Synthesis and evaluation of potent and selective β3 adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres

J . Med. Chem. 2002, 45, 567-583

567

Articles

Syn th esis a n d Eva lu a tion of P oten t a n d Selective â₃Ad r en er gic Recep tor

Agon ists Con ta in in g Acylsu lfon a m id e, Su lfon ylsu lfon a m id e, a n d Su lfon ylu r ea

Ca r boxylic Acid Isoster es^†

David E. Uehling,*^,‡Kelly H. Donaldson,^‡David N. Deaton,^‡Clifton E. Hyman,^‡Elizabeth E. Sugg,^‡

David G. Barrett,^‡Robert G. Hughes,^‡Barbara Reitter,^‡Kim K. Adkison,^§Mary E. Lancaster,^|Frank Lee,^§

Robert Hart,^§Mark A. Paulik,^|Bryan W. Sherman, Timothy True, and Conrad Cowan

Departments of Medicinal Chemistry, Receptor Biology, Research Bioanalysis and Drug Metabolism, and Pharmacology,

GlaxoSmithKline, Research Triangle Park, North Carolina 27709

Received April 2, 2001

Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of

functionally potent and selective â₃adrenergic receptor (AR) agonists containing acylsulfon-

amide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series.

In â₃, â₂, and â₁AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate

analogues were found to be full agonists that were modestly selective against â₁or â₂ARs,

while analogues lacking RHS acid functionality were active at â₃AR but not selective.

Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only

modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with

phenyl or p-toluene afforded compounds with good potency and functional selectivity (â₃AR

pEC₅₀greater than 8; â₁and â₂AR selectivity greater than 40- and 500-fold, respectively).

Our SAR studies suggest that the potency and selectivity profile of the best analogues reported

here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although

all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and

44 did show moderately low clearance in dogs. These two compounds were further evaluated

by thermographic imaging in mice and were found to produce a robust thermogenic response

via oral administration.

In tr od u ction

triggered considerable activity at a number of pharma-

ceutical companies in the search for new antidiabetic

and antiobesity drugs.⁴Before the cloned human recep-

tor became available, early efforts focused on optimiza-

tion using rodent models and led to the identification

of clinical candidates such as 1⁵and 2.⁶Unfortunately,

although some indication of efficacy was seen in clinical

studies with these “first generation” development can-

didates, these and other early â₃AR agonists have not

advanced beyond phase II clinical trials because of lack

of efficacy, poor pharmacokinetics, or dose-limiting

cardiovascular side effects.^7,8

The increasing prevalence of obesity and its associ-

ated comorbidities in industrialized nations, including

type 2 diabetes mellitus and related cardiovascular

disorders, has stimulated efforts to develop effective new

approaches in the treatment of this condition. While

most therapeutic approaches involve altering the bal-

ance of metabolic energy by reducing energy intake, an

alternative approach for the management of obesity is

to effect an increase in the rate of energy expenditure

(thermogenesis).¹In 1984, compounds of the phen-

ethanolamine class having thermogenic properties in

rodents were first disclosed as potential agents in the

treatment of human obesity.²Despite their structural

similarity to known â₁and â₂adrenoceptor (AR) ligands,

pharmacological studies indicated that these compounds

stimulate a third, or “atypical”, â AR that is now

described as “â₃” AR.³Although this receptor was not

characterized for several years, the striking rodent

pharmacology of early phenethanolamine compounds

Despite the failure of early â₃agonists as viable

therapeutic agents, in the past 12 years additional

evidence has accumulated to suggest that â₃AR stimu-

lation may have potential benefit in the treatment of

diabetes and obesity. In 1989, the human,⁹rat,¹⁰and

mouse¹¹â₃ARs were first cloned and characterized.

Evaluation of the activity of numerous compounds on

the cloned rodent and human receptors uncovered

significant interspecies differences in their activities at

the three â AR subtypes.¹²These differences may, in

part, explain the poor efficacy and/or side effect profile

of early clinical candidates.⁷Adding support to the

validity of the â₃AR as an important therapeutic target,

rodent studies have suggested a “reawakening” of

^†Dedicated to the memory of our colleague Barbara Reitter.

* To whom correpsondence should be addressed. Phone: 919-483-

6244. Fax: 919-483-6053. E-mail: deu8774@gsk.com.

^‡Department of Medicinal Chemistry.

^§Department of Research Bioanalysis and Drug Metabolism.

^|Department of Pharmacology.

Department of Receptor Biology.

Published on Web 12/29/2001

568 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Uehling et al.

Ch a r t 1. Phenethanolamine â₃Agonists

dormant â₃AR responsive brown adipose tissue upon

prolonged stimulation with 2.¹³Recent studies in non-

human primates treated with a selective â₃AR agonist

have demonstrated a separation in the dose response

between metabolic rate and cardiovascular response,

along with upregulation of uncoupling protein in axil-

lary fat indicative of increased thermogenic potential.¹⁴

In terms of human validation, â₃ARs have been

detected in human tissues of possible relevance to the

treatment of type 2 diabetes and obesity, including fat

and skeletal muscle.^15,16In human clinical studies,

significant increases in resting metabolic rate were seen

using isoproterenol or 1 that were in part resistant to

the â₁AR and â₂AR blocking effects of nadolol, implying

that â₃AR agonism plays a role in mediating human

energy expenditure.⁷In other studies, compound 2,

reported to have minimal â₁AR and â₂AR activity,^6,12

caused increased insulin sensitivity and glucose utiliza-

tion in lean, healthy volunteers.⁸Finally, it has been

proposed that a Trp64Arg â₃AR mutation in the human

population plays a role in the development of diabetes

and/or obesity in some individuals possessing this

genetic variant.¹⁷

In the past decade, drug discovery efforts have shifted

toward use of cell lines expressing human receptors in

primary screening assays in order to identify potent â₃

AR agonists that are selective over human â₂and â₁

ARs. Several structure-activity relationship (SAR)

studies have now been published that describe com-

pounds characterized in human â₃, â₂, and â₁AR

expressing cell lines. With the exception of two articles

reporting tetrahydroisoquinoline â₃AR agonists,^18a,b

these papers have described compounds in either the

arylethanolamine or aryloxypropanolamine class. Among

these analogues, a great deal of structural diversity has

appeared in the right-hand side (RHS) portion of these

analogues distal to the arylethanolamine or aryloxy-

propanolamine pharmacophore, suggesting a permissive

interaction with the receptor in this portion of the

molecule.¹⁹For example, in a series of papers by workers

at Merck, phenylsulfonamides bearing a variety of RHS

phenyl ring substituents have been described. A repre-

sentative example of this series is the thiazole phenyl-

sulfonamide 4 that has been described as a phase I

clinical candidate.²⁰In another article, a laboratory at

Bristol-Myers Squibb (BMS) has reported the SAR of

phenethanolamines related to 1 with modified RHS

ether substituents. Consistent with earlier SAR studies

in rodent systems,^3,21the BMS work highlighted an

important role of carboxylate and other negatively

charged groups (such as sulfonic acid 5) in providing â₁

and â₂AR selectivity within certain phenethanolamine

analogues^22a(see Chart 1 for structures of some â₃

agonists). Also consistent with these results, a recent

paper has described the use of thiazolidinediones as acid

isostere replacements in both arylethanolamine and

aryloxypropanolamine â₃AR agonists.^22b

weight, and desirable physical properties of 3a moti-

vated us to further optimize this attractive lead. Herein,

we describe SAR studies in which we have varied the

size, position, and acidity of the phenyl RHS substituent

of 3a .²⁴These studies have led to the discovery of a

series of acyl- and sulfonylsulfonamides with very high

potency and promising selectivity. In addition to in vitro

SAR studies, we also describe the evaluation of certain

compounds in this series in intravenous dog pharmaco-

kinetic studies and rodent thermogenesis assays.

Ch em istr y

The general synthetic route to â₃AR agonist targets

is shown in Scheme 1. Reductive amination of aldehyde

10²³with either aniline itself or aniline intermediates

11-19 afforded the corresponding Boc amine silyl ether

intermediates 20-34. Removal of the Boc amine and

silyl ether functionalities under acidic conditions pro-

vided the corresponding phenethanolamine hydro-

chlorides. In the case of amide or sulfonamide isosteric

targets 35-49, chromatography eluting with chloroform-

methanol containing ammonium hydroxide supplied

final targets 35-49 as the free base. For the syntheses

of targets 35 and 36, deprotection of the Boc amine silyl

ether using 4 N HCl in dioxane provided the corre-

sponding methyl ester amine hydrochloride, which was

then converted into the acid target under basic saponi-

fication conditions. The syntheses of carboxylic acid

targets 3a and 3b have been previously described.²³

The synthesis of aldehyde 10 was carried out accord-

ing to the previously disclosed route²³starting from (R)-

In 1995, a Glaxo patent disclosed a series of phen-

ethanolamines containing an anilinophenylacetic acid

RHS subunit, as exemplified by GR9803 (3a ).²³Al-

though it is a potent (<20 nM) agonist at human â₃, 3a

was found to have appreciable activity against human

â₁and â₂ARs and was not progressed into the clinic.

Nevertheless, the â₃activity, relatively low molecular

â₃Adrenergic Receptor Agonists

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 569

Sch em e 1. Synthetic Route to Targets 35-49^a

a

(a) H₂SO₄, MeOH, reflux; (b) tert-butyldimethylsilyl chloride, imidazole, N,N-DMF; (c) DIBAL/toluene, Et₂O, -78 °C; (d) D-alanine

methyl ester hydrochloride, NaBH(OAc)₃, AcOH (cat.), CH₂Cl₂; (e) di-tert-butyl dicarbonate, neat, 90-95 °C; (f) DIBAL, toluene; (g)

NaBH(OAc)₃, AcOH (cat.), CH₂Cl₂; (h) NaCNBH₃, MeOH or N,N-DMF; (i) 6 N aqueous HCl, heat; (j) 4 N HCl/dioxane, room temp, and

then LiOH, MeOH/H₂O.

Ch a r t 2. Anilines Employed in the Syntheses of Amide

mandelic acid 6. Protection of 6 as the corresponding

and Sulfonylsulfonamide Targets

silyl ether methyl ester 7 and subsequent DIBAL

reduction to the corresponding aldehyde followed by

reductive amination with D-alanine methyl ester sup-

plied amino methyl ester 8, which was typically isolated

in greater than 90% diastereomeric excess as the R,R

diastereomer. In the key reductive amination step used

to supply 8, it was found that careful quench of the

DIBAL-H reduction of methyl ester 7 with methanol at

low temperature was necessary in order to minimize

epimerization at the silyloxy stereocenter.

Anilines used for the synthesis of final targets via

reductive amination with aldehyde 10 are shown in

Chart 2. Known anilines 11-14 were obtained from

commercial suppliers, while anilines 15,²⁵19a , and

19b ²⁶were synthesized by standard methods. Non-

commercially available anilines were prepared from the

corresponding nitro intermediates by palladium-cata-

lyzed hydrogenation or tin(II) chloride-mediated reduc-

tion. The corresponding nitro precursor to aniline 19a

was obtained through 1,1-carbonyldiimidazole-mediated

coupling of 4-nitrophenyl carboxylic acid with benzyl-

amine, while the nitro precursor to aniline 19b²⁶was

obtained through reaction of p-toluenesulfonyl chloride

with 2-(4-nitrophenyl)ethylamine.

The remaining aniline intermediates and their nitro

precursors were synthesized as shown in Schemes 2-4.

Anilines 16a -c and 17a were synthesized employing a

1,1′-carbonyldiimidazole-promoted sulfonamide-car-

boxylic acid coupling procedure²⁷with sulfonamides of

interest and 3- or 4-nitrophenylacetic acid to give 50a -

d , followed by reduction of the nitro group as shown in

Scheme 2. Sulfonylurea 17b was synthesized by treating

3-nitrobenzylamine with benzenesulfonyl isocyanate

followed by hydrogenation of the nitro group, as shown

in Scheme 3. The ethyl-linked sulfonylsulfonamide 17c

and “reverse” acylsulfonamide 18 were made via sulfon-

ylation or acylation of primary sulfonamides 54a and

54b, followed by reduction of the nitro group. Sulfon-

amides 54a ,b were obtained through nucleophilic dis-

placement of commercially available bromide 51a or

tosylate 51b²⁸with potassium thioacetate, followed by

oxidation of the alkyl thioacetate product to the corre-

sponding sulfonic acids 53a ,b. The sulfonic acids were

then activated by treatment with thionyl chloride and

converted to the corresponding primary sulfonamide by

treatment with ammonia (Scheme 4).

Typically, a minor degree of epimerization occurred

either in the final aniline-aldehyde reductive amination

step or in the final deprotection of intermediates 20-

34. The diastereomeric composition of purified final

targets, which were observed as a single peak by

570 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Sch em e 2. Preparation of Acylsulfonamides 16-17a ^a

Uehling et al.

Resu lts a n d Discu ssion

All compounds were tested for their ability to cause

cAMP accumulation in cell lines that express human

â₃, â₂, or â₁ARs. The results are reported in terms of

potency (pEC₅₀) and efficacy (E_max, the fitted maximal

response to compound expressed as a percent of the

maximal response) to the nonselective full â AR agonist

isoprenaline (ISO). As a benchmark, lead aniline 3a was

characterized in our assays as a full and potent (pEC₅₀

) 7.8, E_max) 100%) agonist against â₃AR. However,

this compound also generated a strong response at â₂

AR (pEC₅₀) 7.3, E_max) 90%), as well as significant

(pEC₅₀) 7.1) albeit partial activity at the â₁AR (24%

ISO). In our cell lines, 3a was found to have a profile at

the three â AR subtypes similar to that of 2, although

it displayed slightly greater potency at both â₃and â₁

ARs.

a

(a) CDI, then methyl-, phenyl-, or p-toluenesulfonamide, DBU,

CH₂Cl₂; (b) 10% Pd/C, MeOH or EtOAc.

To identify compounds within our series with im-

proved potency and selectivity, we initially compared

lead compound 3a to analogues in which the carboxylic

acid was deleted, replaced with nonacidic amides, or

varied in position. The role of the acetic acid substituent

in the RHS phenyl ring of 3a is revealed by comparing

its â AR profile to that of analogue 39, which lacks

substitution on the RHS phenyl ring. In contrast to 3a ,

which shows modest â₃selectivity, compound 39, which

is also quite active at â₃, was even more potent at â₁

and â₂AR subtypes (Table 1). Likewise, amide 37 and

sulfonamide 38 showed a similarly poor selectivity

profile as 39. In analogy to previous SAR studies,^22athe

comparison of 3a with 37 and 38 demonstrates that the

RHS para acetic acid substitution does confer modest

but appreciable â₃selectivity compared to analogues

lacking a negatively charged para substituent in our

aniline series.

Sch em e 3. Preparation of Sulfonylurea Aniline

Intermediate 17b^a

a

(a) Benzenesulfonyl isocyanate, Et₃N, THF; (b) H₂, 10% Pd/

C, MeOH/THF.

Sch em e 4. Preparation of Ethyl-Linked Acyl- and

Sulfonylsulfonamide Aniline Intermediates 17c and 18^a

The effect of modifying position or tether length of

the RHS carboxylate can be seen by comparing the data

for compounds 3a , 3b, 35, and 36. It was found that

relative to 3a , the meta-substituted analogue 3b has

somewhat weaker â₃AR activity at the human receptors

and also somewhat poorer â₂/â₃selectivity. However, the

shift of the acetic acid substituent to the meta position

significantly improves selectivity at â₁, since this com-

pound showed negligible â₁activity in terms of both

potency and maximum response. In terms of tether

length modifications, a comparison of the â₃AR data

for compounds 35 and 36 with that of 3a indicates that

both longer and shorter RHS phenyl carboxylate chains

help to reduce activity at â₁and â₂AR subtypes.

However, while increasing spacer length to ethylene

(compound 35) retained â₃AR activity, direct attach-

ment of the carboxylate to the RHS phenyl ring (com-

pound 36) led to diminished potency.

Although some of the analogues in Table 1 showed

modest selectivity, we felt that the profile of these

compounds was insufficiently selective to warrant fur-

ther progression. Utilizing the SAR results described

above, we then turned our attention to the synthesis of

a series of targets containing acid isosteres with a one-

or two-atom linker at the meta or para position on the

RHS phenyl ring. As part of this effort,²⁴we became

interested in the synthesis of analogues containing

acylsulfonamide, sulfonylsulfonamide, or sulfonylurea

functional groups in these orientations. Because they

a

(a) Potassium thioacetate, CH₃CN or N,N-DMF; (b) 30% H₂O₂,

AcOH; (c) SOCl₂, N,N-DMF, then 0.5 M NH₃/dioxane; (d) benzene-

sulfonyl choride, Et₃N, CH₃CN, reflux; (e) benzoyl chloride, K₂CO₃,

CH₃CN, reflux; (f) H₂, 10% Pd/C or 20% Pd(OH)₂/C.

reverse-phase HPLC, was determined by ¹H NMR to

be at least 85% of the R,R isomer. In cases where

epimerization occurred, the minor diastereomers were

generally inseparable from the R,R isomer and were not

characterized with regard to R,S versus S,R composi-

tion.²⁹

â₃Adrenergic Receptor Agonists

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 571

Ta ble 1. RHS Carboxylic Acid Analogue Stimulation of cAMP Accumulation in CHO Cells Expressing Human â₃, â₂, and â₁AR

a

Human â₁, â₂, and â₃receptors expressed in CHO cells. pEC₅₀is the negative logarithm of the molar drug concentration that produces

b

a cAMP response equal to 50% of its maximal response. n ) 3 for all compounds except ISO, where n ) 25. E_maxis the fitted maximal

value of the concentration-response expressed as a percent of the maximal response to R-(-)-isoproterenol (Iso). ^cn ) 2 experiments.

d

Curve could not be fitted to the data, and therefore, the maximal individual response to a concentration of compound is given expressed

as a percent of the maximal response to Iso. ^eThe compound produced a negligible response in this experiment.

contain two electron-withdrawing groups attached to

NH, the isosteres we used are comparable in acidity to

that of carboxylate and therefore were seen as poten-

tially beneficial in providing selectivity.^30,31In addition,

varying the substitution of the electron-withdrawing

group on the RHS of these isosteres with large or small

substituents allows for modification of steric bulk in the

RHS portion of the targets relative to 3a or 3b, thus

allowing us to explore the effect of sterics at these

positions on the in vitro profile. Several of these

analogues were therefore prepared and tested against

â₃, â₂, and â₁AR subtypes in functional assays. The

results are shown in Table 2.

As can be seen in Table 2, analogues 40 and 41

containing either thiazole or methylsulfonyl groups

respectively show good potency at â₃AR, although their

â₂and â₁AR selectivity is not enhanced relative to 3a .

On the other hand, increasing the steric bulk of the RHS

electron-withdrawing group attached to nitrogen leads

to a markedly improved profile. Phenyl and p-toluene-

572 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Uehling et al.

Ta ble 2. Amide and Sulfonamide Acid Isostere Stimulation of cAMP Accumulation in CHO Cells Expressing Human â₃, â₂, and â₁

AR

a

Human â₁, â₂, and â₃receptors expressed in CHO cells. pEC₅₀is the negative logarithm of the molar drug concentration that produces

b

a cAMP response equal to 50% of its maximal response. n ) 3 for all compounds except ISO, where n ) 25. E_maxis the fitted maximal

value of the concentration-response expressed as a percent of the maximal response to R-(-)-isoproterenol (Iso). ^cn ) 2 experiments.

d

This number is an average of the maximal response, or point of highest activity, measuring concentration versus response for three

different experiments. A curve could not be fitted to the data, and therefore, the maximal individual response to a concentration of compound

is given expressed as a percent of the maximal response to Iso.

â₃Adrenergic Receptor Agonists

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 573

Ta ble 3. Dog Pharmacokinetic Data for â-3 Acyl- and Sulfonylsulfonamide Acid Isosteres

a

Compounds were dosed intravenously to dogs (n ) 1) in 0.025 M aqueous methanesulfonic acid solution with 5% mannitol at a

b

concentration of 0.2 mg/mL. The plasma drug levels were determined by LC-MS/MS. Rapid clearance resulted in an insufficient number

of data points to quantitate this parameter. ^cPlasma concentration at the 2.5 h time point. BQL ) below quantitation limit.

d

containing acylsulfonamides 42 and 43 are 20 and 13

times more potent at â₃AR than the parent carboxylic

acid analogue 3a , respectively, and in addition, are

substantially less active at the â₁AR subtype. Although

of similar potency at â₂as 3a , both aryl acylsulfon-

amides 42 and 43 have a low maximum response as well

as significantly higher â₂/â₃selectivity ratios. Interest-

ingly, shifting the acylsulfonamide substituent from the

para to the meta position in analogue 44 slightly reduces

â₃potency but leads to even greater â₁and â₂selectivity,

analogous to the change observed when shifting the

acetic acid substituent (i.e., 3a to 3b).

(relative to â₁and â₂) in the sulfonylsulfonamide

analogue.

As mentioned previously, workers at Merck have

reported extensively on a series of potent and selective

benzene sulfonamide analogues such as 5.^20,32With only

one electron-withdrawing functionality attached to ni-

trogen, the sulfonamide functionality of such analogues

is unlikely to be as acidic as either the acylsulfonamides

reported here or thiazole 40. Given that the promising

Merck analogues reported do possess a relatively bulky

aromatic RHS sulfonamide group, we wondered if the

profile of our best analogues described here is solely a

result of steric bulk or rather a combination of both the

size and acidity of the RHS phenyl substituent. In an

attempt to address this question, we prepared and

tested analogues 48 and 49 in which one of the NH

electron-withdrawing groups of 43 was replaced with

methylene. As can be seen in Table 2, these two

analogues were not only less potent than 43 but were

also completely nonselective, suggesting that both the

size and the acidity of the RHS substituent contribute

to the excellent in vitro profile of our most potent and

selective acyl- and sulfonylsulfonamides.

Encouraged by these results, we prepared and tested

additional meta- and para-substituted sulfonamide

acidic isosteres with an additional electron-withdrawing

group. These included the meta-substituted sulfonyl-

urea 45 and sulfonylsulfonamide 46, as well as the para

ethylene-linked “reverse” acylsulfonamide 47. Func-

tional â₃receptor data for these analogues (Table 2)

showed that while sulfonylurea 45 was somewhat

inferior in selectivity to the corresponding acylsulfon-

amide 44, sulfonylsulfonamide 46 had an outstanding

profile with respect to both potency at â₃and selectivity

against â₁and â₂ARs. It is unclear whether the superior

profile of 46 relative to 45 is a result of increased acidity

of the sulfonylsulfonamide relative to sulfonylurea

functionality or a subtle conformational difference that

permits a more favorable interaction with the â₃AR

Because of their encouraging in vitro profiles, ana-

logues 43-47 were evaluated in vivo in dog pharmaco-

kinetic (PK) assays. Each of these compounds was dosed

as a solution (at 0.2 mg/kg) by intravenous administra-

tion in order to identify compounds worthy of further

574 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Uehling et al.

F igu r e 1. (a) Infrared images of the interscapular region of representative individual CD-1 mice following oral administration

of 43 at 0.01, 0.1, and 1.0 mg/kg (1 h postdosing). Note: the view is from above backs of mice with heads oriented toward the top

of the panel. The color scale of the image is indicated to the left of panel A and is adjusted to optimally reveal temperature

changes in IBAT. (b) Graph of time versus temperature change of the interscapular region of CD-1 mice relative to that of the

vehicle control group (n ) 6 per group) following oral administration of 43. (c) Same as (a) with compound 44. (d) Same as (b)

with compound 44.

investigation, as judged by a low serum clearance and

the presence of significant plasma levels of drug after

2.5 h. As can be seen in Table 3, compounds 45-47 had

very high clearance and consequently failed to show

measurable plasma concentrations after 2.5 h. On the

other hand, although their half-lives were also less than

2 h, both acylsulfonamides 43 and 44 showed moder-

ately low clearance values as well as measurable plasma

levels at 2.5 h. Although follow-up studies to determine

the reason for the disappointing pharmacokinetics seen

with compunds 45-47 were not conducted, it is possible

that enzymatic cleavage at one of the electrophilic atoms

adjacent to nitrogen in the acid isostere may be a

significant source of metabolism.³³However, previous

studies in human plasma have demonstrated relatively

low cleavage rates for aliphatic acylsulfonamides and

sulfonylureas,³⁴suggesting that this is not likely to be

an important route for elimination for analogues in our

series.

Since the pharmacokinetic profiles of 43 and 44 are

the best of the compounds studied, we decided to

investigate their ability to elicit an in vivo â₃AR

mediated response. For this purpose, we monitored

thermogenesis in the brown fat rich interscapular region

of CD-1 mice by thermogenic imaging. Known â₃AR

agonists have been shown to elicit a thermogenic

response in this model, causing a temperature increase

in the interscapular region of the animal that is

monitored using an infrared camera that generates

quantifiable image-based readouts.³⁵Following oral

administration of the drug (0.01, 0.1, and 1.0 mg/kg),

the mice were anesthetized and imaged at 1 h time

points. The potent rodent â₃-selective agonist 1 was

included in the experiment as a positive control.⁵The

results for compounds 43, 44, and 1 are shown in Fig-

ure 1. We were pleased to find that, like 1, both acyl-

sulfonamides 43 and 44 produced significant dose-

dependent increases in thermogenesis (see parts a and

c of Figure 1 and legend), resulting in a maximal

increase in interscapular temperature of approximately

1 °C for each compound (parts b and d of Figure 1).

Although both isosteric analogues were active, we were

curious to observe that the response to 43 as seen at

the two lowest doses was significantly more robust than

that of isomeric acylsulfonamide 44, despite their

similar structures and in vitro profiles at human recep-

tors. Of additional note is the duration of the response

seen with 43. Like 1, at the top dose of 1 mg/kg this

compound produced a response that remained at high

levels at the 4 h time point, indicating a prolonged

pharmacodynamic response for both 1 and 43 in this

model.

Finally, compounds 43 and 44 were evaluated along

with initial lead 3a in â₁and â₂binding assays in order

to assess their potential liability as antagonists at â₁

and â₂ARs. As is reported in Table 4, at least a 750-

â₃Adrenergic Receptor Agonists

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 575

Ta ble 4. Comparison of â₃AR Activation with â₂, and â₁AR Binding for Compounds 3a , 43, and 44

a

Human â₁, â₂, and â₃receptors expressed in CHO cells. pEC₅₀is the negative logarithm of the molar drug concentration that produces

b

a cAMP response equal to 50% of its maximal response. n ) 3 for all compounds except ISO, where n ) 25. E_maxis the fitted maximal

value of the concentration-response expressed as a percent of the maximal response to R-(-)-isoproterenol (Iso). ^cReceptor binding assays

were carried out with membranes prepared from human recombinant Sf9 cells expressing the cloned human receptor in the presence of

d

[

¹²⁵I]iodocyanopindolol. Results are given as the mean ( SD from three experiments, unless otherwise indicated. Results of two

experiments (n ) 2).

fold difference in the activation of the â₃receptor

relative to the binding affinity of either the â₁or â₂

receptor was found for both acylsulfonamide analogues

43 and 44. In contrast, the phenylacetic acid derivative

3a had a difference in â₃pEC₅₀relative to â₁and â₂AR

IC₅₀of only ca. 60-fold.

ences in rodent pharmacokinetics between the two

compounds, since neither rodent â₃AR data nor rodent

pharmacokinetic data were obtained. The excellent in

vitro profile of several compounds we have described,

combined with the potent rodent thermogenic activity

of 43 and 44, suggests that these compounds may

represent a viable lead series in the discovery of new

therapies for the treatment of obesity and type 2

diabetes.

Con clu sion

We have described â₃AR potency and selectivity data

from a series of aniline phenethanolamine agonists in

which the carboxylate of RHS phenyl substituents was

varied in position, deleted, or replaced with amide- or

sulfonamide-containing carboxylic acid isosteres. A

comparison of 3a and 3b with other analogues reinforces

earlier SAR studies that demonstrate the benefit of

carboxylate on the RHS aniline ring in providing some

â₁and â₂AR selectivity relative to compounds lacking

a negatively charged group. More importantly, we were

pleased to discover that substituting the carboxylate of

3a or 3b with acylsulfonamide and sulfonylsulfonamide

isosteres augmented not only â₃AR potency but also â₁

and â₂AR selectivity, especially in the case of com-

pounds bearing arylacyl- or sulfonylsulfonamides. The

inclusion of amide 48 or sulfonamide 49 in these SAR

investigations supports a role for both sterics and acidity

of the RHS phenyl substituent in contributing to the

high potency and selectivity of analogues within our

series. Although some of the most potent and selective

compounds we have identified showed disappointing

pharmacokinetics in dogs, the potent and selective

acylsulfonamides 43 and 44 had reasonably low clear-

ance in dogs and were found to be quite orally active in

rodent thermogenesis studies. The greater thermogenic

efficacy of 43 compared to 44 in mice may be a result of

differences in activities at the rodent receptor or differ-

Exp er im en ta l Section

Ch em istr y. Gen er a l Meth od s. Melting points were de-

termined using a Thomas-Hoover melting point apparatus and

are uncorrected. Unless stated otherwise, reagents were

obtained from commercial sources and were used directly.

Reactions involving air- or moisture-sensitive reagents were

carried out under a nitrogen atmosphere. If not specified,

reactions were carried out at ambient temperature. Silica gel

(EM Science, 230-400 mesh) was used for chromatographic

purification unless otherwise indicated. Anhydrous solvents

were obtained from Aldrich (Sure Seal). ¹H NMR spectra were

recorded on a Varian 300 MHz spectrometer; chemical shifts

are reported in parts per million (ppm) relative to TMS. The

following abbreviations are used to describe peak patterns

when appropriate: b ) broad, s ) singlet, d ) doublet, t )

triplet, q ) quartet, m ) multiplet. High-performance liquid

chromatography (HPLC) was performed on a Beckman 126

with a Beckman 166 UV detector (monitoring at 215 nm) with

a Rainin Dynamax-60A column using a gradient consisting of

20/80 A/B to 10/90 A/B over 20 min, where A is 1% aqueous

trifluoroacetic acid (TFA) and B is 1% TFA in CH₃CN. Results

from elemental analyses, performed by Atlantic Microlab, Inc.,

Norcross, GA, were within 0.4% of the theoretical values

calculated for C, H, and N.

Meth yl (2R)-{[ter t-Bu tyl(d im eth yl)silyl]oxy}(3-ch lor o-

p h en yl)eth a n oa te (7).²³This procedure and those for the

preparation of intermediates 8 and 9 follow closely the

576 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Uehling et al.

previously disclosed method.²³A solution of (R)-(-)-3-chloro-

mandelic acid (6, 50 g, 0.268 mmol) in MeOH (500 mL) was

treated with H₂SO₄(2.5 mL). The mixture was heated at reflux

for 4 h and allowed to cool to ambient temperature, and the

solvent was removed with a rotary evaporator. The resulting

oil was partitioned between EtOAc (500 mL) and saturated

aqueous NaHCO₃(200 mL). The organic layer was separated,

and the aqueous layer was extracted with EtOAc (100 mL).

The combined organic layers were dried over Na₂SO₄, filtered,

and concentrated to supply 56.59 g of (R)-(-)-chloromandelic

acid methyl ester. The ester was dissolved in anhydrous N,N-

DMF (250 mL), and imidazole (38.3 g, 0.562 mmol) and tert-

butyldimethylsilyl chloride (63.5 g, 0.422 mmol) were added.

The mixture was stirred for 7 h and partitioned between water

(300 mL) and 5:1 hexane/EtOAc (500 mL). The organic layer

was separated, and the aqueous layer was reextracted with

5:1 hexane/EtOAc (250 mL). The combined organic layers were

dried over Na₂SO₄, filtered, and concentrated to supply, after

placing the residue under high vacuum for 3 days, 81.85 g

(97%) of the product 7 as a colorless oil that solidified upon

4.05-4.15 (m, 0.5H), 4.82-4.95 (m, 0.5 H), 5.00-5.05 (m, 0.5

H), 7.10-7.30 (m, 3H), 7.35 (s, 0.5 H), 7.40 (s, 0.5H).

ter t-Bu tyl (2R)-2-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-2-(3-

ch lor op h en yl)et h yl[(1R)-1-m et h yl-2-oxoet h yl]ca r b a m -

a te (10).²³To a solution of the methyl ester 9 (3.83 g, 8.15

mmol) in anhydrous toluene (40 mL) at -78 °C was added 1.5

M DIBAL in toluene (13.5 mL, 20.3 mmol) dropwise over 2

min. The mixture was stirred at -78 °C for 1 h and quenched

by slow addition of MeOH (3 mL) followed by 15% w/v

potassium sodium tartrate (20 mL). The resulting mixture was

allowed to warm to ambient temperature, stirred vigorously

for 1 h, and filtered through a pad of Celite. After the mixture

was washed with additional EtOAc, the filtrate was partitioned

between water (50 mL) and EtOAc (50 mL). The organic layer

was dried, filtered, and concentrated to afford the product

aldehyde 10 (3.43 g, 96%) as a colorless oil judged by ¹H NMR

integration of aldehyde peaks to be a 13:1 mixture of R,R/

minor diastereomers. ¹H NMR (400 MHz, CDCl₃): δ -0.10 (s,

3H), 0.01 (s, 1.5 H), 0.02 (s, 1.5H), 0.85 (s, 9H), 1.20-1.25 (m,

3H), 1.38 (s, 4.5H), 1.40 (s, 4.5H), 3.0-3.15 (m, 1H), 3.25-

3.40 (m, 1H), 3.3.70-3.85 (m, 1H), 4.90 (t, 0.5H), 5.02 (t, 0.5H),

7.18-7.25 (m, 3H), 7.28 (s, 0.5H), 7.35 (s, 0.5H), 9.20 (s, 0.5H),

9.38 (s, 0.5H).

1

standing. H NMR (400 MHz, CDCl₃): δ 0.02 (s, 3H), 0.10 (s,

3H), 0.90 (s, 9H), 3.68 (s, 3), 5.20 (s, 1H), 7.22 (d, 2H), 7.35

(m, 1H), 7.45 (s, 1H).

Meth yl (2R)-2-{[(2R)-2-{[ter t-Bu tyl(dim eth yl)silyl]oxy}-

2-(3-ch lor op h en yl)eth yl]a m in o}p r op a n oa te (8).²³A me-

chanically stirred mixture of methyl (2R)-{[tert-butyl(dimethyl)-

silyl]oxy}(3-chlorophenyl)ethanoate (7, 20 g, 63.51 mmol) in

anhydrous Et₂O (280 mL) under N₂was cooled to -78 °C and

treated with 1.0 M DIBAL in toluene (105 mL, 105 mmol,

added dropwise over ca. 5 min). The mixture was stirred at

-78 °C for 1.5 h, then quenched by slow addition of MeOH

(20 mL) followed by 15% w/v aqueous potassium sodium

tartrate (250 mL). The mixture was vigorously stirred for 2 h

while warming to ambient temperature, was filtered through

a pad of Celite, and was washed with EtOAc (200 mL). The

filtrate was extracted with additional EtOAc (2 × 150 mL),

and the combined organic extracts were dried over MgSO₄,

filtered, and concentrated to supply 18.19 g of a colorless liquid

judged by ¹H NMR to be a ca. 2:1 mixture of methyl hemiacetal

N-[2-(4-Nit r op h en yl)et h yl]-4-m et h ylb en zen esu lfon -

a m id e.²⁵An N₂-purged flask equipped with a stirring bar was

charged with 2-(4-nitrophenyl)ethylamine hydrochloride (2.0

g, 9.87 mmol), p-toluenesulfonyl chloride (1.88 g, 9.87 mmol),

and anhydrous CH₂Cl₂(50 mL). Triethylamine (1.51 mL, 10.86

mmol) was added, and the resulting mixture was stirred at

ambient temperature for 20 h, diluted with CH₂Cl₂(25 mL),

and washed with 1.0 N aqueous HCl (25 mL). The organic

layer was separated, washed with saturated aqueous NaHCO₃

(25 mL), dried, filtered, and concentrated to give a light-yellow

solid. Trituration with MeOH afforded a solid that was washed

with ether to supply 1.04 g (33% yield) of the product as a

white solid. ¹H NMR (DMSO-d₆): δ 2.47 (s, 3H), 2.94 (t, 2H, J

) 6.9 Hz), 3.31 (q, 2H, J ) 6.9 Hz), 4.51 (t, 1H, J ) 6.3 Hz),

7.29-7.34 (m, 4H), 7.73 (d, 2H, J ) 8.1 Hz), 8.15 (d, 2H, J )

8.4 Hz). MS (ES), m/e (M - H) ) 320.9.

2-(4-Nitr op h en yl)-N-4-m eth ylben zyla ceta m id e. An N₂-

purged flask equipped with a stirring bar was charged with

4-nitrophenylacetic acid (1.0 g, 5.52 mmol), 1,1′-carbonyldi-

imidazole (1.32 g, 8.1 mmol) and anhydrous CH₂Cl₂(25 mL).

The reddish-brown mixture was stirred for 45 min. 4-Methyl-

benzylamine (880 µL, 838 mg) was added via syringe. The

cloudy yellow mixture was stirred for 1 h, then partitioned

betwen CH₂Cl₂and 1 N HCl. The organic layer containing a

white precipitate was separated and washed with saturated

aqueous NaHCO₃. The precipitate was collected by suction

filtration, triturated with MeOH and washed with ether to

provide 0.78 g (53%) of the product as a white solid. MS

(electrospray), m/e: 283.0 (M - H). ¹H NMR (DMSO-d₆): δ 2.30

(s, 3H), 3.68 (s, 2H), 4.26 (d, 2H, J ) 6.0 Hz), 7.15 (s, 4H),

7.58 (d, 1H, J ) 8.7 Hz), 8.22 (d, 1H, J ) 8.4 Hz), 8.65 (t, 1H,

J ) 6.0 Hz).

N-[2-(4-Nitr oph en yl)acetyl]m eth an esu lfon am ide (50a).

A suspension of 4-nitrophenylacetic acid (2.0 g, 11.0 mmol) in

CH₂Cl₂(30 mL) was treated with 1,1′-carbonyldiimidazole

(CDI) (2.4 g, 11.0 mmol), yielding an orange solid. After the

mixture was stirred for 1 h, methanesulfonamide (1.1 g, 11.0

mmol) was added and the mixture was stirred for an additional

1 h. Addition of diazobicyclo[5.4.0]undec-7-ene (1.5.5) (DBU)

(1.7 mL, 11.0 mmol) yielded a purple mixture that was stirred

for 16 h. The reaction mixture was then partitioned between

1 N aqueous HCl and EtOAc, during which time an orange

solid fell out. The solid was partitioned between 1 N aqueous

NaOH and EtOAc. The aqueous layer was acidified with 1 N

aqueous HCl and extracted with EtOAc. The organic layer was

dried over Na₂SO₄, filtered, and concentrated to yield 1.9 g of

the product (67%) as a yellow solid, mp 191-193 °C. ¹H NMR

(DMSO): δ 3.21 (s, 3H), 3.79 (s, 2H), 7.52 (d, 2H, J ) 8.6 Hz),

8.17 (d, 2H, J ) 8.5 Hz).

1

and aldehyde. H NMR (400 MHZ, CDCl₃): δ -0.03 (0.5H, s),

-0.01 (1.5H, s), 0.03 (1.5H, s), 0.05 (s, 1.5H), 0.10 (s, 1H), 0.90

(s, 6H), 0.95 (s, 3H), 3.22-3.40 (m, 3H), 4.40-4.95 (m, 1.5 H),

7.10-7.40 (m, 4H), 9.47 (s, 0.33H).

This hemiacetal/aldehyde mixture was dissolved in CH₂Cl₂

(250 mL), and D-alanine methyl ester (8.91 g, 63.81 mmol),

acetic acid (1 mL), and 4 Å molecular sieves (10 g) were added.

After the mixture was stirred for 1 h, NaBH(OAc)₃(20.3 g,

95.7 mmol) was added. After an additional 2 h, the mixture

was quenched with saturated aqueous NaHCO₃. The organic

layer was separated, washed with additional saturated aque-

ous NaHCO₃, dried over MgSO₄, filtered, and concentrated to

afford 22.4 g (95% overall) of the amino methyl ester 8 as a

pale-green oil, which ¹H NMR indicated to be >95% R,R

diastereomer. ¹H NMR (400 MHZ, CDCl₃): δ -0.15 (s, 3H),

0.05 (s, 3H), 0.95 (s, 9H), 1.25 (d, 3H, J ) 7 Hz), 2.62-2.87

(m, 2H), 3.38 (q, 1H, J ) 7 Hz), 3.67 (s, 3H), 4.65-4.75 (d,

1H), 7.18-7.23 (m, 3H), 7.25 (m, 1H).

Meth yl (2R)-2-{(ter t-Bu toxyca r bon yl)[(2R)-2-{[ter t-bu -

tyl(d im eth yl)silyl]oxy}-2-(3-ch lor op h en yl)eth yl]a m in o}-

p r op a n oa te (9).²³The amine 8 (22.4 g, 60.2 mmol) and di-

tert-butyl dicarbonate (14.3 g, 65.5 mmol) were combined and

heated neat in an oil bath at 90-95 °C for 5 min. (Caution: a

blast shield should be used when heating this mixture). After

the mixture was cooled, additional di-tert-butyl dicarbonate

(2.73 g, 12.5 mmol) was added and the mixture was heated at

95 °C for 10 min. The mixture was allowed to cool to ambient

temperature and was purified by silica gel chromatography

(eluting with 10:1 hexane/EtOAc followed by 5:1 hexane/

EtOAc) to supply 27.1 g (96%) of Boc amine 9 as a colorless

1

oil, which H NMR indicated to be a 60:40 mixture of rotamers.

¹H NMR (400, CDCl₃): δ 0.06 (s, 3H), 0.89 (s, 9H), 1.09 (d,

1.25 H, J ) 7.2 Hz), 1.31 (d, 1.75H, J ) 6.8 Hz), 1.41 (s, 3.6

H), 1.43 (s, 5.4 H), 3.10-3.20 (m, 1H), 3.35 (d, 1H, J ) 6.0

Hz), 3.40-3.50 (m, 1H), 3.69 (s, 3H), 3.82-3.93 (m, 0.5 H),

N-[2-(4-Nitr op h en yl)a cetyl]ben zen esu lfon a m id e (50b).

The foregoing procedure was employed using benzenesulfon-

â₃Adrenergic Receptor Agonists

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 577

amide (945 mg, 6.0 mmol), CDI (900 mg, 5.55 mmol), 4-nitro-

phenylacetic acid (1.0 g, 5.52 mmol), and DBU (0.87 mL, 5.81

mmol) in CH₂Cl₂(20 mL) to yield 1.57 g (89%) of the product

as a yellow solid, mp 145-148 °C. ¹H NMR (400 MHz, DMSO-

d₆): δ 3.73 (s, 2H), 7.40 (d, 2H, J ) 9 Hz), 7.69-7.53 (m, 3H),

7.87 (d, 2H, J ) 7 Hz), 8.11 (d, 2H, J ) 9 Hz), 12.45 (s, 1H).

MS (ES) m/e: 319 (M - H).

2H, J ) 11, 7 Hz), 7.63 (t, 1H, J ) 8 Hz), 7.82 (d, 1H, J ) 8

Hz), 8.12 (d, 1H, J ) 7), 8.23 (s, 1H). MS (CI) m/e: 230 (M -

H).

4-Nit r op h en et h ylsu lfon ic Acid (53b ). A suspension of

4-nitrophenethyl bromide (51a ) (12.9 g, 56.1 mmol) and

potassium thioacetate (11.4 g, 99.8 mmol) was stirred in

DMSO (75 mL) for 24 h, diluted with EtOAc, extracted with

water, dried, and concentrated to give crude 52b as a mobile

brown oil (11.0 g). This material was dissolved in glacial acetic

acid (75 mL), and 32% H₂O₂(25 mL) was added. After 24 h,

addition of water and concentration gave 10.8 g of a pale-yellow

solid (84% crude yield) that was used without further purifica-

tion. ¹H NMR (300 MHz, DMSO-d₆): δ 2.80 (t, 2H), 3.00 (t,

2H), 7.50 (d, 2H), 8.10 (d, 2H).

N-[2-(4-Nitr op h en yl)a cetyl]ben zen esu lfon a m id e (50c).

The general procedure for 50a was employed using p-toluene-

sulfonamide (945 mg, 5.52 mmol), CDI (895 mg, 5.52 mmol),

4-nitrophenylacetic acid (1.0 g, 5.52 mmol), and DBU (0.84 g,

0.82 mL, 5.48 mmol) in CH₂Cl₂(20 mL). The reaction yielded

1.74 g (94%) of the product as a yellow solid, mp 205-214 °C.

1

Low-resolution H NMR (400 MHz, DMSO-d₆): δ 2.35 (s, 3H),

2-(3-Nit r op h en yl)et h a n esu lfon ic Acid Am id e (54a ).

Thionyl chloride (19.7 mL, 20 equiv) was added to 2-(3-

nitrophenyl)ethanesulfonic acid (53a , 3.13 g, 13.53 mmol), and

the resulting solution was heated at reflux for 17 h. The

volatiles were removed under vacuum, NH₃in dioxane (135

mL, 0.5 M, 5.0 equiv) was added, and the reaction mixture

was stirred for 5 h. Water was added followed by saturated

aqueous Na₂CO₃, and the mixture was extracted with EtOAc.

The extracts were dried over Na₂SO₄and concentrated. The

residue was purified by silica gel chromatography, eluting with

EtOAc/hexanes (3:2) to give 1.83 g (59%) of the product. ¹H

NMR (300 MHz, CD₃COCD₃): δ 3.27-3.32 (m, 2H), 3.43-3.48

(m, 2H), 6.22 (s, 2H), 7.62 (t, 1H, J ) 8 Hz), 7.79 (d, 2H, J )

8 Hz), 8.11 (d, 1H, J ) 8 Hz), 8.20 (d, 1H, J ) 2 Hz). MS (CI)

m/e: 230 (M - H).

4-Nitr op h en eth ylsu lfon a m id e (54b). 4-Nitrophenethyl-

sulfonic acid (53b, 23.1 g, 100 mmol) was heated at reflux with

SOCl₂(200 mL) and N,N-DMF (10 mL). After 2 h the SOCl₂

was removed under vacuum, and the residue was taken up in

dioxane (200 mL) and added to 0.5 M NH₃/dioxane (2000 mL).

The mixture was filtered through Celite and then concen-

trated. The residue was dissolved in EtOAc (50 mL), and after

addition of hexane, the product (17.07 g, 74%) precipitated as

a tan solid. ¹H NMR (300 MHz, DMSO-d₆): δ 3.12 (t, 2H), 3.30

(t, 2H), 6.90 (s, 2H), 7.58 (d, 2H), 8.18 (d, 2H). MS (ES) m/e:

229 (M - H).

3.71 (s, 2H), 7.41-7.36 (m, 4H), 7.75 (d, 2H, J ) 8 Hz), 8.11

(d, 2H, J ) 8 Hz), 12.35 (s, 1H). MS (ES) m/e: 33.0 (M - H).

N-[2-(3-Nit r op h en yl)a cet yl]-4-m et h ylb en zen esu lfon -

a m id e (50d ). The general procedure for 50a was employed

using p-toluenesulfonamide (480 mg, 2.80 mmol), CDI (500 mg,

3.08 mmol), 3-nitrophenylacetic acid (450 mg, 2.48 mmol), and

DBU (0.835 g, 0.82 mL, 5.48 mmol) in CH₂Cl₂(15 mL). The

product (600 mg, 65% yield) was obtained as a yellow solid,

mp 175-177 °C. ¹H NMR (400 MHz, DMSO- d₆): δ 2.35 (s,

3H), 3.73 (s, 2H), 7.36 (d, 2H, J ) 8.0 Hz), 7.59-7.52 (m, 2H),

7.74 (d, 2H, J ) 8.0 Hz), 8.03 (s, 1H), 8.07 (dd, 1H, J ) 2.0,

8.0 Hz), 12.35 (s, 1H). MS (ES) m/e: 333.1 (M - H).

1-Nitr o-3-[({[(p h en ylsu lfon yl)a m in o]ca r bon yl}a m in o)-

m eth yl]ben zen e (56). Triethylamine (1.85 mL, 13.3 mmol)

was added to 3-nitrobenzylamine (1.00 g, 5.30 mmol) in THF

(26.5 mL), followed by benzenesulfonyl isocyanate (709.5 µL,

5.30 mmol), and the reaction mixture was stirred for 16 h at

ambient temperature. Aqueous HCl (1 N) was added, and the

mixture was extracted with EtOAc. The organic extracts were

combined and concentrated. The residue was purified by silica

gel chromatography, eluting with EtOAc/hexanes (4:1) to give

440 mg (25%) of the product. ¹H NMR (300 MHz, CD₃-

COCD₃): δ 4.49 (d, 2H, J ) 7 Hz), 7.21 (br s, 1H), 7.53-7.68

(m, 5H), 7.99 (d, 2H, J ) 7 Hz), 8.09 (d, 1H, J ) 7 Hz), 8.10 (s,

1H), 9.73 (br s, 1H). MS (CI) m/e: 334 (M - H).

Tolu en e-4-su lfon ic Acid 2-(3-Nitr op h en yl)eth yl Ester

(51b).²⁸4-(Dimethylamino)pyridine (365.4 mg, 2.99 mmol) was

added to 2-(3-nitrophenyl)ethanol (5.00 g, 29.91 mmol) in

CHCl₃(60 mL) at ambient temperature, followed by triethyl-

amine (5.84 mL, 38.7 mmol) and p-toluenesulfonyl chloride

(6.84 g, 35.8 mmol). The reaction was stirred for 63 h,

quenched with saturated Na₂CO₃, and extracted with CHCl₃.

The organic layer was dried and concentrated, and the residue

was purified by silica gel chromatography, eluting with EtOAc/

hexanes (2:3) to give 6.14 g of the product (64%). ¹H NMR (300

MHz, CDCl₃): δ 2.40 (s, 3H), 3.04 (t, 2H, J ) 6 Hz), 4.26 (t,

2H, J ) 6 Hz), 7.24 (d, 2H, J ) 8 Hz), 7.42 (t, 1H, J ) 8 Hz),

7.47 (d, 1H, J ) 8 Hz), 7.62 (d, 2H, J ) 8 Hz), 7.87 (s, 1H),

8.05 (d, 1H, J ) 8 Hz). MS (CI) m/e: 344 (M + Na).

Th ioa cetic Acid S-[2-(3-Nitr op h en yl)eth yl] Ester (52a ).

Potassium thioacetate (4.36 g, 38.2 mmol) was added to

tosylate 51b (6.14 g, 19.11 mmol) in acetonitrile (64 mL) at

ambient temperature, and the reaction mixture was stirred

for 17 h. The mixture was quenched with water and extracted

with EtOAc, and the separated organic layer was dried,

filtered, and concentrated. The residue was purified by silica

gel chromatography, eluting with EtOAc/hexanes (1:4) to give

4.24 g of the product (98%). ¹H NMR (300 MHz, CDCl₃): δ

2.32 (s, 3H), 2.96 (t, 2H, J ) 7 Hz), 3.13 (t, 2H, J ) 7 Hz), 7.46

(t, 1H, J ) 8 Hz), 7.54 (d, 1H, J ) 7 Hz), 8.07 (s, 1H), 8.08 (d,

1H, J ) 7 Hz). MS (CI) m/e: 150 (M - AcS).

2-(3-Nitr oph en yl)eth an esu lfon ic Acid Ben zen esu lfon yl-

a m id e (55a ). Triethylamine (508.7 µL, 3.64 mmol) was added

to 2-(3-nitrophenyl)ethanesulfonic acid amide (54a , 420.2 mg,

1.83 mmol) in CH₃CN (9 mL), followed by the addition of

benzenesulfonyl chloride (279.4 µL, 2.19 mmol), and the

reaction was heated at reflux for 4 h. Aqueous HCl (1 N) was

then added, and the mixture was extracted with EtOAc. The

combined organic layers were dried, filtered, and concentrated.

The residue was purified by silica gel chromatography, eluting

with MeOH/EtOAc (1:9) to give 362.5 mg (54%) of the product.

¹H NMR (400 MHz, CD₃OD): δ 3.16-3.21 (m, 2H), 3.31-3.35

(m, 2H), 7.45-7.55 (m, 4H), 7.63 (d, 1H, J ) 8 Hz), 7.92-7.94

(m, 2H), 8.07-8.08 (m, 2H). MS (CI) m/e: 369 (M - H).

4-Nitr op h en eth yl-N-ben zoylsu lfon a m id e (55b). A mix-

ture of 4-nitrophenethylsulfonamide (2.3 g, 10.0 mmol), CH₃CN

(40 mL), K₂CO₃(2.80 g, 20.2 mmol), and benzoyl chloride (1.4

g, 10.0 mmol) was heated at reflux. After 3 h the mixture was

diluted with water and EtOAc. Filtration gave the product

1

(1.14 g) as a tan solid (34%). H NMR (300 MHz, DMSO-d₆):

δ 3.10 (t, 2H), 3.30 (m, 1H), 3.58 (t, 2H), 7.38 (t, 2H), 7.41 (m,

1H), 7.50 (d, 1H), 7.52 (d, 1H), 7.86 (d, 2H), 8.08 (d, 2H). MS

m/e: 333 (M - H).

2-(4-Am in oph en yl)-N-th iazol-2-ylacetam ide (15). A slurry

of 2-(4-nitrophenyl)-N-thiazol-2-ylacetamide (523 mg, 1.98

mmol) and 10% Pd/C (286 mg) in 40 mL of THF/ethanol (3:1)

was stirred under 1 atm of H₂for 8 h. The mixture was filtered

through a pad of Celite, which was washed with EtOAc. The

filtrate was concentrated to afford 417 mg (90%) of the product

as a yellow-orange solid. ¹H NMR (CDCl₃): δ 3.41 (s, 2H), 3.78

(bs, 2H), 6.39 (d, 1H), 6.66 (d, 1H), 6.86 (d, 1H), 7.14 (d, 1H),

11.22 (bs, 1H). MS (ES) m/e: 232 (M - H).

2-(3-Nitr op h en yl)eth a n esu lfon ic Acid (53a ). Hydrogen

peroxide (30% aqueous, 10.07 g, 5.0 equiv) was added to

thioacetic acid S-[2-(3-nitrophenyl)ethyl]ester (52a , 4.24 g,

18.82 mmol) in acetic acid (38 mL) at ambient temperature,

and the reaction mixture was stirred for 26 h. The mixture

was concentrated, taken up in a small amount of toluene, and

reconcentrated to give 4.22 g (97%) of the product. ¹H NMR

(300 MHz, CD₃OD): δ 3.30 (dd, 2H, J ) 11, 7 Hz), 3.53 (dd,

N-[2-(4-Am in oph en yl)acetyl]m eth an esu lfon am ide (16a).

N-[2-(4-nitrophenyl)acetyl]methanesulfonamide (50a , 0.9 g, 3.5

mmol) was suspended in MeOH (25 mL) and treated with 10%

578 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Uehling et al.

Pd/C (750 mg) under positive N₂pressure. The reaction

mixture was stirred under 1 atm of H₂for 7 h and then was

filtered through a pad of Celite that was washed with MeOH.

The filtrate was concentrated to give a crude product (750 mg,

94%), which was used without further purification. H NMR

(DMSO-d₆): δ 3.06 (s, 3H), 3.27 (s, 2H), 6.45 (d, 2H, J ) 8.2

Hz), 6.85 (d, 2H, J ) 8.2 Hz).

concentrated to supply the crude product as an off-white solid.

Purification by silica gel chromatography (eluting with 1:1

hexane/EtOAc) afforded 303 mg (66% yield) of the product as

a white solid. ¹H NMR (CDCl₃): δ 2.27 (s, 3H), 3.48 (s, 2H),

3.62 (bs, 2H), 4.32 (d, 2H, J ) 6.0 Hz), 5.60 (bs, 1H), 6.61 (d,

2H, J ) 8.4 Hz), 6.99 (d, 2H, J ) 8.4 Hz), 7.02 (d, 2H, J ) 8.8

Hz), 7.06 (d, 2H, J ) 8.0 Hz). MS (ES) m/e: 255.1 (M + H).

1

N-[2-(4-Am in oph en yl)acetyl]ben zen esu lfon am ide (16b).

The foregoing hydrogenation procedure was used with N-[2-

(4-nitrophenyl)acetyl]benzenesulfonamide (50b, 1.0 g, 3.12

mmol) and a reaction time of 3.5 h to give 470 mg of product

(52%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.25

(s, 2H), 3.28 (bs, 2H), 6.40 (d, 2H, J ) 8 Hz), 6.74 (d, 2H, J )

8 Hz), 7.64-7.51 (m, 3H), 7.82 (d, 2H, J ) 8 Hz). MS (ES⁺)

m/e: 313 (M + Na).

N-2[2-(4-Am in oph en yl)acetyl]ben zen esu lfon am ide (16c).

Tin(II) chloride hydrate (2.0 g, 8.86 mmol) was added to N-[2-

(4-nitrophenyl)acetyl]benzenesulfonamide (50c, 600 mg, 1.79

mmol) in 11.5:1 EtOH/N,N-DMF (33 mL), and the resulting

mixture was heated at 70 °C for 1 h. The mixture was then

poured onto ice, and the pH was adjusted to 8 with saturated

aqueous NaHCO₃. After addition of a small amount of EtOAc,

the mixture was stirred at room temperature for 1 h. The

layers were filtered through a pad of Celite and separated.

The organic layer was dried, filtered, and concentrated to yield

140 mg of the product (26%) as a tan solid. ¹H NMR (400 MHz,

DMSO-d₆): δ 2.31 (s, 3H), 3.14 (s, 2H), 6.75 (d, 2H, J ) 8 Hz),

7.25 (d, 2H, J ) 9 Hz), 7.64 (d, 2H, J ) 8 Hz), 7.92 (s, 3H). MS

m/e: 305.1 (M + H).

N-[2-(4-Am in op h en yl)et h yl]-4-m et h ylb en zen esu lfon -

a m id e (19b).²⁶The foregoing procedure was employed with

N-[2-(4-nitrophenyl)ethyl]-4-methylbenzenesulfonamide (497

mg, 1.55 mmol) and 10% Pd/C (299 mg) in absolute EtOH (35

mL). Crude product was purified by silica gel chromatography

(eluting with 3:2 hexane/EtOAc) to afford 181 mg (40% yield)

of the product as a pink solid. ¹H NMR (CDCl₃): δ 2.39 (s,

3H), 2.60 (t, 2H, J ) 6.8 Hz), 3.10 (q, 2H, J ) 6.8 Hz), 4.21

(m, 1H), 6.55 (d, 2H, J ) 8.0 Hz), 6.81 (d, 2H, J ) 8.0 Hz),

7.25 (d, 2H, J ) 8.0 Hz), 7.64 (d, 2H, J ) 8.0 Hz).

Gen er a l P r oced u r e for Syn th esis of F in a l Ta r gets via

Red u ctive Am in a tion of An ilin es w ith ter t-Bu tyl (2R)-

2-{[ter t-Bu tyl(dim eth yl)silyl]oxy}-2-(3-ch lor oph en yl)eth yl-

[(1R)-1-m eth yl-2-oxoeth yl]ca r ba m a te (10) a n d Dep r otec-

tion . P r oced u r e A. A solution of aldehyde 10 in CH₂Cl₂(0.1-

0.2 M) and aniline intermediate (0.67-1.2 equiv) was stirred

for 10-30 min, and NaBH(OAc)₃(2.0-2.5 equiv), followed by

catalytic glacial acetic acid (1-10 drops), was added. The

resulting mixture was stirred for a period of 8-48 h, then

added to CH₂Cl₂and saturated aqueous Na₂CO₃. The organic

layer was separated, and the aqueous layer was extracted with

CH₂Cl₂. The combined organic layers were dried over Na₂SO₄,

filtered, and concentrated to give the crude aniline intermedi-

ate, which was purified by silica gel chromatography. The

resulting aniline was subjected to acidic deprotection with 4

N HCl/dioxane or 6 N aqueous HCl. The crude target hydro-

chloride, which was obtained by concentration and/or precipi-

tation with Et₂O, was purified by silica gel chromatography

using a mixture of CHCl₃, MeOH, and concentrated NH₄OH

to supply the target as the free base.

N-[2-(3-Am in op h en yl)a cetyl]-4-m eth ylben zen esu lfon -

a m id e (17a ). The foregoing procedure was used with (3-

nitrophenyl)acetyl]benzenesulfonamide (50d , 600 mg, 1.79

1

mmol) to give the product (230 mg, 42%). H NMR (400 MHz,

DMSO-d₆): δ 2.34 (s, 3H), 3.24 (s, 2H), 3.30 (2H + H₂O), 5.00

(bs, 1H), 6.24 (d, 1H, J ) 8 Hz), 6.32 (s, 1H), 6.35 (d, 1H, J )

8 Hz), 6.84 (t, 1H, J ) 8 Hz), 7.32 (d, 2H, J ) 8 Hz), 7.70 (d,

2H, J ) 8 Hz). MS (ES^-) m/e: 303.1 (M - H).

1-Am in o-3-[({[(ph en ylsu lfon yl)am in o]car bon yl}am in o)-

m et h yl]b en zen e (17b ). To 1-nitro-3-[({[(phenylsulfonyl)-

amino]carbonyl}amino)methyl]benzene (56, 431.1 mg, 1.29

mmol) was added 10% Pd/C (43.1 mg) in 3:1 MeOH/THF (12.8

mL) under an argon atmosphere. The mixture was stirred

under 1 atm of H₂for 4 h at ambient temperature, then purged

with N₂, filtered through Celite, and concentrated to give 382.6

P r oced u r e B. A procedure similar to procedure A was

followed except that the aniline and aldehyde 10 were dis-

solved in MeOH and an excess of NaCN(BH)₃and catalytic

acetic acid were added. The mixture was stirred for 12-86 h

and worked up by partitioning between water and EtOAc. The

organic layer was separated and dried to give the crude

intermediate that was deprotected as described in the fore-

going procedure.

1

mg (98%) of the product. H NMR (300 MHz, CD₃OD): δ 4.15

(s, 2H), 6.47 (d, 1H, J ) 8 Hz), 6.54 (s, 1H), 6.58 (d, 1H, J )

8 Hz), 6.99 (t, 1H, J ) 8 Hz), 7.56 (t, 2H, J ) 7 Hz), 7.66 (t,

1H, J ) 7 Hz), 7.94 (d, 2H, J ) 7 Hz). MS (CI) m/e: 304 (M -

H).

Meth yl 4-[((2R)-2-{(ter t-Bu toxyca r bon yl)[(2R)-2-{[ter t-

bu tyl(dim eth yl)silyl]oxy}-2-(3-ch lor oph en yl)eth yl]am in o}-

p r op yl)a m in o]ben zoa te (In ter m ed ia te 20). Procedure B

was employed using methyl 4-aminobenzoate (430 mg, 2.84

mmol), aldehyde 10 (1.5 g, 3.41 mmol), acetic acid (650 mg,

10.8 mmol), MeOH (25 mL), and NaCNBH₃(0.45 g, 7.41

mmol). The reaction mixture was stirred for 3 days, the

reaction was quenched with 15% w/v solution of potassium

sodium tartrate, the mixture was then stirred for 30 min, and

the reaction was worked up. The crude product was purified

by chromatography, eluting with 9:1 hexane/EtOAc, to afford

932 mg of intermediate 20 (59%) as a foamy oil. ¹H NMR

(CDCl₃): δ -0.17 (s, 3H), -04 to 0.02 (m, 3H), 0.77-0.86 (m,

12H), 1.40 (s, 9H), 3.03-3.25 (m, 4H), 3.78 (s, 3H), 4.03-4.07

(m, 1H), 6.45 (d, 2H, J ) 8.6 Hz), 7.09-7.26 (m, 4H), 7.79 (d,

2H, J ) 8.6 Hz). MS (ES) m/e: 577 (M + H)⁺. 4-[((2R)-2-

{[(2R)-2-(3-Ch lor oph en yl)-2-h ydr oxyeth yl]am in o}pr opyl)-

a m in o]ben zoic Acid (36). Intermediate 20 (466 mg, 0.81

mmol) was treated with 4 N HCl/dioxane (10 mL) for 16 h to

give, after addition of Et₂O, 323 mg (85%) of methyl 4-[((2R)-

2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}propyl)amino]-

benzoate hydrochloride as a white solid. ¹H NMR (CD₃OD): δ

1.37 (d, 3H, J ) 6.4 Hz), 3.10-3.73 (m, 6H), 3.78 (s, 3H), 4.98

(dd, 1H, J ) 2.9, 10 Hz), 6.71 (d, 2H, J ) 8.8 Hz), 7.27 (m,

3H), 7.44 (s, 1H), 7.79 (d, 2H, J ) 8.8 Hz). MS (ES) m/e: 363

(M + H).

2-(3-Am in oph en yl)eth an esu lfon ic Acid Ben zen esu lfon -

yla m id e (17c). The foregoing procedure was used with 2-(3-

nitrophenyl)ethanesulfonic acid benzenesulfonylamide (55a ,

362.5 mg, 978.7 µmol) and 10% Pd/C (36.2 mg) in MeOH (4.9

mL). Purification by silica gel chromatography, eluting with

1

MeOH/EtOAc (1:9) gave 338.1 mg (99%) of product. H NMR

(300 MHz, CD₃OD): δ 2.90-3.01 (m, 2H), 3.22-3.26 (m, 2H),

6.50-6.57 (m, 2H), 6.67-6.81 (m, 1H), 6.97-7.12 (m, 1H),

7.43-7.51 (m, 3H), 7.92-7.94 (m, 2H). MS (CI) m/e: 339 (M -

H).

4-Am in op h en eth yl-N-ben zoylsu lfon a m id e (18). 4-Ni-

trophenethyl-N-benzoylsulfonamide (0.60 g) in MeOH (50 mL)

and acetic acid (1 mL) was shaken on a Parr apparatus with

20% Pd(OH)₂/C (0.2 g) under 45 psi of H₂. When no further

uptake was observed, the mixture was filtered through Celite

and evaporated to give a white solid (0.60 g). ¹H NMR (300

MHz, DMSO-d₆): δ 2.90 (t, 2H), 3.70 (m, 2H), 6.61 (d, 2H),

6.98 (d, 2H), 7.42 (m, 2H), 7.60 (m, 1H), 7.80 (m, 2H). MS (ES)

m/e: 303 (M - H).

2-(4-Am in op h en yl)-N-4-m eth ylben zyla ceta m id e (19a ).

An N₂-purged flask was charged with absolute EtOH (40 mL),

2-(4-nitrophenyl)-N-4-methylbenzylacetamide (515 mg, 1.81

mmol), and 10% Pd/C (312 mg). The mixture was placed under

1 atm of H₂and stirred for 16 h, then filtered through a pad

of Celite, washing with additional ethanol. The filtrate was

A portion (253 mg, 0.63 mmol) of the methyl ester obtained

above was dissolved in MeOH/water (12 mL) and treated with

LiOH‚H₂O (146 mg, 3.48 mmol) in water (4 mL). The mixture

â₃Adrenergic Receptor Agonists

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 579

was stirred for 16 h at ambient temperature, heated to 40 °C

for 7 h, then heated at 60 °C for 16 h. The mixture was allowed

to cool to ambient temperature, and the solvent was removed.

The residue was purified by chromatography eluting with

CHCl₃/MeOH/concentrated NH₄OH (6:1:0.1) to afford 172 mg

ter t-Bu tyl (2R)-2-{[ter t-bu tyl(d im eth yl)silyl]oxy}-2-(3-

ch lor oph en yl)eth yl[(1R)-1-m eth yl-2-(4-{[(m eth ylsu lfon yl)-

a m in o]m et h yl}a n ilin o)et h yl]ca r b a m a t e (In t er m ed ia t e

23). General procedure A was followed using aldehyde 10 (1.68

g, 3.80 mmol), N-(4-aminobenzyl)methanesulfonamide hydro-

chloride (14, 720 mg, 3.04 mmol), acetic acid (2 drops), and

NaBH(OAc)₃(1.50 g, 7.08 mmol). Workup and purification by

chromatography (eluting with 2:1 hexane/EtOAc) afforded 1.32

g (69%) of intermediate 23 as a colorless glass. ¹H NMR

(CDCl₃): δ -0.16 (s, 3H), -0.01 (s, 3H), 0.83 (m, 12H), 1.53

(s, 9H), 2.66 (s, 1.5H), 2.67 (s, 1.5H), 2.95-3.20 (m, 4H), 3.80-

4.00 (m, 2H), 4.09 (s, 1H), 4.10 (s, 1H), 6.49 (d, 2H, J ) 8.4

Hz), 7.11 (d, 2H, J ) 8.4 Hz), 7.18-7.22 (m, 4H). MS (ES)

m/e: 626.2, 628.4 (M + H).

N-{4-[((2R)-2-{[(2R)-2-Hydr oxy-2-(3-ch lor oph en yl)eth yl]-

a m in o}p r op yl)a m in o]ben zyl}m eth a n esu lfon a m id e (38).

Intermediate 23 (410 mg, 0.655 mmol) was stirred in 4 N HCl/

dioxane (10 mL) for 3 h and worked up according to the general

procedure to supply the crude material, which was dissolved

in a small amount of CHCl₃/MeOH/concentrated NH₄OH (30:

15:1) and purified by chromatography (eluting with 5:1 EtOAc/

MeOH) to supply 239 mg (89%) of target 38 as a colorless glass

that was judged by ¹H NMR to be a 10:1 mixture of R,R/minor

diastereomers. ¹H NMR (MeOD-d₄): δ 1.20 (d, 3H, J ) 7.2

Hz), 2.57 (s, 3H), 2.95-2.97 (m, 2H), 3.18-3.20 (m, 1H) 4.13

(s, 2H), 4.78-4.83 (m, 1H), 6.62 (d, 2H, J ) 8.4 Hz), 7.14 (d,

2H, J ) 8.4 Hz), 7.25-7.29 (m, 3H), 7.39 (s, 1H). HRMS (M +

H)⁺found: 412.1455. Calcd for C₁₉H₂₆Cl₁N₃O₃S₁: 412.1462.

Anal. (C₁₉H₂₆Cl₁N₃O₃S₁‚0.5H₂O‚0.25CHCl₃) C, H, N.

ter t-Bu tyl (2R)-2-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-2-(3-

ch lor op h en yl)eth yl-((1R)-1-m eth yl-2-{4-[2-oxo-2-(1,3-th i-

a zol-2-yla m in o)eth yl]a n ilin o}eth yl)ca r ba m a te (In ter m e-

d ia te 24). General procedure A was employed using aldehyde

10 (212 mg, 0.482 mmol), 2-(4-aminophenyl)-N-thiazol-2-

ylacetamide (15, 215 mg, 0.922 mmol), acetic acid (2 drops),

and NaBH(OAc)₃(230 mg, 1.09 mmol) in 3:1 CH₂Cl₂/N,N-DMF

(8 mL). The intermediate 24 (267 mg, 82%) was obtained as a

pale-yellow oil following workup and chromatographic purifi-

cation (eluting with 2:1 to 1:1 hexane/EtOAc). ¹H NMR

(CDCl₃): δ -1.15 (s, 3H), -0.01 (s, 3H), 0.80 (m, 12H), 1.43

(s, 9H), 3.00-3.21 (m, 4H), 3.80-4.00 (m, 2H), 3.62 (s, 2H),

3.80-4.00 (m, 2H), 6.50 (d, 2H, J ) 8 Hz), 6.95 (d, 1H, J ) 2

Hz), 7.03 (d, 2H, J ) 8 Hz), 7.10-7.35 (m, 4H), 7.39 (s, 1H).

MS (ES) m/e: 657 (M - H).

1

of acid 36 (78%) as a white solid judged by H NMR analysis

to be a 5.5:1 mixture of R,R/minor diastereomers. ¹H NMR

(400 MHz, CD₃OD) (R,R diastereomer): δ 1.26 (d, 3H, J ) 6.9

Hz), 3.01-3.09 (m, 2H), 3.30-3.38 (m, 3H), 6.62 (d, 2H, J )

8.6 Hz), 7.24-7.39 (m, 3H), 7.41 (s, 1H), 7.76 (d, 2H, J ) 8.6

Hz). HRMS ((M + H)⁺found: 349.1300. Calcd for C₁₈H₂₁

Cl₁N₂O₃: 349.1319. Anal. (C₁₈H₂₁Cl₁N₂O₃‚1.5H₂O) C, H, N.

-

ter t-Bu tyl (1R)-2-An ilin o-1-m eth yleth yl-[(2R)-2-{[ter t-

b u t yl(d im et h yl)silyl]oxy}-2-(3-ch lor op h en yl)et h yl]ca r -

ba m a te (In ter m ed ia te 21). Procedure A was followed using

aldehyde 10 (270.6 mg, 0.61 mmol), aniline (65 µL (0.713

mmol), NaBH(OAc)₃(305 mg, 1.44 mmol), and 1 drop of AcOH

in CH₂Cl₂(4.0 mL). Workup gave the crude product, which

was purified by chromatography (eluting with 10:1 followed

by 5:1 hexane/ethyl acetate) to give 274.0 mg (74%) of the

1

product as a colorless oil. H NMR (400, CDCl₃): δ -0.12 (s,

3H), 0.03 (s, 3H), 0.87 (m, 12H), 1.45 (s, 9H), 3.11-3.20 (m,

4H), 6.55 (d, 2H, J ) 10.8 Hz), 6.67 (t, 1H, J ) 10.8), 7.13-

7.26 (m, 5H), 7.32 (s, 1H).

(1R)-2-{[(1R)-2-An ilin o-1-m eth yleth yl]am in o}-1-(3-ch lo-

r op h en yl)eth a n ol Hyd r och lor id e (39). The product of the

foregoing procedure was dissolved in CH₂Cl₂(5 mL), and TFA

(1 mL) was added. The resulting mixture was stirred for 45

min and concentrated. The residue was taken up in 1:1 THF/6

N aqueous HCl (10 mL), and the mixture was stirred for 16 h.

Concentration followed by chromatography (eluting with 214:

15:1 CHCl₃/MeOH/concentrated NH₄OH) gave 119.1 mg of the

free base product. This material was dissolved in 1:1 CH₃CN/

H₂O (30 mL), and 2 mL of 1.0 N HCl was added. The mixture

was lyophilized to afford 136.9 mg (76% yield) of the product

hydrochloride judged by ¹H NMR analysis to be a 9.8:1 mixture

of R,R/minor diastereomers. ¹H NMR (400 MHz, CD₃OD) (R,R

diastereomer): δ 1.47 (d, 3H, J ) 6.4 Hz), 3.20 (dd, 1H, J )

13.8, 6.0 Hz), 3.53 (dd, 1H, J ) 13.8, 6.0 Hz), 3.70 (s, 1H),

5.04 (dd, 1H, J ) 10.0, 2.8 Hz), 7.05 (t, 1H, J ) 7.6 Hz), 7.34-

7.38 (m, 5H), 7.50 (s, 1H, 3H), 6.62 (d, 2H, J ) 8.6 Hz), 7.24-

7.39 (m, 3H), 7.41 (s, 1H), 7.76 (d, 2H, J ) 8.6 Hz). MS (ES)

m/e: 305.3 (M + H). Anal. (C₁₇H₂₁Cl₁N₂O‚2.0HCl‚0.5H₂O) C,

H, N.

ter t-Bu tyl (1R)-2-{4-[(Acetyla m in o)m eth yl]a n ilin o}-1-

m eth yleth yl-[(2R)-2-{[ter t-bu tyl(d im eth yl)silyl]oxy}-2-(3-

ch lor op h en yl)eth yl]ca r ba m a te (In ter m ed ia te 22). Gen-

eral procedure A was followed using aldehyde 10 (1.68 g, 3.80

mmol), N-(4-aminobenzyl)acetamide (13, 500 mg, 3.04 mmol),

2 drops of glacial acetic acid, and NaBH(OAc)₃(1.52 g, 7.17

mmol). The reaction time was 8 h. Workup and chromatogra-

phy (eluting with 1:1 hexane/EtOAc) afforded 1.18 g (67%) of

the intermediate 22. ¹H NMR (CDCl₃): δ -0.16 (s, 3H), -0.03

(s, 3H), 0.82 (m, 12H), 1.41 (s, 9H), 1.95 (s, 3H), 3.03-3.19

(m, 4H), 4.05-4.11 (m, 1H), 4.25 (d, 2H, J ) 5.6 Hz), 4.93 (bs,

0.5H), 5.20 (bs, 0.5H), 6.47 (d, 2H, J ) 8.8 Hz), 7.03 (d, 2H, J

) 8.4 Hz), 7.18-7.22 (m, 3H), 7.27 (s, 1H). MS (ES) m/e: 590.3,

591.6 (M + H).

2-{4-[((2R)-2-{[(2R)-2-Hydr oxy-2-(3-ch lor oph en yl)eth yl]-

a m in o}p r op yl)a m in o]p h en yl}-N-(1,3-t h ia zol-2-yl)a cet -

a m id e (40). To a solution of intermediate 24 (267 mg, 0.405

mmol) in THF (10 mL) was added 1.0 M tetrabutylammonium

fluoride/THF (610 µL, 0.610 mmol), and the mixture was

stirred for 16 h. The mixture was partitioned between EtOAc

and water, and the organic layer was separated, dried over

Na₂SO₄, filtered, and concentrated to provide 145 mg of a

residue that was dissolved in CH₂Cl₂(5 mL) and TFA (0.5 mL).

The mixture was stirred for 16 h and concentrated. The residue

was purified by chromatography (eluting with 150:30:1 CHCl₃/

MeOH/concentrated NH₄OH) to afford 93.9 mg (52%) of the

product as a bright-yellow solid judged by ¹H NMR analysis

to be a 11:1 mixture of R,R/minor diastereomers. ¹H NMR

(CDCl₃) (R,R diastereomer): δ 1.12 (d, 3H, J ) 6.0 Hz), 2.74

(dd, 1H, J ) 9.2, 12.2 Hz), 2.89 (dd, 1H, J ) 3.6, 12.2 Hz),

2.93-3.01 (m, 2H), 3.15 (d, 1H, J ) 8.4 Hz), 3.70 (s, 2H), 4.11

(bs, 1H), 4.63 (dd, 1H, J ) 3.6, 8.8 Hz), 6.59 (d, 2H, J ) 8.4

Hz), 6.92 (d, 1H, J ) 3.6 Hz), 7.07 (d, 2H, J ) 8.4 Hz), 7.18-

7.26 (m, 3H), 7.32 (d, 1H, J ) 3.6 Hz), 7.35 (s, 1H). HRMS (M

+ H)⁺found: 445.1485. Calcd for C₂₂H₂₅Cl₁N₄O₂S₁: 445.1465.

Anal. (C₂₂H₂₅Cl₁N₄O₂S₁) C, H, N.

N-{4-[((2R)-2-{[(2R)-2-Hydr oxy-2-(3-ch lor oph en yl)eth yl]-

a m in o}p r op yl)a m in o]ben zyl}a ceta m id e (37). Intermedi-

ate 22 (580 mg, 0.982 mmol) was treated with 4 N aqueous

HCl/dioxane (10 mL) for 3 h and worked up according to the

general procedure to supply an amorphous material, which

was dissolved in a small amount of 30:15:1 CHCl₃/MeOH/

concentrated NH₄OH and purified by chromatography (eluting

with 5:1 EtOAc/MeOH) to afford 256 mg of product 37 (69%)

as a colorless glass judged by ¹H NMR analysis to be a 6:1

mixture of R,R/minor diastereomers. ¹H NMR (CD₃OD) (major

diastereomer): δ 1.27 (d, 3H, J ) 6.8 Hz), 1.91 (s, 3H), 3.02-

3.08 (m, 2H), 3.22-3.33 (m, 1H), 4.17 (s, 2H), 6.62 (d, 2H, J )

8.4 Hz), 7.04 (d, 2H, J ) 8.4 Hz), 7.27-7.38 (m, 3H), 7.40 (s,

ter t-Bu tyl (2R)-2-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-2-

(3-ch lor op h en yl)et h yl[(1R)-1-m et h yl-2-(4-{2-[(m et h yl-

su lfon yl)a m in o]-2-oxoeth yl}a n ilin o)eth yl]ca r ba m a te (In -

ter m ed ia te 25). General procedure A was employed using

aldehyde 10 (720 mg, 1.6 mmol), N-[2-(4-aminophenyl)acetyl]-

methanesulfonamide (16a , 750 mg, 3.3 mmol), and NaBH-

(OAc)₃(1.0 g, 4.7 mmol) in CH₂Cl₂/N,N-DMF (8:3). After the

mixture was stirred for 2.5 days, 15% w/v aqueous potassium

1H). HRMS (M + H)⁺found: 376.1768. Calcd for C₂₀H₂₆

-

Cl₁N₃O₂: 376.1792. Anal. (C₂₀H₂₆Cl₁N₃O₂‚1H₂O‚0.5CHCl₃) C,

H, N.

580 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Uehling et al.

sodium tartrate was added and standard workup gave inter-

mediate 25 (1.0 g, 95%). ¹H NMR (DMSO-d₆): δ -0.16 (s, 3H),

-0.19 (s, 3H), 0.70-0.89 (m, 12H), 1.28-1.32 (m, 9H), 2.04

(2, 2H), 2.46-2.47 (m, 5H), 6.39-6.45 (m, 1H), 6.91 (d, 1H, J

) 8.4 Hz), 7.17-7.34 (m, 5H), 7.92 (s, 1H).

CH₂Cl₂(22 mL). After 16 h the reaction was worked up and

the crude material was purified by chromatography, eluting

with hexane/EtOAc (7:3 to 1:1) to yield intermediate 28 as a

white foam (112 mg, 31%). The foam was dissolved in 4 N HCl/

dioxane (10 mL), and the resulting solution was stirred for 16

h to give, after workup, a sticky solid. Purification by chro-

matography (eluting with 6:1:0.1 CHCl₃/MeOH/concentrated

NH₄OH) gave 31 mg (40% from 10) of the target 44 as an off-

N-(2-{4-[((2R)-2-{[(2R)-2-H yd r oxy-2-(3-ch lor op h en yl)-

eth yl]a m in o}p r op yl)a m in o]p h en yl}a cetyl)m eth a n esu l-

fon a m id e (41). Intermediate 25 (1.01 g, 1.5 mmol) was

dissolved in 4 N HCl/dioxane (10 mL), and the mixture was

stirred for 3 h. The solvent was removed, and the residue was

purified by chromatography, eluting with CHCl₃/MeOH/

concentrated NH₄OH (3:1:0.1 to 3:1.5:0.1), to afford target 41

1

white solid, mp 105-110 °C, judged by H NMR to be >95%

1

R,R diastereomer. H NMR (400 MHz, DMSO-d₆): δ 1.26 (d,

3H, J ) 7 Hz), 2.32 (s, 3H), 2.98-3.03 (m, 1H), 3.11-3.18 (m,

2H), 3.29 (s, 2H), 3.41-3.46 (m, 1H), 4.94 (dd, 1H, J ) 10, 3

Hz), 6.48-6.52 (m, 2H), 6.59 (s, 1H), 6.96 (t, 1H, J ) 8 Hz),

7.18 (d, 2H, J ) 8 Hz), 7.27-7.30 (m, 3H), 7.42 (s, 1H),

7.73 (d, 2H, J ) 8 Hz). HRMS (M + H)⁺found: 516.1728.

Calcd for C₂₆H₃₀N₃O₄S₁Cl₁: 516.1724. Anal. (C₂₆H₃₀N₃O₄S₁Cl₁‚

0.1CHCl₃‚0.85CH₃OH): C, H, N.

1

as a clear oil (380 mg, 56%) judged by H NMR to be a 12.3:1

mixture of R,R/minor diastereomers. ¹H NMR (DMSO-d₆) (R,R

diastereomer): δ 1.08 (d, 3H, J ) 5.9 Hz), 2.79-3.09 (m, 4 H),

3.13 (s, 3H), 3.17 (s, 2H), 4.07 (broad s, 1H), 4.71-4.77

(m, 1H), 6.48 (d, 2H, J ) 8.2 Hz), 6.92 (d, 2H, J ) 8.2 Hz),

7.30-7.36 (m, 3H), 7.40 (s, 1H). MS(ES) m/e: 440 (M + H)⁺,

462 (M + Na)⁺. HRMS (M + H)⁺found: 440.1407. Calcd

for C₂₀H₂₆N₃O₄S₁Cl₁: 440.1411. Anal. (C₂₀H₂₆N₃O₄S₁Cl₁‚

1.25H₂O): C, H, N.

1-[((2R)-2-{[(2R)-2-(3-Ch lor op h en yl)-2-h yd r oxyeth yl]-

a m in o}p r op yl)a m in o]-3-[({[(p h e n ylsu lfon yl)a m in o]-

ca r bon yl}a m in o)m eth yl]ben zen e (45). General procedure

B was employed using aldehyde 10 (461.6 mg, 1.04 mmol), and

1-amino-3-[({[(phenylsulfonyl)amino]carbonyl}amino)methyl]-

benzene (17b, 382.6 mg, 1.25 mmol) in MeOH (10.4 mL). The

mixture was heated to 50 °C, and NaCNBH₃(44.0 mg, 0.70

mmol) and acetic acid (45.0 µL, 0.79 mmol) were added. After

the mixture was stirred for 17 h, the reaction was quenched

by addition of a 15% aqueous w/v solution of potassium sodium

tartrate and worked up to yield the crude material. Purifica-

tion by chromatography, eluting with EtOAc/hexanes (2:3),

supplied intermediate 29. This material was dissolved in 4 N

HCl/dioxane (7.8 mL), and the mixture was stirred for 3 h.

Workup gave a material that was purified by chromatography,

eluting with CHCl₃/MeOH (4:1), to afford 184.2 mg (34%) of

target 45 as a tan solid judged by ¹H NMR analysis to be a

7.7:1 mixture of R,R/minor diastereomers. ¹H NMR (300 MHz,

DMSO-d₆) (R,R diastereomer): δ 1.11 (d, 3H, J ) 5.6), 2.86-

3.40 (m, 5H), 4.00 (bs, 2H), 4.77 (m, 1H), 5.58 (bs, 1H), 6.35

(d, 1H, J ) 7.2 Hz), 6.42 (d, 2H, J ) 8.0 Hz), 6.59 (bs, 1H),

6.95 (t, 1H, J ) 7.6 Hz), 7.33-7.38 (m, 4H), 7.43-7.48 (m, 3H),

7.80 (d, 2H, J ) 6.8 Hz). HRMS (M + H)⁺found: 517.1696.

Calcd for C₂₅H₂₉N₄O₄S₁Cl₁: 517.1676. Anal. (C₂₅H₂₉N₄O₄S₁Cl₁‚

0.75H₂O): C, H, N.

N-(2-{4-[((2R)-2-{[(2R)-2-H yd r oxy-2-(3-ch lor op h en yl)-

et h yl]a m in o}p r op yl)a m in o]p h en yl}a cet yl)b en zen esu l-

fon a m id e (42). General procedure A was employed using

aldehyde 10 (187 mg, 0.423 mmol), N-[2-(4-aminophenyl)-

acetyl]benzenesulfonamide (16b, 187 mg, 0.644 mmol), NaBH-

(OAc)₃(850 mg, 4.01 mmol), and acetic acid (3 drops) in 1:2

CH₂Cl₂/N,N-DMF (30 mL). After 16 h, the reaction was

quenched with aqueous 15% w/v potassium sodium tartrate

and worked up as described in the general procedure to afford,

after chromatography (eluting with 7:3 hexane/EtOAc), the Boc

amine silyl ether intermediate 26. This material was dissolved

in 1:1 6 N aqueous HCl/THF (6 mL), and the resulting solution

was stirred for 5 h. Removal of volatiles afforded a residue

that was purified by chromatography, eluting with CHCl₃/

concentrated MeOH/NH₄OH (6:1:0.1), to supply the product

1

(7 mg, 18%) as an off-white solid judged by H NMR analysis

to be a 26:1 mixture of R,R/minor diastereomers. ¹H NMR (400

MHz, CD₃OD) (R,R diastereomer): δ 1.33 (d, 3H, J ) 6.4 Hz),

3.06-3.19 (m, 3H), 3.24-3.31 (m, 3H), 4.92 (dd, 1H, J ) 9.8,

2.8 Hz), 6.57 (d, 2H, J ) 8.4 Hz), 7.02 (d, 2H, J ) 8.4), 7.31-

7.49 (m, 7H), 7.88 (d, 2H, J ) 7.2). HRMS (M + H)⁺found:

502.1532. Calcd for C₂₅H₂₈N₃O₄S₁Cl₁: 502.1567. Anal. (C₂₅H₂₈N₃-

O₄S₁Cl₁‚1.25H₂O): C, H, N.

3-{4-[((2R)-2-{[(2R)-2-(3-Ch lor oph en yl)-2-h ydr oxyeth yl]-

a m in o}p r op yl)a m in o]p h en yl}p r op a n oic Acid (35). Gen-

eral procedure A was employed using aldehyde 10 (520 mg,

1.18 mmol), 3-(4-aminophenyl)propanoic acid (233 mg, 1.41

mmol), NaBH(OAc)₃(394 mg, 1.76 mmol), glacial acetic acid

(81.0 µL, 1.41 mmol), and 1,2-dichloroethane as solvent. The

reaction mixture was stirred for 27.5 h and worked up to give

intermediate 30 (332 mg). A portion of this material (321 mg)

was dissolved in 4 N HCl/dioxane (4.0 mL). After 5 h, the

solution was concentrated and neutralized by addition of 3

drops of concentrated NH₄OH. The residue was purified by

chromatography, eluting with CHCl₃/MeOH/concentrated

NH₄OH (80:15:2, then 60:15:2), to afford material that was

dissolved in EtOH/H₂O (1:1). Lyophilization gave 137 mg (31%

N-({4-[((2R)-2-{[(2R)-2-Hydr oxy-2-(3-ch lor oph en yl)eth yl]-

a m in o}p r op yl)a m in o]p h en yl}a cetyl)-4-m eth ylben zen e-

su lfon a m id e (43). General procedure A was employed using

aldehyde 10 (169 mg, 0.382 mmol), N-[2-(4-aminophenyl)-

acetyl]-4-methylbenzenesulfonamide (16c, 140 mg, 0.460 mmol),

NaBH(OAc)₃(602 mg, 2.84 mmol), and acetic acid (3 drops) in

CH₂Cl₂(22 mL). Workup gave a residue that was purified by

chromatography, eluting with hexane/EtOAc (7:3) to provide

intermediate 27 as white foam (152 mg). This material was

dissolved in 4 N aqueous HCl (10 mL), and the resulting

solution was stirred for 6 h to give, after addition of Et₂O, an

off-white solid. This material was dissolved in CHCl₃/MeOH/

concentrated NH₄OH (6:1:0.2) and purified by chromatography

(eluting with 6:1:0.1 CHCl₃/MeOH/concentrated NH₄OH) to

yield 35 mg (33%) of product 43 as an off-white solid, mp 100-

1

overall) of target 35 judged by H NMR to be a 5.5:1 mixture

of R,R/minor diasteromers. ¹H NMR (300 MHz, DMSO-d₆) (R,R

diastereomer): δ 1.04 (d, 3H, J ) 5.8 Hz), 2.40-2.46 (m, 2H),

2.64-2.69 (m, 2H), 2.72 (d, 2H, J ) 6.2 Hz), 2.80-2.90 (m,

3H), 3.40 (bs, 2H), 4.64 (m, 1H), 5.30 (bs, 1H), 6.49 (d, 2H, J

) 8.4 Hz), 6.92 (d, 2H, J ) 8.4 Hz), 7.29-7.39 (m, 3H), 7.42

(s, 1H). Anal. (C₂₀H₂₅N₂O₃Cl₁‚0.75H₂O‚0.1EtOH): C, H, N.

1

105 °C, judged by H NMR to be >95% R,R diastereomer. H

NMR (400 MHz, CD₃OD): δ 1.36 (d, 3H, J ) 6.4 Hz), 2.38 (s,

3H), 3.12-3.14 (m, 1H), 3.20 (dd, 1H, J ) 12.6, 2.8 Hz), 3.30-

3.40 (m, 1H), 3.49 (m, 1H), 4.94 (dd, 1H, J ) 10.0, 3.2 Hz),

6.60 (d, 2H, J ) 8.0 Hz), 7.01 (d, 2H, J ) 8.4 Hz), 7.27 (d, 2H,

J ) 8.0 Hz), 7.32-7.35 (m, 3H), 7.47 (s, 1H), 7.78 (d, 2H,

2-{3-[((2R)-2-{[(2R)-2-Hydr oxy-2-(3-ch lor oph en yl)eth yl]-

am in o}pr opyl)am in o]ph en yl}-N-(ph en ylsu lfon yl)eth an e-

su lfon a m id e (46). General procedure B was employed using

aldehyde 10 (351.2 mg, 794.6 µmol), (2-(3-aminophenyl)-

ethanesulfonic acid benzenesulfonylamide (17c, 338.1 mg,

0.993 mmol), NaCNBH₃(41.8 mg, 0.67 mmol), and acetic acid

(42.8 µL, 0.75 mmol). The reaction mixture was stirred for 86

h, quenched with 15% w/v solution of potassium sodium

tartrate, and worked up to supply intermediate 31, which was

purified by chromatography, eluting with MeOH/EtOAc (1:4).

This material was dissolved in 4 N HCl in dioxane (5.5 mL),

J

for

) 8.4 Hz). HRMS (M + H)⁺found: 516.1734. Calcd

C₂₆H₃₀N₃O₄S₁Cl₁: 516.1724. Anal. (C₂₆H₃₀N₃O₄S₁Cl₁‚

0.25CHCl₃): C, H, N.

N-({3-[((2R)-2-{[(2R)-2-Hydr oxy-2-(3-ch lor oph en yl)eth yl]-

a m in o}p r op yl)a m in o]p h en yl}a cetyl)-4-m eth ylben zen e-

su lfon a m id e (44). General procedure A was employed using

aldehyde 10 (217 mg, 0.491 mmol), N-[2-(3-aminophenyl)-

acetyl]benzenesulfonamide (17a , 180 mg, 0.591 mmol), NaBH-

(OAc)₃(207 mg, 0.977 mmol), and acetic acid (3 drops) in

â₃Adrenergic Receptor Agonists

J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3 581

and the solution was stirred for 4 h. After concentration, the

residue was purified by chromatography, eluting with CHCl₃/

MeOH (3:1) containing concentrated NH₄OH, to give 142.7 mg

(33%) of product 46 judged by ¹H NMR to be >95% R,R

N-(2-{4-[((2R)-2-{[(2R)-2-H yd r oxy-2-(3-ch lor op h en yl)-

eth yl]a m in o}p r op yl)a m in o]p h en yl}eth yl)-4-m eth ylben -

zen esu lfon a m id e (49). Intermediate 34 (359 mg, 0.50 mmol)

was dissolved in 4 N HCl/dioxane (10 mL), and the mixture

was stirred for 3 h. After removal of solvent, the resulting gum

was purified by chromatography (eluting with 168:15:1 CHCl₃/

MeOH/concentrated NH₄OH) to supply 81.3 mg (32% yield)

of the product 49 as a white foam judged by ¹H NMR analysis

to be a 5.3:1 mixture of R,R/minor diastereomers. ¹H NMR

(CDCl₃) (R,R diastereomer): δ 1.11 (d, 3H, J ) 6.0 Hz), 2.38

(s, 3H), 2.59 (t, 2H, J ) 6.8 Hz), 2.72 (dd, 1H, J ) 8.8, 12.4

Hz), 2.84 (dd, 1H, J ) 3.6, 12.4 Hz), 2.90-2.98 (m, 3H), 3.00-

3.12 (m, 4H), 4.40 (bs, 1H), 4.61 (dd, 1H, J ) 3.6, 8.8 Hz), 6.50

(d, 2H, J ) 8.4 Hz), 6.84 (d, 2H, J ) 8.4 Hz), 7.17-7.25 (m,

5H), 7.32 (s, 1H), 7.64 (d, 2H, J ) 8.0 Hz). HRMS ((M + H)⁺

found: 502.1949. Calcd for C₂₆H₃₂Cl₁N₃O₃S₁: 502.1931. Anal.

(C₂₆H₃₂Cl₁N₃O₃S₁‚0.12CHCl₃) C, H, N.

Biologica l Meth od s. 1. In Vitr o F u n ction a l Assa ys. In

these experiments the â₃AR clone of Granneman and co-

workers was employed.³⁶Chinese hampster ovary (CHO) cells

expressing human â₁, â₂, or â₃AR were grown in DMEM/F12

(with pyroxidine‚HCl, 15 mM HEPES, l-glutamine), supple-

mented with 10% heat-inactivated FBS, 500 µg/mL G418, 2

mM ^L-glutamine, 100 units of penicillin G, and 100 µg of

streptomycin sulfate. One confluent flask of cells was tryp-

sinised and resuspended in the above medium at a concentra-

tion of 30-40000 cells/100 µL and plated into 96-well flat

bottom plates. The cells were then used for assay within 18-

24 h. The medium was aspirated from each well and replaced

with 180 µL of DMEM/F12 with 500 mM IBMX. The plate was

then placed back in the incubator for 30 min. Drugs were then

added to the wells (20 µL, 100 × required final concentration)

for 60 min. Responses were determined by measuring cAMP

levels of a 20 µL sample of extracellular media using a

scintillation proximity based radioimmunoassay (NEN Flash-

plates).

2. Bin d in g Assa ys. Human recombinant Sf9 cells express-

ing the cloned human â₁and â₂receptors were obtained using

the method of Smith and Teitler.³⁷Receptor binding assays

were carried out using the radioligand [¹²⁵I]cyanopindolol at

a concentration of 150 pM and the compound of interest at

six concentrations ranging from 0.21 to 50 µM. Binding

reactions were carried out for 1 h and 30 min for â₁and â₂

receptors, respectively, at 22 °C and terminated by filtration

through glass fiber filters (GF/B, Packard). Bound radioactivity

was measured with a scintillation counter (Topcount, Packard)

using a liquid scintillation cocktail (Microscint 0, Packard).

3. P h a r m a cok in etic Stu d ies in Dogs. Male beagle dogs

(weight range: 8-12 kg) were fasted overnight. On the

morning of the study, each compound was dissolved in 0.025

M methanesulfonic acid containing 5% mannitol and the dogs

were each fitted with two cephalic vein cannulae. Each dog

was dosed with with one compound intravenously via one

cannula at a dose level of 0.2 mg/kg body weight (5 min

infusion period). Blood was collected via the second cephalic

vein cannula at 0, 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2.5, 4, 6, 8, and

24 h. Resulting serum samples were prepared by protein

precipitation with acetonitrile and analyzed for compound

content by APCI LC-MS/MS using a Hypersil BDS C18

column (30 mm × 1 mm, 3µm) at ambient temperature. A

gradient mobile phase of 3-99% acetonitrile in 5 mM am-

monium acetate buffer, pH 4.5, was used at a flow rate of 80

µL/min. Detection was by multiple reaction monitoring (MRM)

on a Sciex API III+ with argon as the collision gas. Data

reduction was performed using Sciex MacQuan software. Non-

compartmental methods were used to calculate pharmaco-

kinetic parameters from the resulting serum concentration vs

time profiles.

1

diastereomer. H NMR (400 MHz, CD₃OD): δ 1.38 (d, 3H, J

) 6.8 Hz), 2.94-3.00 (m, 2H), 3.11-3.17 (m, 1H), 3.21-3.37

(m, 3H), 3.48-3.55 (m, 3H), 4.96 (dd, 1H, J ) 10.2, 2.8 Hz),

6.65 (d, 2H, J ) 8.4 Hz), 7.04 (dd, 2H, J ) 8.4 Hz), 7.30-7.46

(m, 7H), 8.00 (d, 2H, J ) 7.2 Hz). HRMS (M + H)⁺found:

552.1422. Calcd for C₂₅H₃₁Cl₁N₃O₅S₂: 552.1394. Anal. (C₂₅H₃₁

-

Cl₁N₃O₅S₂‚1.0H₂O): C, H, N.

N-Ben zoyl-2-{4-[((2R)-2-{[(2R)-2-(3-ch lor op h en yl)-2-

h yd r oxye t h yl]a m in o }p r o p y l)a m in o ]p h e n y l}e t h a n e -

su lfon a m id e (47). General procedure B was employed using

aldehyde 10 (1.05 g, 2.38 mmol), 4-aminophenethyl-N-ben-

zoylsulfonamide (18, 1.2 g, 3.94 mmol), glacial acetic acid (0.3

mL), and NaCNBH₃(250 mg) in MeOH (25 mL). Workup

afforded crude protected intermediate 32, which was stirred

with 4 N HCl/dioxane for 4 h. The solvent was evaporated,

and the residue was treated with aqueous Na₂CO₃and EtOAc.

The mixture was then filtered to give product 47 as a white

1

solid (110 mg, 9% yield), which was judged by H NMR to be

a 22:1 mixture of R,R/minor diastereomers. ¹H NMR (400

MHz, CD₃OD) (R,R diastereomer): δ 1.11 (d, 3H, J ) 5.6 Hz),

2.85-3.39 (m, 5H), 4.00 (bs, 1H), 4.68-4.88 (m, 1H), 5.55 (bs,

1H), 6.35 (d, 1H, J ) 7.2 Hz), 6.58 (bs, 1H), 6.95 (t, 1H, J )

7.6 Hz), 7.32-7.38 (m, 4H), 7.43-7.48 (m, 3H), 7.80 (d, 2H, J

) 6.8 Hz). MS m/e: 515 (M - H). Anal. (C₂₆H₃₀N₃O₄S₁Cl₁‚

1.0H₂O): C, H, N.

ter t-Bu tyl (2R)-2-{[ter t-Bu tyl(d im eth yl)silyl]oxy}-2-(3-

ch lor op h en yl)eth yl[(1R)-1-m eth yl-2-(4-{2-[(4-m eth ylben -

zyl)a m in o]-2-oxoeth yl}a n ilin o)eth yl]ca r ba m a te (In ter -

m ed ia te 33). General procedure A was employed using

aldehyde 10 (459 mg, 1.30 mmol), 2-(4-aminophenyl)-N-4-

methylbenzylacetamide (19a , 264 mg, 1.04 mmol), acetic acid

(3 drops), and NaBH(OAc)₃(482 mg, 2.28 mmol) in CH₂Cl₂

(10 mL). The mixture was stirred for 16 h and worked up.

Chromatography (eluting with 5:1 hexanes/EtOAc) supplied

1

583 mg (82%) of intermediate 33. H NMR (CDCl₃): δ -0.09

(s, 3H), 0.06 (s, 3H), 0.90 (s, 12H), 1.48 (s, 9H), 2.35 (s, 3H),

3.10-3.30 (m, 4H), 3.55 (S, 3H), 4.1 (bs, 1H), 4.39 (d, 2H, J )

5.7 Hz), 6.55 (d, 2H, J ) 8.4 Hz), 7.06 (d, 2H, J ) 8.4 Hz),

7.10-7.40 (m, 7H). MS (ES), m/e: 679.9, 681.9 (M + H).

2-{4-[((2R)-2-{[(2R)-2-Hydr oxy-2-(3-ch lor oph en yl)eth yl]-

a m in o}p r op yl)a m in o]p h en yl}-N-(4-m et h ylb en zyl)a cet -

a m id e (48). Intermediate 33 (583 mg, 0.857 mmol) was

dissolved in 4 N HCl/dioxane (10 mL), and the reaction mixture

was stirred for 3 h. Approximately 50 mL of Et₂O was added,

and the resulting precipitate was collected and purified by

chromatography (eluting with 168:15:1 CHCl₃/MeOH/concen-

trated NH₄OH) to supply 320 mg of the target 48 (80%) as a

white solid judged by ¹H NMR to be a 5.7:1 mixture of R,R/

minor diastereomers. ¹H NMR (CDCl₃) (R,R diastereomer): δ

1.11 (d, 3H, J ) 5.6 Hz), 2.27 (s, 3H), 2.73 (dd, 1H, J ) 8.4,

12.2 Hz), 2.84 (dd, 1H, J ) 3.6, 12.2 Hz), 2.93-2.97 (m, 2H),

3.11 (d, 1H, J ) 8.0 Hz), 4.31 (d, 2H, J ) 5.6 Hz), 4.40 (dd,

1H, J ) 3.6, 8.8 Hz), 5.68 (bs, 1H), 6.56 (d, 2H, J ) 8.4 Hz),

7.01-7.07 (m, 6H), 7.16-6.23 (m, 3H), 7.32 (s, 1H). HRMS ((M

+ H)⁺found: 466.2250. Calcd for C₂₇H₃₂Cl₁N₃O₂: 466.2261.

Anal. (C₂₇H₃₂Cl₁N₃O₂) C, H, N.

ter t-Bu tyl (2R)-2-{[ter t-bu tyl(d im eth yl)silyl]oxy}-2-

(3-ch lor op h en yl)eth yl{(1R)-1-m eth yl-2-[4-(2-{[(4-m eth yl-

p h en yl)su lfon yl]a m in o}et h yl)a n ilin o]et h yl}ca r b a m a t e

(In ter m ed ia te 34). General procedure A was employed using

aldehyde 10 (309 mg, 0.7 mmol), N-[2-(4-aminophenyl)ethyl]-

4-methylbenzenesulfonamide (19b, 163 mg, 0.56 mmol), NaB-

H(OAc)₃(262 mg, 1.24 mmol), and acetic acid (3 drops) in

anhydrous CH₂Cl₂(7.0 mL). Workup afforded 359 mg (90%)

of intermediate 34 as a colorless glass. ¹H NMR (CDCl₃): δ

-0.08 (s, 9H), 0.07 (s, 3H), 0.91 (m, 12H), 1.49 (s, 9H), 2.46 (s,

3H), 2.66 (t, 2H, J ) 6.9 Hz), 3.13-3.21 (m, 6H), 3.95-4.10

(m, 1H), 4.33 (m, 1H), 6.50 (d, 2H, J ) 8.4 Hz), 6.89 (d, 2H, J

) 8.4 Hz), 7.73 (d, 2H, J ) 8.1 Hz). MS (ES) m/e: 718.9, 715.8

(M + H).

4. Rod en t In fr a r ed Th er m ogr a p h y Stu d ies.³⁵CD-1 mice

(CD-1(ICR)BR) were anesthetized with isoflurane and shaved

to expose the interscapular region before IR imaging. The

animals were orally dosed, and at the appropriate times they

were anesthetized and scanned. Animals were dosed by oral

gavage with either vehicle (0.025 M methanesulfoxide at 10

582 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 3

Uehling et al.

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mL/kg) or the test compound (10 mL/kg (volume), 1 mg/kg,

0.1 mg/kg, and 0.01 mg/kg (concentration)). The mice were

placed in a manifold with nose ports for continual delivery of

isoflurane. To maintain body core temperature during scan-

ning, the rodents were placed on a tightly regulated heating

table (37 ( 0.1 °C). The heating table was housed in an

isothermal, nonreflective chamber (24 ( 0.1 °C, 50% relative

humidity). Upon closure of the chamber door, heat emissions

from the areas of interest were acquired using a high-

resolution InSb IR scanning detector (AGEMA Thermovision

900, Thermogenic Imaging, Billerica, MA) mounted 30 cm

above the area of interest. Images were recorded at 1 min

intervals for 5 min. A frame-averaging rate of 16 frames per

second was used for each designated time point. Acquired

images were analyzed for average temperatures using a

GlaxoWellcome (RTP, NC) image-processing software applica-

tion (RoboImage). Data were expressed as either average

temperature per area or the change in temperature per area

(drug treated minus vehicle treated). The data were calculated

as the mean and standard error of the mean from experiments

performed on 8-10 animals per treatment group. Two tailed

t-tests were performed to calculate P values. Correlation

coefficients were determined by regression analysis using

Sigma Plot.

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J M0101500

Article Doi

Synthesis and evaluation of potent and selective β3 adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres

DOI: 10.1021/jm0101500

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