Synthesis and biological evaluation of 14-alkoxymorphinans. 22. Influence of the 14-alkoxy group and the substitution in position 5 in 14-alkoxymorphinan-6-ones on in vitro and in vivo activities

Article abstract of DOI:10.1021/jm040894o

Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-one derivatives were synthesized and biologically evaluated. Compounds 6-9 and 11 displayed affinities in the subnanomolar range to μ opioid receptors which were comparabl

Full text of DOI:10.1021/jm040894o

3372
J. Med. Chem. 2005, 48, 3372-3378
Synthesis and Biological Evaluation of 14-Alkoxymorphinans. 22.1 Influence of
the 14-Alkoxy Group and the Substitution in Position 5 in
14-Alkoxymorphinan-6-ones on in Vitro and in Vivo Activities
Roberta Lattanzi,† Mariana Spetea,‡,§ Falko Schu¨llner,‡ Silvia B. Rief,‡ Roland Krassnig,‡ Lucia Negri,*,† and
Helmut Schmidhammer*,‡
Department of Human Physiology and Pharmacology, University ‘La Sapienza’, P.le Aldo Moro, 5, I-00185 Rome, Italy,
Department of Pharmaceutical Chemistry, Institute of Pharmacy and Center for Molecular Biosciences Innsbruck,
University of Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria, and Department of Pharmacology and Toxicology,
Institute of Pharmacy, University of Innsbruck, Peter-Mayr-Strasse 1, A-6020 Insbruck, Austria
Received November 9, 2004
Novel 14-alkoxy-substituted (e.g. allyloxy, benzyloxy, naphthylmethoxy) morphinan-6-one
derivatives were synthesized and biologically evaluated. Compounds 6-9 and 11 displayed
affinities in the subnanomolar range to µ opioid receptors which were comparable to 14-O-
methyloxymorphone (1) and 14-methoxymetopon (3), and higher than oxymorphone (2). Opioid
binding affinity was sensitive to the character and length of the substituent in position 14. In
smooth muscle preparations they behaved as potent agonists. Antinociceptive potencies of
compounds 6-11 in the hot-plate test after sc administration in mice were considerably greater
than the potency of morphine. In the colonic propulsion test, the most potent analgesic compound
7 showed negligible constipating activity at the analgesic dose. These findings provide further
evidence that the nature of the substituent at position 14 has a major impact on the abilities
of morphinans to interact with opioid receptors. Introduction of a 5-methyl group has no
significant effect on in vitro biological activities, but resulted in decreased antinociceptive
potency.
Introduction
Morphinans play an important role among therapeu-
tically valuable opioids. They include powerful pain
relieving agents such as naturally occurring alkaloids
(e.g. morphine, codeine), semisynthetic derivatives (e.g.
oxycodone, oxymorphone, buprenorphine), and synthetic
analogues (e.g. levorphanol, butorphanol). The oxymor-
phone derivatives naloxone and naltrexone are clinically
useful opioid antagonists. Naloxone reverses the poten-
tially lethal respiratory depression caused by neurolept
analgesia or opioid overdosage. Naltrexone is being used
for maintenance of former opioid addicts after narcotic
withdrawal and for the treatment of alcoholism.2
Introduction of a 14-alkoxy group into N-methylmor-
phinan-6-ones was described to significantly increase
the antinociceptive potency.2 Thus, 14-O-methyloxy-
morphone (compound 1; Figure 1) was found to possess
ca. 40-fold higher antinociceptive potency than its 14-
hydroxy counterpart oxymorphone (2).3 The 5-methyl
Figure 1.
analogue of 1, namely 14-methoxymetopon (compound
potency is markedly increased with either spinal or
supraspinal administration, where its analgesic potency
3; Figure 1), also exhibits high antinociceptive potency
which is 24- to 20 000-fold greater than that of morphine
is more than 1 million-fold greater than that of mor-
following systemic administration, depending upon the
phine.8 Moreover, 14-methoxymetopon (3) was reported
analgesic test (hot-plate, tail-flick, or acetic acid writh-
to elicit minimal physical dependence and tolerance
ing test) and the animal species used.4-8 This enhanced
compared to morphine.4 It shows significantly lower
potential to induce respiratory depression, hypotension,
and bradycardia than sufentanil, another highly potent
µ opioid analgesic.9 In addition, the effects of 14-
methoxymetopon on gastrointestinal transit, a potential
measure of the ability of an opioid drug to produce
constipation clinically, were far less pronounced than
those observed with morphine.8 The analogue 14-
* To whom correspondence should be addressed. For L. N.: Phone:
(39) 06-49912490. Fax (39) 06-4450307. E-mail: lucia.negri@uniroma1.it.
For H. S.: Phone (43) 512-5075248. Fax (43) 512-5072940. E-mail:
helmut.schmidhammer@uibk.ac.at.
† University ‘La Sapienza’.
‡ Department of Pharmaceutical Chemistry, University of Inns-
bruck.
§ Department of Pharmacology and Toxicology, University of Inns-
bruck.
10.1021/jm040894o CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/09/2005

14-Alkoxymorphinans
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3373
Scheme 1
Scheme 2
ethoxymetopon (4) was reported to produce a slightly
lower analgesic effect and to have similar low physical
dependence scores and tolerance when compared to 3.4
The 5-demethyl analogue 14-O-methyloxymorphone (1)
shows somewhat higher analgesic potency but more
pronounced physical dependence.3 The 14-phenylpro-
poxy analogue of 14-methoxymetopon (PPOM; com-
pound 5) exhibits an extremely high antinoceptive
potency, which is considerably greater than that of
etorphine in different analgesic tests in mice.10
Scheme 3
Further studies to increase our understanding of the
µ opioid receptor system and its involvement in physi-
ological processes require the development of nonpeptide
ligands with high affinity and increased µ selectivity.
Our approach toward this goal was to modify the
structure and to investigate the structure-activity
relationship of the newly developed compounds belong-
ing to the 14-alkoxymorphinan-6-one series. In the
present study, we mainly assessed the character and
length of the substituent in position 14 on opioid affinity
and selectivity. Furthermore, we investigated the influ-
ence of selected substitutents in position 14 on in vitro
agonist activity, antinociceptive potency and inhibition
of gastrointestinal motility. We have synthesized N-me-
thylmorphinan-6-ones substituted in position 14 with
allyloxy (6), benzyloxy (7, 8), 1-naphthylmethoxy (9),
and 2,6-dichlorobenzyloxy (10) (Figure 1). In addition,
the 14-ethoxy-substituted N-(2-phenlyethyl)morphinan-
6-one 11 was prepared to investigate the influence of a
N-phenylethyl group in this class of compounds. More-
over, the effect of a methyl group in position 5 on in
vitro and in vivo activities was examined.
14-hydroxy-5-methylcodeinone (19)11 employing a dif-
ferent route as compared to the synthesis of compound
7 (Scheme 2). Thus, compound 19 was first 3-O-
demethylated using 48% HBr solution to give phenol
20 which was 3,14-bis-O-benzylated to afford compound
21. The 3-O-benzyl protecting group was removed by
catalytic hydrogenation over Pd/C to yield compound 8.
The synthesis of compound 9 was accomplished start-
ing from 3-O-benzylated 7,8-dehydromorphinan 22,12
which was treated with 1-bromomethylnaphthalene in
DMF in the presence of NaH to give compound 23.
Catalytic hydrogenation over Pd/C yielded 14-O-(1-
naphthylmethyl)oxymorphone (9) (Scheme 2).
The N-phenylethyl derivative 11 was prepared from
14-ethoxy-substituted N-nor morphinan 2413 by N-
alkylation with 2-phenylethyl bromide (24) followed by
ether cleavage of 25 with 48% HBr.
Results and Discussion
Chemistry
Opioid Receptor Binding Affinities. Opioid recep-
tor binding affinities of compounds 6-11 were deter-
mined using previously described procedures.14 The
binding affinities to µ and δ receptors were determined
by inhibition of binding of [3H][D-Ala2,Me-Phe4,Gly-ol5]-
enkephalin ([3H]DAMGO) and [3H][Ile5,6]deltorphin II
to rat brain membranes. The affinities of the compounds
to κ receptors were determined by displacement of [3H]-
U69,593 using guinea pig brain membranes. The µ, δ,
and κ opioid receptor binding affinities expressed as
inhibition constant (Ki) and selectivity ratios for com-
pounds 6-11 and reference compounds are shown in
Table 1.
14-O-Allyloxymorphone (6) was prepared starting
from oxymorphone (2). Prior to 14-O-allylation, the
3-OH and 6-keto groups were protected. First, ketal 12
was formed, which was 3-O-benzylated (13) and further
14-O-allylated with allyl bromide in N,N-dimethylfor-
mamide (DMF) in the presence of NaH as base to give
compound 14. Acid hydrolysis with HCl/MeOH yielded
compound 6 (Scheme 1). The 2,6-dichlorobenzyloxy-
substituted N-methylmorphinan-6-one 10 was synthe-
sized analogously from 3-O-benzylated derivative 13 via
compound 15 (Scheme 1).
14-O-Benzyloxymorphone (7) was synthesized start-
ing from 14-hydroxycodeinone (16), which was 14-O-
benzylated to give compound 17 (Scheme 2). Catalytic
hydrogenation over Pd/C afforded 14-O-benzyloxycodone
(18) which was 3-O-demethylated with BBr3 in CH2Cl2
to yield 7. 14-Benzyloxymetopon (8) was prepared from
As expected and in agreement with the previous
determinations of the positive influence of 14-alkoxy
substituents in morphinan-6-ones,2,3,15 all of the tested
14-alkoxymorphinans, except 10, showed very high µ
opioid receptor affinity, with Ki values ranging between

3374 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Lattanzi et al.
Table 1. Opioid Receptor Binding Affinities and Selectivities of Compounds 6-11 and Reference Compounds
Ki (nM) ( SEM
selectivity ratio
compound
[3H]DAMGO (µ)a
[3H][Ile5,6]deltorphin II (δ)a
[3H]U69,593 (κ)b
δ/µ
κ/µ
6
0.61 ( 0.02
0.12 ( 0.01
0.18 ( 0.01
0.18 ( 0.02
10.3 ( 1.3
0.16 ( 0.02
0.10 ( 0.01
0.15 ( 0.01
0.97 ( 0.05
6.55 ( 0.74
36.0 ( 1.5
2.14 ( 0.13
3.67 ( 0.40
2.92 ( 0.35
152 ( 15
3.14 ( 0.41
4.80 ( 0.22
13.3 ( 0.2
80.5 ( 5.5
217 ( 19
33.8 ( 1.9
1.18 ( 0.11
2.46 ( 0.32
0.92 ( 0.08
33.2 ( 3.6
83.2 ( 5.4
10.2 ( 2.0a
25.2 ( 4.9a
61.6 ( 1.2
113 ( 9a
59
18
20
16
15
20
48
89
83
33
55
10
14
5.1
3.2
520
7
8
9
10
11
1c
3d
102
168
51
oxymorphone (2)
morphined
17
a Rat brain membranes were used. b Guinea pig brain membranes were used. c Data taken from ref 24. d Data taken from ref 23.
0.12 and 0.61 nM (Table 1). Compounds 6-9 and 11
displayed a 10- to 54-fold enhanced affinity to the µ
receptor in comparison to morphine, and comparable µ
affinity to 14-O-methyloxymorphone (1) and 14-meth-
oxymetopon (3). Moreover, they showed higher µ affinity
than oxymorphone (2). Comparing 14-O-methyloxymor-
phone (1) with its 14-hydroxy analogue oxymorphone
(2), it became apparent that a 14-methoxy group in-
creased the affinity to opioid receptors in binding assays,
as reported earlier using [3H]naloxone.3
Following the pattern of structure-activity relation-
ships, compounds 6 and 7 had comparable affinity to
the µ receptor, but different binding affinities to δ and
κ sites. It appears that an allyloxy group in position 14
is not favorable for interaction with δ and κ receptors,
thus leading to an enhancement in µ selectivity. An
examination of the affinities of the 14-arylalkoxy target
compounds revealed that 2,6-dichloro substitution at the
aromatic ring of the benzyloxy group in compound 10
has a detrimental effect on the affinity to all three opioid
receptors compared to the 14-benzyloxy analogue 7
(Table 1). However, a 1-naphthylmethoxy group in
position 14 in compound 9 did not affect the interaction
with µ, δ, and κ receptors, displaying similar binding
affinities as the benzyloxy-substituted counterpart 7. We
have found that in the series of morphinan-6-ones, the
presence of larger groups such as 14-O-phenylpropyl
(e.g. PPOM; compound 5) markedly increases binding
affinities to δ and κ opioid receptors while retaining the
high affinity to the µ receptor.10,16 Our present findings
provide further evidence that opioid binding affinity is
sensitive to the character and length of the substituent
in position 14.
When comparing compounds 1 and 7 to their 5-methyl
analogues 3 and 8, respectively, it became apparent that
the presence of a methyl group in position 5 has no
major effect on µ affinity, while only a slight decrease
in binding to δ and κ receptors was observed. Moreover,
the 14-methoxy-substituted compounds 1 and 3 exhib-
ited higher δ/µ and κ/µ selectivity ratios than the 14-
benzyloxy-substituted 7 and 8, indicating that a 14-
methoxy group is superior to a 14-benzyloxy group
regarding to µ selectivity in this class of compounds
(Table 1).
Derivative 11 exhibited very high affinities to µ and
δ opioid receptors, 0.16 and 3.14 nM, respectively, being
comparable to those of 14-O-methyloxymorphone (1),
but showed about 8-fold reduced affinity to the κ site.
Thus, introduction of a N-phenylethyl group did not
significantly alter the interaction with µ and δ receptors,
but affected binding to the κ receptor.
Table 2. Opioid Agonist Activities of Compounds 6-11 and
Reference Compounds in GPI and MVD Preparations
IC50 (nM) ( SEM
compound
GPI
MVD
IC50 MVD/IC50 GPI
6
17.6 ( 2.1
0.9 ( 0.1
0.5 ( 0.1
0.9 ( 0.1
1000 ( 110
1.9 ( 0.3
2.0 ( 0.3
6.1 ( 0.8
311 ( 29
63.0 ( 9.0
1.5 ( 0.2
2.3 ( 0.3
0.8 ( 0.1
209 ( 25
9.7 ( 1.1
30.5 ( 5.0
24.4 ( 3.1
1600 ( 121
3.6
1.7
4.6
0.9
0.2
5.1
15
7
8
9
10
11
1
3
4.0
5.1
morphine
Table 3. Antinociceptive Potencies in the Hot-Plate Test and
Colonic Bead Expulsion in Mice of Compounds 6-11 and
Reference Compounds
HP,a AD50
CBE,b ED50
ED50
CBE/AD50 HP
compound
(nmol/kg, sc)c
(nmol/kg, sc)c
6
35 (27-46)
9.6 (9.0-10.3)
65 (60-71)
37 (27-51)
27 (25-28)
74 (69-80)
1.1
2.8
1.1
0.8
1.5
1.1
0.4
-
7
8
9
10
11
1
14.4 (14.2-14.6) 11.8 (8.4-12.9)
1640 (1040-2570) 2491 (2487-2494)
109 (81-146)
53 (48-58)
280 (273-285)
121 (100-148)
22 (21-24)
n.t.
3
morphine 6690 (4468-9348) 7622 (6336-9170)
1.1
a HP ) hot-plate test. b CBE ) colonic bead expulsion. c Effec-
tive dose 50% (95% confidence limits).
Biological Activities. Compounds 6-11 were fur-
ther evaluated for the agonist activity in vitro on smooth
muscle preparations and in vivo for the analgesic and
constipating effects. The results of in vitro bioassays
using guinea pig ileum (GPI) and mouse vas deferens
(MVD) preparations17,18 (Table 2) are in qualitative
agreement with the binding data. Antinociceptive po-
tencies of compounds 6-11 after subcutaneous (sc)
administration were assessed in the hot-plate test (HP)
in mice.19
As shown in Table 2, introduction of different sub-
stituents in position 14 in the morphinan-6-ones 6-9
and 11 afforded compounds that are potent agonists in
the GPI (IC50 ) 0.5-17.6 nM) and in the MVD (IC50
)
0.8-63 nM) and elicited analgesic potencies 60- to 700-
fold higher than morphine. The 2,6-dichlorobenzyloxy-
substituted derivative 10 showed a significant decrease
in agonistic activity in the GPI and in analgesic potency
(Tables 2 and 3). Substitution in position 14 with
allyloxy (compound 6) produced about 2- and 8-fold
decrease in potency in the MVD and the GPI, respec-
tively, when compared to the methoxy-substituted de-
rivative 1 (Table 2), but left the analgesic potency

14-Alkoxymorphinans
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3375
unaffected (Table 3). However, the presence of a 14-
benzyloxy group in 7 and a 14-(1-naphthylmethoxy)
substituent in 9 yielded the most potent agonists in the
GPI and MVD, which could be due to their very high
affinities to all three opioid receptors, µ, δ, and κ.
Simultaneous stimulation of the different opioid recep-
tors could cooperate in the inhibition of the electrically
stimulated twitch of the smooth muscle preparations
produced by compounds 7 and 9. Derivatives 7 and 9
also displayed the highest antinociceptive potency being
about 700- and 460-fold, respectively, more potent than
morphine, and about 4- to 5-fold more potent than 14-
O-methyloxymorphone (1) in the hot-plate test in mice
(Table 3). Thus, introduction of a benzyloxy or a 1-naph-
thylmethoxy group compared to a methoxy group in
position 14 leads to increased analgesic potency. In an
earlier study,3 it was shown that introduction of a 14-
methoxy group in oxymorphone markedly enhanced the
antinociceptive potency as assessed in the hot-plate test
in mice after sc administration. Recently, we have
reported that the introduction of a 14-phenylpropoxy
group gives rise to extremely potent analgesics in
morphinan-6-ones having a methyl, cyclopropylmethyl,
or allyl group at the morphinan nitrogen.10,16 Thus, it
became apparent that 14-arylalkoxy substitution in-
creases analgesic potency compared to 14-alkoxymor-
phinans such as 14-O-methyloxymorphone (1).
2,6-Dicholoro substitution at the aromatic ring of the
benzyloxy group in position 14 led to compound 10
which was less potent as agonist in the MVD and in
the GPI, and a weaker analgesic, as compared to the
aromatic unsubstituted analogue 7 (Tables 2 and 3). The
decrease in agonist activity and in antinociceptive
potency of analogue 10 compared to 7 correlates very
well with the decrease in affinities to all three opioid
receptors as determined in binding assays (Table 1).
Methylation in position 5 of compound 1 resulted in
analogue 3 which showed about the same agonist
potency as 1 in the MVD and a 3-fold decrease in the
potency in the GPI. In the case of the 14-benzyloxy-
substituted derivative 7, introduction of a 5-methyl
group resulted in 14-benzyloxymetopon (8) with com-
parable potencies in both smooth muscle preparations,
while a 7-fold decrease in antinociceptive potency of
compound 8 was observed (Tables 2 and 3). A similar
decrease in potency has been detected with compound
3, the 5-methyl analogue of 14-O-methyloxymorphone
(1). This indicates that the presence of a methyl group
in position 5 alters the antinociceptive potency in this
class of compounds, although it does not significantly
affect the in vitro biological activities.
Figure 2. Analgesia versus colonic bead expulsion in mice of
compound 7 and reference compounds.
values ranging between 11.8 and 2491 nmol/kg (Table
3). On the basis of the in vitro biological data, these
compounds show increased interaction with the µ recep-
tor, which can explain the inhibitory effect on colonic
propulsion.
The ratios of ED50 CBE vs AD50 HP were calculated,
and the values around the unit indicate the induction
of constipation at analgesic doses (Table 3). Interest-
ingly, the most potent analgesic compound 7 (ED50 CBE
vs AD50 HP ) 2.8) elicited negligible constipating
activity at the analgesic dose (Figure 2). The 14-
benzyloxy-substituted derivative 7 also appeared to be
2.5-fold less constipating than morphine and about
7-fold less constipating than 14-O-methyloxymorphone
(1) after sc administration in mice. Compounds 6 and
8-11 showed similar constipating potency as morphine,
but were about 1.5- to 3-fold less constipating than the
reference compound 1.
Conclusions
The present study on selected 14-alkoxy-substituted
morphinan-6-ones provides further evidence that the
nature of the substituent at position 14 has a major
impact on the ability of morphinans to interact with
opioid receptors, leading to qualitative and quantitative
differences in biological and pharmacological activities.
Introduction of 14-alkoxy substitutents (e.g. allyloxy,
benzyloxy, 1-naphthylmethoxy) led to compounds with
high binding affinities to the µ receptor and generally
potent agonist activities in smooth muscle preparations.
Antinociceptive evaluation in the hot-plate test after sc
administration in mice revealed that 14-arylalkoxy
substitutents (benzyloxy, 1-naphthylmethoxy) are able
to enhance considerably the antinociceptive potency in
N-methylmorphinan-6-ones. A 14-allyloxy and a N-
phenylethyl substituent had only minor influence on the
analgesic potency. The 14-benzyloxy substitution gave
rise to a compound which showed negligible constipating
activity at the analgesic dose after sc administration.
The 2,6-dichloro substitution of the 14-benzyloxy group
decreased µ affinity, agonist and analgesic potencies.
The presence of a methyl group in position 5 has no
significant effect on µ affinity and in vitro agonist
activities, but resulted in decreased antinociceptive
potency compared to the 5-demethylated derivatives.
Taken together, the results of the present study
indicate that the positions 5 and 14 of N-methylmor-
phinan-6-ones represent critical sites that could be a
trigger to develop new compounds with increased µ
affinity and/or selectivity and potent analgesic drugs
with an improved side effect profile compared to cur-
rently available opioids.
Replacement of the N-methyl group in compound 1
with a N-phenylethyl substituent in 11 left the binding
affinities at µ and δ opioid receptors unchanged, and it
did not significantly alter the in vitro agonist activity
and the in vivo antinociceptive potency (Tables 2 and
3).
It is well-recognized that the µ opioid system plays a
primary role in the inhibitory control of gastrointestinal
(GI) motility, one of the most frequent adverse effects
of opioid analgesics.20 Colonic bead expulsion in mice
(CBI) was used to assess the effect on GI motility after
sc administration.21,21 All tested opioid compounds
produced a dose-related inhibition of CBE with ED50

3376 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
Lattanzi et al.
3-Benzyloxy-14-(2′,6′-dichlorobenzyloxy)-4,5R-epoxy-
17-methylmorphinan-6-spiro-2′-(1,3-dioxolane) (15). Com-
pound 15 was prepared essentially by the procedure described
for the synthesis of compound 14. Yield 15: 48%; mp 114-
115 °C (MeOH). Anal. (C33H33NO5Cl2‚0.2MeOH) C, H, N, Cl.
14-(2′,6′-Dichlorobenzyloxy)-4,5R-epoxy-3-hydroxy-17-
methylmorphinan-6-one Hydrochloride (10‚HCl). 10‚HCl
was prepared essentially by the procedure described for the
synthesis of 6‚HCl. Yield 10‚HCl: 48%; mp 187-189 °C (Et2O).
Anal. (C24H23NO4Cl2‚HCl‚1.3H2O) C, H, N.
14-Benzyloxycodeinone (14-Benzyloxy-4,5R-epoxy-7,8-
didehydro-3-methoxy-17-methylmorphinan-6-one; 17).
NaH (800 mg, 33.33 mmol) (obtained from 1.34 g of a 60% NaH
dispersion in oil by washings with petroleum ether) was added
to a solution of 14-hydroxycodeinone (16) (3.0 g, 9.57 mmol),
in 120 mL of anhydrous DMF under N2 at 0 °C (bath
temperature) while stirring. After 20 min, benzyl bromide (1.71
mL, 14.44 mmol) was added and the resulting mixture was
stirred at room temperature for 3 h. Excess NaH was destroyed
carefully by addition of small pieces of ice, and then the
mixture was diluted with H2O (75 mL) and extracted with CH2-
Cl2 (4 × 30 mL). The combined organic layers were washed
with H2O (3 × 50 mL), dried (Na2SO4), and evaporated to yield
4.28 g of a brownish semicrystalline residue, which was treated
with 3 mL of boiling MeOH to yield 2.07 g (52%) of 17 (mp
Experimental Section
The required reagents as well as anhydrous DMF were
purchased from Fluka, Switzerland, in the highest purities
available. The solvents were distilled before usage. Melting
points were measured using a Kofler melting point microscope
and are uncorrected. IR spectra were recorded with a Mattson
Galaxy Series FTIR 3000 spectrometer (in cm-1). 1H NMR (200
MHz) spectra were recorded using a Varian Gemini 200
spectrometer. Chemical shifts (δ) are reported in ppm (relative
to SiMe4 as internal standard), coupling constants (J) in Hz.
Mass spectra were recorded with a Finnigan Mat SSQ 7000
apparatus. Elemental analyses were performed at the Institute
of Physical Chemistry at the University of Vienna, Austria.
For TLC, POLYGRAM SIL G/UV254 precoated plastic sheets
(Macherey-Nagel, Germany) were used (eluent: CH2Cl2/MeOH/
concentrated NH4OH solution, 90:9:1), and for column chro-
matography, silica gel 60 (230-400 mesh ASTM, Fluka,
Switzerland) was used.
4,5R-Epoxy-3,14-dihydroxy-17-methylmorphinan-6-
spiro-2′-(1,3-dioxolane) (12). A solution of oxymorphone
(7.557 g, 19.76 mmol) and methanesulfonic acid (1.92 mL,
29.64 mmol) in 100 mL of ethylene glycol was stirred under
N2 at 80-90 °C (bath temperature) for 24 h. After addition of
H2O (200 mL) and alkalization with concentrated ammonia,
the mixture was extracted with CH2Cl2 (1 × 60 mL, 2 × 20
mL). The combined organic layers were washed with H2O (2
× 200 mL), dried (Na2SO4), and evaporated to give an oil which
was treated with refluxing MeOH to afford crystalline material
which was recrystallized twice from MeOH to yield 4.89 g
(70%) of 12: mp 252-254 °C. Anal. (C19H23NO5) C, H, N.
3-Benzyloxy-4,5R-epoxy-14-hydroxy-17-methylmorphi-
nan-6-spiro-2′-(1,3-dioxolane) (13). A mixture of 12 (4.5 g,
12.7 mmol), potassium carbonate (6.15 g, 44.45 mmol), benzyl
bromide (1.8 mL, 15.24 mmol), and anhydrous DMF (38 mL)
was stirred at 80-90 °C (bath temperature) for 42 h. The
inorganic material was filtered off, and the filtrate was
acidified with 2 N HCl (225 mL) and extracted with Et2O (3 ×
80 mL). The aqueous phase was alkalized with concentrated
ammonia, extracted with CH2Cl2, washed with H2O (2 × 80
mL) and brine (80 mL), dried (Na2SO4), and evaporated to yield
5.1 g of a brownish oily residue. Purification by column
chromatography (silica gel, CH2Cl2/MeOH/NH4OH 90:9:1)
afforded a yellowish oil (2.34 g, 42%) of 13 which was used for
the next synthetic step.
14-Allyloxy-3-benzyloxy-4,5R-epoxy-17-methylmorphi-
nan-6-spiro-2′-(1,3-dioxolane) (14). NaH (1.22 g, 50.9 mmol)
(obtained from 2.05 g of a 60% NaH dispersion in oil by
washings with petroleum ether) was added to a solution of 13
(2.15 g, 4.94 mmol) in 15 mL of anhydrous DMF under N2 at
0 °C (bath temperature) while stirring. After 20 min, allyl
bromide (0.85 mL, 9.87 mmol) was added and the resulting
mixture was stirred at room temperature for 6 h. Excess NaH
was destroyed carefully by addition of small pieces of ice, and
then the mixture was diluted with H2O (100 mL) and extracted
with CH2Cl2 (4 × 25 mL). The combined organic layers were
washed with H2O (3 × 35 mL) and brine (80 mL), dried (Na2-
SO4), and evaporated to yield 2.63 g (91%) of a reddish oil of
14 which was used without further purification for the next
synthetic step.
170-177 °C).
A small portion was recrystallized from
MeOH: mp 177-182 °C. Anal. (C25H25NO4‚0.3MeOH) C, H,
N.
14-O-Benzyloxycodone (14-Benzyloxy-4,5R-epoxy-3-
methoxy-17-methylmorphinan-6-one; 18). A mixture of 17
(1.0 g, 2.48 mmol), 10% Pd/C catalyst (150 mg), and EtOH (50
mL) was hydrogenated at room temperature and 35 psi for
4.5 h. The catalyst was filtered off, and the filtrate was
evaporated. The crystalline residue (972 mg) was recrystallized
from EtOH to yield 710 mg (72%) of 18: mp 136-140 °C. Anal.
(C25H27NO4) C, H, N.
14-O-Benzyloxymorphone Salicylate (14-Benzyloxy-
4,5R-epoxy-3-hydroxy-17-methylmorphinan-6-one Sali-
cylate; 7‚C7H6O3). To a solution of 18 (1.0 g, 2.47 mmol) in 8
mL of CH2Cl2 was added a 1 M solution of BBr3 in CH2Cl2
(14.8 mL) within 10 min at -15 °C (bath temperature) while
stirring. After 5 min, 20 g of ice and 12 mL of concentrated
ammonia were added and the resulting mixture was stirred
at 0 °C (bath temperature) for 30 min. The organic layer was
separated and the aqueous layer extracted with CH2Cl2 (3 ×
20 mL). The combined organic layers were washed with brine,
dried (Na2SO4), and evaporated to yield 950 mg of a slightly
brown foam which was purified by column chromatography
(silica gel, CH2Cl2/MeOH/NH4OH 90:9:1) to give 383 mg of 7
as a colorless foam which was dissolved in MeOH and
converted into the salicylate (7‚C7H6O3) by addition of salicylic
acid. Yield 374 mg (29%); mp 233-240 °C. Anal. (C24H25NO4‚
C7H6O3) C, H, N.
14-Hydroxy-5-methylmorphinone Hydrobromide (7,8-
Didehydro-4,5R-epoxy-3,14-dihydroxy-5,17-dimethylmor-
phinan-6-one Hydrobromide; 20‚HBr). A solution of 14-
hydroxy-5-methylcodeinone (19)11 (2.7 g, 8.62 mmol) in 48%
HBr solution (15 mL) was refluxed for 20 min. After the
solution was evaporated, the residue (a brownish oil) was
dissolved in MeOH and the solution was evaporated again.
This procedure was repeated, the residue dissolved in a little
MeOH, and Et2O was added dropwise to obtain crystalliza-
tion: 2.06 g (61%) of 20‚HBr was isolated. A small amount
was recrystallized from MeOH/Et2O to give an analytical
sample: mp > 230 °C (dec). Anal. (C18H19NO4‚HBr‚1.0H2O)
C, H, N.
3-O-Benzyl-14-benzyloxy-5-methylmorphinone Hydro-
chloride (3,14-Dibenzyloxy-7,8-didehydro-4,5R-epoxy-5,-
17-dimethylmorphinan-6-one Hydrochloride; 21‚HCl).
NaH (570 mg, 23.75 mmol) (obtained from 950 mg of a 60%
NaH dispersion in oil by washings with petroleum ether) was
added to a solution of 20‚HBr (850 mg, 2.16 mmol) in 25 mL
of anhydrous DMF under N2 at 0 °C (bath temperature) while
stirring. After 20 min, benzyl bromide (0.64 mL, 5.4 mmol)
14-Allyloxy-4,5R-epoxy-3-hydroxy-17-methylmorphinan-
6-one Hydrochloride (6‚HCl). A solution of 14 (2.44 g, 5.13
mmol) in MeOH (30 mL) and concentrated HCl (20 mL) was
refluxed for 25 h and then poured on H2O (15 mL). After
alkalization with concentrated ammonia, the mixture was
extracted with CH2Cl2 (1 × 40 mL, 2 × 15 mL), and the
combined organic layers were washed with H2O (2 × 15 mL)
and brine (15 mL), dried (Na2SO4), and evaporated to give 1.53
g of a brown oil. Purification by column chromatography (silica
gel, CH2Cl2/MeOH/NH4OH 90:9:1) yielded a slightly red foam
(610 mg) which was dissolved in Et2O and treated with HCl/
Et2O to give crystalline material which was recrystallized from
MeOH/Et2O to afford 420 mg (22%) of pure 6‚HCl: mp 186-
188 °C. Anal. (C20H23NO4‚HCl‚1.1H2O) C, H, N.

14-Alkoxymorphinans
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9 3377
was added and the resulting mixture was stirred at room
temperature for 4 h. Excess NaH was destroyed carefully by
addition of small pieces of ice, and then the mixture was
diluted with H2O (100 mL) and extracted with CH2Cl2 (1 ×
150 mL, 2 × 50 mL). The combined organic layers were washed
with H2O (3 × 200 mL), dried (Na2SO4), and evaporated to
yield 1.09 g of a brown oil which was converted into the
hydrochloride salt in anhydrous Et2O by addition of Et2O/HCl
to afford 937 mg (82%) of 21‚HCl: mp 150 °C. Anal. (C32H33-
NO4‚HCl‚1.0H2O) C, H, N Cl.
14-Benzyloxymetopon Hydrochloride (14-Benzyloxy-
4,5R-epoxy-3-hydroxy-5,17-dimethylmorphinan-6-one Hy-
drochloride; 8‚HCl). A mixture of 21‚HCl (850 mg, 1.6
mmol), 10% Pd/C catalyst (250 mg), and MeOH (25 mL) was
hydrogenated at room temperature and 40 psi for 2.5 h. The
catalyst was filtered off, and the filtrate was evaporated. The
residue (680 mg yellowish foam) was crystallized from acetone/
MeOH to yield 520 mg (73%) of colorless 8‚HCl: mp > 215 °C
(dec). Anal. (C25H37NO4‚HCl‚0.8H2O) C, H, N, Cl.
3-O-Benzyl-7,8-didehydro-14-(1-naphthylmethoxy)mor-
phinone Hydrochloride (3-Benzyloxy-7,8-didehydro-4,5R-
epoxy-5,17-dimethyl-14-(1-naphthylmethoxy)morphinan-
6-one Hydrochloride; 23‚HCl). NaH (1.8 g, 75.1 mmol)
(obtained from 3 g of a 60% NaH dispersion in oil by washings
with petroleum ether) was added to a solution of 3-O-benzyl-
14-hydroxymorphinone (22)12 (5.87 g, 15.07 mmol) in 30 mL
of anhydrous DMF under N2 at 0 °C (bath temperature) while
stirring. After 15 min, 1-bromomethylnaphthalene (5.0 g, 2.3
mmol) was added and the resulting mixture was stirred at
room temperature for 90 min. Excess NaH was destroyed
carefully by addition of small pieces of ice, and then the
mixture was diluted with H2O (50 mL) and extracted with CH2-
Cl2 (2 × 60 mL). The combined organic layers were washed
with H2O (2 × 20 mL) and brine (20 mL), dried (Na2SO4), and
evaporated to yield 8.32 g of a slightly orange colored foam
which was purified by column chromatography (silica gel, CH2-
Cl2/MeOH/NH4OH 90:9:1) to afford 2.56 g of a colorless oil. A
solution of this oil in ether was treated with Et2O/HCl to yield
2.47 g (29%) of 23‚HCl: 136-138 °C. Anal. (C35H31NO4‚HCl)
C, H, N, Cl.
14-O-(1-Naphthylmethyl)oxymorphone (4,5R-Epoxy-3-
hydroxy-17-methyl-14-(1-naphthylmethoxy)morphinan-
6-one; 9). A mixture of 23‚HCl (1.0 g, 1.9 mmol), glacial acetic
acid (100 mL), and 10% Pd/C-catalyst (100 mg) was hydroge-
nated at room temperature for 8 h. The catalyst was filtered
off, the filtrate evaporated, and the oily residue purified by
column chromatography (silica gel, CH2Cl2/MeOH/NH4OH 250:
2:0.5) to afford 412 mg of a colorless foam which was crystal-
lized from MeOH to yield 250 mg (30%) of 9: mp 147-149 °C.
Anal. (C28H27NO4‚0.8 MeOH‚0.1CH2Cl2) C, H, N.
4,5R-Epoxy-14-ethoxy-3-methoxy-5-methyl-17-(2-
phenylethyl)morphinan-6-one (25). A mixture of 4,5R-
epoxy-14-ethoxy-3-methoxy-5-methylmorphinan-6-one hydro-
chloride (24‚HCl)13 (3.0 g, 7.88 mmol), potassium carbonate
(3.9 g, 28.2 mmol), 2-phenylethyl bromide (1.41 mL, 10.4
mmol), and anhydrous DMF (20 mL) was stirred at 80 °C (bath
temperature) for 2 h. After addition of H2O (130 mL), the
mixture was extracted with Et2O (3 × 60 mL). The combined
organic layers were washed with H2O (3 × 70 mL), dried over
Na2SO4, and evaporated to give 3.6 g of a yellow oil which was
crystallized from MeOH to yield 2.1 g (70%) of 25: mp 86-89
°C. Anal. (C28H33NO4) C, H, N.
4,5R-Epoxy-14-ethoxy-3-hydroxy-5-methyl-17-(2-
phenylethyl)morphinan-6-one Hydrobromide (11‚HBr).
A solution of 25 (1.5 g, 3.35 mmol) in 48% HBr solution (5
mL) was refluxed for 30 min and then evaporated. The residue
was dissolved in MeOH and again evaporated. This procedure
was repeated twice, and the crystalline residue (1.7 g) was
recrystallized from MeOH to yield 950 mg of 11‚HBr: mp >
270 °C (dec). Anal. (C27H31NO4‚HBr) C, H, N, Br.
0.3-0.5 mg protein as described.14 Rat brain homogenates
were incubated either with [3H]DAMGO (0.5 nM, 45 min, 35
°C) or [3H][Ile5,6]deltorphin II (0.5 nM, 45 min, 35 °C). Guinea
pig brain homogenates were incubated with [3H]U69,593 (1
nM, 30 min, 30 °C). Reactions were terminated by rapid
filtration through Whatman GF/B pretreated with 0.1% poly-
ethyleneimine ([3H]U69,593) or GF/C ([3H]DAMGO and [3H]-
[Ile5,6]deltorphin II) glass fiber filters using a Brandel Cell
Harvester, followed by three washings with 5 mL of ice-cold
50 mM Tris-HCl buffer. Nonspecific binding was defined in
the presence of 10 µM unlabeled naloxone. All experiments
were carried out in duplicate. The values presented are the
mean ( SEM of 3-4 independent experiments. Competition
inhibition constant (Ki) values were calculated with the
GraphPad Prism (version 3.0, San Diego, CA) program.
Bioassays. Preparations of the myenteric plexus longitu-
dinal muscle obtained from the small intestine of male guinea-
pigs and preparations of mouse vas deferens were used for field
stimulation with bipolar rectangular pulses of supramaximal
voltage as described earlier.17,18 The GPI is primarily a µ
receptor preparation, even though the ileum does also contain
κ receptors. In the MVD, the opioid effects are predominantly
mediated through δ receptors, but µ and κ receptors also exist
in the tissue. The agonists were evaluated for their ability to
inhibit the electrically evoked twitch. The results are expressed
as IC50 values obtained from concentration-response curves.
The values presented are the mean ( SEM.
Hot-Plate Test in Mice. Male CD-1 mice (20-25 g) were
housed at 22 ( 2 °C with food and water ad libitum. A
standard light/dark circle was maintained with a time-
regulated light period from 6:00 AM to 6:00 PM. Animals were
used after a minimum of 4 days of acclimatization to the
housing conditions. All experiments were conducted between
9:00 AM and 5:00 PM. The IASP guidelines on ethical
standards for investigations of experimental pain in animals
were followed. Compounds were dissolved in sterile Ringer’s
solution and administered to the mice in a volume of 0.05 mL/
10 g of body weight. Each dose was tested in 10 animals after
subcutaneous (sc) administration. Hot-plate latencies were
determined by placing each mouse on a hot-plate kept at 55
( 1 °C and observing the occurrence of nociceptive responses,
licking of a paw or jumping.17 Each animal served as its own
control. Before drug administration, each animal was tested
and the latency to hot-plate recorded (control latency, CL).
Animals not responding within 3 s were not used. The latency
to hot-plate of each drug injected animal was defined as the
test latency (TL). To avoid tissue damage, animals with a test
latency of more than 12 s (cutoff time) were removed from the
nociceptive stimulus and assigned a TL of 12. For drawing the
dose- and time-response curves, the antinociceptive response
was expressed as MPE, calculated from the following equa-
tion: MPE ) (TL - CL)/(12 - CL) × 100. Each dose was tested
in 10 animals. AD50 was defined as the opioid dose that
produced an analgesic peak effect equal to 50% MPE.
Colonic Propulsion Test. Male CD-1 mice (20-25 g) were
used for the experiments which were performed essentially
as previously described.21,22 Five minutes after sc administra-
tion of the compounds at doses ranging from AD10 to AD80 (AD
) analgesic dose), a single 3 mm glass bead was inserted into
the distal colon of each mouse. The time required for expulsion
of the glass bead was determined for each animal. Inhibition
of colonic propulsion was measured as the increase in mean
expulsion time (MET) of the glass bead and expressed as the
percent of the maximum possible effect (MPE) according to
the formula: MPE ) (METp - METv)/(120 - METv) × 100.
METp is the mean expulsion time in drug treated mice, METv
is that in saline-treated mice (8.0 ( 1.2 min), and 120 is the
cutoff time in minutes. ED50 was defined as the opioid dose
that produced a peak effect equal to 50% MPE.
Acknowledgment. We thank Tasmanian Alkaloids
Pty., Ltd., Westbury, Tasmania, Australia, for the
generous gift of thebaine. We further thank Dr. D.
Rakowitz for performing the mass spectra and Andrea
Opioid Receptor Binding Assays. Membranes were
prepared from Sprague-Dawley rat or guinea pig brains as
previously described.14 Binding experiments were performed
in 50 mM Tris-HCl buffer in a final volume of 1 mL containing

3378 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 9
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Limburg (Lahn), Germany.
Supporting Information Available: Spectroscopic data
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25, and 11 and elemental analyses data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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