4-(2-Pyridyl)piperazine-1-carboxamides: Potent vanilloid receptor 1 antagonists

Article abstract of DOI:10.1016/S0960-894X(03)00759-5

A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent in the in vitro assay [IC₅₀=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).

Full text of DOI:10.1016/S0960-894X(03)00759-5

Bioorganic & Medicinal Chemistry Letters 13 (2003) 3611–3616
4-(2-Pyridyl)piperazine-1-carboxamides: Potent Vanilloid
Receptor 1 Antagonists
Qun Sun,* Laykea Tafesse, Khondaker Islam, Xiaoming Zhou, Sam F. Victory,
Chongwu Zhang, Mohamed Hachicha, Lori A. Schmid, Aniket Patel, Yakov Rotshteyn,
Kenneth J. Valenzano and Donald J. Kyle
Purdue Pharma L.P., 6 Cedar Brook Drive, Cranbury, NJ 08512, USA
Received 14 March 2003; accepted 7 May 2003
Abstract—A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and eval-
uated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing
HEK293 cell line. Potent VR1 antagonists were identified through SAR studies. From these studies, 18 was found to be very potent
in the in vitro assay [IC50=4.8 nM (pH) and 35 nM (CAP)] and orally available in rat (F%=15.1).
# 2003 Elsevier Ltd. All rights reserved.
Vanilloid receptor 1, VR1, is a member of the transient
receptor potential (TRP) ion channel family.1 It func-
tions as a ligand-gated nonselective cation channel acti-
vated by capsaicin (CAP), the pungent principle of hot
peppers.2 In humans, activation of VR1 by CAP results
in a sensation of burning pain. VR1 is also activated by
noxious heat (ꢀ42 ꢁC), low extracellular pH (ꢂ6.3),3,4
and endogenous mediators of inflammation such as the
cannabanoid anandamide as well as arachidonic acid
metabolites.5 Knockout of the VR1 gene in mice results
in reductions in both thermal nociception and thermal
hyperalgesia.6,7 These data suggest that VR1 may
represent a useful target for the discovery of novel
analgesics.
rodents. More recently, several new classes of VR1
antagonists have been reported in the literature with
moderate potencies at human and rat VR1 against
CAP-mediated activation.11,12 The chemical structures
of capsaicin and capsazepine are shown in Figure 1.
In this paper, we report for the first time a series of 4-(2-
pyridyl)piperazine-1-carboxamides as potent VR1
antagonists. The synthesis of similar chemical structures
was recently described in a US patent application and
these compounds were claimed to be VR1 antagonists,
although no supporting data was presented.13 A similar
class of compounds as VR1 antagonists was also dis-
closed at a recent conference.14 Our work was initiated
Several classes of compounds have been shown to have
biological activity at VR1.8,9 Structurally-related vanil-
loid analogues of CAP such as olvanil and resinifera-
toxin (RTX) are VR1 agonists. In particular, RTX has a
potency three or four orders of magnitude greater than
that of CAP. The synthetic vanilloid analogue, capsa-
zepine (CPZ), is a competitive VR1 antagonist that has
been well characterized.10 However, capsazepine has
several drawbacks such as moderate potency, poor
metabolic and pharmacokinetic properties, undergoing
extensive first-pass metabolism when dosed orally to
*Corresponding author. Tel.: +1-609-409-5136; fax: +1-609-409-
6936; e-mail: qun.sun@pharma.com
Figure 1. Structures of capsaicin, capsazepine, and compound 1.
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00759-5

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Q. Sun et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3611–3616
when compound 1 (Fig. 1) was discovered as a potent
VR1 antagonist through our internal high-throughput
screening efforts. Similar to CPZ, this compound inhib-
ited CAP-induced activation of rat VR1 with an IC50
value of 58 nM. Moreover, compound 1 was found to
be a potent antagonist against acid-induced activation
of rat VR1 (IC50 value: 39 nM), while CPZ was inactive.
However, further pharmacokinetic (PK) studies indi-
cated that 1 was not orally bioavailable in rat. Thus we
initiated a medicinal chemistry effort aimed to explore
the SAR of this lead molecule as a VR1 antagonist and
improve the oral bioavailability.
and correct molecular weight was confirmed by mass
spectrometry (LC/MS with an electrospray sample inlet
system).15 Structures were further confirmed by 1H
NMR spectroscopy.16
The compounds were evaluated for VR1 antagonist
activity based on their ability to block CAP-induced
activation or low pH-induced activation of the rat VR1
channel in a HEK293 cell line. The tests were carried
out measuring CAP- or pH-mediated calcium influx
with a Fluorometric Imaging Plate Reader (FLIPR).
The synthesis of compound 1 is highly amenable to
parallel synthesis as an efficient way to prepare analo-
gues. Our initial strategy was to synthesize analogues
with modifications to the CF3 group on the pyridine
ring and the isopropyl group on the para position of the
phenyl ring (Scheme 1). Most of the compounds in
Tables 1–3 were synthesized via method A (Scheme 2).
It was started by reacting the piperazine with different
3-substituted 2-chloropyridines at 100 ꢁCin DMSO to
form the intermediate 4-(2-pyridyl)piperazines. The 4-
(2-pyridyl)piperazines were then reacted with a variety
of isocyanates or isothiocyanates to give the final pro-
ducts. In both steps, the reactions were run in parallel.
Table 1. 4-Substituents on phenyl ring and linker variation
No.
R2
X
O
IC50 (nM) pH
IC50 (nM) CAP
1
39.2Æ8.0
57.5Æ13.1
2
3
4
O
O
O
121Æ41
111Æ42
556Æ220
1365Æ635
1551Æ550
5181Æ2354
When the desired isocyanates were not readily available,
method B (Scheme 3) was used to prepare compounds
20, 23, and 31. It involved reacting an aniline or amine
with 4-nitrophenylchloroformate in dichloromethane
(DCM) with triethylamine (TEA) as base to form the
reactive 4-nitrophenylcarbamate intermediate. Without
isolation, 4-(3-chloropyridin-2-yl)piperazine was added
to the reaction mixtures to yield the final products.
5
6
7
8
O
O
S
57.7Æ15.1
916Æ373
575Æ191
441Æ55
11.3Æ4.1
258Æ57
Compounds 15, 16, and 17 were prepared through the
route described in Scheme 4. The synthesis started with
compound 9, which was prepared using method A.
Treatment of compound 9 with DIBAL at 0 ꢁCin tolu-
ene/THF afforded compound 17. Reacting compound
17 with DAST in DCM gave the difluoromethylpyridine
analogue 16. Compound 17 was also subjected to a
Wittig reaction to give the 3-vinylpyridine inter-
mediate, which was reduced with H2 on Pd/Cto
afford the 3-ethylpyridine analogue 15.
872Æ215
246Æ112
S
IC50 values are the meanÆSEM of at least three determinations.
Table 2. 3-Substituents on pyridyl ring
All final compounds were purified to >97%. The purity
of the compounds 2–31 was determined by RP-HPLC
No.
R1
IC50 (nM) pH
IC50 (nM) CAP
1
9
–CF3
–CN
–NO2
–Cl
–Br
39.2Æ8.0
>25,000
57.5Æ13.1
287Æ90
10
11
12
13
14
15
16
17
245Æ21
190Æ50
17.3Æ7.2
27.1Æ11.4
77.4Æ19.9
173Æ82
11.5Æ3.4
4.6Æ1.0
56.7Æ15.3
25.3Æ7.0
230Æ96
–I
–CH3
–CH2CH3
–CHF2
–CHO
828Æ414
61.5Æ18.2
1400Æ856
27.7Æ8.5
201Æ49
Scheme 1. Parallel synthesis of the analogues of compound 1.
IC50 values are the meanÆSEM of at least three determinations.

Q. Sun et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3611–3616
3613
Table 3. Aryl modifications
No.
Ar
IC50 (nM) pH
IC50 (nM) CAP
No.
Ar
IC50 (nM) pH
IC50 (nM) CAP
18
4.8Æ2.5
34.9Æ19.4
25
261Æ39
93.2Æ15.5
19
20
21
22
23
24
91.7Æ18.3
203Æ81
29.8Æ13.6
117Æ58
26
27
28
29
30
31
2669Æ1386
1010Æ585
310Æ141
>25,000
655Æ210
491Æ121
285Æ75
73Æ50
41.6Æ26.8
107Æ11.3
17.4Æ7.6
63.5Æ9.3
56.6Æ31.7
23.3Æ12.3
81.4Æ48.0
1106Æ521
479Æ230
3.9Æ1.6
278Æ123
17.2Æ2.9
IC50 values are the meanÆSEM of at least three determinations.
Scheme 2. Reagents and conditions for method A: (a) DMSO, 100 ꢁC,
6 h; (b) Ar-NCO or Ar-NCS, DCM, rt, 2 h.
Scheme 3. Reagents and conditions for method B: (a) DCM, TEA, rt,
10 min; (b) 4-(2-pyridyl)piperazine, DCM, rt, 2 h.
Either 100 nM CAP or pH 5.5 were used as agonists for
the respective assays.
Substituting a phenoxy group at the 4-position of the
phenyl ring also decreased the potency (analogue 6).
Replacing the urea linker in compound 1 with a
thiourea group (compounds 7 and 8) caused a reduction
in activity in both pH and CAP assays.
Our initial SAR study was focused on modifying the 4-
substituent on the phenyl ring of our lead compound 1.
The IC50 values in both pH and CAP assays for com-
pounds 1–8 are shown in Table 1. The 4-t-butyl analo-
gue 5 had similar activity [IC50=58 nM (pH) and 11
nM (CAP)] compared to compound 1, whereas the 4-
ethyl derivative 2 was slightly less potent and the 4-
methyl and 4-n-butyl analogues 3 and 4 were very weak
VR1 antagonists, suggesting that the i-propyl and t-
butyl substituents were probably optimized substituents
in term of size and shape among the alkyl groups.
In parallel to the modification of the 4-substituent on
the phenyl ring, the SAR of the 3-position of the pyri-
dine moiety of 1 was also explored. The IC50 values in
both pH and CAP assays for compounds 9–17 are
shown in Table 2. Adding more polar substituents, such
as –CN, –NO2, or –CHO, to replace 3-CF3 group on the

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Q. Sun et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3611–3616
Scheme 4. Reagents and conditions: (a) DIBAL, toluene/THF, 0 ꢁC, 16 h; (b) DAST, DCM, rt, 24 h; (c) CH3P(Ph)3Br, t-BuOK, THF, rt, 16 h;
(d) H2, Pd/C, MeOH, rt, 1 h.
assays for these compounds are shown in Table 3.
Table 4. PK parameters of compound 18 following single 3 mg/kg iv
and 40 mg/kg oral dose
Compounds 18–23 varied alkyl substituents, from an
ethyl group to a cyclohexyl group, on the 4-position of
the phenyl ring. While all six compounds were potent
analogues, compound 18 with a t-butyl substituent was
the most potent in the VR1 pH assay (IC50=4.8 nM). 4-
CF3 Phenyl derivative 24 was quite potent in both VR1
FLIPR assays [IC50=81 nM (pH) and 64 nM (CAP)],
whereas compound 25 with a more polar 4-OCF3 sub-
stituent on the phenyl ring reduced the potency, partic-
ularly in the pH assay. Adding a more polar 4-nitro
group to the phenyl ring totally abolished activity in the
pH assay (compound 29), suggesting that hydrophobic
substituents at the 4-position of the phenyl ring are
important for activity. Different halo groups were also
tried at the 4-position of the phenyl ring (compounds
26, 27, and 28). The 4-I phenyl analogue 28 was the
most potent [IC50=310 nM (pH) and 285 nM (CAP)].
The activity was observed to decrease with decreasing
size, 4-I versus 4-Cl substituent. Two other compounds
(30 and 31) were synthesized using a 2-naphthyl group
and a trans-4-t-butyl-cyclohexyl group to replace the
phenyl moiety. The trans-4-t-butyl-cyclohexyl analogue
31 was found to be a very potent compound [IC50=17
nM (pH) and 3.9 nM (CAP)], whereas the 2-naphthyl
compound 30 showed reduced potency.
Vz
5.8 L/kg
4.6 L/h/kg
0.9 h
CL
t1/2
F%
15.1
pyridine fragment significantly reduced the activity,
especially in the pH assay (compounds 9, 10 and 17). 4-
Halo-substituted analogues 11, 12, and 13 were very
potent VR1 antagonists. In particular, 4-Cl derivative
11 and 4-Br analogue 12 were found to be more potent
than compound 1 [IC50=17 nM (pH) and 12 nM (CAP)
for compound 11; 27 nM (pH) and 4.6 nM (CAP) for
compound 12]. 3-Methyl analogue 14 and 3-CHF2
derivative 16 showed good potency. However, adding a
more bulky ethyl group to the 3-position of pyridine
moiety dramatically reduced activity. 3-Ethyl analogue
15 was 5–10-fold less potent than 3-methyl derivative
14. The preliminary SAR study on the 3-position of the
pyridine fragment suggested that relatively non-polar
and smaller substituents, such as Cl, were preferred in
this position.
Having optimized the 3-position of the pyridine frag-
ment, attention was turned to further explore the SAR
of the phenyl moiety in compound 1. All the com-
pounds prepared in this series had a 3-Cl substituent on
the pyridine ring. The IC50 values in both pH and CAP
Compound 18 was one of the most potent analogues
[IC50=4.8 nM (pH) and 35 nM (CAP)] found from our
SAR studies. This compound is approximately 10-fold
more potent in the pH assay and slightly more potent in
the CAP assay compared to compound 1. Thus 18 was

Q. Sun et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3611–3616
3615
selected for in vivo pharmacokinetic (PK) study in rat.
The in vivo profile of 18 is summarized in Table 4. The
PK study was designed to estimate systemic drug expo-
sure following a single 3 mg/kg iv and 40 mg/kg po
administration to rats. Following IV administration of 3
mg/kg, compound 18 showed a moderate terminal half
life (t1/2=0.9 h), due to its relatively rapid clearance
(CL=4.6 L/h/kg). Following oral administration of 40
mg/kg, compound 18 was rapidly absorbed (Tmax=0.5
h, Cmax=1116 ng/mL). More importantly, the oral
dosing confirmed that 18 was orally bioavailable
(F%=15.1), which was clearly lacking in the initial lead
1.
11. Garcia-Martinez, C.; Humet, M.; Planells-Cases, R.;
Gomis, A.; Caprini, M.; Viana, F.; Sanchez-Baeza, F.; Car-
bonell, T.; Felipe, C. D.; Perez-Paya, E.; Belmonte, C.; Mes-
seguer, A.; Ferrer-Montiel, A. Proc. Natl. Acad. Sci. U.S.A.
2002, 99, 2374.
12. Lee, J.-W.; Lee, J.-Y.; Szabo, T.; Gonzalez, A. F.; Welter,
J. D.; Blumberg, P. M. Bioorg. Med. Chem. 2001, 9, 1713.
13. Hutchison, A.; Desimone, R. W.; Hodgetts, K. J.; Krause,
J. E.; White, G. G. PCT WO02/08221, 2002.
14. Dax, S.; Dubin, A.; Jetter, M.; Nasser, N.; Shah, C.;
Swanson, D.; Carruthers, N. I. Drugs Future 2002, 27(Suppl.
A). 17th Int. Symp. on Medicinal Chemistry, Barcelona,
Spain, Sept. 1–5, 2002.
15. LC–MS was performed on an Agilent Series 1100 MSD
instrument with an electrospray sample inlet system. HPLC
profile generated on an Eclipse XDB-C18 rapid resolution
4.6Â50 mm column with a gradient of 85:15 to 10:90 of 0.1%
TFA/acetonitrile with 0.1% TFA and UV detection at 260 nm.
In summary, we have prepared a series of VR1 antago-
nists based on the lead compound 1. The SAR studies
promptly led to a potent and orally available VR1
antagonist 18, which might aid in the elucidation of the
role of the VR1 receptor in the pain pathway and
determine the therapeutic potential of VR1 antagonists
as analgesics.17 Further in vivo studies of 18 in different
rat pain models will be the subject of future publica-
tions.
1
16. NMR data for compounds 2–31: 2: H NMR (400 MHz,
CDCl3) d 8.46 (d, 1H), 7.90 (dd, 1H), 7.27 (d, 2H), 7.12 (d,
2H), 7.06 (dd, 1H), 6.34 (br s, 1H), 3.66–3.62 (m, 4H), 3.36–
3.32 (m, 4H), 2.61 (q, 2H), 1.22 (t, 3H). 3: 1H NMR
(400 MHz, CDCl3) d 8.45 (dd, 1H), 7.90 (dd, 1H), 7.26 (dd,
2H), 7.10 (d, 2H), 7.06–7.04 (m, 1H), 6.32 (s, 1H), 3.63 (t, 4H),
1
3.35 (t, 4H), 2.30 (s, 3H). 4: H NMR (400 MHz, CDCl3): d
8.48 (d, 1H), 7.92 (dd, 1H), 7.28 (d, 2H), 7.13 (d, 2H), 7.07
(dd, 1H), 6.32 (br s, 1H), 3.68–3.64 (m, 4H), 3.39–3.34 (m,
4H), 2.58 (t, 2H), 1.61–1.53 (m, 2H), 1.41–1.32 (m, 2H), 0.93
Acknowledgements
1
(t, 3H). 5: H NMR (400 MHz, CDCl3) d 8.45 (t, 1H), 7.89–
7.88 (m, 1H), 7.45–7.42 (m, 4H), 7.13–7.11 (m, 1H), 6.42 (s,
1H), 3.71–3.70 (m, 4H), 3.31–3.30 (m, 4H), 1.31 (s, 9H). 6: 1H
NMR (400 MHz, CDCl3) d 8.46 (d, 1H), 7.90 (dd, 1H), 7.35–
7.29 (m, 4H), 7.09–7.04 (m, 2H), 7.00–6.96 (m, 4H), 6.35 (br s,
1H), 3.68–3.64 (m, 4H), 3.37–3.33 (m, 4H). 7: 1H NMR
(400 MHz, CDCl3) d 8.44 (d, 1H), 7.90 (dd, 1H), 7.19 (br s,
1H), 7.18 (d, 2H), 7.10 (d, 2H), 7.04 (dd, 1H), 3.99–3.95 (m,
4H), 3.41–3.36 (m, 4H), 2.94–2.84 (m, 1H), 1.24 (d, 6H). 8: 1H
NMR (400 MHz, CDCl3) d 8.45 (d, 1H), 7.89 (dd, 1H), 7.36
(d, 2H), 7.25 (br s, 1H), 7.10 (d, 2H), 7.05 (dd, 1H), 3.99–3.96
(m, 4H), 3.40–3.37 (m, 4H), 1.31 (s, 9H). 9: 1H NMR
(400 MHz, CDCl3) d 8.51 (t,1H), 7.85 (t, 1H), 7.35–7.32 (m,
2H), 7.25–7.22 (m, 2H), 6.86–6.83 (m, 1H), 6.35 (s, 1H), 3.86–
3.84 (m, 4H), 3.73–3.70 (m, 4H), 2.98–2.90 (m, 1H), 1.31 (s,
The authors would like to thank Dr. R. Richard
Goehring for review of the manuscript and Mr. Mike
Williams for technical assistance.
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4. Hayes, P.; Meadows, H.; Gunthope, M.; Harries, M.;
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3.61 (m, 4H), 3.53–3.50 (m, 4H), 2.97–2.91 (m, 1H), 1.31 (s,
1
6H). 11: H NMR (400 MHz, CDCl3) d 8.20 (br d, 1H), 7.62
(d, 1H), 7.29 (d, 2H), 7.15 (d, 2H), 6.87 (dd, 1), 6.58 (br s, 1H),
3.67–3.64 (m, 4H), 3.41–3.39 (m, 4H), 2.91–2.84 (m, 1H), 1.23
(d, 6H). 12: 1H NMR (400 MHz, CDCl3) d 8.27 (dd, 1H), 7.84
(dd, 1H), 7.35–7.29 (m, 4H), 6.85 (dd, 1H), 6.35 (br s, 1H),
3.70–3.67 (m, 4H), 3.42–3.40 (m, 4H), 1.32 (s, 9H). 13: 1H
NMR (400 MHz, CDCl3) d 8.34 (dd, 1H,), 8.15 (dd, 1H), 7.34
(d, 2H), 7.21 (d, 2H), 6.76 (dd, 1H), 6.41 (s, 1H), 3.75–3.72 (m,
4H), 3.39–3.36 (m, 4H), 2.94–2.91 (m, 1H), 1.28 (d, 6H). 14:
1H NMR (400 MHz, CDCl3) d 8.19 (d, 1H), 7.45 (dd, 1H),
7.29 (d, 2H), 7.18 (d, 2H), 6.93 (dd, 1H), 6.38 (br s, 1H), 3.68–
3.64 (m, 4H), 3.25–3.21 (m, 4H), 2.94–2.85 (m, 1H), 2.33 (s,
3H), 1.26 (d, 6H). 15: 1H NMR (400 MHz, CDCl3) d 8.18 (dd,
1H), 7.52 (dd, 1H), 7.27 (d, 2H), 7.16 (d, 2H), 6.97 (dd, 1H),
6.33 (br s, 1H), 3.65–3.63 (m, 4H), 3.19–3.16 (m, 4H), 2.90–
1
2.84 (m, 1H), 2.67 (q, 2H), 1.28 (t, 3H), 1.23 (d, 6H). 16: H
NMR (400 MHz, CDCl3) d 8.44 (d, 1H), 7.95 (d, 1H), 7.27 (d,
2H), 7.17–7.11 (m, 3H), 6.87 (t, 1H), 6.37 (br s, 1H), 3.66–3.63
(m, 4H), 3.27–3.24 (m, 4H), 2.89–2.84 (m, 1H), 1.22 (d, 6H).
17: 1H NMR (400 MHz, CDCl3) d 10.06 (s, 1H); 8.43 (dd, 1H),
8.05 (dd, 1H), 7.30 (d, 2H), 7.18 (d, 2H), 7.00 (dd, 1H), 6.35
(br s, 1H), 3.72 (dd, 4H), 3.57 (dd, 4H), 2.93–2.86 (m, 1H),
1.25 (d, 6H). 18: 1H NMR (400 MHz, CDCl3) d 8.25 (dd, 1H),
10. Walpole, C. S. J.; Bevan, S.; Bovermann, G.; Boelsterli,
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Q. Sun et al. / Bioorg. Med. Chem. Lett. 13 (2003) 3611–3616
7.67 (dd, 1H), 7.39–7.32 (m, 4H), 6.95 (dd, 1H), 6.41 (br s,
1H), 3.73–3.70 (m, 4H), 3.49–3.46 (m, 4H), 1.36 (s, 9H). 19: 1H
NMR (400 MHz, CDCl3) d 8.26 (dd, 1H), 7.68 (dd, 1H), 7.34
(br d, 2H), 7.21 (br d, 2H), 6.94 (dd, 1H), 6.37 (br s, 1H), 3.73–
3.70 (m, 4H), 3.49–3.47 (m, 4H), 2.58–2.45 (m, 1H), 1.96–1.83
1H NMR (400 MHz, CDCl3) d 8.20 (dd, 1H), 7.63 (dd, 1H),
7.33 (d, 2H), 7.27 (d, 2H), 6.90 (dd, 1H), 6.39 (br s, 1H), 3.68–
3.65 (m, 4H), 3.44–3.41 (m, 4H). 27: 1H NMR (400 MHz,
DMSO-d6) d 8.35 (s, 1H), 8.21 (t, 1H), 7.72–7.71 (m, 1H),
7.48–7.43 (m, 2H), 7.45–7.40 (m, 2H), 7.13–7.11 (m, 1H), 3.72
(br s, 4H), 3.23 (br s, 4H). 28: 1H NMR (400 MHz, DMSO-d6)
d 8.35 (s, 1H), 8.15 (s, 1H), 7.73–7.70 (m, 1H), 7.51–7.49 (m,
2H), 7.25–7.23 (m, 2H), 6.96–6.94 (m, 1H), 3.72 (br s, 4H),
1
(m, 4H), 1.83–1.75 (m, 1H), 1.48–1.41 (m, 4H). 20: H NMR
(400 MHz, CDCl3) d 8.19 (dd, 1H), 7.61 (dd, 1H), 7.25 (d,
2H), 7.10 (d, 2H), 6.89 (dd, 1H), 6.34 (s, 1H), 3.67–3.64 (m,
2H), 3.42–3.40 (m, 4H), 2.58 (t, 2H), 1.64–1.51 (m, 2H), 1.40–
1
3.23 (br s, 4H). 29: H NMR (400 MHz, CDCl3) d 8.27–8.24
1
1.27 (m, 2H), 0.91 (t, 3H). 21: H NMR (400 MHz, CDCl3) d
(m, 3H), 7.70 (dd, 1H), 7.62 (dd, 2H), 6.97 (dd, 1H), 6.80 (br s,
1H), 3.78–3.75 (m, 4H), 3.52–3.49 (m, 4H). 30: 1H NMR
(400 MHz, CD3OD) d 8.15 (s, 1H), 7.91 (s, 1H), 7.85–7.75 (m,
4H), 7.59–7.53 (m, 1H), 7.47–7.43 (m, 2H), 7.00 (br s, 1H),
3.75 (br s, 4H), 3.45 (br s, 4H). 31: 1H NMR (400 MHz,
CDCl3) d 8.18 (d, 1H), 7.60 (d, 1H), 6.87 (dd, 1H), 4.38 (d,
1H), 3.67–3.54 (m, 1H), 3.53–3.49 (m, 4H), 3.36–3.32 (m, 4H),
2.09–2.02 (m, 2H), 1.80–1.75 (m, 2H), 1.17–0.99 (m, 4H),
0.98–0.90 (m, 1H), 0.85 (s, 9H).
17. (a) Valenzano, K. J.; Grant, E. R.; Wu, G.; Hachicha, M.;
Schmid, L.; Tafesse, L.; Sun, Q.; Rotshteyn, Y.; Francis, J.;
Limberis, J.; Malik, S.; Whittemore, E. R.; Hodges, D. J.
Pharmacol. Exp. Ther. 2003, 306, 377. (b) Pomonis, J. D.;
Harrison, J. E.; Mark, L.; Whiteside, G. T.; Bristol, D. R.;
Valenzano, K. J.; Walker, M. J. K. J. Pharmacol. Exp. Ther.
2003, 306, 387.
8.10 (s, 1H), 7.62–7.60 (m, 1H), 7.22 (t, 2H), 7.10 (t, 2H), 6.73–
6.70 (m, 1H), 6.41 (s, 1H), 3.73–3.71 (m, 4H), 3.43–3.40 (m,
4H), 2.52–2.48 (m, 2H), 1.54–1.49 (m, 2H), 1.12–0.99 (m, 3H).
22: 1H NMR (400 MHz, CDCl3) d 8.28–8.23 (m, 1H), 7.70–
7.66 (m, 1H), 7.50–7.45 (m, 2H), 7.41–7.36 (m, 2H), 6.98–6.92
(m, 1H), 6.50 (br s, 1H), 3.75–3.69 (m, 4H), 3.50–3.43 (m, 4H),
1
1.62 (br s, 5H). 23: H NMR (400 MHz, CDCl3) d 8.19 (dd,
1H), 7.61 (dd, 1H), 7.28 (d, 2H), 7.10 (d, 2H), 6.88 (dd, 1H),
6.41 (br s, 1H), 3.65 (dd, 4H), 3.41 (dd, 4H), 2.57–2.52 (m,
1H), 1.59–1.52 (m, 2H), 1.20 (d, 3H), 0.80 (t, 3H). 24: 1H
NMR (400 MHz, CDCl3) d 8.20 (t, 1H), 7.62–7.60 (m, 1H),
7.59–7.50 (m, 4H), 6.76–6.74 (m, 1H), 6.65 (s, 1H), 3.72 (br s,
1
4H), 3.51 (br s, 4H). 25: H NMR (400 MHz, CDCl3) d 8.20
(dd, 1H), 7.63 (dd, 1H), 7.40 (d, 2H), 7.15 (d, 2H), 6.90 (dd,
1H), 6.44 (br s, 1H), 3.69–3.66 (m, 4H), 3.44–3.42 (m, 4H). 26: