Biphenylsulfonamide endothelin receptor antagonists. 4. Discovery of N-[[2′-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4- (2-oxazolyl)[1,1′-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), a highly potent and orally active ETA s

Article abstract of DOI:10.1021/jm020289q

We have previously disclosed the selective ET_A receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4′-(2-oxazolyl)[1,1′- biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2′-position of 1 l

Full text of DOI:10.1021/jm020289q

J . Med. Chem. 2003, 46, 125-137
125
Bip h en ylsu lfon a m id e En d oth elin Recep tor An ta gon ists. 4. Discover y of
N-[[2′-[[(4,5-Dim eth yl-3-isoxa zolyl)a m in o]su lfon yl]-4-(2-oxa zolyl)[1,1′-bip h en yl]-
2-yl]m eth yl]-N,3,3-tr im eth ylbu ta n a m id e (BMS-207940), A High ly P oten t a n d
Or a lly Active ETA Selective An ta gon ist
Natesan Murugesan,* Zhengxiang Gu, Steven Spergel, Marian Young, Ping Chen, Arvind Mathur, Leslie Leith,
Mark Hermsmeier, Eddie C.-K. Liu, Rongan Zhang, Eileen Bird, Tom Waldron, Anthony Marino,
Barry Koplowitz, W. Griffith Humphreys, Saeho Chong, Richard A. Morrison, Maria L. Webb,
Suzanne Moreland, Nick Trippodo, and J oel C. Barrish*
Departments of Chemistry, Cardiovascular Agents, Cardiovascular Biochemistry and Pharmacology, Metabolism and
Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New J ersey 08543-5400
Received J uly 3, 2002
We have previously disclosed the selective ETA receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-
4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candi-
date. Additional SAR studies at the 2′-position of 1 led to the identification of several analogues
with improved binding affinity as well as selectivity for the ETA receptor. Following the discovery
that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison
to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2′-substituent
leading to 16a (BMS-207940). Compound 16a is an extremely potent (ETA Ki ) 10 pM) and
selective (80000-fold for ETA vs ETB) antagonist. It is also 150-fold more potent and >6-fold
more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance
and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET
pressor responses with 30-fold greater potency than 1. After oral dosing at 3 µmol/kg, 16a
displays enhanced duration relative to 1.
In tr od u ction
important class of agents for the treatment of the
aforementioned pathological conditions.
The endothelins (ET-1, ET-2, and ET-3) constitute a
family of 21-amino acid vasoconstrictor peptides and are
produced by the endothelium of blood vessels and by
many other tissues.1,2 A large number of studies have
elucidated that endothelins play many important roles
in addition to vasoconstriction, including modulation of
vascular tone, cell proliferation, and hormone pro-
duction.3-5 The endothelins exert their physiological
effects via two specific G-protein coupled receptors
termed ETA and ETB.6,7 Both receptor subtypes are
found on smooth muscle cells and mediate the vasocon-
strictor and pressor actions of endothelin. The ETB
receptor is also found on vascular endothelial cells and
cause endothelin-dependent vasodilatation via release
of nitric oxide and prostacyclin.8 Additionally, ETB
receptors in the lung are a major pathway for the
clearance of ET-1 from plasma.9
A number of selective as well as nonselective endo-
thelin receptor antagonists are being actively developed
as new therapeutic agents.10,11 Extensive preclinical and
clinical studies, mainly with ETA receptor antagonists,
have shown excellent therapeutic benefits in disease
states such as heart failure, pulmonary hypertension,
atherosclerosis, restenosis, systemic hypertension, and
chronic renal failure.12-14 These results indicate endo-
thelin receptor antagonists, especially those selective for
the ETA receptor, may constitute a novel and potentially
Recently we reported a series of biphenylsulfonamides
as potent and selective ETA antagonists.15-17 In these
studies we showed that compounds with a heterocyclic
ring such as an oxazole16 (1, Figure 1) or pyrimidine17
(2) at the 4′-position of the biphenyl moiety showed
remarkable enhancement in potency and metabolic
stability. This work led to the selection of 1 (BMS-
193884, ETA Ki ) 1.4 nM; ETB Ki ) 18700 nM) as a
clinical development compound. In a Phase I oral
ascending single dose tolerance study, 1 was well
tolerated up to a dose of 600 mg and showed a dose-
dependent increase in plasma concentrations. Evalua-
tion of the effect of intravenous doses of 1 on forearm
blood flow after ET-1 infusion indicated that a dose of
50 nmol/min completely abolishes the vasoconstictive
response to ET-1. Compound 1 also showed promising
hemodynamic effects in a phase II clinical trial for
congestive heart failure.18
In the present study, we have focused on the optimi-
zation of the substituents at the 2′-position of the 4′-
oxazolyl biphenylsulfonamides. A wide range of sub-
stituents was investigated at this position in combination
with selected variations of the isoxazole ring. This paper
describes the resulting discovery of a series of second
generation analogues with extremely potent ETA affin-
ity, selectivity, and superior pharmacokinetic properties.
Ch em istr y
* To whom correspondence should be addressed: Natesan Murug-
esan, Ph.D., Bristol-Myers Squibb Pharmaceutical Research Institute,
Princeton, NJ 08543-5400. 609-818-5391 (Telephone); 609-818-3450
(Fax); E-mail: murugesan@bms.com.
The preparation of a library of 160 2′-acylamino-
methyl biphenylsulfonamides of general structure 5 was
10.1021/jm020289q CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/26/2002

126 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Murugesan et al.
F igu r e 1.
Sch em e 1a
a
(a) Methylamine, sodium triacetoxy borohydride, AcOH; (b) RCOOH, diisopropylcarbodiimide, CH2Cl2.
Sch em e 2a
a
(a) NaBH4, MeOH; (b) CBr4, PPh3, DMF; (c) 3,3-dimethyl-2-pyrrolidinone, NaH, DMF; (d) chlorotrimethylsilane, NaI, CH3CN; (e)
CH3NHCH2CH2NH2, sodium triacetoxyborohydride, AcOH; (f) carbonyldiimidazole, CH2Cl2; (g) 6 N aq HCl, EtOH.
accomplished using solution-phase parallel synthesis
techniques as shown in Scheme 1. The aldehyde group
in 4 was converted to the corresponding N-methylami-
nomethyl derivative via reductive amination of 4 in the
presence of methylamine, sodium triacetoxyborohydride,
and acetic acid. Coupling of this intermediate with a
variety of alkyl and aryl carboxylic acids in the presence
of 1,3-diisopropylcarbodiimide afforded the library of
amide derivatives in yields ranging from 60 to 90%, with
purities greater than 90%.
The preparation of the 2′-lactam derivative 8a and
the 2′-cyclic urea derivative 8d is outlined in Scheme
2. Reduction of the aldehyde group in 6 with sodium
borohydride gave the corresponding hydroxymethyl
intermediate, which upon treatment with CBr4 and
PPh3 afforded the bromomethyl derivative 7. Reaction
of 7 with 3,3-dimethyl-2-pyrrolidinone19 in the presence
of sodium hydride followed by deprotection of the MEM
group using TMSCl and sodium iodide in acetonitrile
provided 8a . Lactams 8b and 8c were prepared by an
analogous sequence using either 4,4-dimethyl-2-pyrro-
lidinone20 or 3,3-dimethyl-2-piperidinone,21 respectively.
Compound 8d was prepared from 6 using a three-step
sequence: (a) reductive amination using N-methyl
ethylenediamine, sodium triacetoxyborohydride, and
acetic acid, (b) ring closure using carbonyldiimidazole,
and (c) deprotection of the MEM group using 6 N
aqueous hydrochloric acid in ethanol.
The retroamide derivatives 9a ,b were prepared by
homologation of the aldehyde group in 4 via Wittig

Biphenylsulfonamide Endothelin Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 127
Sch em e 3a
a
(a) (Methoxymethyl)triphenylphosphonium chloride, LDA; (b) p-TSOH, H2O; (c) sulfamic acid, sodium chlorite, THF/water; (d) oxalyl
chloride, CH2Cl2; (e) RNHR′; (f) chlorotrimethylsilane, NaI, CH3CN; (g) ROH, NaH, DMF; (h) 6 N aqueous HCl/EtOH; (i) RNHR′, sodium
triacetoxyborohydride, AcOH.
olefination using methoxymethyltriphenylphosphonium
chloride followed by treatment with p-TsOH. Oxidation
of the resulting aldehyde intermediate to the corre-
sponding carboxylic acid was achieved using sulfamic
acid and sodium chlorite in aqueous THF. Conversion
of the carboxylic acid moiety to acid chloride followed
by coupling with the corresponding alkylamines in the
presence of triethylamine and subsequent deprotection
of the MEM group provided 9a ,b (Scheme 3). The ether
derivatives 9c-e were synthesized from 7 by treatment
with the corresponding sodium alkoxide derivative
followed by deprotection of the MEM group using 6 N
aqueous hydrochloric acid in ethanol (Scheme 3). Amines
9f-h and 9j-k were prepared via reductive amination
of 4 using the corresponding alkyl or arylamine and
sodium triacetoxyborohydide. The olefin derivatives
9l-m were synthesized from 6 via Wittig olefination
using benzyltriphenylphosphonium chloride followed by
deprotection of the MEM group. The cis and trans
isomers were then separated by HPLC. The bisoxazole
9n was prepared via Suzuki-coupling of 2-[4-bromo-3-
(2-oxazolylmethyl)phenyl]oxazole22 and 2-borono-N-(3,4-
dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]ben-
zenesulfonamide15 followed by deprotection of the MEM
group using 6 N aqueous hydrochloric acid. Analogues
9o-q were prepared from 7 by treatment with the
corresponding imidazole or pyrazole heterocycle in the
presence of sodium hydride followed by deprotection of
the MEM group.
2-bromobenzenesulfonyl chloride 10 with 3-amino-4,5-
dimethyl-isoxazole 1123 in pyridine followed by protec-
tion of the sulfonamide moiety using sodium hydride
as base followed by addition of MEM chloride in DMF
at -15 °C provided 12. The low temperature is required
to minimize reaction on the ring nitrogen of the isox-
azole. Metalation of 12 with n-BuLi followed by quench-
ing with trimethyl borate and subsequent hydrolysis
provided the corresponding boronic acid intermediate
13. Suzuki coupling of 13 with 14 under standard
conditions followed by deprotection of the MEM group
provided 15. Reductive amination of 15 using methyl-
amine and sodium triacetoxy borohydride followed by
acylation using tert-butylacetyl chloride in the presence
of triethylamine afforded the key derivative 16a . Reduc-
tive amination of the aldehyde 15 with 3-carboxy-3-
methylbutylammonium chloride gave, after direct cy-
clization with dicyclohexylcarbodiimide, the lactam
derivative 16b.
Resu lts a n d Discu ssion
Compound 1 (BMS-193884) is a selective and com-
petitive ETA antagonist with 10000-fold greater affinity
for the human ETA receptor than for the ETB receptor.
In our efforts to identify a second generation compound
possessing even greater potency and selectivity for the
ETA receptor as well as improved pharmacokinetics
relative to 1, the structure-activity relationships of the
pendant phenyl ring was investigated. This led to the
discovery that the 2′-acylaminomethyl substituent (3,
ETA Ki ) 0.2 nM; ETB Ki ) 4,400 nM) improves both
The synthesis of the 3-isoxazolyl biphenylsulfonamide
derivative 16a is outlined in Scheme 4. Coupling of

128 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Murugesan et al.
Sch em e 4a
a
(a) Pyridine; (b) MEMCl, NaH; (c) (i) n-BuLi, -95 °C, (ii) B(OMe)3, (iii) 3 N aq HCl; (d) compound 14, (Ph3P)4Pd, aqueous Na2CO3,
EtOH/toluene; (e) 6 N aqueous HCl/EtOH; (f) CH3NH2, sodium triacetoxy borohydride, AcOH; (g) (CH3)3CCH2COCl, triethylamine.
ETA binding affinity and functional activity 5-10-fold,
resulting for the first time in sub-nanomolar biphenyl-
sulfonamide antagonists. However, 3 had poor oral
bioavailability in rats (<10%) and showed only modest
bioavailability (17%) in cynomologous monkeys. Ad-
ditional pharmacokinetic studies indicated that poor
absorption was the primary contributor to low oral
bioavailability. Poor absorption was also suggested by
the Caco-2 cell assay results, where 3 had low perme-
ability (Pc ) 13 nm/s) compared to 1 (Pc ) 213 nm/s).
Comparison of the structural and physical properties
of 3 to those of 1 suggested that the reduced oral
absorption observed might be due to a combination of
increased hydrogen bond number, decreased lipophilic-
ity and an overall increase in the desolvation energy.
In an effort to optimize the 2′-amide group in an efficient
fashion, a library of 160 additional analogues were
synthesized by an automated high throughput ap-
proach. The activities of some key compounds, 5a -p ,
from this set are shown in Table 1.
N-Methylation of the amide group of 3 to give 5a did
not improve permeability through Caco-2 cells despite
reducing the hydrogen bond number (Table 1). This
modification also had little effect on ETA activity or
lipophilicity. The excellent binding affinity for 5a indi-
cated that a hydrogen bond donor group at 2′ may not
be necessary for the enhanced activity of the 2′-
substituted analogues. Replacement of the acetyl group
in 5a with larger and more lipophilic alkyl groups such
as isopropyl (5c) or tert-butyl (5e) resulted in increases
in both ETA binding affinity and Caco-2 cell perme-
ability. Additional improvements in ETA selectivity and
Caco-2 cell permeability were observed with homologa-
tion to the neopentyl group in 5g (ETA Ki ) 0.02 nM).
We also investigated alternative N-alkyl groups. A
larger, lipophilic N-alkyl substituent, such as isopropyl
(5b) or cyclopropyl (5d ), was tolerated when combined
with a small acyl group but less so for a large acyl group
(5f). The excellent binding activity of 5g suggested that
the 2′-side chain may be accessing a lipophilic pocket
at the receptor. In fact, highly lipophilic N-methyl amide
side chains such as phenethyl (5k ), 3,4-dichlorophenyl
(5l), and p-CF3-benzyl (5m ) provided analogues with
exceptionally potent ETA binding affinity (ETA Ki ) 1-9
pM).
Constraining the tert-butyl and N-methyl groups of
5e into the lactam 8a resulted in a substantial increase
in ETA binding affinity (ETA Ki ) 0.005 nM) (Table 2).
The 4,4-dimethyl regioisomer 8b was 10 fold less active
than 8a and the six-membered ring homologue 8c was
80-fold less potent than 8a . The cyclic urea analogue
8c was equipotent to 8a in its ETA binding affinity but
showed significantly reduced Caco cell permeability.
We also investigated the effect of replacing the 2′
amide group by a variety of amide surrogates (Table 3).
Compound 9a , the retroamide of 5a , was 5-fold less
active than 5a in its ETA binding affinity. This result
suggested that the position of the carbonyl group may
be important for its putative role as a hydrogen bond
acceptor or that the retroamide positions the lipophilic
alkyl group differently than the amide group does. The
related tert-butyl retroamide 9b was also substantially
less potent for the ETA receptor. Replacement of the
amide moiety by an ether linker (9c-e) also resulted
in a markedly reduced ETA activity. In an effort to
evaluate the effects of basicity and lipophilicity on ETA
activity and cell permeability, the 2′-amine derivatives
9f-k were prepared. Conversion of the amide in 5c to
the corresponding tertiary amine derivative 9f resulted
in a pronounced drop in ETA activity suggesting that
strongly basic groups are not tolerated at this position.
However, 2′-groups incorporating substantially less
basic amine derivatives showed improved ETA activity
as well as Caco-2 cell permeability. For example, the
N-methyl aniline analogue 9g was a potent ETA-
selective antagonist with significant Caco cell perme-

Biphenylsulfonamide Endothelin Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 129
Ta ble 1. SAR of 2′-Substituted Amide Derivatives
a
b
Ki’s were determined using human ETA and ETB receptors stably expressed in CHO cells. KB’s were determined by assaying for the
inhibition of ET-1 induced contractions in rabbit carotid artery rings; KB* ) apparent KB values; Standard deviations are less than 10%
of the mean values for all of the assays; ND ) not determined.
ability. The trifluoroethylamine derivative 9h was also
slightly more potent than 1 with good Caco-2 cell
permeability. N-Methylation (9i) resulted in an increase
in binding affinity and improved Caco-2 cell perme-
ability but decreased ETA functional potency in the
rabbit carotid tissue assay. The heterocyclic amine
derivatives 9j-k were also 10 fold more potent than 1
but 9j showed reduced functional potency as well as cell
permeability.
styrene derivatives 9l-m were prepared but each
displayed reduced binding affinity at ETA relative to 1.
Heterocyclic groups are also well-known amide sur-
rogates. The bis-oxazole 9n displayed ETA activity and
Caco cell permeability similar to that observed for 1.
However, the 2′-pyrazole 9o and 2′-imidazole 9p showed
improved ETA binding affinity and selectivity compared
to 1. Substitution at the 3-position of the pyrazole ring
in 9o with a lipophilic group such as trifluoromethyl
resulted in 9q, which showed significantly improved
ETA binding affinity and selectivity relative to 1. Among
In an attempt to access the putative lipophilic pocket
reached by the aryl substituted amide analogues, the

130 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Ta ble 2. SAR of 2′-Substituted Lactam Derivatives
Murugesan et al.
a
b
Ki’s were determined using human ETA and ETB receptors stably expressed in CHO cells. KB’s were determined by assaying for the
inhibition of ET-1 induced contractions in rabbit carotid artery rings; KB* ) apparent KB values. Standard deviations are less than 10%
of the mean values for all of the assays; ND ) not determined.
resistant to this degradation of the isoxazole ring in
vitro.
On the basis of the above analysis, analogous combi-
nations of the 3-aminoisoxazole with the amide and
lactam 2′-substituents found in 5g and 8a , respectively,
were prepared. Analogue 16a , the 3-aminoisoxazole
isomer of 5g, showed excellent potency and selectivity
for the ETA receptor. (ETA Ki ) 0.01 nM; ETB Ki ) 810
F igu r e 2. Metabolism of compound 1 in rats.
nM; Table 4). These data indicate that 16a is ap-
proximately 80,000-fold selective for human ETA recep-
the 2′-heterocyclic substituted analogues studied, 9q
shows the best overall in vitro profile, with substantial
ETA binding affinity, selectivity, and permeability.
tors and displays 140-fold greater ETA binding affinity
and 6-fold greater selectivity for the human ETA vs ETB
receptors compared to 1. Lactam 16b, the 3-aminoisox-
azole isomer of 8a , also shows similarly improved
potency and selectivity for the ETA receptor compared
to 1 (ETA Ki ) 0.04 nM; ETB Ki ) 770 nM). Significantly,
both analogues displayed enhanced stability to degrada-
tion of the isoxazole ring in vitro by rat GI homogenate.
Pharmacokinetic studies in rats showed that 16a has
superior (100%) oral bioavailbility (Table 5). In addition,
16a also showed improved systemic clearance (Cl) and
steady-state volume of distribution (Vss) in comparison
to 1. The pharmacokinetic profile of the lactam deriva-
tive 16b in rats was similar to that of 16a . On the basis
of its excellent potency and ETA selectivity, in addition
to its promising pharmacokinetic properties, 16a (BMS-
207940) was selected for additional studies.
A number of compounds described above were tested
in a rat pharmacokinetic model and the amide 5g, the
lactam 8a , and the pyrazole 9q, in particular, displayed
desirable properties (Table 5). 5g and 9q each displayed
slightly increased clearance and volume of distribution
in comparison to BMS-193884, in addition to a longer
plasma elimination half-life and acceptable oral bio-
availability. 8a also showed adequate oral bioavailabil-
ity and slightly higher volume of distribution and
clearance after iv administration in rats. However, at
this juncture, it was observed that the modest oral
bioavailability for the above analogues may be related
to presystemic metabolism resulting from enzymatic
cleavage of the 5-isoxazole ring by bacteria in the rat
GI tract. A similar metabolic pathway was also observed
for 1, although to a lesser extent possibly due to its rapid
absorption from the GI tract (Figure 2). The more potent
2′-substituted analogues were invariably less permeable
(based on Caco-2 data) and thus more likely to be
exposed to bacteria within the GI tract prior to absorp-
tion. It was subsequently determined that analogues
containing the 3-aminoisoxazole regioisomer appear
Compound 16a was tested for its ability to inhibit big
ET-1 (1 nmol/kg, iv)-induced vasoconstriction in con-
scious, normotensive rats. This compound blocked the
pressor response in a dose-dependent manner when
administered orally or intravenously in rats (ED25
)
0.004 µmol/kg iv and 0.13 µmol/kg, po). After oral
administration at 3 µmol/kg, 16a inhibited the big ET-1
pressor response 60-70% for the duration of observa-

Biphenylsulfonamide Endothelin Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 131
Ta ble 3. SAR of 2′-Substituted Biphenylsulfonamide Derivatives
a
b
Ki’s were determined using human ETA and ETB receptors stably expressed in CHO cells. KB’s were determined by assaying for the
inhibition of ET-1 induced contractions in rabbit carotid artery rings; KB* ) apparent KB values; Standard deviations are less than 10%
of the mean values for all of the assays; ND ) Not determined.
tion, whereas no inhibition was observed for 1 except
at the 15-min time point (Figure 3). Thus, 16a is a more
potent ET antagonist as compared with 1 in vivo and
has a longer duration of action.
Pharmacokinetic studies in monkeys, in vivo, showed
that the systemic clearance and volume of distribution
of 16a are higher than found previously for 1. In
addition, 16a also showed improved half-life compared
to 1 and its oral availability in monkeys averaged 26%
(Table 6).
pressor response (40 ( 8% and 40 ( 11%) at 15 and 90
min, respectively, after treatment (Figure 4). Significant
inhibition of the ET-1 pressor activity was still present
5 h after the compounds were administered. Thus, 16a
blocks the ET pressor response with a magnitude and
duration similar to that of 1 in this model.
Con clu sion
In summary, introduction of a wide range of func-
tional groups such as an amido, lactam, amines, or
heterocyclic rings at the 2′-position of the 4′-oxazolyl
biphenylsulfonamides resulted in substantial improve-
ments in both ETA binding and functional activity
compared to the 2′-unsubstituted analogue, 1. This
Intravenous injection of ET-1 (0.3 nmol/kg) elicits a
transient pressor response in conscious, normotensive
cynomolgus monkeys. Oral administration of 10 µmol/
kg of 16a or 1 produced maximal inhibition of the ET-1

132 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Ta ble 4. 2′-Substituted 3-aminoisoxazolyl Biphenylsulfonamides
Murugesan et al.
a
b
Ki’s were determined using human ETA and ETB receptors stably expressed in CHO cells. KB’s were determined by assaying for the
inhibition of ET-1 induced contractions in rabbit carotid artery rings. Standard deviations are less than 10% of the mean values for all
of the assays; ND ) not determined.
Ta ble 5. Pharmacokinetic Properties of Select Compounds in Ratsa
1
5g
8a
9q
16a
16b
Intravenous
10
28 ( 1.9
dose (µmol/kg)
Cl (mL/min/kg)
Vss (L/kg)
10
20
20
34
1.5
10
10
2.6 ( 1.0
0.08 ( 0.03
2.0 ( 0.5
13 ( 5.1
0.7 ( 0.3
8.2 ( 0.3
5.4 ( 0.5
1.1 ( 0.1
3.4 ( 0.1
9.3 ( 5.3
2.3 ( 1.2
4.7 ( 0.2
0.32 ( 0.16
1.2 ( 0.2
t1/2 (h)
4
Oral
10
0.44 ( 0.10
0.28 ( 0.07
21
dose (µmol/kg)
Tmax (h)
Cmax (µM)
F%
10
20
20
20
10
0.4 ( 0.1
24 ( 9.8
43
0.7 ( 0.3
4.7 ( 1.1
27
0.5 ( 0.01
0.4 ( 0.1
0.6 ( 0.4
3.0 ( 0.5
28 ( 7.8
7.7 ( 2.6
33
100
78
a
Mean ( SD (n ) 3), except 9q intravenous group (mean only n ) 2).
F igu r e 3. Inhibition of the pressor response to big ET-1 in rats after administration of 16a and 1. A. Dose-response curves for
the ET antagonists 5 min after iv administration (n ) 3-13 rats per dose). B. Time-course of inhibition following oral dosing with
antagonist at 3 µmol/kg (n ) 3-8 rats per compound).
process resulted in the identification of the 2′-N-methyl-
tert-butylacetamide moiety present in 5g as one of the
optimal groups. Following the discovery that a 3-amino-
isoxazole group displays significantly improved meta-
bolic stability in comparison to its 5-regioisomer, the
3-isoxazole group was combined with the optimal 2′-
substituent leading to 16a (BMS-207940). Compound
16a is an extremely potent (ETA Ki ) 10 pM) and
selective (80,000-fold for ETA vs ETB) ETA antagonist
and is 150-fold more potent and >6-fold more selective
than 1. Compound 16a also showed a superior phar-
macokinetic profile in rats compared to 1. The bioavail-
ability was 100% in rats and the systemic clearance and
volume of distribution of 16a are higher than found
previously for 1. In rats, intravenous 16a blocks big ET
pressor responses with 30-fold greater potency than 1,
and after oral dosing at 3 µmol/kg with enhanced
duration.
Exp er im en ta l Section
Ra d ioliga n d Bin d in g Assa ys. The receptor binding assays
were performed using CHO cells stably expressing human ETA
or ETB receptors as previously described.16 The inhibition
constants (Ki) were calculated from IC50 values.
In Vitr o F u n ction a l Assa y. Functional assays (inhibition
of ET-1 induced contractions in rabbit carotid artery rings)
were performed as previously described.16 KB values were
obtained from experiments in which at least 3 different

Biphenylsulfonamide Endothelin Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 133
Ta ble 6. Comparison of Pharmacokinetic Properties of 16a
(n ) 3) and 1 (n ) 4) in Monkeys
P h a r m a cok in etics a n d Or a l Bioa va ila bility in Mon -
k eys. Single doses of 1 a n d 16a were given intravenously (30
min infusion; 5% sodium bicarbonate solution) or orally
(gavage; PEG-400 solution) to three to four fasted male
cynomolgus monkeys. Serial blood samples were collected at
various time points for at least 72 h, and plasma was prepared
by centrifugation. Drug concentrations were determined by a
LC/MS assay with a quantifiable limit of 4 nM and the
pharmacokinetic parameters determined similarly as in rat
study.
Melting points were recorded on a Thomas-Hoover capillary
apparatus and are uncorrected. All chemical experiments were
run under a positive pressure of argon. All solvents and
reagents were used as obtained. Solutions were dried with
magnesium sulfate unless otherwise noted. Proton NMR (1H
NMR) and carbon NMR (13C NMR) spectra were recorded on
J EOL FX-270 or GX-400 spectrometers with tetramethylsilane
as an internal standard. Chromatography was performed using
EM Science silica 0.040-0.063 mm particle size. Analytical
and preparative HPLC were performed on YMC columns (S-
5, 120A ODS, 4.6 × 150 mm; S-10, 120A ODS, 30 × 500 mm)
with MeOH: water gradients containing 0.1% trifluoroacetic
acid. Solutions were dried with magnesium sulfate unless
otherwise noted.
mean ( SD
parameter
dose
AUC∞
Cl
Vss
t1/2
MRT
units
1
16a
Intravenous
50
µmol/kg
25
161 ( 50
2.7 ( 0.73
0.25 ( 0.04
14 ( 5.0
1.6 ( 0.28
µM × h
1000 ( 210
mL/min/kg
0.86 ( 0.18
L/kg
0.13 ( 0.02
8.3 ( 2.6
h
h
2.7 ( 0.22
Oral
dose
AUC∞
Tmax
Cmax
t1/2
µmol/kg
50
25
µM × hr
704 ( 124
2.4 ( 0.75
180 ( 25
8.7 ( 3.9a
71 ( 7.0
41.5 ( 29
1.2 ( 0.29
16.1 ( 15.9
17 ( 12
hr
µM
hr
bioavailability
%
26b
a
n ) 3; insufficient data in the terminal phase of one monkey.
b
Individual bioavailability values and SD could not be estimated
since different monkeys received the iv and po doses.
Repr esen tative P r ocedu r e for Com pou n ds 5a-p. N-[[2′-
[[(3,4-Dim e t h yl-5-isoxa zolyl)a m in o]su lfon yl]-4-(2-ox-
a zolyl)[1,1′-bip h en yl]-2-yl]m eth yl]-N,3,3-tr im eth ylbu ta n -
a m id e (5g). To a solution of 0.15 g (0.35 mmol) of 417 in 15
mL of dichloromethane, methylamine (33% solution in absolute
ethanol, 0.13 mL, 1.06 mmol), glacial acetic acid (0.12 g, 2
mmol), and 1 g of 3 Å molecular sieves were added. The
mixture was stirred at room temperature for 1 h. Sodium
triacetoxyboro-hydride (0.22 g, 1.06 mmol) was added, and the
mixture was stirred overnight. The solution was then filtered,
washed once with water, dried, and evaporated to afford 0.15
g of 2′-[(methylamino)methyl]-N-(3,4-dimethyl-5-isoxazolyl)-
4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide as a colorless gum.
To a solution of this material (32.9 mg, 0.075 mmol) and tert-
butylacetic acid (0.075 mol) in 0.3 mL of CH2Cl2 was added
0.1 mL of DMF followed by a solution of 1,3-diisopropylcar-
bodiimide in CH2Cl2 (0.28N, 0.320 mL, 0.09 mmol). The
reaction mixture was vortexed for 3 min and then let stand at
room temperature for 24 h. The mixture was then loaded onto
1.5 g of a Strong Anion Exchange (Quaternary Amine) resin
and eluted with 20 mL of CH2Cl2 followed by 10 mL of 3%
F igu r e 4. Inhibition of ET-1 pressor responses in monkeys
following dosing with 16a at 10 µmol/kg po, 1, at 10 µmol/kg
po or vehicle (n ) 4).
1
TFA in CH2Cl2 to give 5g as a white solid. H NMR (CDCl3):
concentrations of test compound were studied. Apparent KB
values were calculated when only one antagonist concentration
was used.
δ 0.95 (s, 9H), 1.92 (s, 3H), 2.16 (s, 3H), 2.30 (m, 2H), 3.25 (s,
3H), 4.0-4.6 (m, 2H), 7.25-8.00 (m, 9H). Anal. (C28H32N4O5S)
C, H, N, S.
In Vivo Ra t P r essor Stu d ies. This study was performed
as previously described.16 Four iv challenges of ET-1 (0.1 nmol/
kg) or big ET-1 (1.0 nmol/kg) were given. Ninety minutes were
allowed between challenges to allow blood pressure to return
to baseline. The initial challenge was preceded by vehicle
administration to establish a control response to the agonist.
Three doses of vehicle, BMS-207940 (0.3, 1, 3, 10, 30 µmol/kg,
iv) were given prior to the subsequent agonist challenges.
BMS-207940 was also administered orally at doses of 3, 10,
and 30 µmol/kg prior to ET-1 challenges.
P h a r m a cok in etics a n d Or a l Bioa va ila bility in Ra ts.
Male Sprague-Dawley rats (Harlan Sprague-Dawley, India-
napolis, IN) were surgically prepared with an indwelling
jugular vein cannula 1 day prior to drug administration. Rats
were fasted overnight prior to dosing and fed 8 h after dosing.
They were allowed access to water ad libitum and were
conscious and unrestrained during the study. Rats were given
a single intravenous dose as a short 10 min infusion or oral
dose via gavage. The dosing vehicles were propylene glycol for
iv and PEG-400 for PO dose. Serial blood samples were
collected at various time points for at least 24 h, and plasma
prepared by centrifugation. Drug concentrations were deter-
mined by a LC/MS assay with a quantifiable limit of 4 nM,
and the pharmacokinetic analysis was performed with the
CENTROS (in house) computer program. The bioavailability
estimate was based on average AUC values.
2′-(Br om om eth yl)-N-(3,4-d im eth yl-5-isoxa zolyl)-N-[(2-
m eth oxyeth oxy)m eth yl]-4′-(2-oxa zolyl)[1,1′-bip h en yl]-2-
su lfon a m id e (7). To a solution of 6 (204 mg, 0.4 mmol) in 10
mL of methanol at 0 °C under an argon atmosphere was added
sodium borohydride (19 mg, 0.5 mmol). The mixture was
stirred at 0 °C for 2.5 h, and 2 mL of a saturated aqueous
solution of sodium hydrogen sulfate was added. After stirring
for 20 min, 1 N sodium hydroxide (20 mL) was added. The
mixture was then extracted with ethyl acetate. The combined
ethyl acetate extracts were washed with water and brine and
dried to afford 195 mg of a colorless oil. To a solution of this
material in 4 mL of DMF at 0 °C under an argon atmosphere
were added carbon tetrabromide (182 mg, 0.548 mmol) and
triphenylphosphine (144 mg, 0.548). The mixture was stirred
at 0 °C for 2.5 h, diluted with 20 mL of saturated sodium
bicarbonate and extracted with ethyl acetate. The organic
extract was washed with aqueous 5% lithium chloride, brine
and then dried and evaporated. The crude product was
chromatographed on silica gel using 1:1 hexane/ethyl acetate
to afford 165 mg (78%) of 7 as a colorless oil, which solidified
on standing. This material was used in the next step without
any further purification.
N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-[(3,3-d im et h yl-2-oxo-
1-p yr r olid in yl)m et h yl]-4′-(2-oxa zolyl)[1,1′-b ip h en yl]-2-
su lfon a m id e (8a ). To a solution of 3,3-dimethyl-2-pyrrolidi-

134 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Murugesan et al.
none (0.035 g, 0.31 mmol) in 2 mL of DMF, NaH (50%
suspension in mineral oil, 0.015 g, 0.31 mmol) was added, and
the mixture was stirred at room temperature under argon for
30 min. 7 (0.121 g, 0.21 mmol) in 2 mL of DMF was added,
and the mixture was stirred overnight. The mixture was then
added to water and extracted with EtOAc. The combined
organic extracts were washed with water and dried and
evaporated. The residue thus obtained was chromatographed
on silica gel using 1:1 hexane:EtOAc to afford 0.072 g as a
colorless gum. To a solution of this material in 2 mL of
acetonitrile were added chlorotrimethylsilane (0.1 g, 0.92
mmol) and sodium iodide (0.138 g, 0.92 mmol), and the mixture
was stirred at room temperature for 2 h. Additional portions
of chlorotrimethylsilane (0.01 g, 0.092 mmol) and sodium
iodide (0.014 g, 0.092 mmol) were added, and the mixture was
stirred for an additional 1 h. The mixture was diluted with
water and extracted with EtOAc. The combined organic
extracts were then washed once with water and dried and
evaporated. The residue was purified by reverse phase pre-
parative HPLC on a 30 × 500 mm ODS S10 column using 71%
solvent B (90% MeOH, 10% H2O, 0.1% TFA) and 29% solvent
A (10% MeOH, 90% H2O, 0.1% TFA). The appropriate fractions
were collected and neutralized with aqueous sodium bicarbon-
ate to pH 7 and concentrated to 10 mL. The solution was then
acidified to pH 4 using aqueous sodium bisulfate, and the
white solid was filtered and dried to provide 0.019 g (51%) of
To (methoxymethyl)triphenylphosphonium chloride (1.22 g,
3.56 mmol) in 20 mL of THF at -78 °C was added lithium
diisopropylamide in THF (1.5 M in cyclohexane, 2.73 mL, 4.09
mmol). The mixture was warmed to 0 °C and stirred for 20
min. The solution was then cooled to -78 °C, and 6 (910 mg,
1.78 mmol) in 5 mL THF was added dropwise. The cold bath
was removed, and the reaction was stirred at room tempera-
ture for 1 h. The mixture was added to water and extracted
with EtOAc. The combined organic extracts were washed with
water and brine, dried, and concentrated. The residue was
chromatographed on silica gel using hexane/EtOAc to afford
a colorless gum. To a solution of this material (870 mg, 1.61
mmol) in 20 mL of dioxane, a solution of p-toluenesulfonic acid
(0.3 g) in water was added, and the mixture was refluxed for
4 h. The mixture was cooled and diluted with EtOAc. The
organic layer was washed with water and brine, dried, and
concentrated. The residue was chromatographed on silica gel
using hexane/EtOAc to afford N-(3,4-dimethyl-5-isoxazolyl)-
2′-(formylmethyl)-N-[(2-methoxyethoxy)methyl]-4′-(2-oxazolyl)-
[1,1′-biphenyl]-2-sulfonamide (535 mg, 63%) as a colorless gum.
To a solution of this material (300 mg, 0.57 mmol) and sulfamic
acid (111 mg, 1.14 mmol) in 15 mL of THF at 0 °C was added
an ice-cooled solution of sodium chlorite (103 mg, 1.14 mmol)
in 15 mL of water. The mixture was stirred at 0 °C for 2 min
and then diluted with dichloromethane. The organic layer was
separated, washed with brine, dried, and concentrated. To a
solution of this product (90 mg, 0.17 mmol) and 0.01 mL of
DMF in 4 mL of dichloromethane was added oxalyl chloride
(2 M solution in dichloromethane, 0.21 mL, 0.42 mmol). The
mixture was stirred for 1 h and then concentrated. To the
residue in 3 mL of THF, 40% aqueous dimethylamine (1 mL)
was added. The mixture was stirred at room temperature for
1 h, diluted with EtOAc, washed with water and brine, dried,
and concentrated. The residue was chromatographed on silica
gel using 1:2 hexane/EtOAc to afford a colorless gum. To a
solution of this material (77 mg, 0.135 mmol) in 2 mL of
acetonitrile were added chlorotrimethylsilane (74 mg, 0.68
mmol)) and sodium iodide (101 mg, 0.68 mmol). The mixture
was stirred at room temperature for 2 h. Additional portions
of chlorotrimethylsilane (60 mg, 0.54 mmol) and sodium iodide
(82 mg, 0.54 mmol) were added, and the mixture was stirred
for an additional 1 h. The mixture was diluted with water and
extracted with EtOAc. The combined organic extracts were
then washed once with water, dried, and evaporated. The
residue was purified by reverse phase preparative HPLC to
provide 9a (40 mg, 62%) as a white solid, mp 89-96 °C
(amorphous). 1H NMR (CDCl3): δ 1.90 (s, 3H), 2.17 (s, 3H),
2.85 (s, 3H), 3.02 (s, 3H), 3.66 (m, 2H), 7.26-7.93 (m, 9H).
Anal. (C24H24N4O5S‚0.6 H2O) C, H, N, S.
1
8a as a white solid. mp > 200 °C (dec). H NMR (CDCl3): δ
1.13 (d, J ) 7.6 Hz, 6H), 1.86 (s, 3H), 1.89 (m, 2H), 2.15 (s,
3H), 3.31 (m, 2H), 4.26 (ABq, J ) 16.4, 16.4 Hz, 2H), 7.22-
8.00 (m,9H). Anal. (C27H28N4O5S‚0.2 H2O) C, H, N, S.
N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-[(4,4-d im et h yl-2-oxo-
1-p yr r olid in yl)m et h yl]-4′-(2-oxa zolyl)[1,1′-b ip h en yl]-2-
su lfon a m id e (8b). Compound 8b was prepared from 7 and
4,4-dimethyl-2-pyrrolidinone in the same manner as 8a . 1H
NMR (CDCl3): δ 1.19(s, 3H), 1.23 (s, 3H), 1.90(s, 3H), 2.17(s,
3H), 2.25(m, 2H), 3.21 (m, 2H), 4.27(m, 2H), 7.25-8.01(m, 9H).
HRMS calcd 521.1859 (C27H29N4O5S), Found 521.1870. Anal.
(C27H28N4O5S‚0.3 H2O) C, H, N, S.
N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-[(3,3-d im et h yl-2-oxo-
1-p ip er id in yl)m eth yl]-4′-(2-oxa zolyl)[1,1′-bip h en yl]-2-su l-
fon a m id e (8c). Compound 8c was prepared from 7 and 3,3-
dimethyl-2-piperidone in the same manner as 8a . 1H NMR
(CDCl3): δ 1.09(s, 3H), 1.24 (s, 3H), 1.75 (m, 2H), 1.85-2.10
(m, 2H), 1.93 (s, 3H), 2.17 (s, 3H), 3.48 (m, 2H), 3.94-4.52 (m,
2H), 7.25-8.98 (m, 10H). HRMS calcd 535.2015 (C28H31N4O5S),
Found 535.2026.
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2-oxa zolyl)-2′-[(2-oxo-
3-m eth yl-1-im id a zolid in yl)m eth yl][1,1′-bip h en yl]-2-su l-
fon a m id e (8d ). To a solution of 0.3 g (0.586 mmol) of 6 in 15
mL of dichloromethane were added 1 g of 3 Å molecular sieves,
0.074 g (0.997 mmol) of N-methyl ethylenediamine, and 0.105
g (1.76 mmol) of acetic acid and stirred under argon for 10
min. Sodium triacetoxyborohydride 0.372 g (1.45 mmol) was
then added to the mixture and stirred at room temperature
for 12 h. The solution was then filtered through Celite, and
the filtrate was washed with of water, dried, and evaporated
to afford 0.33 g of a colorless gum. To a solution of this material
in 10 mL of dichloromethane was added 0.104 g (0.645 mmol)
carbonyldiimidazole. The mixture was stirred at room tem-
perature for 24 h. The mixture was then washed with water,
dried, and evaporated to provide 0.26 g of a colorless gum. To
a solution of this material in 10 mL of 95% ethanol was added
10 mL of 6 N aqueous hydrochloric acid, and the solution was
refluxed for 1 h. The mixture was then diluted with water and
extracted with EtOAc. The combined organic extracts were
then washed once with water, dried, and evaporated. The
residue was purified by reverse phase preparative HPLC to
provide 0.039 g (17%) of 8d as a white solid. mp 105-115 °C
(amorphous).
2′-[[(3,4-Dim eth yl-5-isoxa zolyl)a m in o]su lfon yl]-N-ter t-
bu tyl-4-(2-oxa zolyl)[1,1′-biph en yl]-2-a ceta m id e (9b). Com-
1
pound 9b was prepared in the same manner as 9a . H NMR
(CDCl3): δ 1.26 (s, 9H), 1.91 (s, 3H), 2.04 (s, 3H), 3.33 (m, 2H),
7.13-7.93 (m, 9H).
N -(3,4-Dim e t h yl-5-isoxa zolyl)-2′-[(1-m e t h yle t h oxy)-
m eth yl]-4′-(2-oxa zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (9c).
To a solution of 2-propanol (0.104 g, 1.73 mmol) in 2 mL of
DMF was added NaH (50% suspension in mineral oil, 0.033
g, 0.69 mmol). The mixture was stirred at room temperature
under argon for 10 min. Compound 7 (0.2 g, 0.346 mmol) in 1
mL of DMF was then added, and the mixture was stirred for
12 h. The mixture was then added to water, and the solution
was extracted with EtOAc. The combined organic extracts were
washed with water, dried, and evaporated. The crude residue
was chromatographed on silica gel using 1:1 hexane:EtOAc
to afford 0.19 g as a colorless gum. This material was dissolved
in 2.5 mL of 95% EtOH and 2.5 mL of 6 N aqueous HCl was
added. The solution was refluxed for 1 h. The mixture was
then concentrated and diluted with water and extracted with
EtOAc. The combined organic extracts were then washed once
with water, dried, and evaporated to provide 0.015 g of a
colorless gum. The residue was purified by reverse phase
preparative HPLC to provide 0.06 g (40%) of 9c. 1H NMR
1H NMR (CDCl3): δ 1.91 (s, 3H), 2.17 (s, 3H), 2.73 (s, 3H),
3.39 (m, 4H), 4.18 (s, 3H), 7.25-8.26 (m, 9H). HRMS calcd
508.1674(C25H25N5O5S), Found 508.1655.
2′-[[(3,4-Dim et h yl-5-isoxa zolyl)a m in o]su lfon yl]-N,N-
d im eth yl-4-(2-oxa zolyl)[1,1′-bip h en yl]-2-a ceta m id e (9a ).

Biphenylsulfonamide Endothelin Receptor Antagonists
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 135
(CDCl3): δ 1.01 (d, 3H), 1.04 (d, 3H), 1.89 (s, 3H), 2.17 (s, 3H),
3.58 (m, 1H), 4.38 (ABq, J ) 16.8, 11.2 Hz, 2H), 7.25-8.17
(m, 9H).
After cooling to 0 °C, sodium borohydride (12 mg; 0.3 mmol)
was added to the mixture followed by 0.2 mL of MeOH. After
stirring for 24 h, the reaction mixture was concentrated and
the residue was purified by preparative HPLC to afford 29 mg
(54%) of 9j as a white powder. mp 156-167 °C. 1H NMR (CD3-
OD): δ 1.71 (s, 3H), 2.15 (s, 3H), 4.60 (d, J ) 15 Hz, 1H), 4.68
(d, J ) 15 Hz, 1H), 6.68 (d, J ) 7.5 Hz, 1H), 7.14 (d, J ) 7.5
Hz, 1H), 7.34 (m, 2H), 7.60 (t, J ) 7.5 Hz, 1H), 7.66 (t, 7.5 Hz,
1H), 7.91 (d, J ) 8 Hz, 1H), 8.02 (m, 2H), 8.07 (m, 2H), 8.46
(s, 1H). HRMS calcd 502.1423 (C25H22N6O4S), Found 502.1491.
N-(3,4-Dim eth yl-5-isoxa zolyl)-2′-[[(5-m eth yl-3-isoxa zol-
yl)a m in o]m eth yl]-4′-[2-oxa zolyl)[1,1′-bip h en yl]-2-su lfon -
a m id e (9k ). Compound 9k was prepared in the same manner
as 9j using 5-methyl 3-isoxazolamine. 1H NMR (CD3OD): δ
1.71 (s, 3H), 1.72 (s, 3H), 2.02 (s, 3H), 2.13 (s, 3H), 4.17 (d, J
) 15.5 Hz, 1H), 4.25 (d, J ) 15.5 Hz, 1H), 7.12 (d, J ) 8 Hz,
1H), 7.32 (s, 1H), 7.37 (d, J ) 7.5 Hz, 1H), 7.63 (t, J ) 8 Hz,
1H), 7.70 (t, 7.5 Hz, 1H), 7.87 (d, J ) 7.5 Hz, 1H), 8.00 (s, 1H),
8.10 (s, 1H), 8.11 (d, J ) 8 Hz, 1H). HRMS calcd 519.1576
(C26H25N5O5S), Found 519.1636.
(Z)-N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-oxa zolyl)-2′-(2-
ph en yleth en yl)[1,1′-biph en yl]-2-su lfon am ide (9l). To benz-
yltriphenylphosphonium chloride (300 mg, 0.77 mmol) in 10
mL of THF at -78 °C was added n-butyllithium (2 M in
pentane, 0.39 mL, 0.78 mmol). The cold bath was removed,
and the mixture was stirred at room temperature for 45 min
before cooling to -78 °C again. Compound 6 (304 mg, 0.59
mmol) was added at -78 °C, and the reaction mixture was
then stirred at room temperature for 2.5 h. Ten milliliters of
water and 40 mL of ethyl acetate were added. The organic
layer was separated and washed with saturated aqueous
ammonium chloride and brine, dried, and concentrated. The
residue was dissolved in 6 mL of 95% ethanol and 6 mL of 6
N aqueous hydrochloric acid was added and refluxed for 1 h.
The reaction mixture was concentrated and diluted with ethyl
acetate. The organic layer was separated, washed with brine,
dried, and concentrated. The residue was purified by prepara-
tive HPLC to provide 9l (73 mg, 19% for two steps) as a white
solid. mp. 102-109 °C (amorphous): 1H NMR (CDCl3): δ 1.86
(s, 3H), 2.16 (s, 3H), 6.38-6.51 (m, J ) 12.3 Hz, 2H), 6.60-
7.98 (m, 15H). HRMS calcd 498.1488 (C28H24N3O4S), Found
498.1482.
N -(3,4-D i m e t h y l-5-i s o x a z o ly l)-4′-(2-o x a z o ly l)-2′-
p h en oxym eth yl)[1,1′-bip h en yl]-2-su lfon a m id e (9e). Com-
1
pound 9e was prepared in the same manner as 9c. H NMR
(CDCl3): δ 1.83 (s, 3H), 2.05 (s, 3H), 4.81 (m, 2H), 6.79-8.13
(m, 14H). Anal. (C27H23N3O5S‚0.1 H2O) C, H, N, S.
N -(3,4-Dim e t h yl-5-isoxa zolyl)-2′-[[m e t h yl(2-m e t h y-
p r op yl)a m in o]m et h yl]-4′-(2-oxa zolyl)[1,1′-b ip h en yl]-2-
su lfon a m id e (9f). A mixture of 4 (100 mg; 0.24 mmol),
isobutylmethylamine (0.087 mL; 0.71 mmol), AcOH (0.08 mL;
1.34 mmol), and 3 Å molecular sieves (670 mg) in 2 mL of
dichloromethane was stirred for 1 h at room temperature.
Sodium triacetoxyborohydride (150 mg; 0.71 mmol) was then
added to the mixture and stirred for 18 h. The reaction mixture
was filtered through Celite, and the filtrate was partitioned
between EtOAc and saturated aqueous sodium bicarbonate.
The organic layer was then washed with water and brine,
dried, and evaporated. The residue was chromatographed on
silica gel using 5% MeOH in CH2Cl2 to afford 9f (88 mg, 83%)
1
as a white powder. mp 90-100 °C. H NMR (CD3OD): δ 0.72
(d, J ) 6.5 Hz, 3H), 0.84 (d, J ) 6.5 Hz, 3H), 1.69 (m, 1H),
1.88 (s, 3H), 2.09 (s, 3H), 2.51 (m, 1H), 2.55 (s, 3H), 2.81 (m,
1H), 3.48 (d, J ) 13 Hz, 1H), 4.19 (d, J ) 12.5 Hz, 1H), 7.12
(d, J ) 6.5 Hz, 1H), 7.26 (d, J ) 7 Hz, 1H), 7.52 (m, 3H), 7.74
(m, 1H), 8.06 (m, 2H), 8.11 (d, J ) 7.5 Hz, 1H). HRMS calcd
494.1988 (C26H30N4O4S), Found 494.2061.
The following compounds were prepared using a procedure
similar to the above and substituting with the appropriate
amine.
N-(3,4-Dim eth yl-5-isoxazolyl)-2′-[(m eth ylph en ylam in o)-
m eth yl]-4′-(2-oxa zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (9g).
1H NMR (CD3OD): δ 1.72 (s, 3H), 2.10 (s, 3H), 3.09 (s, 3H),
4.22 (d, J ) 16 Hz, 1H), 4.53 (d, J ) 16 Hz, 1H), 6.81 (d, J )
7.5 Hz, 2H), 6.95 (m, 2H), 7.10 (d, J ) 8 Hz, 1H), 7.21 (m,
2H), 7.31 (s, 1H), 7.63 (m, 2H), 7.90 (d, 7.5 Hz, 1H), 7.98 (s,
1H), 8.05 (s, 1H), 8.12 (m, 1H). HRMS calcd 514.1675
(C28H26N4O4S), Found 514.1749.
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2-oxa zolyl)-2′-[[(2,2,2-
t r iflu or oet h yl)a m in o]m et h yl][1,1′-b ip h en yl]-2-su lfon a -
m id e (9h ). 1H NMR (CD3OD): δ 1.73 (s, 3H), 2.13 (s, 3H),
3.95 (q, J ) 9 Hz, 2H), 4.11 (d, J ) 14 Hz, 1H), 4.29 (d, J ) 14
Hz, 1H), 7.31 (d, J ) 8 Hz, 1H), 7.40 (s, 1H), 7.44 (d, J ) 7.5
Hz, 1H), 7.73 (t, J ) 8.5 Hz, 1H), 7.81 (t, 7.5 Hz, 1H), 8.07 (d,
J ) 8.5 Hz, 1H), 8.08 (s, 1H), 8.17 (d, J ) 8 Hz, 1H), 8.31 (s,
1H). HRMS calcd 506.1236 (C23H21F3N4O4S), Found 506.1230.
N-(3,4-Dim eth yl-5-isoxa zolyl)-2′[[m eth yl(2,2,2-tr iflu o-
r oet h yl)a m in o]m et h yl]-4′-(2-oxa zolyl)[1,1′-b ip h en yl]-2-
su lfon a m id e (9i). Sodium cyanoborohydride (51 mg; 0.76
mmol) was added to a solution of 9h (138 mg; 0.254 mmol)
and 37% formaldehyde solution (0.21 mL; 2.54 mmol) in 1.2
mL of acetonitrile at room temperature. A vigorous and
exothermic evolution of gas was observed. After the reaction
cooled back to room temperature, 25 mL of AcOH was added
and the reaction mixture was stirred 2 h. After partitioning
the reaction mixture between EtOAc (30 mL) and saturated
aqueous NaHCO3 solution (30 mL), the aqueous layer was
extracted with EtOAc (15 mL). The combined organic layers
were washed with brine (15 mL), dried, and concentrated. The
residue was subjected to preparative HPLC to afford 41 mg
(E)-N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2-oxa zolyl)-2′-(2-
p h en yleth en yl)[1,1′-bip h en yl]-2-su lfon a m id e (9m ). Sub-
sequent elution of the HPLC column from above provided 9m
(27 mg, 7% for two steps) as a light yellow solid. mp 109-116
°C (amorphous). 1H NMR (CDCl3): δ 1.74 (s, 3H), 2.01(s, 3H),
6.72-7.10 (m, 2H), 7.17-7.98 (m, 15H).
N -(3,4-Dim e t h yl-5-isoxa zolyl)-4′-(2-oxa zolyl)-2′-(2-
oxa zolylm eth yl)[1,1′-bip h en yl]-2-su lfon a m id e (9n ). This
compound was prepared from 2-[4-bromo-3-(2-oxazolylmethyl)-
phenyl]oxazole22 and 2-borono-N-(3,4-dimethyl-5-isoxazolyl)-
N-[(2-methoxyethoxy)methyl]-benzenesulfonamide using a Su-
zuki-coupling procedure described previously16 followed by
deprotection of the MEM group using 6 N aqueous hydrochloric
acid to provide 9n as a colorless gum. mp 88-95 °C (amor-
1
phous). H NMR (CDCl3): δ 1.89 (s, 3H), 2.16 (s, 3H), 4.11 (s,
2H), 7.03-8.30 (m, 12H).
N-(3,4-Dim eth yl-5-isoxazolyl)-4′-(2-oxazolyl)-2′-(1H-pyr a-
zol-1-ylm eth yl)[1,1′-bip h en yl]-2-su lfon a m id e (9o). A solu-
tion of pyrazole (22.3 mg, 0.34 mmol) in 2.5 mL of THF was
cooled to 0 °C under an argon atmosphere, and 60% sodium
hydride (12 mg, 0.34 mmol) was added. After stirring at 0 °C
for 0.5 h, compound 7 (130 mg, 0.225 mmol) in 0.5 mL of DMF
was added to the mixture and stirred overnight. The reaction
was diluted with water and extracted with ethyl actate. The
organic extract was washed with brine, dried, and evaporated.
The crude product was purified by column chromatography
on silica eluting with methanol/methylene chloride to provide
118 mg of a colorless gum. This material was dissolved in 1.5
mL of ethanol and 1.5 mL of 6 N aqueous HCl, and the mixture
was refluxed for 2.5 h. The mixture was concentrated to
dryness, dissolved in ethyl acetate, washed with sodium
bicarbonate, water, and brine, and dried over sodium sulfate.
1
(25%) of 9i as a white powder. mp 49 °C. H NMR (CD3OD):
δ 1.71 (s, 3H), 2.15 (s, 3H), 2.29 (s, 3H), 2.92 (m, 1H), 3.05 (m,
1H), 3.47 (d, J ) 14 Hz, 1H), 3.54 (d, J ) 14 Hz, 1H), 7.10 (d,
J ) 8 Hz, 1H), 7.29 (d, J ) 7.5 Hz, 1H), 7.33 (s, 1H), 7.63 (t,
J ) 8 Hz, 1H), 7.70 (t, 7.5 Hz, 1H), 7.87 (d, J ) 7.5 Hz, 1H),
8.02 (s, 1H), 8.10 (d, J ) 8 Hz, 1H), 8.24 (s, 1H). HRMS calcd
520.1392 (C24H23F3N4O4S), Found 520.1469.
N-(3,4-Dim eth yl-5-isoxazolyl)-2′-[(4-pyr im idin ylam in o)-
m eth yl]-4′-(2-oxa zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (9j).
A mixture of 4-aminopyrimidine (20 mg; 0.2 mmol), 4 (42 mg;
0.1 mmol). and MgSO4 (0.1 g) in 2 mL of toluene was heated
to reflux for 10 h. After cooling to room temperature, the
reaction mixture was filtered and concentrated to ca. 1 mL.

136 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Murugesan et al.
The crude product was purified on silica eluting with methanol/
methylene chloride yielding 40 mg of 9o as a colorless solid,
mp 140-146 °C. 1H NMR (CDCl3): δ 1.94 (s, 3H), 2.15 (s, 3H),
5.13 (d, J ) 16 Hz, 1H), 5.24 (d, J ) 16 Hz, 1H), 7.21-7.99
(m, 12H). HRMS calcd 476.1393 (C24H21N5O4S), Found 476.1382.
15 (13.17 g, 92%) as a white solid. 1H NMR (CDCl3/CD3OD
4:1): δ 1.66 (s, 3H), 2.23 (s, 3H), 7.28-8.62 (m, 9H), 9.58 (s,
1H).
N-[[2′-[[(4,5-Dim eth yl-3-isoxa zolyl)a m in o]su lfon yl]-4-
(2-oxa zolyl)[1,1′-b ip h en yl]-2-yl]m et h yl]-N,3,3-t r im et h -
ylbu ta n a m id e (16a ). To a solution of 15 (12.91 g, 30.48 mmol)
in 300 mL of dichloromethane was added acetic acid (4.58 g,
76.20 mmol) followed by methylamine (8.03 M in EtOH, 13.29
mL, 106.68 mmol). The mixture was stirred for 15 min sodium
triacetoxyborohydride (19.38 g, 91.44 mmol) was added, and
the mixture was stirred for an additional 2 h. The solution
was then filtered, washed with water, and dried, and evapo-
rated to provide N-(4,5-dimethyl-3-isoxazolyl)-2′-[(methylami-
no)methyl]-4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide as a
gray white solid. To a solution of this material in 300 mL of
CH2Cl2 at 0 °C was added triethylamine (6.17 g, 60.96 mmol)
and stirred for 5 min. To the mixture was added tert-
butylacetyl chloride (3.98 g, 29.57 mmol) dropwise over 10 min,
and the mixture was then slowly warmed to room temperature
and stirred for 1 h. The organic layer was washed with water
and brine, dried, and concentrated. The residue was chro-
matographed on silica gel using 60:40:1 hexane/EtOAc/AcOH
to provide 16a (13.10 g, 80% for two steps) as a white solid.
mp 120-128 °C (amorphous). 1H NMR (CDCl3): δ 1.03 (s, 9H),
1.85 (s, 3H), 2.25 (s, 3H), 2.33 (m, 2H), 3.16 (s, 3H), 4.21-4.61
(m, 2H), 7.25-8.12 (m, 9H). Anal. (C28H32N4O5S) C, H, N, S.
N-(4,5-Dim et h yl-3-isoxa zolyl)-2′-[(3,3-d im et h yl-2-oxo-
1-p yr r olid in yl)m et h yl]-4′-(2-oxa zolyl)[1,1′-b ip h en yl]-2-
su lfon a m id e (16b). To a mixture of 15 (2.00 g, 4.72 mmol),
3-carboxy-3-methylbutylammonium chloride (1.58 g, 9.45 mmol),
and 3 Å molecular sieves (0.5 g) in 50 mL of dichloromethane
was added AcOH (0.85 g, 14.17 mmol) followed by sodium
acetate (0.77 g, 9.45 mmol). The mixture was stirred for 10
min, and sodium triacetoxyborohydride (3.00 g, 14.17 mmol)
was added. The reaction mixture was stirred at room temper-
ature for 2 h, diluted with dichloromethane, and filtered
through Celite. The filtrate was washed with water and brine,
dried, and concentrated to yield a colorless gum. This material
was dissolved in 50 mL of dichloromethane, and 1,3-diisopro-
pylcarbodiimide (775 mg, 6.14 mmol) was added. The mixture
was stirred at room temperature for 1 h, diluted with dichlo-
romethane, washed with water and brine, dried, and concen-
trated. The residue was chromatographed on silica gel using
50:50:1 hexane/EtOAc/AcOH to provide 16b (1.47 g, 60% for
two steps) as a white solid, mp 206-208 °C. 1H NMR (CDCl3):
δ 1.17 (d, J ) 7.6 Hz, 6H), 1.82 (s, 3H), 1.90 (m, 2H), 2.25 (s,
3H), 3.30 (m, 2H), 4.25 (ABq, J ) 16.2, 16.2 Hz, 2H), 7.25-
8.17 (m, 9H). Anal. (C27H28N4O5S) C, H, N, S.
The following compounds were prepared using a procedure
similar to the above and substituting with the appropriate
heterocycle.
N-(3,4-Dim eth yl-5-isoxa zolyl)-2′-(1H-im id a zol-1-ylm e-
th yl)-4′-(2-oxazolyl)[1,1′-biph en yl]-2-su lfon am ide (9p). mp
1
135-145 °C. H NMR (CD3OD): δ 1.73 (s, 3H), 2.15 (s, 3H),
5.32 (d, 2H), 7.22-8.64 (m, 12H).
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2-oxa zolyl)-2′-[(3-tr i-
flu or om et h yl-1H -p yr a zol-1-yl)m et h yl][1,1′-b ip h en yl]-2-
1
su lfon a m id e (9q). H NMR (CDCl3): δ 1.92 (s, 3H), 2.15 (s,
3H), 5.24 (s, 2H), 7.16-8.08 (m, 11H). HRMS calcd 544.1266
(C25H20F3N5O4S), Found 544.1246.
2-Br om o-N-(4,5-d im eth yl-3-isoxa zolyl)-N-[(2-m eth oxy-
eth oxy)m eth yl] ben zen esu lfon a m id e (12). To a solution
of 4,5-dimethyl-3-isoxazolamine (13.14 g, 117.79 mmol) and
4-(dimethylamino)pyridine (1.44 g, 11.78 mmol) in 80 mL
pyridine at 0 °C was added 2-bromobenzenesulfonyl chloride
(28.59 g, 111.90 mmol) in portions over 10 min. The mixture
was stirred at 40 °C for 6.5 h and concentrated. The residue
was dissolved in 3% aqueous sodium bicarbonate, any residual
solid was filtered off, and the aqueous filtrate was acidified to
pH 1 with 6 N aqueous HCl at 0 °C and extracted with ethyl
acetate. The extracts were washed with aqueous 1 N HCl,
water, and brine, dried, and concentrated to give 2-bromo-N-
(4,5-dimethyl-3-isoxazolyl)benzenesulfonamide (34.32 g, 84%).
To a solution of this material (32.60 g, 102.78 mmol) in 350
mL of dimethylformamide at -15 °C, NaH (60% in mineral
oil, 4.93 g, 123.34 mmol) was added in portions. After stirring
at room temperature for 30 min, the mixture was cooled with
in ice-salt bath, and 2-methoxyethoxymethyl chloride (16.00
g, 128.48 mmol) was added dropwise over 20 min. The reaction
was stirred with an ice-salt bath for 20 min and then at room
temperature for 1.5 h. The mixture was diluted with EtOAc,
and the organic layer was separated, washed with water and
brine, dried, and concentrated. The residue was chromato-
graphed on silica gel using hexane/EtOAc to afford 12 (32.12
g, 75%) as an oil. 1H NMR (CDCl3): δ 1.99 (s, 3H), 2.29 (s,
3H), 3.37 (s, 3H), 3.57 (m, 2H), 3.94 (m, 2H), 5.36 (s, 2H), 7.37-
8.03 (m, 4H).
N-(4,5-Dim eth yl-3-isoxa zolyl)-2′-for m yl-N-[(2-m eth oxy-
et h oxy)m et h yl]4′-(2-oxa zolyl)[1,1′-b ip h en yl]-2-su lfon a -
m id e (15). To a solution of 12 (22.16 g, 52.85 mmol) in 260
mL of THF at -95 °C was added n-butyllithium (2 M solution
in pentane, 29.07 mL, 58.14 mmol). The mixture was stirred
at -95 °C for 10 min, and trimethylborate (6.59 g, 63.42 mmol)
was added and stirred at -78 °C for an additional 15 min.
The cold bath was removed, and the mixture was slowly
warmed to room temperature and stirred for 0.5 h. The
mixture was then cooled to 0 °C, and 100 mL of 3 N aqueous
HCl was added dropwise. After stirring for 30 min, the mixture
was extracted with dichloromethane. The combined organic
extracts were washed with brine, dried, and concentrated to
give 2-borono-N-(4,5-dimethyl-3-isoxazolyl)-N-[(2-methoxy-
ethoxy)methyl]benzenesulfonamide (13) as a gum. To a solu-
tion of this crude material and 1416 (13.32 g, 58.14 mmol) in
260 mL of toluene and 130 mL of 95% ethanol were added
100 mL of 2 M aqueous sodium carbonate and tetrakis-
(triphenylphosphine)palladium(0) (6.11 g, 5.29 mmol), and the
reaction mixture was heated under argon at 85 °C for 4 h,
cooled, and diluted with EtOAc. The organic layer was
separated and washed with water and brine, dried, and
concentrated. The residue was chromatographed on silica gel
using 1:1 hexane/EtOAc to afford a colorless gum. To a solution
of this material (16.95 g, 33.14 mmol) in 400 mL of 95% ethanol
was added 400 mL of 6 N aqueous hydrochloric acid and
refluxed for 1 h. The mixture was concentrated and diluted
with 800 mL of ice water. After standing for 2 h, a white
precipitate was formed and was collected by filtration yielding
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