Synthesis and structure-activity relationships of 4-hydroxy-4-phenylpiperidines as nociceptin receptor ligands: Part 2

Article abstract of DOI:10.1016/j.bmcl.2007.03.062

A series of 4-[2-(aminomethyl)phenyl]-1-[bis(2-chlorophenyl)methyl]-4-hydroxypiperidine analogs has been identified as nociceptin receptor ligands. These compounds display high affinity and functional activity at the nociceptin receptor. The synthesis and

Full text of DOI:10.1016/j.bmcl.2007.03.062

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3028–3033
Synthesis and structure–activity relationships of
4-hydroxy-4-phenylpiperidines as nociceptin receptor ligands: Part 2
Ginny D. Ho,a,* Ana Bercovici,a Deen Tulshian,a William J. Greenlee,a Ahmad Fawzi,b
Xiomara Fernandez,b Robbie L. McLeod,b April Smith Torhanb and Hongtao Zhangb
aDepartment of Chemical Research—CV & CNS, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth,
NJ 07033, USA
bDepartment of Neurobiology, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 31 January 2007; revised 14 March 2007; accepted 19 March 2007
Available online 21 March 2007
Abstract—A series of 4-[2-(aminomethyl)phenyl]-1-[bis(2-chlorophenyl)methyl]-4-hydroxypiperidine analogs has been identified as
nociceptin receptor ligands. These compounds display high affinity and functional activity at the nociceptin receptor. The synthesis
and structure–activity relationships at the C-4 phenyl and N-1 positions are described and the antitussive activity of a selected
compound is reported.
Ó 2007 Elsevier Ltd. All rights reserved.
In the previous communication, we have disclosed the
preparation and biological evaluation of a series of
N-benzhydryl substituted 4-hydroxy-4-phenylpiperi-
dines as nociceptin receptor ligands.1 The nociceptin
receptor, NOP (previously termed ORL-1 (opioid
receptor-like-1) or OP4), is a G protein-coupled recep-
tor that was cloned in 1994.2 It bears high homology to
the classic opioid l, j, and d receptors (MOP, KOP,
and DOP), but has little cross-reactivity with their na-
tive ligands. Nociceptin (or orphanin FQ), the endoge-
neous ligand to NOP, was discovered in 1995 and
shown to be a peptide ligand that activates the NOP
receptor, but not the classic opioid receptors.3 There-
fore, the nociceptin receptor is pharmacologically dis-
tinct from the classic opioid receptors. Since the
nociceptin receptor is widely distributed throughout
the nervous system, it may participate in a broad spec-
trum of pharmacological processes. In vivo studies
with nociceptin and its peptide and non-peptide ligands
have demonstrated that the nociceptin/NOP system
may have important roles in the regulation of cough,
urinary incontinence, pain, stress and anxiety, feeding,
learning and memory, locomotor activity, substance
abuse, cardiovascular function, sleep disturbance, and
Parkinson’s disease.4 Since the nociceptin receptor is
pharmacologically distinct from the classic opioid
receptors, development of drugs targeting the nocicep-
tin receptor should be devoid of traditional opioid lia-
bilities. Accordingly, we have initiated a program to
identify nociceptin receptor agonists for the manage-
ment of cough. In this communication, we will report
the results of an expanded SAR study to identify noci-
ceptin receptor ligands that exhibit enhanced affinity
and improved selectivity relative to the lead compound
1. In addition, we will report the antitussive activity of
a selected compound 70. Our lead compound 1 dis-
plays high affinity for NOP with a binding affinity of
13 nM and moderate to excellent selectivity over
MOP, KOP, and DOP.
Ph OH
4
NOP Ki= 13 nM
DOP Ki= 1666 nM
KOP Ki= 364 nM
MOP Ki= 233 nM
N
1
1
Keywords: Nociceptin; Orphnin FQ; Nociceptin receptor (NOP);
Opioid receptor-like-1 (ORL-1); G protein-coupled receptor; Opioid
receptors (MOP, KOP, DOP).
*
Schemes 1 and 2 outline the preparation of 4-phenyl
modification compounds of types 4 and 7. Alkylation
Corresponding author. Tel.: +1 908 740 3502; fax: +1 908 740
7152; e-mail: ginny.ho@spcorp.com
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.03.062

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3028–3033
3029
9. The lithium anion is generated and reacted with
1-benzyl-4-piperidone to produce 10 after aqueous work-
up and chromatographic purification on silica gel. Com-
pound 10 is protected as its tert-butyl carbamate 11
followed by debenzylation to give 12 as an advantaged
intermediate for parallel synthesis. Alkylation of 12 with
an appropriate alkyl halide or reductive amination with
an aldehyde followed by deprotection provides 13.
O
R
OH
Br
a
b
N
Ph
Ph
N
2
Ph
Ph
Ph
Ph
4
3
Scheme 1. Reagents: (a) 4-piperidone monohydrate hydrochloride,
K2CO3, MeCN; (b) RLi or RMgBr, THF or Et2O.
NHTBDPS
a
9
Ar
OH
Ph
b
Li
a
Ar-X
Ar-M
14
N
6a, M= Li
6b, M= MgBr
NH2
OH
NR2R3
OH
5a, X= Br
5b, X= I
5c, X= H
O
O
Ph
7
d
b
c
Ar= aryl or
heteroaryl
N
N
N
N
H.HCl
R'
R'
R'
18
Scheme 2. Reagents: (a) n-BuLi/hexanes or t-BuLi/pentane (5a, 5c) or
i-PrMgCl/Et2O (5b), THF or ether; (b) 3, THF or Et2O.
15
16
17
Cl
Cl
of 4-piperidone hydrochloride with bromodiphenyl-
methane (2) produces the 4-piperidone intermediate 3.
Treatment of 3 with an appropriate lithium or Grignard
reagent affords the 4-alkyl analogs of type 4. The 4-aryl
analogs of type 7 are prepared by reaction of 6a or 6b
with 3. The lithium reagents 6a are either purchased or
prepared from lithium–halogen exchange of aryl
bromides or iodides or deprotonation of the appropriate
heteroaryls with n-butyllithium or tert-butyllithium. The
Grignard reagents 6b are either purchased or prepared
by Grignard exchange of the aryl or heteroaryl iodides
with isopropylmagnesium chloride.
R'=
Scheme 4. Reagents and condition: (a) n-BuLi, THF; (b) (2-
ClPh)2CHBr, K2CO3, MeCN, 80 °C; (c) i—14, THF; ii—NH4Cl
(aq); (d) R4SO2Cl, Et3N, CH2Cl2 (R2 = SO2R4, R3 = H), or R4NCO
(R2 = CONHR4, R3 = H).
N
N R
NH2
OH
OH
Cl
Cl
a
The synthesis of 4-(2-aminomethyl)phenyl analogs of
type 13 is diagrammed in Scheme 3. 2-Bromobenzyl-
amine (8) is protected as its tert-butyldiphenylsilyl ether
N
N
R'=
R'
R'
19
17
Scheme 5. Reagents and condition: (a) RN(CH2CH2Cl)2.HCl
(R = CH3, CH2Ph), DMF, 135 °C.
NH2
OH
NH2
Br
NHTBDPS
c
a
b
N
NBoc
N
OH
a
Br
N
b
Br
NBoc
Ph
8
9
10
Br
Br
21
N
20
R'
22
NH2
NHBoc
OH
NHBoc
OH
OH
e
d
N
N
N
NH
R
d
OH
c
OH
N
N
N
H
R1
R2
Ph
N
12
13
N
11
R'
19
R'
Scheme 3. Reagents: (a) Ph2Si(t-Bu)Cl, Et3N or imidazole, CH3CN;
(b) i—n-BuLi, 1-benzyl-4-piperidone, THF; ii—NH4Cl (aq); (c) di-tert-
butyl dicarbonate, CH2Cl2; (d) Pd(OH)2/C, HCO2NH4, MeOH;
(e) i—R1R2CHX (X@Cl or Br), K2CO3, NaI (X@Cl), CH3CN or
R1CHO, NaBH(OAc)3, THF; ii—4 M HCl/dioxane, CH2Cl2.
23
Scheme 6. Reagents: (a) 1-Boc-piperazine, (i-Pr)2NEt, CH2Cl2;
(b) i—n-BuLi, THF; ii—16; (c) 4 M HCl/dioxane; (d) R4SO2Cl, EtN,
CH2Cl2(R = SO2R4).

3030
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3028–3033
Table 1. SAR of 4-phenyl modification analogs
R
OH
4
N
Compound
R
Ki (nM)a
NOP
DOP
KOP
MOP
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
2-F–Ph
3-F–Ph
34
23
6990
5610
1738
1994
759
589
705
4-F–Ph
4-Cl–Ph
14
24
3325
6364
771
936
1702
2612
818
4-Br–Ph
2-Me–Ph
3-Me–Ph
4-Me–Ph
4-Et–Ph
51
11
15,240
1668
7796
1057
74
27
55
1151
4054
11,355
19,695
nd
273
940
12,115
24,900
33,345
nd
1281
1745
9155
85
3433
11,430
nd
4- n-Pr–Ph
4-n-Bu–Ph
2-MeO–Ph
3-MeO–Ph
4-MeO–Ph
4-Me2N–Ph
4-CN–Ph
2-HOCH2–Ph
2-H2NCH2–Ph
c-Pr
4392
9585
4160
3668
10,928
nd
983
180
588
4544
1449
16
2988
11,050
nd
19,220
nd
28,380
4363
61,045
2769
1658
26,405
7390
4563
1073
9221
387
8382
186
1.6
376
433
23
13,905
130,550
52,825
18,800
56,600
17,865
8105
125
18,365
13,230
272
i-Pr
n-Bu
t-Bu
n-Hex
62
3599
8899
407
1147
17
c-Hex
PhCH2
2176
1667
136
48
15,010
13,750
14,455
8446
1438
1801
9644
3412
2574
nd
10,390
3364
4554
1734
756
Ph(CH2)3
2-Furanyl
2-Thienyl
3-Me–2-thienyl
2-Thiazolyl
2-Pyridinyl
15
8885
nd
1273
313
nd
11,540
45,590
13,180
a Values are means of two and three experiments (nd, not determined).
The benzylamine modification analogs of type 18 are
prepared as shown in Schemes 4–6. Scheme 4 illustrates
the preparation of the sulfonamide and urea analogs.
The construction of piperazine analogs is outlined in
Schemes 5 and 6. The N-methyl and N-benzylpiperizine
analogs are prepared by reaction of 17 with an appropri-
ate bis(2-chloroethyl)amine (Scheme 5). The sulfon-
amide and tert-butyl carbamate analogs are achieved
by the procedures summarized in Scheme 6.
presence of GDP, using membranes isolated from cells
transfected with the nociceptin receptor.5
The SAR of 4-phenyl modifications is delineated in
Table 1. The methyl, methoxy, trifluoromethyl, fluorine,
chlorine, and bromine substitutions are tolerated at the
ortho, meta, or para position of the C-4 phenyl ring.
Moving the methyl or methoxy from the ortho to the
meta or para position reduces affinity at the NOP
receptor (29, 30, 31, and 35, 36, 37). In contrast, moving
the fluorine from the ortho to the meta or para enhances
the potency (24, 25, 26). Increasing the size of the substi-
tuent at the para position of the C-4 phenyl leads to
decreases in affinity at the NOP receptor (26, 27, 28,
and 31, 32, 33, 34). Introduction of an N,N-dimethyl
or cyano substituent at the para position of the C-4 phe-
nyl results in a substantial loss of potency (38 and 39).
The 2-hydroxymethylphenyl analog 40 displays compa-
rable NOP affinity to compound 1 with ꢀ11-fold selec-
tivity over MOP and greater than 100-fold selectivity
Target compounds have been tested for 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 are performed with CHO cell membranes
expressing the human opioid receptors using [3H]-dipre-
norphine as the radioligand. The Ki values are deter-
mined from dose–response curves. The functional
activities of selected compounds are evaluated by their
ability to enhance the binding of [35S]GTPcS in the

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3028–3033
3031
Table 2. Functional activity of selected 4-phenyl modification analogs
Table 4. Functional activity of selected N-benzhydryl modification
analogs
Compound
GTPcS % Stim
at [lM]
Compound
GTPcS % Stim
at [lM]
Compound
GTPcS % Stim
at [lM]
Compound
GTPcS % Stim
at [lM]
1
107 at 10
61 at 100
104 at 10
103 at 10
69 at 100
40
41
44
47
52
87 at 10
94 at 10
69 at 10
121 at 100
96 at 10
25
26
27
29
55
56
57
58
59
60
97 at 10
92 at 10
119 at 0.1
116 at 0.1
115 at 1
94 at 1
17
63
64
65
66
67
102 at 1
119 at 10
86 at 10
104 at 1
67% inh. at 1
43% inh. at 10
over DOP and KOP. Introduction of an aminomethyl at
the ortho position of the C-4 phenyl enhances affinity at
NOP and shows a dramatic improvement in selectivity
over DOP, KOP, and MOP (41). Lower alkyl and cyclo-
alkyl moieties are tolerated at the C-4 of the piperidine
(42–47). The 4-n-butyl and 4-cyclohexyl analogs 44
and 47 have comparable NOP affinity to compound 1
and exhibit excellent selectivity over DOP and KOP,
and moderate selectivity over MOP. Replacement of
the C-4 phenyl with a benzyl or phenethyl decreases po-
tency at the NOP receptor (48 and 49). The oxygen and
nitrogen containing heteroaryl at the C-4 of piperidine
reduces affinity at NOP (50, 53, 54). The 4-thienyl ana-
logs (51 and 52) have improved potency compared to the
oxygen and nitrogen containing heteroaryl analogs.
Table 2 tabulates the functional activity of the 4-phenyl
modification analogs when the nociceptin receptor
binding is less than 25 nM.
Encouraged by the potency and selectivity of compound
41, we have further examined variations of the piperidine
nitrogen substitution in 41. Table 3 catalogs the SAR of
the analogs modified at the N-benzhydryl group.
Removal of one of the phenyl groups leads to a ꢀ28-fold
loss of potency at the NOP receptor and produces a par-
tial agonist response (compound 10). The N-benzyl ana-
logs generally are less potent and possess antagonist or
weak agonist response. Replacement of one of phenyls
on 41 with n-butyl or n-pentyl produces high affinity for
NOP, KOP, and MOP, but weaker affinity for DOP (55
and 56). The methyl, chlorine, bromine, and fluorine are
well tolerated at the ortho position(s) of one or both of
the phenyls (57–65 and17). The 2,20-dichloro, 2,20-di-
methyl, and 2,20-dibromo analogs display a dramatic
improvement in the selectivity over the MOP receptor
compared with the corresponding 2-chloro, 2-methyl,
Table 3. SAR of N-benzhydryl modification analogs
NH2
OH
N
R1
R2
Compound
R1
R2
Ki(nM)a
NOP
DOP
KOP
MOP
10
55
56
41
57
58
59
60
61
17
62
63
64
65
Ph
Ph
H
n-Bu
455
0.4
0.5
1.6
0.7
0.5
1.1
0.5
110
0.5
674
0.5
9.6
1.8
nd
nd
15
nd
2
1212
606
Ph
Ph
n-Pent
Ph
30
2
13,905
2867
3702
3291
8435
8900
2998
3990
3702
9383
3204
1658
725
425
279
450
1056
747
2092
116
771
278
125
28
Ph
Ph
2-Me–Ph
2-Cl–Ph
2-Br–Ph
2-Me–Ph
4-Me–Ph
2-Cl–Ph
4-Cl–Ph
2-F–Ph
3-F–Ph
2-Br–Ph
72
83
Ph
2-Me–Ph
4-Me–Ph
2-Cl–Ph
4-Cl–Ph
2-F–Ph
3-F–Ph
2-Br–Ph
190
502
249
3085
37
530
614
66
H
4.6
5.5
99,505
23,400
664
452
181
67
1354
=
R1
R2
a Values are means of two-three experiments (nd, not determined).

3032
G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3028–3033
Table 5. SAR of benzylic nitrogen modification analogs
aValues are means of two-three experiments (nd, not determined).
and 2-bromo analogs (57 and 60, 58 and 17, 59, and 65).
Moving the fluorine from the ortho to the meta (63 and 64)
or moving the methyl or chlorine from the ortho to the
para (60 and 61, 17 and 62) reduces affinity at NOP.
The cyclooctylmethyl analog 66 and the tetralinyl analog
67 provide high affinity at NOP and good to excellent
selectivity over MOP, KOP, and DOP, and also produce
an antagonist response. Table 4 shows the functional
activity of the benzhydryl modification analogs when
the nociceptin receptor binding is less than 10 nM. With
the exception of 66 and 67, these compounds in Table 3
display a potent agonist response.
of representative compounds. In general, this modifica-
tion yields high affinity NOP agonists. The 1°-, 2°-,
and 3°-amines, sulfonamides, and ureas are well toler-
ated. A number of these compounds also display good
selectivity over the MOP, KOP, and DOP receptors.
Table 6 shows the functional activity of the benzylic
Table 6. Functional activity of selected benzylic nitrogen modification
analogs
Compound
GTPcS % Stim
at [lM]
Compound
GTPcS % Stim
at [lM]
68
69
70
71
72
95 at 10
23
74
75
76
122 at 10
123 at 10
126 at 10
124 at 10
114 at 10
146 at 10
120 at 10
118 at 10
Additional SAR work on the potent and selective NOP
agonist 17 centers on the benzylic nitrogen modification
of the C-4 phenyl. Table 5 includes the binding affinity

G. D. Ho et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3028–3033
3033
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nitrogen modification analogs. All of these compounds
exhibit a good nociceptin receptor agonist activity.
To investigate the in vivo pharmacology of nociceptin
receptor agonists, selected compounds have been evalu-
ated for their antitussive activity in a capsaicin-induced
guinea pig model.4a,b The most potent antitussive com-
pound in the 4-hydroxy-4-phenyl series is compound
70. Compound 70 exhibits oral antitussive activity with
an ED50 of 0.06 mg/kg at 2 h and 0.15 mg/kg at 6 h.
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In summary, the SAR development of N-benzhydryl
substituted 4-hydroxy-4-phenylpiperidines has identified
a series of 4-[2-(aminomethyl)phenyl]-1-[bis(2-chlor-
ophenyl)methyl]-4-hydroxypiperidine analogs that exhi-
bit enhanced affinity and functional activity and
improved selectivity relative to the lead compound 1.
Compound 70 exhibits an good excellent in vivo efficacy
in the guinea pig model of capsaicin-induced cough.
Acknowledgments
The authors would like to thank Dr. Jesse Wong and his
group for the preparation of intermediates 12 and 16;
Drs. Michael Czarniecki, Ashit Ganguly, John Hey,
John Hunter, John Piwinski, and Catherine Strader
for helpful discussions.
References and notes
1. Please see the preceding paper in this journal.
2. (a) Mollereau, C.; Parmentier, M.; Mailleux, P.;
Butour, J.; Moisand, C.; Chalon, P.; Caput, D.;
5. Fawzi, A. B.; Zhang, H.; Weig, B.; Hawes, B.; Graziano,
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