Novel ligands for the opioid receptors: Synthesis and structure-activity relationships among 5′-aryl and 5′-heteroaryl 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinans

Article abstract of DOI:10.1016/S0968-0896(03)00432-2

A series of pyridomorphinans possessing an aryl (10a-s) or heteroaryl (11a-h) substituent at the 5′-position of the pyridine ring of 17-cyclopropylmethyl-4,5α-epoxypyrido[2′,3′:6,7]morphinan was synthesized and evaluated for binding and functional activit

Full text of DOI:10.1016/S0968-0896(03)00432-2

Bioorganic & Medicinal Chemistry 11 (2003) 4143–4154
Novel Ligands for the Opioid Receptors: Synthesis and Structure–
Activity Relationships among 50-Aryl and 50-Heteroaryl 17-
Cyclopropylmethyl-4,5ꢀ-epoxypyrido[20,30:6,7]morphinans
Subramaniam Ananthan,a,* Naveen K. Khare,a Surendra K. Saini,a Peg Davis,b
Christina M. Dersch,c Frank Porrecab and Richard B. Rothmanc
aOrganic Chemistry Department, Southern Research Institute, Birmingham, AL 35255, USA
bDepartment of Pharmacology, The University of Arizona Health Sciences Center, Tucson, AZ 85724, USA
cClinical Psychopharmacology Section, IRP, National Institute on Drug Abuse, Baltimore, MD 21224, USA
Received 14 February 2003; accepted 9 April 2003
Abstract—A series of pyridomorphinans possessing an aryl (10a–s) or heteroaryl (11a–h) substituent at the 50-position of the pyri-
dine ring of 17-cyclopropylmethyl-4,5a-epoxypyrido[20,30:6,7]morphinan was synthesized and evaluated for binding and functional
activity at the opioid d, m, and k receptors. All of these pyridomorphinans bound with higher affinity at the d site than at m or k
sites. The binding data on isomeric compounds revealed that there exists greater bulk tolerance for substituents placed at the
o-position of the phenyl ring than at m- or p-positions. Among the ligands examined, the 2-chlorophenyl (10l), 2-nitrophenyl (10n),
2-pyridyl (11a), and 4-quinolinyl (11g) compounds bound to the d receptor with subnanomolar affinity. Compound 10c with the
p-tolyl substituent displayed the highest m=d selectivity (ratio=42) whereas compound 10l with the 2-chlorophenyl substituent dis-
played the highest k=d selectivity (ratio=23). At 10 mM concentration, the in vitro functional activity determined using [35S]GTP-g-
S binding assays showed that all of the compounds were antagonists devoid of any significant agonist activity at the d, m, and k
receptors. Antagonist potency determinations of three selected ligands revealed that the p-tolyl compound 10c is a potent d selective
antagonist. In the [35S]GTP-g-S assays this compound had a functional antagonist Ki value of 0.2, 4.52, and 7.62 nM at the d, m, and
k receptors, respectively. In the smooth muscle assays 10c displayed d antagonist potency with a Ke value of 0.88 nM. As an
antagonist, it was 70-fold more potent at the d receptors in the MVD than at the m receptors in the GPI. The in vitro d antagonist
profile of this pyridomorphinan 10c resembles that of the widely used d selective antagonist ligand naltrindole.
# 2003 Elsevier Ltd. All rights reserved.
Introduction
1–6 (Chart 1). Among these, the indolomorphinan nal-
trindole (2, NTI) has been used widely as a biochemical
and pharmacological tool due to its selective antagonist
properties at the opioid d receptors. Studies with d
antagonists have indicated that d antagonist ligands
may be useful for the treatment of cocaine,17 metham-
phetamine18 and alocohol19 abuse, and their immuno-
suppressive effects may lead to useful treatments
for preventing rejection in organ transplants.20 In addi-
tion, it has been shown that d antagonists can prevent
the development of tolerance and dependence to m agon-
ists such as morphine without affecting m mediated
antinociception.21,22
In the search for novel ligands for the opioid m, d, and k
receptors, several compounds derived from naltrexone
have gained prominence due to the differential binding
profile and varying intrinsic functional activity that they
possess.1À3 A variety of such ligands arising by the
fusion of a heteroaromatic system to the C-ring of the
morphinan framework present in naltrexone have been
explored recently. Some of the heterocyclic systems that
have been annulated to the morphinan unit include
indole,4À10 benzofuran,8,11 pyrazole,12 pyrrole,13,14 pyr-
imidine12,15,16 and pyridine16 represented by structures
In our earlier investigations on C-ring heteroaryl fused
morphinans of the type 5 and 6, we discovered that
the pyridine compounds 6, in general, bind with high
*Corresponding author. Tel.: +1-205-581-2822; fax: +1-205-581-
2726; e-mail: ananthan@sri.org
0968-0896/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0968-0896(03)00432-2

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S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
affinity to the opioid receptors and that the introduction
of a phenyl group at the 50-position on the pyridine ring
(7) enhances d antagonist potency. The introduction of
a chlorine substituent at the para position of the phenyl
ring gave a compound (8) that displayed a mixed d
antagonist/m agonist profile of activity.16 Moreover, our
recent studies have revealed that while non-aromatic
substituents such as cyano, carbethoxy, nitro, and
amino groups at the 50-position of the pyridomorphinan
did not provide any significant improvements in d
binding affinity or d antagonist potency, the placement
of the heteroaromatic 1-pyrrolyl moiety (9) enhanced
the d binding affinity, d binding selectivity and d
antagonist potency of the parent compound (6,
R=R1=R2=H).23 In view of these findings, it was of
interest to explore ligands possessing various aromatic
groups at the 50-position of the pyridomorphinan unit
to study their effect on binding and agonist or antago-
nist intrinsic activity at the opioid d, m, and k receptors.
In this paper, we describe the synthesis and biological
activity of a series of such aryl and heteroaryl analogues
10a–s and 11a–h (Chart 2).
Chemistry
The target compounds 10c,d,n, and 11a–h were synthe-
sized from naltrexone (12) or its hydrochloride by
condensation with appropriate 2-aryl- or 2-hetero-
arylmalondialdehydes (13) and ammonium acetate in
refluxing acetic acid as depicted in Scheme 1. The target
compounds 10a,b,e,f–j,l,m,p–s were obtained through a
similar pyridine annulation method using 2-aryl-3-
Chart 1.
Chart 2.
Scheme 1.

S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
4145
(dimethylamino)acroleins (15) as malondialdehyde
equivalents. The dimethylaminoacrolein intermediates
were prepared by Vilsmeier-Haack decarboxylative
diformylation of arylacetic acids according to the gen-
eral procedure of Arnold (Scheme 2).24,25 While the 4-
biphenyl compound 10g, was obtained by the ring
synthesis reaction, the 3-biphenyl and 2-biphenyl iso-
mers 10k and 10o were obtained from the corresponding
bromo compounds 10i and 10m by the Suzuki coupling
reaction with phenylboronic acid (Scheme 3).26,27
cies among the unsubstituted and p-substituted analo-
gues at the d site is: H>CH3 >F, Cl >CF3 >NO2
>OCH3 >Br >C6H5. The fact that all of the p-sub-
stituted compounds displayed lower affinity than the
unsubstituted compound suggests the presence of steric
inhibition for binding at the d receptors. Compounds
possessing the electron donating methoxy group (10d)
as well as the electron withdrawing nitro group (10f)
displayed nearly equal affinity (3.8 and 5.0 nM). The
observed order of affinity does not correlate with the
lipophilicity substituent constants (p values) for the p-
substituents. However, there appears to be a rough
correlation of decreasing binding affinity of these ana-
logues with increasing molar refractivity, which is a
function of molecular size and polarizability of the
group.31 The calculated molar refractivity (CMR)
values for these analogues increase in the following
order of the p-substituent: H (12.88)<F (12.90)<CH3
(13.30)<Cl (13.37)<CF3 (13.39)<NO2 (13.49)<CH3O
(13.50)<Br (13.60)<C6H5 (15.39).32
Results and Discussion
Opioid receptor binding
The binding affinities of the target compounds for the
opioid d and m receptors were determined by inhibition
of binding of [3H]DADLE28 and [3H]DAMGO29 to rat
brain membranes. The affinities of the compounds for
the k receptors were determined by inhibition of binding
of [3H]U69,59330 to guinea pig brain membranes using
previously reported procedures.7,16 The d, m, and k
opioid receptor binding affinities along with binding
selectivity ratios for the target compounds are given in
Table 1. The affinity data for compounds 7 and 8 are
included in the table for comparison.
The m-substituted compounds 10h–k bind with nearly
equal affinity to the d receptor and the binding affinities
of the chloro- (10h), bromo- (10i) and trifluoromethyl
(10j) compounds are similar to those of the p-isomers 8,
10b, and 10e, respectively. Interestingly, the o-sub-
stituted chloro- (10l), bromo- (10m), nitro- (10n) and
phenyl- (10o) compounds all display higher affinities
than their m- or p- substituted counterparts. Therefore it
appears that the d receptor binding site has greater tol-
erance for substituents at the o-position of the 50-phenyl
group than at the m- or p-position, as illustrated by the
affinities of the o-, m-, and p-biphenyl isomers 10o
(Ki=2.8 nM), 10k (Ki=4.8 nM) and 10g (Ki=14.0 nM),
respectively. Of the two isomeric dichlorophenyl analo-
gues 10p and 10q, the 2,4-dichloro isomer 10q binds
with higher affinity (Ki=3.5 nM) than the 3,4-dichloro
isomer 10p (Ki=7.0 nM). Indeed even among the 1-
naphthyl- and 2-naphthyl isomers, it is the 1-napthyl
isomer 10s that displays higher affinity (Ki=3.6 nM)
than the 2-naphthyl isomer 10r (Ki=7.1nM). Differ-
ences in steric tolerance at the binding site or subtle
differences in the electronic or conformational properties
All of the pyridomorphinans examined in the present
study bind with high affinity to the opioid d receptor
with Ki values ranging from 0.51–14.0 nM. All of the
compounds display higher affinity at the d site in com-
parison to their affinity at the m and k sites. Thus the
pyridomorphinans are d selective ligands with d over m
selectivity ranging from 1.3 to 42 and d over k selectivity
ranging from 1.3 to 23. Among the compounds studied,
the o-nitrophenyl compound 10n and the 2-pyridyl
analogue 11a displayed the highest binding affinity at
the d site (Ki=0.51nM). Compounds 10a–g together
with 8 represent a series of analogues possessing elec-
tron donating, electron withdrawing, and bulky groups
at the p-position on the exocyclic phenyl ring of the
parent compound 7. The observed rank order of poten-
Scheme 2.
Scheme 3.

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S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
Table 1. Binding affinities of the pyridomorphinans 10a–s and 11a–h in rodent brain membranes
Compd
50-Substituent
Ki (nM)ÆSEM
Selectivity ratio
m/d
da
mb
kc
k/d
10a
10b
10c
10d
10e
10f
10g
10h
10i
4-Fluorophenyl
4-Bromophenyl
4-Methylphenyl
4-Methoxyphenyl
4-Trifluoromethylphenyl
4-Nitrophenyl
4-Biphenyl
3-Chlorophenyl
3-Bromophenyl
3-Trifluoromethylphenyl
3-Biphenyl
2-Chlorophenyl
2-Bromophenyl
2-Nitrophenyl
2-Biphenyl
3,4-Dichlorophenyl
2,4-Dichlorophenyl
2-Naphthyl
2.2Æ0.05
6.6Æ0.9
43.0Æ4.0
143Æ9.0
51.0Æ4.5
29.0Æ1.1
84.0Æ14
95.0Æ4.6
81.0Æ3
9
12.0Æ11 5.4
17.0Æ1.1
10.6Æ0.6
9.0Æ0.3
14.0Æ1315.1
9.3Æ1.2
19.0Æ2
21
42
5.8
2.5
8.8
1.8
1.2Æ0.08
5.0Æ0.8
2.7Æ0.11
3.8Æ0.49
14.0Æ0.8
3.4Æ0.26
6.3Æ0.43
2.4Æ0.20
4.8Æ0.33
0.62Æ0.07
1.1Æ0.11
0.51Æ0.04
2.8Æ0.3
25
5.7
10
5.4
25
6.2
2.4
1.3
7.3
3.9
10
34.0Æ0.9
34.0Æ1.7
61.0Æ7
25.0Æ1.5
25.0Æ0.8
24.0Æ1.5
31.0Æ0.7
14.6Æ2
10j
10k
10l
30.0Æ0.9
9.5Æ0.5
6.3Æ0.39
6.4
5
1
1
23
10m
10n
10o
10p
10q
10r
10s
11a
11b
11c
11d
11e
11f
16.0Æ154.7
Æ0.2
1.9Æ0.012.2
3.8Æ0.02
237.7.0Æ0.811
24.0Æ1.2
99.0Æ6
3.7
1.3
3.8
6.8
13
2.8
29
13
12
5.5
17
10
5.9
3.9
16
4.3
4.2
1.9
5.1
2.5
2.6
5.6
3.4
4.2
3.3
1.8
4.1
3.9
2.7
20
12.0Æ0.5
Æ1.2
7.0Æ0.4
3.5Æ0.3
18.0Æ1.6
18.0Æ1.5
9.4Æ0.96
2.9Æ0.17
7.9Æ0.6
8.5Æ0.4
9.7Æ1.3
6.0Æ0.54
9.2Æ1.9
3.6Æ0.4
6.3Æ0.7
17.6Æ1.6
20.0Æ1.04
35.8Æ4.0
7.1Æ0.6
1-Naphthyl
2-Pyridyl
4-Pyridyl
4-Pyrimidinyl
2-Pyrazinyl
2-Benzoxazolyl
2-Quinolinyl
4-Quinolinyl
2-Quinoxalinyl
Phenyl
4-Chlorophenyl
3.6Æ0.26
0.51Æ0.04
2.3Æ0.08
2.0Æ0.3
10.4Æ0.67
15.0Æ1.4
32.0Æ2
24.0Æ2
2.9Æ0.09
3.3Æ0.28
2.2Æ0.08
0.92Æ0.06
2.3Æ0.10
0.87Æ0.07
2.2Æ0.16
0.41Æ0.09
16.0Æ0.7
59.0Æ5.0
23.5Æ1.2
5.5Æ0.4
11g
11h
7d
9.0Æ0.7
13.5Æ1.0
51.0Æ8.0
99.0Æ4.6
8d
16
24187
9.1
2, NTId
aDisplacement of [3H]DADLE (1.3–2.0 nM) in rat brain membranes using 100 nM DAMGO to block binding to m sites.
bDisplacement of [3H]DAMGO (1.4–3.0 nM) in rat brain membranes.
cDisplacement of [3H]U69,593 (1.2–2.2 nM) in guinea pig brain membranes.
dData from ref 16.
of the ligands caused by the o-substituent may con-
tribute to the observed ortho effect. Interestingly, a
comparison of the affinity data for the analogues pos-
sessing the three substituents Cl, Br, and C6H5 at the o-,
m- and p-positions on the phenyl ring reveals that the o-
substituted isomers bind with higher affinity than the m-
and p-substituted isomers at all three receptor types, the
d, m, and k sites.
10m all of the compounds displayed k=d selectivity
ratios of ꢀ10.
In vitro functional assays
To determine the agonist or antagonist nature of the
ligands, all of the target compounds were evaluated in
the in vitro [35S]GTP-g-S binding assays using guinea
pig caudate membranes. The agonist activity was deter-
mined by measuring the stimulation of [35S]GTP-g-S
binding by the compounds in the absence and presence
of fixed concentrations of selective antagonists: CTAP
to block m receptors, TIPP to block d receptors, and
nor-BNI to block k receptors, as described previously.33
The antagonist properties of the compounds were
determined by measuring the test compound’s ability to
inhibit stimulation of [35S]GTP-g-S binding produced
by the selective agonists: SNC-80 for d receptor,
DAMGO for m receptor, and U69,593 for k receptor.34
The compounds were initially evaluated at a concen-
tration of 10 mM. Even at this high concentration none
of the compounds displayed any significant agonist
activity at the d, m, or k receptors. At the same 10 mM
concentration, all of the compounds displayed antago-
nist effects at the d, m, and k receptors (84–100%). On
the basis of the high m=d selectivity ratios in the binding
assays, compound 10c, from the 50-aryl series and com-
The heteroaryl analogues 11a–h bind to the d site with
affinities in the narrow range of 0.51–3.3 nM. Of the two
pyridine isomers, the 2-pyridyl compound 11a displayed
higher affinity than the 4-pyridyl analogue 11b. Inter-
estingly, among the ligands examined, the 2-pyridyl
compound 11a and the 2-nitrophenyl compound 10f
possessing electron deficient aromatic systems turned
out to be the ligands with the highest affinity for the d
receptor.
With regard to selectivity in binding among the d, m,
and k receptors, compounds 10a–c, 10e, 10j, 11a and
11e displayed m=d selectivity ratios higher than that of
the unsubstituted phenyl compound 8. Among the
compounds studied, the p-tolyl compound 10c displayed
the highest d over m selectivity (42-fold). This enhanced
selectivity of 10c is primarily due to its relatively dimin-
ished affinity at the m site. With the exception of 10l and

S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
4147
Table 2. Antagonist activity of 10c, 11a and 11e on agonist stimu-
lated [35S]GTP-g-S binding in guinea pig caudate membranes
Table 3. Agonist and antagonist potencies of 10c, 11a and 11e in the
MVD and GPI smooth muscle preparations
Compd
Apparent functional Ki (nMÆSD)
m=d
k=d
Compd Agonist activity (%)
Antagonist activity
Ratio
d
m
k
MVDa
GPIb
MVD Ke (nM)c GPI Ke (nM)d
SNC-80a
DAMGOb
U69,593c
10c
11a
11e
8e
2, NTIe
17
0
0
63211
16
0
0
0.88Æ0.28
4.8Æ0.4
62Æ1
36Æ7
9
70
10c
11a
11e
0.20Æ0.014.52
0.27Æ0.03
Æ0.36
1.59Æ0.12
5.44Æ0.57
Æ0.42
7.62Æ0.58
2.27Æ0.14
6.32Æ0.38
11.18Æ0.44
8.85Æ0.8
23
38
8.4
10
62
143
7
5.8
8.8
43
19
Æ22f
4.0Æ0.7
41Æ6
1
0
g
0.62Æ0.03
0.91Æ0.48
—
81
8
0.18Æ0.017.80
18
0.53Æ0.18
43Æ3
2,d NTI
0.062Æ0.006
3.21Æ0.20
52
aInhibition of electrically stimulated contraction at a concentration of
aApparent functional Ki (versus 10 mM SNC-80, an agonist selective
for d opioid receptor).
1 mM in the MVD.
bInhibition of electrically stimulated contraction at a concentration of
1 mM in the GPI.
bApparent functional Ki (versus 10 mM DAMGO, an agonist selective
for m opioid receptor).
cDetermined using DPDPE as the d selective agonist ligand.
dDetermined using PL-017 as the m selective agonist ligand.
eData included for comparison.
cApparent functional Ki (versus 10 mM U69,593, an agonist selective
for k opioid receptor).
dData from ref 34 included for comparison.
fAgonist IC50 value in nM.
gThe agonist effects precluded the determination of antagonist effects.
pounds 11a and 11e from the 50-heteroaryl series were
selected as interesting compounds. The antagonist
potencies of these compounds were determined at the d,
m, and k receptors and the results are presented in Table
2. The three compounds examined displayed potent
antagonist activity at the d receptors with functional Ki
values <0.62 nM. Among the three compounds, the p-
tolyl analogue 10c was the most potent (Ki=0.2 nM). In
this assay 10c displayed 1=3 the antagonist potency of
the standard d antagonist ligand NTI (2). The antago-
nist potencies of these compounds at the m and k sites
were lower than their potencies at the d site.
Among the compounds examined in the present study,
the profile of 10c stands out in that it displayed highest
d selectivity in the binding assay, in the GTP-g-S assay,
and in the smooth muscle assay. The d antagonist
potency of 10c in the MVD is similar to that of the
chloro analogue 8 and that of NTI (2) with antagonist
Ki values in the subnanomolar range (Table 3). Whereas
8 displayed m agonist activity in the GPI, 10c is devoid
of such m agonist action. The profile of 10c therefore
more closely resembles the profile of NTI than that of
the mixed d antagonist/m agonist 8.
The functional activity profile of 10c, 11a and 11e were
also determined in the electrically stimulated mouse vas
deferens (MVD) and guinea pig ileum (GPI) smooth
muscle preparations as described previously.16,35,36 The
opioid antagonist and agonist potencies of the target
compounds in the MVD and GPI are listed in Table 3.
At 1 mM concentration, the selected ligands displayed
no or weak agonist activity both in the MVD and the
GPI. All three compounds displayed potent antagonist
activity in the MVD and the GPI. Their antagonist
potencies at the d site in the MVD were greater than
their antagonist potencies at the m site in the GPI. While
pyridine 11a and benzoxazole 11e were moderately
potent as d antagonists (Ke for 11a=4.8 nM, Ke for
11e=4.0 nM), the p-tolyl compound 10c turned out to
be the most potent and selective d antagonist ligand
(Ke=0.88 nM, GPI/MVD selectivity ratio=70).
Summary and Conclusions
A series of novel pyridomorphinan ligands possessing
various substituted aryl and heteroaryl systems at the 50-
position of the pyridine ring was prepared and eval-
uated for binding at the opioid d, m, and k receptors. All
of the pyridomorphinans displayed higher affinity for
binding at the d site than at m or k sites. The observed
structure–affinity relationship indicates that sterically
bulky groups are tolerated better at the o-position of the
50-phenyl ring than they are at the m- or p-positions.
Functional assays in vitro indicated that all of the
ligands possess an antagonist profile of activity at the d,
m, and k receptors and are devoid of any significant
agonist activity. Among the three compounds evaluated
for antagonist potencies in vitro in smooth muscle
assays, the p-tolyl compound 10c displayed antagonist
potency and selectivity nearly equal to that of the stan-
dard ligand naltrindole. Further studies are needed to
ascertain the potential usefulness of these pyr-
idomorphinans as biochemical and pharmacological
tools and as drugs.
While the antagonist potency data from GTP-g-S assays
and the smooth muscle assays are qualitatively similar,
there are quantitative differences between them. For
example, the order of d antagonist potencies for the
three compounds in the GTP-g-S assays (10c ffi 11a
>11e) and the MVD smooth muscle assays (10c >11e
ffi 11a) are different. Similar differences are discernable
between the GTP-g-S assays for the m receptor and the
potencies observed in the GPI. The reasons for these
differences between the GTP-g-S assays and smooth
muscle assays are not known but could reflect the dif-
ferences in the assay systems (brain tissue versus smooth
muscles) used in assessing the opioid receptor function.
Experimental
General methods
Melting points were determined in open capillary tubes
with a Mel-Temp melting point apparatus and are
uncorrected. 1H NMR spectra were recorded on a

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S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
Nicolet 300NB spectrometer operating at 300.635 MHz.
Chemical shifts are expressed in parts per million
downfield from tetramethylsilane. Spectral assignments
were supported by proton decoupling. Mass spectra
were recorded on a Varian MAT 311A double-focusing
mass spectrometer in the fast atom bombardment
(FAB) mode or on a Bruker BIOTOF II in electrospray
ionization (ESI) mode. Elemental analyses were per-
formed by Atlantic Microlab, Inc. (Atlanta, GA, USA)
or by the Spectroscopic and Analytical Laboratory of
Southern Research Institute. Thin layer chromato-
graphy (TLC) was performed on Analtech silica gel GF
0.25 mm plates. Flash column chromatography was
performed with E. Merck silica gel 60 (230–400 mesh).
Yields are of purified compounds and were not opti-
mized. Naltrexone and naltrexone hydrochloride were
obtained from Mallinckrodt. 2-Aryl- and 2-hetero-
arylmalondialdehydes were purchased from Acros
Organics. All other reagents were obtained from
Aldrich.
NH4OH (99:0.5:0.5) as the eluent to obtain the desired
product.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50-(4-fluorophenyl)pyrido[20,30:6,7]morphinan
(10a). This compound was obtained from naltrexone
hydrochloride
and
3-(dimethylamino)-2-(4-fluoro-
phenyl)acrolein37 by procedure B. Yield 38%, mp 164–
166 ꢁC; TLC, Rf 0.3 (CH2Cl2–MeOH–NH4OH,
96.5:3:0.5); 1H NMR (CDCl3) d 0.14–0.19 and 0.55–
0.60 (2m, 4H, cyclopropyl CH2CH2), 0.87–0.91(m, 1H,
cyclopropyl CH), 1.81–1.85 (m, 1H, C-15H), 2.35–2.46
(m, 4H, C-15H, C-16H, and NCH2-cyclopropyl), 2.63–
2.81(m, 4H, C-8 H2, C-10H, C-16H), 3.17 (d, 1H,
J=18.6 Hz, C-10H), 3.31 (d, 1H, J=6.3 Hz, C-9H),
4.60–5.50 (broad hump, 2H, C-3 OH, C-14 OH), 5.59 (s,
1H, C-5H), 6.58 (d, 1H, J=8.1Hz, C-2H), 6.69 (d, 1H,
J=8.1 Hz, C-1H), 7.09–7.15 (m, 2H, C-300 H, C-500 H),
7.40–7.46 (m, 3H, C-40 H, C-200 H, C-600 H), 8.65 (d, 1H,
J=2.1Hz, C-6 0 H); MS m/z 471(MH) +. Anal. calcd for
.
C29H27FN2O3 0.1H2O: C, 73.74; H, 5.80; N, 5.93.
Found: C, 73.54; H, 5.68; N, 5.79.
Procedure A: condensation of naltrexone or naltrexone
hydrochloride with 2-aryl- or 2-heteroarylmalondi-
aldehydes
50-(4-Bromophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-
3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morphinan
(10b). This compound was obtained from naltrexone
hydrochloride and 2-(4-bromophenyl)-3-(dimethylami-
no)acrolein38 by procedure B. Yield 36%, mp 148–
150 ꢁC; TLC, Rf 0.3 (CH2Cl2–MeOH–NH4OH,
A solution of naltrexone (0.341g, 1.0 mmol) or naltrex-
one hydrochloride (0.378 g, 1.0 mmol), the mal-
ondialdehyde (1.2 mmol) and ammonium acetate
(0.154 g, 2.0 mmol) in AcOH (10 mL) was heated to
reflux in an oil bath at 130–135 ꢁC under an argon
atmosphere until TLC analysis of the reaction mixture
using EtOAc/cyclohexane/Et3N (1:1:0.02) as the solvent
system indicated complete disappearance of the ketone
(approximately 20 h). The reaction mixture was cooled
to room temperature and the solvent was removed
under reduced pressure. The residue was treated with
water and the pH of the mixture was adjusted to 8 with
saturated aqueous NaHCO3 solution. The solid that
separated was collected by filtration and dried. The
crude product was chromatographed over a column of
silica, using CHCl3–MeOH (98:2) or CHCl3–MeOH–
NH4OH (99:0.5:0.5) as the eluent to obtain the desired
product.
1
95:5:0.5); H NMR (CDCl3) d 0.14–0.19 and 0.54–0.60
(2m, 4H, cyclopropyl CH2CH2), 0.87–0.91(m, H1 ,
cyclopropyl CH), 1.81–1.84 (m, 1H, C-15H), 2.34–2.49
(m, 4H, C-15H, C-16H, and NCH2-cyclopropyl), 2.63–
2.80 (m, 4H, C-8 H2, C-10H, C-16H), 3.17 (d, 1H,
J=18.6 Hz, C-10H), 3.30 (d, 1H, J=6.4 Hz, C-9H),
4.60–5.50 (broad hump, 2H, C-3 OH, C-14 OH), 5.58 (s,
1H, C-5H), 6.59 (d, 1H, J=8.1Hz, C-2H), 6.68 (d, 1H,
J=8.1 Hz, C-1H), 7.31–7.35 (m, 2H, C-300 H, C-500 H),
7.45 (d, 1H, J=2.1Hz, C-4 0 H), 7.54–7.56 (m, 2H, C-200
H, C-600 H), 8.65 (d, 1H, J=2.1Hz, C-6 0 H); MS m/z
531(MH) +. Anal. calcd for C29H27 BrN2O3 H2O: C,
.
63.39; H, 5.32; N, 5.10. Found: C, 63.31; H, 4.96; N,
5.02.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (4 - methylphenyl)pyrido[20,30:6,7]morph-
inan (10c). This compound was obtained from naltrex-
one hydrochloride and 2-(4-methylphenyl)malondialde-
hyde by procedure A. Yield 29%, mp 150–152 ꢁC; TLC,
Rf 0.6 (CHCl3–MeOH, 9:1); 1H NMR (DMSO-d6) d
0.12–0.19 and 0.48–0.54 (2m, 4H, cyclopropyl
CH2CH2), 0.82–0.94 (m, 1H, cyclopropyl CH), 1.56–
1.62 (m, 1H, C-15H), 2.14–2.46 (m, 4H, C-15H, C-16H,
and NCH2-cyclopropyl), 2.34 (s, 3H, CH3), 2.58–2.74
(m, 4H, C-8 H2, C-10H, C-16H), 3.03–3.13 (m, 1H, C-
10H), 3.21–3.28 (m, 1H, C-9H), 4.80 (s, 1H, C-14 OH),
5.35 (s, 1H, C-5H), 6.52 (app s, 2H, C-1H, C-2H), 7.29
(app d, 2H, J=8.0 Hz, C-300 H, C-500 H), 7.64 (app d,
2H, J=8.0 Hz, C-200 H, C-600 H), 7.70 (d, 1H, J=2.2 Hz,
C-40 H), 8.76 (d, 1H, J=2.2 Hz, C-60 H), 9.03 (s, 1H, C-
Procedure B: condensation of naltrexone or naltrexone
hydrochloride with 2-aryl-3-(dimethylamino)acroleins
To a solution of naltrexone (1.02 g, 3.0 mmol) or nal-
trexone hydrochloride (1.13 g, 3.0 mmol) and ammo-
nium acetate (0.925 g, 12.0 mmol) in glacial acetic acid
(20 mL) was added the 2-aryl-3-(dimethylamino)acro-
lein (6.0 mmol) and the mixture was stirred under reflux
at 135–140 ꢁC in an oil bath until TLC indicated com-
pletion of reaction (approximately 20 h). The solvent
was removed under reduced pressure and the residue
was partitioned between CH2Cl2 and saturated aqueous
NaHCO3. The layers were separated, the aqueous layer
was extracted with CH2Cl2 and the combined extracts
were washed with saturated aqueous NaCl, dried
(Na2SO4), filtered, and the solvent was removed under
reduced pressure. The crude product thus obtained
was purified by chromatography over a column of
silica using CHCl3–MeOH (98:2) or CHCl3–MeOH–
3
OH), MS m/z 515 (MH)+. Anal. calcd for
.
C30H30N2O3 0.4CHCl3: C, 70.99, H, 5.96; N, 5.45.
Found: C, 70.72; H, 5.94; N, 5.22.

S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
4149
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50 -(4-methoxyphenyl)pyrido[20,30:6,7]morph-
inan (10d). This compound was obtained from naltrex-
one hydrochloride and 2-(4-methoxyphenyl)malondi-
aldehyde by procedure A. Yield 69%, mp 172–174 ꢁC;
added dropwise to phosphorous oxychloride (10.0 g,
65.2 mmole) with efficient stirring while maintaining the
temperature of the reaction mixture below 30 ꢁC with
external cooling. After the addition was complete, the
mixture was stirred for 5 min and then a solution of
4-biphenylacetic acid (5.20 g, 24.5 mmol) in dimethyl-
formamide (15.0 mL) was added dropwise over a period
of 5 min. The resulting solution was stirred at 70 ꢁC for
18 h and then poured onto ice. The solution was neu-
tralized by the addition of anhydrous K2CO3 and then
made strongly basic by addition of 50% aqueous NaOH
maintaining the temperature of the mixture at 50 ꢁC.
After the evolution of dimethylamine ceased, the mix-
ture was cooled and the solid obtained was collected by
filtration, washed with water and dried to yield 5.71g
(75%) of 2-(4-biphenyl)-3-(dimethylamino)acrolein: mp
1
TLC, Rf 0.2 (CHCl3–MeOH–NH4OH, 97:2.5:0.5); H
NMR (CDCl3) d 0.12–0.18 and 0.47–0.53 (2m, 4H,
cyclopropyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl
CH), 1.57–1.61 (m, 1H, C-15H), 2.19–2.41 (m, 4H, C-
15H, C-16H, and NCH2-cyclopropyl), 2.60–2.72 (m,
4H, C-8 H2, C-10H, C-16H), 3.06–3.12 (m, 1H, C-10H),
3.24–3.26 (m, 1H, C-9H), 3.79 (s, 3H, –OCH3), 4.80 (s,
1H, C-14 OH), 5.34 (s, 1H, C-5H), 6.51 (app s, 2H, C-
1H, C-2H), 7.02–7.06 (m, 2H, C-300 H, C-500 H), 7.61–
7.65 (m, 2H, C-200 H, C-600 H), 7.68 (d, 1H, J=2.2 Hz,
C-40 H), 8.75 (d, 1H, J=2.2 Hz, C-60 H), 9.04 (s, 1H, C-
154–156 ꢁC; TLC, Rf 0.66 (CHCl3–MeOH, 9.5:0.5); H
1
3
OH); MS m/z 483 (MH)+. Anal. calcd for
.
C30H30N2O4 0.2H2O: C, 74.11; H, 6.30; N, 5.76. Found:
C, 74.22; H, 6.32; N, 5.77.
NMR (CDCl3) d 2.88 [br s, 6H, N(CH3)2], 6.85 (br s,
1H, ¼CH–N), 7.21–7.24 (m, 2H, C-20 H, C-60 H), 7.42–
7.44 (m, 3H, C-400 H, C-300 H, C-500 H), 7.59–7.61(m,
4H, C-30 H, C-50 H, C-200 H, C-600 H), 9.13 (s, 1H,
CHO); MS m/z 252 (MH)+. Anal. calcd for
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50-[4-(trifluoromethyl)phenyl]pyrido[20,30:6,7]-
morphinan (10e). This compound was obtained from
naltrexone hydrochloride and 3-(dimethylamino)-2-[4-
(trifluoromethyl)phenyl]acrolein38 by procedure B.
Yield 27%, mp 158–160 ꢁC; TLC, Rf 0.3 (CH2Cl2–
MeOH–NH4OH, 96.5:3:0.5); 1H NMR (CDCl3) d 0.15–
0.19 and 0.55–0.61 (2m, 4H, cyclopropyl CH2CH2),
0.85–0.92 (m, 1H, cyclopropyl CH), 1.83–1.86 (m, 1H,
C-15H), 2.36–2.51 (m, 4H, C-15H, C-16H, and NCH2-
cyclopropyl), 2.66–2.84 (m, 4H, C-8 H2, C-10H, C-
16H), 3.18 (d, 1H, J=18.6 Hz, C-10H), 3.32 (d, 1H,
J=6.3 Hz, C-9H), 5.59 (s, 1H, C-5H), 6.59 (d, 1H,
J=8.1Hz, C-2H), 6.69 (d, 1H, J=8.1Hz, C-1H), 7.52
(d, 1H, J=2.2 Hz, C-40 H), 7.60 (d, 2H, J=8.1Hz, C-3 00
H, C-500 H), 7.69 (d, 2H, J=8.1Hz, C-2 00 H, C-600 H),
8.72 (dd, 1H, J=2.2, 0.6 Hz, C-60 H); MS m/z 521
.
C17H17NO 0.2H2O: C, 80.10; H, 6.88; N, 5.49. Found:
C, 80.16; H, 6.90; N, 5.74.
The enaminoaldehyde thus obtained was reacted with
naltrexone hydrochloride according to the procedure B
to obtain the title compound 10g: Yield 38%, mp 158–
160 ꢁC; TLC, Rf 0.3 (CH2Cl2–MeOH–NH4OH,
96.5:3:0.5); 1H NMR (CDCl3) d 0.15–0.19 and 0.55–
0.61(2m, 4H, cyclopropyl C H2CH2), 0.88–0.92 (m, 1H,
cyclopropyl CH), 1.83–1.86 (m, 1H, C-15H), 2.36–2.51
(m, 4H, C-15H, C-16H, and NCH2-cyclopropyl), 2.66–
2.85 (m, 4H, C-8 H2, C-10H, C-16H), 3.18 (d, 1H,
J=18.6 Hz, C-10H), 3.32 (d, 1H, J=6.4 Hz, C-9H),
4.80–5.60 (broad hump, 2H, C-3 OH, C-14 OH), 5.61 (s,
1H, C-5H), 6.59 (d, 1H, J=8.1Hz, C-2H), 6.69 (d, 1H,
J=8.1 Hz, C-1H), 7.36–7.68 (m, 10H, C-40 H, biphenyl-
H), 8.79 (d, 1H, J=2.2 Hz, C-60 H); MS m/z 529
(MH)+. Anal. calcd for C35H32N2O3: C, 79.52; H, 6.10;
N, 5.30. Found: C, 79.73; H, 6.11; N, 5.50.
+
.
(MH) . Anal. calcd C30H27F3N2O3 0.3H2O: C, 68.51;
H, 5.29; N, 5.33. Found: C, 68.29; H, 5.22; N, 5.30.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50 -(4-nitrophenyl)pyrido[20,30:6,7]morphinan
(10f). This compound was obtained from naltrexone
and 3-(dimethylamino)-2-(4-nitrophenyl)acrolein39 by
procedure B. Yield 48%, mp 146–150 ꢁC; TLC, Rf 0.25
(CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); 1H NMR
(CDCl3) d 0.15–0.20 and 0.55–0.61 (2m, 4H, cyclopro-
pyl CH2CH2), 0.86–0.91(m, H1 , cyclopropyl C H),
1.83–1.86 (m, 1H, C-15H), 2.36–2.51 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.67–2.85 (m, 4H, C-8
H2, C-10H, C-16H), 3.19 (d, 1H, J=18.7 Hz, C-10H),
3.33 (d, 1H, J=6.1Hz, C-9H), 4.8–5.4 (broad hump,
2H, C-3 OH, C-14 OH), 5.59 (s, 1H, C-5H), 6.60 (d, 1H,
J=8.1Hz, C-2H), 6.68 (d, 1H, J=8.1Hz, C-1H), 7.57
(d, 1H, J=2.0 Hz, C-40 H), 7.67 (d, 2H, J=9.0 Hz, C-200
H, C-600 H), 8.31(d, 2H, J=9.0 Hz, C-300 H, C-500 H),
8.77 (d, 1H, J=2.0 Hz, C-60 H); MS m/z 498 (MH)+.
50 -(3-Chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehy-
dro - 3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morph-
inan (10h). This compound was obtained from naltrex-
one and 2-(3-chlorophenyl)-3-(dimethylamino)acro-
lein40 by procedure B. Yield 33%, mp 132–136 ꢁC; TLC,
1
Rf 0.2 (CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); H NMR
(CDCl3) d 0.15–0.20 and 0.55–0.61 (2m, 4H, cyclopro-
pyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl CH),
1.82–1.86 (m, 1H, C-15H), 2.35–2.48 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.64–2.83 (m, 4H, C-8
H2, C-10H, C-16H), 3.17 (d, 1H, J=18.6 Hz, C-10H),
3.31(d, 1H, J=6.4 Hz, C-9H), 5.59 (s, 1H, C-5H), 6.59
(d, 1H, J=8.1Hz, C-2H), 6.68 (d, 1H, J=8.1Hz, C-
1H), 7.34–7.39 (m, 3H, C-400 H, C-500 H, C-600 H), 7.46–
7.49 (m, 2H, C-40 H, C-200 H), 8.67 (d, 1H, J=2.0 Hz, C-
60 H); MS m/z 487 (MH)+. Anal. calcd for
.
Anal. calcd for C29H27N3O5 0.5H2O: C, 68.76; H, 5.57;
N, 8.30. Found: C, 68.88; H, 5.73; N, 8.83.
.
C29H27ClN2O3 0.1H2O: C, 71.26; H, 5.61; N, 5.73.
Found: C, 70.72; H, 5.45; N, 6.01.
50 -(4-Biphenyl)-17-(cyclopropylmethyl)-6,7-didehydro-
3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morphinan
(10g). Dimethylformamide (6.45 g, 88.2 mmol) was
50 -(3-Bromophenyl)-17-(cyclopropylmethyl)-6,7-didehy-
dro - 3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morph-

4150
S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
inan (10i). Reaction of 3-bromophenylacetic acid (5.0 g,
23.35 mmol) with Vilsmeier reagent prepared from
dimethylformamide (6.12 g, 83.7 mmol) and phosphor-
ous oxychloride (9.97 g, 65.0 mmol) according to the
procedure described under 10g gave 5.11 g (86%) of 2-
(3-bromophenyl)-3-(dimethylamino)acrolein: mp 78–
NaCl (40 mL). The layers were separated and the aqu-
eous layer was extracted with EtOAc (40 mL). The
organic extracts were combined, dried (Na2SO4), fil-
tered, and the filtrate was concentrated under reduced
pressure. The crude product obtained was then purified
by flash column chromatography over silica using
CH2Cl2–MeOH–NH4OH (98.5:1:0.5) as the eluent to
obtain 0.7 g (68%) of 10k: mp 162–164 ꢁC; TLC, Rf 0.3
(CH2Cl2–MeOH–NH4OH, 96.5:3:0.5); 1H NMR
(CDCl3) d 0.15–0.19 and 0.55–0.61 (2m, 4H, cyclopro-
pyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl CH),
1.83–1.86 (m, 1H, C-15H), 2.36–2.46 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.65–2.83 (m, 4H, C-8
H2, C-10H, C-16H), 3.17 (d, 1H, J=18.7 Hz, C-10H),
3.31(d, 1H, J=6.2 Hz, C-9H), 5.61(s, 1H, C-5H), 6.58
(d, 1H, J=8.1Hz, C-2H), 6.69 (d, 1H, J=8.1Hz, C-
1H), 7.38–7.70 (m, 10H, C-40 H, biphenyl-H), 8.76 (d,
1H, J=1.9 Hz, C-60 H); MS m/z 529 (MH)+. Anal.
80 ꢁC; TLC, Rf 0.6 (CHCl3–MeOH, 9.5:0.5); H NMR
1
(CDCl3) d 2.88 [br s, 6H, N(CH3)2], 6.85 (br s, 1H,
¼CH–N), 7.11–7.16 (m, 1H, C-40 H), 7.18–7.30 (m, 1H,
C-50 H), 7.32–7.34 (m, 1H, C-20 H), 7.36–7.41(m, 1H,
C-60 H), 9.07 (s, 1H, CHO); MS m/z 254 (MH)+. Anal.
calcd for C11H12BrNO: C, 51.99; H, 4.76; N, 5.51.
Found: C, 51.98; H, 4.67; N, 5.59.
The above enaminoaldehyde was reacted with naltrex-
one hydrochloride as described in procedure B to obtain
10i: Yield 32%, mp 158–160 ꢁC; TLC, Rf 0.3 (CH2Cl2–
MeOH–NH4OH, 96.5:3:0.5); 1H NMR (CDCl3) d 0.15–
0.19 and 0.55–0.61 (2m, 4H, cyclopropyl CH2CH2),
0.87–0.92 (m, 1H, cyclopropyl CH), 1.83–1.87 (m, 1H,
C-15H), 2.35–2.48 (m, 4H, C-15H, C-16H, and NCH2-
cyclopropyl), 2.64–2.82 (m, 4H, C-8 H2, C-10H, C-
16H), 3.17 (d, 1H, J=18.6 Hz, C-10H), 3.31 (d, 1H,
J=6.4 Hz, C-9H), 5.59 (s, 1H, C-5H), 6.59 (d, 1H,
J=8.1Hz, C-2H), 6.68 (d, 1H, J=8.1Hz, C-1H), 7.28–
7.53 (m, 4H, C-40 H, C-400 H, C-500 H, C-600 H), 7.63–
.
calcd for C35H32N2O3 0.1H2O: C, 79.25; H, 6.12; N,
5.28. Found: C, 79.00; H, 5.98; N, 5.16.
50 -(2-Chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehy-
dro - 3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morph-
inan (10l). This compound was obtained from naltrex-
one and 2-(2-chlorophenyl)-3-(dimethylamꢁino)acro-
lein38 by procedure B. Yield 29%, mp 164–166 C; TLC,
7.64 (m, 1H, C-200 H), 8.69 (d, 1H, J=2.0 Hz, C-60 H);
Rf 0.4 (CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); H NMR
1
+
MS
m/z
531(MH)
.
.
Anal.
calcd
for
(CDCl3) d 0.15–0.19 and 0.55–0.60 (2m, 4H, cyclopro-
pyl CH2CH2), 0.86–0.91(m, H1 , cyclopropyl C H),
1.83–1.86 (m, 1H, C-15H), 2.36–2.47 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.64–2.84 (m, 4H, C-8
H2, C-10H, C-16H), 3.17 (d, 1H, J=18.6 Hz, C-10H),
3.31–3.33 (m, 1H, C-9H), 5.07–5.09 (br s, 2H, C-3 OH,
C-14 OH), 5.61 (s, 1H, C-5H), 6.59 (d, 1H, J=8.1Hz,
C-2H), 6.69 (d, 1H, J=8.1Hz, C-1H), 7.27–7.33 (m,
3H, C-40 H, C-300 H, C-500 H), 7.45–7.49 (m, 2H, C-400 H,
C-600 H), 8.63 (dd, 1H, J=2.2, 0.7 Hz, C-60 H); MS m/z
487 (MH)+. Anal. calcd for C29H27ClN2O3: C, 71.52,
H, 5.59; N, 5.75. Found: C, 71.39; H, 5.71; N, 5.73.
C29H27BrN2O3 0.25H2O: C, 64.99; H, 5.17; N, 5.23.
Found: C, 64.75; H, 5.08; N, 5.13.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50-[3-(trifluoromethyl)phenyl]pyrido[20,30:6,7]-
morphinan (10j). This compound was obtained from
naltrexone hydrochloride and 3-(dimethylamino)-2-[3-
(trifluoromethyl)phenyl]acrolein37 by procedure B.
Yield 22%, mp 146–148 ꢁC; TLC, Rf 0.3 (CH2Cl2–
MeOH–NH4OH, 96.5:3:0.5); 1H NMR (CDCl3) d 0.15–
0.19 and 0.55–0.61 (2m, 4H, cyclopropyl CH2CH2),
0.88–0.92 (m, 1H, cyclopropyl CH), 1.82–1.86 (m, 1H,
C-15H), 2.32–2.51 (m, 4H, C-15H, C-16H, and NCH2-
cyclopropyl), 2.67–2.83 (m, 4H, C-8 H2, C-10H, C-
16H), 3.18 (d, 1H, J=18.6 Hz, C-10H), 3.32 (d, 1H,
J=6.3 Hz, C-9H), 5.59 (s, 1H, C-5H), 6.59 (d, 1H,
J=8.1Hz, C-2H), 6.69 (d, 1H, J=8.1Hz, C-1H), 7.53–
50 -(2-Bromophenyl)-17-(cyclopropylmethyl)-6,7-didehy-
dro - 3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morph-
inan (10m). Reaction of 2-bromophenylacetic acid
(5.0 g, 23.35 mmol) with Vilsmeier reagent prepared
from dimethylformamide (6.12 g, 83.7 mmol) and phos-
phorous oxychloride (9.97 g, 65.0 mmol) according to
the procedure described under 10g gave an oil after the
treatment with aqueous NaOH. The product was
extracted with CH2Cl2, washed with saturated aqueous
NaCl, dried (Na2SO4) and the solvent was removed
under reduced pressure to obtain 5.43 g (92%) of 2-(2-
bromophenyl)-3-(dimethylamino)acrolein as a viscous
7.73 (m, 5H, C-40 H, C-200 H, C-400 H, C-500 H, C-600 H),
8.71(d, 1H, J=2.2 Hz, C-60 H); MS m/z 521(MH)
.
+
.
Anal. calcd for C30H27F3N2O3 0.2H2O: C, 68.75; H,
5.27; N, 5.34. Found: C, 68.54; H, 5.42; N, 5.15.
50 -(3-Biphenyl)-17-(cyclopropylmethyl)-6,7-didehydro-
3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morphinan
(10k). Under an atmosphere of argon, 0.113 g
(0.098 mmol) of tetrakis(triphenylphosphine)palladium
was added to a solution of 10i (1.04 g, 1.96 mmol) in
toluene (42 mL) and the mixture was stirred at room
temperature for 30 min. A solution of phenylboronic
acid (0.359 g, 2.94 mmol) in EtOH (11.6 mL) was then
added. The resulting mixture was treated with saturated
aqueous NaHCO3 (21mL) and the biphasic reaction
mixture was heated under reflux in an oil bath at 120 ꢁC
for 16 h. The reaction mixture was allowed to cool to
room temperature and poured into saturated aqueous
1
oil. TLC, Rf 0.62 (CHCl3–MeOH, 9.5:0.5); H NMR
(CDCl3) d 2.85 [br s, 6H, N(CH3)2], 6.87 (br s, 1H,
¼CH–N), 7.10–7.18 (m, 1H, C-40 H), 7.20–7.27 (m, 1H,
0
C-50 H), 7.28–7.31(m, H1 , C-3
H), 7.59 (dd, 1H,
J=7.9, 0.9 Hz, C-60 H), 9.07 (s, 1H, CHO); MS m/z 254
(MH)+. The crude product thus obtained was used in
the next step without further purification.
The enaminoaldehyde obtained as described above was
reacted with naltrexone hydrochloride according to
procedure B to obtain 10m: Yield 21%, mp 140–142 ꢁC;

S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
4151
1
TLC, Rf 0.3 (CH2Cl2–MeOH–NH4OH, 96.5:3:0.5); H
NMR (CDCl3) d 0.14–0.19 and 0.55–0.60 (2m, 4H,
cyclopropyl CH2CH2), 0.87–0.90 (m, 1H, cyclopropyl
CH), 1.83–1.86 (m, 1H, C-15H), 2.36–2.51 (m, 4H, C-
15H, C-16H, and NCH2-cyclopropyl), 2.64–2.84 (m,
4H, C-8 H2, C-10H, C-16H), 3.17 (d, 1H, J=18.6 Hz,
C-10H), 3.32 (d, 1H, J=6.4 Hz, C-9H), 4.90–5.50
(broad hump, 2H, C-3 OH, C-14 OH), 5.60 (s, 1H, C-
5H), 6.60 (d, 1H, J=8.1Hz, C-2H), 6.70 (d, 1H,
one and 2-(3,4-dichlorophenyl)-3-(dimethylamino)acro-
lein25 by procedure B. Yield 32%, mp 154–158 ꢁC; TLC,
Rf 0.2 (CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); H NMR
1
(CDCl3) d 0.15–0.19 and 0.55–0.61 (2m, 4H, cyclopro-
pyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl CH),
1.82–1.85 (m, 1H, C-15H), 2.35–2.46 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.65–2.83 (m, 4H, C-8
H2, C-10H, C-16H), 3.17 (d, 1H, J=18.7 Hz, C-10H),
3.31(d, 1H, J=6.4 Hz, C-9H), 4.6–5.8 (broad hump,
2H, C-3 OH, C-14 OH), 5.59 (s, 1H, C-5H), 6.59 (d, 1H,
J=8.1Hz, C-2H), 6.67 (d, 1H, J=8.1Hz, C-1H), 7.33
(dd, 1H, J=8.4, 2.2 Hz, C-600 H), 7.48 (d, 1H,
J=2.1Hz, C-4 0 H), 7.51(d, 1H, J=8.4 Hz, C-500 H),
7.58 (d, 1H, J=2.2 Hz, C-200 H), 8.69 (d, 1H, J=2.1Hz,
C-60 H); MS m/z 521(MH) +. Anal. calcd for C29H26
00
J=8.1Hz, C-1H), 7.20–7.28 (m, 2H, C-3 H, C-500 H),
7.34–7.39 (m, 1H, C-400 H), 7.43 (d, 1H, J=2.1Hz, C-4 0
H), 7.66 (dd, 1H, J=7.8, 1.0 Hz, C-600 H), 8.60 (dd, 1H,
J=2.1, 0.7 Hz, C-60 H); MS m/z 531(MH) +. Anal.
.
calcd for C29H27BrN2O3 0.75H2O: C, 63.92; H, 5.27; N,
5.14. Found: C, 63.53; H, 5.24; N, 5.27.
.
Cl2N2O3 H2O: C, 64.57; H, 5.23; N, 5.19. Found: C,
64.91; H, 4.92; N, 9.07.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50 -(2-nitrophenyl)pyrido[20,30:6,7]morphinan
(10n). This compound was obtained from naltrexone
hydrochloride and 2-(2-nitrophenyl)malondialdehyde
by procedure A. Yield 30%, mp 170–172 ꢁC; TLC, Rf
0.3 (CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); 1H NMR
(CDCl3) d 0.14–0.19 and 0.54–0.60 (2m, 4H, cyclopro-
pyl CH2CH2), 0.86–0.91(m, H1 , cyclopropyl C H),
1.82–1.87 (m, 1H, C-15H), 2.36–2.50 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.60–2.83 (m, 4H, C-8
H2, C-10H, C-16H), 3.14–3.20 (m, 1H, C-10H), 3.20–
3.32 (m, 1H, C-9H), 4.96 (br s, 2H, C-3 OH, C-14 OH),
5.59 (s, 1H, C-5H), 6.60 (d, 1H, J=8.1Hz, C-2H), 6.70
(d, 1H, J=8.1Hz, C-1H), 7.31 (d, 1H, J=2.2 Hz, C-40
H), 7.37 (dd, 1H, J=7.6, 1.4 Hz, C-600 H), 7.54 (dt, 1H,
J=8.0, 7.6, 1.4 Hz, C-400 H), 7.66 (dt, 1H, J=7.6, 7.7,
1.4 Hz, C-500 H), 7.95 (dd, 1H, J=8.0, 1.4 Hz, C-300 H),
8.52 (dd, 1H, J=2.2, 0.5 Hz, C-60 H); MS m/z 498
(MH)+. Anal. calcd for C29H27N3O5: C, 70.01; H, 5.47;
N, 8.45. Found: C, 69.89; H, 5.74; N, 8.27.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50-(2,4-dichlorophenyl)pyrido[20,30:6,7]morph-
inan (10q). This compound was obtained from naltrex-
one and 2-(2,4-dichlorophenyl)-3-(dimethylamꢁino)acro-
lein41 by procedure B. Yield 27%, mp 145–148 C; TLC,
1
Rf 0.2 (CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); H NMR
(CDCl3) d 0.14–0.19 and 0.55–0.60 (2m, 4H, cyclopro-
pyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl CH),
1.83–1.87 (m, 1H, C-15H), 2.36–2.47 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.63–2.84 (m, 4H, C-8
H2, C-10H, C-16H), 3.17 (d, 1H, J=18.6 Hz, C-10H),
3.32 (d, 1H, J=6.4 Hz, C-9H), 4.90–5.30 (broad hump,
2H, C-3 OH, C-14 OH), 5.60 (s, 1H, C-5H), 6.59 (d, 1H,
J=8.1Hz, C-2H), 6.69 (d, 1H, J=8.1Hz, C-1H), 7.22
(dd, 1H, J=8.2, 0.2 Hz, C-600 H), 7.31(dd, 1H, J=8.2,
2.1Hz, C-5 00 H), 7.43 (d, 1H, J=2.1Hz, C-4 0 H), 7.49
(dd, 1H, J=2.1, 0.2 Hz, C-300 H), 8.58 (dd, 1H, J=2.1,
0.6 Hz, C-60 H); MS m/z 521(MH) +. Anal. calcd for
.
C29H26Cl2N2O3 0.5H2O: C, 65.67; H, 5.13; N, 5.28.
Found: 65.67; H, 4.93; N, 5.53.
50 -(2-Biphenyl)-17-(cyclopropylmethyl)-6,7-didehydro-
3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morphinan
(10o). Compound 10m (0.27 g, 0.51mmol) was reacted
with phenylboronic acid (0.094 g, 0.77 mmol) in the
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (2 - naphthyl)pyrido[20,30:6,7]morphinan
(10r). This compound was obtained from naltrexone
and 3-(dimethylamino)-2-(2-naphthyl)acrolein25 by pro-
cedure B. Yield 36%, mp 160–164 ꢁC; TLC, Rf 0.25
(CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); 1H NMR
(CDCl3) d 0.15–0.20 and 0.55–0.61 (2m, 4H, cyclopro-
pyl CH2CH2), 0.86–0.93 (m, 1H, cyclopropyl CH),
1.84–1.87 (m, 1H, C-15H), 2.36–2.49 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.67–2.87 (m, 4H, C-8
H2, C-10H, C-16H), 3.18 (d, 1H, J=18.6 Hz, C-10H),
3.33 (d, 1H, J=6.5 Hz, C-9H), 4.80–5.40 (broad hump,
2H, C-3 OH, C-14 OH), 5.63 (s, 1H, C-5H), 6.60 (d, 1H,
J=8.1Hz, C-2H), 6.69 (d, 1H, J=8.1Hz, C-1H), 7.48–
7.54 (m, 2H, C-500 H, C-600 H), 7.63 (m, 1H, C-1000 H),
7.64 (d, 1H, J=1.9 Hz, C-40 H), 7.84–7.97 (m, 4H, C-200
H, C-400 H, C-700 H, C-900 H), 8.87 (d, 1H, J=1.9 Hz, C-
60 H); MS m/z 503 (MH)+. Anal. calcd for
C33H30N2O3: C, 78.87; H, 6.02; N, 5.57. Found: C,
78.58; H, 6.09; N, 5.48.
presence
of
tetrakis(triphenylphosphine)palladium
(0.03 g, 0.026 mmol) in a biphasic medium containing
toluene (10.8 mL), EtOH (3 mL) and saturated aqueous
NaHCO3 (5.4 mL) as described for the preparation of
10k to obtain 0.098 g (36%) of the title compound 10o:
mp 122–124 ꢁC; TLC, Rf 0.3 (CH2Cl2–MeOH–NH4OH,
96.5:3:0.5); 1H NMR (CDCl3) d 0.13–0.18 and 0.53–
0.59 (2m, 4H, cyclopropyl CH2CH2), 0.85–0.90 (m, 1H,
cyclopropyl CH), 1.77–1.80 (m, 1H, C-15H), 2.32–2.74
(m, 8H, C-8 H2, C-10H, C-15H, C-16 H2, and NCH2-
cyclopropyl), 3.14 (d, 1H, J=18.7 Hz, C-10H), 3.25 (d,
1H, J=6.2 Hz, C-9H), 4.90 (br s, 2H, C-3 OH, C-14
OH), 5.50 (s, 1H, C-5H), 6.57 (d, 1H, J=8.1Hz, C-2H),
6.67 (d, 1H, J=8.1 Hz, C-1H), 7.09–7.71 (m, 10H, C-40
H0, biphenyl-H), 8.23 (d, 1H, J=2.2 Hz, C-60 H); MS m/
+
.
z 529 (MH) . Anal. calcd for C35H32N2O3 0.4H2O: C,
78.45; H, 6.17; N, 5.23. Found: C, 78.27; H, 6.27; N,
5.12.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50-(3,4-dichlorophenyl)pyrido[20,30:6,7]morph-
inan (10p). This compound was obtained from naltrex-
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (1 - naphthyl)pyrido[20,30:6,7]morphinan
(10s). This compound was obtained from naltrexone

4152
S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
and 3-(dimethylamino)-2-(1-naphthyl)acrolein42 by pro-
cedure B. Yield 24%, mp 150–154 ꢁC; TLC, Rf 0.25
(CH2Cl2–MeOH–NH4OH, 97:2.5:0.5); 1H NMR
(CDCl3) d 0.15–0.20 and 0.55–0.61 (2m, 4H, cyclopro-
pyl CH2CH2), 0.87–0.94 (m, 1H, cyclopropyl CH),
1.86–1.89 (m, 1H, C-15H), 2.38–2.48 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.66–2.88 (m, 4H, C-8
H2, C-10H, C-16H), 3.19 (d, 1H, J=18.6 Hz, C-10H),
3.34 (d, 1H, J=6.5 Hz, C-9H), 4.80–5.40 (broad hump,
2H, C-3 OH, C-14 OH), 5.67 (s, 1H, C-5H), 6.61 (d, 1H,
J=8.1Hz, C-2H), 6.72 (d, 1H, J=8.1Hz, C-1H), 70.36
(dd, 1H, J=7.1, 1.2 Hz, C-1000 H), 7.41(m, 4H, C-4 H,
C-400 H, C-500 H, C-900 H), 7.81(dd, 1H, J=8.2, 0.7 Hz,
C-600 H), 7.87–7.92 (m, 2H, C-300 H, C-800 H), 8.68 (d,
1H, J=1.9 Hz, C-60 H); MS m/z 503 (MH)+. Anal.
by procedure A. Yield 33%, mp >260 ꢁC dec; TLC, Rf
0.35 (CHCl3–MeOH–NH4OH, 97:2.5:0.5); 1H NMR
(DM2SO-d6) d 0.13–0.18 and 0.48–0.53 (2m, 4H, cyclo-
propyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl CH),
1.58–1.63 (m, 1H, C-15H), 2.20–2.41 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.61–2.73 (m, 4H, C-8
H2, C-10H, C-16H), 3.07–3.13 (m, 1H, C-10H), 3.26–
3.27 (m, 1H, C-9H), 4.83 (s, 1H, C-14 OH), 5.38 (s, 1H,
C-5H), 6.52 (app s, 2H, C-1H, C-2H), 8.15 (dd, 1H,
J=5.4, 1.4 Hz, C-500 H), 8.24 (d, 1H, J=2.1Hz, C-4 0 H),
8.91(dd, 1H, J=5.4, 0.3 Hz, C-600 H), 9.07 (s, 1H, C-3
OH), 9.27 (d, 1H, J=2.1Hz, C-6 0 H), 9.28 (dd, 1H,
J=1.4, 0.3 Hz, C-300 H); MS m/z 455 (MH)+. Anal.
calcd for C27H26N4O3: C, 71.35; H, 5.77; N, 12.33.
Found: C, 71.03; H, 5.76; N, 12.27.
.
calcd for C33H30N2O3 0.5H2O: C, 77.47; H, 6.11; N,
5.48. Found: C, 77.74; H, 6.03; N, 5.59.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (2 - pyrazinyl)pyrido[20,30:6,7]morphinan
(11d). This compound was obtained from naltrexone
hydrochloride and 2-(2-pyrazinyl)malondialdehyde by
procedure A. Yield 24%, mp 178–180 ꢁC; TLC, Rf 0.2
(CHCl3–MeOH–NH4OH, 97:2.5:0.5); 1H NMR
(CDCl3) d 0.13–0.18 and 0.48–0.53 (2m, 4H, cyclopro-
pyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl CH),
1.59–1.63 (m, 1H, C-15H), 2.17–2.41 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.61–2.72 (m, 4H, C-8
H2, C-10H, C-16H), 3.07–3.13 (m, 1H, C-10H), 3.26–
3.28 (m, 1H, C-9H), 4.83 (s, 1H, C-14 OH), 5.38 (s, 1H,
C-5H), 6.52 (app s, 2H, C-1H, C-2H), 8.17 (d, 1H,
J=2.1Hz, C-4 0 H), 8.67 (d, 1H, J=2.5 Hz, C-300 H),
8.75 (dd, 1H, J=2.5, 1.5 Hz, C-400 H), 9.07 (s, 1H, C-3
OH), ), 9.21(d, 1H, J=2.1Hz, C-6 0 H), 9.29 (d, 1H,
J=1.5 Hz, C-600 H); MS m/z 455 (MH)+. Anal. calcd
for C27H26N4O3: C, 71.35; H, 5.77; N, 12.33. Found: C,
70.93; H, 5.91; N, 12.22.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (2 - pyridinyl)pyrido[20,30:6,7]morphinan
(11a). This compound was obtained from naltrexone
hydrochloride and 2-(2-pyridyl)malondialdehyde by
procedure A. Yield 20%, mp 160–163 ꢁC; TLC, Rf 0.55
1
(CHCl3–MeOH, 9:1); H NMR (DMSO-d6) d 0.14–0.8
and 0.46–0.52 (2m, 4H cyclopropyl CH2CH2), 0.82–0.96
(m, 1H, cyclopropyl CH), 1.57–1.62 (m, 1H, C-15H),
2.18–2.25 (m, 4H, C-15H, C-16H, and NCH2-cyclopro-
pyl), 2.61–2.74 (m, 4H, C-8 H2, C-10H, C-16H), 3.05–
3.14 (m, 1H, C-10H), 3.26 (d, 1H, J=6.2 Hz, C-9H),
4.78 (s, 1H, C-14H), 5.37 (s, 1H, C-5H), 6.52 (app s, 2H,
C-1H, C-2H), 7.41 (ddd, 1H, J=7.4, 4.7, 1.1 Hz, C-500
H), 7.92 (ddd, 1H, J=8.0, 7.4, 1.7 Hz, C-400 H), 8.01
(ddd, 1H, J=8.0, 1.1, 0.8 Hz, C-300 H), 8.10 (d, 1H,
J=2.2 Hz, C-40 H), 8.69 (ddd, 1H, J=4.7, 1.7, 0.8 Hz,
C-600 H), 9.05 (s, 1H, C-3 OH), 9.18 (d, 1H, J=2.2 Hz,
C- 60 H), MS m/z 454 (MH)+. Anal. calcd for
.
C28H27N3O3 0.5H2O: C, 72.71; H, 6.10; N, 9.08. Found:
C, 72.51; H, 6.13; N, 9.15.
50 -(2-Benzoxazolyl)-17-(cyclopropylmethyl)-6,7-didehy-
dro - 3,14 - dihydroxy - 4,5ꢀ - epoxypyrido[20,30:6,7]morph-
inan (11e). This compound was obtained from naltrex-
one hydrochloride and 2-(2-benzoxazolyl)malondi-
aldehyde by procedure A. Yield 28%, mp 155–159 ꢁC;
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (4 - pyridinyl)pyrido[20,30:6,7]morphinan
(11b). This compound was obtained from naltrexone
hydrochloride and 2-(4-pyridyl)malondialdehyde by
procedure A. Yield 23%, mp 240–245 ꢁC dec; TLC, Rf
0.47 (CHCl3–MeOH, 9:1); 1H NMR (DMSO-d6) d
0.15–0.18 and 0.45–0.58 (2m, 4H cyclopropyl CH2CH2),
0.86–0.95 (m, 1H, cyclopropyl CH), 1.56–1.61 (m, 1H,
C-15H), 2.19–2.42 (m, 4H, C-15H, C-16H, and NCH2-
cyclopropyl), 2.65–2.72 (m, 4H, C-8 H2, C-10H, C-
16H), 3.06–3.14 (m, 1H, C-10H), 3.22–3.24 (m, 1H, C-
9H), 4.85 (s, 1H, C-14 OH), 5.37 (s, 1H, C-5H) 6.52
(app s, 2H, C-1H, C-2H), 7.76 (dd, 2H, J=6.2, 1.5 Hz,
C-300 H, C-500 H), 7.93 (d, 1H, J=2.0 Hz, C-40 H), 8.67
(dd, 2H, J=6.2, 1.5 Hz, C-200 H, C-600 H), 8.91(d, 1H,
1
TLC, Rf 0.36 (EtOAc); H NMR (DMSO-d6) d 0.10–
0.21and 0.44–0.56 (m, 4H, cyclopropyl C H2CH2), 0.82–
0.96 (m, 1H, cyclopropyl CH), 1.58–1.66 (m, 1H, C-
15H), 2.14–2.48 (m, 4H, C-15H, C-16H, and N-CH2
cyclopropyl), 2.60–2.86 (m, 4H, C-8 H2, C-10H, C-
16H), 3.07–3.14 (m, 1H, C-10H), 3.18–3.24 (m, 1H, C-
9H), 4.86 (s, 1H, C-14 OH), 5.34 (s, 1H, C-5H), 6.54
(app s, 2H, C-1H, C-2H), 7.42–7.51 (m, 2H, C-500 H, C-
600 H), 7.80–7.88 (m, 2H, C-400 H, C-700 H), 8.27 (d, 1H,
J=2.1Hz, C-400 H), 9.06 (s, 1H, C-3 OH), 9.28 (d, 1H,
J=2.1Hz, C-6 H), MS m/z 494 (MH)+. Anal. calcd for
.
C30H27N3O4 0.5H2O: C, 71.70; H, 5.62; N, 8.36. Found:
C, 71.38; H, 5.48; N, 8.16.
J=2.0 Hz, C-60 H), 9.06 (s, 1H, C-3 OH), MS m/z 454
+
.
(MH) . Anal. calcd for C28H27N3O3 0.5CHCl3: C,
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (2 - quinolinyl)pyrido[20,30:6,7]morphinan
(11f). This compound was obtained from naltrexone
hydrochloride and 2-(2-quinolinyl)malondialdehyde by
procedure A. Yield 22%, mp 158–160 ꢁC; TLC, Rf 0.57
(CHCl3–MeOH, 9:1); 1H NMR (DMSO-d6) d 0.10–0.20
and 0.45–0.56 (2m, 4H, cyclopropyl CH2CH2), 0.84–
0.96 (m, 1H, cyclopropyl CH), 1.56–1.62 (m, 1H, C-
66.70; H, 5.40; N, 8.19. Found: C, 67.04; H, 5.62; N,
8.08.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ-epoxy-50 -(4-pyrimidinyl)pyrido[20,30:6,7]morphinan
(11c). This compound was obtained from naltrexone
hydrochloride and 2-(4-pyrimidinyl)malondialdehyde

S. Ananthan et al. / Bioorg. Med. Chem. 11 (2003) 4143–4154
4153
15H), 2.18–2.48 (m, 4H, C-15H, C-16H, and NCH2-
cyclopropyl), 2.60–2.82 (m, 4H, C-8 H2, C-10H, C-
16H), 3.04–3.18 (m, 1H, C-10H), 3.22–3.24 (m, 1H, C-
9H), 4.80 (s, 1H, C-14 OH), 5.48 (s, 1H, C-5H), 6.52
(app s, 2H, C-1H, C-2H), 7.60–7.76 (m, 1H, C-700 H),
7.72–7.74 (m, 1H, C-600 H), 8.02 ( d, 1H, J=6.8 Hz, C-500
H), 8.08 (d, 1H, J=8.2 Hz, C-800 H), 8.17 (d, 1H,
J=8.7 Hz, 300 H), 8.28 (d, 1H, J=2.2 Hz, C-40 H), 8.52
(d, 1H, J=8.7 Hz, C-4000 H), 9.03 (s, 1H, C-3 OH), 9.34
(d, 1H, J=2.2 Hz, C-6 H), MS m/z 504 (MH)+. Anal.
encouragement, valuable comments and suggestions
during the course of this work.
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.
calcd for C32H29N3O3 0.25H2O: C, 75.64; H, 5.85; N,
8.27. Found: C, 75.38; H, 5.87; N, 8.16.
17-(Cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-
4,5ꢀ - epoxy - 50 - (4 - quinolinyl)pyrido[20,30:6,7]morphinan
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procedure A. Yield 26%, mp 240–242 ꢁC; TLC, Rf 0.2
(CHCl3–MeOH–NH4OH, 97.5:2:0.5); 1H NMR
(DMSO-d6) d 0.15–0.17 and 0.48–0.53 (2m, 4H, cyclo-
propyl CH2CH2), 0.87–0.92 (m, 1H, cyclopropyl CH),
1.61–1.65 (m, 1H, C-15H), 2.22–2.43 (m, 4H, C-15H, C-
16H, and NCH2-cyclopropyl), 2.61–2.72 (m, 4H, C-8
H2, C-10H, C-16H), 3.08–3.14 (m, 1H, C-10H), 3.27 (d,
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.
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Acknowledgements
This investigation was supported by the National Insti-
tute on Drug Abuse, Grant No. DA08883. We thank
Dr. James M. Riordan, Mr. Mark D. Richardson, Ms.
Joan C. Bearden, and Ms. Jackie W. Truss for analy-
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