Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists

Article abstract of DOI:10.1021/jm960274q

A novel class of endothelin-A receptor ligands was discovered by high-throughput screening. Lead structure optimization led to highly potent antagonists which can be synthesized in a short sequence. The compounds are endothelin-A-selective, are orally available, and show a long duration of action.

Full text of DOI:10.1021/jm960274q

J . Med. Chem. 1996, 39, 2123-2128
2123
Expedited Articles
Discover y a n d Op tim iza tion of a Novel Cla ss of Or a lly Active Non p ep tid ic
En d oth elin -A Recep tor An ta gon ists
Hartmut Riechers,*,† Hans-Peter Albrecht,† Willi Amberg,† Ernst Baumann,† Harald Bernard,†
Hans-J oachim Bo¨hm,† Dagmar Klinge,† Andreas Kling,† Stefan Mu¨ller,† Manfred Raschack,‡ Liliane Unger,‡
Nigel Walker,† and Wolfgang Wernet‡
Hauptlaboratorium, BASF AG, 67056 Ludwigshafen, Germany, and Knoll AG, 67008 Ludwigshafen, Germany
Received February 19, 1996X
A novel class of endothelin-A receptor ligands was discovered by high-throughput screening.
Lead structure optimization led to highly potent antagonists which can be synthesized in a
short sequence. The compounds are endothelin-A-selective, are orally available, and show a
long duration of action.
In tr od u ction
Endothelin is a recently discovered peptide consisting
of 21 amino acids.1 First characterized as a potent
vasoconstrictor, endothelin-1 (ET-1) and the close ho-
mologs ET-2 and ET-3 have been shown to be implicated
in a number of diseases such as hypertension, congestive
heart failure, renal failure, cerebral vasospasm, and
atherosclerosis.2-8 At present, two receptor subtypes
known as ETA and ETB have been identified.9-12 The
ETA receptor exhibits a higher affinity for ET-1 and
ET-2 and is predominantly found in smooth muscle
cells. This receptor therefore appears to be the primary
target for cardiovascular diseases.
F igu r e 1.
Ch em istr y
The synthesis of compound 6 is shown in Scheme 1.
Reaction of a symmetrically substituted benzophenone
derivative (2) with methyl chloroacetate gave the gly-
cidic ester 3 in 70-95% yield. The epoxide 3 was then
opened via Lewis acid-catalyzed addition of an alcohol
providing R-hydroxy ester 4 in about 90% yield. Nu-
cleophilic substitution of a pyrimidine derivative with
4 resulted in compound 5 in 70-80% yield. Finally, the
methyl ester was hydrolyzed using KOH to produce the
carboxylic acid 6 in 70-90% yield.
A number of ET antagonists have been reported
including the ETA-selective compounds BQ123,13,14
FR139317,15 SB 209670,16 L-749,329,17 BMS 182874,18
and PD155080,19 the balanced ETA/ETB antagonists Ro
46-20058 and Ro 47-0203,20 and the ETB-selective
compounds BQ-78821 and IPI-950.22
In the present article we wish to report the discovery
of a novel class of nonpeptidic ETA-selective receptor
antagonists. Two initial lead structures, LU 110896 and
LU 110897, compounds 1a ,b (originally designed as
herbicides), were discovered by screening the chemical
library of BASF for compounds that bind to the recom-
binant human ETA receptor (Figure 1). 1a ,b bind to
the ETA receptor with Ki values of 250 and 160 nM,
respectively. The binding to the ETB receptor is much
weaker (Ki ) 3000 and 4700 nM). 1a ,b have two
stereocenters. The primary goal was to enhance the
binding affinity while simplifying the structure. As our
first attempt to improve our lead, we decided to syn-
thesize compounds with the general structure 6 (Scheme
1). The idea was to introduce two identical substituents
at one chiral center. This effort immediately resulted
in the discovery of a novel series of potent ETA-selective
antagonists.
Resu lts a n d Discu ssion
The structure-activity relationships of our novel
series of endothelin receptor antagonists are sum-
marized in Tables 1-3. The effect of the substitution
pattern of R1 is shown in Table 1. None of the
investigated substituents resulted in improved binding
as compared to the unsubstituted compound 6a . Those
substituents in meta-position, which have been pre-
pared, seem to be tolerated. Table 2 highlights our
results for the variation of R2. Compounds 6 with R2 )
Me and Et show the highest receptor affinities. Longer
or more bulky groups lead to a reduced affinity. Re-
placement of R2 ) Me by R2 ) H strongly decreased the
binding affinity to Ki ) 130 nM (ETA).
Table 3 describes the structure-activity relationships
for a variation of R3. The selection of possible substit-
uents R3 was guided in part by a structural comparison
of 6a with 7.16 Both compounds contain a carboxy group
roughly in the center of the structure flanked by two
lipophilic side chains. A comparison of the putative 3D-
structures of 6a with 7 is shown in Figure 2.
* To whom correspondence should be addressed. Tel: +49 621 60
49628. Fax: +49 621 60 20440.
† BASF AG.
This structural overlay suggested that an annellated
ring as a lipophilic substituent R3 at the pyrimidine
‡ Knoll AG.
X Abstract published in Advance ACS Abstracts, May 1, 1996.
S0022-2623(96)00274-9 CCC: $12.00 © 1996 American Chemical Society

2124 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11
Riechers et al.
Sch em e 1
a
For specification of residues R1, R2, and R3, see Tables 1-3.
Ta ble 1. Effect of a Variation of R1 on the Binding Affinity
was 6s. In view of the rather small structural difference
between 6a and 6s, the 50-fold improvement in binding
affinity seems remarkable. It should be noted that the
ETA/ETB receptor binding ratio does not change signifi-
cantly between compounds 6a , 6p , 6q, and 6s.
Compound 6a was separated into the pure enanti-
omers, and these exhibited Ki values of 3 and 150 nM
(ETA). In order to establish the absolute configuration
of the biologically active enantiomer, the derivative 4a
(the corresponding free carboxylic acid of compound 4)
was crystallized with (R)-phenylethylamine. The X-ray
structure of the salt revealed the S-configuration for the
enantiomer 4a . Synthesis of 6a starting from this
enantiomerically pure compound led to the more potent
enantiomer. We therefore conclude (S)-6a as the bio-
logically active enantiomer.
Functional vascular ET-1 antagonism was determined
in rabbit aorta rings with intact endothelium.23 pA2
values are summarized in Table 4. The pA2 values cor-
relate with the binding affinities for the ETA receptor.24
Finally, the model of ET-induced sudden death was
used to demonstrate the oral bioavailability of selected
compounds.23 The results are summarized in Table 5.
Four hours after treatment with 30 mg/kg po compound
6a , a complete protection was observed. Even 8 h after
treatment with 6a (100 mg/kg po), complete protection
still exists. In comparison, 10 mg/kg iv 6a was neces-
sary to obtain the same effect. Compound 6p showed
higher in vivo potency than 6a after intravenous
administration (ED 100% ) 3 mg/kg iv). However, after
po administration the in vivo activity of 6p was less
than that of 6a .
Ki, nM (n)
compd
R1
ETA
ETB
6a
6b
6c
6d
6e
6f
H
6 ( 0.87 (3) 1000 (1), h-ETB: 371 ( 106 (3)
33 ( 14.5 (3) 970 (1)
p-F
p-Cl
245 (1)
200 ( 94 (3)
1300 (1)
1000 (1)
p-Me
m-F
m-OMe
m-Me
o-F
11 ( 1.8 (3) 1800 (1)
22 ( 9.7 (3) 1300 (1)
24 ( 10.8 (3) 1300 (1)
6g
6h
150 (1)
6000 (1)
Ta ble 2. Effect of a Variation of R2 on the Binding Affinity
Ki, nM (n)
compd
R2
ETA
ETB
6i
6j
6k
6l
6m
Et
Pr
Ph
7 ( 4.2 (3)
19 ( 9 (3)
86 ( 12 (3)
340 ( 80 (3)
130 ( 19 (3)
2500 (1)
1700 (1)
1500 (1)
1400 (1)
3500 (1)
In summary, we have discovered a novel class of
nonpeptidic endothelin receptor antagonists. Com-
pound 6a is an orally active, highly ETA-selective
receptor antagonist with a long duration of action.
(CH2)2-tBu
H
should improve the binding affinity because the struc-
ture-activity relationships of analogs of 7 (SB 209670)
showed a strong dependence of the binding affinity on
the substituent at the corresponding position. This
consideration led to the design and synthesis of 6p ,q,
which were found to be very potent antagonists with
binding constants of 0.9 and 0.4 nM (ETA), respectively,
and weaker binding to the ETB receptor (Ki ) 24.5 and
20.4 nM, data for the h-ETB). However, the most potent
compound in vitro in the present series of compounds
Exp er im en ta l Section
Ra d ioliga n d Bin d in g Assa ys.24 All receptor binding
studies were carried out as follows. Membranes (50 mg of
protein) from stably transfected CHO cells expressing human
ETA receptors or human ETB receptors or guinea pig cerebel-
lum containing ETB receptors were incubated with either 25
pmol/L [125I]ET-1 or [125I]ET-3 with or without drugs. Non-
specific binding was defined at 0.1 mmol/L ET-1. Ki values
were determined by nonlinear regression analysis.

Nonpeptidic ETA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11 2125
Ta ble 3. Effect of a Variation of R3 on the Binding Affinity
Ki, nM (n)
compd
R3
ETA
ETB
6n
6o
6p
6q
6r
6s
6t
6u
4,6-OEt
4,6-Me
4-OMe, 5,6-CH2CH2O-
4-OMe, 5,6-CH2CH2CH2-
4-Me
4-OMe, 6-Me
4,6-Et
4-Et, 6-Me
174 ( 33 (3)
1 ( 0.39 (3)
0.9 ( 0.09 (3)
0.4 ( 0.06 (3)
19 (1)
2500 (1)
195 (1)
57 ( 10 (3), h-ETB: 24.5 ( 10.5 (3)
56 ( 18 (3), h-ETB: 20.4 ( 6.9 (3)
1900 (1)
29 (1), h-ETB: 19.7 ( 7.6 (3)
1100 (1)
160 (1)
0.12 ( 0.06 (3)
1 ( 0.8 (3)
0.7 ( 0.12 (3)
Ta ble 4. Functional Vascular ET-1 Antagonism24
compda
pA2
6a (LU 127043)
6p (LU 134981)
6q (LU 136181)
Ro 46-2005
BMS 182874
7 (SB 209670)
7.34
9.03
9.24
<6
7.09
9.80
a
Ro 46-2005, 4-tert-butyl-N-[6-(2-hydroxyethoxy)-5-(3-methox-
yphenoxy)-4-pyrimidinyl]benzenesulfonamide; BMS 182874, 5-(dim-
ethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfona-
mide; 7 (SB 209670), (1S,2R,3S)-3-[2-(carboxymethoxy)-4-meth-
oxyphenyl]-1-[3,4-(methylenedioxy)phenyl]-5-(prop-1-yloxy)indan-
2-carboxylic acid.
Ta ble 5. Prevention of ET-1-Induced Sudden Death in Rats23
10
30
100
ED 100%
(mg/kg)
compd
mg/kg po mg/kg po mg/kg po
6a (LU 127043)
6p (LU 134981)
6q (LU 136181)
Ro 46-2005
BMS 182874
7 (SB 209670)
5/5a
6/6
nd
nd
nd
0/6
2/6
9/9
nd
nd
6/6
nd
30b
100
100
>100
>100
100
0/5
0/5
6/6
6/6
0/6
nd
a
b
Lethatliy: x/n. With 8 h pretreatment: ED 100% ) 100 mg/
kg.
none and the 4,4′-substituted analogs used as starting materi-
als were purchased from Aldrich; 3,3-difluorobenzophenone
was available from Acros Organics; the other derivatives were
prepared according to the procedure described in ref 25.
F igu r e 2. Superposition of the calculated 3D-structures of
6a (dark bonds) and SB 209670 (gray bonds). The carboxylate
groups are in the center, and the dimethoxypyrimidine group
of 6a is on the right.
All reactions were performed under nitrogen atmosphere
unless specifically noted. Melting points were determined on
a Bu¨chi 530 apparatus and are uncorrected. Analytical TLC
was performed on silica gel plates (Merck silica gel 60 F254).
All final compounds were shown to be a single homogeneous
peak by gradient HPLC on a HP 1090 liquid chromatograph
with UV detection. 1H-NMR spectra were recorded using a
Bruker AC250 spectrometer (250 MHz), and all values are
reported as chemical shifts in δ units (ppm) relative to
tetramethylsilane as internal standard. Mass spectral analy-
sis was accomplished on a Finnigan MAT 90 instrument using
direct chemical ionization techniques. Elemental analyses
were determined on a Leco CHN 800 apparatus; oxygen was
determined separately on a Leco RO-478. All values are
consistent with the theoretical data to within (0.4% unless
indicated otherwise.
In Vitr o F u n ction a l Assa y.23 Va scu la r ET-1 a n ta go-
n ism : In rabbit aorta segments (2 mm length, 2 g) preloaded
in Krebs-Henseleit solution, after 1 h relaxation, a reference
contraction to KCl (40 mmol/L) was registered isometrically;
30 min after washout, a cumulative ET-1 concentration-
response curve was established without (control) or with 15
min antagonist preincubation. pA2 values were determined
by comparing collectives of 4-5 rings/concentration to control
rings from the same aorta.
In Vivo Stu d ies.23 P r even tion of ET-1-in d u ced su d d en
d ea th in r a ts by p r etr ea tm en t w ith en d oth elin r ecep tor
a n ta gon ists: ET-1 (6 nmol/kg) causing severe ECG distur-
bances and lethality within a few minutes was injected into a
tail vein of male Sprague-Dawley rats of 280-320 g (control).
After po (4 h) pretreatment with ET antagonists, the doses
providing complete protection were determined (ED 100%).
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. Benzophe-
Abbr evia tion s: DMF, dimethylformamide; NaOMe, sodium
methoxide; THF, tetrahydrofuran.
3,3′-Dim eth ylben zop h en on e. (a) A solution of 8.55 g (50
mmol) of 3-bromotoluene in 10 mL of THF was added slowly
to 1.3 g (53 mmol) of magnesium in 10 mL of THF and refluxed

2126 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11
Riechers et al.
for 2 h. After cooling to room temperature the mixture was
treated with 16.25 g (50 mmol) of tributyltin chloride in 15
mL of THF and refluxed for 2 h. The reaction was then
quenched with an aqueous solution of ammonium chloride; the
organic layer was separated and the aqueous layer extracted
again with CH2Cl2. The combined organic layers were dried
(MgSO4) and evaporated yielding 18 g of the organotin
compound as an oil. The crude product was used in the next
step without further purification.
(b) To a mixture of 6.95 g (45 mmol) of 3-methylbenzoic acid
chloride and 150 mg of bis(triphenylphosphine)palladium(II)
chloride in 9 mL of CHCl3 was added the crude organotin
compound in 36 mL of CHCl3, and the whole mixture was
heated for 10 h to reflux temperature. Afterwards the solu-
tion was diluted with 200 mL of diethyl ether and extracted
twice with H2O. The organic layer was washed with an
aqueous KF solution and the resulting precipitate (tributyl-
tin fluoride) removed by filtration. The organic layer was
dried (MgSO4), evaporated, and purified by chromatography
on silica gel (heptane/ethyl acetate, 4:1) to give 7 g (58%) of
the product as an oil: 1H-NMR (CDCl3) δ 2.40 (s, 6H), 7.25-
7.65 (m, 8H).
3,3′-Dim eth oxyben zop h en on e. The compound was pre-
pared as described for 3,3′-dimethylbenzophenone using 3-meth-
oxybromobenzene and 3-methoxybenzoic acid chloride as
starting material giving 6.2 g (50%) of the product as an oil:
1H-NMR (CDCl3) δ 3.85 (s, 6H), 7.10 (m, 2H), 7.35 (m, 6H).
2,2′-Diflu or oben zop h en on e. The compound was pre-
pared as described for 3,3′-dimethylbenzophenone using 2-flu-
orobromobenzene and 2-fluorobenzoic acid chloride as starting
material giving 5.8 g (46%) of the product as an oil: 1H-NMR
(CDCl3) δ 6.80-7.80 (m, 8H).
3,3-Dip h en yloxir a n e-2-ca r boxylic Acid Meth yl Ester
(3, R1 ) H). In a 2 L flask 259 g (4.8 mol) of NaOMe was
stirred in 800 mL of THF and cooled to 0 °C. A solution of
500 g (2.74 mol) of benzophenone and 420 mL (4.8 mol) of
chloroacetic acid methyl ester in 100 mL of THF was added.
The mixture was stirred for 0.5 h and then partitioned between
diethyl ether (2 × 500 mL) and water (2 L). The organic phase
was separated, washed with brine, and dried over magnesium
sulfate. The solvents were evaporated in vacuo to give an oil
which was crystallized from diethyl ether/hexane to give 620
g (89%) of compound 3 as a white solid: 1H-NMR (CDCl3) δ
3.50 (s, 3H), 3.98 (s, 1H), 7.30-7.45 (m, 10H); mass spectra
(CI+) 255; mp 50-51 °C. Anal. (C16H14O3) C, H, O.
diethyl ether (3 × 200 mL). The organic layer was dried over
magnesium sulfate, the solvent was removed, and the product
was crystallized from diethyl ether to give 6 g (62%) of 6a as
a white solid: 1H-NMR (CDCl3) δ 3.32 (s, 3H), 3.83 (s, 6H),
5.75 (s, 1H), 6.11 (s, 1H), 7.22-7.55 (m, 10H); mass spectra
(CI+) 379 (M+ - MeOH); mp 165-168 °C. Anal. (C22H22N2O6)
C, H, N, O.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3,3-b is(4-flu o-
r op h en yl)-3-m eth oxyp r op ion ic Acid (6b). Compound 6b
was synthesized as in example 6a starting with 4,4′-difluo-
robenzophenone giving 2.3 g (55%, final step): 1H-NMR
(CDCl3) δ 3.28 (s, 3H), 3.90 (s, 6H), 5.75 (s, 1H), 6.08 (s, 1H),
6.95-7.50 (m, 8H); mass spectra (CI+) 415 (M+ - MeOH); mp
163-165 °C. Anal. (C22H20F2N2O6) C, H, N, O, F.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3,3-b is(4-ch lo-
r op h en yl)-3-m eth oxyp r op ion ic Acid (6c). Compound 6c
was synthesized as in example 6a starting with 4,4′-dichlo-
robenzophenone giving 1.8 g (65%, final step): 1H-NMR
(CDCl3) δ 3.33 (s, 3H), 3.83 (s, 6H), 5.77 (s, 1H), 6.02 (s, 1H),
7.22-7.42 (m, 8H); mass spectra (CI+) 447 (M+ - MeOH); mp
186-190 °C. Anal. (C22H20Cl2N2O6) Calcd: C, 55.13; H, 4.21;
O, 20.03; N, 5.84; Cl, 14.79. Found: C, 56.1; H, 4.9; O, 18.6;
N, 5.3; Cl, 13.
2-[(4,6-Dim eth oxyp yr im id in -2-yl)oxy]-3,3-bis(4-m eth -
ylp h en yl)-3-m eth oxyp r op ion ic Acid (6d ). Compound 6d
was synthesized as in example 6a starting with 4,4′-dimeth-
ylbenzophenone giving 1.9 g (50%, final step): 1H-NMR
(CDCl3) δ 2.30 (s, 3H), 2.32 (s, 3H), 3.26 (s, 3H), 3.84 (s, 6H),
5.73 (s, 1H), 6.18 (s, 1H), 7.10-7.40 (m, 8H); mass spectra (CI+)
407 (M+ - MeOH); mp 168-170 °C. Anal. (C24H26N2O6) C,
H, N, O.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3,3-b is(3-flu o-
r op h en yl)-3-m eth oxyp r op ion ic Acid (6e). Compound 6e
was synthesized as in example 6a starting with 3,3′-difluo-
robenzophenone giving 0.8 g (63%, final step): 1H-NMR
(CDCl3) δ 3.44 (s, 3H), 3.82 (s, 6H), 5.97 (s, 1H), 6.14 (s, 1H),
7.05-7.45 (m, 8H); mass spectra (CI+) 447; mp 175-177 °C.
Anal. (C22H20F2N2O6) C, H, N, O, F.
2-[(4,6-Dim eth oxyp yr im id in -2-yl)oxy]-3,3-bis(3-m eth -
oxyp h en yl)-3-m eth oxyp r op ion ic Acid (6f). Compound 6f
was synthesized as in example 6a starting with 3,3′-dimethox-
ybenzophenone giving 1.2 g (55%, final step): 1H-NMR (CDCl3)
δ 3.33 (s, 3H), 3.70 (s, 3H), 3.74 (s, 3H), 3.85 (s, 6H), 5.75 (s,
1H), 6.15 (s, 1H), 6.70-7.34 (m, 8H); mass spectra (CI+) 439
(M+ - MeOH); mp 137-140 °C. Anal. (C24H26N2O8) C, H, N,
O.
2-[(4,6-Dim eth oxyp yr im id in -2-yl)oxy]-3,3-bis(3-m eth -
ylp h en yl)-3-m eth oxyp r op ion ic Acid (6g). Compound 6g
was synthesized as in example 6a starting with 3,3′-dimeth-
ylbenzophenone giving 2.4 g (68%, final step): 1H-NMR
(CDCl3) δ 2.30 (s, 3H), 2.35 (s, 3H), 3.30 (s, 3H), 2.85 (s, 6H),
5.75 (s, 1H), 6.12 (s, 1H), 7.10-7.32 (m, 8H); mass spectra (CI+)
407 (M+ - MeOH); mp 152-156 °C. Anal. (C24H26N2O6)
Calcd: O, 21.89. Found: O, 22.1.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3,3-b is(2-flu o-
r op h en yl)-3-m eth oxyp r op ion ic Acid (6h ). Compound 6h
was synthesized as in example 6a starting with 2,2′-difluo-
robenzophenone giving 0.6 g (45%, final step): 1H-NMR
(CDCl3) δ 3.50 (s, 3H), 3.82 (s, 6H), 5.92 (s, 1H), 6.30 (s, 1H),
7.00-7.83 (m, 8H); mass specttra (CI+) 447; mp 193-194 °C.
Anal. (C22H20F2N2O6) C, H, N, O, F.
2-H yd r oxy-3-m et h oxy-3,3-d ip h en ylp r op ion ic Acid
Meth yl Ester (4, R1 ) H, R2 ) Me). A solution of 156.4 g
(0.61 mol) of 3 in 50 mL of MeOH was cooled to 0 °C, and 1
mL of BF3-Et2O was added. After 20 min 500 mL of H2O
was added, and the solution was extracted three times with
300 mL of Et2O. The organic layer was cooled to 0 °C and the
precipitate collected by filtration to give 171 g (98%) of a white
solid (4, R1 ) H, R2 ) Me): 1H-NMR (CDCl3) δ 3.18 (s, 3H),
3.63 (s, 3H), 5.18 (d, 1H), 7.25-7.42 (m, 10H); mass spectra
(CI+) 255 (M+ - MeOH); mp 90-92 °C. Anal. (C17H18O4) C,
H, O.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3-m et h oxy-3,3-
d ip h en ylp r op ion ic Acid Meth yl Ester (5, R1 ) H, R2
)
Me, R3 ) 4,6-OMe). 4 (10 g, 35 mmol) was dissolved in 100
mL of DMF; 2.4 g (17.5 mmol) of K2CO3 was added and the
suspension stirred for 0.5 h; 7.63 g (35 mmol) of 2-(methyl-
sulfonyl)-4,6-dimethoxypyrimidine was added, and the mixture
was stirred at 90 °C for 3 h; 200 mL of ethyl acetate was added,
and the solution was washed with water (50 mL), citric acid
(50 mL, 2 N), and brine (50 mL). The organic layer was
separated and dried over magnesium sulfate. The solvent was
evaporated, and the resulting oil was crystallized from diethyl
ether/hexane to give 13 g (87%) of 5 as a white solid: 1H-NMR
(CDCl3) δ 3.43 (s, 3H), 3.50 (s, 3H), 3.85 (s, 6H), 5.70 (s, 1H),
6.05 (s, 1H), 7.22-7.50 (m, 10H); mass spectra (CI+) 392 (M+
- MeOH); mp 80-82 °C. Anal. (C23H24N2O6) C, H, N, O.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3-m et h oxy-3,3-
d ip h en ylp r op ion ic Acid (6a ). 5 (10 g, 23.6 mmol) was
dissolved in 100 mL of dioxane and 50 mL of NaOH (1 N) and
stirred for 3 h at 80 °C. The solution was diluted with water
(100 mL), neutralized with HCl (1 N), and extracted with
2-[(4,6-Dim e t h oxyp yr im id in -2-yl)oxy]-3-e t h oxy-3,3-
d ip h en ylp r op ion ic Acid (6i). Compound 6i was synthesized
as in example 6a starting with compound 3 and ethanol giving
6.8 g (58%, final step): 1H-NMR (CDCl3) δ 1.27 (t, 3H), 3.50
(m, 2H), 3.88 (s, 6H), 5.76 (s, 1H), 6.22 (s, 1H), 7.25-7.55 (m,
10H); mass spectra (CI+) 379 (M+ - EtOH); mp 93-94 °C.
Anal. (C23H24N2O6) C, H, N, O.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3-p r op oxy-3,3-
d ip h en ylp r op ion ic Acid (6j). Compound 6j was synthesized
as in example 6a starting with compound 3 and propanol
giving 4.3 g (52%, final step): 1H-NMR (CDCl3) δ 0.95 (t, 3H),
1.63 (m, 2H), 3.40 (m, 2H), 3.90 (s, 6H), 5.75 (s, 1H), 6.23 (s,
1H), 7.24-7.60 (m, 10H); mass spectra (CI+) 379 (M+ - PrOH);
mp 172-174 °C. Anal. (C24H26N2O6) C, H, N, O.

Nonpeptidic ETA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11 2127
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3-p h en oxy-3,3-
d ip h en ylp r op ion ic Acid (6k ). Compound 6k was synthe-
sized as in example 6a starting with compound 3 and phenol
giving 5.1 g (46%, final step): 1H-NMR (CDCl3) δ 3.85 (s, 6H),
5.72 (s, 1H), 6.33 (s, 1H), 6.79-7.78 (m, 15H); mass spectra
(CI+) 379 (M+ - PhOH); mp 136-140 °C. Anal. (C27H24N2O6)
C, H, N, O.
2-[(4,6-Dim eth oxyp yr im id in -2-yl)oxy]-3-(3,3-d im eth yl-
bu toxy)-3,3-d ip h en ylp r op ion ic Acid (6l). Compound 6l
was synthesized as in example 6a starting with compound 3
and 3,3-dimethylbutanol giving 1.7 g (50%, final step): 1H-
NMR (CDCl3) δ 0.85 (s, 9H), 1.58 (m, 2H), 3.40 (m, 1H), 3.50
(m, 1H), 3.87 (s, 6H), 5.72 (s, 1H), 6.22 (s, 1H), 7.25-7.55 (m,
10H); mass spectra (CI+) 481; mp 154-157 °C. Anal.
(C27H32N2O6) C, H, N, O.
2-[(4,6-Dim et h oxyp yr im id in -2-yl)oxy]-3-h yd r oxy-3,3-
d ip h en ylp r op ion ic Acid (6m ). Compound 6m was synthe-
sized by debenzylation of 3-(benzyloxy)-2-[(4,6-dimethoxypy-
rimidin-2-yl)oxy]-3,3-diphenylpropionic acid using H2 and Pd/C
as a catalyst giving 4 g (96%, final step): 1H-NMR (DMSO) δ
3.82 (s, 6H), 5.90 (s, 1H), 6.10 (s, 1H), 6.20-6.40 (1H), 7.15-
7.50 (m, 10H); mass spectra (CI+) 397; mp 178-180 °C. Anal.
(C21H20N2O6) C, H, N, O.
2-[(4,6-Die t h oxyp yr im id in -2-yl)oxy]-3-m e t h oxy-3,3-
d ip h en ylp r op ion ic Acid (6n ). Compound 6n was synthe-
sized as in example 6a starting with compound 4 and
2-(methylsulfonyl)-4,6-diethoxypyrimidine giving 0.7 g (45%,
final step): 1H-NMR (CDCl3) δ 1.33 (t, 3H), 3.31 (s, 3H), 4.30
(q, 2H), 5.70 (s, 1H), 6.15 (s, 1H), 7.25-7.55 (m, 10H); mass
spectra (CI+) 407 (M+ - MeOH); mp 138-140 °C. Anal.
(C24H26N2O6) Calcd: C, 65.74; H, 5.98; O, 21.89; N, 6.39.
Found: C, 64.7; H, 6.2; O, 22.2; N, 5.8.
(methylsulfonyl)pyrimidine giving 1.1 g (50%, final step): 1H-
NMR (CDCl3) δ 1.24 (t, 6H), 2.65 (q, 4H), 3.36 (s, 3H), 6.38 (s,
1H), 6.70 (s, 1H), 7.22-7.58 (m, 10H); mass spectra (CI+) 407;
mp 142-143 °C. Anal. (C2H26N2O4) C, H, N, O.
2-[(4-E t h yl-6-m et h ylp yr im id in -2-yl)oxy]-3-m et h oxy-
3,3-d ip h en ylp r op ion ic Acid (6u ). Compound 6u was syn-
thesized as in example 6a starting with compound 4 and
4-ethyl-2-(methylsulfonyl)-6-methylpyrimidine giving 0.8 g
(46%, final step): 1H-NMR (CDCl3) δ 1.23 (t, 3H), 2.40 (s, 3H),
2.65 (q, 2H), 3.35 (s, 3H), 6.38 (s, 1H), 6.70 (s, 1H), 7.22-7.57
(m, 10H); mass spectra (CI+) 361 (M+ - MeOH); mp 163-165
°C. Anal. (C23H24N2O4) C, H, N, O.
Su p p or tin g In for m a tion Ava ila ble: Experimental data
for intermediates of the type 3-5 (Scheme 1) (13 pages).
Ordering information can be found on any current masthead
page.
Refer en ces
(1) Yanagisawa, M.; Kurihara, H.; Kimura, S.; Tomobe, Y.; Koba-
yashi, M.; Mitsui, Y.; Yazaki, Y.; Goto, K.; Masaki, T. A novel
potent vasoconstrictor peptide produced by vascular endothelial
cells. Nature 1988, 332, 411-415.
(2) Inoue, A.; Yanagisawa, M.; Kimura, S.; Kasuya, Y.; Miyauchi,
T.; Goto, K.; Masaki, T. The human endothelin family; three
structurally and pharmacologically distinct isopeptides predicted
by three separate genes. Proc. Natl. Acad. Sci. U.S.A. 1989, 86,
2863-2867.
(3) Watanabe, T.; Suzuki, N.; Shimamoto, N.; Fujino, M.; Imada,
A. Endothelin in myocardial infarction. Nature 1990, 344, 114.
(4) Saito, Y.; Nakao, K.; Mukoyama, M.; Imura, H. Increased plasma
endothelin level in patients with essential hypertension. N.
Engl. J . Med. 1989, 322, 205.
(5) Giaid, A.; Yanagisawa, M.; Langleben, D.; Michel, R.; Levy, R.;
Shennib, H.; Kimra, S.; Masaki, T.; Duguid, W.; Path, F. R. C.;
Stewart, D. J . Expression of endothelin-1 in the lungs of patients
with pulmonary hypertension. N. Engl. J . Med. 1993, 328,
1732-1739.
(6) Takahashi, K.; Totsune, K.; Mouri, T. Endothelin in chronic renal
failure. Nephron 1994, 66, 373-379.
(7) Cosentino, F.; Katusic, Z. S. Does Endothelin-1 play a role in
the pathogenesis of cerebral vasospasm? Stroke 1994, 25, 904-
908.
2-[(4,6-Dim e t h ylp yr im id in -2-yl)oxy]-3-m e t h oxy-3,3-
d ip h en ylp r op ion ic Acid (6o). Compound 6o was synthe-
sized as in example 6a starting with compound 4 and
2-(methylsulfonyl)-4,6-dimethylpyrimidine giving 0.3 g (51%,
final step): 1H-NMR (DMSO) δ 2.35 (s, 6H), 3.38 (s, 3H), 6.15
(s, 1H), 6.95 (s, 1H), 7.20-7.38 (m, 10H); mass spectra (CI+)
347 (M+ - MeOH); mp 190-191 °C. Anal. (C22H22N2O4)
Calcd: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.2; H, 6.0; N,
7.0.
3-Met h oxy-2-[(4-m et h oxy-5,6-d ih yd r ofu r o[2,3-d ]p yr i-
m id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (6p ). Com-
pound 6p was synthesized as in example 6a starting with
compound 4 and 2-(methylsulfonyl)-4-methoxy-5,6-dihydro-
furo[2,3-d]pyrimidine giving 2.8 g (58%, final step): 1H-NMR
(CDCl3) δ 3.02 (t, 2H), 3.3 (s, 3H), 3.92 (s, 3H), 4.64 (t, 2H),
6.20 (s, 1H), 7.20-7.50 (m, 10H); mass spectra (CI+) 391 (M+
- MeOH) mp 126-128 °C. Anal. (C23H22N2O6) C, H, N, O.
3-Meth oxy-2-[(4-m eth oxy-6,7-dih ydr o-5H-cyclopen tapy-
r im id in -2-yl)oxy]-3,3-d ip h en ylp r op ion ic Acid (6q). Com-
pound 6q was synthesized as in example 6a starting with
compound 4 and 2-(methylsulfonyl)-4-methoxy-6,7-dihydro-5H-
cyclopentapyrimidine giving 4.2 g (60%, final step): 1H-NMR
(DMSO) δ 2.10 (t, 2H), 2.70 (t, 2H), 2.83 (m, 2H), 3.38 (s, 3H),
(8) Clozel, M.; Breu, V.; Burri, K.; Cassao, J .-M.; Fischli, W.; Gray,
G. A.; Hirth, G.; Loffler, B.-M.; Muller, M.; Neidhart, W.; Ramuz,
H. Pathophysiological role of endothelin revealed by the first
orally active endothelin receptor antagonist. Nature 1993, 365,
759-761.
(9) Arai, H.; Hori, S.; Aramori, I.; Ohkubo, H.; Nakanishi, S. Cloning
and expression of a cDNA encoding an endothelin receptor.
Nature 1990, 348, 730-732.
(10) Sakurai, T.; Yanagisawa, M.; Takuwa, Y.; Miyazaki, H.; Kimura,
S.; Goto, K.; Masaki, T. Cloning of a cDNA encoding a non-
isopeptide-selective subtype of the endothelin receptor. Nature
1990, 348, 732-735.
(11) Sakamoto, A.; Yanagisawa, M.; Sakurai, T.; Takuwa, Y.; Yanag-
isawa, H.; Masaki, T. Cloning and functional expression of
human cDNA for the ETB endothelin receptor. Biochem. Bio-
phys. Res. Commun. 1991, 178, 656-663.
(12) Hosoda, K.; Nakao, K.; Arai, H.; Suga, S.; Ogawa, Y.; Mukoyama,
M.; Shirakami, G.; Saito, Y.; Nakanishi, S.; Imura, H. Cloning
and expression of human endothelin-1 receptor cDNA. FEBS
Lett. 1991, 187, 23-26.
(13) Ishikawa, K.; Fukami, T.; Nagase, T.; Fujita, K.; Hayama, T.;
Niyama, K.; Mase, T.; Ihara, M.; Yano, M. Cyclic pentapeptide
endothelin antagonists with ETA selectivity. Potency and
solubility enhanding modifications. J . Med. Chem. 1992, 35,
2139-2142.
(14) Ihara, M.; Noguchi, K.; Saeki, T.; Fukoroda, T.; Tsuchida, S.;
Kimura, S.; Fukami, F.; Ishikawa, K.; Nishikibe, M.; Yano, M.
Biological profiles of highly potent novel endothelin antagonists
selective for ETA receptor. Life Sci. 1991, 50, 247-255.
(15) Sogabe, K.; Nirei, H.; Shoubo, M.; Nomoto, A.; Ao, S.; Notsu, Y.;
Ono, T. Pharmacological profile of FR 139317, a novel, potent
endothelin ETA receptor antagonist. J . Pharmacol. Exp. Ther.
1993, 264, 1040-1046.
(16) Elliott, J . D.; Lago, M. A.; Cousins, R. D.; Gao, A.; Leber, J . D.;
Erhard, K. F.; Nambi, P.; Elshourbagy, N. A.; Kumar, C.; Lee,
J . A.; Bean, J . W.; DeBrosse, C. W.; Eggleston, D. S.; Brooks, D.
P.; Feuerstein, G.; Ruffolo, R. R.; Weinstock, J .; Gleason, J . G.;
Peishoff, C. E.; Ohlstein, E. H. 1,3-Diarylindan-2-carboxylic
acids, potent and selective non-peptide endothelin receptor
antagonists. J . Med. Chem. 1994, 37, 1553-1557.
3.88 (s, 3H), 6.12 (s, 1H), 7.20-7.40 (m, 10H); 389 (M+
MeOH); mp 149-151 °C. Anal. (C24H24N2O5) C, H, N, O.
-
3-Meth oxy-2-[(4-m eth ylp yr im id in -2-yl)oxy]-3,3-d ip h e-
n ylp r op ion ic Acid (6r ). Compound 6r was synthesized as
in example 6a starting with compound 4 and 2-(methylsulfo-
nyl)-4-methylpyrimidine giving 0.2 g (38%, final step): 1H-
NMR (DMSO) δ 2.40 (s, 3H), 3.38 (s, 3H), 6.15 (s, 1H), 6.85
(d, 1H), 7.12-7.40 (m, 10H), 8.34 (d, 1H); mass spectra (CI+)
333 (M+ - MeOH); mp 174-175 °C. Anal. (C21H20N2O4) C,
H, N, O.
3-Meth oxy-2-[(4-m eth oxy-6-m eth ylpyr im idin -2-yl)oxy]-
3,3-d ip h en ylp r op ion ic Acid (6s). Compound 6s was syn-
thesized as in example 6a starting with compound 4 and
2-(methylsulfonyl)-4-methoxy-6-methylpyrimidine giving 5.2
g (66%, final step): 1H-NMR (CDCl3) δ 2.33 (s, 3H), 3.31 (s,
3H), 3.85 (s, 3H), 6.20 (s, 1H), 6.23 (s, 1H), 7.22-7.50 (m, 10H);
mass spectra (CI+) 363 (M+ - MeOH); mp 148-150 °C. Anal.
(C22H22N2O5) C, H, N, O.
2-[(4,6-Dieth ylpyr im idin -2-yl)oxy]-3-m eth oxy-3,3-diph e-
n ylp r op ion ic Acid (6t). Compound 6t was synthesized as
in example 6a starting with compound 4 and 4,6-diethyl-2-

2128 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 11
Riechers et al.
(17) Walsh, T. F.; Fitch, K. J .; Chakravarty, K.; Williangs, D. L.;
Murphy, K. A.; Nolan, N. A.; O’Brien, J . A.; Lis, E. V.; Pettibone,
D. J .; Kivlighn, S. D.; Gabel, R. A.; Zingaro, G. J .; Krause, S.
M.; Siegl, P. K. S.; Clineschmidt, B. V.; Greenlee, W. J . Discovery
of L-749,329, a highly potent, orally active antagonist of endot-
helin receptors. ACS National Meeting, Washington, August
1994; MEDI 145.
(18) Stein, P. D.; Hunt, J . T.; Floyd, D. M.; Moreland, S.; Dickinson,
K. E. J .; Mitchell, C.; Liu, E. C.-K.; Webb, M. L.; Murugesan,
N.; Dickey, J .; McMullen, D.; Zhang, R.; Lee, V. G.; Serafino,
R.; Delaney, C.; Schaeffer, T. R.; Kozlowski, M. The discovery
of sulfonamide endothelin antagonists and the development of
the orally active ETA antagonist 5-(dimethylamino)-N-(3,4-
dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide. J . Med. Chem.
1994, 37, 329-331.
(19) Doherty, A. M.; Patt, W. C.; Edmunds, J . J .; Berryman, K. A.;
Reisdorph, B. R.; Plummer, M. S.; Shahripour, A.; Lee, C.;
Cheng, X. M.; Walker, D. M.; Haleen, S. J .; Keiser, J . A.; Flynn,
M. A.; Welch, K. M.; Hallak, H.; Taylor, D. G.; Reynolds, E. E.
Discovery of a Novel Series of Orally Active Non-Peptide
Endothelin-A (ETA) Receptor-Selective Antagonists. J . Med.
Chem. 1995, 38, 1259-1263.
(20) Roux, S. P.; Clozel, M.; Sprecher, U.; Gray, G.; Clozel, J . P. Ro
47-0203, a new endothelin receptor antagonist reverses chronic
vasospasm in experimental subarachnoid hemorrhage. Circula-
tion 1993, 88, I-170.
(21) Ishikawa, K.; Ihara, M.; Noguchi, K.; Mase, T.; Mino, N.; Saeki,
T.; Fukuroda, T.; Fukami, T.; Ozaki, S.; Nagase, T.; Nishikibe,
J .; Yano, M. Biochemical and pharmacological profile of a potent
and selective endothelin B-receptor antagonist BQ-788. Proc.
Natl. Acad. Sci. U.S.A. 1994, 91, 4892-4896.
(22) Chan, M. F.; Kois, A.; Raju, B.; Castillo, R. S.; Verner, E. J .;
Wu, C.; Venkatachalapathi, Y. V.; Okun, I.; Stavros, F. D.; Balaji,
V. N. The Discovery of Non-Peptide, Low Molecular Weight, ETB
Selective Endothelin Antagonists. ACS National Meeting,
Anaheim, April 1995; MEDI 168.
(23) Raschack, M.; Unger, L.; Riechers, H.; Klinge, D. Receptor
Selectivity of Endothelin Antagonists and Prevention of Vaso-
constriction and Endothelin-Induced Sudden Death. J . Cardio-
vasc. Pharmacol. 1995, 26 (Suppl. 3), S397-S399.
(24) (a) Arai, H.; Hori, S.; Aramori, I.; Ohkubo, H.; Nakanishi, S.
Cloning and expression of a cDNA encoding an endothelin
receptor. Nature 1990, 348, 730-732. (b) Sokolovsky, M.;
Ambar, I.; Galron, R. A novel subtype of endothelin receptors.
J . Biol. Chem. 1992, 29, 20551-20554.
(25) Labadie, J . W.; Stille, J . K. Mechanisms of the Palladium-
Catalyzed Couplings of Acid Chlorides with Organotin Reagents.
J . Am. Chem. Soc. 1983, 105 (No. 19), 6129-6137.
J M960274Q