Cinnamoyl derivatives of 7α-aminomethyl-6,14-endo- ethanotetrahydrothebaine and 7α-aminomethyl-6,14-endo- ethanotetrahydrooripavine and related opioid ligands

Article abstract of DOI:10.1021/jm070255o

A new series of ligands has been synthesized where the cinnamoyl group of the 14-cinnamoylamino morphinones has been introduced to the 7α-substituent of the 6,14-bridged oripavine series. In vitro the compounds were mostly low efficacy partial agonists or

Full text of DOI:10.1021/jm070255o

5176
J. Med. Chem. 2007, 50, 5176-5182
Cinnamoyl Derivatives of 7r-Aminomethyl-6,14-endo-ethanotetrahydrothebaine and
7r-Aminomethyl-6,14-endo-ethanotetrahydrooripavine and Related Opioid Ligands
David Rennison,† Adrian P. Neal,† Gerta Cami-Kobeci,† Mario D. Aceto,‡ Fernando Martinez-Bermejo,† John W. Lewis,† and
Stephen M. Husbands*,†
Department of Pharmacy and Pharmacology, UniVersity of Bath, Bath, BA2 7AY, UK and Department of Pharmacology and Toxicology,
Virginia Commonwealth UniVersity, Richmond, Virginia 23298
ReceiVed March 7, 2007
A new series of ligands has been synthesized where the cinnamoyl group of the 14-cinnamoylamino
morphinones has been introduced to the 7R-substituent of the 6,14-bridged oripavine series. In vitro the
compounds were mostly low efficacy partial agonists or antagonists with some selectivity for the mu opioid
receptor, with evidence of mu efficacy in vivo. The similarity in SAR between these 6,14-bridged oripavines
and the 14-cinnamoylamino series suggests a similar mode of interaction with the mu opioid receptor.
Introduction
corresponding cinnamyl bromide, owing to the predominant
formation of the dialkylated tertiary amine product. Instead a
reductive amination approach was utilized. A two-stage protocol,
treating amines 11 and 12 with the corresponding cinnamalde-
hyde, followed by reduction of the imine intermediate using
sodium borohydride, was employed (Scheme 1).
The 6,14-bridged oripavines with 7R-substituents have been
extensively studied and have yielded the important veterinary
medicines etorphine (1) and diprenorphine (2b) as well as
buprenorphine (2c) which has found use as a clinical analgesic
and more recently as a treatment for opiate abuse and depen-
dence (Chart 1).1 As mu opioid receptor (MOR) antagonists
equivalent to naltrexone,2 â-FNA,3 and clocinnamox (C-CAM,
3a),4 the N-cyclopropylmethylnororipavine series has provided
the hydroxyethyl derivative (2a)5 and the cinnamoylamino-
methyl derivatives (4).6 The latter are, like 3, high potency
irreversible MOR antagonists with no in vivo antinociceptive
activity. The antagonists 2a, 2b, 3, 4 all possess a cyclopropy-
lmethyl group at N17 and in various opioid series it has been
found that replacing this with a methyl group greatly increases
efficacy, particularly at MOR.7 We here report an investigation
of a series of 17-methyl analogues (5, 6) of 4 from which long
acting MOR partial agonists could emerge as alternatives to
buprenorphine in the treatment of opiate abuse and dependence.
Synthesis. 7R-Aminomethyl-6,14-endo-ethanotetrahydrothe-
baine (11) was prepared from the known thebaine adduct (9)8
in three steps (Scheme 1). Treatment of 9 with hydroxylamine
hydrochloride under reflux afforded the oxime, with subsequent
reduction using lithium aluminum hydride leading to amine 10.
Catalytic hydrogenation of the olefin bond gave 7R-amino-
methyl-6,14-endo-ethanotetrahydrothebaine (11) in an overall
yield of 23%. Boron tribromide9-mediated 3-O-demethylation
at room-temperature gave 7R-aminomethyl-6,14-endo-ethan-
otetrahydrooripavine (12).
C7,C8 ring-constrained analogues 18a and 18b were prepared
as depicted in Scheme 2. First, cycloaddition of thebaine (13)
with N-benzylmaleimide gave rise to 14 in quantitative yield
with sequential reduction (to give 15) and debenzylation,
performed under standard hydrogenolysis conditions, affording
16. This latter step proceeded in poor yield and under these
conditions the 6,14-etheno bridge was not reduced. Demethyla-
tion of 16 at C3, was best performed with boron tribromide,
affording 17 in good yield. BBr3 is known to demethylate opioid
ligands at both C3 and C6;9 however, the authors suggested that
selective demethylations at C3 could be achieved with an
aminomethyl group in the 7R-position, which forms a complex
with the boron atom thus blocking the reaction at C-6. It would
appear that the constrained aminomethyl moiety of 16 was
behaving similarly to the nonconstrained example. In a similar
manner to the synthesis of 5 and 6, the secondary amine was
acylated to give rise to 18a and 18b in moderate yield.
Results
In displacement binding assays in recombinant human opioid
receptors in which the displaced radioligands were [3H]DAMGO
(MOR), [3H]U69593 (KOR), and [3H]Cl-DPDPE (DOR),10 the
new ligands (5, 6) showed high affinity for MOR. This was
particularly true for the oripavine derivatives (6) which all had
subnanomolar MOR affinity (Table 1). They had affinity for
KOR and DOR in the nanomolar range resulting in MOR
selectivity which was higher for the unsubstituted cinnamoy-
lamino ligand (6a) than for the substituted analogues (6b-f).
MOR affinity of the thebaine derivatives (5) was lower than
that of the oripavine derivatives (6). The reduction in affinity
was least in the 2′-chloro derivative (6c to 5c; 2.5-fold) and
greatest in the 4′-methyl derivative (6d to 5d; 51-fold).
Reduction in KOR and DOR affinity in the thebaine derivatives
(5) compared to the oripavine derivatives (6) was as great, or
greater, than reduction in MOR affinity so that MOR selectivity
was higher in 5 than in 6. Greatest selectivity was shown by
Acylation of 7R-aminomethyl-6,14-endo-ethanotetrahydrothe-
baine (11) using the appropriate acid chloride gave target
compounds 5a-f, while EDC promoted coupling with the
appropriate acid furnished 5g-i. In the acylation of 7R-
aminomethyl-6,14-endo-ethanotetrahydrooripavine (12) a second
equivalent of the acid chloride was used to afford the bis-
acylated derivative as an intermediate, with subsequent hy-
drolysis giving the desired phenols 6a-f (Scheme 1).
As expected the 7R-cinnamylaminomethyl analogues 7, 8
could not be accessed directly via an alkylation using the
* Author to whom correspondence should be addressed. Tel: (0)1225
383103; Fax: (0)1225 386114; E-mail: prssmah@bath.ac.uk.
† University of Bath.
‡ Virginia Commonwealth University.
10.1021/jm070255o CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/22/2007

Cinnamoyl DeriVatiVes
Chart 1. Structures
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5177
the 4′-nitro thebaine derivative (5f) which was 153-fold selective
for MOR over DOR and 67-fold selective for MOR over KOR
in the binding assays.
the equivalent oripavines for the unsubstituted (5a) and 2′-
substituted derivatives (5b, 5c) but lower for the 4′-substituted
derivatives (5d, 5e, 5f). There was exceptional difference
between the 2′-methyl thebaine derivative (5b; KOR agonist)
and the equivalent oripavine derivative (6b; potent KOR
antagonist).
The in vitro assay used to determine opioid receptor functional
activity was the [35S]GTPγS stimulation assay which, like the
binding assays, was performed on recombinant opioid receptors
transfected into CHO cells.10,11 Agonist efficacy at each opioid
receptor was determined in comparison to the standard selective
agonists DAMGO (MOR), U69593 (KOR), and DPDPE (DOR).
In the MOR assay the oripavine derivatives (6) were potent low
efficacy partial agonists with the exception of the 4′-methyl
derivative (6d) which had very low MOR agonist efficacy
(<20%) and was a potent antagonist of DAMGO (Table 2).
The oripavine derivatives (6) were also KOR and DOR partial
agonists of lower potency, in keeping with their OR binding
affinities. The thebaine derivatives (5) showed greater potency
as MOR partial agonists than as KOR and DOR partial agonists,
though selectivity for MOR was less impressive than in the
binding assays.
The effect of replacing the amide carbonyl by methylene was
investigated for the unsubstituted and 4′-chloro derivatives. In
opioid receptor binding (Table 1) there was no great difference
between the two series, but the amines (7, 8) generally had lower
affinity than the equivalent amides (5, 6). The most significant
feature in the [35S]GTPγS assays (Table 2) was the higher MOR
and KOR efficacy of the amine derivatives (7a, 7b; 8a, 8b)
when compared to the equivalent amides (5a, 5e; 6a, 6e).
Binding affinities for the conformationally constrained ana-
logues (18a, 18b) were quite similar to those of the equivalent
aminomethyl derivatives (6b, 6d) (Table 1). In the functional
assays (Table 2) 18a and 18b were moderately potent partial
agonists for all three OR with no particular selectivity. The main
differences from the equivalent aminomethyl derivatives (6b,
6d) were in the KOR efficacy of the 2′-methyl-substituted
ligands and in MOR efficacy of the 4′-methyl derivatives. In
both cases the constrained analogues had substantially higher
efficacy.
There was no great difference in MOR efficacy between the
thebaine derivatives (5) and the equivalent oripavine derivatives
(6) in the [35S]GTPγS assays, but the potency of the thebaine-
derived ligands was substantially lower (Table 2). KOR efficacy
in the thebaine derivatives was higher than KOR efficacy in

5178 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Rennison et al.
Scheme 1a
a Reagents and conditions: (i) NH2OH·HCl, EtOH/H2O (1:1), reflux, 6 h, 78%; (ii) LiAlH4, THF, reflux, overnight, 61%; (iii) H2, Pd-C, EtOH, 50 °C,
40 psi, overnight, 60%; (iv) BBr3, DCM, r.t., 0.25 h, 65%; (v) acid chloride, NEt3, DCM, r.t., overnight; or acid, EDC, HOBt, DCM, r.t., overnight (vi);
K2CO3, MeOH/H2O (9:1), r.t., overnight; (vii) cinnamaldehyde, DCM, r.t., overnight, then NaBH4, MeOH, r.t., 3 h.
Scheme 2a
a Reagents and conditions: (i) N-benzylmaleimide, toluene, reflux, 18 h, quantitative; (ii) LiAlH4, THF, reflux, 16 h, 74%; (iii) 10% Pd/C, EtOH, HCl
(concd), H2 at 40 psi, 5 days, 22%; (iv) BBr3, DCM, 15 min, 72%; (v) acid chloride, NEt3, DCM, r.t., overnight.
Two of the new oripavine derivatives (6b, 6d) were selected
for evaluation in mouse antinociceptive assays (Table 3). 6b in
particular had a profile in [35S]GTPγS assays similar to that of
buprenorphine, i.e., moderate partial agonist at MOR and
antagonist at KOR.7 There was a difference at DOR where 6b
was a partial agonist and buprenorphine an antagonist,7 but this
was perceived not to be an important difference. Though no
qualitative difference of antinociceptive effect between 6b and
6d was found (Table 3), there was a potency difference with
the 2′-CH3 (6b) derivative having 2-4-fold greater potency than
the 4′-CH3 (6d) derivative. Neither 6b nor 6d showed any
antagonism of morphine when administered 30 min before the
agonist in the tail flick assay (data not shown) whereas
buprenorphine had AD50 1.0 (0.3-3.3) mg/kg in this assay.12
The substantial in vivo agonist effects of 6d and the lack of
demonstrable MOR antagonist effects is in contrast to the lack
of any antinociceptive effect of the equivalent N-cyclopropyl-
methyl (N-CPM) derivative (4c) which is a powerful pseudoir-
reversible MOR antagonist.6 Loss of MOR efficacy when N-Me
is replaced by N-CPM is normal SAR in epoxymorphinan series
of opioids.7,13
6b was further evaluated to determine duration of action in
the mouse tail flick assay. An ED80 dose (3 mg/kg, s.c.) proved
not to be long-acting with a duration of less than 2 h (Table 4).
This is in contrast to the equivalent 14â-cinnamoylamino
morphinone (20a) for which an ED80 dose had, in the same
assay, a much longer duration of action, retaining 30% of its
activity at 3 h and only becoming inactive at around 8 h.19 At

Cinnamoyl DeriVatiVes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5179
Table 1. Binding Affinities of 7R-Cinnamoylamino- and 7R-Cinnamylamino-6,14-endo-ethanotetrahydrothebaine Derivatives and Corresponding
Oripavine Derivatives to Cloned Human Opioid Receptors Transfected into Chinese Hamster Ovary (CHO) Cellsa
Ki (nM)
ligand
R
R′
MOR
KOR
DOR
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
1.69 ( 0.34
0.74 ( 0.20
0.63 ( 0.17
11.8 ( 2.3
2.61 ( 0.18
0.87 ( 0.07
2.96 ( 0.91
1.98 ( 0.20
12.8 ( 3.24
0.25 ( 0.04
0.14 ( 0.03
0.25 ( 0.07
0.23 ( 0.01
0.18 ( 0.01
0.19 ( 0.03
11.3 ( 0.14
34.2 ( 1.65
0.39 ( 0.01
0.68 ( 0.02
0.22 ( 0.0
0.48 ( 0.14
0.68 ( 0.11
0.60 ( 0.01
0.15 ( 0.005
1.5 ( 0.8
23.7 ( 5.8
21.0 ( 8.8
22.2 ( 6.2
159 ( 54.0
155 ( 20.8
58 ( 5.3
86.4 ( 16.4
65.7 ( 23.0
94.1 ( 31.9
246 ( 88
2-CH3
2-Cl
4-CH3
4-Cl
4-NO2
2- NO2
2- OCH3
4- OCH3
H
2-CH3
2-Cl
4-CH3
4-Cl
4-NO2
H
289 ( 105
133 ( 2.3
29.8 ( 1.91
44.7 ( 2.74
109 ( 7.41
5.30 ( 0.47
1.82 ( 0.06
1.64 ( 0.12
3.11 ( 0.27
1.85 ( 0.23
1.72 ( 0.04
26.4 ( 2.6
67.9 ( 19.7
6.60 ( 0.86
9.95 ( 2.03
0.52 ( 0.17
1.41 ( 0.22
2.5 ( 0.32
6.4 ( 2.0
111 ( 0.40
87.9 ( 7.0
322 ( 37.4
11.1 ( 0.46
3.41 ( 0.70
7.59 ( 0.80
6.53 ( 1.84
8.0 ( 0.42
5.38 ( 0.4
395 ( 100
741.55 ( 192
38.6 ( 4.39
60.3 ( 12.8
2.36 ( 0.61
4.83 ( 0.81
0.58 ( 0.08
1.0 ( 0.04
0.08 ( 0.02
4.5 ( 0.4
H
H
H
H
H
7a
7b
8a
8b
18a
18b
CH3
CH3
H
H
H
4-Cl
H
4-Cl
2-CH3
4-CH3
2-Cl
4-Cl
2-Cl
-
H
19bb
CH3
CH3
H
-
-
19db
20b
0.54 ( 0.20
0.8 ( 0.09
0.40 ( 0.10
46.9 ( 14.5
buprenorphine
naltrexone
morphine
-
-
0.20 ( 0.01
1.1 ( 0.05
10.8 ( 3.00
140 ( 1.5
-
a Ki (nM) versus [3H]DAMGO (mu), [3H]U69593 (kappa), and [3H]DPDPE (delta). Mean of two experiments, each carried out in triplicate. b Data from
Nieland et al.13 c All data supplied by NIDA Addiction Treatment Discovery Program.
Table 2. Functional Activity at Opioid Receptors from Stimulation of [35S]GTPγS Binding
EC50 (nM): % stimulation
ligand
R
R′
MOR
KOR
DOR
5a
5b
5c
5d
5e
5f
5g
5h
5i
6a
6b
6c
6d
6e
6f
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
41.5 ( 9.7; 34
15.1 ( 3.6; 52
10.6 ( 1.8; 47
47.4 ( 13; ANT
32.3 ( 9.0; ANT
26.0 ( 1.25; 24
14.3 ( 1.28; 26
11.7 ( 0.88; 62
74.2 ( 4.17; 27
3.12 ( 1.2; 34
0.25 ( 0.04; 44
0.30 ( 0.08; 38
0.33 ( 0.02; ANT
2.46 ( 0.86; 25
1.30 ( 0.32; 32
139 ( 17; 69
131 ( 18; 51
74.4 ( 18; 80
56.7 ( 12; 84
290 ( 4.8; 27
196 ( 5.7; ANT
133 ( 25; 22
160 ( 2.5; 74
85.3 ( 22.3; 87
106 ( 14; 77
ND
2-CH3
2-Cl
4-CH3
4-Cl
4-NO2
2- NO2
2-OCH3
4-OCH3
H
2-CH3
2-Cl
4-CH3
4-Cl
4-NO2
H
ND
214 ( 35; 90
216 ( 18.8; 58
164 ( 45.2; 64
ND
59.2 ( 13; 36
7.23 ( 0.78; 63
3.36 ( 0.18; 60
15.9 ( 0.91; 51
35.4 ( 0.03; 63
11.3 ( 0.48; 84
ND
285 ( 19.3; 23
159 ( 7.11; 16
680 ( 115; 52
41.7 ( 2.6; 26
4.02 ( 0.50; ANT
3.52 ( 0.09; 40
9.88 ( 4.4; 43
8.62 ( 0.04; 36
7.49 ( 1.4; 43
106 ( 34; 79
H
H
H
H
H
7a
7b
8a
8b
18a
18b
CH3
CH3
H
H
H
4-Cl
H
149 ( 29; 34
233 ( 77; 75
ND
5.51 ( 1.35; 93
5.37 ( 0.41; 67
2.59 ( 0.46; 68
3.10 ( 0.34; 48
0.50 ( 0.20; 108
0.90 ( 0.45; 28
0.04 ( 0.005; 126
14.8 ( 3; 18
1.78 ( 0.47; 88
14.2 ( 3.7; 24
3.95 ( 0.88; 88
3.33 ( 0.22; 75
8.5 ( 1.6; 78
26.2 ( 6.4; 33
62.5 ( 11; 39
1.80 ( 0.07; 54
14.4 ( 0.38; 70
2.2 ( 0.95; 110
5.0 ( 1.2; 50
0.10 ( 0.005; 115
ND
4-Cl
2-CH3
4-CH3
2-Cl
4-Cl
2-Cl
-
H
19bb
CH3
CH3
H
-
-
19db
35 ( 11; 26
0.10 ( 0.03; 59
> 10000; 0
1.9 ( 0.16; ANT
484 ( 213; 62
20bb
buprenorphine
naltrexone
morphine
-
-
0.59 ( 0.04; ANT
15.6 ( 0.5; 93
5.4 ( 0.75; ANT
316 ( 4.9; 103
-
a Percent maximal stimulation with respect to the standard agonists DAMGO (mu), U69593 (kappa), and DPDPE (delta). ANT indicates antagonist
activity (Ke/nM) versus DAMGO, U69593, and DPDPE. Values are the mean of five or six experiments. ND indicates not determined. b Data from Nieland
et al.13 c All data supplied by NIDA Addiction Treatment Discovery Program.
105 min an ED80 dose of 6b caused no antagonism of
morphine’s actions in the tail flick assay (data not shown).
thebaine and oripavine derivatives (5, 6) with the equivalent
14-cinnamoylamino codeinone and morphinone derivatives (19,
20). Of particular interest was the effect on MOR efficacy in
the in vitro [35S]GTPγS assays of orientation of methyl, chloro,
and nitro substituents in the cinnamoyl aromatic ring. The 2′-
methyl and 2′-chloro thebaine derivatives (5b, 5c) clearly
Discussion
The primary objective of the study was to compare structure-
activity relationships (SAR) for 7R-cinnamoylaminomethyl-

5180 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Table 3. Antinociceptive Potencies of 6b and 6da
Rennison et al.
phenylquinone
tail flick ED50
(mg/ kg)
hot plate ED50
(mg/ kg)
writhing ED50
(mg/kg)
ligand
6b
6d
1.76 (1.48-2.11)
6.37 (2.57-15.80)
0.4 (0.09-0.23)
5.8 (5.7-5.9)
1.00 (0.58-1.75)
2.28 (1.34-3.88)
0.035 (0.028-0.045)
0.98 (0.83-1.1)
0.63 (0.44-0.90)
2.70 (1.74-4.20)
0.016 (0.005-0.042)
0.23 (0.20-0.25)
buprenorphine
morphine
a ED50 (95% confidence limits). Assays were performed by the Drug Evaluation Committee (DEC) of the College on Problems of Drug Dependence
(CPDD). Full experimental details for these methods are given in ref 18.
stimuli.15 No MOR antagonism was observed in the tail flick
Table 4. Duration of Action of an ED80 Dose of 6b in the Mouse Tail
Flick Assaya
assay using the standard protocol18 where the test ligand is
minutes
% MPE ( SEM
administered just prior to morphine, nor did 6b act as a delayed
antagonist once its agonist effects had diminished. Thus for 6d
there was substantial disparity between its MOR profile in vitro
and in vivo. In the [35S]GTPγS assay it was a potent MOR
antagonist without agonist activity whereas in vivo it was a quite
potent antinociceptive agent suggesting MOR efficacy equiva-
lent to morphine. This kind of disparity has been found
previously in the 14-cinnamoylamino series (19-24) and related
to the lipophilicity of the side chain and its effect on the kinetics
of MOR binding.13,14 The predominant MOR agonism observed
after peripheral administration in vivo would result from there
being insufficient brain concentrations to effect significant
receptor blockade. In vitro the test ligand is present in sufficient
concentration to bind pseudoirreversibly via the lipophilic side
chain so that its efficacy appears to be quite low.
20
40
60
83 ( 9.2
78 ( 11
57 ( 12
35 ( 7.6
31 ( 9.2
7.0 ( 5.1
2.0 ( 2.6
90
105
120
150
a Full experimental details for these methods are given in ref 18.
showed higher MOR and KOR efficacy than the 4′-substituted
isomers (5d, 5e) with the unsubstituted derivative (5a) coming
in between. In this regard, the SAR for the new cinnamoylamino
derivatives is similar to the SAR for the equivalent 14â-
cinamoylamino-7,8-dihydrocodeinones (19b, 19d; Table 2). In
the thebaine series we were also able to compare the 2′-nitro-
and 4′-nitrocinnamoyl derivatives (5g, 5f). There was little
difference in MOR and KOR efficacy and potency between 5g
and 5f in contrast to the differences seen between the 2′- and
4′-chloro and -methyl thebaine derivatives (5b, 5c, 5d, 5e). This
difference of effect of substituent orientation was also seen in
the 14-cinnamoylamino series where the 4′-nitro derivative (3b)
had greater MOR efficacy and potency in vivo than the 2′-nitro
derivative (3c).13
Though the 2′-substituted oripavine derivatives (6b, 6c) had
higher MOR efficacy in vitro than the 4′-substituted isomers
(6d, 6e), the differences were less marked than between the
equivalent thebaine derivatives (5b, 5c, 5d, 5e) and even less
impressive when compared to the 14-cinnamoylamino deriva-
tives (19b, 19d). Despite these differences and the lower binding
affinity and in vitro efficacy and potency of the thebaine and
oripavine derivatives (5, 6) when compared to the dihydroco-
deinones (19) and dihydromorphinones (20), there is sufficient
similarity of SAR between the series to make the general
conclusion that the cinnamoyl aromatic rings in the 7R-position
of the new series and the 14â-position of the codeinones and
morphinones are also able to interact with MOR and KOR in a
similar if not identical way.
The effects of replacing the amide carbonyl by methylene
(in structures 7, 8) and in constraining the amine group in a
pyrrolidine ring (in structures 18) were not dramatic, but they
generally showed higher MOR and KOR efficacy in [35S]GTPγS
assays than the unconstrained amides (5, 6). This is in contrast
with SAR in series of 14-amino-17-cyclopropylmethyl-7,8-
dihydromorphinone derivatives (21-24) where over a range of
side chain structures there was no significant difference in MOR
efficacy in [35S]GTPγS assays between the amide (e.g., 21, 22)
and equivalent amine (23, 24) side-chain structures.14
In vivo evaluation of 6b and 6d in mouse antinociceptive
tests revealed them to be reasonably potent in assays using both
thermal (tail flick and hot plate) and chemical (phenylquinone
writhing) nociceptors. This suggests they have fairly high MOR
efficacy since only MOR agonists respond well to thermal
The lack of an extended duration of action for 6b in the tail
flick assay is in contrast to that reported for 20a, appearing to
confirm the conclusions drawn from the in vitro assays that
suggest a similar but nonidentical mode of binding to the
receptor for the two series.
Experimental Section
Proton and carbon-13 nuclear magnetic resonance (NMR) spectra
were obtained on a JEOL JNM-GX FT 300 MHz spectrometer.
Chemical shifts (δ), with tetramethylsilane as a standard, are
measured in parts per million (ppm) and coupling constants in hertz.
Mass spectra were recorded on Fisons Autospectrometer using
electron impac. Infra red (IR) spectra were obtained using a Perkin-
Elmer 881 spectrometer. Microanalysis were obtained from a Carlo
Erba EA 1108 analyzer, and the results were within (0.4% of the
theoretical values.
General Procedure A. A suspension of oxalyl chloride (8.8
equiv) and the corresponding carboxylic acid (1.1 equiv) in
anhydrous toluene was heated at reflux for 1 h. The resulting
solution was allowed to cool to rt and the solvent removed in vacuo.
The residue was redissolved in anhydrous DCM and added dropwise
to a solution of 7R-aminomethyl-6,14-endo-ethanotetrahydrothe-
baine (1.0 equiv) and triethylamine (1.1 equiv) in anhydrous DCM,
and the mixture stirred at rt overnight. The solvent was removed
in vacuo and the crude residue purified by column chromatography
(5% MeOH in DCM). In the acylation of 7R-aminomethyl-6,14-
endo-ethanotetrahydrooripavine, a second equivalent (2.2 equiv)
of the corresponding acid chloride was used to afford the bis-
acylated derivative. The crude residue was redissolved in methanol/
water (9:1) before adding K2CO3 (5.0 equiv), and the mixture was
stirred at room temperature overnight. The solvent was removed
in vacuo and the crude residue purified by column chromatography
(5% MeOH in DCM).
General Procedure B. EDC (2.0 equiv) was added to a stirred
solution of the appropriate cinnamic acid (1.1 equiv) in DCM(5
mL), followed by HOBt (0.5 equiv). The reaction mixture was
stirred for 10 min, and then 7R-aminomethyl-6,14-endo-ethanotet-
rahydrothebaine (11) (1.0 equiv) was added. After 16 h the solvent
was removed in vacuo and the crude residue purified by column
chromatography (DCM:MeOH:NH4OH, 200:10:1) to afford the
desired amides.

Cinnamoyl DeriVatiVes
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21 5181
General Procedure C. To a solution of 7R-aminomethyl-6,14-
endo-ethanotetrahydrothebaine/oripavine (1.0 equiv) in anhydrous
CH2Cl2 was added the corresponding cinnamaldehyde (1.0 equiv),
and the mixture was stirred at rt overnight. The solvent was removed
in vacuo, the crude residue redissolved in MeOH and cooled to
0 °C, and sodium borohydride (3 equiv) added slowly, with further
stirring for 3 h. The reaction was quenched through the addition of
HCl (1 N), basified with NH3 solution and extracted with DCM.
The combined organic phases were washed with water and dried
over MgSO4, and the solvent was removed in vacuo. The crude
residue was purified by column chromatography (5% MeOH in
DCM).
heated at reflux for 16 h. The mixture was then filtered through
celite and the solvent removed in vacuo. The residue was then
purified by gravity elution chromatography (DCM:MeOH, 97:3)
to afford 15 as a white foam (1.52 g, 3.23 mmol, 74%).
[7r,8r:3′,4′]-Pyrrolidino-6,14-endo-ethenotetrahydrothe-
baine (16). To a solution of 15 (1.41 g, 3.0 mmol) in ethanol (10
mL) were added concentrated hydrochloric acid (0.62 mL, 7.52
mmol) and 10% palladium-on-carbon (40% w/w), and the mixture
was hydrogenated (40 psi) at room temperature for 5 d. The mixture
was then filtered through celite and the solvent removed in vacuo
to afford 16 as a white solid (0.24 g, 0.64 mmol, 22%); with 63%
recovery of starting material.
[7r,8r:3′,4′]-Pyrrolidino-6,14-endo-ethenotetrahydrooripa-
vine (17). To a solution of 16 (0.07 g, 0.15 mmol) in anhydrous
DCM (6 mL) at rt under nitrogen was added a solution of boron
tribromide (2.0 mL, 2.0 mmol, 1 M in CH2Cl2), and the mixture
was stirred for 15 min. The mixture was then quenched with ice/
ammonia (50:50) and stirred for further 30 min. The organic layer
was extracted with DCM:MeOH (3:1), the combined organic phases
were washed with brine and dried over anhydrous MgSO4, and the
solvent removed in vacuo. The crude residue was then purified by
gravity elution chromatography (DCM:MeOH:NH4OH, 82.5:15:
2.5) to afford 17 as a light brown foam (40 mg, 0.11 mmol, 72%).
1′-(p-Methylcinnamoyl)-[7r,8r:3′,4′]-pyrrolidino-6,14-endo-
ethenotetrahydrooripavine (18b). 17 was treated as in general
procedure A with purification by gravity elution chromatography
(CHCl3:CH3OH:NH4OH, 94:5:1) and preparative thin layer chro-
matography affording 18b as a white solid (90 mg, 0.18 mmol,
43%). Anal. (HCl) (C32H35N2O4Cl‚CHCl3‚0.25H2O) C, H, N.
7r-(Aminomethyl)-6,14-endo-ethenotetrahydrothebaine (10).
A solution of 98 (3.38 g, 9.21 mmol) and hydroxylamine hydro-
chloride (1.28 g, 18.43 mmol) in EtOH/water (60 mL, 1:1) was
heated at reflux for 6 h. The solvent was removed in vacuo, and
the mixture made basic with aqueous ammonia. The aqueous layer
was extracted with DCM, the combined organic phases were washed
with brine and dried over anhydrous MgSO4, and the solvent was
removed in vacuo to afford the oxime intermediate as a solid
(quant), which was used without further purification. A solution
of the oxime (0.2 g, 0.52 mmol) in anhydrous THF (5 mL) was
added to a slurry of LAH (0.06 g, 1.62 mmol) in anhydrous THF
and the mixture heated at reflux under nitrogen overnight. The
excess LAH was decomposed using sodium sulfate decahydrate,
the mixture filtered through celite, and the solvent removed in vacuo
to afford 10 as a white solid (1.62 g, 4.4 mmol, 48%).
7r-(Aminomethyl)-6,14-endo-ethanotetrahydrothebaine (11).
A solution of 10 (0.16 g, 0.44 mmol) in EtOH (10 mL) was added
to a slurry of 10% palladium-on-carbon (40% w/w) in EtOH (10
mL) and subsequently hydrogenated (40 psi) at 50 °C overnight.
The mixture was then filtered through celite, the solvent removed
in vacuo, and the crude residue purified by gravity elution
chromatography (DCM:MeOH:NH4OH, 83:15:2) to afford 11 as a
white foam (100 mg, 0.27 mmol, 61%).
Acknowledgment. This work was funded through NIDA
grants DA00254 and DA07315 and the in vitro characterization
of compounds carried out through the NIDA Abuse Treatment
Discovery Program (ATDP). The in vivo studies were performed
by DA1-7725.
7r-[(4′-Chlorocinnamoyl)-aminomethyl]-6,14-endo-ethanotet-
rahydrothebaine (5e). 11 was treated with 4′-chlorocinnamoyl
chloride as in general procedure A to afford 5e as a white solid
(147 mg, 0.27 mmol, 76%). Anal. (oxalate) (C33H37N2ClO8·2H2O)
C, H, N.
Supporting Information Available: Full experimental details
including 1H NMR, 13C NMR, mass spectra, and microanalysis data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
7r-(Aminomethyl)-6,14-endo-ethanotetrahydrooripavine (12).
To a solution of 11 (0.07 g, 0.20 mmol) in anhydrous dichlo-
romethane (8 mL) was added a solution of boron tribromide (2.6
mL, 2.6 mmol, 1 M in CH2Cl2), and the mixture was stirred at
room temperature under nitrogen for 15 min. The reaction was
quenched with ice/ammonium hydroxide (1:1) and stirred for a
further 30 min. Following extraction with chloroform/methanol (3:
1), the organic layer was washed with brine and dried (MgSO4)
and the solvent removed in vacuo. Purification by gravity elution
chromatography (DCM:MeOH:NH4OH, 82.5:15:2.5) afforded 12
as a solid (52 mg, 0.14 mmol, 70%).
7r-[(4′-Chlorocinnamoyl)-aminomethyl]-6,14-endo-ethanotet-
rahydrooripavine (6e). 12 was treated with 4′-chlorocinnamoyl
chloride as in general procedure A to afford 6e as a white solid
(76 mg, 0.15 mmol, 43%). Anal. (oxalate) (C32H35N2ClO8·2H2O)
C, H, N.
7r-[(Cinnamyl)-aminomethyl]-6,14-endo-ethanotetrahydro-
oripavine (8a). 12 was treated with cinnamyl bromide as
in general procedure C to afford 8a as a white solid (109 mg,
0.23 mmol, 61%). Anal. (oxalate) (C32H38N2O7. CH2Cl2·H2O) C,
H, N.
1′-Benzyl-2′,5′-dioxo-[7r,8r:3′,4′]-pyrrolidino-6,14-endo-
ethenotetrahydrothebaine (14). A mixture of thebaine (13) (1.6
g, 5.1 mmol) and N-benzylmaleimide (1.4 g, 7.7 mmol) in toluene
(30 mL) was heated at reflux for 18 h. The solvent was removed
in vacuo to afford 14 as an orange solid (quant), which was used
without further purification.
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