Synthesis and biological activity of 8β-substituted hydrocodone indole and hydromorphone indole derivatives

Article abstract of DOI:10.1016/S0960-894X(01)00689-8

The 8β-unsubstituted and substituted analogues of hydrocodone indole and hydromorphone indole were synthesized and their binding affinities to opioid receptors were determined. Introduction of an 8β-methyl group into the indolomorphinan nucleus increased

Full text of DOI:10.1016/S0960-894X(01)00689-8

Bioorganic & Medicinal Chemistry Letters 12 (2002) 165–168
Synthesis and Biological Activity of 8ꢀ-Substituted Hydrocodone
Indole and Hydromorphone Indole Derivatives
Han Yu,a,y Thomas Prisinzano,a Christina M. Dersch,b Jamila Marcus,b
Richard B. Rothman,b Arthur E. Jacobsona and Kenner C. Ricea,*
aLaboratory of Medicinal Chemistry, NIDDK, National Institutes of Health, Bethesda, MD 20892, USA
bClinical Psychopharmacology Section, NIDA, Addiction Research Center, Baltimore, MD 21224, USA
Received 18 September 2001; accepted 16 October 2001
Abstract—The 8b-unsubstituted and substituted analogues of hydrocodone indole and hydromorphone indole were synthesized and
their binding affinities to opioid receptors were determined. Introduction of an 8b-methyl group into the indolomorphinan nucleus
increased affinity at all opioid receptors. 6,7-Dehydro-4,5a-epoxy-8b-methyl-6,7,20,30-indolomorphinan (9) was found to be a d
antagonist with subnanomolar affinity (0.7 nM) for the d-opioid receptor, and to have good d-selectivity (m/d=322). Published by
Elsevier Science Ltd.
Three types of opioid receptors (d, k, and m) have been
identified and cloned and there is substantial pharma-
cological evidence for subtypes for each.1 It is known
that each receptor mediates distinct pharmacological
events.2,3 Opioid antagonists that selectively interact
with the d receptor may find utility as drug abuse treat-
ment agents,4,5 while agonists that interact with m and/
or d receptors effect the perception of pain. Ligands
selective to m or k receptors have side effects that may
not be shared by d-selective receptor ligands, although
the latter are likely to have other, perhaps less detri-
mental, types of side effects. The development of potent
and selective agonists and antagonists for the d receptor
is currently being vigorously undertaken.
and dihydromorphinone.9a,c Studies also showed that
a bulkier substituent in the 8b-position, such as ethyl,
n-propyl, or n-butyl, decreased antinociceptive activi-
ty.9a In addition, substitution of the N-methyl moiety
with N-substituents known to convert opioid agonists
to antagonists in these epoxymorphinans, resulted in
partial agonists with mixed agonist and antagonist
properties.
In an effort to develop new opioid receptor ligands,
especially those that might interact with good affinity
and selectivity at d receptors, we decided to synthesize
and evaluate the biological activities of several 8-alkyl
substituted hydrocodone indole- and hydromorphone
indole-based derivatives, since Portoghese et al. repor-
ted that the addition of an indole ring to the epoxy-
morphinans increased affinity for d receptors.10 Based
on the reported SAR for dihydromorphinone and dihy-
drocodeinone,9a,c we chose to evaluate the indole deriva-
tives of both 8b-methyl- and 8b-n-butyl-hydromorphone
and hydrocodone. In addition, several 8b-methylhy-
dromorphone indole derivatives were also prepared
with different N-substituents (13–15).11
Oxymorphindole (OMI, 1) is a nonpeptide that has been
found to possess partial agonist activity and binds with
high affinity and selectivity to d receptors (Fig. 1).6 It
has been extensively reported that the 14-hydroxy group
is an important contributor to the efficacy of 1 at d
receptors.7,8 However, there are few reports on the
effects of substitution in the C-8 position of oxymor-
phindole-like compounds on opioid receptors.9
Previous studies have shown that 8b-methyl dihy-
drocodeinone and dihydromorphinone retain good
antinociceptive activity compared to dihydrocodeinone
yCurrent Address: Eli Lilly & Company, Lilly Corporate Center, DC
4813, Indianapolis, IN 46285, USA.
*Corresponding author. Tel.:+1-301-496-1856; fax:+1-301-402-0589;
e-mail: kr21f@nih.gov
Figure 1. Structure of oxymorphindole (1).
0960-894X/02/$ - see front matter Published by Elsevier Science Ltd.
PII: S0960-894X(01)00689-8

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H. Yu et al. / Bioorg. Med. Chem. Lett. 12 (2002) 165–168
Scheme 1. (a) 10% Pd/C, MeOH–EtOAc, H2; (b) RLi, CuI, Et2O; (c) PhNHNH2, HOAc; (d) BBr3, CH2Cl2; (e) (1) CNBr, CHCl3; (2) 2 N HCl;
(f) PhNHNH2, HCl, MeOH; (g) RX, K2CO3, DMF; (h) oxalic acid, acetone.
The starting material, codeinone, was synthesized from
thebaine following a known procedure (Scheme 1).9
Hydrogenation of codeinone led to 8-unsubstituted
dihydrocodeinone 2. Alternatively, 1,4-addition to the
codeinone with alkyllithium and CuI gave the 8-alkyl
substituted hydrocodone 3 or 4, with the substitution
predominately in the b position as previously deter-
mined.9 The ketones (2–4) were converted into the
corresponding indoles (5–7) by heating with phenylhy-
drazine hydrochloride and HOAc under reflux.12 The
hydrocodone indole derivatives were then converted to
hydromorphone indole derivatives 8–10 using BBr3 in
CH2Cl2 at 0 ꢀC.
further enhance the m/d selectivity of this ligand by
modifying the N-substituent. Based on our previous
work, the cyclopropylmethyl, 2-methylallyl, and the
trans-crotonyl groups were selected.11 The replacement
of the methyl group in 9 with either a cyclopro-
pylmethyl group (i.e., 13) or a 2-methylallyl substituent
(i.e., 14) led to a decrease in m/d selectivity compared to
9. The introduction of the trans-crotonyl group (i.e., 15)
decreased d affinity and gave only a modest enhance-
ment of m/d selectivity.
Several of the more interesting analogues were exam-
ined in GTPgS functional assays (Table 2).19 Hydro-
codone indole derivatives (i.e., 5, 6, and 7) were inactive
as antagonists at m and k receptors. Compounds 5 and
6, however, had a little d antagonist activity. The
hydromorphone indoles were more active than the
N-Alkylated derivatives 13–15 were prepared in several
steps from 8b-methyldihydrocodeinone (3).13À16 Com-
pound 3 was N-demethylated to 11 with cyanogen bro-
mide followed by acid hydrolysis.9 Treatment of 11 with
phenylhydrazine under Fisher indolization conditions
gave indole 12. Alkylation of indole 12 with the appro-
priate alkylating agent in DMF, followed by treatment
with BBr3 in CH2Cl2, afforded targets 13–15.
Table 1. Opioid receptor affinity of compounds 5–15a
The binding affinities of compounds 5–10 and 13–15 for m,
d, and k receptors were determined using previously
described methods (Table 1).17 Compounds 5 (hydro-
codone indole) and 8 (hydromorphone indole) were
resynthesized and found to be in reasonable agreement
with previous reported values.18 These binding data indi-
cated, as expected, that hydromorphone indole derivatives
have higher affinity than the hydrocodone indole deriva-
tives. The results also showed that a b-methyl group in the
C-8 position of hydromorphone indole, for example, 6,7-
dehydro-4,5a-epoxy-8b-methyl-6,7,20,30-indolomorphinan
(9), increased affinity at all opioid receptors compared to 8.
However, the extension of the 8b-methyl group to an n-
butyl group (10) led to a reduction in affinity at all three
opioid receptor sites, compared to 9, in accord with pre-
vious SAR.9a,c The introduction of an 8b-methyl group
to 5 (i.e., 6) led to a modest increase in m/d selectivity.
Compd R1 R2 R3
mb
dc
kd
m/d
5e
6
H Me Me
Me Me Me
>5000
>4800
>4300
95 (Æ8)
27 (Æ1)
>6100
>6300
>7000
>6000
>53
>177
>12
296
322
50
7
n-Bu Me Me
370 (Æ11)
8f
9
H
Me
n-Bu
Me
Me
Me
H
H
H
H
H
H
Me 710 (Æ66) 2.4 (Æ0.3)
Me 240 (Æ15) 0.7 (Æ0.1) 126 (Æ5)
Me 1100 (Æ74) 22 (Æ1) 720 (Æ60)
10
13
14
15
CPM
66 (Æ4)
2.3 (Æ0.2) 36 (Æ3)
29
MA 1080 (Æ122) 9 (Æ1) 850 (Æ118) 120
TC 1020 (Æ39) 2.3 (Æ0.2) 120 (Æ22) 441
CPM, cyclopropylmethyl; MA, 2-methylallyl; TC, trans-crotonyl.
aThe Ki values were determined in the above assays as described in
ref 11.
bDisplacement of [3H]DAMGO.
cDisplacement of [3H]DADL.
dDisplacement of [3H]U69593.
eHydrocodone indole18 re-evaluated.
fHydromorphone indole18 re-evaluated.
After our initial efforts identified compound 9 as a very
selective d ligand with high affinity, we attempted to

H. Yu et al. / Bioorg. Med. Chem. Lett. 12 (2002) 165–168
167
Table 2. Inhibition of opioid agonist stimulated [35S]GTPgS binding
(KiÆSD, nM)a
11. McLamore, S.; Ullrich, T.; Rothman, R. B.; Xu, H.;
Dersch, C.; Coop, A.; Davis, P.; Porreca, F.; Jacobson, A. E.;
Rice, K. C. J. Med. Chem. 2001, 44, 1471.
Compd R1
R2 R3
mb
dc
kd
m/d
12. General procedure. A mixture of 39 (2.4 g, 7.7 mmol) and
phenylhydrazine hydrochloride (2.2 g, 15.3 mmol) in HOAc
(40 mL) was heated under reflux for 3 h. After the reaction
mixture was cooled, 40 mL of water was added, followed by
10 mL of NH4OH. The mixture was extracted with CH2Cl2
(3Â80 mL), and the layers were separated. The combined
organic extract was dried (Na2SO4) and concentrated. The
residue was chromatographed to give 6, which is crystallized
from MeOH as 6.H2O (1.7 g, 4.5 mmol, 58% yield) as a white
solid: mp 152 ꢀC, 1H NMR d 8.23 (s, 1H, NH), 7.64 (d, J=9.0
Hz, 1H, H-70), 7.32 (d, J=9.0 Hz, 1H, H-40), 7.15 (t, J=7.2
Hz, 1H, H-60), 7.02 (t, J=7.2 Hz, 1H, H-50), 6.61 (s, 2H, H-1
and H-2), 5.64 (s, 1H, H-5), 3.75 (s, 3H, OCH3), 2.50 (s, 3H,
NCH3), 1.58 (d, J=6.9 Hz, 3H, CH3), EIMS m/z 386 (M+),
5e
6
H
Me Me Inactivef 290 (Æ19) Inactiveg
—
—
—
Me Me Me Inactivef 330 (Æ29) Inactiveg
7
n-Bu Me Me Inactivef
H
Me
Inactiveh
15 (Æ2)
49 (Æ5)
46 (Æ4)
Inactiveg
8i
9
H
H
H
Me 202 (Æ36)
Me Inactivef
Me 561 (Æ54)
731 (Æ72) 14
398 (Æ36)
272 (Æ24) 12
—
10
n-Bu
aThe Ki values were determined in the above assays as described in
ref 11.
bInhibition of DAMGO.
cInhibition of SNC80.
dInhibition of U69593.
eHydrocodone indole18 re-evaluated.
fKi>600 nM=inactive.
gKi>350 nM=inactive.
ꢁ
Anal. (C25H26N2O2 H2O) C, H, N.
hKi>750 nM=inactive.
13. General procedure. Phenylhydrazine hydrochloride (1.4 g,
9.6 mmol) was added to a solution of 8b-methyldihy-
dronorcodeinone hydrochloride (11)9 (3.2 g, 9.6 mmol) in a
mixture of absolute MeOH (40 mL) and 6 N HCl (10 mL).
The resulting mixture was heated at reflux for 6 h. The pre-
cipitate was collected, washed with CHCl3 (3Â30 mL), and
dried to afford 3.2 g (82%) of 6,7-didehydro-4,5a-epoxy-3-
methoxy-8b-methyl-[6,7:20,30]-indolomorphinan hydrochloride
(12) as a white solid, mp >300 ꢀC.
iHydromorphone indole18 re-evaluated.
hydrocodone indoles. Interestingly, compound
8
appears to be a more efficacious d antagonist than 9
despite the fact that 9 binds with higher affinity at d
receptors (3-fold) and was found to be slightly more m/d
selective than 8. Compound 9 was found to have little m
antagonist activity (Ki>1100 nM). If its m-opioid affi-
nity is mostly due to its m-agonist activity, this com-
pound may represent a new lead for the development of
a m agonist/d antagonist dual ligand. Further studies are
currently underway to further explore this possibility.
Compounds with that mixed activity might prove very
valuable as new analgesics or treatment agents.
14. General procedure. A suspension of 12 (1.1 g, 2.7 mmol),
K2CO3 (1.1 g, 8.1 mmol), and bromomethylcyclopropane (0.4
g, 3.2 mmol) in dry DMF (30 mL) was heated at reflux for 2 h.
H2O (200 mL) was added and the mixture was extracted with
ethyl acetate (3Â50 mL). The combined ethyl acetate portion
was washed with H2O (2Â75 mL) and saturated NaCl (50 mL)
and dried (Na2SO4). Removal of the solvent under reduced
pressure afforded a crude oil that was dissolved in dry acetone.
An excess of oxalic acid was added and the solvent was
removed under reduced pressure. Anhydrous Et2O was added
and the precipitate was collected and dried to afford 1.2 g
(86%) of N-cyclopropylmethyl-6,7-didehydro-4,5a-epoxy-3-
methoxy-8b-methyl-[6,7:20,30]-indolomorphinan oxalate as a
white solid, mp 276–279 ꢀC. A solution of the above com-
pound (0.5 g, 1.3 mmol) in dry CH2Cl2 (20 mL) at 0 ꢀC was
treated with BBr3 (4 mmol, 4 mL of 1.0 M solution in
CH2Cl2). The mixture was stirred at room temperature for 1 h,
2 N HCl (25 mL) was added and the mixture was heated at
reflux for 30 min. The pH was adjusted to pH 9 by the addi-
tion of concd NH4OH and the mixture was extracted with
CH2Cl2 (3Â50 mL). The combined CH2Cl2 portion was
washed with saturated NaCl (100 mL) and dried (Na2SO4).
The solvent was removed under reduced pressure to afford a
crude solid that was dissolved in dry acetone. An excess of
oxalic acid was added and the precipitate was collected and
dried. Recrystallization from absolute EtOH afforded 0.3 g
(50%) of 13 as a white solid, mp 236–238 ꢀC.
Acknowledgements
The authors would like to thank Noel Whittaker of the
Laboratory of Bioorganic Chemistry, NIDDK for mass
spectral data. Partial support of this work is by the
National Institute on Drug Abuse.
References and Notes
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1983, 18, 22.
15. Compounds 6, 7, 9, and 10 were characterized by 1H
NMR (300 MHz, DMSO-d6) and by elemental analysis of
their free base or hydrochloride salt. The results were in
agreement with the assigned structures: 6: mp 152 ꢀC,
ꢁ
(C25H26N2O2 H2O): d 8.23 (s, 1H, NH), 7.64 (d, J=9.0 Hz,
1H, H-70), 7.32 (d, J=9.0 Hz, 1H, H-40), 7.15 (t, J=7.2 Hz,
1H, H-60), 7.02 (t, J=7.2 Hz, 1H, H-50), 6.61 (s, 2H, H-1 and
H-2), 5.64 (s, 1H, H-5), 3.75 (s, 3H, OCH3), 2.50 (s, 3H,
NCH3), 1.ꢀ58 (d, J=6.9 Hz, 3H, CH3), EIMS m/z 386 (M+), 7:
ꢁ
mp >215 C, (C28H32N2O2 HCl): d 8.23 (s, 1H, NH), 7.57 (d,
J=7.8 Hz, 1H, H-70), 7.30 (d, J=8.1 Hz, 1H, H-40), 7.15 (t,
J=6.0 Hz, 1H, H-60), 7.01 (t, J=7.2 Hz, 1H, H-50), 6.60 (s,
2H, H-1 and H-2), 5.64 (s, 1H, H-5), 3.75 (s, 3H, OCH3), 2.51
(s, 3H, NCH3), CIMS m/z 429 (MH+), 9: mp 202 ꢀC,
10. Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori,
A. E. J. Med. Chem. 1988, 31, 281.
ꢁ
(C24H24N2O2 H2O): d 8.11 (s, 1H, NH), 7.65 (d, J=9.0 Hz,

168
H. Yu et al. / Bioorg. Med. Chem. Lett. 12 (2002) 165–168
1H, H-70), 7.32 (d, J=9.0 Hz, 1H, H-40), 7.16 (t, J=7.8 Hz,
1H, H-60), 7.02 (t, J=7.8 Hz, 1H, H-50), 6.56 (m, 2H, H-1 and
H-2), 5.65 (s, 1H, H-5), 2.51 (s, 3H, NCH3), 1.58 (d, J=6.9
Hz, 3H, CH3), EIMS m/z 372 (M+), 10: mp 172 ꢀC,
1H, NH), 6.6–7.3 (m, 4H, indole), 6.4 (m, 2H, aromatic), 5.5 (s,
1H, H5), 4.8 (d, 2H, J=20 Hz, ¼CH2), 4.2 (bs, H2O), 2.2 (s,
3H, NCH2), 1.6 (s, 3H, CH3), 1.4 (m, 3H, CH3), 15: mp 200–
204 ꢀC, (C27H28N2O2.C2H2O4.1.0H2O): d 11.3 (s, 1H, NH),
6.9–7.6 (m, 4H, indole), 6.6 (s, 2H, aromatic), 5.9 (m, 1H,
CH=), 5.7 (s, 1H, H5), 5.6 (s, 1H, CH¼), 4.4 (bs, H2O), 2.5 (s,
3H, NCH2), 1.7 (d, 3H, J=4.8 Hz, CH3), 1.5 (m, 3H, CH3).
17. Kubota, K.; Rothman, R. B.; Dersch, C.; McCullough,
K.; Pinto, J.; Rice, K. C. Bioorg. Med. Chem. Lett. 1998, 8,
799.
18. Maguire, P. A.; Perez, J. J.; Tsai, N. F.; Rodriguez, L.;
Beatty, M. F.; Villar, H. O.; Kamal, J. J.; Upton, C.; Casy,
A. F.; Loew, G. H. Mol. Pharmacol. 1993, 44, 1246.
19. Coop, A.; Rothman, R. B.; Dersch, C. M.; Partilla, J.;
Porreca, F.; Davis, P.; Jacobson, A. E.; Rice, K. C. J. Med.
Chem. 1999, 42, 1673.
ꢁ
(C27H30N2O2 H2O): d 8.23 (s, 1H, NH), 7.74 (d, J=8.1 Hz,
1H, H-70), 7.24 (m, 1H, H-40), 7.11 (t, J=7.2 Hz, 1H, H-60),
6.99 (t, J=7.5 Hz, 1H, H-50), 6.56 (m, 2H, H-1 and H-2), 5.62
(s, 1H, H-5), 2.48 (s, 3H, NCH3), CIMS m/z 415 (MH+).
16. Compounds 13–15 were characterized by 1H NMR
(300 MHz, DMSO-d6) and by elemental analysis of their oxa-
late salt. The results weꢀre in agreement with the assigned struc-
ꢁ
ꢁ
tures: 13: mp 236–238 C, (C27H28N2O2 C2H2O4 1.25H2O): d
11.0 (s, 1H, NH), 6.6–7.3 (m, 4H, indole), 6.3 (m, 2H, aro-
matic), 5.4 (s, 1H, H5), 5.0 (bs, H2O), 2.2 (s, 2H, NCH2), 1.2 (m,
3H, CH3), 0.8 (sꢀ, 1H, CH), 0.3 (s, 2H, CH2), 0.1 (s, 2H, CH2),
ꢁ
ꢁ
14: mp 216–220 C, (C27H28N2O2 C2H2O4 1.0H2O): d 11.0 (s,