Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(Aryloxy)ethoxy)-4-pyrimidinyl) sulfonamide derivatives

Article abstract of DOI:10.1021/jm000538f

In the preceding article, we outlined the discovery and structure-activity relationship of a potent and selective ET_A receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET_A receptor antagonist a

Full text of DOI:10.1021/jm000538f

J . Med. Chem. 2001, 44, 3369-3377
3369
P oten t a n d Selective ET-A An ta gon ists. 2. Discover y a n d Eva lu a tion of P oten t
a n d Wa ter Solu ble N-(6-(2-(Ar yloxy)eth oxy)-4-p yr im id in yl)su lfon a m id e
Der iva tives
Hiroshi Morimoto, Noriko Ohashi, Hideshi Shimadzu, Emi Kushiyama, Hiroyuki Kawanishi, Toshihiro Hosaka,
Yasushi Kawase, Kosuke Yasuda, Kohei Kikkawa, Rikako Yamauchi-Kohno, and Koichiro Yamada*
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50 Kawagishi, Toda, Saitama, J apan 335-8505
Received December 18, 2000
In the preceding article,1 we outlined the discovery and structure-activity relationship of a
potent and selective ETA receptor antagonist 1 and its related compounds. Metabolites of 1
having potent selective ETA receptor antagonist activity were identified. This study suggested
the metabolic pathways of 1 were considerably affected by species. Consequently, structural
modification of 1 intended to improve the complexity of the metabolic pathway, and water
solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl
moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water
solubility, a uniform metabolic pathway among species, and very high affinity and selectivity
for the human ETA receptor (Ki for ETA receptor: 0.015 ( 0.004 nM; for ETB receptor: 41 ( 21
nM).
In tr od u ction
We here report a study of the metabolic pathway of 1
over species and the discovery of a potent and highly
water soluble ETA-selective antagonist, 6b.
In the preceding article,1 we described the preparation
and evaluation of a potent ETA-selective inhibitor, 4-tert-
butyl-N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-
methylphenyl)-4-pyrimidinyl)benzenesulfonamide (1),
exhibiting extremely high affinity and selectivity for the
cloned human ETA receptor (Ki for human ETA: 0.0042
( 0.0038 nM; for ETB: 130 ( 50 nM). However, it
showed low bioavailability resulting from its lower
water solubility (0.0016 mg/mL at pH 7.5) and a
significant difference of metabolic pathways among
animal species.
It is known that lipophilic compounds are converted
to the hydrophilic forms by metabolic reactions to be
excreted into urine or bile, and some active metabolites
are often better therapeutic candidates than the parent
compounds2 from the standpoint of water solubility and
pharmacokinetic characteristics. Therefore, it was ex-
pected that some of the more hydrophilic derivatives of
1, including the metabolites of 1, might show good water
solubility and that they would show a smaller difference
in metabolic pathways among animal species than did
1 because of the higher oxidized functional groups, such
as carboxylic acid and hydroxyl groups, in the former.
The functional groups would reduce the number of sites
susceptible to metabolism and direct the metabolic
pathway. On the basis of the expectation, we identified
the metabolites and synthesized more hydrophilic com-
pounds than 1. As shown in Figure 1, carboxylic acid
and hydroxyl groups were introduced into each end of
the three side chains on the nucleus pyrimidine of 1 and
the 5-(methylthio)pyrimidin-2-yl derivative 2, which
showed extremely high antagonistic activity for the ETA
receptor.1
Ch em istr y
A structural modification of 1 intended to improve its
bioavailability by increasing its water solubility was
performed in the following steps: (1) replacement of the
bromo group on the side chain pyrimidine with carbox-
ylic acid or hydroxymethyl groups (compounds 3a ,b);
(2) conversion of the methyl moiety into the two groups
above in the tolyl group (compounds 4a ,b and 5b); and
(3) conversion of the methyl moiety into the two groups
above in the tert-butyl group in the sulfonamide part
(compounds 6a ,b). Methods of introduction of carboxylic
acid and alcohol into the side chain pyrimidine (com-
pounds 3a ,b) and the tolyl group (compounds 4a ,b and
5b) are shown in Scheme 1. 5-Pyrimidinecarboxylic acid
moiety was introduced into the reported compound 73
by the method described in the preceding article1 to
afford the intended compound 3a . Formylation at the
5-position of the side chain pyrimidine of 1 and following
reduction to alcohol gave the hydroxymethyl derivative
3b. Palladium-catalyzed cross-coupling of the 5-bromo-
pyrimidine derivative 10, prepared from 9 by the
method described in the preceding article,1 with methyl
4-tributylstannylbenzoate4 and 4-tributylstannybenz-
aldehyde diethyl acetal5 afforded the methyl ester 11
and the diethyl acetal 12, respectively, which were
converted to the carboxylic acid 4a by alkali hydrolysis
and to the alcohol 4b by treatment with acid and sub-
sequent reduction. Palladium-catalyzed cross-coupling
of 9 with 4-tributylstannylbenzaldehyde diethyl acetal,
followed by introduction of a 5-bromopyrimidinyl group,
deacetalization, and reduction of the aldehyde, afforded
5b.
Introduction of carboxylic acid and alcohol into the
sulfonamide moiety (compounds 6a ,b) was performed
* To whom correspondence should be addressed. Phone: 81-48-433-
2602. Fax: 81-48-433-2610. E-mail: koichiro@tanabe.co.jp.
10.1021/jm000538f CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/14/2001

3370 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Morimoto et al.
F igu r e 1. Structures of compound 1 and designed compounds.
Sch em e 1. Introduction of Carboxylic Acid and Alcohol into the Side Chain Pyrimidine and the Tolyl Groupa
a
Reagents: (a) NaH, 2-chloro-5-pyrimidinecarboxylic acid; (b) n-BuLi, N,N-dimethylformamide; (c) NaBH4; (d) NaH, 2-chloro-5-
methylthiopyrimidin; (e) methyl 4-tributylstannylbenzoate, PdCl2(PPh3)2, PPh3, CuBr, 2,6-di-tert-butylcresol; (f) 4-tributylstannylben-
zaldehyde diethyl acetal, PdCl2(PPh3)2, PPh3, CuBr, 2,6-di-tert-butylcresol; (g) aq NaOH; (h) p-toluenesulfonic acid; (i) NaH, 5-bromo-2-
chloropyrimidin.
as shown in Scheme 2. The sulfonamides 17 and 18,
synthesized from ethyl 1-methyl-1-phenylpropionate
(15), were reacted with 4,6-dichloro-5-(4-methylphenyl)-
pyrimidine1 in the presence of K2CO3 to afford 19 and
20, respectively. Protection of the alcohol of 20 with a
tetrahydropyranyl group provided 21. The standard
transformations1 led to 6a and 6b.
The diol form 26, one of the metabolites of 1 (men-
tioned below), was prepared as in Scheme 3. Acetylation
of 6b and followed by bromination of the methyl moiety

Potent and Selective ET-A Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3371
Sch em e 2. Introduction of Carboxylic Acid and Alcohol
Sch em e 3. Synthetic Route of the Diol Form, One of
the Metabolites of 1a
into the Sulfonamide Parta
a
Reagents: (a) Ac2O, pyridine; (b) NBS, AIBN, CCl4; (c) AcOK,
NaI; (d) aq NaOH.
The metabolic experiment in vivo was supported by
a metabolic study in vitro using hepatic microsomal
fractions of several animals, including humans (Figure
3). Metabolic rates from 1 to M1 were 48 ( 13, 176 (
53, and 64 ( 49 ng/mg protein/min in rats, dogs, and
humans, respectively, and those from 1 to M2 were
calculated as 67 ( 15, 49 ( 7, and 60 ( 15 ng/mg
protein/min, respectively. The level of the dihydrox-
ylated form (M4) was below the detectable limit. From
these results, it was estimated that the main metabolic
pathways in dogs and rats were hydroxylation at the
tolyl and at the tert-butyl moiety, respectively. The
proposed metabolic pathway of 1 is shown in Figure 4.
a
Reagents: (a) ClSO3H, SOCl2; (b) NH4OH; (c) aq NaOH; (d)
NaBH4, BF3‚Et2O; (e) 5-p-tolyl-4,6-dichloropyrimidine, K2CO3; (f)
3,4-dihydro-2H-pyran, 10-camphorsulfonic acid; (g) NaH, ethylene
glycol; (h) NaH, 5-bromo-2-chloropyrimidine; (i) p-toluenesulfonic
acid.
in the tolyl group with N-bromosuccinimide (NBS) in
the presence of a catalytic amount of azobis(isobutyro-
nitrile) (AIBN) in CCl4 afforded the compound 24. The
bromo group of 24 was substituted by an acetyloxy
group (compound 25), and all the acetyl groups were
removed by alkali hydrolysis to give the diol derivative
26.
Table 1 shows the binding affinities of the synthesized
derivatives 3a ,b-6a ,b for the ETA receptor. Introduc-
tion of carboxylic acid drastically diminished the affinity
(3a , 4a , 6a ). On the other hand, introduction of a
hydroxymethyl group, especially 3b or 6b, maintained
the high affinity for the ETA receptor (3b: IC50 ) 2.6
pM; 6b: IC50 ) 6.2 pM). The binding potency of Na salts
of 3b and 6b on ET receptor subtypes are shown in
Table 2 (ETA on rat A10 cells vs ETB on human GH
cells). Both of these compounds showed high ETA-
selectivity. Since Na salt of 6b exhibited higher water
solubility (5.8 mg/mL at pH 7.5 and more than 120 mg/
mL at pH 9.5), the potency on the human cloned ETA
and ETB receptor subtypes expressed on the CHO cell
membrane was evaluated6 (Table 2). Compound 6b
showed very high affinity and selectivity for the human
ETA receptor (Ki ) 0.015 ( 0.004 nM for human ETA
receptor and Ki ) 41 ( 21 nM for human ETB receptor).
The Ki values of bosentan were 81 ( 26 nM for human
ETA and 140 ( 26 nM for human ETB.6 Because these
Resu lts a n d Discu ssion
ESI mass chromatograms of unchanged 1 and its
metabolites in the plasma 4 h after oral administration
of 1 (0.3 mg/kg) to rats and dogs are shown in Figure 2.
The [M+H]+ peaks of the compounds were observed at
m/z 598 (unchanged form), m/z 614 (M1), m/z 614 (M2),
m/z 628 (M3), and m/z 630 (M4). The structures of these
metabolites were identified as being in the hydroxylated
form at the methyl group of the tolyl moiety (M1, 5b),
in the hydroxylated and carboxylic acid form at the tert-
butyl groups (M2, 6b and M3, 6a ), and in the dihy-
droxylated form at the tert-butyl and the methyl part
of the tolyl moiety (M4, 26) by comparison with the
synthesized authentic samples using LC-MS/MS. As
shown in Figure 2, the hydroxylated forms M1 and M2
were found to be major metabolites in plasma. In rats,
hydroxylation at the tert-butyl group seemed to be
dominant; the hydroxylation of the tolyl group seemed
to be slightly faster than that of the tert-butyl in dogs
(data not shown).

3372 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Morimoto et al.
F igu r e 2. ESI mass chromatograms of metabolites in plasma from rats [A] and dogs [B] 4 h after oral administration of compound
1 (0.3 mg/kg).
Ta ble 1. Binding Affinity of Carboxylic Acid and
Hydroxymethyl Derivatives for the ETA Receptor
compd
3a
4a
6a
3b
4b
5b
6b
IC50 (nM)a
mp (°C)
mol. formulab
>10
>10
1.4
222-225
C28H29N5O6S‚0.6H2O
226-227
C
C
28H29N5O6S2‚H2O
130-137 (dec)
27H26BrN5O6S‚CH2Cl2
0.0026 172-173
0.040
0.040
C28H31N5O5S
172-173
194-195
C
28H31N5O5S2
C27H28BrN5O5S
27H28BrN5O5S
0.0062 179.5-180
C
1
2
<0.001
<0.001
7.5
bosentan
a
Inhibition of [125I]-ET-1 binding in vitro to ETA receptors in
porcine aortic membrane. Values are from a single experiment.
b
Analyses (C, H, N) were within (0.4% of theoretical values.
results indicated that 6b was preferable to 1, 6b was
further studied.
The metabolism and pharmacokinetics of 6b were
investigated in rats. The main metabolite of 6b was in
carboxylic acid form (M3), the minor one was in dihy-
droxylated form (M4) in rats,7 and the species difference
of metabolic pathway was not observed between rats
and dogs (data not shown). The bioavailability after oral
administration of 6b (0.3 mg/kg) was calculated as 60%
higher than that of 1.7 The plasma concentration of 6b
declined with an elimination half-life (t1/2) of 1.8 h (1-8
h after dosing),7 but a long duration of action was
observed in vivo.6 From the measurement of concentra-
tion in target tissues after oral administration, it was
considered that the pharmacological effects of 6b were
not mirrored in the concentration in plasma but rather
in the concentration in tissues.8
In previously published pharmacological studies, 6b,
code named TA-0201, inhibited the ET-1-induced con-
traction of the isolated endothelium-denuded rabbit
pulmonary artery and also the pressor response to
exogenous big ET-1 in the anesthetized rats in a dose-
dependent manner after both iv and po administration.6
In cardiomyopathic hamsters with chronic heart failure,
chronic ETA receptor blockade by 6b greatly ameliorated
F igu r e 3. Time course of the hydroxyl metabolites M1 (b)
and M2 (O) from compound 1 in rat [A], dog [B], and human
liver microsomes [C]. All data points were from a single
experiment.

Potent and Selective ET-A Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3373
F igu r e 4. Proposed metabolic pathway of compound 1.
Ta ble 2. Binding Potencies of 3b, 6b, 1, and Bosentan on ET Receptor Subtypes
ETA (A 10 cell)
IC50 (nM)a
ETB (GH cell)
IC50 (nM)b
human ETA
human ETB
compd
Ki (nM)c
Ki (nM)c
ETA-selectivityd
3b‚Na salt
6b‚Na salt
1
0.034 ( 0.009
0.33 ( 0.09
0.039 ( 0.011
31 ( 3
8.3 ( 0.9
38 ( 3
0.015 ( 0.004e
0.0042 ( 0.0038f
81 ( 26e
41 ( 21e
130 ( 50f
140 ( 26e
2700
29000
1.7
bosentan
a
IC50 for inhibition of specific binding of [125I]-ET-1 (20 pM) to rat A 10 cells which express ETA receptors (n ) 3, means ( SEM).
IC50 for inhibition of specific binding of [125I]-ET-1 (20 pM) to human GH cells which express ETB receptors (n ) 3, means ( SEM).c Ki
b
values on [125I]-ET-1 binding to human cloned ET receptors expressed on CHO cell membrane, means ( SEM. IC50 for human ETB/IC50
d
for human ETA. e n ) 6. f n ) 3.
the cardiac dysfunction and improved the survival rate.9
extracted three times with CHCl3. The combined extracts were
washed with brine, dried over anhydrous Na2SO4, and con-
centrated in vacuo. The residue was separated by silica gel
column chromatography (CHCl3:MeOH, 100:1, v/v then CHCl3:
Further, oral administration of 6b to hypoxic rats
inhibited the hypoxia-induced right ventricular hyper-
trophy.10
MeOH:AcOH, 30:1:1, v/v) and recrystallized from CH2Cl2-i-
Pr2O to afford 2-chloropyrimidine-5-carboxylic acid as colorless
Con clu sion
solid (640 mg, 26%): mp 126-131 °C; 1H NMR (DMSO-d6, 300
MHz) δ 14.01 (1H, br s), 9.16 (2H, s); IR (Nujol) cm-1 3330,
Modification of 1 to improve its lower water solubility
and metabolic problems led to a new potent and ETA-
selective antagonist 6b. This orally active ETA antago-
nist is so potent and selective that it is expected to
constitute a new class of drugs for treatment of various
cardiovascular diseases, such as chronic heart failure.
The clinical trial of 6b is now underway.
1700, 1570, 1545, 1460; EI-MS m/z 158 (M+), 141, 130, 123.
2-(2-((6-(4-ter t-Bu t yl)b en zen esu lfon a m id o-5-(4-m et h -
ylp h en yl)-4-p yr im id in yl)oxy)et h oxy)p yr im id in e-5-ca r -
boxylic Acid (3a ). To a stirred solution of 4-tert-butyl-N-(6-
(2-h ydr oxyet h oxy)-5-(4-m et h ylph en yl)-4-pyr im idin yl)-
benzenesulfonamide3 (7) (840 mg, 1.90 mmol) in dry THF (10
mL)-dry N,N-dimethylacetamide (DMAc) (2 mL) was added
60% NaH in mineral oil dispersion (380 mg, 9.50 mmol). After
10 min, 2-chloropyrimidine-5-carboxylic acid (453 mg, 2.86
mmol) was added, and the mixture was stirred at room
temperature for 2 h. The reaction mixture was diluted with
aqueous NH4Cl and 10% aqueous HCl, extracted with EtOAc.
The organic extracts was washed with H2O and brine, dried
over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(CHCl3:AcOEt, 3:1, v/v then CHCl3:MeOH, 50:1-10:1, v/v), and
recrystallized from EtOH-EtOAc to afford 3a as colorless
Exp er im en ta l Section
All melting points were determined on a Bu¨chi 535 digital
melting point apparatus and are uncorrected. Infrared (IR)
spectra were taken on an Analect RFX-65 or an Analect FX-
6200 FT-IR spectrophotometer. 1H NMR spectra were recorded
on a J EOL J NM-FX200, a Varian Gemini 300 spectrometer,
or a J EOL J NM-GSX400. Mass spectra were recorded on a
J EOL J MS-HX100 mass spectrometer. Elemental analyses
were performed on a Perkin-Elmer 2400 C, H, N analyzer and
a HITACHI Z-7000 atomic absorption spectrophotometer for
Na, and values were within (0.4% of the calculated values.
2-Ch lor op yr im id in e-5-ca r boxylic Acid . To a solution of
5-bromo-2-chloropyrimidine11,12 (3.00 g, 15.5 mmol) in dry THF
(200 mL) was added n-BuLi (1.63 M in hexane) (10.0 mL, 16.3
mmol) dropwise over 10 min at -90 °C, and the mixture was
stirred at the same temperature for 15 min. The solution was
poured onto solid carbon dioxide, and the whole was allowed
to warm to -20 °C, acidified with 10% aqueous HCl, and
1
crystalline powder (199 mg, 19%): mp 222-225 °C; H NMR
(DMSO-d6, 300 MHz) δ 8.95 (2H, s), 8.32 (1H, s), 7.81-7.90
(2H, m), 7.52-7.59 (2H, m), 7.07-7.16 (4H, m), 4.57-4.69 (4H,
m), 2.32 (3H, s), 1.29 (9H, s); IR (Nujol) cm-1 3380, 1705, 1595,
1565, 1460, 1450, 1430, 1410; FAB-MS m/z 564 (M+H+), 424,
307, 257, 154; Anal. (C28H29N5O6S‚0.6H2O) C, H, N.
4-t er t -Bu t yl-N -(6-(2-((5-for m yl-2-p yr im id in yl)oxy)-
e t h oxy)-5-(4-m e t h ylp h e n yl)-4-p yr im id in yl)b e n ze n e -
su lfon a m id e (8). To a stirred solution of 4-tert-butyl-N-(6-

3374 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Morimoto et al.
(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4-
pyrimidinyl)benzenesulfonamide1 (1) (700 mg, 1.17 mmol) in
dry THF (15 mL) was added 1.6 M n-BuLi in hexane (1.46
mL, 2.34 mmol) dropwise over 10 min at -78 °C. After 15 min,
DMF (3.9 mL, 50.4 mmol) was added dropwise over 50 min,
and the mixture was stirred at -78 °C for 15 min. Aqueous
NH4Cl (3 mL) was added dropwise, and the mixture was
allowed to warm to room temperature over 1 h, acidified with
aqueous HCl, and extracted with EtOAc. The organic extract
was washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was separated by silica gel
column chromatography (CHCl3:EtOAc, 100:1-30:1, v/v) to
afford 8 as colorless crystalline powder (198 mg, 31%): mp
184-187 °C; 1H NMR (CDCl3, 300 MHz) δ 10.00 (1H, s), 8.89
(2H, s), 8.38 (1H, s), 8.01 (2H, d, J ) 8.8 Hz), 7.51 (2H, d, J )
8.8 Hz), 7.22 (2H, d, J ) 7.7 Hz), 7.10 (2H, d, J ) 8.1 Hz),
4.66-4.76 (4H, m), 2.38 (3H, s), 1.34 (9H, s); IR (Nujol) cm-1
1695, 1600, 1570, 1460, 1445, 1340; FAB-MS m/z 548 (M+H+).
4-ter t-Bu tyl-N-(6-(2-((5-h yd r oxym eth yl-2-p yr im id in yl)-
oxy)eth oxy)-5-(4-m eth ylp h en yl)-4-p yr im id in yl)ben zen e-
su lfon a m id e (3b). To a suspension of 8 (143 mg, 0.261 mmol)
in THF (4 mL)-2-propanol (4 mL) was added NaBH4 (13 mg,
0.344 mmol) at 0 °C, and the mixture was stirred at 0 °C for
2 h, diluted with aqueous NH4Cl (20 mL) and H2O (50 mL),
and extracted EtOAc. The organic extract was washed with
brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CHCl3:EtOAc, 20:1, v/v then CHCl3:MeOH, 200:1-
50:1, v/v) and recrystallized from EtOAc-hexane to afford 3b
as colorless crystalline powder (96 mg, 67%): mp 172-173 °C;
1H NMR (CDCl3, 300 MHz) δ 8.46 (2H, s), 8.38 (1H, s), 8.01
(2H, d, J ) 8.7 Hz), 7.52 (2H, d, J ) 8.7 Hz), 7.25 (2H, d, J )
7.9 Hz), 7.13 (2H, d, J ) 8.2 Hz), 7.17 (1H, br s), 4.65 (2H, d,
J ) 5.5 Hz), 4.65-4.70 (2H, m), 4.58-4.62 (2H, m), 2.40 (3H,
s), 1.89 (1H, t, J ) 5.5 Hz), 1.34 (9H, s); IR (Nujol) cm-1 3400,
1560, 1465, 1450; FAB-MS m/z 550 (M+H+), 424, 153; Anal.
(C28H31N5O5S) C, H, N.
4-ter t-Bu tyl-N-(6-(2-((5-h yd r oxym eth yl-2-p yr im id in yl)-
oxy)eth oxy)-5-(4-m eth ylp h en yl)-4-p yr im id in yl)ben zen e-
su lfon a m id e Sod iu m Sa lt (Na Sa lt of 3b). To a solution of
3b (3.05 g, 5.54 mmol) in dry THF (60 mL) was added 28%
NaOMe in MeOH (1.05 g, 5.54 mmol) dropwise over 10 min
at 0 °C, and the mixture was concentrated in vacuo. The
residue was dissolved in EtOH, then Et2O was added. The
resulting precipitate was collected, washed with Et2O, and
dried in vacuo at 60 °C for 12 h to afford Na salt of 3b as
colorless crystalline powder (3.14 g, 98%): mp 175 °C-. Anal.
(C28H31N5NaO5S‚0.5H2O) C, H, N, Na.
Meth yl 4-(4-(4-ter t-Bu tylben zen esu lfon a m id o)-6-(2-((5-
m et h ylt h io-2-p yr im id in yl)oxy)et h oxy)-5-p yr im id in yl)-
ben zoa te (11). Under Ar atmosphere, a mixture of 4-tert-
butyl-N-(6-(2-((5-methylthio-2-pyrimidinyl)oxy)ethoxy)-5-bromo-
4-pyrimidinyl)benzenesulfonamide1 (10) (509 mg, 0.917 mmol),
PdCl2(PPh3)2 (256 mg, 0.365 mmol), PPh3 (48 mg, 0.182 mmol),
CuBr (26 mg, 0.182 mmol), 2,6-di-tert-butylcresol (a few
crystals), and methyl 4-tributylstannylbenzoate4 (1.17 g, 2.75
mmol) in dry dioxane (15 mL) was refluxed for 8 h, cooled to
room temperature, and diluted with EtOAc and 10% aqueous
KF, and the mixture was stirred at room temperature for 15
min. Insoluble materials were removed by filtration on Celite.
The organic layer of the filtrate was washed with H2O and
brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CHCl3:EtOAc, 5:1, v/v) and preparative TLC (CHCl3:
EtOAc, 4:1, v/v), and recrystallized from EtOAc-hexane to
afford 11 as colorless crystalline powder (201 mg, 36%): mp
171-172 °C; 1H NMR (CDCl3, 300 MHz) δ 8.42 (3H, s), 8.06-
8.11 (2H, m), 7.99-8.04 (2H, m), 7.49-7.55 (2H, m), 7.32-
7.37 (2H, m), 7.06 (1H, br s), 4.63-4.69 (2H, m), 4.54-4.60
(2H, m), 3.96 (3H, s), 2.44 (3H, s), 1.34 (9H, s); IR (Nujol) cm-1
3250, 1715, 1570, 1460, 1440, 1425; FAB-MS m/z 610 (M+H+),
468, 169.
oic Acid (4a ). A mixture of 11 (142 mg, 0.232 mmol) and 1 N
aqueous NaOH (0.46 mL, 0.46 mmol) in THF (3 mL)-H2O (1
mL) was stirred at room temperature for 8 h, diluted with H2O,
acidified with 10% aqueous HCl, and extracted twice with
CHCl3. The combined organic extracts were washed with H2O
and brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was separated by preparative TLC (CHCl3:
MeOH, 10:1 v/v), and recrystallized from EtOAc-hexane to
afford 4a as colorless crystalline powder (56 mg, 41%): mp
226-227 °C; 1H NMR (CDCl3+DMSO-d6, 300 MHz) δ 8.43 (2H,
s), 8.38 (1H, s), 8.05-8.10 (2H, m), 7.95-8.01 (2H, m), 7.48-
7.53 (2H, m), 7.34-7.39 (2H, m), 4.63-4.69 (2H, m), 4.56-
4.60 (2H, m), 2.45 (3H, s), 1.34 (9H, s); IR (Nujol) cm-1 3180,
1690, 1610, 1580, 1560, 1540; FAB-MS m/z 596 (M+H+), 454,
309, 155, 137, 119; Anal. (C28H29N5O6S2‚H2O) C, H, N.
4-ter t-Bu t yl-N-(5-(4-d iet h oxym et h yl)p h en yl-6-(2-((5-
m et h ylt h io-2-p yr im id in yl)oxy)et h oxy)-4-p yr im id in yl)-
ben zen esu lfon a m id e (12). Under Ar atmosphere, a mixture
of 10 (1.50 g, 2.70 mmol), PdCl2(PPh3)2 (386 mg, 0.550 mmol),
PPh3 (283 mg, 1.08 mmol), CuBr (155 mg, 1.08 mmol), 2,6-di-
tert-butylcresol (a few crystals), and 4-tributylstannybenz-
aldehyde diethyl acetal5 (3.80 g, 8.10 mmol) in dry dioxane
(20 mL) was refluxed for 4 h, cooled to room temperature, and
diluted with EtOAc and 10% aqueous KF. The mixture was
stirred at room temperature for 30 min, and the insoluble
materials were removed by filtration on Celite. The filtrate
was extracted twice with EtOAc. The combined organic
extracts were washed with H2O and brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (CHCl3:EtOAc,
5:1, v/v) and recrystallized from EtOAc-hexane to afford 12
as colorless crystalline powder (650 mg, 37%): mp 165.5-166.5
°C; 1H NMR (CDCl3, 300 MHz) δ 8.44 (2H, s), 8.39 (1H, s),
7.99-8.04 (2H, m), 7.49-7.58 (4H, m), 7.22-7.28 (2H, m), 7.15
(1H, br s), 5.53 (1H, s), 4.64-4.69 (2H, m), 4.54-4.59 (2H, m),
3.55-3.75 (4H, m), 2.44 (3H, s), 1.34 (9H, s), 1.28 (6H, t, J )
7.1 Hz); IR (Nujol) cm-1 1590, 1570, 1560, 1540, 1460, 1450,
1430, 1375, 1335; FAB-MS m/z 654 (M+H+), 608, 438, 169.
4-ter t-Bu t yl-N-(5-(4-h yd r oxym et h yl)p h en yl-6-(2-((5-
m et h ylt h io-2-p yr im id in yl)oxy)et h oxy)-4-p yr im id in yl)-
ben zen esu lfon a m id e (4b). (1) A mixture of 12 (558 mg, 0.853
mmol) and p-toluenesulfonic acid monohydrate (50 mg, 0.263
mmol) in THF (18 mL)-H2O (6 mL) was stirred at room
temperature for 1 h, diluted with EtOAc, washed with H2O
and brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CHCl3:EtOAc, 2:1, v/v), and recrystallized from
CH2Cl2-EtOAc to afford 4-tert-butyl-N-(5-(4-formyl)phenyl-6-
(2-((5-methylthio-2-pyrimidinyl)oxy)ethoxy)-4-pyrimidinyl)ben-
zenesulfonamide as colorless crystalline powder (345 mg,
70%): mp 223-224 °C; 1H NMR (CDCl3, 300 MHz) δ 8.44 (1H,
s), 8.41 (2H, s), 7.99-8.05 (2H, m), 7.91-7.96 (2H, m), 7.50-
7.56 (2H, m), 7.43-7.48 (2H, m), 7.06 (1H, br s), 4.65-4.71
(2H, m), 4.55-4.61 (2H, m), 2.44 (3H, s), 1.34 (9H, s); IR (Nujol)
cm-1 1680, 1665, 1600, 1580, 1560, 1540, 1460; FAB-MS m/z
580 (M+H+), 309, 273, 257.
(2) To a stirred solution of the obtained formyl derivative
(120 mg, 0.207 mmol) in THF (6 mL)-2-propanol (3 mL) was
added NaBH4 (12 mg, 0.317 mmol) at 0 °C, and the mixture
was stirred at the same temperature for 15 min. The reaction
mixture was diluted with 10% aqueous HCl and extracted
twice with EtOAc. The combined organic extracts were washed
with H2O and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was separated by prepara-
tive TLC (CHCl3:EtOAc, 1:1 v/v), and recrystallized from
EtOAc-hexane to afford 4b as colorless crystalline powder (79
mg, 66%): mp 172-173 °C; 1H NMR (CDCl3, 300 MHz) δ 8.42
(2H, s), 8.40 (1H, s), 7.98-8.04 (2H, m), 7.49-7.55 (2H, m),
7.41-7.46 (2H, m), 7.21-7.26 (2H, m), 7.14 (1H, br s), 4.75
(2H, d, J ) 5.9 Hz), 4.64-4.69 (2H, m), 4.56-4.61 (2H, m),
2.44 (3H, s), 1.87 (1H, t, J ) 6.0 Hz), 1.34 (9H, s); IR (Nujol)
cm-1 3470, 1570, 1550, 1460, 1440, 1430, 1375; FAB-MS m/z
582 (M+H+), 440, 309, 242, 169; Anal. (C28H31N5O5S2) C, H,
N.
4-(4-(4-ter t-Bu t ylb en zen esu lfon a m id o)-6-(2-((5-m et h -
ylt h io-2-p yr im id in yl)oxy)et h oxy)-5-p yr im id in yl)b en z-

Potent and Selective ET-A Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3375
4-ter t-Bu t yl-N-(5-(4-d iet h oxym et h yl)p h en yl-6-(2-h y-
d r oxyeth oxy)-4-p yr im id in yl)ben zen esu lfon a m id e (13).
The same method as for compound 11 started from N-(5-
bromo-6-(2-hydroxyethoxy)-4-pyrimidinyl)-4-tert-butylbenzene-
sulfonamide1 (9) afforded 13 as pale yellow foam (61%): 1H
NMR (CDCl3, 300 MHz) δ 8.42 (1H, s), 8.02 (2H, d, J ) 8.6
Hz), 7.62 (2H, d, J ) 8.6 Hz), 7.56 (2H, d, J ) 8.2 Hz), 7.28
(2H, d, J ) 8.2 Hz), 7.20 (1H, s), 4.37-4.42 (2H, m), 3.67-
3.72 (6H, m), 1.34 (3H, s), 1.34 (9H, s), 1.30 (3H, s); IR (Nujol)
cm-1 3380, 3240, 1365, 1170; ESI-MS m/z 530 (M+H+).
1, v/v) to afford 17 as colorless crystalline powder (1.77 g,
94%): mp 134 °C-; 1H NMR (DMSO-d6, 300 MHz) δ 12.51 (1H,
br s), 7.78 (2H, d, J ) 8.7 Hz), 7.53 (2H, d, J ) 8.7 Hz), 7.30
(2H, s), 1.50 (6H, s); IR (Nujol) cm-1 3330, 3260, 1730, 1715,
1460, 1315; FAB-MS m/z 243 (M+H+), 198, 170.
4-(2-H y d r o x y -1,1-d i m e t h y le t h y l)b e n z e n e s u lfo n -
a m id e (18). To a suspension of NaBH4 (2.34 g, 61.8 mmol) in
dry THF (50 mL) was added BF3‚Et2O (0.84 mL, 68.3 mmol)
dropwise at 0 °C over 5 min, and the mixture was stirred at
the same temperature for 30 min. A solution of 17 (5.00 g,
20.6 mmol) in dry THF (25 mL) was added dropwise at the
same temperature over 30 min, and the mixture was stirred
at room temperature for 3 h. MeOH was added to the reaction
mixture until H2 gas generation stopped. The mixture was
diluted with 10% aqueous HCl and extracted twice with
EtOAc. The combined organic extracts were washed with H2O
and brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CHCl3:MeOH, 100:1-10:1, v/v), and crystallized
from CHCl3 to afford 18 as colorless prisms (4.61 g, 98%): mp
102-104 °C; 1H NMR (DMSO-d6, 300 MHz) δ 7.73 (2H, d, J )
8.6 Hz), 7.26 (2H, br s), 7.54 (2H, d, J ) 8.7 Hz), 4.75 (1H, t,
J ) 5.3 Hz), 3.44 (2H, d, J ) 5.3 Hz), 1.24 (6H, s); IR (Nujol)
cm-1 3500, 3340, 3260, 3080, 1325; FAB-MS m/z 230 (M+H+),
213, 195.
N -(6-(2-((5-Br om o-2-p yr im id in yl)oxy)e t h oxy)-5-(4-
d ieth oxym eth yl)p h en yl-4-p yr im id in yl)-4-ter t-bu tylben -
zen esu lfon a m id e (14). To a suspension of 60% NaH in
mineral oil dispersion (81 mg, 2.01 mmol) in THF (2 mL) was
added a solution of 13 (355 mg, 0.672 mmol) in dry DMAc (1
mL)-dry THF (5 mL) dropwise over 5 min at room tempera-
ture. 5-Bromo-2-chloropyrimidine11,12 (195 mg, 1.01 mmol) was
added. The mixture was stirred at room temperature for 2.5
h, diluted with ice-saturated aqueous NH4Cl, and extracted
twice with EtOAc. The combined organic extracts were washed
with H2O and brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The residue was purified by silica gel
column chromatography (CHCl3:EtOAc, 5:1, v/v), and recrys-
tallized from Et2O-hexane to afford 14 as colorless crystalline
1
powder (303 mg, 66%): mp 200-201.5 °C; H NMR (DMSO-
d6, 300 MHz) δ 8.67 (2H, s), 8.40 (1H, s), 7.90 (2H, d, J ) 7.8
Hz), 7.58 (2H, d, J ) 7.7 Hz), 7.39 (2H, d, J ) 7.9 Hz), 7.23
(2H, d, J ) 7.8 Hz), 5.50 (1H, s), 4.58-4.63 (4H, m), 3.52-
3.58 (4H, m), 1.30 (9H, s), 1.19 (6H, t, J ) 7.2 Hz); IR (Nujol)
cm-1 1340, 1160; ESI-MS m/z 686 (M+H+).
N -(6-(2-((5-Br om o-2-p yr im id in yl)oxy)e t h oxy)-5-(4-
h yd r oxym et h yl)p h en yl-4-p yr im id in yl)-4-ter t-b u t ylb en -
zen esu lfon a m id e (5b). The same method as for compound
4b started from 14 afforded 5b as colorless crystalline powder
(76%): mp 194-195 °C; 1H NMR (DMSO-d6, 300 MHz) δ 10.38
(1H, br s), 8.70 (1H, s), 8.36 (1H, s), 7.90 (2H, d, J ) 8.4 Hz),
7.58 (2H, d, J ) 8.4 Hz), 7.32 (2H, d, J ) 7.7 Hz), 7.19 (2H, d,
J ) 7.7 Hz), 5.32 (1H, s), 4.58-4.63 (2H, m), 4.52-4.58 (4H,
m), 1.29 (9H, s); IR (Nujol) cm-1 3497, 1568, 1549, 1461, 1447,
1431; ESI-MS m/z 612(M-H-); Anal. (C27H28BrN5O5S) C, H,
N.
Eth yl 2-Meth yl-2-(4-su lfa m oylp h en yl)p r op ion a te (16).
(1) To a solution of ethyl 2-methyl-2-phenylpropionate (15)
(2.00 g, 10.4 mmol) in CH2Cl2 (20 mL) was added ClSO3H (1.73
mL, 26.0 mmol) dropwise over 3 min at 0 °C, and the mixture
was allowed to stir at room temperature for 22 h. After
evaporation of the volatile, SOCl2 (20 mL) was added, and the
reaction mixture was stirred at 60 °C for 3 h. The volatile was
evaporated. The residue was poured into ice-water and
extracted with ether. The organic extract was washed with
H2O and brine, dried over anhydrous MgSO4, and concentrated
in vacuo to afford crude ethyl 2-(4-chlorosulfonylphenyl)-2-
methylpropionate as pale brown oil (2.33 g).
2-(4-(N-(6-Ch lor o-5-(4-m et h ylp h en yl)-4-p yr im id in yl)-
su lfa m oyl)p h en yl)-2-m eth ylp r op ion ic Acid (19). To a
solution of 4,6-dichloro-5-(4-methylphenyl)pyrimidine3 (2.95 g,
12.3 mmol) and 17 (3.00 g, 12.3 mmol) in dry DMSO (21 mL)
was added 60% NaH in mineral oil dispersion (1.58 g, 39.5
mmol) in some portions over 10 min at room temperature, and
the mixture was stirred at the same temperature for 22 h,
diluted with ice-10% aqueous HCl, and extracted twice with
EtOAc. The combined organic extracts were washed with H2O
and brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CHCl3:MeOH, 100:1, v/v), and the residual solid was
triturated with i-Pr2O to afford 19 as colorless crystalline
powder (1.54 g, 28%): dec 239-241 °C; 1H NMR (CDCl3+
DMSO-d6, 300 MHz) δ 8.52 (1H, s), 8.02 (2H, d, J ) 8.4 Hz),
7.55 (2H, d, J ) 8.7 Hz), 7.36 (2H, d, J ) 8.1 Hz), 7.19 (2H, d,
J ) 8.1 Hz), 2.46 (3H, s), 1.59 (6H, s); IR (Nujol) cm-1 3250,
1695, 1540, 1445, 1345; FAB-MS m/z 446 (M+H+).
N-(6-Ch lor o-5-(4-m et h ylp h en yl)-4-p yr im id in yl)-4-(2-
h yd r oxy-1,1-d im eth yleth yl)ben zen esu lfon a m id e (20). A
mixture of 18 (3.06 g, 13.3 mmol), 4,6-dichloro-5-(4-methyl-
phenyl)pyrimidine3 (3.19 g, 13.3 mmol), and K2CO3 (5.51 g,
39.9 mmol) in dry DMSO (60 mL) was stirred at 80 °C for 1.5
h, cooled to room temperature, poured into ice-aqueous HCl,
and extracted twice with EtOAc. The combined organic
extracts were washed with H2O and brine, dried over anhy-
drous Na2SO4, and concentrated in vacuo. The residual solid
was recrystallized from EtOAc-hexane to afford 20 as colorless
1
crystalline powder (4.11 g, 71%): mp 228-229 °C; H NMR
(2) To a solution of the obtained sulfonyl chloride (2.33 g)
in ice-H2O (25 mL)-EtOAc (25 mL) was added concentrated
NH4OH (4 mL). The mixture was stirred at room temperature
for 2 h and acidified with 10% aqueous HCl. The organic layer
was separated, washed with H2O and brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residual
oil was crystallized from i-Pr2O-hexane to afford 16 as
(CDCl3, 300 MHz) δ 8.56 (1H, s), 8.06 (2H, d, J ) 8.8 Hz),
7.56 (2H, d, J ) 8.8 Hz), 7.37 (2H, d, J ) 7.8 Hz), 7.21 (1H, br
s), 7.15 (2H, d, J ) 8.1 Hz), 3.66 (2H, d, J ) 6.2 Hz), 1.37 (1H,
t, J ) 6.2 Hz), 1.36 (6H, s); IR (Nujol) cm-1 3540, 1540, 1455,
1380, 1335; FAB-MS m/z 432 (M+H+), 220, 154, 137, 119.
N -(6-C h lo r o -5-(4-m e t h y lp h e n y l)-4-p y r im id in y l)-4-
(1,1-d im et h yl-2-((t et r a h yd r o-2H -p yr a n -2-yl)oxy)et h yl)-
ben zen esu lfon a m id e (21). A mixture of 20 (500 mg, 1.15
mmol), 3,4-dihydro-2H-pyran (125 mg, 1.49 mmol), and 10-
camphorsulfonic acid (13 mg, 0.0560 mmol) in CH2Cl2 (60 mL)
was stirred at room temperature for 1.5 h, diluted with 10%
aqueous NaHCO3, and extracted twice with CHCl3. The
combined organic extracts were washed with H2O and brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(CHCl3:EtOAc, 15:1, v/v), and recrystallized from CH2Cl2-
EtOAc to afford 21 as colorless crystalline powder (444 mg,
83%): mp 182-183 °C; 1H NMR (CDCl3, 300 MHz) δ 8.55 (1H,
s), 8.00-8.05 (2H, m), 7.54-7.60 (2H, m), 7.35-7.40 (2H, m),
7.12-7.18 (3H, m), 4.48-4.52 (1H, m), 3.79 (1H, d, J ) 9.4
1
colorless crystalline powder (1.56 g, 42%): mp 73-78 °C; H
NMR (CDCl3, 300 MHz) δ 7.88 (2H, d, J ) 8.8 Hz), 7.49 (2H,
d, J ) 8.9 Hz), 5.01 (2H, br s), 4.13 (2H, q, J ) 7.2 Hz), 1.59
(6H, s), 1.19 (3H, t, J ) 7.2 Hz); IR (Nujol) cm-1 3360, 3275,
1720, 1550, 1460, 1330; EI-MS m/z 271 (M+), 227, 198.
2-Meth yl-2-(4-su lfa m oylp h en yl)p r op ion ic Acid (17). To
a solution of 16 (2.23 g, 8.22 mmol) in MeOH (10 mL) was
added a solution of NaOH (1.14 g, 28.5 mmol) in H2O (10 mL)
at 0 °C. The mixture was allowed to stir at room temperature
for 22 h, acidified with 10% aqueous HCl, saturated with NaCl,
and extracted twice with EtOAc. The combined organic
extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (CHCl3:MeOH, 20:1-10:

3376 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21
Morimoto et al.
Hz), 3.55-3.64 (1H, m), 3.37-3.45 (1H, m), 3.33 (1H, d, J )
9.4 Hz), 2.46 (3H, s), 1.25-1.75 (6H, m), 1.38 (6H, s); IR (Nujol)
cm-1 3240, 1540, 1445, 1375, 1345; FAB-MS m/z 516 (M+H+),
432, 414, 350, 220, 154, 137, 119.
N -(6-(2-((5-Br om o-2-p yr im id in yl)oxy)e t h oxy)-5-(4-
m eth ylp h en yl)-4-p yr im id in yl)-4-(2-h yd r oxy-1,1-d im eth -
yleth yl)ben zen esu lfon a m id e Sod iu m Sa lt (Na Sa lt of 6b).
To a solution of 6b (10.20 g, 16.4 mmol) in THF (100 mL)-
MeOH (20 mL) was added 28% NaOMe in MeOH (3.10 g, 16.1
mmol) dropwise over 15 min at 0 °C, and the solvent was
evaporated. The residue was dissolved in MeOH, then con-
centrated in vacuo. i-PrOH was added, and the resulting
precipitate was collected, washed with i-Pr2O, and dried in
vacuo at 60 °C for 18 h to afford Na salt of 6b as colorless
crystalline powder (10.40 g, 96%): mp 182 °C- (dec); Anal.
(C27H28BrN5NaO5S‚1.5H2O) C, H, N, Na.
2-(4-(N-Acet yl-N-(6-(2-((5-b r om o-2-p yr im id in yl)oxy)-
et h oxy)-5-(4-m et h ylp h en yl)-4-p yr im id in yl)su lfa m oyl)-
p h en yl)-2-m eth ylp r op yl Aceta te (23). To a solution of 6b
(500 mg, 0.814 mmol) in dry pyridine (3 mL) was added acetic
anhydride (0.23 mL, 2.44 mmol) at 0 °C. The mixture was
stirred at room temperature for 18 h, diluted EtOAc, washed
with 10% aqueous HCl, H2O, and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (hexane:EtOAc, 2:1, v/v)
to afford 23 as colorless foam (498 mg, 88%): 1H NMR (CDCl3,
300 MHz) δ 8.77 (1H, s), 8.48 (2H, s), 8.09 (2H, d, J ) 8.7 Hz),
7.52 (2H, d, J ) 8.6 Hz), 7.29 (2H, d, J ) 8.2 Hz), 7.20 (2H, d,
J ) 7.9 Hz), 4.82 (2H, m), 4.72 (2H, m), 4.15 (2H, s), 2.40 (3H,
s), 2.01 (3H, s), 1.83 (3H, s), 1.38 (6H, s); IR (Nujol) cm-1 1740,
1718, 1375, 1315; FAB-MS m/z 722 (M+Na+), 700 (M+H+).
2-(4-(N-(5-((4-Acet oxym et h yl)p h en yl)-6-(2-((5-b r om o-
2-p yr im id in yl)oxy)eth oxy)-4-p yr im id in yl)-N-a cetylsu lf-
a m oyl)p h en yl)-2-m eth ylp r op yl Aceta te (25). (1) A mixture
of 23 (200 mg, 0.286 mmol), NBS (60 mg, 0.336 mmol), and
AIBN (3 mg, 0.0153 mmol) in CCl4 (2 mL) was refluxed for 2
h. After cooling, the precipitate was removed by filtration, and
the filtrate was concentrated in vacuo. The residue was
separated by silica gel column chromatography (hexane:
EtOAc, 2:1-1:1, v/v) to afford crude 2-(4-(N-acetyl-N-(5-((4-
bromomethyl)phenyl)-6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-
4-pyrimidinyl)sulfamoyl)phenyl)-2-methylpropyl acetate (24)
as colorless foam (218 mg).
2-(4-(N-(6-(2-((5-Br om o-2-p yr im id in yl)oxy)eth oxy)-5-(4-
m eth ylp h en yl)-4-p yr im id in yl)su lfa m oyl)p h en yl)-2-m eth -
ylp r op ion ic Acid (6a ). (1) To ethylene glycol (30 mL) was
added 60% NaH in mineral oil dispersion (0.78 g, 19.5 mmol)
in some portions at room temperature over 30 min, and 19
(1.50 g, 3.25 mmol) was added. The mixture was stirred at
110 °C for 2 days, cooled to room temperature, diluted with
ice-10% aqueous HCl, and extracted twice with EtOAc. The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by silica gel column chromatography (CHCl3:
MeOH, 100:1-10:1, v/v) to afford 2-(4-(N-(6-(2-hydroxyethoxy)-
5-(4-methylphenyl)-4-pyrimidinyl)sulfamoyl)phenyl)-2-meth-
ylpropionic acid as pale yellow crystalline powder (1.28 g,
84%): mp 189-191 °C; 1H NMR (DMSO-d6+D2O+TFA*, 200
MHz) δ 8.37 (1H, s), 7.92 (2H, d, J ) 8.3 Hz), 7.52 (2H, d, J )
8.8 Hz), 7.26 (2H, d, J ) 8.8 Hz), 7.21 (2H, d, J ) 8.8 Hz),
4.27-4.33 (2H, m), 3.53-3.59 (2H, m), 2.37 (3H, s), 1.50 (6H,
s) (*The peaks observed were broad without addition of D2O
and TFA.); IR (Nujol) cm-1 3480, 3270, 3250, 1720, 1560, 1435,
1305; FAB-MS m/z 472 (M+H+), 428, 308, 154.
(2) To a suspension of 60% NaH in mineral oil dispersion
(344 mg, 8.59 mmol) in dry DMAc (3 mL)-dry THF (3 mL)
was added the obtained hydroxyethoxy derivative (900 mg,
1.91 mmol) in dry DMAc (5 mL)-dry THF (5 mL) dropwise
over 10 min at room temperature. 5-Bromo-2-chloropyrimi-
dine11,12 (1.48 g, 7.63 mmol) was added. The mixture was
stirred at room temperature for 3 h, diluted with ice-10%
aqueous HCl, and extracted twice with EtOAc. The combined
organic extracts were washed with brine, dried over anhydrous
Na2SO4, and concentrated in vacuo. The residue was purified
by silica gel column chromatography (CHCl3:MeOH, 100:1-
20:1, v/v), and recrystallized from CH2Cl2-i-Pr2O to afford 6a
as colorless prisms (988 mg, 73%): dec 130-137 °C; 1H NMR
(DMSO-d6, 300 MHz) δ 12.54 (1H, br s), 10.39 (1H, br s), 8.69
(2H, s), 8.36 (1H, s), 7.94 (2H, d, J ) 7.9 Hz), 7.52 (2H, d, J )
8.1 Hz), 7.18 (2H, d, J ) 8.0 Hz), 7.11 (2H, d, J ) 7.9 Hz),
4.58-4.64 (2H, m), 4.52-4.58 (2H, m), 2.35 (3H, br s), 1.49
(6H, s); IR (Nujol) cm-1 3240, 1720, 1570, 1560, 1460, 1430,
1420, 1340; FAB-MS m/z 630 (M+H+); Anal. (C27H26BrN5O6S‚
CH2Cl2) C, H, N.
(2) A mixture of crude 24 (200 mg, 0.286 mmol), potassium
acetate (267 mg, 2.72 mmol), and sodium iodide (4 mg, 0.0272
mmol) in dry DMF (2 mL) was stirred at 60 °C for 3 h. The
reaction mixture was poured into ice-water and extracted
with EtOAc. The extract was washed with H2O and brine,
dried over anhydrous Na2SO4, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
(hexane:EtOAc, 3:1-1:1, v/v) to afford 25 as colorless foam (106
mg, 52% from 23): 1H NMR (CDCl3, 300 MHz) δ 8.46 (2H, s),
8.40 (1H, s), 8.06 (2H, d, J ) 8.4 Hz), 7.51 (2H, d, J ) 8.8 Hz),
7.45 (2H, d, J ) 7.8 Hz), 7.26 (2H, d, J ) 8.4 Hz), 7.12 (1H,
br), 5.16 (2H, s), 4.67 (2H, m), 4.58 (2H, m), 4.13 (2H, s), 2.17
(3H, s), 1.99 (3H, s), 1.38 (6H, s); IR (Nujol) cm-1 1735, 1377,
1227; FAB-MS m/z 716 (M+H+).
N-(6-(2-((5-Br om o-2-p yr im id in yl)oxy)eth oxy)-5-((4-h y-
d r oxym et h yl)p h en yl)-4-p yr im id in yl)-4-(2-h yd r oxy-1,1-
d im eth yleth yl)ben zen esu lfon a m id e (26). To a solution of
25 (91 mg, 0.127 mmol) in THF (1 mL)-MeOH (1 mL) was
added 1 N aqueous NaOH (0.5 mL) at 0 °C, and the mixture
was stirred at the same temperature for 1 h. The reaction
mixture was neutralized with saturated aqueous NH4Cl, and
the volatile was evaporated. The residue was dissolved in
EtOAc-H2O, and the separated organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The residue was purified by silica gel column chroma-
tography (CHCl3:MeOH, 30:1, v/v), and recrystallized from
Et2O-hexane to afford 26 as colorless crystalline powder (70
mg, 87%): mp 199-201 °C; 1H NMR (CDCl3, 300 MHz) δ 8.45
(2H, s), 8.39 (1H, s), 8.05 (2H, d, J ) 8.6 Hz), 7.54 (2H, d, J )
8.6 Hz), 7.44 (2H, d, J ) 8.1 Hz), 7.25 (2H, d, J ) 8.4 Hz),
7.19 (1H, br), 4.75 (2H, d, J ) 5.3 Hz), 4.66 (2H, m), 4.58 (2H,
m), 3.67 (2H, d, J ) 5.7 Hz), 1.85 (1H, br), 1.36 (6H, s); IR
(Nujol) cm-1 3489, 1571, 1336; FAB-MS m/z 632 (M+H+); Anal.
(C27H28BrN5O6S‚0.2H2O) C, H, N.
N -(6-(2-((5-Br om o-2-p yr im id in yl)oxy)e t h oxy)-5-(4-
m eth ylp h en yl)-4-p yr im id in yl)-4-(1,1-d im eth yl-2-((tetr a -
h ydr o-2H-pyr an -2-yl)oxy)eth yl)ben zen esu lfon am ide (22).
The same procedure as for 6a started from 21 afforded 22 as
colorless foam (395 mg, 76%): 1H NMR (CDCl3, 300 MHz) δ
8.44 (2H, s), 8.37 (1H, s), 8.01 (2H, d, J ) 8.7 Hz), 7.55 (2H, d,
J ) 8.7 Hz), 7.24 (2H, d, J ) 8.3 Hz), 7.15 (1H, br s), 7.09 (2H,
d, J ) 8.1 Hz), 4.62-4.67 (2H, m), 4.56-4.61 (2H, m), 4.50
(1H, t, J ) 3.3 Hz), 3.78 (1H, d, J ) 9.4 Hz), 3.54-3.63 (1H,
m), 3.35-3.43 (1H, m), 3.32 (1H, d, J ) 9.4 Hz), 2.41 (3H, s),
1.20-1.76 (6H, m), 1.37 (6H, s); IR (Nujol) cm-1 3360, 1565,
1455, 1420; FAB-MS m/z 698 (M+H+), 524, 414, 203, 201.
N -(6-(2-((5-Br om o-2-p yr im id in yl)oxy)e t h oxy)-5-(4-
m eth ylp h en yl)-4-p yr im id in yl)-4-(2-h yd r oxy-1,1-d im eth -
yleth yl)ben zen esu lfon a m id e (6b). A mixture of 22 (200 mg,
0.286 mmol) and p-toluenesulfonic acid monohydrate (50 mg,
0.0263 mmol) in MeOH (4 mL)-THF (2 mL) was stirred at
room temperature for 16 h, diluted with EtOAc, washed with
H2O and brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. The residue was separated by preparative TLC
(CHCl3:EtOAc, 5:1, v/v), and recrystallized from EtOAc-
hexane to afford 6b as colorless crystalline powder (153 mg,
1
87%): mp 179.5-181 °C; H NMR (CDCl3, 300 MHz) δ 8.44
(2H, s), 8.37 (1H, s), 8.02-8.08 (2H, m), 7.50-7.56 (2H, m),
7.21-7.26 (2H, m), 7.17 (1H, br s), 7.08-7.13 (2H, m), 4.63-
4.68 (2H, m), 4.56-4.61 (2H, m), 3.65 (1H, d, J ) 6.3 Hz), 2.41
(3H, s), 1.36 (6H, s), 1.33 (1H, t, J ) 6.3 Hz); IR (Nujol) cm-1
3500, 3240, 1565, 1550, 1460, 1440, 1430; FAB-MS m/z 614
(M+H+), 461, 309; Anal. (C27H28BrN5O5S) C, H, N.

Potent and Selective ET-A Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 21 3377
(3) (a) Burri, K.; Clozel, M.; Fischli, W.; Hirth, G.; Lo¨ffler, B.-M.;
Ramuz, H. (F. Hoffmann-La Roche AG). Eur. Pat. Appl. EP
510526, 28 Oct. 1992. (b) Breu, V.; Clozel, M.; Fischli, W.; Hirth,
G.; Lo¨ffler, B.-M.; Neidhart, W.; Ramuz, H. (F. Hoffmann-La
Roche AG). Eur. Pat. Appl. EP 526708, 10 Feb. 1993.
(4) (a) Hylarides, M. D.; Wilbur, D. S.; Hadley, S. W.; Fritzberg, A.
R. Synthesis and Iodination of Methyl 4-tributylstannylbenzoate,
p-(Methoxycarbonyl)phenylmercuric chloride and p-(Methoxy-
carbonyl)phenylboronic acid. J . Organomet. Chem. 1989, 367,
259-265. (b) Ohmomo, Y.; Murakami, K.; Hirata, M.; Magata,
Y.; Tanaka, C.; Yokoyama, A. Radioiodinated N-(2-Aminoethyl)-
2-chloro-4-iodobenzamide: A New Ligand for Monoamine Oxi-
dase B Studies with Single Photon Emission Computed Tomog-
raphy. Chem. Pharm. Bull. 1994, 42, 913-916.
(5) 4-Tributylstannylbenzaldehyde diethyl acetal was prepared in
a reaction of 4-bromobenzaldehyde diethyl acetal with 1.2 equiv
of Mg in THF (reflux, 40 min) and following treatment with 0.9
equiv of tributylstannyl chloride (from -78 °C to room temper-
ature, 3 h) (colorless oil, 86% yield).
(6) Hoshino, T.; Yamauchi, R.; Kikkawa, K.; Yabana, H.; Murata,
S. Pharmacological Profile of T-0201, A Highly Potent and Orally
Active Endothelin Receptor Antagonist. J . Pharmacol. Exp.
Ther., 1998, 286, 634-649.
ETA Recep tor Bin d in g Assa y on P or cin e Aor tic Mem -
br a n e. These binding experiments were performed in
a
manner similar to Ihara et al.13 with minor modification.1
Bin d in g Stu d ies on Cu ltu r ed Cells (r a t A10 cells for
ETA r ecep tor s a n d h u m a n GH cells for ETB r ecep tor s)
a n d on Mem br a n es of CHO Cells (exp r essin g clon ed
h u m a n ETA a n d ETB r ecep tor s). These binding studies were
carried out as reported.6
Met a b olic a n d P h a r m a cok in et ic St u d ies of Com -
p ou n d 1. (1) In vivo study (determination of 1 and its major
metabolites): Compound 1 (0.3 mg/kg/10 mL in 0.25% CMC)
was administered to three rats and dogs. Blood samples were
collected with a heparinized syringe 4 h after administration
(Cmax point). Sample preparation and analyses were carried
out as reported.7,8 (2) In vitro study (analyses of metabolic
pathway in species): The species difference of metabolic
activities and formation of the metabolites from 1 were studied
using the liver microsome of rat, dog, and human. The
experiments were carried out as reported.7
Meta bolic a n d P h a r m a cok in etic Stu d ies of 6b. These
(7) Ohashi, N.; Ohashi, R.; Yoshikawa, M. Studies on the Metabolic
Fate of a Novel Orally Active Nonpeptide Endothelin Antagonist
TA-0201: Metabolism and First-pass Metabolism of TA-0201 in
Rats. Xenobiot. Metabol. and Dispos. 1998, 13, 546-556.
(8) Ohashi, N.; Nakamura, S.; Yoshikawa, M. Determination of TA-
0201, A Novel Orally Active Non-peptide Endothelin Antagonist,
studies were described in the reported articles.7,8
Ack n ow led gm en t. The authors thank the staff of
the analytical section of our laboratory for spectral
measurements and elemental analyses.
in Rat Plasma and Tissues by
a Liquid Chromatography-
electrospray Ionization-tandem Mass Spectrometry System. J .
Pharm. Biomed. Anal. 1999, 19, 491-499.
Refer en ces
(9) Yamauchi-K, R.; Miyauchi, T.; Hoshino, T.; Kobayashi, T.;
Aihara, H.; Sakai, S.; Yabana, H.; Goto, K.; Sugishita, Y.;
Murata, S. Role of Endothelin in Deterioration of Heart Failure
Due to Cardiomyopathy in Hamsters. Circulation 1999, 99,
2171-2176.
(1) Morimoto, H.; Shimadzu, H.; Kushiyama, E.; Kawanishi, H.;
Hosaka, T.; Kawase, Y.; Yasuda, K.; Kikkawa, K.; Yamauchi,
R.; Yamada, K. Potent and Selective ET-A Antagonists. 1.
Syntheses and Structure-Activity Relationships of N-(6-(2-
(Aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide Derivatives. J . Med.
Chem. 2001, 44, 3355-3368.
(2) (a) Walter, S. I.; de-Vries, J . X.; Kreiner, C.; Ittensohn, A.;
Stenzhorn, G.; Voss, A.; Weber, E. Bioequivalence of Allopurinol
Preparations: to be Assessed by the Parent Drug or the Active
Metabolite? Clin. Invest. 1993, 71, 240-246. (b) Wong, P. C.;
Price, W. A., J r.; Chiu, A. T.; Duncia, J . V.; Carini, D. J .; Wexler,
R. R.; J ohnson, A. L.; Timmermans, P. B. Nonpeptide Angio-
tensin II Receptor Antagonists. XI. Pharmacology of EXP3174:
An Active Metabolite of DuP 753, An Orally Active Antihyper-
tensive Agent. J . Pharmacol. Exp. Ther. 1990, 255, 211-217.
(c) Cohen, M. L.; Kurz, K. D.; Fuller, R. W.; Calligaro, D. O.
Comparative 5-HT2-Receptor Antagonist Activity of Amesergide
and its Active Metabolite 4-Hydroxyamesergide in Rats and
Rabbits. J . Pharm. Pharmacol. 1994, 46, 226-229.
(10) Itoh, H.; Yokochi, A.; Yamauchi-K, R.; Maruyama, K. Effects of
the Endothelin ETA Receptor Antagonist, TA-0201, on Pulmo-
nary Arteries Isolated from Hypoxic Rats. Eur. J . Pharmacol.
1999, 376, 233-238.
(11) Crosby, D. G.; Berthold, R. V. n-Butyl 5-Chloro-2-pyrimidoxy-
acetate-A Plant Growth Regulator Analogue. J . Org. Chem.
1960, 25, 1916-1919.
(12) Brown, D. J .; Lyall, J . M. Pyrimidine Reactions VI. The Ami-
nation of Chloropyrimidines with n-Alkylamines. Aust. J . Chem.
1964, 17, 794-802.
(13) Ihara, M.; Fukuroda, T.; Saeki, T.; Nishikibe, M.; Kojiri, K.;
Suda, H.; Yano, M. An Endothelin Receptor (ETA) Antagonist
Isolated from Streptomyces Misakiensis. Biochem. Biophys. Res.
Commun. 1991, 178, 132-137.
J M000538F