Synthesis and biological evaluation of 14-alkoxymorphinans. 17. Highly δ opioid receptor selective 14-alkoxy-substituted indolo- and benzofuromorphinans

Article abstract of DOI:10.1021/jm020940p

14-Alkoxy analogues of naltrindole and naltriben differently substituted in positions 5 and 17 and at the indole nitrogen (compounds 28-44) have been synthesized in an effort to enhance the δ potency and/or δ selectivity and in order to further elaborate

Full text of DOI:10.1021/jm020940p

5378
J . Med. Chem. 2002, 45, 5378-5383
Syn th esis a n d Biologica l Eva lu a tion of 14-Alk oxym or p h in a n s. 17. High ly δ
Op ioid Recep tor Selective 14-Alk oxy-Su bstitu ted In d olo- a n d
Ben zofu r om or p h in a n s
J ohannes Schu¨tz,† Christina M. Dersch,‡ Robert Horel,‡ Mariana Spetea,† Martin Koch,† Ruth Meditz,†
Elisabeth Greiner,† Richard B. Rothman,*,‡ and Helmut Schmidhammer*,†
Department of Pharmaceutical Chemistry, Institute of Pharmacy, University of Innsbruck, Innrain 52a,
A-6020 Innsbruck, Austria, and Clinical Psychopharmacology Section, Addiction Research Center,
National Institute on Drug Abuse, Baltimore, Maryland 21244
Received May 23, 2002
14-Alkoxy analogues of naltrindole and naltriben differently substituted in positions 5 and 17
and at the indole nitrogen (compounds 28-44) have been synthesized in an effort to enhance
the δ potency and/or δ selectivity and in order to further elaborate on structure-activity
relationships of this class of compounds. Introduction of a 14-alkoxy instead of the 14-hydroxy
group present in naltrindole resulted in somewhat lower δ binding affinity, while in many
cases (compounds 31, 34, 37, 40, 41, 44, HS 378) the δ receptor selectivity was considerably
increased. An ethoxy group in position 14 is superior to other alkoxy groups concerning δ affinity
and selectivity (34, 41, 42, 44, HS 378). In [35S]GTPγS binding, compounds 34, 41, and HS 378
exhibited about one-tenth the antagonist potency of naltrindole at δ opioid receptors while
their δ antagonist selectivity was considerably higher. 17-Methyl-substituted compounds 35
and 44 were found to be pure δ receptor agonists in this test.
In tr od u ction
On the basis of pharmacological, behavioral, and
biochemical studies, opioid receptors have been classi-
fied into three major types: µ, δ, and κ. They belong to
the G-protein-coupled receptor superfamily.1 Receptor
type selective opioid agonists and antagonists are of
interest both as pharmacological tools and as potential
F igu r e 1. 1 (NTI): R1 ) CPM, R2 ) H, R3 ) H, X ) NH. 2
(NTB): R1 ) CPM, R2 ) H, R3 ) H, X ) O. 3 (OMI): R1 ) Me,
therapeutic agents. During the past 3 decades, one of
the major aims of opioid pharmacology has been to
develop opioids with high affinity and/or selectivity for
each of the three receptor types.2-5 Recently δ opioid
receptors have been studied extensively and it was
found that they are involved in many biological pro-
cesses.6 Besides the analgesic effect of δ agonists,7,8 they
show for instance stimulatory effects on respiration9 or
immunomodulatory effects10-12 that were found to be
immunostimulant.13,14 δ Antagonists, like naltrindole
(NTI, 1, Figure 1), were found to have immunosuppres-
sive potency and less toxicity than the presently used
immunosuppressive compound cyclosporin.15-17 Such
agents can be used after organ transplantation to
suppress the rejection of the foreign organ and also in
the treatment of autoimmune diseases (e.g., rheumatoid
arthritis).
R2 ) H, R3 ) H, X ) NH. 4 (HS 378): R1 ) CPM, R2 ) Et, R3
) Me, X ) NH. CPM: cyclopropylmethyl.
naltrindole (oxymorphindole, OMI, 3) clearly exhibits
partial agonism.22 Recently it was reported that modi-
fication of the substituent in position 17 (R1) causes
major changes in affinity, selectivity, and potency of the
ligands.23 For instance, it was apparent from this work
that the effect of some 17-substituents (e.g., ethyl or
pentyl) is dissimilar in ligands selective for δ or µ opioid
receptors. The 17-ethyl and 17-pentyl analogues of NTI
showed clear δ opioid antagonism. Structure-activity
studies on NTI analogues focusing on the indolic ben-
zene ring revealed that substituents in the 7′ position
did not significantly alter δ affinity and δ selectivity,
while substituents in 4′, 5′, and 6′ positions had major
influence in affinity and subtype specificity.18,22,24-30
In the search for selective non-peptide δ opioid recep-
tor ligands, indolo- and benzofuromorphinans derived
from the nonselective antagonist naltrexone display
selectivity toward δ receptors. The prototype antago-
nists NTI18 and naltriben (NTB, 2)19 also show some
agonist effects,20,21 while the 17-methyl analogue of
Introduction of a 14-ethoxy and a 5-methyl group onto
the NTI molecule resulted in a pure opioid antagonist
(HS 378, 4) with somewhat lower δ potency but much
higher δ selectivity in bioassays,31 functional assay, and
receptor binding.32 Recently Spetea et al.33 have found
that HS 378 possesses an immunosuppressive potency
in vitro on T-lymphocyte proliferation that is more than
10-fold higher compared to NTI. Introduction of a 14-
ethoxy and a 5-methyl group onto the OMI molecule
resulted in a pure δ opioid receptor agonist in the
MVD.31 Another study showed that a 5-methyl group
* To whom correspondence should be addressed. For H.S.: phone,
(43) 512-507-5248; fax, (43) 512-507-2940; e-mail, Helmut.
Schmidhammer@uibk.ac.at. For R.B.R.: phone, 410-550-1487; fax,
410-550-2997; e-mail: rrothman@belite.com.
† University of Innsbruck.
‡ National Institute on Drug Abuse.
10.1021/jm020940p CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/29/2002

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5379
Sch em e 1a
indole cyclization of ketones 14, 15, 16, 17, 18, 19,39 20,39
and 2140 with phenylhydrazine hydrochloride in glacial
acetic acid gave indoles 27, 36, 37, 38, 39, 40, 41, and
43, respectively. Benzofuromorphinan 42 was prepared
from compound 2039 using O-phenylhydroxylamine
hydrochloride and methanesulfonic acid in MeOH. The
syntheses of compounds 31,34 34,34 35,34 and 4431 have
been previously described.
For ketones. 5:35 R1 ) Me, R2 ) H, R3 ) Me, R4 ) Me, ∆.7,8 6:
a
R1 ) Me, R2 ) dimethylallyl, R3 ) Me, R4 ) Me, ∆.7,8 7: R1 ) Me,
R2 ) isoamyl, R3 ) Me, R4 ) Me. 8:32 R1 ) H, R2 ) Pr, R3 ) Me,
R4 ) Me 9 R1 ) CPM, R2 ) Pr, R3 ) Me, R4 ) Me. 10:36 R1 ) H,
R2 ) Et, R3 ) Me, R4 ) Me. 11: R1 ) 2-phenylethyl, R2 ) Et, R3
) Me, R4 ) Me. 12: R1 ) CBM, R2 ) Et, R3 ) Me, R4 ) Me. 13:37
R1 ) H, R2 ) Me, R3 ) H, R4 ) Me. 14: R1 ) CHM, R2 ) Me, R3
) H, R4 ) Me. 15: R1 ) Me, R2 ) isoamyl, R3 ) Me, R4 ) H. 16:
R1 ) CPM, R2 ) Pr, R3 ) Me, R4 ) H. 17: R1 ) 2-phenylethyl, R2
Biologica l Testin g
Op ioid Recep tor Bin d in g Assa ys. The binding
affinities of the target compounds for δ and µ receptors
were determined by inhibition of binding of [3H]-
DADLE41 and [3H]DAMGO42 to rat brain membranes.
The affinities for κ receptors were assessed by inhibition
of binding of [3H]U69,59343 to guinea pig brain mem-
branes. The results are shown in Table 1. These data
show that introduction of a 14-alkoxy instead of the 14-
hydroxy group present in NTI results in a somewhat
lower δ affinity, while in many cases (compounds 31,
34, 37, 40, 41, 44, HS 378) the δ receptor selectivity was
considerably increased. 14-Ethoxy substitution seems
to be superior to 14-methoxy and 14-propoxy substitu-
tion.
[35S]GTP γS Assa ys. The ability of compounds 34, 41,
and HS 378 to inhibit [35S]GTPγS binding in guinea pig
caudate stimulated by selective opioid agonists was
determined. The studies were conducted employing
SNC80 (δ), DAMGO (µ), and U69,593 (κ) as selective
agonists.44 The results obtained are shown in Table 2.
) Et, R3 ) Me, R4 ) H. 18: R1 ) CBM, R2 ) Et, R3 ) Me, R4
)
H. 19:39 R1 ) allyl, R2 ) Me, R3 ) H, R4 ) H. 20:39 R1 ) allyl, R2
) Et, R3 ) H, R4 ) H. 21:40 R1 ) Me, R2 ) Me, R3 ) Me, R4 ) H.
For indoles/benzofuranes. 22:38 R1 ) CPM, R2 ) H, R3 ) H, R4
)
Bz, X ) NH. 23: R1 ) CPM, R2 ) allyl, R3 ) H, R4 ) Bz, X )
N-allyl. 24:34 R1 ) allyl, R2 ) H, R3 ) H, R4 ) Bz, X ) NH. 25: R1
) allyl, R2 ) Me, R3 ) H, R4 ) Bz, X ) N-Me. 26: R1 ) allyl, R2
) CH2Ph(2-Cl), R3 ) H, R4 ) Bz, X ) N-CH2Ph(2-Cl). 27: R1
CHM, R2 ) Me, R3 ) H, R4 ) Me, X ) NH. 28: R1 ) CPM, R2
)
)
Pr, R3 ) H, R4 ) H, X ) N-Pr. 29: R1 ) allyl, R2 ) Me, R3 ) H,
R4 ) H, X ) N-Me. 30: R1 ) Pr, R2 ) Me, R3 ) H, R4 ) H, X )
N-Me. 31:34 R1 ) allyl, R2 ) allyl, R3 ) H, R4 ) H, X ) N-allyl.
32: R1 ) allyl, R2 ) CH2Ph(2-Cl), R3 ) H, R4 ) H, X ) N-CH2Ph(2-
Cl). 33: R1 ) CHM, R2 ) Me, R3 ) H, R4 ) H, X ) NH. 34:34 R1
) CPM, R2 ) Et, R3 ) H, R4 ) H, X ) O. 35:34 R1 ) Me, R2 ) Pr,
R3 ) Me, R4 ) H, X ) NH. 36: R1 ) Me, R2 ) isoamyl, R3 ) Me,
R4 ) H, X ) NH. 37: R1 ) CPM, R2 ) Pr, R3 ) Me, R4 ) H, X )
NH. 38: R1 ) 2-phenylethyl, R2 ) Et, R3 ) Me, R4 ) H, X ) NH.
39: R1 ) CBM, R2 ) Et, R3 ) Me, R4 ) H, X ) NH. 40: R1
)
allyl, R2 ) Me, R3 ) H, R4 ) H, X ) NH. 41: R1 ) allyl, R2 ) Et,
R3 ) H, R4 ) H, X ) NH. 42: R1 ) allyl, R2 ) Et, R3 ) H, R4
)
H, X ) O. 43: R1 ) Me, R2 ) Me, R3 ) Me, R4 ) H, X ) NH. 44:31
R1 ) Me, R2 ) Et, R3 ) Me, R4 ) H, X ) NH. CPM )
cyclopropylmethyl. CBM ) cyclobutylmethyl. CHM ) cyclohexyl-
methyl. Bz ) benzyl.
Discu ssion a n d Con clu sion
From the biological results obtained with the present
series of compounds, the following conclusions can be
drawn concerning the effects of various changes to the
naltrindole and HS 378 molecules.
did not change δ affinity but decreased µ and κ affinities,
thus resulting in increased δ selectivity.34
The present data show that introduction of a 14-
alkoxy instead of the 14-hydroxy group present in NTI
results in somewhat lower δ affinity, while in many
cases (compounds 29, 31, 34, 37, 40, 41, 44, HS 378)
the δ receptor selectivity was considerably increased.
14-Ethoxy substitution seems to be somewhat superior
to 14-methoxy and particularly 14-propoxy substitution.
Introduction of a 14-isoamyloxy group results in lower
δ affinity and selectivity, while a 14-allyloxy group is
either detrimental to δ selectivity (compound 28) or δ
affinity (compound 31). It also became apparent that
the nature of X (O, NH, or N-Me) does not have much
influence on affinity and selectivity. As reported earlier,
a 5-methyl group is not necessary for high δ affinity.33
The replacement of the 17-cyclopropylmethyl group
by 17-allyl or 17-Me has little influence on δ binding
affinity and selectivity, while introduction of a 17-propyl
or a 17-cyclobutylmethyl group results in lower δ
affinity. 17-Cyclohexylmethyl and 17-(2-phenylethyl)
groups decrease δ affinity considerably.
In an attempt to enhance the δ potency and/or δ
selectivity and in order to further elaborate on structure-
activity relationships of 14-alkoxy-substituted indolo-
and benzofuromorphinans, we prepared a series of
compounds differently substituted in positions 5, 14, and
17 and at the indole nitrogen.
Ch em istr y
Compound 6 (Scheme 1) was prepared from 14-
hydroxy-5-methylcodeinone (5)35 by 14-O-alkylation with
allyl bromide in anhydrous DMF in the presence of NaH
as a base. Compound 7 was obtained by hydrogenation
of compound 6 in glacial acetic acid. N-alkylation of
compounds 8,32 10,36 and 1337 in anhydrous DMF in the
presence of K2CO3 afforded compounds 9, 11, 12, and
14, respectively. Compounds 15, 16, 17, 18, and 33 were
synthesized from the corresponding 3-O-methyl ethers
7, 9, 11, 12, and 27, respectively, by ether cleavage with
HBr or BBr3. Simultaneous alkylation of the 14-OH
group and the indole-N in compounds 2238 and 2434 was
performed with 7 equiv of NaH in anhydrous DMF to
yield indoles 23, 25, and 26, respectively. The 3-O-
benzyl groups of 23, 25, and 26 were cleaved either by
hydrogenation in EtOH (in the case of compound 25 the
double bound of the 17-allyl group was hydrogenated,
too) or by a dilute HCl solution in MeOH to afford
compounds 28, 29, 30, and 32, respectively. Fischer
In [35S]GTPγS binding, compounds 34, 41, and HS 378
exhibited about one-tenth the antagonist potency of NTI
at δ opioid receptors, while their δ antagonist selectivity
was considerably increased. Compounds 35 and 44 were
found to be pure δ receptor agonists in this test. These
data confirm once more the well-known fact that in this
class of compounds a 17-Me group increases opioid

5380 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
Schu¨tz et al.
Ta ble 1. Opioid Receptor Binding of Compounds 28-44 and Reference Compounds
Ki (nM) ( SEM
selectivity ratio
κ/δ
2.4
compd
[3H]DADLE (δ)
[3H]DAMGO (µ)
[3H]U69,593 (κ)
µ/δ
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
1.28 ( 0.30
1.97 ( 0.23
11.5 ( 1.5
7.3 ( 0.5
14.8 ( 2.0
731 ( 82
106 ( 11
1001 ( 82
1231 ( 158
13978 ( 3377
185 ( 9
30.0 ( 3.8
238 ( 25
555 ( 47
14.0 ( 0.8
409 ( 51
869 ( 61
1368 ( 117
22.8 ( 1.6
58 ( 5
3.1 ( 0.5
149 ( 12
115 ( 29
763 ( 54
721429 ( 142
3250 ( 231
94 ( 6
556 ( 36
1263 ( 116
504 ( 34
3639 ( 181
378 ( 36
233 ( 31
349 ( 25
68 ( 5
12
371
9.2
137
8.2
38
157
5.7
19
105
0.5
32
229
526
19
76
10
105
4800
8.8
80
105
99
95
117
30
61
134
57
387
186
30
151 ( 12
370 ( 30
1.18 ( 0.08
5.3 ( 0.3
12.8 ( 0.4
5.3 ( 0.7
31.0 ( 3.3
12.6 ( 1.2
3.80 ( 0.49
2.60 ( 0.13
1.20 ( 0.13
3.95 ( 0.25
3.90 ( 0.42
4.4 ( 0.5
1527 ( 137
725 ( 69
134 ( 30
15.8 ( 4.0
395 ( 26
15
132
77
16
86
44
515 ( 48
340 ( 29
13.0 ( 0.8
171 ( 15
HS 378
NTI
OMI
0.81 ( 0.06
2.0 ( 0.2
20
198
Ta ble 2. Antagonist Ki Values of Compounds 34, 41, HS 378,
and NTI Determined in the [35S]GTPγS Assay in Guinea Pig
Caudatae
from MeOH to give 1.37 g (38%) of pure 6: colorless crystals;
mp 119-123 °C; IR (KBr) 1668 (CdO); 1H NMR (DMSO-d6) δ
7.21 (d, J ) 10.1, 1 olef H), 6.66 (d, J ) 8.0, 1 arom H), 6.62
(d, J ) 8.0, 1 arom H), 6.08 (d, J ) 10.1, 1 olef H), 5.23 (m,
CH2CHdC), 3.68 (s, CH3O), 2.35 (s, CH3N), 1.68 (s, C(CH3)2),
1.59 (s, C(CH3)2), 1.52 (s, CH3-C(5)); EI-MS m/z 395 (M+).
Anal. (C24H29NO4) C, H, N.
Ki (nM) ( SEM
compd
δa
µb
κc
34
41
0.88 ( 0.05
1.00 ( 0.08
0.96 ( 0.07
0.062 ( 0.006
>10000d
>10000d
>10000d
3.2 ( 0.2
>10000d
>10000d
>10000d
8.9 ( 0.8
4,5r-Ep oxy-3-m eth oxy-5â,17-d im eth yl-14â-[(3-m eth yl-
bu tyl)oxy]m or p h in a n -6-on e (7). A mixture of 6 (1.34 g, 3.39
mmol), AcOH (30 mL), and 10% Pd/C (0.13 g) was hydroge-
nated at room temperature and 30 psi for 19 h. The catalyst
was filtered off, and the filtrate was reduced, alkalinized with
concentrated NH4OH solution, and partitioned between H2O
(100 mL) and CH2Cl2 (3 × 60 mL). The combined organic layers
were washed with H2O (100 mL) and brine (100 mL), dried
(Na2SO4), and evaporated to give 0.66 g (49%) of 7 as yellow
oil, which was pure by TLC (CH2Cl2/MeOH/concentrated NH4-
OH solution, 90:9:1) and not crystallized for the next step. No
HS 378
NTIe
a
b
Antagonism of SNC80. Antagonism of DAMGO. c Antago-
d
nism of U69,593. The compounds were screened for antagonism
at µ and κ opioid receptors, but they did not inhibit stimulation of
10 µM DAMGO or 10 µM U69,593, respectively, by at least 50%
at that concentration. e Taken from ref 44.
agonism while 17-cyclopropylmethyl and 17-allyl groups
increase opioid antagonism.
In conclusion, introduction of a 14-alkoxy group into
the NTI molecule results in compounds with consider-
able higher δ opioid receptor selectivity.
1
elemental analysis was performed. IR (CCl4) 1728 (CdO); H
NMR (CDCl3) δ 6.64 (d, J ) 8.2, 1 arom H), 6.58 (d, J ) 8.2,
1 arom H), 3.87 (s, CH3O), 2.36 (s, CH3N), 1.61 (s, CH3-C(5)),
0.96 (d, J ) 2.7, C(CH3)2), 0.34 (d, J ) 2.7, C(CH3)2); EI-MS
m/z 399 (M+).
Exp er im en ta l Section
Gen er a l P r oced u r e for th e Syn th esis of 9, 11, 12, a n d
14. A mixture of the corresponding N-nor compound (8‚HCl,32
10‚HCl,36 and 13‚HCl37), 4 equiv of K2CO3, 1.2 equiv of
alkylation reagent, and anhydrous DMF was stirred under N2
at 80 °C for 20 h. The inorganic material was filtered off, the
filtrate was evaporated, and the residue was partitioned
between H2O and CH2Cl2. The combined organic layers were
washed with H2O and brine, dried (Na2SO4), and evaporated.
The products were either crystallized from MeOH (11) or
precipitated as hydrochloride from Et2O (9, 12, and 14).
17-Cyclop r op ylm eth yl-4,5r-ep oxy-3-m eth oxy-5â-m eth -
Melting points were measured on a Kofler melting point
microscope and are uncorrected. IR spectra were recorded with
a Mattson Galaxy series FTIR 3000 spectrometer (in cm-1).
1H NMR spectra were recorded on a Bruker AM 300 (300 MHz)
or on a Varian Gemini 200 (200 MHz) spectrometer. Chemical
shifts (δ) are reported in ppm (relative to SiMe4 as internal
standard), and coupling constants (J ) are reported in hertz.
Mass spectra were recorded on a Varian MAT 44S or on a
Finnigan Mat SSQ 7000 apparatus. Elemental analyses were
performed at the Institute of Physical Chemistry at the
University of Vienna, Austria. For TLC, POLYGRAM SIL
G/UV254 precoated plastic sheets (Macherey-Nagel, Germany)
were used, and for column chromatography, silica gel 60 (230-
400 mesh ASTM, Fluka, Switzerland) was used.
7,8-Did eh yd r o-4,5r-ep oxy-3-m et h oxy-5â,17-d im et h yl-
14â-[(3-m eth ylbu t-2-en yl)oxy]m or ph in an -6-on e (6). A mix-
ture of 535 (3.00 g, 9.16 mmol), NaH (0.45 g, 18.75 mmol,
obtained from 0.75 g of 60% NaH dispersion in oil by washing
with hexane), and anhydrous DMF (50 mL) was stirred at 0
°C. After 20 min, 3,3-dimethylallyl bromide (2.07 g, 13.89
mmol) was added at once and stirring was continued for 2 h
at room temperature. Excess NaH was destroyed with ice and
120 mL of H2O, the mixture was extracted with CH2Cl2 (3 ×
70 mL), and the combined organic layers were washed with
H2O (3 × 100 mL) and brine (100 mL), dried (Na2SO4), and
evaporated. The residue (3.67 g brown oil) was crystallized
yl-14â-p r op oxym or p h in a n -6-on e
h yd r och lor id e
(9‚
HCl): yellow powder; yield 55%; mp 156-158 °C; IR (KBr)
1723 (CdO); 1H NMR (DMSO-d6) δ 8.57 (s, NH+), 6.85 (d, J )
8.2, 1 arom H), 6.75 (d, J ) 8.2, 1 arom H), 3.79 (s, CH3O),
1.51 (s, CH3-C(5)), 0.87 (t, J ) 7.4, CH3CH2); CI-MS m/z 412
(M+ + 1). Anal. (C25H33NO4‚HCl‚0.6H2O) C, H, N, Cl.
4,5r-E p oxy-14â-et h oxy-3-m et h oxy-5r-m et h yl-17-[(2-
ph en yl)eth yl]m or ph in an -6-on e (11): colorless crystals; yield
70%; mp 86-89 °C; IR (KBr) 1725 (CdO); 1H NMR (CDCl3) δ
7.30-7.13 (m, 5 arom H), 6.64 (d, J ) 8.2, 1 arom H), 6.54 (d,
J ) 8.2, 1 arom H), 3.85 (s, CH3O), 1.60 (s, CH3-C(5)), 1.12 (t,
J ) 6.8, CH3CH2); CI-MS m/z 448 (M+ + 1). Anal. (C28H33
NO4) C, H, N.
-
17-Cyclobu tylm eth yl-4,5r-epoxy-14â-eth oxy-3-m eth oxy-
5â-m eth ylm or p h in a n -6-on e h yd r och lor id e (12‚HCl): col-
orless crystals; yield 70%; mp 151-152 °C; IR (KBr) 1725

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5381
1
(CdO); H NMR (DMSO-d6) δ 8.61 (s, br, NH+), 6.85 (d, J )
1′-Allyl-14â-allyloxy-3-ben zyloxy-17-cyclopr opylm eth yl-
4,5r-ep oxyin d olo[2′,3′:6,7]m or p h in a n h yd r och lor id e (23‚
HCl): colorless crystals; yield 86%; mp 182-185 °C; 1H NMR
(DMSO-d6) δ 8.65 (s, NH+), 7.43-6.99 (m, 9 arom H), 6.90 (d,
J ) 8.2, 1 arom H), 6.74 (d, J ) 8.2, 1 arom H), 6.06 (s,
H-C(5)); CI-MS m/z 585 (M+ + 1). Anal. (C39H40N2O3‚HCl‚
2.5H2O) C, H, N.
8.2, 1 arom H), 6.75 (d, J ) 8.2, 1 arom H), 3.78 (s, CH3O),
1.49 (s, CH3-C(5)), 1.33 (t, J ) 6.8, CH3CH2); CI-MS m/z 412
(M+ + 1). Anal. (C25H33NO4‚HCl‚1.5H2O) C, H, N.
17-Cycloh exylm eth yl-4,5r-ep oxy-3,14â-d im eth oxym or -
p h in a n -6-on e h yd r och lor id e (14‚HCl): colorless crystals;
1
yield 59%; mp 176 °C (dec); IR (KBr) 1723 (CdO); H NMR
(DMSO-d6) δ 10.40 (s, br, NH+), 6.75 (d, J ) 8.8, 1 arom H),
6.67 (d, J ) 8.8, 1 arom H), 3.92 (s, CH3O-C(3)), 3.29 (s,
CH3O-C(14)); CI-MS m/z 412 (M+ + 1). Anal. (C25H33NO4‚HCl)
C, H, N.
17-Allyl-3-ben zyloxy-4,5r-ep oxy-14â-m eth oxy-1′-m eth -
ylin d olo[2′,3′:6,7]m or p h in a n h yd r och lor id e (25‚HCl): col-
1
orless crystals; yield 59%; mp 173-178 °C; H NMR (DMSO-
d6) δ 11.21 (s, br, NH+), 7.42-7.04 (m, 9 arom H), 6.75 (d, J )
8.2, 1 arom H), 6.63 (d, J ) 8.2, 1 arom H), 6.33 (m, 1 olef H),
5.85 (s, H-C(5)), 5.64 (m, 2 olef H), 3.86 (s, CH3N), 3.28 (s,
CH3O); CI-MS m/z 519 (M+ + 1). Anal. (C34H34N2O3‚HCl‚
1.9H2O) C, H, N.
Gen er a l P r oced u r e for th e Syn th esis of 15 a n d 17. A
mixture of the corresponding 3-O-methyl ether (7 and 11) and
48% HBr was refluxed for 20 min and then evaporated. The
residue was dissolved in MeOH and evaporated again to give
a beige foam that was crystallized from MeOH.
17-Allyl-3-b en zyloxy-1′-(2-ch lor ob en zyl)-14â-[(2-ch lo-
r oben zyl)oxy]-4,5r-ep oxyin d olo[2′,3′:6,7]m or p h in a n (26):
colorless crystals; yield 50%; mp 155-157 °C; 1H NMR (CDCl3)
δ 7.43-6.87 (m, 17 arom H), 6.70 (d, J ) 8.2, 1 arom H), 6.60
(d, J ) 8.2, 1 arom H), 6.08-5.78 (m, 1 olef H), 5.71 (d, J )
18.4, 1 H, NCH2(2-Cl-Ph)), 5.67 (s, H-C(5)), 5.55 (d, J ) 18.4,
1 H, NCH2(2-Cl-Ph)), 5.30-5.15 (m, 2 olef H), 4.91 (d, J )
12.8, 1 H, OCH2(2-Cl-Ph)), 4.44 (d, J ) 12.8, 1 H, OCH2(2-
Cl-Ph)); CI-MS m/z 739 (M+ + 1). Anal. (C46H40N2O3Cl2‚
0.3H2O) C, H, N, Cl.
Gen er a l P r oced u r e for th e Syn th esis of 28 a n d 30. A
mixture of the corresponding 3-O-benzyl ether (23‚HCl and
25‚HCl), EtOH, and 10% Pd/C was hydrogenated at room
temperature and 30 psi for 2 h. The catalyst was filtered off,
the filtrate was evaporated, the residue was alkalinized with
concentrated NH4OH solution, and the result was partitioned
between H2O and CH2Cl2. The combined organic layers were
washed with H2O and brine, dried (Na2SO4), and evaporated.
The residue was precipitated as hydrochloride either from Et2O
(28) or from acetone (30).
4,5r-Ep oxy-3-h yd r oxy-5â,17-d im eth yl-14â-[(3-m eth yl-
bu tyl)oxy]m or p h in a n -6-on e h yd r obr om id e (15‚HBr ): col-
orless crystals; yield 33%; mp >260 °C (dec); IR (KBr) 3427
1
(OH), 1724 (CdO); H NMR (DMSO-d6) δ 9.40 (s, OH), 8.35
(s, NH+), 6.64 (s, 2 arom H), 2.94 (s, CH3N), 1.48 (s, CH3-
C(5)), 0.95 (d, J ) 2.6, C(CH3)2), 0.93 (d, J ) 2.6, C(CH3)2);
EI-MS m/z 385 (M+). Anal. (C23H31NO4‚HBr‚0.8H2O) C, H, N.
4,5r-E p oxy-14â-e t h oxy-3-h yd r oxy-5â-m e t h yl-17-[(2-
p h en yl)eth yl]m or p h in a n -6-on e h yd r obr om id e (17‚HBr ):
colorless crystals; yield 63%; mp >270 °C (dec); IR (KBr) 1720
(CdO); 1H NMR (DMSO-d6) δ 9.38 (s, OH), 8.48 (s, NH+),
7.38-7.25 (m, 5 arom H), 6.68 (d, J ) 8.2, 1 arom H), 6.64 (d,
J ) 8.2, 1 arom H), 1.51 (s, CH3-C(5)), 1.34 (t, J ) 6.8, CH3-
CH2); CI-MS 434 (M+ + 1). Anal. (C27H31NO4‚HBr) C, H, N,
Br.
Gen er a l P r oced u r e for th e Syn th esis of 16, 18, a n d 33.
A mixture of the corresponding 3-O-methyl ether (9‚HCl, 12‚
HCl, and 27‚HBr), 7 equiv of 1 M BBr3 solution in CH2Cl2,
and CH2Cl2 was stirred under N2 at 0 °C for 1.5 h. The reaction
was ended by adding ice and concentrated NH4OH solution,
and the mixture was extracted with CH2Cl2. The combined
organic layers were washed with H2O and brine, dried
(Na2SO4), evaporated, and the products were crystallized from
MeOH either as free base (16 and 18) or as hydrobromide
(33).
17-Cyclop r op ylm eth yl-4,5r-ep oxy-3-h yd r oxy-5â-m eth -
yl-14â-p r op oxym or p h in a n -6-on e (16): beige crystals; yield
55%; mp 184-186 °C; IR (KBr) 3390 (OH), 1720 (CdO); 1H
NMR (CDCl3) δ 10.24 (s, br, OH), 6.73 (d, J ) 8.2, 1 arom H),
6.65 (d, J ) 8.2, 1 arom H), 1.62 (s, CH3-C(5)), 1.00 (t, J )
7.3, CH3CH2); CI-MS m/z 398 (M+ + 1). Anal. (C24H31NO4‚
0.6MeOH) C, H, N.
17-Cyclobu tylm eth yl-4,5r-epoxy-14â-eth oxy-3-h ydr oxy-
5â-m eth ylm or p h in a n -6-on e (18): colorless crystals; yield
57%; mp 168-174 °C; IR (KBr) 3567 (OH), 1725 (CdO); 1H
NMR (DMSO-d6) δ 9.07 (s, br, OH), 6.52 (d, J ) 8.2, 1 arom
H), 6.48 (d, J ) 8.2, 1 arom H), 1.45 (s, CH3-C(5)), 1.17 (t, J
) 7.0, CH3CH2); EI-MS m/z 397 (M+). Anal. (C24H31NO4‚
0.9H2O) C, H, N.
17-Cyc lop r op ylm e t h yl-4,5r-e p oxy-14â-p r op oxy-1′-
p r op ylin d olo[2′,3′:6,7]m or p h in a n -3-ol h yd r och lor id e (28‚
HCl): colorless crystals; yield 73%; mp 212-215 °C; IR (KBr)
3376 (OH); 1H NMR (DMSO-d6) δ 8.40 (s, br, 2 H, OH, NH+),
7.48-6.97 (m, 4 arom H), 6.67 (d, J ) 8.1, 1 arom H), 6.61 (d,
J ) 8.1, 1 arom H), 6.01 (s, H-C(5)); CI-MS m/z 499 (M+ + 1).
Anal. (C32H38N2O3‚HCl‚2.1H2O) C, H, N.
4,5r-E p oxy-14â-m et h oxy-1′-m et h yl-17-p r op ylin d olo-
[2′,3′:6,7]m or p h in a n -3-ol h yd r och lor id e (30‚HCl): colorless
1
crystals; yield 40%; mp 243-249 °C; IR (KBr) 3387 (OH); H
NMR (DMSO-d6) δ 9.28 (s, OH), 8.97 (s, br, NH+), 7.46-7.02
(m, 4 arom H), 6.67 (d, J ) 8.2, 1 arom H), 6.62 (d, J ) 8.2, 1
arom H), 6.05 (s, H-C(5)), 3.84 (s, CH3N), 3.11 (s, CH3O); CI-
MS m/z 431 (M+ + 1). Anal. (C27H30N2O3‚HCl‚2.4H2O) C, H,
N.
Gen er a l P r oced u r e for th e Syn th esis of 29 a n d 32. A
mixture of the corresponding 3-O-benzyl ether (25‚HCl and
26), MeOH, and concentrated HCl was refluxed for 6 h, cooled
to room temperature, alkalinized with concentrated NH4OH
solution, and partitioned between H2O and CH2Cl2. The
combined organic layers were washed with H2O and brine,
dried (Na2SO4), and evaporated. The residue was precipitated
as hydrochloride from Et2O.
17-Allyl-4,5r-ep oxy-14â-m eth oxy-1′-m eth ylin d olo[2′,3′:
6,7]m or ph in an -3-ol h ydr och lor ide (29‚HCl): colorless crys-
tals; yield 92%; mp 182-185 °C; IR (KBr) 3387 (OH); 1H NMR
(DMSO-d6) δ 9.33 (s, br, 2 H, OH, NH+), 7.48-6.98 (m, 4 arom
H), 6.68 (d, J ) 8.2, 1 arom H), 6.62 (d, J ) 8.2, 1 arom H),
6.05 (s, H-C(5)), 5.95 (m, 1 olef H), 5.64 (m, 2 olef H), 3.08 (s,
CH3O); CI-MS m/z 429 (M+ + 1). Anal. (C27H28N2O3‚HCl‚
1.1H2O) C, H, N.
17-Allyl-1′-(2-ch lor oben zyl)-14â-[(2-ch lor oben zyl)oxy]-
4,5r-ep oxyin d olo[2′,3′:6,7]m or p h in a n -3-ol h yd r och lor id e
(32‚HCl): colorless crystals; yield 37%; mp 141-142 °C; IR
(KBr) 3412 (OH); 1H NMR (DMSO-d6) δ 9.33 (s, OH), 9.05 (s,
NH+), 7.62-6.92 (m, 12 arom H), 6.69 (s, 2 arom H), 6.05-
5.97 (m, 1 olef H), 5.90 (s, NCH2(2-Cl-Ph)), 5.76 (s, H-C(5)),
5.68-5.60 (m, 2 olef H), 4.71 (d, J ) 12.9, 1 H, OCH2(2-Cl-
17-Cycloh exylm eth yl-4,5r-ep oxy-14â-m eth oxyin d olo-
[2′,3′:6,7]m or p h in a n -3-ol h yd r obr om id e (33‚HBr ): color-
1
less crystals; yield 14%; mp >250 °C (dec); H NMR (DMSO-
d6) δ 11.33 (s, NH), 9.25 (s, OH), 8.58 (s, NH+), 7.34-6.95 (m,
4 arom H), 6.64 (s, 2 arom H), 5.85 (s, H-C(5)), 3.11 (s, CH3O);
CI-MS m/z 471 (M+ + 1). Anal. (C30H34N2O3‚HBr‚0.7H2O) C,
H, N, Br.
Gen er a l P r oced u r e for th e Syn th esis of 23, 25, a n d 26.
A mixture of the corresponding 14-OH indole (22‚HCl38 and
24‚HCl34), 7 equiv of NaH (obtained from 60% NaH dispersion
in oil by washing with hexane), and anhydrous DMF was
stirred at 0 °C. After 20 min, an amount of 3 equiv of alkylation
reagent was added at once and stirring was continued for 2 h
at 0 °C. Excess NaH was destroyed with ice and H2O, the
mixture was extracted with CH2Cl2, and the combined organic
layers were washed with H2O and brine, dried (Na2SO4), and
evaporated. The residue was either precipitated as hydrochlo-
ride from Et2O (23 and 25) or purified by column chromatog-
raphy (silica gel, CH2Cl2/MeOH/concentrated NH4OH solution,
290:9:0.1) and then crystallized from i-PrOH (26).

5382 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24
Schu¨tz et al.
Ph)), 4.59 (d, J ) 12.9, 1 H, OCH2(2-Cl-Ph)); CI-MS m/z 649
(M+ + 1). Anal. (C39H34N2O3Cl2‚HCl‚1.1H2O) C, H, N, Cl.
Gen er a l P r oced u r e for th e Syn th esis of 27, 36-41, a n d
43. A mixture of the corresponding 6-keto compound (14‚HCl,
15‚HBr, 16, 17‚HBr, 18, 19,39 20,39 and 21‚Br40), 2 equiv of
phenylhydrazine hydrochloride, and AcOH was refluxed for
24 h, evaporated, alkalinized with concentrated NH4OH solu-
tion, and partitioned between H2O and CH2Cl2. The combined
organic layers were washed with H2O and brine, dried
(Na2SO4), and evaporated. The residue was either purified by
column chromatography (silica gel, CH2Cl2/MeOH/concen-
trated NH4OH solution 90:10:1) and then crystallized from
MeOH as hydrobromide (27) or crystallized as methane-
sulfonate from MeOH (36, 37, 40, and 41) or crystallized as
free base from MeOH (43) or precipitated from Et2O as
hydrochloride (38 and 39).
17-Cycloh exylm et h yl-4,5r-ep oxy-3,14â-d im et h oxyin -
d olo[2′,3′:6,7]m or p h in a n h yd r obr om id e (27‚HBr ): color-
less crystals; yield 18%; mp 226-232 °C; IR (KBr) 3398 (OH);
1H NMR (DMSO-d6) δ 11.37 (s, NH), 8.60 (s, br, NH+), 7.37-
6.95 (m, 4 arom H), 6.83 (d, J ) 8.4, 1 arom H), 6.76 (d, J )
8.4, 1 arom H), 5.92 (s, H-C(5)), 3.68 (s, CH3O-C(3)), 3.12 (s,
CH3O-C(14)); CI-MS 485 (M+ + 1). Anal. (C31H36N2O3‚HBr‚
0.2H2O) C, H, N, Br.
NH), 8.78 (s, OH), 7.32-6.91 (m, 4 arom H), 6.44 (s, 2 arom
H), 3.32 (s, CH3O), 2.33 (s, CH3N), 1.81 (s, CH3-C(5)); CI-MS
m/z 403 (M+ + 1). Anal. (C25H26N2O3‚1.9MeOH) C, H, N.
17-Allyl-4,5r-ep oxy-14â-eth oxyben zofu r o[2′,3′:6,7]m or -
p h in a n -3-ol sa licyla te (42‚C7H6O3). A mixture of 205 (0.30
g, 0.84 mmol), O-phenylhydroxylamine hydrochloride (0.16 g,
1.10 mmol), methanesulfonic acid (0.1 mL, 1.04 mmol), and
MeOH (10 mL) was refluxed for 6 days, evaporated, alkalinized
with concentrated NH4OH solution, and extracted with CH2-
Cl2 (3 × 65 mL). The combined organic layers were washed
with H2O (3 × 100 mL) and brine (100 mL), dried (Na2SO4),
and evaporated. The residue (0.31 g of brown foam) was
crystallized as salicylate from MeOH/i-Pr2O: beige crystals;
1
yield 0.15 g (31%); mp 144-147 °C; IR (KBr) 3426 (OH); H
NMR (DMSO-d6) δ 9.20 (s, OH), 9.06 (s, NH+), 7.73-6.72 (m,
8 arom H), 6.55 (s, 2 arom H), 5.82 (m, 1 olef H), 5.64 (s,
H-C(5)), 5.41-5.20 (m, 2 olef H), 0.94 (t, J ) 7.1, CH3CH2);
CI-MS m/z 430 (M+ + 1). Anal. (C27H27NO4‚C7H6O3‚0.8H2O)
C, H, N.
Biologica l Assa ys. Recep tor Bin d in g Assa ys. These
assays were performed as previously described.41-43
[
35S]GTP γS F u n ction a l Assa ys. These assays were per-
formed as previously described.23,44
4,5r-E p o x y -5â,17-d im e t h y l-14â-[(3-m e t h y lb u t y l)-
oxy]in d olo[2′,3′:6,7]m or p h in a n -3-ol m et h a n esu lfon a t e
(36‚CH3SO3H): colorless crystals; yield 36%; mp >250 °C (dec);
IR (KBr) 3406 (OH); 1H NMR (DMSO-d6) δ 11.27 (s, NH), 9.21
(s, OH), 8.46 (s, NH+), 7.39-6.90 (m, 4 arom H), 6.58 (s, 2 arom
H), 2.96 (s, CH3N), 1.85 (s, CH3-C(5)), 0.68 (d, J ) 5.4,
C(CH3)2), 0.34 (d, J ) 5.4, C(CH3)2); CI-MS m/z 459 (M+ + 1).
Anal. (C29H34N2O3‚CH3SO3H‚1.0H2O) C, H, N, S.
Ack n ow led gm en t. We thank Tasmanian Alkaloids
Ltd., Australia, for the generous gift of thebaine. We
further thank Prof. Dr. K.-H. Ongania (Institute of
Organic Chemistry, University of Innsbruck) and Dr.
D. Rakowitz (Institute of Pharmacy, University of
Innsbruck) for performing the mass spectra. The work
was in part supported by the Austrian Science Founda-
tion (Projects P11382 and P12668).
17-Cyclop r op ylm eth yl-4,5r-ep oxy-5â-m eth yl-14â-p r o-
p oxyin d olo[2′,3′:6,7]m or p h in a n -3-ol m et h a n esu lfon a t e
(37‚CH3SO3H): colorless crystals; yield 36%; mp 295-298 °C;
IR (KBr) 3539 (OH); 1H NMR (DMSO-d6) δ 11.31 (s, NH), 9.16
(s, OH), 8.01 (s, NH+), 7.35-6.92 (m, 4 arom H), 6.59 (s, 2 arom
H), 1.89 (s, CH3-C(5)), 0.60 (t, J ) 7.0, CH3CH2); FAB-MS
m/z 471 (M+ + 1). Anal. (C30H34N2O3‚CH3SO3H) C, H, N, S.
4,5r-Ep oxy-14â-eth oxy-5â-m eth yl-17-[(2-p h en yl)eth yl]-
in d olo[2′,3′:6,7]m or p h in a n -3-ol h yd r och lor id e (38‚HCl):
beige crystals; yield 51%; mp >225 °C (dec); IR (KBr) 3400
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1
(OH); H NMR (DMSO-d6) δ 11.34 (s, NH), 9.19 (s, OH), 8.97
(s, NH+), 7.35-6.91 (m, 9 arom H), 6.62 (d, J ) 8.4, 1 arom
H), 6.57 (d, J ) 8.4, 1 arom H), 1.87 (s, CH3-C(5)), 0.96 (t, J
) 6.9, CH3CH2); CI-MS m/z 507 (M+ + 1). Anal. (C33H34N2O3‚
HCl‚1.8H2O) C, H, N, Cl.
17-Cyclobu tylm eth yl-4,5r-ep oxy-14â-eth oxy-5â-m eth -
ylin d olo[2′,3′:6,7]m or p h in a n -3-ol h yd r och lor id e (39‚HCl):
colorless crystals; yield 34%; mp >250 °C; IR (KBr) 3400 (OH);
1H NMR (DMSO-d6) δ 11.35 (s, br, NH), 9.22 (s, br, OH), 8.47
(s, br, NH+), 7.35-6.95 (m, 4 arom H), 6.60 (d, J ) 8.2, 1 arom
H), 6.56 (d, J ) 8.2, 1 arom H), 1.86 (s, CH3-C(5)), 0.97 (t, J
) 7.0, CH3CH2); EI-MS m/z 471 (M+). Anal. (C30H34N2O3‚HCl‚
1.5H2O) C, H, N, Cl.
17-Allyl-4,5r-ep oxy-14â-m et h oxyin d olo[2′,3′:6,7]m or -
p h in a n -3-ol m eth a n esu lfon a te (40‚CH3SO3H): colorless
1
crystals; yield 42%; mp 258-261 °C; IR (KBr) 3416 (OH); H
NMR (DMSO-d6) δ 11.32 (s, NH), 9.25 (s, br, OH), 8.96 (s, br,
NH+), 7.39-6.94 (m, 4 arom H), 6.67 (d, J ) 8.1, 1 arom H),
6.63 (d, J ) 8.1, 1 arom H), 5.92 (m, 1 olef H), 5.82 (s, H-C(5)),
5.64 (m, 2 olef H), 3.08 (s, CH3O); CI-MS m/z 415 (M+ +1).
Anal. (C26H26N2O3‚CH3SO3H‚0.7H2O) C, H, N, S.
17-Allyl-4,5r-ep oxy-14â-eth oxyin d olo[2′,3′:6,7]m or p h i-
n a n -3-ol m eth a n esu lfon a te (41‚CH3SO3H): colorless crys-
tals; yield 51%; mp 275-278 °C; IR (KBr) 3425 (OH); 1H NMR
(DMSO-d6) δ 11.30 (s, NH), 8.57 (s, br, NH+), 7.37-6.93 (m, 4
arom H), 6.65 (d, J ) 8.1, 1 arom H), 6.63 (d, J ) 8.1, 1 arom
H), 5.90 (m, 1 olef H), 5.83 (s, H-C(5)), 5.65 (m, 2 olef H), 0.97
(t, J ) 6.8, CH3CH2); CI-MS m/z 429 (M+ + 1). Anal.
(C27H28N2O3‚CH3SO3H‚0.7H2O) C, H, N, S.
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4,5r-Epoxy-14â-m eth oxy-5â,17-dim eth ylin dolo[2′,3′:6,7]-
m or p h in a n -3-ol (43): beige crystals; yield 67%; mp 273-276
°C (dec); IR (KBr) 3300 (OH); 1H NMR (DMSO-d6) δ 11.10 (s,

14-Alkoxymorphinans
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 24 5383
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