions: (i) TIPSCl, NaH, THF, 0 °C–rt, 14 h, quant.; (ii) morpholine, TiCl4, toluene, reflux, 14 h; (iii) (a) BH3–dimethylsulfide, THF, 0 °C, 5 h;
(b)MeOH, rt, 12 h; (c) H2O2, THF, rt, 2 h, 64% from 12; (iv) AD-mix-b, MeSO2NH2, t-BuOH, H2O, 1–5 °C, 10 h, (v) (a) TMSCl, MeC(OMe)3, CHCl3, rt, 1 h, (b) K2CO3, MeOH, rt, 4.5 h,
70% from 14; (vi), 2-methoxy-6-sulfanylphenol, DIEA, MeOH, rt, 14 h, 92%; (vii) Amberlyst-15, toluene, 45 °C, 21 h; (viii) (a) TBAF, AcOH, THF, rt, 1 h; (b) crystallized from
EtOAc/hexane, 49% from 17; (ix) 3-(pyrrolidin-1-yl)propan-1-ol, ADDP, n-Bu3P, THF, rt, 13 h, 87%; (x) (a) m-CPBA, CHCl3, rt, 2.5 h; (b) saturated aq NaHSO3, saturated aq
NaHCO3, rt, 13.5 h, 28%.
Table 4
250
Pharmacokinetic parameters of 5k in rats and dogs
**
200
150
100
50
*
iv (Rat: 1 mg/kg, Dog: 0.3 mg/kg)
po (Rat: 3 mg/kg, Dog: 1 mg/kg)
CLp (mL/
min/kg)
Vdss
(L/kg)
t1/2
(h)
Cmax
M)
AUC0-1
M h)
Fc
(%)
(
l
(
l
Rata
44
25
21.5
10
6.6
5.7
0.28
0.16
2.41
1.21
86
78
Dogb
a
The values represent the mean, n = 3 animals.
The values represent the mean, n = 2 animals.
Based on AUC0-1 values after iv and po dosings.
b
c
0
Vehicle
1
3
10
Compound 5k (mg/kg)
Table 5
Brain penetration and P-gp transport ratio of 5k
Figure 1. Brain tele-methylhistamine levels in SD rats after oral administration of
vehicle or compound 5k (1, 3, and 10 mg/kg). Values are means SE, determined
from five experiments. *P < 0.05, **P < 0.01 (ANOVA Dunnett) compared with the
vehicle control.
Compd
Brain penetration in SD ratsa
P-gp transporter assay
transcellular transport ratio
(B-to-A)/(A-to-B)
Plasma (
l
M) Brain (nmol/g) CSF (
l
M) MDR1b
mdr1ac
5k
0.56
1.38 0.077
2.6
2.6
a
The values represent the mean for n = 3. The concentrations were determined at
3 mg/kg (the minimum effective dose in the histamine release as-
say) of 5k, ex vivo receptor occupancy in rat brain slices was deter-
mined to be approximately 100%.
In conclusion, we have synthesized and evaluated a new series
of dihydrobenzoxathiin derivatives as H3 receptor inverse agonists.
An initial issue was potent hERG inhibitory activity of lead com-
pound 1a. A number of potent H3 active compounds with reduced
hERG activity were identified. Of them, compound 5k was shown
to have excellent brain exposure, pharmacokinetic profile, and
in vivo efficacy. Further evaluation of 5k is currently underway.
2 h after 10 mg/kg po.
Transcellular transport ratio ((B-to-A)/(A-to-B)) was determined by human P-
glycoprotein transporter assays with a human MDR1-transfected porcine renal
b
epithelial cell line.
c
Transcellular transport ratio ((B-to-A)/(A-to-B)) was determined by mouse P-
glycoprotein transporter assays with a mouse mdr1a-transfected porcine renal
epithelial cell line.
Having demonstrated the excellent potency, selectivity, and
pharmacokinetic profile of 5k, this compound was tested for brain
histamine release assay in SD rats.39 As shown in Figure 1, com-
pound 5k showed significant and dose-proportional increase in
tele-methylhistamine levels in SD rats following 3 mg/kg oral dos-
ing, indicating that 5k significantly elevated histamine levels in the
rat brain. In order to investigate the correlation between efficacy in
the histamine release assay and brain H3 receptor occupancy in the
rat brain, an ex vivo receptor occupancy study with 5k was per-
formed in SD rats. Two hours following oral administration of
Acknowledgments
We thank Mioko Hirayama for [35S]MK-499 binding assays, Hir-
oaki Suwa for HPLC purity analyses, Nancy Tsou, Dr. Michael
McNevin and Dr. Richard G. Ball for the determination of the abso-
lute stereochemistry of 5k. We also thank Dr. Peter T. Meinke
(Merck Research Laboratories, Rahway, NJ) for the editing of this
manuscript.

4236
T. Sasaki et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4232–4236
D.; Jennings, C.; Jones, D. N. C.; Lacroix, L. P.; Martyn, A.; Ociepka, S.; Ray, A.;
Supplementary data
Regan, C. M.; Roberts, J. C.; Schogger, J.; Southam, E.; Stean, T. O.; Trail, B. K.;
Upton, N.; Wadsworth, G.; Wald, J. A.; White, T.; Witherington, J.; Woolley, M.
L.; Worby, A.; Wilson, D. M. J. Pharmacol. Exp. Ther. 2007, 321, 1032.
24. Nagase, T.; Mizutani, T.; Ishikawa, S.; Sekino, E.; Sasaki, T.; Fujimura, T.; Ito, S.;
Mitobe, Y.; Miyamoto, Y.; Yoshimoto, R.; Tanaka, T.; Ishihara, A.; Takenaga, N.;
Tokita, S.; Fukami, T.; Sato, N. J. Med. Chem. 2008, 51, 4780.
Supplementary data (X-ray crystal structure of compound 5k)
associated with this article can be found, in the online version, at
doi:10.1016/j.bmcl.2009.05.101.
25. Nagase, T.; Mizutani, T.; Sekino, E.; Ishikawa, S.; Ito, S.; Mitobe, Y.; Miyamoto,
Y.; Yoshimoto, R.; Tanaka, T.; Ishihara, A.; Takenaga, N.; Tokita, S.; Sato, N. J.
Med. Chem. 2008, 6889.
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30. Colourless block-shaped crystals of compound 5k were obtained from a 2:2:1
solution of isopropyl alcohol/hexanes/CH2Cl2, Mr = 431.546, orthorhombic,
P212121, a = 14.015(9) Å, b = 14.234(9) Å, c = 21.145(13) Å, V = 4218(5) Å3,
Z = 8, Dx = 1.359 g cmꢀ3
l
,
monochromatized radiation k(Mo) = 0.71073 Å,
= 0.19 mmꢀ1, F(0 0 0) = 1840, T = 100 K. Data were collected on a Bruker
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r
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-
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parameters and all 9077 data. All non-hydrogen atoms were refined with
anisotropic thermal displacements. The final agreement statistics are:
R = 0.037 (based on 8278 reflections with I > 2r(I)), wR = 0.086, S = 1.06 with
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0.284 e Åꢀ3 and this peak is without chemical significance. The choice of the
absolute configuration is confirmed by the calculated Flack parameter, 0.06(5).
CCDC 726589 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif. See Supplementary data
for the X-ray crystal structure of 5k.
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