Novel (4-piperidin-1-yl)-phenyl sulfonamides as potent and selective human β3 agonists

Article abstract of DOI:10.1016/S0968-0896(01)00114-6

A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human β₃-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl

Full text of DOI:10.1016/S0968-0896(01)00114-6

Bioorganic & Medicinal Chemistry 9 (2001) 2045–2059
Novel (4-Piperidin-1-yl)-phenyl Sulfonamides as Potent
and Selective Human ꢀ3 Agonists
Baihua Hu,a,* John Ellingboe,a Stella Han,b Elwood Largis,b
Kitae Lim,a Michael Malamas,a Ruth Mulvey,b Chuansheng Niu,a
Alexander Oliphant,a Jeffrey Pelletier,a Thiruvikraman Singanallore,a
Fuk-Wah Sum,a Jeff Tillettb and Victoria Wonga
aChemical Sciences, Wyeth-Ayerst Research, Pearl River, NY 10965, USA
bCardiovascular/Metabolic Diseases Research, Wyeth-Ayerst Research, Pearl River, NY 10965, USA
Received 8 December 2000; accepted 19 March 2001
Abstract—A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the
human b3-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl
sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the b3 receptor. Modification of
the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human b3 agonists with low
affinities for b1- and b2-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the b3 potency while
maintaining the selectivity. For example, sulfonamide 48 is a potent full b3 agonist (EC50=0.004 mM, IA=1.0) with >500-fold
selectivity over b1- and b2-ARs. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
rate increase (b1-AR activity), and muscle tremor (b2-
AR activity). In addition, these compounds have shown
antihyperglycemic effects in animal models of non-insu-
lin-dependent diabetes mellitus (NIDDM).6 However,
human clinical trials with these early b3-AR agonists
have been disappointing due to a lack of selectivity or
potency. Subsequently, cloning and expression of the
human and rat b3-ARs indicated a significant difference
between the two.5 Thus, a cloned human receptor assay
would offer major advantages over rodent models for
the identification of potent and selective b3-AR ago-
nists.
The subdivision of b-adrenergic receptors (b-AR) into
b1- and b2-ARs has led to the development of b1- and
b2-antagonists and/or agonists which have been useful
for the treatment of cardiovascular disease and asthma.
A third ‘atypical’ b-AR, now called b3-AR, was identi-
fied in the early 80s. It was found that the b3 receptor
mediates various pharmacological and physiological
effects such as lipolysis in white adipocyte tissue (WAT),
thermogenesis in brown adipocyte tissue (BAT), and
relaxation of urinary bladder detrusor tissue.1 Conse-
quently, a potent and selective b3-AR agonist2,3 has the
potential to be a therapeutic agent in the treatment of
obesity, type II diabetes, and frequent urination. Early
developments in the b3-AR agonist field, which were
based on the rodent b3-AR receptor, are represented by
CL 316243 (1),3c BRL 37344 (2),4 and CGP 12177A (3)5
(Chart 1). These compounds produced great agonist
activity for the stimulation of lipolysis and energy
expenditure (b3-AR activity), and to a small extent heart
L-770644 (4a),2b thiazole benzenesulfonamide (4b),7 and
SB-226552 (5)8 represent the compounds of the next
generation currently emerging from preclinical develop-
ment. These compounds were evaluated in Chinese
hamster ovary (CHO) cells expressing the cloned human
b3-AR receptor that would more accurately predict the
effects that can be expected in humans. These com-
pounds are full agonists and highly selective at the
human b3-AR. Despite all these recent developments
there is still not a single therapy available for the treat-
ment of type II diabetes (NIDDM), obesity, frequent
urination and related diseases. A potent and selective
*Corresponding author. Fax: +1-845-732-5561; e-mail: hub@war.
wyeth.com
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00114-6

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B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
Chart 1. Compounds 1–6.
b3-AR agonist is therefore highly desirable for the
potential treatment of such disease states. Herein we
report the discovery of novel (4-piperidin-1-yl)-phenyl
sulfonamides of general structure 6 as potent and selec-
tive agonists of the human b3-AR receptor.
aminoketone 13. Reduction of 13 with NaBH4 afforded
the ethanolamine 14, which was used as a LHS moiety
without debenzylation.
Scheme 3 depicts the synthesis of racemic aminoalcohol
18. The requisite dibenzylaminoalcohol 17 was obtained
starting from the chloride 1511 by the same dibenzyla-
mine/NaBH4 sequence, which was described in Scheme
2. Compound 17 was then transformed into the desired
racemic aminoalcohol 18 by catalytic hydrogenolysis
with Pd on charcoal.
Chemistry
The (4-piperidin-1-yl)-phenyl sulfonamides of general
structure 6 were readily prepared by utilizing reductive
amination of right-hand side (RHS) piperidones with
appropriate left-hand side (LHS) arylethanolamines or
aryloxypropanolamines. Many of arylethanolamines or
aryloxypropanolamines are commercially available or
easily prepared by known methods.9 A synthesis of the
carbostyril LHS moiety is shown in Scheme 1. Alkyla-
tion of phenol 79c with equimolecular amounts of (2S)-
glycidyl 3-nitrobenzene sulfonate (8) in DMF using
potassium carbonate as a base provided enantiomeri-
cally pure oxirane 9. Regioselective ring opening of
oxirane 9 with dibenzylamine followed by debenzylation
with ammonium formate/Pd on charcoal in methanol
furnished the desired phenoxypropanolamine 11.
The corresponding R-enantiomer 21 was prepared from
the enantiomerically enriched bromohydrin 19, which
was obtained according to a literature procedure.11
Nucleophilic substitution of bromide 19 with sodium
azide in DMSO at ambient temperature provided azide
20 in high yield. Debenzylation and azide reduction by
Scheme 2. Synthesis of pyridyl ethanol amine 14: (a) Bn2NH, DMF,
61%; (b) NaBH4, MeOH, 73%.
Synthesis of 3-pyridyl ethanol amine 14 was achieved as
illustrated in Scheme 2. Treatment of chloracetyl pyri-
dine 1210 with dibenzylamine yielded the corresponding
Scheme 1. Synthesis of phenoxypropanolamine 11: (a) K2CO3, ace-
tone, 75%; (b) Bn2NH, MeOH; (c) HCO2NH4, Pd/C, MeOH, 78%
over (b) and (c).
Scheme 3. Synthesis of racemic 18: (a) Bn2NH, DMF, 61%; (b)
NaBH4, MeOH/THF, 90%; (c) H2, Pd/C, MeOH, 91%.

B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
2047
catalytic hydrogenation with ammonium formate/Pd on
charcoal furnished the desired phenethanolamine 21
(Scheme 4).
carbazole13 analogue 33 is a partial b3-AR agonist with
an IA of 0.63. Thus, only the 5-carbostyril (8-hydroxy-
3,4-dihydro-1H-quinolin-2-one)14 and benzimidazo-
lone15 LHS moieties were further explored for their b1/
b2-AR selectivity profiles. Many sulfonamide analogues
were prepared in both the benzimidazole and carbostyril
series, and the results are shown in Tables 2 and 3. In
both series, highly substituted benzenesulfonamides
(31a–31e, 32a, 32b, 32e) and simple alkyl sulfonamides
(31f, 31g, 32f) (see Figure 1 for definitions of a–f) are
potent (0.16ꢀ0.001 mM) at the b3-AR receptor and
selective against the b2-AR receptor, but these deriva-
tives showed basically no selectivity against the b1-AR
receptor. All of the tested phenoxypropanolamines
showed potent activity (EC50=0.03ꢀ0.002 mM) at the
b1-AR receptor even though they are partial agonists.
Hence, these phenoxypropanolamine derivatives were
not pursued further due to the lack of b3-AR selectivity.
Sulfonamides of general structure 27 were conveniently
prepared as outlined in Scheme 5. The nitro group in
2212 was reduced by catalytic hydrogenation to provide
aniline 23. Sulfonylation of the aniline 23 with sulfonyl
chlorides followed by hydrolysis of the ketal with con-
centrated HCl gave the corresponding piperidones 27.
Alternatively, the piperidones were synthesized by the
same reduction/sulfonylation sequence starting from the
ketone 2512 instead of the ketal 22. The desired final
products (29–43) were prepared by utilizing reductive
amination of piperidones 27 with the appropriate aryl-
ethanolamines or aryloxypropanolamines 28. The
reductive aminations were carried out with hydrogen
and catalytic palladium in ethanol, or with sodium tri-
acetoxyborohydride in DMF. Either hydrolysis of alkyl
esters in NaOH or hydrogenation of benzyl esters with
Pd on charcoal gave the desired carboxylic acids. The
aniline substituents (R1) for compounds 24, 27, 31, 32,
42, and 43 are illustrated in Figure 1.
Next, we examined various phenethanolamine LHS
moieties. Since the natural agonists adrenaline and nor-
adrenaline are catechols, many sulfonamides with
different catechol bioisosteres were prepared. As antici-
pated, the catechol analogue 37 is a very potent
(EC50=0.008 mM) full b3-AR agonist (IA=0.93). The
orientation of the two hydroxyl groups (3,4-di-OH) is
essential for maintaining b3-AR activity as the isomeric
2,4-dihydroxyl analogue 38 and 3-methoxy-4-hydroxyl
analogue 39 are both at least 100-fold less potent.
Unsubstituted analogue 34, mono hydroxyl analogues
(35 and 36), and 7-amide indole analogue 40 all showed
anticipated low potency. Surprisingly, replacement of the
catechol LHS with 3-pyridine, which has been demon-
strated2 to be a potent catechol bioisostere, resulted in a
low potency agonist 41 in our series (Table 4).
The N-butyl substituted analogue 48 was prepared as
outlined in Scheme 6. Reductive amination between
aniline 23 and butyraldehyde furnished the desired ketal
44, which was transformed into the corresponding
ketone 45 by HCl hydrolysis. Sulfonylation followed by
reductive amination, as previously described in Scheme
5, furnished the N-butyl analogue 47. Carboxylic acid
48 was produced by catalytic hydrogenation of sulfo-
namide 46 with amine 21.
Biological Activity
In order to expedite the identification of potent b3-AR
agonists with high selectivity versus b2- and b1-ARs, we
first optimized the LHS moiety of the agonist while
holding the piperidone-aniline RHS constant. The cur-
rent b3-AR agonist LHS moieties belong to two general
structural classes:1 phenoxypropanolamines and phe-
nethanolamines. First we examined agonists with a
variety of phenoxypropanolamines for their ability to
stimulate an increase in cAMP in CHO cells expressing
the cloned human b3-AR receptor. As illustrated in
Table 1, unsubstituted analogue 29 is a 1.55 mM partial
agonist (defined as IA=0.2 ꢀ 0.90) with 57% activa-
tion relative to (À)-isoproterenol. The 4-hydroxyl ana-
logue 30 also has low potency (EC50=0.96 mM) at the
b3-AR receptor, but it is a full agonist (defined as
IA>0.90) with IA value of 0.97. A few heterocyclic
derivatives were also examined, led to the identification
of three potent analogues (31a, 32a, 33). However, the
Scheme 4. Synthesis of R-enantiomer 21. (a) NaN3, DMSO, 94%; (b)
HCO2NH4, Pd/C, EtOH, 76%.
Scheme 5. Synthesis of sulfonamides 29–43.

2048
B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
Figure 1. Anline substituents (R1) for compounds 24, 27, 31, 32, 42 and 43.
Table 1. Variation of LHS of Phenoxypropanolamines
Compound
Ar
EC50 (mm)
(b3-AR)a
IA
(b3-AR)b
29
30
31a
32a
33
Phenyl
4-OH-Phenyl
4-(2-Benzimidazolone)
5-Carbostyril
4-(9H-Carbazole)
1.55
0.96
0.16
0.004
0.022
0.57
0.97
1.15
1.0
0.63
ab3-AR Agonistic activity was assessed by measurement of cAMP
accumulation levels in CHO cells expressing the human b3-AR.
bThe maximal amount of cAMP obtained by (À)-isoproterenol was
defined as 100% and the relative maximal response of each compound
was expressed as intrinsic activity (IA).
Scheme 6. Synthesis of N-butyl sulfonamide 48: (a) PrCHO, NaB-
H(OAc)3, THF, 41%; (b) HCl, 82%; (c)BnCO2CH2SO2Cl, Et3N,
CH2Cl2, 19%: (d) NaBH(OAc)3, DMF, 35%; (e) Pd/C, EtOH, 31%.
showed very limited selectivity (ꢀ100-fold against b2-
and b1-ARs). Little or no improvement in selectivity
was achieved by a variety of sulfonamides, which
included 3,4-dimethoxy benzenesulfonamide 42e, het-
erocyclic sulfonamides (42d and 43h), urea benzene-
sulfonamides (42b and 43b, 42c) and aliphatic
sulfonamides (42f and 42g). To our delight, the intro-
duction of a free carboxylic acid group (43i) decreased
b1- and b2-AR activities (for b1-AR: IA=0.09; for b2-
AR: EC50=7.40 mM, IA=0.30), but retained b3-AR
activity (EC50=0.05 mM, IA=0.97), thus providing
the desired b3-AR selectivity. The corresponding ester
43j is much less selective. This observation seems to
be consistent with an earlier discovery16 that a free
carboxylic group enhanced b3-AR selectivity. It was
subsequently found that this was a general phenom-
enon; the related thiophene analogue 43m, phenoxy
We speculated that the catechol portion may be chemi-
cally or enzymatically unstable. To improve the stability
of the LHS moiety, a combination2a of 4-hydroxyl and
3-methyl sulfonamide was examined. Our results
showed that 43a is a potent (0.013 mM) b3-AR agonist
and exhibited full intrinsic activity (IA=1.07). Pre-
sumably the bulky methyl sulfonamide improves the
stability while the sulfonamide N–H is able to mimic a
hydroxyl group.
Since the racemate 42b and the R-isomer 43b exhibited
comparable activity/selectivity profile, the racemic mix-
tures 42c–42g (see Figure 1 for definitions of R1) were
then screened for a structure–activity relationship study
(Table 5). Although 43a is a potent b3-AR agonist, it

B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
2049
acetic acid 43k and aliphatic sulfonamide 43o
were likewise found to be potent and selective at the
b3-AR receptor while the corresponding esters (such
as 43l and 43n) were found to be much less selective
(Table 6).
Both the activity and selectivity could be further mod-
ified by substitution of the sulfonamide N–H with an
alkyl group. Compared to 43o, the N-butyl analogue 48
has increased (9-fold) b3-AR activity (EC50=0.004 mM,
IA=1.0) while maintaining the selectivity (1250-fold vs
the b2-AR and 500-fold vs the b1-AR).17
Table 2. Variation of RHS of Benzimidazolones
Conclusions
In this study, we have shown that a combination of 4-
hydroxyl with a 3-methyl sulfonamide substituent on
the aromatic nucleus of LHS of the (4-piperidin-1-yl)-
phenyl) sulfonamides is a potent bioisostere for the
catechol group, resulting in the identification of many
potent full agonists at the human b3-AR. The introduc-
tion of a polar carboxylic acid functionality on the RHS
of the compounds diminished both b1- and b2-AR
activities while retaining activity at b3-AR. N-Alkyla-
tion with a hydrophobic alkyl group on the (4-piperidin-
1-yl)-phenyl sulfonamide (43o) further increased the b3
Compound
b3-ARa
EC50 mm (IA)
b2-AR
b1-AR
EC50 mm (IA)a
EC50 mm (IA)a
31a
31b
31c
31d
31e
31f
31g
0.16 (1.15)
0.1 (0.73)
100 (0.4)
(0)
(0)
0.014 (0.44)
0.023 (0.41)
0.007 (0.33)
0.01 (0.31)
0.012 (0.23)
0.002 (0.4)
0.011 (0.34)
0.003 (0.58)
0.01 (1.04)
0.016 (0.96)
0.008 (0.81)
0.059 (0.78)
(0.01)
(0.03)
(0)
(0)
potency. Thus,
a highly potent (EC50=0.004 mM,
IA=1.0) and selective (500-fold against b1- and 1250-fold
against b2-AR agonist activity) human b3-AR agonist
(48) has been identified.
ab-ARs agonistic activities were assessed by measurement of cAMP
accumulation levels in CHO cells expressing the human b-ARs; the
intrinsic activities were given as a fraction of the maximal stimulation
with isoproterenol.
Table 3. Variation of RHS of Carbostyrils
Table 5. Variation of RHS of Phenethanolamines
Compound
b3-AR
b2-AR
b1-AR
EC50 mm (IA)a
EC50 mm (IA)a
EC50 mm (IA)a
Compound
b3-AR
b2-AR
b1-AR
EC50 mm (IA)a
EC50 mm (IA)a
EC50 mm (IA)a
32a
32b
32e
32f
0.004 (1.1)
0.001 (1.0)
0.02 (0.96)
0.005 (1.1)
(0.02)
(0)
(0.03)
(0.02)
0.03 (0.63)
0.01 (0.97)
0.009 (1.04)
0.03 (0.63)
43a
43b
42b
42c
42d
42e
42f
42g
43h
43i
0.013 (1.07)
0.001 (1.1)
0.003 (1.2)
0.066 (1.24)
0.033 (1.07)
0.02 (1.16)
0.006 (0.87)
0.016 (1.0)
0.079 (1.3)
0.05 (0.97)
0.013 (1.0)
1.35 (0.35)
1.00 (1.0)
1.62 (0.99)
0.09 (0.9)
0.07 (1.0)
0.12 (0.56)
0.25 (0.65)
1.33 (0.65)
0.32 (0.96)
0.37 (0.71)
0.25 (0.99)
(0.09)
1.16 (0.94)
4.47 (1.05)
0.87 (0.57)
0.083 (0.45)
0.17 (0.5)
4.55 (1.02)
6.49 (1.08)
7.40 (0.3)
aSee footnote a in Table 2.
Table 4. Variation of LHS of Phenethanolamines
43j
0.073 (0.46)
0.03 (0.42)
aSee footnote a in Table 2.
Compound
Ar
*Config. EC50 (mm)a IAb
(b3-AR) (b3-AR)
Table 6. Carboxyl-promoted enhancement of b3-AR selectivity
34
35
36
37
38
39
40
Phenyl
3-OH-Phenyl
4-OH-Phenyl
R
3.16
0.61
0.92
0.008
0.80
0.7
Compound
b3-AR
b2-AR
b1-AR
EC50 mm (IA)a
EC50 mm (IA)a
EC50mm (IA)a
R+S
R+S
R
R+S
R+S
R+S
0.88
0.97
0.93
0.64
1.0
43k
43l
43m
43n
43o
47
0.013 (1.0)
0.011 (0.87)
0.013 (1.05)
0.002 (0.89)
0.035 (0.92)
0.002 (0.89)
0.004 (1.0)
0.015 (0.9)
1.87 (0.55)
0.26 (0.77)
1.95 (0.57)
0.082 (0.46)
(0.12)
0.082 (0.46)
5.0 (0.45)
2.42 (0.59)
4.92 (0.67)
0.097 (0.61)
2.40 (0.65)
0.33 (0.24)
(0.12)
0.33 (0.24)
2.0 (0.51)
2.17 (0.86)
3,4-di-OH-Phenyl
2,4-di-OH-Phenyl
3-OMe-4-OH-Phenyl
4-(1H-Indole-7-
15.4
3.84
1.05
carboxylic acid amide)
3-Pyridyl
4-OH-3-MeSO2NH-Phenyl
41
43a
R+S
R
10.6
0.013
0.83
1.07
48
4a
aSee footnote a in Table 1.
bSee footnote b in Table 1.
aSee footnote a in Table 2.

2050
B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
Experimental
of 2-chloro-1-pyridin-3-yl-ethanone (12)10 (9.65 g,
50 mmol) in 100 mL of DMF. The mixture was stirred
at 60 ꢁC for 2 h. The solvent was removed and residue
was purified by column chromatography on silica gel
using EtOAc/hexanes (1: 4) as the eluent to give the title
compound (9.6 g, 61%) as a white solid: 1H N MR
(CDCl3) 3.72 (s, 4H), 3.78 (s, 2H), 7.20–7.50 (m, 11H),
8.02–8.07 (m, 1H), 8.73 (dd, J=4.8, 1.8 Hz, 1H), 9.03
(brs, 1H); MS (ES) m/z : 317.0 (MH+); HRMS calcd
for C21H20N2O (M+): 316.1576; found: 316.1547. Anal.
calcd for C21H20N2O: C, 79.72; H, 6.37; N, 8.85; found:
C, 79.52; H, 6.41; N, 8.68.
General
1H NMR spectra were determined with a Bruker DPX-
300 spectrometer at 300 MHz. Chemical shifts d are
expressed in parts per million relative to the internal
standard tetramethylsilane and J (coupling constant) in
Hz. Electrospray (ES) mass spectra were recorded in
positive or negative mode on a Micromass Platform
spectrometer. Electron impact and high-resolution mass
spectra were obtained on a Finnigan MAT-90 spectro-
meter. Combustion analyses were obtained using a
Perkin-Elmer Series II 2400 CHNS/O analyzer. Chro-
matographic purifications were performed by flash
chromatography using Baker 40 mm silica gel. Thin-
layer chromatography (TLC) was performed on Anal-
tech silica gel GHLF 250 M prescored plates.
2-Dibenzylamino-1-pyridin-3-yl-ethanol (14). To a stirred
solution of 13 (0.95 g, 3 mmol) in 100 mL of MeOH at rt
was added NaBH4 (0.56 g, 15 mmol). After 2 h, the
solution was poured into water, extracted with Et2O,
dried with MgSO4, and concentrated. Recrystallization
from Et2O/hexanes gave the title compound (0.7 g,
73%) as a crystalline solid: 1H NMR (CDCl3) 2.55–2.70
(m, 2H), 3.53 (d, J=13.3 Hz, 2H), 3.82 (s, 1H), 3.91 (d,
J=13.3 Hz, 2H), 4.69 (dd, J=8.9, 5.9 Hz, 1H), 7.21 (dd,
J=7.4, 4.4 Hz, 1H), 7.20–7.50 (m, 12H), 7.50–7.60 (m,
1H), 8.47 (dd, J=4.8, 1.7 Hz, 1H); MS (ES) m/z: 319.2
(MH+); HRMS calcd for C21H23N2O (MH+):
319.1810; found: 319.1809. Anal. calcd for C21H22N2O:
C, 79.21; H, 6.96; N, 8.80; found: C, 79.26; H, 6.92; N,
8.94.
8-Benzyloxy-(5S)-5-oxiranylmethoxy-3,4-dihydro-1H-qui-
nolin-2-one (9). A solution of 8-benzyloxy-5-hydroxy-
3,4-dihydro-1H-quinolin-2-one (7)9c (3.0 g, 11.1 mmol)
and (2S)-(+)glycidyl 3-nitrobenzenesulfonate (2.87 g,
11.1 mmol) in 150 mL of acetone was treated with
K2CO3 (1.84 g, 13.3 mmol) and stirred at reflux for 1
day. The suspension was cooled to rt; the solid was fil-
tered; and the filtrate was concentrated to dryness. The
residue was partitioned between CH2Cl2 and water. The
aqueous layer was extracted with CH2Cl2. The organic
layers were combined and dried over MgSO4 and
concentrated. The residue was purified by silica gel
chromatography using 10–50% EtOAc/hexanes as
eluent to give the title compound as an off-white
solid (2.7 g, 75%): 1H NMR (DMSO-d6) d 2.41 (t,
J=7.1 Hz, 2H), 2.69 (dd, J=5.1, 2.7 Hz, 1H), 2.75–
2.86 (m, 4H), 3.78 (dd, J=11.4, 6.3 Hz, 1H), 4.23
(dd, J=11.4, 2.6 Hz, 1H), 5.09 (s, 2H), 6.54 (d,
J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 7.25–7.45
(m, 3H), 7.51 (d, J=8.2 Hz, 2H), 9.08 (s, 1H); MS (ES)
m/z 326.0 (MH+); HRMS calcd for C19H20NO4
(MH+): 326.1392; found: 326.1343. Anal. calcd for
C19H19NO4: C, 70.14, H, 5.89; N, 4.30; found: C, 70.14;
H, 5.69; N, 4.20.
N-[2-Benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-
methanesulfonamide (16). Prepared from N-[2-benzyl-
oxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide
(15)11 as described for 13 to give the title compound as a
1
white solid in 61% yield: H NMR (CDCl3) d 2.94 (s,
3H), 3.77 (s, 2H), 3.82 (s, 2H), 5.16 (s, 2H), 6.75 (brs,
1H), 6.96 (d, J=8.7 Hz, 1H), 7.20–7.50 (m, 15H), 7.67
(dd, J=8.7, 2.1 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H); MS
(ES) m/z: 515.2 (MH+); HRMS calcd for C30H30N2O4S
(M+): 514.1926; found: 514.1927. Anal. calcd for
.
C30H30N2O4S 0.25H2O: C, 69.45; H, 5.92; N, 5.40;
found: C, 69.15; H, 5.61; N, 5.16.
N-[2-Benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-
phenyl]-methanesulfonamide (17). Prepared from 16 as
described for 14 to give the title compound as a crystal-
5-(3-Amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-di-
hydro-1H-quinolin-2-one (11). Dibenzylamine (1.46 g,
7.4 mmol) was added to a stirred solution of 9 (2.0 g,
6.2 mmol) in 100 mL of MeOH. After refluxing over-
night the mixture was cooled down to rt and 10% Pd/C
(0.5 g) and HCO2NH4 (3.15 g, 50 mmol) were added.
The suspension was refluxed for another 2 h. After
cooling the suspension the reaction mixture was filtered
through Celite. The filtrate was concentrated to give the
title compound as a pale grey solid (1.20 g, 78%): 1H
NMR (DMSO-d6) d 2.42 (t, J=7.1 Hz, 2H), 2.74
(dd, J=12.8, 8.2 Hz, 1H), 2.81 (t, J=7.0 Hz, 2H),
2.95 (dd, J=12.8, 3.4 Hz, 1H), 3.65–3.95 (m, 3H),
6.45 (d, J=8.8 Hz, 2H), 6.62 (d, J=8.8 Hz, 2H),
8.38 (s, 1H), 8.77 (brs, 1H); MS (ES) m/z 252.9
(MH+); HRMS calcd for C12H16N2O4 (M+): 252.1188;
found: 252.1199.
1
line solid in 90% yield: H NMR (CDCl3) d 2.58 (d,
J=6.7 Hz, 2H), 2.86 (s, 2H), 2.92 (s, 2H), 3.55 (d,
J=13.5 Hz, 2H), 3.70 (d, J=13.5 Hz, 2H), 4.11 (s, 1H),
4.64 (t, J=6.7 Hz, 1H), 5.10 (s, 2H), 6.92 (d, J=8.5 Hz,
1H), 7.00 (dd, J=8.5, 2.0 Hz, 1H), 7.20–7.50 (m, 16H),
7.89 (brs, 1H); MS (ES) m/z 517.1 (MH+); HRMS calcd
for C30H32N2O4S (M+): 516.2083; found: 516.2074.
.
Anal. calcd for C30H32N2O4S 0.37H2O: C, 68.88; H,
6.31; N, 5.36; found: C, 68.52; H, 6.13; N, 5.12.
N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-me-
thanesulfonamide (18). To a stirred suspension of 17
(1.03 g, 2 mmol) and 10% Pd/C (0.4 g) in MeOH
(100 mL) at rt was added anhydrous HCO2NH4 (1.26 g,
20 mmol) under a N2 atmosphere. The resulting mixture
was refluxed for 2 h. After cooling to rt the catalyst was
removed by filtration through a Celite pad and washed
with MeOH. The filtrate was evaporated under reduced
2-Dibenzylamino-1-pyridin-3-yl-ethanone (13). Dibenzyl-
amine (29.6 g, 150 mmol) was added to a stirred solution

B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
2051
pressure to give the title compound9b as a pale yellowish
solid (0.45 g, 91%): H NMR (DMSO-d6) d 2.62 (dd,
J=12.6, 8.7 Hz, 1H), 2.75 (dd, J=12.6, 3.7 Hz, 1H),
2.90 (s, 3H), 4.47 (dd, J=8.7, 3.7 Hz, 1H), 6.84 (d,
J=9.1 Hz, 1H), 6.96 (dd, J=9.1, 2.0 Hz, 1H), 7.16 (d,
J=2.1 Hz, 1H), 8.44 (s, 1H); MS (ES) m/z 246.7
(MH+); HRMS calcd for C9H14N2O4S (M+): 246.0674;
found: 246.0672. Anal. calcd for C9H14N2O4S
reaction was stirred for 18 h. The reaction mixture was
concentrated. The residue was dissolved in CH2Cl2 and
washed with diluted HCl. The white solid in water layer
was collected and dried to give the title compound as a
1
1
white solid (2.5 g, 43%): H NMR (DMSO-d6) d 1.92
(brs, 4H), 2.06 (s, 3H), 3.68 (brs, 4H), 3.93 (s, 4H), 7.06
(d, J=8.4 Hz, 2H), 7.33 (brs, 2H), 7.68 (d, J=9.0 Hz,
2H), 7.71 (d, J=9.0 Hz, 2H), 10.24 (brs, 1H), 10.38 (s,
1H); MS (ES) m/z 432.3 (MH+); HRMS calcd for
C21H25N3O5S (M+): 431.1515; found: 431.1530.
.
.
0.7H2O 0.4MeOH: C, 41.58; H, 6.31; N, 10.30; found:
C, 41.37; H, 5.98; N, 9.90.
N-[5-((1R)-2-Azido-1-hydroxy-ethyl)-2-hydroxy-phenyl]-
methanesulfonamide (20). To a stirred solution of N-[2-
benzyloxy-5-(2-bromo-(1R)-1-hydroxy-ethyl)-phenyl]-
methanesulfonamide (19)11 (15.05 g, 0.038 mol) in
DMSO (150 mL) was added NaI (3.76 g, 0.038 mol) and
NaN3 (9.48 g, 0.15 mol). The mixture was stirred for 5
days under a N2 atmosphere. The reaction mixture was
poured onto water and extracted three times with
EtOAc. The combined organic layers were dried over
Na2SO4 and concentrated. The residue was triturated
with water and hexanes to give the title compound as
1-(4-Amino-phenyl)-piperidin-4-one hydrochloride (26). A
mixture of 1-(4-nitro-phenyl)-piperidin-4-one (25)12
(4.0 g, 18 mmol) and 500 mg of 10% Pd/C in 75 mL of
CH2Cl2 was hydrogenated under H2 (5ꢀ10 psi) for 1 h.
The catalyst was then removed by filtering through a
short pad of silica gel. The filtrate was treated with HCl
gas and the precipitate was collected to give 2.0 g (58%)
of the title compound as a tan solid: 1H NMR (DMSO-
d6) d 2.44 (t, J=6.0 Hz, 4H), 3.65 (t, J=6.0 Hz, 4H),
7.14 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 2H); MS
(ES) m/z 190.9 (MH+); HRMS calcd for C11H15N2O
(MH+): 190.1106; found: 190.1096. Anal. calcd for
1
a yellow solid (12.85 g, 94%): H NMR (CDCl3) d 2.93
.
.
(s, 3H), 3.45 (d, J=9.0 Hz, 2H), 3.46 (m, 1H), 5.11
(s, 2H), 6.80 (s, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.15
(dd, J=6 Hz, 2.1Hz, 1H), 7.26 (s, 1H), 7.39 (s, 5H), 7.53
(d, J=2.1 Hz, 1H); MS (ES) m/z 361.4 (M-H)À. Anal.
C11H14N2O 1.8H2O 2HCl: C, 44.69; H, 6.68; N, 9.48;
found: C, 44.57; H, 6.76; N, 9.18.
N-{4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-
acetamide (27a). Compound 24 (2.2 g, 5.1 mmol) was
treated with concentrated HCl (50 mL) at 0 ꢁC and then
allowed to warm to rt. After 30 min, ꢀ20 mL of 5 N
NaOH was added dropwise and the precipitate was
collected by filtration, and dried over P2O5 to give the
.
.
calcd for C16H18N4O4S 0.75H2O 0.1 hexanes: C,
51.69; H, 5.46; N, 14.53; found: C, 51.45; H, 5.29; N,
14.52.
N-[5-(2-Amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-
methanesulfonamide (21). Prepared from 20 as described
for 18 to give the title compound as a tan solid in 76%
1
title compound as a white solid (1.2 g, 61%): H N MR
(DMSO-d6) d 2.06 (s, 3H), 2.43 (t, J=5.8 Hz, 4H), 3.53
(t, J=5.8 Hz, 4H), 6.85–7.05 (m, 4H), 7.62 (d,
J=9.0 Hz, 2H), 7.71 (d, J=9.0 Hz, 2H), 9.81 (s, 1H),
10.35 (s, 1H); MS (ES) m/z 388.3 (MH+); HRMS calcd
for C19H21N3O4S (M+): 387.1253; found: 387.1272.
1
yield: H NMR (MeOH-d4) d 2.95 (s, 3H), 2.99 (dd,
J=9.7, 9.2 Hz, 1H), 3.07 (dd, J=9.7, 3.6 Hz, 1H), 4.75
(dd, J=9.2, 3.6 Hz, 1H), 6.90 (d, J=8.3 Hz, 1H), 7.12
(dd, J=8.3, 2.1 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 8.44
(s, 1H); MS (ES) m/z 246.7 (MH+); HRMS calcd for
C9H14N2O4S (M+): 246.0674; found: 246.0672. Anal.
General procedure for the preparation of benzene
sulfonamides 27b–h, k, l, n
.
calcd for C9H14N2O4S 1.6MeOH: C, 42.78; H, 6.85; N,
9.42; found: C, 42.57; H, 6.45; N, 9.06.
To a stirred solution of 26 (1 equiv) in dioxane (0.05–
0.5 M) was added Et3N(5–10 equiv) followed by the
benzenesulfonyl chloride (as specified) (1–1.5 equiv).
After being stirred over 1 day, the mixture was con-
centrated and the residue was purified by silica gel
chromatography using 0–10% MeOH/CH2Cl2 as
eluant.
4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylamine (23).
A mixture of 8-(4-nitro-phenyl)-1,4-dioxa-8-aza-spir-
o[4.5]decane (22)12 (3.5 g, 13.3 mmol) and 10% Pd/C
(0.5 g) in 100 mL of EtOH/CH2Cl2 (2:1) was pressurized
with 30 psi H2 and shaken over 1 h. The catalyst was
then removed by filtering through a short pad of silica
gel to give the title compound (2.8 g, 90%) as a grey
solid. The compound was characterized as a di-HCl salt:
1H NMR (DMSO-d6) d 1.85–2.00 (m, 4H), 3.00–3.10
(m, 4H), 3.93 (s, 4H), 6.60 (d, J=6.0 Hz, 2H), 6.80 (d,
J=6.0 Hz, 2H); MS (ES) m/z 235.2 (MH+); HRMS
calcd for C13H18N2O2 (M+): 234.1380; found: 234.1371.
4-(3-Hexyl-ureido)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-
benzenesulfonamide (27b). 4-(3-Hexylureido)benzene-
sulfonyl chloride,2c grey solid, 42% yield: 1H N MR
(CDCl3) d 0.88 (t, J=7.0 Hz, 3H), 1.20–1.60 (m, 8H),
2.45–2.60 (m, 4H), 3.20–3.75 (m, 2H), 3.50–3.60 (m,
4H), 4.90 (brs, 1H), 6.50 (brs, 1H), 6.82 (d, J=8.5 Hz,
2H), 6.97 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.7 Hz, 2H),
7.56 (d, J=8.7 Hz, 2H); MS (ES) m/z 473.5 (MH+);
HRMS calcd for C24H25N4O4S (MH+): 473.2233;
found: 473.2220.
.
.
Anal. calcd for C13H18N2O2 0.25H2O 2 HCl: C, 50.01;
H, 6.63; N, 8.99; found: C, 49.89; H, 6.50; N, 8.90.
N-{4-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-phenylsulfa-
moyl]-phenyl}-acetamide (24). To a stirred solution of 23
(2.8 g, 11.9 mol) in 1.4-dioxane (150 mL) and Et3N
(7 mL) was added a solution of N-acetylsulfanilyl chlo-
ride (3.5 g, 15 mmol) in 75 mL of 1,4-dioxane at rt. The
4-[4-(3-Cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazol-1-
yl])-N-[4-(4-oxo-piperidin-1-yl)-phenyl]benzenesulfona-

2052
B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
mide (27c). 4-[(3-Cyclopentyl-propyl)-5-oxo-4,5-dihy-
dro-tetrazol-1-yl]-phenylsulfonyl chloride,2b yellowish
solid, 22% yield: H NMR (DMSO-d6) d 0.90–1.80 (m,
2H), 6.98 (d, J=12 Hz, 2H), 7.40 (m, 1H), 7.97 (dd,
J=3 Hz, 1H), 8.75 (dd, J=6 Hz, 1H), 8.90 (d, J=3 Hz,
1H); MS (ES) m/z 331.9 (MH+); HRMS calcd for
C16H17N3O3S (MH+): 332.1063; found: 332.1063. Anal.
calcd for C16H16N3O3S 0.3H2O: C, 57.05; H, 5.27; N,
12.48; found: C, 56.91; H, 5.31; N, 12.19.
1
17H), 2.36 (t, J=6.0 Hz, 2H), 3.49 (t, J=6.0 Hz, 2H),
3.96 (t, J=7.0 Hz, 2H), 6.86 (d, J=6.7 Hz, 2H), 6.94 (d,
J=6.7 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 8.06 (d,
J=8.8 Hz, 2H), 9.92 (s, 1H); MS (ES) m/z 525.1
(MH+); HRMS calcd for C26H32N6O4S (M+ ):
524.2205; found: 524.2193. Anal. calcd for C26H32N6O4S:
C, 59.52; H, 6.15; N, 16.02; found: C, 59.50; H, 6.28; N,
15.81.
.
4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid
(27i). To a stirred solution of 26 (free base) (2.85 g,
15 mmol) in acetone (150 mL) was added 4-(chloro-
sulfonyl)benzoic acid (1.10 g, 5 mmol) in three portions.
After 2 h, the acetone was removed and the residue was
treated with diluted aqueous NaHCO3. The solid was
filtered off and the filtrate was acidified with diluted
HCl. The precipitate was collected and dried to give the
title compound as a pale grey solid (0.9 g, 48%): 1H
NMR (DMSO-d6) d 2.36 (t, J=6.0 Hz, 4H), 3.49 (t,
J=6.0 Hz, 4H), 6.87 (d, J=9.3 Hz, 2H), 6.91 (d,
J=9.3 Hz, 2H), 7.77 (d, J=8.1 Hz, 2H), 8.04 (d,
J=8.1 Hz, 2H), 9.97 (s, 1H), 13.10 (brs, 1H); MS (ES)
m/z 374.9 (MH+); HRMS calcd for C18H19N2O5S
(MH+): 375.1009; found: 375.1009. Anal. calcd for
5-Pyridin-2-yl-thiophene-2-sulfonic acid [4-(4-oxo-piperi-
din-1-yl)-phenyl]-amide (27d). 5-Pyridin-2-yl-thiophene-
1
2-sulfonyl chloride, white solid, 41% yield: H N MR
(DMSO-d6) d 2.37 (t, J=6.0 Hz, 4H), 3.52 (t, J=6.0 Hz,
4H), 6.89 (d, J=9.0 Hz, 2H), 7.02 (d, J=9.0 Hz,
2H), 7.39 (dd, J=4.2, 1.5 Hz, 1), 7.42 (d, J=2.1 Hz,
1H), 7.76 (d, J=2.1 Hz, 1H), 7.90 (dd, J=7.8, 1.5 Hz,
1H), 8.00 (d, J=7.8 Hz, 1H), 8.53 (d, J=4.2 Hz, 1H),
10.05 (s, 1H); MS (ES) m/z 413.9 (MH+); HRMS
calcd for C20H19N3O3S2 (M+): 413.0867; found:
.
.
413.0877. Anal. calcd for C20H19N3O3S2 0.44H2O: C,
57.00; H, 4.74; N, 9.97; found: C, 57.01; H, 4.71; N,
9.81.
C18H18N2O5S 0.16H2O: C, 57.30; H, 4.89; N, 7.43;
found: C, 57.03; H, 5.18; N, 7.35.
4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-benzoic acid
ethyl ester (27j). A stirred solution of 27i (1.4 g,
3.74 mmol) in 50 mL of EtOH was treated with HCl gas
at rt. After 4 h the solution was concentrated and the
residue was dissolved in concentrated HCl (200 mL) at
rt. After another 3 h the pH was adjusted to ꢀ 5 and the
precipitate was collected by filtration, and dried over
P2O5 to give the title compound as a yellowish solid
3,4-Dimethoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benze-
nesulfonamide (27e). 3,4-Dimethoxybenzenesulfonyl
chloride, dull yellow solid, 26%: H NMR (CDCl3) d
2.54 (t, J=4.5 Hz, 4H), 3.55 (t, J=4.5 Hz, 4H), 3.83 (s,
3H), 3.91 (s, 3H), 6.21 (brs, 1H), 6.83–6.87 (m, 3H),
6.94–7.03 (m, 2H), 7.12 (d, J=1.5 Hz, 2H); MS (ES) m/z
391.0 (MH+); HRMS calcd for C19H23N2O5S (MH+):
391.1328; found: 391.1333.
1
1
(1.1 g, 70%): H NMR (CDCl3) d 1.40 (t, J=7.1 Hz,
3H), 2.36 (t, J=6.0 Hz, 4 ), 3.56 (t, J=6.0 Hz, 4H), 4.41
(q, J=7.1 Hz, 2H), 6.82 (d, J=8.9 Hz, 2H), 6.97 (d,
J=8.9 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 8.07 (d,
J=8.3 Hz, 2H); MS (ES) m/z 403.2 (MH+); HRMS
calcd for C20H23N2O5S (MH+): 403.1328; found:
403.1330. Anal. calcd for C20H22N2O5S: C, 59.69; H,
5.51; N, 6.96; found: C, 59.71; H, 5.79; N, 6.74.
Butane-1-sulfonic acid [4-(4-oxo-piperidin-1-yl)-phenyl]-
amide (27f). 1-Butanesulfonyl chloride, crystalline solid,
55% yield: H NMR (DMSO-d6) d 0.83 (t, J=7.3 Hz,
1
3H), 1.25–1.40 (m, 2H), 1.55–1.70 (m, 2H), 2.40
(t, J=5.9 Hz, 4H), 2.94 (t, J=7.6 Hz, 2H), 3.54
(t, J=5.9 Hz, 4H), 7.00 (d, J=9.0 Hz, 2H), 7.09
(d, J=9.0 Hz, 2H), 9.34 (s, 1H); MS (ES) m/z 311.0
(MH+); HRMS calcd for C15H22N2O2S (M+):
310.1351; found: 310.1375. Anal. calcd for
C15H22N2O2S: C, 58.04; H, 7.14; N, 9.02; found: C,
57.78; H, 6.95; N, 8.83.
{4-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-phenoxy}-
acetic acid methyl ester (methyl ester of 27k). (4-
Chlorosulfonyl-phenoxy)-acetic acid methyl ester,18
grey solid, 28% yield: 1H NMR (CDCl3) d 2.54 (t,
J=6.0 Hz, 4H), 3.55 (t, J=6.0 Hz, 4H), 3.82 (s, 3H),
4.67 (s, 2H), 6.80–7.20 (m, 6H), 7.64 (d, J=68.7 Hz,
2H); MS (ES) m/z 418.9 (MH+); HRMS calcd for
C20H23N2O6S (MH+): 419.1271; found: 419.1271.
Octane-1-sulfonic acid [4-(4-oxo-1-piperidinyl)-phenyl]-
amide (27g). 1-Octanesulfonyl chloride, white solid,
1
60% yield: H NMR (DMSO-d6) d 0.84 (t, J=5.4 Hz,
3H), 1.15–1.40 (m, 10H), 1.60–1.75 (m, 2H), 2.40
(t, J=4.5 Hz, 4H), 2.94 (t, J=5.7 Hz, 2H), 3.54
(t, J=4.5 Hz, 4H), 6.99 (d, J=6.9 Hz, 2H), 7.09
(d, J=6.9 Hz, 2H), 9.31 (s, 1H); MS (ES) m/z 367.0
(MH+); HRMS calcd for C19H30N2O2S (M+):
366.1977; found: 366.1969. Anal. calcd for
C19H30N2O2S: C, 62.26; H, 8.25; N, 7.64; found: C,
62.40; H, 7.98; N, 7.59.
3-[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-thiophene-
2-carboxylic acid methyl ester (27l)
2-(Methoxycarbonyl)thiophene-3-sulfonyl
chloride,
1
white solid, 29% yield: H NMR (DMSO-d6) d 2.37 (t,
J=6.0 Hz, 4H), 3.50 (t, J=6.0 Hz, 4H), 3.89 (s, 3H),
6.90 (d, J=9.1 Hz, 2H), 6.96 (d, J=9.1 Hz, 2H), 7.33 (d,
J=6.9 Hz, 1H), 7.90 (d, J=6.9 Hz, 1H), 9.50 (s, 1H);
MS (ES) m/z: 395.0 (MH+); HRMS calcd for
C17H19N2O5S2 (MH+): 395.0736; found: 395.0721.
Anal. calcd for C17H18N2O5S2: C, 51.76; H, 4.60; N,
7.10; found: C, 51.87; H, 4.49; N, 7.05.
Pyridine-3-sulfonic acid[4-(4-oxo piperidin-1-yl)-phenyl]
amide (27h). 3-Pyridinesulfonyl chloride, yellow solid,
1
13% yield: H NMR (CDCl3) d 2.54 (t, J=6 Hz, 4H),
3.56 (t, J=6 Hz, 4H), 6.79 (s, 1H), 6.85 (d, J=12 Hz,

B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
2053
[4-(4-Oxo-piperidin-1-yl)-phenylsulfamoyl]-acetic
benzyl ester (27n)
acid
1.40–1.65 (m, 2H), 1.95–2.10 (m, 2H), 2.06 (s, 3H),
2.50–3.20 (m, 5H), 3.55–3.75 (m, 2H), 3.96 (d,
J=5.2 Hz, 2H), 4.15–4.25 (m, 1H), 5.70 (brs, 1H), 6.80
(d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 6.90–7.00
(m, 3H), 7.25–7.35 (m, 2H), 7.59 (d, J=9.0 Hz, 2H),
7.69 (d, J=9.0 Hz, 2H), 9.70 (s, 1H), 10.37 (s, 1H); MS
(ES) m/z 539.1 (MH+); HRMS calcd for C28H35N4O5S
(MH+): 539.2328; found: 539.2357.
Benzyloxycarbonylmethylsulfonylchloride,19 white solid,
1
50% yield: H NMR (DMSO-d6) d 2.42 (t, J=6.0 Hz,
4H), 3.55 (t, J=6.0 Hz, 4 H), 4.16 (s, 2H), 5.16 (s, 2H),
6.99 (d, J=9.0 Hz, 2H), 7.10 (d, J=9.0 Hz, 2H), 9.73 (s,
1H); MS (ES) m/z: 403.2 (MH+); HRMS calcd for
C20H22N2O5S (M+): 402.1250; found: 402.1237. Anal.
calcd for C20H22N2O5S: C, 59.69; H, 5.51; N, 6.96;
found: C, 59.69; H, 5.82; N, 6.90.
N-(4-{[4-(4-{[(2S)-2-Hydroxy-3-(4-hydroxyphenoxy)pro-
pyl]amino}-1-piperidinyl) anilino]sulfonyl}phenyl)aceta-
mide (30). Method A: 27a and (2S)-1-amino-3-(4-
benzyloxy-phenoxy)-propan-2-ol,21 grey solid, 58%
1
yield: H NMR (DMSO-d6) d 1.40–1.65 (m, 2H), 1.95–
General procedures for the preparation of compounds
29–43, 47, 48
2.15 (m, 2H), 2.06 (s, 3H), 2.50–3.20 (m, 5H), 3.55–3.70
(m, 2H), 3.80–3.90 (m, 1H), 4.05–4.20 (m, 1H), 5.70
(brs, 1H), 6.67 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz,
2H), 6.78 (d, J=9.0 Hz, 2H), 6. 88 (d, J=9.0 Hz, 2H),
7.58 (d, J=9.0 Hz, 2H), 7.69 (d, J=9.0 Hz, 2H), 8.97 (s,
1H), 10.37 (s, 1H); MS (ES) m/z 555.1 (MH+); HRMS
calcd for C28H35N4O6S (MH+): 555.2277; found:
555.2267.
Method A
A mixture of the piperidone (as specified, 1 equiv) and the
arylethanolamine or aryloxypropanolamine (as specified, 1
equiv) in EtOH (0.01–0.5M) was hydrogenated in the
presence of 10% Pd/C (5–15 weight%) under H2 (5ꢀ20
psi) for overnight. The catalyst was then removed by fil-
tering through a short pad of silica gel. The filtrate was
concentrated and purified by preparative TLC or silica gel
chromatography using 0–10% MeOH/CH2Cl2 as eluent.
N-[4-({4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-
benzimidazol-4-yl)oxy] propyl}amino)-1-piperidinyl]anili-
no}sulfonyl)phenyl]acetamide (31a). Method A: 27a and
(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-
1
benzimidazol-2-one,15 white solid, 52% yield: H N MR
Method B
(DMSO-d6) d 1.60–1.80 (m, 2H), 2.00–2.15 (m, 2H),
2.06 (s, 3H), 2.50–2.70 (m, 2H), 2.90–3.20 (m, 3H),
3.60–3.75 (m, 2H), 4.15–4.25 (m, 1H), 5.70 (brs, 1H),
6.61 (t, J=8.7 Hz, 1H), 6.80–6.92 (m, 5H), 7.60 (d,
J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 9.72 (brs, 1H),
10.42 (s, 1H), 10.65 (s, 1H), 10.80 (s, 1); MS (ES) m/z
595.2 (MH+); HRMS calcd for C29H35N6O6S (MH+):
595.2339; found: 595.2332.
The piperidone (as specified, 1 equiv) and the aryl-
ethanolamine or aryloxypropanolamine (as specified, 1
equiv) were mixed in DMF (0.05–0.3 M) and then treated
with NaBH(OAc)3 (1.5–5 equiv) and acetic acid (1.5–5
equiv). After stirring at rt under a N2 atmosphere for 1–
24 h the mixture was quenched with 1 NNaOH and
then poured into a saturated aqueous NaHCO3. The
precipitate which formed was collected and purified by
preparative TLC or silica gel chromatography using 0–
10% MeOH/CH2Cl2 as eluent.
4 - {[(Hexylamino)carbonyl]amino} - N - {4 - [4 - ({(2S) - 2 -
hydroxy-3-[(2-oxo-2,3-dihydro-1H-benzimidazol-4-yl)ox-
y]propyl}amino)-1-piperidinyl]phenyl}benzenesulfonamide
(31b). Method A: 27b and (S)-4-[2-hydroxy-3-amino-
propoxy]-1,3-dihydro-2H-benzimidazol-2-one,15 white
solid, 57% yield: 1H NMR (DMSO-d6) d 0.86 (t,
J=6.8 Hz, 3H), 1.20–1.60 (m, 10H), 1.90–2.05 (m, 2H),
2.50–3.50 (m, 9H), 3.50–3.65 (m, 1H), 3.95–4.05 (m,
2H), 6.43 (t, J=5.6 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H),
6.61 (d, J=8.2 Hz, 1H), 6.70–6.89 (m, 5H), 7.46 (d,
J=9.0 Hz, 2H), 7.51 (d, J=9.0 Hz, 2H), 9.06 (s, 1H),
9.60 (brs, 1H), 10.60 (s, 1H), 10.75 (s, 1H); MS (ES) m/z
680.3 (MH+); HRMS calcd for C34H46N7O6S (MH+):
680.3230; found: 680.3221.
Method C
To a stirred solution of the alkyl ester (as specified, 1 equiv)
in distilled water (0.01–0.5 M) was added 1 NNaOH (1–10
equiv). The reaction was stirred at rt for 2–24h. The reac-
tion mixture was made acidic (pH 6) with glacial acetic
acid, and the solid was collected and dried over P2O5.
HPLC analysis
Samples were dissolved in DMSO or ACN/water and
analyzed with a Prodigy ODS3, C-18, 4.6Â150 mm col-
umn. The mobile phase was a gradient of A: 10 mM
phosphate buffer pH 3.0 or 0.02%TFA/water and B:
acetonitrile (0 min 10%, 10ꢀ30 min 90%). Flow rate
was 1 mL/min, detection was at 215 nm, temperature
was 40 ꢁC, and injection volume was 8 mL. The retention
time and HPLC purity of selected compounds were listed.
4-[4-(3-Cyclopentylpropyl)-5-oxo-4,5-dihydro-1H-tetra-
azol-1-yl]-N-{4-[4-({(2S)-2-hydroxy-3-[(2-oxo-2,3-dihydro
-1H-benzimidazol-4-yl)oxy]propyl}amino)-1-piperidinyl]-
phenyl}benzenesulfonamide (31c). Method A: 27c and
(S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-
1
benzimidazol-2-one,15 pale green solid, 12% yield: H
NMR (DMSO-d6) d 0.90–4.00 (m, 29H), 5.10–5.30 (m,
1H), 6.58 (d, J=7.9 Hz, 1H), 6.61 (d, J=7.9 Hz, 1H),
6.81 (d, J=8.9 Hz, 2H), 6.89 (d, J=8.9 Hz, 2H), 6.90
(dd, J=7.9, 7.9 Hz, 1H), 7.86 (d, J=8.5 Hz, 2H), 8.07
(d, J=8.5 Hz, 2H), 10.70 (s, 1H), 10.80 (s, 1H); MS (ES)
N-(4-{[4-(4-{[(2S)-2-Hydroxy-3-phenoxypropyl]amino}-
1-piperidinyl) anilino] sulfonyl}phenyl)acetamide (29).
Method A, 27a and (2S)-1-amino-3-phenoxy-propan-2-
ol,20 white solid, 33% yield: 1H NMR (DMSO-d6) d

2054
B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
m/z 732.3 (MH+); HRMS calcd for C36H46N9O6S
N-[4-({4-[4-({(2S)-2-Hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-
tetrahydro-5-quinolinyl) oxy]propyl}amino)-1-piperidinyl]-
anilino}sulfonyl)phenyl]acetamide (32a). Method A: 27a
(MH+): 732.3292; found: 732.3294.
1
N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-ben-
zimidazol-4-yl)oxy]propyl} amino)-1-piperidinyl]phenyl}-
5-(2-pyridinyl)-2-thiophenesulfonamide (31d). Method B:
27d and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihy-
dro-2H-benzimidazol-2-one,15 pale yellowish solid, 26%
and 11, white solid, 40% yield: H NMR (DMSO-d6) d
1.20–1.40 (m, 2H), 1.75–1.90 (m, 2H), 2.05 (s, 3H), 2.39
(t, J=7.5 Hz, 2H), 2.50–2.80 (m, 5H), 2.83 (t, J=7.5 Hz,
2H), 3.40–3.55 (m, 2H), 3.70–3.85 (m, 3H), 6.44 (d,
J=8.7 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.76 (d,
J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 7.58 (d,
J=9.0 Hz, 2H), 7.67 (d, J=9.0 Hz, 2H), 8.72 (s, 1H),
10.27 (s, 1H); MS (ES) m/z 623.9 (MH+); HRMS calcd
for C31H38N5O7S (MH+): 624.2492; found: 624.2469.
HPLC purity 96% at 6.0 min.
1
yield: H NMR (DMSO-d6) d 1.25–1.40 (m, 2H), 1.80–
1.90 (m, 2H), 2.50–2.90 (m, 5H), 3.53 (brd, J=9.0 Hz,
2H), 3.85–4.00 (m, 2H), 4.00–4.10 (m, 1H), 4.91 (brs,
1H), 6.56 (d, J=5.7 Hz, 1H), 6.61 (d, J=5.7 Hz, 1H),
6.80–6.90 (m, 3H), 6.96 (d, J=6.6 Hz, 2H), 7.36 (dd,
J=3.3, 1.2 Hz, 1H), 7.41 (d, J=3.0 Hz, 1H), 7.75 (d,
J=3.0 Hz, 1H), 7.88 (dd, J=6.0, 1.2 Hz, 1H), 7.98 (d,
J=6.0 Hz, 1H), 8.54 (d, J=3.3 Hz, 1H), 10.60 (s, 1H),
10.70 (s, 1H); MS (ES) m/z 621.0 (MH+); HRMS calcd
for C30H33N6O5S2 (MH+): 621.1954; found: 621.1952.
4 - {[(Hexylamino)carbonyl]amino} - N - {4 - [4 - ({(2S) - 2 -
hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-tetrahydro-5-quino-
linyl)oxy]propyl}amino)-1-piperidinyl]phenyl} benzenesul-
fonamide (32b). Method A: 27b and 11, white solid,
1
63% yield: H NMR (DMSO-d6) d 0.86 (t, J=5.1 Hz,
N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-ben-
zimidazol-4-yl)oxy propyl}amino)-1-piperidinyl]phenyl}-
3,4-dimethoxybenzenesulfonamide (31e). Method B: 27e
and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-
3H), 1.20–1.35 (m, 8H), 1.35–1.50 (m, 2H), 1.75–1.90
(m, 2H), 2.39 (t, J=5.1 Hz, 2H), 2.50–2.75 (m, 5H), 2.82
(t, J=5.1 Hz, 2H), 3.05 (q, J=5.1 Hz, 2H), 3.40–3.55
(m, 2H), 3.75–3.85 (m, 3H), 4.90 (brs, 1H), 6.30 (t,
J=5.1 Hz, 1H), 6.44 (d, J=6.6 Hz, 1H), 6.59 (d,
J=6.6 Hz, 1H), 6.76 (d, J=6.9 Hz, 1H), 6.85 (d,
J=6.9 Hz, 1H), 7.46 (d, J=6.9 Hz, 2H), 7.50 (d,
J=6.9 Hz, 2H), 8.67 (s, 1H), 8.84 (s, 1H), 9.10 (brs, 1H),
9.50 (brs, 1H); MS (ES) m/z 709.2 (MH+); HRMS calcd
for C36H49N6O7S (MH+): 709.3383; found: 709.3391.
HPLC purity 95% at 10.9 min.
1
benzimidazol-2-one,15 gray solid, 5% yield: H N MR
(DMSO-d6) d 1.49–1.55 (m, 2H), 1.99–2.17 (m, 2H),
2.58–2.65 (m, 2H), 2.85–2.98 (m, 2H), 3.07–3.09 (m,
2H), 3.59–3.63 (m, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 4.01
(s, 3H), 5.35 (brs, 1H), 6.57–6.64 (m, 2H), 6.79–6.92 (m,
5H), 7.01–7.04 (d, J=8.4 Hz, 1H), 7.18–7.25 (m, 2H),
8.18 (s, 1H), 9.62 (brs, 1H), 10.61 (s, 1H), 10.72 (s, 1H);
MS (ES) m/z 598.1 (MH+); HRMS calcd for
C29H36N5O7S: 598.2335; found: 598.2348. HPLC purity
98% at 15.4 min.
N-{4-[4-({(2S)-2-Hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-
tetrahydro-5-quinolinyl)
oxy]propyl}amino)-1-piperidi-
(32e).
nyl]phenyl}-3,4-dimethoxybenzenesulfonamide
N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-ben-
zimidazol-4-yl)oxy]propyl} amino)-1-piperidinyl]phenyl}-
1-butanesulfonamide (31f). Method A: 27f and (S)-4-[2-
hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimida-
zol-2-one,15 off-white solid, 12% yield: 1H N MR
(DMSO-d6) d 0.83 (t, J=7.2 Hz, 3H), 1.20–1.70 (m,
6H), 1.95–2.10 (m, 2H), 2.67 (brt, J=11.7 Hz, 2H),
2.70–3.20 (m, 7H), 3.62–3.75 (m, 2H), 3.95–4.10 (m,
3H), 6.59 (d, J=7.5 Hz, 1H), 6.63 (d, J=8.0 Hz, 1H),
6.80–7.00 (m, 3H), 7.06 (d, J=9.0 Hz, 2H), 9.32 (brs,
1H), 10.61 (brs, 1H), 10.73 (brs, 1H); MS (ES) m/z 518.1
(MH+); HRMS calcd for C25H36N5O5S (MH+):
518.2437; found: 518.2452. HPLC purity 99% at 2.3 min.
Method A: 27e and 11, white solid, 46% yield: 1H
NMR (DMSO-d6) d 1.20–1.40 (m, 2H), 1.80–1.95 (m,
2H), 2.39 (t, J=7.2 Hz, 2H), 2.50–2.75 (m, 5H), 2.82 (t,
J=7.2 Hz, 2H), 3.45–3.55 (m, 2H), 3.63 (s, 3H), 3.72 (s,
3H), 3.70–3.85 (m, 3H), 4.91 (brs, 1H), 6.44 (d,
J=8.8 Hz, 1H), 6.60 (d, J=8.8 Hz, 1H), 6.78 (d,
J=9.1 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H), 7.02 (d,
J=8.5 Hz, 1H), 7.18 (dd, J=8.5, 2.1 Hz, 1H), 7.36 (d,
J=2.1 Hz, 1H), 8.72 (s, 1H), 9.17 (brs, 1H); MS (ES) m/
z: 627.1 (MH+); HRMS calcd for C31H39N4O8S
(MH+): 627.2489; found: 627.2458.
N-{4-[4-({(2S)-2-Hydroxy-3-[(8-hydroxy-2-oxo-1,2,3,4-
tetrahydro-5-quinolinyl) oxy]propyl}amino)-1-piperidi-
nyl]phenyl}-1-butanesulfonamide (32f). Method A: 27f
N-{4-[4-({(2S)-2-Hydroxy-3-[(2-oxo-2,3-dihydro-1H-ben-
zimidazol-4-yl)oxy]propyl} amino)-1-piperidinyl]phenyl}-
1-octanesulfonamide (31g). Method A: 27g and (S)-4-[2-
hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimida-
zol-2-one,15 off-white solid, 59% yield: 1H N MR
(DMSO-d6) d 0.85 (t, J=7.0 Hz, 3H), 1.10–1.40 (m,
10H), 1.50–1.70 (m, 4H), 1.95–2.16 (m, 2H), 2.67 (brt,
J=11.1 Hz, 2H), 2.93 (brt, J=7.9 Hz, 2H), 2.95–3.20
(m, 3H), 3.62–3.75 (m, 2H), 4.00–4.12 (m, 2H), 4.12–
4.30 (m, 1H), 6.59 (d, J=7.8 Hz, 1H), 6.63 (d,
J=8.3 Hz, 1H), 6.80–7.00 (m, 3H), 7.07 (d, J=9.0 Hz,
2H), 9.33 (brs, 1H), 10.60 (brs, 1H), 10.75 (brs, 1H); MS
(ES) m/z 574.1 (MH+); HRMS calcd for C29H44N5O5S
(MH+): 574.3063; found: 574.3084. HPLC purity 99%
at 22.3 min.
1
and 11, white solid, 31% yield: H NMR (DMSO-d6) d
0.82 (t, J=7.3 Hz, 3H), 1.20–1.40 (m, 4H), 1.50–1.70
(m, 2H), 1.80–1.95 (m, 2H), 2.39 (t, J=7.3 Hz, 2H),
2.50–2.80 (m, 5H), 2.85 (t, J=7.3 Hz, 2H), 2.85–3.00
(m, 2H), 3.45–3.60 (m, 2H), 3.75–3.85 (m, 3H), 6.44 (d,
J=8.7 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.89 (d,
J=9.0 Hz, 2H), 7.04 (d, J=9.0 Hz, 2H), 8.74 (s, 1H);
MS (ES) m/z 546.9 (MH+); HRMS calcd for
C27H39N4O6S (MH+): 547.2590; found: 547.2583.
N-(4-{[4-(4-{[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxy-
propyl]amino}-1-piperidinyl) anilino]sulfonyl}phenyl)ace-
tamide (33). Method A: 27a and (2S)-3-(9H-carbazol-4-
yloxy)-2-hydroxy-propylamine,13 yellowish solid, 5%

B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
2055
1
yield: H NMR (DMSO-d6) d 1.55–1.75 (m, 2H), 2.00–
phenyl)-ethanol, pale yellowish solid, 45% yield: 1H
NMR (DMSO-d6) d 1.55–1.75 (m, 2H), 1.95–2.15 (m,
2H), 2.08 (s, 3H), 2.50–3.20 (m, 5H), 3.60–3.70 (m, 2H),
5.04–5.10 (m, 1H), 6.65–6.75 (m, 1H), 6.24 (dd, J=8.1,
2.1 Hz, 1H), 6.32 (d, J=2.1 Hz, 1H), 6.80 (d, J=9.0 Hz,
2H), 6.88 (d, J=9.0 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H),
7.59 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 9.26 (s,
1H), 9.71 (brs, 1H), 10.44 (s, 1H); MS (ES) m/z 541.4
(MH+); HRMS calcd for C27H33N4O6S (MH+):
541.2121; found: 541.2084.
2.15 (m, 2H), 2.06 (s, 3H), 2.50–2.70 (m, 2H), 3.00–3.50
(m, 3H), 3.60–3.70 (m, 2H), 4.10–4.25 (m, 2H), 4.35–
4.50 (m, 1H), 5.97 (brs, 1H), 6.72 (d, J=8.0 Hz, 1H),
6.80 (d, J=8.0 Hz, 2H), 6.88 (d, J=8.0 Hz, 2H), 7.10–
7.50 (m, 5H), 7.59 (d, J=8.7 Hz, 2H), 7.69 (d,
J=8.7 Hz, 2H), 8.22 (d, J=7.8 Hz, 1H), 9.71 (s, 1H),
10.40 (s, 1H), 11.32 (s, 1H); MS (ES) m/z 627.9 (MH+);
HRMS calcd for C34H38N5O5S (MH+): 628.2594;
found: 628.2593.
N-(4-{4-[4-((2R)-2-Hydroxy-2-phenyl-ethylamino)-piperi-
(34).
N-(4-{[4-(4-{[2-Hydroxy-2-(4-hydroxy-3-methoxyphenyl)-
ethyl]amino} - 1 - piperidinyl)anilino]sulfonyl}phenyl)acet-
amide (39). Method A: 27a and dl-normetanephrine,
din-1-yl]-phenylsulfamoyl}-phenyl)-acetamide
Method A: 27a and (1R)-2-amino-1-(3-chloro-phenyl)-
ethanol, white solid, 59% yield: 1H NMR (DMSO-d6) d
1.55–1.75 (m, 2H), 2.06 (s, 3H), 2.00–2.15 (m, 2H),
2.50–3.20 (m, 5H), 3.55–3.70 (m, 2H), 4.90–5.00 (m,
1H), 6.00–6.20 (brs, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.89
(d, J=9.0 Hz, 2H), 7.25–7.52 (m, 5H), 7.59 (d,
J=8.7 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 10.41 (s, 1H);
MS (ES) m/z 509.2 (MH+); HRMS calcd for
C27H33N4O4S (MH+): 509.2223; found: 509.2194.
1
white solid, 87% yield: H NMR (DMSO-d6) d 1.40–
1.60 (m, 2H), 1.90–2.06 (m, 2H), 2.06 (s, 3H), 2.50–3.50
(m, 5H), 3.55–3.65 (m, 2H), 3.77 (s, 3H), 4.70–4.80 (m,
1H), 5.70–5.85 (brs, 1H), 6.70–6.90 (m, 7H), 7.59 (d,
J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 8.95 (brs, 1H),
10.37 (s, 1H); MS (ES) m/z 555.2 (MH+); HRMS calcd
for C28H35N4O6S (MH+): 555.2277; found: 555.2265.
5-[2-({1-[4-({[4-(Acetylamino)phenyl]sulfonyl}amino)phe-
nyl]-4-piperidinyl}amino)-1-hydroxyethyl]-1H-indole-7-
carboxamide (40). Method A: 27a and 5-(2-amino-1-
hydroxy-ethyl)-1H-indole-7-carboxamide,22 pale grey
N-[4-(4-{4-[2-Hydroxy-2-(3-hydroxy-phenyl)-ethyla-
mino]-piperidin-1-yl}-phenylsulfamoyl)-phenyl]-acetamide
(35). Method A: 27a and dl-norphenylephrine, white
1
1
solid, 36% yield: H NMR (DMSO-d6) d 1.35–1.50 (m,
solid, 36% yield: H NMR (DMSO-d6) d 1.60–1.80 (m,
2H), 1.80–2.00 (m, 2H), 2.06 (s, 3H), 2.50–2.90 (m, 5H),
3.45–3.60 (m, 2H), 4.55–4.65 (m, 1H), 5.55 (brs, 1H),
6.60–6.70 (m, 1H), 6.70–6.85 (m, 4H), 6.86 (d,
J=9.3 Hz, 2H), 7.11 (t, J=7.8 Hz, 1H), 7.58 (d,
J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 9.35 (s, 1H),
10.33 (s, 1H); MS (ES) m/z 525.4 (MH+); HRMS calcd
for C27H33N4O5S (MH+): 525.2172; found: 525.2177.
2H), 2.00–2.15 (m, 2H), 2.06 (s, 3H), 2.50–2.70 (m, 2H),
3.10–3.20 (m, 3H), 3.60–3.75 (m, 2H), 4.95–5.05 (m,
1H), 6.13 (brs, 1H), 6.49 (t, J=2.7 Hz, 1H), 6.81 (d,
J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.35 (t,
J=2.7 Hz, 1H), 7.42 (brs, 1 H), 7.59 (d, J=9.0 Hz, 2H),
7.69 (d, J=9.0 Hz, 2H), 7.77 (s, 1 H), 8.11 (s, 1H), 9.72
(s, 1H), 10.40 (s, 1H); MS (ES) m/z 591.1 (MH+);
HRMS calcd for C30H35N6O5S (MH+): 591.2390;
found: 591.2392.
N-(4-{[4-(4-{[2-Hydroxy-2-(4-hydroxyphenyl)ethyl]a-
mino}-1-piperidinyl)anilino]
sulfonyl}phenyl)acetamide
(36). Method A: 27a and dl-octopamine, white solid,
N-(4-{4-[4-(2-Hydroxy-2-pyridin-3-yl-ethylamino)-piperi-
din-1-yl]-phenylsulfamoyl}-phenyl)-acetamide
1
19% yield: H NMR (DMSO-d6) d 1.55–1.75 (m, 2H),
(41).
1
2.00–2.15 (m, 2H), 2.06 (s, 3H), 2.50–3.20 (m, 5H),
3.60–3.70 (m, 2H), 4.80–4.90 (m, 1H), 6.00 (brs, 1H),
6.76 (d, J=9.7 Hz, 2H), 6.80 (d, J=9.7 Hz, 2H), 6.88 (d,
J=9.0 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.59 (d,
J=9.0 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 9.47 (s, 1H),
10.43 (s, 1H); MS (ES) m/z 525.3 (MH+); HRMS
calcd for C27H33N4O5S (MH+): 525.2172; found:
525.2178.
Method A: 27a and 14, pale grey solid, 30% yield: H
NMR (DMSO-d6) d 1.55–1.75 (m, 2H), 2.07 (s, 3H),
2.00–2.20 (m, 2H), 2.50–3.20 (m, 5H), 3.55–3.70 (m,
2H), 5.10–5.21 (m, 1H), 6.30–6.40 (brs, 1H), 6.81 (d,
J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 7.45–7.50 (m,
1H), 7.59 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H),
7.84 (d, J=7.8 Hz, 1H), 8.45–8.65 (m, 2H), 10.47 (s,
1H); MS (ES) m/z 510.2 (MH+); HRMS calcd for
C26H32N5O4S (MH+): 510.2175; found: 510.2201.
HPLC purity 94% at 9.2 min.
N-(4-{[4-(4-{[(2R)-2-(3,4-Dihydroxyphenyl)-2-hydroxy-
ethyl]amino}-1-piperidinyl) anilino]sulfonyl}phenyl)acet-
amide (37). Method A: 27a and l-norepinephrine, grey
4-{[(Hexylamino)carbonyl]amino}-N-(4-{4-[(2-hydroxy-2
- {4 - hydroxy - 3 - [(methylsulfonyl)amino]phenyl}ethyl)-
amino]-1-piperidinyl}phenyl) benzenesulfonamide (42b).
Method A: 27b and 17, grey solid, 80% yield: 1H
NMR (DMSO-d6) d 0.86 (t, J=6.9 Hz, 3H), 1.20–1.80
(m, 10H), 1.95–2.15 (m, 2H), 2.50–2.70 (m, 3H), 2.95 (s,
3H), 3.00–3.20 (m, 4H), 3.65 (brd, J=12.3 Hz, 2H), 4.80
(brd, J=7.9 Hz, 1H), 5.90–6.10 (m, 1H), 6.48 (t,
J=5.6 Hz, 1H), 6.83 (d, J=9.2 Hz, 2H), 6.90 (d,
J=9.2 Hz, 2H), 6.91(d, J=8.4 Hz, 1H), 7.07 (dd,
J=8.4, 2.0 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.46 (d,
J=9.2 Hz, 2H), 7.51 (d, J=9.2 Hz, 1H), 8.50–8.90 (brs,
1H), 9.39 (s, 1H), 9.61 (s, 1H); MS (ES) m/z 703.4
1
solid, 15% yield: H NMR (DMSO-d6) d 1.50–1.72 (m,
2H), 1.95–2.10 (m, 2H), 2.06 (s, 3H), 2.50–3.20 (m, 5H),
3.55–3.70 (m, 2H), 4.05–4.20 (brs, 1H), 4.60–4.75 (m,
1H), 5.75–5.90 (brs, 1H), 6.60–6.90 (m, 7H), 7.59 (d,
J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 8.93 (brs, 1H),
10.42 (s, 1H); MS (ES) m/z 541.6 (MH+); HRMS
calcd for C27H33N4O6S (MH+): 541.2121; found:
541.2133.
N-(4-{[4-(4-{[2-(2,4-Dihydroxyphenyl)-2-hydroxyethyl]-
amino}-1-piperidinyl) anilino]sulfonyl}phenyl)acetamide
(38). Method A: 27a and 2-amino-1-(2,4-dihydroxy-

2056
B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
(MH+); HRMS calcd for C33H47N6O7S2 (MH+):
703.2948; found: 703.2968.
2H), 4.49 (dd, J=8.0, 4.1 Hz, 1H), 6.82 (d, J=8.3 Hz,
1H), 6.88 (d, J=8.0 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz,
1H), 7.04 (d, J=8.0 Hz, 2H), 7.17 (d, J=2.0 Hz, 1H);
MS (ES) m/z 597.1 (MH+); HRMS calcd for
C28H45N4O6S2 (MH+): 597.2781; found: 597.2776.
4-[4-(3-Cyclopentyl-propyl)-5-oxo-4,5-dihydro-tetrazol-1-
yl]-N-(4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonyl-
amino-phenyl)-ethaylamino]-piperidin-1-yl}-phenyl)-benz-
enesulfonamide (42c). Method A: 27c and 18, grey solid,
N-{4-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methyl-
sulfonyl)amino]phenyl}ethyl) amino]-1-piperidinyl}anili-
no)sulfonyl]phenyl}acetamide (43a). Method A: 27a and
1
46% yield: H NMR (DMSO-d6) d 0.95–2.80 (m, 24H),
2.95 (s, 3H), 3.55–3.70 (m, 2H), 4.70–4.85 (m, 1H),
5.50–5.80 (m, 1H), 6.80–7.60 (m, 7H), 7.86 (d,
J=8.7 Hz, 2H), 8.07(d, J=8.7 Hz, 2H); MS (ES) m/z
754.9 (MH+); HRMS calcd for C35H47N8O7S2 (MH+):
755.3009; found: 755.2997.
1
21, off-white solid, 57% yield: H NMR (DMSO-d6) d
1.40–1.70 (m, 2H), 1.90–2.10 (m, 2H), 2.06 (s, 3H),
2.50–2.65 (m, 2H), 2.90–3.15 (m, 3H), 2.94 (s, 3H),
3.55–3.70 (m, 2H), 4.65–4.80 (m, 1H), 6.79 (d,
J=9.0 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 7.00 (d,
J=8.0 Hz, 1H), 7.06 (dd, J=8.0, 1.2 Hz, 1H), 7.22 (d,
J=1.2 Hz, 1H), 7.40 (d, J=8.7 Hz, 2H), 7.69 (d,
J=8.7 Hz, 2H), 10.42 (s, 1H), 10.44 (s, 1H); MS (ES) m/
z 618.0 (MH+); HRMS calcd for C28H36N5O7S2
(MH+): 618.2056; found: 618.2056.
N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-
amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-5-(2-pyr-
idinyl)-2-thiophenesulfonamide (42d). Method B: 27d and
1
18, off-white solid, 47% yield: H NMR (DMSO-d6) d
1.20–1.40 (m, 2H), 1.80–1.90 (m, 2H), 2.45–2.75 (m,
5H), 2.91 (s, 3H), 3.40–3.60 (m, 2H), 4.47 (dd, J=8.0,
4.1 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.82 (d, J=8.0 Hz,
2H), 6.95 (d, J=8.0 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz,
1H), 7.17 (d, J=2.0 Hz, 1H), 7.37 (dd, J=4.8, 1.7 Hz,
1H), 7.40 (d, J=3.9 Hz, 1H), 7.75 (d, J=3.9 Hz,
1H), 7.88 (dd, J=8.0, 1.7 Hz, 1H), 7.98 (d, J=8.0 Hz,
1H), 8.54 (brd, J=4.8 Hz, 1H); MS (ES) m/z 644.1
(MH+); HRMS calcd for C29H34N5O6S3 (MH+):
644.1671; found: 644.1663. HPLC purity 98% at 15.1
min.
4 - {[(Hexylamino)carbonyl]amino} - N - (4 - {4 - [((2R) - 2 -
hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}-
ethyl)amino]-1-piperidinyl}phenyl) benzenesulfonamide
1
(43b). Method A: 27b and 21, grey solid, 27% yield: H
NMR (DMSO-d6) d 0.86 (t, J=6.9 Hz, 3H), 1.20–1.80
(m, 10H), 1.95–2.15 (m, 2H), 2.50–3.30 (m, 7H), 2.95 (s,
3H), 3.63 (brd, J=12.0 Hz, 2H), 4.76 (brd, J=7.8 Hz,
1H), 5.90–6.10 (m, 1H), 6.44 (t, J=5.6 Hz, 1H), 6.83 (d,
J=9.1 Hz, 2H), 6.90 (d, J=9.1 Hz, 2H), 6.91(d,
J=8.4 Hz, 1H), 7.07 (dd, J=8.4, 1.9 Hz, 1H), 7.24 (d,
J=1.9 Hz, 1H), 7.46(d, J=9.2 Hz, 2H), 7.51 (d,
J=9.2 Hz, 1H), 9.10 (brs, 1H), 9.60 (s, 1H); MS (ES) m/
z 703.4 (MH+); HRMS calcd for C33H47N6O7S2
(MH+): 703.2948; found: 703.2946.
N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-
amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-3,4-di-
methoxybenzenesulfonamide (42e). Method B: 27e and
18, brown solid, 45%: 1H NMR (DMSO-d6) d 1.50–1.59
(m, 2H), 1.95–2.05 (m, 2H), 2.54–2.62 (m, 2H), 2.72
(brs, 2H), 2.94 (s, 3H), 3.00–3.04 (m, 2H), 3.56 (brd,
J=12.0 Hz, 2H), 3.72 (s, 3H), 3.78 (s, 3H), 4.10 (brs,
1H), 4.70 (brd, J=7.8 Hz, 1H), 5.95 (brs, 1H), 6.81 (d,
J=9.09 Hz, 1H), 6.86–6.92 (m, 2H), 7.01–7.04 (m, 2H),
7.17–7.24 (m, 5H), 8.45 (brs, 1H), 9.16 (s, 1H); MS (ES)
m/z 621.0 (MH+); HRMS calcd for C28H37N4O8S2
(MH+): 621.2052; found: 621.2079. HPLC purity 99%
at 2.1 min.
N-(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfo-
nyl)amino]phenyl} ethyl)amino]-1-piperidinyl}phenyl)-3-
pyridinesulfonamide (43h). Method B: 27h and 21, yel-
1
low solid, 15% yield: H NMR (DMSO-d6) d 1.25–1.45
(m, 2H), 1.80–1.95 (m, 2H), 2.50–2.80 (m, 5H), 2.92 (s,
3H), 3.40–3.55 (m, 2H), 4.45–4.60 (m, 1H), 6.85–6.90
(m, 5H), 7.02 (dd, J=8.3, 2.0 Hz, 1H), 7.18 (d,
J=2.0 Hz, 1H), 7.59 (dd, J=7.4, 4.4 Hz, 1H), 7.95–8.05
(m, 2H), 8.70–8.80 (m, 2H); MS (ES) m/z: 561.95
(MH+); HRMS calcd for C25H32N5O6S2 (MH+):
562.1788; found: 562.1774. HPLC purity 95% at 6.3
min.
N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-
amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-butane-
sulfonamide (42f). Method A: 27f and 17, off-white
solid, 71% yield: 1H NMR (DMSO-d6) d 0.83 (t,
J=7.2 Hz, 3H), 1.20–1.40 (m, 2H), 1.50–1.70 (m, 4H),
1.95–2.10 (m, 2H), 2.40–2.60 (m, 2H), 2.94 (s, 3H),
2.90–3.20 (m, 5H), 3.62–3.75 (m, 2H), 4.70–4.80 (m,
1H), 5.95 (brs, 1H), 6.85–6.95 (m, 3H), 7.00–7.10 (m,
3H), 7.24 (d, J=2.0 Hz, 1H), 8.70 (brs, 1H), 9.33 (brs,
1H); MS (ES) m/z 541.0 (MH+); HRMS calcd for
C24H37N4O6S2 (MH+): 541.2155; found: 541.2161.
HPLC purity 97% at 22.7 min.
4-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfo-
nyl)amino]phenyl} ethyl)amino]-1-piperidinyl}anilino)sul-
fonyl]benzoic acid (43i). Method B: 27i and 21, white
1
solid, 31% yield: H NMR (DMSO-d6) d 1.35–1.50 (m,
2H), 1.75–2.00 (m, 2H), 2.50–2.95 (m, 5H), 2.92 (s, 3H),
3.45–3.60 (m, 2H), 4.60–4.70 (m, 1H), 6.77 (d,
J=9.3 Hz, 2H), 6.80–6.90 (m, 3H), 7.02 (dd, J=8.4,
1.8 Hz, 1H), 7.20 (d, J=1.8 Hz, 1H), 7.60 (d, J=8.4 Hz,
2H), 7.93 (d, J=8.4 Hz, 2H); MS (ES) m/z 603.2
(M–H)À; HRMS calcd for C27H31N4O8S2 (M–H)À:
603.1588; found: 603.1572. HPLC purity 97% at 9.4
min.
N-(4-{4-[(2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-
amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-1-octane-
sulfonamide (42g). Method A: 27g and 17, off-white
solid, 64% yield: 1H NMR (DMSO-d6) d 0.84 (t,
J=7.0 Hz, 3H), 1.15–1.40 (m, 12H), 1.50–1.70 (m, 2H),
1.80–1.95 (m, 2H), 2.50–2.92 (m, 7H), 3.50–3.65 (m,
Ethyl 4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methyl-
sulfonyl)amino]phenyl} ethyl)amino]-1-piperidinyl}anilino)-

B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
2057
sulfonyl]benzoate (43j). Method B: 27j and 21, pale
yellowish solid, 37% yield: 1H NMR (DMSO-d6)
d 1.20–1.40 (m, 2H), 1.32 (t, J=7.1 Hz, 3H), 1.75–
1.90 (m, 2H), 2.50–2.70 (m, 5H), 2.91 (s, 3H), 3.40–3.55
(m, 2H), 4.32 (q, J=7.1 Hz, 2H), 4.47 (dd, J=8.1,
4.2 Hz, 1H), 6.70–6.90 (m, 5H), 6.99 (dd, J=8.3, 2.0 Hz,
1H), 7.17 (d, J=2.0 Hz, 1H), 7.79 (d, J=8.5 Hz,
2 H), 8.07 (d, J=8.5 Hz, 2H); MS (ES) m/z 633.3
(MH+); HRMS calcd for C29H37N4O8S2 (MH+):
633.2047; found: 633.2013. HPLC purity 98% at 9.0
min.
Benzyl [(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methyl-
sulfonyl)amino]phenyl} ethyl)amino]-1-piperidinyl}anilino)-
sulfonyl]acetate (43n). Method B: 27n and 21, white
solid, 47% yield: 1H NMR (DMSO-d6) d 1.20–1.40
(m, 2H), 1.70–1.95 (m, 2H), 2.50–2.75 (m, 2H), 2.92
(s, 3H), 3.50–3.60 (m, 3H), 4.13 (s, 2H), 4.48 (dd,
J=8.0, 4.3 Hz, 1H), 5.15 (s, 2H), 6.82 (d, J=8.3 Hz,
1H), 6.86 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz,
1H), 7.06 (d, J=9.0 Hz, 2H), 7.18 (d, J=2.0 Hz, 1H),
7.30–7.40 (m, 5H); MS (ES) m/z 633.3 (MH+); HRMS
calcd for C29H37N4O8S2 (MH+): 633.2047; found:
633.2031.
4-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfony-
lamino-phenyl)-ethylamino]-piperidin-1-yl}-phenylsulf-
amoyl)-phenoxy]-acetic acid (43k). The methyl ester of
43k was prepared from the methyl ester of 27k and 21 as
described in Method B in 7% yield as an off-white solid:
1H NMR (DMSO-d6) d 1.20–1.40 (m, 2H), 1.75–1.90
(m, 2H), 2.50–2.80 (m, 5H), 2.92 (s, 3H), 3.65–3.75 (m,
2H), 3.67 (s, 3H), 4.47 (dd, J=8.0, 4.1 Hz, 1H), 4.87 (s,
2H), 6.50–6.90 (m, 8H), 7.17 (d, J=1.8 Hz, 1H), 7.59 (d,
J=8.9 Hz, 2H); MS (ES) m/z 649.0 (MH+); HRMS
calcd for C29H37N4O9S2 (MH+): 649.2004; found:
649.2014.
[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfon-
yl)amino]phenyl}ethyl) amino]-1-piperidinyl}anilino)sulfon-
yl]acetic acid (43o). Method A: 27n and 21, off-white
1
solid, 6% yield: H NMR (DMSO-d6) d 1.40–1.60 (m,
2H), 1.90–2.05 (m, 2H), 2.50–2.90 (m, 5H), 2.94 (s, 3H),
3.50–3.65 (m, 2H), 4.65–4.75 (m, 1H), 6.80–6.90 (m,
3H), 7.00–7.10 (m, 3H), 7.23 (d, J=2.0Hz, 1H); MS
(ES) m/z 543.3 (MH+); HRMS calcd for C29H37N4O8S2
(MH+): 543.1578; found: 543.1572.
Butyl-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-amine
(44). To a stirred mixture, under N2 atmosphere, of
the aniline 26 (free base) (11.46 g, 49 mmol), buty-
aldehyde (4.43 mL, 49 mmol) in THF (250 mL) was
added NaBH(OAc)3 (14.62 g, 68.6 mmol), and glacial
acetic acid (2.82 mL, 49 mmol). The reaction was stirred
for 2 h. The reaction was quenched with 1 NNaOH
(50 mL), diluted with water, extracted with Et2O three
times and dried over Na2SO4. The product was purified
by flash silica gel chromatography eluting with 1:1
EtOAc/hexanes to give the title compound as an oil
(5.80 g, 41%). The compound was characterized as a
The title acid was made from the above methyl ester
according to Method C in 71% yield as a pale yellowish
1
solid: H NMR (DMSO-d6) d 1.20–1.40 (m, 2H), 1.75–
1.90 (m, 2H), 2.50–2.85 (m, 5H), 3.30–3.50 (m, 2H), 3.69
(s, 3H), 3.80–4.05 (m, 3H), 4.87 (s, 2H), 6.56 (d,
J=7.8 Hz, 1H), 6.61 (d, J=8.1 Hz, 1H), 6.65–6.90 (m,
5H), 7.02 (d, J=9.0 Hz, 2H), 7.59 (d, J=9.0 Hz, 2H),
10.60 (s, 1H), 10.75 (br s, 1H); MS (ES) m/z 626.1
(MH+); HRMS calcd for C30H36N5O8S (MH+):
626.2285; found: 626.2298.
1
diHCl salt: H NMR (DMSO-d6) d 0.89 (t, J=7.0 Hz,
Methyl 3-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(me-
thylsulfonyl)amino]phenyl} ethyl)amino]-1-piperidinyl}-
anilino)sulfonyl]-2-thiophenecarboxylate (43l). Method
B: 27l and 21, pale yellowish solid, 50% yield: 1H N MR
(DMSO-d6) d 1.20–1.40 (m, 2H), 1.70–1.90 (m, 2H),
2.50–2.75 (m, 5H), 3.40–3.55 (m, 2H), 3.89 (s, 2H),
4.46 (dd, J=8.0, 4.2 Hz, 1H), 6.75–6.85 (m, 3H),
6.90 (d, J=9.0 Hz, 2H), 7.00 (dd, J=8.3, 2.0 Hz,
1H), 7.16 (d, J=2.0 Hz, 1H), 7.32 (d, J=3.3 Hz,
1H), 7.89 (d, J=3.3 Hz, 1H); MS (ES) m/z 624.9
(MH+); HRMS calcd for C26H34N4O8S3 (MH+):
625.1455; found: 625.1441. HPLC purity 98% at 13.2
min.
3H), 1.25–1.45 (m, 2H), 1.50–1.75 (m, 2H), 1.90–2.10
(m, 4H), 3.11 (t, J=8.0 Hz, 2H), 3.35–3.50 (m, 4H), 3.95
(s, 4H), 6.90–7.20 (m, 2H), 7.20–7.60 (m, 3H); MS (ES)
m/z 291.1 (MH+); HRMS calcd for C17H27N2O2
(MH+): 291.2067; found: 291.2065. Anal. calcd for
.
C17H26N2O2 2HCl: C, 56.20; H, 7.77; N, 7.71; found: C,
56.05; H, 7.52; N, 7.53.
1-[4-(Butylamino)phenyl]-4-piperidinone (45). A solution
of 44 (5.80 g, 19.9) in a 1:1 mixture of perchloric
acid/HCl (100 mL) was stirred at rt for three days.
The reaction mixture was poured onto ice and made
basic with concentrated NH4OH, extracted with Et2O
four times, dried over Na2SO4 and concentrated to
give a yellow oil. The yellowish oil was purified by
flash silica gel chromatography eluting with 1:1 EtOAc/
hexanes to give the title compound as oil (3.84 g,
82%). The compound was characterized as a diHCl
3-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfo-
nyl)amino]phenyl} ethyl)amino]-1-piperidinyl}anilino)sul-
fonyl]-2-thiophenecarboxylic acid (43m). Method C:
from 43l, pale grey solid, 54% yield: 1H NMR (DMSO-
d6) d 1.50–1.70 (m, 2H), 1.95–2.10 (m, 2H), 2.50–2.70
(m, 2H), 2.95 (s, 3H), 3.00–3.30 (m, 3H), 3.60–3.70 (m,
2H), 4.75–4.85 (m, 1H), 6.10 (brs, 1H), 6.80 (d,
J=9.0 Hz, 2H), 6.85–6.95 (m, 3H), 7.04 (d, J=5.4 Hz,
1H), 7.08 (dd, J=8.4, 1.8 Hz, 1H), 7.26 (d, J=1.8 Hz,
1H), 7.39 (d, J=5.4 Hz, 1H), 8.73 (brs, 1H), 9.96 (brs,
1H); MS (ES) m/z 610.7 (MH+); HRMS calcd for
C25H31N4O8S3 (MH+): 611.1299; found: 611.1284.
HPLC purity 99% at 8.0 min.
1
salt: H NMR (DMSO-d6) d 0.88 (t, J=7.0 Hz, 3H),
1.25–1.40 (m, 2H), 1.55–1.70 (m, 2H), 2.50 (t,
J=4.4 Hz, 4H), 3.16 (t, J=5.8 Hz, 2H), 3.67 (t,
J=4.4 Hz, 4H), 7.17 (d, J=6.3 Hz, 2H), 7.37 (d,
J=6.3 Hz, 2H), MS (ES) m/z 247.1 (MH+); HRMS
calcd for C15H23N2O2 (MH+): 247.1805; found:
.
.
247.1800. Anal. calcd for C15H22N2O2 2HCl 0.45H2O:
C, 55.04; H, 7.67; N, 8.56; found: C, 55.10; H, 7.45; N,
8.38.

2058
B. Huet al. / Bioorg. Med. Chem. 9 (2001) 2045–2059
Benzyl
[(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-
cent of the maximal isoproterenol response at 10À5 M.
Activity curves were plotted using the SAS statistical
and graphics software. EC50 values were generated for
each compound and the maximal response developed
for each compound was compared to the maximal
response of isoproternol at 10À5 M from the following
formula:
[(methylsulfonyl)amino] phenyl}ethyl)amino]-1-piperidi-
nyl}anilino)sulfonyl]acetate (47). To a stirred mixture of
45 (1.39 g, 5.6 mmol) in 100 mL of CH2Cl2, and benzy-
loxycarbonylmethylsulfonyl-chloride (1.39 g, 5.6 mmol)19
was added Et3N(2.18 g, 22 mmol) dropwise. After being
stirred for 18 h the reaction mixture was washed with
diluted HCl and dried over Na2SO4. The product was
purified by flash silica gel chromatography eluting with
2–10% MeOH/CH2Cl2 to give {butyl-[4-(4-oxo-piper-
idin-1-yl)-phenyl]-sulfamoyl}-acetic acid benzyl ester
(46) as a yellow oil (0.5 g, 19%). The title benzyl ester
was prepared from 21 and 46 as described in Method B
in 35% yield as an off-white solid: 1H NMR (DMSO-d6)
d 0.79 (t, J=7.2 Hz, 3H), 1.10–1.40 (m, 6H), 1.80–1.95
(m, 2H), 2.55–2.80 (m, 5H), 2.92 (s, 3H), 3.45 (t,
J=7.1 Hz, 2H), 4.24 (s, 2H), 4.49 (dd, J=7.9, 4.2 Hz,
1H), 5.20 (s, 2H), 6.82 (d, J=8.2 Hz, 1H), 6.92 (d,
J=9.0 Hz, 2H), 7.00 (dd, J=8.2, 2.0 Hz, 1H), 7.10–7.20
(m, 3H), 7.30–7.45 (m, 5H); MS (ES) m/z 689.1 (MH+);
HRMS calcd for C33H45N4O8S2 (MH+): 689.2673;
found: 689.2679.
intrinsic activity (IA)=% activity of compound divide
by% activity of isoproterenol.
Acknowledgements
The authors acknowledge the members of the Wyeth-
Ayerst Discovery Analytical Chemistry group for ana-
lytical and spectral determinations.
References and Notes
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1
grey solid; 31% yield: H NMR (DMSO-d6) d 0.79 (t,
J=7.1 Hz, 3H), 1.10–1.35 (m, 4H), 1.50–1.70 (m, 2H),
2.00–2.10 (m, 2H), 2.55–3.10 (m, 5H), 2.92 (s, 3H),
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In vitro functional assays
CHO cells expressing either human b1-, b2-, or b3-AR
subtypes were used as previously described.23 Clones
expressing receptor levels of 70 to 110 fmols/mg protein
were used in the assays. CHO cells were grown in 24-
well tissue culture plates in Dulbecco’s Modified Eagle
Media (DMEM) with 10% Fetal bovine serum, MEM
non-essential amino acids, Penicillin-Streptomycin and
Geneticin. On the day of assay, growth medium was
replaced with preincubation media (Dulbecco’s Mod-
ified Eagle Media (Gibco, #1199-065) and incubated for
30 min at 37 ꢁC. Preincubation medium was replaced
with 0.2 mL treatment medium containing DMEM
media containing 250 uM IBMX (isobutyl-1-methyl-
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dissolved in DMSO. Test compounds were tested over a
concentration range of 10À9 M to 10À5 M for b3-AR
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standard for comparison of activity. Cells were incu-
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