2-Aminothiazole-Derived Opioids. Bioisosteric Replacement of Phenols

Article abstract of DOI:10.1021/jm049978n

A series of aminothiazole-derived morphinans, benzomorphans, and morphine were synthesized. Although their affinities were somewhat lower than their phenol prototypes, one compound (9a, ATPM) has been identified possessing high affinity and selectivity at the κ receptor. Functional assays showed that 9a was a full κ but partial μ agonist; the efficacy at κ was significantly greater than at μ receptors. This novel compound may be valuable for the development of long-acting analgesics and drug abuse medication.

Full text of DOI:10.1021/jm049978n

1886
J . Med. Chem. 2004, 47, 1886-1888
Ch a r t 1
2-Am in oth ia zole-Der ived Op ioid s.
Bioisoster ic Rep la cem en t of P h en ols
Ao Zhang,† Wennan Xiong,† J ames E. Hilbert,‡
Emily K. DeVita,‡ J ean M. Bidlack,‡ and
J ohn L. Neumeyer*,†
In our earlier report,13 we synthesized two aminothia-
zole-derived morphinans 4 and 5 from commercially
available levorphanol 1, which was first triflated and
then subjected to reduction followed by nitration (Scheme
1). The resulting two nitrated isomers (2 and 3) were
separated and reduced to their corresponding amines
followed by cyclization, which occurred selectively and
produced the aminothiazole products 4 and 5, respec-
tively. However, the isolation of the nitro intermediates
2 and 3 was cumbersome and resulted in low yields that
limited the application of this procedure to the synthesis
of other aminothiazolomorphinans. Alternatively, a Pd-
catalyzed amination approach was used in our current
synthesis.6a,14 Thus, the phenolic opioids including mor-
phinans 6a (cyclorphan), 6b, and 6c and benzomor-
phans 6d and 6e were employed as the substrates
(Scheme 2). After triflation of phenols 6a -e, the corre-
sponding triflates 7a -e were subjected to palladium-
catalyzed amination yielding the amines 8a -e in mod-
erate yield. Upon cyclization of 8a -e by a reported
procedure,13 the aminothiazoles 9a -e were obtained in
moderate yields. A similar strategy was used to prepare
the aminothiazole-derived morphine 14 (Scheme 3).
First, the phenolic hydroxyl function of morphine was
selectively triflated followed by protection of the 6-hy-
droxyl group with a tert-butyldiphenylsilyl moiety (TB-
DPS). The resulting triflate 11 was subjected to the
same amination procedure described above to yield the
TBDPS-protected 3-aminomorphine 12,15 which was
followed by the formation of aminothiazole ring to yield
13. After deprotection of 6-hydroxyl group in 13 with
tetrabutylammonium fluoride (TBAF), aminothiazole-
derived morphine 14 was obtained in 62% yield.
All new compounds including 4, 5, 9a -e, and 14 were
evaluated for their binding affinity at all three opioid
receptors (µ, κ, and δ) (Table 1) using a previously
reported procedure.6,16 For comparison purposes, opioid
binding affinity data for the phenol precursors including
116 (levorphanol), 6a 6a (cyclorphan) and its N-cyclo-
butylmethyl analogue 6b,6a ketomorphinan 6c,6a ben-
zomorphan 6d ,15 and morphine15 were also included.
From the data shown in Table 1, the binding affinities
of the 2-aminothiazole-derived opioids were generally
lower than the binding affinities of the phenol precur-
sors, but the selectivity for κ over µ and δ receptors was
improved. A difference was observed between the re-
gioisomers 4 and 5. Compared to the phenol 1, the 2,3-
fused isomer 4 displayed only slightly lower affinity (3-
to 5-fold) at κ and µ receptors, while a remarkable
decrease (14- to 60-fold) in affinity was observed in the
1,2-fused isomer 5, and the selectivity of µ over κ
receptors was reversed. It is noteworthy that ami-
nothiazole 9a (ATPM), which is derived from the κ
agonist cyclorphan 6a , retained the same high affinity
(Ki ) 0.049 nM) at the κ receptor, although a decrease
Alcohol and Drug Abuse Research Center, McLean Hospital,
Harvard Medical School, 115 Mill Street,
Belmont, Massachusetts 02478, and
Department of Pharmacology and Physiology, School of
Medicine and Dentistry, University of Rochester,
Rochester, New York 14642
Received J anuary 6, 2004
Abstr a ct: A series of aminothiazole-derived morphinans,
benzomorphans, and morphine were synthesized. Although
their affinities were somewhat lower than their phenol pro-
totypes, one compound (9a , ATPM) has been identified pos-
sessing high affinity and selectivity at the κ receptor. Func-
tional assays showed that 9a was a full κ but partial µ agonist;
the efficacy at κ was significantly greater than at µ receptors.
This novel compound may be valuable for the development of
long-acting analgesics and drug abuse medication.
It is generally accepted that two sites, the basic
nitrogen and the phenol moiety, are necessary for
narcotic analgesic binding to its receptors.1,2 The phe-
nolic hydroxyl group is recognized as a requisite for the
formation of a hydrogen bond with a dipolar site on the
receptor and for good antinociceptive activity.2,3 How-
ever, the free hydroxyl group is also a potential site for
metabolism, conjugation, and excretion resulting in low
oral bioavailability and short duration of action.4,5 One
of the approaches to improve the pharmacological
properties of analgesics such as morphine and morphi-
nan analogues is to modify this phenolic hydroxyl
function. Recently, we have synthesized and identified
several potent compounds by replacing the hydroxyl
moiety of morphinans with other functional groups
(amino, carboxamido, etc).6 In the current communica-
tion, we investigated the replacement of the phenolic
hydroxyl moiety by a heterocyclic bioisostere: 2-ami-
nothiazole. The rationale for this approach was strength-
ened by the fact that the 2-aminothiazole functionality
has been successfully applied as a heterocyclic bio-
isostere of the phenol moiety in dopamine agonists such
as B-HT 920,7 PD 118440,8 and the widely used anti-
parkinsonian agent pramipexole9-11 (Chart 1). These
medications resulted in improved pharmacological prop-
erties including longer duration of action and better
bioavailability. Although the 2-aminothiazole moiety,
strictly speaking, cannot be considered as a bioisosteric
replacement12 of the phenol group, it can be viewed as
an extension of the aromatic functionality of the mol-
ecule. The 2-amino group may effectively substitute the
phenolic hydroxyl group to form a presumed hydrogen
bond on its receptor binding site, which may result in
improved pharmacological properties.
* To whom correspondence should be addressed. Phone: 617-855-
3388. Fax: 617-855-2519. E-mail: Neumeyer@mclean.harvard.edu.
† Harvard Medical School.
‡ University of Rochester.
10.1021/jm049978n CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/11/2004

Letters
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 8 1887
Ta ble 1. Ki Values Inhibition of δ, κ, and µ Opioid Binding to Chinese Hamster Ovary Membranes by Novel Compoundsa
Ki ( SEM (nM)
selectivity
compd
[3H]DAMGO (µ)
[3H]naltrindole (δ)
[3H]U69,593 (κ)
µ:κ
δ:κ
1 (levorphanol)
6a (cyclorphan)
6b (MCL-101)
6c
0.21 ( 0.02
0.062 (0.003
0.23 ( 0.01
3.3 ( 0.4
0.32 ( 0.02
0.88 ( 0.14
130 ( 6
1.1 ( 0.1
1.5 ( 0.2
7.1 ( 0.5
200 ( 43
48 ( 6
8.3 ( 0.2
30 ( 3
4.2 ( 2.3
1.9 ( 0.1
5.9 ( 0.6
260 ( 55
1.1 ( 0.0
140 ( 18
1100 ( 30
190 ( 10
29 ( 2
2.3 ( 0.3
0.09
2
3
2
60
70
540
6.1
5.8
38
30
590
290
>770
140
190
0.14
0.034 ( 0.002
0.079 ( 0.003
0.48 ( 0.03
0.18 ( 0.02
24 ( 2
7
6d
1.8
0.04
4.5
0.17
30
9.0
15
7.1
17
morphine
5 (MCL-186)
4 (MCL-187)
9a (ATPM)
9b (ATBM)
9c (MCL-168)
9d (MCL-185)
9e (MCL-184)
14 (MCL-188)
29 ( 1
6.4 ( 0.5
0.049 ( 0.005
0.79 ( 0.02
13 ( 2
6.7 ( 0.3
0.49 ( 0.03
220 ( 10
230 ( 21
>10 µM
940 ( 19
93 ( 10
32 ( 3
0.13
a
Chinese hamster ovary membranes, 0.5 mg of protein/sample, were incubated with 12 different concentrations of the compounds in
the presence of receptor-specific radioligands at 25 °C, in a final volume of 1 mL of 50 mM Tris-HCl, pH 7.5. Nonspecific binding was
determined using 10 µM naloxone. Data are the mean values ( SEM from three experiments, performed in triplicate. Data for 1
(levorphanol), 6a (cyclorphan), 6b (MCL-101), 6c, 6d , and morphine were obtained from the literature.6a,15,16
Sch em e 1a
Sch em e 3a
a
a
Reagents and conditions: (i) PhNTf2, Et3N; (ii) TBDSCl,
Reagents and conditions: (i) PhNTf2, Et3N, CH2Cl2; (ii) Pd/C
imidazole, THF; (iii) Pd(OAc)2, BINAP, Ph2CdNH, Cs2CO3; (iv)
NaOAc, NH2OH.HCl; (v) KSCN, Br2, AcOH; (vi) TBAF, THF.
(10%), HCO2NH4; (iii) HNO3, H2SO4, CH3NO2; (iv) Pd/C (10%),
HCO2NH4; (v) KSCN, Br2, AcOH.
clobutylmethyl analogue 9e displayed higher affinity
than the cyclopropylmethyl analogue 9d at all three
opioid receptors, especially at the κ receptor. The
morphine derived aminothiazole 14 displayed a decrease
of 34-fold at µ, 9-fold at κ, but a 4-fold increase at δ
receptors. Compared to the high affinity and selectivity
of morphine at the µ receptor, 14 was equipotent at µ
and δ and 7-fold higher than at κ receptors. [35S]GTPγS
binding studies showed that 9a , similar to phenol 6a ,
was a full κ but partial µ agonist. It produced greater
stimulation at κ than at µ receptors. Compared to the
phenol 6b, the cyclobutylmethyl analogue 9b was a κ
agonist with a very weak agonist activity at the µ
receptor (Table 2).
Sch em e 2a
In summary, a series of aminothiazole-derived mor-
phinans, benzomorphans, and morphine were synthe-
sized with a palladium-catalyzed amination as the key
step. Although the affinity of this novel series was
somewhat reduced from that of their phenol prototypes,
one compound (9a ) has been identified as possessing
high affinity and selectivity at the κ receptor. The
functional assays showed that 9a was a full κ but partial
µ agonist, and the efficacy at κ was considerably greater
than at µ receptors. In view of the short duration of
action of traditional narcotic analgesics and the suc-
cessful application of the 2-aminothiazole functionality
as a heterocyclic bioisostere of the phenol moiety in DA
agonists, as well as the potential application of κ
agonists as a treatment for cocaine abuse, this novel
compound may be valuable for the development of long-
a
Reagents and conditions: (i) PhNTf2, Et3N, CH2Cl2; (ii)
Ph2CdNH, BINAP, Pd(OAc)2, Cs2CO3; (iii) NaOAc, NH2OH.HCl;
(iv) KSCN, Br2, AcOH.
of 2.5-fold at µ and 15-fold at δ was observed. This
resulted in a high selectivity for κ over µ (30-fold) and δ
(590-fold) receptors. The cyclobutylmethyl analogue 9b
(ATBM), compared to the phenol 6b, showed a 30- to
40-fold decrease in affinity at µ and δ but only 10-fold
decrease at the κ receptor, which also displayed a good
selectivity for κ versus µ and δ receptors. A pronounced
decrease in affinity at all three receptors was observed
in the aminothiazole-derived ketomorphinan 9c. Simi-
larly, an appreciable decrease in affinity (37- to 850-
fold) was also observed in 9d , which was derived from
the benzomorphan 6d . It is noteworthy that the cy-

1888 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 8
Ta ble 2. Emax and EC50 Values for the Stimulation of
Letters
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[
35S]GTPγS by Novel Compoundsa
compd
Emax ( SE (% stimulation)
EC50 ( SE (nM)
κ Opioid Receptor
90 ( 10
6a 6b
0.2 ( 0.0
1.3 ( 0.4
2.4 ( 0.6
29 ( 4
6b6b
80 ( 7
9a (ATPM)
9b (ATBM)
80 ( 6
80 ( 1
µ Opioid Receptor
40 ( 3
6a 6b
0.8 ( 0.1
1.6 ( 0.1
73 ( 5
6b6b
50 ( 2
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9a (ATPM)
9b (ATBM)
45 ( 4
26 ( 1
>1 µM
a
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acting analgesics and drug abuse medication. Further
pharmacological evaluation is in progress.
Ack n ow led gm en t. This work was supported, in
part, by NIDA Grants K05-DA 00360 and R01-DA14251
and the Branfman Family Foundation. Levorphanol
tartrate was generously donated by Mallinckrodt Inc.,
and the benzomorphan used to prepare 6d and 6e was
kindly supplied by Prof. Mark P. Wentland.
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nothiazole derived morphinans. Tetrahedron Lett. 2003, 44,
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compounds. This material is available free of charge via the
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J M049978N