Discovery and synthesis of (S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2(4,6- dimethylpyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 302872), a novel orally active mixed ET(A)/ET(B) receptor antagonist

Article abstract of DOI:10.1021/jm9910425

Structural variation of the endothelin A-selective antagonist (S)-3- methoxy-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 135252) led to analogues which retain ETA affinity but exhibit substantial ET(B) affinity as well. The most active derivative obtained is (S)-3-[2- (3,4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)-3,3- diphenylpropionic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via an acid-catalyzed transetherification. It has a K(i) = 2.15 nM for binding to the ETA receptor and a K(i) = 4.75 nM for binding to the ET(B) receptor, is orally available, and antagonizes the big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea pigs each time at a dose of 10 mg/kg.

Full text of DOI:10.1021/jm9910425

3026
J . Med. Chem. 1999, 42, 3026-3032
Expedited Articles
Discover y a n d Syn th esis of (S)-3-[2-(3,4-Dim eth oxyp h en yl)eth oxy]-2-
(4,6-d im eth ylp yr im id in -2-yloxy)-3,3-d ip h en ylp r op ion ic Acid (LU 302872), a Novel
Or a lly Active Mixed ETA/ETB Recep tor An ta gon ist
Willi Amberg,*,† Stefan Hergenro¨der,‡ Heinz Hillen,† Rolf J ansen,† Georg Kettschau,† Andreas Kling,†
Dagmar Klinge,† Manfred Raschack,‡ Hartmut Riechers,† and Liliane Unger‡
Hauptlaboratorium, BASF AG, 67056 Ludwigshafen, Germany, and Knoll AG, 67008 Ludwigshafen, Germany
Received March 22, 1999
Structural variation of the endothelin A-selective antagonist (S)-3-methoxy-2-(4,6-dimethoxy-
pyrimidin-2-yloxy)-3,3-diphenylpropionic acid (LU 135252) led to analogues which retain ETA
affinity but exhibit substantial ETB affinity as well. The most active derivative obtained is
(S)-3-[2-(3,4-dimethoxyphenyl)ethoxy]-2-(4,6-dimethylpyrimidin-2-yloxy)-3,3-diphenylpropion-
ic acid (LU 302872), which can be prepared in enantiomerically pure form in eight steps via
an acid-catalyzed transetherification. It has a Ki ) 2.15 nM for binding to the ETA receptor
and a Ki ) 4.75 nM for binding to the ETB receptor, is orally available, and antagonizes the
big ET-induced blood pressure increase in rats and the big ET-induced bronchospasm in guinea
pigs each time at a dose of 10 mg/kg.
In tr od u ction
Ch em istr y
Endothelins (ET) are a family of 21 amino acid
peptides (ET-1, ET-2, ET-3)1 which act as modulators
of the vascular tone, cell proliferation, and hormone
production.2 Their actions are mediated by two recep-
tors, the ETA and the ETB receptor, which are seven
transmembrane domain receptors that couple to differ-
ent intracellular signaling pathways via heterotrimeric
G proteins. Due to their pronounced physiological effects
and because elevated levels of ET-1 have been found in
a number of disease states, ET is considered to be
relevant in the pathogenesis of several diseases such
as myocardial infarction,3 hypertension,4 congestive
heart failure,5 atherosclerosis,6 cerebral vasospasm,7
renal failure,8 asthma,9 and prostate hyperplasia.10
With regard to the different localizations and functions
of ET receptor subtypes, it might be beneficial to block
specifically only one receptor or both receptors at the
same time.11
Meanwhile, a number of potent balanced ET receptor
antagonists has been reported including SB-209670,12
L-749,329,13 and A-182086.14 All these compounds
strongly depend on the presence of a benzodioxole
moiety which in other cases has been shown to be
metabolically unstable.15 Other balanced antagonists
are Bosentan (Ro 47-0203)16 and Ro 48-569517 belonging
to a group of sulfonamides and IRL 346118 which might
be considered as peptidic.
SAR studies in the development of the selective ETA
antagonist (S)-3-methoxy-2-(4,6-dimethoxypyrimidin-2-
yloxy)-3,3-diphenylpropionic acid LU 135252 (1, active
enantiomer of LU 12704319) demonstrated the impor-
tance of the substituent in the â-position. If the methoxy
group was replaced by a more lipophilic side chain
containing a phenyl group, the ETB affinity was im-
proved substantially whereas the ETA affinity was
essentially retained. The general synthesis of these
compounds is shown in Scheme 1. A detailed protocol
describing the preparation of 4 has been published
previously.19 The hydroxy ester 4 is hydrolyzed by KOH
to produce the carboxylic acid 5 in over 90% yield.
Conversion of 5 to the dianion and reaction with an
appropriate pyrimidine derivative gives the final prod-
uct 6 in up to 80% yield. As indicated in Scheme 1, this
short sequence allows a broad variation of the core
structure.
The desired endothelin receptor antagonists have
been prepared in enantiomerically pure form by optical
resolution of compounds 5 or 6 in several cases, but this
strategy sometimes gave poor results which was par-
ticularly true for the preparation of the hydroxy car-
boxylic acid (S)-10. This problem was solved by a three-
In the present article we report the discovery of a
novel class of nonpeptidic mixed ETA/ETB receptor
antagonists.
* To whom correspondence should be addressed. Tel: +49 621
6042536. Fax: + 49 621 6020440. E-mail: wilhelm.amberg@basf-ag.de.
† BASF AG.
‡ Knoll AG.
10.1021/jm9910425 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/24/1999

Synthesis of a Mixed ETA/ ETB Receptor Antagonist
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3027
Ta ble 1. Effect of a Spacer between a Phenyl Group and an Oxygen Atom in â-Position
Ki (nM)a
compd
spacer
R2
ETA
ETB
A/B ratio
11a
11b
11c
11d
11e
11f
11g
11h
CH2-CH2
4-Me
4-Me
4-Me
3,4,5-TriOMe
3,4,5-TriOMe
3,4-DiOMe
3,4-DiOMe
3,4-DiOMe
3,4-DiOMe
32.5
23
32
1.38 ( 0.2
48
0.48 ( 0.09
2
3.49 ( 0.75
2.15 ( 0.66
55
170
320
3.21 ( 0.19
20
1.7
7.4
10
2.3
0.4
125
31
CH2-CH2-CH2
CHdCH-CH2
CH2-CH2
CHdCH-CH2
60
63
CH2
CH2-CH2
CH2-CH2
7.15 ( 0.63
4.75 ( 0.57
2.0
2.2
(S)-11h (LU 302872)
a
Ki’s ( SE were determined from the inhibition of [125I]ET-1 (ETA assay) or [125I]ET-3 (ETB assay) binding to cloned human ETA or
ETB receptor as described in the Experimental Section.
Sch em e 1. General Synthesis of the Endothelin
Receptor Antagonists
Sch em e 2. Synthesis of Enantiomerically Pure
Hydroxy Acid (S)-10
affinity than over the ETA binding. With regard to the
ETA/ETB ratio and the receptor affinity, the optimal
chain length seems to be 2 carbon atoms as incorpora-
tion of a C-1 or a C-3 spacer already resulted in a
decrease in binding affinity toward the ETB receptor.
Table 2 highlights the effect of the substituent at the
phenyl ring. A methyl group or a sterically equivalent
chlorine atom in the para position afforded compounds
with a balanced antagonism, but with a low affinity for
both receptors. Introduction of alkoxy substituents
improved markedly the binding activity which was
particularly pronounced for compounds 11d and 11h .
A free hydroxy group instead of a methoxy group is
tolerated (12e), whereas the introduction of a carboxylic
acid in the para position (12g) surprisingly resulted in
an almost selective ETA antagonist.
Once the spacer length and the substitution pattern
of the phenyl group of the side chain were established,
compounds 12a and 11h were taken for further varia-
tions of R1 and R3. Introduction of a substituted phenyl
ring in the â-position afforded compounds with an ETA/
ETB ratio of 1 or even less, but it was unfortunately
accompanied by a substantial loss of binding affinity to
both receptors. This result matches the findings of the
previously reported ETA selective antagonist 1.19 On the
contrary, variation of R3 gave no clear SAR. Replace-
ment of one methyl group in 11h by a methoxy group
(13e) gave a compound with an inferior ETA/ETB ratio,
but reverse cases were also found (not shown in the
step procedure (Scheme 2): the (S)-hydroxy acid 7 (ee
> 99%), already used in large quantities for the prepa-
ration of 1, is first converted to the methyl ester (S)-8.
Then, the methoxy group is replaced by 2-(3,4-dimethoxy-
phenyl)ethanol in an acid-catalyzed transetherification
without loss of enantiomeric purity. The resulting
methyl ester (S)-9 is finally hydrolyzed to the hydroxy
carboxylic acid (S)-10 with an ee of >99%. This three-
step synthesis can be performed without purification of
intermediates in an overall yield of 60% on a kilogram
scale.
Resu lts a n d Discu ssion
SAR studies for the novel balanced receptor antago-
nists are summarized in Tables 1-3. As shown in Table
1, it was possible to substantially improve ETB affinity
through modification of the spacer between the â-oxygen
atom and the aromatic group. The length of this alkyl
chain, varying from zero to three carbon atoms, was
found to have a much stronger influence over ETB

3028 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Ta ble 2. Effect of the Variation of R2 on the Binding Affinity
Amberg et al.
mM MnCl2, 40 µg/mL bacitracin, and 0.2% BSA, with 25 pM
[
125I]ET-1 (ETA assay) or 25 pM [125I]ET-3 (ETB assay) in the
presence or absence of the test compound. Nonspecific binding
was measured with 0.1 µM ET-1. All assays were performed
in triplicate and repeated at least once.
After incubation, membranes were collected on GF/B glass
fiber filters and radioactivity was determined by liquid scintil-
lation counting.
Eva lu a tion . The specific radioligand binding to each recep-
tor was defined as the difference between total binding and
nonspecific binding determined in the presence of an excess
of unlabeled ligand (ET-1, 10-7 M). Ki values were determined
either from IC50 values according to Cheng and Prusoff (for
determinations based on three concentrations of test com-
pound) or by nonlinear regression analysis using a program
similar to LIGAND.20,21 Standard errors were determined by
simultaneous fitting of two or three repeated inhibition curves.
Ki (nM)a
A/B
ratio
compd
R2
ETA
ETB
11a
11d
11h
12a
12b
12c
12d
12e
12f
12g
4-Me
32.5
55
1.7
2.3
2.0
4.0
4.7
8.0
9.2
4.7
12
3,4,5-TriOMe
3,4-DiOMe
4-OMe
1.38 ( 0.75
3.49 ( 0.75
6.03 ( 0.89
19.8 ( 3.5
3.13 ( 0.66
25
3.21 ( 0.19
7.15 ( 0.63
24.2 ( 6.1
94.1 ( 18.5
25.1 ( 6.6
4-Cl
3-OMe, 4-OEt
H
Or a l Activity in Ra ts a n d Gu in ea P igs. In h ibition of
ET-In d u ced Blood P r essu r e In cr ea se in Ra ts. The ET
antagonists were given orally in a dose of 10 mg/kg to male
Sprague-Dawley rats. The animals were anesthetized with
urethane (1.6 g/kg i.p.) and tracheotomized 90 min later. The
left carotid artery was cannulated for blood pressure deter-
mination and the left jugular vein for administration of big
ET-1. Next, 120 min after oral administration of the ET
antagonists, 20 µg/kg big ET-1 was given i.v.22 Blood pressure
was recorded over 30 min, and the area under the data
(AUD30min) was calculated.
230
4-OH
3.48 ( 1.21
1.92 ( 0.92
1.5
16.2 ( 3.4
24
115
3-OMe, 4-OCH2COOH
4-COOH
77
Ki’s ( SE were determined from the inhibition of [125I]ET-1
(ETA assay) or [125I]ET-3 (ETB assay) binding to cloned human
ETA or ETB receptor as described in the Experimental Section.
a
table). Fortunately, the 4,6-dimethylpyrimidine that
gave the best results (Table 3) is most easily synthesized
as well.
In h ib it ion of E T-In d u ced Br on ch osp a sm in Gu in ea
P igs. Bronchospasm was investigated using a modification of
Konzett’s and Ro¨ssler’s method.23,24 Male guinea pigs (Dunkin
Hartley, Harlan) weighing 300-450 g were orally treated with
the ET antagonists and were anesthetized with pentobarbital
(60 mg/kg i.p.) 90 min later. The animals were artificially
ventilated using a Starling pump with an inspiratory pressure
of 100 mm H2O, a tidal volume of 5 mL/100 g body weight,
and 60 strokes/min. Excess air not taken up by the lungs was
bypassed. Respiratory volume (mL) was measured as the
pressure difference using a whole body plethysmograph and
a Fleisch tube. At 120 min after oral treatment with ET
antagonists, the anesthetized guinea pigs received an i.v.
injection of 20 µg/kg big ET-1. This induces a long lasting
bronchospasm, as indicated by the reduction of respiratory
volume, which was monitored over 30 min, followed by
calculation of the area under the data (AUD30min).
As several compounds showed a good binding profile
to both receptors, functional ET-1 antagonism was
examined in vivo to assess their oral bioavailability. The
results for the big ET-1 induced blood pressure increase
in rats (ETA antagonism) are summarized in Table 4.10
Two compounds, 12c and 11h , showed a very pro-
nounced effect, which is even equal to our selective ETA
antagonist 1. On the contrary, identical doses of Bosen-
tan (Roche) did not show any activity under the same
conditions. The weak effect of 12f might be explained
by its higher polarity. Compound 11h was chosen for
further evaluation because it showed a better affinity
to the ETB receptor; in addition the corresponding
phenethyl alcohol is easier to synthesize than the
alcohol necessary for 12c.
Gen er a l Ch em ica l P r oced u r es. Unless otherwise speci-
fied, all solvents and reagents were obtained from commercial
suppliers and used without further purification. Synthesis of
substituted benzophenones is described in ref 19. Melting
points were determined with a Bu¨chi 530 apparatus and are
uncorrected. Analytical TLC was performed on silica gel plates
(Merck silica gel 60 F254). All final products were shown to be
homogeneous by gradient HPLC on a HP 1090 liquid chro-
matograph with UV detection. 1H NMR spectra were recorded
using Bruker DPX200 (200 MHz), Bruker AC250 (250 MHz),
or Bruker AC270 (270 MHz) spectrometers. All values are
reported as chemical shifts in δ units (ppm) relative to
tetramethylsilane as internal standard. Mass spectral analysis
was accomplished with a Finnigan MAT 90 instrument using
direct chemical ionization techniques, or a Micromass Q-TOF
for high-resolution MS (HRMS). Optical rotation was deter-
mined on a Perkin-Elmer 241 polarimeter. The following
abbreviations are used in the Experimental Section: DMF,
dimethylformamide; NaOMe, sodium methoxide; THF, tetra-
hydrofuran.
To demonstrate the ETB antagonism and the ef-
fectiveness in a second species as well, compound 11h
was tested for inhibition of big ET 1-induced broncho-
spasm in guinea pigs. The results are summarized in
Table 5. Two hours after treatment with 10 mg/kg p.o.
of compound (S)-11h (LU 302872) or its racemate 11h ,
a very strong protection (79% and 67%, respectively)
against bronchospasm was observed. This effect could
not be achieved with the ETA-selective antagonist 1 even
using 30 mg/kg p.o.
Compound 11h was synthesized in both enantiomeric
forms which show Ki values of 2.15 and 73 nM, respec-
tively, for the ETA receptor and 4.75 and 170 nM,
respectively, for the ETB receptor. The biologically active
enantiomer should have the (S)-configuration, as the
(S)-enantiomer of 5 was used for its preparation. The
bioavailability of (S)-11h was determined to be 50-70%
in dog.
3-[2-(3,4-Dim et h oxyp h en yl)et h oxy]-2-[(4,6-d im et h yl-
p yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11h ).
(a ) 3-[2-(3,4-Dim et h oxyp h en yl)et h oxy]-2-h yd r oxy-3,3-
d ip h en ylp r op ion ic Acid Meth yl Ester . A solution of 3,3-
diphenyloxirane-2-carboxylic acid methyl ester19 (7.00 g; 27.5
mmol) and 2-(3,4-dimethoxyphenyl)ethanol (5.50 g; 30.2 mmol)
in dichloromethane (20 mL) was treated with boron trifluoride
etherate (5 drops) at room temperature and subsequently
Exp er im en ta l Section
Recep tor Bin d in g Stu d ies. The binding studies were
performed using CHO cells stably expressing human ETA or
ETB receptors. Membrane protein (10-50 µg) was incubated
for 30 min at 25 °C in 50 mM Tris-HCl, pH 7.4, containing 5

Synthesis of a Mixed ETA/ ETB Receptor Antagonist
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3029
Ta ble 3. Effect of the Variation of R1 and R3 on the Binding Affinity
Ki (nM)a
compd
R1
X
R3
ETA
ETB
A/B ratio
12a
13a
13b
13c
13d
11h
13e
13f
13g
13h
H
H
Me
ethyl
ethyl
H
H
Cl
Cl
ethyl
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
4,6-DiMe
6.3 ( 0.89
24.2 ( 6.1
23.2 ( 3.9
71.2 ( 11.4
195
160
7.15 ( 0.63
14.7 ( 1.7
130
215
40 ( 2.3
3.8
11.8
0.7
0.8
1
2.0
6.2
0.6
0.7
1
4-OMe, 6-Me
4-OMe, 5,6-(CH2)2-O-
4,6-DiMe
4-OMe, 6-Me
4,6-DiMe
4-OMe, 6-Me
4-OMe, 6-Me
4-OMe, 5,6-(CH2)3
4-OMe, 6-Me
1.95 ( 0.53
105 ( 25
250
155
3.49 ( 0.75
2.37 ( 0.48
230
290
39.3 ( 8.9
a
Ki’s ( SE were determined from the inhibition of [125I]ET-1 (ETA assay) or [125I]ET-3 (ETB assay) binding to cloned human ETA or
ETB receptor as described in the Experimental Section.
Ta ble 4. Inhibition of Big ET-Induced Blood Pressure Increase
in Rats with LU 135252 and Balanced ETA/B Receptor
Antagonistsa
3.85 (3 H, s), 3.6 (1 H, dt), 3.4 (1 H, OH), 3.2 (1 H, dt), 2.8 (2
H, t); mp 92-93 °C.
(c) 11h . To a slurry of lithium amide (9.00 g; 390 mmol) in
DMF (35 mL) was added a solution of 3-(2-(3,4-dimethoxy-
phenyl)ethoxy)-2-hydroxy-3,3-diphenylpropionic acid (55.0 g;
130 mmol) in DMF (150 mL) over a period of 15 min after
which 2-methylsulfonyl-4,6-dimethylpyrimidine (25.0 g; 137
mmol), dissolved in DMF (75 mL), was added slowly. The
resulting mixture was stirred at room temperature for 18 h;
then, the reaction product was poured into ice/water (2 L),
followed by acidification with citric acid. The precipitate was
isolated by suction, washed with water, and while still moist,
dissolved in dichloromethane. The solution of the crude product
was dried over magnesium sulfate and evaporated to give an
oily residue which was dissolved in ether. The ethereal solution
was extracted with 1 N NaOH (130 mL); the aqueous layer
was neutralized with 1 N HCl (130 mL) which resulted in the
formation of a crystalline precipitate. After the precipitate
dried, the pure product (64 g) was obtained: 1H NMR (CDCl3,
250 MHz) δ 7.3 (10 H, m), 6.7 (4 H, m), 6.3 (1 H, s), 3.9 (3 H,
s), 3.85 (3 H, s), 3.75 (1 H, m), 3.6 (1 H, m), 2.8 (2 H, t), 2.3 (6
H, s); mass spectra 529 (M + H)+; mp 125-130 °C. Anal.
(C31H32N2O6) see (S)-11h .
3-[2-(4-Met h ylp h en yl)et h oxy]-2-[(4,6-d im et h ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11a ). Com-
pound 11a was synthesized as described for 11h using 2-(4-
methylphenyl)ethanol in the first step: 1H NMR (CDCl3, 200
MHz) δ 7.3 (10 H, m), 7.0 (4 H, m), 6.7 (1 H, s), 6.3 (1 H, s),
3.7 (1 H, m), 3.5 (1 H, m), 2.8 (2 H, t), 2.3 (6 H, s), 2,25 (3 H,
s); mp foam. HRMS calcd, 483.2282; found, 483.2271 [M + H]+.
3-[3-(4-Meth ylp h en yl)p r op oxy]-2-[(4,6-d im eth ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11b). Com-
pound 11b was synthesized as described for 11h using 3-(4-
methylphenyl)propanol in the first step: 1H NMR (DMSO-d6,
270 MHz) δ 7.4-7.1 (10 H, m), 7.05 (4 H, m), 6.9 (1 H, m), 6.2
(1 H, s), 3.7 (1 H, m), 3.55 (1 H, m), 2.7 (2 H, t), 2.3 (6 H, s),
2.2 (1 H, m), 1.8 (2 H, m); mp 163-167 °C (dec). HRMS calcd,
497.2438; found, 497.2431 [M + H]+. Anal. (C31H32N2O4) C,
H, N.
b
BP increase (AUD30min
)
[mmHg × min]
compd
12a
12c
12f
11d
11h
(S)-11h
Bosentan
LU 135252
control
drug-treated
% reduction
1464 ( 89
1464 ( 89
1476 ( 117
1487 ( 113
1507 ( 86
1507 ( 86
1507 ( 86
1507 ( 86
976 ( 121
475 ( 218c
1294 ( 456
1123 ( 176
641 ( 120c
583 ( 140c
1399 ( 92
636 ( 178c
33 ( 8
68 ( 15c
14 ( 31
25 ( 12
58 ( 8c
61 ( 9c
7 ( 6
58 ( 12c
a
b
10 mg/kg p.o., 2 h pretreatment. All values reported as mean
( SEM. c p < 0.05 vs control.
Ta ble 5. Inhibition of Big ET-Induced Bronchospasm in
Guinea Pigs with LU 135252 and Balanced ETA/B Receptor
Antagonistsa
reduction in respiratory volume
b
AUD30min [mL × min]
compd
11h
(S)-11h
LU 135252
control
drug-treated
% inhibition
213 ( 41
213 ( 41
213 ( 41
71 ( 16c
46 ( 15c
172 ( 26d
67 ( 8c
79 ( 7c
19 ( 12
a
b
10 mg/kg p.o., 2 h pretreatment. All values reported as mean
( SEM. c p < 0.05 vs control. 30 mg/kg p.o.
d
stirred for 2 h. The solvent was evaporated, and the crude
residue (10.7 g; 89%) was used without further purification.
(b) 3-[2-(3,4-Dim eth oxyp h en yl)eth oxy]-2-h yd r oxy-3,3-
diph en ylpr opion ic Acid. 3-(2-(3,4-Dimethoxyphenyl)ethoxy)-
2-hydroxy-3,3-diphenylpropionic acid methyl ester (12.0 g; 27.5
mmol) was dissolved in dioxane (110 mL), followed by treat-
ment with 1 N NaOH (55 mL). The resulting mixture was
stirred at 80 °C for 2 h. After cooling to room temperature,
the reaction mixture was diluted with water and extracted
with ether (2×). The aqueous layer was acidified with 1 N HCl
and extracted with ether again. The organic layer was dried
over magnesium sulfate and the solvent was evaporated. The
crude residue was crystallized from diethyl ether/n-hexane to
yield the desired carboxylic acid as colorless crystals (10.2 g;
87%): 1H NMR (CDCl3, 270 MHz) δ 7.4-7.1 (10 H, m), 6.8 (1
H, d), 6.7 (1 H, dbr), 6.6 (1 H, sbr), 5.0 (1 H, s), 3.9 (3 H, s),
3-[3-(4-Meth ylp h en yl)p r op -(2E)-en oxy]-2-[(4,6-d im eth -
ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11c).
Compound 11c was synthesized as described for 11h using
3-(4-methylphenyl)prop-(2E)-enol in the first step: 1H NMR
(CDCl3, 200 MHz) δ 7.5-7.0 (14 H, m), 6.7 (1 H, s), 6.6 (1 H,
d), 6.4 (1 H, s), 6.2 (1 H, dt), 4.3 (1 H, dd), 4.1 (1 H, dd), 2.35
(6 H, s), 2.3 (3 H, s); mp 181-182 °C. HRMS calcd, 495.2282;
found, 495.2281 [M + H]+.

3030 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16
Amberg et al.
3-[2-(3,4,5-Tr im et h oxyp h en yl)et h oxy]-2-[(4,6-d im et h -
ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11d ).
Compound 11d was synthesized as described for 11h using
2-(3,4,5-trimethoxyphenyl)ethanol in the first step: 1H NMR
(CDCl3, 200 MHz) δ 7.3-7.1 (10 H, m), 6.7 (1 H, s), 6.35 (2 H,
s), 6.3 (2 H, s), 3.9 (9 H, m), 3.8 (1 H, m), 3.6 (1 H, m), 2.8 (2
H, t), 2.3 (6 H, s); mp 154-155 °C. HRMS calcd, 559.2442;
found, 559.2426 [M + H]+.
ic Acid (12f). Compound 12f was synthesized as described
for 11h using 2-(3-methoxy-4-methoxycarbonylmethoxy-
phenyl)ethanol in step (a). Deprotection of the methyl ester
was carried out during step (b) allowing a trianion during the
last step: 1H NMR (DMSO-d6, 200 MHz) δ 7.3-7.1 (10 H, m),
6.9-6.6 (4 H, m), 6.1 (1 H, s), 4.5 (1 H, s), 4.0 (1 H, m), 3.8 (3
H, s), 3.7 (1 H, m), 2.8 (2 H, t), 2.3 (6 H, s); mp foam. HRMS
calcd, 573.2235; found, 573.2225 [M + H]+.
3-[3-(3,4,5-Tr im eth oxyp h en yl)p r op -(2E)-en oxy]-2-[(4,6-
d im eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid
(11e). Compound 11e was synthesized as described for 11h
using 3-(3,4,5-trimethylphenyl)prop-(2E)-enol in the first
step: 1H NMR (CDCl3, 200 MHz) δ 7.5-7.2 (10 H, m), 6.8 (1
H, m), 6.55 (1H, s), 6.5 (1 H, d), 6.3 (1 H, s), 6.15 (1 H, dt), 4.3
(1 H, dd), 4.1 (1 H, dd), 3.9 (6 H, s), 3.85 (3 H, s), 2.3 (6 H, s);
mass spectra 571 (M + H)+; mp foam.
3-(3,4-Dim eth oxyp h en oxy)-2-[(4,6-d im eth ylp yr im id in -
2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11f). Compound 11f
was synthesized as described for 11h using 3,4-dimethoxy-
phenol in the first step: 1H NMR (CDCl3, 200 MHz) δ 7.75 (2
H, m), 7.4-7.1 (8 H, m), 6.7 (1 H, m), 6.55 (2 H, m), 6.45 (1 H,
dd); 6.2 (1 H, d), 3.8 (3 H, s), 3.6 (3 H, s), 2.3 (6 H, s); mp
115-116 °C. HRMS calcd, 501.2024; found, 501.2029 [M + H]+.
Anal. (C33H34N2O7) C, N; H calcd, 5.6; found, 6.1.
3-(3,4-Dim eth oxyben zyloxy)-2-[(4,6-dim eth ylpyr im idin -
2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (11g). Compound
11g was synthesized as described for 11h using 3,4-dimethoxy-
benzyl alcohol in the first step: 1H NMR (CDCl3, 200 MHz) δ
7.5-7.2 (10 H, m), 6.95-6.8 (3 H, m), 6.7 (1 H, s); 6.3 (1 H, s),
4.6 (1 H, d), 4.5 (1 H, d), 3.85 (3 H, s), 3.8 (3 H, s), 2.3 (6 H, s);
mp 125-126 °C. HRMS calcd, 515.2180; found, 515.2159 [M
+ H]+.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12a ). Com-
pound 12a was synthesized as described for 11h using 2-(4-
methoxyphenyl)ethanol in the first step: 1H NMR (DMSO-
d6, 270 MHz) δ 7.4-7.1 (12 H, m), 6.7 (3 H, m), 6.2 (1 H, sbr),
4.0 (1 H, m), 3.7 (3 H, s), 3.65 (1 H, m), 2.8 (2 H, t), 2.3 (6 H,
s); mp foam. HRMS calcd, 499.2231; found, 499.2210 [M + H]+.
3-[2-(4-Ch lor op h en yl)et h oxy]-2-[(4,6-d im et h ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12b). Com-
pound 12b was synthesized as described for 11h using 2-(4-
chlorophenyl)ethanol in the first step: 1H NMR (CDCl3, 200
MHz) δ 7.3-7.0 (14 H, m), 6.7 (1 H, s), 6.3 (1 H, s), 3.75 (1 H,
m), 3.6 (1 H, m), 2.8 (2 H, m), 2.3 (6 H, s); mp 108-110 °C.
HRMS calcd, 503.1736; found, 503.1733 [M + H]+.
3-[2-(4-E t h oxy-3-m e t h oxyp h e n yl)e t h oxy]-2-[(4,6-d i-
m eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid
(12c). Compound 12c was synthesized as described for 11h
using 2-(4-ethoxy-3-methoxyphenyl)ethanol in the first step:
1H NMR (DMSO-d6, 270 MHz) δ 7.4-7.1 (10 H, m), 6.9-6.65
(4 H, m), 6.2 (1 H, s), 4.1-3.9 (3 H, m), 3.7 (3 H, s), 3.6 (1 H,
m), 2.8 (2 H, t), 2.3 (6 H, s), 1.3 (3 H, t); mp 123-125 °C (dec).
Anal. (C32H34N2O6) H, N; C: calcd, 72.2; found, 71.7. HRMS
calcd, 543.2493; found, 543.2494 [M + H]+.
3-(2-P h en ylet h oxy)-2-[(4,6-d im et h ylp yr im id in -2-yl)-
oxy]-3,3-d ip h en ylp r op ion ic Acid (12d ). Compound 12d was
synthesized as described for 11h using 2-phenylethanol in the
first step: 1H NMR (CDCl3, 200 MHz) δ 7.3 (15 H, m), 6.7 (1
H, s), 6.3 (1 H, s), 3.8 (1 H, m), 3.6 (1 H, m), 2.9 (2 H, t), 2.3 (6
H, s); mp 130-133 °C. HRMS calcd, 469.2126; found, 469.2120
[M + H]+.
3-[2-(4-Hyd r oxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12e). Com-
pound 12e was synthesized as described for 11h using 2-(4-
benzyloxyphenyl)ethanol in the first step. Deprotection of the
hydroxy group was carried out as last step via catalytic
hydrogenation (palladium on charcoal in ethyl acetate): 1H
NMR (CDCl3, 270 MHz) δ 7.35-7.15 (10 H, m), 6.9 (2 H, d),
6.7 (1 H, s), 6.6 (2 H, d), 6.3 (1 H, s), 3.75 (1 H, m), 3.6 (1 H,
m), 2.8 (2 H, t), 2.3 (6 H, s); mp 126-127 °C (dec). HRMS calcd,
485.2075; found, 485.2071 [M + H]+.
3-[2-(4-Ca r boxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (12g). Com-
pound 12g was synthesized as described for 11h using 2-(4-
carboxyphenyl)ethanol in step (a), allowing a trianion during
the last step: 1H NMR (CDCl3, 200 MHz) δ 7.9 (2 H, d), 7.4 (2
H, d), 7.3-7.1 (10 H, m), 6.6 (1 H, m), 6.2 (1 H, s), 4.2 (1 H,
m), 3.9 (1 H, m), 2.8 (2 H, m), 2.3 (6 H, s); mp foam. HRMS
calcd, 513.2024; found, 513.2005 [M + H]+.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4-m eth oxy-6-m eth -
ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (13a ).
Compound 13a was synthesized as described for 11h using
using 2-(4-methoxyphenyl)ethanol in step (a) and 2-(methyl-
sulfonyl)-4-methoxy-6-methylpyrimidine in step (c): 1H NMR
(DMSO-d6, 270 MHz) δ 7.4-7.1 (12 H, m), 6.8 (2 H, d), 6.4 (1
H, s), 6.1 (1 H, s), 4.0 (1 H, m), 3.8 (3 H, s), 3.7 (3 H, s), 3.65
(1 H, m), 2.8 (2 H, t), 2.2 (3 H, s); mp foam. HRMS calcd,
515.2180; found, 515.2162 [M + H]+.
3-[2-(4-Met h oxyp h en yl)et h oxy]-2-[(4-m et h oxy-5,6-d i-
h ydr ofu r o[2,3-d]pyr im idin -2-yl)oxy]-3,3-bis(4-m eth ylph en -
yl)p r op ion ic Acid (13b). Compound 13b was synthesized as
described for 11h using 2-(4-methoxyphenyl)ethanol and 3,3-
bis-(4-methylphenyl)oxirane-2-carboxylic acid methyl ester19
during step (a) and 2-(methylsulfonyl)-4-methoxy-5,6-dihydro-
furo[2,3-d]pyrimidine in step (c): 1H NMR (DMSO-d6, 200
MHz) δ 7.3-7.0 (10 H, m), 6.8 (2 H, d), 6.0 (1 H, s), 4.6 (2 H,
t), 3.8 (3 H, s), 3.75 (1 H, m), 3.65 (1 H, s), 3.5 (1 H, m), 3.0 (2
H, t), 2.8 (2 H, t), 2.2 (6 H, s); mp foam. HRMS calcd, 571.2442;
found, 571.2462 [M + H]+.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4,6-d im eth ylp yr im -
idin -2-yl)oxy]-3,3-bis-(4-eth ylph en yl)pr opion ic Acid (13c).
Compound 13c was synthesized as described for 11h using
2-(4-methoxyphenyl)ethanol and 3,3-bis-(4-ethylphenyl)oxirane-
2-carboxylic acid methyl ester19 during step (a): 1H NMR
(CDCl3, 200 MHz) δ 7.3-7.0 (10 H, m), 6.8 (2 H, d), 6.6 (1 H,
s), 6.3 (1 H, s), 3.75 (3 H, s), 3.6 (1 H, m), 3.45 (1 H, m), 2.8 (2
H, t), 2.6 (4 H, m), 2.3 (6 H, s), 1.2 (6 H, m); mp 130-133 °C
(dec). HRMS calcd, 555.2857; found, 555.2865 [M + H]+. Anal.
(C34H38N2O5) C, H, N.
3-[2-(4-Meth oxyp h en yl)eth oxy]-2-[(4-m eth oxy-6-m eth -
ylp yr im id in -2-yl)oxy]-3,3-b is-(4-et h ylp h en yl)p r op ion ic
Acid (13d ). Compound 13d was synthesized as described for
11h using 2-(4-methoxyphenyl)ethanol and 3,3-bis-(4-ethyl-
phenyl)oxirane-2-carboxylic acid methyl ester during step (a)
and 2-(methylsulfonyl)-4-methoxy-6-methylpyrimidine in step
(c): 1H NMR (CDCl3, 200 MHz) δ 7.3-7.0 (10 H, m), 6.8 (2 H,
d), 6.3 (1 H, s), 6.25 (1 H, s), 3.85 (3 H, s), 3.75 (3 H, s), 3.6 (1
H, m), 3.45 (1 H, m), 2.8 (2 H, t), 2.6 (4 H, m), 2.3 (3 H, s), 1.2
(6 H, m); mp 151-155 °C. HRMS calcd, 571.2806; found,
501.2811 [M + H]+. Anal. (C34H38N2O6) C, H, N.
3-[2-(3,4-Dim et h oxyp h en yl)et h oxy]-2-[(4-m et h oxy-6-
m eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid
(13e). Compound 13e was synthesized as described for 11h
using 2-(methylsulfonyl)-4-methoxy-6-methylpyrimidine in step
(c): 1H NMR (CDCl3, 200 MHz) δ 7.3 (10 H, m), 6.7 (3 H, m),
6.2 (1 H, s), 6.18 (1 H, s), 3.9 (9 H, m), 3.8 (1 H, m), 3.6 (1 H,
m), 2.8 (2 H, tr), 2.3 (3 H, s); mass spectra 545 (M + H)+; mp
foam.
3-[2-(3,4-Dim et h oxyp h en yl)et h oxy]-2-[(4-m et h oxy-6-
m eth ylp yr im id in -2-yl)oxy]-3,3-bis-(4-ch lor op h en yl)p r o-
p ion ic Acid (13f). Compound 13f was synthesized as de-
scribed for 11h using 3,3-bis-(4-chlorophenyl)oxirane-2-car-
boxylic acid methyl ester during step (a) and 2-(methylsul-
fonyl)-4-methoxy-6-methylpyrimidine in step (c): 1H NMR
(CDCl3, 200 MHz) δ 7.2 (8 H, m), 6.7 (3 H, m), 6.3 (1 H, s), 6.0
3-[2-(4-Ca r boxym eth oxy-3-m eth oxyp h en yl)eth oxy]-2-
[(4,6-d im eth ylp yr im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion -

Synthesis of a Mixed ETA/ ETB Receptor Antagonist
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 16 3031
(1 H, s), 3.9 (6 H, s), 3.85 (3 H, s), 3.65 (2 H, m), 2.8 (2 H, m),
2.3 (3 H, s); mp foam. HRMS calcd, 613.1506; found, 613.1509
[M + H]+.
was replaced simultaneously to ensure a continuous removal
of methanol. This procedure was performed for 5 h at a bath
temperature of 60 °C after which the reaction mixture was
cooled to room temperature and diluted with ether (300 mL).
The resulting solution was washed with aqueous sodium
bicarbonate and then, repeatedly, with water. The organic
layer was dried over magnesium sulfate and evaporated to
yield an oily residue (43 g), which was used without further
purification.
(S)-3-[2-(3,4-Dim eth oxyp h en yl)eth oxy]-2-h yd r oxy-3,3-
d ip h en ylp r op ion ic Acid ((S)-10). Compound (S)-10 was
synthesized from (S)-9 by ester hydrolysis as described for
compound 11h in step (b): yield 60% starting from (S)-8; [R]20
) +25.4 (c ) 1; methanol).
3-[2-(3,4-Dim eth oxyp h en yl)eth oxy]-2-[(4-m eth oxy-6,7-
dih ydr o-5H-cyclopen tapyr im idin -2-yl)oxy]-3,3-bis-(4-ch lo-
r op h en yl)p r op ion ic Acid (13g). Compound 13g was syn-
thesized as described for 11h using 3,3-bis-(4-chlorophenyl)-
oxirane-2-carboxylic acid methyl ester19 during step (a) and
2-(methylsulfonyl)-4-methoxy-6,7-dihydro-5H-cyclopentapyrim-
idin in step (c): 1H NMR (CDCl3, 200 MHz) δ 7.2 (8 H, m), 6.7
(4 H, m), 6.0 (1 H, s), 3.9 (3 H, s), 3.85 (3 H, s), 3.8 (3 H, s), 3.7
(2 H, m), 2.8 (6 H, m), 2.1 (2 H, quin); mp foam. HRMS calcd,
639.1663; found, 639.1653 [M + H]+. Anal. (C33H32Cl2N2O7)
C, H, N.
(S)-3-[2-(3,4-Dim eth oxyp h en yl)eth oxy]-2-(4,6-d im eth -
ylp yr im id in -2-yloxy)-3,3-d ip h en ylp r op ion ic Acid ((S)-
11h ). Compound (S)-11h was synthesized from (S)-10 as
described for compound 11h in step (c): [R]20 ) +122.3 (c ) 1;
methanol). Anal. (C31H32N2O6) C, H, N.
3-[2-(3,4-Dim et h oxyp h en yl)et h oxy]-2-[(4-m et h oxy-6-
m eth ylp yr im id in -2-yl)oxy]-3,3-bis-(4-eth ylp h en yl)p r op i-
on ic Acid (13h ). Compound 13h was synthesized as described
for 11h using 3,3-bis-(4-ethylphenyl)oxirane-2-carboxylic acid
methyl ester during step (a) and 2-(methylsulfonyl)-4-methoxy-
6-methylpyrimidine in step (c): 1H NMR (CDCl3, 200 MHz) δ
7.0-7.4 (8 H, m), 6.6 (3 H, m), 6.25 (1 H, s), 6.2 (1 H, s), 3.8 (9
H, m), 3.7 (1 H, m), 3.45 (1 H, m), 2.75 (2 H, tr), 2.6 (4 H, m),
2.3 (3 H, s), 1.2 (6 H, m); mp foam. HRMS calcd, 601.2911;
found, 601.2914 [M + H]+.
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(S)-2-Hyd r oxy-3-m eth oxy-3,3-d ip h en ylp r op ion ic Acid
((S)-7). A solution of sodium methoxide (44.6 g; 826 mmol) in
methanol (130 mL) was added dropwise to a solution of
L-proline methyl ester hydrochloride (137 g, 826 mmol) in
methanol (130 mL) at room temperature, followed by the
addition of methyl tert-butyl ether (2.4 L) and 3-methoxy-2-
hydroxy-3,3-diphenylpropionic acid19 (225 g; 826 mmol). The
resulting mixture was heated in order to distill off a mixture
of methanol and methyl tert-butyl ether (2.68 L) whereas
methyl tert-butyl ether (2.4 L) was added simultaneously.
During subsequent cooling to room temperature, (R)-3-meth-
oxy-2-hydroxy-3,3-diphenylpropionic acid‚L-proline methyl es-
ter precipitated. The crystals, containing the not-desired
enantiomer (R)-7, were separated by filtration and washed
with methyl tert-butyl ether (150 mL). The mother liquor was
concentrated by distilling off methyl tert-butyl ether (1.5 L),
after which water (1.0 L) was added and the mixture was
acidified to pH 1.2 by treatment with concentrated hydrochlo-
ric acid. After the mixture was stirred and the organic layer
was separated, the aqueous layer was extracted again with
methyl tert-butyl ether (400 mL). The organic layers were
combined, washed with water (400 mL), and evaporated. The
residue was dissolved in refluxing toluene, and the desired
enantiomer was crystallized by slowly cooling to room tem-
perature and by the addition of seeding crystals. Separation
from the mother liquor by suction, washing with toluene, and
drying in vacuo yielded (S)-2-hydroxy-3-methoxy-3,3-diphen-
ylpropionic acid (78.7 g, 35% yield corresponding to the racemic
mixture employed). Optical purity: 100% (chiral HPLC);
chemical purity: 99.8% (HPLC).
(S)-2-Hyd r oxy-3-m eth oxy-3,3-d ip h en ylp r op ion ic Acid
Meth yl Ester ((S)-8). Sodium methoxide (10.8 g; 200 mmol)
and (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid (54.4
g; 200 mmol) were suspended in DMF (300 mL). The resulting
slurry was treated dropwise with dimethyl sulfate (21.0 mL;
210 mmol) over a period of 15 min during which the mixture
warmed to 50 °C and became less viscous. The mixture was
stirred overnight and poured into water/ice (1.5 L), followed
by extraction with ether (2 × 500 mL). The combined organic
layers were washed with water (2 × 200 mL), dried over
magnesium sulfate, and evaporated. The resulting crude oil
(55.8 g) was used without further purification.
(S)-3-[2-(3,4-Dim eth oxyp h en yl)eth oxy]-2-h yd r oxy-3,3-
d ip h en ylp r op ion ic Acid Meth yl Ester ((S)-9). (S)-2-Hy-
droxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (27.9
g; 100 mmol), p-toluenesulfonic acid (1 g), and 2-(3,4-dimethoxy-
phenyl)ethanol (18.2 g; 100 mmol) were dissolved in dichloro-
methane (75 mL). The resulting solution was heated in order
to distill off the solvent and methanol generated by the
transetherification of the starting material; dichloromethane
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