2-Aminobenzophenones as a novel class of bradykinin B1 receptor antagonists

Article abstract of DOI:10.1021/jm800199h

Selective bradykinin (BK) B₁ receptor antagonists could be novel therapeutic agents for the treatment of pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead compound 1 provided potent hBK B₁ receptor antagonists with excellent receptor occupancy in the CNS of hBK B₁ transgenic rats.

Full text of DOI:10.1021/jm800199h

3946
J. Med. Chem. 2008, 51, 3946–3952
2-Aminobenzophenones as a Novel Class of Bradykinin B1 Receptor Antagonists
Dai-Shi Su,*,† John L. Lim,† Elizabeth Tinney,† Bang-Lin Wan,† Kathy L. Murphy,‡ Duane R. Reiss,‡ C. Meacham Harrell,‡
Stacy S. O’Malley,‡ Rick W. Ransom,‡ Raymond S. L. Chang,‡ Douglas J. Pettibone,‡ Jian Yu,§ Cuyue Tang,§
Thomayant Prueksaritanont,§ Roger M. Freidinger,† Mark G. Bock,† and Neville J. Anthony†
Departments of Medicinal Chemistry, Neuroscience Drug DiscoVery, and Drug Metabolism, Merck Research Laboratories,
West Point, PennsylVania 19486
ReceiVed February 26, 2008
Selective bradykinin (BK) B1 receptor antagonists could be novel therapeutic agents for the treatment of
pain and inflammation. Elucidation of the structure activity relationships of the structurally novel HTS lead
compound 1 provided potent hBK B1 receptor antagonists with excellent receptor occupancy in the CNS of
hBK B1 transgenic rats.
Introduction
Bradykinin (BKa), an autacoid peptide, plays a variety of roles
in the pathophysiological processes accompanying pain and
inflammation. Its biological actions are mediated by two known
G-protein coupled receptors named B1 and B2. The BK B2
receptor is constitutively expressed in most cell types and evokes
acute pain responses following tissue injury, whereas the BK
B1 receptor is induced during inflammatory insults or painful
stimuli.1 In animal models, BK B1 receptor agonists, such as
des-Arg9-bradykinin (DABK) and des-Arg10-kallidin (DAK),
Figure 1. HTS lead.
produce hyperalgesia, an effect that can be blocked by peptide
Scheme 1a
BK B1 receptor antagonists such as des-Arg9-Leu8-bradykinin
(DALBK) and des-Arg10-Leu9-kallidin (DALK).2 A study result
from the BK B1 receptor knockout mouse has implicated a role
for the BK B1 receptor in inflammation, algesia, and neuropathic
pain.3 In addition to the accepted peripheral mode of action of
the BK B1 receptor, the BK B1 receptor has also been accorded
a central role on the basis of recent results that demonstrate
that the BK B1 receptor is constitutively expressed in the central
nervous system (CNS) of mice and rats.4 Accordingly, selective
and effective BK B1 receptor antagonists hold promise as novel
therapeutic agents for the treatment of pain and inflammation.5
The current study was initiated with a high-throughput screen
(HTS) lead, compound 1, a 2-aminobenzophenone derivative
(Figure 1). This paper reports the SAR study results of this novel
structural class of compounds that exhibit excellent binding
affinity, good pharmacokinetic profile, and excellent receptor
a (a) (i) 4-Nitrobenzene sulfonyl chloride, pyridine, DCM, 31%; (ii) Fe,
EtOH/HOAc/H2O, 100 °C, 90%. (b) Triphosgene, 3-piperidin-1-ylpropan-
1-amine, TEA,THF, 0 °C to rt, 69%. (c) Triphogene, tetrohydrofurfuryl
occupancy in an ex vivo receptor occupancy assay.
Chemistry. Compounds described in this paper were prepared
straightforwardly according to the route depicted in Scheme 1.
From the commercially available benzophenone, sulfonamide
formation followed by the reduction of the nitro group afforded
the aniline derivative (1a). Treatment of the aniline with
triphosgene followed by an amine or an alcohol gave the desired
alcohol, TEA, THF, 0 °C to rt. (d) nBuLi, 0 °C THF, 58%.
compounds 20 and 26, respectively. The amide derivatives were
prepared by coupling of intermediate 1a with either acids (EDC/
HOBT) or acid chlorides. The (2-aminophenyl)(5-fluoropyridin-
2-yl)methanone (1b) was synthesized by the metal halogen
exchange of bromopyridine and addition to 2-amino-benzoac-
etonitrile. The other benzophenones were prepared in an
analogous fashion.
Biological Results and Discussion. Compound 1 was
considered a good starting point in terms of binding affinity
for hB1 receptor (Table 1). However, several potential issues
of this compound were revealed after detailed triage. While
compound 1 is not a substrate for P-glycoprotein (P-gp)
mediated efflux6,7 and not a potassium channel blocker (human
* To whom correspondence should be addressed. Phone: 215-652-6830.
Fax: 215-652-3971. E-mail: daishi_su@merck.com.
†
Department of Medicinal Chemistry, Merck Research Laboratories.
Department of Neuroscience Drug Discovery, Merck Research
‡
Laboratories.
§
Department of Drug Metabolism, Merck Research Laboratories.
a Abbreviations: BK, bradykinin; DABK, des-Arg9-bradykinin; DAK,
des-Arg10-kallidin; DALBK, des-Arg9-Leu8-bradykinin; DALK, des-Arg10
-
Leu9-kallidin; HTS, high-throughput screen; hERG, human ether-a-go-go-
related gene; P-gp, P-glycoprotein; PXR, pregnane X-receptor; HLM, human
liver microsomes; RLM, rat liver microsomes; DLM, dog liver microsomes;
MLM, monkey liver microsomes; GSH, glutathione.
10.1021/jm800199h CCC: $40.75
2008 American Chemical Society
Published on Web 06/14/2008

2-Aminobenzophenones as BK B1 Receptor Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3947
Table 2. Amide SAR: Binding Affinities of hB1 Receptor Antagonists
Table 1. A-Ring SAR: Binding Affinities of hB1 Receptor Antagonistsa
a Values represent the numerical average of at least two experiments.
Interassay variability was (25%.
ether-a-go-go-related gene (hERG): IC50 > 10 µM),8 it is a
pregnane X-receptor (PXR) agonist9 (Table 4). Compound 1
has modest clearance, short half-life, and poor bioavailablity
in rats and short half-life in dogs (Table 4). The poor PK profile
could be attributed in part to its rapid metabolism in liver
microsomes (Table 5). After incubation of compound 1 in liver
microsomes in the presence of NADPH for 30 min, the
remaining amount of parent compound is less than 10% in all
species examined (humans, dogs, rats, and monkeys).
than compound 11. Gratifyingly, the microsomal stability of
compound 14 was good (Table 5).
C-ring substitution and replacement with a variety of different
heterocycles proved to be poorly tolerated. The amide side chain,
on the other hand, was much more amendable to modification.
While the replacement of amide with carbamate (compound 16)
caused a significant loss of binding affinity, the urea analogues
17 and 18 were only 4-fold less potent than compound 1 (Table
2). Appending a basic amine group at the side chain improved
the binding affinity 11-fold (Compound 19). The potency could
be improved to subnanomolar by increasing chain length and
appending a piperidine ring in the amide chain (compound 20).
Compound 20 has an excellent binding affinity for the hB1
receptor and exhibits a good PXR, PK profiles (Table 4).
However, compound 20 is susceptible to Pgp mediated efflux
(MDR1, (B/A)/(A/B): 14) and has increased affinity for hERG:
IC50 ) 1 µM. We speculated that the basicity of amine could
be the culprit for the undesired ancillary activities. Therefore,
the importance of the basicity of compound 20 was investigated.
Introduction of ꢀ-fluorine at the piperidine ring to reduce the
pKa of compound10 gave compound 21 with about 5-fold loss
of potency and no significant improvement for hERG activity
(IC50 ) 1.6 µM). Multiple fluorine substitution further debili-
tated the binding affinity of analogue by 5-fold and improved
potassium channel activity (IC50 ) 6.2 µM) (compound 22).
Replacement of piperidine ring with less basic morpholine ring
(compound 23) impaired potency 10-fold relative to parent
compound 20. As anticipated, compound 23 shows improvement
in terms of P-gp susceptibility (MDR1, (B/A)/(A/B): 4.8, Papp:
21.4 × 10-6cm/s) and hERG blockade (IC50 ) 6.5 µM).
The study was then focused on replacing the basic amine
with other neutral group. Replacement of methyl amine in
compound 19 with a methoxyl group yielded an equally potent
compound 24 (Table 3). Introduction of ring constraint tetrahy-
drofuran (analogue 25, racemic) was also tolerated. Although
the carbamate analogue, 16, was not active, replacement of urea
linker in compound 25 with carbamate led to a compound, 26
Initial SAR study results revealed that the benzophenone
motif can be replaced with a biaryl ether but with less potency
than benzophenone. The ketone linker otherwise is intolerant
to replacement with other functionalities. Likewise, replacement
of the sulfonamide moiety with amide, urea, carbamate, alkyl,
and aryl linkers led to inactive compounds. B-ring substitution
and replacement with heterocycle were similarly unfruitful.
To explore A-ring substitution, the fluorine atom was used
as a probe. Among the three positions on the phenyl A-ring
(compound 2 to 4), the para-fluoro compound 4 showed a 2-fold
improvement in potency versus the lead compound 1 (Table
1). A similar trend was observed for the chlorine analogues
(compounds 5 to 7), which were less potent than the corre-
sponding fluorine analogues. Other substituents, such as methyl,
methoxyl, cyano, hydroxyl, and trifluoromethyl, at the para-
position of the A-ring decreased binding affinity significantly.
Difluorosubstitution was tolerated but offered no significant
advantage (compounds 8-10). Replacement of the A-ring
phenyl with pyridines was examined (compounds 11-13).
Although the potency of pyridine derivative 11 was decreased
by 5-fold, compound 11 reduced PXR activation (Table 4) and
attenuated the rate of metabolism in liver microsomes (stability:
d > h > r > m) (Table 5). Compound 11 shows modest
clearance similar to 1 (24 mL/min/kg), but improved half-life
(1.2 h), measurable bioavailability (11%) in rats, and low
clearance (1.2 mL/min/kg) in dogs (Table 4). Combining this
finding with the potency enhancing para-F led to compounds
14 and 15. Fluoro pyridine compound 14 was 8-fold more potent

3948 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Table 3. Binding Affinities of hB1 Receptor Antagonistsa
Su et al.
P-gp substrate nor an ion channel blocker and has an improved
PXR profile vs 1 (Table 4). The microsomal stability of 27 was
improved marginally versus compound 1 (Table 5). However,
the bioavailabilty of 27 was improved although it had high
clearance in rats (Table 4). Resolution of 27 by chiral chroma-
tography yielded compounds 28, the first eluted compound, and
29, the second eluted compound.
As anticipated, receptor binding affinity and the configuration
of the asymmetric center were linked. Compound 29 with a
subnanomaolar Ki is 2-fold more potent than compound 28.
Unexpectedly, the stability of compound 28 was poor (data not
shown), and the PK profile of compound 29 was not improved
vs 27. A similar SAR result was observed for the 4-fluro-2-
pyrido analogue. Compound 30, in a racemic form, has a Ki of
0.2 nM, which is more potent than compound 27. However,
compound 30 was microsomal unstable (Table 5). Chiral
separation of 30 delivered the two enantiomers, 31 and 32. Once
again, the second eluted isomer (32) was more potent than the
first eluted isomer (compound 31) but showed poor rat PK and
PXR profiles.
To assess the selectivity of this series compounds, compound
29 was screened in a panel of assays11 representing 170
enzymes, receptors, and transporters. Compound 29 showed a
no-hit in the screen (except BK B1 receptor inhibition) and
demonstrated an excellent selectivity.
The in vitro liver microsomes stability study results showed
that the metabolism of compounds in this series was both
NADPH and species dependent (Table 5). A similar trend of
stability across species was observed (liver microsomal stability:
dog > human > rat > monkey). Further study of compound
26 revealed that it underwent extensive mono- and dioxidation
in both human liver microsomes (HLM) and rat liver mi-
crosomes (RLM). In the presence of glutathione (GSH),
significant GS-adduct were formed.
a Values represent the numerical average of at least two experiments.
Interassay variability was ( 25%.
Table 4. Ancillary Activities and Pharmacokinetics of Selected hB1
Receptor Antagonists
Pgpa
rat PKd
dog PKe
To determine the extent to which the compounds in this series
occupy the human BK B1 receptor in vivo, 26 was examined
in an ex vivo receptor occupancy study in transgenic rats in
which the human BK B1 receptor is constitutively overex-
pressed.12 In this study, 26 showed dose dependent occupancy
following iv infusion over 30 min (Table 6). At a dose of 12
mg/kg, compound 26 shows 74 and 80% of receptor occupancy
in both brain and spinal cord at concentrations of 5837 and 9427
nM, respectively. These data suggest that compound 26
penetrates the blood-brain barrier and occupies the receptor
in the CNS which is in accordance with the finding that
compound 26 is not a substrate for P-gp mediated efflux (Table
4).
Conclusion. In summary, the compounds disclosed in this
paper represent a new structural class of BK B1 receptor
antagonists. Several compounds possess excellent binding
affinities for the hB1 receptor. Modification of HTS lead,
compound 1, led to 26 which exhibited promising ex vivo
receptor occupancy in transgenic rats. Compound 27 showed a
balanced profile in terms of potency, P-gp susceptibility, hERG
blockade, and pharmacokinetics.
compound MDR1 Papp hERGb PXRc F (%) CL t1/2 CL t1/2
1
4
2.5
27 >10
>10
81
3
26 0.3 7.5 0.5
18 3.7 11 1.4
24 1.2 1.2 1.2
3.6 0.9
70 16
37 11
24
13 41
88
40 17
39
39
56
11
14
20
26
27
28
29
30
32
14
2.3
2.6
34 1.0
26 8.2
31 >10
>10
33 >30
26 >10
>30
29 14
43 9.7 17
17
1.5
1.9
3
40 1.4 3.4 1.4
3.1 2.6
40 1.7 2.9 2.2
4.2
3.1
3
14
1.8
63 <1
26 1.1 6.2 2.8
a MDR1 directional transport ratio (B/A)/(A/B). Values represent the
average of three experiments and interassay variability was (20%. Papp:
× 10-6cm/s. b IC50 in µm. Inhibition of MK-499 binding to hERG in
HEK293cells.c %activationrelativetorifampicin@10µm.d Sprague-Dawley
rats (n ) 3). F: % oral bioavailability; t1/2: hours; CL: mL/min/kg. Oral
dose: 10 mg/kg; iv dose: 2 mg/kg. Interanimal variability was less than
20%. e Mongrel dogs (n ) 2). iv coadministration with other analogues;
t1/2: hours; CL: mL/min/kg; iv dose: 0.25 mg/kg. Interanimal variability
was less than 20%.
(racemic), which displays subnanomolar binding affinity for the
hB1 receptor. Lacking the basic amine group, compound 26 now
possessed a good profile for P-gp efflux and improved IKr
activity (Table 4). However, compound 26 is a PXR activator
and has high clearance and poor bioavailablity in rats (Table
4), which is in accordance with the finding that it is rapidly
metabolized in liver microsomes (Table 5).
To ameliorate the microsomal stability of compound, the
stable A-ring moieties (ref compounds 11 and 14) were
incorporated into 26 to afford compounds 27 and 30, respec-
tively. Compound 27 (racemic) has a binding affinity of 2.6
nM (about 3-fold less potent than compound 26) and is neither
Experimental Procedures
General Procedures. 1H and 13C (300, 400, or 600 MHz)
NMR spectra were recorded on a Varian VXR 300, Unity Inova
400, or Unity Inova 600 spectrometer. The chemical shifts are
reported in δ (ppm) using the δ 0.00 signal of Me4Si as an
internal standard. LC/MS data were obtained on a Waters 2690
separations module and Micromass ZM. High resolution MS
(HRMS) data were obtained on a Bruker 3T or 7T FTICR MS
with either electrospray ionization or APCI. HPLC spectra were

2-Aminobenzophenones as BK B1 Receptor Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3949
Table 5. In Vitro Liver Microsomes Stability Study of Selected Compoundsa
a Compound was incubated in liver microsomes for 30mins. For compound 1, 11, and 26, the stabilities of compounds were examined only in the
presence of NADPH.
Table 6. Ex Vivo Receptor Occupancy Study Results of Compound 26
(0 °C) 3N HCl and stirred for 15 min. Then 5N NaOH was added
until basic and then extracted with CH2Cl2 (3 × 100 mL). The
combined organic layer was washed with brine (1 × 100 mL), dried
over sodium sulfate, filtered, and concentrated in vacuo. Flash
chromatography of crude residue (0-30% EtOAc/hexanes) gave
6 g (58%) of (2-aminophenyl)(5-fluoropyridin-2-yl)methanone as
a solid (LC/MS found: 217.2).
dose (mg/kg)
0.12
compartment
occupancy (%)
conc (nM)
plasma
brain
spinal cord
plasma
brain
spinal cord
plasma
brain
80
70
97
995
438
22
28
1.2
12
49
62
597
1-[3-({[(4-{[(2-Benzoylphenyl)amino]sulfonyl}phenyl)amino]-
carbonyl}amino)propyl]piperidinium trifluoroacetate (20). Triph-
osgene (28 mg, 1/3 equiv) was dissolved in 1 mL of THF and the
solution was cooled to 0 °C. A solution of 4-amino-N-(2-
benzoylphenyl)benzenesulfonamide (100 mg) in 3 mL of THF and
0.15 mL of triethylamine was added to the triphosgene solution.
The reaction mixture was warmed to rt and stirred for 30 min.
A solution of 3-(piperidin-1-yl)propan-1-amine (60 mg, 1.5
equiv) in 3 mL of THF and 0.15 mL of triethylamine was added
and the reaction mixture was stirred at room temperature
overnight. The reaction was quenched with water and diluted
with EtOAc. The organic layer was washed once each with water
and brine, dried over sodium sulfate, filtered, and concentrated in
vacuo. The title product was obtained as the TFA salt (130 mg)
following reverse phase chromatography (5-95% acetonitrile/water/
13245
5837
9427
74
80
spinal cord
recorded on a Hewlett-Packard 1100 with a YMC-Pack Pro C-18
column or Atlantis dC18 column with a 5-95% CH3CN/H2O
gradient at 215 nm. Chiral HPLC spectra were recorded on a
Hewlett-Packard 1100 with a ChiralPak AD column utilizing
40% hexanes (containing 0.1% diethylamine) and 60% EtOH
as eluent at 230 nm.
4-Amino-N-(2-benzoylphenyl)benzenesulfonamide (I). 2-Ami-
nobenzophenone (20 mg) was dissolved in 1 mL of methylene
chloride and 4-nitrobenzenesulfonyl chloride (34 mg, 1.5 equiv)
was added thereto followed by pyridine (ꢁ.ꢁ16 mL, 2 equiv). After
10 min, the reaction mixture was concentrated in vacuo and
subjected to flash chromatography (eluting with 0-25% EtOAc/
hexane) to provide N-(2-benzoylphenyl)-4-nitrobenzenesulfonamide
(12 mg, 31%). LC/MS, M + H+ found: 383.1. This reaction was
also carried out in multi-gram scale. The crude material was carried
on to the next reaction without further purification.
The above nitrobenzenesulfonamide (500 mg) was dissolved in
10 mL of 2:2:1 EtOH/HOAc/water and elemental iron (508 mg,
7.4 equiv) was added thereto followed by 5 µL of concentrated
HCl. The reaction mixture was heated to 100 °C for 10 min and
then cooled to rt and diluted with 35 mL of water. The layers were
separated, and the aqueous layer was extracted three times with
methylene chloride. The organic layer was washed twice with
saturated sodium bicarbonate and twice with water, back extracted
once with methylene chloride, and dried over sodium sulfate,
filtered, and concentrated in vacuo. Crude 4-amino-N-(2-ben-
zoylphenyl)benzenesulfonamide (416 mg, 90%), which was used
without further purification. Purity was determined by LC/MS (M
+ H+ found: 353.1).
(2-Aminophenyl)(5-fluoropyridin-2-yl)methanone (II). 2-Bromo-
5-fluoropyridine (10 g, 56.8 mmol) and 2-aminobenzonitrile (5.6
g, 47.4 mmol) were dissolved in 100 mL of toluene and cooled to
-30 °C. To the resulting solution was added nBuLi (1.6 M in
hexanes, 65 mL, 104 mmol, 2.2 equv) dropwise and warmed to 0
°C for 90 min. The reaction was then poured into 100 mL of cooled
1
0.1% TFA). H NMR (400 MHz, CDCl3, ppm): δ 1.25 (s, 1H),
1.45 (m, 1H), 1.97 (m, 4H), 2.50 (m, 2H), 2.65 (m, 2H), 3.05 (m,
2H), 3.38 (t, J ) 5 Hz, 2H), 3.47 (d, J ) 12 Hz, 2H), 7.08 (t, J )
7 Hz, 1H), 7.40 (m, 6H), 7.52 (m, 3H), 7.77 (d, J ) 8 Hz, 1H),
9.22 (s, 1H), 10.05 (s, 1H) and 10.55 (m, 1H). ESMS, M + H+
found: 521.2. High resolution MS: m/z found 521.2229 (M + 1),
calculated 521.2217 (M + 1).
Tetrahydrofuran-2-ylmethyl 4-{[(2-benzoylphenyl)amino]sul-
fonyl}phenylcarbamate (26). Triphosgene (28 mg, 1/3 equiv) was
dissolved in 1 mL of THF and the solution was cooled to 0 °C. A
solution of 4-amino-N-(2-benzoylphenyl)benzenesulfonamide (100
mg) in 3 mL of THF and 0.15 mL of triethylamine was added to
the triphosgene solution.The reaction mixture was warmed to room
temperature and stirred for 30 min. A solution of tetrahyhdrofurfuryl
alcohol (44 mg, 1.5 equiv) in 3 mL of THF and 0.15 mL of
triethylamine was added to the reaction mixture and the mixture
was stirred overnight. The reaction was quenched with water and
diluted with EtOAc. The organic layer was washed once each with
water and brine, dried over sodium sulfate, filtered, and concentrated
in vacuo. The title product was obtained following flash chroma-
tography (10-95% EtOAc/hex). 1H NMR (400 MHz, CDCl3, ppm):
δ 1.95 (m, 2H), 2.06 (m, 1H), 2.67 (d, J ) 9.5, 1H), 3.88 (m, 2H),
4.06 (m, 1H), 4.14 (m, 1H), 4.29 (dd, J ) 3, 11, 1H), 6.71 (s, 1H),
7.10 (m, 1H), 7.40 (m, 6H), 7.56 (m, 2H), 7.64 (m, 2H), 7.79 (d,
J ) 8 hz, 1H) and 10.50 (s, 1H). ESMS, M + H+ found 481.8.

3950 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13
Su et al.
High resolution MS: m/z found 481.1441 (M + 1), calculated
481.1428 (M + 1).
N-[4-({[2-(2-Fluorobenzoyl)phenyl]amino}sulfonyl)phenyl]-
acetamide (2). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s, 3H),
7.09 (m, 3H), 7.20 (m, 1H), 7.38 (m, 1H), 7.50 (m, 4H), 7.80 (m,
3H), and 10.82 (s, 1H). High Resolution MS: m/z found 413.0966
(M + 1), calculated 413.0966 (M + 1).
N-{4-[({2-[(5-Fluoropyridin-2-yl)carbonyl]phenyl}amino)sul-
fonyl]phenyl}acetamide (14). 1H NMR (400 MHz, CDCl3, ppm):
δ 2.17 (s, 3H), 7.13 (m, 2H), 7.45 (d, J ) 8.7 Hz, 2H), 7.55 (m,
2H), 7.69 (d, J ) 8.9 Hz, 2H), 7.76 (t, J ) 7.2 Hz, 2H), 7.95 (q,
J ) 4.5 Hz, 1H), 8.46 (d, J ) 2.8 Hz, 1H) and 10.27 (s, 1H). High
resolution MS: m/z found 414.0917 (M + 1), calculated 414.0919
(M + 1).
N-[4-({[2-(3-Fluorobenzoyl)phenyl]amino}sulfonyl)phenyl]-
acetamide (3). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s, 3H),
4.12 (d, J ) 7 Hz, 1H), 7.04 (d, J ) 8.5 Hz, 1H), 7.12 (m, 1H),
7.25 (m, 2H), 7.40 (m, 4H), 7.54 (m, 1H), 7.62 (d, J ) 7.7 Hz,
2H), 7.89 (d, J ) 7.7 Hz, 1H), and 9.90 (s, 1H). High resolution
MS: m/z found 413.0970 (M + 1), calculated 413.0966 (M + 1).
N-[4-({[2-(4-Fluorobenzoyl)phenyl]amino}sulfonyl)phenyl]-
acetamide (4). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s, 3H),
7.06 (td, J ) 2, 9 Hz, 2H), 7.15 (m, 2H), 7.26 (d, J ) 2 Hz, 1H),
7.35 (m, 1H), 7.46 (td, J ) 2, 5 Hz, 2H), 7.56 (m, 3H), 7.79 (d, J
) 8 Hz, 1H), and 9.70 (s, 1H). High resolution MS: m/z found
413.0983 (M + 1), calculated 413.0966 (M + 1).
N-[4-({[2-(2-Chlorobenzoyl)phenyl]amino}sulfonyl)phenyl]-
acetamide (5). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s, 3H),
6.99 (t, J ) 7 Hz, 1H), 7.18 (d, J ) 7 Hz, 1H), 7.33 (m, 2H), 7.42
(m, 2H), 7.50 (t, J ) 8.8 Hz, 1H), 7.58 (d, J ) 8.6 Hz, 2H), 7.82
(m, 3H), and 11.10 (s, 1H). High resolution MS: m/z found
429.0669 (M + 1), calculated 429.0671 (M + 1).
N-[4-({[2-(3-Chlorobenzoyl)phenyl]amino}sulfonyl)phenyl]-
acetamide (6). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s, 3H),
7.14 (m, 2H), 7.35 (m, 3H), 7.42 (d, J ) 8.7 Hz, 2H), 7.31 (m,
1H), 7.57 (m, 3H), 7.80 (d, J ) 8.1 Hz, 1H), and 9.80 (s, 1H).
High resolution MS: m/z found 429.0669 (M + 1), calculated
429.0671 (M + 1).
N-[4-({[2-(4-Chlorobenzoyl)phenyl]amino}sulfonyl)phenyl]-
acetamide (7). 1H NMR (400 MHz, CDCl3, ppm): δ 2.09 (s, 3H),
7.15 (d, J ) 7.8 Hz, 1H), 7.30 (m, 1H), 7.40 (m, 1H), 7.75 (m,
9H), and 9.78 (s, 1H). High resolution MS: m/z found 429.0666
(M + 1), calculated 429.0671 (M + 1).
N-{4-[({2-[(6-Fluoropyridin-3-yl)carbonyl]phenyl}amino)sul-
fonyl]phenyl}acetamide (15). 1H NMR (400 MHz, CDCl3, ppm):
δ 2.19 (s, 3H), 7.01 (dd, J ) 8.5, 3 Hz, 1H), 7.20 (t, J ) 7.5 Hz,
1H), 7.35 (s, 1H), 7.37 (m, 3H), 7.81 (d, J ) 8.3 Hz, 1H), 8.02 (td,
J ) 7.5, 6 Hz, 1H) and 8.10 (d, J ) 2 Hz, 1H). High resolution
MS: m/z found 414.0930 (M + 1), calculated 414.0919 (M + 1).
Methyl (4-{[(2-Benzoylphenyl)amino]sulfonyl}phenyl)carbamate
(16). 1H NMR (400 MHz, CDCl3, ppm): δ 3.63 (m, 3H), 6.44 (m,
2H), 7.48 (m, 5H), 7.58 (m, 2H), 7.64 (m, 2H) and 7.76 (m, 2H).
ES MS: m/z ) 411.2 (M + 1).
N-(2-Benzoylphenyl)-4-{[(methylamino)carbonyl]amino}benzene-
sulfonamide (17). LC/MS: m/z ) 410.3 (M + 1).
N-(2-Benzoylphenyl)-4-{[(dimethylamino)carbonyl]amino}-
1
benzenesulfonamide (18). H NMR (400 MHz, CDCl3, ppm): δ
3.02 (s, 6H), 6.32 (s, 1H), 7.08 (t, J ) 6.6 Hz, 1H), 7.39 (m, 2H),
7.40 (m, 3H), 7.53 (m, 2H), 7.62 (m, 2H), 7.78 (d, J ) 8 Hz, 1H)
and 10.12 (s, 1H). High resolution MS: m/z found 424.1329 (M +
1), calculated 424.1326 (M + 1).
2-({[(4-{[(2-Benzoylphenyl)amino]sulfonyl}phenyl)amino]carbonyl}
amino)-N-methylethanaminium Chloride (19). 1H NMR (400
MHz, CDCl3, ppm): δ 2.57 (t, J ) 5 Hz, 3H), 3.00 (m, 2H), 3.37
(d, J ) 6 Hz, 2H), 6.64 (m, 1H), 7.18 (d, J ) 8 Hz, 1H), 7.26 (t,
J ) 7 Hz, 1H), 7.38 (d, J ) 6 Hz, 1H), 7.50 (m, 8H), 7.64 (t, J )
7 Hz, 1H), 8.45 (m, 2H), 9.36 (s, 1H) and 9.88 (s, 1H). High
resolution MS: m/z found 453.1590 (M + 1), calculated 453.1591
(M + 1).
1-[3-({[(4-{[(2-Benzoylphenyl)amino]sulfonyl}phenyl)amino]-
1
carbonyl}amino)propyl]piperidinium trifluoroacetate (20). H
NMR (400 MHz, CDCl3, ppm): δ 1.25 (s, 1H), 1.45 (m, 1H), 1.97
(m, 4H), 2.50 (m, 2H), 2.65 (m, 2H), 3.05 (m, 2H), 3.38 (t, J ) 5
Hz, 2H), 3.47 (d, J ) 12 Hz, 2H), 7.08 (t, J ) 7 Hz, 1H), 7.40 (m,
6H), 7.52 (m, 3H), 7.77 (d, J ) 8 Hz, 1H), 9.22 (s, 1H), 10.05 (s,
1H) and 10.55 (m, 1H). High resolution MS: m/z found 521.2229
(M + 1), calculated 521.2217 (M + 1).
N-[4-({[2-(2,4-Difluorobenzoyl)phenyl]amino}sulfonyl)phenyl]-
acetamide (8). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s, 3H),
6.86 (t, J ) 7.4 Hz, 1H), 6.95 (t, J ) 8.5 Hz, 1H), 7.05 (t, J ) 8
Hz, 1H), 7.33 (m, 2H), 7.53 (m, 3H), 7.76 (m, 3H) and 10.60 (s,
1H). High resolution MS: m/z found 431.0886 (M + 1), calculated
431.0872 (M + 1).
N-(2-Benzoylphenyl)-4-[({[3-(3-fluoropiperidin-1-yl)propyl]-
amino}carbonyl)amino]benzenesulfonamide (21). 1H NMR (400
MHz, CDCl3, ppm): δ 1.47 (m, 1H), 1.63 (m, 3H), 1.90 (m, 1H),
2.14 (m, 2H), 2.52 (m, 1H), 2.66 (m, 1H), 2.95 (m, 1H), 3.22 (m,
2H), 3.63 (m, 1H), 4.87 (s, 1H), 5.03 (s, 1H), 6.72 (d, J ) 8.6 Hz,
1H), 7.06 (t, J ) 7.6 Hz, 1H), 7.33 (m, 3H), 7.43 (m, 4H). 7.58
(m, 3H), 7.77 (d, J ) 8 Hz, 1H) and 10.05 (s, 1H). High resolution
MS: m/z found 539.2123 (M + 1), calculated 539.2123 (M + 1).
1-[3-({[(4-{[(2-Benzoylphenyl)amino]sulfonyl}phenyl)amino]-
carbonyl}amino)propyl]-3,3-difluoropiperidinium trifluoroac-
etate (22). 1H NMR (400 MHz, CDCl3, ppm): δ 2.02 (s, 2H), 2.15
(s, 4H), 3.18 (s, 4H), 3.38 (s, 4H), 7.09 (t, J ) 7.6 Hz, 1H), 7.37
(m, 7H), 7.56 (m, 4H), 7.75 (d, J ) 8 Hz, 1H), 9.03 (s, 1H) and
10.08 (s, 1H). High resolution MS: m/z found 557.2025 (M + 1),
calculated 557.2029 (M + 1).
4-[3-({[(4-{[(2-Benzoylphenyl)amino]sulfonyl}phenyl)amino]-
carbonyl}amino)propyl]morpholin-4-ium Trifluoroacetate (23).
1H NMR (400 MHz, CDCl3, ppm): δ 2.06 (m, 2H), 2.88 (m, 2H),
3.14 (m, 2H), 3.38 (m, 4H), 3.91 (t, J ) 12 Hz, 2H), 4.48 (m, 2H),
7.08 (t, J ) 8.5 Hz, 1H), 7.40 (m, 7H), 7.51 (m, 2H), 7.57 (d, J )
8 Hz, 2H), 7.77 (d, J ) 8 Hz, 1H), 8.75 (s, 1H) and 10.08 (s, 1H).
High resolution MS: m/z found 523.2009 (M + 1), calculated
523.2010 (M + 1).
N-[4-({[2-(3,4-Difluorobenzoyl)phenyl]amino}sulfonyl)
phenyl]acetamide (9). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19
(s, 3H), 7.06 (m, 2H), 7.18 (m, 1H), 7.34 (m, 2H), 7.54 (m, 3H),
7.78 (m, 3H), and 10.70 (s, 1H). LC/MS: m/z ) 431.2 (M + 1).
N-[4-({[2-(2,3-Difluorobenzoyl)phenyl]amino}sulfonyl)
phenyl]acetamide (10). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19
(s, 3H), 7.18 (m, 4H), 7.34 (dd, J ) 7.7, 1.4 Hz, 1H), 7.38 (d, J )
8.8 Hz, 2H), 7.58 (d, J ) 8.8 Hz, 3H), 7.80 (d, J ) 8.2 Hz, 1H),
and 9.60 (s, 1H). High resolution MS: m/z found 431.0883 (M +
1), calculated 431.0872 (M + 1).
N-[4-({[2-(Pyridin-2-ylcarbonyl)phenyl]amino}sulfonyl)phe-
nyl]acetamide (11). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s,
3H), 7.08 (t, J ) 8.3, 1H), 7.50 (m, 4H), 7.76 (m, 2H), 7.83 (m,
1H), 7.89 (td, J ) 2, 8 Hz, 1H), 8.65 (d, J ) 1 Hz, 1H) and 10.70
(s, 1H). High resolution MS: m/z found 396.1009 (M + 1),
calculated 396.1013 (M + 1).
N-[4-({[2-(Pyridin-3-ylcarbonyl)phenyl]amino}sulfonyl)phe-
nyl]acetamide (12). 1H NMR (400 MHz, CDCl3, ppm): δ 2.17 (s,
3H), 7.16 (t, J ) 7.8 Hz, 1H), 7.26 (m, 1H), 7.40 (m, 4H), 7.60
(m, 3H), 7.82 (d, J ) 8.3 Hz, 1H), 7.88 (d, J ) 7.8 Hz, 1H), 8.50
(s, 1H), 8.76 (s, 1H) and 9.92 (s, 1H). High resolution MS: m/z
found 396.1019 (m + 1), calculated 396.1013 (M + 1).
N-(4-{[(2-Isonicotinoylphenyl)amino]sulfonyl}phenyl)
acetamide (13). 1H NMR (400 MHz, CDCl3, ppm): δ 2.19 (s, 3H),
7.13 (t, J ) 7.7, 1H), 7.25 (m, 3H), 7.35 (d, J ) 8 Hz, 1H), 7.48
(d, J ) 8.8 Hz, 2H), 7.61 (t, J ) 8.6 Hz, 1H), 7.69 (d, J ) 8.7 Hz,
2H), 7.81 (d, J ) 8.6 Hz, 1H) 8.74 (s, 2H) and 10.16 (s, 1H). High
resolution MS: m/z found 396.1008 (M + 1), calculated 396.1013
(M + 1).
N-(2-Benzoylphenyl)-4-({[(2-methoxyethyl)amino]carbonyl}-
amino)benzenesulfonamide (24). 1H NMR (400 MHz, CDCl3,
ppm): δ 3.42 (m, 5H), 3.52 (m, 2H), 4.92 (m, 1H), 7.80 (t, J ) 7
Hz, 2H), 7.23 (m, 2H), 7.40 (m, 4H), 7.50 (m, 2H), 7.60 (d, J )
9 Hz, 2H), 7.78 (d, J ) 8 Hz, 1H) and 10.05 (s, 1H). High resolution
MS: m/z found 454.1426 (M + 1), calculated 454.1431 (M + 1).

2-Aminobenzophenones as BK B1 Receptor Antagonists
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 13 3951
J. B.; Calixto, J. B. Reduced nerve injury-induced neuropathic pain
in kinin B1 receptor knock-out mice. J. Neurosci. 2005, 25 (9), 2405–
2412.
N-(2-Benzoylphenyl)-4-({[(tetrahydrofuran-2-ylmethyl)ami-
no]carbonyl}amino)benzenesulfonamide (25). 1H NMR (400
MHz, CDCl3, ppm): δ 1.64 (m, 1H), 1.98 (m, 3H), 3.12 (m, 1H),
3.55 (m, 1H), 3.83 (m, 2H), 4.03 (m, 1H), 4.90 (m, 1H), 7.10 (m,
1H), 7.26 (m, 2H), 7.40 (m, 5H), 7.50 (m, 2H), 7.58 (m, 2H), 7.78
(d, J ) 8 Hz, 1H) and 10.06 (s, 1H). High resolution MS: m/z
found 480.1556 (M + 1), calculated 480.1588 (M + 1).
Tetrahydrofuran-2-ylmethyl[4-({[2-(pyridin-2-ylcarbonyl)phenyl}-
amino}sulfonyl)phenyl]carbamate (27). 1H NMR (400 MHz, CDCl3,
ppm): δ 1.97 (m, 1H), 2.03 (m, 1H), 2.65 (d, J ) 9.2 Hz, 2H),
3.83 (m, 1H), 3.87 (m, 1H), 4.05 (m, 1H), 4.14 (m, 1H), 4.27 (dd,
J ) 11, 3 Hz, 1H), 6.80 (s, 1H), 7.09 (t, J ) 8 Hz, 1H), 7.33 (d,
J ) 9 Hz, 2H), 7.47 (m, 2H), 7.70 (d, J ) 9 Hz, 2H), 7.76 (t, J )
8 Hz, 2H), 7.86 (m, 2H), 7.87 (d, J ) 6 Hz, 1H) and 10.56 (s, 1H).
High resolution MS: m/z found 482.1417 (M + 1), calculated
482.1381 (M + 1).
Tetrahydrofuran-2-ylmethyl[4-({[2-(pyridin-2-ylcarbonyl)phenyl}-
amino}sulfonyl)phenyl]carbamate (1st Eluting) (28). LC/MS: m/z )
482.2 (M + 1).
Tetrahydrofuran-2-ylmethyl[4-({[2-(pyridin-2-ylcarbonyl)phenyl}-
amino}sulfonyl)phenyl]carbamate (2nd Eluting) (29). LC/MS: m/z )
482.2 (M + 1).
Tetrahydrofuran-2-ylmethyl{4-[({2-[(5-fluoropyridin-2-
yl)carbonyl]phenyl}amino)sulfonyl]phenyl}carbamate (30). 1H
NMR (400 MHz, CDCl3, ppm): δ 1.93 (m, 2H), 2.06 (m, 1H),
3.84 (q, J ) 8 Hz, 1H), 3.90 (q, J ) 8 Hz, 1H), 4.05 (m, 1H), 4.14
(m, 1H), 4.28 (dd, J ) 3, 11 Hz, 1H), 6.78 (s, 1H), 7.10 (t, J ) 6
Hz, 1H), 7.29 (d, J ) 9 Hz, 2H), 7.75 (m, 2H), 7.94 (m, 2H), 8.46
(d, J ) 3 Hz, 1H), and 10.24 (s, 1H). High resolution MS: m/z
found 500.1290 (M + 1), calculated 500.1286 (M + 1).
Tetrahydrofuran-2-ylmethyl{4-[({2-[(5-fluoropyridin-2-
yl)carbonyl]phenyl}amino)sulfonyl]phenyl}carbamate (1st Elut-
ing) (31). LC/MS: m/z ) 500.2 (M + 1).
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Tetrahydrofuran-2-ylmethyl{4-[({2-[(5-fluoropyridin-2-
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(7) P-gp mediated directional transport were performed in LLC-PK1 cells
expressing genes for human P-gp (MDR1), and the ratio of transport
from basalateral to apical (B to A) direction to the ratio of transport
from apical to basalateral (A to B) direction was measured. for the
assay protocols, please see ref 5d.
Acknowledgment. We are pleased to acknowledge the
efforts of Kathy Schirripa, June Kim, Drs. P. Kunapuli, S. M.
Pitzenberger, and C. W. Ross, J. S. Murphy, and C. F. Homnick.
we are grateful to Drs. S. D. Kuduk, M. R. Wood, and D-M.
Feng for useful discussions.
Supporting Information Available: PK procedures and me-
tabolite ID data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(8) For hERG binding assay protocol, see the following, Butcher, J. W.;
Claremon, D. A.; Connolly, T. M.; Dean, D. C.; Karczewski, J.;
Koblan, K. S.; Kostura, M. J.; Liverton, N. J.; Melillo, D. G.
Radioligand and binding assay. PCT International Patent Appl.
WO0205860A1, 2002.
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