Biphenylsulfonamide endothelin receptor antagonists. 2. Discovery of 4'-oxazolyl biphenylsulfonamides as a new class of potent, highly selective ET(A) antagonists

Article abstract of DOI:10.1021/jm000105c

The synthesis and structure-activity relationship (SAR) studies of a series of 4'-oxazolyl-N-(3,4-dimethyl-5-isoxazolyl)[1, 1'-biphenyl]-2-sulfonamide derivatives as endothelin-A (ET(A)) receptor antagonists are described. The data reveal a remarkable improvement in potency and metabolic stability when the 4'-position of the biphenylsulfonamide is substituted with an oxazole ring. Additional 2'-substitution of an acylaminomethyl group further increased the binding activity and provided one of the first subnanomolar ET(A)-selective antagonists in the biphenylsulfonamide series (17, ET(A) K(i) = 0.2 nM). Among the compounds described, 3 (N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-s ulfonamide; BMS-193884) had the optimum pharmacological profile and was therefore selected as a clinical candidate for studies in congestive heart failure.

Full text of DOI:10.1021/jm000105c

J . Med. Chem. 2000, 43, 3111-3117
3111
Bip h en ylsu lfon a m id e En d oth elin Recep tor An ta gon ists. 2. Discover y of
4′-Oxa zolyl Bip h en ylsu lfon a m id es a s a New Cla ss of P oten t, High ly Selective
ETA An ta gon ists
Natesan Murugesan,* Zhengxiang Gu, Philip D. Stein, Steven Spergel, Arvind Mathur, Leslie Leith,
Eddie C.-K. Liu, Rongan Zhang, Eileen Bird, Tom Waldron, Anthony Marino, Richard A. Morrison,
Maria L. Webb, Suzanne Moreland, 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 March 6, 2000
The synthesis and structure-activity relationship (SAR) studies of a series of 4′-oxazolyl-N-
(3,4-dimethyl-5-isoxazolyl)[1,1′-biphenyl]-2-sulfonamide derivatives as endothelin-A (ETA) recep-
tor antagonists are described. The data reveal a remarkable improvement in potency and
metabolic stability when the 4′-position of the biphenylsulfonamide is substituted with an
oxazole ring. Additional 2′-substitution of an acylaminomethyl group further increased the
binding activity and provided one of the first subnanomolar ETA-selective antagonists in the
biphenylsulfonamide series (17, ETA Ki ) 0.2 nM). Among the compounds described, 3 (N-
(3,4-dimethyl-5-isoxazolyl)-4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide; BMS-193884) had the
optimum pharmacological profile and was therefore selected as a clinical candidate for studies
in congestive heart failure.
Ch a r t 1
In tr od u ction
Endothelins are a family of closely related 21-amino
acid peptides (ET-1, ET-2, and ET-3) with ET-1 being
one of the most potent vasoconstrictors identified to
date.1,2 These peptides cause numerous biological effects
in addition to vasoconstriction and are the subject of
several recent reviews.3-5 The endothelins have been
implicated in a variety of disease states including
hypertension,6 congestive heart failure,7-9 renal fail-
ure,10,11 pulmonary hypertension,12 and metastatic pros-
tate cancer.13 The endothelins exert their physiological
activities via two specific G-protein coupled receptors
termed ETA and ETB.14,15 The ETA receptor is selective
for ET-1 and is expressed predominately in vascular
smooth muscle cells where it mediates vasoconstrictive
and proliferative responses. The ETB receptor is non-
selective and binds all three ET isopeptides with equal
affinity. The ETB receptors are mostly found on endo-
thelial cells and mediate ET-1-induced vasodilation
possibly through the release of nitric oxide. A small
population of ETB receptors is also found on some
smooth muscle cells where their activation leads to
vasoconstriction.16
A variety of endothelin antagonists with varying
degrees of subtype selectivity have been reported in the
literature.5,17,18 A number of these antagonists are
currently being investigated to determine the role of
endothelin and its receptors in mediating various patho-
physiologies.19,20
Previously, we described a series of benzene- and
naphthalenesulfonamides leading to the identification
of 1 (BMS-182874) as a moderately potent and selective
ETA antagonist (ETA Ki ) 55 nM).21,22 Subsequent
structure-activity studies (SAR) led to the identification
of biphenylsulfonamide ETA-selective antagonists with
improved binding affinity as well as functional activity.
Optimization via substitution off the pendant phenyl
ring led initially to the 4′-isobutyl biphenylsulfonamide
derivative 2 (ETA Ki ) 18 nM). Additional substitution
of 2 with a 2′-amino group led to the identification of
the 2′-amino-4′-isobutyl biphenylsulfonamide derivative
2a (BMS-187308) as one of our key lead compounds
(Chart 1).23 However, subsequent preclinical pharma-
cokinetic studies indicated that this compound under-
went rapid and extensive hydroxylation of the 4′-
isobutyl group resulting in inadequate plasma concentra-
tions of 2a in vivo.24 We therefore initiated studies
focused on identifying metabolically stable replacements
for the isobutyl group that maintained or improved the
activity of 2a . This paper describes the resulting dis-
* To whom correspondence should be addressed. Tel: 609-818-5391.
Fax: 609-818-3450. E-mail: murugesan@bms.com.
10.1021/jm000105c CCC: $19.00 © 2000 American Chemical Society
Published on Web 07/19/2000

3112 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Murugesan et al.
Sch em e 1a
a
(a) Polyphosphoric acid, 16 °C; (b) sulfolane, 14 °C; (c) (Ph3P)4Pd, aq Na2CO3, EtOH/toluene; (d) 6 N aq HCl/EtOH.
covery of a 4′-oxazolyl biphenylsulfonamide as a highly
presence of triethylamine then afforded the target
potent and ETA-selective antagonist.
compound 17.
Ch em istr y
Resu lts a n d Discu ssion
The 4′-oxazolyl biphenylsulfonamide 3 was synthe-
sized as shown in Scheme 1. Reaction of 4-bromophenyl
carboxamide 4 with vinylene carbonate 5 and polyphos-
phoric acid provided the oxazole 6. Alternatively, 6 may
also be prepared by the reaction of the acid chloride 7
with either trimethylsilyl triazole 8 or triazole 9 in the
presence of potassium carbonate in sulfolane. Suzuki
coupling of the oxazole 6 with our previously reported
boronic acid derivative 1023 using palladium tetrakis-
triphenylphosphine as the catalyst gave the biphenyl-
sulfonamide 11. Removal of the MEM group was
achieved using 6 N aqueous hydrochloric acid in reflux-
ing ethanol to afford compound 3. Compounds 3a -i
were prepared by an analogous sequence to that shown
in Scheme 1. The corresponding oxazole intermediates
6a -i were prepared using known methods.
The 2′-acylaminomethyl-4′-oxazolyl biphenylsulfon-
amide derivative 17 was prepared as depicted in Scheme
2. The 4-bromo-3-methyl carboxamide 12 was prepared
from the corresponding, commercially available car-
boxylic acid. Treatment of 12 with vinylene carbonate
5 and polyphosphoric acid provided the oxazole 13. The
methyl group was then converted to the aldehyde 14
using a two-step sequence. Treatment of 13 with N-
bromosuccinimide in the presence of benzoyl peroxide
gave the corresponding bromomethyl derivative which
upon oxidation using anhydrous trimethylamine N-
oxide in DMSO provided the aldehyde intermediate 14.
Suzuki coupling of 14 with the boronic acid 10 afforded
15 which upon deprotection of the MEM group gave 16.
The aldehyde group in 16 was then converted to the
corresponding aminomethyl derivative via reductive
amination of 16 in the presence of ammonium acetate,
sodium triacetoxyborohydride, and acetic acid. Acylation
of this intermediate using acetic anhydride in the
P r im a r y SAR Eva lu a tion . In our previous report
from these laboratories, we described the design and
synthesis of a series of biphenylsulfonamides as ETA-
selective antagonists exemplified by the 2′-amino-4′-
isobutyl biphenylsulfonamide derivative 2a (BMS-
187,308, ETA Ki ) 5 nM, ETB Ki ) 1700 nM).23
Compound 2a also had good oral activity as determined
by inhibition of the pressor effect caused by ET-1
infusion in rats. However, subsequent pharmacokinetic
studies in rats revealed that the compound was rapidly
cleared and the plasma elimination half-life was short
(15 min) after intravenous administration. Two major
metabolites were detected, both hydroxylated on the
isobutyl side chain. Because metabolism of the isobutyl
side chain of 2a probably contributed to the rapid
decline of plasma concentration in vivo, we embarked
on a program focused on identifying metabolically stable
replacements for this group that would also maintain
or improve the ETA activity and ETA selectivity of 2a .
Previous SAR of the biphenylsulfonamides suggested
steric and conformational limitations at the 4′-position.
For example, it was found that introduction of groups
larger than isobutyl resulted in significant loss of
activity suggesting the need for a substituent with an
optimal size and shape.23 We, therefore, investigated
small heteroaromatic rings as potential replacements
for the isobutyl group. The 4′-oxazole derivative 3 was
one of the first compounds to be synthesized as a part
of this effort. Compound 3 was found to be a very potent
ETA receptor antagonist (Ki ) 1.4 nM) and displayed
weaker binding to the ETB receptor (Ki ) 18 700 nM).
These data indicate that 3 is greater than 10 000-fold
selective for the ETA receptor. Therefore, replacement
of the isobutyl group in 2 (ETA Ki ) 18 nM, ETB Ki )
1700 nM) by an oxazole results in greater than 10-fold

Biphenylsulfonamide ETA Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3113
Sch em e 2a
a
(a) Polyphosphoric acid, 16 °C; (b) (i) N-bromosuccinimide/benzoyl peroxide, (ii) trimethylamine N-oxide, DMSO; (c) compound 10,
(Ph3P)4Pd, aq Na2CO3, EtOH/toluene; (d) 6 N aq HCl/EtOH; (e) (i) ammonium acetate, sodium triacetoxyborohydride, AcOH, (ii) acetic
anhydride, triethylamine.
improvement in ETA activity and selectivity. Oxazole 3
is also a potent functional antagonist with a KB value
of 19 nM in inhibiting ET-1 induced contraction in
rabbit carotid artery rings.
The additive effect of a 2′-substituent observed in the
isobutyl series was also seen in this case. Compound
17 showed extremely high affinity for the ETA receptor
(ETA Ki ) 0.2 nM) and is the first subnanomolar
antagonist discovered in the biphenylsulfonamide series.
The ETA selectivity was also maintained as it was a
relatively weak antagonist for the ETB receptor (ETB
Ki ) 1700 nM).
Secon d a r y Eva lu a tion s. On the basis of its excel-
lent binding affinity, selectivity, functional potency, and
ease of synthesis, 3 (BMS-193884) was chosen for
further evaluation. BMS-193884 was tested for its
ability to inhibit big ET-1 (1 nmol/kg, iv)-induced
vasoconstriction in conscious, normotensive rats. This
compound blocked the pressor response in a dose-
dependent manner when administered orally or intra-
venously in rats (ED25 ) 0.2 µmol/kg, iv and 1.1 µmol/
kg, po) (Figure 1).
The high level of tissue ET-1 in DOCA salt hyper-
tensive rats suggested that endothelin might play a role
in this model of hypertension. Lowering of blood pres-
sure in this model has been shown with the ETA-
selective antagonists BMS-182874 25 and EMD-122946.26
BMS-193884 (30 µmol /kg) had marked depressor effect
in this model, lowering mean arterial pressure by 30
mmHg for 6 h (Figure 2).
BMS-193884 has also been reported to show beneficial
effects in a pig model of congestive heart failure.27 In
pigs with chronic heart failure induced by pacing, BMS-
193884 at 12.5 and 50 mg/kg improved left ventricular
fractional shortening, reduced plasma norepinephrine,
and also normalized systemic vascular resistance. Basal
blood pressure was reduced at the 50 mg dose (from 102
Prompted by the above result, biphenylsulfonamides
containing several substituted and unsubstituted ox-
azole derivatives at the 4′-position were prepared (Table
1). Substitution of the oxazole ring by a methyl group
at the 4-position of the oxazole ring (3a ) did not lead to
any improvement in activity, while a methyl substitu-
tion at the 5-position (3b) was not well tolerated
resulting in a 8-fold loss of ETA binding activity. The
4,5-dimethyloxazole derivative 3c was also 10-fold less
potent than 3, while the benzoxazole analogue 3d
showed strikingly poor ETA binding affinity resulting
in a 2000-fold loss of activity compared to 3, thereby
reinforcing the size limitations at 4′-position of the
molecule. Insertion of a methylene spacer between the
pendant phenyl ring and the oxazole (3e) again resulted
in loss of activity. The isomeric 4-oxazole analogue 3f
was approximately equipotent in both the ETA binding
and functional assays. Substitution of 3f with methyl
groups (3g,h ) resulted in a loss in binding affinity. The
5-oxazole isomer 3i was slightly less potent than the
other two regioisomers.
Our prior work in the 4′-isobutyl series had shown
that addition of an appropriate 2′-substituent such as
an amine, hydroxyl, or acylaminomethyl group resulted
in substantial improvement in activity.23 Among the
substituents studied in this series, the acylaminomethyl
group was found to be an optimal substituent. Com-
pound 17 incorporating a 4′-oxazole and containing a
2′-acetylaminomethyl group was therefore prepared.

3114 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Ta ble 1. Substitution of Biphenylsulfonamides with a 4′-Heterocycle
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.
to 84 mmHg), and the endothelin pressor response was
reduced by more than 50% at both doses.
Pharmacokinetic studies on BMS-193884, in vivo,
showed that it has good oral bioavailability in rats
(43%). It also had excellent oral bioavailability (71%)
in cynomolgus monkeys. The plasma elimination half-
life averaged about 9 h in monkeys, and it also had a
slow clearance rate (Cl ) 0.86 mL/min/kg). The mean

Biphenylsulfonamide ETA Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3115
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.23 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.23 KB values were
obtained from experiments in which at least 3 different
concentrations of test compound were studied. Apparent KB
values were calculated when only one antagonist concentration
was used.
In Vivo Ra t P r essor Stu d ies. This study was performed
as previously described.25 Four iv challenges of ET-1 (0.1 nmol/
kg) or big ET-1 (1.0 nmol/kg) were given; 90 min was allowed
between challenges to allow blood pressure to return to
baseline. The initial challenge was preceded by vehicle ad-
ministration to establish a control response to the agonist.
Three doses of vehicle, compound 20 (0.3, 1, 3, 10, 30 µmol/
kg, iv), were given prior to the subsequent agonist challenges.
Compound 20 was also administered orally at doses of 3, 10,
and 30 µmol/kg prior to ET-1 challenges.
Gen er a l. Melting points were recorded on a Thomas-Hoover
capillary apparatus and are uncorrected. All chemical experi-
ments 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
under flash conditions 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.
F igu r e 1. Inhibition of the pressor response to big ET-1 in
rats after iv and oral administration of 3 (BMS-193884).
2-(4-Br om op h en yl)oxa zole (6). Meth od 1.28 A mixture
of 4-bromobenzenecarboxamide (4 g, 20 mmol), vinylene
carbonate (1.72 g, 20 mmol) and 10 g of polyphosphoric acid
was heated at 170 °C for 3 h. After cooling, the mixture was
partitioned between 200 mL of water and 200 mL of ethyl
acetate. The aqueous layer was extracted with ethyl acetate
and the combined organic liquid was washed with water, dried
and concentrated. The residue was chromatographed on silica
gel using 10:1 hexane/ethyl acetate to afford 6 (2.49 g, 56%)
as a white solid.
Meth od 2.29 A mixture of 4-bromobenzoyl chloride (0.66 g,
3.0 mmol) and 2-(trimethylsilyl)-1,2,3-triazole (0.47 g, 3.3
mmol) was heated at 140 °C for 3 h. Workup and purification
as described above gave 0.55 g (82%) of 6 as a white solid.
Meth od 3. A mixture of 4-bromobenzoyl chloride (0.72 g,
3.3 mmol), 1H-1,2,3-triazole (0.21 g, 3.0 mmol) and potassium
carbonate (0.91 g, 6.6 mmol) in 40 mL of sulfolane was heated
at 140 °C for 15 h. Workup and purification as described above
gave 0.49 g (73%) of 6 as a white solid.
F igu r e 2. Time course of lowering of mean arterial pressure
(MAP) in DOCA salt hypertensive rats following oral admin-
istration of vehicle (thin line, no symbol) or 30 µmol/kg 3 (BMS-
193884); n ) 7-9 rats.
N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-oxa zolyl)[1,1′-b i-
p h en yl]-2-su lfon a m id e (3). To a solution of 315 mg (0.82
mmol) of compound 6 and 0.062 g (0.05 mmol) of tetrakis-
(triphenylphosphine)palladium(0) in 10 mL of toluene under
argon was added 5.0 mL of 2 M aq sodium carbonate followed
by 456 mg (2.05 mmol) of 2-borono-N-(3,4-dimethyl-5-isox-
azolyl)-N′-(methoxyethoxymethyl)benzenesulfonamide (10)22 in
6 mL of 95% EtOH. The mixture was refluxed for 2 h, diluted
with 50 mL of water and extracted with 3 × 50 mL of EtOAc.
The combined organic extracts were washed once with 50 mL
of brine, dried and evaporated. The residue was chromato-
graphed on silica gel using hexanes/EtOAc (2:1) to afford 279
mg (70%) of N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)-
methyl]-4′-(2-oxazolyl)[1,1′-biphenyl]-2-sulfonamide (11) as a
colorless gum. To a solution of compound 11 (276 mg, 0.57
mmol) in 10 mL of 95% ethanol was added 10 mL of 6 N aq
hydrochloric acid and refluxed for 1 h. The mixture was
concentrated and diluted with 10 mL of water. The solution
was neutralized using satd aq NaHCO3 and reacidified to pH
residence time was about 2.5 h, and the volume of
distribution was 0.13 L/kg, indicating that the extravas-
cular distribution of BMS-193884 is relatively low.24
In summary, introduction of an oxazole at the 4′-
position of the biphenylsulfonamides resulted in sub-
stantial improvements in both ETA binding and func-
tional activity. The 4′-oxazolyl biphenylsulfonamide
BMS-193884 is a potent, selective, and orally active
antagonist. Additional 2′-substitution of an acylamino-
methyl group further increased the binding activity and
provided one of the first subnanomolar ETA-selective
antagonists in this class. On the basis of the in vitro
and in vivo profile described above, BMS-193884 was
chosen as a clinical candidate for studies in congestive
heart failure.

3116 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16
Murugesan et al.
4 using glacial AcOH. The mixture was extracted with 3 × 40
mL of EtOAc and the combined organic extracts were washed
once with 50 mL of brine, dried and evaporated. Chromatog-
raphy of the residue on 50 g of silica gel using hexanes/EtOAc
(1:1) provided 3 (117 mg, 52%) as a white solid: mp 90-98 °C
(amorphous). 1H NMR (CDCl3): δ 1.81 (s, 3H), 2.12 (s, 3H),
7.16-8.70 (m, 11H). 13C NMR (CDCl3): δ 6.59, 10.77, 107.87,
125.67, 126.04, 128.03, 128.20, 129.38, 130.33, 132.46, 132.92,
138.19, 138.48, 140.50, 140.93, 154.55, 161.00, 161.81. Anal.
(C20H17N3O4S) C, H, N, S.
(CDCl3): δ 1.88 (s, 3H), 2.14 (s, 3H), 7.03-8.13 (m, 10H). 13C
NMR (CDCl3): δ 6.56, 10.77, 105.77, 120.68, 123.16, 126.62,
127.97, 129.76, 130.74, 132.61, 132.92, 138.11, 139.17, 140.70,
155.01, 161.81 (two aromatic carbons unresolved). Anal.
(C20H17N3O4S‚0.28H2O) C, H, N, S.
2-(4-Br om o-3-m eth ylp h en yl)oxa zole (13). A mixture of
12 (12 g, 56 mmol) and vinylene carbonate (6.5 g, 75.5 mmol)
in 25 g of polyphosphoric acid was heated at 170 °C for 3 h.
The residue was then added to 700 mL of water and extracted
with 3 × 250 mL of EtOAc. The combined organic extracts
were washed once with water, dried and evaporated. The
residue was chromatographed on 200 g of silica gel using
CH2Cl2 to provide 6.7 g (50%) of 13 as a white solid.
The following compounds were prepared using a Suzuki
coupling procedure described for 3 using 10 and the appropri-
ate 4-bromophenyl oxazole derivative30 followed by the depro-
tection of the MEM group using 6 N hydrochloric acid.
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(4-m eth yl-2-oxa zolyl)-
[1,1′-bip h en yl]-2-su lfon a m id e (3a ): mp 85-95 °C (amor-
2-Br om o-5-(2-oxa zolyl)ben za ld eh yd e (14). A mixture of
13 (6.5 g, 27.3 mmol), N-bromosuccinimide (9.72 g, 54.6 mmol)
and benzoyl peroxide (250 mg) in 250 mL of carbon tetrachlo-
ride was refluxed for 8 h while illuminating the solution with
a sun lamp. The mixture was then cooled and filtered. The
filtrate was concentrated to provide 10 g of a light yellow solid.
To a solution of 7 g of this crude material in 15 mL of
anhydrous DMSO under argon was added 5.5 g of anhydrous
trimethylamine N-oxide and the mixture stirred at 55 °C for
6 h. The mixture was then cooled and added to 150 mL of ice/
water and extracted with 3 × 100 mL of EtOAc. The combined
organic extracts were washed once with 100 mL of brine, dried
and evaporated. The residue was chromatographed on silica
gel using hexanes/EtOAc 8:1 to afford 2.2 g (72%) of 14 as a
white solid.
1
phous). H NMR (CDCl3): δ 1.78 (s, 3H), 2.09 (s, 3H), 2.19 (s,
3H), 7.35-8.05 (m, 9H). 13C NMR (CDCl3): δ 6.45, 10.69, 11.38,
108.26, 125.63, 126.78, 128.03, 129.12, 130.14, 132.41, 132.93,
134.46, 137.68, 138.06, 140.40, 140.54, 154.24, 160.79, 161.71.
Anal. (C21H19N3O4S‚0.25H2O) C, H, N, S.
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(5-m eth yl-2-oxa zolyl)-
[1,1′-bip h en yl]-2-su lfon a m id e (3b): mp 90-100 °C (amor-
1
phous). H NMR (CDCl3): δ 1.80 (s, 3H), 2.11 (s, 3H), 2.40 (s,
3H), 6.74-9.53 (m, 10H). 13C NMR (CDCl3): δ 7.37, 11.61,
11.78, 108.39, 124.57, 126.01, 126.68, 128.69, 130.22, 131.00,
133.27, 135.62, 139.20, 141.28, 141.48, 149.40, 155.68, 160.43,
162.56. Anal. (C21H19N3O4S) C, H, N, S.
N -(3,4-Dim e t h yl-5-isoxa zolyl)-4′-(4,5-d im e t h yl-2-ox-
a zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (3c): mp 96-102 °C
(amorphous). 1H NMR (CDCl3): δ 1.78 (s, 3H), 2.10 (s, 3H),
2.11 (s, 3H), 2.31 (s, 3H), 7.35-8.04 (m, 8H). 13C NMR (CDCl3):
δ 6.48, 10.03, 10.72, 11.03, 108.27, 125.28, 127.07, 127.97,
129.12, 130.10, 131.98, 132.47, 132.93, 138.15, 140.02, 140.51,
143.63, 154.30, 158.54, 161.71, 173.14. Anal. (C22H21N3O4S‚
0.24H2O) C, H, N, S.
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2-ben zoxa zolyl)[1,1′-
bip h en yl]-2-su lfon a m id e (3d ): white solid; mp 95-101 °C
(amorphous). 1H NMR (CDCl3): δ 2.03 (s, 3H), 2.11 (s, 3H),
7.33-8.11 (m, 12H). 13C NMR (CDCl3): δ 6.54, 10.74, 108.48,
110.46, 120.05, 124.77, 125.35, 126.33, 127.05, 128.23, 129.32,
130.39, 132.38, 133.04, 138.14, 140.30, 141.65, 142.05, 150.52,
154.26, 161.86, 162.35. Anal. (C24H19N3O4S‚0.9H2O) C, H, N,
S.
N-(3,4-Dim eth yl-5-isoxa zolyl)-2′-for m yl-4′-(2-oxa zolyl)-
[1,1′-bip h en yl]-2-su lfon a m id e (16). This compound was
prepared from aldehyde 14 and the boronic acid 10 using a
Suzuki coupling procedure described for 3 followed by depro-
tection of the MEM group using 6 N aq hydrochloric acid to
provide 16 as a colorless foam (1.46 g, 90%).
N-(3,4-Dim eth yl-5-isoxazolyl)-2′-[(acetylam in o)m eth yl]-
4′-(2-oxa zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (17). To a so-
lution of 0.28 g (0.66 mmol) of 16 in 25 mL of MeOH were
added 5 g of ammonium acetate and 1 g of 3 Å molecular sieves
and stirred at room tempertaure for 1 h. Sodium triacetoxy-
borohydride (0.42 g, 1.98 mmol) was added and the mixture
was stirred for an additional 45 min. The solution was then
filtered and concentrated to 10 mL, diluted with 25 mL of
water and extracted with 3 × 25 mL of EtOAc. The combined
organic extracts were then washed once with water, dried and
evaporated. The residue was chromatographed on silica gel
using 5% MeOH in CH2Cl2 to afford 0.1 g (36%) of N-(3,4-
dimethyl-5-isoxazolyl)-2′-(aminomethyl)-4′-(2-oxazolyl)[1,1′-bi-
phenyl]-2-sulfonamide as a white solid. To a solution of 0.075
g (0.177 mmol) of this material in 10 mL of CH2Cl2 at 0 °C
were added 0.019 g (0.19 mmol) of acetic anhydride and 0.019
g triethylamine. The mixture was then slowly warmed to room
temperature and stirred for 1 h. The mixture was then diluted
with 10 mL of CH2Cl2 and washed with 20 mL of 0.1 N aq
hydrochloric acid and then with 20 mL of water. The organic
layer was then dried and evaporated. The residue was purified
by reverse phase preparative HPLC on a 30 × 500 mm ODS
S10 column using 58% solvent B (90% MeOH, 10% H2O, 0.1%
TFA) and 42% solvent A (10% MeOH, 90% H2O, 0.1% TFA).
The appropriate fractions were collected and neutralized with
aq sodium bicarbonate to pH 7 and concentrated to 10 mL.
The solution was then acidified to pH 4 using dilute hydro-
chloric acid and the white solid was filtered and dried to
provide 0.041 g (50%) of 22: mp 105-107 °C. 1H NMR (CDCl3
+ CD3OD): δ 1.87 (s, 3H), 1.95 (s, 3H), 2.17 (s, 3H), 4.18 (ABq,
J ) 14.5, 15.8 Hz, 2H), 7.21-8.00 (m, 9H). 13C NMR (CDCl3
+ CD3OD): δ 7.3, 11.5, 23.4, 42.2, 108.2, 124.9, 125.1, 125.9,
127.8, 128.7, 129.5, 130.2, 131.4, 132.8, 134.0, 138.1, 138.7,
139.1, 139.8, 140.8, 155.7, 171.9, 172.0. Anal. (C23H22N4O5S‚
0.42H2O) C, H, N, S.
N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-oxa zolylm et h yl)-
[1,1′-bip h en yl]-2-su lfon a m id e (3e): mp 65-70 °C. 1H NMR
(CDCl3): δ 1.80 (s, 3H), 2.11 (s, 3H), 4.16 (s, 2H), 7.04 (s, 1H),
7.27-8.02 (m, 10H). 13C NMR (CDCl3): δ 7.0, 11.2, 34.7, 108.1,
127.5, 128.3, 128.9, 129.5, 130.8, 133.1, 133.4, 135.9, 137.9,
138.5, 139.4, 141.2, 154.7, 162.3, 163.4.
N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(4-oxa zolyl)[1,1′-b i-
1
p h en yl]-2-su lfon a m id e (3f): mp 85-93 °C (amorphous). H
NMR (CDCl3): δ 1.83 (s, 3H), 2.12 (s, 3H), 6.50 (br s, 1H),
7.37-8.04 (m, 9H). 13C NMR (CDCl3): δ 7.23, 11.38, 108.97,
125.81, 128.58, 129.67, 131.11, 131.28, 133.24, 133.70, 134.80,
138.71, 139.03, 141.33, 152.22, 154.67, 162.50 (one aromatic
carbon unresolved). Anal. (C20H17N3O4S‚0.21H2O) C, H, N, S.
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2-m eth yl-4-oxa zolyl)-
[1,1′-bip h en yl]-2-su lfon a m id e (3g): mp 90-100 °C (amor-
1
phous). H NMR (CDCl3): δ 1.80 (s, 3H), 2.10 (s, 3H), 2.52 (s,
3H), 6.78 (s,1H), 7.36-8.02 (m, 9H). 13C NMR (CDCl3): δ 7.84,
12.09, 15.23, 109.64, 126.31, 129.19, 130.29, 131.61, 132.36,
133.98, 134.33, 134.96, 139.43, 141.33, 142.08, 155.47, 163.11,
163.46. Anal. (C21H19N3O4S) C, H, N, S.
N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(5-m eth yl-4-oxa zolyl)-
[1,1′-bip h en yl]-2-su lfon a m id e (3h ): mp 86-96 °C (amor-
1
phous). H NMR (CDCl3): δ 1.84 (s, 3H), 2.12 (s, 3H), 2.57 (s,
3H), 6.70 (s, br, 1H), 7.37-8.03 (m, 9H). 13C NMR (CDCl3): δ
6.65, 10.83, 11.98, 108.39, 126.10, 127.92, 129.04, 130.33,
132.03, 132.72, 133.10, 133.39, 137.50, 138.08, 140.82, 144.65,
149.20, 154.12, 161.90. Anal. (C21H19N3O4S‚0.16H2O) C, H, N,
S.
Su p p or tin g In for m a tion Ava ila ble: Summary of ana-
lytical data for compounds 3, 3a -i, and 22. This material is
available free of charge via the Internet at http://pubs.acs.org.
N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(5-oxa zolyl)[1,1′-b i-
p h en yl]-2-su lfon a m id e (3i): mp 189-191 °C. 1H NMR

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