7-Spiroindanyl derivatives of naltrexone and oxymorphone as selective ligands for δ opioid receptors

Article abstract of DOI:10.1021/jm9700880

A series consisting of spiroindanyl (5-7), benzospiroindanyl (8-10), and spiroperinaphthyl (11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the role of an orthogonal-oriented 'address' for δ opioid receptors. All of

Full text of DOI:10.1021/jm9700880

1720
J . Med. Chem. 1997, 40, 1720-1725
7-Sp ir oin d a n yl Der iva tives of Na ltr exon e a n d Oxym or p h on e a s Selective
Liga n d s for δ Op ioid Recep tor s
S. Ohkawa,† B. DiGiacomo,† D. L. Larson,† A. E. Takemori,‡ and P. S. Portoghese*,†
Department of Medicinal Chemistry, College of Pharmacy, and Department of Pharmacology, Medical School,
University of Minnesota, Minneapolis, Minnesota 55455
Received J anuary 7, 1997X
A series consisting of spiroindanyl (5-7), benzospiroindanyl (8-10), and spiroperinaphthyl
(11) derivatives of naltrexone and oxymorphone were synthesized in order to investigate the
role of an orthogonal-oriented “address” for δ opioid receptors. All of the ligands exhibited a
preference for δ receptors in vitro. The 7-benzospiroindanyl derivative 8 (BSINTX) was the
most selective δ opioid receptor antagonist in vitro. In mice BSINTX antagonized the δ1-
selective agonist, [D-Pen2,D-Pen5]enkephalin without significantly affecting the antinociceptive
potency of δ2, µ, and κ agonists. The results of this study are consistent with an orthogonally-
oriented address favoring δ1 activity.
In tr od u ction
to be a potent and selective δ antagonist in vitro, its in
vivo profile, while favoring δ1 receptors, had relatively
low antagonist selectivity.
It is now firmly established that there are at least
three major types of receptors (µ, κ, µ) that have high
affinity for endogenous opioid peptides.1 The enkepha-
lins appear to be generally accepted as the endogenous
ligands for δ opioid receptors, and in vivo pharmacologi-
cal studies now suggest the presence of two subtypes:
δ1 and δ2.2,3
Two nonpeptide antagonists, 7-benzylidenenaltrex-
one4 (1, BNTX) and naltriben2 (2, NTB), are presently
widely employed as δ1 and δ2 antagonists, respectively.
BNTX selectively antagonizes the agonist effect of
[D-Pen2,D-Pen5]enkephalin (DPDPE), while NTB selec-
In this paper we present the synthesis and biological
evaluation of a series of compounds (5-11) that contain
substituted spiroindanyl (5-7), benzospiroindanyl (8-
10), and spiroperinaphthyl (11) groups in an effort to
explore the structure-selectivity relationship of ligands
that possess an orthogonal aromatic system relative to
ring C of the morphinan.
Ch em istr y
tively blocks [D-Ser2,D-Leu5]enkephalin-Thr6 (DSLET)
and deltorphin II. The fact that the preferred confor-
mation of the benzylidene phenyl group is approxi-
mately orthogonal to ring C of BNTX led to the
suggestion that this orientation favors δ1 activity.5 In
contrast, the aromatic group of the δ2 antagonist, NTB,
is coplanar to ring C.
Subsequent studies involved the synthesis of 7-spiroin-
danyloxymorphone (3, SIOM) and 7-spiroindanylnal-
trexone (4, SINTX).6,7 The rationale for the design of
these ligands was to rigidly hold the benzene moiety of
the indanyl substituent in an orthogonal position rela-
tive to ring C of the morphinan because molecular
dynamics simulations of the δ1 agonist, DPDPE,8-10
revealed that many of the conformations of its Phe4
phenyl group matched BNTX better than NTB. The fact
that SIOM was more potently antagonized by BNTX
than by NTB in vivo was consistent with the orthogonal
orientation of its “address”. Although SINTX was found
The target compounds 5-11 were prepared (Scheme
1) from O-benzyl-protected derivatives of naltrexone (12)
or oxymorphone (13) by double alkylation with bis-
(bromomethyl) derivatives of methoxybenzene (14, 15)
or naphthalene (16-18). The alkylation was effected
with a combination of lithium hexamethyldisilazane
(LHMDS) and 12-crown-4 in tetrahydrofuran (THF).
The yields of the benzyl-protected spiro intermediates
5a -11a were in the range of 42-83%. In the absence
of crown ether, no product was obtained, and starting
material was recovered when the reaction was con-
ducted in THF.
The O-benzyl group of the intermediates 5a -11a was
removed by catalytic hydrogenation (Pd-C) to afford
target compounds 5-11. Compounds 5-7 and 10 were
obtained as mixtures of two C-7 epimers which were
present in approximately equal amounts.
The bis(bromomethyl) derivatives of anisole (14, 15)
and naphthalene (16-18) that were employed in the
double alkylation reaction were prepared using two
different methods. Compounds 14-16 were obtained
from the corresponding dimethyl derivatives using
† Department of Medicinal Chemistry.
‡ Department of Pharmacology.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
S0022-2623(97)00088-5 CCC: $14.00 © 1997 American Chemical Society

Spiroindan Derivatives of Naltrexone and Oxymorphone
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1721
Ch a r t 1
ligands were incubated with the preparation for 15 min
prior to testing. The standard agonists morphine (M),
ethylketazocine (EK), and [D-Ala2,D-Leu5]enkephalin14
(DADLE) were employed when testing for antagonist
activity. They are selective µ, κ, and δ opioid agonists,
respectively. Three or more replicate determinations
were carried out for each compound. The antagonist
potency is expressed as an IC50 ratio, which is the IC50
of the agonist in the presence of the antagonist (100 nM)
divided by the control IC50 in the same preparation.
Ligands that were not full agonists were tested at a
concentration of 1 µM, and the agonist activity is
expressed as a percent of the maximal response. SIOM
(3) and SINTX (4) were employed as reference com-
pounds.
All of the cyclopropylmethyl-substituted target com-
pounds (5, 7, 8, 10, 11) were δ-selective antagonists in
the MVD preparation, with IC50 ratios ranging from 12
to 85 for DADLE (Table 1). The most δ-selective
antagonist in the series was the benzoindanyl analog 8
(BSINTX) which was more selective than SINTX. Most
of the cyclopropyl-substituted compounds exhibited
partial agonist activity in the smooth muscle prepara-
tions. This ranged up to 14% in the MVD and 52% in
the GPI. The N-methyl derivative 6 was found to be a
full agonist in the MVD and GPI, with a potency in the
MVD about the same as that of SIOM (3).
In Vivo Stu d ies. Compounds 5, 6, 8, and 9 were
evaluated for opioid agonist or antagonist activity using
the tail-flick15 procedure in ICR mice. The o-methoxy-
spiroindan 6 exhibited agonist activity (icv), with an
ED50 of 71 (57-90) nmol/mouse. The benzospiroindan
analogs 8 and 9 were inactive as agonists at 80 nmol/
mouse icv and 60 µmol/kg sc, respectively.
The ability of 5, 8, and 9 to antagonize the antinoci-
ceptive effect of selective agonists is reported as ED50
ratios in Table 2. Administration of 5, 8, or 9 was timed
so that the peak antagonistic effect (20 min) coincided
with the center of the observation period. The ED50
values of the standard agonists [D-Pen2,D-Pen5]en-
kephalin16 (DPDPE), [D-Ser2,Leu5]enkephalin-Thr617
(DSLET), morphine, and trans-(()-dichloro-N-methyl-
N-(2-pyrrolidinylcyclohexyl)benzeneacetamide18 (U50488)
were determined alone and in the presence of 5, 8, or
9. At a dose of 10 nmol icv, 8 antagonized the δ1 agonist,
DPDPE, without significant antagonism of the δ2-, µ-,
or κ-selective ligands. Compound 5 was nonselective,
as suggested by ED50 ratios that were greater than unity
for all of the standard agonists. The oxymorphone
N-bromosuccinimide and benzoylperoxide in carbon
tetrachloride (method 1). The bis(bromomethyl)naph-
thalenes 17 and 18 were prepared by reduction of the
corresponding dicarboxylic acid or anhydride with lithium
aluminum hydride in THF followed by treatment of the
diols 17a and 18a with phosphorous tribromide (method
2).
Biologica l Resu lts
Sm ooth Mu scle P r ep a r a tion s. The opioid activity
of 5-11 was evaluated on the electrically-stimulated
guinea pig ileum11 (GPI) and the mouse vas deferens12
(MVD) preparations as reported previously.13 The
Ta ble 1. Opioid Agonist and Antagonist Potencies of 7-Spiroindanyl Derivatives of Naltrexone and Oxymorphone
GPI MVD
antagonism IC50 ratio
antagonist selectivity ratioc
agonismb IC50
antagonism IC50
agonismb IC50
compd
M (µ)
EK (κ)
(nM) or % max resp ratio DADLE (δ) (nM) or % max resp
δ/µ
δ/κ
3 (SIOM)
4 (SINTX)
5
6
7
8 (BSINTX) 3.4 ( 1.2
9
10
11
1.2 ( 0.5
24.9 ( 4.3
6.2 ( 1.1
d
0.99 ( 0.33
1.95 ( 0.47
2.40 ( 0.37
d
2.8 ( 0.6
0.24 ( 0.04
55 ( 11%
d
23 ((9) nM
-8 ( 6%
16 ( 9%
130 ( 30
85 ( 15
d
11.8 ( 2.4
48 ( 11
1.1 ( 0.3
25 ( 6
12.6 ( 2.5
5.2
67
-4.5 ( 5.3%
148 ( 51 nM
-52 ( 49%
52 ( 2%
13.4 ( 6.7%
13.9 ( 4.5%
11.2 ( 6.3%
-18 ( 13%
27 ( 9 nM
0.6 ( 9%
13.7
35
6.9 ( 1.7
1.7
4.2
4.9 ( 6.5%
57 ( 6%
14.1
1.0
48
1.0
0.58 ( 0.08 1.2 ( 0.4
1.0 ( 0.3 1.7 ( 0.7
0.93 ( 0.10 0.78 ( 0.22
14 ( 8%
25
12.6
14.7
12.6
17.6 ( 2.7%
a
b
Ratio of agonist IC50 values with and without antagonist present. Partial agonist activity is expressed as the percentage inhibition
of contraction at a concentration of 1 µM. Full agonist activity is expressed as an IC50 (nM). c The δ IC50 ratio divided by the µ or κ IC50
ratio; if the IC50 ratio is less than unity a minimum value of 1 is employed in the calculation. Not determined due to full agonist activity.
d

1722 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Ohkawa et al.
Sch em e 1
Ta ble 2. Antagonism of the Antinociceptive Effect of Opioid Agonists by 5, 8, and 9 in Mice
ED50 ratio (95% confidence limits)a
compdb
DPDPE (δ1)c
DSLET (δ2)c
morphine (µ)d
U50488 (κ)d
1 (BNTX)e
5
8 (BSINTX)
9
7.2 (5.2-10.5)
5.6 (3.4-9.1)
4.4 (2.6-7.1)
1.5 (1.0-2.1)
0.91 (0.37-2.0)
4.3 (2.6-8.3)
1.5 (1.0-2.2)
0.9 (0.7-1.3)
0.80 (0.47-2.1)
2.5 (1.2-6.7)
0.8 (0.3-1.6)
2.0 (1.4-2.9)
1.2 (1.0-1.6)
3.4 (1.9-7.7)
0.8 (0.3-2.3)
3.0 (1.9-5.3)
a
b
ED50 ratio ) ED50 of agonist in the presence of icv-administered antagonist divided by the control ED50
.
Compounds 5 and 9 were
tested as HCl salts at a dose of 5 nmol; 8 was tested as the phosphate salt at a dose of 10 nmol. c Administered icv. Administered sc.
d
e Taken from ref 4.
Ta ble 3. Opioid Receptor Binding
for this result could be a noncompetitive type of inter-
action. While the ligands exhibited greater affinity for
δ receptors, the binding of 6 and 9 was not much greater
than to µ receptors. Compound 5 possessed the highest
δ1/µ selectivity ratio, with a value of 17. It can be noted
that the cyclopropylmethyl compounds 4, 5, and 8 more
effectively inhibited [3H]NTI binding when compared to
the methyl analogs 3, 6, and 9. All four ligands had
very low affinity for κ receptors.
Ki, nM
compdb
[3H]NTI (δ)
[3H]DAMGO (µ) [3H]U69594 (κ)
3a
4b
5
6
8
2.75 ( 0.42 (3)
0.25 ( 0.06 (6)
14.3 ( 3.9 (8)
>3000 (2)
1.53 ( 0.62 (3) >3000 (3)
0.028 ( 0.013 (3) 0.44 ( 0.11 (3) >3000 (2)
5.49 ( 1.47 (4)
c
31.6 ( 14.4 (3)
9.24 ( 3.06 (3) >3000 (2)
7.81 ( 1.56 (4)
125 ( 48 (3)
1029 ( 369 (4)
>3000 (4)
9
Data obtained from ref 6. Data obtained from ref 7. c Appar-
a
b
ent noncompetitive inhibition of [3H]NTI binding.
Discu ssion
In an effort to explore the conformational role of the
“address” moiety in conferring δ selectivity to nonpep-
tide opioid ligands, we have previously reported on the
conformationally-restricted 6-spiroindanyl opiates 3 and
4 and their substantially greater preference for δ
receptors relative to the corresponding parent com-
pounds oxymorphone and naltrexone.6,7 It was con-
cluded that both coplanar and orthogonal conformations
(relative to ring C of the opiate) of the aromatic address
moiety are capable of conferring δ antagonist activity.
However, the δ1 agonism appeared to be associated with
an orthogonal-like conformation of the address. The
present study was undertaken to investigate further the
role of an orthogonally-oriented address moiety with
regard to the nature of the aromatic group.
derivative 9 appeared to marginally antagonize the κ
antagonist, U50488, with little or no antagonism of
other selective agonists.
Bin d in g. Opioid receptor binding data for com-
pounds 5, 6, 8, and 9 were obtained with ICR mouse
brain membranes using a modification of the procedure
of Werling et al.19 Binding was evaluated by competi-
tion of the compounds with the following selective radio-
ligands: [3H]naltrindole20,21 ([3H]NTI) (δ), [3H][D-Ala2,-
Glyol5]enkephalin17 ([3H]DAMGO) (µ), and [3H]-5R,7R,8â-
(-)-N-methyl-N-(1-pyrroldinyl)-1-oxaspiro[4.5]dec-8-yl-
benzeneacetamide22 ([3H]U69593).
The Ki values are reported in Table 3. The binding
of BSINTX (8) to δ sites could not be determined due to
the very flat competition curve over a 9 decade concen-
tration range. This was characterized by the inhibition
of [3H]NTI binding (40% bound) at exceptionally low
concentrations (10-16 M) of 8. One possible explanation
The attachment of a methoxy substituent to the
6-spiroindanyl group (5-7) or the replacement of the
benzene moiety with naphthalene (8-11) afforded ligands

Spiroindan Derivatives of Naltrexone and Oxymorphone
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1723
obtained on a Finnigan 40000, a AEIMS-30, or a VG7070EHF
spectrometer. All reagents and solvents were reagent grade.
Naltrexone and oxymorphone were supplied by Mallinckrodt.
Meth od 1: Bis(br om om eth yl)a r yl Der iva tives fr om
Dim eth yla n isole a n d Dim eth yln a p h th a len e. 2,3-Bis-
(br om om eth yl)a n isole (14). A mixture of 2,3-dimethylani-
sole (5.0 g, 36.5 mmol), N-bromosuccinimide (13.0 g, 73.4
mmol), and benzoyl peroxide (40 mg) in carbon tetrachloride
(75 mL) was refluxed for 15 h. The resulting succinimide was
removed by filtration, and the filtrate was concentrated in
vacuo. The residue was chromatographed on silica gel (chlo-
roform-hexane, 1:4) and then recrystallized from ether-
hexane to afford 14 (5.4 g, 68%): mp 78-79 °C; 1H NMR
(CDCl3) δ 3.82 (3H, s), 4.63 (2H, s), 6.84 (1H, dd, J ) 8.4, 2.4
Hz), 6.91 (1H, d, J ) 2.4 Hz), 7.30 (1H, d, J ) 8.4 Hz).
3,4-Bis(br om om eth yl)a n isole (15): yield 65%; mp 49-50
with reduced δ agonist and antagonist potency relative
to the unsubstituted spiro prototypes 3 and 4 when
tested in smooth muscle preparations. However, be-
cause these modifications generally reduced µ and κ
antagonist components to a greater degree than δ
antagonist potency, the δ/µ and δ/κ selectivity ratios are
in most cases greater.
Two of the more potent compounds (5, 8) in the
cyclopropylmethyl series were evaluated for antagonist
activity in mice. Although the binding data indicated
5 to be a high-affinity, δ-selective ligand, its in vivo
profile showed it to be nonselective. In contrast to 5,
the benzospiroindanyl derivative 8 (BSINTX) antago-
nized only the antinociceptive effect of the δ1 agonist,
DPDPE. No Ki value could be determined for BSINTX
because of the flat binding curve that spanned a nine
decade concentration range. It was observed that even
at a concentration of 10-16 M BSINTX, the maximum
percentage of [3H]NTI bound was only 40% and in
marked contrast with the normal binding curves ob-
tained from competition with µ and κ radioligands. The
results suggest that the binding sites for [3H]NTI and
BSINTX on the δ receptor may differ.
Although BSINTX (8) was a partial agonist in the
GPI, with no agonist activity in the MVD, it exhibited
no significant agonist activity in vivo. The N-methyl
analog 9 also was inactive as an agonist in vivo, but in
contrast to BSINTX, it displayed nonselective antago-
nist activity in mice. The binding selectivity of 9 was
low for δ receptors, but because of the unusual binding
of 8, a direct comparison of these compounds was not
possible. The spiroindanyl analog 6 exhibited agonist
activity in mice consistent with full agonist activity in
both smooth muscle preparations. The finding that 6
had approximately the same affinity for δ and µ recep-
tors suggests that the in vivo agonist activity was
mediated through both δ and µ receptors.
The marked difference in affinity between 5 and 6
(∼200-fold) for δ sites and the dramatic disparity
between the binding of 8 and 9 suggests profoundly
different modes of interaction with δ receptors for the
N-methyl and N-cyclopropylmethyl analogs. The re-
ported7 different conformational requirement for the
“address” moiety of δ agonists and antagonists also is
consistent with the present study in that it may also
be due to different modes of interaction with the
receptor.
1
°C; H NMR (CDCl3) δ 3.90 (3H, s), 4.62 (2H, s), 4.75 (2H, s),
6.87 (1H, d, J ) 8.4 Hz), 6.98 (1H, d, J ) 8.4 Hz), 7.27 (1H, t,
J ) 8.4 Hz).
1,2-Bis(br om om eth yl)n a p h th a len e (16): yield 82%; mp
149-150 °C; 1H NMR (CDCl3) δ 4.77 (2H, s), 5.10 (2H, s), 7.43
(1H, d, J ) 8.7 Hz), 7.54 (1H, m), 7.64 (1H, m), 7.85 (2H, m),
8.15 (1H, d, J ) 8.7 Hz).
Meth od 2: Bis(br om om eth yl)n aph th alen es fr om Naph -
t h a len ed ica r b oxylic Acid s. 2,3-Bis(h yd r oxym et h yl)-
n a p h th a len e (17a ). To a suspension of LAH (1.7 g, 44.2
mmol) in THF (50 mL) was added a solution of dimethyl 2,3-
naphthalenedicarboxylate (5.4 g, 22.1 mmol) in THF (20 mL),
and the mixture was refluxed for 18 h. The cooled mixture
was poured into ice-water, neutralized with 1 N HCl, and
extracted with EtOAc. The extract was washed with water,
dried over anhydrous MgSO4, and concentrated. The crystals
of 17a (2.8 g, 67%), were collected and dried in vacuo: mp 160-
1
161 °C, H NMR (CDCl3) δ 4.67 (4H, d, J ) 4.8 Hz), 5.23 (2H,
t, J ) 4.8 Hz), 7.42 (2H, m), 7.85 (4H, m).
1,8-Bis(h yd r oxym eth yl)n a p h th a len e (18a ): yield from
1,8-naphthalic anhydride, 53%; mp 157-158 °C; 1H NMR
(DMSO-d6) δ 5.05 (4H, d, J ) 6.0 Hz), 5.25 (2H, d, J ) 6.0
Hz), 7.42 (2H, d, J ) 8.0 Hz), 7.59 (2H, d, J ) 8.0 Hz), 7.83
(2H, d, J ) 8.0 Hz).
2,3-Bis(br om om eth yl)n a p h th a len e (17). To a solution
of 17a (2.0 g, 10.6 mmol) in THF (30 mL) was added PBr3 (3.8
g, 14.2 mmol), and the mixture was refluxed for 1 h and then
cooled. The mixture was diluted with water, and the product
was extracted with EtOAc. The extract was washed with
aqueous sodium bicarbonate solution and dried and the solvent
removed. The residue was recrystallized from chloroform-
1
hexane to afford 17 (2.7 g, 81%): mp 147-148 °C; H NMR
(CDCl3) δ 4.89 (4H, s), 4.52 (2H, m), 7.81 (2H, m), 7.87 (2H,
s).
1,8-Bis(br om om eth yl)n a p h th a len e (18): from 18a using
the same procedure, yield 83%; mp 131-132 °C; 1H NMR
(CDCl3) δ 5.31 (4H, s), 7.46 (2H, t, J ) 14.7 Hz), 7.63 (2H, d,
J ) 14.7 Hz), 7.89 (2H, d, J ) 14.7 Hz).
3-O-Ben zyl-7-(4′-m eth oxy-2′-sp ir oin d a n yl)n a ltr exon e
(5a ). To a solution of hexamethyldisilazane (0.4 mL, 1.8 mmol)
and 12-crown-4 (0.24 g, 1.38 mmol) in THF (4 mL) was added
a 2.5 M solution of n-BuLi in hexane (0.54 mL, 1.38 mmol) at
-78 °C with stirring. After the mixture stirred for 10 min, a
solution of 3-O-benzylnaltrexone (200 mg, 0.46 mmol) in THF
(2 mL) was added followed by a solution of 3,4-bis(bromo-
methyl)anisole (15) (320 mg, 1.5 mmol). The mixture was
allowed to stand for 15 min at room temperature and then
refluxed for 3 h. The cooled mixture was diluted with brine,
and the product was extracted with EtOAc. The extract was
washed with brine and dried, and the solvent was removed.
The residue was chromatographed on silica gel (hexane-
EtOAc, 4:1) to afford a mixture of 5a epimers (217 mg, 83%):
In conclusion, the present study has uncovered a
selective δ1 opioid receptor antagonist, BSINTX (8). The
δ1 selectivity of BSINTX appears in part to be a
consequence of its orthogonal aromatic “address” moiety.
In this connection, it has been suggested from prior
studies that factors such as differential access to δ
receptor subtypes might also contribute to such selectiv-
ity.23 Finally, while the in vitro and in vivo pharmacol-
ogy suggests that BSINTX mediates its antagonist
activity through δ receptors, it appears that BSINTX
might not share the same recognition site as the
prototypical δ antagonist naltrindole (NTI).
high-resolution MS (FAB) (M + H+) 564.2772 (calcd for C36H38
-
NO5 564.2750); 1H NMR (CDCl3) δ 0.14 (2H, m, H-20â, H-21â),
0.55 (2H, m, H-20R, H-21R), 0.85 (1H, m, H-19), 1.56 (1H, d,
J ) 12.3 Hz, H-15), 1.70 (1H, br s, 14-OH), 1.83 (1H, d, J )
13.5 Hz, H-8), 2.06 (1H, d, J ) 13.5 Hz, H-8), 2.10 (1H, m,
H-15), 2.37 (1H, d, J ) 17.1 Hz, indan CH2), 2.35-2.55 (3H,
m, H-16, H-18), 2.58 (1H, hidden, H-10), 2.71 (1H, d, J ) 8.4
Hz), 3.03 (1H, d, J ) 18.3 Hz, H-10), 3.13 (1H, d, J ) 4.8 Hz,
Exp er im en ta l Section
Melting points were determined in open capillary tubes with
a Thomas-Hoover melting point apparatus and are uncor-
rected. Analyses were performed by M-H-W Laboratories,
Phoenix, AZ. NMR spectra were recorded at ambient tem-
perature on a GE 300 MHz spectrometer. Mass spectra were

1724 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11
Ohkawa et al.
H-9), 3.21 and 3.23 (1H, d, J ) 17.1 Hz, indan CH2), 3.52 and
3.54 (1H, d, J ) 17.1 Hz, indan CH2), 3.75 (1H, d, J ) 17.1
Hz, indan CH2), 3.78 and 3.80 (3H, s, OMe), 5.01 and 5.06 (1H,
s, H-5), 5.21 (1H, d, J ) 12.3 Hz, Bz CH2), 5.36 (1H, d, Bz
aromatic H), 6.74 (1H, d, J ) 7.5 Hz, H-2), 6.78 (1H, d, J )
7.5 Hz, Bz aromatic H).
3-O-Be n zyl-7-(4′-m e t h oxy-2′-sp ir oin d a n yl)oxym or -
p h on e (6a ): yield 25%; FAB-MS m/ z 524 [M + H]+; 1H NMR
(CDCl3) δ 7.38 (m, 5H, Bz aromatic H), 7.08 (m, 1H, indan
aromatic H), 6.77 (m, 1H, indan aromatic H), 6.74 (d, 1H, J )
8.4 Hz, H-2), 6.62 (d, 1H, J ) 7.8 Hz, indan aromatic H), 6.58
(d, 1H, J ) 8.4 Hz, H-1), 5.38 (d, 1H, J ) 11.7 Hz, Bz CH2),
5.21 (d, 1H, J ) 11.7 Hz, Bz CH2), 5.05 and 5.00 (2s, 1H, H-5),
3.80 and 3.77 (2s, 3H, OCH3), 3.75 (m, 2H, indan CH2), 3.52
and 3.21 (m, 2H, indan CH2), 3.13 (d, 1H, J ) 18.9 Hz, H-10â),
2.82 (d, 1H, J ) 5.4 Hz, H-9), 2.39 (s, 3H, NCH3).
H-15), 2.29 (2H, m, H-18), 2.45 (1H, hidden, H-16), 2.50 (1H,
br s, 14-OH), 2.52 (1H, d, J ) 18.3 Hz, H-10), 2.57 (1H, d, J )
15.9 Hz, naphthyl CH2), 2.72 (1H, dd, J ) 12.3, 5.1 Hz, H-16),
2.91 (1H, s, H-9), 2.94 (1H, d, J ) 18.3 Hz, H-10), 3.42 (1H, d,
J ) 15.9 Hz, naphthyl CH2), 3.45 (1H, d, J ) 15.9 Hz), 3.92
(1H, d, J ) 15.9 Hz, naphthyl CH2), 5.04 (1H, s, H-5), 5.24
(1H, d, J ) 12.0 Hz, Bz CH2), 5.34 (1H, d, J ) 12.0 Hz, Bz
CH2), 6.55 (1H, d, J ) 8.4 Hz, H-1), 6.76 (1H, d, J ) 8.4 Hz,
H-2), 7.13 (1H, d, J ) 3.6 Hz, naphthyl H), 7.20-7.60 (8H, m,
Bz aromatic H, naphthyl H), 7.66 (1H, d, J ) 8.4 Hz, naphthyl
H), 7.70 (1H, d, J ) 8.7 Hz, naphthyl H).
7-(4′-Meth oxy-2′-sp ir oin d a n yl)n a ltr exon e (5). A solu-
tion of 5a (170 mg, 0.3 mmol) in EtOH with a few drops of 1
N HCl was stirred for 10 h with 10% Pd-C under H2 at
atmospheric pressure. The catalyst was removed by filtration,
and the filtrate was evaporated. To the residue were added
EtOAc and aqueous sodium bicarbonate solution, and the
mixture was shaken. The organic layer was separated, dried,
and evaporated. The residue was chromatographed on silica
gel (hexane-EtOAc, 2:1) to afford 5 (90 mg, 63%), which was
dissolved in EtOH and treated with a few drops of HCl. The
solution was evaporated, the residue was again dissolved in
3-O-Ben zyl-7-(5′-m eth oxy-2′-sp ir oin d a n yl)n a ltr exon e
(7a ): yield 83%; 1H NMR (CDCl3) δ 0.15 (2H, m, H-20â,
H-21â), 0.55 (2H, m, H-20R, H-21R), 0.86 (1H, m, H-19), 1.25
(1H, br s, OH), 1.57 (1H, d, J ) 9.9 Hz, H-15), 1.82 and 1.83
(1H, d, J ) 13.2 Hz, H-8), 2.04 (1H, d, J ) 13.2 Hz, H-8), 2.11
(1H, t, J ) 10.8 Hz, H-15), 2.33 (1H, d, J ) 14.4 Hz, indan
CH2), 2.40 (2H, m, H-18), 2.48 (1H, m, H-16), 2.58 (1H, dd, J
) 18.3, 3.6 Hz, H-10), 2.71 (1H, d, J ) 11.1 Hz), 3.03 (1H, d,
J ) 18.3 Hz, H-10), 3.13 (1H, d, J ) 4.8 Hz, H-9), 3.18 and
3.20 (1H, d, J ) 16.8 Hz, indan CH2), 3.43 and 3.46 (1H, d, J
) 16.8 Hz, indan CH2), 3.79 (1H, d, J ) 16.8 Hz, indan CH2),
4.07 (3H, s, OMe), 5.02 (1H, s, H-5), 5.21 (1H, d, J ) 12.3 Hz,
Bz CH2), 5.36 (1H, d, J ) 12.3 Hz, Bz CH2), 6.58 (1H, d, J )
8.4 Hz, H-1), 6.63-6.75 (2H, m, indan aromatic H), 6.74 (1H,
d, J ) 8.4 Hz, H-2), 6.74 (1H, d, J ) 8.4 Hz, indan aromatic
H), 7.04 (1H, m, indan aromatic H), 7.25-7.50 (5H, m, Bz
aromatic H).
3-O-Ben zyl-7-(5′,6′-b en zo-2′-sp ir oin d a n yl)n a lt r exon e
(8a ): yield 68%; 1H NMR (CDCl3) δ 0.15 (2H, m, H-20â,
H-21â), 0.55 (2H, m, H-20R, H-21R), 0.86 (1H, m, H-19), 1.59
(1H, d, J ) 12.3 Hz, H-15), 1.87 (1H, br s, 14-OH), 1.87 (1H,
d, J ) 14.7 Hz, H-8), 2.05 (1H, d, J ) 14.7 Hz, H-8), 2.13 (1H,
t, J ) 9.6 Hz, H-15), 2.39 (2H, m, H-16), 2.54 (1H, d, J ) 15.9
Hz, indan CH2), 2.54 (2H, hidden, H-18), 2.66 (1H, m, H-10),
3.04 (1H, d, J ) 18.3 Hz, H-10), 3.14 (1H, d, J ) 3.6 Hz, H-9),
3.40 (1H, d, J ) 16.3 Hz, indan CH2), 3.64 (1H, d, J ) 16.3
Hz, indan CH2), 3.95 (1H, d, J ) 15.9 Hz, indan CH2), 5.03
(1H, s, H-5), 5.21 (1H, d, J ) 11.1 Hz, Bz CH2), 5.35 (1H, d, J
) 11.1 Hz, Bz CH2), 6.59 (1H, d, J ) 8.7 Hz, H-1), 6.75 (1H, d,
J ) 8.7 Hz, H-2), 7.25-7.50 (7H, m, naphthyl H, Bz aromatic
H), 7.60 (2H, s, naphthyl H), 7.72 (2H, m, naphthyl H).
3-O-Be n zyl-7-(5′,6′-b e n zo-2′-sp ir oin d a n yl)oxym or -
p h on e (9a ): yield 48%; mp 207 °C; FAB-MS m/ z 544 [M +
H]+; 1H NMR (CDCl3) δ 7.73-7.70 (m, 2 H, naphthyl H), 7.60
(s, 2H, naphthyl H), 7.47 (m, 2H, naphthyl H), 7.39-7.21 (m,
5H, Bz aromatic H), 6.76 (d, 1H, J ) 7.8 Hz, H-2), 6.61 (d, 1H,
J ) 8.4 Hz, H-1), 5.35 (d, 1H, J ) 11.7 Hz, Bz CH2), 5.21 (d,
1H, J ) 11.7 Hz, Bz CH2), 5.02 (s, 1H, C-5), 3.93 (d, 1H, J )
17.1 Hz, indan CH2), 3.63 (d, 1H, J ) 15.9 Hz, indan CH2),
3.40 (d, 1H, J ) 17.1 Hz, indan CH2), 3.14 (d, 1H, J ) 18.3
Hz, H-10â), 2.85 (m, 1H, H-9), 2.41 (s, 3H, NCH3).
EtOH, and Et2
O was added. The resulting solid was collected,
washed with Et2O, and dried to afford an epimeric mixture of
5‚HCl (75 mg, 75%): mp 225-230 °C dec; HRMS (FAB) (M +
H
+) 474.2281 (calcd for C29H32NO5 474.2280); 1H NMR (CDCl3)
δ 0.13 (2H, m, H-20â, H-21â), 0.54 (2H, m, H-20R, H-21R), 0.85
(1H, m, H-19), 1.52 (1H, d, J ) 12.0 Hz, H-15), 1.82 (1H, d, J
) 9.0 Hz, H-8), 2.04 (1H, d, J ) 9.0 Hz, H-8), 2.04 (1H, d, J )
9.0 Hz, H-8), 2.12 (1H, t, J ) 12.0 Hz, H-15), 2.29 (1H, d, J )
15.9 Hz, indan CH2
), 2.32-2.50 (3H, m, H-16, H-18), 2.57 (1H,
dd, J ) 18.3, 4.8 Hz, H-10), 2.70 (1H, d, J ) 8.7 Hz, H-16),
3.03 (1H, d, J ) 18.3 Hz, indan CH2), 3.14 (1H, d, J ) 2.7 Hz,
H-9), 3.18 and 3.21 (1H, d, J ) 15.6 Hz, indan CH2), 3.47 and
3.50 (1H, d, J ) 15.6 Hz, indan CH2), 3.74 (1H, d, J ) 18.3
Hz, indan CH2), 3.77 and 3.80 (3H, s, OMe), 4.96 and 4.99 (1H,
s, H-5), 6.60 (1H, d, J ) 8.7 Hz, H-1), 6.63 (1H, d, J ) 8.4 Hz,
indan aromatic H), 6.73 (1H, d, J ) 8.7 Hz, H-2), 6.75 (1H,
hidden, indan aromatic H), 7.10 (1H, t, J ) 8.4 Hz, indan
aromatic). Anal. (C29H31NO5‚HCl) C, H, N.
7-(4′-Meth oxy-2′-sp ir oin d a n yl)oxym or p h on e (6): yield
58%; FAB-MS m/ z 434 [M + H]+, 432 [M - H]-; 1H NMR
(CDCl3) δ 7.09 (t, 1H, J ) 7.8 Hz, indan aromatic H), 6.76 and
6.63 (2d, 2H, J ) 7.8 Hz, indan aromatic H), 6.74 (d, 1H, J )
8.4 Hz, H-2), 6.58 (d, 1H, J ) 8.7 Hz, H-1), 4.97 (s, 1H, H-5),
3.80 and 3.76 (2s, 3H, OCH3), 3.54 and 3.50 (2d, 1H, J ) 15.9
Hz, indan CH2), 3.22 and 3.18 (2d, 1H, J ) 17.4 Hz, indan
CH2), 3.11 (d, 1H, J ) 18.9 Hz, H-10â), 2.84 (d, 1H, J ) 5.4
Hz, H-9), 2.37 and 2.36 (2s, 3H, NCH3); 13C NMR (CDCl3) δ
210.67 (C-6), 156.46 and 156.28 (indan C-1), 120.38 and 120.35
(C-1), 118.88 and 118.81 (C-2), 117.38 and 117.08 (indan C-2),
89.83 and 89.78 (C-5), 65.37 (C-14), 55.91 and 55.78 (OCH3).
Anal. (C26H27NO5‚HCl‚1.5H2O) C, H, N.
7-(5′-Meth oxy-2′-sp ir oin d a n yl)n a ltr exon e (7): yield 63%;
1H NMR (CDCl3) δ 0.14 (2H, m, H-20â, H-21â), 0.54 (2H, m,
H-20R, H-21R), 0.85 (1H, m, H-19), 1.25 (1H, s, OH), 1.53 (1H,
dd, J ) 13.2, 2.4 Hz, H-15), 1.81 and 1.82 (1H, d, J ) 13.4 Hz,
H-8), 2.03 (1H, d, J ) 14.4 Hz, H-8), 2.13 (H, dt, J ) 12.3, 2.4
Hz, H-15), 2.32 (1H, d, J ) 15.9 Hz, indan CH2), 2.39 (2H, m,
H-18), 2.46 (1H, dd, J ) 12.3, 3.6 Hz, H-16), 2.56 (1H, dd, J )
19.5, 6.0 Hz, H-10), 2.70 (1H, dd, J ) 12.3, 3.6 Hz, H-16), 3.03
(1H, d, 3.40) or 3.42 (1H, d, J ) 15.9 Hz, indan CH2), 3.76
(3H, s, OMe), 3.78 (1H, d, J ) 14.7 Hz, indan CH2), 4.95 and
4.96 (1H, s, H-5), 6.59 (1H, d, J ) 8.7 Hz, H-1), 6.64-6.72 (2H,
m, indan aromatic H), 6.73 (1H, d, J ) 8.7 Hz, H-2), 7.03 (1H,
t, J ) 7.2 Hz, indan aromatic CH); HRMS (FAB) (M + H)+
474.2281 (calcd for C29H32NO5 474.2280). Anal. (C29H31NO5‚
HCl‚2H2O) C, H, N.
3-O-Ben zyl-7-(4′,5′-b en zo-2′-sp ir oin d a n yl)n a lt r exon e
(10a ): yield 42%; 1H NMR (CDCl3) δ 0.14 (2H, m, H-20â,
H-21â), 0.50 (2H, m, H-20R, H-21R), 0.87 (1H, m, H-19), 1.43
(1H, d, J ) 14.4 Hz, H-15), 1.90 and 1.93 (1H, d, 14.2 Hz, H-8),
2.12 (1H, br s, 14-OH), 2.15 (1H, J ) 14.2 Hz, H-8), 2.25-2.80
(6H, m, H-10, H-15, H-16, H-18, indan CH2), 2.54 (2H, hidden,
H-18), 3.05 (1H, d, J ) 18.6 Hz, H-10), 3.15 (1H, d, J ) 4.8
Hz, H-9), 3.36 and 3.56 (1H, d, J ) 17.0 Hz, indan CH2), 3.74
and 3.99 (1H, d, J ) 15.8 Hz, indan CH2), 4.18 (1H, d, J )
16.2 Hz, indan CH2), 5.07 and 5.08 (1H, s, H-5), 5.22 (1H, d, J
) 12.0 Hz, Bz CH2), 5.35 (1H, d, J ) 12.0 Hz, Bz CH2), 6.59
(1H, d, J ) 8.2 Hz, H-1), 6.75 and 6.76 (1H, d, J ) 8.2 Hz,
H-2), 7.20-7.60 (8H, m, naphthyl H, Bz aromatic H), 7.60-
7.90 (3H, s, naphthyl H).
7-(5′,6′-Ben zo-2′-sp ir oin d a n yl)n a ltr exon e (8): yield 68%;
1H NMR (CDCl3) δ 0.14 (2H, m, H-20â, H-21â), 0.54 (2H, m,
H-20R, H-21R), 0.85 (1H, m, H-19), 1.25 (1H, s, 14-OH), 1.51
(1H, dd, J ) 12.3, 2.4 Hz, H-15), 1.86 (1H, d, J ) 14.7 Hz,
H-8), 2.04 (1H, d, J ) 14.7 Hz, H-8), 2.12 (1H, dt, J ) 12.3,
3.6 Hz, H-15), 2.39 (2H, m, H-18, H-16), 2.53 (1H, d, J ) 16.8
Hz, indan CH2), 2.56 (1H, dd, J ) 18.3, 6.0 Hz, H-10), 2.69
(1H, d, J ) 18.3 Hz, H-16), 3.03 (1H, d, J ) 18.3 Hz, H-10),
3-O-Ben zyl-7-(2′,3′-d ih yd r o-2′-sp ir op er in a p h t h en yl)-
1
n a ltr exon e (11a ): yield 79%; H NMR (CDCl3) δ 0.06 (2H,
m, H-20â, H-21â), 0.48 (2H, m, H-20R, H-21R), 0.76 (1H, m,
H-19), 1.48 (1H, d, J ) 13.2 Hz, H-8), 1.60 (1H, dd, J ) 12.3,
2.4 Hz, H-15), 1.79 (1H, d, J ) 13.2 Hz, H-8), 2.05 (1H, m ,

Spiroindan Derivatives of Naltrexone and Oxymorphone
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 11 1725
(4) Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori, A. E. A
Highly Selective δ1-Opioid Receptor Antagonist: 7-benzylidenen-
altrexone. Eur. J . Pharmacol. 1992, 218, 195-196.
3.13 (1H, d, J ) 4.8 Hz, H-9), 3.37 (1H, d, J ) 16.8 Hz, indan
CH2), 3.58 (1H, d), 6.60 (1H, d, J ) 8.7 Hz, H-1), 6.73 (1H, d,
J ) 8.7 Hz, H-2), 7.37 (2H, m, naphthyl H), 7.59 (2H, s,
naphthyl H), 7.73 (2H, m, naphthyl H); HRMS (FAB) (M +
(5) Portoghese, P. S. The Design of δ-Selective Opioid Receptor
Antagonists. Farmaco 1993, 48, 243-251.
H)+ 494.2334 (calcd for C32H32NO4 494.2331). Anal. (C32H31
-
(6) Portoghese, P. S.; Moe, S. T.; Takemori, A. E. A Selective δ1
Opioid Receptor Agonist Derived from Oxymorphone. Evidence
for Separate Recognition Sites for δ1 Opioid Receptor Agonists
and Antagonists. J . Med. Chem. 1993, 36, 2572-2574.
(7) Portoghese, P. S.; Sultana, M.; Moe, S. T.; Takemori, A. E.
Synthesis of Naltrexone-Derived δ-Opioid Antagonists. Role of
Conformation of the δ Address Moiety. J . Med. Chem. 1994, 37,
579-585.
(8) Hruby, V. J .; Kao, L. F.; Pettit, B. M.; Karplus, M. The
Conformational Properties of the Delta Opioid Peptide [D-Pen2,D-
Pen5]-Enkephalin in Aqueous Solution Determined by NMR and
Energy Minimization Calculations. J . Am. Chem. Soc. 1988, 110,
3351-3359.
NO4‚H2O) C, H, N.
7-(5′,6′-Ben zo-2′-sp ir oin d a n yl)oxym or p h on e (9): yield
1
75%; mp 235 °C; FAB-MS 454 [M + H]+; H NMR (CDCl3) δ
7.74-7.71 (m, 2H, naphthyl H), 7.52 (s, 2H, naphthyl H), 7.32-
7.29 (m, 2H, naphthyl H), 6.64 (d, 1H, J ) 8.1 Hz, H-2), 6.53
(d, 1H, J ) 7.8 Hz, H-1), 4.82 (s, 1H, H-5), 3.75 (d, 1H, J )
16.8 Hz, indan CH2), 3.40 (d, 1H, J ) 15.9 Hz, indan CH2),
3.32 (d, 1H, J ) 17.7 Hz, indan CH2), 3.06 (d, 1H, J ) 18.9
Hz, H-10â), 2.96 (d, 1H, J ) 5.4 Hz, H-9), 2.39 (s, 3H, NCH3).
Anal. (C29H27NO4) C, H, N.
7-(4′,5′-Ben zo-2′-sp ir oin d a n yl)n a ltr exon e (10): 1H NMR
(CDCl3) δ 0.16 (2H, m, H-20â, H-21â), 0.56 (2H, m, H-20R,
H-21R), 0.87 (1H, m, H-19), 1.56 (1H, dd, J ) 14.4, 2.4 Hz,
H-15), 1.83 and 1.95 (1H, d, J ) 14.2 Hz, H-8), 2.15 (2H, m,
H-8, 14-OH), 2.30-2.80 (6H, m, H-10, H-15, H-16, H-18, indan
CH2), 3.05 (1H, d, J ) 18.6 Hz, H-10), 3.18 (1H, d, J ) 4.8 Hz,
H-9), 3.30 and 3.52 (1H, d, J ) 16.8 Hz, indan CH2), 3.68 and
3.95 (1H, d, J ) 15.8 Hz, indan CH2), 4.18 (1H, d, J ) 17.0
Hz), 4.98 and 5.02 (1H, s, H-5), 6.60 (1H, d, J ) 8.2 Hz, H-1),
6.74 (1H, d, J ) 8.2 Hz, H-2), 7.20-7.60 (4H, m, naphthyl H),
7.65 (1H, m, naphthyl H), 7.90 (1H, m, naphthyl H); HRMS
(FAB) (M + H)+ 494.2334 (calcd for C32H32NO4 494.2331). Anal.
(C32H31NO4‚HCl‚1.5H2O) C, H, N.
7-(2′,3′-Dih yd r o-2′-sp ir op e r in a p h t h e n yl)n a lt r e xon e
(11): yield 74%; 1H NMR (CDCl3) δ 0.06 (2H, m, H-20â,
H-21â), 0.48 (2H, m, H-20R, H-21R), 0.76 (1H, m, H-19), 1.48
(1H, d, J ) 14.4 Hz, H-8), 1.57 (1H, d, J ) 12.9 Hz, H-15),
1.79 (1H, d, J ) 14.4 Hz, H-8), 2.09 (1H, dt, J ) 2.4, 12.0 Hz,
H-15), 2.30 (2H, m, H-18), 2.44 (1H, hidden, H-16), 2.50 (1H,
br s, OH), 2.51 (1H, dd, J ) 18.3, 2.4 Hz, H-10), 2.57 (1H, dd,
J ) 15.9 Hz, naphthyl CH2), 2.70 (1H, dd, J ) 12.3, 3.9 Hz,
H-16), 2.91 (1H, s, H-9), 2.94 (1H, d, J ) 18.3 Hz, H-10), 3.39
(1H, d, J ) 14.4 Hz, naphthyl CH2), 3.43 (1H, d, J ) 14.4 Hz,
naphthyl CH2), 3.93 (1H, d, J ) 15.9 Hz, naphthyl CH2), 4.99
(1H, d, J ) 2.4 Hz, H-5), 6.10 (1H, br s, aromatic OH), 6.57
(1H, dd, J ) 8.4, 2.4 Hz, H-1), 6.73 (1H, dd, J ) 8.4, 2.4 Hz,
H-2), 7.10-7.75 (6H, m, naphthyl); HRMS (FAB) (M + H)+
474.2350 (calcd for C32H32NO4 494.2331). Anal. (C32H31NO4‚
HCl) C, H, N.
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Stereospecific Deuteration, NMR, Distance Geometry, and En-
ergy Minimization for the Conformational Analysis of the Highly
Delta Opioid Receptor Selective Peptide [D-Pen2
,D-Pen5]-
enkephalin. J . Am. Chem. Soc. 1990, 112, 822-829.
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Ack n ow led gm en t. This research was supported by
the National Institute on Drug Abuse. We thank
Veronika Phillips, Michael Powers, J oan Naeseth, Idalia
Sanchez, and Reynold Francis for their capable techni-
cal assistance.
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