Design and synthesis of novel sulfonamide-containing bradykinin hB 2 receptor antagonists. 1. Synthesis and SAR of α,α- dimethylglycine sulfonamides

Article abstract of DOI:10.1021/jm060137l

We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol. Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing human B ₂ receptor (hB₂R) ant

Full text of DOI:10.1021/jm060137l

3602
J. Med. Chem. 2006, 49, 3602-3613
Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 1.
Synthesis and SAR of r,r-Dimethylglycine Sulfonamides
Daniela Fattori,*,† Cristina Rossi,† Christopher I. Fincham,† Marco Berettoni,† Federico Calvani,† Fernando Catrambone,†
Patrizia Felicetti,† Martina Gensini,‡ Rosa Terracciano,† Maria Altamura,‡ Alessandro Bressan,† Sandro Giuliani,‡
Carlo A. Maggi,‡ Stefania Meini,‡ Claudio Valenti,‡ and Laura Quartara‡
Menarini Ricerche, Via Tito Speri 10, 00040 Pomezia (Roma), Italy, and Menarini Ricerche, Via Rismondo 12A, Firenze, Italy
ReceiVed February 8, 2006
We recently published the extensive in vivo pharmacological characterization of MEN 16132 (J. Pharmacol.
Exp. Ther. 2005, 616-623; Eur. J. Pharmacol. 2005, 528, 7), a member of the sulfonamide-containing
human B2 receptor (hB2R) antagonists. Here we report, in detail, how this family of compounds was designed,
synthesized, and optimized to provide a group of products with subnanomolar affinity for the hB2R and
high in vivo potency after topical administration to the respiratory tract. The series was designed on the
basis of indications from the X-ray structures of the key structural motifs A and B present in known antagonists
and is characterized by the presence of an R,R-dialkyl amino acid. The first lead (17) of the series was
submitted to extensive chemical work to elucidate the structural requirements to increase hB2 receptor affinity
and antagonist potency in bioassays expressing the human B2 receptor (hB2R). The following structural
features were selected: a 2,4-dimethylquinoline moiety and a piperazine linker acylated with a basic amino
acid. The representative lead compound 68 inhibited the specific binding of [3H]BK to hB2R with a pKi of
9.4 and antagonized the BK-induced inositolphosphate (IP) accumulation in recombinant cell systems
expressing the hB2R with a pA2 of 9.1. Moreover, compound 68 when administered (300 nmol/kg)
intratracheally in the anesthetized guinea pig, was able to significantly inhibit BK-induced bronchoconstriction
for up to 120 min after its administration, while having a lower and shorter lasting effect on hypotension.
Introduction
antihypertensive and cardioprotective effects of ACE inhibi-
tors,12 and acute changes in cardiovascular parameters produced
by kinin B2 receptor antagonists have been observed.13 This
indicates that in targeting airway inflammatory pathologies it
is important to avoid interfering at the cardiovascular level.
A number of studies have been carried out on peptide14 and
non-peptide BK antagonists.15 One series of non-peptide
antagonists (FR-173657, Chart 1) was derived by Fujisawa
researchers from extensive medicinal chemistry modifications
on a lead discovered by screening a series of angiotensin II
receptor antagonists.16
Further work has been carried out by Fournier researchers,
by substituting the 2,4-dichloro-phenyl-N-methylamide moiety
with a 2,4-dichlorophenyl prolinyl sulfonamide (LF16-0687,
Chart 1).17 This paper describes our work on the 2,4-dichloro-
3-(2,4-methyl-8-quinolyloxymethyl) phenyl framework under-
taken with the aim of developing new, selective hB2R antago-
nists suitable for local administration (aerosol, intratracheal, or
intranasal routes), free from cardiovascular side effects.
The N-methylamide moiety attached to the dichlorobenzene
ring of FR-173657 and its analogues plays a key role in receptor
recognition;18 in fact, this kind of system tends to adopt a cis-
conformation, with the amide and the phenyl plane almost
perpendicular to one another.19 Data on the conformation of
LF16-0687 and its analogues have not been reported in the
literature, but it can intuitively be anticipated that the system
should be relatively rigid.
Bradykinin (BK) is an endogenous nonapeptide (Arg1-Pro2-
Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9) that has been shown to be
involved in a variety of pathophysiological responses such as
inflammation, rhinitis, asthma, and tissue injury and remodeling.
Together with kallidin (KD, [Lys0]BK), BK is the major
mammalian representative of the kinin family of oligopeptide
hormones. These two linear peptides are predominantly released
by the action of tissue and plasma kallikrein enzymes on large
inactive precursors (kininogens), thus acting as local hormones.
In mammals, the biological effect of kinins are mediated
through activation of two distinct cell surface receptors,
designated B1 and B2.2 These membrane-bound receptors are
members of the type 1 G protein coupled receptors (GPCR)
superfamily.3 Whereas B1 receptors are inducible, or poorly
expressed, under physiological conditions,4 B2 receptors are
constitutively expressed in several cell types and mediate most
of the known effects of BK and KD.5 Inhaled BK induces potent
bronchoconstriction and cough in asthmatic patients6 and
rhinitis-like symptoms when instilled into the nose.7 Further-
more, BK is generated in human nasal secretions during
rhinovirus infections8 and allergic rhinitis.9 On the basis of these
findings, a potential therapeutic role for kinin B2 receptor
antagonists has been hypothesized in the treatment of airway
inflammatory pathologies associated with hyper-responsiveness
to BK, such as chronic bronchial asthma,10 or with the release
of BK, such as perennial and seasonal allergic rhinitis.11 On
the other hand, kinins also exert effects on the cardiovascular
system: several studies suggest that BK contributes to the
An analysis of the Cambridge Crystallographic Database
(CCDB) indicated that the turn induced by the sulfonamide
moiety mimics quite well that of the N-methyl aryl amide.
Moreover, the introduction of a proline moiety in the place of
the glycine unit increases the rigidity of the system which then
finds some release for optimal phenylamidino interaction with
the receptor, via the flexible propylendiamine linker. In fact,
* To whom correspondence should be addressed. Phone: +39 06
91184522. Fax: +39 06 9106137. E-mail: Dfattori@menarini-ricerche.it.
† Menarini Ricerche, Roma.
‡ Menarini Ricerche, Firenze.
10.1021/jm060137l CCC: $33.50 © 2006 American Chemical Society
Published on Web 05/20/2006

Synthesis of R,R-Dimethylglycine Sulfonamides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3603
Chart 1. Competitive, Nonpeptidic hB2 Receptor Antagonists FR-173657 and Anatibant, and MEN 16132
the substitution of the proline unit with a glycine or an R-alkyl
amino acid causes a large drop in binding affinity,20 probably
due to excessive flexibility. We wondered if the known
propensity of R,R-dialkyl amino acids to induce turns21 could
be exploited to introduce the necessary rigidity into the system,
while at the same time leaving chemical space for pharmaco-
dynamic (PD) and pharmacokinetic (PK) property optimization.
Indeed, a comparison of the X-ray structures22 of N-(2,4-
dichloro-3-methylphenyl)-N-methylacetamide (A), (R)-1-(2,4-
dichloro-3-methyl benzenesulfonyl)-pyrrolidine-2-carboxylic acid
methyl ester (B), and 2,4-dichlorosulfonylamide of R,R-dimethyl
glycine methyl ester (C) (Figure 1), prepared in our labs as
model compounds, showed that the induced turn was quite
similar and that the terminal carboxylate was pointing in the
same direction, albeit at a different angle.
Following these positive indications, extensive chemical work
was undertaken to explore the SARs for a series of 2,4-
dichlorosulfonamides of R,R-dimethylglycine. Compounds were
first evaluated for their ability to inhibit the binding of tritiated
BK to hB2R. Whenever the pKi value was greater than 8.4, the
molecules were evaluated using a functional assay in CHO cells
expressing the hB2R. The receptor selectivity of the compounds
was also assessed by measuring their ability to inhibit the
binding of [3H][desArg9]Lys-BK to the hB1R.
Acid cleavage of the tert-butyl ester and coupling with amines
NHR1R2 produced products 7a,b.
Hydroxyquinoline 8a is commercially available, while 8b was
prepared according to the synthetic sequence shown in Scheme
2. Condensation of 3-hydroxybenzaldehyde with acetone to give
the R,â-unsaturated ketone 10 was followed by â-methylation
with lithium dimethyl cuprate.23 The oxime 12, obtained via
condensation of ketone 11 with 2,4-dinitrohydroxylamine,24 was
submitted to intramolecular cyclization under Narasaka25 condi-
tions to obtain 8b in high yield and in good purity.
When R1 or R2 contained a BOC-protected amino group, this
was used to further functionalize the molecules, as shown in
Scheme 3.
The BOC group was removed with 4 N HCl in dioxane, and
the resulting free amine was coupled with a carboxylic acid to
obtain amides 14, converted into a guanidino group (15) with
Goodman’s reagent,26 or submitted to reductive amination with
an aldehyde or ketone to obtain amines 16.
Results and Discussion
When we started our research program, the reported non-
peptidic hB2R antagonists had been developed for oral delivery.
Since we were optimizing molecules for airway delivery, the
optimization pathway we followed was quite different. In fact,
in contrast to the intestinal mucosa, the pulmonary epithelium
has been shown to be highly permeable to compounds with high
molecular polar surface areas (e.g., PSA ) 479 Å),27 and this
allowed us to fully exploit the receptor’s extremely high affinity
for positively charged compounds.28 The initial insertion of our
scaffold into the structure LF16-0687 (18, Table 1) confirmed
that the conformation induced by the R,R-dimethylglycine was
slightly different from that of the parent compound: the pKi of
amidine 18 was 7.7, compared to 9.1 for LF16-0687. These
data were interesting anyway, and using R,R-dimethylglycine
as a starting point, we undertook a systematic modification of
the chain linked to the carboxylate function to define primary
SARs for our system (Table 1).
Chemistry
The compounds described in this study are shown in Tables
1 and 2, and the synthetic methods for their preparation are
outlined in Schemes 1-3.
Commercially available 2,6-dichlorotoluene 1 was converted
into the 3-sulfonyl chloride derivative 2 by treatment with
chlorosulfonic acid. Coupling of 2 with the tert-butyl ester of
R,R-dimethyl glycine afforded the corresponding sulfon-
amide 3, which was then brominated with NBS to give benzyl
bromide 4. Nucleophilic substitution with hydroxyquinolines
8a or 8b, mediated by sodium hydride in DMF, gave ether 5.

3604 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
Fattori et al.
Figure 1. (a) Superposition of the X-ray structures obtained for test compounds A (green), B (white), and C (magenta). The figure was made with
WebLab ViewerLite 4.0. (b) ORTEP representation for fragments A, B, and C.
A short neutral chain containing a phenyl ring (19-22) or
solubilizing methoxy groups (23, 24) were of no use in
improving affinity. A slightly better result was obtained with
the introduction of a basic moiety, either as an amino group
(25-29) or a guanidino group (30-32). It is interesting to note
that compounds 31 and 32 show almost the same affinity as
18, despite their simpler structure. The inclusion of the terminal
amino group into a piperidine, piperazine, or morpholine ring
(33-38) was detrimental to binding.
Reductive amination on the propylendiamine linker was
undertaken with the idea of maintaining the basic amino group
and the hope of gaining some binding energy from the
interaction of an aromatic group, with a flexible linker, with
the surrounding portion of the receptor (39-50) through generic
aromatic interactions (we had no receptor model to guide our
work). However, despite all the substituents introduced, the
affinity for the hB2R was always lower or equal to that of the
simpler aliphatic amines and guanidines.
Indeed, rigidification of the linker, via the use of piperazine,
gave compound 53, which showed a net improvement in binding
affinity over its flexible analogue 25. Furthermore, its guanidine
derivative, 54, had a pKi > 8. Elongation of the terminal chain
and introduction of a second positively charged group was also
beneficial for binding (55-61).
The best results were obtained with the insertion of the
charged group into a chiral amino terminal amino acid moiety;
both R- and â-amino acids gave compounds with excellent
affinity, while the acylation of the primary amino group (71)
was detrimental, supporting the critical role of basic groups.
Only the optimal enantiomers are shown in Table 2 (62-71);
the other enantiomers were less active (results not reported).
As mentioned previously, compounds having a pKi value
higher than 8.4 were assessed for their ability to antagonize
BK-induced functional responses, i.e., inositolphosphate (IP)
accumulation as an index of receptor-activated phospholipase
C, coupled to the hB2R expressed in CHO cells. These data
were considered critical not only for the evaluation of the
antagonist activity but also to explore the effect of our
We then decided to try to gain some binding energy by
modifying the entropy of the molecule through constraint of
the linker/basic group into a ring (Table 2).

Synthesis of R,R-Dimethylglycine Sulfonamides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3605
Table 1. Binding of LF16-0687 and Compounds 17-50 to the hB2 Receptor Expressed in CHO Cells
a pKi for inhibition of specific binding of [3H]BK to hB2 receptor in stably transfected CHO cells membrane preparations. For details see the Experimental
Section.
compounds on living cells. Generally, the functional values
roughly correlated with the pKi values.
210 min, while only showing a weak and transient reduction
(ca. 30% for 60 min) in the hypotensive effect.
Remarkable data came from the compounds where the
dimethylquinoline was introduced in place of the monometh-
ylquinoline (55/56, 62/63, 64/65, 67/68, 69/70). In fact, the
dimethyl derivatives, while maintaining almost the same binding
affinity, displayed higher antagonist potency. The reasons for
this phenomenon were not clear. A partial agonist behavior for
the monomethyl derivatives was excluded, since the compounds
did not show agonist responses at the concentration used. None
of the compounds showed a pKi > 5.5 on the hB1R binding
test.
Conclusions
The R,R-dimethylsulfonamide described in this paper repre-
sent a novel class of hB2R antagonists that may be used to design
agents to treat local airway diseases involving kinin B2 receptor
stimulation. The highly promising result showed by compound
68 was used as a starting point for further PK and PD
improvements, eventually leading to MEN 16132,1 a compound
able to significantly inhibit BK-induced bronchoconstriction for
at least 210 min at a dose of 0.1 µmol/kg after intratracheal
administration, with minimal systemic side effects. Details of
this work will be published shortly.
Compound 68, which had both excellent affinity and potency,
was first evaluated in a GPI bioassay, where it showed a pA2 )
10, and was subsequently tested in the guinea pig for its ability
to reduce the BK-induced bronchoconstriction. After intratra-
cheal administration at 300 nmol/kg, it was able to significantly
inhibit (ca. 80%) BK-induced bronchoconstriction for at least
Experimental Section
(A) Chemistry. Commercial chemicals and solvents were of
reagent grade and used without further purification. The following
abbreviations are used for reagents and solvents: AcOH, acetic

3606 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
Fattori et al.
Table 2. Binding and in Vitro Functional Activity on the hB2 Receptor of Compounds 51-71
a See Table 1. b pA2 for the hB2 mediated accumulation of inositol monophosphate in stably transfected CHOdhfr-/hB2R cells. For details see the Experimental
Section.
acid; AcCN, acetonitrile; DCM, dichloromethane; DDQ, dichlo-
(A) in 20 min; and system C, Jupiter RP-18 column, 5µm, 150 ×
4.6 mm, λ ) 210, 240 nm; from 80% to 20% solvent (A) in 20
min.
rodimethylquinone; DMF, dimethylformamide; DMSO, dimethyl
sulfoxide; EDAC, N-(3-dimethylaminopropyl)-N′-ethylcarbodi-
imide; EtOAc, ethyl acetate; Et2O, diethyl ether; EtOH, ethanol;
HOAt, 7-aza-1-hydroxybenzotriazole; MeOH, methanol; NBS,
N-bromosuccinimide; TES, triethylsilane; TFA, trifluoroacetic acid.
Preparative reverse phase HPLC was performed on a Waters600E
apparatus with a Jasco 874 UV detector or on a Waters Delta-Prep
3000 apparatus. The mobile phases were the same as for the
analytical systems. Gradient elution was employed. The columns
used were either a SymmetryPrep C18, 7 µm, 19 × 300 mm, a
Hibar Lichrosorb RP-18, 7 µm, 25 × 250 mm, or a Vydac C18,
10 µm, 22 × 250 mm. Peak detection was at 220 and 254 nm.
Chemical yields are not optimized.
NMR experiments were recorded on a Varian Gemini 200 model
J200 HC, a Varian 300 MHz spectrometer (equipped with a 5 mm
inverse probe), or a Bruker Avance 400 MHz and are referenced
to residual solvent signals: CDCl3 (δ 7.26) or DMSO-d6 (δ 2.49).
Chemical shifts are reported in δ units (parts per million) and are
assigned as singlets (s), doublets (d), doublets of doublets (dd),
triplets (t), quartet (q), quintet (quin), multiplets (m), broad signals
(br), or very broad signals (vbr). Coupling constants (J) are reported
in hertz (Hz).
Merck silica gel (Kieselgel 60) was used for analytical thin-
layer chromatography (TLC, F254 plates) and flash chromatography
(230-400 mesh).
Purity evaluation was performed through analytical HPLC using
either a 600 E Waters pump, coupled to a Jasco 875 UV detector,
and a Merck-Hitachi D-2500 integrator, a system comprising a Jasco
PU-980 pump, LG-980-02 gradient unit, UV-975 UV/vis detector,
and a Merck-Hitachi D-2500 integrator, or a Beckman System Gold
apparatus. Solvents were (A) water 0.1% TFA and (B) AcCN 0.1%
TFA, flow 1 mL/min. HPLC systems were as follows: system A,
Vydac RP-18 column, 5 µm, 250 × 4.6 mm, λ ) 220 nm; from
80% to 8% solvent (A) in 24 min; system B, Symmetry 300 RP-
18 column, 250 × 4.6 mm, λ ) 220 nm; from 80% to 20% solvent

Synthesis of R,R-Dimethylglycine Sulfonamides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3607
Scheme 1a
a Reagents: (a) chlorosulfonic acid; (b) 1,1-dimethylglycine tert-butyl ester, NaHCO3, H2O/AcCN; (c) NBS, benzoyl peroxide, CCl4; (d) NaH, DMF, 8a
or 8b; (e) TFA, TES, DCM; (f) HOAt, EDAC, NHR1R2.
Scheme 2a
a Reagents: (a) acetone, NaOH; (b) CuCl, MeMgBr, THF; (c) O-(2,4-dinitrophenyl)hydroxylamine, HCl; (d) NaH, DDQ, dioxane.
Scheme 3a
a Reagents: (a) 4 N HCl, dioxane; (b) HOAt, EDAC, DMF; (c) Goodman’s reagent, DIPEA; (d) NHR3R4, (polystyrylmethyl)trimethyl cyanoborohydride
resin, DCM/AcOH.
Mass spectra were recorded using a Waters Alliance 2795 HPLC
system fitted with a UV-PDS 996 diode array detector, a ZMD
mass spectrometer, and a GL Science Inertsil ODS-3 column (50
× 3 mm, 3 µm) or a ThermoFinnigan LCQ equipped with APCI
or ESI source.
2,4-Dichloro-3-methylbenzenesulfonyl Chloride (2). 2,6-
Dichlorotoluene 1 (4.8 mL, 37.3 mmol) was added dropwise over
2 h to chlorosulfonic acid (10 mL, 151 mmol). At the end of the
addition, the resulting mixture was heated at 40 °C for 2 h. The
solution turned violet. Then it was cooled to room temperature and
poured with caution onto a water/ice mixture (0.5 L) under vigorous
stirring. A white solid separated that was filtered off, washed with
water, and dried in vacuo in the presence of KOH. The resulting
solid was treated with hexane (200 mL) with vigorous stirring.
Filtration and concentration of the organic layer afforded the desired
product (8.23 g, 85% yield). 1H NMR (300 MHz, CDCl3): δ 7.96
(1H, d, J ) 8.5 Hz), 7.51 (1H, d, J ) 8.5 Hz), 2.66 (3H, s). MS
m/z calcd for C7H5Cl3O2S: 259.54. Found: 260.2 [M + H]+.
2-(2,4-Dichloro-3-methylbenzenesulfonylamino)-2-methylpro-
pionic Acid tert-Butyl Ester (3). A solution of the sulfonyl chloride
2 (569 mg, 2.18 mmol) in acetonitrile (10 mL) was added dropwise
to a solution of the 1,1-dimethylglycine tert-butyl ester (512 mg,

3608 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
Fattori et al.
2.62 mmol) in aq NaHCO3 (224 mg in 5 mL water). At the end of
the addition, a second identical portion of NaHCO3 solution was
added and stirring continued at room temperature. At the end of
the reaction (HPLC control), the solvent was distilled off in vacuo
and the residue partitioned between EtOAc (75 mL) and 1 N HCl
(75 mL). The two layers were separated, and the organic phase
was further washed with 1 N HCl (75 mL), water (2 × 75 mL),
5% NaHCO3 (2 × 75 mL), and brine (75 mL); dried over Na2SO4;
filtered; and concentrated in vacuo to afford 3 (682 mg, 82%) as a
In some cases, the crude reaction mixture was poured directly
onto a silica gel flash column and eluted with hexane/EtOAc
mixtures. In others, the DCM solution was washed with 1 N HCl,
5% Na2CO3, water, and brine; dried over Na2SO4, and concentrated
in vacuo.
(E)-4-(3-Hydroxyphenyl)but-3-en-2-one (10). To an ethanol
solution (150 mL) of 3-hydroxybenzaldehyde 9 (25.5 g, 0.209 mol)
and acetone (60.6 g, 1.05 mol) was added 10% aqueous sodium
hydroxide (150 mL) at 0 °C. The mixture was stirred for 2 h at 0
°C (TLC, silica, petroleum ether/EtOAc 2:1) and then neutralized
by adding 1 N aq HCl. The organic material was extracted with
EtOAc, and the combined extracts were washed with saturated NaCl
and dried over Na2SO4. The solvent was removed in vacuo and
the crude material was treated with Et2O (200 mL), stirred for 3 h,
filtered, washed with Et2O, and dried to give 17 g of pure 4-(3-
hydroxyphenyl)but-3-en-2-one. Concentration of the ethereal layers
resulted in a batch of crude 10 (19 g) which was purified by flash
column chromatography (petroleum ether/EtOAc 2:1) to give an
additional 12 g of 10 (86%). 1H NMR (300 MHz, CDCl3): δ 7.50
(1H, d, J ) 16 Hz), 7.30 (1H, dd, J ) 7.7 Hz), 7.15 (1H, dd, J )
7.2 Hz), 7.10 (1H, s), 6.96 (1H, dd, J ) 7.2 Hz), 6.70 (1H, d, J )
16 Hz), 6.45 (1H, s), 2.45 (3H, s). MS m/z calcd for C10H10O2:
162.0. Found: 163.0 [M + H]+.
1
pale orange solid. H NMR (400 MHz, DMSO-d6): δ 8.35 (1H,
s), 7.85 (1H, d, J ) 8.6 Hz), 7.65 (1H, d, J ) 8.6 Hz), 2.37 (3H,
s), 1.38 (9H, s), 1.26 (6H, s). MS m/z calcd for C15H21Cl2NO4S:
382.0. Found: 383.0 [M + H]+.
2-(3-Bromomethyl-2,4-dichlorobenzenesulfonylamino)-2-
methylpropionic Acid tert-Butyl Ester (4). A solution of 3 (1.00
g, 2.6 mmol), NBS (2.50 g, 13.0 mmol), and benzoyl peroxide (100
mg, 0.41 mmol) in CCl4 (40 mL) was heated at 95 °C under
nitrogen. After 4 h an additional portion (100 mg, 0.41 mmol) of
benzoylperoxide was added. At the end of the reaction (HPLC
control, RP-C18), the mixture was cooled to room temperature,
the insoluble succinimide filtered off, and the solvent distilled off
in vacuo. Flash chromatographic purification (silica, hexane/EtOAc
18:1) afforded 1.03 g (86% yield) of bromo derivative 4. 1H NMR
(300 MHz, CDCl3): δ 8.04 (1H, d, J ) 8.6 Hz), 7.50 (1H, d, J )
8.6 Hz), 6.13 (1H, s), 4.82 (2H, s), 1.50 (9H, s), 1.42 (6H, s). MS
m/z calcd for C15H20BrCl2NO4S: 459.0. Found: 460.0 [M + H]+.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methylpropionic Acid tert-Butyl Ester (5a) and
2-[2,4-Dichloro-3-(2,4-dimethylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methylpropionic Acid tert-Butyl Ester (5b). A
solution of quinoline (8a or 8b, 5.46 mmol) in DMF (10 mL) was
cooled in an ice bath. Sodium hydride (80% in mineral oil, 180
mg, 6.00 mmol) was added portionwise and the mixture was left
to reach room temperature. When gas production ceased, a solution
of benzyl bromide 4 (2.10 g, 4.55 mmol) in DMF (10 mL) was
added dropwise. At the end of the reaction (TLC or HPLC control)
the mixture was poured over water/ice (400 mL). A precipitate
formed, which was filtered off, washed with cold water, and dried
4-(3-Hydroxyphenyl)pentan-2-one (11). Anhydrous CuCl (1.00
g, 10.1 mmol) was added with stirring to a 3 N ethereal solution
of MeMgBr (48 mL, 140 mmol) at 0 °C. 4-(3-Hydroxyphenyl)-
but-3-en-2-one (10) (9.35 g, 57.6 mmol) in dry tetrahydrofuran (200
mL) was slowly added to the reaction mixture at 0 °C. Along with
the addition of the ketone, more CuCl (1.00 g) was added
portionwise. The reaction mixture was stirred at room temperature
for 1 h (TLC, silica, petroleum ether/EtOAc 4:1) and then quenched
under cooling (ice/salt) by the slow addition of 6 N HCl under
vigorous stirring. The organic material was extracted with ethyl
acetate, and the combined extracts were washed with water,
saturated aqueous Na2S2O3, and again with water and dried over
Na2SO4. After the solvent was removed in vacuo, the crude material
was purified by flash column chromatography (petroleum ether/
EtOAc 4:1) to give 4-(3-hydroxyphenyl)pentan-2-one 11 (7.0 g,
1
1
in vacuo to give the desired product in quantitative yield. (5a) H
67%). H NMR (300 MHz, CDCl3): δ 7.20 (1H, t, J ) 7.5 Hz),
NMR (400 MHz, DMSO-d6): δ 8.47 (1H, br s), 8.21 (1H, d, J )
8.4 Hz), 8.01 (1H, d, J ) 8.7 Hz), 7.76 (1H, d, J ) 8.7 Hz), 7.56-
7.32 (4H, m), 5.53 (2H, s), 2.62 (3H, s), 1.41 (9H, s), 1.26 (6H, s).
MS m/z calcd for C25H28Cl2N2O5S: 538.1. Found: 539.1 [M +
6.80 (1H, d, J ) 8 Hz), 6.70 (1H, s), 6.65 (1H, d, J ) 7 Hz), 5.25
(1H, br s), 3.25 (1H, m), 2.80 (1H, dd, J ) 17, 7.0 Hz), 2.55 (1H,
dd, J ) 17, 7.5 Hz), 2.10 (3H, s), 1.30 (3H, d, J ) 6 Hz). MS m/z
calcd for C11H14O2: 178.2. Found: 179 [M + H]+.
1
H]+. (5b) H NMR (400 MHz, CDCl3): δ 8.07 (1H, d, J ) 8.6
4-(3-Hydroxyphenyl)pentan-2-one O-(2,4-Dinitrophenyl)-
oxime (12). O-(2,4-Dinitrophenyl)hydroxylamine (10.22 g, 51.33
mmol) was dissolved in EtOH (500 mL) by warming on a steam
bath. 4-(3-Hydroxyphenyl)pentan-2-one 11 (9.15 g, 51.3 mmol) was
added, and the solution was swirled until it was homogeneous.
Concentrated HCl (20 drops) was added and the mixture stirred at
room temperature. After 1 h (TLC, silica, petroleum ether/EtOAc
4:1) the mixture was concentrated to half volume and diluted with
EtOAc (1.5 L). The organic solution was washed with saturated
NaHCO3, water, and saturated NaCl; dried (Na2SO4); and concen-
trated under reduced pressure to give 20 g of crude 12 (2:1 mixture
of E/Z isomers, 80% HPLC purity, 87% yield) which was used in
the next step without purification. MS m/z calcd for C17H17N3O6:
359.1. Found: 360 [M + H]+.
2,4-Dimethylquinolin-8-ol (8b). To a 1,4-dioxane (200 mL)
suspension of sodium hydride (17.45 g, 55% in mineral oil,
previously washed with hexane, 0.400 mol) was added a 1,4-
dioxane solution (500 mL) of 4-(3-hydroxyphenyl)pentan-2-one
O-2,4-dinitrophenyloxime 12 (18 g, 80%, 0.04 mol) and the mixture
heated to 50 °C. After 20 h, the reaction mixture was acidified
with AcOH (40 mL) and then a 1,4-dioxane solution (200 mL) of
DDQ (4.54 g, 0.02 mmol) was added. The resulting mixture was
immediately heated to reflux. After 2 h (TLC, silica, petroleum
ether/EtOAc 4:1) the reaction mixture was diluted with water (300
mL) and neutralized with saturated aqueous NaHCO3, and the
organic material was extracted with EtOAc. The organic phase was
washed with saturated NaCl and dried over Na2SO4. After evapora-
tion of the solvent the crude material was purified by flash
Hz), 7.62 (1H, d, J ) 8.4 Hz), 7.46 (1H, d, J ) 8.6 Hz), 7.38 (1H,
dd, J ) 8.4, 8.4 Hz), 7.22 (1H, d, J ) 8.4 Hz), 7.15 (1H, s), 6.11
(1H, s), 5.67 (2H, s), 2.65 (3H, s), 2.62 (3H, s), 1.46 (9H, s), 1.54
(6H, s). MS m/z calcd for C26H30Cl2N2O5S: 552.1. Found: 553.1
[M + H]+.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methylpropionic Acid (6a) and 2-[2,4-Dichloro-
3-(2,4-dimethylquinolin-8-yloxymethyl)benzenesulfonylamino]-
2-methylpropionic Acid (6b). A solution of tert-butyl ester (5a
or 5b, 2.50 g, 4.64 mmol), TES (1.83 mL, 11.6 mmol), and TFA
(17 mL, 232 mmol) in DCM (100 mL) was stirred at room
temperature. At the end of the reaction (HPLC control), Et2O was
added (150 mL). After 15 min of stirring a white precipitate was
formed, which was filtered off, washed with Et2O, and dried in
vacuo to obtain the desired acid in quantitative yield. (6a) 1H NMR
(400 MHz, CDCl3): δ 8.67 (1H, d, J ) 8.6 Hz), 8.15 (1H, d, J )
8.6 Hz), 7.83 (1H, t), 7.70-7.50 (4H, m), 6.37 (1H, vbr s), 5.63
(2H, s), 2.93 (3H, s), 1.53 (6H, s). (6b) 1H NMR (400 MHz, DMSO-
d6): δ 8.40 (1H, s), 8.05 (1H, d, J ) 8.5 Hz), 7.85-7.30 (5H, m),
5.50 (2H, s), 2.75 (3H, br s), 2.65 (3H, br s), 1.30 (6H, s).
General Method for the Preparation of Amides 7a and 7b.
A solution of the carboxylic acid 6a or 6b (11.4 mmol), HOAt
(1.510 g, 11.09 mmol), and EDAC (2.47 g, 11.7 mmol) in DCM
(20 mL) was stirred in an ice bath for 30 min. A solution of the
desired, neutral amine (15.68 mmol) in DCM (3 mL) was added
and stirring continued at 0° for 30 min and then at room temperature
till the end of the reaction (HPLC control).

Synthesis of R,R-Dimethylglycine Sulfonamides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3609
chromatography (petroleum ether/EtOAc 4:1) to afford 2,4-dimeth-
yl-8-hydroxyquinoline 8b, which was recrystallized from ethanol
(4.86 g, 70%). 1H NMR (300 MHz, CDCl3): δ 7.40 (2H, m), 7.25
(1H, s), 7.05 (1H, d, J ) 7 Hz), 2.65 (3H, s), 2.60 (3H, s). MS m/z
calcd for C11H11NO: 173.1. Found: 174 [M + H]+.
General Synthesis of Amides 14. A solution of the carboxylic
acid (0.09 mmol) and HOAt (14 mg, 0.09 mmol) in DMF (2.5
mL) was cooled in an ice bath and EDAC (17 mg, 0.09 mmol)
was added. Stirring was continued at 0 °C for 0.5-1.0 h, a solution
of the amine (0.06 mmol) was added, and stirring continued for an
additional 30 min at 0 °C and then at room temperature overnight.
The solvent was distilled off in vacuo and the resulting crude
mixture was purified by RP chromatography to obtain the desired
product.
(5H, m), 1.22 (6H, s). MS m/z calcd for C29H29Cl2N3O4S: 585.1.
Found: 586.1 [M + H]+. HPLC purity: system C, 97.1%, tR
)
13.15 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-(3-phenylpropyl)propionamide Tri-
1
fluoroacetate Salt (22). H NMR (600 MHz, DMSO-d6): δ 8.32
(1H, br s), 8.08 (1H, d), 8.06 (1H, s), 7.78 (1H, d), 7.39-7.33
(5H, m), 7.28-7.12 (4H, m), 5.53 (2H, s), 3.07 (2H, m), 2.39 (3H,
s), 2.56 (2H, m), 1.69 (2H, m), 1.30 (3H, s), 1.25 (3H, s). MS m/z
calcd for C30H31Cl2N3O4S: 599.1. Found: 600.1 [M + H]+. HPLC
purity: system C, 96.6%, tR ) 13.92 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-(2-methoxyethyl)-2-methylpropionamide Tri-
1
fluoroacetate Salt (23). H NMR (600 MHz, DMSO-d6): δ 8.51
(1H, br s), 8.15 (1H, s), 8.07 (1H, d), 7.78 (1H, d), 7.73-7.46
(4H, m), 5.58 (2H, s), 3.32 (2H, t), 3.23 (3H, s), 3.21 (2H, t), 2.73
(3H, br s), 1.28 (6H, s). MS m/z calcd for C24H27Cl2N3O4S: 539.1.
General Synthesis of Guanidines 15. A solution of the amine
(2.34 mmol), Goodman’s reagent (1.06 g, 2.72 mmol), and DIPEA
(2.81 mmol) in DCM (4 mL) was stirred at room temperature for
2 days. At the end of the reaction (HPLC control) the solvent was
distilled off in vacuo and the crude product purified by flash
chromatography (silica) with the opportune eluant. The Boc
protecting group was removed via treatment with TFA/DCM (1:1)
to obtain the desired guanidines as their trifluoroacetate salts.
Found: 540.1 [M + H]+. HPLC purity: system C, >99%, tR
)
9.13 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-(3-methoxypropyl)-2-methylpropionamide Tri-
1
fluoroacetate Salt (24). H NMR (600 MHz, DMSO-d6): δ 8.49
(1H, br s), 8.07 (1H, d), 8.02 (1H, s), 7.77 (1H, d), 7.71-7.48
(4H, m), 5.58 (2H, s), 3.31 (2H, t), 3.19 (3H, s), 3.09 (2H, t), 2.71
(3H, br s), 1.64 (2H, tt), 1.25 (6H, s). MS m/z calcd for C25H29-
Cl2N3O4S: 553.1. Found: 554.1 [M + H]+. HPLC purity: system
D, 99%, tR ) 9.13 min.
General Synthesis of Amines 16. A solution of the amine (0.065
mmol) and the opportune aldehyde (0.067 mmol) in DCM-AcOH
(10:1) (2 mL) was stirred at room temperature for 30 min. The
(polystyrylmethyl)trimethyl cyanoborohydride resin (22 mg, 0.09
mmol) was added and stirring was continued at room temperature
overnight. At the end of the reaction (HPLC control), the mixture
was filtered and the resin was washed with DCM (2 × 4 mL). The
resulting solution was concentrated in vacuo and the residue was
purified by preparative HPLC (RP-C18) to obtain the desired
products as the corresponding trifluoroacetate salts.
N-[3-(4-Carbamimidoylphenylamino)propyl]-2-[2,4-dichloro-
3-(2,4-dimethylquinolin-8-yloxymethyl)benzenesulfonylamino]-
2-methylpropionamide Trifluoroacetate Salt (17). 1H NMR (400
MHz, DMSO-d6): δ 9.40 (2H, s), 9.19 (2H, s), 8.85 (1H, t), 8.10
(2H, m), 8.00 (2H, m), 7.90 (2H, m), 7.85-7.40 (6H, m), 5.55
(2H, s), 3.30 (2H, m), 3.10 (2H, m), 2.70 (3H, s), 2.60 (3H, s),
1.70 (2H, m), 1.30 (6H, s). MS m/z calcd for C33H36Cl2N6O4S:
698.1. Found: 699 [M + H]+. HPLC purity: system A, 95.8%, tR
) 13.9 min.
N-(2-Aminoethyl)-2-[2,4-dichloro-3-(2-methylquinolin-8-yloxy-
methyl)benzenesulfonylamino]-2-methylpropionamide Hydro-
1
chloride Salt (25). H NMR (600 MHz, DMSO-d6): δ 8.65 (1H,
br s), 8.14 (1H, s), 8.08 (1H, d), 7.83-7.56 (4H, m), 7.79 (1H, d),
5.58 (2H, s), 3.29 (2H, m), 2.83 (2H, m), 2.78 (3H, br s), 1.31
(3H, s). MS m/z calcd for C23H26Cl2N4O4S: 524.1. Found: 525.1
[M + H]+. HPLC purity: system A, >99%, tR ) 5.90 min.
N-(3-Aminopropyl)-2-[2,4-dichloro-3-(2-methylquinolin-8-
yloxymethyl)benzenesulfonylamino]-2-methylpropionamide Tri-
fluoroacetate Salt (26). 1H NMR (400 MHz, CDCl3): δ 8.05 (2H,
m), 7.85 (1H, t), 7.55 (1H, d), 7.50 (1H, d), 7.40 (1H, t), 7.3 (3H,
m), 5.80 (2H, s), 3.43 (2H, m), 2.95 (2H, m), 2.82 (3H, s), 1.73
(2H, m), 1.40 (6H, s). MS m/z calcd for C24H28Cl2N4O4S: 538.1.
Found: 539.1 [M + H]+. HPLC purity: system B, 99.0%, tR
8.88 min.
)
N-[3-(4-Carbamimidoylphenylamino)propyl]-2-[2,4-dichloro-
3-(2-methylquinolin-8-yloxymethyl)benzenesulfonylamino]-2-
methylpropionamide Trifluoroacetate Salt (18). H NMR (400
N-(3-Aminopropyl)-2-[2,4-dichloro-3-(2,4-dimethylquinolin-
1
8-yloxymethyl)benzenesulfonylamino]-2-methylpropionamide Tri-
1
MHz, DMSO-d6): δ 9.37 (2H, br s), 9.00 (2H, br s), 8.68 (1H, t),
8.30 (1H, br s), 8.10 (1H, d), 8.00 (2H, d), 7.87 (2H, d), 7.77 (1H,
d), 7.70 (1H, t), 7.60-7.33 (4H, m), 5.53 (2H, s), 3.30 (2H, m),
3.13 (2H, m), 2.63 (3H, s), 1.70 (2H, m), 1.28 (6H, s). MS m/z
calcd for C32H34Cl2N6O5S: 684.2. Found: 685.1 [M + H]+. HPLC
purity: system B, 94.1%, tR ) 10.07 min.
fluoroacetate Salt (27). H NMR (400 MHz, DMSO-d6): δ 8.15
(1H, s), 8.05 (1H, d), 7.81 (1H, d), 7.81-7.30 (8H, m), 5.58 (2H,
s), 3.19 (2H, m), 2.85 (2H, m), 2.69 (3H, s), 2.61 (3H, s), 1.73
(2H, m), 1.31 (6H, s). MS m/z calcd for C25H30Cl2N4O4S: 552.1.
Found: 553.1 [M + H]+. HPLC purity: system A, 99.0%, tR
6.38 min.
)
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
N-(4-Aminobutyl)-2-[2,4-dichloro-3-(2,4-dimethylquinolin-8-
sulfonylamino]-2-methyl-N-phenylpropionamide Trifluoro-
acetate Salt (19). H NMR (600 MHz, DMSO-d6): δ 9.28 (1H,
yloxymethyl)benzenesulfonylamino]-2-methylpropionamide Tri-
fluoroacetate Salt (28). H NMR (600 MHz, DMSO-d6): δ 8.31
1
1
s), 8.30 (1H, br s), 8.16 (1H, s), 8.06 (1H, d), 7.73 (1H, d), 7.64-
7.42 (4H, m), 7.50 (1H, d), 7.42-7.25 (3H, m), 7.08 (1H, t), 5.43
(2H, s), 2.62 (3H, s): 1.39 (6H, s). MS m/z calcd for C27H25-
Cl2N3O4S: 557.0. Found: 558.2 [M + H]+. HPLC purity: system
C, 95.72%, tR ) 12.42 min.
N-Benzyl-2-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)-
benzenesulfonylamino]-2-methylpropionamide Trifluoroacetate
Salt (20). 1H NMR (600 MHz, DMSO-d6): δ 8.39 (1H, br s), 8.14-
8.09 (2H, m), 8.09 (1H, d), 7.76 (1H, d), 7.67-7.34 (4H, m), 4.34-
7.21 (5H, m), 5.33 (2H, s), 4.28 (2H, d): 2.67 (3H, br s), 1.33
(6H, s). MS m/z calcd for C28H27Cl2N3O4S: 571.1. Found: 572.1
[M + H]+. HPLC purity: system C, 96.1%, tR ) 12.40 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-phenethylpropionamide Trifluoro-
acetate Salt (21). 1H NMR (600 MHz, DMSO-d6): δ 9.35 (1H, br
s), 8.44 (1H, br s), 8.07 (1H, d), 8.00 (1H, s), 7.77 (1H, d), 7.71-
7.42 (5H, m), 7.31-7.15 (4H, m), 5.55 (2H, s), 3.27 (4H, m), 2.68
(1H, br s), 8.07 (1H, d), 8.02 (1H, s), 7.70-7.36 (7H, m), 5.68
(2H, s), 3.07 (2H, m), 2.77 (2H, m), 2.63 (3H, br s), 1.48 (4H, m),
1.26 (6H, s). MS m/z calcd for C25H30Cl2N4O4S: 552.1. Found:
553.1 [M + H]+. HPLC purity: system C, 97.6%, tR ) 6.36 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-(3-(dimethylamino)propyl)-2-methylpropion-
1
amide Trifluoroacetate Salt (29). H NMR (600 MHz, DMSO-
d6): δ 9.24 (1H, br s), 8.32 (1H, br s), 8.17 (1H, s), 8.07 (1H, d),
7.82 (1H, m), 7.78 (1H, d), 7.65-7.38 (4H, m), 5.54 (2H, s), 3.16
(2H, m), 3.04 (2H, m), 2.77 (6H, s), 2.65 (3H, br s), 1.78 (2H, m),
1.27 (6H, s). MS m/z calcd for C26H32Cl2N4O4S: 566.1. Found:
567.3 [M + H]+. HPLC purity: system C, 97.6%, tR ) 5.98 min.
2,4-Dichloro-N-(2-guanidino-1,1-dimethyl-2-oxoethyl)-3-(2-
methylquinolin-8-yloxymethyl)benzenesulfonamide Trifluoro-
1
acetate Salt (30). H NMR (400 MHz, DMSO-d6): δ 10.5 (1H,
s), 8.71 (1H, s), 8.50 (2H, br s), 8.29 (3H, br s), 8.08 (1H, d), 7.83
(1H, d), 7.63-7.37 (4H, m), 5.54 (2H, s), 2.62 (3H, s), 1.37 (6H,

3610 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
Fattori et al.
s). MS m/z calcd for C22H23Cl2N5O4S: 523.1. Found: 524.0 [M +
H]+. HPLC purity: system A, 97.0%, tR ) 7.32 min.
7.84 (1H, m), 7.77 (1H, d), 7.55-7.40 (9H, m), 5.55 (2H, s), 2.21
(2H, m), 3.16 (2H, m), 2.90 (2H, m), 2.64 (3H, s), 1.81 (2H, m),
1.55 (6H, s). MS m/z calcd for C31H34Cl2N4O4S: 528.1 Found:
529.1 [M + H]+. HRMS calcd for C31H35Cl2N4O4S [M + H]+:
629.1756. Found: 629.1712. HPLC purity: system A, 99%, tR )
8.40 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-[3-(4-fluorobenzylamino)propyl]-2-methylpro-
pionamide Trifluoroacetate Salt (40). 1H NMR (400 MHz,
DMSO-d6): δ 8.67 (2H, br s), 8.32 (1H, br s), 8.16 (1H, s), 8.06
(1H, d), 7.85 (1H, m), 7.75 (1H, d), 7.62-7.41 (6H, m), 7.29 (2H,
m), 5.56 (2H, s), 4.12 (2H, m), 3.18 (2H, m), 2.91 (2H, m), 2.65
(3H, s), 1.76 (2H, m), 1.26 (6H, s). MS m/z calcd for C31H33Cl2-
FN4O4S: 546.1. Found: 547.0 [M + H]+. HRMS calcd for C31H34-
Cl2FN4O4S [M + H]+: 647.1662. Found: 647.1680. HPLC
purity: system B 98.2%, tR ) 11.86 min.
2N-[3-(4-Chlorobenzylamino)propyl]-2-[2,4-dichloro-3-(2-
methylquinolin-8-yloxymethyl)benzenesulfonylamino]-2-meth-
ylpropionamide Trifluoroacetate Salt (41). 1H NMR (400 MHz,
DMSO-d6): δ 8.71 (2H, br s), 8.26 (1H, br s), 8.15 (1H, s), 8.06
(1H, d), 7.82 (1H, t), 7.80 (1H, d), 7.62-7.35 (8H, m), 5.53 (2H,
s), 4.15 (2H, m), 3.18 (2H, m), 2.91 (2H, m), 2.62 (3H, s), 1.79
(2H, m), 1.26 (6H, s). MS m/z calcd for C31H33Cl3N4O4S: 662.1.
Found: 663.0 [M + H]+. HRMS calcd for C31H34Cl3N4O4S [M +
H]: 665.1337. Found: 665.1301. HPLC purity: system A, > 99%,
tR ) 9.38 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-(2-guanidinoethyl)-2-methylpropionamide (31).
1H NMR (600 MHz, DMSO-d6): δ 8.34 (1H, br s), 8.14 (1H, s),
8.06 (1H, d), 7.70 (2H, m), 7.77-7.31 (4H, m), 6.97 (4H, vbr s),
5.56 (2H, s), 3.17 (4H, m), 2.66 (3H, br s), 1.29 (6H, s). MS m/z
calcd for C24H28Cl2N6O4S: 566.1. Found: 567.3 [M + H]+. HPLC
purity: system C, 94.3%, tR ) 6.51 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-(3-guanidinopropyl)-2-methylpropionamide
1
Trifluoroacetate Salt (32). H NMR (400 MHz, DMSO-d6): δ
8.38 (1H, br s), 8.08 (2H, m), 7.79 (1H, d), 7.67 (1H, m), 7.54
(4H, m), 5.58 (2H, s), 3.12 (4H, m), 2.71 (3H, s), 1.62 (2H, m),
1.33 (6H, s). MS m/z calcd for C25H30Cl2N6O4S: 580.1. Found:
581.1 [M + H]+. HPLC purity: system A, 98.3%, tR ) 13.06 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-piperidin-4-ylpropionamide Tri-
1
fluoroacetate Salt (33). H NMR (600 MHz, DMSO-d6): δ 8.48
(1H, br m), 8.24 (2H, br m), 8.08 (1H, d), 8.00 (1H, s), 7.79 (1H,
d), 7.61-7.36 (5H, m), 5.56 (2H, s), 3.26 (3H, m), 2.98 (2H, m),
2.64 (3H, s), 1.86 (2H, m), 1.60 (2H, m), 1.26 (6H, s). MS m/z
calcd for C26H30Cl2N4O4S: 564.1. Found: 565.1 [M + H]+. HPLC
purity: system A, 99%, tR ) 6.18 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-piperidin-4-ylmethyl-ropionamide
1
Trifluoroacetate Salt (34). H NMR (600 MHz, DMSO-d6): δ
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-[3-(4-methoxybenzylamino)propyl]-2-methyl-
8.43 (1H, m), 8.28 (1H, br s), 8.10 (1H, m), 8.07 (1H, s), 8.10
(1H, d), 7.78 (1H, d), 7.69 (1H, t), 7.64-7.36 (4H, m), 5.58 (2H,
s), 3.26 (2H, m), 3.00 (2H, m), 2.88 (2H, m), 2.62 (3H, br s), 1.74
(2H, m), 1.72 (1H, m), 1.27 (6H, s), 1.25 (2H, m). MS m/z calcd
for C27H32Cl2N4O4S: 578.1. Found: 579.2 [M + H]+. HPLC
purity: system A, 99%, tR ) 6.15 min.
1
propionamide Trifluoroacetate Salt (42). H NMR (400 MHz,
DMSO-d6): δ 8.63 (2H, br s), 8.28 (1H, br s), 8.17 (1H, s), 8.01
(1H, d), 7.83 (1H, m), 7.79 (1H, d), 7.60-7.50 (4H, m), 7.50 (2H,
d), 7.00 (2H, d), 5.54 (2H, d), 4.01 (2H, m), 3.75 (3H, s), 3.17
(2H, m), 2.87 (2H, m), 2.67 (3H, s), 1.75 (2H. m), 1.25 (6H, s).
MS m/z calcd for C32H36Cl2N4O5S: 658.1. Found: 659.0 [M +
H]+. HRMS calcd for C32H37Cl2N4O5S [M + H]+: 659.1862.
Found: 659.1864. HPLC purity: system A, >99%, tR ) 8.49 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-[3-(4-hydroxybenzylamino)propyl]-2-methyl-
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-(2-piperidin-1-yl-ethyl)propion-
1
amide Trifluoroacetate Salt (35). H NMR (600 MHz, DMSO-
d6): δ 9.04 (1H, br s), 8.36 (1H, br s), 8.24 (1H, s), 8.06 (1H, d),
8.00 (1H, t), 7.79 (1H, d), 7.65-7.37 (4H, m), 5.55 (2H, s), 3.45
(4H, m), 3.10 (2H, m), 2.95 (2H, m), 2.65 (3H, s), 1.81 (2H, m),
1.63 (3H, m), 1.37 (1H, m), 1.27 (6H, s). MS m/z calcd for C28H34-
Cl2N4O4S: 592.1. Found: 593.3 [M + H]+. HPLC purity: system
C, 90.2%, tR ) 7.27 min.
1
propionamide Trifluoroacetate Salt (43). H NMR (400 MHz,
DMSO-d6): δ 9.68 (1H, s), 8.55 (2H, br s), 8.27 (1H, br s), 8.18
(1H, s), 8.10 (1H, d), 7.86 (1H, m), 7.82 (1H, d), 7.64-7.36 (4H,
m), 7.27 (2H, d), 6.82 (2H, d), 5.52 (2H, s), 4.00 (2H, s), 3.14
(2H, m), 2.82 (2H, m), 2.59 (3H, s), 1.73 (2H, m), 1.23 (6H, s).
MS m/z calcd for C32H34Cl2N4O5S: 644.1. Found: 645.0 [M +
H]+. HRMS calcd for C32H35Cl2N4O5S [M + H]: 645.1705.
Found: 645.1710. HPLC purity: system A, >99%, tR ) 7.30 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-[3-(4-methylbenzylamino)propyl]-
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-(2-morpholin-4-ylethyl)propion-
1
amide Trifluoroacetate Salt (36). H NMR (600 MHz, DMSO-
d6): δ 9.62 (1H, br s), 8.32 (1H, br s), 8.25 (1H, s), 8.05 (1H, d),
7.96 (1H, t), 7.80 (1H, d), 7.67-7.37 (4H, m), 5.55 (2H, s), 3.98
(2H, m), 3.62 (2H, m), 3.44 (4H, m), 3.15 (4H, m), 2.64 (3H, s),
1.28 (6H, s). MS m/z calcd for C27H32Cl2N4O5S: 594.1. Found:
595.1 [M + H]+. HPLC purity: system A, 99%, tR ) 6.32 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-(3-morpholin-4-yl-propyl)propion-
1
propionamide Trifluoroacetate Salt (44). H NMR (400 MHz,
DMSO-d6): δ 8.62 (2H, br s), 8.25 (1H, br s), 8.14 (1H, s), 8.01
(1H, d), 7.83 (2H, m), 7.79 (1H, s), 7.62-7.37 (4H, m), 7.37 (2H,
d), 7.25 (2H, d), 5.50 (2H, s), 4.10 (2H, m), 3.12 (2H, m), 2.85
(2H, m), 2.62 (3H, s), 2.30 (3H, s), 1.75 (2H, m), 1.25 (6H, s). MS
m/z calcd for C32H36Cl2N4O4S: 642.1. Found: 643.1 [M + H]+.
HRMS calcd for C32H37Cl2N4O4S [M + H]: 643.1913. Found:
643.1897. HPLC purity: system A, 98.4%, tR ) 9.61 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-[3-(4-methanesulfonylbenzylamino)propyl]-2-
1
amide Trifluoroacetamide (37). H NMR (600 MHz, DMSO-
d6): δ 9.53 (1H, br s), 8.33 (1H, br s), 8.18 (1H, s), 8.08 (1H, d),
7.84 (1H, t), 7.81 (1H, d), 7.68-7.35 (4H, m), 5.54 (2H, s), 3.95
(2H, m), 3.63 (2H, m), 3.39 (2H, m), 3.16 (2H, m), 3.07 (4H, m),
2.64 (3H, s), 1.82 (2H, m), 1.29 (6H, s). MS m/z calcd for C28H34-
Cl2N4O5S: 608.1. Found: 609.1 [M + H]+. HPLC purity: system
A, 99%, tR ) 6.27 min.
methylpropionamide Trifluoroacetate Salt (45).
1H NMR (400
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-[3-(4-methylpiperazin-1-yl)propyl]-
propionamide Trfluoroacetate Salt (38). H NMR (600 MHz,
MHz, DMSO-d6): δ 8.87 (2H, br s), 8.30 (1H, br s), 8.17 (1H, s),
8.09 (1H, d), 8.00 (2H, d), 7.91 (1H, m), 7.89 (1H, d), 7.85 (2H,
d), 7.65-7.39 (4H, m), 5.57 (2H, s), 4.30 (2H, s), 3.22 (3H, s),
3.13 (2H, m), 2.96 (2H, m), 2.61 (3H, s), 1.83 (2H, m), 1.26 (6H,
s). MS m/z calcd for C32H36Cl2N4O6S2 : 706.1. Found: 706.9 [M
+ H]+. HRMS calcd for C32H37Cl2N4O6S2 [M + H]+: 707.1532.
Found: 707.1524. HPLC purity: system A, >99%, tR ) 7.54 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-2-methyl-N-{3-[(pyridin-2-ylmethyl)amino]-
propyl}propionamide Trifluoroacetate Salt (46). 1H NMR (400
MHz, DMSO-d6): δ 9.00 (2H, br s), 8.65 (1H, m), 8.40 (1H, br s),
8.15 (1H, s), 8.05 (1H, d), 7.90 (1H, m), 7.80 (2H, m), 7.90-7.40
1
DMSO-d6): δ 8.34 (1H, br s), 8.14 (1H, s), 8.07 (1H, d), 7.79
(1H, d), 7.72 (1H, br s), 7.65-7.60 (4H, m), 5.56 (2H, s), 3.37
(8H, br m), 3.12 (4H, m), 2.74 (3H, s), 2.65 (3H, s), 1.70 (2H, m),
1.23 (6H, s). MS m/z calcd for C29H37Cl2N5O4S: 621.2. Found:
622.2 [M + H]+. HPLC purity: system A, 99%, tR ) 5.45 min.
N-(3-Benzylaminopropyl)-2-[2,4-dichloro-3-(2-methylquino-
lin-8-yloxymethyl)benzenesulfonylamino]-2-methylpropion-
1
amide Trifluoroacetate Salt (39). H NMR (400 MHz, DMSO-
d6): δ 8.74 (2H, br s), 8.29 (1H, s), 8.16 (1H, br s), 8.06 (1H, d),

Synthesis of R,R-Dimethylglycine Sulfonamides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3611
(6H, m), 5.55 (2H, s), 4.30 (2H, m), 3.15 (2H, m), 3.00 (2H, m),
2.65 (3H, s), 1.83 (2H, m), 1.30 (6H, s). MS m/z calcd for C30H33-
Cl2N5O4S: 629.1. Found: 630.0 [M + H]+. HRMS calcd for
C30H34Cl2N5O4S [M + H]: 630.1719. Found: 630.1697. HPLC
purity: system A, 98.1%, tR ) 7.30 min.
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-[3-(4-(dimethylamino)benzylamino)propyl]-
2-methylpropionamide Trifluoroacetate Salt (47). 1H NMR (400
MHz, DMSO-d6): δ 8.52 (2H, br s), 8.32 (1H, br s), 8.16 (1H, s),
8.08 (1H, d), 7.84 (1H, m), 7.76 (1H, d), 7.62-7.40 (4H, m), 7.24
(2H, d), 6.72 (2H, d), 5.56 (2H, s), 4.00 (2H, m), 3.16 (2H, m),
2.88 (6H, s), 2.84 (2H, m), 2.64 (3H, s), 1.80 (2H, m), 1.28 (6H,
s). MS m/z calcd for C33H39Cl2N5O4S: 671.2. Found: 672.1 [M +
H]+. HPLC purity: system A, 99.2%, tR ) 6.53 min.
4-[(3-{2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)-
benzenesulfonylamino]-2-methylpropionylamino}propylamino)-
methyl]benzamide Trifluoroacetate Salt (48). 1H NMR (400
MHz, DMSO-d6): δ 8.83 (2H, br s), 8.39 (1H, br s), 8.22 (1H, s),
8.11 (1H, d), 8.11 (1H, m), 7.93 (2H, d), 7.85 (2H, m), 7.83-7.43
(6H, m), 5.56 (2H, s), 4.22 (2H, br s), 3.22 (2H, m), 3.00 (2H, m),
2.65 (3H, s), 1.83 (2H, m), 1.26 (6H, s). MS m/z calcd for C32H35-
Cl2N5O5S: 671.1. Found: 672.1 [M + H]+. HPLC purity: system
A, 95.3%, tR ) 6.29 min.
(3H, s), 1.23 (6H, s). MS m/z calcd for C26H30Cl2N6O4S: 592.1.
Found: 593.3 [M + H]+. HPLC purity: system A, 97.6%, tR
)
6.34 min.
N-(3-Aminopropyl)-4-{2-[2,4-dichloro-3-(2-methylquinolin-8-
yloxymethyl)benzenesulfonylamino]-2-methylpropionyl}-
piperazine-1-carboxamidine Trifluoroacetate Salt (55). 1H NMR
(400 MHz, DMSO-d6): δ 8.72 (1H, s), 8.32 (1H, br s), 8.08 (1H,
d), 7.98-7.72 (7H, m), 7.64-7.40 (4H, m), 5.62 (2H, s), 3.75-
3.52 (8H, m), 3.26 (2H, m), 2.88 (2H, m), 2.66 (3H, s), 1.80 (2H,
m), 1.22 (6H, s). MS m/z calcd for C29H37Cl2N7O4S: 649.2.
Found: 650.2 [M + H]+. HPLC purity: system A, >99%, tR
8.50 min.
)
N-(3-Aminopropyl)-4-{2-[2,4-dichloro-3-(2,4-dimethylquino-
lin-8-yloxymethyl)benzenesulfonylamino]-2-methylpropionyl}-
piperazine-1-carboxamidine Trifluoroacetate Salt (56). 1H NMR
(400 MHz, DMSO-d6): δ 8.58 (1H, s), 8.08 (1H, d), 7.80 (8H,
m), 7.62-7.36 (3H, m), 5.62 (2H, s), 3.75-3.45 (8H, m), 3.28
(2H, m), 2.86 (2H, m), 2.68 (3H, s), 2.64 (3H, s), 1.80 (2H, m),
1.66 (6H, s). MS m/z calcd for C30H39Cl2N7O4S: 663.2. Found:
664.3 [M + H]+. HRMS calcd for C30H40Cl2N7O4S [M + H]+:
664.2224. Found: 664.2239. HPLC purity: system B, 99.8%, tR
) 9.36 min.
N-(6-Aminohexyl)-4-{2-[2,4-dichloro-3-(2-methylquinolin-8-
yloxymethyl)benzenesulfonylamino]-2-methylpropionyl}-
piperazine-1-carboxamidine Trifluoroacetate Salt (57). 1H NMR
(400 MHz, DMSO-d6): δ 8.71 (1H, s), 8.33 (1H, br s), 8.08 (1H,
d), 7.79 (1H, d), 7.67 (7H, m), 7.64-7.40 (4H, m), 5.60 (2H, s),
3.70-3.45 (8H, m), 3.19 (2H, m), 2.77 (2H, m), 2.64 (3H, s), 1.52
(4H, m), 1.25 (4H, m), 1.21 (6H, s). MS m/z calcd for C32H43-
Cl2N7O4S: 691.2. Found: 692.1 [M + H]+. HPLC purity: system
B, 99.8%, tR ) 9.16 min.
2,4-Dichloro-N-{2-[4-(2-guanidinoethyl)piperazin-1-yl]-1,1-di-
methyl-2-oxoethyl}-3-(2-methylquinolin-8-yloxymethyl)ben-
zenesulfonamide Trifluoroacetate Salt (58). 1H NMR (600 MHz,
DMSO-d6): δ 10.05 (1H, vbr s), 8.71 (1H, s), 8.32 (1H, br s),
8.05 (1H, d), 7.82 (1H, d), 7.77-7.16 (8H, m), 5.55 (2H, s), 4.71-
2.84 (8H, vbr m), 2.64 (3H, s), 1.56 (6H, s). MS m/z calcd for
C28H35Cl2N7O4S: 635.3. Found: 636.2 [M + H]+. HPLC purity:
system A, 99%, tR ) 5.68 min.
2,4-Dichloro-N-{2-[4-(6-guanidinohexyl)piperazin-1-yl]-1,1-
dimethyl-2-oxoethyl}-3-(2-methylquinolin-8-yloxymethyl)ben-
zenesulfonamide Trifluoroacetate Salt (59). 1H NMR (400 MHz,
DMSO-d6): δ 9.83 (1H, br s), 8.93(1H, br s), 8.76 (1H, s), 8.31
(1H, br s), 8.05 (1H, d), 7.81 (1H, d), 7.64-7.38 (5H, m), 5.57
(2H, s), 4.57 (2H, m), 3.62 (2H, m), 3.09 (6H, m), 3.00 (2H, m),
2.62 (3H, s), 1.67 (2H, m), 1.48 (2H, m), 1.35 (4H, m), 1.26 (6H,
s). MS m/z calcd for C32H43Cl2N7O4S: 691.2. Found: 692.2 [M +
H]+. HPLC purity: system A, 99.4%, tR ) 6.46 min.
N-{2-[4-(6-Aminohexyl)piperazin-1-yl]-1,1-dimethyl-2-oxo-
ethyl}-2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)ben-
zenesulfonamide Trifluoroacetate Salt (60). 1H NMR (400 MHz,
DMSO-d6): δ 8.73 (1H, s), 8.25 (1H, br s), 8.00 (1H, d), 7.79
(1H, d), 7.71 (4H, br s), 7.60-7.30 (5H, m), 5.54 (2H, s), 4.58
(2H, br s), 3.56 (4H, m), 3.15 (4H, m), 2.94 (2H, m), 2.75 (2H,
m), 2.58 (3H, s), 1.67 (2H, m), 1.50 (2H, m), 1.33 (6H, m), 1.25
(4H, m). calcd for C31H41Cl2N5O4S: 649.2. Found: 650.2 [M +
H]+. HPLC purity: system A, 99.0%, tR ) 6.26 min.
2,4-Dichloro-N-{1,1-dimethyl-2-oxo-2-[4-(2-piperazin-1-
ylacetyl)piperazin-1-yl]ethyl}-3-(2-methylquinolin-8-yloxymeth-
yl)benzenesulfonamide Trifluoroacetate Salt (61). 1H NMR (400
MHz, DMSO-d6): δ 8.85 (1H, br s), 8.71 (1H, s), 8.31 (2H, br s),
8.08 (1H, d), 7.81 (1H, d), 7.64-7.40 (4H, m), 5.56 (2H, s), 3.54
(8H, m), 3.25 (6H, m), 3.06 (4H, m), 2.67 (3H, s), 1.60 (4H, m),
1.25 (6H, s). MS m/z calcd for C31H38Cl2N6O5S: 676.2. Found:
677.1 [M + H]+. HPLC purity: system B, 99.4%, tR ) 7.67 min.
N-{2-[4-((S)-3-Amino-6-(dimethylamino)hexanoyl)piper-
azin-1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2-methyl-
quinolin-8-yloxymethyl)benzenesulfonamide Trifluoroacetate
Salt (62). 1H NMR (400 MHz, DMSO-d6): δ 9.50 (1H, br s), 8.67
(1H, s), 8.24 (1H, d), 8.05 (1H, d), 7.81 (4H, m), 7.57-7.45 (4H,
m), 5.57 (2H, s), 3.65-345 (8H, m), 3.03 (2H, m), 2.76 (6H, s),
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-{3-[(furan-3-ylmethyl)amino]propyl}-2-meth-
ylpropionamide Trifluoroacetate Salt (49). 1H NMR (400 MHz,
DMSO-d6): δ 8.65 (2H, br s), 8.35 (1H, br s), 8.18 (1H, s), 8.01
(1H, d), 7.83 (4H, m), 7.76-7.41 (4H, m), 6.61 (1H, s), 5.59 (2H,
s), 4.0 (2H, br s), 3.15 (2H, m), 2.91 (2H, m), 2.63 (3H, s), 1.78
(2H, m), 1.30 (6H, s). MS m/z calcd for C29H32Cl2N4O5S: 618.1.
Found: 619.1 [M + H]+. HPLC purity: system A, 98.0%, tR
7.95 min.
)
2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)benzene-
sulfonylamino]-N-{3-[(1H-imidazol-4-ylmethyl)amino]propyl}-
2-methylpropionamide Trifluoroacetate Salt (50). 1H NMR (400
MHz, DMSO-d6): δ 8.93 (2H, br s), 8.64 (1H, br s), 8.32 (1H, m),
8.18 (1H, s), 8.04 (1H, d), 8.04 (1H, m), 7.82 (2H, m), 7.68-7.42
(7H, m), 5.75 (1H, s), 5.55 (2H, s), 4.18 (2H, br s), 3.18 (2H, m),
2.95 (2H, m), 2.66 (3H, s), 1.77 (2H, m), 1.25 (6H, s). MS m/z
calcd for C28H32Cl2N6O4S: 618.1. Found: 619.0 [M + H]+. HPLC
purity: system A, >99%, tR ) 5.75 min.
N-(2-Azepan-1-yl-1,1-dimethyl-2-oxoethyl)-2,4-dichloro-3-(2-
methylquinolin-8-yloxymethyl)benzenesulfonamide Trifluoro-
1
acetate Salt (51). H NMR (600 MHz, DMSO-d6): δ 8.76 (1H,
s), 8.20 (2H, br s), 8.13 (1H, m), 8.01 (1H, d), 7.84 (1H, d), 7.61-
7.35 (4H, m), 5.56 (2H, s), 3.85-3.17 (8H, vbr m), 2.62 (3H, s),
2.12 (2H, m), 1.93 (2H, m), 1.23 (6H, s). MS m/z calcd for C27H32-
Cl2N4O4S: 578.1. Found: 579.2 [M + H]+. HPLC purity: system
A, 99%, tR ) 7.47 min.
2,4-Dichloro-N-(2-[1,4]diazepan-1-yl-1,1-dimethyl-2-oxoethyl)-
3-(2-methylquinolin-8-yloxymethyl)benzenesulfonamide Tri-
1
fluoroacetate Salt (52). H NMR (600 MHz, DMSO-d6): δ 8.74
(1H, s), 8.63 (2H, br s), 8.29 (1H, m), 8.08 (1H, d), 7.83 (1H, d),
7.62-7.36 (4H, m), 5.58 (2H, s), 3.89-3.17 (8H, vbr m), 2.63 (3H,
s), 2.07 (2H, m), 1.25 (6H, s). MS m/z calcd for C26H30Cl2N4O4S:
564.1. Found: 565.1 [M + H]+. HPLC purity: system C, 95.9%,
tR ) 6.20 min.
2,4-Dichloro-N-[1,1-dimethyl-2-(4-methylpiperazin-1-yl)-2-
oxoethyl]-3-(2-methylquinolin-8-yloxymethyl)benzenesulfon-
amide (53). 1H NMR (600 MHz, DMSO-d6): δ 9.83 (1H, m), 8.68
(1H, s), 8.34 (1H, br s), 8.06 (1H, d), 7.82 (1H, d), 7.66-7.38
(4H, m), 5.58 (2H, s), 4.58 (2H, m), 3.51 (2H, m), 3.17 (2H, m),
3.00 (2H, m), 2.60 (3H, s), 1.22 (6H, s). MS m/z calcd for C26H30-
Cl2N4O4S: 564.1. Found: 565.2 [M + H]+. HPLC purity: system
C, 99%, tR ) 6.09 min.
4-{2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxymethyl)ben-
zenesulfonylamino]-2-methylpropionyl}piperazine-1-carbox-
amidine Trifluoroacetate Salt (54). 1H NMR (600 MHz, DMSO-
d6): δ 8.70 (1H, s), 8.26 (1H, br s), 8.05 (1H, d), 7.81 (1H, d),
7.36 (1H, m), 7.48-7.41 (6H, m), 5.57 (2H, s), 3.50 (8H, m), 3.63

3612 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12
Fattori et al.
2.76 (2H, m), 2.62 (3H, s), 2.62 (1H, m), 1.69 (2H, m), 1.59 (2H,
N-{2-[4-((S)-2-Amino-6-(dimethylamino)hexanoyl)piperazin-
1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2,4-dimethylquin-
olin-8-yloxymethyl)benzenesulfonamide Trifluoroacetate Salt
(70). 1H NMR (400 MHz, DMSO-d6): δ 9.50 (1H, br s), 8.65 (1H,
s), 8.15 (3H, br s), 8.08 (1H, d), 7.85 (1H, d), 7.85-7.47 (4H, m),
5.60 (2H, s), 4.50 (1H, m), 3.77 (8H, m), 3.06 (2H, m), 2.77 (6H,
s), 2.73 (3H, s), 2.67 (3H, s), 1.72 (2H, m), 1.62 (2H, m), 1.33
(2H, m), 1.25 (6H, s). MS m/z calcd for C34H46Cl2N6O5S: 720.2.
m), 1.24 (6H s). MS m/z calcd for C33H44Cl2N6O5S: 706.2.
Found: 707.3 [M + H]+. HPLC purity: system B, >99%, tR
7.64 min.
)
N-{2-[4-((S)-3-Amino-6-(dimethylamino)hexanoyl)piper-
azin-1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2,4-dimethyl-
quinolin-8-yloxymethyl)benzenesulfonamide Trifluoroacetate
Salt (63). 1H NMR (400 MHz, DMSO-d6): δ 9.50 (1H, br s), 8.70
(1H, s), 8.05 (1H, d), 7.77 (4H, m), 7.77-7.25 (4H, m), 5.55 (2H,
s), 3.65-3.20 (8H, m), 3.05 (2H, m), 2.75 (6H, s), 2.85-2.55 (10H,
m), 1.70 (2H, m), 1.57 (2H, m), 1.23 (6H, s). MS m/z calcd for
C34H46Cl2N6O5S: 720.2. Found: 721.2 [M + H]+. HPLC purity:
system B, 98.9%, tR ) 13.56 min.
N-{2-[4-((S)-3-Amino-7-(dimethylamino)heptanoyl)piperazin-
1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2-methylquinolin-
8-yloxymethyl)benzenesulfonamide Trifluoroacetate Salt (64).
1H NMR (400 MHz, DMSO-d6): δ 9.43 (1H, br s), 8.69 (1H, s),
8.29 (1H, br s), 8.07 (1H, d), 7.81 (1H, d), 7.76 (3H, m), 7.62-
7.28 (4H, m), 5.57 (2H, s), 3.83-3.29 (8H, m), 3.00 (2H, m), 2.78
(6H, s), 2.78-2.57 (4H, m), 2.62 (3H, s), 1.59 (4H, m), 1.36 (2H,
m), 1.24 (6H, s). MS m/z calcd for C34H46Cl2N6O5S: 720.2.
Found: 721.2 [M + H]+. HPLC purity: system B, 99.32%, tR )
7.59 min.
N-{2-[4-((S)-3-Amino-7-(dimethylamino)heptanoyl)piperazin-
1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2,4-dimethylquin-
olin-8-yloxymethyl)benzenesulfonamide (65). 1H NMR (400
MHz, DMSO-d6): δ 9.43 (1H, br s), 8.68 (1H, s), 8.07 (1H, d),
7.79 (1H, d), 7.75 (3H, m), 7.61-7.23 (3H, m), 5.59 (2H, s), 3.73-
3.20 (8H, m), 3.00 (2H, m), 2.77-2.55 (10H, m), 1.61 (4H, m),
1.36 (2H, m), 1.25 (6H, s). MS m/ z calcd for C35H48Cl2N6O5S:
734.2. Found: 735.2 [M + H]+. HPLC purity: system B, 99.8%,
tR ) 13.56 min.
N-{2-[4-((S)-3-Amino-7-guanidinoheptanoyl)piperazin-1-yl]-
1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2-methylquinolin-8-
yloxymethyl)benzenesulfonamide Trifluoroacetate Salt (66). 1H
NMR (400 MHz, DMSO-d6): δ 8.98 (2H, br s), 8.69 (1H, s), 8.32
(1H, br s), 8.09 (1H, d), 7.82 (1H, d), 7.71 (3H, br s), 7.64-7.33
(4H, m), 7.09 (5H, br s), 5.58 (2H, s), 3.73-3.20 (8H, m), 3.09
(3H, m), 2.82 (1H, d), 2.66 (3H, s), 2.60 (1H, m), 1.60 (2H, m),
1.47 (2H, m), 1.35 (2H, m), 1.27 (6H, s). MS m/z calcd for C33H44-
Cl2N8O5S: 734.3. Found: 735.0 [M + H]+. HPLC purity: system
B, 93.6%, tR ) 7.90 min.
N-{2-[4-((S)-2-Amino-5-(dimethylamino)pentanoyl)piperazin-
1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2-methylquinolin-
8-yloxymethyl)benzenesulfonamide Trifluoroacetate Salt (67).
1H NMR (400 MHz, DMSO-d6): δ 9.57 (1H, br s), 8.52 (1H, s),
8.20 (4H, br s), 8.05 (1H, d), 7.82 (1H, d), 7.59-7.32 (4H, m),
5.54 (2H, s), 4.55 (1H, m), 3.55 (8H, m), 3.04 (2H, m), 2.77 (6H,
s), 2.64 (3H, s), 1.73 (4H, m), 1.27 (3H, s), 1.23 (3H, s). MS m/z
calcd for C32H42Cl2N6O5S: 692.2. Found: 693.1 [M + H]+. HPLC
purity: system B, 99.2%, tR ) 7.28 min.
N-{2-[4-((S)-2-Amino-5-(dimethylamino)pentanoyl)piperazin-
1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2,4-dimethylquin-
olin-8-yloxymethyl)benzenesulfonamide Trifluoroacetate Salt
(68). 1H NMR (400 MHz, DMSO-d6): δ 9.48 (1H, br s), 8.76 (1H,
s), 8.19 (3H, br s), 8.04 (1H, d), 7.86 (1H, d), 7.76-7.24 (4H, m),
6.59 (2H, s), 4.57 (1H, m), 3.50 (8H, m), 3.07 (2H, m), 2.81 (6H,
s), 2.66 (3H, s), 2.62 (3H, s), 1.71 (4H, m), 1.28 (3H, s), 1.21 (3H,
s). MS m/z calcd for C33H44Cl2N6O5S: 706.2. Found: 706.9 [M +
H]+. HPLC purity: system B, 99.8%, tR ) 13.44 min.
N-{2-[4-((S)-2-Amino-6-(dimethylamino)hexanoyl)piperazin-
1-yl]-1,1-dimethyl-2-oxoethyl}-2,4-dichloro-3-(2-methylquinolin-
8-yloxymethyl)benzenesulfonamide Trifluoroacetate Salt (69).
1H NMR (400 MHz, DMSO-d6): δ 9.32 (1H, br s), 8.72 (1H, s),
8.30 (1H, br s), 8.15 (3H, br s), 8.10 (1H, d), 7.85 (1H, d), 7.65-
7.40 (4H, m), 5.55 (2H, s), 4.50 (1H, m), 3.50 (8H, br s), 3.00
(2H, m), 2.80 (6H, s), 2.67 (3H, s), 1.73 (2H, m), 1.60 (2H, m),
1.37 (2H, m), 1.25 (3H, s). MS m/z calcd for C33H44Cl2N6O5S:
706.2. Found: 707.2 [M + H]+. HPLC purity: system B, 99.9%,
tR ) 8.16 min.
Found: 721.2 [M + H]+. HPLC purity: system B, 99.6%, tR
)
13.34 min.
N-[(S)-1-(4-{2-[2,4-Dichloro-3-(2-methylquinolin-8-yloxy-
methyl)benzenesulfonylamino]-2-methylpropionyl}piperazine-
1-carbonyl)-5-(dimethylamino)pentyl]acetamide Trifluoroace-
tate Salt (71). 1H NMR (400 MHz, DMSO-d6): δ 9.30 (1H, br s),
8.71 (1H, s), 8.47 (1H, br s), 8.25 (1H, d), 8.07 (1H, d), 7.82 (1H,
d), 7.82 (1H, d), 7.69-7.44 (4H, m), 5.62 (2H, s), 4.75 (1H, m),
3.58 (8H, m), 3.02 (2H, m), 2.75 (6H, s), 2.71 (3H, s), 1.89 (3H,
s), 1.62 (4H, m), 1.29 (2H, m), 1.29 (6H, s). MS m/z calcd for
C35H46Cl2N6O6S: 748.2. Found: 749.1 [M + H]+. HPLC purity:
system B, <99%, tR ) 8.12 min.
(B) Biology. Receptor Binding Assays. Binding assays were
performed using membranes of CHO cells expressing the hB2R as
previously described.29 The buffer used for binding experiments
was N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid (10
mM, pH 7.4) containing 1,10-phenanthroline (1 mM), bacitracin
(140 µg/mL), and bovine serum albumin (1 g/L). Binding assays
were performed at room temperature in a final volume of 0.5 mL,
and an incubation time of 60 min was used. The [3H]BK
concentration was comparable with its calculated Kd value (0.1-
0.2 nM), and the membrane concentration was 100-150 µg/mL.
Competing ligands were tested under a wide range of concentrations
(1 pM-10 µM). Nonspecific binding was defined as the amount
of labeled ligand bound in the presence of 1 µM BK. The final
concentration of DMSO in the binding assay was 1% and did not
affect binding parameters. Reactions were stopped by filtration with
UniFilter-96 plates GF/B (Packard Instrument Company), presoaked
for at least 2 h in polyethylenimine 0.6%, and using a MicroMate
96 cell harvester (Packard Instrument Co.). The tubes and filters
were then washed five times with 0.5-mL aliquots of Tris buffer
(50mM, pH 7.4, 4 °C). The filters were dried and soaked in
Microscint 40 (50 µL/well, Packard Instrument Co.), and the bound
radioactivity was counted using a TopCount Microplate Scintillation
Counter (Packard Instrument Co.). Binding parameters were evalu-
ated using GraphPad Prism 4.0 (GraphPad, San Diego, CA) to
determine the ligand concentration inhibiting the radioligand binding
of the 50% (IC50). The -log of Ki values (pKi) were calculated
from the Cheng-Prusoff equation Ki ) IC50/(1 + [radioligand]/
Kd).
Measurement of Inositol Monophosphate Accumulation. The
assay was performed according to the method of Berridge.30 CHO
cells stably transfected with the hB2R were plated in 24-well plates
(1.8 × 105 cells/well) and incubated at 37 °C overnight. Cells were
labeled in the presence of a labeling medium (Ham’s F-12/MEMR
) 1/1, 1% dyalized FCS, 2 mM glutamine and 50 IU/mL penicillin/
streptomycin) by adding 1 µCi/well [1,2-3H(N)]-myo-inositol for
24 h. The labeled culture medium was aspirated, and the cells were
preincubated in the absence (control) or presence of an opportune
nanomolar concentration of the chosen compound for 20 min and
then incubated in the absence or the presence of 1 × 10-11 up to
1 × 10-5 M BK for 40 min at 37 °C in IP1 modified buffer (135
mM PBS, 20 mM Na/Hepes pH 7.4, 2 mM CaCl2, 1.2 mM MgSO4,
1mM EGTA, 11.1 mM glucose, 25 mM LiCl, 0.05% BSA, 1mM
1,10-phenantroline, and 140 µg/mL bacitracin). At the end of the
incubation period, 1 mL of ice-cold methanol/0.1 N HCl (2:1 v/v)
was added to liberate the inositol phosphate formed. The aqueous
phase was applied to an anion exchange column (AG 1-X8 Bio-
Rad, Hercules, CA) and the inositol monophosphate eluted with
0.2 M ammonium formate/0.1 M formic acid. In the IP1 fraction,
the radioactivity was determined by liquid scintillation spectrometry.
Agonist concentration-response curves in the absence and presence
of antagonists were fitted by sigmoidal nonlinear regression

Synthesis of R,R-Dimethylglycine Sulfonamides
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 12 3613
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from the equation pA2 ) log [CR - 1] - log [antagonist
concentration], where CR is the concentration-ratio of equieffective
concentrations of agonist (EC50) obtained in the presence and in
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Acknowledgment. We are grateful to Mr. Ricci and Mr.
Fabbri for technical assistance, to Dr. A. Madami for the Figure
1a, to Dr. A. Cartoni and Dr. A. Triolo for analytical assistance,
to Dr. A. Ettorre and Dr. G. Balacco for NMR spectra, to Dr.
A. Guerri for X-rays structures, and Dr. G. Raucci for HRMS.
This work was supported by grants from the Italian Ministry
of University and Research (RIF.506/DSPAR 98).
Supporting Information Available: Experimental details of
the X-ray data collections and crystallographic parameters. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Appl. WO 09900387, 1999.
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Inamura, N.; Asano, M.; Hatori, C.; Katayama, A.; Oku, T.; Tanaka,
H. A novel class of orally active non-peptide bradykinin B2 receptor
antagonists. 2. Overcoming the species difference between guinea
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