Synthesis and biological evaluation of 14-alkoxymorphinans. 18.1 N-substituted 14-phenylpropyloxymorphinan-6-ones with unanticipated agonist properties: Extending the scope of common structure-activity relationships

Article abstract of DOI:10.1021/jm021118o

The synthesis, biological, and pharmacological evaluations of 14β-O-phenylpropyl-substituted morphinan-6-ones are described. The most striking finding of this study was that all of the compounds from the novel series of differently N-substituted 14β-O-phenylpropylmorphinans acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and allyl, which are usually associated with distinct antagonist properties, only agonists were obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of the new ligands were nonselective and exhibited binding affinities in the subnanomolar range at opioid receptors (μ, κ, δ), with the N-propyl derivative 19 displaying the highest affinity for the μ-receptor (K_i = 0.09 nM).

Full text of DOI:10.1021/jm021118o

1758
J . Med. Chem. 2003, 46, 1758-1763
Syn th esis a n d Biologica l Eva lu a tion of 14-Alk oxym or p h in a n s. 18.1 N-Su bstitu ted
14-P h en ylp r op yloxym or p h in a n -6-on es w ith Un a n ticip a ted Agon ist P r op er ties:
Exten d in g th e Scop e of Com m on Str u ctu r e-Activity Rela tion sh ip s
Elisabeth Greiner,§,# Mariana Spetea,§ Roland Krassnig,§ Falko Schu¨llner,§ Mario Aceto,† Louis S. Harris,†
J ohn R. Traynor,‡ J ames H. Woods,‡ Andrew Coop,| and Helmut Schmidhammer*,§
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a,
A-6020 Innsbruck, Austria, Department of Pharmacology and Toxicology, Medical College of Virginia,
Virginia Commonwealth University, Richmond, Virginia 23298-0613, Department of Pharmacology,
University of Michigan Medical School, 1150 W. Medical Center Drive, Ann Arbor, Michigan 48109,
and Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy,
20 N. Pine Street, Baltimore, Maryland 21201
Received December 16, 2002
The synthesis, biological, and pharmacological evaluations of 14â-O-phenylpropyl-substituted
morphinan-6-ones are described. The most striking finding of this study was that all of the
compounds from the novel series of differently N-substituted 14â-O-phenylpropylmorphinans
acted as powerful opioid agonists. Even with N-substituents such as cyclopropylmethyl and
allyl, which are usually associated with distinct antagonist properties, only agonists were
obtained. Compared to morphine, the N-cyclopropylmethyl derivative 15 showed considerably
increased potency in the in vivo assays in mice (600-fold in the tail-flick assay, 60-fold in the
paraphenylquinone writhing test, and 400-fold in the hot-plate assay). Remarkably, most of
the new ligands were nonselective and exhibited binding affinities in the subnanomolar range
at opioid receptors (µ, κ, δ), with the N-propyl derivative 19 displaying the highest affinity for
the µ-receptor (Ki ) 0.09 nM).
In tr od u ction
Established and generally accepted structure-activity
relationship (SAR) models have assigned critical im-
portance in the development of opioid agonist/antagonist
properties of morphinan-6-ones to the N-substituent.2-4
Substituents such as cyclopropylmethyl (CPM) or allyl
on the nitrogen have been commonly associated with
F igu r e 1.
an antagonist character in this series of opioids.3 While
14-methoxy-N-methylmorphinan-6-ones (Figure 1) such
of any influence of the C14-O substituent in modulating
as 14-O-methyloxymorphone5,6 (1) and 14-methoxy-
the agonist and antagonist profile of morphinan-6-
metopon7-11 (2) are known to act as agonists at the
ones.12,15
µ-opioid receptor, the replacement of the N-methyl
On the basis of these findings and also from the fact
group by an allyl or a CPM group typically results in a
that the introduction of a 14-alkoxy group not only
complete loss of agonist activity, thus leading to pure
usually markedly increases the affinity to opioid recep-
tors but also considerably enhances the antinociceptive
potency of N-methyl-6-ketomorphinans,5 we have de-
antagonists. Well-known examples are the nonselective
opioid receptor antagonists naloxone (3), naltrexone (4)
(Figure 1), and their 14-O-methyl and 14-O-ethyl
derivatives.4,5,12-14 In addition, there is no evidence for
an increase of agonist activity upon methylation or
ethylation of the C14-O.12 In agreement with these
results, the introduction of methyl and ethyl groups at
the C14-O in morphinan derivatives was described as
slightly enhancing the antagonist properties of the
compounds. Thus, there is only some minor indication
cided to prepare several N-substituted 14â-phenylpro-
pyloxymorphinan derivatives. In an effort to develop
new partial opioid agonists that would interact with the
µ-opioid receptor and hence might be subject to lesser
side effects, we undertook the synthesis of this series.
Furthermore, we were also interested in replacing the
substitutent on the nitrogen with substituents that
usually produce pure, potent antagonists, e.g., allyl or
CPM, in order to increase the lipophilicity above the
level of their analogues naloxone and naltrexone. Since
opioid antagonists are used in the treatment of drug
abuse, enhanced lipophilic properties would broaden
their therapeutic scope, e.g., use in transdermal sys-
tems. The latter is known to be advantageous with
regard to patients’ compliance to the therapy and thus
possibly to increase the success of the treatment.
* To whom correspondence should be addressed. Phone: (43) 512-
507-5248. Fax: (43) 512-507-2940. E-mail: Helmut.Schmidhammer@
uibk.ac.at.
§ University of Innsbruck.
#
Current address: Laboratory of Medicinal Chemistry, Building 8,
Room B1-21, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, DHHS, Bethesda, MD 20892-
0815.
† Medical College of Virginia.
‡ University of Michigan Medical School.
| University of Maryland School of Pharmacy.
10.1021/jm021118o CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/29/2003

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 9 1759
Sch em e 1a
a
(i) NaH, cinnamyl bromide, DMF; (ii) H2/Pd/C; (iii) 1-chloroethyl chloroformate, NaHCO3, C2H4Cl2, reflux, MeOH, reflux; (iv) RX,
K2CO3, DMF, 80 °C; (v) HBr 48%, reflux; (vi) H2/Pd/C.
Ta ble 1. Chemical Structures of Compounds 9-19
Ta ble 2. Results of in Vitro Radioligand Binding Studies of
Compounds 12-19 in Comparison to 14-Methoxymetopon (2)
and Morphine
selectivity
Ki (nM)
ratio
compd
12
µ
δ
κ
κ/µ
δ/µ
3.80 ( 1.3
1.90 ( 0.4
0.20 ( 0.01
0.34 ( 0.06
0.25 ( 0.07
0.20 ( 0.04
1.10 ( 0.4
0.09 ( 0.05
6.20 ( 0.2 61.4 ( 1.9 16.2
5.40 ( 1.2 1.40 ( 0.7 0.74
0.26 ( 0.07 0.11 ( 0.05 0.55
0.48 ( 0.05 0.41 ( 0.09 1.96
0.46 ( 0.16 0.49 ( 0.25 1.96
0.09 ( 0.02 0.08 ( 0.02 0.40
1.25 ( 0.5 0.60 ( 0.2 0.55
0.93 ( 0.18 0.37 ( 0.17 4.11
1.64
2.84
1.30
1.84
1.84
0.45
1.14
10.3
13
14
15a
16
17
18
19
2
compd
compd
R1
for R2 ) CH3
for R2 ) H
allyl
9
10
11
12
13
14
15
16
17
18
19
CPMa
CBMb
0.023 ( 0.008 40.9 ( 7.4 304 ( 52
13217 1178
17.3
morphinea 6.55 ( 0.74
217 ( 19
113 ( 9
33.1
(()-tetrahydrofurfuryl
2-phenylethyl
propyl
a
Binding data determined in rat brain membranes using
[3H]DAMGO (µ), [3H]Ile5,6deltorphin II (δ), and [3H]U69593 (κ) in
nM.31
a
b
CPM ) cyclopropylmethyl. CBM ) cyclobutylmethyl.
Ch em istr y
the previous determination of the positive influence of
14-alkoxy substituents,4,5 all of the newly synthesized
compounds showed very high opioid receptor affinity.
Among the tested ligands the 3-hydroxy analogues 14-
19 displayed extremely low Ki values in the picomolar
range (Table 2). Only the N-propyl derivative 19 showed
moderate preference for µ over κ and δ receptors (4-fold
and 10-fold, respectively); all other compounds com-
pletely lacked selectivity. Following the pattern of SARs
in 4,5-epoxymorphinans, the presence of a 3-hydroxy
group produces compounds with a much higher level of
opioid potency than in the corresponding 3-methoxy
derivatives, which usually show a significant drop in
affinity and potency.3,18 This also holds true for our
compounds carrying a 3-methoxy group (12, 13). How-
ever, although the opioid receptor affinity of the 3-meth-
oxy derivatives 12 and 13 was considerably lower
compared to that of their corresponding 3-hydroxy
analogues 17 and 18, these compounds still displayed
high affinity for all opioid receptors in the low nano-
molar range (1-60 nM, Table 2).
The target derivatives 9-19 were synthesized from
thebaine following a procedure shown in Scheme 1. 14-
Hydroxycodeinone (5) is readily available from thebaine
by oxidation with performic acid.16 14-O-Alkylation with
cinnamyl bromide in DMF using NaH as a base gave
14-cinnamyloxycodeinone (6). Catalytic hydrogenation
over Pd/C catalyst afforded the corresponding 7,8-
dihydro-14â-phenylpropyloxy derivative 7. N-Demethy-
lation was accomplished by treatment of 7 with 1-chlo-
roethyl chloroformate in 1,2-dichloroethane in the
presence of NaHCO3. Cleavage of the resulting carbam-
ate intermediate to give 8 was performed in refluxing
MeOH. Direct alkylation of the N-nor derivative 8 with
various alkyl halides in DMF using K2CO3 as a base
provided the N-substituted compounds 9-13. 3-O-
Demethylation with 48% HBr solution yielded deriva-
tives 14-18. Further catalytic hydrogenation of 14 over
Pd/C catalyst afforded compound 19 (Table 1).
Resu lts a n d Discu ssion
Op ioid Recep tor Bin d in g. The binding affinities on
compounds 12-19 were determined using a previously
described method.17 As expected and in agreement with
An tin ocicep tive Assa ys. Most surprisingly and in
contrast to published data,3-6,14 all of the compounds
in this series appeared to be very potent opioid receptor

1760 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 9
Greiner et al.
Ta ble 3. Results of the in Vivo Activities of Compounds 12-19 in Comparison to Morphine and 14-Methoxymetopon (2)
ED50 (95% confidence limit) (sc) in mice, mg/kg
compd
12
13
14
15
16
17
18
TFa
PPQb
HPc
0.76 (0.29-1.98)
0.08 (0.05-0.14)
d
0.7 (0.29-1.61)
0.06 (0.02-0.17)
0.006 (0.0027-0.0144)
0.006 (0.003-0.0107)
0.003 (0.0016-0.0062)
0.008 (0.0034-0.0197)
0.007 (0.004-0.014)
0.11 (0.060-0.20)
0.002 (0.0009-0.0027)
0.03 (0.010-0.60)
1.9 (0.89-4.14)
d
0.006 (0.0037-0.0094)
0.002 (0.0011-0.0047)
0.004 (0.0008-0.0172)
0.001 (0.0006-0.003)
0.01 (0.0049-0.0282)
0.002 (0.0008-0.0036)
0.03 (0.010-0.050)
0.85 (0.39-1.86)
0.006 (0.0031-0.0125)
0.0003 (0.00002-0.006)
0.002 (0.0017-0.0041)
0.009 (0.0041-0.027)
0.0009 (0.0005-0.0017)
0.009 (0.003-0.023)
0.40 (0.20-0.80)
19
2
morphine
a
b
d
TF ) tail-flick test. PPQ ) paraphenylquinone writhing test. c HP ) hot-plate test. Inconsistent dose response.
agonists in vivo (Table 3). All of the tested opioid ligands
acted as antinociceptives in the mouse tail-flick test
(TF), and their potency was considerably greater than
that of morphine. In addition, they also displayed very
high antinociceptive potency in the paraphenylquinone
writhing test (PPQ) and hot-plate assay (HP) (Table 3).
Con clu sion s
Our present results on differently N-substituted 14â-
O-phenylpropylmorphinan derivatives provide further
evidence that the nature of the substituent at the
oxygen in position 14 has a major impact on the ability
of the compounds to bind to opioid receptors. These
ligands exhibit significantly increased binding affinities
at all opioid receptors without any specific preference
for any one receptor type. It is remarkable that the
presence of the 14-O-phenylpropyl substituent leads to
an alteration of the pharmacological profile in this class
of compounds. This substituent obviously annuls the
decisive influence of the N-substituent on the determi-
nation of the antagonist properties of the new molecules.
Even with N-substituents that usually produce com-
pounds with distinct antagonist properties (e.g., allyl,
CPM), only agonists were obtained. This discovery
seems to revise the established structure-activity re-
lationships and opens up an entirely new approach to
the development of highly potent opioid agonists with
exceptionally high binding affinities in the series of
morphinan-6-ones.
The results for the N-allyl derivative 14 indicate
distinct opioid agonist properties. Its potency is about
300-fold higher compared to that of morphine in the TF.
The N-CPM analogue 15 is approximately 600 times
more potent than morphine in the TF (ED50 ) 0.003
mg/kg for 15, compared with 1.9 mg/kg for morphine).
The N-cyclobutylmethyl derivative 16 was more than
1300-fold more potent in the PPQ than morphine.
Compound 17, the N-tetrahydrofurfuryl derivative, also
proved to be a very potent agonist (about 850 times more
potent in the HP, 200 times more potent in the PPQ,
and 270-fold more potent in the TF, respectively,
compared to morphine). The antinociceptive activity of
the N-phenethyl derivative 18 was slightly lower com-
pared to that of the other analogues with a 3-hydroxy
group in this series and was only about 17-fold higher
compared to that of morphine in the TF. An N-phenethyl
group was previously described to produce pure agonists
in the series of morphinan-6-ones.3 The N-propyl de-
rivative 19 with the highest affinity of this series for
the µ-opioid receptor was also shown to be an extremely
potent antinociceptive agent. The in vivo assays re-
vealed more than 400 times higher potency than mor-
phine in the PPQ and also in the HP, respectively, and
it was also found to be about 950-fold more potent than
morphine in the TF. Although the tested compounds
from the subset carrying a 3-methoxy group (12, 13)
displayed less pronounced antinociceptive properties
compared to their 3-hydroxy analogues, the potencies
were still notably high. Compound 13, which showed
the lowest opioid receptor affinity, was still significantly
more potent than morphine. Most of the compounds in
this series also surpassed 14-methoxymetopon (2) in
potency, which was previously described as an ex-
tremely potent µ-opioid agonist.8-10 Compound 19 dis-
played 10-fold greater potency in the PPQ and about
15-fold in TF and in HP compared to 2, and derivative
16 was 30 times more potent than 2 in the PPQ. In
alignment with these findings, none of the compounds
showed measurable antagonist activity. All of the
compounds were essentially inactive as antagonists in
the TF assay versus morphine. None of the compounds
exhibited sufficient antagonist activity to enable the
determination of its AD50.
Exp er im en ta l Section
Thebaine was obtained from Tasmanian Alkaloids Ltd.,
Australia. Melting points were determined with a Kofler
melting-point microscope. The 1H NMR spectra were obtained
on
a Varian Gemini 200 spectrometer in DMSO-d6 and
tetramethylsilane (TMS) as internal standard. All chemical
shift values were recorded as δ (ppm). Coupling constants J
are given in hertz. IR spectra were taken on a Mattson Galaxy
FTIR series 3000 in KBr pellets. Mass spectra were taken on
a Varian MAT 44 S apparatus. Elemental analyses were
performed at the Institute of Physical Chemistry of the
University of Vienna and were within (4% of theoretical
values. Column chromatography was carried out on silica gel
60 (0.040-0.063 mm) from Fluka. TLC was performed on silica
gel plates Polygram SIL G/UV254 with CH2Cl2/MeOH/NH4-
OH, 90:9:1.
14-Cin n a m yloxycod ein on e (6). NaH (1.0 g, 40.4 mmol)
obtained from 1.6 g of a 55-60% NaH dispersion in oil by
washings with petroleum ether was added to a solution of 14-
hydroxycodeinone16 (5) (3.0 g, 9.6 mmol) in anhydrous DMF
(100 mL) under N2 at 5 °C. After 20 min, cinnamyl bromide
(2.3 g, 11.6 mmol) was added and the resulting mixture was
stirred at 5 °C for 30 min and then for 4.5 h at room
temperature. Excess NaH was destroyed by addition of ice.
H2O (100 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 100 mL). The combined organic layers were
washed with brine (2 × 100 mL), dried (Na2SO4), and evapo-
rated to yield a brown oil that was crystallized from MeOH to
afford 6 as colorless crystals (2.49 g, 60%): mp 214-217 °C;
1H NMR (DMSO-d6) δ 7.46-7.17 (m, 5H ar, phenyl), 7.19 (d,
3
3
1H olef, J 7/8 ) 10.2 Hz, CH-8), 6.74/6.65 (2d, 2H ar, J 1/2
)

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 9 1761
8.3 Hz, CH-1/2), 6.51-6.59 (m, 1H olef, O-CH2-CHdCH-
Phe), 6.34 (trans)/6.26 (cis) (2 ps-d, 1H olef, O-CH2-CHdH-
(7 mL) was heated at 80 °C for 24 h. Purification by column
chromatography (silica gel, CH2Cl2/MeOH/NH4OH (conc), 250:
2:0.5) followed by formation of the hydrochloride salt from Et2O
gave 11‚HCl (0.4 g, 69%) as colorless crystals: mp 128-133
°C; 1H NMR (DMSO-d6) δ 8.48 (s, 1H, NH+-17), 7.30-7.15 (m,
5H, phenyl), 6.87 (d, 1H, J ) 8.4 Hz, CH-2), 6.77 (d, 1H, J )
8.4 Hz, CH-1), 4.93 (s, 1H, CH-5), 4.04 (ps-d, 1H, CH-9), 3.81
3
Phe, cis/trans ) 1:1), 6.18 (d, 1H olef, J 7/8 ) 10.2 Hz, CH-7),
2
4.85 (s, 1H, CH-5), 4.26/4.11 (2 d × d × d, 2H, for δ 4.11 J )
13.7 Hz, 3J ) 5.6 Hz, 4J ) 0.5 Hz, O-CH2-), 3.73 (s, 3H,
O-CH3), 2.36 (s, 3H, N-CH3). Anal. (C27H27NO4) C, H, N.
4,5r-Ep oxy-3-m eth oxy-17-m eth yl-14â-(3-p h en ylp r op yl-
oxy)m or p h in a n -6-on e (7). A mixture of 6 (6.3 g, 14.6 mmol)
and Pd/C (0.3 g, 20%) in acetic acid (200 mL) was hydrogenated
at 30 psi and room temperature for 3 h. The catalyst was
filtered off, and the filtrate was evaporated. The oily residue
was then dissolved in H2O and basified to pH 9 with NH4OH.
The product was extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were washed with brine (3 × 70 mL),
dried (Na2SO4), and evaporated to give a yellow oil, which was
crystallized from MeOH to afford 7 as colorless crystals (4.9
(s, 3H, 3-O-CH3); MS m/z (CI) 488 [M + 1]+. Anal. (C31H38
NO4Cl‚1.75H2O) C, H, N.
-
4,5r-Epoxy-3-m eth oxy-17-(2-m eth yltetr ah ydr ofu r fu r yl)-
14â-(3-p h en ylp r op yloxy)m or p h in a n -6-on e H yd r och lo-
r id e (12‚HCl). Following the procedure described for 9‚HCl,
a suspension of compound 8‚HCl (1.0 g, 2.4 mmol), K2CO3 (0.6
g, 4.4 mmol), and (()-tetrahydrofurfuryl chloride (5.0 mL, 0.7
mmol) was heated at 150 °C for 15 h. Purification by column
chromatography (silica gel, CH2Cl2/MeOH/NH4OH (conc), 250:
1.5:0.5 f 250:3.5:0.5) followed by formation of the hydrochlo-
ride salt from Et2O gave 12‚HCl (0.6 g, 48%) as colorless
crystals: mp 121-123 °C; 1H NMR (DMSO-d6) δ 8.18/7.64 (2s,
2 × 0.5H, NH+-17, 2 epimeres 1:1), 7.08-6.96 (m, 5H, phenyl),
6.68-6.52 (m, 2H, CH-2, CH-1), 4.75, 4.73 (2s, 2 × 0.5H, CH-
5); MS m/z (CI) 504 [M + 1]+. Anal. (C31H38NO5Cl‚0.5H2O) C,
H, N.
4,5r-E p oxy-3-m et h oxy-17-(2-p h en ylet h yl)-14â-(3-p h e-
n ylp r op yloxy)m or p h in a n -6-on e Hyd r och lor id e (13‚HCl).
Following the procedure described for 9‚HCl, a suspension of
compound 8‚HCl (1.0 g, 2.4 mmol), K2CO3 (3.0 g, 21.7 mmol),
and 2-phenylethyl bromide (1.2 mL, 8.8 mmol) in dry DMF
(10 mL) was heated at 80 °C for 12 h. Purification by column
chromatography (silica gel, CH2Cl2/MeOH/NH4OH (conc), 250:
2:0.5) followed by formation of the hydrochloride salt from Et2O
gave 13‚HCl (0.5 g, 36%) as colorless crystals: mp 128-130
°C; 1H NMR (DMSO-d6) δ 8.84 (s, 1H, NH+-17), 7.39-7.17 (m,
10H, 2 × phenyl), 6.89 (d, 1H, J ) 8.2 Hz, CH-2), 6.79 (d, 1H,
J ) 8.4 Hz, CH-1), 4.95 (s, 1H, CH-5), 4.44 (ps-d, 1H, CH-9),
3.81 (s, 3H, 3-O-CH3); MS m/z (CI) 524 [M + 1]+. Anal.
(C29H34NO4Cl‚1H2O) C, H, N.
1
g, 78%): mp 116-119 °C; H NMR (CDCl3) δ 7.35-7.15 (m,
3
5H ar, phenyl), 6.68 (d, 1H ar, J 1/2 ) 8.2 Hz, CH-2), 6.60 (d,
3
1H ar, J 1/2 ) 8.2 Hz, CH-1), 4.63 (s, 1H, CH-5), 3.89 (s, 3H,
O-CH3), 2.34 (s, 3H, N-CH3); MS m/z (EI) 433 [M]+. Anal.
(C27H31NO4) C, H, N.
7,8-Dih ydr o-14â-(3-ph en ylpr opyloxy)n or codein on e Hy-
d r och lor id e (8‚HCl). A mixture of 7 (5.0 g, 11.5 mmol),
NaHCO3 (6.8 g, 80.9 mmol), ethyl chloroformate (7.5 mL, 67.5
mmol), and EtOH-free ClCH2CH2Cl (30 mL) was stirred under
reflux conditions for 17 h. The inorganic material was filtered
off, and the filtrate was evaporated to give the carbamate
derivative as a brown oil, which was not further purified and
characterized. This oil was dissolved in MeOH (100 mL) and
heated to reflux for 1 h. Evaporation and crystallization from
acetone afforded 8‚HCl (4.9 g, 93%) as colorless crystals: mp
>220 °C (dec); 1H NMR (CDCl3) δ 10.55/8.68 (2s, 2H, NH+-
17), 7.28-7.10 (m, 5H, phenyl), 6.75 (d, 1H, J ) 8.3 Hz, CH-
2), 6.71 (d, 1H, J ) 8.3 Hz, CH-1), 4.41 (s, 1H, CH-5), 3.89 (s,
3H, 3-O-CH3); MS m/z (EI) 419 [M]+.
17-Allyl-4,5r-epoxy-3-m eth oxy-14â-(3-ph en ylpr opyloxy)-
m or p h in a n -6-on e Hyd r och lor id e (9‚HCl). A suspension of
8‚HCl (2.0 g, 4.8 mmol), K2CO3 (4.0 g, 28.9 mmol), and allyl
bromide (0.6 mL, 6.6 mmol) in dry DMF (15 mL) was heated
at 80 °C for 7 h. Then H2O (200 mL) was added and the
mixture was extracted with CH2Cl2 (3 × 100 mL). The
combined CH2Cl2 portions were washed with H2O (3 × 100
mL) and brine (2 × 100 mL) and dried (Na2SO4). Removal of
the solvent under reduced pressure afforded a crude oil that
was chromatographed (silica gel, CH2Cl2/MeOH/NH4OH (conc),
250:2:0.5), dissolved in ether, and converted into the hydro-
chloride salt. Recrystallization from 2-propanol afforded 9‚HCl
17-Allyl-4,5r-epoxy-3-h ydr oxy-14â-(3-ph en ylpr opyloxy)-
m or p h in a n -6-on e Hyd r och lor id e (14‚HCl). A solution of
9‚HCl (1.5 g, 3.0 mmol) in 48% HBr solution (5 mL) was
refluxed for 15 min. Upon cooling, the solution was basified
to pH 9 with concentrated NH4OH and extracted with CH2-
Cl2 (3 × 80 mL). The combined organic layers were washed
with H2O (3 × 50 mL) and brine (2 × 50 mL), dried (Na2SO4),
and evaporated. Purification by column chromatography (silica
gel, CH2Cl2/MeOH/NH4OH (conc), 250:2:0.5) followed by for-
mation of the hydrochloride salt from Et2O yielded 14‚HCl (0.5
g, 34%) as colorless crystals: mp >205 °C (dec); 1H NMR
(DMSO-d6) δ 9.51 (s, 1H, 3-OH), 8.81 (s, 1H, NH+-17), 7.30-
7.16 (m, 5H, phenyl), 6.71 (d, 1H, J ) 8.0 Hz, CH-2), 6.64 (d,
1H, J ) 8.0 Hz, CH-1), 6.05-5.80 (m, 1H, N+CH2CHdH2), 5.68
1
(1.5 g, 69%) as colorless crystals: mp 129-130 °C; H NMR
(DMSO-d6) δ 8.98 (s, 1H, NH+-17), 7.30-7.18 (m, 5H, phenyl),
6.89 (d, 1H, J ) 8.4 Hz, CH-2), 6.83 (d, 1H, J ) 8.4 Hz, CH-1),
3
6.05-5.73 (m, 1H, NH+-CH2-CHdH2), 5.69 (d, 1H, J trans
)
18 Hz, NH+-CH2-CHdCHHcis), 5.57 (d, 1H, J cis ) 9.8 Hz,
NH+-CH2-CHdCHHtrans), 4.94 (s, 1H, CH-5), 4.07 (ps-d, 1H,
CH-9), 3.81 (s, 3H, 3-O-CH3); MS m/z (CI) 460 [M + 1]+. Anal.
(C29H34NO4Cl‚2H2O) C, H, N.
(d, 1H, J trans ) 16 Hz, NH+-CH2-CHdCHHcis), 5.55 (d, 1H,
3
3
3J cis ) 10 Hz, NH+-CH2-CHdCHHtrans), 4.87 (s, 1H, CH-5),
4.04 (ps-d, 1H, CH-9); MS m/z (CI) 446 (M + 1]+. Anal. (C28H32
NO4Cl‚0.75H2O) C, H, N.
-
17-Cyclop r op ylm et h yl-4,5r-ep oxy-3-m et h oxy-14â-(3-
phenylpropyloxy)morphinan-6-one Hydrochloride (10‚HCl).
Following the procedure described for 9‚HCl, a suspension of
compound 8‚HCl (1.5 g, 3.6 mmol), K2CO3 (3.0 g, 21.7 mmol),
and cyclopropylmethyl bromide (1.0 mL, 6.6 mmol) in dry DMF
(10 mL) was heated at 80 °C for 4 h. Purification by column
chromatography (silica gel, CH2Cl2/MeOH/NH4OH (conc), 250:
2:0.5) followed by formation of the hydrochloride salt from Et2O
gave 10‚HCl (0.6 g, 53%) as colorless crystals: mp 130-133
°C; 1H NMR (DMSO-d6) δ 8.30 (s, 1H, NH+-17), 7.31-7.18 (m,
5H, phenyl), 6.88 (d, 1H, J ) 8.4 Hz, CH-2), 6.78 (d, 1H, J )
8.4 Hz, CH-1), 4.96 (s, 1H, CH-5), 4.51 (ps-d, 1H, CH-9), 3.81
(s, 3H, 3-O-CH3), 0.80-0.40 (m, 5H, c-propyl); MS m/z (EI)
473 [M + 1]+. Anal. (C29H34NO4Cl‚1H2O) C, H, N.
17-Cyclop r op ylm et h yl-4,5r-ep oxy-3-h yd r oxy-14â-(3-
phenylpropyloxy)morphinan-6-one Hydrochloride (15‚HCl).
This compound was prepared in 34% yield starting from 10‚
HCl using the procedure described for 14‚HCl. Recrystalliza-
tion of 15‚HCl from 2-propanol gave colorless crystals: mp
1
175-178 °C; H NMR (DMSO-d6) δ 9.52 (s, 1H, 3-OH), 8.20
(s, 1H, NH+-17), 7.30-7.18 (m, 5H, phenyl), 6.71 (d, 1H, J )
8.0 Hz, CH-2), 6.64 (d, 1H, J ) 8.0 Hz, CH-1), 4.89 (s, 1H,
CH-5), 4.50 (ps-d, 1H, CH-9); MS m/z (CI) 460 [M + 1]+. Anal.
(C29H34NO4Cl‚0.75H2O) C, H, N.
17-Cyclobu tylm eth yl-4,5r-ep oxy-3-h yd r oxy-14â-(3-p h e-
n ylp r op yloxy)m or p h in a n -6-on e Hyd r och lor id e (16‚HCl).
This compound was prepared in 24% yield starting from 11‚
HCl using the procedure described for 14‚HCl: mp >227 °C
1
17-Cyclobu tylm eth yl-4,5r-epoxy-3-m eth oxy-14â-(3-ph e-
n ylp r op yloxy)m or p h in a n -6-on e Hyd r och lor id e (11‚HCl).
Following the procedure described for 9‚HCl, a suspension of
compound 8‚HCl (0.5 g, 1.2 mmol), K2CO3 (1.0 g, 7.2 mmol),
and cyclobutylmethyl bromide (0.6 mL, 5.3 mmol) in dry DMF
(dec) (Et2O); H NMR (DMSO-d6) δ 9.51 (s, 1H, 3-OH), 8.30
(s, 1H, NH+-17), 7.29-7.18 (m, 5H, phenyl), 6.70 (d, 1H, J )
8.4 Hz, CH-2), 6.63 (d, 1H, J ) 8.3 Hz, CH-1), 4.86 (s, 1H,
CH-5), 3.99 (ps-d, 1H, CH-9); MS m/z (CI) 474 [M + 1]+. Anal.
(C30H36NO4Cl‚0.75H2O) C, H, N.

1762 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 9
Greiner et al.
(2) Feinberg, A. P.; Creese, I.; Snyder, S. H. The opiate receptor: A
model explaining structure-activity relationships of opiate
agonists and antagonists. Proc. Natl. Acad. Sci. U.S.A 1976, 73,
4215-4219.
4,5r-Epoxy-3-h ydr oxy-17-(2-m eth yltetr ah ydr ofu r fu r yl)-
14â-(3-p h en ylp r op yloxy)m or p h in a n -6-on e H yd r och lo-
r id e (17‚HCl). This compound was prepared in 36% yield
starting from 12‚HCl using the procedure described for 14‚
(3) Casy, A. F.; Parfitt, R. T. Opioid Analgesics: Chemistry and
Receptors; Plenum Press: New York, 1986.
1
HCl: mp 170-172 °C (Et2O); H NMR (DMSO-d6) δ 9.45 (s,
1H, 3-OH), 8.45, 7.85 (2s, 2 × 0.5H, NH+-17, epimeres 1:1),
7.30-7.21 (m, 5H, phenyl), 6.70-6.65 (m, 2H, CH-1, CH-2),
4.90/ 4.87 (2s, 2 × 0.5H, CH-5, epimeres 1:1); MS m/z (CI) 490
[M + 1]+. Anal. (C30H36NO5Cl‚1H2O) C, H, N.
(4) Schmidhammer, H.; Burkard, W. P.; Eggstein-Aeppli, L. Syn-
thesis and Biological Evaluation of 14-Alkoxymorphinans. 4.
Opioid Agonists and Partial Opioid Agonists in a Series of
N-(Cyclobutylmethyl)-14-Methoxymorphinan-6-Ones. Helv. Chim.
Acta 1989, 72, 1233-1240.
(5) Schmidhammer, H.; Aeppli, L.; Atwell, L.; Fritsch, F.; J acobson,
A. E.; Nebuchla, M.; Sperk, G. Synthesis and Biological Evalu-
ation of 14-Alkoxymorphinans. 1. Highly Potent Opioid Agonists
in the Series of (-)-14-Methoxy-N-methylmorphinan-6-ones. J .
Med. Chem. 1984, 27, 1575-1579.
(6) Schmidhammer, H. 14-AlkoxymorphinanssA Series of Highly
Potent Opioid Agonists, Antagonists, and Partial Agonists. Curr.
Top. Med. Chem. 1993, 1, 261-276.
(7) King, M. A.; Su, W.; Nielan, C.; Chang, A. H.; Schmidhammer,
H.; Pasternak, G. W. 14-Methoxymetopon, a very potent mu
opioid analgesic with an unusual pharmacological profile. Eur.
J . Pharmacol., in press.
(8) Fu¨rst, Z.; Buzas, B.; Friedmann, T.; Schmidhammer, H.; Borsodi,
A. Highly Potent Novel Opioid Receptor Agonist in the 14-
Alkoxymetopon Series. Eur. J . Pharmacol. 1993, 236, 209-215.
(9) Schmidhammer, H.; Schratz, A.; Mitterdorfer, J . Synthesis and
Biological Evaluation of 14-Alkoxymorphinans. 8. 14-Meth-
oxymetopon, an Extremely Potent Opioid Agonist. Helv. Chim.
Acta 1990, 73, 1784-1787.
(10) Freye, E.; Schmidhammer, H.; Latasch, L. 14-Methoxymetopon,
a potent opioid, induces no respiratory depression, less sedation,
and less bradycardia than Sufentanil in the dog. Anesth. Analg.
2000, 90, 1359-1364.
(11) Urigu¨en, L.; Fernandez, B.; Romero, E. M.; De Pedro, N.;
Delgado, M. J .; Guaza, C.; Schmidhammer, H.; Viveros, M. P.
Effects of 14-methoxymetopon, a potent opioid agonist, on the
responses to the tail electric stimulation test and plus-maze
activity in male rats: Neuroendocrine correlates. Brain Res.
Bull. 2002, 57, 661-666.
(12) Kobylecki, R. J .; Carling, R. W.; Lord, J . A. H.; Smith, C. F. C.;
Lane, A. C. Common Anionic Receptor Site Hypothesis: Its
Relevance to the Action of Naloxone. J . Med. Chem. 1982, 25,
116-120.
(13) Schmidhammer, H.; Burkard, W. P.; Eggstein-Aeppli, L.; Smith,
C. F. C. Synthesis and Biological Evaluation of 14-Alkoxymor-
phinans. 2. (-)-N-(Cyclopropylmethyl)-4,14-dimethoxymorphi-
nan-6-one, a Selective µ Opioid Receptor Antagonist. J . Med.
Chem. 1989, 32, 418-421.
(14) Schmidhammer, H. Opioid Receptor Antagonists; Elsevier: New
York, 1998; pp 83-132.
(15) Loew, G. H.; Berkowitz, D. S. Quantum Chemical Studies of
Morphine-Like Opiate Narcotics. Effect of N-Substituent Varia-
tions. J . Med. Chem. 1975, 18, 656-662.
(16) Iijima, I.; Minamikawa, J .; J acobson, A. E.; Brossi, A.; Rice, K.
C. Studies in the (+)-morphinan series. 5. Synthesis and
biological properties of (+)-naloxone. J . Med. Chem. 1978, 21,
398-400.
(17) Lee, K. O.; Akil, H.; Woods, J . H.; Traynor, J . R. Differential
binding properties of oripavines at cloned mu- and delta-opioid
receptors. Eur. J . Pharmacol. 1999, 378, 323-330.
(18) May, E. L.; Murphy, J . G. Structures Related to Morphine. IV.
m-Substituted Phenylcyclohexane Derivatives. J . Org. Chem.
1955, 20, 1197-1201.
(19) Woods, J . H.; Traynor, J . R. Evaluation of new compounds for
opioid activity 2001; NIDA Research Monograph Series 182;
NIDA: Washington, DC, 2002; p 139.
(20) Cheng, Y.-C.; Prusoff, W. H. Relationship between the Inhibition
Constant (Ki) and the Concentration of Inhibitor Which Causes
50 Percent Inhibition (IC50) of an Enzymatic Reaction. Biochem.
Pharmacol. 1973, 22, 3099-3108.
(21) Emmerson, P. J .; Clark, M. J .; Mansour, A.; Akil, H.; Woods, J .
H.; Medzihradsky, F. Characterization of opioid agonist efficacy
in a C-6 glioma cell line expressing the mu opioid receptor. J .
Pharmacol. Exp. Ther. 1996, 278, 1121-1127.
4,5r-E p oxy-3-h yd r oxy-17-(2-p h en ylet h yl)-14â-(3-p h e-
n ylp r op yloxy)m or p h in a n -6-on e Hyd r och lor id e (18‚HCl).
This compound was prepared in 15% yield starting from 13‚
HCl using the procedure described for 14‚HCl: mp >218 °C
1
(dec) (Et2O); H NMR (DMSO-d6) δ 9.51 (s, 1H, 3-OH), 8.80
(s, 1H, NH+-17), 7.39-7.17 (m, 10H, 2 × phenyl), 6.72 (d, 1H,
J ) 8.4 Hz, CH-2), 6.66 (d, 1H, J ) 8.3 Hz, CH-1), 4.87 (s, 1H,
CH-5), 4.41 (ps-d, 1H, CH-9); MS m/z (CI) 510 [M + 1]+. Anal.
(C33H36NO4Cl‚0.75H2O) C, H, N.
4,5r-Ep oxy-3-h yd r oxy-14â-(3-p h en ylp r op yloxy)-17-(n -
p r op yl)m or p h in a n -6-on e Hyd r och lor id e (19‚HCl). A mix-
ture of 14‚HCl (0.3 mg, 0.6 mmol), Pd/C (35 mg, 10%), and
MeOH (50 mL) was hydrogenated at 30 psi and room temper-
ature for 3 h. The catalyst was filtered off, and the filtrate
was evaporated. Purification as the hydrochloride salt from
Et2O gave 19‚HCl as colorless crystals (0.3 g, 95%): mp 162-
163 °C; 1H NMR (DMSO-d6) δ 9.51 (s, 1H, 3-OH), 8.50 (s, 1H,
3
NH+-17), 7.30-7.18 (m, 5H ar, phenyl), 6.75 (d, 1H ar, J 1/2
)
3
8.4 Hz, CH-2), 6.64 (d, 1H ar, J 1/2 ) 8.4 Hz, CH-1), 4.86 (s,
1H, CH-5), 4.25 (ps-d, 1H, CH-9), 3.81 (s, 3H, N-CH2CH2CH3);
MS m/z (CI) 448.3 [M + 1]+. Anal. (C28H34NO4Cl‚0.5H2O) C,
H, N.
Op ioid Recep tor Bin d in g Assa ys. Details of the binding
assay have been described previously.17,19 Aliquots of a mem-
brane preparation were incubated with [3H]diprenorphine (0.3
nM) in the presence of different concentrations of the drug
under investigation at 25 °C for 1 h. Specific (i.e., opioid-
receptor-related) binding was determined as the difference in
binding obtained in the absence and presence of 10 µM
naloxone. The potency of the drugs in displacing the specific
binding of [3H]diprenorphine was determined from data using
Graphpad Prism (GraphPAD, San Diego, CA) and converted
into Ki values.20 Opioid binding was performed in membranes
from C6 rat glioma cells expressing recombinant µ21 or δ22 (rat)
and CHO cells expressing the recombinant κ23 (human). The
affinity (Kd) values of [3H]diprenorphine at the receptors were
the following: µ (0.15 nM), δ (0.45 nM), κ (0.25 nM).
In Vivo Assa ys. Gen er a l Meth od s. ICR male mice (Har-
lan Sprague-Dawley, Inc., Indianapolis, IN) weighing 20-30
g were used, and each animal was tested only once. All drugs
were administered by the subcutaneous route. At least 3 doses
were tested, and 6-10 animals per dose were used.
Ta il-F lick Test (TF ) a n d Ta il-flick vs Mor p h in e (TF
vs M) Assa ys.24-26 The original procedures and their modifi-
cations have been described earlier.
Hot-P la te (HP ) Assa y. The original procedures and their
modifications have been previously described.26-28
P h en ylqu in on e Abd om in a l Wr ith in g (P P Q) Assa y. The
original procedures and their modifications have been previ-
ously described.26,29,30
Ack n ow led gm en t. We thank Tasmanian Alkaloids
Ltd., Australia, for the generous gift of thebaine. This
work was supported by the Austrian Science Foundation
(Project P12668). The biological and pharmacological
evaluation was carried out under the auspices of the
Drug Evaluation Committee of the College on Problems
of Drug Dependence of the U.S.A.
(22) Clark, M. J .; Emmerson, P. J .; Mansour, A.; Akil, H.; Woods, J .
H.; Portoghese, P. S.; Remmers, A. E.; Medzihradsky, F. Opioid
efficacy in a C6 glioma cell line stably expressing the delta opioid
receptor. J . Pharmacol. Exp. Ther. 1997, 283, 501-510.
(23) Zhu, J . M.; Luo, L. Y.; Li, J . G.; Chen, C. G.; LiuChen, L. Y.
Activation of the cloned human kappa opioid receptor by agonists
enhances [S-35]GTP gamma S binding to membranes: Deter-
mination of potencies and efficacies of ligands. J . Pharmacol.
Exp. Ther. 1997, 282, 676-684.
Refer en ces
(1) Part 17 of this series: Schu¨tz, J .; Dersch, C, M.; Horel, R.;
Spetea, M.; Koch, M.; Meditz, R.; Greiner, E.; Rothman, R. B.;
Schmidhammer, H. Synthesis and Biological Evaluation of 14-
Alkoxymorphinans. 17. Highly δ Opioid Receptor Selective 14-
Alkoxy-Substituted Indolo- and Benzofuromorphinans. J . Med.
Chem. 2002, 45, 5378-5383.
(24) D’Amour, F. E.; Smith, D. L. A method for determining loss of
pain sensation. J . Pharmacol. Exp. Ther. 1941, 72, 74-79.

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 9 1763
(25) Dewey, W. L.; Harris, L. S. Antinociceptive activity of the
narcotic antagonists analogues and antagonistic activity of
narcotic analgesics in rodents. J . Pharmacol. Exp. Ther. 1971,
179, 652-659.
(28) Eddy, N. B.; Leimbach, D. Synthetic analgesics. II. Dithienyl-
butenyl- and dithienylbutylamines. J . Pharmacol. Exp. Ther.
1953, 107, 385-393.
(29) Pearl, J .; Harris, L. S. Inhibition of writhing by narcotic
antagonists. J . Pharmacol. Exp. Ther. 1966, 154, 319-323.
(30) Aceto, M. D.; Harris, L. S.; Bowman, E. R. Etorphines: µ-opioid
receptor-selective antinociception and low physical dependence
capacity. Eur. J . Pharmacol. 1997, 338, 215-223.
(31) Spetea, M.; Nevin, S. T.; Hosztafi, S.; Ronai, A. Z.; Toth, G.;
Borsodi, A. Affinity profiles of novel δ-receptor selective benzo-
furan derivatives of non-peptide opioids. Neurochem. Res. 1998,
23, 1213-1218.
(26) May, E. L.; Aceto, M. D.; Bowman, E. R.; Bentley, C.; Martin,
B. R.; Harris, L. S.; Medzihradsky, F.; Mattson, M. V.; J acobson,
A. E. Antipodal R-N-(Methyl through decyl)-N-normetazocines
(5,9R-dimethyl-2′-hydroxy-6,7-benzomorphans): in Vitro and in
Vivo Properties. J . Med. Chem. 1994, 37, 3408-3418.
(27) May, E. L.; J acobson, A. E.; Mattson, M. V.; Traynor, J . R.;
Woods, J . H.; Harris, L. S.; Bowman, E. R.; Aceto, M. D.
Synthesis and in vitro and in vivo activity of (-)-(1R,5R,9R)-
and (+)-(1S,5S,9S)-N-alkenyl-, -N-alkynyl-, and -N-cyanoalkyl-
5,9-dimethyl-2′-hydroxy-6,7-benzomorphan homologues. J . Med.
Chem. 2000, 43, 5030-5036.
J M021118O