Novel calcium antagonists with both calcium overload inhibition and antioxidant activity. 2. Structure-activity relationships of thiazolidinone derivatives

Article abstract of DOI:10.1021/jm9900927

CP-060 (1), 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2- [3,4-(methylenedioxy)-phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one, is a novel type of Ca²⁺ antagonist possessing both Ca²⁺ overload inhibition and antioxida

Full text of DOI:10.1021/jm9900927

3134
J . Med. Chem. 1999, 42, 3134-3146
Novel Ca lciu m An ta gon ists w ith Both Ca lciu m Over loa d In h ibition a n d
An tioxid a n t Activity. 2. Str u ctu r e-Activity Rela tion sh ip s of Th ia zolid in on e
Der iva tives
Tatsuya Kato,* Tomokazu Ozaki, Kazuhiko Tamura, Yoshiyuki Suzuki, Michitaka Akima, and Nobuhiro Ohi
Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Company, Ltd., 135, 1-Chome Komakado,
Gotemba City, Shizuoka 412-8513, J apan
Received March 1, 1999
CP-060 (1), 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-methyl-N-[2-[3,4-(methylenedioxy)-
phenoxy]ethyl]amino]propyl]-1,3-thiazolidin-4-one, is a novel type of Ca2+ antagonist possessing
both Ca2+ overload inhibition and antioxidant activity. The structure-activity relationships
for this series of compounds were studied by synthesizing the analogues and evaluating these
three kinds of activity. Ca2+ antagonistic activity was largely determined by the lipophilicity
of the phenyl group at the 2-position and the length of the alkyl chains. As for the antioxidant
activity, it was demonstrated that the phenolic hydroxyl group is an essential structural
element. Compounds with potent activity were evaluated for their effect on the coronary blood
flow in vivo. Among these compounds, compound 1 was shown to be the most potent.
Furthermore, the enantiomers of 1 were resolved by high-performance liquid chromatography
with a chiral column. Compound (-)-1 showed about 10 times higher Ca2+ antagonistic activity
than (+)-1, though both enantiomers had similar potency in Ca2+ overload inhibition and
antioxidant activity. An X-ray crystal structure determination of (-)-1 hydrogen fumarate
identified (-)-1 as having S configuration at the 2-position.
In tr od u ction
In a previous paper,1 we reported the design, synthe-
sis, and pharmacological evaluation of a series of 2-(3,5-
di-tert-butyl-4-hydroxyphenyl)-3-(aminopropyl)-1,3-thi-
azolidin-4-ones. These compounds have proved to be a
novel class of Ca2+ antagonists possessing both Ca2+
overload inhibition and antioxidant activity. In particu-
lar, 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-3-[3-[N-meth-
yl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amino]-
propyl]-1,3-thiazolidin-4-one (1) was found to be highly
potent and to possess a well-balanced combination of
these three actions in vitro. We demonstrated that the
Ca2+ antagonistic and Ca2+ overload inhibitory activities
depended on the substituents at the amino group.
However, we could not clarify structure-activity rela-
tionships (SARs) at other parts of the molecule: sub-
stituent type in the phenyl group at the 2-position, R1-
R4; length of the methylene chain, m; substituent type
in the amino group, R5 and R6; and stereochemistry at
the 2-position in the thiazolidinone ring, as shown in
the general formula 2.
In this paper, we describe the synthesis, pharmaco-
logical evaluation, and SARs of the 2-aryl-3-(ami-
noalkyl)-1,3-thiazolidinone derivatives and their optical
isomers.
or phosphorus tribromide to give the corresponding
chlorides 8a -m or bromide 9a (Table 9). Finally,
aminations of 8a -m or 9a with amines 10 produced the
target compounds 11-27 (method A or B).
Thiazolidinone derivative 32, bearing a two-carbon
chain (m ) 2), was prepared as shown in Scheme 2,
because the amination was not successful in this case.
The possible reason for this is that the chloride 8k may
decompose via intramolecular cyclization. Initially, ami-
nation of N-(2-bromoethyl)phthalimide (28) with amine
10a gave 29, and then 29 was transformed into diamine
30 by treatment with methylamine. Subsequently, the
diamine 30 was condensed with aldehyde 3a to give
imine 31, and further condensation of 31 with R-mer-
captoacetic acid 6 produced 32.
Ch em istr y
The aminoalkylthiazolidinone derivatives 11-27 were
synthesized by a general method1 as shown in Scheme
1. Initially, benzaldehydes 3 were condensed with
ω-amino alcohols 4 to give imines 5. A further conden-
sation of the imines 5 with R-mercaptoacetic acid 6
afforded the key intermediates 7a -m (Table 8). Com-
pounds 7a -m were then treated with thionyl chloride
10.1021/jm9900927 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/02/1999

Novel Calcium Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3135
Sch em e 1a
a
Reagents and reaction conditions: (a) reflux in benzene with a Dean-Stark trap; (b) for X ) Cl, SOCl2, CH2Cl2, reflux; (c) for X ) Br,
PBr3, Et2O, rt; (d) for X ) Cl, Na2CO3, NaI, DMF, 80 °C (method A); (e) for X ) Br, K2CO3, acetone, reflux (method B).
Sch em e 2a
a
Reagents and reaction conditions: (a) K2CO3, DMF, 90 °C; (b) MeNH2, MeOH, rt; (c) reflux in benzene with a Dean-Stark trap.
The elimination of a tert-butyl group from the phenyl
ring of 1 proceeded in HBr/H2O/AcOH to give 33.
Sulfoxide 34 was prepared by oxidation of 1 with H2O2.
A thiolactam 35 was obtained by treating 1 with
Lawesson’s reagent2 (Scheme 3).
Op tica l Resolu tion . The optical resolution of 1 was
carried out by using preparative HPLC with a chiral
column composed of cellulose 3,5-dimethylphenylcar-
bamate (Chiralcel OD).3
Absolu te Con figu r a tion . The absolute configuration
of (-)-1 was determined by means of an X-ray crystal-
lographic analysis using its hydrogen fumarate salt. The
X-ray crystal structure of (-)-1 hydrogen fumarate, as
shown in Figure 1, revealed that the absolute configu-
ration of the 2-position in the thiazolidinone ring was
S.
F igu r e 1. ORTEP drawing of (-)-1 hydrogen fumarate which
establishes its absolute stereochemistry.
The results are summarized in Tables 1-4. The anti-
oxidant activity of representative thiazolidinone deriva-
tives was examined, and the results are summarized
in Table 5.
Resu lts a n d Discu ssion
Ca 2+ An ta gon istic Activity. The in vitro Ca2+
antagonistic activity of compounds was evaluated by
means of a K+-depolarized isolated rat aorta.4 As shown
in Table 1, substituents in the phenyl group at the
The compounds prepared in this study were initially
tested for Ca2+ antagonistic activity, and some com-
pounds were tested for Ca2+ overload inhibitory activity.

3136 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Kato et al.
Sch em e 3
2-position, R1-R4, affected the activity significantly.
When R1 and R4 were OH and H, respectively, the
effects of substituents R2 and R3 were shown to be in
the following order of potency: tBu > iPr > Et > Me >
H > MeO > Cl. When one tert-butyl group of 1 was
replaced with a methyl group, as in 17, or with a
hydrogen atom, as in 33, this activity declined. In
contrast, replacement of the phenolic hydroxyl group by
a methoxy group, as in 19, slightly increased the
activity. In terms of results, it may be speculated that
Ca2+ antagonistic activity in this series was enhanced
by increased lipophilicity of the phenyl group at the
2-position of the thiazolidinone structure. The carbon
chain length (m, n) was then optimized. The most potent
activity was observed with m ) 3 and n ) 2-3 as shown
in Table 2. The effect of the N-methyl substituent in
the amine moiety was also examined. As shown in Table
3, the potency order was Me (1) ) Et (25) > H (24) >
had efficacy comparable with that of 1; however, N-
isopropyl compound 26 was less potent.
An t ioxid a n t Act ivit y. The antioxidant activity of
some compounds was evaluated through the determi-
nation of their in vitro inhibitory activity on soybean
lipoxygenase-induced lipid peroxidations of rabbit low-
density lipoprotein (LDL).6 All test compounds except
for 19 exhibited potency similar to the known antioxi-
dant 3,5-di-tert-butyl-4-hydroxytoluene (BHT).7 In con-
trast, compound 19, where the phenolic hydroxyl group
was replaced by the methoxy group, showed signifi-
cantly reduced activity. Therefore, it was suggested that
the phenolic hydroxyl group is an essential structure
for potent antioxidant activity.
From these results, 1, 22, and 25 were regarded as
having these three kinds of activity in vitro. We further
assessed their effect on coronary blood flows in anes-
thetized dogs. As shown in Table 6, 1 was found to be
the most potent compound for increasing coronary blood
flow.
We resolved 1 into its enantiomers. The chiral com-
pound (-)-1 showed about 10 times more potent Ca2+
antagonistic activity than (+)-1, though both enanti-
omers had similar potency in Ca2+ overload inhibitory
and antioxidant activities. Furthermore, (-)-1 showed
more coronary blood flow-increasing activity than dilt-
iazem.
Compound (-)-1 was submitted to an extensive
pharmacological evaluation as a novel Ca2+ antagonist.
The binding studies to the L-type Ca2+ channel sug-
gested that (-)-1 interacts with a new binding site
distinct from the principal binding sites.8 On the basis
of electrophysiological studies, (-)-1 inhibited not only
a Ca2+ current but also a noninactivating Na+ current
without suppressing physiological Na+ channel activity.9
This mechanism would be considered to contribute to
the cardioprotective effect against ischemic injury caused
by Na+ and Ca2+ overload.10,11 Actually, (-)-1 inhibited
i
CH2CH2OH (27) > Pr (26). Moreover, oxidation of the
sulfur atom in the thiazolidinone ring, as in the sulfox-
ide 34, and conversion to the thiocarbonyl group at the
4-position, as in the thiolactam 35, both resulted in a
decreased activity.
Ca 2+ Over loa d In h ibit or y Act ivit y. The Ca2+
overload inhibitory activity of compounds was evaluated
as the protective effect in a veratridine-induced Ca2+
overload model of rat cardiac myocytes.5 With respect
to the substituents of the phenyl group at the 2-position,
11, having the isopropyl groups in place of the tert-butyl
groups, exhibited similar potency to that of 1. Replace-
ment of the phenolic hydroxyl group by a methoxy
group, as in 19, decreased the activity. As for the
methylene chain lengths (m, n), the optimum length of
m was 3 (1); on the other hand, Ca2+ overload inhibitory
activity was less sensitive to changes in n as demon-
strated by equipotent compounds 1 (n ) 2), 22 (n ) 3),
and 23 (n ) 4), as shown in Table 2. As for the N-alkyl
substituent in the amine moiety, N-ethyl compound 25

Novel Calcium Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3137
Ta ble 1. Effect of Substituents R1, R2, R3, and R4
i
j
a
Molar concentration required to inhibit 30 mM K+ contraction of rat aorta by 50%. Diltiazem was used as a standard compound.
Each value indicates a mean ( standard error from 2-8 experiments. The number of experiments performed is shown in parentheses.
b
Molar concentration required to inhibit veratridine-induced rat myocardiac cell death by >80%. The results were determined from 2-8
experiments, and more than 50 rod-shaped myocytes were used in each experiment. c Ac, acetone; iPr, diisopropyl ether. C4H4O4, fumaric
d
acid. e All compounds gave satisfactory elemental analyses ((0.4%) for C, H, and N, unless otherwise noted. f See ref 1. N.T., not tested.
g
h
The parent compound is an oil, and the corresponding salt was prepared as an amorphous solid after trituration with acetone-diisopropyl
ether, AcOEt-hexane, or MeOH-water. Compound failed to give crystal. m/z (EI, M+, C22H26N2O5S) calcd 430.1561, found 430.1562.
i
j
m/z (EI, M+, C26H34N2O5S) calcd 486.2225, found 486.2188.
1
uncorrected. H NMR spectra were measured with a Hitachi
R-24B spectrometer (60 MHz), a J EOL J NM-FX200 spectrom-
eter (200 MHz), or a J EOL J NM-EX270 spectrometer (270
MHz), with tetramethylsilane as the internal standard. In-
frared spectra were recorded on a Hitachi Model 270-3 infrared
spectrometer. EI mass spectra were determined on a Shimadzu
GCMS-QP1000 instrument. HPLC analyses were performed
on a Shimadzu SPD-10A (UV detector) with a Shimadzu LC-
6AD (pump); a YMC-Pack A-312 S-5 120A ODS column was
used; eluent CH3CN-H2O-TFA system at a flow rate of 1.0
mL/min. TLC was routinely performed on a Merck Kieselgel
60 F254. Benzene was dried over MS4A before use. Organic
extracts were dried over anhydrous sodium sulfate and
concentrated by a rotary evaporator.
ischemia- and reperfusion-induced arrhythmias in rats
and reduced the size of myocardial infarct in dogs.12,13
These cardioprotective effects seem likely to be ex-
plained by synergistically preventing Ca2+ overload and/
or scavenging oxygen free radicals as well as blocking
Ca2+ channels.14 We are convinced that (-)-1 (CP-060S)
would be beneficial for patients with ischemic heart
diseases.
Exp er im en ta l Section
Gen er a l Com m en ts. The melting points were determined
on a Yanagimoto micro melting point apparatus and are

3138 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Ta ble 2. Effect of the Length of the Methylene Chain (m, n)
Kato et al.
a-g
See footnotes a-g for Table 1.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Ar yl-3-
(ω-h yd r oxya lk yl)-1,3-th ia zolid in -4-on e. To a suspension of
the appropriate aldehyde 3 (0.10 mol) in dry benzene (150 mL)
was added the appropriate ω-amino alcohol 4 (0.10 mol), and
the mixture was refluxed for 1.5 h in a flask equipped with a
Dean-Stark trap under nitrogen atmosphere. After cooling
to room temperature, R-mercaptoacetic acid (6) (0.10 mol) was
added dropwise to the solution, and the resulting mixture was
refluxed for 2 h. It was then cooled and concentrated under
reduced pressure. The obtained residue was poured into water
and extracted with CHCl3. The extract was dried and concen-
trated under reduced pressure. The residue was purified by
chromatography on silica gel to give the corresponding com-
pound.
2-(3,5-Diisop r op yl-4-h yd r oxyp h en yl)-3-(3-h yd r oxyp r o-
p yl)-1,3-th ia zolid in -4-on e (7b): 1H NMR (CDCl3, 60 MHz)
δ 1.23 (12H, d, J ) 6.6 Hz), 1.0-1.8 (2H, m), 2.5-3.8 (7H, m),
3.73 (2H, brs), 5.50 (2H, brs), 6.92 (2H, s); IR (neat) 3400, 2950,
1652 (CdO), 1464, 1200, 760 cm-1; MS m/z 337 (M+), 304, 262.
2-(3,5-Dieth yl-4-h yd r oxyp h en yl)-3-(3-h yd r oxyp r op yl)-
1,3-th ia zolid in -4-on e (7c): 1H NMR (CDCl3, 60 MHz) δ 1.20
(6H, t, J ) 7.5 Hz), 1.0-1.7 (2H, m), 2.55 (4H, q, J ) 7.5 Hz),
2.8-3.6 (5H, m), 3.77 (2H, brs), 5.27 (1H, brs), 5.47 (1H, brs),
6.87 (2H, s); IR (neat) 3400, 2960, 1658 (CdO), 1410, 1200
cm-1; MS m/z 309 (M+), 276, 234.
3.2-3.3 (1H, m), 3.4-3.8 (2H, m), 3.73 and 3.86 (2H, ABq, J
) 16 Hz), 5.04 (1H, brs), 5.48 (1H, s), 6.92 (2H, s); IR (KBr)
3300, 2930, 1630 (CdO), 1204, 1150 cm-1; MS m/z 281 (M+),
206, 135.
2-(4-Hyd r oxyp h en yl)-3-(3-h yd r oxyp r op yl)-1,3-t h ia zo-
lid in -4-on e (7e):
1H NMR (CDCl3, 200 MHz) δ 1.3-1.7 (2H,
m), 2.0 (1H, brs), 2.9-3.2 (1H, m), 3.3-3.8 (3H, m), 3.74 and
3.82 (2H, ABq, J ) 16 Hz), 5.57 (1H, s), 6.84 (2H, d, J ) 8.0
Hz), 7.20 (2H, d, J ) 8.0 Hz), 7.26 (1H, brs); IR (KBr) 3300,
2940, 1640 (CdO), 1450, 1260, 750 cm-1; MS m/z 253 (M+),
194, 107.
2-(3,5-Dim eth oxy-4-h yd r oxyp h en yl)-3-(3-h yd r oxyp r o-
p yl)-1,3-th ia zolid in -4-on e (7f): 1H NMR (CDCl3, 200 MHz)
δ 1.4-1.7 (2H, m), 2.9-3.2 (1H, m), 3.3-4.1 (4H, m), 3.72 and
3.85 (2H, ABq, J ) 16 Hz), 3.89 (6H, s), 5.55 (1H, s), 6.07 (1H,
brs), 6.56 (2H, s); IR (KBr) 3300, 2950, 1650 (CdO), 1214, 1114
cm-1; MS m/z 313 (M+), 238.
2-(3,5-Dich lor o-4-h ydr oxyph en yl)-3-(3-h ydr oxypr opyl)-
1,3-th ia zolid in -4-on e (7g): 1H NMR (CDCl3, 60 MHz) δ 1.67
(2H, quint, J ) 6.0 Hz), 2.7-4.0 (7H, m), 5.47 (1H, s), 6.87
(1H, s), 7.17 (2H, s); IR (KBr) 3450, 2950, 1630 (CdO), 1420,
1310, 1234, 1168 cm-1; MS m/z 321 (M+), 262, 175.
2-(3-ter t-Bu tyl-4-h ydr oxy-5-m eth ylph en yl)-3-(3-h ydr oxy-
p r op yl)-1,3-th ia zolid in -4-on e (7h ): 1H NMR (CDCl3, 60
MHz) δ 1.35 (9H, s), 1.0-2.1 (2H, m), 2.22 (3H, s), 2.7-3.8
(5H, m), 3.72 (2H, brs), 5.27 (1H, brs), 5.43 (1H, brs), 6.8-7.2
(2H, m); IR (neat) 3500, 2950, 1658 (CdO), 1434, 1230, 760
cm-1; MS m/ z 323 (M+), 290, 248.
2-(3,5-Dim eth yl-4-h ydr oxyph en yl)-3-(3-h ydr oxypr opyl)-
1,3-th ia zolid in -4-on e (7d ): 1H NMR (CDCl3, 200 MHz) δ
1.4-1.7 (2H, m), 1.68 (1H, brs), 2.26 (6H, s), 2.9-3.1 (1H, m),

Novel Calcium Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3139
Ta ble 3. Effect of Substituent R6 in the Amino Group
i
j
a-h
See footnotes a-h for Table 1. i m/z (EI, M+, C31H44N2O5S) calcd 556.2971, found 556.2950. j m/z (EI, M+, C32H46N2O5S) calcd 570.3127,
found 570.3136.
2-(2,3,5-Tr im eth yl-4-h yd r oxyp h en yl)-3-(3-h yd r oxyp r o-
2-(3,5-Diisopr opyl-4-h ydr oxyph en yl)-3-(3-ch lor opr opyl)-
1,3-th ia zolid in -4-on e (8b): 1H NMR (CDCl3, 60 MHz) δ 1.23
(12H, d, J ) 6.6 Hz), 1.5-2.1 (2H, m), 2.6-3.8 (6H, m), 3.67
(2H, brs), 5.20 (1H, s), 5.50 (1H, brs), 6.88 (2H, s); IR (KBr)
3400, 2960, 1658 (CdO), 1460, 1202 cm-1; MS m/ z 355 (M+),
280.
p yl)-1,3-th ia zolid in -4-on e (7i): 1H NMR (CDCl3, 60 MHz)
δ 1.58 (2H, quint, J ) 6.0 Hz), 2.17 (9H, s), 2.6-3.9 (5H, m),
3.70 (2H, brs), 5.43 (1H, s), 5.83 (1H, brs), 6.72 (1H, s); IR
(neat) 3400, 2950, 1660 (CdO), 1218, 760 cm-1; MS m/z 295
(M+), 220, 162.
2-(3,5-Di-ter t-bu tyl-4-m eth oxyph en yl)-3-(3-h ydr oxypr o-
p yl)-1,3-th ia zolid in -4-on e (7j): 1H NMR (CDCl3, 60 MHz)
δ 1.40 (18H, s), 1.2-1.7 (2H, m), 2.8-3.7 (5H, m), 3.65 (3H,
s), 3.72 (2H, brs), 5.50 (1H, brs), 7.13 (2H, s); IR (KBr) 3450,
2950, 1670 (CdO), 1410, 1220 cm-1; MS m/ z 379 (M+), 322.
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-(2-h yd r oxyeth -
yl)-1,3-th ia zolid in -4-on e (7k ): 1H NMR (CDCl3, 60 MHz) δ
1.42 (18H, s), 2.6-4.0 (7H, m), 5.37 (1H, s), 5.67 (1H, s), 7.03
2-(3,5-Diet h yl-4-h yd r oxyp h en yl)-3-(3-ch lor op r op yl)-
1,3-th ia zolid in -4-on e (8c): 1H NMR (CDCl3, 60 MHz) δ 1.23
(6H, t, J ) 7.5 Hz), 1.7-2.2 (2H, m), 2.4-3.2 (5H, m), 3.3-3.6
(3H, m), 3.70 (2H, brs), 5.20 (IH, s), 5.50 (1H, brs), 6.87 (2H,
s); IR (KBr) 3350, 2960, 1650 (CdO), 1442, 1200 cm-1; MS m/ z
327 (M+), 252.
2-(3,5-Dim eth yl-4-h yd r oxyp h en yl)-3-(3-ch lor op r op yl)-
1,3-th ia zolid in -4-on e (8d ): 1H NMR (CDCl3, 200 MHz) δ
1.6-2.2 (2H, m), 2.26 (6H, s), 2.8-3.1 (1H, m), 3.47 (2H, t, J
) 6.5 Hz), 3.5-3.8 (1H, m), 3.67 and 3.82 (2H, ABq, J ) 16
Hz), 5.23 (1H, brs), 5.53 (1H, s), 6.91 (2H, s); IR (KBr) 3300,
1642 (CdO), 1200, 1142 cm-1; MS m/ z 299 (M+), 224.
2-(4-Hydr oxyph en yl)-3-(3-ch lor opr opyl)-1,3-th iazolidin -
4-on e (8e): 1H NMR (CDCl3, 200 MHz) δ 1.7-2.1 (2H, m),
2.8-3.1 (1H, m), 3.48 (2H, t, J ) 6.6 Hz), 3.5-3.8 (1H, m),
3.69 and 3.83 (2H, ABq, J ) 16 Hz), 5.59 (2H, brs), 6.86 (2H,
d, J ) 8.0 Hz), 7.22 (2H, d, J ) 8.0 Hz); IR (KBr) 3100, 1640
(CdO), 1440, 1230 cm-1; MS m/z 271 (M+), 196, 107.
2-(3,5-Dim eth oxy-4-h ydr oxyph en yl)-3-(3-ch lor opr opyl)-
1,3-th ia zolid in -4-on e (8f): 1H NMR (CDCl3, 200 MHz) δ 1.7-
2.1 (2H, m), 2.8-3.1 (1H, m), 3.49 (2H, t, J ) 6.3 Hz), 3.5-3.7
(1H, m), 3.69 and 3.82 (2H, ABq, J ) 16 Hz), 3.90 (6H, s),
5.58 (1H, s), 5.82 (1H, brs), 6.56 (2H, s); IR (KBr) 3300, 1658
(CdO), 1104 cm-l; MS m/ z 331 (M+), 256.
(2H, s); IR (KBr) 3450, 2950, 1660 (CdO), 1430, 1232 cm-1
MS m/ z 351 (M+), 260.
;
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-(4-h yd r oxybu -
tyl)-1,3-th ia zolid in -4-on e (7l): 1H NMR (CDCl3, 60 MHz) δ
1.37 (18H, s), 1.2-1.9 (4H, m), 2.6-3.2 (2H, m), 3.3-3.4 (3H,
m), 3.67 (2H, brs), 5.30 (1H, brs), 5.53 (1H, brs), 7.00 (2H, s);
IR (KBr) 3350, 2950, 1660 (CdO), 1434, 1070 cm-1; MS m/ z
379 (M+), 306, 234.
2-(3,5-Di-ter t-bu tyl-4-h ydr oxyph en yl)-3-(5-h ydr oxypen -
tyl)-1,3-th ia zolid in -4-on e (7m ): 1H NMR (CDCl3, 60 MHz)
δ 1.40 (18H, s), 1.0-1.8 (6H, m), 2.23 (1H, s), 2.4-3.0 (1H,
m), 3.2-3.8 (3H, m), 3.68 (2H, brs), 5.33 (1H, s), 5.53 (1H, brs),
7.03 (2H, s); IR (KBr) 3450, 2950, 1658 (CdO), 1430 cm-1; MS
m/ z 393 (M+), 234.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Ar yl-3-
(ω-ch lor oa lk yl)-1,3-th ia zolid in -4-on e. To a solution of the
appropriate alcohol 7 (14 mmol) in CH2Cl2 (50 mL) was added
thionyl chloride (21 mmol) at room temperature under nitrogen
atmosphere, and the mixture was refluxed for 1 h. After
cooling, the reaction mixture was poured into brine and
extracted with CHCl3. The extract was dried and concentrated
under reduced pressure. The residue was purified by chroma-
tography on silica gel to give the corresponding chloride.
2-(3,5-Dich lor o-4-h yd r oxyp h en yl)-3-(3-ch lor op r op yl)-
1,3-th ia zolid in -4-on e (8g): 1H NMR (CDCl3, 200 MHz) δ
1.6-2.2 (2H, m), 2.8-3.1 (1H, m), 3.3-3.6 (3H, m), 3.68 and
3.82 (2H, ABq, J ) 16 Hz), 5.51 (1H, s), 6.37 (1H, s), 7.24 (2H,
s); IR (KBr) 3450, 2940, 1656 (CdO), 1280 cm-1; MS m/ z 341
(M+ + 2), 339 (M+), 304, 266.

3140 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Ta ble 4. Related Compounds of Compound 1
Kato et al.
a,b
d-g
See footnotes a,b for Table 1. c Ac, acetone; iPr, diisopropyl ether; Cl, chloroform; Hex, n-hexane.
See footnotes d-g for Table 1.
Ta ble 5. Antioxidant Activities of Thiazolidinone Derivatives
Ta ble 6. Effects on Coronary Blood Flow by Intravenous
Administration of Compounds 1, 22, 25, and Diltiazem in
Anesthetized Dogs
a
Each value indicates a mean ( standard error from 5-6
experiments, and the ones without standard errors are the result
of a single experiment. Diltiazem was used as
compound in all experiments.
a standard
(1H, m), 3.52 (2H, t, J ) 6.6 Hz), 3.64 and 3.73 (2H, ABq, J )
16 Hz), 3.7-3.9 (1H, m), 4.73 (1H, s), 5.92 (1H, s), 6.74 (1H,
s); IR (neat) 3400, 2940, 1656 (CdO), 1408, 1292, 1248, 1090,
752 cm-1; MS m/ z 313 (M+), 238, 179.
2-(3,5-Di-ter t-bu tyl-4-m eth oxyp h en yl)-3-(3-ch lor op r o-
p yl)-1,3-th ia zolid in -4-on e (8j): 1H NMR (CDCl3, 60 MHz)
δ 1.40 (18H, s), 1.5-2.2 (2H, m), 2.6-3.6 (2H, m), 3.40 (2H, t,
J ) 6.5 Hz), 3.63 (3H, s), 3.68 (2H, brs), 5.52 (1H, brs), 7.13
(2H, s); IR (KBr) 2950, 1690 (CdO), 1404, 1218 cm-l; MS m/z
397 (M+), 382, 322.
a
Inhibition of rabbit LDL oxidation induced by soybean lipoxy-
genase. All results are shown as percent of control.
2-(3-ter t-Bu tyl-4-h yd r oxy-5-m eth ylp h en yl)-3-(3-ch lor o-
p r op yl)-1,3-th ia zolid in -4-on e (8h ): 1H NMR (CDCl3, 200
MHz) δ 1.40 (9H, s), 1.7-2.1 (2H, m), 2.26 (3H, s), 2.9-3.1
(1H, m), 3.4-3.5 (2H, m), 3.5-3.7 (1H, m), 3.68 and 3.80 (2H,
ABq, J ) 15 Hz), 5.10 (1H, s), 5.55 (1H, s), 6.97 (1H, s), 7.01
(1H, s); IR (KBr) 3372, 2952, 1670, 1650 (CdO), 1426, 1172
cm-1; MS m/ z 341 (M+), 304, 266.
2-(2,3,5-Tr im eth yl-4-h ydr oxyph en yl)-3-(3-ch lor opr opyl)-
1,3-th ia zolid in -4-on e (8i): 1H NMR (CDCl3, 200 MHz) δ 1.8-
2.2 (2H, m), 2.20 (3H, s), 2.22 (3H, s), 2.23 (3H, s), 2.8-3.0
2-(3,5-Di-ter t-bu tyl-4-h ydr oxyph en yl)-3-(2-ch lor oeth yl)-
1,3-th ia zolid in -4-on e (8k ): 1H NMR (CDCl3, 270 MHz) δ 1.43
(18H, s), 3.0-3.2 (1H, m), 3.3-3.5 (1H, m), 3.5-3.7 (1H, m),
3.7-3.9 (1H, m), 3.75 (2H, brs), 5.35 (1H, s), 5.76 (1H, s), 7.11
(2H, s); IR (KBr) 3540, 2956, 1660 (CdO), 1424, 1100 cm-1
MS m/ z 369 (M+), 354.
;
2-(3,5-Di-ter t-bu tyl-4-h ydr oxyph en yl)-3-(4-ch lor obu tyl)-
1,3-th ia zolid in -4-on e (8l): 1H NMR (CDCl3, 60 MHz) δ 1.40

Novel Calcium Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3141
Ta ble 7. Enantiomers of Compound 1
a,b
d
See footnotes a,b for Table 1. c See footnote a for Table 5. See footnote a for Table 6. e Configuration of the 2-position of the
thiazolidinone ring. f Ac, acetone; iPr, diisopropyl ether; Me, methanol; Wt, water. g C4H4O4, fumaric acid. All compounds gave satisfactory
h
elemental analyses ((0.4%) for C, H, and N.
(18H, s), 1.2-2.0 (4H, m), 2.6-3.0 (1H, m), 3.2-3.6 (3H, m),
3.67 (2H, brs), 5.27 (1H, s), 5.50 (1H, brs), 7.02 (2H, s); IR (KBr)
3550, 2960, 1660 (CdO), 1430, 1240, 1110 cm-1; MS m/ z 397
(M+), 322.
2-(3,5-Diet h yl-4-h yd r oxyp h en yl)-3-[3-[N-m et h yl-N-[2-
[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-1,3-
th ia zolid in -4-on e h yd r ogen fu m a r a te (12): method A
(34%); 1H NMR (CDCl3, free form, 60 MHz) δ 1.18 (6H, t, J )
7.2 Hz), 1.4-1.8 (2H, m), 2.17 (3H, s), 2.3-3.1 (9H, m), 3.3-
3.8 (1H, m), 3.65 (2H, brs), 3.83 (2H, t, J ) 5.7 Hz), 5.00 (1H,
brs), 5.52 (1H, s), 5.78 (2H, s), 6.0-6.7 (3H, m), 6.80 (2H, s);
IR (KBr) 3450, 3000, 1680 (CdO), 1498, 1198, 1050 cm-1; MS
m/z 486 (M+), 335, 292; HPLC analysis (CH3CN-H2O-TFA
(50:50:0.1)) tR ) 2.9 min (14.2%, fumaric acid) and tR ) 5.4
min (84.3%, free form of 12), 98.5% pure.
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-(5-ch lor op en -
1
tyl)-1,3-th ia zolid in -4-on e (8m ): H NMR (CDCl3, 60 MHz)
δ 1.40 (18H, s), 1.1-2.0 (6H, m), 2.4-3.0 (1H, m), 3.2-3.8 (3H,
m), 3.67 (2H, brs), 5.27 (1H, s), 5.50 (1H, brs), 7.00 (2H, s); IR
(KBr) 3570, 2950, 1660 (CdO), 1420, 1230, 1110 cm-1; MS m/ z
411 (M+), 336.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Ar yl-3-
(ω-a m in oa lk yl)-1,3-th ia zolid in -4-on e (Meth od A). To a
solution of the appropriate chloride 8 (1.0 mmol) and the
appropriate amine (1.0 mmol) in DMF (5 mL), under nitrogen
atmosphere, were added Na2CO3 (2.0 mmol) and NaI (0.1
mmol), and the mixture was stirred overnight at 80 °C. After
cooling, the reaction mixture was poured into water and
extracted with CHCl3. The extract was washed with brine,
dried, and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel to give the free
form of the corresponding compound.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Ar yl-3-
(ω-a m in oa lk yl)-1,3-th ia zolid in -4-on e (Meth od B). To a
solution of the appropriate bromide 9 (1.0 mmol) and the
appropriate amine (1.2 mmol) in acetone (25 mL), under
nitrogen atmosphere, was added K2CO3 (1.2 mmol), and the
mixture was refluxed for 10 h. After cooling, the reaction
mixture was filtered and washed with acetone, and the
resulting filtrate was concentrated under reduced pressure.
The residue was purified by chromatography on silica gel to
give the free form of the corresponding compound.
2-(3,5-Dim eth yl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-N-[2-
[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-1,3-
th ia zolid in -4-on e h yd r ogen fu m a r a te (13): method A
1
(53%); H NMR (CDCl3, free form, 200 MHz) δ 1.5-1.8 (2H,
m), 2.23 (6H, s), 2.26 (3H, s), 2.3-2.5 (2H, m), 2.68 (2H, t, J )
5.7 Hz), 2.7-2.9 (1H, m), 3.5-3.7 (1H, m), 3.65 and 3.81 (2H,
ABq, J ) 16 Hz), 3.91 (2H, t, J ) 5.7 Hz), 4.90 (1H, brs), 5.56
(1H, s), 5.90 (2H, s), 6.2-6.7 (3H, m), 6.88 (2H, s); IR (KBr)
3420, 2940, 1676 (CdO), 1498, 1188, 1040 cm-1; MS m/z 458
(M+), 135; HPLC analysis (CH3CN-H2O-TFA (30:70:0.1)) tR
) 3.3 min (9.9%, fumaric acid) and tR ) 7.8 min (89.5%, free
form of 13), 99.4% pure.
2-(4-Hyd r oxyp h en yl)-3-[3-[N-m eth yl-N-[2-[3,4-(m eth yl-
en ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-1,3-th ia zolid in -
4-on e h yd r och lor id e (14): method A (35%); 1H NMR (CDCl3,
free form, 200 MHz) δ 1.5-1.8 (2H, m), 2.27 (3H, s), 2.3-2.5
(2H, m), 2.73 (2H, t, J ) 5.7 Hz), 2.6-3.1 (1H, m), 3.5-3.7
(1H, m), 3.66 and 3.80 (2H, ABq, J ) 16 Hz), 3.94 (2H, t, J )
5.7 Hz), 5.59 (1H, s), 5.88 (2H, s), 6.2-7.2 (8H, m); IR (KBr)
3440, 3240, 2980, 1670 (CdO), 1498, 1198, 1046 cm-1; MS m/ z
430 (M+), 279, 236; HPLC analysis (CH3CN-H2O-TFA (30:
70:0.1)) tR ) 10.2 min (99.4%).
A solution of the free form in EtOH was treated with an
equimolar amount of fumaric acid and concentrated under
reduced pressure. The residue was triturated with iPr2O,
AcOEt-hexane, or MeOH-H2O, and the precipitated solid was
collected by filtration. The obtained solid was dried in vacuo
to give the corresponding hydrogen fumarate salt.
2-(3,5-Dim eth oxy-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-N-
[2-[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-
1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te (15): method A
1
(55%); H NMR (CDCl3, free form, 200 MHz) δ 1.5-1.8 (2H,
2-(3,5-Diisop r op yl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-N-
[2-[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-
1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te (11): method A
m), 2.25 (3H, s), 2.3-2.5 (2H, m), 2.70 (2H, t, J ) 5.7 Hz),
2.7-2.9 (1H, m), 3.6-3.8 (1H, m), 3.67 and 3.79 (2H, ABq, J
) 16 Hz), 3.85 (6H, s), 3.93 (2H, t, J ) 5.7 Hz), 5.63 (1H, s),
5.89 (2H, s), 6.2-6.7 (6H, m); IR (KBr) 3440, 2930, 1670 (Cd
O), 1180, 1108 cm-1; MS m/z 490 (M+), 339, 137; HPLC
analysis (CH3CN-H2O-TFA (30:70:0.1)) tR ) 3.3 min (9.6%,
fumaric acid) and tR ) 10.0 min (90.2%, free form of 15), 99.8%
pure.
1
(36%); H NMR (CDCl3, free form, 60 MHz) δ 1.23 (12H, d, J
) 6.6 Hz), 1.4-1.9 (2H, m), 2.17 (3H, s), 2.3-3.8 (8H, m), 3.67
(2H, brs), 3.87 (2H, t, J ) 5.7 Hz), 5.00 (1H, brs), 5.57 (1H, s),
5.80 (2H, s), 6.0-6.7 (3H, m), 6.90 (2H, s); IR (KBr) 3450, 2980,
1674 (CdO), 1498, 1198, 1050 cm-1; MS m/ z 514 (M+), 363,
320; HPLC analysis (CH3CN-H2O-TFA (50:50:0.1)) tR ) 2.9
min (15.3%, fumaric acid) and tR ) 7.4 min (83.7%, free form
of 11), 99.0% pure.
2-(3,5-Dich lor o-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-N-[2-
[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-1,3-
th ia zolid in -4-on e h yd r och lor id e (16): method A (36%); 1H

3142 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Ta ble 8. 2-Aryl-3-(ω-hydroxyalkyl)-1,3-thiazolidin-4-onesa
Kato et al.
a
b
Structures of all compounds were confirmed by 1H NMR, IR, and MS spectra. Cl, chloroform; Hex, n-hexane.
NMR (CDCl3, free form, 200 MHz) δ 1.5-2.0 (2H, m), 2.37 (3H,
s), 2.3-2.9 (3H, m), 2.86 (2H, t, J ) 5.7 Hz), 3.5-3.8 (1H, m),
3.64 and 3.79 (2H, ABq, J ) 16 Hz), 4.02 (2H, t, J ) 5.7 Hz),
5.51 (1H, s), 5.88 (2H, s), 6.1-6.9 (4H, m), 7.14 (2H, s); IR
(KBr) 3450, 2940, 1670 (CdO), 1490, 1180, 1040 cm-1; MS m/z
498 (M+), 347, 304; HPLC analysis (CH3CN-H2O-TFA (50:
50:0.1)) tR ) 4.4 min (96.2%).
3440, 2920, 1674 (CdO), 1486, 1180, 1034 cm-1; MS m/z 472
(M+), 321; HPLC analysis (CH3CN-H2O-TFA (50:50:0.1)) tR
) 2.9 min (11.9%, fumaric acid) and tR ) 4.4 min (85.7%, free
form of 18), 97.6% pure.
2-(3,5-Di-ter t-bu tyl-4-m eth oxyp h en yl)-3-[3-[N-m eth yl-
N-[2-[3,4-(m eth ylen edioxy)ph en oxy]eth yl]am in o]pr opyl]-
1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te (19): method A
1
2-(3-ter t-Bu tyl-4-h ydr oxy-5-m eth ylph en yl)-3-[3-[N-m eth -
yl-N -[2-[3,4-(m e t h yle n e d ioxy)p h e n oxy]e t h yl]a m in o]-
p r op yl]-1,3-t h ia zolid in -4-on e h yd r ogen fu m a r a t e (17):
method B (58%); 1H NMR (CDCl3, free form, 200 MHz) δ 1.39
(9H, s), 1.2-1.8 (2H, m), 2.21 (3H, s), 2.24 (3H, s), 2.2-2.5
(2H, m), 2.67 (2H, t, J ) 5.7 Hz), 2.6-2.9 (1H, m), 3.5-3.8
(1H, m), 3.67 and 3.80 (2H, ABq, J ) 16 Hz), 3.91 (2H, t, J )
5.7 Hz), 5.19 (1H, brs), 5.58 (1H, s), 5.88 (2H, s), 6.1-7.1 (5H,
(69%); H NMR (CDCl3, free form, 200 MHz) δ 1.41 (18H, s),
1.2-1.8 (2H, m), 2.20 (3H, s), 2.3-2.5 (2H, m), 2.69 (2H, t, J
) 5.7 Hz), 2.6-2.9 (1H, m), 3.4-3.7 (1H, m), 3.65 (3H, s), 3.64
and 3.67 (2H, ABq, J ) 16 Hz), 3.80 (2H, t, J ) 5.7 Hz), 5.57
(1H, s), 5.89 (2H, s), 6.2-6.8 (3H, m), 7.06 (2H, s); IR (KBr)
3470, 2980, 1684 (CdO), 1496, 1198, 1048 cm-1; MS m/ z 556
(M+), 405, 362; HPLC analysis (CH3CN-H2O-TFA (50:50:0.1))
tR ) 2.9 min (14.2%, fumaric acid) and tR ) 31.1 min (84.6%,
free form of 19), 98.8% pure.
m); IR (KBr) 3440, 2980, 1670 (CdO), 1492, 1198, 1046 cm-1
;
MS m/z 500 (M+), 349, 306; HPLC analysis (CH3CN-H2O-
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[4-[N-m eth yl-
N-[2-[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]bu tyl]-
1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te (20): method A
TFA (50:50:0.1)) tR ) 2.9 min (10.9%, fumaric acid) and tR
7.0 min (88.3%, free form of 17), 99.2% pure.
)
1
2-(2,3,5-Tr im eth yl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-N-
[2-[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-
1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te (18): method A
(48%); H NMR (CDCl3, free form, 60 MHz) δ 1.40 (18H, s),
1.1-1.9 (4H, m), 2.22 (3H, s), 2.2-2.8 (3H, m), 2.65 (2H, t, J
) 5.7 Hz), 3.2-3.8 (1H, m), 3.65 (2H, brs), 3.88 (2H, t, J ) 5.7
Hz), 5.30 (1H, brs), 5.52 (1H, brs), 5.82 (2H, s), 6.1-6.9 (3H,
m), 7.00 (2H, s); IR (KBr) 3450, 2970, 1672 (CdO), 1488, 1186,
1040 cm-1; MS m/z 556 (M+), 405; HPLC analysis (CH3CN-
H2O-TFA (50:50:0.1)) tR ) 2.9 min (18.4%, fumaric acid) and
tR ) 14.5 min (79.7%, free form of 20), 98.1% pure.
1
(50%); H NMR (CDCl3, free form, 200 MHz) δ 1.5-1.9 (2H,
m), 2.17 (3H, s), 2.19 (3H, s), 2.21 (3H, s), 2.29 (3H, s), 2.3-
2.5 (2H, m), 2.70 (2H, t, J ) 5.7 Hz), 2.6-2.9 (1H, m), 3.4-3.8
(1H, m), 3.61 and 3.76 (2H, ABq, J ) 16 Hz), 3.91 (2H, t, J )
5.7 Hz), 5.87 (3H, brs), 5.95 (1H, s), 6.1-6.9 (4H, m); IR (KBr)

Novel Calcium Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3143
Ta ble 9. 2-Aryl-3-(ω-haloalkyl)-1,3-thiazolidin-4-onesa
a
b
See footnote a for Table 8. Cl, chloroform; Hex, n-hexane; Et, diethyl ether.
1
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[5-[N-m eth yl-
N-[2-[3,4-(m eth ylen edioxy)ph en oxy]eth yl]am in o]pen tyl]-
1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te (21): method A
(47%); H NMR (CDCl3, free form, 200 MHz) δ 1.43 (18H, s),
1.3-1.9 (6H, m), 2.07 (3H, m), 2.1-2.5 (4H, m), 2.6-3.0 (1H,
m), 3.4-3.7 (1H, m), 3.67 and 3.80 (2H, ABq, J ) 16 Hz), 3.86
(2H, t, J ) 5.7 Hz), 5.30 (1H, s), 5.58 (1H, s), 5.88 (2H, s),
6.1-6.8 (3H, m), 7.07 (2H, s); IR (KBr) 3450, 2960, 1672 (Cd
O), 1488, 1184, 1038 cm-1; MS m/z 570 (M+), 433, 348; HPLC
analysis (CH3CN-H2O-TFA (50:50:0.1)) tR ) 2.9 min (7.1%,
fumaric acid) and tR ) 19.0 min (92.2%, free form of 23), 99.3%
pure.
1
(65%); H NMR (CDCl3, free form, 60 MHz) δ 1.40 (18H, s),
1.0-1.8 (6H, m), 2.23 (3H, s), 2.1-3.0 (3H, m), 2.67 (2H, t, J
) 5.7 Hz), 3.2-3.8 (1H, m), 3.67 (2H, brs), 3.90 (2H, t, J ) 5.7
Hz), 5.33 (1H, brs), 5.50 (1H, brs), 5.80 (2H, s), 6.1-6.7 (3H,
m), 7.02 (2H, s); IR (KBr) 3460, 2970, 1678 (CdO), 1492, 1192,
1042 cm-1; MS m/z 570 (M+), 419; HPLC analysis (CH3CN-
H2O-TFA (50:50:0.1)) tR ) 2.9 min (11.4%, fumaric acid) and
tR ) 16.8 min (85.5%, free form of 21), 96.9% pure.
2-(3,5-Di-ter t-b u t yl-4-h yd r oxyp h en yl)-3-[3-[N-[2-[3,4-
(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-1,3-th ia -
zolid in -4-on e h yd r ogen fu m a r a te (24): method A (36%);
1H NMR (CDCl3, free form, 200 MHz) δ 1.42 (18H, s), 1.5-1.7
(3H, m), 2.61 (2H, t, J ) 6.9 Hz), 2.8-2.9 (1H, m), 2.89 (2H, t,
J ) 5.3 Hz), 3.6-3.7 (1H, m), 3.68 and 3.78 (2H, ABq, J ) 16
Hz), 3.95 (2H, t, J ) 5.3 Hz), 5.34 (1H, brs), 5.60 (1H, s), 5.90
(2H, s), 6.2-6.8 (3H, m), 7.08 (2H, s); IR (KBr) 3450, 2970,
1680 (CdO), 1490, 1188, 1040 cm-1; MS m/z 528 (M+), 377;
HPLC analysis (CH3CN-H2O-TFA (50:50:0.1)) tR ) 2.9 min
(10.4%, fumaric acid) and tR ) 14.7 min (88.0%, free form of
24), 98.4% pure.
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[3-[N-eth yl-N-
[2-[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-
1,3-th ia zolid in -4-on e h yd r och lor id e (25): method A (8%);
1H NMR (CDCl3, free form, 200 MHz) δ 0.97 (3H, t, J ) 6.8
Hz), 1.43 (18H, s), 1.2-1.8 (2H, m), 2.4-2.6 (4H, m), 2.7-3.0
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-
N -[3-[3,4-(m e t h y le n e d io x y )p h e n o x y ]p r o p y l]a m in o ]-
p r op yl]-1,3-t h ia zolid in -4-on e h yd r ogen fu m a r a t e (22):
method A (52%); 1H NMR (CDCl3, free form, 200 MHz) δ 1.43
(18H, s), 1.2-2.0 (4H, m), 2.11 (3H, s), 2.2-2.4 (2H, m), 2.40
(2H, t, J ) 7.1 Hz), 2.7-2.9 (1H, m), 3.4-3.6 (1H, m), 3.66
and 3.80 (2H, ABq, J ) 16 Hz), 3.87 (2H, t, J ) 5.7 Hz), 5.31
(1H, s), 5.57 (1H, s), 5.88 (2H, s), 6.2-6.8 (3H, m), 7.07 (2H,
s); IR (KBr) 3450, 2950, 1670 (CdO), 1494, 1180, 1034 cm-1
;
MS m/ z 556 (M+), 222; HPLC analysis (CH3CN-H2O-TFA
(50:50:0.1)) tR ) 2.9 min (11.3%, fumaric acid) and tR ) 16.2
min (87.0%, free form of 22), 98.3% pure.
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-
N-[4-[3,4-(m eth ylen edioxy)ph en oxy]bu tyl]am in o]pr opyl]-
1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te (23): method A

3144 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Kato et al.
(1H, m), 2.74 (2H, t, J ) 5.7 Hz), 3.4-3.7 (1H, m), 3.66 and
3.79 (2H, ABq, J ) 16 Hz), 3.89 (2H, t, J ) 5.7 Hz), 5.33 (1H,
s), 5.61 (1H, s), 5.89 (2H, s), 6.2-6.8 (3H, m), 7.08 (2H, s); IR
(KBr) 3440, 2950, 1668 (CdO), 1482, 1180, 1038 cm-1; MS m/z
556 (M+), 405, 348; HPLC analysis (CH3CN-H2O-TFA (50:
50:0.1)) tR ) 17.6 min (97.7%).
2-(3,5-Di-ter t-bu tyl-4-h ydr oxyph en yl)-3-[3-[N-isopr opyl-
N-[2-[3,4-(m eth ylen edioxy)ph en oxy]eth yl]am in o]pr opyl]-
1,3-th ia zolid in -4-on e h yd r och lor id e (26): method A (7%);
1H NMR (CDCl3, free form, 200 MHz) δ 0.93 (6H, d, J ) 6.3
Hz), 1.43 (18H, s), 1.2-1.7 (2H, m), 2.41 (2H, t, J ) 5.7 Hz),
2.6-3.0 (4H, m), 3.4-3.7 (1H, m), 3.62 and 3.75 (2H, ABq, J
) 16 Hz), 3.80 (2H, t, J ) 5.7 Hz), 5.33 (1H, s), 5.57 (1H, s),
5.89 (2H, s), 6.2-6.8 (3H, m), 7.06 (2H, s); IR (KBr) 3440, 2960,
1672 (CdO), 1488, 1438, 1184, 1038 cm-1; MS m/z 570 (M+),
433, 348; HPLC analysis (CH3CN-H2O-TFA (50:50:0.1)) tR
) 19.2 min (98.9%).
2-(3,5-Di-ter t-bu tyl-4-h ydr oxyph en yl)-3-[3-[N-(2-h ydr oxy-
eth yl)-N-[2-[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]-
p r op yl]-1,3-t h ia zolid in -4-on e h yd r ogen fu m a r a t e (27):
method B (47%); 1H NMR (CDCl3, free form, 200 MHz) δ 1.41
(18H, s), 1.4-2.0 (2H, m), 2.4-3.0 (7H, m), 3.4-3.7 (4H, m),
3.64 and 3.77 (2H, ABq, J ) 16 Hz), 3.89 (2H, t, J ) 5.7 Hz),
5.30 (1H, s), 5.54 (1H, s), 5.89 (2H, s), 6.1-6.8 (3H, m), 7.06
(2H, s); IR (KBr) 3440, 2950, 1664 (CdO), 1488, 1180, 1038
cm-1; MS m/z 572 (M+), 421, 234; HPLC analysis (CH3CN-
H2O-TFA (50:50:0.1)) tR ) 2.9 min (11.5%, fumaric acid) and
tR ) 12.7 min (87.6%, free form of 27), 99.1% pure.
N-[2-[N-Met h yl-N-[2-[3,4-(m et h ylen ed ioxy)p h en oxy]-
et h yl]a m in o]et h yl]p h t h a lim id e (29). A suspension of
N-methyl-N-[2-[3,4-(methylenedioxy)phenoxy]ethyl]amine (10a)
(2.0 g, 10 mmol), N-(2-bromoethyl)phthalimide (28) (2.7 g, 11
mmol), and K2CO3 (1.6 g, 11 mmol) in DMF (20 mL) was
stirred overnight at 90 °C under nitrogen atmosphere. After
cooling, the reaction mixture was poured into brine and
extracted with CHCl3. The extract was dried and concentrated
under reduced pressure. The residue was purified by chroma-
tography on silica gel with CHCl3-MeOH (10:1) to give 900
mg (24%) of 29 as a pale-yellow oil: 1H NMR (CDCl3, 60 MHz)
δ 2.85 (3H, s), 3.6-4.4 (8H, m), 5.84 (2H, s), 6.1-6.8 (3H, m),
7.1-8.0 (4H, m).
N-(2-Am in oet h yl)-N-m et h yl-N-[2-[3,4-(m et h ylen ed i-
oxy)p h en oxy]eth yl]a m in e (30). To a solution of 29 (900 mg,
2.5 mmol) in MeOH (10 mL) was added a solution of 40%
MeNH2 in MeOH (10 mL, 116 mmol), and the mixture was
stirred for 3 days at room temperature. The reaction mixture
was concentrated under reduced pressure. To the residual oil
were added CHCl3 and 2 N HCl, and the aqueous layer was
separated. The aqueous layer was made basic with 10% Na2-
CO3 solution and extracted with CHCl3. The extract was dried
and concentrated under reduced pressure. The residue was
purified by chromatography on silica gel with CHCl3-MeOH-
NEt3 (50:50:1) to give 440 mg (75%) of 30 as a pale-orange oil:
1H NMR (CDCl3, 60 MHz) δ 2.34 (3H, s), 2.0-3.2 (8H, m), 3.90
(2H, t, J ) 6 Hz), 5.85 (2H, s), 6.0-6.9 (3H, m).
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[2-[N-m eth yl-
N-[2-[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]eth yl]-
1,3-th ia zolid in -4-on e Hyd r ogen F u m a r a te (32). To a sus-
pension of 3,5-di-tert-butyl-4-hydroxybenzaldehyde (3a ) (410
mg, 1.76 mmol) in dry benzene (30 mL) was added 30 (420
mg, 1.76 mmol), and the mixture was refluxed for 2 h in a
A solution of the free form of 32 in EtOH was treated with
an equimolar amount of fumaric acid and concentrated under
reduced pressure. The residue was triturated with AcOEt-
hexane, and the precipitated solid was collected by filtration.
The obtained solid was dried in vacuo to give 32 as colorless
crystals: IR (KBr) 3450, 2950, 1708 (CdO), 1482, 1180, 1034
cm-1; MS m/z 528 (M+), 208; HPLC analysis (CH3CN-H2O-
TFA (50:50:0.1)) tR ) 2.9 min (8.1%, fumaric acid) and tR
13.7 min (90.6%, free form of 32), 98.7% pure.
)
2-(3-ter t-Bu tyl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-N-[2-
[3,4-(m eth ylen ed ioxy)p h en oxy]eth yl]a m in o]p r op yl]-1,3-
th ia zolid in -4-on e Hyd r och lor id e (33). To a solution of 1
(350 mg, 0.65 mmol) in AcOH (5 mL) was added 47% HBr in
H2O (5 mL, 43 mmol), and the mixture was stirred for 7 days
at room temperature. The reaction mixture was poured into
5% Na2CO3 solution, and extracted with CHCl3. The extract
was washed with brine, dried, and concentrated under reduced
pressure. The residue was purified by chromatography on silica
gel with CHCl3-MeOH (98:2) to give 50 mg (16%) of the free
amine of 33 as a pale-yellow oil: 1H NMR (CDCl3, 200 MHz)
δ 1.37 (9H, s), 1.2-1.9 (2H, m), 2.26 (3H, s), 2.1-2.5 (2H, m),
2.71 (2H, t, J ) 5.7 Hz), 2.6-3.0 (1H, m), 3.4-3.8 (1H, m),
3.67 and 3.80 (2H, ABq, J ) 16 Hz), 3.94 (2H, t, J ) 5.7 Hz),
5.60 (1H, s), 5.82 (1H, s), 5.88 (2H, s), 6.1-7.0 (5H, m), 7.14
(1H, s).
To a solution of the free amine of 33 in MeOH was added a
small excess of 4 N HCl in dioxane, and the mixture was
concentrated under the reduced pressure. The residue was
triturated with AcOEt-hexane, and the precipitated solid was
collected by filtration. The obtained solid was dried in vacuo
to give 33 as a colorless amorphous powder: IR (KBr) 3450,
2970, 1672 (CdO), 1492, 1192, 1042 cm-1; MS m/z 486 (M+),
335, 292; HPLC analysis (CH3CN-H2O-TFA (50:50:0.1)) tR
) 6.5 min (97.0%).
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-
N-[2-[3,4-(m eth ylen edioxy)ph en oxy]eth yl]am in o]pr opyl]-
1,3-th ia zolid in -4-on e 1-Oxid e (34). To a solution of 1 (300
mg, 0.55 mmol) in AcOH (5 mL) was added 35% H2O2 in H2O
(200 mg, 3.7 mmol), and the mixture was stirred overnight at
room temperature. The reaction mixture was poured into 5%
K2CO3 solution and extracted with AcOEt. The extract was
dried and concentrated under reduced pressure. The residue
was purified with chromatography on silica gel with CHCl3-
MeOH (98:2) to give 120 mg (39%) of 34 as colorless crystals:
1H NMR (CDCl3, 200 MHz) δ 1.41 (18H, s), 1.4-2.0 (2H, m),
2.28 (3H, s), 2.3-2.7 (2H, m), 2.72 (2H, t, J ) 5.7 Hz), 2.9-3.2
(1H, m), 3.37 and 3.69 (2H, ABq, J ) 16 Hz), 3.8-4.2 (3H, m),
5.40 (1H, s), 5.61 (1H, s), 5.87 (2H, s), 6.1-6.8 (3H, m), 6.94
(2H, s); IR (KBr) 3624, 3480, 2950, 1682, 1670 (CdO), 1488,
1184, 1040 cm-1; MS m/z 558 (M+), 407; HPLC analysis (CH3-
CN-H2O-TFA (50:50:0.1)) tR ) 7.6 min (99.3%).
2-(3,5-Di-ter t-bu tyl-4-h yd r oxyp h en yl)-3-[3-[N-m eth yl-
N-[2-[3,4-(m eth ylen edioxy)ph en oxy]eth yl]am in o]pr opyl]-
1,3-th ia zolid in e-4-th ion e Hyd r ogen F u m a r a te (35). A
suspension of 1 (217 mg, 0.40 mmol) and Lawesson’s reagent
(194 mg, 0.48 mmol) in THF (5 mL) was stirred for 5 h at room
temperature. The reaction mixture was concentrated under
reduced pressure. The residue was treated with H2O and
extracted with CHCl3. The extract was washed with brine,
dried, and concentrated under reduced pressure. The residue
was purified by chromatography on silica gel with CHCl3-
MeOH (99:1) to give 181 mg (81%) of the free amine of 35 as
a pale-yellow oil: 1H NMR (CDCl3, 200 MHz) δ 1.41 (18H, s),
1.3-1.8 (2H, m), 2.20 (3H, s), 2.3-2.5 (2H, m), 2.70 (2H, t, J
) 5.7 Hz), 3.1-3.3 (1H, m), 3.93 (2H, t, J ) 5.7 Hz), 3.9-4.1
(1H, m), 4.36 and 4.40 (2H, ABq, J ) 16 Hz), 5.34 (1H, s),
6.18 (2H, s), 6.04 (1H, s), 6.2-7.0 (3H, m), 7.07 (2H, s).
flask equipped with
a Dean-Stark trap under nitrogen
atmosphere. After cooling to room temperature, R-mercap-
toacetic acid (6) (160 mg, 1.76 mmol) was added dropwise to
the solution, and the resulting mixture was refluxed for 2 h.
It was then cooled and concentrated under reduced pressure.
The obtained residue was poured into water and extracted with
CHCl3. The extract was dried and concentrated under reduced
pressure. The residue was purified by chromatography on silica
gel with CHCl3-MeOH (97:3) to give 200 mg (22%) of the free
form of 32 as a pale-brown oil: 1H NMR (CDCl3, 60 MHz) δ
1.40 (18H, s), 2.20 (3H, s), 2.5-3.0 (5H, m), 3.3-4.1 (3H, m),
3.65 (2H, brs), 5.23 (1H, s), 5.73 (1H, s), 5.82 (2H, s), 6.0-6.8
(3H, m), 7.00 (2H, s).
A solution of the free form of 35 in EtOH was treated with
an equimolar amount of fumaric acid and concentrated under
reduced pressure. The residue was recrystallized from CHCl3-
hexane to give 35 as colorless crystals: IR (KBr) 3450, 2960,
1688 (CdO), 1482, 1182, 1038 cm-1; MS m/z 558 (M+), 421,
364; HPLC analysis (CH3CN-H2O-TFA (50:50:0.1)) tR ) 2.9

Novel Calcium Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3145
min (7.2%, fumaric acid) and tR ) 25.3 min (88.3%, free form
of 35), 95.5% pure.
prepared from the heart of male Sprague-Dawley rats (300-
500 g; Charles River J apan Inc.), using an enzyme-perfusion
method.16 The thus obtained rod-shaped normal myocytes were
treated with a test compound or diltiazem for 30 min, and 50
µg/mL veratridine was added. Five minutes later, the shape
of the cells was observed to obtain a survival rate thereby to
evaluate the efficacy of the compound. The results obtained
are shown in Tables 1-4.
In h ibitor y Action on Lip id P er oxid a tion . A test com-
pound was added to rabbit LDL prepared according to the
method of Havel et al.,17 and then a soybean lipoxygenase type-
IS (SLO) was added to a final concentration of 40 µg/mL.
Oxidation of LDL was carried out by incubation at 37 °C in a
CO2 incubator for 24 h. The oxidized LDL solution was
analyzed by gel-permeation chromatography, and the fluores-
cence intensity of the LDL fraction was measured at an
excitation wavelength of 360 nm and an emission wavelength
of 430 nm. The results of measurements expressed as a
percentage of control are shown in Table 5.
Op tica l Resolu tion of 1. Compound 1 (400 mg) was
i
dissolved in PrOH (8 mL) and injected in 0.1-mL aliquots into
a preparative chiral column (Chiralcel OD, i.d. 2 cm × 25 cm).
i
The HPLC condition was as follows: mobile phase, PrOH:
hexane (20:80); flow rate, 13.2 mL/min; detection wavelength,
280 nm. Two pools of material were isolated with retention
times of 11.4 min (180 mg, colorless oil) and 14.1 min (170
mg, colorless oil), respectively. The column isolates were
individually treated with an equimolar amount of fumaric acid,
and each was then recrystallized from MeOH-H2O to give the
corresponding hydrogen fumarate salts as colorless crystals.
Each of them was examined by analytical chiral column
(Chiralcel OD, i.d. 0.46 cm × 25 cm) for optical purity. The
i
HPLC condition was as follows: mobile phase, PrOH:hexane
(20:80); flow rate, 0.7 mL/min; detection wavelength, 280 nm.
(R)-(+)-2-(3,5-Di-ter t-b u t yl-4-h yd r oxyp h en yl)-3-[3-[N-
m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en oxy]eth yl]am in o]-
p r op yl]-1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te ((+)-
1): colorless crystals; mp 143-145 °C (MeOH-H2O); 99.6%
ee; [R]D ) +33.3° (c ) 1.166, EtOH).
(S)-(-)-2-(3,5-Di-ter t-b u t yl-4-h yd r oxyp h en yl)-3-[3-[N-
m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en oxy]eth yl]am in o]-
p r op yl]-1,3-th ia zolid in -4-on e h yd r ogen fu m a r a te ((-)-
1): colorless crystals; mp 143-144 °C (MeOH-H2O); 99.5%
ee; [R]D ) -33.5° (c ) 1.071, EtOH).
Effect on Cor on a r y Blood F low in An esth etized Dogs.
Male beagle dogs (9-14 kg) were anesthetized with sodium
pentobarbital (PB; 35 mg/kg, iv) and maintained by infusion
of PB (3-5 mg/kg/h, iv). Polyethylene catheters were inserted
into the right cephalic vein for drug administration. After
artificial respiration, the thoracotomy was performed through
the left fifth intercostal space. The pericardium was opened
and reflected to form a cradle for suspending the heart. An
electromagnetic flow probe connected to an electromagnetic
flow meter (Nihon Kohden Co., Ltd., MFV-2100) was placed
around the left circumflex coronary artery to measure coronary
blood flow (CBF). After the completion of surgery, the prepara-
tion was allowed for stabilization. A test compound was
administered intravenously. The CBF-increasing activity was
expressed as a maximal percent change from the preadmin-
istration value. The results are shown in Table 6.
Sin gle-Cr ysta l X-r a y An a lysis of (-)-1. Suitable crystals
of (-)-1, C30H42N2O5S‚C4H4O4, FW ) 658.81, were grown in
AcOEt-hexane. A clear, colorless crystal, 0.24 × 0.17 × 0.35
mm, was used for the structural determination. A least-
squares refinement, using 25 centered reflections within 59.08°
< 2θ < 59.89°, gave the orthorhombic P212121 cell, a ) 11.863-
(2) Å, b ) 25.798(2) Å, c ) 11.348(2) Å, V ) 3473.1(7) Å3, Z )
4, Dcalcd ) 1.260 g cm-3. A Rigaku AFC7R diffractometer with
graphite monochromated Cu KR radiation (λ ) 1.54178 Å, T
) 296 K) was used for data collection. A total of 6060
Ack n ow led gm en t. We gratefully acknowledge Prof.
H. Kuriyama for his valuable suggestions; O. Cynshi
and Y. Takashima for the antioxidant test; Y. Kumagai
for the X-ray analysis; K. Tsuzuki and Dr. H. Matsuoka
for their helpful advice in the preparation of this paper;
and Dr. V. A. Khlebnikov for language editing.
reflections were measured in the ω - 2 θ mode to 2 θmax
)
120°. Corrections were applied for Lorentz and polarization
effects. The structure was solved by direct methods with the
aid of the program SHELXS86,15 and the non-H atoms were
refined by using the full-matrix least-squares method. Hydro-
gen atoms were located on a difference Fourier map and
subsequently entered at idealized positions. The final R factors
for the 5261 reflections (I > 3σ(I)) were R ) 0.041 and Rw
)
Su p p or tin g In for m a tion Ava ila ble: Tables of atomic
positional parameters, intramolecular bond distances, and
intramolecular bond angles for (-)-1. This material is available
free of charge via the Internet at http://pubs.acs.org.
0.061.
Ca lciu m An ta gon istic Activity. Thoracic aortas were
removed from male Sprague-Dawley rats (350-550 g; Charles
River J apan Inc.), dissected free from surrounding connective
tissue, and cut into ring segments each about 2-3 mm long.
Each strip of smooth muscle was mounted for isometric tension
recording in an organ bath filled with 10 mL of Krebs-
Henseleit (K-H) solution (pH 7.4). This bathing solution was
maintained at 37 °C and bubbled with 95% O2/5% CO2. The
strips were given a stretched tension of 2 g and allowed to
equilibrate for more than 30 min. Isometric tension changes
were monitored using an isometric transducer (Nihon Kohden
Co., Ltd., TB-611T) and recorded on a self-balancing poten-
tiometric recorder (Yokogawa Co., Ltd., 3066). After the
equilibration period, a precontraction was produced by chang-
ing the solution in the bath to one containing 30 mM K+. After
the contraction was maintained for 20 min, the preparation
was washed with K-H solution. Sixty minutes thereafter (the
K-H solution was exchanged for a fresh one every 20 min),
contraction was again induced in the same manner as de-
scribed above. After the contraction stabilized, a test compound
or diltiazem was added to the system in a cumulative manner
in half-log-unit increments to obtain a concentration-response
curve. Taking the contraction at 30 mM K+ as 100%, the
concentration of the drug at which the contraction was relaxed
to 50% was deemed the IC50. The results obtained are shown
in Tables 1-4.
Refer en ces
(1) Kato, T.; Ozaki, T.; Tamura, K.; Suzuki, Y.; Akima, M.; Ohi, N.
Novel Calcium Antagonists with Both Calcium Overload Inhibi-
tion and Antioxidant Activity. 1. 2-(3,5-Di-tert-butyl-4-hydrox-
yphenyl)-3-(aminopropyl)thiazolidinones. J . Med. Chem. 1998,
41, 4309-4316.
(2) Cava, M. P.; Levinson, M. I. Thionation Reaction of Lawesson’s
Reagents. Tetrahedron 1985, 41, 5061-5087.
(3) Okamoto, Y.; Kawashima, M.; Hatada, K. Chromatographic
Resolution XI. Controlled Chiral Recognition of Cellulose Triph-
enylcarbamate Derivatives Supported on Silica Gel. J . Chro-
matogr. 1986, 363, 173-186.
(4) Godfraind, T.; Kaba, A. Blockade or Reversal of the Contraction
Induced by Calcium and Adrenaline in Depolarized Arterial
Smooth Muscle. Br. J . Pharmacol. 1969, 36, 549-560.
(5) Ver Donck, L.; Pauwels, P. J .; Vandeplassche, G.; Borgers, M.
Isolated Rat Cardiac Myocytes as an Experimental Model to
Study Calcium Overload: The Effect of Calcium-Entry Blockers.
Life Sci. 1986, 38, 765-772.
(6) Kawabe, Y.; Cynshi, O.; Takashima, Y.; Suzuki, T.; Ohba, Y.;
Kodama, T. Oxidation-Induced Aggregation of Rabbit Low-
Density Lipoprotein by Azo Inhibitor. Arch. Biochem. Biophys.
1994, 310, 489-496.
(7) Yoshioka, T.; Fujita, T.; Kanai, T.; Aizawa, Y.; Kurumada, T.;
Hasegawa, K.; Horikoshi, H. Studies on Hindered Phenols and
Analogues. 1. Hypolipidemic and Hypoglycemic Agents with
Ability to Inhibit Lipid Peroxidation. J . Med. Chem. 1989, 32,
421-428.
P r otective Effects in th e Ver a tr id in e-In d u ced Ca l-
ciu m Over loa d Mod el. Isolated ventricular myocytes were

3146 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Kato et al.
(8) Suzuki, Y.; Tamura, K.; Adachi, Y.; Fukazawa, M.; Kato, T. CP-
060S Interacts with Three Principal Binding Sites on The L-Type
Ca2+ Channel. Eur. J . Pharmacol. 1998, 342, 347-351.
(9) Tanabe, S.; Fukazawa, M.; Tamura, K.; Kimura, J .; Kuromaru,
O. Electrophysiological Effects of CP-060S, A Novel Cardiopro-
tective Agent, In Guinea Pig Papillary Muscles and Cardiomyo-
cytes. FASEB J . 1997, 11, A499.
(10) Tamura, K.; Suzuki, Y.; Koga, T.; Akima, M.; Kato, T.; Nabata,
H. Actions of CP-060S on Veratridine-Induced Ca2+ Overload
in Cardiomyocytes and Mechanical Activities in Vascular Strips.
Eur. J . Pharmacol. 1996, 312, 195-202.
(11) Ohya, Y.; Adachi, N.; Setoguchi, M.; Abe, I.; Fujishima, M. Effects
of CP-060S on Membrane Channels of Vascular Smooth Muscle
Cells from Guinea Pig. Eur. J . Pharmacol. 1997, 330, 93-99.
(12) Koga, T.; Fukazawa, M.; Suzuki, Y.; Akima, M.; Adachi, Y.;
Tamura, K.; Kato, T.; Kuromaru, O. The Protective Effects of
CP-060S on Ischaemia- and Reperfusion-Induced Arrhythmias
in Anaesthetized Rats. Br. J . Pharmacol. 1998, 123, 1409-1417.
(13) Suzuki, Y.; Tamura, K.; Akima, M.; Adachi, Y.; Fukazawa, M.;
Kato, T. CP-060S,
A Novel Cardioprotective Drug, Limits
Myocardial Infarct Size in Anesthetized Dogs. J . Cardiovasc.
Pharmacol. 1998, 31, 400-407.
(14) Suzuki, Y.; Akima, M.; Tamura, K. Effects of CP-060S, A Novel
Cardioprotective Drug, on Cardiac Function and Myocardial
Oxygen Consumption. Gen. Pharmacol. 1999, 32, 57-63.
(15) Sheldrick, G. M. Phase Annealing in SHELX-90: Direct Methods
for Larger Structures. Acta Crystallogr. 1990, A46, 467-473.
(16) Powell, T.; Twist, V. W. A Rapid Technique for the Isolation and
Purification of Adult Cardiac Muscle Cells Having Respiratory
Control and a Tolerance to Calcium. Biochem. Biophys. Res.
Commun. 1976, 72, 327-333.
(17) Havel, R. J .; Eder, H. A.; Bragdon, J . H. The Distribution and
Chemical Composition of Ultracentrifugally Separated Lipopro-
teins in Human Serum. J . Clin. Invest. 1955, 34, 1345-1353.
J M9900927