Novel thyroid hormone receptor antagonists with an N-alkylated diphenylamine skeleton

Article abstract of DOI:10.1016/j.bmc.2007.02.053

Thyroid hormones play important roles in growth, development and homeostasis, and disruption of their functions induces serious disease, so novel synthetic thyroid hormone analogues are candidates for clinical application. We designed and synthesized nove

Full text of DOI:10.1016/j.bmc.2007.02.053

Bioorganic & Medicinal Chemistry 15 (2007) 3115–3126
Novel thyroid hormone receptor antagonists with an N-alkylated
diphenylamine skeleton
Takuma Komatsu, Tomoya Hirano, Chalermkiat Songkram,
Emiko Kawachi and Hiroyuki Kagechika*
School of Biomedical Science, Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University,
2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan
Received 16 February 2007; revised 24 February 2007; accepted 27 February 2007
Available online 3 March 2007
Abstract—Thyroid hormones play important roles in growth, development and homeostasis, and disruption of their functions
induces serious disease, so novel synthetic thyroid hormone analogues are candidates for clinical application. We designed and syn-
thesized novel diphenylamine derivatives with a thiazolidinedione moiety as the terminal polar group as thyroid hormone receptor
(TR) antagonists. Compounds bearing an appropriately sized N-alkyl group showed antagonistic activities towards both the hTRa1
and hTRb1 subtypes.
ꢀ 2007 Elsevier Ltd. All rights reserved.
I
I
1. Introduction
I
O
I
I
O
I
3'
NH2
COOH
Thyroid hormones (THs), 3,30,5-triiodothyronine (T3,
Fig. 1) and 3,30,5,50-tetraiodothyronine (T4), are pro-
duced by the thyroid gland and peripheral tissues, and
regulate various physiological processes associated with
growth, homeostasis and development.1 They regulate
gene transcription through binding with thyroid hor-
mone receptors (TRs),2 which are ligand-inducible tran-
scriptional factors belonging to the nuclear receptor
superfamily, and they also influence basal and adaptive
metabolism, lipid levels, bone and muscle metabolism
and heart rate. Disruption of these regulatory functions
causes various diseases. For example, abnormal eleva-
tion of circulating TRs results in hyperthyroidism,
which manifests clinically as weight loss, lowering of
serum lipid levels, cardiac arrhythmias and heart failure.
Present clinical treatment of hyperthyroidism involves
direct reduction of TH production by inhibiting the
synthesizing enzymes, or by ablating the thyroid gland
surgically or with radioiodine, but because of the long
half-life of THs, these therapies take several weeks to re-
store a normal state. In contrast, the direct suppression
COOH
HO
HO
5'
X
T3: X = H
T4: X = I
Triac
I
O
S
O
NH
HO
O
COOH
HO
I
O
1
GC-1
Figure 1. Structures of endogenous and synthetic TR agonists.
of TR functions is expected to be quick. Therefore, in
addition to TR agonists,3–11 such as Triac,3,4 GC-15
and 1,6 several TR antagonists have been synthesized
(Fig. 2).12–21 Most of them, except for a few compounds
such as HY-4, are analogues of Triac or GC-1 bearing a
bulky group at the 50-position of the phenol moiety
(outer ring). However, the structure-activity relationship
study of GC-1416 and NH-317 showed that the agonist/
antagonist activity balance varied depending on the
substituent on the phenyl or phenylethynyl group, which
means that the bulkiness of the 50-substituent is not the
only factor determining the activity of these types of
TR antagonists.18 In this article, we designed and
synthesized a series of novel TR antagonists, and
elucidated their activities towards the TR subtypes.
Keywords:
Thiazolidinedione.
*
Thyroid
hormone;
Antagonist;
Diphenylamine;
Corresponding author. Tel.: +81 3 5280 8032; fax: +81 3 5280
8127; e-mail: kage.omc@tmd.ac.jp
These authors contributed equally to this work.
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2007.02.053

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T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
R
N
O
N
O
Br
(CH )
2 10
S
NH
HO
Br
COOH
HO
HO
O
COOH
O
DIBRT
HY-4
CH3 : 3a
: 3b
: 3e
: 3f
GC-14: X = none
NH-3: X =
HO
O
COOH
R =
X
: 3c
5
: 3g
NO2
: 3d
Br
HO
Br
COOH
Figure 3. Structures of newly synthesized TR antagonist candidates.
priately sized N-alkyl group. As for the terminal polar
group, we previously reported that compound 1 is as
active as T3,6 and a thiazolidinedione group is a good
bioisoster for carboxylic acid, as has also been found
with ligands of other nuclear hormone receptors.28,29
Thus, we designed and synthesized 3a–3g as TR
antagonist candidates.
N
2
Figure 2. Structures of typical TR antagonists.
2. Results
2.1. Design of new antagonist candidates
2.2. Synthesis
The crystal structures of several nuclear receptor
ligand-binding domains (LBD) indicated that in binding
with agonists, the C-terminal helix 12 (H12) forms a lid
over the ligand-binding pocket, thereby providing an
accessible surface structure suitable for coactivator
binding.22–24 Prevention of this proper packing of H12
by a bulky group introduced into the structure of some
antagonists could explain the antagonistic activity.
For the synthesis of 3a–3g, we planned to derive the
thiazolidinedione group from an aldehyde group at the
final stage in the synthesis. The diphenylamine com-
pound 4 can be synthesized by Buchward’s amination
reaction between a protected 4-bromo-2-isopropylphe-
nol, 6a or 6b, and aniline derivatives with an aldehyde
(7a), a protected aldehyde (7b) or a cyano group as
the precursor for aldehyde (7c) (Fig. 4).
In the case of TRs, the crystal structures of holo-recep-
tors with some agonists, including T3, have already been
reported.25,26 In these structures, the 50 position of the
ligand is oriented in the direction of the loop between
helix 11 and H12, so the introduction of a bulky group
at this position might yield antagonists. Based on this
concept, several synthetic TR antagonists, such as DIB-
RT,19 GC-14, NH-3 or 2,20 were reported. However,
modification at the 50 position also caused variation in
the TR agonist/antagonist activity ratio, and therefore
we designed different types of TR antagonist candidates.
R
O
N
S
NH
HO
O
3a – 3g
R
N
O
S
TR ligands consist of three parts, that is, a phenolic out-
er ring, another benzene ring (inner ring) bearing the ter-
minal polar group and their linking atom. The terminal
polar group is significant for the interaction with TRs
and may be associated with the selectivity between
TRa and b subtypes.27 The linking atom in the endoge-
nous ligand is oxygen. Recently, various TR analogues
with a methylene linker have been developed, and intro-
duction of a long substituent on the methylene linker
afforded antagonistic activity in the case of HY-4. Con-
sidering these results, we designed compounds 3 as TR
antagonist candidates (Fig. 3). In the structure of 3,
the nitrogen atom was used as the linker between the
outer and inner rings, and antagonistic activity was ex-
pected to be generated by the introduction of an appro-
NH
+
CHO
R'O
O
4
5
Br
H2N
+
R'O
X
6a: R' = CH3
6b: R' = CH2OCH3
7a: X = CHO
7b: X = CH(SEt)2
7c: X = CN
Figure 4. Synthetic strategy for 3.

T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
3117
H2N
H2N
H2N
H2N
(i)
(ii)
SEt
7b SEt
CHO
Br
CN
96%
76%
7a
8
7c
H
N
Br
Br
Br
H2N
(iii)
+
H3CO
CHO
H3CO
16%
CHO
7a
7b
7c
6a
6a
9a
H
N
(iii)
H2N
no coupling
(iv)
SEt
SEt
+
+
H3CO
H3CO
SEt
SEt
9b
H
N
H2N
R'O
CN
R'O
CN
6a: R' = CH3
6b: R' = CH2OCH3
9c: R' = CH3 (82%)
9d: R' = CH2OCH3 (76%)
Scheme 1. Reagents: (i) EtSH, TMSCl, CHCl3; (ii) CuI, KI, CuCN, N,N0-dimethylethylenediamine, DMF; (iii) Pd2(dba)3, t-BuONa, 2-(di-tert-
butylphosphino)biphenyl, toluene; (iv) Pd2(dba)3, t-BuONa, 2-(di-cyclohexylphosphino)biphenyl, toluene.
The methyl-protected p-bromophenols 6a and 7a were
prepared by the method in the literature5,30 (Scheme 1).
However, the coupling reaction of 6a and 7a proceeded
only in low yield (16%), mainly due to the high reactivity
of the aldehyde group. To prevent side reactions, the
aldehyde group was protected with thiolate to form a
thioacetal moiety, 7b, but this could not be coupled with
6a, probably because the sulfur atoms would chelate
palladium, preventing the catalytic reaction.à Thus, a
cyano group (7c) was used as a precursor of aldehyde.
The cyano derivative 7c was synthesized from 8 via a
Sonogashira-like reaction.31 The coupling reaction of
7c with 6a proceeded to afford 9c in 82% yield. In this
reaction, the phosphine ligand, 2-(di-cyclohexylphosph-
ino)biphenyl, is important for high yield. The meth-
oxymethyl-protected molecule 6b was also coupled
with 7c to afford the diphenylamine 9d in 76% yield.
2.3. Biological activity
The activity of the synthesized molecules was examined
by means of transient transactivation assay in COS-1
cells transfected with hTRa1 or hTRb1. None of the
compounds activated transcription via either of the
subtypes, except that 3a had a slight agonist activity
towards TRa1 and TRb1, being less than one-tenth as
potent as T3 at the concentration of 10ꢀ6 M (data not
shown). Then, the antagonistic activities towards T3 in
TR activation were examined. All the compounds,
except for 3a, exhibited antagonistic activity (Fig. 5).
The difference in the activity depending upon the N-sub-
stituent was small, and the similar tendency was
observed between two TR subtypes. Compounds with
a bulky N-alkyl group, such as a benzyl (3d) and
cyclohexylmethyl group (3g), were moderately effective
among the synthesized compounds.
After methylation of 9c, 10 was reduced to the aldehyde
(11) via Knoevenagel condensation with thiazolidinedi-
one (5) to afford 12 (Scheme 2). The reduction of 12 with
Pd/C or LiBH4 was unsuccessful because of decomposi-
tion or slow reaction, but the method using cobalt–dim-
ethylglyoxime complex successfully reduced 12 to 13.
However, demethylation of 13 proved difficult. There-
fore, we used the methoxymethyl group for protection
of the phenolic hydroxyl group. Starting from 6b, the
same reactions proceeded to afford 17a, and deprotec-
tion of the methoxymethyl group proceeded easily to
give 3a. Compounds 3b–3g were similarly synthesized.
3. Discussion
Compounds 3b–3g showed antagonist activities towards
both subtypes of TRs, while 3a exhibited very weak par-
tial-agonistic activity, and this difference must be due to
the difference of substituents at the nitrogen atom.
Among the TR antagonists so far known, only HY-4
has a bulky substituent on the linker atom.12 However,
HY-4 has an extremely long chain, and compounds with
a shorter allyl group, such as 18 (Fig. 6), show weak
agonistic activity. In our case, such a long substituent
is unnecessary, and a C4–C8 alkyl group is sufficient
for antagonist activity against both TR subtypes. A pos-
sible reason for this difference is the difference of the lin-
ker atom, carbon in HY-4 and 18, and nitrogen in our
à
The compound 7a could not be converted to the acetal derivatives by
the typical reaction conditions.

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T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
R
N
R
H
N
N
(i)
(ii)
(iii)
R'O
CN
R'O
CN
R'O
CHO
R' = CH , R = CH
11: R' = CH3, R = CH3
9c: R' = CH3
10:
3
3
R' = CH OCH
R' = CH OCH
9d: R' = CH2OCH3
14a – 14g:
15a – 15g:
2
3
2
3
R
R
N
R
O
O
O
N
N
S
S
(iv)
S
(v)
NH
NH
NH
R'O
HO
R'O
O
O
O
3a – 3g
12: R' = CH3, R = CH3
R' = CH , R = CH
13:
3
3
R' = CH OCH
16a – 16g:
R' = CH OCH
17a – 17g:
2
3
2
3
Scheme 2. Synthesis of 3a–3g. In compounds 3 and 14–17, R is (a) CH3, (b) cyclopropylmethyl, (c) n-hexyl, (d) benzyl, (e) iso-butyl, (f) prenyl and (g)
cyclohexylmethyl. Reagents: (i) NaH, R–X (Cl, Br or I), DMF; (ii) DIBAL-H, toluene; (iii) 5, piperidine, EtOH; (iv) 1—Co-DMG, DMF;
2—NaBH4, H2O; (v) HCl, CH3OH–CH2Cl2.
(I) Antagonist activity of 3a – 3g against TRα1 at 3 x 10-9 M of T3
150
100
% RLU
50
0
10-7
10-7
10-7
10-7
10-7
10-7
10-7
control
10-6
10-6
10-6
10-6
10-6
10-6
10-6
3a
3b
3c
3d
3e
3f
3g
(II) Antagonist activity of 3a – 3g against TRβ1 at 3 x 10-9 M of T3
150
100
% RLU
50
0
10-7 10-6 10-7 10-6 10-7 10-6 10-7 10-6 10-7 10-6 10-7 10-6 10-7 10-6
control
3a
3b
3c
3d
3e
3f
3g
Figure 5. Transactivation profile for 3 with (I) TRa1 and (II) TRb1. COS-1 cells were transfected with TR expression vector and luciferase reporter
genes, and were treated with the indicated concentration of 3 in the presence of 3 · 10ꢀ9 M T3. The values were normalized to b-galactosidase
activities and expressed relative to that obtained when 3 · 10ꢀ9 M T3 was added, and the results are shown as percentages, with the value for T3 taken
as 100%. Values are means SD for separate experiments (n = 3).
molecules. The orientation of the substituent would be
different in the two cases, and this might account for
the difference of threshold between agonist and antago-
nist. Crystal structures of holo-TR ligand binding
domains show that the introduction of the bulky substi-
tuent at 50-position of T3 may disturb the proper confor-
mation of helix 12 that is significant for the active form
HO
O
COOH
18
Figure 6. Structure of 18.

T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
3119
of TR. If the compounds 3 bind to TRs with similar con-
formation with that of T3 or GC-1, the substituent on
the linker nitrogen atom was thought to face to helix 7
or 8. The further study for elucidation of the structural
factors for the antagonism of novel compounds 3 is
ongoing.
concentrated in vacuo. Purification by silica gel column
chromatography (ethyl acetate/n-hexane = 1:1) yielded
the 7b as a brown solid (332 mg, 96%).
1
Compound 7b: H NMR (400 MHz, CDCl3) d 7.04 (s,
2H), 4.82 (s, 1H), 2.56 (q, 4H, J = 7.4 Hz), 2.23 (s,
6H), 1.23 (t, 6H, J = 7.4 Hz); 13C NMR (125 MHz,
CDCl3) d 142.4, 129.4, 127.6, 121.6, 52.3, 26.3, 17.7,
14.3; HRMS (ESI) calcd for C13H21N1Na1S2 (M+Na+)
278.1008; found 278.0996.
The key intermediate 9d should be a convenient syn-
thetic intermediate for obtaining various derivatives
with different N-substituents. In addition, the cyano
(9d) or aldehyde group (15) can be easily transformed
to other polar groups. Crystallographic studies have
shown that only one amino acid residue is different
(Ser277 in hTRa1, Asn331 in hTRb1) in the ligand bind-
ing cavities of the two TR subtypes.32 Although these
residues do not directly contact the ligand, they partici-
pate in a hydrogen-bonding network with the terminal
polar group. In the study of GC-1, a b-selective agonist,
the terminal polar group (oxoacetic acid) was found to
be important for its b-selectivity. In our case, although
no subtype selectivity was observed, it is possible that
modification at the terminal polar group may afford po-
tent TR subtype-selective antagonists. We are now
developing a TR ligand library by using 9d as the key
intermediate. It is also possible that other combinations
of linker atom and terminal polar group may yield selec-
tive TR agonists and antagonists.
5.2.2. Synthesis of 4-amino-3,5-dimethylbenzonitrile (7c).
An oven-dried, round-bottomed flask was charged with
CuCN (5.85 g, 65.3 mmol), CuI (1.04 g, 5.46 mmol), 8
(10.8 g, 54.2 mmol) and KI (1.91 g, 11.5 mmol) under
argon. Anhydrous DMF (39 mL) and N,N0-dimethyle-
thylenediamine (5.80 mL, 54.4 mmol) were added, and
the reaction mixture was stirred at 100 ꢁC for 24 h.
The resulting suspension was allowed to warm to room
temperature, diluted with 28% aqueous ammonia and
extracted with ethyl acetate. The organic fractions were
washed with brine, dried over sodium sulfate and con-
centrated in vacuo. Purification by silica gel column
chromatography (ethyl acetate/n-hexane = 1:3) yielded
the 6c as a white solid (6.05 g, 76%).
1
Compound 7c: H NMR (400 MHz, CDCl3) d 7.22 (s,
2H), 4.04 (br s, 2H), 2.17 (s, 6H); 13C NMR
(125 MHz, CDCl3) d 141.8, 130.5, 123.6, 109.4, 17.4;
HRMS (ESI) calcd for C9H9N2 (MꢀH+) 145.0761;
found 145.0768.
4. Conclusion
We have designed and synthesized novel TR antago-
nists, 3b–3g. This new class of antithyroid compounds
should provide candidate drugs for clinical application
and tools for elucidation of the physiological functions
of thyroid hormone receptors.
5.2.3. Synthesis of 4-[(3-isopropyl-4-methoxyphenyl)-
amino]-3,5-dimethylbenzaldehyde (9a). An oven-dried,
round-bottomed flask was charged with Pd2(dba)3
(4.4 mg,4.25 lmol), 2-(di-tert-butylphosphino)biphenyl
(4.3 mg, 14.4 lmol), t-BuONa (63.0 mg, 0.656 mmol)
and 7a (82.0 mg, 0.550 mmol) under argon. A separate
flame-dried, two-necked, pear-shaped flask was charged
with 6a (103 mg, 0.451 mmol) and dry toluene (1.7 mL)
under argon. This solution was added to the round-bot-
tomed flask via cannula. The resulting mixture was stir-
red for 3 days at 100 ꢁC. After the addition of water and
aqueous HCl to the reaction mixture at 0 ꢁC, the aque-
ous phase was extracted with ethyl acetate. The organic
fractions were washed with brine, dried over sodium sul-
fate and concentrated in vacuo. Purification by silica gel
column chromatography (ethyl acetate/n-hexane = 1:9)
yielded the 9a as a brown oil (21.4 mg, 16%).
5. Experimental
5.1. General information
All reagents were purchased from Sigma–Aldrich Chem-
ical Co., Tokyo Kasei Kogyo Co., Wako Pure Chemical
Industries and Kanto Kagaku Co., Inc. Silica gel for
column chromatography was purchased from Kanto
1
Kagaku Co., Inc. H and 13C NMR spectra were re-
corded on Bruker ARX400 or Bruker Avance 500 spec-
trometer. Mass spectral data were obtained on a Bruker
Daltonics microTOF-2focus in the positive and negative
ion detection modes.
1
Compound 9a: H NMR (400 MHz, CDCl3) d 9.87 (s,
1H), 7.58 (s, 2H), 6.71 (d, 1H, J = 8.6 Hz), 6.66–6.48
(m, 2H), 3.79 (s, 3H), 3.28 (septet, 1H, J = 6.9 Hz),
2.20 (s, 6H), 1.16 (d, 6H, J = 6.9 Hz); HRMS (ESI)
calcd for C19H22N1O2 (MꢀH+) 296.1645; found
296.1633.
5.2. Synthesis
5.2.1. Synthesis of 4-[bis(ethylthio)methyl]-2,6-dimethy-
laniline (7b). To a solution of 7a (202 mg, 1.36 mmol) in
anhydrous chloroform (5.0 mL) at room temperature
were added trimethylsilyl chloride (0.43 mL, 3.36 mmol)
and ethanethiol (0.25 mL, 3.38 mmol) under argon
atmosphere. The reaction mixture was stirred for 2 h.
After the addition of aqueous NaOH, the aqueous phase
was extracted with chloroform. The organic fractions
were washed with brine, dried over sodium sulfate and
5.2.4. Synthesis of 4-[(3-isopropyl-4-methoxyphenyl)-
amino]-3,5-dimethylbenzonitrile (9c). An oven-dried,
round-bottomed flask was charged with Pd2(dba)3
(104 mg, 0.100 mmol), 2-(di-cyclohexylphosphino)biphe-
nyl (48.9 mg, 0.140 mmol), t-BuONa (0.633 g,
6.59 mmol) and 7c (0.751 g, 5.14 mmol) under argon. A

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T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
separate flame-dried, two-necked, pear-shaped flask was
charged with 6a (1.31 g, 5.72 mmol) and dry toluene
(29 mL) under argon. This solution was added to the
round-bottomed flask via cannula. The resulting mixture
was stirred for 19 h at 100 ꢁC. After the addition of water
and aqueous HCl to the reaction mixture at 0 ꢁC, the
aqueous phase was extracted with ethyl acetate. The or-
ganic fractions were washed with brine, dried over sodium
sulfate and concentrated in vacuo. Purification by silica
gel column chromatography (ethyl acetate/n-hex-
ane = 1:4) yielded the 9c as a white solid (1.24 g, 82%).
(3.0 mL) under argon, DIBAL-H (0.99 M solution in
toluene, 0.90 mL, 0.891 mmol) was slowly added at
0 ꢁC. The reaction mixture was stirred for 20 min at
room temperature. After the addition of saturated
ammonium chloride, the aqueous phase was extracted
with ethyl acetate. The organic fractions were washed
with brine, dried over sodium sulfate and concentrated
in vacuo. Purification by silica gel column chromatogra-
phy (ethyl acetate/n-hexane = 1:6) yielded the 11 as a
yellow oil (133 mg, 63%).
1
Compound 11: H NMR (400 MHz, CDCl3) d 9.97 (s,
1
Compound 9c: H NMR (400 MHz, CDCl3) d 7.35 (s,
1H), 7.65 (s, 2H), 6.72 (d, 1H, J = 8.8 Hz), 6.30 (br s,
1H), 6.21 (d, 1H, J = 6.5 Hz), 3.76 (s, 3H), 3.24 (septet,
1H, J = 6.9 Hz), 3.17 (s, 3H), 2.15 (s, 6H), 1.12 (d, 6H,
J = 6.9 Hz).
2H), 6.70 (d, 1H, J = 8.6 Hz), 6.61 (d, 1H, J = 2.8 Hz),
6.41 (dd, 1H, J = 8.6 Hz, 2.8 Hz), 5.35 (s, 1H), 3.78 (s,
3H), 3.27 (septet, 1H, J = 6.9 Hz), 2.15 (s, 6H), 1.16
(d, 6H, J = 6.9 Hz); 13C NMR (125 MHz, CDCl3) d
151.9, 144.8, 138.2, 137.3, 132.6, 132.1, 119.6, 116.3,
115.1, 111.3, 105.7, 55.9, 26.9, 22.6, 18.7; HRMS (ESI)
calcd for C19H21N2O1 (MꢀH+) 293.1648; found
293.1646.
5.2.8. Synthesis of (Z)-5-[4-[N-(3-isopropyl-4-methoxy-
phenyl)-N-methylamino]-3,5-dimethylphenylmethylene]-
thiazolidine-2,4-dione (12). To a solution of 11 (133 mg,
0.402 mmol) in dry ethanol (11 mL) under argon, piper-
idine (50 lL, 0.453 mmol) and 2,4-thiazolidinedione (5,
53.1 mg, 0.453 mmol) were added at room temperature.
The reaction mixture was refluxed for 20 h, and the sol-
vent was concentrated in vacuo. After the addition of
water, the aqueous phase was extracted with ethyl ace-
tate. The organic fractions were washed with brine,
dried over sodium sulfate and concentrated in vacuo.
Purification by silica gel column chromatography (ethyl
acetate/n-hexane = 1:3) yielded the 12 as a brown oil
(122 mg, 74%).
5.2.5. Synthesis of 4-[[3-isopropyl-4-(methoxymethoxy)-
phenyl]amino]-3,5-dimethylbenzonitrile (9d). Compound
9d was prepared from 7c (3.81 g, 26.2 mmol) and 6b
(6.01 g, 23.2 mmol) according to the procedure
described for 9c in yield 76% (5.73 g, white solid).
1
Compound 9d: H NMR (500 MHz, CDCl3) d 7.34 (s,
2H), 6.92 (d, 1H, J = 8.6 Hz), 6.56 (d, 1H, J = 2.7 Hz),
6.39 (dd, 1H, J = 8.6 Hz, 2.8 Hz), 5.34 (s, 1H), 5.13 (s,
2H), 3.49 (s, 3H), 3.29 (septet, 1H, J = 6.9 Hz), 2.16 (s,
6H), 1.17 (d, 6H, J = 6.9 Hz); 13C NMR (125 MHz,
CDCl3) d 149.2, 144.5, 139.0, 138.5, 132.6, 132.6,
119.6, 115.5, 115.5, 114.9, 106.2, 95.4, 56.0, 27.0, 22.8,
18.7; HRMS (ESI) calcd for C20H23N2O2 (MꢀH+)
323.1754; found 323.1751.
1
Compound 12: H NMR (400 MHz, CDCl3) d 8.65 (br
s, 1H), 7.83 (s,1H), 7.27 (s, 2H), 6.72 (d, 1H,
J = 8.8 Hz), 6.32 (s, 1H), 6.20 (d, 1H, J = 8.8 Hz), 3.76
(s, 3H), 3.24 (septet, 1H, J = 6.9 Hz), 3.16 (s, 3H), 2.13
(s, 6H), 1.13 (d, 6H, J = 6.9 Hz).
5.2.6. Synthesis of 4-[N-(3-isopropyl-4-methoxyphenyl)-
N-methylamino]-3,5-dimethylbenzonitrile (10). To a sus-
pension of NaH (25.7 mg, 1.07 mmol) in dry DMF
(1.0 mL) under argon, 9c (200 mg, 0.679 mmol) was
slowly added at 0 ꢁC. The reaction mixture was warmed
up to room temperature and stirred for 30 min. To the
mixture, iodomethane (140 lL, 2.25 mmol) was slowly
added at 0 ꢁC. The reaction mixture was warmed to
room temperature and stirred for 1 h. After the addition
of water to the reaction mixture at 0 ꢁC, the aqueous
phase was extracted with ethyl acetate. The organic frac-
tions were washed with brine, dried over sodium sulfate
and concentrated in vacuo. Purification by silica gel col-
umn chromatography (ethyl acetate/n-hexane = 1:6)
yielded the 10 as a brown oil (196 mg, 94%).
5.2.9. Synthesis of 5-[4-[N-(3-isopropyl-4-methoxyphe-
nyl)-N-methylamino]-3,5-dimethylphenylmethyl]thiazoli-
dine-2,4-dione (13). To a rapidly stirred mixture of 12
(33.9 mg, 82.6 lmol) in THF (360 lL) and 1M NaOH
(90.0 lL) at room temperature, CoCl2–DMG complex
solution (18.0 lL, made from 11.6 mg of cobalt chloride,
125 mg of dimethylglyoxime and 2.5 mL DMF) was
added. After 30 min, sodium borohydride (18.0 mg,
0.476 mmol) in water (0.5 mL) was added and the mix-
ture was stirred at 35 ꢁC for 9 h. After the addition of
water and aqueous HCl to the reaction mixture at
0 ꢁC, the aqueous phase was extracted with ethyl ace-
tate. The organic fractions were washed with brine,
dried over sodium sulfate and concentrated in vacuo.
Purification by silica gel column chromatography (ethyl
acetate/n-hexane = 1:3) yielded the 13 as a brown oil
(25.2 mg, 74%).
1
Compound 10: H NMR (400 MHz, CDCl3) d 7.42 (s,
2H), 6.72 (d, 1H, J = 8.8 Hz), 6.28 (d, 1H, J = 1.9 Hz),
6.19 (dd, 1H, J = 8.3 Hz, 1.9 Hz), 3.75 (s, 3H), 3.24 (sep-
tet, 1H, J = 6.9 Hz), 3.15 (s, 3H), 2.11 (s, 6H), 1.12 (d,
6H, J = 6.9 Hz).
1
Compound 13: H NMR (400 MHz, CDCl3) d 8.70 (br
s, 1H), 6.97 (s, 2H), 6.71 (d, 1H, J = 8.8 Hz), 6.25 (s,
1H), 6.15 (d, 1H, J = 7.1 Hz), 4.56 (dd, 1H,
J = 10.4 Hz, 3.8 Hz), 3.75 (s, 3H), 3.55 (dd, 1H,
J = 13.9 Hz, 3.8 Hz), 3.23 (septet, 1H, J = 6.9 Hz), 3.14
(s, 3H), 3.03 (dd, 1H, J = 14.0 Hz, 10.4 Hz), 2.06 (s,
6H), 1.12 (d, 6H, J = 6.9H).
5.2.7. Synthesis of 4-[N-(3-isopropyl-4-methoxyphenyl)-
N-methylamino]-3,5-dimethylbenzaldehyde (11). To a
solution of 10 (196 mg, 0.637 mmol) in dry toluene

T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
3121
5.2.10. Synthesis of 4-[N-[3-isopropyl-4-(methoxymeth-
oxy)phenyl]-N-methylamino]-3,5-dimethylbenzonitrile (14a).
Compound 14a was prepared from 9d (197 mg,
0.606 mmol) and iodomethane (250 lL, 4.02 mmol)
according to the procedure described for 10 in yield
72% (147 mg, brown oil).
sodium sulfate and concentrated in vacuo. Purification
by silica gel column chromatography (ethyl acetate/n-
hexane = 1:2) yielded the 3a as a white amorphous solid
(79.9 mg, 94%).
Compound 3a: 1H NMR (500 MHz, CD3OD) d 7.01 (s,
2H), 6.57 (d, 1H, J = 8.6 Hz), 6.16 (s, 1 H), 6.04 (d, 1H,
J = 7.3 Hz), 4.74 (dd, 1H, J = 9.5 Hz, 4.2 Hz), 3.43 (dd,
1H, J = 13.9 Hz, 4.1 Hz), 3.17 (septet, 1H, J = 6.9 Hz),
3.10 (s, 3H), 3.06 (dd, 1H, J = 14.1 Hz, 9.7 Hz), 2.03
(s, 6H), 1.07 (d, 6H, J = 6.9 Hz); 13C NMR (125 MHz,
CD3OD) d 177.6, 173.6, 146.1, 145.5, 143.6, 139.4,
137.0, 136.3, 130.8, 130.7, 117.2, 110.0, 109.8, 54.7,
38.9, 37.7, 28.2, 23.1, 18.2; HRMS (ESI) calcd for
C22H26N2O3SNa (M+Na+) 421.1566; found 421.1566.
1
Compound 14a: H NMR (500 MHz, CDCl3) d 7.42 (s,
2H), 6.91 (d, 1H, J = 8.8 Hz), 6.25 (s, 1 H), 6.15 (d, 1H,
J = 6.9 Hz), 5.09 (s, 2H), 3.49 (s, 3H), 3.26 (septet, 1H,
J = 6.9 Hz), 3.14 (s, 3H), 2.10 (s, 6H), 1.14 (d, 6H,
J = 6.9 Hz).
5.2.11. Synthesis of 4-[N-[3-isopropyl-4-(methoxymeth-
oxy)phenyl]-N-methylamino]-3,5-dimethylbenzaldehyde (15a).
Compound 15a was prepared from 14a (227 mg,
0.670 mmol) according to the procedure described for
11 in yield 60% (147 mg, yellow oil).
5.2.15. Synthesis of 4-[N-(cyclopropylmethyl)-N-[3-iso-
propyl-4-(methoxymethoxy)phenyl]amino]-3,5-dimethylbenzo-
nitrile (14b). Compound 14b was prepared from 9d
(142 mg, 0.437 mmol) and cyclopropylmethyl bromide
(250 lL, 2.58 mmol) according to the procedure
described for 10 in yield 61% (102 mg, colourless oil).
1
Compound 15a: H NMR (400 MHz, CDCl3) d 9.97 (s,
1H), 7.65 (s, 2H), 6.91 (d, 1H, J = 8.8 Hz), 6.27 (s, 1H),
6.18 (d, 1H, J = 6.6 Hz), 5.09 (s, 2H), 3.49 (s, 3H), 3.26
(septet, 1H, J = 6.9 Hz), 3.17 (s, 3H), 2.15 (s, 6H), 1.13
(d, 6H, J = 6.9 Hz).
1
Compound 14b: H NMR (500 MHz, CDCl3) d 7.42 (s,
2H), 6.90 (d, 1H, J = 8.9 Hz), 6.29 (d, 1H, J = 2.8 Hz),
6.19 (dd, 1H, J = 8.9 Hz, 2.9 Hz), 5.08 (s, 2H), 3.49 (s,
3H), 3.33 (d, 2H, J = 6.7 Hz), 3.26 (septet, 1H,
J = 6.9 Hz), 2.16 (s, 6H), 1.13 (d, 6H, J = 6.9 Hz), 1.11–
1.09 (m, 1H), 0.48–0.44 (m, 2H), 0.05–0.02 (m, 2H).
5.2.12. Synthesis of (Z)-5-[4-[N-[3-isopropyl-4-(methoxy-
methoxy)phenyl]-N-methylamino]-3,5-dimethylphenyl-
methylene]thiazolidine-2,4-dione (16a). Compound 16a
was prepared from 15a (137 mg, 0.401 mmol) and 2,4-
thiazolidinedione (5, 55.3 mg, 0.472 mmol) according
to the procedure described for 12 in yield 94%
(165 mg, orange solid).
5.2.16. Synthesis of 4-[N-(cyclopropylmethyl)-N-[3-iso-
propyl-4-(methoxymethoxy)phenyl]amino]-3,5-dimethyl-
benzaldehyde (15b). Compound 15b was prepared from
14b (89.8 mg, 0.237 mmol) according to the procedure
described for 11 in yield 89% (77.5 mg, yellow oil).
1
Compound 16a: H NMR (400 MHz, CDCl3) d 7.81 (s,
1H), 7.26 (s, 2H), 6.91 (d, 1H, J = 8.8 Hz), 6.29 (s, 1H),
6.16 (m, 1H), 5.09 (s, 2H), 3.49 (s, 3H), 3.27 (septet, 1H,
J = 6.9 Hz), 3.16 (s, 3H), 2.13 (s, 6H), 1.14 (d, 6H,
J = 6.9 Hz).
1
Compound 15b: H NMR (500 MHz, CDCl3) d 9.97 (s,
1H), 7.65 (s, 2H), 6.90 (d, 1H, J = 8.9 Hz), 6.32 (d, 1H,
J = 2.8 Hz), 6.23 (dd, 1H, J = 8.8 Hz, 2.8 Hz), 5.08 (s,
2H), 3.49 (s, 3H), 3.36 (d, 2H, J = 6.7 Hz), 3.26 (septet,
1H, J = 6.9 Hz), 2.21 (s, 6H), 1.2–1.1 (m, 1H), 1.40 (d,
6H, J = 6.9 Hz), 0.5–0.4 (m, 2H), 0.1–0.0 (m, 2H).
5.2.13. Synthesis of 5-[4-[N-[3-isopropyl-4-(methoxy-
methoxy)phenyl]-N-methylamino]-3,5-dimethylphenyl-
methyl]thiazolidine-2,4-dione (17a). Compound 17a was
prepared from 16a (165 mg, 0.375 mmol) according to
the procedure described for 13 in yield 86% (143 mg,
white solid).
5.2.17. Synthesis of (Z)-5-[4-[N-(cyclopropylmethyl)-N-
[3-isopropyl-4-(methoxymethoxy)phenyl]amino]-3,5-dim-
ethylphenylmethylene]thiazolidine-2,4-dione (16b). Com-
pound 16b was prepared from 15b (68.5 mg,
0.186 mmol) and 2,4-thiazolidinedione (5, 33.6 mg,
0.287 mmol) according to the procedure described for
12 in yield 86% (65.9 mg, orange solid).
Compound 17a: 1H NMR (500 MHz, CDCl3) d 7.80 (br
s, 1H), 6.97 (s, 2H), 6.89 (d, 1 H, J = 8.9 Hz), 6.23 (br s,
1H,), 6.11 (br, 1H,), 5.07 (s, 2H), 4.56 (dd, 1H,
J = 10.2 Hz, 3.8 Hz), 3.54 (dd, 1H, J = 13.8 Hz,
3.8 Hz), 3.49 (s, 3H), 3.25 (septet, 1H, J = 7.0 Hz),
3.13 (s, 3 H), 3.05 (dd, 1H, J = 14.0 Hz, 10.3 Hz), 2.06
(s, 6H), 1.13 (d, 6H, J = 6.9 Hz).
Compound 16b: 1H NMR (500 MHz, CDCl3) d 8.03 (br
s, 1H), 7.81 (s, 1H), 7.27 (s, 2H), 6.89 (d, 1H,
J = 8.8 Hz), 6.34 (d, 1 H, J = 2.8 Hz), 6.21 (dd, 1H,
J = 8.8 Hz, 2.7 Hz), 5.08 (s, 2H), 3.49 (s, 3H), 3.34 (d,
2H, J = 6.6 Hz), 3.26 (septet, 1H, J = 6.9 Hz), 2.18 (s,
6H), 1.2–1.1 (m, 1H), 1.15 (d, 6H, J = 6.9 Hz), 0.5–0.4
(m, 2H), 0.1–0.0 (m, 2H).
5.2.14. Synthesis of 5-[4-[N-(4-hydroxy-3-isopropylphe-
nyl)-N-methylamino]-3,5-dimethylphenylmethyl]thiazoli-
dine-2,4-dione (3a). To a stirred solution of 17a (94.7 mg,
0.214 mmol) in methanol (21 mL) and dichloromethane
(1.0 mL), 5 M HCl (4.0 mL) was added and stirred at
room temperature for 9 h. Then, the reaction mixture
was concentrated in vacuo. After the addition of water,
the aqueous phase was extracted with ethyl acetate. The
organic fractions were washed with brine, dried over
5.2.18. Synthesis of 5-[4-[N-(cyclopropylmethyl)-N-[3-iso-
propyl-4-(methoxymethoxy)phenyl]amino]-3,5-dimethyl-
phenylmethyl]thiazolidine-2,4-dione (17b). Compound
17b was prepared from 16b (53.8 mg, 0.112 mg) according

3122
T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
to the procedure described for 13 in yield 89% (48.0 mg,
white solid).
zolidinedione (5, 24.2 mg, 0.207 mmol) according to
the procedure described for 12 in yield 89% (74.6 mg, or-
ange solid).
Compound 17b: 1H NMR (500 MHz, CDCl3) d 8.37 (br s,
1H), 6.97 (s, 2H), 6.87 (d, 1H, J = 8.9 Hz), 6.27 (d, 1H,
J = 2.7 Hz), 6.16 (dd, 1H, J = 8.5 Hz, 2.5 Hz), 5.08 (s,
2H), 4.56 (dd, 1H, J = 10.2 Hz, 4.1 Hz), 3.54 (dd, 1H,
J = 14.0 Hz, 10.2 Hz), 3.49 (s, 3H), 3.32 (d, 2 H,
J = 6.6 Hz), 3.25 (septet, 1H, J = 6.9 Hz), 3.05 (dd, 1H,
J = 13.9 Hz, 10.2 Hz), 2.11 (s, 6H), 1.2–1.1 (m, 1H), 1.13
(d, 6H, J = 6.9 Hz), 0.5–0.4 (m, 2H), 0.1–0.0 (m, 2H).
Compound 16c: 1H NMR (500 MHz, CDCl3) d 8.04 (br s,
1H), 7.81 (s, 1H), 7.27 (s, 2H), 6.88 (d, 1H, J = 8.9 Hz),
6.26 (d, 1H, J = 2.8 Hz), 6.13 (dd, 1H, J = 8.9 Hz,
2.9 Hz), 5.08 (s, 2H), 3.49 (s, 3H), 3.5–3.4 (m, 2H), 3.25
(septet, 1H, J = 6.9 Hz), 2.14 (s, 6H), 1.7–1.6 (m, 2H),
1.4–1.2 (m, 6H), 1.13 (d, 6H, J = 6.9 Hz), 0.89 (t, 3H,
J = 7.0 Hz).
5.2.19. Synthesis of 5-[4-[N-(cyclopropylmethyl)-N-(4-
hydroxy-3-isopropylphenyl)amino]-3,5-dimethylphenyl-
methyl]thiazolidine-2,4-dione (3b). Compound 3b was
prepared from 17b (48.0 mg, 99.5 mmol) according to
the procedure described for 3a in yield 91% (44.0 mg,
white amorphous solid).
5.2.23. Synthesis of 5-[4-[N-n-hexyl-N-[3-isopropyl-4-
(methoxymethoxy)phenyl]amino]-3,5-dimethylphenyl-
methyl]thiazolidine-2,4-dione (17c). Compound 17c was
prepared from 16c (74.6 mg, 0.146 mmol) according to
the procedure described for 13 in yield 84% (63.2 mg,
white solid).
Compound 3b: 1H NMR (500 MHz, CD3OD) d 7.02 (s,
2H), 6.56 (d, 1H, J = 8.7 Hz), 6.23 (d, 1H, J = 2.7 Hz),
6.10 (dd, 1H, J = 8.6 Hz, 2.8 Hz), 4.75 (dd, 1H,
J = 9.2 Hz, 4.1 Hz), 3.42 (dd, 1H, J = 13.9 Hz, 9.1 Hz),
3.31 (d, 2H, J = 6.0 Hz), 3.18 (septet, 1H, J = 6.9 Hz),
3.10 (dd, 1H, J = 13.9 Hz, 9.2 Hz), 2.09 (s, 6H), 1.2–
1.0 (m, 1H), 1.08 (d, 6H, J = 6.8 Hz), 0.5-0.4 (m, 2H),
0.1–0.0 (m, 2H); 13C NMR (125 MHz, CD3OD) d
177.5, 173.5, 146.1, 144.6, 143.2, 139.8, 139.8, 137.0,
136.0, 130.9, 130.8, 117.2, 110.4, 110.1, 57.1, 54.6,
38.8, 23.2, 18.7, 14.3, 11.1, 4.6; HRMS (ESI) calcd for
C25H29N2O3S (MꢀH+) 437.1904; found 437.1911.
Compound 17c: 1H NMR (500 MHz, CDCl3) d 7.74 (br
s, 1H), 7.05 (s, 2H), 6.86 (d, 1H, J = 8.9 Hz), 6.19 (br s,
1H), 6.08 (dd, 1H, J = 8.8 Hz, 2.7 Hz), 5.07 (s, 2H), 4.56
(dd, 1H, J = 10.3 Hz, 3.8 Hz), 3.54 (dd, 1H, J = 14.1 Hz,
3.9 Hz), 3.53 (s, 3H), 3.5–3.4 (m, 2 H), 3.24 (septet, 1H,
J = 6.9 Hz), 3.05 (dd, 1H, J = 14.0 Hz, 10.4 Hz), 2.07 (s,
6H), 1.62 (br m, 2H), 1.31 (br m, 6H), 1.12 (d, 6H,
J = 6.9 Hz), 0.89 (t, 3H, J = 2.5 Hz).
5.2.24. Synthesis of 5-[4-[N-n-hexyl-N-(4-hydroxy-3-iso-
propylphenyl)amino]-3,5-dimethylphenylmethyl]thiazoli-
dine-2,4-dione (3c). Compound 3c was prepared from
17c (63.2 mg, 0.123 mmol) according to the procedure
described for 3a in yield 88% (47.7 mg, white amorphous
solid).
5.2.20. Synthesis of 4-[N-n-hexyl-N-[3-isopropyl-4-(meth-
oxymethoxy)phenyl]amino]-3,5-dimethylbenzonitrile (14c).
Compound 14c was prepared from 9d (142 mg,
0.437 mmol) and n-hexyl bromide (300 lL, 2.14 mmol)
according to the procedure described for 10 in yield
25% (73.2 mg, colourless oil).
1
Compound 3c: H NMR (500 MHz, CD3OD) d 7.01 (s,
2H), 6.54 (d, 1H, J = 8.7 Hz), 6.16 (d, 1H, J = 2.6 Hz),
5.99 (dd, 1H, J = 8.6 Hz, 2.7 Hz), 4.72 (dd, 1H,
J = 9.5 Hz, 4.1 Hz), 3.5–3.3 (m, 3H), 3.17 (septet, 1 H,
J = 6.9 Hz), 3.05 (dd, 1H, J = 14.0 Hz, 9.6 Hz), 2.04 (s,
6H), 1.7–1.5 (m, 2H), 1.4–1.2 (m, 6H), 1.07 (d, 6H,
J = 6.8 Hz), 0.9–0.8 (m, 3H); 13C NMR (125 MHz,
CD3OD) d 177.4, 173.4, 146.0, 144.7, 143.0, 139.7, 136.9,
136.1, 130.8, 117.2, 110.4, 110.2, 54.6, 52.8, 38.9, 32.9,
29.5, 28.1, 28.1, 23.7, 23.2, 18.8, 14.4; HRMS (ESI) calcd
for C27H35N2O3S (MꢀH+) 467.2374; found 467.2375.
1
Compound 14c: H NMR (500 MHz, CDCl3) d 7.43 (s,
2H), 6.88 (d, 1H, J = 8.9 Hz), 6.22 (d, 1H, J = 2.9 Hz),
6.11 (dd, 1H, J = 8.8 Hz, 3.0 Hz), 5.08 (s, 2H), 3.49 (s,
3H), 3.5–3.4 (m, 2H), 3.25 (septet, 1H, J = 6.9 Hz),
2.12 (s, 6H), 1.7–1.6 (m, 2H), 1.4–1.3 (m, 6H), 1.12 (d,
6H, J = 6.9 Hz), 0.89 (t, 3H, J = 6.9 Hz).
5.2.21. Synthesis of 4-[N-n-hexyl-N-[3-isopropyl-4-(meth-
oxymethoxy)phenyl]amino]-3,5-dimethylbenzaldehyde (15c).
Compound 15c was prepared from 14c (73.2 mg,
0.179 mmol) according to the procedure described for 11
in yield 92% (67.5 mg, yellow oil).
5.2.25. Synthesis of 4-[N-benzyl-N-[3-isopropyl-4-(meth-
oxymethoxy)phenyl]amino]-3,5-dimethylbenzonitrile (14d).
Compound 14d was prepared from 9d (217 mg,
0.669 mmol) and benzyl chloride (274 lL, 2.38 mmol)
according to the procedure described for 10 in yield
59% (164 mg, colourless oil).
1
Compound 15c: H NMR (500 MHz, CDCl3) d 9.97 (s,
1H), 7.63 (s, 2H), 6.88 (d, 1H, J = 8.9 Hz), 6.24 (d, 1H,
J = 2.8 Hz), 6.15 (dd, 1H, J = 8.8 Hz, 2.0 Hz), 5.08 (s,
2H), 3.49 (s, 3H), 3.5–3.4 (m, 2H), 3.25 (septet, 1H,
J = 6.9 Hz), 2.17 (s, 6H), 1.7-1.6 (m, 2H), 1.4–1.2 (m,
6H), 1.12 (d, 6H, J = 6.9 Hz), 0.89 (t, 3H, J = 6.9 Hz).
1
Compound 14d: H NMR (500 MHz, CDCl3) d 7.41 (s,
2H), 7.3-7.2 (m, 5H), 6.86 (d, 1H, J = 8.9 Hz), 6.35 (d,
1H, J = 3.0 Hz), 6.21 (dd, 1H, J = 8.9 Hz, 3.1 Hz), 5.08
(s, 2H), 4.67 (s, 2H), 3.48 (s, 3H), 3.23 (septet, 1H,
J = 6.9 Hz), 2.10 (s, 6H), 1.06 (d, 6H, J = 6.9 Hz).
5.2.22. Synthesis of (Z)-5-[4-[N-n-hexyl-N-[3-isopropyl-4-
(methoxymethoxy)phenyl]amino]-3,5-dimethylphenylm-
ethylene]thiazolidine-2,4-dione (16c). Compound 16c was
prepared from 15c (67.5 mg, 0.164 mmol) and 2,4-thia-
5.2.26. Synthesis of 4-[N-benzyl-N-[3-isopropyl-4-(meth-
oxymethoxy)phenyl]amino]-3,5-dimethylbenzaldehyde (15d).
Compound 15d was prepared from 14d (164 mg,

T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
3123
0.396 mmol) according to the procedure described
for 11 in yield 95% (156 mg, yellow oil).
0.618 mmol) and isobutyl bromide (200 lL, 1.85 mmol)
according to the procedure described for 10 in yield 41%
(95.2 mg, pale yellow oil).
Compound15d:1H NMR (500 MHz, CDCl3)d9.67(s, 1H),
7.63 (s, 2H), 7.4–7.2 (m, 5H), 6.85 (d, 1H, J = 8.9 Hz), 6.37
(d, 1H, J = 2.9 Hz), 6.23 (dd, 1H, J = 8.8 Hz, 2.9 Hz), 5.07
(s, 2H), 4.70 (s, 2H), 3.48 (s, 3H), 3.22 (septet, 1H,
J = 6.9 Hz), 2.15 (s, 6H), 1.05 (d, 6H, J = 6.9 Hz).
1
Compound 14e: H NMR (500 MHz, CDCl3) d 7.43 (s,
2H), 6.86 (d, 1H, J = 8.9 Hz), 6.27 (d, 1H, J = 3.0 Hz),
6.10 (dd, 1H, J = 8.9 Hz, 3.0 Hz), 5.08 (s, 2H), 3.48 (s,
3H), 3.28 (d, 2H, J = 6.4 Hz), 3.25 (septet, 1H,
J = 6.9 Hz), 2.14 (s, 6H), 1.96 (heptet, 1H, J = 6.6 Hz),
1.12 (d, 6H, J = 6.9 Hz), 0.94 (d, 6H, J = 6.7 Hz).
5.2.27. Synthesis of (Z)-5-[4-[N-benzyl-N-[3-isopropyl-4-
(methoxymethoxy)phenyl]amino]-3,5-dimethylphenyl-
methylene]thiazolidine-2,4-dione (16d). Compound 16d
was prepared from 15d (156 mg, 0.374 mmol) and 2,4-
thiazolidinedione (5, 49.2 mg, 0.420 mmol) according to
the procedure described for 12 in quant (214 mg, orange
solid).
5.2.31. Synthesis of 4-[N-isobutyl-N-[3-isopropyl-4-
(methoxymethoxy)phenyl]amino]-3,5-dimethylbenzalde-
hyde (15e). Compound 15e was prepared from 14e
(95.2 mg, 0.250 mmol) according to the procedure de-
scribed for 11 in yield 91% (87.0 mg, yellow oil).
1
Compound 16d: 1H NMR (500 MHz, CDCl3) d 7.93 (br s,
1H), 7.80 (s, 1H), 7.4–7.2 (m, 7H), 6.85 (d, 1H,
J = 8.9 Hz), 6.38 (d, 1H, J = 2.9 Hz), 6.22 (dd, 1H,
J = 9.1 Hz, 3.1 Hz), 5.07 (s, 2H), 4.69 (s, 2H), 3.48 (s,
3H), 3.26 (septet, 1H, J = 7.0 Hz), 2.13 (s, 6H), 1.06 (d,
6H, J = 6.9 Hz).
Compound 15e: H NMR (500 MHz, CDCl3) d 9.97 (s,
1H), 7.65 (s, 2H), 6.86 (d, 1H, J = 8.9 Hz), 6.29 (d, 1H,
J = 3.0 Hz), 6.13 (dd, 1H, J = 8.9 Hz, 3.1 Hz), 5.08 (s,
2H), 3.48 (s, 3H), 3.32 (d, 2H, J = 6.5 Hz), 3.25 (septet,
1H, J = 6.9 Hz), 2.19 (s, 6H), 1.99 (septet, 1H,
J = 6.6 Hz), 1.12 (d, 6H, J = 6.9 Hz), 0.94 (d, 6H,
J = 6.7 Hz).
5.2.28. Synthesis of 5-[4-[N-benzyl-N-[3-isopropyl-4-
(methoxymethoxy)phenyl]amino]-3,5-dimethylphenylm-
ethyl]thiazolidine-2,4-dione (17d). Compound 17d was
prepared from 16d (193 mg, 0.374 mg) according to
the procedure described for 13 in yield 87% (169 mg, yel-
low solid).
5.2.32. Synthesis of (Z)-5-[4-[N-isobutyl-N-[3-isopropyl-
4-(methoxymethoxy)phenyl]amino]-3,5-dimethylphenyl-
methylene]thiazolidine-2,4-dione (16e). Compound 16e
was prepared from 15e (87.0 mg, 0.227 mmol) and
2,4-thiazolidinedione (5, 32.6 mg, 0.278 mmol) accord-
ing to the procedure described for 12 in yield 89%
(97.4 mg, yellow solid).
Compound 17d: 1H NMR (500 MHz, CDCl3) d 7.71 (br
s, 1H), 7.4–7.2 (m, 5H), 7.05 (s, 2H), 6.83 (d, 1H,
J = 8.9 Hz), 6.31 (d, 1H, J = 3.0 Hz), 6.18 (dd, 1H,
J = 8.6 Hz, 2.8 Hz), 5.06 (s, 2H), 4.67 (s, 2H), 4.55 (dd,
1H, J = 10.1 Hz, 2.9 Hz), 3.52 (dd, 1H, J = 14.0 Hz,
4.0 Hz), 3.48 (s, 3H), 3.22 (septet, 1H, J = 6.7 Hz),
3.05 (dd, 1H, J = 14.2 Hz, 10.4 Hz), 2.06 (s, 6H), 1.05
(d, 6H, J = 6.9 Hz).
Compound 16e: 1H NMR (500 MHz, CDCl3) d 8.13 (br
s, 1H), 7.81 (s, 1H), 7.27 (s, 2H), 6.85 (d, 1H,
J = 8.9 Hz), 6.32 (d, 1H, J = 3.0 Hz), 6.11 (dd, 1H,
J = 8.9 Hz, 3.1 Hz), 5.08 (s, 2H), 3.49 (s, 3H), 3.30 (d,
2H, J = 6.5 Hz), 3.27 (septet, 1H, J = 6.9 Hz), 2.16 (s,
6 H), 1.98 (septet, 1H, J = 6.6 Hz), 1.13 (d, 6H,
J = 6.9 Hz), 0.95 (d, 6H, J = 6.7 Hz).
5.2.29. Synthesis of 5-[4-[N-benzyl-N-(4-hydroxy-3-isopropyl-
phenyl)amino]-3,5-dimethylphenylmethyl]thiazolidine-2,
4-dione (3d). Compound 3d was prepared from 17d
(169 mg,0.327 mmol)accordingtotheproceduredescribed
for 3a in yield 77% (112 mg, white amorphous solid).
5.2.33. Synthesis of 5-[4-[N-isobutyl-N-[3-isopropyl-4-
(methoxymethoxy)phenyl]amino]-3,5-dimethylphenyl-
methyl]thiazolidine-2,4-dione (17e). Compound 17e was
prepared from 16e (97.4 mg, 0.202 mg) according to
the procedure described for 13 in yield 72% (70.5 mg,
pale yellow solid).
Compound 3d: 1H NMR (500 MHz, CD3OD) d 7.28 (d,
2H, J = 7.5 Hz), 7.22 (t, 2H, J = 7.7 Hz), 7.16 (t, 1H,
J = 7.2 Hz), 6.97 (s, 2H), 6.52 (d, 1 H, J = 8.7 Hz), 6.27
(d, 1H, J = 2.8 Hz), 6.09 (dd, 1H, J = 8.7 Hz, 2.9 Hz),
4.69 (dd, 1H, J = 9.3 Hz, 4.2 Hz), 4.62 (s, 2H), 3.38
(dd, 1H, J = 14.0 Hz, 4.1 Hz), 3.14 (septet, 1H,
J = 6.9 Hz), 3.05 (dd, 1H, J = 14.0 Hz, 9.4 Hz), 2.01 (s,
6H), 1.00 (d, 6H, J = 6.9 Hz); 13C NMR (125 MHz,
CD3OD) d 177.3, 173.4, 146.6, 145.6, 143.2, 140.8,
139.6, 136.7, 136.2, 131.1, 131.1, 129.1, 129.0, 127.7,
116.9, 112.0, 111.7, 56.6, 54.5, 38.8, 28.0, 23.1, 19.2;
HRMS (ESI) calcd for C28H29N2O3S (MꢀH+)
473.1904; found 473.1893.
Compound 17e: 1H NMR (400 MHz, CDCl3) d 7.74 (br
s, 1H), 6.98 (s, 2H), 6.84 (d, 1H, J = 8.9 Hz), 6.25 (d, 1H,
J = 2.9 Hz), 6.07 (dd, 1H, J = 9.0 Hz, 3.0 Hz), 5.07 (s,
2H), 4.56 (dd, 1H, J = 10.4 Hz, 3.9 Hz), 5.07 (s, 2H),
4.56 (dd, 1H, J = 10.4 Hz, 3.9 Hz), 3.55 (dd, 1 H,
J = 14.1 Hz, 4.1 Hz), 3.48 (s, 3H), 3.25 (d, 2H,
J = 6.8 Hz), 3.24 (septet, 1H, J = 6.7 Hz), 3.04 (dd, 1H,
J = 13.9 Hz, 10.3 Hz), 2.09 (s, 6H), 1.96 (septet, 1H,
J = 6.9 Hz), 1.12 (d, 6H, J = 6.9 Hz), 0.96 (d, 6H,
J = 6.7 Hz).
5.2.34. Synthesis of 5-[4-[N-(4-hydroxy-3-isopropylphe-
nyl)-N-isobutylamino]-3,5-dimethylphenylmethyl]thiazoli-
dine-2,4-dione (3e). Compound 3e was prepared from
17e (70.5 mg, 0.146 mmol) according to the procedure
5.2.30. Synthesis of 4-[N-isobutyl-N-[3-isopropyl-4-
(methoxymethoxy)phenyl]amino]-3,5-dimethylbenzonitri-
le (14e). Compound 14e was prepared from 9d (201 mg,

3124
T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
described for 3a in yield 80% (51.3 mg, pale yellow
amorphous solid).
was prepared from 16f (173 mg, 0.350 mg) according to
the procedure described for 13 in yield 70% (122 mg, pale
yellow solid).
Compound 3e: 1H NMR (500 MHz, CD3OD) d 7.02 (s,
2H), 6.53 (d, 1H, J = 8.7 Hz), 6.20 (d, 1H, J = 2.8 Hz),
6.01 (dd, 1H, J = 8.7 Hz, 2.9 Hz), 4.71 (dd, 1H,
J = 9.4 Hz, 4.1 Hz), 3.42 (dd, 1H, J = 14.0 Hz,
4.1 Hz), 3.25 (d, 1H, J = 6.5 Hz), 3.17 (septet, 1H,
J = 6.9 Hz), 3.06 (dd, 1H, J = 14.0 Hz, 9.4 Hz), 2.06
(s, 6H), 1.92 (septet, 1H, J = 6.6 Hz), 1.07 (d, 6H,
J = 6.9 Hz), 0.94 (d, 6H, J = 6.7 Hz); 13C NMR
(125 MHz, CD3OD) d 177.4, 173.4, 146.2, 145.4,
143.6, 139.3, 136.7, 135.9, 131.1, 131.0, 117.0, 110.9,
110.7, 61.7, 54.6, 38.9, 30.1, 28.9, 23.2, 21.7, 19.0;
HRMS (ESI) calcd for C25H31N2O3S1 (MꢀH+)
439.2050; found 439.2058.
Compound 17f: 1H NMR (500 MHz, CDCl3) d 7.77 (br
s, 1H), 7.05 (s, 2H), 6.85 (d, 1H, J = 8.8 Hz), 6.25 (br s,
1H), 6.10 (d, 1H, J = 7.2 Hz), 5.4–5.3 (m, 1 H), 4.56 (dd,
1H, J = 10.2 Hz, 3.9 Hz), 4.04 (d, 2H, J = 6.3 Hz), 3.53
(dd, 1H, J = 14.1 Hz, 4.2 Hz), 3.48 (s, 3H), 3.24 (septet,
1H, J = 6.8 Hz), 2.08 (s, 6H), 1.69 (br s, 3H), 1.62 (br s,
3H), 1.11 (d, 6H, J = 6.9 Hz).
5.2.39. Synthesis of 5-[4-[N-(4-hydroxy-3-isopropylphe-
nyl)-N-(3-methyl-2-butenyl)amino]-3,5-dimethylphenyl-
methyl]thiazolidine-2,4-dione (3f). Compound 3f was
prepared from 17f (122 mg, 0.245 mmol) according to
the procedure described for 3a in yield 55% (61.1 mg,
orange amorphous solid).
5.2.35. Synthesis of 4-[N-[3-isopropyl-4-(methoxymeth-
oxy)phenyl]-N-(3-methyl-2-butenyl)amino]-3,5-dimethyl-
benzonitrile (14f). Compound 14f was prepared from 9d
(203 mg, 0.627 mmol) and prenyl bromide (220 lL,
1.87 mmol) according to the procedure described for
10 in yield 80% (198 mg, pale yellow oil).
1
Compound 3f: H NMR (500 MHz, CD3OD) d 6.99 (s,
2H), 6.53 (d, 1H, J = 8.7 Hz), 6.21 (d, 1H, J = 2.7 Hz),
6.00 (dd, 1H, J = 8.6 Hz, 2.8 Hz), 5.4–5.3 (m, 1H),
4.71 (dd, 1H, J = 9.3 Hz, 4.2 Hz), 4.02 (d, 2H,
J = 6.4 Hz), 3.40 (dd, 1H, J = 13.9 Hz, 4.1 Hz), 3.17
(septet, 1H, J = 6.9 Hz), 3.06 (dd, 1H, J = 14.0 Hz,
9.3 Hz), 2.05 (s, 6H), 1.67 (s, 3H), 1.58 (s, 3H), 1.07
(d, 6H, J = 6.7 Hz); 13C NMR (125 MHz, CD3OD) d
177.4, 173.4, 146.1, 145.0, 143.1, 139.7, 136.9, 136.0,
134.5, 130.8, 123.5, 117.2, 110.8, 110.6, 54.6, 50.1,
38.8, 29.1, 25.9, 23.2, 18.8, 17.9; HRMS (ESI) calcd
for C26H31N2O3S1 (MꢀH+) 451.2050; found 451.2060.
1
Compound 14f: H NMR (500 MHz, CDCl3) d 7.41 (s,
2H), 6.88 (d, 1H, J = 8.9 Hz), 6.27 (d, 1H, J = 2.4 Hz),
6.13 (dd, 1H, J = 8.8 Hz, 2.6 Hz), 5.4–5.3 (m, 1H),
4.05 (d, 2H, J = 6.3 Hz), 3.48 (s, 3H), 3.25 (septet, 1H,
J = 6.9 Hz), 2.13 (s, 6H), 1.70 (br m, 3H), 1.62 (br s,
3H), 1.12 (d, 6H, J = 6.9 Hz).
5.2.36. Synthesis of 4-[N-[3-isopropyl-4-(methoxymeth-
oxy)phenyl]-N-(3-methyl-2-butenyl)amino]-3,5-dimethyl-
benzaldehyde (15f). Compound 15f was prepared from
14f (198 mg, 0.504 mmol) according to the procedure
described for 11 in yield 90% (179 mg, yellow oil).
5.2.40. Synthesis of 4-[N-(cyclohexylmethyl)-N-[3-isopro-
pyl-4-(methoxymethoxy)phenyl]amino]-3,5-dimethylbenzo-
nitrile (14g). Compound 14g was prepared from 9d
(200 mg, 0.616 mmol) and cyclohexylmethyl bromide
(260 lL, 1.88 mmol) according to the procedure
described for 10 in yield 69% (180 mg, orange oil).
1
Compound 15f: H NMR (500 MHz, CDCl3) d 9.96 (s,
1H), 7.63 (s, 2H), 6.87 (d, 1H, J = 8.9 Hz), 6.29 (d, 1H,
J = 2.0 Hz), 6.16 (dd, 1H, J = 8.6 Hz, 2.1 Hz), 5.4–5.3
(m, 1H), 5.08 (s, 2H), 4.08 (d, 2H, J = 6.3 Hz), 3.49 (s,
3H), 3.25 (septet, 1H, J = 6.9 Hz), 2.18 (s, 6H), 1.70 (s,
3H), 1.62 (s, 3H), 1.05 (d, 6H, J = 6.9 Hz).
1
Compound 14g: H NMR (500 MHz, CDCl3) d 7.43 (s,
2H), 6.86 (d, 1H, J = 8.9 Hz), 6.24 (d, 1H, J = 2.8 Hz),
6.09 (dd, 1H, J = 8.9 Hz, 2.8 Hz), 5.08 (s, 2H), 3.48 (s,
3H), 3.25 (septet, 1H, J = 7.0 Hz), 2.13 (s, 6H), 1.8–1.7
(m, 4H), 1.7–1.6 (m, 2H), 1.3–1.1 (m, 3H), 1.12 (d,
6H, J = 6.9 Hz), 1.0–0.9 (m, 2H).
5.2.37. Synthesis of (Z)-5-[4-[N-[3-isopropyl-4-(meth-
oxymethoxy)phenyl]-N-(3-methyl-2-butenyl)amino]-3,5-
dimethylphenylmethylene]thiazolidine-2,4-dione
(16f).
5.2.41. Synthesis of 4-[N-(cyclohexylmethyl)-N-[3-isopro-
pyl-4-(methoxymethoxy)phenyl]amino]-3,5-dimethylbenz-
aldehyde (15g). Compound 15g was prepared from 14g
(180 mg, 0.427 mmol) according to the procedure de-
scribed for 11 in yield 90% (162 mg, yellow oil).
Compound 16f was prepared from 15f (179 mg,
0.452 mmol) and 2,4-thiazolidinedione (5, 60.5 mg,
0.517 mmol) according to the procedure described for
12 in yield 77% (173 mg, orange solid).
1
Compound 16f: 1H NMR (500 MHz, CDCl3) d 8.01 (br
s, 1H), 7.81 (s, 1H), 7.26 (s, 2H), 6.87 (d, 1H,
J = 8.9 Hz), 6.31 (d, 1H, J = 3.1 Hz), 6.14 (dd, 1H,
J = 9.0 Hz, 3.1 Hz), 5.4–5.3 (m, 1H), 5.08 (s, 2H), 4.07
(d, 2H, J = 6.2 Hz), 3.49 (s, 3H), 3.25 (septet, 1H,
J = 6.9 Hz), 2.15 (s, 6H), 1.70 (br m, 3H), 1.64 (s, 3H),
1.11 (d, 6H, J = 6.9 Hz).
Compound 15g: H NMR (500 MHz, CDCl3) d 9.97 (s,
1H), 7.65 (s, 2H), 6.87 (d, 1H, J = 8.9 Hz), 6.26 (d, 1H,
J = 3.0 Hz), 6.13 (dd, 1H, J = 8.8 Hz, 3.0 Hz), 5.08 (s,
2H), 3.49 (s, 3H), 3.32 (d, 2H, J = 6.2 Hz), 3.25 (septet,
1H, J = 6.9 Hz), 2.18 (s, 6H), 1.8–1.6 (m, 7H), 1.3–1.1
(m, 2H), 1.12 (d, 6H, J = 6.9 Hz), 1.0–0.9 (m, 2H).
5.2.42. Synthesis of (Z)-5-[4-[N-(cyclohexylmethyl)-N-[3-
isopropyl-4-(methoxymethoxy)phenyl]amino]-3,5-dimeth-
ylphenylmethylene]thiazolidine-2,4-dione (16g). Com-
pound 16g was prepared from 15g (162 mg,
5.2.38. Synthesis of 5-[4-[N-[3-isopropyl-4-(methoxymeth-
oxy)phenyl]-N-(3-methyl-2-butenyl)amino]-3,5-dimethyl-
phenylmethyl]thiazolidine-2,4-dione (17f). Compound 17f

T. Komatsu et al. / Bioorg. Med. Chem. 15 (2007) 3115–3126
3125
0.382 mmol) and 2,4-thiazolidinedione (5, 49.9 mg,
0.426 mmol) according to the procedure described for
12 in yield 83% (167 mg, yellow solid).
to attach to the plates. Then, the medium was exchanged
for 0.4 mL of serum-free DMEM and transfection was
performed by use of the transfection reagent Lipofect-
AMINE 2000 (Invitrogen) according to the manufac-
turer’s instructions. For each well, cells were
transfected with 100 ng of receptor-expression plasmid,
200 ng of (TREpal)3-TKLUC, 100 ng of the reference
plasmid pCMVb (Clontech) and carrier plasmid
pUC18, to adjust the total DNA amount to 800 ng
DMEM (0.1 mL) containing transfection reagent–DNA
complex was added to each well. After 4–5 h of culture
at 37 ꢁC in 5% CO2, 0.5 mL DMEM with 10% charcoal
dextran-treated FBS (Hyclone) and test compounds were
added to cells. Each test compound was added as an
EtOH solution (final 0.5% EtOH). After an additional
40 h of incubation, the cells were harvested, and luciferase
assay was performed with the Luciferase Assay System
(Toyo Ink Mfg. Co., Ltd.). The luciferase activities were
normalized to b-galactosidase activities. Assay was done
in triplicate under each condition.
Compound 16g: 1H NMR (500 MHz, CDCl3) d 8.08 (br
s, 1H), 7.81 (s, 1H), 7.27 (s, 2H), 6.86 (d, 1H,
J = 8.9 Hz), 6.28 (d, 1H, J = 2.9 Hz), 6.11 (dd, 1H,
J = 8.9 Hz, 3.0 Hz), 5.08 (s, 2H), 3.49 (s, 3H), 3.30 (d,
2H, J = 6.2 Hz), 3.26 (septet, 1H, J = 6.9 Hz), 2.15 (s,
6H), 1.9–1.6 (m, 6H), 1.3–1.1 (m, 3H), 1.13 (d, 6H,
J = 6.9 Hz), 1.0–0.9 (m, 2H).
5.2.43. Synthesis of 5-[4-[N-(cyclohexylmethyl)-N-[3-iso-
propyl-4-(methoxymethoxy)phenyl]amino]-3,5-dimethyl-
phenylmethyl]thiazolidine-2,4-dione (17g). Compound
17g was prepared from 16g (167 mg, 0.319 mg) accord-
ing to the procedure described for 13 in yield 87%
(146 mg, yellow solid).
Compound 17g: 1H NMR (400 MHz, CDCl3) d 7.78 (br
s, 1H), 6.98 (s, 2H), 6.84 (d, 1H, J = 8.9 Hz), 6.22 (d, 1H,
J = 3.0 Hz), 6.07 (dd, 1H, J = 8.9 Hz, 3.0 Hz), 5.07 (s,
2H), 4.57 (dd, 1H, J = 10.3 Hz, 3.8 Hz), 3.55 (dd, 1H,
J = 13.9 Hz, 3.7 Hz), 3.48 (s, 3H), 3.26 (d, 2 H,
J = 6.4 Hz), 3.24 (septet, 1H, J = 6.8 Hz), 3.04 (dd, 1H,
J = 14.0 Hz, 10.4 Hz), 2.08 (s, 6H), 1.9–1.5 (m, 6H),
1.3–1.1 (m, 3H).
Acknowledgments
We thank Dr. Hiroshi Fukasawa, Institute of Medicinal
Molecular Design, Inc., Japan, for his valuable com-
ments. This work was partially supported by Grants-
in-Aid for Scientific Research from The Ministry of
Education, Science, Sports and Culture, Japan (Priority
Areas 18032026), and from the Japan Society for the
Promotion of Science (JSPS). T.H. thanks The Mochida
Memorial Foundation for Medical and Pharmaceutical
Research for financial support. C.S., a postdoctoral fel-
low from Prince of Songkla University, Thailand,
acknowledges the support of JSPS in the form of a Fel-
lowship for Foreign Researchers.
5.2.44. Synthesis of 5-[4-[N-(cyclohexylmethyl)-N-(4-hydro-
xy-3-isopropylphenyl)amino]-3,5-dimethylphenylmethyl]-
thiazolidine-2,4-dione (3g). Compound 3g was prepared
from 17g (146 mg, 0.278 mmol) according to the proce-
dure described for 3a in yield 52% (69.9 mg, pale yellow
amorphous solid).
Compound 3g: 1H NMR (500 MHz, CD3OD) d 7.02 (s,
2H), 6.52 (d, 1H, J = 8.7 Hz), 6.00 (dd, 1H, J = 11.7 Hz,
3.0 Hz), 4.73 (dd, 1H, J = 9.4 Hz, 4.1 Hz), 3.43 (dd, 1H,
J = 14.0 Hz, 4.1 Hz), 3.26 (d, 2H, J = 6.2 Hz), 3.15 (sep-
tet, 1H, J = 6.9 Hz), 3.07 (dd, 1H, J = 14.0 Hz, 9.4 Hz),
2.05 (s, 6H), 1.9–1.7 (m, 2H), 1.7–1.5 (m, 4H), 1.07 (d,
6H, J = 6.9 Hz), 1.1–0.9 (m, 2H); 13C NMR
(125 MHz, CD3OD) d 177.5, 173.5, 146.2, 145.5,
143.7, 139.3, 136.8, 135.9, 131.1, 131.0, 117.0, 110.9,
110.7, 60.5, 54.6, 40.0, 38.9, 33.4, 28.1, 27.6, 27.4, 23.2,
18.9; HRMS (ESI) calcd for C28H35N2O3S1 (MꢀH+)
479.2363; found 479.2372.
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