Biphenylsulfonamide endothelin antagonists: Structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N-(3,4- dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphenyl]-2-sulfonamide (BMS- 187308)

5198

J . Med. Chem. 1998, 41, 5198-5218

Bip h en ylsu lfon a m id e En d oth elin An ta gon ists: Str u ctu r e-Activity

Rela tion sh ip s of a Ser ies of Mon o- a n d Disu bstitu ted An a logu es a n d

P h a r m a cology of th e Or a lly Active En d oth elin An ta gon ist 2′-Am in o-N-

(3,4-d im eth yl-5-isoxa zolyl)-4′-(2-m eth ylp r op yl)[1,1′-bip h en yl]-2-su lfon a m id e

(BMS-187308)

Natesan Murugesan,*^,†Zhengxiang Gu,^†Philip D. Stein,^†Sharon Bisaha,^†Steve Spergel,^†Ravi Girotra,^†

Ving G. Lee,^†J ohn Lloyd,^†Raj N. Misra,^†J oan Schmidt,^†Arvind Mathur,^†Leslie Stratton,^†Yolanda F. Kelly,^†

Eileen Bird,^‡Tom Waldron,^‡Eddie C.-K. Liu,^§Rongan Zhang,^‡Helen Lee,^§Randy Serafino,^‡

Benoni Abboa-Offei,^‡Parker Mathers,^‡Mary Giancarli,^‡Andrea Ann Seymour,^‡Maria L. Webb,^§

Suzanne Moreland,^‡J oel C. Barrish,^†and J ohn T. Hunt^†

Departments of Chemistry, Cardiovascular Agents, Cardiovascular Biochemistry, and Pharmacology,

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New J ersey 08543-4000

Received December 30, 1997

Substitution at the ortho position of N-(3,4-dimethyl-5-isoxazolyl) benzenesulfonamide led to

the identification of the biphenylsulfonamides as a novel series of endothelin-A (ET_A) selective

antagonists. Appropriate substitutions on the pendant phenyl ring led to improved binding

as well as functional activity. A hydrophobic group such as isobutyl or isopropoxyl was found

to be optimal at the 4′-position. Introduction of an amino group at the 2′-position also led to

improved analogues. Combination of the optimal 4′-isobutyl substituent with the 2′-amino

function afforded an analogue (20, BMS-187308) with improved ET_Abinding affinity and

functional activity. Compound 20 also has good oral activity in inhibiting the pressor effect

caused by an ET-1 infusion in rats. Doses of 10 and 30 µmol/kg iv 20 attenuated the pressor

responses due to the administration of exogenous ET-1 to conscious monkeys, indicating that

the compound inhibits the in vivo activity of endothelin-1 in nonhuman primates.

In tr od u ction

for this notion. Therefore, it is widely expected that the

discovery of selective or nonselective antagonists would

prove to be useful in the treatment of these diseases.⁹

Endothelin-1 (ET-1), originally isolated from cultured

porcine endothelial cells, is a potent vasoconstrictor

peptide consisting of 21 amino acids.¹Two additional

related isopeptides, ET-2 and ET-3, have subsequently

been characterized.²It is now known that these pep-

tides are produced by a number of other cell types and

that they possess additional important biological activi-

ties in addition to potent vasoconstriction.³The endot-

helins elicit their diverse biological effects through at

least two distinct G-protein-coupled receptors termed

ET_Aand ET_B.^4,5The ET_Asubtype, which is selective

for ET-1 and ET-2 over ET-3, is found principally in

peripheral tissues such as vascular smooth muscle.⁶The

ET_Areceptor mediates vasoconstriction and vascular

smooth muscle proliferation. The ET_Breceptor, which

is nonselective for all three ET peptides,⁷appears to

mediate either vasodilation or vasoconstriction depend-

ing on the tissue type.⁸The diversity of physiological

effects elicited by the endothelins has implicated these

peptides in the pathogenesis of a variety of disease

states including restenosis, pulmonary hypertension,

renal failure, vasospasm, and congestive heart failure.^3,9

Elevated levels of endothelins have been observed in

many of these disease states providing further support

A number of peptidic as well as nonpeptidic endo-

thelin antagonists have been reported in the litera-

ture.^9,10Peptidic antagonists that are selective for the

ET_Areceptor include the cyclic pentapeptide BQ-123,¹¹

TAK-044,¹²and the tripeptide FR139317.¹³A nonselec-

tive peptide antagonist, PD 142893,¹⁴as well as the

ET_B-selective peptide BQ 788¹⁵have also been reported.

Nonpeptidic ET_A-selective agents include BMS-

182874,^16,17PD 156707,¹⁸and A-127722;¹⁹compounds

that are nonselective for either receptor include Ro 47-

0203 (Bosentan),²⁰SB 209670,²¹and L-749,329.²²

Previously, we described a series of benzenesulfona-

mides and the subsequent identification of the dansyl-

sulfonamide BMS-182,874 (Chart 1) as a potent and

selective ET_Aantagonist.^16,17We subsequently discov-

ered that ortho substitution of the phenyl ring of the

benzenesulfonamides leads to improved ET_Aantagonist

activity. Further development of the structure-activity

relationship (SAR) around this position led to the

identification of several biphenylsulfonamide analogues

with improved binding potency. In the present paper,

we report the SAR on this class of compounds and show

that certain optimally disubstituted derivatives provide

highly potent and selective endothelin antagonists in

vitro and in vivo.

* To whom correspondence should be addressed. Phone: 609-252-

5391. Fax: 609-252-6804. E-mail: Murugesan@bms.com.

^†Department of Chemistry, Cardiovascular Agents.

^‡Department of Pharmacology.

^§Department of Cardiovascular Biochemistry.

Published on Web 11/25/1998

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5199

Ch a r t 1

using literature methods. Compounds 6b and 6f were

prepared by reductive amination of the corresponding

2′- or 3′-amino derivatives (6a or 6e, respectively) using

formaldehyde and sodium cyanoborohydride. The 4′-

carboxylic acid derivative 6i was prepared via the

oxidation of the 4′-aldehyde intermediate, which in turn

was prepared via the Suzuki coupling of 4 and the

commercially available 4-formylphenylboronic acid.

The 2-heteroarylbenzenesulfonamides 9a -c and 9f

(Table 3) were prepared via a Suzuki coupling reaction

between the boronic acid derivative 7 and the corre-

sponding heteroaryl bromide followed by deprotection

of the MEM group (Scheme 2). Compounds 9d , 9e, and

9g were prepared using the reaction sequence in

Scheme 1.

Exploration of the SAR of the isoxazole moiety was

facilitated by the sequence of reactions described in

Scheme 3. Suzuki coupling between 4-isobutylben-

zeneboronic acid and the sulfonylpyrrole 10 provided the

biarylsulfonylpyrrole 11. Hydrolysis under basic condi-

tions gave the sulfonic acid 12 which was then converted

to the sulfonyl chloride derivative 13 using phosphorus

pentachloride. Treatment of 13 with a variety of amino

heterocylic derivatives then provided compounds 14a -h

(Table 4).

Ch em istr y

The sulfonamides 3a -f and 6 (Table 1) were prepared

by condensation of the arylsulfonyl chlorides with the

commercially available 3,4-dimethyl-5-isoxazolamine in

pyridine. Compounds 3e and 3f were prepared from

sulfonyl chlorides previously described in the literature

(3e,²³3f²⁴). Hydrogenation of 3c afforded compound 3b.

The biphenylsulfonamide analogues listed in Table 2

were prepared using the Suzuki coupling^25,26as a key

reaction as described in Scheme 1. Initial attempts to

perform the couplings in the presence of the unprotected

sulfonamide 3 were unsuccessful presumably because

of the acidic sulfonamide moiety poisoning the Pd(0)

catalyst. The sulfonamide 3 was therefore protected

using MEM chloride and sodium hydride to provide

intermediate 4. Coupling of 4 with a variety of arylbo-

ronic acids under Suzuki conditions followed by depro-

tection of the MEM group under acidic conditions

afforded the biphenylsulfonamide derivatives 6. The

arylboronic acids were either commercially available or

readily prepared from the corresponding aryl halides

The 2′-amino-4′-isobutylbiphenylsulfonamide deriva-

tive 20 was synthesized as shown in Scheme 4. Wittig

olefination of m-nitrobenzaldehyde using isopropyl triph-

enylphosphonium iodide followed by hydrogenation us-

ing Pt/C afforded the aniline derivative 16. It was found

Sch em e 1^a

a

(a) Pyridine, RT; (b) NaH, methoxyethoxymethyl chloride; (c) ArB(OH)₂, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (d) 6 N aqueous

HCl/EtOH.

Sch em e 2^a

a

(a) (i) n-BuLi, THF, -78 °C, (ii) triisopropyl borate, (iii) HCl; (b) heteroaryl bromide, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (c)

6 N aqueous HCl/EtOH.

5200 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Murugesan et al.

Sch em e 3^a

a

(a) KH, THF; (b) ArB(OH)₂, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (c) 5 N NaOH, MeOH; (d) PCl₅; (e) amino heterocycle, Py,

DMAP.

Sch em e 4^a

a

(a) (CH₃)₂CHP(Ph)₃Br, n-BuLi; (b) H₂/Pt/C, MeOH; (c) (CH₃)₃CCOCl, (Et)₃N, CH₂Cl₂; (d) H₂/Pd/C, EtOAc; (e) (i) t-BuLi, TMEDA,

diethyl ether, (ii) B(OMe)₃, (iii) HCl; (f) 4, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (g) (i) DIBAL, (ii) 6 N aqueous HCl.

Sch em e 5^a

a

(a) (CH₃)₂CHP(Ph)₃I, n-BuLi; (b) H₂/Pt/C, MeOH; (c) (i) t-BuLi, TMEDA, diethyl ether, (ii) B(OMe)₃, (iii) HCl; (d) 4, (Ph₃P)₄Pd, aqueous

Na₂CO₃, EtOH/toluene; (e) 6 N aqueous HCl/EtOH; (f) BBr₃/CH₂Cl₂.

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5201

Sch em e 6^a

a

(a) Isobutyl-9-BBN, (Ph₃P)₄Pd, aqueous NaOH; (b) (i) t-BuLi, TMEDA, diethyl ether, (ii) B(OMe)₃, (iii) HCl; (c) 4, (Ph₃P)₄Pd aqueous

Na₂CO₃, EtOH/toluene; (d) COCl₂/DMSO; (e) 6 N aqueous HCl; (f) ammonium acetate, sodium triacetoxyborohydride, AcOH; (g) acetic

formic anhydride, triethylamine, CH₂Cl₂.

Sch em e 7^a

a

(a) i-PrOH/pyridine; (b) 4-isobutylphenylboronic acid, (Ph₃P)₄Pd, aqueous Na₂CO₃, EtOH/toluene; (c) (i) n-BuLi, THF, -78 °C, (ii)

MeI; (d) (i) aqueous NaOH, MeOH, (ii) PCl₅; (e) 5-amino-3,4-dimethylisoxazole, pyridine.

that the olefin bond could not be reduced further under

these conditions. Amine 16 was then converted to the

pivaloyl amide derivative and hydrogenation of this

compound using Pd/C then proceeded rapidly to provide

17. Ortho lithiation of 17 using t-BuLi/TMEDA followed

by quenching with trimethyl borate and subsequent

hydrolysis using dilute hydrochloric acid provided the

key boronic acid intermediate 18. None of the other

possible regiomeric product was isolated from this

reaction indicating that the ortho lithiation was highly

regioselective. Suzuki coupling²⁶between 18 and the

sulfonamide derivative 4 under standard conditions

afforded the biphenylsulfonamide derivative 19. Direct

removal of the pivaloyl group under acidic conditions

was found to be problematic. However, deprotection

could be carried out by reduction to the hemiaminal

using diisobutylaluminum hydride and subsequent

treatment with 6 N aqueous hydrochloric acid, which

hydrolyzed both the hemiaminal and the MEM groups

to provide 20. The N-alkyl derivatives 20a -g were

prepared via reductive amination of 20 in the presence

of sodium cyanoborohydride or sodium triacetoxyboro-

hydride with the appropriate aldehydes.

Compounds 25 and 26 were prepared as shown in

Scheme 5. The boronic acid 23 was prepared from 22

in an analogous manner to the method outlined above.

Coupling of 23 with 4 followed by deprotection of the

MEM group afforded the 2′-methoxy derivative 25.

Demethylation of 25 using boron tribromide then gave

26. The fluoro analogue 20j was prepared starting from

3-fluorobenzaldehyde by an analogous sequence.

The 2′-formylaminomethyl derivative 34 was synthe-

sized as depicted in Scheme 6. Palladium-catalyzed

cross-coupling of 3-bromobenzyl alcohol with isobutyl-

9-BBN provided 3-isobutylbenzyl alcohol 28. Ortho

lithiation using t-BuLi/TMEDA in ether followed by

5202 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Murugesan et al.

Sch em e 8^a

a

(a) Me₂SO₄/aqueous NaOH; (b) PCl₅; (c) t-BuNH₂, CHCl₃; (d) (i) n-BuLi, (ii) BrF₂CCF₂Br; (e) 4-isobutylphenylboronic acid, (Ph₃P)₄Pd,

aqueous Na₂CO₃, EtOH/toluene; (f) TFA; (g) (i) NO₂/CCl₄, (ii) aqueous NaOH; (h) 3,4-dimethyl-5-aminoisoxazole, Py, DMAP; (i) BBr₃,

CH₂Cl₂; (j) NaH, methoxyethoxymethyl chloride, THF; (k) NaH, ethyl bromoacetate, DMF; (l) LiBH₄, MeOH, ether; (m) 6 N aqueous

HCl/EtOH; (n) (i) KOH/MeOH, (ii) aqueous LiOH.

sequential treatment with trimethyl borate and dilute

HCl provided the cyclic borate ester 29. Again no

regioisomeric product was obtained. Suzuki coupling

of 29 with 4 afforded 30. The 2′-aldehyde analogue 32

was then obtained by Swern oxidation of 30 followed

by treatment with 6 N HCl. Reductive amination using

ammonium acetate and sodium triacetoxyborohydride

provided the aminomethyl derivative 33 which was then

converted to 34 by treatment with acetic formic anhy-

dride and triethylamine.

The 3-methyl derivative 40 was prepared starting

from the sulfonate ester 36 which can be readily

obtained by treatment of the commercially available

2-bromobenzenesulfonyl chloride with 2-propanol in

pyridine (Scheme 7). Suzuki coupling of 36 with

4-isobutylphenylboronic acid afforded 37. Treatment of

37 with n-BuLi in THF followed by quenching with MeI

provided 38. The sulfonate ester was then hydrolyzed

using aqueous NaOH, and the sulfonic acid thus ob-

tained was converted to the sulfonyl chloride using PCl₅

to afford 39. Condensation of 39 with 3,4-dimethyl-5-

isoxazolamine gave 40.

lithiation using butyllithium and subsequent quenching

with 1,2-dibromo-1,1,2,2-tetraflouroethane to provide

43. Submission of 43 to palladium-catalyzed Suzuki

coupling conditions with 4-isobutylphenylboronic acid

afforded 44. The tert-butyl group in 44 was then

removed using TFA, and treatment of the resulting

primary sulfonamide with NO₂/CCl₄afforded the sul-

fonic acid derivative 45. Sulfonamide derivative 46 was

then prepared from 45 using a sequence similar to that

described in Scheme 7. Demethylation of 46 using BBr₃

provided the 6-hydroxy derivative 47. It was necessary

to protect the sulfonamide function in order to alkylate

the hydroxy group. Accordingly, the sulfonamide func-

tion was first protected using the MEM group and

subsequent alkylation with ethyl bromoacetate afforded

48. Deprotection of the MEM group using 6 N HCl

followed by hydrolysis of the ester using aqueous KOH

gave the acid derivative 49. The hydroxyethyl analogue

50 was also derived from 48 first by reducing the ester

using lithium borohydride followed by the removal of

the MEM group.

Str u ctu r e-Activity Rela tion sh ip s

The synthesis of the 6-substituted analogues 47, 49,

and 50 was carried out as shown in Scheme 8. The tert-

butylsulfonamide 42, prepared from the sulfonic acid

41, was regiospecifically brominated via ortho-directed

In our previous reports from these laboratories,^16,17

we demonstrated that certain para-substituted N-isox-

azolylbenzenesulfonamides showed moderate affinity for

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5203

Ta ble 2. N-Isoxazolylbiphenylsulfonamide Derivatives

Ta ble 1. N-Isoxazolylbenzenesulfonamide Analogues

a

K_i’s ( SE were determined from the inhibition of [¹²⁵I]ET-1

binding to membranes prepared from A10 rat thoracic aorta

smooth muscle cells (ET_A) as described in the Experimental

Section.

the endothelin receptor. Optimization of this lead series

then led to the development of the 5-amino-1-naphtha-

lenesulfonamide derivative BMS-182874, which is a

selective ET_Aantagonist. We then observed that a

number of electronically dissimilar substituents at the

ortho position of the benzenesulfonamides (e.g., 3b,

2-NH₂, and 3c, 2-NO₂; Table 1) also showed improved

receptor binding affinity. This suggested a conforma-

tional effect by the 2-substituent resulting in a preferred

relative orientation of the phenyl and heterocyclic rings.

Following up on this hypothesis, we synthesized a

number of analogues by increasing the size of the

2-substituent. The improved binding affinity observed

with compounds 3c-f showed the generality of this

effect. However, none of these compounds showed

significant functional antagonist activity in a tissue-

based assay. The biphenylsulfonamide 6 was then

synthesized due to the large size of a phenyl substituent

and also because the biphenyl moiety is found to be a

useful scaffold in a variety of G-protein-coupled receptor

ligands. Compound 6 showed improved binding affinity

(K_i) 90 nM) and, more importantly, modest functional

activity (K_B) 7.6 µM) as well.

Because a 5-dimethylamino substituent contributed

dramatically to the activity of the naphthalenesulfona-

mide series of compounds,¹⁷we wanted to determine

whether analogous substitution on the pendant phenyl

ring of the biphenylsulfonamides would provide similar

results (Table 2). Substitution at the 2′-, 3′-, or 4′-

position of the pendant ring (compounds 6b, 6f, or 6h )

with a dimethylamino group did not result in any

significant improvement in activity. However, during

this exercise, it was found that compound 6a , incorpo-

rating a primary amine substituent at the 2′-position,

showed improved binding affinity as well as functional

antagonist activity. This suggested that the relatively

small amino group at this position may be behaving as

an H-bond donor or acceptor. The dimethylamino

function may be less active due to its large size, possibly

because of a undesirable effect on the dihedral angle

between the sulfonamide and the biaryl moieties.

Substitution at the 4′-position with a methyl group

(6j) also resulted in improved binding and functional

a

K_i’s ( SE were determined using membranes prepared from

A10 rat thoracic aorta smooth muscle cells (ET_A) and from rat

cerebellum (ET_B) as described in the Experimental Section. K_B’s

( SE were determined by assaying for the inhibition of ET-1-

induced contractions in rabbit carotid artery rings as described

in the Experimental Section. ND, not determined.

b

antagonist activity. In fact, increasing the chain length

of the alkyl substituent at this position increased both

binding affinity and functional potency. The 4′-isobutyl

analogue 6l (ET_AK_i) 18 nM, ET_BK_i) 210 nM) was

found to be the optimal alkyl substituent, and it showed

dramatically improved binding as well as functional

activity compared to the unsubstituted biphenylsulfona-

mide 6. Because the 3′-isobutyl analogue 6g suffered a

10-fold loss of binding affinity compared to 6l, the

increased activity of the 4′-alkyl derivatives is likely due

to a specific binding interaction of this moiety at the

receptor site rather than a general lipophilic effect.

Attempts to improve activity by introducing even larger

lipophilic groups (e.g., 6m -q) resulted in significant loss

of activity suggesting steric limitations at this position.

Interestingly, the 4′-alkyl-substituted derivatives also

showed improved ET_Baffinity although the selectivity

for the ET_Areceptor was still found to be greater than

100-fold.

Substitution at the 4′-position with alkoxy substitu-

ents also resulted in a similar improvement in activity,

5204 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Ta ble 3. 2-Heteroarylphenylsulfonamide Derivatives

Murugesan et al.

Ta ble 4. Biological Activity of N-Heterocyclic

4′-Isobutylbiphenylsulfonamide Analogues

a

K_i’s ( SE were determined using membranes prepared from

a

A10 rat thoracic aorta smooth muscle cells (ET_A) and from rat

cerebellum (ET_B) as described in the Experimental Section.

K_i’s ( SE were determined using membranes prepared from

A10 rat thoracic aorta smooth muscle cells (ET_A) and from rat

cerebellum (ET_B) as described in the Experimental Section. K_B’s

b

( SE were determined by assaying for the inhibition of ET-1

induced contractions in rabbit carotid artery rings as described

in the Experimental Section. ND, not determined.

but the functional activity of these analogues was less

than that of the corresponding alkyl derivatives. The

isopropoxy derivative 6s was found to be the optimal

alkoxy substituent at this position. We also examined

several alkylamino, alkylthio, and alkylsulfonyl substi-

tutions (Table 2), but these were generally found to have

lower binding affinity than their 4′-alkyl or 4′-alkoxy

counterparts. The 4′-carboxyl derivative 6i showed

dramatically lower binding affinity indicating that

anionic groups are not tolerated at this position.

Replacement of the pendant phenyl ring with hetero-

cyclic rings was also investigated (Table 3). Substitu-

tion with a 2- or 3-pyridinyl (9a or 9b), 2-pyrimidinyl

(9c), 2- or 3-thienyl (9d or 9e), or 2- or 3-indolyl group

(9f or 9g) did not lead to improved binding affinity

compared to the unsubstituted biphenylsulfonamide 6.

Analogues 14a -h were prepared in order to study the

structure-activity relationships of the isoxazole region

of the molecule in the biphenyl class of compounds

(Table 4). This work revealed that the requirements

in the isoxazole region are stringent and generally

similar to those of the naphthalenesulfonamide class of

compounds reported previously.¹⁷Specifically, replace-

ment of the methyl group at the 3-position with a

hydrogen (14a ) resulted in a large reduction in potency.

Introduction of electron-withdrawing groups such as

nitro (14b) or ethoxycarbonyl (14c) at the 4-position also

resulted in loss of binding activity. Constraining the

3- and 4-substituents into a six-membered ring (14d )

reduced activity as well. Attempts to improve affinity

by introducing larger lipophilic groups in place of the

4-methyl (14e) indicated that large groups are not

tolerated at this position. Replacement of the isoxazole

with other heterocyclic rings such as a pyridazine (14g)

or a substituted pyrimidine (14h ) also led to a reduction

in binding activity. No further optimization was per-

formed on this heterocyclic series. The 3-isoxazole

analogue 14f was equipotent to the corresponding

5-isoxazole analogue 6l, indicating that the heteroatoms

in the isoxazole ring can be interchanged.

The SAR of the monosubstituted biphenylsulfona-

mides to this point revealed that a 2′-amino substituent

or an appropriate 4′-alkyl group such as isobutyl

provides analogues with high binding affinity. The

improvement in ET_Aactivity independently seen with

the 4′-isobutyl as well as the 2′-amino substituents

prompted us to prepare 20, the analogue incorporating

both of these modifications (Table 5). Compound 20

showed an additional 4-fold improvement in ET_Abind-

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5205

Ta ble 5. 2′-Substituted Analogues

The role of the amino group as a hydrogen bond

acceptor or donor was then investigated by preparation

of analogues 20a -i (Table 5). Another goal was to gain

additional binding interactions by introducing groups

on the nitrogen atom. The N-methyl analogue 20a

shows 3-fold less potent binding activity compared to

20 but maintained the functional activity. The N,N-

dimethyl analogue 20b was significantly less active

indicating that hydrogen bond donation may be impor-

tant, although the increased steric requirements of the

bulky dimethylamino group may also be detrimental.

The N-ethyl derivative 20c was equipotent compared

to 20, and a hydroxyethyl group on the 2′-nitrogen (20f)

maintained potency as well. However, a carboxymethyl

group (20g) led to a 20-fold loss of inhibitory potency

compared to 20. Compound 20h containing a 2′-

formamido function was 3-fold less active, and the urea

derivative 20i was also less active. This exercise

revealed that secondary amines with small alkyl groups

are tolerated at the 2′-position.

Alternative 2′-substitutions in the 4′-isobutyl series

were then investigated (Table 5). While the 2′-fluoro

analogue 20j was less potent, the 2′-hydroxy derivative

26 was substantially more potent than the correspond-

ing methoxy derivative 25 indicating that a hydrogen

bond donor at the 2′-position leads to improved ET_A

activity. However, the 2′-methyl derivative 20h was

equipotent to 20 in its binding affinity to the ET_A

receptor suggesting that an effect on the biphenyl

conformation may also be important. Nevertheless, its

functional potency was 4-fold less than that of 20. The

2′-carboxyl derivative 20m as well as the aminomethyl

analogue 33 were dramatically less active suggesting

that charged groups are not tolerated at this position.

Interestingly, removal of the positive charge in 33 by

formylating the amine resulted in 34 (ET_AK_i) 2.0 nM,

ET_BK_i) 1200 nM), one of the most potent receptor

antagonists prepared in this series.

a

K_i’s ( SE were determined using membranes prepared from

A10 rat thoracic aorta smooth muscle cells (ET_A) and from rat

cerebellum (ET_B) as described in the Experimental Section. K_B’s

( SE were determined by assaying for the inhibition of ET-1-

induced contractions in rabbit carotid artery rings as described

in the Experimental Section. ND, not determined.

A number of analogues which explore alternative

substitution on the core phenyl ring were also prepared

(Table 6). All of these derivatives maintained the

optimal isobutyl group at the 4′-position of the pendant

ring. The 3-methyl derivative 40 was much less potent

compared to 6l suggesting that substitution at this

position might force the sulfonamide and the heterocylic

groups into a disfavored conformation. Substitutions

at each of the 4- and 5-positions with certain large

substituents also led to substantial decreases in potency.

The poor potency of the analogues 40e-h was particu-

larly dramatic, suggesting that these groups exceed the

steric limitations of the receptor binding site. Both the

6-methoxy (46)- and 6-hydroxy (47)-substituted com-

pounds showed equivalent or better ET_Aactivity com-

pared to 6l. The hydroxyethoxy-substituted analogue

50 (ET_AK_i) 2.7 nM, ET_BK_i) 2300 nM) showed more

than 6-fold improvement in binding affinity and 4-fold

improvement in functional activity compared to 6l while

maintaining ET_Aselectivity. However, the glycolic acid

derivative 49 was less active indicating that charged

groups may not be tolerated. The structure-activity

relationships at the C-6 position appeared analogous to

those previously determined at C-2′, suggesting that

substituents at these two positions may be interacting

with similar regions of the receptor.

b

ing activity (ET_AK_i) 4.7 nM, ET_BK_i) 1700 nM)

compared to 6l or 6a . A 2-fold improvement in func-

tional activity for the ET_Areceptor was observed

compared to 6l. The reason for the large differences

between the K_ivalues and the K_Bis not understood, but

similar differences have been observed with other

endothelin antagonists (e.g., FR 139317: K_i) 0.53 nM,

K_B) 63 nM).¹³We do not believe it is due to species

differences since we have previously shown that the

functional potency of several ET receptor agonists and

antagonists (e.g., FR 139317 and BQ-123) was similar

at both rabbit carotid and rat aorta.²⁷We have also

previously suggested that the differences in binding

affinity and functional potency may reflect differences

in cellular versus tissue preparations.¹⁷While the SAR

of this class of compounds was developed primarily

based on the binding affinity of the compounds, the

functional data was used to understand whether the

compound is an agonist or an antagonist and whether

the compound is active in a more intact cellular system.

5206 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Ta ble 6. Substitution of the Core Phenyl Ring

Murugesan et al.

F igu r e 1. Effects of oral administration of 20 (BMS-187308)

on the pressor response to ET-1 (0.1 nmol/kg iv) in conscious,

normotensive rats.

a

K_i’s ( SE were determined using membranes prepared from

A10 rat thoracic aorta smooth muscle cells (ET_A) and from rat

cerebellum (ET_B) as described in the Experimental Section. K_B’s

b

( SE were determined by assaying for the inhibition of ET-1-

induced contractions in rabbit carotid artery rings as described

in the Experimental Section. ND, not determined.

On the basis of the above results, compound 20 (BMS-

187308) was chosen for further evaluation. Although

radioligand binding studies revealed that 20 bound to

the ET_Breceptor with much less affinity than to the ET_A

receptor, functionally the compound was rather nonse-

lective as shown in experiments using isolated blood

vessels. Isolated rabbit carotid artery contracts in

response to ET-1 primarily via activation of ET_Arecep-

tors:⁸compound 20 blocked these contractions in a

concentration-dependent fashion (ET_AK_B) 0.12 ( 0.02

µM). The activity of ET_Breceptors can be observed in

vitro by contracting Wistar rat isolated aorta with

phenylephrine and then relaxing that contraction with

ET_B-selective peptide sarafotoxin s6c.²⁸Compound 20

blocked the relaxations in a concentration dependent

manner (ET_BK_B) 0.64 ( 0.1 µM).

Compound 20 was also tested for its ability to inhibit

ET-1 (0.1 nmol/kg iv)-induced vasoconstriction in con-

scious, normotensive rats. After oral administration of

30 µmol/kg, 20 inhibited the pressor response to ET-1

by 56 ( 15%. Essentially the same level of inhibition

was still present 3 h after dosing (60 ( 4%) indicating

20 has an acceptable pharmacological duration of effect

(Figure 1). Inhibition of the big ET-1 pressor response

by 20 (ED₂₅) 1.2 µmol/kg iv) was similar to inhibition

of the ET-1 pressor response by 20 (Figure 2). Maxi-

mum inhibition of the pressor effect of big ET-1 after

injection of the iv dose of 3 µmol/kg 20 was 49 ( 5%.

We were unable to achieve total inhibition of the pressor

effects of ET-1 or big ET-1 after administration of up to

30 µmol/kg compound 20. Inhibition reached a peak at

approximately 50-60%. We reported similar findings

of 40% inhibition of the ET-1-induced pressor response

after infusion of the ET_A-selective receptor antagonist

F igu r e 2. Effects of iv administration of 20 (BMS-187308)

on the pressor response to ET-1 (0.1 nmol/kg iv) and big ET-1

(1.0 nmol/kg iv) in conscious, normotensive rats.

BQ-123.²⁹Incomplete inhibition of the pressor response

to ET-1 was also reported for other ET antagonists.³⁰

Similar effects were observed in rabbit isolated carotid

arteries: compound 20 competitively inhibited ET-1 and

big ET-1 contractions with apparent K_Bvalues of 0.16

( 0.06 and 0.11 ( 0.05 µM, respectively. Maximum

inhibition of the pressor effect of big ET-1 after injection

of the iv dose of 3 µmol/kg 20 was 49 ( 5%. The

pharmacokinetics of 20 was evaluated in rats following

a 100 µmol/kg intravenous or oral gavage dose.³¹After

oral administration to rats, compound 20 was rapidly

absorbed (T_max< 30 min), and oral bioavailability was

found to be 48%.

Compound 20 was further examined for its ability,

after iv administration, to inhibit the increase in mean

arterial blood pressure due to the administration of

exogenous ET-1 (0.3 µmol/kg iv) to conscious monkeys.

After vehicle administration, endothelin-1 increased

blood pressure by 30 ( 4 mmHg in the conscious

monkeys, while doses of 10 and 30 µmol/kg iv 20

attenuated the pressor responses (Figure 3), indicating

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5207

Compound 20 was also administered orally at doses of 3, 10,

and 30 µmol/kg prior to ET-1 challenges.

In Vivo Mon k ey P r essor Stu d ies. Conscious male and

female cynomolgus monkeys in which chronic arterial and

venous catheters had been surgically implanted were seated

in restraining chairs. The arterial catheters were connected

via Gould-Statham strain gauge transducers to a Beckman

recorder for measurement of mean arterial blood pressure

(MAP). The pressor responses to 0.3 nmol/kg iv endothelin-1

(dissolved in 0.1 mg/kg saline) were determined after sequen-

tial treatment with vehicle (0.1 mL/kg of 5% NaHCO₃) and

0.1, 1, 10, and 30 µmol/kg iv compound 20. MAP was allowed

to return to baseline before administration of the next dose of

compound 20. The pressor responses were expressed as

percentages of the pressor activity obtained after vehicle

treatment. All data are given as mean ( SEM.

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

a J EOL FX-270 or GX-400 spectrometer with tetramethylsi-

lane as an internal standard. Chromatography was performed

under flash conditions using EM Science silica gel, 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. THF was

distilled from Na/benzophenone. Solutions were dried with

magnesium sulfate unless otherwise noted. The arylboronic

or heteroarylboronic acids were either commercially available

or easily prepared from the aryl halides using literature

methods.²⁶

N-(3,4-Dim eth yl-5-isoxa zolyl)-2-br om oben zen esu lfon -

a m id e (3). 3,4-Dimethyl-5-isoxazolamine (1.32 g, 11.74 mmol)

was added to a solution of 2-bromobenzenesulfonyl chloride

(3.0 g, 11.74 mmol) in 10 mL of pyridine, and the mixture was

stirred at room temperature overnight. The solution was

added to 150 mL of ice water and filtered. The filtrate was

acidified to pH 2 using 6 N hydrochloric acid, and the solid

was filtered and dried. Crystallization from ethanol/water

afforded 3.5 g (90%) of 3 as a white solid: mp 125-126 °C. ¹H

NMR (CDCl₃+ CD₃OD): δ 1.83 (s, 3H), 2.14 (s, 3H), 7.45 (m,

2H), 7.78 (m, 1H), 8.05 (m, 1H). ¹³C NMR (CDCl₃+ CD₃OD):

δ 5.84, 10.25, 106.29, 119.88, 127.51, 131.11, 134.02, 135.14,

138.77, 154.61, 161.60. Anal. (C₁₁H₁₁BrN₂O₃S‚0.32H₂O) C,

H, N, S.

F igu r e 3. Effects of iv administration of 20 (BMS-187308)

on the pressor response to ET-1 (0.3 nmol/kg iv) in conscious

monkeys.

that the compound inhibits the in vivo activity of

endothelin-1 in nonhuman primates.

Con clu sion

In summary, investigation of the SAR of ortho-

substituted benzenesulfonamide derivatives resulted in

the discovery of the biphenylsulfonamide class of en-

dothelin antagonists. Substitution of the pendant phen-

yl ring led to the identification of the 2′- and 4′-positions

as sites where appropriate substitution led to improved

binding affinity. An alkyl or alkoxy group such as

isobutyl or isopropoxyl was found to be optimal at the

4′-position. A 2′-primary amino group was found to

improve the activity of the parent compound. Combina-

tion of the optimal 4′-isobutyl substituent with the 2′-

amino function afforded an analogue (20, BMS-187308)

with potent ET_Abinding affinity and functional activity.

Compound 20 also had good oral activity in inhibiting

the pressor effect caused by an ET-1 infusion in rats.

Compound 20 appears to be a suitable tool for investi-

gating the role of endothelin in certain disease models.

Further structure-activity relationship studies are in

progress and will be the subject of future publications.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2-flu or oben zen esu lfon -

a m id e (3a ): tan solid; mp 122-124 °C. Anal. (C₁₁H₁₁FN₂O₃S)

C, H, N, S.

Exp er im en ta l Section

N-(3,4-Dim eth yl-5-isoxa zolyl)-2-a m in oben zen esu lfon -

a m id e (3b). To a suspension of 135 mg of 10% Pd/C in 20

mL of MeOH under argon was added 0.9 g (3.03 mmol) of 3c

in 20 mL of MeOH, and the mixture was hydrogenated at 1

atm for 90 min. The mixture was then filtered and concen-

trated to afford 0.9 g of a gum. This material was chromato-

graphed on silica using hexanes/EtOAc (1:1) to provide 0.2 g

Ra d ioliga n d Bin d in g Assa ys. The receptor binding as-

says were performed using membranes prepared from A10 rat

thoracic aorta smooth muscle cells (ET_A) and from rat cerebel-

lum (ET_B) as previously described.¹⁷Competition binding data

were analyzed by iterative curve fitting to a one- or two-site

binding model. The inhibition constants (K_i) were calculated

from IC₅₀values.

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.¹⁷K_Bvalues were

obtained from experiments in which at least three different

concentrations of test compound were studied. Apparent K_B

values were calculated when only one antagonist concentration

was used. The ET_Bfunctional assays were performed as

previously described.²⁸

In Vivo Ra t P r essor Stu d ies. This study was performed

as previously described.³²Four 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

administration 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.

(24%) of 3b as

(C₁₁H₁₃N₃O₃S) C, H, N, S.

a white solid: mp 116-118 °C. Anal.

N-(3,4-Dim et h yl-5-isoxa zolyl)-2-n it r ob en zen esu lfon -

am ide (3c):light-yellowsolid;mp 91-94°C. Anal. (C₁₁H₁₁N₃O₅S)

C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2-(tr iflu or om eth yl)ben -

zen esu lfon a m id e (3d ): white crystalline needles; mp 99-

100 °C. ¹H NMR (CDCl₃): δ 1.89 (s, 3H), 2.17 (s, 3H), 7.27-

8.07 (m, 4H). Anal. (C₁₂H₁₁F₃N₂O₃S) C, H, N, S.

N -(3,4-Dim e t h yl-5-isoxa zolyl)-2-isop r op ylb e n ze n e -

su lfon a m id e (3e). ¹H NMR (CDCl₃): δ 1.29 (d, J ) 6.8 Hz,

6H), 1.84 (s, 3H), 2.15 (s, 3H), 3.70 (m, 1H), 7.20-7.80 (m, 4H).

Anal. (C₁₄H₁₈N₂O₃S‚0.58H₂O) C, H, N, S.

N -(3,4-D im e t h y l-5-is o x a zo ly l)-2-p h e n o x y b e n ze n e -

su lfon a m id e (3f): mp 181-182 °C. Anal. (C₁₇H₁₆N₂O₄S) C,

H, N, S.

5208 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Murugesan et al.

N-(3,4-Dim eth yl-5-isoxa zolyl)[1,1′-bip h en yl]-2-su lfon -

a m id e (6): mp 171-173 °C. ¹H NMR (DMSO-d₆): δ 1.71 (s,

3H), 2.16 (s, 3H), 7.38-8.14 (m, 9H). Anal. (C₁₇H₁₆N₂O₃S) C,

H, N, S.

(CDCl₃): δ 1.84 (s, 3H), 2.11 (s, 3H), 3.01 (s, 6H), 5.90 (br s,

1H), 6.76-7.98 (m, 8H). ¹³C NMR (CDCl₃): δ 7.11, 11.20,

40.72, 108.82, 112.07, 125.81, 127.54, 128.95, 131.40, 133.44,

133.50, 138.77, 141.88, 150.78, 154.78, 162.24. Anal.

(C₁₉H₂₁N₃O₃S) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-m eth yl[1,1′-bip h en yl]-

2-su lfon a m id e (6j): mp 126-127 °C. ¹H NMR (CDCl₃): δ

1.85 (s, 3H), 2.12 (s, 3H), 2.42 (s, 3H), 5.79 (br s, 1H), 7.26-

7.99 (m, 8H). ¹³C NMR (CDCl₃): δ 6.62, 10.77, 21.28, 108.48,

127.68, 128.69, 128.86, 129.90, 132.72, 133.04, 135.46, 138.05,

138.48, 141.04, 154.03, 161.86. Anal. (C₁₈H₁₈N₂O₃S) C, H, N,

S.

N-(3,4-Dim eth yl-5-isoxazolyl)-4′-n -pr opyl[1,1′-biph en yl]-

2-su lfon a m id e (6k ): colorless gum. ¹H NMR (CDCl₃): δ 0.97

(t, J ) 7.3 Hz, 3H), 1.70 (m, 2H), 1.81(s, 3H), 2.10 (s, 3H),

2.63 (t, J ) 7.8 Hz, 2H), 6.05 (br s, 1H), 7.24-7.99 (m, 8H).

¹³C NMR (CDCl₃): δ 6.51, 10.63, 13.80, 24.25, 37.66, 108.01,

127.56, 128.08, 128.60,129.76, 132.67, 132.90, 135.64, 138.00,

141.09, 143.02, 154.07, 161.71. Anal. (C₂₀H₂₂N₂O₃S) C, H, N,

S

N -(3,4-Dim e t h yl-5-isoxa zolyl)-4′-(2-m e t h ylp r op yl)-

[1,1′-bip h en yl]-2-su lfon a m id e (6l): mp 126 °C. ¹H NMR

(CDCl₃): δ 0.94 (d, J ) 6.4 Hz, 6H), 1.84 (s, 3H), 1.92 (m, 1H),

2.12 (s, 3H), 2.53 (d, J ) 7.0 Hz, 2H), 5.83 (br s, 1H), 7.22-

7.99 (m, 8H). ¹³C NMR (CDCl₃): δ 6.59, 10.74, 22.40, 30.09,

45.12, 108.24, 127.68, 128.66, 128.86, 129.76, 132.72, 133.01,

135.72, 138.08, 141.10, 142.22, 154.09, 161.86. Anal.

(C₂₁H₂₄N₂O₃S) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-isop r op yl[1,1′-bip h en -

yl]-2-su lfon a m id e (6m ): mp 162-163 °C. ¹H NMR

(CDCl₃): δ 1.30 (d, J ) 7.0 Hz, 6H), 1.83 (s, 3H), 2.12 (s, 3H),

2.97 (m, 1H), 5.85 (s, 1H), 7.26-7.99 (m, 8H). ¹³C NMR

(CDCl₃): δ 6.62, 10.77, 23.90, 33.87, 108.27, 126.25, 127.45,

127.68, 128.72, 129.99, 132.81, 133.04, 135.77, 138.02, 141.13,

149.31, 154.12, 161.87. Anal. (C₂₀H₂₂N₂O₃S‚0.30H₂O) C, H,

N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-n -bu tyl[1,1′-bip h en yl]-

2-su lfon a m id e (6n ). ¹H NMR (CD₃OD): δ 0.95 (t, J ) 7.0

Hz, 3H), 1.40 (m, 2H), 1.64 (m, 2H), 1.84 (s, 3H), 2.12 (s, 3H),

2.67 (t, J ) 7.0 Hz, 2H), 5.80 (s, 1H), 7.26-8.00 (m, 8H). ¹³C

NMR (CD₃OD): δ 6.59, 10.74, 13.94, 22.43, 33.40, 35.39,

108.33, 127.65, 128.17, 128.66, 129.90, 132.75, 133.01, 135.60,

138.05, 141.10, 143.46, 154.09, 161.84. Anal. (C₂₁H₂₄N₂O₃S‚

0.07H₂O) C, H, N, S.

2-Br om o-N-(3,4-d im et h yl-5-isoxa zolyl)-N′-(m et h oxy-

eth oxym eth yl)ben zen esu lfon a m id e (4). To a solution of

1.1 g (3.33 mmol) of 3 in 15 mL of THF at room temperature

under argon was added 0.19 g (4.8 mmol) of sodium hydride

(60% suspension in mineral oil) in portions, and the mixture

was stirred for 10 min. Methoxyethoxymethyl chloride (0.55

g, 4.4 mmol) was added, and the solution was stirred overnight.

The mixture was concentrated, diluted with 30 mL of water,

and extracted with 3 × 40 mL of EtOAc. The combined organic

extracts were washed with brine, dried, and evaporated to

provide 1.2 g (87%) of 4 as a brown gum.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2′a m in o[1,1′-bip h en yl]-

2-su lfon a m id e (6a ). To a solution of 0.5 g (1.19 mmol) of

compound 4 and 0.062 g (0.05 mmol) of tetrakis(triphenylphos-

phine)palladium(0) in 10 mL of benzene under argon was

added 4.0 mL of 2 M aqueous sodium carbonate followed by

0.245 g (1.79 mmol) of 2-aminophenylboronic acid³³in 5 mL

of 95% EtOH. The mixture was refluxed for 10 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 75 g of silica gel using hexanes/EtOAc (2:1) to

afford 0.39 g (76%) of 2′-amino-N-(3,4-dimethyl-5-isoxazolyl)-

N′-(methoxyethoxymethyl)[1,1′-biphenyl]-2-sulfonamide (5) as

a colorless gum. To a solution of 0.35 g (0.81 mmol) of

compound 5 in 10 mL of 95% aqueous EtOH was added 10

mL of 6 N aqueous HCl, and the mixture was refluxed for 2 h.

The mixture was concentrated and diluted with 10 mL of

water. The solution was neutralized using saturated aqueous

NaHCO₃and reacidified to pH 4 using glacial AcOH. The

mixture was extracted with 3 × 25 mL of EtOAc, and the

combined organic extracts were washed once with 50 mL of

brine, dried, and evaporated (0.31 g). Chromatography of the

residue on 50 g of silica gel using hexanes/EtOAc (1:1) provided

0.087 g (31%) of 6a as a gum. An analytically pure sample

was obtained by repeated crystallizations from EtOAc/MeOH/

hexanes: mp 182-183 °C. ¹H NMR (CDCl₃+ CD₃OD): δ 1.87

(s, 3H), 2.17 (s, 3H), 6.85-8.00 (m, 8H). ¹³C NMR (CDCl₃+

CD₃OD): δ 6.04, 10.22, 106.39, 116.26, 118.71, 125.72, 128.26,

129.03, 129.41, 130.30, 132.99, 133.39, 137.86, 138.81, 143.05,

155.31, 161.77. Anal. (C₁₇H₁₇N₃O₃S) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-ter t-bu tyl[1,1′-bip h en -

yl]-2-su lfon a m id e (6o): mp 169-170 °C. ¹H NMR (CD₃OD):

δ 1.37 (s, 9H), 1.83 (s, 3H), 2.04 (s, 3H), 5.88 (s, 1H), 7.36-

8.00 (m, 8H). ¹³C NMR (CD₃OD): δ 6.56, 10.72, 31.28, 34.69,

108.18, 125.05, 127.62, 128.66, 129.70, 132.78, 133.02, 135.38,

137.98, 141.06, 151.59, 154.10, 161.83. Anal. (C₂₁H₂₄N₂O₃S‚

0.05H₂O) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2,2-d im eth ylp r op yl)-

[1,1′-bip h en yl]-2-su lfon a m id e (6p ): mp 54-57 °C. ¹H NMR

(CDCl₃): δ 0.94 (s, 9H), 1.83 (s, 3H), 2.12 (s, 3H), 2.55 (s, 2H),

5.85 (s, br, 1H), 7.21-7.99 (m, 8H). ¹³C NMR (CDCl₃): δ 6.59,

10.72, 29.41, 31.74, 49.89, 108.15, 127.65, 128.66, 129.24,

130.16, 132.67, 132.99, 135.81, 138.06, 140.25, 141.09, 154.07,

161.83. Anal. (C₂₂H₂₆N₂O₃S‚0.30H₂O) C, H, N, S.

The following compounds were prepared using a procedure

similar to the above and substituting with the appropriate

arylboronic acids.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2′-n itr o[1,1′-bip h en yl]-2-

su lfon a m id e (6c): mp 128-130 °C. ¹H NMR (CDCl₃): δ 1.75

(s, 3H), 2.09 (s, 3H), 7.32-8.25 (m, 8H). ¹³C NMR (CDCl₃): δ

6.48, 10.74, 107.70, 123.05, 124.60, 128.81, 129.04, 129.59,

132.61, 133.44, 135.95, 137.91, 138.86, 140.30, 147.53, 153.89,

162.07. Anal. (C₁₇H₁₅N₃O₅S) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2′-(h yd r oxym eth yl)-[1,1′-

bip h en yl]-2-su lfon a m id e (6d ): mp 70-80 °C. ¹H NMR

(CDCl₃): δ 1.88 (s, 3H), 2.16 (s, 3H), 4.36 (ABq, J ) 12.3 Hz,

2H), 7.27-7.92 (m, 9H). ¹³C NMR (CDCl₃): δ 7.43, 11.55,

63.47, 108.99, 128.00, 129.12, 129.81, 130.19, 130.47, 133.24,

133.82, 138.32, 138.67, 139.56, 140.08, 155.25, 162.78. Anal.

(C₁₈H₁₈N₂O₄S‚0.26H₂O) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-3′-a m in o[1,1′-bip h en yl]-

2-su lfon a m id e (6e): mp 157-160 °C. Anal. (C₁₇H₁₇N₃O₃S‚

0.10cyclohexane) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-3′-(2-m eth ylp r op yl)[1,1′-

bip h en yl]-2-su lfon a m id e (6g): colorless gum. ¹H NMR

(CDCl₃): δ 1.04 (d, J ) 6.4 Hz, 6H), 1.94 (s, 3H), 2.02 (m, 1H),

2.26 (s, 3H), 2.64 (d, J ) 7.0 Hz, 2H), 6.66 (br s, 1H), 7.32-

8.16 (m, 8H). ¹³C NMR (CDCl₃): δ 6.25, 10.37, 22.08, 29.96,

45.04, 107.55, 126.87, 127.59, 128.51, 129.06, 130.51, 132.55,

132.90, 137.74, 138.12, 141.18, 141.44, 154.33, 161.74. Anal.

(C₂₁H₂₄N₂O₃S‚0.42H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(3-m et h ylb u t yl)[1,1′-

bip h en yl]-2-su lfon a m id e (6q): mp 125-127 °C. ¹H NMR

(CDCl₃): δ 0.96 (d, J ) 6 Hz, 6H), 1.56 (m, 3H), 1.84 (s, 3H),

2.12 (s, 3H), 2.67 (m, 2H), 5.83 (s, 1H), 7.26-7.99 (m, 8H). ¹³

C

NMR (CDCl₃): δ 6.59, 10.72, 22.49, 27.79, 33.50, 40.57, 108.30,

127.62, 128.08, 128.66, 129.90, 132.73, 132.99, 135.58, 138.03,

141.09, 143.66, 154.07, 161.83. Anal. (C₂₂H₂₆N₂O₃S) C, H, N,

S.

N-(3,4-Dim eth yl-5-isoxazolyl)-4′-m eth oxy[1,1′-biph en yl]-

2-su lfon a m id e (6r ): mp 179-181 °C. ¹H NMR (CD₃OD): δ

1.85 (s, 3H), 2.12 (s, 3H), 3.86 (s, 3H), 5.79(s, 1H), 6.98-7.99

(m, 8H). ¹³C NMR (CD₃OD): δ 6.62, 10.75, 55.28, 108.53,

113.57, 127.62, 128.72, 130.42, 131.37, 132.93, 133.07, 138.15,

140.80, 154.01, 159.72, 161.86. Anal. (C₁₈H₁₈N₂O₄S‚0.04H₂O)

C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(d im eth yla m in o)[1,1′-

bip h en yl]-2-su lfon a m id e (6h ): mp 135-136 °C. ¹H NMR

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5209

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(1-m eth yleth oxy)[1,1′-

bip h en yl]-2-su lfon a m id e (6s): mp 49-52 °C. ¹H NMR (CD₃-

OD): δ 1.37 (d, J ) 6.0 Hz, 6H), 1.83 (s, 3H), 2.10 (s, 3H), 4.60

(m, 1H), 6.10 (s, 1H), 6.93-7.99 (m, 8H). ¹³C NMR (CD₃OD):

δ 6.54, 10.65, 21.97, 69.80, 108.16, 115.04, 115.33, 127.45,

128.63, 130.02, 131.22, 132.92, 138.08, 140.84, 154.06, 157.98,

161.75. Anal. (C₂₀H₂₂N₂O₄S‚0.10H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op oxy)-

[1,1′-bip h en yl]-2-su lfon a m id e (6t): mp 50-53 °C. ¹H NMR

(CD₃OD): δ 1.05 (d, J ) 6.0 Hz, 6H), 1.84 (s, 3H), 2.10 (s, 3H),

2.13 (m, 1H), 3.76 (d, J ) 6.0 Hz, 2H), 6.03 (s, 1H), 6.95-7.99

(m, 8H). ¹³C NMR (CD₃OD): δ 6.56, 10.69, 19.20, 28.20, 74.35,

108.30, 114.01, 114.30, 127.51, 128.66, 130.13, 130.68, 131.23,

132.93, 138.12, 140.86, 154.07, 159.35, 161.77. Anal.

(C₂₁H₂₄N₂O₄S‚0.67H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(p h en ylm et h yloxy)-

[1,1′-b ip h en yl]-2-su lfon a m id e (6u ). ¹H NMR (CDCl₃): δ

1.93 (s, 3H), 2.20 (s, 3H), 5.20 (s, 2H), 6.32 (br s, 1H), 7.14-

8.11 (m, 13H). ¹³C NMR (CDCl₃): δ 6.48, 10.62, 69.92, 108.01,

114.29, 127.45, 127.97, 128.52, 128.66, 130.68, 131.20, 132.87,

132.92, 136.52, 138.05, 140.73, 154.00, 158.75, 161.72. Anal.

(C₂₄H₂₂N₂O₄S) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxazolyl)-4′-((1-m eth yleth yl)am in o)-

[1,1′-bip h en yl]-2-su lfon a m id e (6v): mp 62-64 °C. ¹H NMR

(CD₃OD): δ 1.24 (d, J ) 7 Hz, 6H), 1.84 (s, 3H), 2.10 (s, 3H),

3.68 (m, 1H), 6.63-7.97 (m, 8H). ¹³C NMR (CD₃OD): δ 6.59,

10.72, 22.92, 44.09, 108.30, 112.36, 125.98, 127.07, 128.46,

131.17, 132.93, 133.04, 138.29, 141.41, 147.64, 154.30, 161.74.

Anal. (C₂₀H₂₃N₃O₃S‚0.13H₂O) C, H, N, S.

graphed on silica gel using hexanes/EtOAc (3:1) to afford 0.21

g (42%) of 6f as an off-white solid: mp 67-70 °C. Anal.

(C₁₉H₂₁N₃O₃S‚0.25H₂O) C, H, N, S.

2′-[[N-(3,4-Dim eth yl-5-isoxa zolyl)a m in o]su lfon yl][1,1′-

bip h en yl]-4-ca r boxylic Acid (6i). Suzuki coupling of 4 and

4-formylphenylboronic acid as described for 6a provided 2′-

[[N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-

amino]sulfonyl][1,1′-biphenyl]-4-carboxaldehyde in 84% yield.

To a solution of this material (1.0 g, 2.25 mmol) and sulfamic

acid (437 mg, 4.5 mmol) in 22 mL of THF at 0 °C was added

an ice-cooled solution of sodium chlorite (407 mg, 4.5 mmol)

in 22 mL of H₂O. The mixture was stirred at 0 °C for 3 min

and then diluted with 200 mL of CH₂Cl₂. The organic layer

was separated, washed with brine, dried, and concentrated.

The residue was chromatographed on silica gel using CH₂Cl₂/

MeOH to afford 2′-[[N-(3,4-dimethyl-5-isoxazolyl)-N-[(2-meth-

oxyethoxy)methyl]amino]sulfonyl][1,1′-biphenyl]-4-carboxyl-

ic acid (950 mg, 92%) as a colorless gum: R_f) 0.20, silica gel,

20:1 CH₂Cl₂/MeOH. Treatment of this material with 6 N

aqueous hydrochloric acid as described for 6a then provided

6i (30 mg, 12%) as a white solid: mp >180 °C dec. ¹H NMR

(CD₃OD): δ 1.65 (s, 3H), 2.10 (s, 3H), 7.34-8.13 (m, 8H). ¹³C

NMR (CD₃OD): δ 6.50, 10.56, 105.76, 129.46, 129.80, 130.38,

130.70, 131.73, 133.66, 133.92, 140.20, 142.10, 145.35, 157.51,

163.18, 170.21. Anal. (C₁₈H₁₆N₂O₅S‚0.46H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(1-m et h ylet h ylt h io)-

[1,1′-bip h en yl]-2-su lfon a m id e (6x). This compound was

prepared from 7 and 1-bromo-4-(1-methylethylthio)benzene

using a Suzuki coupling procedure described for 6a followed

by deprotection of the MEM group using 6 N aqueous

hydrochloric acid to provide 6x as an amorphous white foam.

¹H NMR (CDCl₃): δ 1.17 (d, J ) 6.4 Hz, 6H), 1.84 (s, 3H),

2.12 (s, 3H), 3.73 (s, 1H), 7.26-7.99 (m, 8H). Anal.

(C₂₀H₂₂N₂O₃S₂) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxazolyl)-4′-(1-m eth yleth ylsu lfon yl)-

[1,1′-bip h en yl]-2-su lfon a m id e (6y). This compound was

prepared from 7 and 1-bromo-4-(1-methylethylsulfonyl)ben-

zene using a Suzuki coupling procedure described for 6a

followed by deprotection of the MEM group using 6 N aqueous

hydrochloric acid to provide 6y as an amorphous white foam.

¹H NMR (CDCl₃): δ 1.33 (d, J ) 7.1 Hz, 6H), 1.88 (s, 3H),

2.12 (s, 3H), 3.28 (s, 1H), 7.27-8.07 (m, 8H). Anal.

(C₂₀H₂₂N₂O₅S₂‚0.22H₂O) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(N,N-d im eth ylsu lfon -

yla m id o)[1,1′-bip h en yl]-2-su lfon a m id e (6z). This com-

pound was prepared from 7 and 4-bromo-N,N-dimethylben-

zenesulfonamide using a Suzuki coupling procedure described

for 6a followed by deprotection of the MEM group using 6 N

aqueous hydrochloric acid to provide 6z as a white solid: mp

175-176 °C. ¹H NMR (CDCl₃): δ 1.82 (s, 3H), 2.12 (s, 3H),

2.77 (s, 6H), 6.39 (br s, 1H), 7.27-8.86 (m, 8H). ¹³C NMR

(CDCl₃): δ 6.68, 10.78, 37.98, 108.68, 127.20, 128.70, 129.48,

130.60, 132.31, 133.26, 135.59, 137.87, 139.58, 143.32, 153.71,

162.04. Anal. (C₁₉H₂₁N₃O₅S₂) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(N-m eth yl-N-(1-m eth -

yleth yla m in o))[1,1′-bip h en yl]-2-su lfon a m id e (6w ): yellow

oil. ¹H NMR (CDCl₃): δ 1.10 (d, J ) 6.4 Hz, 6H), 1.84 (s, 3H),

2.12 (s, 3H), 2.75 (s, 3H), 4.10 (m, 1H), 5.83 (br s, 1H), 7.22-

7.99 (m, 8H). ¹³C NMR (CDCl₃): δ 6.66, 18.75, 19.45, 29.64,

48.39, 188.38, 111.96, 125.83, 127.01, 128.46, 131.05, 132.96,

133.04, 138.32, 141.44, 141.92, 154.36, 161.77. Anal.

(C₂₁H₂₅N₃O₃S‚0.22C₆H₁₄) C, H, N, S.

2′-(N,N-Dim eth yla m in o)-N-(3,4-d im eth yl-5-isoxa zolyl)-

[1,1′-bip h en yl]-2-su lfon a m id e (6b). To a solution of 0.45 g

(1.04 mmol) of 5 in 15 mL of MeOH were added glacial AcOH

(1 mL) and 37% aqueous formaldehyde (0.25 mL, 3.13 mmol),

and the mixture was stirred for 15 min at room temperature.

Sodium cyanoborohydride (0.197 g, 3.13 mmol) in 5 mL of

MeOH was then added dropwise over 15 min, and the mixture

was stirred for 24 h. The mixture was concentrated, added to

water (25 mL), and extracted with 2 × 50 mL of EtOAc. The

combined organic extracts were dried and evaporated to

provide 0.39 g (81%) of a light-brown gum which solidified on

standing. To a solution of this material in 10 mL of 95%

aqueous EtOH was added 10 mL of 6 N aqueous HCl, and the

mixture was refluxed for 2 h. The solution was concentrated

in vacuo, 5% aqueous NaHCO₃(10 mL) was added to the

residue, and the resulting solution was reacidified to pH 4

using glacial AcOH. The solution was then concentrated to

about 5 mL and extracted with 3 × 10 mL of EtOAc. The

combined organic extracts were dried and evaporated. The

residue was chromatographed on silica gel using 3:1 hexanes/

EtOAc followed by crystallization from a mixture of CH₂Cl₂/

hexanes to afford 0.14 g (62%) of 6b as colorless prisms: mp

148-150 °C. ¹H NMR (CDCl₃): δ 2.00 (s, 3H), 2.21 (s,3H),

2.62 (s, 6H), 7.15-7.76 (m, 8H). ¹³C NMR (CDCl₃): δ 7.08,

10.88, 43.60, 118.04, 123.82, 128.37, 128.52, 129.24, 132.20,

133.13, 133.53. Anal. (C₁₉H₂₁N₃O₃S) C, H, N, S.

3′-(N,N-Dim eth yla m in o)-N-(3,4-d im eth yl-5-isoxa zolyl)-

[1,1′-bip h en yl]-2-su lfon a m id e (6f). To a solution of 0.46 g

(1.34 mmol) of 6e in 15 mL of MeOH were added 37% aqueous

formaldehyde (0.44 mL, 5.36 mmol) and glacial acetic acid

(0.49 g), and the mixture was stirred at room temperature.

Sodium cyanoborohydride (0.34 g, 5.36 mmol) was then added

over 10 min, and the solution was stirred overnight. The

mixture was then concentrated to about 10 mL, diluted with

40 mL water, and extracted with 3 × 35 mL of EtOAc. The

combined organic extracts were washed with brine, dried, and

evaporated. The gummy solid thus obtained was chromato-

2-Bor on o-N-(3,4-d im et h yl-5-isoxa zolyl)-N′-(m et h oxy-

eth oxym eth yl)ben zen esu lfon a m id e (7). To a solution of

4 (1.69 g, 4.03 mmol) in 40 mL of dry ether and 10 mL of THF

at -78 °C was added n-BuLi (2 M solution in cyclohexane,

2.52 mL, 5.04 mmol) over 10 min. The resulting solution was

stirred at -78 °C for 15 min, and triisopropyl borate (1.52 g,

8.06 mmol) was added. The mixture was slowly warmed to

room temperature and stirred overnight. The solution was

cooled to 0 °C, 40 mL of 10% aqueous HCl was added, and the

mixture was stirred for 10 min. The organic layer was

separated, and the aqueous layer was extracted with 2 × 30

mL of EtOAc. The combined organic layers were washed once

with 20 mL of brine, dried, and concentrated to give 7 (600

mg, 39%) as a light-yellow solid. This compound was used in

the next step without any further purification.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2-(2-p yr id in yl)ben zen e-

su lfon a m id e (9a ). This compound was prepared from 7 and

2-bromopyridine using a Suzuki coupling procedure described

for 6a followed by deprotection of the MEM group using 6 N

aqueous hydrochloric acid to provide 9a as white crystals: mp

5210 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Murugesan et al.

136-137 °C. ¹H NMR (CDCl₃): δ 1.90 (s, 3H), 2.19 (s, 3H),

7.26-8.66 (m, 8H). Anal. (C₁₆H₁₅N₃O₃S) C, H, N, S.

134.7, 136.0, 138.7, 155.0, 161.7. Anal. (C₁₉H₁₇N₃O₃S‚

0.43H₂O) C, H, N.

The following compounds were prepared similar to the

procedure described for 9a .

N-(2-Br om op h en ylsu lfon yl)p yr r ole (10). Potassium hy-

dride (35% oil dispersion, 5.76 g, 50 mmol; washed three times

with hexanes) was covered with dry tetrahydrofuran (200 mL),

and the suspension was cooled to 0 °C. Pyrrole (4.16 mL, 60

mmol) in tetrahydrofuran (60 mL) was added dropwise over

20 min. The ice bath was removed, and the solution was

stirred at ambient temperature until the gas evolution ceased

(20 min), whereupon 2-bromobenzenesulfonyl chloride (10.22

g, 40 mmol) in tetrahydrofuran (60 mL) was added dropwise

over 20 min. After stirring for 1 h, the mixture was filtered

through Celite, and the filter pad was rinsed with tetrahy-

drofuran (100 mL). The filtrate was evaporated, and the

resulting white solid was recrystallized from methanol to

afford 7.47 g (65%) of 10: mp 85.0-87.0 °C. ¹H NMR

(CDCl₃): δ 6.25 (m, 2H), 7.14 (m, 2H), 7.36 (m, 2H), 7.64 (m,

2H).

N-(3,4-Dim eth yl-5-isoxa zolyl)-2-(3-p yr id in yl)ben zen e-

su lfon a m id e (9b): mp 147-150 °C. ¹H NMR (CDCl₃): δ 1.82

(s, 3H), 2.12 (s, 3H), 7.19-8.51 (m, 9H). ¹³C NMR (CDCl₃): δ

6.51, 10.72, 105.04, 122.69, 128.34, 128.60, 129.99, 131.92,

132.06, 132.70, 135.61, 136.82, 138.84, 139.56, 146.92, 147.21,

155.69, 161.69. Anal. (C₁₆H₁₅N₃O₃S‚0.25H₂O) C, H, N, S.

N -(3,4-D i m e t h y l-5-i s o x a z o ly l)-2-(3-p y r i m i d i n y l)-

ben zen esu lfon am ide (9c): mp 160-162 °C. ¹H NMR (CDCl₃):

δ 1.94 (s, 3H), 2.20 (s, 3H), 7.39-8.93 (m, 7H), 10.32 (s, 1H).

¹³C NMR (CDCl₃): δ 6.72, 10.93, 107.65, 116.13, 119.93, 129.34,

130.32, 133.37, 133.60, 136.49, 138.36, 155.87, 157.05, 161.96,

165.04. Anal. (C₁₅H₁₄N₄O₃S‚0.72H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-2-(2-t h ien yl)b en zen e-

su lfon a m id e (9d ): mp 112-115 °C. ¹H NMR (CDCl₃): δ 1.83

(s, 3H), 2.11 (s, 3H), 6.30 (s, br, 1H), 7.11-8.03 (m, 7H). ¹³C

NMR (CDCl₃): δ 6.51, 10.69, 108.24, 127.33, 127.79, 128.49,

129.21, 129.81, 132.96, 133.19, 133.97, 138.44, 138.73, 153.84,

161.80. Anal. (C₁₅H₁₄N₄O₃S₂) C, H, N, S.

N -[[4′-(2-Me t h ylp r op yl)[1,1′-b ip h e n yl]yl]su lfon yl]-

p yr r ole (11). This compond was prepared from 10 and

4-isobutylphenylboronic acid using a Suzuki coupling proce-

dure described for 6a : yield 86%. ¹H NMR (CDCl₃): δ 1.11

(m, 6H), 2.07 (m, 1H), 2.67 (m, 2H), 6.20 (m, 2H), 6.72 (m,

2H), 7.20 (m, 4H), 7.43 (d, J ) 7.9 Hz, 1H), 7.61 (t, J ) 7.9

Hz, 1H), 7.73 (t, J ) 7.9 Hz, 1H), 8.09 (d, J ) 7.9 Hz, 1H).

N-(3,4-Dim et h yl-5-isoxa zolyl)-2-(3-t h ien yl)b en zen e-

su lfon a m id e (9e): mp 147-148 °C. ¹H NMR (CDCl₃): δ 1.86

(s, 3H), 2.11 (s, 3H), 6.00 (br s, 1H), 7.25-8.01 (m, 7H). ¹³C

NMR (CDCl₃): δ 7.86, 12.00, 109.71, 126.99, 127.14, 129.21,

130.16, 131.22, 133.99, 134.33, 137.16, 139.32, 139.43, 155.15,

163.13. Anal. (C₁₅H₁₄N₄O₃S₂) C, H, N, S.

4′-(2-Met h ylp r op yl)[1,1′-b ip h en yl]-2-su lfon ic

Acid ,

Sod iu m Sa lt (12). A solution of 11 (3.8 g, 11 mmol) and 5 N

aqueous sodium hydroxide (53 mL) in methanol (70 mL) was

refluxed for 6.5 h. Evaporation of the solvent afforded a white

solid which was collected and dried under vacuum. Recrys-

tallization from water (40 mL) afforded 3.05 g (88%) of 12 as

a white solid. ¹H NMR (CDCl₃): δ 0.94 (m, 6H), 1.90 (m, 1H),

2.49 (m, 2H), 7.11 (d, J ) 7.6 Hz, 2H), 7.21 (m, 1H), 7.39 (m,

2H), 7.41 (d, J ) 7.6 Hz, 2H), 8.09 (d, J ) 7.6 Hz, 1H).

4′-(2-Meth ylp r op yl)[1,1′-bip h en yl]-2-su lfon yl Ch lor id e

(13). Compound 12 (1.6 g, 5 mmol) and phosphorus pen-

tachloride (3.1 g, 15 mmol) were ground together with a glass

rod, and the mixture was heated at 60 °C for 2.5 h. Ice water

was added, and the mixture was extracted twice with ethyl

acetate. The combined organic layers were washed with brine,

dried, and evaporated to afford 1.45 g (94%) of 13. This

compound was used in the next step without any furthur

purification.

N -(3,4-Dim e t h yl-5-isoxa zolyl)-2-(1H -in d ol-2-yl)b e n -

zen esu lfon a m id e (9f). a . 2-Iod o-1-(p h en ylsu lfon yl)-

in d ole: A solution of 1-(phenylsulfonyl)indole (1.35 g; 5.24

mmol) in 10 mL of THF was added dropwise over 10 min to a

-78 °C solution of LDA in 15 mL of THF prepared from

diisopropylamine (0.86 mL, 5.9 mmol) and 2.5 M n-BuLi (2.2

mL; 5.5 mmol). After stirring for 1 h at -78 °C, the mixture

was allowed to warm to 0 °C over 1 h. After recooling to -78

°C, iodine (1.78 g, 6.81 mmol) was added in one portion, and

the resulting mixture was stirred for 2 h at -78 °C and for 18

h at room temperature. The reaction mixture was partitioned

between EtOAc (75 mL) and saturated NaHCO₃solution (50

mL). The organic layer was washed with saturated aqueous

NaHSO₃solution (2 × 50 mL) and brine (50 mL). Drying and

concentration afforded a ruby-colored oil which was crystal-

lized from ether/hexane to afford 965 mg (48%) of the product

as a tan crystalline solid. ¹H NMR (CDCl₃): δ 6.99 (s, 1H),

7.21 (m, 1H), 7.26 (m, 1H), 7.41 (m, 3H), 7.54 (m, 1H), 7.89 (d,

J ) 7.5 Hz, 2H), 8.27 (d, J ) 7.5 Hz, 1H).

b. N-(3,4-Dim eth yl-5-isoxa zolyl)-2-(1H-in d ol-2-yl)ben -

zen esu lfon a m id e (9f). This compound was prepared from

7 and 2-iodo-1-(phenylsulfonyl)indole using a Suzuki coupling

procedure described for 6a followed by deprotection of the

MEM group using 6 N aqueous hydrochloric acid and depro-

tection of the phenylsulfonyl moiety using 1 N aqueous KOH

in MeOH at 55 °C to afford 9f as a yellow powder: mp 172-

175 °C. ¹H NMR (CDCl₃): δ 1.77 (s, 3H), 2.02 (s, 3H), 6.38

(br s, 1H), 6.96 (s, 1H), 7.18 (t, J ) 7.5 Hz, 1H), 7.26 (m, 1H),

7.49 (m, 2H), 7.68 (m, 2H), 7.73 (d, J ) 6.5 Hz, 1H), 8.06 (d, J

) 8 Hz, 1H), 9.31 (brs, 1H). ¹³C NMR (CDCl₃): δ 6.5, 10.7,

105.9, 108.9, 111.6, 120.7, 121.2, 123.3, 128.2, 128.5, 129.4,

131.8, 133.2, 133.5, 134.1, 136.8, 137.4, 153.4, 161.8. MS

(HR): calcd for C₁₉H₁₈N₃O₃S, 368.1068; found, 368.0968.

N -(3,4-Dim e t h yl-5-isoxa zolyl)-2-(1H -in d ol-3-yl)b e n -

zen esu lfon a m id e (9g). This compound was prepared from

4 and 1-(phenylsulfonyl)indole-3-boronic acid using a Suzuki

coupling procedure described for 6a followed by deprotection

of the MEM group using 6 N aqueous hydrochloric acid and

deprotection of the phenylsulfonyl moiety using 1 N aqueous

KOH in MeOH at 55 °C to afford 9g as a colorless solid: mp

184-186 °C. ¹H NMR (CDCl₃/CD₃OD, 9:1): δ 1.54 (s, 3H),

2.01 (s, 3H), 7.12 (t, J ) 7.8 Hz, 1H), 7.23 (t, J ) 7.5 Hz, 1H),

7.45 (m, 2H), 7.54 (d, J ) 7.5 Hz, 1H), 7.64 (s, 1H), 7.65 (d, J

) 9 Hz, 2H), 8.12 (d, J ) 7.5 Hz, 1H), 10.09 (br s, 1H). ¹³C

NMR (CDCl₃/CD₃OD, 9:1): δ 6.0, 10.6, 105.9, 111.6, 112.1,

119.5, 120.4, 122.5, 126.7, 126.8, 127.2, 129.5, 133.0, 134.5,

N-(4-Met h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)[1,1′-b i-

p h en yl]-2-su lfon a m id e (14a ). Sulfonyl chloride 13 (0.65 g,

2.1 mmol) in pyridine (1.0 mL) was added to a solution of

4-methyl-5-isoxazolamine (0.29 g, 2.9 mmol) and DMAP (58

mg, 0.46 mmol) in 1 mL of pyridine. The solution was stirred

at 75 °C for 2.5 h, cooled to room temperature, and diluted

with water. The solution was adjusted to pH 3 with 1 N

aqueous hydrochloric acid and extracted with ether (2 × 50

mL). The combined organic layers were washed with brine,

dried, and evaporated. The residue was purified by flash

chromatography using ethyl acetate/methylene chloride to

afford 0.12 g (15%) of 14a as a white solid: mp 153-155 °C.

¹H NMR (CDCl₃): δ 0.94 (m, 6H), 1.57 (m, 1H), 1.93 (s, 3H),

2.54 (m, 2H), 5.76 (s, 1H), 7.25 (d, J ) 8.2 Hz, 2H), 7.41 (m,

2H), 7.48 (d, J ) 8.2 Hz, 2H), 7.62 (t, J ) 8.0 Hz, 1H), 7.97 (d,

J ) 8.0 Hz, 1H), 7.98 (s, 1H). ¹³C NMR (CDCl₃): δ 7.1, 22.4,

30.1, 45.2, 127.7, 128.7, 129.0, 129.8, 132.8, 133.1, 142.4, 153.8.

Anal. (C₂₀H₂₂N₂O₃S‚0.39H₂O) C, H, N, S.

The following compounds were prepared similar to the

procedure described for 14a . The corresponding isoxazolamine

starting materials were prepared as described previously.¹⁷

N-(3-Meth yl-4-n itr o-5-isoxa zolyl)-4′-(2-m eth ylp r op yl)-

[1,1′-bip h en yl]-2-su lfon a m id e (14b): mp 124-126 °C. ¹H

NMR (CDCl₃): δ 0.96 (m, 6H), 1.93 (m, 1H), 2.45 (s, 3H), 2.55

(m, 2H), 7.15 (d, J ) 8.2 Hz, 2H), 7.19 (d, J ) 8.2 Hz, 2H),

7.37 (d, J ) 7.6 Hz, 1H), 7.60 (t, J ) 7.6 Hz, 1H), 7.70 (t, J )

7.6 Hz, 1H), 8.35 (d, J ) 7.6 Hz, 1H), 8.59 (s, 1H). ¹³C NMR

(CDCl₃): δ 11.5, 22.4, 30.1, 45.1, 128.2, 128.4, 129.0, 130.3,

133.0, 134.4, 134.8, 136.5, 141.7, 142.6, 143.0, 155.4, 159.2.

Anal. (C₂₀H₂₁N₃O₅S) C, H, N, S.

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5211

N -(4,5,6,7-T e t r a h y d r o -2,1-b e n zis o x a zo l-3-y l)-4′-(2-

m et h ylp r op yl)[1,1′-b ip h en yl]-2-su lfon a m id e (14d ): mp

111-114 °C. ¹H NMR (CDCl₃): δ 0.94 (m, 6H), 1.70 (m, 4H),

1.93 (m, 1H), 2.40 (t, J ) 6.4 Hz, 2H), 2.54 (m, 2H), 2.60 (t, J

) 6.4 Hz, 2H), 5.88 (s, 1H), 7.24 (d, J ) 8.2 Hz, 2H), 7.38 (m,

1H), 7.46 (d, J ) 8.2 Hz, 2H), 7.47 (m, 1H), 7.61 (t, J ) 7.8

Hz, 1H), 8.02 (t, J ) 7.8 Hz, 1H). ¹³C NMR (CDCl₃): δ 19.0,

22.1, 22.2, 22.4, 30.1, 45.2, 126.4, 127.7, 128.8, 128.9, 129.7,

132.8, 133.1, 135.6, 142.3. Anal. (C₂₃H₂₆N₂O₃S) C, H, N, S.

N-(3-Meth yl-4-(p h en ylm eth yl)-5-isoxa zolyl)-4′-(2-m eth -

ylp r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (14e): mp 137.0-

138.5 °C. ¹H NMR (CDCl₃): δ 0.94 (m, 6H), 1.26 (m, 1H), 1.93

(s, 3H), 2.54 (m, 2H), 3.69 (s, 2H), 5.72 (s, 1H), 7.04 (d, J ) 7.1

Hz, 2H), 7.23 (d, J ) 8.1 Hz, 1H), 7.26, (m, 5H), 7.40 (t, J )

7.8 Hz, 1H), 7.47 (d, J ) 8.1 Hz, 2H), 7.62 (t, J ) 7.1 Hz, 1H),

8.01 (d, J ) 7.8 Hz, 1H). ¹³C NMR (CDCl₃): δ 11.1, 22.4, 27.7,

30.1, 45.2, 126.6, 127.7, 128.3, 128.6, 128.8, 129.0, 129.8, 132.8,

133.1, 135.7, 154.9. Anal. (C₂₇H₂₈N₂O₃S‚0.86H₂O) C, H, N,

S.

N-(4,5-Dim eth yl-3-isoxa zolyl)-4′-(2-m eth ylp r op yl)[1,1′-

bip h en yl]-2-su lfon a m id e (14f): mp 131.5-133.0 °C. ¹H

NMR (CDCl₃): δ 0.94 (m, 6H), 1.64 (s, 3H), 1.91 (m, 1H), 2.19

(s, 3H), 2.52 (m, 2H), 5.94 (s, 1H), 7.20 (d, J ) 8.2 Hz, 2H),

7.30 (m, 1H), 7.33 (d, J ) 8.2 Hz, 2H), 7.47 (d, J ) 7.6 Hz,

1H), 7.57 (t, J ) 7.6 Hz, 1H), 8.15 (d, J ) 7.6 Hz, 1H). ¹³C

NMR (CDCl₃): δ 6.5, 11.1, 24.7, 29.8, 44.9, 127.8, 128.9, 129.5,

132.5, 132.9, 136.0, 137.3, 140.9, 142.1. Anal. (C₂₁H₂₄N₂O₃S)

C, H, N, S.

N-(4,6-Dim eth oxy-2-p yr im id in yl)-4′-(2-m eth ylp r op yl)-

[1,1′-bip h en yl]-2-su lfon a m id e (14h ): mp 131-134 °C. ¹H

NMR (CDCl₃): δ 0.95 (m, 6H), 1.92 (m, 1H), 2.53 (m, 2H), 3.61

(s, 6H), 5.59 (s, 1H), 6.33 (s, 1H), 7.10 (d, J ) 8.2 Hz, 2H),

7.14 (d, J ) 8.2 Hz, 2H), 7.26 (d, J ) 6.8 Hz, 1H), 7.53 (t, J )

7.8 Hz, 1H), 7.59 (t, J ) 6.8 Hz, 1H), 8.35 (d, J ) 7.8 Hz, 1H).

¹³C NMR (CDCl₃): δ 22.4, 30.2, 45.1, 54.0, 84.7, 127.2, 128.5,

128.8, 130.3, 132.3, 132.6, 135.9, 141.8, 154.7, 171.5. Anal.

(C₂₂H₂₅N₃O₄S) C, H, N, S.

3-Meth yl-5-[[[4′-(2-m eth ylp r op yl)[1,1′-bip h en yl]-2-yl]-

su lfon yl]a m in o]-4-isoxa zoleca r boxylic Acid , Eth yl Ester

(14c). a . N-(1,1-Dim eth yleth yl)-2-br om oben zen esu lfon a -

m id e. To a solution of tert-butylamine (3.6 mL, 34 mmol) in

chloroform (50 mL) at 0 °C was added dropwise a solution of

2-bromobenzenesulfonyl chloride (4.00 g, 15.7 mmol) in chlo-

roform (15 mL). The reaction was allowed to come to room

temperature and was stirred for 17 h. The combined filtrates

were washed (25 mL of saturated NaHCO₃), dried, and

concentrated to afford a white solid. ¹H NMR (CDCl₃): δ 1.22

(s, 9H), 5.18 (br s, 1H), 7.35-7.49 (m, 2H), 7.71 (dd, J ) 8, 1

Hz, 1H), 8.17 (dd, J ) 8, 2 Hz, 1H).

b. N-(1,1-Dim eth yleth yl)-4′-(2-m eth ylp r op yl)[1,1′-bi-

p h en yl]-2-su lfon a m id e. Suzuki coupling of the preceding

sulfonamide and 4-isobutylbenzeneboronic acid as described

in 6a yielded the product as a white solid. ¹H NMR (CDCl₃,

270 MHz): δ 8.17 (dd, J ) 8, 1 Hz, 1H), 7.44-7.56 (m, 4H),

7.33 (dd, J ) 8, 1 Hz, 1H), 7.24 (d, J ) 8 Hz, 2H), 3.52 (br s,

1H), 2.53 (d, J ) 7 Hz, 2H), 1.91 (m, 1H), 0.96 (s, 9H), 0.93 (d,

J ) 6 Hz, 6 H).

c. 4′-(2-Met h ylp r op yl)[1,1′-b ip h en yl]-2-su lfon a m id e.

The preceding sulfonamide was dissolved in cold trifluoroacetic

acid (5 mL). The reaction was brought to room temperature

and was stirred for 5 h. The solvent was removed in vacuo,

and the residue was passed through a silica plug with ethyl

acetate to provide the product as an oil (306 mg, 100%): R_f

(silica, 25% ethyl acetate/hexanes) 0.23.

d . 3-Meth yl-5-[[[4′-(2-m eth ylp r op yl)[1,1′-bip h en yl]-2-

yl]su lfon yl]a m in o]-4-isoxa zoleca r b oxylic Acid , E t h yl

Ester (14c). The preceding sulfonamide (306 mg, 1.01 mmol),

ethyl 5-bromo-3-methyl-4-isoxazolecarboxylate (389 mg), and

cesium carbonate (658 mg, 2.02 mmol) were heated at 80 °C

in DMF (4 mL) for 2 h. The solvent was removed in vacuo,

the residue was diluted with saturated NaCl (10 mL), and the

pH was brought to 2 with 1 N HCl. The mixture was extracted

with ethyl acetate, and the combined organic layers were

washed with brine, dried, and concentrated. Chromatography

(silica, ethyl acetate/hexanes) yielded the product as a yellow-

white solid. Recrystallization from ethanol provided 137 mg

(31%) of 14c as fine white needles: mp 133.5-134.0 °C. ¹H

NMR (CD₃OD/CDCl₃): δ 0.94 (d, J ) 7 Hz, 6H), 1.22 (t, J ) 7

Hz, 3H), 1.90 (m, 1H), 2.27 (s, 3H), 2.50 (d, J ) 7 Hz, 2H),

4.01-4.14 (m, 2H), 7.12-7.18 (m, 3H), 7.31-7.78 (m, 4H), 7.78

(m, 1H). ¹³C NMR (CD₃OD/CDCl₃): δ 12.2, 13.8, 22.0, 29.9,

44.9, 126.7, 127.3, 127.9, 128.9, 131.0, 132.4, 137.4, 140.1,

140.5, 141.0, 159.1, 165.9, 170.3. Anal. (C₂₃H₂₆N₂O₅S‚

0.13H₂O) C, H, N, S

N-(6-Ch lor o-1,2-p yr id a zin yl)-4′-(2-m eth ylp r op yl)[1,1′-

bip h en yl]-2-su lfon a m id e (14g). Treatment of 4′-(2-meth-

ylpropyl)[1,1′-biphenyl]-2-sulfonamide with 3,6-dichloropy-

ridazine as described for 14c, step d, provided 14g as a tan

solid: mp 108-110 °C. ¹H NMR (CDCl₃): δ 0.90 (d, J ) 6.2

Hz, 6H), 1.8 (m, 1H), 2.4 (d, J ) 7.2 Hz, 2H), 7.0 (d, J ) 7.9

Hz, 2H), 7.1 (d, J ) 9.5 Hz, 1H), 7.25 (m, 3H), 7.5 (m, 2H), 8.2

(d, J ) 7.8 Hz, 1H). ¹³C NMR (CDCl₃): δ 22.3, 30.0, 44.9,

127,5, 128.1, 128.3, 129.1, 129.2, 129.3, 132.1, 132.2, 132.3,

132.4, 135.9, 141.2, 141.4, 152.3. Anal. (C₂₀H₂₀ClN₃O₂S‚

0.13H₂O) C, H, N, S.

3-(2-Met h yl-1-p r op en yl)a n ilin e (16). To isopropyl tri-

phenylphosphonium iodide (74 g, 170 mmol) in 1:1 ether/

tetrahydrofuran (850 mL) at -15 °C was added n-butyllithium

(1.6 M in hexane, 118 mL, 188 mmol) dropwise. The mixture

was stirred at room temperature for 3 h and cooled to -50 °C,

and a solution of 3-nitrobenzaldehyde (28.4 g, 188 mmol) in

tetrahydrofuran (60 mL) was added dropwise. The mixture

was stirred at room temperature overnight, cold water and

hexane were added, and the mixture was stirred for several

minutes and filtered. The organic phase of the filtrate was

separated washed three times with water, dried, and concen-

trated. The residue was chromatographed on silica gel with

50:1 hexanes/ethyl acetate to afford 3-(2-methyl-1-propenyl)-

nitrobenzene (23 g, 76%) as a light-yellow liquid. A mixture

of this compound (4.0 g, 22 mmol) and 5% Pt/C (400 mg) in

methanol (40 mL) was hydrogenated at 45 psi overnight. The

mixture was filtered and the filtrate concentrated to provide

16 (3.11 g, 92%). ¹H NMR (CDCl₃): δ 1.85 (d, J ) 1.5 Hz, 3H),

1.87 (d, J ) 1.2 Hz, 3H), 3.60 (br s, 2H), 6.18 (br s, 1H), 6.51-

7.35 (m, 4H).

N-(2,2-Dim et h yl-1-oxop r op yl)-3-(2-m et h yl-1-p r op yl)-

a n ilin e (17). To a mixture of 16 (3.11 g, 21.1 mmol) and

trimethylacetyl chloride (3.31 g, 27.5 mmol) in methylene

chloride (53 mL) at 0 °C was added triethylamine (4.28 g, 42.2

mmol). The mixture was stirred at 0 °C for 1 h and at room

temperature for 15 min and poured into ice water. The

aqueous layer was extracted twice with ethyl acetate, and the

combined organic phases were washed with brine, dried, and

concentrated. The residue was chromatographed on silica gel

with 25:2 hexanes/ethyl acetate to provide N-(2,2-dimethyl-1-

oxopropyl)-3-(2-methyl-1-propenyl)aniline (3.81 g, 78%) as a

white solid. A mixture of this compound (3.47 g, 15 mmol)

and 10% Pd/C (520 mg) in ethyl acetate (35 mL) was hydro-

genated at 60 psi for 1 h. The mixture was filtered and the

filtrate concentrated to provide 17 (3.41 g, 98%). ¹H NMR

(CDCl₃): δ 1.04 (d, J ) 7.0 Hz, 6H), 1.46 (s, 9H), 2.02 (m, 1H),

2.59 (d, J ) 7.0 Hz, 2H), 7.02-7.54 (m, 4H).

2-(2,2-Dim et h yl-1-oxo-1-p r op yla m in o)-4-(2-m et h yl-1-

p r op yl)p h en ylbor on ic Acid (18). To compound 17 (2.86 g,

12.3 mmol) and tetramethylethylenediamine (4.28 g, 36.8

mmol) in ether (25 mL) at -40 °C was added tert-butyllithium

(1.7 M in pentane, 21.6 mL, 36.8 mmol) dropwise. The solution

was stirred at room temperature for 2.5 h and cooled to -20

°C, and trimethyl borate (3.82 g, 36.8 mmol) was added

dropwise. The mixture was stirred at -10 to 0 °C for 1 h and

at room temperature for 3 h and cooled to 0 °C, and 10%

aqueous hydrochloric acid was added. The aqueous layer was

extracted three times with methylene chloride, and the

combined organic phases were washed with brine, dried, and

concentrated. The residue was triturated with ether to afford

18 as a white solid (2.52 g, 74%): mp >250 °C. ¹H NMR

(CDCl₃): δ 0.90 (d, J ) 6.5 Hz, 6H), 1.06 (s, 9H), 1.85 (m, 1H),

5212 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Murugesan et al.

2.44 (d, J ) 7.0 Hz, 2H), 7.0 (d, J ) 8.2 Hz, 1H), 7.95 (d, J )

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-2′-

(eth ylam in o)[1,1′-biph en yl]-2-su lfon am ide (20c). ¹H NMR

(CDCl₃): δ 0.95 (d, J ) 7 Hz, 6H), 1.11(t, J ) 7 Hz, 3H), 1.90

(m, 1H), 1.92 (s, 3H), 2.17 (s, 3H), 2.49 (d, J ) 7 Hz, 2H), 3.10

(m, 2H), 6.61-7.90(m, 7H). ¹³C NMR (CDCl₃): δ 7.20, 11.27,

14.81, 22.94, 30.56, 39.45, 46.17, 108.76, 113.52, 119.52,

123.38, 128.95, 129.55, 130.68, 133.85, 134.05, 138.35, 139.97,

144.15, 145.22, 155.66, 162.35. Anal. (C₂₃H₂₉N₃O₃S‚0.20H₂O)

C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-2′-

(p r op yla m in o)[1,1′-bip h en yl]-2-su lfon a m id e (20d ). ¹H

NMR (CDCl₃): δ 0.86 (t, J ) 6 Hz, 3H), 0.95 (d, J ) 6 Hz, 6H),

1.50 (m, 2H), 1.92 (s, 3H), 1.93 (m, 1H), 2.17 (s, 3H), 2.49 (d,

J ) 7 Hz, 2H), 3.02 (t, J ) 6 Hz, 2H), 6.61-7.90 (m, 7H). ¹³C

NMR (CDCl₃): δ 7.29, 11.36, 12.03, 22.82, 23.08, 30.66, 46.29,

46.87, 108.83, 113.56, 119.38, 123.28, 129.05, 129.65, 130.72,

133.92, 134.15, 138.48, 140.09, 144.25, 145.46, 155.73, 162.45.

Anal. (C₂₄H₃₁N₃O₃S‚0.28H₂O) C, H, N, S.

7.6 Hz, 1H), 7.96 (s, 1H), 10.43 (br s, 1H).

2′-(2,2-Dim eth yl-1-oxo-1-pr opylam in o)-N-(3,4-dim eth yl-

5-isoxa zolyl)-N-[(2-m eth oxyeth oxy)m eth yl]-4′-(2-m eth yl-

p r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (19). To a solution

of 4 (6.18 g, 22.30 mmol) and 18 (9.35 g, 22.30 mmol) in 200

mL of toluene and 160 mL of 95% EtOH under argon was

added tetrakis(triphenylphosphine)palladium(0) (2.58 g, 2.23

mmol) followed by 120 mL of 2 M aqueous sodium carbonate.

The mixture was heated at 75 °C for 3 h, cooled, and diluted

with 500 mL of EtOAc. The organic layer was separated,

washed with 3 × 150 mL of brine, dried, and concentrated.

The residue was chromatographed on silica gel using 4:1

hexane/EtOAc to afford 19 (9.14 g, 72%) as a colorless gum.

¹H NMR (CDCl₃): δ 0.94 (d, J ) 6.5 Hz, 6H), 1.01 (s, 9H),

1.94 (s, 3H), 1.95 (m, 1H), 2.15 (s, 3H), 2.54 (d, J ) 7.0 Hz,

2H), 3.31 (s, 3H), 3.45 (m, 2H), 3.60 (m, 2H), 4.1 (AB_q, J )

11.7, 91.7 Hz, 2H), 7.06-7.99 (m, 7H).

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-2′-

((1-m eth yleth yl)am in o)[1,1′-biph en yl]-2-su lfon am ide (20e).

¹H NMR (CDCl₃): δ 0.93 (d, J ) 6 Hz, 6H), 1.03 (d, J ) 6 Hz,

3H), 1.10 (d, J ) 6 Hz, 3H), 1.90 (m, 1H), 1.91 (s, 3H), 2.16 (s,

3H), 2.48 (d, J ) 7 Hz, 2H), 3.58 (m, 1H), 6.61-7.87 (m, 7H).

¹³C NMR (CDCl₃): δ 6.70, 10.79, 22.28, 22.43, 22.48, 22.71,

30.11, 44.72, 45.70, 108.59, 113.78, 118.79, 123.08, 128.47,

129.10, 130.42, 133.25, 133.56, 138.03, 139.58, 143.47, 143.56,

155.22, 161.84. Anal. (C₂₄H₃₁N₃O₃S‚0.16H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-2′-

((2-h yd r oxyet h yl)a m in o)[1,1′-b ip h en yl]-2-su lfon a m id e

(20f). ¹H NMR (CDCl₃): δ 0.94 (d, J ) 6 Hz, 6H), 1.90 (m,

1H), 1.91 (s, 3H), 2.15 (s, 3H), 2.47 (d, J ) 7 Hz, 2H), 3.22-

3.81 (m, 4H), 6.58-7.93 (m, 7H). ¹³C NMR (CDCl₃): δ 6.89,

10.96, 22.64, 22.70, 30.29, 45.89, 46.04, 60.28, 108.86, 112.61,

118.58, 122.36, 128.67, 129.48, 130.17, 133.75, 133.95, 137.87,

139.34, 144.02, 145.08, 154.89, 162.22. Anal. (C₂₃H₂₉N₃O₄S‚

0.15H₂O) C, H, N, S.

[N-[2′-[[(3,4-Dim eth yl-5-isoxa zolyl)a m in o]su lfon yl]-4-

(2-m eth ylp r op yl)[1,1′-bip h en yl]-2-yl]a m in o]a cetic a cid

(20g): mp 147-150 °C. ¹H NMR (1:1 CD₃OD/CDCl₃): δ 0.96

(m, 6H), 1.85 (s, 3H), 1.90 (m, 1H), 2.16 (s, 3H), 2.47 (d, J ) 7

Hz, 2H), 3.85 (s, 2H), 6.38-7.98 (m, 7H). ¹³C NMR (1:1 CD₃-

OD/CDCl₃): δ 6.69, 10.78, 22.67, 22.78, 30.77, 45.86, 46.29,

107.26, 112.14, 119.06, 123.36, 129.07, 130.17, 130.95, 134.26,

134.52, 138.76, 140.15, 143.72, 144.42, 162.64, 174.41. Anal.

(C₂₃H₂₇N₃O₅S‚0.8H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-2′-

for m a m id o[1,1′-bip h en yl]-2-su lfon a m id e (20h ). Treat-

ment of 20 with formic acid in refluxing toluene provided 20h

as an off-white solid. ¹H NMR (CDCl₃): δ 0.95 (m, 6H), 1.83

(s, 3H), 1.92 (m, 1H), 2.13 (s, 3H), 2.52 (m, 2H), 7.04-8.37 (m,

9H). ¹³C NMR (CDCl₃): δ 6.55, 10.79, 22.41, 30.06, 45.08,

107.90, 121.92, 124.52, 125.79, 126.34, 127.89, 128.93, 129.05,

129.34, 130.26, 130.58, 132.85, 133.11, 133.72, 134.21, 135.05,

136.58, 136.84, 138.88, 143.67, 144.07, 154.05, 159.77, 162.02,

162.88. Anal. (C₂₂H₂₅N₃O₄S) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-[[(m et h yla m in o)ca r -

b on yl]a m in o]-4′-(2-m et h ylp r op yl)[1,1′-b ip h en yl]-2-su l-

fon a m id e (20i). Treatment of 20 with methyl isocyanate in

methylene chloride afforded 20i as a white solid: mp 172-

174 °C. ¹H NMR (CDCl₃): δ 0.93 (d, J ) 6 Hz, 6H), 1.80 (s,

3H), 1.90 (m, 1H), 2.10 (s, 3H), 2.48 (d, J ) 7 Hz, 2H), 2.55 (d,

J ) 4 Hz, 2H), 4.94 (s, br, 1H), 6.30 (s, br, 1H), 6.92-7.98 (m,

7H). ¹³C NMR (CDCl₃): δ 6.48, 10.72, 22.43, 26.81, 30.04,

45.16, 106.50, 124.77, 125.00, 128.40, 129.18, 130.42, 132.81,

132.99, 135.78, 137.51, 139.39, 143.28, 157.01, 161.80. Anal.

(C₂₃H₂₈N₄O₄S‚0.49H₂O) C, H, N, S.

2′-Am in o-N-(3,4-d im et h yl-5-isoxa zolyl)-4′-(2-m et h yl-

p r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (20). To a solution

of 19 (7.55 g, 13.2 mmol) in 75 mL of THF at -78 °C under

argon diisobutylaluminum hydride (1 M solution in hexane,

26.2 mL, 26.2 mmol) over 15 min, and the mixture was stirred

for 2 h. Additional diisobutylaluminum hydride (5.2 mL, 5.2

mmol) was added, and the mixture was stirred for an ad-

ditional 3 h. Saturated aqueous ammonium chloride (100 mL)

was added slowly to the mixture. The mixture was extracted

with 3 × 125 mL of methylene chloride, and the combined

organic extracts were washed with brine, dried, and concen-

trated. The residue thus obtained was dissolved in 150 mL of

95% EtOH and 150 mL of 6 N aqueous hydrochloric acid was

added, and the solution was refluxed for 1 h. The solution

was concentrated in vacuo to about 100 mL, and the solution

was neutralized to pH 7 using saturated aqueous sodium

bicarbonate. This solution was then reacidified to pH 5 using

glacial acetic acid and extracted with 3 × 200 mL of EtOAc.

The combined organic extracts were washed with brine, dried,

and concentrated. The residue was purified by chromatogra-

phy on silica with 2:1 hexanes/EtOAc to afford 20 (3.0 g, 57%)

as a white solid: mp 60-70 °C (amorphous). ¹H NMR (CDCl₃/

CD₃OD, 4:1): δ 0.93 (d, J ) 6 Hz, 6H), 1.88 (s, 3H), 2.16 (s,

3H), 2.44 (d, J ) 7 Hz, 2H), 3.91 (s, br, 2H), 6.66-7.94 (m,

7H). ¹³C NMR (CDCl₃/CD₃OD, 4:1): δ 6.33, 10.46, 22.20, 22.28,

29.78, 45.01, 107.17, 117.27, 120.24, 123.47, 128.26, 129.01,

130.10, 133.19, 133.39, 137.86, 138.93, 142.22, 143.20, 155.28,

161.83. Anal. (C₂₁H₂₅N₃O₃S‚0.25H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-2′-

(m eth yla m in o)[1,1′-bip h en yl]-2-su lfon a m id e (20a ). To a

suspension of 20 (135 mg, 0.34 mmol), NaOAc (28 mg, 0.34

mmol), and AcOH (41 mg, 0.68 mmol) in 4 mL of MeOH were

added H₂CO (37% in H₂O, 0.033 mL, 0.41 mmol) and NaC-

NBH₃(21 mg, 0.34 mmol). The mixture was stirred at room

temperature for 1 h and concentrated. The mixture was

diluted with EtOAc, washed with H₂O and brine, dried, and

concentrated. Purification of the residue using silica gel

chromatography using hexanes and EtOAc provided 20a (23

mg, 16%) as a white solid as well as 20b (30 mg, 20%). 20a :

mp 125-128 °C. ¹H NMR (CDCl₃): δ 0.95 (d, J ) 7 Hz, 6H),

1.93 (m, 4H), 2.17 (s, 3H), 2.50 (d, J ) 7 Hz, 2H), 2.76 (s, 3H),

6.61-7.91 (m, 7H). ¹³C NMR (CDCl₃): δ 6.57, 10.63, 22.35,

29.92, 30.78, 45.56, 107.84, 112.25, 118.93, 122.76, 128.32,

128.95, 129.82, 133.30, 133.42, 137.53, 139.26, 143.67, 145.37,

154.98, 161.78. Anal. (C₂₂H₂₇N₃O₃S‚0.20H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-2′-

(N ,N -d im e t h y la m in o )[1,1′-b ip h e n y l]-2-s u lfo n a m id e

(20b): mp 125-128 °C. ¹H NMR (CDCl₃): δ 0.95 (d, J ) 6

Hz, 6H), 1.90 (m, 1H), 2.00 (s, 3H), 2.20 (s, 3H), 2.53 (d, J )

7 Hz, 2H), 2.61 (s, 6H), 6.94-7.73 (m, 7H). ¹³C NMR (CDCl₃):

δ 7.05, 10.83, 22.43, 30.13, 43.63, 45.42, 106.39, 118.77, 124.53,

128.20, 128.49, 131.77, 131.86, 133.04, 133.62, 138.29, 142.91,

156.72, 162.12. Anal. (C₂₃H₂₉N₃O₃S) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-flu or o-4′-(2-m et h yl-

p r op yl)[1,1′-b ip h en yl]-2-su lfon a m id e (20j). This com-

pound was prepared similar to the procedure described for 25

starting from 3-(fluoroisobutyl)benzene: mp 139-141 °C. ¹H

NMR (CDCl₃): δ 0.94 (d, J ) 6 Hz, 6H), 1.80 (s, 3H), 1.92 (m,

1H), 2.13 (s, 3H), 2.51 (d, J ) 7 Hz, 2H), 6.50 (s, br, 1H), 6.93-

7.96 (m, 7H). ¹³C NMR (CDCl₃): δ 6.91, 11.15, 22.75, 30.39,

45.36, 108.09, 116.29, 116.60, 123.84, 124.82, 128.95, 129.67,

The following compounds were prepared similar to the

procedure described for 20a from 20 using the corresponding

aldehyde.

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5213

131.11, 133.42, 133.56, 135.44, 138.93, 145.48, 145.59, 154.59,

158.17, 161.80, 162.32. Anal. (C₂₁H₂₃FN₂O₃S) C, H, F, N, S.

in vacuo to provide 11.1 g (59%) of compound 22 as a colorless

liquid: bp 87-88 °C (10 mmHg). ¹H NMR (CDCl₃): δ 0.90

(d, J ) 6.5 Hz, 6H), 1.85 (m, 1H), 2.44 (d, J ) 7.0 Hz, 2H),

3.79 (s, 3H), 6.70-7.25 (m, 4H).

N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-m et h yl-4′-(2-m et h yl-

p r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (20k ). Suzuki cou-

pling between 4 and 2-methyl-4-isobutylphenylboronic acid

followed by deprotection of the MEM group using 6 N aqueous

hydrochloric acid provided 20k as a white solid: mp 90-92

°C. ¹H NMR (CDCl₃): δ 0.93 (d, J ) 6.5 Hz, 6H), 1.87 (s, 3H),

1.94 (m, 1H), 2.09 (s, 3H), 2.16 (s, 3H), 2.49 (d, J ) 7.6 Hz,

2H), 5.93 (br s, 1H), 7.05-7.98 (m, 7H). ¹³C NMR (CDCl₃): δ

6.71, 10.79, 20.38, 22.49, 30.09, 45.12, 108.10, 112.22, 125.89,

127.77, 128.80, 128.87, 130.79, 131.25, 132.38, 133.18, 135.20,

137.42, 138.14, 140.70, 142.43, 154.21, 161.95, 180.15. Anal.

(C₂₂H₂₆N₂O₃S‚0.55H₂O) C, H, N, S.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2′-(h yd r oxym eth yl)-4′-(2-

m eth ylp r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (20l). Depro-

tection of the MEM group in 30 using 6 N aqueous hydrochloric

acid provided 20l as a white solid: mp 60-67 °C. ¹H NMR

(CDCl₃): δ 0.94 (d, J ) 6 Hz, 6H), 1.86 (s, 3H), 1.92 (m, 1H),

2.14 (s, 3H), 2.51 (d, J ) 7 Hz, 2H), 4.35 (s, 2H), 7.10-7.90

(m, 7H). ¹³C NMR (CDCl₃): δ 6.62, 10.74, 22.37, 30.00, 45.06,

62.69, 108.01, 127.91, 128.11, 128.92, 129.38, 129.96, 132.64,

132.92, 134.80, 138.05, 138.39, 139.49, 142.60, 154.58, 161.92.

Anal. (C₂₂H₂₆N₂O₄S‚0.18H₂O) C, H, N, S.

4-Isobu tyl-2-m eth oxyp h en ylbor on ic Acid (23). To a

solution of 22 (4.0 g, 24.3 mmol) in 100 mL of ether under

argon at -78 °C was added TMEDA (11.0 mL, 73.0 mmol)

followed by tert-butyllithium (1.7 M solution in pentane, 43

mL) over 5 min. The mixture was warmed to room temperaure

and stirred for 5 h. The solution was cooled to -78 °C, and

trimethyl borate (7.59 g) was added in one portion. The

mixture was slowly warmed to room temperature, stirred

overnight, and cooled to 0 °C; 20% aqueous HCl (250 mL) was

added, and the mixture was stirred for 10 min. The solution

was extracted with ether (2 × 200 mL), and the combined ether

extracts were extracted with 1 M NaOH (3 × 100 mL). A white

precipitate was formed which was found to be the sodium salt

of 23. This was filtered and added to the aqueous NaOH

extracts. The aqueous extracts were acidified with dilute HCl

to pH 2 and extracted with 2 × 200 mL of ether. The combined

ether extracts were washed once with water (100 mL), dried,

and evaporated to afford 4.3 g of a white solid. Crystallization

from hexanes provided 2.13 g (42%) of pure 23 as a white solid

in two crops: mp 68-75 °C.

4′-(2-Meth ylp r op yl)-2′-m eth oxy-N-(3,4-d im eth yl-5-isox-

a zolyl)-N-(m et h oxyet h oxym et h yl)[1,1′-b ip h en yl]-2-su l-

fon a m id e (24). This compound was prepared from 4 and 23

using a Suzuki coupling procedure described for 19: yield 67%.

2′-[[(3,4-Dim et h yl-5-isoxa zolyl)a m in o]su lfon yl]-4′-(2-

m eth ylp r op yl)[1,1′-bip h en yl]-2-ca r boxylic Acid (20m ). To

a solution of 32 and sulfamic acid (48.5 mg, 0.5 mmol) in 2.5

mL of THF at -10 °C was added a solution of sodium chlorite

(45.2 mg, 0.5 mmol) in 2.5 mL H₂O and the mixture was stirred

for 5 min. The mixture was diluted with CH₂Cl₂, washed with

H₂O, dried, and concentrated. The residue was purified by

preparative HPLC on a reverse-phase 30 × 500-mm ODS S10

column (68% methanol, 32% water, 0.1% TFA) to afford 20m

(32 mg, 30%) as a white solid: mp >185 °C. ¹H NMR (1:1

CDCl₃/CD₃OD): δ 0.97 (d, J ) 6 Hz, 6H), 1.70 (s, 3H), 1.95 (m,

1H), 2.15 (s, 3H), 2.57 (d, J ) 7 Hz, 2H), 6.96-8.00 (m, 7H).

¹³C NMR (1:1 CDCl₃/CD₃OD): δ 5.47, 9.74, 21.51, 29.58, 44.32,

105.00, 126.96, 128.03, 129.50, 130.07, 130.25, 131.23, 131.92,

136.94, 137.34, 141.00, 141.29, 161.40, 168.64. Anal.

(C₂₂H₂₄N₂O₅S‚0.50H₂O) C, H, N, S.

2′-[[(3,4-Dim et h yl-5-isoxa zolyl)a m in o]su lfon yl]-4′-(2-

m eth ylp r op yl)[1,1′-bip h en yl]-2-ca r boxa m id e (20n ). Oxi-

dation of 31 using sulfamic acid and sodium chlorite as

described for 20m provided the 2′-carboxy derivative which

was converted into the corresponding acid chloride using oxalyl

chloride. Treatment of this material with 30% aqueous

ammonium hydroxide in THF followed by deprotection of the

MEM group using 6 N aqueous HCl provided 20n as a white

solid: mp 85-93 °C. ¹H NMR (CDCl₃): δ 0.95 (m, 6H), 1.87

(s, 3H), 1.90 (m, 1H), 2.17 (s, 3H), 2.53 (d, J ) 7 Hz, 2H), 6.26

(s, 2H), 7.24-8.70 (m, 8H). ¹³C NMR (CDCl₃): δ 6.35, 10.44,

21.98, 22.07, 29.62, 44.56, 107.15, 127.58, 128.04, 128.38,

130.11, 130.23, 131.59, 132.54, 134.12, 134.30, 137.56, 139.29,

141.85, 154.83, 161.55, 172.08. Anal. (C₂₂H₂₅N₃O₄S) C, H, N,

S.

3-Isobu tyla n isole (22). To a flask containing 200 mL of

ether at 0 °C under argon was added a solution of 2.0 M

butyllithium in pentane (56 mL). Isopropyltriphenylphospho-

nium iodide (48.2 g, 0.11 mol) was then added to the mixture

in portions over 15 min, and the mixture was warmed to room

temperature and stirred for 3 h. The solution was cooled to

-78 °C, and a solution of 3-methoxybenzaldehyde (15.5 g, 0.11

mol) in 100 mL of ether was added dropwise over 30 min. The

mixture was slowly warmed to room temperature and stirred

for 48 h. The mixture was filtered, and the solid cake was

washed with 200 mL of ether. The combined filtrate was

washed with 2 × 150 mL of water, dried, and evaporated. The

residual liquid was distilled in vacuo to provide 13.1 g of 3-(2-

methyl-1-propenyl)anisole as a colorless liquid: bp 95-97 °C

(10 mmHg). This compound was then dissolved in 200 mL of

ethyl acetate, and the solution was added to a suspension of

10% Pd/C (1 g) in 20 mL of ethyl acetate under argon. The

mixture was hydrogenated at 50 psi for 12 h and filtered. The

filtrate was evaporated, and the residual liquid was distilled

4′-(2-Meth ylp r op yl)-2′-m eth oxy-N-(3,4-d im eth yl-5-isox-

a zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (25). To a solution of

1.40 g (2.78 mmol) of 24 in 20 mL of 95% EtOH was added 20

mL of 6 N aqueous HCl and the mixture was refluxed for 3 h.

The mixture was concentrated to 20 mL, diluted with 50 mL

of water, and extracted with 3 × 50 mL of EtOAc. The

combined organic extracts were washed once with 100 mL of

brine, dried, and evaporated to provide a white foam (1.13 g).

Crystallization from hexanes/EtOAc afforded 1.03 g (89%) of

25 as a white crystalline solid: mp 143-144 °C. ¹H NMR

(CDCl₃): δ 0.95 (d, J ) 6.5 Hz, 6H), 1.86 (s, 3H), 1.93(m, 1H),

2.15 (s, 3H), 2.52 (d, J ) 7.0 Hz, 2H), 3.75 (s, 3H), 6.80 (s,

1H), 6.84 (d, J ) 7.6 Hz, 1H), 7.17 (d, J ) 7.6 Hz, 1H), 7.33 (d,

J ) 7.6 Hz, 1H), 7.40 (t, J ) 7.6 Hz, 1H), 7.58 (t, J ) 7.6 Hz,

1H), 7.83 (d, J ) 8.2 Hz, 1H). ¹³C NMR (CDCl₃): δ 6.59, 10.71,

22.37, 30.06, 45.47, 56.09, 107.26, 112.82, 121.55, 125.81,

127.80, 128.66, 130.19, 132.92, 133.01, 137.93, 138.31, 144.01,

154.87, 156.31. Anal. (C₂₂H₂₆N₂O₄S‚0.38H₂O) C, H, N, S.

4′-(2-Meth ylp r op yl)-2′-h yd r oxy-N-(3,4-d im eth yl-5-isox-

a zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (26). To a solution of

0.3 g (0.72 mmol) of 25 in 25 mL of dry CH₂Cl₂at -78 °C under

argon was added 1.1 mL of 1M BBr₃in CH₂Cl₂. The mixture

was stirred for 3 h, slowly warmed to room temperature, and

stirred overnight. The solution was diluted with 50 mL of CH₂-

Cl₂, washed with 2 × 100 mL of water, dried, and evaporated.

The residue was chromatographed on silica gel using 1%

MeOH/CH₂Cl₂to provide 0.18 g (62%) of 26 as a white foam.

Crystallization from hexanes/EtOAc afforded analytically pure

26 as colorless prisms: mp 175 °C. ¹H NMR (CDCl₃): δ 0.93

(d, J ) 6.5 Hz, 6H), 1.87 (s, 3H), 1.93(m, 1H), 2.14 (s, 3H),

2.46 (d, J ) 7.6 Hz, 2H), 6.71 (br s, 1H), 6.82 (s, 1H), 6.83 (d,

J ) 7.0 Hz, 1H), 7.22 (t, J ) 8.2, 9.4 Hz, 1H), 7.40 (d, J ) 7.0

Hz, 1H), 7.47 (t, J ) 7.6, 7.0 Hz, 1H), 7.65 (t, J ) 7.6, 6.5 Hz,

1H), 7.92 (d, J ) 7.0 Hz, 1H). ¹³C NMR (CDCl₃): δ 6.65, 10.80,

22.43, 29.95, 45.12, 108.45, 118.09, 121.95, 123.77, 128.55,

129.01, 130.50, 133.61, 136.67, 138.83, 144.73, 152.62, 154.29,

162.04. Anal. (C₂₁H₂₄N₂O₄S‚0.46H₂O) C, H, N, S

3-(2-Meth ylp r op yl)p h en ylm eth a n ol (28). To a solution

of isobutylene (4.4 g, 78 mmol) in 11 mL of tetrahydrofuran

at -78 °C was added 9-BBN (0.5 M in tetrahydrofuran, 157

mL, 78 mmol). The mixture was stirred at -78 °C for 3 h,

warmed to room temperature, and stirred overnight. In a

separate flask containing 3-bromobenzyl alcohol (13.3 g, 71.3

mmol) in 36 mL of tetrahydrofuran were added tetrakis-

(triphenylphosphine)palladium(0) (2.47 g, 2.14 mmol) and 60

mL of 3 M sodium hydroxide. The 9-isobutyl-BBN solution

5214 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Murugesan et al.

was transferred quickly into the flask under argon, and the

mixture was refluxed for 21 h. After cooling with an ice bath,

18 mL of 30% hydrogen peroxide was added slowly; the

mixture was stirred for 30 min, concentrated to about 100 mL,

and partitioned between water and ethyl acetate. The aqueous

phase was extracted with ethyl acetate. The combined organic

extracts were washed with brine, dried, and concentrated. The

residue was chromatographed on silica gel using 9:1 hexanes/

ethyl acetate to afford 28 (8.16 g, 70%) as a liquid.

1,3-Dih yd r o-1-h yd r oxy-5-(2-m et h ylp r op yl)-2,1-b en z-

oxa bor ole (29). 29 was prepared as a light-yellow solid from

28 as described for 23: mp 96-100 °C. ¹H NMR (DMSO-d₆):

δ 0.86 (d, J ) 6.4 Hz, 6H), 1.84 (m, 1H), 2.49 (d, J ) 7.0 Hz,

2H), 4.95 (s, 2H), 7.13 (s, 1H), 7.16 (d, J ) 8.2 Hz, 1H), 7.63

(d, J ) 7.6 Hz, 1H), 9.09 (br s, 1H).

N-(3,4-Dim et h yl-5-isoxa zolyl)-N-[(2-m et h oxyet h oxy)-

m et h yl]-2′-(h yd r oxym et h yl)-4′-(2-m et h ylp r op yl)[1,1′-b i-

p h en yl]-2-su lfon a m id e (30). 30 was prepared from 4 and

29 as described for 19. Chromatography on silica gel using

2.5:1 hexanes/ethyl acetate afforded 30 as a colorless gum. ¹H

NMR (CDCl₃): δ 0.95 (d, J ) 6.5 Hz, 6H), 1.93 (s, 3H), 1.93-

(m, 1H), 2.15 (s, 3H), 2.55 (d, J ) 7.1 Hz, 2H), 3.30 (s, 3H),

3.45 (m, 2H), 3.90 (m, 2H), 4.02 (d, J ) 11.7 Hz, 1H), 4.35 (m,

3H), 7.09-7.93 (m, 7H).

N-(3,4-Dim et h yl-5-isoxa zolyl)-N-[(2-m et h oxyet h oxy)-

m et h yl]-2′-for m yl-4′-(2-m et h ylp r op yl)[1,1′-b ip h en yl]-2-

su lfon a m id e (31). To oxalyl chloride (2 M in methylene

chloride, 9 mL, 18 mmol) in 26 mL of methylene chloride at

-78 °C was added a solution of dimethyl sulfoxide (2.8 g, 36

mmol) in 39 mL of methylene chloride. The solution was

stirred for 10 min, 30 (2.4 g, 4.8 mmol) in 40 mL of methylene

chloride was added, and the mixture was stirred at -78 °C

for 2 h. Triethylamine (6.1 g, 60 mmol) was added, and the

mixture was stirred at -78 °C for 5 min and warmed to room

temperature over 15 min. The mixture was partitioned

between 0.5 N HCl and methylene chloride, the aqueous phase

was extracted with methylene chloride, and the combined

organic extracts were dried and concentrated. The residue was

chromatographed on silica gel using 3.5:1 hexanes/ethyl

acetate to afford 31 (1.83 g, 77%) as a gum.

N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-for m yl-4′-(2-m et h yl-

p r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (32). 32 was pre-

pared from 31 as described for 25, using 6 N hydrochloric acid

and with refluxing for 1.5 h. Chromatography on silica gel

using 2.5:1 hexanes/ethyl acetate provided 32 as an amorphous

white solid: mp 60-66 °C. ¹H NMR (CDCl₃): δ 0.95 (d, J )

7.0 Hz, 6H), 1.82 (s, 3H), 1.99 (m, 1H), 2.14 (s, 3H), 2.59 (d, J

) 7.6 Hz, 2H), 7.26-8.03 (m, 7H), 9.68 (s, 1H). Anal.

(C₂₂H₂₄N₂O₄S‚0.28H₂O) C, H, N, S

N-(3,4-Dim et h yl-5-isoxa zolyl)-2′-(a m in om et h yl)-4′-(2-

m eth ylp r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (33). A mix-

ture of 32 (480 mg, 1.16 mmol), ammonium acetate (15.44 g,

232 mmol), and 3A molecular sieves in 60 mL of MeOH was

stirred overnight. Sodium triacetoxyborohydride (740 mg, 3.49

mmol) was added, and the mixture was stirred for 1 h,

concentrated to about 30 mL, diluted with 150 mL CH₂Cl₂,

and filtered. The filtrate was washed with 25 mL of H₂O,

dried, and concentrated. The residue was chromatographed

on silica gel using 100:6 CH₂Cl₂/MeOH to provide 33 (250 mg,

52%) as a white solid: mp >200 °C dec. ¹H NMR (DMSO-d₆):

δ 0.93 (d, J ) 6 Hz, 6H), 1.54 (s, 3H), 1.91 (m, 4H), 2.50 (m,

2H), 3.64 (m, 2H), 6.93-8.00 (m, 10H). ¹³C NMR (DMSO-d₆):

δ 6.51, 10.37, 22.17, 29.34, 44.26, 90.68, 127.45, 127.57, 127.77,

129.15, 129.53, 130.33, 130.59, 131.40, 136.64, 138.60, 140.01,

145.45, 159.10, 165.73. Anal. (C₂₂H₂₇N₃O₃S‚0.26H₂O) C, H,

N, S.

using 100:2.5 CH₂Cl₂/MeOH to afford 34 as a white solid: mp

78-83 °C. ¹H NMR (CDCl₃): δ 0.92 (m, 6H), 1.86 (m, 1H),

1.89 (s, 3H), 2.16 (s, 3H), 2.49 (d, J ) 7 Hz, 2H), 3.76-4.62

(m, 2H), 6.53-8.05 (m, 10H). ¹³C NMR (CDCl₃): δ 8.08, 12.23,

23.77, 23.85, 31.50, 41.19, 46.50, 109.75, 129.19, 129.45,

129.80, 130.61, 130.89, 134.12, 134.79, 136.29, 137.79, 139.29,

140.73, 144.45, 155.55, 162.71, 163.46. Anal. (C₂₃H₂₇N₃O₄S‚

0.36H₂O) C, H, N, S.

2-Br om oben zen esu lfon ic Acid , Isop r op yl Ester (36).

To a solution of 990 mg (16.5 mmol) of 2-propanol and 2.48 g

(31.4 mmol) of pyridine cooled to -5 °C was added in one

portion 4.00 g (15.7 mmol) of 2-bromobenzenesulfonyl chloride.

The mixture became homogeneous after several minutes, and

a precipitate formed. The mixture was stirred at 0 °C for 5 h

and partitioned between 20 mL of methylene chloride and 20

mL of 1 M aqueous HCl solution. The aqueous layer was

separated and extracted with an additional 20 mL of methyl-

ene chloride. The combined organic layers were washed with

two 15-mL portions of 1 M aqueous HCl solution, dried, and

concentrated in vacuo to give 4.10 g (14.7 mmol, 94%) of 36 as

a colorless oil which solidified upon cooling in a refrigerator.

4′-(2-Meth ylp r op yl)[1,1′-bip h en yl]-2-su lfon ic Acid , Iso-

p r op yl Ester (37). Suzuki coupling between 36 and 4-isobu-

tylbenzeneboronic acid as described for 19 provided 37 (22%)

as a pale-yellow oil.

3-Met h yl-4′-(2-m et h ylp r op yl)[1,1′-b ip h en yl]-2-su lfon -

ic Acid , Isop r op yl Ester (38). To a solution of 910 mg (2.74

mmol) of 37 in 4 mL of THF cooled to -78 °C was added

dropwise 2.0 mL (1.6 M in hexanes, 3.2 mmol) of n-butyl-

lithium over 5 min. The yellow anion solution was warmed

to -65 °C and stirred for 7 h, and 0.35 mL (5.6 mmol, filtered

through basic alumina) of iodomethane was added. The

mixture was stirred at -65 °C for 5 min and at 0 °C for 45

min. The resulting solution was quenched by addition of 25

mL of water and extracted with two 20-mL portions of ethyl

acetate. The organic extracts were combined, dried (magne-

sium sulfate), and concentrated in vacuo to a yellow oil. TLC

and HPLC analysis indicated the crude material was ∼1:1

starting material/product. The crude oil was purified by flash

chromatography (silica, 1:20 ethyl acetate/hexane) to afford

303 mg (0.88 mmol, 32%) of 38 as a colorless oil.

N-(3,4-Dim et h yl-5-isoxa zolyl)-3-m et h yl-4′-(2-m et h yl-

p r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (40). A mixture of

298 mg (0.86 mmol) of 38, 2.5 mL of methanol, 1 mL of THF,

and 2.5 mL of 1 M aqueous NaOH solution was stirred at room

temperature for 18 h. The mixture was heated to 60 °C for

20 h, cooled to room temperature, added to 25 mL of 6 N

aqueous HCl solution, and extracted with two 20-mL portions

of methylene chloride. The organic extracts were combined,

dried, and concentrated in vacuo to give a dark oil. The oil

was solubilized in 20 mL of methylene chloride, washed with

two 25-mL portions of 6 N aqueous HCl solution, dried, and

concentrated in vacuo to give 241 mg (0.79 mmol, 92%) of crude

sulfonic acid as a dark oil. To a solution of 235 mg (0.77 mmol)

of the sulfonic acid in 2 mL of anhydrous ether was added at

room temperature 31 mg (60% in oil, 0.77 mmol) of sodium

hydride dispersion. The mixture was stirred for 10 min and

concentrated in vacuo to give the sodium salt as a white solid.

To the crude sodium salt was added 482 mg (2.31 mmol) of

phosphorus pentachloride. The two solids were mixed with a

glass rod, and the mixture turned yellow-brown. After 10 min

the mixture was heated to 90° for 1 h during which time the

solids melted. The resulting mixture was cooled to room

temperature, quenched by the addition of 20 g of ice, and

extracted with two 15-mL portions of methylene chloride. The

organic extracts were combined, dried (sodium sulfate), and

concentrated in vacuo to give crude 39 as a brown-yellow oil.

The crude 39 was solubilized in 2 mL of pyridine, and 130 mg

(1.16 mmol) of 5-amino-3,4-dimethylisoxazole was added at

room temperature. The mixture was heated to 70 °C for 4 h,

cooled to room temperature, and concentrated in vacuo and

the residue partitioned between 20 mL of 3 N aqueous HCl

solution and 20 mL of ethyl acetate. The organic layer was

separated, dried, and concentrated in vacuo to give a dark oil.

N-(3,4-Dim eth yl-5-isoxa zolyl)-2′-(for m yla m in om eth yl)-

4′-(2-m eth ylp r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (34). To

a solution of 33 (48 mg, 0.12 mmol) in 0.5 mL of CH₂Cl₂was

added acetic formic anhydride (41 mg, 0.47 mmol) followed by

Et₃N (47 mg, 0.47 mmol). The mixture was stirred at room

temperature overnight, diluted with 30 mL of CH₂Cl₂, washed

with 5 mL of 0.2 N HCl and 0.5 mL H₂O, dried, and

concentrated. The residue was chromatographed on silica gel

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5215

The crude material was purified by flash chromatography

(silica, 1:3 ethyl acetate/hexane) to afford 25 mg (0.063 mmol,

8%) of 40 as an oil. ¹H NMR (CDCl₃): δ 0.92 (d, J ) 6.5 Hz,

6H), 1.78 (s, 3H), 1.93 (m, 1H), 2.13 (s, 3H), 2.51 (d, J ) 7.0

Hz, 2H), 2.66 (s, 3H), 7.18-7.41 (m, 7H). ¹³C NMR (CDCl₃):

δ 6.50, 10.74, 22.34, 23.12, 30.06, 45.06, 107.84, 128.83, 129.38,

130.94, 131.54, 132.43, 137.62, 138.77, 141.88, 142.02, 154.40,

161.72. MS (HR): calcd for C₂₂H₂₇O₃N₂S, 399.1728; found,

399.1742.

138.9, 142.1, 154.0, 157.7, 161.9. Anal. (C₂₈H₃₀N₂O₄S‚

0.17H₂O) C, H, N, S.

4-Hyd r oxy-4′-(2-m eth ylp r op yl)-N-(3,4-d im eth yl-5-isox-

a zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (40b). Treatment of

the corresponding 4-methoxy derivative (prepared using a

similar procedure described for 40a ) with boron tribromide in

methylene chloride as described for 26 provided a white foam

which was recrystallized from ethyl acetate/hexanes to afford

40b (86%) as white crystals: mp 159.5-160.0 °C. ¹H NMR

(CDCl₃): δ 0.94 (d, J ) 7 Hz, 6H), 1.73 (s, 3H), 1.85-1.95 (m,

1H), 2.13 (s, 3H), 2.51 (d, J ) 7 Hz, 2H), 7.03 (dd, J ) 8, 2 Hz,

1H), 7.13-7.17 (m, 3H), 7.27 (d, J ) 8 Hz, 2H), 7.49 (d, J ) 2

Hz, 1H). ¹³C NMR (CDCl₃): δ 6.4, 10.6, 22.4, 30.3, 45.3, 106.2,

115.6, 120.1, 128.5, 130.1, 132.5, 134.4, 136.5, 138.7, 141.3,

156.5, 162.0. Anal. (C₂₁H₂₄N₂O₄S‚0.62H₂O) C, H, N, S.

5-Meth oxy-4′-(2-m eth ylp r op yl)-N-(3,4-d im eth yl-5-isox-

a zolyl)[1,1′-b ip h en yl]-2-su lfon a m id e (40c). a . N-(3,4-

Dim e t h yl-5-isoxa zolyl)-2-b r om o-4-m e t h oxyb e n ze n e -

su lfon a m id e. To chlorosulfonic acid (10 mL) held at 0 °C was

added, dropwise, 3-bromoanisole (9.3 g, 50 mmol) at such a

rate that the internal temperature remained below 5 °C. After

stirring at 0 °C for 2 h, the reaction was added to ice. The

mixture was extracted with methylene chloride, and the

combined organic layers were dried and concentrated in vacuo.

The residue (756 mg), a colorless oil, was dissolved in dry

pyridine (5 mL) along with 3,4-dimethyl-5-isoxazolamine (386

mg, 3.44 mmol) and 4-(dimethylamino)pyridine (65 mg, 0.53

mmol). The mixture was heated at 70 °C for 2 h. The reaction

was then cooled to room temperature and poured into water.

The pH of the mixture was adjusted to 8 with saturated

aqueous sodium bicarbonate, and the mixture was extracted

with ether (2 × 50 mL). The aqueous layer was brought to

pH 2 with 6 N HCl and was extracted with ether (3 × 30 mL).

The extracts were combined, dried, and concentrated in vacuo

to provide a mixture of the title compound and the regiomeric

N-(3,4-dimethyl-5-isoxazolyl)-4-bromo-2-methoxy sulfonamide

as a tan foam. Chromatography (silica, methanol/chloroform)

provided pure N-(3,4-dimethyl-5-isoxazolyl)-2-bromo-4-meth-

oxybenzenesulfonamide (288 mg, 30%). ¹H NMR (CDCl₃): δ

1.82 (s, 3H), 2.13 (s, 3H), 3.85 (s, 3H), 6.85 (dd, J ) 9, 3 Hz,

1H), 7.24 (d, J ) 3 Hz, 1H), 7.89 (d, J ) 9 Hz, 1H).

b . N-(3,4-Dim et h yl-5-isoxa zolyl)-N-(m et h oxyet h oxy-

m eth yl)-2-br om o-4-m eth oxyben zen esu lfon a m id e. Treat-

ment of the preceding sulfonamide with sodium hydride in

THF followed by treatment with methoxyethoxymethyl chlo-

ride as described in 4 provided the title compound as an oil

(88%). ¹H NMR (CDCl₃): δ 1.93 (s, 3H), 2.16 (s, 3H), 3.38 (s,

3H), 3.56-3.59 (m, 2H), 3.85 (s, 3H), 3.90-3.93 (m, 2H), 5.29

(s, 2H), 6.82 (dd, J ) 9, 2 Hz, 1H), 7.24 (d, J ) 2 Hz, 1H), 7.86

(d, J ) 9 Hz, 1H).

c. 5-Met h oxy-4′-(2-m et h ylp r op yl)-N-(3,4-d im et h yl-5-

isoxa zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (40c). This com-

pound was prepared from the preceding sulfonamide and

4-isobutylphenylboronic acid using a Suzuki coupling proce-

dure described for 6a followed by deprotection of the MEM

group using 6 N aqueous hydrochloric acid to provide 40c as

a colorless foam (160 mg, 66%). ¹H NMR (CDCl₃, 270 MHz):

δ 7.88 (d, J ) 9 Hz, 1H), 7.46-7.49 (m, 2H), 7.26 (m, 1H),

7.24 (d, J ) 3 Hz, 1H), 6.85-6.90 (m, 2H), 5.73 (br s, 1H),

3.86 (s, 3H), 2.53 (d, J ) 7 Hz, 2H), 2.13 (s, 3H), 1.85-1.92

(m, 1H), 1.84 (s, 3H), 0.94 (d, J ) 7 Hz, 6H). ¹³C NMR

(CDCl₃): δ 162.7, 161.9, 154.4, 143.3, 142.2, 135.7, 131.2, 129.6,

128.8, 118.1, 112.5, 108.0, 55.7, 45.1, 30.1, 22.4, 10.8, 6.6.

Anal. (C₂₂H₂₆N₂O₄S‚0.11H₂O) C, H, N, S.

N-(3,4-Dim et h yl-5-isoxa zolyl)-4′-(2-m et h ylp r op yl)-4-

(p h en ylm eth oxy)[1,1′-bip h en yl]-2-su lfon a m id e (40a ). a .

Sod iu m 3-(P h en ylm eth oxy)ben zen esu lfon a te. A solution

of 3-hydroxybenzenesulfonic acid (10.0 g, 57.4 mmol) in water

(80 mL) was adjusted to pH 12 with 5 N aqueous NaOH.

Benzyl bromide (7.2 mL, 60 mmol) was added dropwise to the

vigorously stirred solution. After the mixture stirred for 18

h, ca. 50 mL of the water was removed in vacuo. The residue

was chilled to 4 °C, and then the precipitate was collected by

filtration, washed with ice water, and dried to provide a white

solid (11.2 g, 68%). ¹H NMR (CD₃OD): δ 5.11 (s, 2H), 7.04-

7.08 (m, 1H), 7.24-7.48 (m, 8H).

b. N-(3,4-Dim et h yl-5-isoxa zolyl)-2-b r om o-5-(p h en yl-

m eth oxy)ben zen esu lfon a m id e. A solution of bromine (2.24

g, 14.0 mmol) in water (60 mL) was added dropwise to a stirred

solution of sodium 3-(phenylmethoxy)benzenesulfonate (4.00

g, 14.0 mmol) in water (25 mL) and THF (15 mL) at 0 °C. After

the mixture stirred for 2 h, the pH of the reaction was brought

to 8.5 with 0.5 N aqueous sodium carbonate, excess bromine

was discharged with sodium bisulfite, and the reaction was

concentrated in vacuo to provide a solid. To this solid was

added phosphorus pentachloride (5.82 g, 27.9 mmol). An

exotherm ensued and the mixture liquified. After the exo-

therm subsided, the mixture heated at 50 °C for 1 h and cooled

to room temperature. The resultant paste was mixed with

crushed ice. After the ice had melted, the mixture diluted with

water (25 mL) and was extracted with ether (2 × 100 mL).

The combined organic layers were dried (Na₂SO₄) and con-

centrated in vacuo. The brownish solid (4 g) thus obtained

was dissolved in pyridine (10 mL). Isoxazole 2 (1.6 g, 14 mmol)

and DMAP (0.27 g, 2.2 mmol) were added. After 2 h at room

temperature the pyridine was removed in vacuo. The residue

was partitioned between ether (250 mL) and 0.5 N HCl (250

mL). The aqueous layer was extracted with ether (2 × 100

mL). The combined organic layers were washed with 0.5 N

HCl (2 × 50 mL). The acid washings and original acid layer

were combined, and the whole was extracted with methylene

chloride (2 × 100 mL). The methylene chloride and ether

extracts were dried and concentrated in vacuo. Chromatog-

raphy (silica, ethyl acetate/hexanes) provided 361 mg (7%) of

the product as a foam. ¹H NMR (CDCl₃): δ 1.89 (s, 3H), 2.16

(s, 3H), 5.04 (s, 2H), 7.03 (dd, J ) 9, 3 Hz, 1H), 7.38-7.40 (m,

5H), 7.61-7.65 (m, 2H).

c. N-(3,4-Dim eth yl-5-isoxazolyl)-N-((2-m eth oxyeth oxy)-

m e t h yl)-2-b r om o-5-(p h e n ylm e t h oxy)b e n ze n e su lfon -

a m id e. Treatment of the preceding sulfonamide with sodium

hydride in THF followed by treatment with methoxyethoxym-

ethyl chloride as described in 4 yielded 614 mg (79%) of the

title compound as a yellow oil. ¹H NMR (CDCl₃): δ 1.90 (s,

2H), 2.17 (s, 3H), 3.37 (s, 3H), 3.55-3.59 (m, 2H), 3.89-3.92

(m, 2H), 3.89-3.92 (m, 2H), 5.03 (s, 2H), 5.27 (s, 2H), 7.00 (dd,

J ) 9, 3 Hz, 1H), 7.35-7.39 (m, 5H), 7.58-7.63 (m, 2H).

d . N-(3,4-Dim eth yl-5-isoxa zolyl)-4′-(2-m eth ylp r op yl)-

4-(p h en ylm eth oxy)[1,1′-bip h en yl]-2-su lfon a m id e (40a ).

This compound was prepared from the preceding sulfonamide

and 4-isobutylphenylboronic acid using a Suzuki coupling

procedure described for 6a followed by deprotection of the

MEM group using 6 N aqueous hydrochloric acid to provide

40a as a white powder (52%): mp 96.0-101.0 °C. ¹H NMR

(CDCl₃): δ 0.93 (d, J ) 7 Hz, 6H), 1.80-1.95 (m, 1H), 1.83 (s,

3H), 2.13 (s, 3H), 2.52 (d, J ) 7 Hz, 2H), 5.09 (s, 2H), 5.77 (br

s, 1H), 7.15-7.48 (m, 11H), 7.59 (d, J ) 3 Hz, 1H). ¹³C NMR

(CDCl₃): δ 6.6, 10.8, 22.4, 30.1, 45.1, 70.5, 108.3, 114.5, 119.6,

127.6, 128.3, 128.7, 128.9, 130.2, 133.3, 133.9, 135.4, 136.0,

5-Am in o-4′-(2-m et h ylp r op yl)-N-(3,4-d im et h yl-5-isox-

a zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (40d ). a . 2-Br om o-

4-[(1-oxoeth yl)a m in o]-N-(3,4-d im eth yl-5-isoxa zolyl)ben -

zen esu lfon a m id e. To 3-bromo-1-(oxoethyl)aniline (6.2 g, 29

mmol) was added chlorosulfonic acid (20 mL). The solution

was heated at 57 °C for 3 h, an additional 10 mL of chloro-

sulfonic acid was added, and the solution was heated at 67 °C

for 6 h. The mixture was added dropwise to ice water, and

the heterogeneous mixture was extracted with ethyl acetate.

The organic extract was washed once with brine, dried, and

5216 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26

Murugesan et al.

evaporated to afford 6.9 g (82%) of the crude sulfonyl chloride

as a brown foamy gum. A solution of this material (6.9 g, 22

mmol) was treated with 3,4-dimethyl-5-isoxazolamine (2) (3.96

g, 35.3 mmol) and 4-(dimethylamino)pyridine (0.42 g, 3.5

mmol) as described in 40a , step b, to afford 3.72 g (43%) of

the product as a yellow foam.

b. 2-Br om o-4-[(1-oxoeth yl)a m in o]-N-(m eth oxyeth oxy-

m e t h yl)-N -(3,4-d im e t h yl-5-isoxa zolyl)b e n ze n e su lfon -

a m id e. Treatment of the preceding sulfonamide with sodium

hydride in THF followed by treatment with methoxyethoxym-

ethyl chloride as described in 4 yielded the product as a yellow

foamy gum.

c. 5-Am in o-4′-(2-m eth ylp r op yl)-N-(3,4-d im eth yl-5-isox-

a zolyl)[1,1′-b ip h en yl]-2-su lfon a m id e (40d ). This com-

pound was prepared from the preceding sulfonamide and

4-isobutylphenylboronic acid using a Suzuki coupling proce-

dure described for 6a followed by deprotection of the MEM

group using 6 N aqueous hydrochloric acid to provide 40d as

a white foamy solid: mp 69-79 °C. ¹H NMR (CDCl₃): δ 0.93

(d, J ) 6.4 Hz, 6H), 1.82 (s, 3H), 1.90 (m, 1H), 2.11 (s, 3H),

2.52 (d, J ) 7 Hz, 2H), 4.20 (br s, 2H), 5.82 (s, 1H), 6.53 (m,

2H), 7.20 (d, J ) 8.2 Hz, 2H), 7.43 (d, J ) 7.6 Hz, 2H), 7.70 (d,

J ) 8.2 Hz, 1H). ¹³C NMR (CDCl₃): δ 6.59, 10.74, 22.37, 30.06,

45.09, 107.14, 112.25, 117.83, 126.21, 128.60, 129.47, 131.22,

136.06, 141.88, 143.18, 150.55, 154.69, 161.78. Anal.

(C₂₁H₂₅N₃O₃S‚0.16H₂O) C, H, N, S.

5-Acetam ido-4′-(2-m eth ylpr opyl)-N-(3,4-dim eth yl-5-isox-

a zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (40e). Acetylation of

40d provided 40e as a tan solid: mp 150-154 °C. ¹H NMR

(CDCl₃): δ 0.93 (d, J ) 6.8 Hz, 6H), 1.85 (s, 3H), 1.94 (m, 1H),

2.11 (s, 3H), 2.17 (s, 3H), 2.51 (d, J ) 6.8 Hz, 2H), 5.70 (s,

1H), 5.82 (s, 1H), 7.30 (s, 1H), 7.20 (d, J ) 8.2 Hz, 2H), 7.42

(d, J ) 7.7 Hz, 2H), 7.57 (m, 1H), 7.64 (m, 1H), 7.87 (d, J )

8.6 Hz, 1H). ¹³C NMR (CDCl₃): δ 6.54, 10.69, 22.33, 25.0,

30.04, 45.04, 117.37, 122.62, 128.45, 128.61, 128.69, 129.49,

130.13, 131.82, 131.96, 135.35, 142.13, 142.18, 155.0, 162.5.

Anal. (C₂₃H₂₇N₃O₄S‚0.95H₂O) C, H, N, S.

starting material remained. The mixture was cooled to room

temperature, brought to pH 7, concentrated in vacuo to ca. 20

mL, and cooled to 0 °C. The precipitate was collected by

filtration, washed with ice water, and dried in vacuo to provide

sodium 3-methoxybenzenesulfonate as an off-white solid (9.50

g, 79%). To this compound was added, portionwise, phospho-

rus pentachloride (18.9 g, 90.4 mmol). The reaction was

exothermic and the mixture liquified. The mixture was stirred

at room temperature for 2 h, poured onto crushed ice (200 g),

diluted with water (200 mL), and extracted with ether (3 ×

150 mL). The combined ether layers were washed with cold

water (8 × 50 mL), dried, and concentrated in vacuo to an oil

(7.00 g, 75%). This oil was dissolved in chloroform (50 mL)

and was added dropwise to a solution of tert-butylamine (10.0

mL, 95.2 mmol) in chloroform (50 mL) at 0 °C. The mixture

was stirred for 22 h and was filtered through Celite. The pad

was rinsed with chloroform (2 × 10 mL), the combined filtrates

were concentrated, and the residue was purified on a silica

column using hexanes/EtOAc to afford 7.00 g (85%) of 42 as

white crystals. ¹H NMR (CDCl₃): δ 1.23 (s, 9H), 3.85 (s, 3H),

4.96 (br s, 1H), 6.61-6.65 (m, 1H), 6.84 (t, J ) 8 Hz, 1H), 7.49-

7.53 (m, 1H), 7.58 (t, J ) 2 Hz, 1H). ¹³C NMR (CDCl₃): δ

30.1, 54.7, 55.6, 111.6, 118.5, 119.1, 129.9, 144.6, 159.7.

2-Br om o-N -(1,1-d im e t h yle t h yl)-3-m e t h oxyb e n ze n e -

su lfon a m id e (43). To a suspension of 42 (7.00 g, 28.8 mmol)

in ether (100 mL) at 0 °C was added dropwise n-butyllithium

(2.5 M in hexanes, 24 mL) so as to keep the internal

temperature below 6 °C. The mixture was stirred for 1 h at

which time the mixture was homogeneous. 1,2-Dibromo-

1,1,2,2-tetraflouroethane (4.13 mL, 34.6 mmol) was added

dropwise over a 15-min period. The mixture was stirred at 0

°C for 2 h and was quenched by the addition of 1 N HCl (75

mL). The mixture was diluted with methylene chloride (200

mL) and water (100 mL). The organic phase was washed with

water (100 mL), dried, and concentrated in vacuo. The residue

was crystallized from ether to provide 2.39 g (80%) of 43. ¹H

NMR (CDCl₃): δ 1.02 (s, 9H), 3.12 (s, 3H), 6.23 (dd, J ) 8, 1

Hz, 1H), 6.79 (t, J ) 8 Hz, 1H), 7.90 (dd, J ) 8, 1 Hz, 1H). ¹³C

NMR (CDCl₃): δ 29.6, 54.7, 56.7, 105.7, 115.0, 122.2, 128.3,

143.6, 156.7.

5-Ben za m id o-4′-(2-m et h ylp r op yl)-N-(3,4-d im et h yl-5-

isoxa zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (40f). Benzoy-

lation of 40d using benzoyl chloride and triethylamine in THF

provided 40e as a tan solid: mp 207-211 °C. ¹H NMR

(DMSO-d₆): δ 0.91 (d, J ) 6.6 Hz, 6H), 1.60 (s, 3H), 1.90 (m,

1H), 2.08 (s, 3H), 2.50 (d, J ) 6.8 Hz, 2H), 7.15-8.0 (m, 12H).

¹³C NMR (DMSO-d₆): δ 6.36, 10.65, 22.57, 29.99, 44.70, 118.57,

123.73, 128.12, 128.34, 128.46, 128.85, 129.00, 130.36, 132.42,

134.57, 135.93, 137.00, 143.04, 162.18, 165.98. Anal.

(C₂₈H₂₉N₃O₄S‚1.15H₂O) C, H, N, S.

N-(1,1-Dim eth yleth yl)-4′-(2-m eth ylp r op yl)-6-m eth oxy-

[1,1′-bip h en yl]-2-su lfon a m id e (44). Suzuki coupling be-

tween 43 and 4-isobutylbenzeneboronic acid as described for

19 provided 44 (74%). ¹H NMR (CDCl₃): δ 0.93 (d, J ) 7 Hz,

6H), 1.04 (s, 9H), 1.84-1.99 (m, 1H), 2.53 (d, J ) 8 Hz, 2H),

3.31 (br s, 1H), 3.74 (s, 3H), 7.13-7.49 (m, 6H), 7.79 (m, 1H).

4′-(2-Meth ylp r op yl)-6-m eth oxy[1,1′-bip h en yl]-2-su lfon -

ic Acid , Sod iu m Sa lt (45). Compound 44 (2.07 g, 5.51 mmol)

was dissolved in TFA (15 mL). The mixture was allowed to

stand at room temperature for 2 h, concentrated in vacuo, and

chromatographed (flash, silica, 80% methylene chloride/hex-

anes) to provide 4′-(2-methylpropyl)-6-methoxy[1,1′-biphenyl]-

2-sulfonamide (1.56 g, 89%). A solution of NO₂in carbon

tetrachloride (6.8 M, 2.2 mL) was diluted with additional

carbon tetrachloride (3 mL), and this solution was added

dropwise to a solution at -20 °C of the sulfonamide (1.55 g,

4.85 mmol) in acetonitrile over a 20-min period. The mixture

was allowed to stir for 30 min, and most of the solvent was

removed in vacuo. The brown residue was partitioned between

2 N NaOH (10 mL) and ether (25 mL). The aqueous layer

was brought to pH 2 with 1 N HCl and was loaded onto a 10-g

acetonitrile-activated, water-equilibrated Waters t-C18 SepPak

cartridge. The cartridge was eluted with water (20 mL) and

then with acetonitrile (20 mL). The acetonitrile eluent was

concentrated in vacuo to provide 1.55 g (93%) of 45 as a solid.

¹H NMR (CD₃OD): δ 0.95 (d, J ) 8 Hz, 6H), 1.83-1.98 (m,

1H), 2.48 (d, J ) 8 Hz, 2H), 3.65 (s, 3H), 7.01-7.30 (m, 5H),

7.31-7.39 (m, 1H), 7.68-7.84 (m, 1H). ¹³C NMR (CD₃OD) δ

23.0, 31.4, 46.5, 56.6, 114.4, 121.0, 128.7, 131.2, 131.5, 134.9,

140.8, 145.7, 159.3.

5-[(Ca r boxym eth yl)a m in o]-4′-(2-m eth ylp r op yl)-N-(3,4-

d im e t h yl-5-isoxa zolyl)[1,1′-b ip h e n yl]-2-su lfon a m id e

(40g): mp 73-78 °C; prepared similar to the procedure

described for 20a from 40d and glyoxylic acid. ¹H NMR

(CDCl₃): δ 0.95 (d, J ) 6.6 Hz, 6H), 1.84 (s, 3H), 1.90 (m, 1H),

2.14 (s, 3H), 2.54 (d, J ) 7.2 Hz, 2H), 6.40 (m, 2H), 7.20 (d, J

) 8.1 Hz, 2H), 7.48 (d, J ) 8.1 Hz, 2H), 7.74 (d, J ) 8.7 Hz,

1H). Anal. (C₂₃H₂₇N₃O₅S‚0.4C₆H₁₄‚0.6AcOH‚0.2CHCl₃) C, H,

N.

5-[(Am in oa cetyl)a m in o]-4′-(2-m eth ylp r op yl)-N-(3,4-d i-

m eth yl-5-isoxa zolyl)[1,1′-bip h en yl]-2-su lfon a m id e (40h ).

This compound was prepared from 40d by treatment with the

acid chloride of BOC-glycine in the presence of triethylamine

followed by deprotection of the BOC group using 10% concen-

trated HCl in formic acid: mp 135-138 °C. ¹H NMR (CD₃-

OD): δ 0.93 (d, J ) 6.6 Hz, 6H), 1.67 (s, 3H), 1.85 (m, 1H),

2.10 (s, 3H), 2.53 (d, J ) 6.8 Hz, 2H), 3.87 (s, 2H), 7.13-8.06

(m, 7H). Anal. (C₂₃H₂₈N₄O₄S‚1.45H₂O‚1.5CF₃COOH) C, H,

N, S.

N -(1,1-D im e t h y le t h y l)-3-m e t h o x y b e n ze n e s u lfo n -

a m id e (42). 3-Hydroxybenzenesulfonic acid (10.0 g, 57.4

mmol) was dissolved in water (20 mL) and brought to pH 14

with 5 N sodium hydroxide solution. The mixture was cooled

to 0 °C, and dimethyl sulfate (2.9 mL, 30.1 mmol) was added

dropwise over a 5-min period. The mixture was brought to

room temperature and heated to 85 °C. Additional dimethyl

sulfate was added in 2.9-mL portions every 2 h until no

N-(3,4-Dim eth yl-5-isoxa zolyl)-6-m eth oxy-4′-(2-m eth yl-

p r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (46). Compound 45

(1.63 g, 4.76 mmol) was mixed with phosphorus pentachloride

(1.98 g, 9,52 mmol). Once the exotherm had subsided, the

Biphenylsulfonamide Endothelin Antagonists

J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 26 5217

reaction was placed in a 50 °C bath for 2 h. The mixture was

cooled to room temperature and diluted with ice (10 g). After

the ice had melted, the water was decanted from the organic

gum. The gum was further rinsed with water (10 mL) and

was dissolved in ether (75 mL). The organic layer was washed

with water (6 × 10 mL), and was dried (Na₂SO₄), and

concentrated in vacuo. The brown residue was extracted with

hot hexanes, and the combined hexanes extracts were con-

centrated in vacuo to provide 1.34 g of 4′-(2-methylpropyl)-6-

methoxy-[1,1′-biphenyl]-2-sulfonyl chloride. 3,4-Dimethyl-5-

isoxazolamine (413 mg, 3.68 mmol) and DMAP (75 mg, 0.61

mmol) were sequentially added to a solution of the above

compound (1.04 g, 3.07 mmol) in pyridine (8 mL). The mixture

was heated at 80 °C for 2 h, cooled, and poured into 0.5 N

Na₂CO₃(150 mL). The mixture was extracted with ether (50

mL). A precipitate formed which was collected by filtration.

The aqueous layer of the biphasic filtrate was washed with

ether (2 × 50 mL). The combined organic layers were washed

with 0.5 N Na₂CO₃(2 × 15 mL) and discarded. The combined

aqueous layers were brought to pH 2 with HCl and were

extracted with ether (2 × 50 mL). The precipitate was

dissolved in methanol (5 mL), and the solution was poured

into 0.01 N HCl (100 mL). The pH was adjusted to 2, and the

mixture was extracted with ether (3 × 50 mL). The ether

extracts were dried and concentrated in vacuo, and the residue

was chromatographed (silica, 25% ethyl acetate/hexanes) to

provide 46 as a white solid (648 mg, 51%). Recrystallization

from ethanol/water (2:1) provided colorless crystals: mp

175.5-176.0 °C. ¹H NMR (CDCl₃): δ 0.96 (d, J ) 7 Hz, 6H),

1.70 (s, 3H), 1.89-1.94 (m, 1H), 2.14 (s, 3H), 2.50 (d, J ) 7

Hz, 2H), 3.71 (s, 3H), 7.01-7.12 (m, 4H), 7.28 (d, J ) 8 Hz,

1H), 7.49 (t, J ) 8 Hz, 1H), 7.66-7.70 (m, 1H). ¹³C NMR

(CDCl₃): δ 6.6, 10.7, 22.8, 31.1, 46.1, 56.7, 106.4, 116.7, 121.5,

128.9, 129.6, 130.9, 131.6, 132.4, 141.0, 141.7, 154.5, 159.4,

162.9. Anal. (C₂₂H₂₆N₂O₄S) C, H, N, S.

0.24 mmol) was added. The mixture was stirred for 1 h at

room temperature and diluted with ether (40 mL), and the

mixture was washed with water (5 × 10 mL), dried, and

concentrated. The resultant oil (120 mg) was triturated with

hexanes (1 mL) to provide 48 as a solid. ¹H NMR (CDCl₃): δ

0.94 (d, J ) 6 Hz, 6H), 1.22 (t, J ) 7 Hz, 3H), 1.90 (s and m,

3H and 1H), 2.14 (s, 3H), 2.54 (d, J ) 7 Hz, 2H), 3.31 (s, 3H),

3.42-3.46 (m, 2H), 3.63-3.66 (m, 2H), 4.04 (s, 2H), 4.17 (q, J

) 7 Hz, 2H), 4.49 (s, 2H), 7.07 (dd, J ) 8, 1 Hz, 1H), 7.21-

7.38 (m, 4H), 7.32 (t, J ) 8 Hz, 1H), 7.62 (dd, J ) 8, 1 Hz,

1H).

[[6-[[(3,4-Dim eth yl-5-isoxa zolyl)a m in o]su lfon yl]-4′-(2-

m eth ylp r op yl)[1,1′-bip h en yl]-2-yl]oxy]a cetic Acid , Dil-

ith iu m Sa lt (49). Deprotection of the MEM group was

accomplished by treatment of 48 with 6 N aqueous HCl in

EtOH as described for 25. The ester group was then hydro-

lyzed using aqueous 2 N KOH in methanol at 70 °C for 4 h.

The crude product thus obtained was dissolved in aqueous

LiOH, and chromatography of this mixture on HP-20 (gradient

elution of water to acetone) provided 49: mp >250 °C. ¹H

NMR (CD₃OD): δ 0.94 (d, J ) 6 Hz, 6H), 1.59 (s, 3H), 1.85-

1.97 (m, 1H), 1.99 (s, 3H), 2.48 (d, J ) 7 Hz, 2H), 4.17 (s, 2H),

7.01-7.05 (m, 3H), 7.16-7.19 (m, 2H), 7.28 (t, J ) 8 Hz, 1H),

7.79 (dd, J ) 8, 1 Hz, 1H). ¹³C NMR (CD₃OD): δ 6.8, 10.7,

23.0, 31.5, 46.7, 70.6, 93.6, 117.6, 122.6, 128.3, 128.6, 131.7,

132.0, 134.6, 140.7, 146.6, 159.2, 161.7, 167.4, 176.9. Anal.

(C₂₃H₂₄Li₂N₂O₆S‚3.8H₂O) C, H, N.

N-(3,4-Dim eth yl-5-isoxa zolyl)-6-(2-h yd r oxyeth oxy)-4′-

(2-m eth ylp r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (50). To

a mixture of 48 (57 mg, 0.099 mmol) and lithium borohydride

(4.3 mg, 0.20 mmol) in ether (2 mL) was added methanol (0.01

mL). After 2 h, the mixture was diluted with ether (20 mL),

washed with water (2 × 5 mL), dried, and concentrated to

afford an oil. The oil was dissolved in ethanol (1.5 mL), and

concentrated HCl (0.50 mL) was added. The mixture was

heated at 70 °C for 38 h. The cooled mixture was diluted with

ether (30 mL), washed with water (4 × 10 mL), dried, and

concentrated to an oil. Chromatography (silica, ether) pro-

vided an oil which was triturated with hexanes to provide 50

as a white solid: mp 94.0-95.5 °C. ¹H NMR (CDCl₃): δ 0.93

(d, J ) 7 Hz, 6H), 1.45 (t, J ) 7 Hz, 1H), 1.87-1.95 (m, 1H),

1.87 (s, 3H), 2.15 (s, 3H), 2.54 (d, J ) 7 Hz, 2H), 3.66-3.71

(m, 2H), 4.00-4.04 (m, 2H), 5.71 (br s, 1H), 7.20-7.65 (m, 7H).

¹³C NMR (CDCl₃): δ 6.7, 10.8, 22.4, 30.1, 45.2, 61.0, 70.9, 108.5,

118.4, 121.4, 128.8, 129.0, 130.5, 130.7, 139.6, 142.3, 154.1,

157.2, 161.9. Anal. (C₂₃H₂₈N₂O₅S) C, H, N.

N-(3,4-Dim eth yl-5-isoxa zolyl)-6-h yd r oxy-4′-(2-m eth yl-

p r op yl)[1,1′-bip h en yl]-2-su lfon a m id e (47). To a solution

at -78 °C of 46 (608 mg, 1.47 mmol) in methylene chloride

(15 mL) was added boron tribromide (1 M in methylene

chloride, 11.8 mL). The solution was allowed to come to room

temperature and was stirred for 17 h. The mixture was poured

onto crushed ice (100 g). The organic layer was separated,

and the aqueous layer was extracted with methylene chloride

(3 × 50 mL). The combined organic layers were washed with

water (100 mL), dried (MgSO₄), and concentrated in vacuo.

Chromatography (flash, silica, 3% then 6% ethyl acetate/

methylene chloride) provided a white solid which was recrys-

tallized from toluene to provide 47 as a white powder (445 mg,

76%): mp 136.7-137.0 °C. ¹H NMR (CDCl₃): δ 0.95 (d, J )

7 Hz, 6H), 1.86 (s, 3H), 1.87-2.14 (m, 1H), 2.15 (s, 3H), 2.55

(d, J ) 7 Hz, 2H), 7.23 (dd, J ) 8, 1 Hz, 1H), 7.34 (t, J ) 8 Hz,

1H), 7.31-7.47 (m, 4H), 7.55 (dd, J ) 8, 1 Hz, 1H). ¹³C NMR

(CDCl₃): δ 6.7, 10.8, 22.4, 30.0, 45.2, 108.4, 120.9, 121.0, 125.9,

128.2, 129.0, 130.3, 131.1, 138.7, 143.7, 154.0, 154.5, 162.0.

Anal. (C₂₁H₂₄N₂O₄S‚0.28H₂O) C, H, N, S.

[[6-[((3,4-Dim et h yl-5-isoxa zolyl)((2-m et h oxyet h oxy)-

m e t h y l)a m in o )s u lfo n y l]-4′-(2-m e t h y lp r o p y l)[1,1′-b i-

p h en yl]-2-yl]oxy]a cetic Acid , Eth yl Ester (48). To a

stirred suspension at 0 °C of sodium hydride (16.5 mg of 80%

oil dispersion, 0.55 mmol) in THF (3 mL) was added, dropwise,

a solution of 47 (200 mg, 0.500 mmol) in THF (1 mL). After

20 min, MEM-Cl (0.060 mL, 0.525 mmol) was added. The

mixture was allowed to come to room temperature, and after

6 h the reaction was poured into water (25 mL). The mixture

was brought to pH 2 with 1 N HCl and was extracted with

ether (2 × 30 mL). The combined organic layers were dried

and concentrated. The resultant oil was chromatographed

(silica, 30% ethyl acetate/hexanes) to provide N-(3,4-dimethyl-

5-isoxazolyl)-N-((2-methoxyethoxy)methyl)-6-hydroxy-4′-(2-me-

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J M970872K

Article Doi

Biphenylsulfonamide endothelin antagonists: Structure-activity relationships of a series of mono- and disubstituted analogues and pharmacology of the orally active endothelin antagonist 2'-amino-N-(3,4- dimethyl-5-isoxazolyl)-4'-(2-methylpropyl)[1,1'-biphenyl]-2-sulfonamide (BMS- 187308)

DOI: 10.1021/jm970872k

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