Synthesis and structure-activity relationships of a new series of 2α-substituted trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine as μ-selective opioid antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.11.010

Structure-activity relationships at the 2α-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine μ-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl) are tol

Full text of DOI:10.1016/j.bmcl.2005.11.010

Bioorganic & Medicinal Chemistry Letters 16 (2006) 864–868
Synthesis and structure–activity relationships of a new series of
2a-substituted trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine as
l-selective opioid antagonists
Bertrand Le Bourdonnec,a,* Allan J. Goodman,a Mathieu Michaut,a Hai-Fen Ye,a
Thomas M. Graczyk,b Serge Belanger,b Robert N. DeHavenb and Roland E. Dollea
aDepartment of Chemistry, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA
bDepartment of Pharmacology, Adolor Corporation, 700 Pennsylvania Drive, Exton, PA 19341, USA
Received 3 October 2005; revised 2 November 2005; accepted 3 November 2005
Available online 18 November 2005
Abstract—Structure–activity relationships at the 2a-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)
piperidine l-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl)
are tolerated at the 2a-position of the piperidine ring of this series.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The series of trans-3,4-dimethyl-4-(3-hydroxyphe-
nyl)piperidines (Formula A),1 exemplified by the N-
phenethyl derivative 12 (see Table 1), have been widely
investigated as opioid receptor antagonists. These 4-
phenyl piperidine antagonists were structurally unique
since opioid antagonists were generally structural ana-
logs of morphine. Structure–activity relationship
(SAR) in this trans-3,4-dimethyl-4-(3-hydroxyphenyl)-
piperidine series has been focused largely on the substi-
tution of the piperidine nitrogen,2–5 and, more recently,
on modification of the OH phenolic position.6,7
served among all the opioid receptors.8 Earlier studies
demonstrated that both the binding potency and efficacy
of the antagonists of Formula A were directly related to
the structure of the N-substituent, with the most potent
compounds incorporating a lipophilic entity.2 Introduc-
tion of substituents at the a-position of the piperidine
nitrogen of the trans-3,4-dimethyl-4-(3-hydroxyphe-
nyl)piperidine series has not been investigated. We
now wish to report the synthesis, opioid receptor bind-
ing properties, and in vitro functional activity of a series
of 2a-substituted trans-4,5-dimethyl-4-(3-substituted-
phenyl)piperidines.9
OH
The target compounds 2–24 were prepared according to
Schemes 1 and 2. The key step of the chemistry relied on
the addition of Grignard reagents to the nitrone derived
from (+)-4(R)-(3-benzyloxyphenyl)-3(R),4-dimethyl-1-
piperidine (25).10 Oxidation of 25 using sodium tung-
state and hydrogen peroxide provided a mixture of
N
R
A
1
nitrones 26a/26b (1:4 ratio as determined by H NMR)
that could not be separated by column chromatography.
Addition of allylmagnesium chloride to the mixture 26a/
26b provided the hydroxylamine derivative 27 in 56%
isolated yield. The other regio- and stereoisomers (i.e.,
2b, 6a, and 6b), analogs of 27, were detected but were
of insufficient quantity to be isolated in meaningful
amounts. Treatment of 27 with zinc powder in acetic acid
under sonication conditions afforded the 2a-allyl piperi-
dine derivative 28. In order to assign unequivocally the
Virtually all the opioid ligands feature a basic nitrogen,
which is protonated at physiological pH and is thought
to interact with a conserved aspartate residue, located
inside the receptor transmembrane domain and con-
Keywords: Opioid; l; Antagonist.
*
Corresponding author. Tel.: +1 484 595 1061; fax: +1 484 595
1551; e-mail: blebourdonnec@adolor.com
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.11.010

B. Le Bourdonnec et al. / Bioorg. Med. Chem. Lett. 16 (2006) 864–868
865
Table 1. Opioid receptor (l, j, and d) binding data and in vitro antagonist activity (l) of N-phenethyl-trans-4,5-dimethyl-2a-substituted-4-(3-
hydroxyphenyl)piperidines
OH
R
N
Compound
R
H
Ki (l) (nM)a
IC50 (l) (nM)b
Ki (j) (nM)a
Ki (d) (nM)a
1
2
3
1.9
15
2.0
50
17
100
710
33
65
75
90
680
4
5
6
7
20
270
110
780
15
620
120
390
110
>1000
200
120
>1000
580
NH2
O
510
>1000
8
9
190
59
130
130
620
200
>1000
710
N
H
O
N
H
N
10
11
12
13
14
>1000
280
>1000
>1000
280
>1000
290
>1000
260
290
920
800
160
210
790
610
230
360
260
320
a The potencies of the compounds were determined by testing the ability of a range of concentrations of each compound to inhibit the binding of the
non-selective opioid antagonist, [3H]diprenorphine, to cloned human l-, j-, and d-opioid receptors, expressed in separate cell lines. Ki values are
geometric means computed from at least three separate determinations.
b The potencies of the antagonists were assessed by their abilities to inhibit agonist (loperamide)-stimulated [35S]GTPcS binding to membranes
containing the cloned l-opioid receptor.
absolute regio- and stereochemistry of 28, X-ray crystal-
lography was conducted on the piperidine derivative 15,
obtained from 28 by hydrogenation. The crystal struc-
ture of 15,11 shown in Figure 1, indicates that the propyl
side chain is positioned at the 2a-substitution of the
piperidine ring. Condensation of 28 with the desired
aldehydes under reductive amination conditions afforded
the corresponding tertiary amines, which were converted
to the compounds 17, 18, and 20–24 by hydrogenation.
Alternatively, coupling of 28 with the desired acyl chlo-
ride derivatives provided the corresponding amides,
which were converted to the compounds 16, 19, and 4
in two steps. Addition of various Grignard reagents to
the nitrones 26a/26b, followed by de-hydroxylation of
the resulting hydroxylamine derivatives, provided the
corresponding 2a-substituted piperidine derivatives
29a–e, using the reaction conditions similar to the ones
described for the synthesis of 28. The N-phenethyl deriv-
atives 2, 3, 5, 11, and 12 were then obtained from 29a–e
in two or three steps (Scheme 1). Oxidative cleavage of
the olefinic bond of 30 using osmium tetroxide and
sodium periodate provided the aldehyde 31 (Scheme 2).
Treatment of 31 with phenylmagnesium chloride gave
the alcohol 32 (diastereomeric mixture), which was con-
verted to 33 in three steps. Hydrogenation of 33 followed
by borane reduction of the resulting amide provided the
derivative 13. Condensation of 31 with pyrrolidine under
reductive amination conditions afforded the correspond-
ing pyrrolidine derivative, which was converted to the
target compound 10 in four steps. The primary amine
34, obtained from 31 under reductive amination condi-
tions, was converted to the N-phenethyl derivative 7.
Acylation of 7 with acetyl chloride or benzoyl chloride
provided the amides 8 and 9, respectively. Treatment of
31 with ethyltriphenylphosphonium iodide or benzyltri-
phenylphosphonium chloride provided the Wittig

866
B. Le Bourdonnec et al. / Bioorg. Med. Chem. Lett. 16 (2005) 864–868
O
O
O
OH
O
O
a
c
d
b
+
N+
O-
N+
O-
N
H
N
H
N
N
H
OH
28
26b
15
25
26a
27
OH
R2 = H, C2H5, C3H7, C4H9,
C5H11, C6H13, C2H4C6H5
i, d
N
28
R2
j or k, d, h
4, 16-24
R2 = CH3, C6H5, CH2C6H5
OH
O
R1 = C2H5
f, d
e, c
R1
N
26a / 26b
R1
N
H
2, 3, 5, 11, 12
g, d, h
R1 = CH3, CH(CH3)2,
C6H5, CH2C6H5
29a-e
Scheme 1. Reagents and conditions: (a) Na2WO4, H2O2, H2O/CH2Cl2/CH3OH, 0–25 ꢁC, 76%; (b) CH2@CHCH2MgCl, THF, 0–25 ꢁC, 56%; (c) Zn,
CH3CO2H/H2O, sonication, 25 ꢁC, 84–100%; (d) H2, Pd/C, C2H5OH, 25 ꢁC, 26–100%; (e) R1MgCl, THF, 0–25 ꢁC, 18–53%; (f) C6H5CH2CHO,
BH3 Æ C5H5N, C2H5OH, 25 ꢁC, 6%; (g) C6H5CH2COOH, i-Pr2EtN, TBTU, CH3CN, 25 ꢁC, 64–77%; (h) BH3 Æ S(CH3)2, THF, reflux, 33–64%; (i)
R2CHO, BH3 Æ C5H5N, C2H5OH, 25 ꢁC, 53–100%; (j) CH3COCl or C6H5CH2COCl, Et3N, DMAP, CH2Cl2, 61–87%; (k) C6H5CO2H, i-Pr2EtN,
TBTU, CH3CN, 25 ꢁC, 64%.
Table 2. Opioid receptor (l, j, and d) binding data and in vitro antagonist activity (l) of N-substituted-trans-4,5-dimethyl-2a-propyl-4-(3-
hydroxyphenyl)piperidines
OH
N
R
Compound
R
Ki (l) (nM)a
IC50 (l) (nM)b
Ki (j) (nM)a
Ki (d) (nM)a
15
H
560
>1000
690
>1000
16
700
170
360
880
17
18
19
19
520
410
16
170
100
74
220
270
180
>1000
>1000
20
430
320
360
>1000
21
22
23
24
550
380
47
290
210
39
610
570
150
57
>1000
>1000
340
13
9
80
a The potencies of the compounds were determined by testing the ability of a range of concentrations of each compound to inhibit the binding of the
non-selective opioid antagonist, [3H]diprenorphine, to cloned human l-, j-, and d-opioid receptors, expressed in separate cell lines. Ki values are
geometric means computed from at least three separate determinations.
b The potencies of the antagonists were assessed by their abilities to inhibit agonist (loperamide)-stimulated [35S]GTPcS binding to membranes
containing the cloned l-opioid receptor.

B. Le Bourdonnec et al. / Bioorg. Med. Chem. Lett. 16 (2006) 864–868
867
O
O
O
O
O
a
b
O
d-f
c
28
N
N
HO
N
O
N
O
O
O
O
O
O
O
33
32
31
30
g, h
i, e-h
OH
OH
N
N
N
13
10
OH
OH
O
O
j
k, e-h
l
H2N
N
31
R
N
H
N
H2N
N
O
O
7
34
8, 9
OH
O
O
e, f
m
g, h
R
31
N
R
N
R
N
O
O
O
36a, b
6, 14
35a, b
Scheme 2. Reagents and conditions: (a) Boc2O, Et3N, THF, 0–25 ꢁC, 79%; (b) OsO4, NMO, NaIO4, THF/H2O, 25 ꢁC, 87%; (c) C6H5MgCl, THF, 0–
25 ꢁC, 87%; (d) (CH3CO)2O, Et3N, DMAP, CH2Cl2, 0–25 ꢁC, 100%; (e) HCl/dioxane, CH3OH, 25 ꢁC, 75–100%; (f) C6H5CH2CO2H, i-Pr2EtN,
TBTU, CH3CN, 25 ꢁC, 48–73%; (g) H2, Pd/C, C2H5OH, 25 ꢁC, 40–100%; (h) BH3 Æ S(CH3)2, THF, reflux, 5–62%; (i) pyrrolidine, BH3 Æ C5H5N,
C2H5OH, 25 ꢁC, 70%; (j) CH3CO2NH4, NaBH3CN, CH3OH, reflux, 100%; (k) C6H5CH2OCOCl, Et3N, THF, 25 ꢁC, 37%; (l) CH3COCl or
C6H5COCl, Et3N, THF, 0–25 ꢁC, 68–69%; (m) C2H5P(C6H5)3I or C6H5CH2P(C6H5)3Cl, KOt-Bu, THF, C6H6, 25 ꢁC reflux, 62–99%.
products 35a,b (E/Z mixture), which were converted to
the N-phenethyl derivatives 6 and 14, respectively (see
Table 2).
the basis of the structure of 1, the 2a-hydrogen of the
piperidine ring was replaced by various moieties (Table
1) in order to define the SAR at this position. Introduc-
tion of a methyl group at the 2a position of the piperi-
dine ring of 1 (compound 2) resulted in an 8-fold
decrease in l-binding. Changing the methyl group of 2
to an ethyl (compound 3), propyl (compound 4), isopro-
pyl (compound 5), or butyl (compound 6) moiety result-
ed in a further decrease in the affinity toward the l
receptor. Similarly, introduction of additional lipophilic
functionalities (compounds 11–14) or alkyl chain
containing polar substituents (7–10) at the 2a-postion
resulted in a marked decrease in l binding affinity. Inter-
estingly, compound 4, which binds to the l receptor
with a Ki of 20 nM, displayed good in vitro antagonist
activity (IC50(l) = 15 nM). The SAR at the piperidine
Opioid receptor binding data are found in Table 1.12
Compounds 1–24 were tested for their affinities toward
the cloned human l-, d-, and j-opioid receptors as mea-
sured by their abilities to displace [3H]diprenorphine
from its specific binding sites.12 The antagonist poten-
cies of compounds 1–24 are assessed by their abilities
to inhibit agonist (loperamide)-stimulated guanosine
50-O-(3-[35S]thio)triphosphate ([35S]GTPcS) binding to
membranes containing l-opioid receptors.12 The antag-
onist potencies of compounds 1–24 were expressed as
IC50 values. No agonist activity was detectable for
compounds 1–24 at concentrations up to 10 lM. On

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B. Le Bourdonnec et al. / Bioorg. Med. Chem. Lett. 16 (2005) 864–868
References and notes
1. Zimmerman, D. M.; Nickander, R.; Horng, J. S.; Wong,
D. T. Nature 1978, 275, 332.
2. Zimmerman, D. M.; Leander, J. D.; Cantrell, B. E.; Reel,
J. K.; Snoddy, J.; Mendelsohn, L. G.; Johnson, B. G.;
Mitch, C. H. J. Med. Chem. 1993, 36, 2833.
3. Mitch, C. M.; Leander, J. D.; Mendelsohn, L. G.; Shaw,
W. N.; Wong, D. T.; Cantrell, B. E.; Johnson, B. G.; Reel,
J. K.; Snoddy, J. D.; Takemori, A. E.; Zimmerman, D. M.
J. Med. Chem. 1993, 36, 2842.
4. Zimmerman, D. M.; Gidda, J. S.; Cantrell, B. E.; Schoepp,
D. D.; Johnson, B. G.; Leander, J. D. J. Med. Chem. 1994,
37, 2262.
5. Thomas, J. B.; Fall, M. J.; Cooper, J. B.; Rothman, R. B.;
Mascarella, S. W.; Xu, H.; Partilla, J. S.; Dersch, C. M.;
McCullough, K. B.; Cantrell, B. E.; Zimmerman, D. E.;
Carroll, F. I. J. Med. Chem. 1998, 41, 5188.
6. Le Bourdonnec, B.; Belanger, S.; Cassel, J. A.; Stabley, G.
J.; DeHaven, R. N.; Dolle, R. E. Bioorg. Med. Chem. Lett.
2003, 13, 4459.
7. Diaz, N.; Benvenga, M.; Emmerson, P.; Favors, R.;
Mangold, M.; McKizie, J.; Patel, N.; Peters, S.; Quimby,
S.; Shannon, H.; Siegel, M.; Statnick, M.; Thomas, E.;
Woodland, J.; Surface, P.; Mitch, C. Bioorg. Med. Chem.
Lett. 2005, 15, 3844.
8. Aldrich, J. V.. In Wolff, M. E., Ed.; Burgerꢀs Medicinal
Chemistry and Drug Discovery; Wiley: New York, 1996;
Vol. 3, p 321.
9. Goodman, A. J.; Le Bourdonnec, B.; Michaut, M.; Ye, H.
F.; Graczyk, T. M.; Belanger, S.; DeHaven, R. N.; Dolle,
R. E. Abstracts of Papers, 230th National Meeting of the
American Chemical Society, Washington, DC, August
28–September 01, 2005; MEDI 107.
10. Thomas, J. B.; Mascarella, S. W.; Rothman, R. B.;
Partilla, J. S.; Xu, H.; McCullough, K. B.; Dersch, C. M.;
Cantrell, B. E.; Zimmerman, D. M.; Carroll, F. I. J. Med.
Chem. 1998, 41, 1980.
Figure 1. Crystal structure of 15.
nitrogen of 4 was then investigated. It has been previ-
ously determined in the phenolic series that maximum
potency and selectivity for the l-opioid receptor were
achieved when the N-substituent incorporated a lipo-
philic entity (phenyl ring or cyclohexyl) separated from
the piperidine nitrogen by three atoms.2 In this series,
the N-phenpropyl derivative 17 bound with a compara-
ble affinity (Ki = 19 nM) to l-opioid receptors than its
N-phenethyl analog (compound 4). However, the benzyl
derivative 16 binds very weakly to the l-opioid receptor
(Ki = 700 nM). With regard to N-alkylation, increase in
the size of the chain length results in an increase in the
affinity toward the l-opioid receptor. In particular, the
most active compound in this series, the 1-heptyl-2a-
propyl piperidine derivative 24, displayed potent l in
vitro antagonist activity (IC50(l) = 9 nM).
11. Crystal structure data (SR-200307034.02) for 15:
C16H25NO, Mr = 247.38, crystal dimensions 0.40 ·
0.23 · 0.10 mm3, T = 150 K, monoclinic, space group
C2(#5), a = 21.2960 (13), b = 8.7501 (3), c = 25.2605 (15)
3
˚
˚
˚
A, b = 101.101 (3)ꢁ, Z = 12, V = 4619.0 (4) A ,
calcd = 1.067 g cmꢀ3, MoKa radiation (k0 = 0.71073 A),
In summary, we have varied the substituent pattern at
the 2a-position of the piperidine ring of the trans-4,5-di-
methyl-4-(3-hydroxyphenyl)piperidine series and exam-
ined the resultant effects on l-opioid receptor binding
affinity. This study showed that only small linear alkyl
groups (methyl, propyl) are tolerated at the 2a-position
of the piperidine ring of this series. The 2a-substitution
also led to decreased selectivity for l versus d and j
receptors. The highest l in vitro antagonist activity
was observed in the 1-heptyl-2a-propyl piperidine deriv-
ative 24. Further SAR studies are in progress.
q
l = 0.061 mmꢀ1, 2hmax = 50.02ꢁ; of 13643 reflections col-
lected 7383 were independent (Rint = 0:060); refinement
method: full-matrix least squares on F2, 521 refined
parameters, GOF = 1.018, R = 0:049, Rw = 0:098. Full
crystallographic details of 15 have been deposited at the
Cambridge Crystallographic Data Centre and allocated
the deposition number CCDC288363.
12. For a full description of the biological methods, see:
Schlechtingen, G.; DeHaven, R. N.; Daubert, J. D.;
Cassel, J. A.; Chung, N. N.; Schiller, P. W.; Taulane, J. P.;
Goodman, M. J. Med. Chem. 2003, 46, 2104.