Brief Articles
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 16 3195
cloudy and viscous. After stirring for 3 h at room temperature,
the reaction was quenched with saturated NH4Cl solution (100
mL). The layers were separated and the aqueous layer was
extracted with Et2O (2 × 100 mL). The combined organic layers
were combined, evaporated, redissolved in Et2O (100 mL), and
extracted with 10% HCl (2 × 100 mL). The combined aqueous
layers were washed with Et2O (3 × 75 mL). The aqueous layer
was then carefully free based at 0 °C with concentrated NH4-
OH to pH 10 and extracted with CHCl3 (3 × 100 mL). The
combined organic layers were dried over Na2SO4, and the
solvent evaporated to give a light brown solid. This solid was
recrystallized in 4:1 acetonitrile:water to afford 8.1 (79%) of 2
as white crystals: mp 122.7-123.1 °C (lit.6 mp 122-123 °C);
1H NMR and MS data were identical with those previously
published.6 Anal. (C28H39N3O2) C, H, N.
None of the examined compounds significantly inhibited
δ-agonist-stimulated GTPγS binding and thus show
little or no efficacy as δ-opioid receptor antagonists.
We have, thus, synthesized a series of 4-substituted
analogues of (+)-2 and found that they were all δ-selec-
tive ligands (since their affinity to both the µ- and
κ-opioid receptors was slight (Ki > 1 µM)). Their
δ-receptor affinities and efficacies, however, were quite
different. The 4-crotyl, 2-methylallyl, and benzyl com-
pounds 3h ,g,j were the most interesting. The 4-crotyl
analogue 3h had the highest affinity (comparable to the
affinity of the previously reported N-propyl-substituted
analogue)9 and was as efficacious as (+)-2 in the GTPγS
functional assay. The 4-(2-methylallyl) 3g and benzyl
3j analogues had efficacies comparable to that of (+)-2,
but their affinities for the δ-opioid receptor were slightly
lower. The 4-cyclopropylmethyl analogue, as well as the
4-H, and 4-alkyl analogues (methyl, ethyl, butyl to
hexyl), on the other hand, had much less efficacy in the
GTPγS assay, and the 4-(2-phenyl)ethyl and 4-(3-
phenyl)propyl analogues had even less efficacy than the
4-alkyl-substituted compounds. The effect of the N-
cyclopropylmethyl, N-allyl, and N-benzyl substituents,
among others in the (RR)-R-(2S,5R)-diethylbenzamide
series, at the δ-opioid receptor, is distinctly different
from their µ-receptor effects in the morphinan system,
and the observed structure-activity relationships in-
dicate that the absolute stereochemistry of these ana-
logues is critical for high δ-binding affinity. The experi-
mental data indicating that naltrindole, an N-cyclopropyl-
methyl-substituted noroxymorphindole, is a potent δ-o-
pioid antagonist15 and that 3i, the (RR)-R-(2S,5R)-N-
cyclopropylmethyl derivative of the diethylbenzamide,
is an agonist without efficacy in the GTPγS assay (Table
1), as well as the agonist activity of the N-benzyl and
2-methylallyl analogues of (+)-2 (Table 1), give further
credence to the LMC recognition pharmacophore.16
Thus, N-substituted morphinans and oxymorphindoles
appear to have quite different effects than comparably
substituted analogues of (+)-2. The LMC δ-recognition
pharmacophore16 noted that the N-substituents in di-
ethylbenzamides based on (+)-2 exist in a different
three-dimensional spatial area than those in the mor-
phinans and oxymorphindoles, and thus, comparably
N-substituted compounds from these series should be
pharmacologically dissimilar.
(+)-4-[(RR)-R-((2S,5R)-2,5-Dim et h yl-1-p ip er a zin yl)-3-
m eth oxyben zyl]-N,N-d ieth ylben za m id e (3a ). A suspension
of (+)-2 (1.15 g, 2.56 mmol), AcOH (0.3 mL, 5.2 mmol) and
10% Pd/C (0.1 g) in H2O (2 mL) was heated at reflux overnight.
The solution was cooled, the catalyst was filtered through
Celite, and the aqueous filtrate was free based with concen-
trated NH4OH. The mixture was extracted with CHCl3 (3×)
and dried with Na2SO4. After removal of the solvent, the
resultant brown oil was chromatographed with CHCl3:CH3-
OH:NH4OH (80:20:2) to afford 1.0 g (95%) of the pure product
as a viscous yellow oil. This was dissolved in a minimum
amount of Et2O, and a 1.0 M solution of HCl in Et2O was added
until the resulting mixture was acidic to moist pH paper.
Removal of the solvent, and drying overnight in a vacuum oven
afforded 3a ‚HCl as a light yellow amorphous powder: mp 75
1
°C (soften); H NMR δ 0.93-0.95 (d, J ) 6.4 Hz, 3 H), 1.04-
1.34 (m, 9 H), 1.57-1.64 (t, J ) 9.0 Hz, 1 H), 2.38-2.47 (m, 2
H), 2.65-2.78 (m, 2 H), 2.83-2.96 (m, 2 H), 3.19-3.68 (pair
of br s, 4 H), 3.79 (s, 3 H), 5.33 (s, 1 H), 6.70-6.88 (m, 3 H),
7.25-7.31 (m, 3 H), 7.43-7.49 (d, 2 H); CIMS m/z 410 (MH+);
[R]20 ) +24.9° (c 0.3, MeOH). Anal. (C25H35N3O2‚HCl‚2.25
D
H2O) C, H, N.
R ep r esen t a t ive Syn t h esis: (+)-4-[(RR)-R-((2S,5R)-4-
Met h yl-2,5-d im et h yl-1-p ip er a zin yl)-3-m et h oxyb en zyl]-
N,N-d ieth ylben za m id e (3b). A mixture of 3a (0.61 g, 1.5
mmol), iodomethane (103 µL, 1.65 mmol), and K2CO3 (0.25 g,
4.5 mmol) in DMF (2 mL) was heated to 85 °C for 2 h whereby
TLC showed completion of reaction. The solution was cooled,
water was added, and the aqueous mixture was extracted with
ether (3 × 25 mL). The combined organic extracts were dried
with Na2SO4, and the solvent was evaporated. Chromatogra-
phy with ethyl acetate afforded 0.47 g (75%) of the pure
product as a viscous yellow oil. This was dissolved in a
minimum amount of ether, and a 1.0 M solution of HCl in ether
was added until the resulting mixture was acidic to moist pH
paper. Removal of the solvent and drying overnight in a
vacuum oven afforded the salt 3b as a white amorphous
powder: mp 82 °C dec; 1H NMR δ 0.88-1.00 (δ, J ) 6.3 Hz, 3
H), 1.01-1.38 (m, 9 H), 1.79-1.86 (t, J ) 9.0 Hz, 1 H), 2.15-
2.31 (m, 4 H), 2.53-2.79 (m, 4 H), 3.17-3.64 (pair of br s, 4
H), 3.80 (s, 3 H), 5.35 (s, 1 H), 6.68-6.87 (m, 3 H), 7.19-7.39
Exp er im en ta l Section
(+)-4-[(RR)-R-((2S,5R)-4-Allyl-2,5-d im et h yl-1-p ip er a -
zin yl)-3-m eth oxyben zyl]-N,N-d ieth ylben za m id e [(+)-2].
This material was prepared by Zhang’s1,10 modification of
Bishop’s application11 of the Katritzky tertiary amine method
used for the synthesis of (+)-BW373U86. A solution of 3-meth-
oxyphenylmagnesium bromide was prepared by dropwise
addition of 3-bromoanisole (8.49 g, 45.4 mmol) to a mixture of
magnesium turnings (1.10 g, 45.4 mmol) in THF (40 mL),
followed by a 1 h reflux. The Grignard solution was cooled and
transferred via cannula into a three necked round-bottomed
flask equipped with a mechanical stirrer. The imine adduct 7
was prepared by refluxing 51 (4.66 g, 22.7 mmol), (-)-1-allyl-
(2R,5S)-trans-dimethylpiperazine (6)5,6,12 (3.5 g, 22.7 mmol)
and benzotriazole (2.70 g, 22.7 mmol) overnight in 60 mL of
anhydrous benzene with a Dean-Stark trap attached to
remove water. The imine solution was cooled and transferred
dropwise to the chilled (0 oC) vigorously stirred Grignard
solution by means of a cannula. The mixture became very
(m, 3 H), 7.43-7.56 (d, 2 H); CIMS m/z 424 (MH+); [R]20
)
D
+20.2° (c 0.5, MeOH). Anal. (C26H37N3O2‚HCl‚2.0H2O) C, H,
N.
Ack n ow led gm en t. We thank Noel Whittaker of the
Laboratory of Bioorganic Chemistry for mass spectral
data. We also express our appreciation to Qiao-Xi Zheng
for excellent technical work.
Su p p or tin g In for m a tion Ava ila ble: Remaining synthe-
ses, biological methods, and elemental analyses. This material
s.org.