Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists

Article abstract of DOI:10.1016/j.bmcl.2011.01.056

Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.

Full text of DOI:10.1016/j.bmcl.2011.01.056

Bioorganic & Medicinal Chemistry Letters 21 (2011) 1338–1341
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists
Robert G. Schmidt, Erol K. Bayburt, Steven P. Latshaw, John R. Koenig, Jerome F. Daanen, Heath A. McDonald,
Bruce R. Bianchi, Chengmin Zhong, Shailen Joshi, Prisca Honore, Kennan C. Marsh, Chih-Hung Lee,
⇑
Connie R. Faltynek, Arthur Gomtsyan
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1
antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted
the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute
pain models, and compounds with the ability to cross the blood–brain barrier were shown to be highly
efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of
bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as
methyl can minimize the inhibition.
Received 23 November 2010
Revised 11 January 2011
Accepted 13 January 2011
Available online 21 January 2011
Keywords:
TRPV1 antagonists
Pain
Ó 2011 Elsevier Ltd. All rights reserved.
Chromanyl urea
Tetrahydroquinolinyl urea
Transient receptor potential vanilloid 1 (TRPV1) is the best
characterized member of the TRP superfamily of ion channels.
TRPV1 can be activated by a range of stimuli, including exogenous
capsaicin as well as chemical (acid) and physical (heat) stimuli
among others.1 Its key role in nociceptive signal transduction path-
ways has been extensively discussed.2,3 In the last decade signifi-
cant efforts have been devoted to the design and synthesis of
TRPV1 antagonists as analgesic agents.4 Several TRPV1 antagonists
have entered to human clinical trials in recent years. Some reports
from these studies described signals of efficacy in dental pain trials,
but also unwanted temperature effects for TRPV1 antagonists.5–7 In
the meantime the search for TRPV1 antagonists with suitable
ADME, pharmacological, physico-chemical and toxicological pro-
file continues.
The early lead compound 1 (Fig. 1) from Abbott urea class of
TRPV1 antagonists was characterized by good potency at the tar-
get, modest efficacy in animal pain models, and less than desirable
pharmacokinetic profile.8–10 A series of structural modifications,
including rigidification of the benzylic fragment in 3, led to the in-
dan urea 4 characterized by good potency and significantly opti-
mized pharmacokinetic profile.11 Conformational restriction of
the benzylic group can also be achieved by generating the chroman
and tetrahydroquinoline bicyclic scaffolds, which generally con-
tribute to a higher solubility of the resulting ureas compared with
analogous indan ureas. This paper describes the SAR studies of the
chroman and tetrahydroquinoline TRPV1 antagonists of type 5 and
6, as well as the pharmacokinetic properties and in vivo character-
ization of these compounds in animal pain models.
Synthesis of the target chroman and tetrahydroquinoline ureas
was accomplished by reacting activated carbamate 7 with the
appropriately substituted chromanyl amine 8 or tetrahydroquin-
olinyl amine 9 as shown in Scheme 1.
Scheme 2 illustrates the general protocol for the synthesis of the
chromanyl amines 8. Alkylation of the functionalized phenol 12
with propargyl bromide generated ether 13, chlorination of which
at the terminal site of the propargyl aryl ether with N-chloro-suc-
cinimide and silver acetate afforded 14.12 Reaction conditions for
rearrangement of 14 to the chromanone 15 depended on the nature
of the substituent: aryl ethers with electron donating substituents
such as the tert-butyl group cyclized in refluxing ethylene glycol,
while aryl ethers with electron withdrawing substituents such as
the trifluoromethyl group cyclized in concentrated sulfuric acid.
Chromamone 15 was converted to the methyl oxime 16, which
was then reduced by hydrogenation to the chromanyl amine 8.
Synthesis of the piperidinyl–chromanyl amine 8n started with
chromanone 17 as shown in Scheme 3. Bromination of 17 with
N-bromosuccinimide in concentrated sulfuric acid proceeded
regioselectively to generate 18. After converting the latter to a
methyl oxime 19, a Buchwald amination13 was performed in the
presence of piperidine in a microwave reactor to yield 20. Finally,
dechlorination and reduction of the oxime in a one-pot hydrogena-
tion procedure afforded the desired chromanyl amine 8n.
In vitro SAR of the chroman ureas is presented in Table 1. A vari-
ety of substituents such as the small lipophilic trifluoromethyl
group, bulky tert-butyl group, even the basic piperidine ring are
⇑
Corresponding author. Tel.: +1 847 935 4214; fax: +1 847 937 9195.
E-mail address: arthur.r.gomtsyan@abbott.com (A. Gomtsyan).
0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2011.01.056

R. G. Schmidt et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1338–1341
1339
O
O
O
HN
N
H
HN
N
H
HN
N
H
CF3
CF3
CF3
N
N
N
N
H
1
2
3
hTRPV1 IC50 = 4 nM
hTRPV1 IC50 = 22 nM
hTRPV1 IC50 = 47 nM
O
O
O
O
N
HN
N
H
HN
N
H
HN
N
H
CF3
CF3
CF3
N
N
N
N
H
N
H
N
H
4
5
6
hTRPV1 IC50 = 3 nM
hTRPV1 IC50 = 11 nM
hTRPV1 IC50 = 7 nM
Figure 1.
O
O
O
X
N
X
HN
O
a, b
HN
N
R1
H
+
O
H2N
R1
N
N
N
N
H
MeO2C
7
8 (X=O)
9 (X=NR2)
10 (X=O)
11 (X=NR2)
Scheme 1. Reagents and conditions: (a) DIPEA, DMF, 30 min, rt; (b) MeOH, H2O, TEA, 1 h, reflux, 70–90% for two steps.
H
Cl
O
O
a
b
c or d
R1
R1
R1
R1
OH
O
O
12
13
14
15
OMe
O
O
N
O
NH2
e
f
g
HN
N
R1
H
R1
R1
O
N
N
16
8a-r
10a-r
H
Scheme 2. Reagents and conditions: (a) propargyl bromide, K2CO3, MeCN, 96 h, rt, 80–99%; (b) NCS, AgOAc, acetone, 4 h, reflux; (c) when R1 = CF3, concd H2SO4, 30 min, rt,
15–85%; (d) when R1 = tBu, ethylene glycol, 4 h, reflux, 20–65%; (e) MeONH2ÁHCl, Py, 24 h, rt, 80–99%; (f) H2, 60 psi, 10% Pd/C, NH3–MeOH, 1 h, rt, 80–99%; (g) see Scheme 1.
OMe
OMe
N
O
N
NH2
O
O
O
O
Cl
Cl
Cl
Cl
b
a
c
d
O
O
Br
19
N
N
Br
18
17
20
8n
Scheme 3. Reagents and conditions: (a) concd H2SO4, NBS, 3 h, rt, 99%; (b) MeONH2ÁHCl, Py, 24 h, rt, 82%; (c) piperidine, NaOtBu, Pd2(dba)3, BINAP, dioxane, 30 min, 170 °C,
w, 20%; (d) H2, 60 psi, 10% Pd/C, NH3–MeOH, 18 h, 50 °C, 37%.
l
well tolerated. The site of the functional group placement appears
to be the key to in vitro potency. Thus, substitutions at 7- and 8-
positions afforded the most potent compounds, whereas substitu-
tions at the 6-position led to a dramatic drop in activity. Chirality
also has an effect on in vitro activity. For example, the (R)-enantio-
mer 10f exhibits greater potency than the (S)-enantiomer 10g. The

1340
R. G. Schmidt et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1338–1341
Table 1
in vitro SAR of the chroman ureas strongly correlates with the SAR
of the indane ureas.11
In vitro functional potencies of selected chroman TRPV1 antagonists in human TRPV1
Ca2+ influx assay
Most of the chroman ureas were efficacious in the rat model of
CFA-induced thermal hyperalgesia, but lacked efficacy in other
pain models. The exception was compound 10j, which was highly
efficacious in multiple animal pain models (Table 2). This TRPV1
antagonist possessed a brain/plasma ratio of 0.42 in rats, which
was higher than the brain penetration of the other chroman ureas
evaluated. These data are consistent with the hypothesis that CNS
penetration is a desirable characteristic for a broad-spectrum
analgesic effects of a potent, selective TRPV1 antagonist.14
Complimenting the indane and chroman ureas were the tetra-
hydroquinoline ureas, another structural series with a rigid scaf-
O
O
6
8
HN
N
H
R1
5
7
N
N
H
a
Compd
R1
hTRPV1 IC50 (nM)
10a
10b
10c
10d
10e
10f
10g
10h
10i
10j
10k
10l
10m
10n
10o
10p
10q
10r
7-CF3
11
4
43
8
43
31
1200
5
5
5
3
19
15
16
110
933
718
234
7-CF3-R
7-CF3-S
7-OCF3
7-tBu
7-tBu-R
7-tBu-S
8-CF3
8-OCF3
8-tBu
8-tBu-R
8-tBu-S
fold. Scheme
4 illustrates the general synthetic route of
preparing the target molecules in this series. Acylation of the func-
tionalized aniline 21 with bromopropionyl chloride afforded amide
22, which was then cyclized to b-propiolactam 23. Next, triflic acid
was utilized to initiate a Fries rearrangement to yield dihydroquin-
olinone 24.15 N-Substitution of 24 by either reductive amination
with aldehydes or alkylation with alkyl halides gave 25. Finally,
the methyl oxime 26 was prepared, and then reduced by hydroge-
nation to generate the tetrahydroquinoline amine 9.
SAR of the tetrahydroquinoline ureas presented in Table 3
strongly correlates with the SAR of the chroman ureas. Placement
of the aryl substituent is a key factor for in vitro potency as dem-
onstrated with the shifting positions of the tert-butyl group in
compounds 11d–f. Once more, the 7- and 8-positions are the favor-
able sites for higher potency. A variety of substituents are well tol-
erated, both on the aryl ring and on the nitrogen. Evidently, better
in vitro activity is obtained from large N-substituents such as the
benzyl group. For instance, benzyl substituted 11j is seven-fold
more potent then its methyl analog 11f. Unlike chromans, the tet-
rahydroquinoline ureas were found to be inhibitors of the CYP3A4
enzyme as shown in Table 3. Large bulky substituents such as the
benzyl group generated compounds that were especially potent
inhibitors. However, replacement of the benzyl moiety with a
methyl group on the nitrogen has a major effect in decreasing
the inhibition (11k vs 11g). The best combination of potency and
CYP inhibition was achieved with 11c.
8-Cyclohexyl
8-Piperidino
8-Morpholino
6-Me
6-F
H
a
All values are means SEM of at least three separate experiments.
Table 2
Analgesic effects of 10ja
O
O
HN
N
H
N
N
H
Rat models of pain
In summary, we have demonstrated that the chroman and tetra-
hydroquinoline ureas are potent TRPV1 antagonists. They share an
in vitro SAR profile with the original rigid bicyclic scaffold, the ind-
anes. The chroman ureas also exhibited a broad-spectrum analgesic
profile when the compounds crossed the blood–brain barrier into
the CNS. The tetrahydroquinolines were hampered by inhibition of
the CYP3A4 enzyme, yet the correct selection of substituents can
alleviate this liability and still provide potent TRPV1 antagonists.
Capsaicin-induced acute pain
Carrageenan-induced thermal hyperalgesia
CFA-induced thermal hyperalgesia
89%b
10c
15c
MIA-induced osteoarthritis pain (grip force)
56%b
a
Positive controls are A-78416814 (Capsaicin model), diclofenac (Carrageenan
and CFA-models), celecoxib (MIA model).
b
% inhibition at 30
lmol/kg po.
c
ED50 (lmol/kg) po.
O
a
c
d or e
b
O
N
R1
R1
R1
R1
O
NH2
N
H
N
N
H
21
22
23
24
Br
R2
OMe
O
N
O
NH2
g
h
f
HN
N
R1
R1
R1
R1
H
N
N
N
N
R2
R2
R2
N
H
25
26
9
11
Scheme 4. Reagents and conditions: (a) 3-bromopropionyl chloride, K2CO3, CH2Cl2, 3 h, rt, 80–99%; (b) NaOtBu, DMF, 2 h, rt, 80–99%; (c) TfOH, DCE, 80–99%; (d) R2CHO, DCE,
cat AcOH, 30 min, rt, then NaBH(OAc)3, 18 h, 55 °C, 80–99%; (e) R2Br, DIPEA, MeCN, 30 min, 150 °C,
lw, 80–99%; (f) MeONH2ÁHCl, Py, 24 h, rt, 80–99%; (g) H2, 60 psi, RaNi,
NH3–MeOH, 4 h, rt, 80–99%; (h) see Scheme 1.

R. G. Schmidt et al. / Bioorg. Med. Chem. Lett. 21 (2011) 1338–1341
1341
Table 3
In vitro functional potencies of selected tetrahydroquinoline TRPV1 antagonists in human TRPV1 Ca+ influx assay and their CYP3A4 inhibition
R2
O
N
8
HN
N
H
R1
5
7
N
6
N
H
a
Compd
R1
R2
hTRPV1 IC50 (nM)
CYP3A4 % inhibitionb
11a
11b
11c
11d
11e
11f
11g
11h
11i
H
7-F
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Methyl
Benzyl
Benzyl
Benzyl
Benzyl
215
34
7
65
66
47
7-CF3
8-tBu
7-tBu
6-tBu
6-OMe
H
6
115
853
1380
70
59
94
6-F
66
11j
11k
11l
6-tBu
6-OMe
6-OMe
8-Cl
121
160
196
11
97
93
Cyclohexylmethyl
3-Methylbutyl
11m
a
All values are means SEM of at least three separate experiments.
At 10 lM.
b
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