Aminothiazolomorphinans with mixed κ and μ opioid activity

Article abstract of DOI:10.1021/jm101542c

A series of N-substituted and N′-substituted aminothiazole-derived morphinans (5) were synthesized for expanding the structure-activity relationships of aminothiazolo-morphinans. Although their affinities were somewhat lower thn their prototype aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole derivatives of cyclorphan (1) containing a primary amino group displayed high affinity and selectivity at the κ and μ opioid receptors. [³⁵S]GTPγS binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid receptor. These novel N′-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse medications.

Full text of DOI:10.1021/jm101542c

ARTICLE
pubs.acs.org/jmc
Aminothiazolomorphinans with Mixed K and μ Opioid Activity§
Tangzhi Zhang,† Zhaohua Yan,† Anna Sromek,† Brian I. Knapp,‡ Thomas Scrimale,‡ Jean M. Bidlack,‡ and
John L. Neumeyer*,†
†Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478,
United States
‡Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642,
United States
ABSTRACT: A series of N-substituted and N0-substituted aminothia-
zole-derived morphinans (5) were synthesized for expanding the
structure-activity relationships of aminothiazolo-morphinans.
Although their affinities were somewhat lower than their prototype
aminothiazolo-N-cyclopropylmorphinan (3), 3-aminothiazole deriva-
tives of cyclorphan (1) containing a primary amino group displayed
high affinity and selectivity at the κ and μ opioid receptors. [35S]GTPγS
binding assays showed that the aminothiazolomorphinans were κ agonists with mixed agonist and antagonist activity at the μ opioid
receptor. These novel N0-monosubstituted aminothiazole-derived morphinans may be valuable for the development of drug abuse
medications.
’ INTRODUCTION
antinociceptive tolerance, with less potential to develop toler-
ance and reduce heroin self-administration with a lower sedative
effect.12 However, recent in vivo studies of 3 in mice in the 55 °C
tail-flick test showed that this compound does not appear to have
a longer duration of action than the phenolic compound 1.13
Aiming to extend duration of action and to improve oral
bioavailability, a structure-activity relationship (SAR) study
has been conducted to investigate the effect of modifications of
N-substituent (R3) and N0-3-amino-substituted (R1 and R2) of
the morphinan 5 (Figure 1).
Herein, we report the synthesis and pharmacological evalua-
tion of a series of N-substituted (R3) and N0-3-amino-substituted
(R1 and R2) analogues of morphinan. The highly potent (-)-3-
hydroxy-N-(E)-iodoallylmorphinan14 suggested the replacement
of the N-cyclopropylmethyl group in cyclorphan with a fluo-
ropropyl group to make compounds 7c and its analogues 9c, 11,
13c, and 19c and introduced a trifluoroethyl substituent to the
amino group of the aminothiazole component in 3 to make
compound 15 (Schemes 1 and 2).
The opioid system modulates several key physiological and
behavioral processes, such as pain perception, the stress re-
sponse, the immune response, and neuroendocrine function.1
With the discovery of the three different opioid receptors [κ
opioid receptor (κOR), μ opioid receptor (μOR), and δ opioid
receptor (δOR)], different functions and effects of the three
receptor subtypes have been elucidated. Notably, it was found
that the κOR plays a role in the development of drug addiction,
specifically by altering the dopamine reward pathway. Thus, the κ
receptor has been implicated as a primary target for the devel-
opment of pharmacotherapies for the treatment of cocaine
dependence.2,3 Recent behavioral studies suggested that κ/μ
opioids may be useful for the treatment of cocaine abuse and
dependence.4 We reported that both acute and chronic treat-
ment with mixed κ/μ opioids cyclorphan (1)5 and butorphan5,6
reduced cocaine self-administration dose dependently and pro-
duced fewer side effects than κ-selective agonists.7 However, the
opioid derivatives are not metabolically stable: The free phenolic
hydroxyl group in cyclorphan (1) and butorphan is also a
potential site for metabolism, conjugation, and excretion, result-
ing in low oral bioavailability and short duration of action.1,8,9 In
an attempt to further extend the duration of action and to
manipulate relative affinity and efficacy at κOR, modification of
the phenolic hydroxyl group of cyclorphan has been performed,
by incorporating 3-amino (2),10 3-aminothiazole (3, ATPM),10
and 2-aminooxazole (4)11 isosteres (Figure 1).
’ CHEMISTRY
The synthesis of all target compounds was initiated from
commercially available levorphanol tartrate, which, after conver-
sion to its free base, could be demethylated to norlevorphanol
(6). Next, 6 was alkylated with either cyclopropylmethyl bro-
mide, cyclobutylmethyl bromide, fluoropropyl bromide, or
(-)-(s)-tetrahydrofurfuryl (R)-camphor-10-sulfonate to yield
7a-d, respectively. Subsequent triflation of morphinans 7a-d
Among this series, one compound, 3 (Figure 1), has been
identified to possess high affinity at κOR (Ki = 0.049 nM)
and mixed κ agonist and μ agonist/antagonist.10c (Table 1).
Previous studies have shown that 3 inhibited morphine-induced
Received: December 2, 2010
Published: February 25, 2011
r
2011 American Chemical Society
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derivative 29, the N-cyclopropyl compound 3 displayed a much
higher (130-fold) affinity at κ the receptor. From the data shown
in Table 1, the N-fluoropropyl derivative 11 had high affinity at κ
(0.30 nM) and good selectivity for κ over μ (9-fold) and δ (180-
fold) receptors. N-Tetrahydrofurylmethylmorphinan 12 also
showed high affinity at κ (0.83 nM) and moderate affinity at μ
(2.4 nM). Introducing a small alkyl group at N0, 13a had similar
affinity with 3 at the κ receptor, with a Ki value of 0.066 nM.
Compound 13a also displayed high selectivity for κ over μ (45-
fold) and δ (380-fold) receptors. When the size of alkyl group at
N0 increased, we observed a smooth decrease in affinity at κ and μ
receptors in 19a, 15, and 16a. However, they still displayed high
affinity at κ (Ki = 0.15-1.6 nM). N0-Acetyl aminothiazolomor-
phinan 18a showed low affinity at κ (13 nM) and μ (57 nM),
perhaps due to the lowered basicity of nitrogen in this analogue.
When the N0-substituent on amine was either benzyl (22),
3-OH-benzyl (23), or 3-MeO-benzyl (21), binding affinities
were low [Ki = 2.1-4.8 nM (κ) and Ki = 9.1-10 nM (μ)].
Analogues 26 and 27, which contained N0-aryl and (hetero)aryl
groups, were prepared. As compared to the alkyl-substituted
aminothiazole analogues (13a, 15, and 19a), an unexpected
decrease of affinity at κ and μ receptors was observed in 26
and 27. The N0-piperazine-substituted aminothiazolomorphinan
displayed very low affinity at κ (110 nM) and μ (2700 nM). To
explore the possibility that incorporation of an additional polar
group into the N0-substitution would further enhance affinity, we
prepared a thiourea analogue as a probe. However, the N0-
ethylthiourea analogue displayed low affinity at κ (18 nM) and
μ (130 nM).
Figure 1. Structures of opioid ligands butorphan and 1-5.
afforded triflates 8a-d, which were subjected to palladium-
catalyzed amination to afford amines 9a-d in moderate yields.
The aminothiazoles 3 and 10-12 were then synthesized in 55-
61% yield according to the literature procedure (Scheme 1).6,10
For the synthesis of N0-methyl-substituted aminothiazolomor-
phinans 13a-c, aminothiazolomorphinans 3, 10, and 11 were
formylated with freshly prepared formyl acetate (prepared by
heating a mixture of HCOOH and Ac2O), followed by reduction,
yielding the novel N0-methyl-3-aminothiazolomorphinans
13a-c in 34-45% yields (Scheme 2).15 Treatment of 13a and
13c with paraformaldehyde and NaBH4 yielded dimethyl-sub-
stituted aminothiazolomorphinans 17a and 17c in 83-89%
yields.16 N0-Trifluoroethyl derivative 15 was prepared in 45%
yield by treating 3 with trifluoroacetic anhydride in the presence
of Et3N, followed by reduction.17 N0-Ethyl-substituted ami-
nothiazolomorphinans 19a-c were prepared analogously17 in
which compounds 3, 10, and 11 were first acylated and then
reduced. Treatment of 13a and 19a with acetic anhydride
produced N0-disubstituted derivatives 14 and 20. Compounds
3 and 11 were also condensed with propionaldehyde, followed
by reduction of the resulting imines to N0-propyl-substituted
aminothiazolomorphinans 16a and 16c in 47-55% yields18
(Scheme 2).
It was found that N0-disubstituted aminothiazolo-N-cyclopro-
pylmorphinans generally had lower affinity when compared to
N0-monosubstituted aminothiazolo-N-cyclopropylmorphinans.
N0-Dimethyl-substituted derivative (17a) was the most potent
compound in the series of N0-disubstituted compounds synthe-
sized, with an affinity of 0.45 nM at the κ receptor and 10 nM at
the μ receptor. Ki values for N0-methyl derivative (13b) and N0-
ethyl derivative (19b) were 2.4 and 3.7 nM for κ, respectively. N-
Fluoropropyl N0-methyl (13c) and N0-ethyl (19c) morphinan
analogues were very potent, with Ki values being <1 nM for
binding to the κOR. N-Fluoropropyl N0-propyl (16c) and N0-
dimethyl (17c) morphinan analogues showed low affinity at the
κ and μ receptors. From a SAR perspective, the binding affinities
of substituted aminothiazolomorphinan analogues at all three
receptors were generally lower than the binding affinities of the
aminothiazole precursors (3, 10, and 11). However, most of the
N0-monosubstituted analogues showed high affinities at κ (Ki =
0.06-0.94 nM).
Using literature procedures,19 3 was reductively aminated to
afford 21 and 22 in 65-68% yields. Methoxybenzylated deriva-
tive 21 was demethylated with BBr3 to give 23 in 74% yield.20
Furthermore, 3 was treated with EtSCN to yield thiourea 24 in
45% yield (Scheme 3).21
For preparation of aryl-substituted derivatives 26 and 27, 3
was converted to 3-bromo-thiazolo-N-cyclopropylmethylmor-
phinan 25 through the Sandmeyer reaction.22 Compound 25
was treated with aniline and 2-aminopyridine, respectively, to
yield 26 and 27 in 70-72% yields. Treatment of 25 with
piperazine produced 28 in 63% yield (Scheme 4).23
To characterize the relative efficacy of these ligands, 1, 3, and
10 were selected for the [35S]GTPγS assay. The stimulation and
inhibition of [35S]GTPγS binding mediated by κORs and μORs
are shown in Tables 2 and 3, respectively.
These ligands produced maximal stimulation of [35S]GTPγS
binding (Emax) at κ comparable to that of ligand 3. Ligands 13c,
15, 19a, and 19c produced a higher Emax than that of selective
agonist U50,488. None of these compounds inhibited U50,488-
stimulated [35S]GTPγS at κ, demonstrating that all of these
ligands were full κ agonists.
’ RESULTS AND DISCUSSION
Target compounds were screened for their affinity and
selectivity for μORs, κORs, and δORs with Chinese hamster
ovary (CHO) cell membranes stably expressing the human
opioid receptors. The data were summarized in Table 1. For
comparison purposes, opioid binding affinity data for cyclorphan
1, 2, 3, 4, and N-methyl-3-aminothiazolo-morphinan (29) were
also included.
Previous reports from our laboratories indicated that changing
N-substituted group (R3) in the aminothiazolomorphinan dras-
tically altered potency and efficacy. As compared to the N-methyl
From the data shown in Table 3, ligands 11, 13a,
and 17a displayed partial agonist activity at μ receptor. Ligands
12, 13c, 19a, and 19c showed full agonist activity at the
μ
receptor; they did not inhibit DAMGO-stimulated
[35S]GTPγS binding.
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ARTICLE
Table 1. Binding Affinities of Novel Compounds to Human KORs, μORs, and δORsa
a Membranes from CHO cells, expressing either human κORs, μORs, or δORs, 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. b Data are the mean values ( SEMs from three experiments, performed in triplicate. Data for 1- 4, and 29 were obtained from the
literature.5c,10c,11
’ CONCLUSION
and δ (380-fold) receptors. N0-Disubstituted aminothiazolo-N-
cyclopropylmorphinan analogues 17a, 14, 20, and 17c had lower
affinity at all three opioid receptors. However, N0-dimethyl
aminothiazolo-N-cyclopropylmorphinan 17a was also a potent
and selective compound, with an affinity of 0.45 nM at the
κ receptor and 10 nM at the μ receptor. The same pattern
was observed with the replacement of the cyclopropylmethyl
group in 1 with the fluoropropyl group. Compounds 13a, 19a,
and 17a may prove to be useful for the potential development as
medications for cocaine or opioid abuse. The [35S]GTPγS
We have extended the SARs of aminothiazolomorphinans by
introducing different groups to N- and N0-positions. A series of
aminothiazolomorphinans and their N0-mono- and disubstituted
derivatives were synthesized, and their pharmacological proper-
ties at opioid receptors were evaluated. It was found that
substituents at the aminothiazole nitrogen tended to reduce
the affinity of the compounds, with the exception of the methyl
group (13a), which retained high affinity at the κ receptor
(0.066 nM) as well as good selectivity for κ over μ (45-fold)
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ARTICLE
Scheme 1a
a Reagents and conditions: (i) Cyclopropylmethyl bromide, cyclobutylmethyl bromide, fluoropropyl bromide, or (-)-(s)-tetrahydrofurfuryl (R)-
camphor-10-sulfonate, K2CO3, DMF. (ii) PhNTf2, Et3N, CH2Cl2. (iii) Ph2CdNH, BINAP, Pd(OAc)2, Cs2CO3, THF. (iv) NaOAc, NH2OH.HCl,
MeOH. (v) KSCN, Br2, AcOH.
Scheme 2a
a Reagents and conditions: (i) HCOOH, Ac2O, THF. (ii) LiAlH4, THF. (iii) Ac2O, pyridine. (iv) CF3CO(O)OCCF3, Et3N, toluene. (v)
Propionaldehyde, CH3CN. (vi) NaBH4, MeOH. (vii) (CHO)n, NaBH4, TFA, THF.
binding assay revealed that all new compounds were full agonists
at the κ receptors, ligands 11, 13a, and 17a were partial agonists
at the μ receptors, and ligands 12, 13c, 19a, and 19c were full
agonists at the μ receptors. Preliminary evaluation of 3 in
nonhuman primates reduced self-administration and attenuated
food intake, probably due to its κ agonist properties.24
reported uncorrected. Elemental analyses, performed by Atlantic Micro-
labs (Atlanta, GA), were within 0.4% of theoretical values. Analytical
thin-layer chromatography (TLC) was carried out on 0.2 μm Kieselgel
60F-254 silica gel plastic sheets (EM Science, Newark, NJ). Flash
chromatography was used for the routine purification of reaction
products. Eluent systems are described for the individual compounds.
General Procedure6 for the Preparation of 3-Hydroxy-N-
alkyl-morphinans (7a-d). The mixture of norlevorphanol (5
mmol), K2CO3 or NaHCO3 (7.5 mmol), and either bromomethyl
cyclopropane, bromomethyl cyclobutane, 1-bromo-3-fluoropropane, or
(S)-tetrahydrofurfuryl (1R)-camphor-10-sulfonate (7.5 mmol) in 20 mL
of anhydrous DMF was stirred at 90-95 °C for overnight. After the
reaction was judged complete by TLC, the reaction mixture was cooled,
poured into water, and extracted with CHCl3. The organic phase washed
’ EXPERIMENTAL SECTION
General Synthetic Methods. 1H (and 13C NMR) spectra were
recorded at 300 MHz (75 MHz) on a Varian Mercury 300 spec-
trometer. Chemical shifts are given as δ values (ppm) downfield
from tetramethylsilane as an internal reference. Melting points were
determined on a Thomas-Hoover capillary tube apparatus and are
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ARTICLE
Scheme 3a
a Reagents and conditions: (i) Benzaldehyde, p-toluenesulfonic acid, toluene. (ii) NaBH4, MeOH. (iii) m-Anisaldehyde, p-toluenesulfonic acid, toluene.
(iv) BBr3, CH2Cl2. (v) EtSCN, Et3N, toluene.
Scheme 4a
a Reagents and conditions: (i) CuBr2/t-butyl nitrite, CH3CN. (ii) NaH, THF. (iii) Piperazine, NaH, THF.
Table 2. Pharmacological Properties of Compounds in
3-Hydroxy-N-fluoropropylmorphinan (7c). White crystals
(73%); mp 148-150 °C. 1H NMR (300 MHz, CDCl3): δ 7.04-6.88
(m, 1H), 6.71 (s, 1H), 6.66-6.55 (m, 1H), 4.64-4.53 (m, 1H), 4.49-
4.37 (m, 1H), 2.97-2.83 (m, 2H), 2.71-2.48 (m, 5H), 2.33-2.24 (m,
Stimulating [35S]GTPγS Binding Mediated by the KORa
compound Emax ( SEM (% maximal stimulation) EC50 ( SEM (nM)
1H), 2.15-2.01 (m, 1H), 1.97-1.58 (m, 5H), 1.54-1.07 (m, 7H). 19
F
(-)-U50,488
110 ( 2.0
90 ( 10
46 ( 16
0.2 ( 0.0
2.4 ( 0.6
29 ( 4
NMR (282 MHz, CDCl3): δ 29.21 (m). 13C NMR (75 MHz, CDCl3): δ
154.35, 141.81, 128.72, 113.03, 111.91, 82.71 (d, J = 163.5 Hz), 56.44,
50.92 (d, J = 5.2 Hz), 45.61, 44.69, 41.63, 37.66, 36.51, 28.50 (d, J = 21.5
Hz), 26.82, 26.48, 24.20, 22.20, 22.11.
1b
3b
10b
80 ( 6
80 ( 1
General Procedure6,10 for the Preparation of Triflates
8a-d. 3-Hydroxy-N-alkyl-morphinan 7a-d (3.5 mmol) was dis-
solved in anhydrous DCM (20 mL) and Et3N (3.5 mL). The mixture
was cooled to 0 °C, and then, PhNTf2 (1.94 g, 5.4 mmol) was
added. The mixture was allowed to warm to room temperature
overnight. The solution was diluted with DCM (40 mL), washed
with 1 N HCl followed by brine, and then dried with anhydrous
Na2SO4. The solvent was removed in vacuo to afford the crude product,
which was purified by flash silica gel column to give corresponding
triflates. The analytical data for 8a,b was in agreement with literature
values.6
11
100 ( 4.8
190 ( 21
82 ( 10
32 ( 5.5
14 ( 1.5
14 ( 3.1
120 ( 6.7
120 ( 16
46 ( 8.9
22 ( 5.1
89 ( 8.0
12
13a
13c
15
170 ( 6.3
120 ( 0.33
110 ( 14
190 ( 6.4
150 ( 3.9
17a
19a
19c
a Membranes from CHO cells that stably expressed the human κOR
were incubated with varying concentrations of the compounds in the
presence of 0.08 nM [35S]GTPγS. Data are the mean values ( SEMs
from three experiments, performed in triplicate. None of the compounds
inhibited U50,488-stimulated [35S]GTPγS binding, indicating that the
compounds were agonists devoid of any antagonist properties at the
κOR. b See refs 5c and 10c.
N-(Fluoropropyl)-morphinan-3-yl Trifluoromethanesulfo-
nate (8c). Yellow oil (99%). 1H NMR (300 MHz, CDCl3): δ 7.17 (d,
J = 8.6, 1H), 7.12 (d, J = 2.5, 1H), 7.02 (dd, J = 2.6, 8.4 Hz, 1H), 4.69-
4.37 (m, 2H), 2.99 (d, J = 18.6 Hz, 1H), 2.93-2.85 (m, 1H), 2.74-2.50
(m, 4H), 2.29 (d, J = 14.1 Hz, 1H), 2.07-1.51 (m, 7H), 1.47-1.14 (m,
5H), 1.11-0.98 (m, 1H). 19F NMR (282 MHz, CDCl3): δ 29.21 (m),
-73.22. 13C NMR (75 MHz, CDCl3): δ 148.38, 143.51, 138.36, 129.33,
118.76 (d, J = 318.7 Hz), 118.23, 118.15, 82.58 (d, J = 162.8 Hz), 56.16,
50.77 (d, J = 5.2 Hz), 45.01, 44.65, 41.75, 38.10, 36.44, 28.80 (d, J = 19.5
Hz), 26.66, 26.37, 24.81, 21.85.
by brine, dried over anhydrous Na2SO4, and concentrated in vacuo to
give crude product, purified by flash silica gel column (DCM:MeOH =
20:1-5:1) to give the corresponding morphinans 7a-d. The analytical
data for 7a-b,d was in agreement with literature values.6
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Table 3. Agonist and Antagonist Properties of Compounds in Stimulating [35S]GTPγS Binding Mediated by the μORa
ARTICLE
compound
pharmacological properties
Emax (% maximal stimulation)
EC50 (nM)
Imax (% maximal inhibition)
NIa
IC50 (nM)
DAMGO
1b
3b
10b
agonist
120 ( 12
40 ( 2.9
45 ( 4
110 ( 9.0
0.8 ( 0.1
73 ( 5
NI
partial agonist
agonist
50 ( 1.2
1.7 ( 0.40
NI
NI
partial agonist
partial agonist
agonist
26 ( 1
>1 μM
29 ( 7.4
85 ( 5.8
NA
11
65 ( 1.4
120 ( 15
40 ( 0.87
100 ( 5.3
57 ( 4.7
83 ( 2.5
97 ( 2.9
130 ( 11
71 ( 4.2
47 ( 9.0
420 ( 17
140 ( 6.5
29 ( 4.6
240 ( 12
40 ( 1.4% inhibition at 10 μM
12
NI
NI
13a
13c
17a
19a
19c
agonist
NI
NI
agonist
NI
NI
partial agonist
agonist
40 ( 0.73% inhibition at 10 μM
NA
NI
NI
agonist
NI
NI
a Membranes from CHO cells that stably expressed only the μOR were incubated with varying concentrations of the compounds in the presence of 0.08
nM [35S]GTPγS. Data are the mean values ( SEMs from three experiments, performed in triplicate. NI, no inhibition; NA, not applicable; no value
could be determined because a maximal inhibition of binding was not obtained. b See refs 5c and 10c.
N-((S)-Tetrahydrofurfuryl)-morphinan-3-yl Trifluoromet-
hanesulfonate (8d). Yellow oil (95%). 1H NMR (300 MHz,
CDCl3): δ 7.18 (d, J = 5.8 Hz, 1H), 7.12 (d, J = 1.8 Hz, 1H), 7.04
(m, 1H), 4.31-4.10 (m, 2H), 3.92-3.64 (m, 3H), 3.24-2.72 (m, 5H),
2.52-0.89 (m, 15H).
corresponding aminothiazole. The analytical data for 3 and 10 were in
agreement with literature values.10c
Aminothiazolo[5,4-b]-N-fluoropropylmorphinan (11). Slightly
yellow solid (52%); mp 114-117 °C. 1H NMR (300 MHz, CDCl3): δ
7.46 (s, 1H), 7.32 (s, 1H), 5.33 (s, 2H), 4.68-4.37 (m, 2H), 3.04 (d, J =
18.1 Hz, 1H), 2.92-2.82 (m, 1H), 2.80-2.38 (m, 5H), 2.13-1.99 (m,
1H), 1.96-1.59 (m, 5H), 1.55-1.29 (m, 6H), 1.22-1.03 (m, 1H). 19F
NMR (282 MHz, CDCl3): δ 9.72 (m). 13C NMR (75 MHz, CDCl3): δ
164.97, 151.21, 139.04, 132.40, 129.09, 119.43, 115.92, 82.77 (d, J =
163.5 Hz), 56.52, 58.85 (d, J = 5.2 Hz), 45.39, 45.20, 42.40, 37.84, 36.81,
28.85 (d, J = 18.8 Hz), 26.90, 26.60, 25.13, 22.11. Anal. calcd for
C20H26FN3S 3HCl 0.5H2O: C, 50.27; H, 6.33; N, 8.79. Found: C,
General Procedure6,10 for the Preparation of Aminomor-
phinans 9a-d. The triflate 8a-d (900 mg, 1.92 mmol) in 20 mL of
THF was added to Pd(OAc)2 (21 mg, 0.096 mmol), BINAP (95.4 mg,
0.151 mmol), CsCO3 (936 mg, 2.88 mmol), and benzophenone imine
(150 mg, 420 uL, 2.49 mmol) under N2. The mixture was heated to
reflux with stirring overnight. When the starting material was consumed,
the solvent was removed. The residue was diluted with EtOAc, washed
with brine, dried, and concentrated. The crude product was purified by
flash silica gel column to yield the imine intermediate as a yellow oil. To a
solution of the imine intermediate in MeOH (50 mL) at room
temperature were added NaOAc (654 mg, 8.4 mmol) and hydroxyl-
amine hydrochloride (85 mg, 3.9 mmol). The mixture was stirred at
room temperature for 36 h. The solvent was removed, and the
residue was directly purified by flash silica gel column to yield the
corresponding amine. The analytical data for 9a,b were in agreement
with literature values.6,10
3
3
50.49; H, 6.58: N, 8.63.
Aminothiazolo[5,4-b]-N-(S)-tetrahydrofurylmethylmorphi-
nan (12). White solid (46%); mp 127-130 °C. 1H NMR (300 MHz,
CDCl3): δ 7.46 (s, 1H), 7.32 (s, 1H), 5.23 (s, 2H), 3.88 (m, 3H), 3.02 (m,
2H), 2.60 (m, 5H), 1.93 (m, 7H), 1.44 (m, 7H), 1.11 (m, 1H). 13C NMR
(75 MHz, CDCl3): δ 164.83, 151.13, 139.23, 132.76, 129.03, 119.41,
115.95, 77.65, 68.08, 60.22, 57.01, 45.98, 44.94, 42.30, 37.66, 36.77, 30.28,
26.87, 26.61, 25.42 (2C), 22.14. Anal. calcd for C22H29N3OS
3
2HCl 1.4H2O: C, 54.86; H, 7.07; N, 8.72; Found: C, 54.85; H, 7.15:
3
3-Amino-N-fluoropropyl-morphinan (9c). Yellow oil (68%).
1H NMR (300 MHz, CDCl3): δ 6.88 (d, J = 8.0, 1H), 6.61 (s, 1H),
6.55-6.44 (m, 1H), 4.69-4.32 (m, 2H), 3.52 (s, 2H), 2.87 (d, J = 18.0
Hz, 2H), 2.73-2.44 (m, 4H), 2.30 (d, J = 9.2 Hz, 1H), 2.16-2.03 (m,
1H), 1.96-1.60 (m, 5H), 1.50 (s, 1H), 1.44-1.24 (m, 5H), 1.22-1.09
(m, 1H). 13C NMR (75 MHz, CDCl3): δ 144.44, 141.32, 128.38,
127.88, 113.15, 111.86, 82.81 (d, J = 165.0 Hz), 56.51, 50.83 (d, J = 5.2
Hz), 45.54, 45.32, 42.03, 37.58, 36.58, 28.85 (d, J = 19.5 Hz), 26.88,
26.61, 24.23, 22.28.
3-Amino-N-(S)-tetrahydrofurfuryl-morphinan (9d). Yellow
oil (41%). 1H NMR (300 MHz, CDCl3): δ 6.88 (d, J = 5.8 Hz, 1H), 6.59
(d, J = 1.8 Hz, 1H), 6.50-6.47 (m, 1H), 4.02-3.96 (m, 1H), 3.88-3.71
(m, 2H), 3.50 (br, 2H), 3.94-2.86 (m, 2H), 2.68-2.48 (m, 4H), 2.28
(m, 1H), 2.16-1.10 (m, 15H). 13C NMR (75 MHz, CDCl3): δ 144.31,
141.30, 128.22, 127.97, 112.99, 111.71, 77.47, 67.91, 60.06, 57.04, 45.93,
44.82, 41.77, 37.27, 36.42, 30.15, 26.72, 26.50, 25.30, 24.48, 22.19.
General Procedure6,10 for the Preparation of Aminothia-
zolomorphinans 3 and 10-12. The amine (1.1 mmol) and
KSCN (426 mg, 4.4 mmol) were dissolved in 10 mL of glacial acetic
acid. A solution of Br2 (180 mg, 1.1 mmol) in 2 mL of glacial acetic acid
was added dropwise. The mixture was stirred for 48 h, then basified with
10% NaOH, and extracted with CHCl3. The organic layer was washed
with brine, dried over anhydrous Na2SO4, and concentrated in vacuo.
The crude product was purified by flash silica gel column to yield
N, 8.44.
General Procedure for Synthesis of N0-Methyl-aminothia-
zolomorphinans 13a-c. At room temperature and under nitrogen
atmosphere, freshly made HCOOAc (0.7 mL, 5.0 mmol, this reagent
was prepared by heating a mixture of 1.8 mL of HCOOH and 3.8 mL of
HOAc at 50 °C for 2 h) was slowly added to a solution of 3-aminothia-
zolo-morphinan (0.88 mmol). The mixture was stirred at room tem-
perature for 24 h. The resulting mixture was then concentrated to
dryness and directly separated by flash silica gel column to give the
intermediate formate. The intermediate (0.65 mmol) was dissolved in 5
mL of anhydrous THF followed by the addition of LiAlH4 (50 mg, 1.3
mmol, added in one portion at 0 °C). Then, the resulting suspension was
stirred at room temperature for 16 h. After the reaction was judged to be
complete by TLC, 1 mL of water was added slowly to quench the
reaction, followed by addition of 1 mL of aqueous 2 N NaOH. The
resulting olution was diluted with 50 mL of CH2Cl2 and washed with
water and brine. The organic layer was dried over anhydrous Na2SO4
and concentrated in vacuo. The crude product was purified by flash silica
gel column to give corresponding morphinans.
N0-Methylaminothiazolo[5,4-b]-N-cyclopropylmethylmor-
phinan (13a). Slightly yellow foam (39%); mp (HCl salt) 212-
1
215 °C. H NMR (300 MHz, CDCl3): δ 7.50 (s, 1H), 7.30 (s, 1H),
5.27 (br, 1H), 3.19-3.07 (m, 4H), 3.05-2.94 (m, 1H), 2.81-2.64 (m,
2H), 2.58-2.28 (m, 3H), 2.11-1.97 (m, 1H), 1.96-1.74 (m, 2H),
1908
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Journal of Medicinal Chemistry
ARTICLE
C23H28F3N3S 2HCl 1.9H2O: C, 50.90; H, 6.28; N, 7.74. Found: C,
1.69-1.59 (m, 1H), 1.55-1.32 (m, 6H), 1.25 (s, 1H), 0.96-0.80 (m,
1H), 0.58-0.45 (m, 2H), 0.19-0.07 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 167.26, 151.62, 139.00, 131.58, 127.90, 119.31, 115.58, 59.94,
55.86, 45.73, 45.08, 42.22, 37.90, 36.82, 31.57, 26.94, 26.65, 24.65, 22.19,
9.36, 4.09, 3.64. Anal. calcd for C22H29N3S 2HCl 1.3H2O: C, 56.96; H,
3
3
51.10; H, 6.21; N, 7.24.
General Procedure for Synthesis of N0-Propyl-aminothia-
zolomorphinans 16a and 16c. A mixture of aminothiazolomor-
phinan (0.3 mmol) and proponialdehyde (43 μL, 0.6 mmol) in 2 mL of
MeOH was stirred at 60 °C for overnight. The reaction was judged to be
complete by TLC. Next, NaBH4 (45.6 mg, 1.2 mmol) was added, and
the resulting mixture was stirred at 60 °C for 8 h. After this period, the
solvents were removed in vacuo. The residue was then directly purified
by flash silica gel column to give the corresponding morphinans.
N0-Propyl-aminothiazolo[5,4-b]-N-cyclopropylmethylmor-
phinan (16a). White foam (55%); mp (HCl salt) 212-214 °C (dec).
1H NMR (300 MHz, CDCl3): δ 7.46 (s, 1H), 7.29 (s, 1H), 5.19 (s, 1H),
3.39 (s, 2H), 3.18-3.06 (m, 1H), 3.05-2.91 (m, 1H), 2.78 -2.65 (m,
2H), 2.55-2.40 (m, 2H), 2.38-2.28 (m, 1H), 2.08-1.96 (m, 1H),
1.93-1.59 (m, 5H), 1.53-1.30 (m, 6H), 1.00 (t, J = 7.4 Hz, 3H), 0.86 (d,
J = 6.7 Hz, 2H), 0.56-0.45 (m, 2H), 0.18-0.05 (m, 2H). 13C NMR (75
MHz, CDCl3): δ 166.61, 151.60, 138.96, 131.51, 127.78, 119.28, 115.49,
59.94, 55.86, 47.11, 45.74, 45.10, 42.22, 37.90, 36.83, 26.95, 26.66, 24.66,
3
3
7.30; N, 9.06. Found: C, 56.99; H, 7.14; N, 8.84.
N0-Methyl-aminothiazolo[5,4-b]-N-cyclobutylmethylmor-
phinan (13b). White solid (45%); mp (HCl salt) >217 °C (dec). 1H
NMR (300 MHz, CDCl3): δ 7.49 (s, 1H), 7.32 (s, 1H), 5.33 (s, 1H),
3.14-3.01 (m, 4H), 2.89-2.37 (m, 6H), 2.15-1.58 (m, 11H), 1.53-
1.27 (m, 6H). 13C NMR (75 MHz, CDCl3): δ 167.31, 151.57, 138.98,
131.65, 127.86, 119.33, 115.54, 61.48, 55.98, 45.86, 45.01, 42.20, 37.74,
36.79, 34.85, 31.57, 27.91, 26.94, 26.61, 24.80, 22.17, 18.83. Anal. calcd
for C23H31N3S 2HCl 1.1H2O: C, 58.24; H, 7.48; N, 8.86. Found: C,
3
3
58.38; H, 7.47; N, 8.56.
N0-Methyl-aminothiazolo[5,4-b]-N-fluoropropylmorphi-
nan (13c). Slightly yellow foam (55%); mp (HCl salt) 205-207 °C
(dec). 1H NMR (300 MHz, CDCl3): δ 7.50 (s, 1H), 7.31 (s, 1H), 5.22
(br, 1H), 4.68-4.37 (m, 2H), 3.11 (s, 3H), 3.03 (d, J = 18.1 Hz, 1H),
2.92-2.83 (m, 1H), 2.80-2.40 (m, 5H), 2.14-2.01 (m, 1H), 1.97-
1.59 (m, 5H), 1.54-1.10 (m, 7H). 13C NMR (75 MHz, CDCl3): δ
167.29, 151.66, 138.93, 131.57, 127.97, 119.35, 115.62, 82.78 (d, J =
162.8 Hz), 56.59, 50.87 (d, J = 5.2 Hz), 45.44, 45.25, 42.41, 37.88,
36.83, 31.58, 28.86 (d, J = 19.5 Hz), 26.94, 26.64, 25.11, 22.20. Anal.
calcd for C21H28FN3S 2HCl 1.5H2O: C, 53.27; H, 7.03; N, 8.87.
22.86, 22.19, 11.36, 9.37, 4.09, 3.64. Anal. calcd for C24H33N3S
3
2HCl 2.1H2O: C, 56.93; H, 7.80; N, 8.30. Found: C, 57.19; H, 7.69;
3
N, 7.84.
N0-Propyl-aminothiazolo[5,4-b]-N-fluoropropylmorphinan
(16c). White foam (47%); mp (HCl salt) 215-217 °C (dec). 1H NMR
(300 MHz, CDCl3): δ 7.46 (s, 1H), 7.31 (s, 1H), 5.49 (s, 1H), 4.71-
4.36 (m, 2H), 3.39 (t, J = 6.6 Hz, 2H), 3.07-2.41 (m, 6H), 2.07 (t, J =
11.6 Hz, 1H), 1.97-1.58 (m, 7H), 1.54-1.23 (m, 8H), 1.06-0.95 (m,
3H). 13C NMR (75 MHz, CDCl3): δ 166.91, 151.59, 138.76, 131.22,
127.78, 119.33, 115.37, 82.73 (d, J = 163.5 Hz), 56.55, 50.82 (d, J =
5.2 Hz), 47.21, 45.44, 45.04, 42.24, 37.81, 36.77, 28.69 (d, J = 19.5 Hz),
26.90, 26.60, 25.08, 22.85, 22.16, 11.35. Anal. calcd for C23H32
FN3S 2HCl 0.9H2O: C, 56.29; H, 7.35; N, 8.56. Found: C, 56.24; H,
3
3
Found: C, 53.38; H, 7.20; N, 8.75.
Synthesis of N0-Acetyl-N0-methyl-aminothiazolo[5,4-b]-N-
cyclopropylmethyl-morphinan (14). A solution of N0-methyl-
aminothiazolo[5,4-b]-N-cyclopropyl-methylmorphinan (40 mg, 0.11
mmol), acetic anhydride (0.5 mL), and pyridine (2 mL) was stirred at
room temperature for 5 h. After the reaction was over, the volatile
components were removed in vacuo. The residue was purified by flash
silica gel column (hexane:EtOAc:Et3N = 10:10:0.5) to afford a white
3
3
7.48; N, 8.19.
General Procedure for Synthesis of N0,N0-Dimethyl-ami-
nothiazolomorphinans 17a and 17c. To a stirred mixture of N0-
methyl-aminothiazolomorphinan (0.15 mmol), paraformaldehyde (44
mg, 1.5 mmol), and NaBH4 (28.8 mg, 0.76 mmol) in THF (3 mL) at
room temperature under nitrogen atmosphere was added dropwise
trifluoroacetic acid (1.5 mL). The resulting mixture was stirred at room
temperature for 24 h and then poured into a mixture of 25% aqueous
NaOH (5 mL) and ice to make a strongly alkaline solution, which was
then diluted with saturated NaCl solution (5 mL) and extracted with
CH2Cl2. The combined extracts were dried by anhydrous Na2SO4,
filtered, and concentrated in vacuo to afford a yellow solid. The solid was
treated with 10% HCl. The aqueous layer was washed with CH2Cl2, and
then, 10% NaOH was added to make the free base. The resulting
aqueous layer was extracted with CH2Cl2. The combined extracts were
washed with brine, then dried by anhydrous Na2SO4, filtered, and
concentrated in vacuo to give the corresponding morphinans.
1
solid (40 mg, 90%); mp 67-70 °C. H NMR (300 MHz, CDCl3): δ
7.76 (s, 1H), 7.51 (s, 1H), 3.79 (s, 3H), 3.15-3.06 (m, 2H), 2.82-2.68
(m, 2H), 2.54-2.48 (m, 2H), 2.45 (s, 3H), 2.36-2.29 (m, 2H), 2.04-
1.78 (m, 3H), 1.64 (m, 1H), 1.55-1.11 (m, 6H), 0.88 (m, 1H), 0.52-
0.49 (m, 2H), 0.16-0.07 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
170.55, 159.06, 147.21, 139.53, 134.33, 130.78, 119.28, 117.78, 59.97,
55.81, 45.67, 45.16, 42.57, 38.08, 36.87, 35.85, 26.95, 26.64, 24.87, 23.54,
22.19, 9.40, 4.04, 3.59. Anal. calcd for C25H33N3OS 0.1H2O: C, 70.58;
H, 7.87; N, 9.88. Found: C, 70.38; H, 7.91; N, 9.72.
3
Synthesis of N0-Trifluoroethyl-aminothiazolo[5,4-b]-N-cy-
clopropylmethyl-morphinan (15). Et3N (0.6 mL) was added to
the solution of aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan
(71 mg, 0.2 mmol) in 1.5 mL of toluene. Trifluoroacetic anhydride (0.6
mL) was added to the mixture and then stirred at 100 °C for overnight.
The volatile components were removed in vacuo. The residue was
purified by flash silica gel column (EtOAc:MeOH:Et3N = 60:1:1) to
afford the intermediate. LiAlH4 (10 mg, 0.25 mmol) was added to a
solution of intermediate (50 mg, 0.11 mmol) in 2 mL of THF. The
mixture was stirred at room temperature overnight. Next, 0.2 mL of
water was added to quench the reaction, followed by the addition of 0.2
mL of 2 N aqueous NaOH. The resulting mixture was stirred for 30 min
and then filtered. The resulting solid was washed with CH2Cl2 (2 ꢀ 2
mL). The filtrate was concentrated in vacuo. The residue obtained was
purified by flash silica gel column (Hex:EtOAc:Et3N = 10:10:1) to afford
a white foam (15 mg, 31%); mp (HCl salt) >198 °C (dec). 1H NMR
(300 MHz, CDCl3): δ 7.53 (s, 1H), 7.32 (s, 1H), 4.19 (m, 2H), 3.12 (m,
1H), 3.01 (d, J = 18.2 Hz, 1H), 2.72 (m, 2H), 2.42 (m, 3H), 1.91 (m,
3H), 1.44 (m, 8H), 0.89 (m, 1H), 0.51 (dd, J = 1.4, 8.0 Hz, 2H), 0.11 (m,
2H). 13C NMR (75 MHz, CDCl3): δ 164.93, 150.72, 139.46, 132.84,
128.06, 119.43, 116.38, 59.99, 55.82, 45.98, 45.69, 45.08, 42.25, 37.99,
36.81, 26.95, 26.64, 24.76, 22.19, 9.39, 4.09, 3.63. Anal. calcd for
N0,N0-Dimethyl-aminothiazolo[5,4-b]-N-cyclopropylmethy-
lmorphinan (17a). Pale yellow solid (89%); mp (HCl salt) 193-
195 °C (dec.). 1H NMR (300 MHz, CDCl3): δ 7.51 (s, 1H), 7.31 (s,
1H), 3.19 (s, 6H), 3.15-3.10 (m, 1H), 3.04-2.93 (m, 1H), 2.82-2.64
(m, 2H), 2.57-2.26 (m, 3H), 2.11-1.74 (m, 3H), 1.70-1.58 (m, 1H),
1.54-1.30 (m, 6H), 1.26-1.10 (m, 1H), 1.00-0.79 (m, 1H), 0.61-
0.42 (m, 2H), 0.19-0.06 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
168.25, 152.29, 138.99, 128.52, 119.14, 115.36, 59.99, 55.95, 45.80,
45.15, 42.26, 40.21, 37.94, 36.82, 26.97, 26.67, 24.65, 22.27, 22.21, 9.38,
4.09, 3.65. Anal. calcd for C22H29N3S 3HCl H2O: C, 54.27; H, 7.13; N,
3
3
8.26. Found: C, 54.47; H, 7.18: N, 8.16.
N0,N0-Dimethyl-aminothiazolo[5,4-b]-N-fluoropropylmethyl-
morphinan (17c). Pale yellow solid (83%); mp (HCl salt) 198-
1
200 °C (dec.). H NMR (300 MHz, CDCl3): δ 7.51 (s, 1H), 7.33
(s, 1H), 4.72-4.33 (m, 2H), 3.19 (s, 6H), 3.10-2.42 (m, 6H),
1909
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Journal of Medicinal Chemistry
ARTICLE
2.19-2.05 (m, 1H), 2.01-1.71 (m, 4H), 1.69-1.31 (m, 8H), 0.97-
0.74 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 168.31, 152.40, 138.65,
130.46, 128.68, 119.20, 115.36, 82.66 (d, J = 163.5 Hz), 56.71, 50.89
(d, J = 5.2 Hz), 45.55, 44.90, 42.12, 40.20, 37.79, 36.70, 29.68, 28.56
(d, J = 19.5 Hz), 26.88, 26.56, 25.04, 22.21. Anal. calcd for
C22H30FN3S 2HCl 1.3H2O: C, 54.61; H, 7.21; N, 8.68. Found: C,
26.65, 24.81, 22.18, 18.85, 14.96. Anal. calcd for C24H33
N3S 2HCl 1.4H2O: C, 58.38; H, 7.72; N, 8.51. Found: C, 58.70; H,
3
3
7.60; N, 8.13.
N0-Ethyl-aminothiazolo[5,4-b]-N-fluoropropylmorphinan
1
(19c). White solid (93%); mp 113-115 °C. H NMR (300 MHz,
CDCl3): δ 7.48 (s, 1H), 7.31 (s, 1H), 5.24 (br, 1H), 4.68 -4.38 (m,
2H), 3.57-3.40 (m, 2H), 3.03 (d, J = 18.1 Hz, 1H), 2.92-2.85 (m, 1H),
2.80-2.40 (m, 5H), 2.15-2.00 (m, 1H), 1.97-1.59 (m, 5H), 1.54-
1.10 (m, 11H). 19F NMR (282 MHz, CDCl3): δ 9.24 (m). 13C NMR
(75 MHz, CDCl3): δ 166.42, 151.64, 138.85, 131.48, 127.86, 119.32,
115.53, 82.78 (d, J = 162.8 Hz), 56.58, 50.88 (d, J = 5.2 Hz), 45.45,
45.21,42.37, 40.08, 37.85, 36.81, 28.82 (d, J = 19.5 Hz), 26.91, 26.62,
25.07, 22.17, 14.96. Anal. calcd for C22H30FN3S 2HCl 1.8H2O: C,
3
3
54.82; H, 7.30; N, 8.35.
General Procedure for Synthesis of N0-Acetyl-aminothia-
zolomorphinans 18a and 18c. The mixture of aminothiazolo-
morphinan (0.41 mmol), pyridine (2.1 mL), and acetic anhydride (1.1
mL) was stirred at room temperature for 24 h. The volatile components
were removed in vacuo. The residue was purified by flash silica gel
column to afford the corresponding morphinans.
3
3
N0-Acetyl-aminothiazolo[5,4-b]-N-cyclopropylmethylmor-
phinan (18a). Slightly yellow solid (78%); mp 148-151 °C. 1H
NMR (300 MHz, CDCl3): δ 7.67 (s, 1H), 7.54 (s, 1H), 3.20-3.03 (m,
2H), 2.86-2.67 (m, 1H), 2.60-2.33 (m, 2H), 2.29 (s, 3H), 2.01-1.82
(m, 2H), 1.77-1.59 (m, 4H), 1.56-1.27 (m, 6H), 1.17-1.09 (m, 1H),
0.93-0.81 (m, 1H), 0.57-0.46 (m, 2H), 0.18-0.08 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 168.90, 159.47, 147.08, 140.31, 139.91, 129.48,
120.16, 117.18, 60.28, 56.03, 45.87, 45.40, 42.89, 38.40, 37.22, 27.19,
26.86, 25.17, 23.68, 22.38, 9.47, 4.32, 3.82. Anal. calcd for
53.61; H, 7.28; N, 8.52. Found: C, 53.63; H, 7.25; N, 8.46.
Synthesis of N0-Acetyl-N0-ethyl-amino-thiazolo[5,4-b]-N-
cyclopropylmethyl-morphinan (20). A solution of N0-ethyl-
aminothiazolo[5,4-b]-N-cyclopropyl-methylmorphinan (55 mg, 0.14
mmol), acetic anhydride (0.5 mL), and pyridine (2 mL) was stirred at
room temperature for 24 h. After the reaction was judged complete by
TLC, the volatile components were removed in vacuo. The resulting
residue was purified by flash silica gel column (EtOAc:Et3N = 60:1) to
afford a white solid (40 mg, 65%); mp 88-90 °C. 1H NMR (300 MHz,
CDCl3): δ 7.75 (s, 1H), 7.51 (s, 1H), 4.31 (m, 2H), 3.14-3.06 (m, 2H),
2.81-2.67 (m, 2H), 2.54-2.48 (m, 2H), 2.45 (s, 3H), 2.04-1.78 (m,
3H), 1.64 (m, 1H), 1.54 (m, 1H), 1.48-1.36 (m, 10H), 0.88 (m, 1H),
0.54-0.49 (m, 2H), 0.13-0.09 (m, 2H). 13C NMR (75 MHz, CDCl3):
δ 170.19, 147.48, 139.44, 134.31, 130.82, 119.21,117.86, 60.02, 55.85,
45.69, 45.28, 43.66, 42.62, 38.10, 36.89, 26.96, 26.66, 24.88, 22.95, 22.19,
C23H29N3OS 0.1H2O: C, 69.52; H, 7.41; N, 10.57. Found: C, 69.62;
3
H, 7.58; N, 10.22.
N0-Acetyl-aminothiazolo[5,4-b]-N-fluoropropylmorphinan
(18c). Slightly yellow solid (60%); mp (HCl salt) 215-217 °C (dec.).
1H NMR (300 MHz, CDCl3): δ 11.77 (s, 1H), 7.68 (s, 1H), 7.58 (s,
1H), 4.69-4.38 (m, 2H), 3.14 (d, J = 18.1 Hz, 1H), 2.98-2.39 (m, 5H),
2.28 (s, 3H), 2.10-1.98 (m, 1H), 1.96-1.08 (m, 13H). 19F NMR (282
MHz, CDCl3): δ 9.59 (m). 13C NMR (75 MHz, CDCl3): δ 168.62,
159.10, 146.86, 139.90, 134.48, 129.27, 119.97, 116.98, 82.69 (d, J =
162.8 Hz), 56.44, 50.85 (d, J = 5.2 Hz), 45.30, 45.13, 42.66, 38.05, 36.90,
28.83 (d, J = 19.5), 26.88, 26.56, 25.31, 23.48, 22.10. Anal. calcd for
C22H28FN3OS 2HCl 0.7H2O: C, 54.25; H, 6.50; N, 8.63. Found: C,
13.77, 9.48, 4.04, 3.56. Anal. calcd for C24H31N3OS 0.2H2O: C, 69.76;
3
H, 7.66; N, 10.17. Found: C, 70.00; H, 7.92; N, 9.80.
Synthesis of N0-Benzyl-aminothiazolo[5,4-b]-N-cyclopro-
pylmethylmorphinan (22). A mixture of ATPM (70 mg, 0.20
mmol), benzaldehyde (84 uL, 0.8 mmol), and a crystal of p-toluene-
sulfonic acid (20 mg) in 25 mL of dry toluene was refluxed using a
Dean-Stark apparatus for 18 h. Toluene was then removed in vacuo.
The resulting residue was dissolved in 8 mL of MeOH, and NaBH4 (31
mg, 0.8 mmol) was added. The resulting mixture was refluxed for 6 h.
MeOH was then removed in vacuo. The residue was then dissolved in 10
mL of 1 N HCl and washed with ethyl acetate (10 mL ꢀ 2) and then
basified with ammonium hydroxide until pH ∼ 11 was reached. The
aqueous solution was then extracted with CH2Cl2 (10 mL ꢀ 3). The
organic layer was washed with brine and dried over anhydrous Na2SO4.
The solvent was removed in vacuo, and the residue was purified by flash
silica gel column to give product 15 as a white foam (43 mg, 62%); mp
3
3
54.34; H, 6.41: N, 8.47.
General Procedure for Synthesis of N0-Ethyl-aminothia-
zolomorphinans 19a-c. At room temperature, a solution of N0-
acetyl-aminothiazolomorphinan (N0-acetyl-20-aminothiazolo-N-cyclo-
butylmorphinan 18b was prepared using same procedure with 12a)
(0.31 mmol) in 1 mL of dry THF was added to a suspension of LiAlH4
(24 mg, 0.62 mmol) in 2 mL of dry THF. After the mixture was stirred
for 24 h, 0.2 mL of water was added to quench the reaction followed by
the addition of 0.2 mL of 2 N aqueous NaOH. The resulting mixture was
then stirred for 30 min and filtered, and the resulting solid was washed
with CH2Cl2. The filtrate was concentrated in vacuo. The resulting
residue was then purified by flash silica gel column to afford the
corresponding morphinans.
1
(HCl salt) >216 °C (dec.). H NMR (300 MHz, CDCl3): δ 7.48 (s,
1H), 7.35 (m, 6H), 5.77 (s, 1H), 4.65 (s, 2H), 3.11 (m, 1H), 2.99 (d, J =
18.3, 1H), 2.72 (m, 2H), 2.41 (m, 3H), 1.91 (m, 3H), 1.62 (s, 1H), 1.31
(m, 7H), 0.89 (m, 1H), 0.51 (m, 2H), 0.11 (m, 2H). 13C NMR (75
MHz, CDCl3): δ 166.37, 151.42, 139.10, 137.65, 131.85, 128.76, 127.89,
127.77, 127.63, 119.33, 115.69, 59.98, 55.86, 49.16, 45.73, 45.13, 42.26,
37.92, 36.82, 26.96, 26.66, 24.69, 22.20, 9.40, 4.09, 3.62. Anal. calcd for
C29H35N3OS 2HCl 1.2H2O: C, 62.49; H, 7.00; N, 7.81. Found: C,
N0-Ethyl-aminothiazolo[5,4-b]-N-cyclopropylmethylmor-
1
phinan (19a). White solid (86%); mp 95-98 °C. H NMR (300
MHz, CDCl3): δ 7.47 (s, 1H), 7.30 (s, 1H), 5.81 (s, 1H), 3.54-3.43 (m,
2H), 3.21-2.90 (m, 2H), 2.83-2.64 (m, 2H), 2.57-2.30 (m, 3H),
2.07-1.75 (m, 2H), 1.54-1.05 (m, 11H), 1.00-0.78 (m, 1H), 0.60-
0.39 (m, 2H), 0.13 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 166.61,
151.57, 138.73, 131.14, 127.73, 119.24, 115.29, 59.78, 55.81, 45.66,
44.85, 42.03, 40.06, 37.78, 36.74, 26.85, 26.56, 24.61, 22.10, 14.89, 9.16,
4.06, 3.63. Anal. calcd for C23H31N3OS 2HCl 1.3H2O: C, 57.80; H,
3
3
62.73; H, 6.92; N, 8.00.
Synthesis of N0-(3-Methoxybenzyl)-aminothiazolo[5,4-b]-
N-cyclopropylmethyl-morphinan (21). A mixture of 3 (135 mg,
0.38 mmol), m-anisaldehyde (93 μL, 0.76 mmol), and a crystal of p-
toluenesulfonic acid (20 mg) in 25 mL of dry toluene was refluxed using
a Dean-Stark apparatus for 18 h. Toluene was then removed in vacuo.
The residue was dissolved in 8 mL of MeOH, and NaBH4 (31 mg, 0.8
mmol) was added. The resulting mixture was refluxed for 6 h, and then,
the solvent was removed in vacuo. The residue was dissolved in 10 mL of
1 N HCl and washed with ethyl acetate (10 mL ꢀ 2) and then basified
with ammonium hydroxide until pH ∼ 11 was reached. The aqueous
solution was extracted with CH2Cl2 (10 mL ꢀ 3). The organic layer was
3
3
7.51; N, 8.79. Found: C, 57.88; H, 7.50; N, 8.55.
N0-Ethyl-aminothiazolo[5,4-b]-N-cyclobutylmethylmorphi-
1
nan (19b). White solid (84%); mp (HCl salt) >220 °C (dec.). H
NMR (300 MHz, CDCl3): δ 7.47 (s, 1H), 7.31 (s, 1H), 5.23 (s, 1H),
3.57-3.42 (m, 2H), 3.06 (d, J = 17.9, 1H), 2.82 (s, 1H), 2.75-2.36 (m,
6H), 2.14-1.57 (m, 11H), 1.43-1.26 (m, 9H). 13C NMR (75 MHz,
CDCl3): δ 166.40, 151.53, 139.00, 131.71, 127.73, 119.29, 115.49,
61.55, 55.97, 45.85, 45.15, 42.30, 40.09, 37.77, 36.83, 34.97, 27.91, 26.96,
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Journal of Medicinal Chemistry
ARTICLE
washed with brine and dried over anhydrous Na2SO4. The solvent was
evaporated, and the residue was purified by flash silica gel column to give
product 21 as a white foam (122 mg, 68%); mp (HCl salt) 205-207 °C
(dec.). 1H NMR (300 MHz, CDCl3): δ 7.48 (s, 1H), 7.28 (m, 2H), 6.95
(m, 2H), 6.84 (dd, J = 2.2, 8.0 Hz, 1H), 5.77 (s, 1H), 4.62 (s, 2H), 3.79
(s, 3H), 3.05 (m, 2H), 2.71 (m, 2H), 2.40 (m, 3H), 1.74 (m, 11H), 0.88
(m, 1H), 0.50 (m, 2H), 0.10 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
166.35, 159.89, 151.37, 139.22, 139.13, 131.91, 129.81, 127.85, 119.81,
119.32, 115.67, 113.16, 60.02, 55.84, 55.22, 49.11, 45.74, 45.18, 42.31,
37.93, 36.83, 26.96, 26.66, 24.64, 22.20, 9.45, 4.09, 3.60. Anal. calcd for
C29H35N3OS 2HCl 1.2H2O: C, 61.30; H, 6.99; N, 7.40. Found: C,
MHz, CDCl3): δ 151.65, 140.60, 137.61, 136.57, 134.51, 119.49, 119.12,
60.01, 55.62, 45.51, 44.94, 42.44, 38.14, 36.80, 26.93, 26.56, 24.97, 21.98,
9.44, 4.09, 3.61.
General Procedure for Synthesis of N0-Aryl-aminothiazo-
lomorphinans (26 and 27) and 3-(Piperazin-1-yl)-thiazolo-
[5,4-b]-N-cyclopropylmethylmorphinan (28). To a solution of
either aniline, 2-aminopyridine, or piperazine (1.32 mmol) in dry THF
(4 mL), NaH (55 mg; 1.32 mmol, ω = 0.6) was added and stirred for 30
min at 50-60 °C. Next, 20-bromo-thiazolo[5,4-b]-N-cyclopropyl-
methyl-morphinan 25 (137 mg, 0.33 mmol) was added, and the reaction
mixture was left to stir for 4 h. The reaction mixture was then
concentrated in vacuo. The residue was then dissolved in CH2Cl2 and
washed with water and brine. The organic layer was dried over Na2SO4,
filtered, and concentrated. The crude product was purified by flash silica
gel column to give the corresponding morphinans 26-28.
3
3
61.33, H, 7.08; N, 7.28.
Synthesis of N0-(3-Hydroxybenzyl)-aminothiazolo[5,4-b]-
N-cyclopropylmethyl-morphinan (23). To the solution of com-
pound 21 (80 mg, 0.17 mmol) in 4 mL of CH2Cl2 was added BBr3 (1 M
in CH2Cl2, 3 mL) at 0 °C and then stirred at room temperature for 3.5 h.
The reaction was quenched with MeOH, and then, the solvent was
removed in vacuo. The resulting dark oil was redissolved in MeOH and
refluxed 15 min. MeOH was removed in vacuo, and the residue was
dissolved in 10 mL of 1 M HCl, washed with ethyl acetate twice, then
basified with ammonium hydroxide, extracted with CH2Cl2, and dried
over Na2SO4. The crude product was purified by flash silica gel column
(EtOAc/MeOH/Et3N = 50/1/1) to give product 17 as a white solid (57
N0-Phenyl-aminothiazolo[5,4-b]-N-cyclopropylmethylmor-
phinan (26). Slightly yellow foam (72%); mp (HCl salt) >212 °C
(dec.). 1H NMR (300 MHz, CDCl3): δ 7.55-7.46 (m, 3H), 7.38 (m,
3H), 7.18-7.08 (m, 1H), 3.13 (s, 1H), 3.02 (d, J = 18.8 Hz, 1H), 2.74
(m, 2H), 2.58-2.44 (m, 1H), 2.43-2.25 (m, 2H), 2.11-1.74 (m, 4H),
1.62 (s, 1H), 1.42 (m, 7H), 0.89 (m, 1H), 0.51 (ps. d, J = 7.5 Hz, 2H),
0.12 (m, 2H). 13C NMR (75 MHz, CDCl3): δ 163.45, 150.64, 139.97,
139.33, 132.59, 129.47, 127.39, 123.95, 119.86, 119.30, 116.13, 59.98,
55.86, 45.74, 45.05, 42.28, 37.96, 36.78, 26.95, 26.64, 24.77, 22.21, 9.37,
4.11, 3.66. Anal. calcd for C27H31N3S HCl 1.6H2O: C, 65.53; H, 7.17;
1
mg, 74%); mp 180-182 °C. H NMR (300 MHz, CDCl3): δ 7.42
(s, 1H), 7.29 (s, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.79 (m, 3H), 4.53 (s, 2H),
3.20 (m, 1H), 3.01 (d, J = 18.3 Hz, 1H), 2.78 (m, 2H), 2.46 (m, 3H),
2.09 (m, 1H), 1.54 (m, 11H), 0.56 (m, 2H), 0.16 (m, 2H). 13C NMR (75
MHz, CDCl3): δ 168.15, 157.66, 151.66, 140.07, 138.77, 131.42, 130.14,
128.31, 119.94, 119.24, 115.19, 114.87, 114.81, 60.08, 56.21, 46.37,
45.00, 42.14, 38.22, 37.27, 27.43, 27.07, 25.04, 22.59, 8.95, 4.35, 4.18.
3
3
N, 8.49. Found: C, 65.34; H, 6.87; N, 8.30.
N0-(Pyridin-2-yl)-aminothiazolo[5,4-b]-N-cyclopropylmethyl-
morphinan (27). Slightly yellow foam (39%); mp (HCl salt) >223 °C
(dec.). 1H NMR (300 MHz, CDCl3): δ 8.41 (d, J = 3.9, 1H), 7.63 (s,
1H), 7.57-7.48 (m, 2H), 6.99 (d, J = 8.3 Hz, 1H), 6.94-6.87 (m, 1H),
3.17 (s, 1H), 3.10 (d, J = 18.4 Hz, 1H), 2.89-2.68 (m, 2H), 2.59-2.50
(m, 1H), 2.42-2.32 (m, 2H), 2.11-1.23 (m, 11H), 0.96-0.85 (m, 1H),
0.55-0.49 (m, 2H), 0.16-0.13 (m, 2H). 13C NMR (75 MHz, CDCl3):
δ 161.20, 151.72, 147.90, 146.89, 139.14, 137.73, 132.47, 129.54, 119.56,
116.78, 115.66, 111.11, 59.93, 55.89, 45.76, 45.03, 42.47, 38.02, 36.79,
26.96, 26.66, 24.83, 22.39, 9.33, 4.10, 3.66. Anal. calcd for
C26H30N4S 2HCl 2H2O: C, 57.88; H, 6.73; N, 10.38. Found: C,
Anal. calcd for C28H33N3OS 0.6H2O: C, 71.48; H, 7.33; N, 8.93.
3
Found: C, 71.52; H, 7.44; N, 8.89.
Synthesis of N0-Ethylthiourea-thiazolo[5,4-b]-N-cyclopro-
pylmethylmorphinan (24). To a solution of 3 (141 mg, 0.4 mmol)
in dry toluene (6 mL) were added Et3N (33 μL, 0.22 mmol) and ethyl
isothiocyanate (50 mg, 0.56 mmol). The reaction mixture was stirred in
the microwave reactor (150 W, 130 °C) for 150 min. After it was cooled,
the residue was directly purified by flash silica gel column (hexanes/
EtOAc/Et3N 20/20/1) to give product 24 as a white foam (62 mg,
3
3
58.21; H, 6.95; N, 9.97.
N0-(Piperazin-1-yl)-thiazolo[5,4-b]-N-cyclopropylmethyl-
morphinan (28). White foam (63%); mp (HCl salt) >245 °C
1
35%); mp (HCl salt) >255 °C (dec.). H NMR (300 MHz, CDCl3):
1
(dec.). H NMR (300 MHz, CDCl3): δ 7.50 (s, 1H), 7.33 (s, 1H),
δ 11.10 (s, 1H), 7.62 (s, 1H), 7.41 (s, 1H), 3.94 - 3.76 (m, 2H), 3.16 (s,
1H), 3.05 (d, J = 18.5 Hz, 1H), 2.84-2.65 (m, 2H), 2.59-2.26 (m, 3H),
2.03-1.77 (m, 3H), 1.74-1.06 (m, 11H), 0.94- 0.82 (m, 1H), 0.52 (ps.
d, J = 7.4 Hz, 2H), 0.21-0.06 (m, 2H). 13C NMR (75 MHz, CDCl3): δ
177.54, 159.43, 148.79, 140.02, 134.81, 127.15, 119.60, 117.28, 59.93,
55.68, 45.60, 44.96, 42.35, 40.52, 38.03, 36.79, 26.89, 26.56, 24.89, 22.19,
14.01, 9.34, 4.09, 3.65. Anal. calcd for C24H32N4S2 HCl 1.5H2O: C,
3.63-3.55 (m, 4H), 3.23 (s, 1H), 3.02-2.95 (m, 4H), 2.85-2.73 (m,
2H), 2.70 -2.37 (m, 4H), 2.17-1.79 (m, 3H), 1.70-1.30 (m, 8H),
0.98-0.95 (m, 1H), 0.62-0.47 (m, 2H), 0.24-0.11 (m, 2H). 13C
NMR (75 MHz, CDCl3): δ 168.61, 151.77, 138.81, 130.94, 128.07,
119.24, 115.68, 59.59, 55.81, 49.50, 45.66, 45.44, 44.50, 41.82, 37.78,
36.65, 26.85, 26.53, 24.74, 22.17, 8.90, 4.08, 3.75. Anal. calcd for
C25H34N4S 3HCl 3.1H2O: C, 51.08; H, 7.41; N, 9.53. Found: C,
3
3
57.18; H, 7.20; N, 11.11. Found: C, 57.41; H, 7.07; N, 10.72.
3
3
51.37; H, 7.49; N, 9.05.
Synthesis of 3-Bromo-thiazolo[5,4-b]-N-cyclopropylmethyl-
morphinan (25). t-Butyl nitrite (76 uL, 0.65 mmol) was added to the
solution of CuBr2 (145 mg, 0.65 mmol) in dry acetonitrile (8 mL). The
reaction mixture was stirred for 10 min at room temperature. After 10
min, 3 (115 mg, 0.32 mmol) was added in portions at 60 °C. The
reaction mixture was left to stir at 60 °C for 30 min, and then, an
additional amount of t-butyl nitrite (76 uL, 0.65 mmol) was added. After
1.5 h of stirring at room temperature, the reaction mixture was poured
on water (30 mL) and extracted with CH2Cl2. The organic layer was
dried over Na2SO4, filtered, and concentrated. The residue was purified
twice by flash silica gel column (first with hexanes/EtOAc 1/3 then with
hexanes/EtOAc/Et3N 20/20/1) to give product 25 as a slightly yellow
oil (60 mg, 45%). 1H NMR (300 MHz, CDCl3): δ 7.90 (s, 1H), 7.51
(s, 1H), 3.18-3.02 (m, 2H), 2.82-2.67 (m, 2H), 2.54-2.42 (m, 2H),
2.37-2.26 (m, 1H), 2.02-1.79 (m, 3H), 1.70-1.22 (m, 8H), 0.95-
0.82 (m, 1H), 0.57-0.48 (m, 2H), 0.17-0.06 (m, 2H). 13C NMR (75
Opioid Binding to the Human KORs, δORs, and μORs.
CHO cells stably transfected with the human κOR (hKOR-CHO) and
δOR (hDOR-CHO) were obtained from Dr. Larry Toll (SRI Interna-
tional, Palo Alto, CA), and the μOR (hMOR-CHO) was obtained from
Dr. George Uhl (NIDA Intramural Program, Baltimore, MD). The cells
were grown in 100 mm dishes in Dulbecco's modified Eagle's media
(DMEM) supplemented with 10% fetal bovine serum (FBS) and
penicillin-streptomycin (10,000 U/mL) at 37 °C in a 5% CO2 atmo-
sphere. The affinity and selectivity of the compounds for the multiple
opioid receptors were determined by incubating the membranes with
radiolabeled ligands and 12 different concentrations of the compounds
at 25 °C in a final volume of 1 mL of 50 mM Tris-HCl, pH 7.5.
Incubation times of 60 min were used for the κ-selective peptide
[3H]DAMGO and the j-selective ligand [3H]U69,593. A 3 h incubation
was used with the δ-selective antagonist [3H]naltrindole.
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Journal of Medicinal Chemistry
ARTICLE
[35S]GTPγS Binding Studies To Measure Coupling to G
Proteins. Membranes from CHO cells stably expressing either the
human κOR or the μOR were used in the experiments. Cells were
scraped from tissue culture plates and then centrifuged at 1000g for 10
min at 4 °C. The cells were resuspended in phosphate-buffered saline,
pH 7.4, containing 0.04% EDTA. After centrifugation at 1000g for 10
min at 4 °C, the cell pellet was resuspended in membrane buffer, which
consisted of 50 mM Tris-HCl, 3 mM MgCl2, and 1 mM EGTA, pH 7.4.
The membranes were homogenized with a Dounce homogenizer, fol-
lowed by centrifugation at 40000g for 20 min at 4 °C. The membrane
pelletwas resuspendedin membrane buffer, and those transfected with the
centrifugation stepwere repeated. The membraneswere thenresuspended
in assay buffer, which consisted of 50 mM Tris-HCl, 3 mM MgCl2, 100
mM NaCl, and 0.2 mM EGTA, pH 7.4. The protein concentration was
determined by the Bradford assay using bovine serum albumin as the
standard. The membranes were frozen at -80 °C until used.
CHO cell membranes expressing either the human κOR (15 μg of
protein per tube) or the μOR (7.5 μg of protein per tube) were
incubated with 12 different concentrations of the agonist in assay buffer
for 60 min at 30 °C in a final volume of 0.5 mL. The reaction mixture
contained 3 μM GDP and 80 pmol of [35S]GTPγS. The basal activity
was determined in the presence of 3 μM GDP and in the absence of an
agonist, and nonspecific binding was determined in the presence of 10
μM unlabeled GTPγS. Then, the membranes were filtered onto glass
fiber filters by vacuum filtration, followed by three washes with 3 mL of
ice-cold 50 mM Tris-HCl, pH 7.5. Samples were counted in 2 mL of
Ecoscint A scintillation fluid. Data represent the percent of agonist
stimulation [35S]GTPγS binding over the basal activity, defined as
[(specific binding/basal binding) ꢀ 100] - 100. All experiments were
repeated at least three times and were performed in triplicate. To
determine the antagonist activity of a compound at the μORs, CHO
membranes expressing the μOR were incubated with the compound in
the presence of a 200 nM concentration of the agonist DAMGO. To
determine antagonist activity of a compound at the κORs, CHO
membranes expressing the κOR were incubated with the compound
in the presence of a 100 nM concentration of the κ agonist U50,488.
Acta Helv. 2000, 74, 337–344. (b) Schenk, S.; Partridge, B.; Shippenberg,
T. Effects of the Kappa-Opioid Receptor Agonist, U69593 on the
Development of Sensitization and on the Maintenance of Cocaine
Self-Administration. Neuropsychopharmacology 2001, 24, 441–450. (c)
Chefer, V.; Moron, J. A.; Hope, B.; Rea, W.; Shippenberg, T. S. Kappa-
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pamine Neurotransmission That Occur during Abstinence from Co-
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Effects of Kappa Opioids Agonists on Schedule-Controlled Behavior
and Cocaine Self-Administration by Rhesus Monkeys. J. Pharmacol. Exp.
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3-Substituted-3-desoxymorphinan Analogues as Mixed κ and μ Opioid
Ligands: Synthesis and Biological Evaluation of Their Binding Affinity at
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(6) Neumeyer, J. L.; Bidlack, J. M.; Zong, R.; Bakthavachalam, V.;
Gao, P.; Cohen, D. J.; Negus, S. S.; Mello, N. K. Synthesis and
Opioid Receptor Affinity of Morphinan and Benzomorphan Derivatives:
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’ AUTHOR INFORMATION
Corresponding Author
*Tel: 617-855-3388. Fax: 617-855-2519. E-mail: Neumeyer@
mclean.harvard.edu.
(9) Hori, M.; Iwamura, T.; Morita, T.; Imai, E.; Oji, H.; Kataoka, T.;
Shimizu, H.; Ban, M.; Nozaki, M.; Niwa, M.; Fujimura, H. Facile
Synthesis of 8-Benzoylthio-2,6-methano-3-benzazocines and 3-Ben-
zoylthiomorphinans having Small-Ring Substituents. Chem. Pharm. Bull.
1989, 37, 2222–2224.
(10) (a) Zhang, A.; Van Vliet, S.; Neumeyer, J. L. Synthesis of
Aminothiazole Derived Morphinans. Tetrahedron Lett. 2003, 44, 6459–
6462. (b) Zhang, A.; Neumeyer, J. L. Microwave-Promoted Pd-Cata-
lyzed Cyanation of Aryl Triflates: A Fast and Versatile Access to
3-Cyano-3-desoxy-10-ketomorphinans. Org. Lett. 2003, 5, 201–203.
(c) Zhang, A.; Xiong, W.; Hilbert, J. E.; DeVita, E. K.; Bidlack, J. M.;
Neumeyer, J. L. 2-Aminothiazole-Derived Opioids. Bioisosteric Re-
placement of Phenols. J. Med. Chem. 2004, 47, 1886–1888. (d)
Neumeyer, J. M; Zhang, A. Mixed kappa/mu opioids and uses thereof.
PCT Int. Appl. 2004, 56.
Notes
§Reported in part at the 72nd College on Problems of Drug
Dependence in Scottsdale, Arizona, June, 2010.
’ ACKNOWLEDGMENT
This work was supported by NIH Grants R01-DA14251(J.L.N.),
K05-DA00360 (J.M.B.), and T32 DA 007252 (A.W.S.).
’ ABBREVIATIONS USED
(11) Peng, X.; Knapp, B. I.; Bidlack, J. M.; Neumeyer, J. L. In Vitro
Investigation of Oxazol and Urea Analogues of Morphinan at Opioid
Receptors. Bioorg. Med. Chem. 2007, 15, 4106–4112.
(12) Wang, Y.-J.; Tao, Y.-M.; Li, F.-Y.; Wang, Y.-H.; Xu, X.-J.; Chen,
J.; Cao, Y.-L.; Chi, Z.-L.; Neumeyer, J. L; Zhang, A.; Liu, J.-G.
Pharmacological Characterization of ATPM [(-)-3-Amino-thiazolo-
[5,4-b]-N-cyclopropylmorphinan hydrochloride], a novel mixed κ-Ago-
nist and μ-agonist/antagonist that attenuates morphine antinociceptive
tolerance and herion self-administration behavior. J. Pharmacol. Exp.
Ther. 2009, 329, 306–313.
κOR, κ opioid receptor; μOR, μ opioid receptor; δOR, δ opioid
receptor; SAR, structure-activity relationship; ATPM, amino-
thiazolo-N-cyclopropylmorphinan; ATBM, aminothiazolo-N-
cyclobutylmorphinan
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Journal of Medicinal Chemistry
ARTICLE
Abstracts of Papers, 232nd ACS National Meeting, San Francisco, CA,
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