Structure-activity relationships of 3-substituted N-benzhydryl-nortropane analogs as nociceptin receptor ligands for the treatment of cough

Article abstract of DOI:10.1016/j.bmcl.2008.10.088

A series of 3-axial-aminomethyl-N-benzhydryl-nortropane analogs have been synthesized and identified to bind to the nociceptin receptor with high affinity. Many of these analogs showed high binding selectivity over classic opioid receptors such as μ recep

Full text of DOI:10.1016/j.bmcl.2008.10.088

Bioorganic & Medicinal Chemistry Letters 18 (2008) 6340–6343
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Structure–activity relationships of 3-substituted N-benzhydryl-nortropane
analogs as nociceptin receptor ligands for the treatment of cough
a
a
a
b
Shu-Wei Yang a, , Ginny Ho , Deen Tulshian , William J. Greenlee , Xiomara Fernandez ,
*
Robbie L. McLeod b, Stephen Eckel b, John Anthes b
a Department of Chemical Research—CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
b Neurobiology Department of Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 3-axial-aminomethyl-N-benzhydryl-nortropane analogs have been synthesized and identified
Received 18 September 2008
Revised 15 October 2008
Accepted 20 October 2008
Available online 1 November 2008
to bind to the nociceptin receptor with high affinity. Many of these analogs showed high binding selec-
tivity over classic opioid receptors such as
l receptor. The synthesis and structure–activity relationships
around the C-3 nortropane substitution are described. Selected compounds with potent oral antitussive
activity in the guinea pig model are disclosed.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Nociceptin
NOP
ORL-1
MOP
Antitussive
Cough
Nortropane
SAR
The nociceptin receptor (NOP, ORL-1), an orphan opioid recep-
tor, was discovered as a member of the G protein-coupled receptor
superfamily in 1994.1 Its sequence has ꢀ50% homology to those of
unpleasant withdrawal symptoms. There is an unmet medical need
for the treatment of cough. Nociceptin has been shown to display
antitussive activity in guinea pig model through peripheral (IV)
or central (ICV) administration, and this effect was blocked by a
NOP selective antagonist, J113397.4 Thus, selective NOP agonists
provide a novel therapeutic approach for the management of
cough.
In our nociceptin agonist program, we have reported structure–
activity relationships (SAR) related to two early lead series based
on the 4-hydroxy-4-phenyl piperidinyl5,6 and spiropiperidinyl7
scaffolds, originally derived from high throughput screening. In
the 4-hydroxy-4-phenyl piperidinyl series, the N-2,20-dichloro-
benzhydryl analogs demonstrated improved binding affinity.5,6
Further SAR development was focused on the N-2,20-dichloro-
benzhydryl substituted nortropane scaffold, a conformationally-re-
stricted analog of piperidine. In this paper, we disclose synthesis
and SAR of a new 3-axial-aminomethyl-N-benzhydryl-nortropane
series as potential replacement of the C-3 hydroxyl group which
could undergo elimination. Furthermore the aminomethyl func-
tionality allowed us to explore different chemical functionality
on the C-3 axial position to further modulate DMPK profile of the
tropane series.
the opioid receptor family
l, j, and d (also known as MOP, KOP,
and DOP, respectively). However NOP displays low binding affinity
for the classical synthetic and endogenous opioid ligands. NOP is
widely distributed throughout the brain and spinal cord and thus
is expected to participate in various physiological processes. Fol-
lowing the discovery of NOP, there has been remarkable advance
toward understanding its pharmacological significance. Nociceptin
(orphanin FQ or OFQ), the NOP endogenous ligand,2 does not inter-
act with the other opioid receptors. It has been reported to mediate
various physiological processes, for instance, pain, cough, anxiety,
feeding, sleep, substance abuse, and cognition.3 Thus, selective
NOP agonists or antagonists might have clinical potential for the
treatment of related diseases with better side effect profile associ-
ated with the other opioid receptors, such as physical dependency,
respiratory depression, and constipation.
Codeine is the most widely used narcotic antitussive agent.
However it is not long acting and possesses significant adverse ef-
fects such as drowsiness, constipation, respiratory depression, and
The synthetic route to the 4-a-substituted nitrile is outlined in
* Corresponding author. Tel.: +1 908 740 7291; fax: +1 908 740 7164.
E-mail address: shu-wei.yang@spcorp.com (S.-W. Yang).
Scheme 1. Commercially available tropinone (1) was de-methylated
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.10.088

S.-W. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6340–6343
6341
3
Cl
O
O
Cl
a
O
c
N
CN
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Br Cl
a, b
c
N
N
R
b
R
4
1
7
Cl
Cl
3
12
2
d
11
e
Scheme 3. Reagents and conditions: (a) Cl(CH2)3COCl, Et3N, DCM, rt; (b) KO-t-Bu,
THF, rt; (c) LAH, THF, reflux.
CN
R'
Cl
CN
Cl
N
Cl
N
R
Cl
6
CH3
5
O
O
NH
R = H, F, or OMe
R' = substituted 2-, or
3-pyridyl, or benzyl
Cl
NH
Cl
b
a
N
N
Scheme 1. Reagents and conditions: (a) a-chloroethyl chloroformate, DCE, reflux;
7
Cl
R
(b) 2, K2CO3, CH3CN, reflux; (c) KO-t-Bu, tosylmethyl isocyanide, DME, ꢁ40 °C to rt;
Cl
R
(d) RPhF, KHMDS, neat, microwave, 100 °C; (e) NaHMDS, R0X, THF, ꢁ78 °C to rt.
14
13
CH3
N Ac
Cl
using
a-chloroethyl chloroformate and subsequently alkylated
using 2,20-dichloro-benzhydryl bromide (2)5 in the presence of
K2CO3 to afford the ketone intermediate 3. Single step transforma-
tion of 3 to the nitrile intermediate 4 was carried out using tosylm-
ethyl isocyanide and KO-t-Bu in DME.8 Further nucleophilic
c
N
Cl
R
15
addition of a phenyl group through the less hindered
a
-equatorial
Scheme 4. Reagents and conditions: (a) ClCO2Me, aq K2CO3, DCM, rt; (b) LAH, THF,
reflux; (c) Ac2O, pyridine, 0 °C.
direction was achieved under neat microwave condition with excess
fluorobenzene and KHMDS as base at 100 °C (ꢀ78% when R = H) to
obtain 5. The benzyl or pyridinyl derivatives (6) could be prepared
using the corresponding benzyl halides or pyridinyl halides and
NaHMDS as base.9
reduced by LAH to afford the N-methyl analog 14. Further acetyla-
tion of 14 gave the target 15.
The conformationally restrained analog 17 was designed by
connecting the C-3 aminomethyl to the ortho-position of the phe-
nyl group. The synthesis was achieved in two steps as shown in
Scheme 5. Aldehyde 16 was prepared by reduction of the nitrile
4 using DIBAL. Formation of the 3H-indole on C-3 was achieved
using phenylhydrazine and trifluoroacetic acid in DCM at 40 °C.
Further reduction of the 3H-indole to the spiro 2,3-dihydro-1H-in-
dole (17) was accomplished by subsequently adding NaBH(OAc)3
to the above reaction mixture.11
Further transformation of the C-3 nitrile to the aminomethyl or
substituted aminomethyl group is detailed in Schemes 2–4. Thus,
the nitriles (5 or 6) were reduced to aminomethyl 7 using LAH,
and acetylated with acetic anhydride or di-methylated under
reductive amination condition to afford the target analogs 8 and
9, respectively. The N-ethyl analogs (10) were obtained by reduc-
tion of N-acetyl 8 with DIBAL in THF. The stereochemistry of C-3
for 8 was confirmed by the NOE experiment. The methylene pro-
tons between C-3 and the nitrogen displayed significant NOE cor-
relations with the protons on the top ethylene bridge.
The pyrrolidinone and pyrrolidine analogs were synthesized as
described in Scheme 3. Acylation of 7 with 4-chloro-butyryl chlo-
ride and further cyclization in the presence of KO-t-Bu produced
pyrrolidinone 11 in one pot.10 Reduction of the cyclic amide (11)
with LAH generated pyrrolidine 12.
Target compounds were tested for their affinity at the cloned
human nociceptin receptor expressed in CHO cell membranes by
measuring their ability to compete with [125I][Tyr14]nociceptin
FQ. The opioid receptor binding assays were performed with CHO
cell membranes expressing the human opioid receptors using
[3H]-diprenorphine as the radioligand. The Ki values were deter-
mined from dose–response curves. The functional activities of se-
lected compounds were evaluated as their ability to enhance the
To prepare the N-methyl-N-acetyl substituted analog 15, a
three-step synthesis was carried out as shown in Scheme 4. Carba-
mate 13 generated from 7 and ClCO2Me under basic condition was
binding of [35S]GTP
cS in the presence of GDP, using membranes
isolated from cells transfected with the nociceptin receptor.
Compound 18 showed potent NOP binding affinity with Ki 6 nM
and superior selectivity over MOP binding (ꢀ112-fold). Additional
methyl, dimethyl, or acetyl substitution on the nitrogen (19–21)
slightly reduced NOP binding affinity (Ki between 10 and 20 nM,
Table 1). The carbamate substitution (22) was tolerated, whereas
the N-methyl-N-acetyl analog 23 showed poor NOP affinity (Ki
210 nM) and reduced selectivity over MOP receptor (ꢀ13-fold).
Large substitutions at the nitrogen such as pyrrolidine in 24 and
NHAc
NH2
Cl
Cl
5
or
6
a
b
N
R
N
R
Cl
Cl
7
8
R = Ph, Bn, or 2-pyridyl
c
d
H
N
NH
N
Cl
Cl
Cl
Cl
N
R
H
b, c
a
N
N
R
N
Cl
4
O
Cl
10
Cl
9
R
Cl
17
16
Scheme 2. Reagents and conditions: (a) LAH, ether, rt; (b) Ac2O, Pyr, 0 °C; (c) HCHO,
HCO2H, 100 °C (R = Ph) or HCHO, AcOH, NaBCNH3, MeOH, rt; (d) DIBAL, THF, ꢁ78 °C
to rt.
Scheme 5. Reagents and conditions: (a) DIBAL, toluene, ꢁ78 °C to rt; (b) R-phenyl-
hydrazine, TFA, DCM, 40 °C; (c) NaBH(OAc)3, DCM, rt.

6342
S.-W. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6340–6343
Table 1
Since the para-position of the phenyl ring is a potential site of
SAR of the C-3 phenyl substituted analogs.
metabolism, the SAR of the para-substitution on the phenyl ring
was evaluated. Fluoro substitution at the para-position (26) main-
tained binding affinity for NOP with a better selectivity (68-fold)
for MOP, when compared to 21. In contrast, the para-methoxyl
substitution caused ꢀ6-fold reduction of NOP binding affinity,
and led to poor selectivity, as concluded from comparison of Ki data
from 21 and 27. The spiro 2,3-dihydro-1H-indole analogs (28–30)
displayed decreased NOP affinity (Ki 39 to 74 nM).
R1
Cl 8
N
3
2
R2
Cl
Compound
R1
R2
NOP Ki (nM)
MOP Ki (nM)
SAR of the C-3 benzyl substituted analogs (31–39) was summa-
rized in Table 2. Additional carbon extension of the phenyl group
was tolerated (31–33, 38). Compound 31 showed potent NOP bind-
ing affinity (Ki 11 nM) and excellent selectivity (ꢀ121-fold) over
MOP. Large alkyl substitution on the nitrogen reduced binding
affinity (35, 36). The fluoro substitution at the para-position did
not affect binding significantly (37–39).
SAR data of the C-3 2-pyridinyl analogs (40–56) are listed in Ta-
ble 3. Replacement of the C-3 phenyl with a 2-pyridinyl group was
tolerated. All four derivatives 40–43 with or without simple N-sub-
stitution showed Ki with single digit nM and high selectivity over
MOP receptor binding ranging from 75- to 124-fold. With the 6-
fluoro substitution on the pyridine ring (44–46), the potency of
the ligands dropped ꢀ4- to 15-fold. The NOP binding affinity was
not affected significantly by the 6-methoxyl substitution on the
pyridine ring (47–49), however the selectivity over MOP binding
dropped notably. The substitution on the 3-position of the pyridine
ring with a methyl or piperidinyl-methyl group reduced NOP bind-
ing activity (50–53).
18
19
20
21
22
23
NH2
NHCH3
N(CH3)2
NHAc
NHCO2CH3
N(CH3)(Ac)
H
H
H
H
H
H
6
10
17
20
20
674
566
1486
777
905
2620
210
24
25
H
70
68
4169
nd
N
O
N
H
26
27
NHAc
NHAc
4-F
4-OMe
31
118
2106
2407
H
N
a
28
50
1204
H
N
a
a
29
39
74
1706
998
Replacement of the C-3 phenyl with a 3-pyridinyl group
showed reduced NOP binding affinity. The values of Ki increased
to 82 and 35 nM for compounds 57 and 58, respectively, as shown
in Table 4. The racemic 2-piperidinyl analogs 59 and 60 were pre-
pared by reduction of the 2-pyridinyl analogs 40 and 41, respec-
tively, using PtO2 as catalyst under 1 atm H2 atmosphere. Both
59 and 60 showed potent NOP binding affinity.
F
H
N
30
CH3
Selected compounds (18, 20, 21, 31, 32, 40, and 47) were eval-
uated for selectivity over DOP and KOP receptors. These com-
pounds from different series displayed excellent selectivity over
a
Partial structures represent C-3 substitution.
pyrrolidinone in 25 led to ꢀ10-fold reduction in binding affinity
compared to 18.
Table 3
Table 2
SAR of the C-3 2-pyridinyl substituted analogs.
SAR of the C-3 benzyl substituted analogs.
R1
R1
Cl
Cl
6
N
R2
N
Cl
N
5
3
Cl
R2
Compound
R1
R2
NOP Ki (nM)
MOP Ki (nM)
Compound
R1
R2
NOP Ki (nM)
MOP Ki (nM)
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
NH2
H
H
H
H
6-F
6-F
6-F
7
5
6
617
374
743
785
nd
1284
3976
123
251
442
nd
nd
nd
758
3447
752
nd
NHAc
NHEt
N(CH3)2
NH2
NHAc
N(CH3)2
NH2
NHAc
NHEt
NH2
NHAc
NH2
31
32
33
34
NH2
H
H
H
H
11
12
39
55
1336
458
nd
NHAc
NHEt
N(CH3)2
7
29
24
104
11
4
20
50
173
245
670
62
27
99
nd
35
36
H
H
116
336
nd
nd
N
O
6-OCH3
6-OCH3
6-OCH3
3-CH3
3-CH3
3-Piperidinyl-methyl
3-Piperidinyl-methyl
5-OCH3
N
NH2
37
38
4-F
4-F
34
15
1414
782
NHAc
NHAc
NHAc
NHAc
NHAc
5-Br
5-Piperidinyl
39
4-F
58
nd
N
nd, not determined.
nd, not determined.

S.-W. Yang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 6340–6343
6343
Table 4
Table 5
SAR of the 3-pyridinyl and 2-piperidinyl substituted analogs.
Functional activity of selected compounds.
Compound
GTPc
S EC50 (nM)
GTPcS % Stim, conc. [lM]
R1
Cl
20
21
37
38
43
483
269
124
129
156
104%, 5.5
122%, 10
87%, 5.5
124%, 10
97%, 5.5
R2
N
Cl
Compound
R1
R2
NOP Ki (nM)
potent oral antitussive activity in the capsaicin-induced guinea pig
model with an ED50 of 0.19 mg/kg at 2 h.
57
CH2NH2
82
N
N
58
59
CH2NHAc
CH2NH2
35
17
Acknowledgments
H
N
The authors acknowledge Dr. Jianshe Kong, Dr. Jesse Wong, and
Mr. Meng Tao for preparation of intermediates, Dr. Tze-Ming Chan
for structure confirmation of some analogs.
H
N
60
CH2NHAc
27
References and notes
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DOP receptor (300- to 780-fold) and medium to good selectivity
over KOP receptor (30- to 190-fold).
Functional activity (EC50) was evaluated for selected com-
pounds using a GTP
EC50 of the compounds 20, 21, 37, 38, and 43, which demonstrated
full agonist activity in the GTP S functional assay.
cS assay. The data listed in Table 5 showed
c
Some compounds demonstrated decent DMPK profiles (data not
shown) were evaluated for the in vivo antitussive activity using the
capsaicin-induced guinea pig model.4 Compound 21 demonstrated
potent oral antitussive activity with an ED50 of 0.19 mg/kg at 2 h,
comparable to the previous lead compound possessing piperidinyl
skeleton.6 Compounds 20 and 38 showed antitussive activity at
0.3 mg/kg with 36% and 23% of cough suppression, respectively,
compared to the placebo. Compound 26 did not display oral anti-
tussive activity at low dose (0.3 mg/kg).
In conclusion, several potent NOP receptor agonists were iden-
tified with excellent selectivity in C-3 axial aminomethyl nortro-
pane series. Large substitution on the axial aminomethyl
nitrogen led to reduced NOP binding activity in general. The fluoro
substitution on the para-position of the phenyl or benzyl ring only
slightly diminished NOP binding affinity and selectivity over MOP
receptor. In general, substitution on 2-pyridinyl ring led to reduced
NOP affinity. Among the potent NOP agonists identified, 21 showed
11. Cheng, Y.; Chapman, K. T. Tetrahedron Lett. 1997, 38, 1497.