Synthesis and opioid-receptor binding of novel amino-substituted morphan analogues

Article abstract of DOI:10.1002/1521-4184(200109)334:8/9<284::AID-ARDP284>3.0.CO;2-B

Starting with methyl 4,6-O-benzylidene-α-D-glucopyranoside (4), an optimized procedure is reported for preparation of the bromide 7, which is transformed into the N-acylated heptopyranosamine 9. After introduction of an axially positioned azido moiety in

Full text of DOI:10.1002/1521-4184(200109)334:8/9<284::AID-ARDP284>3.0.CO;2-B

284 Amino-substituted morphan analogues
Georg Höfnera),
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 284–290
Benedikt Streicherb),
Bernhard Wünschc)
Synthesis and opioid-receptor binding of
novel amino-substituted morphan analogues
Starting with methyl 4,6-O-benzylidene-α-D-glucopyranoside (4), an optimized proce-
dure is reported for preparation of the bromide 7, which is transformed into the N-acylated
heptopyranosamine 9. After introduction of an axially positioned azido moiety in position
3 intramolecular N/O-acetal formation succeeds to provide the morphan analogue 17.
In receptor binding studies with radioligands the amines 18b-18d reveal higher affinity
for µ-receptors than for κ-receptors. The most µ-active compound 18b (Ki = 14 nM)
contains two aryl substituents, which presumably may occupy both aryl binding sites of
µ-receptors.
a) Institut für Pharmazie - Zentrum für
Pharmaforschung der Universität
München, Butenandt Str. 5-13,
D-81377 München, Germany
b)
Klinge Pharma GmbH, Berg-am-
Laim-Straße 129, D-81673 München,
Germany
c)
Pharmazeutisches Institut der Uni- Key Words: Opioid receptor ligands; Morphan analogues; Intramolecular N/O-acetal
versität Freiburg, Hermann-Herder-
Straße 9, D-79104 Freiburg, Germany
formation; Receptor binding studies
Received: May 15, 2001 [FP580]
morphan skeleton 2. The morphan ring system 2 repre-
Introduction
sents a substructure of the opioid analgesic morphine and
strong analgesia as well as opioid receptor binding are
observed with suitable substituted morphan derivatives[3].
Conditions of severe pain may be treated with opioid anal-
gesics. Among the opioids κ-receptor agonists possess a
unique activity profile, since they cause strong analgesic
effects accompanied by minimal physical dependence,
respiratory depression, and constipation liability. However,
sedation, dysphoria, and strong diuresis are usually asso-
ciated with κ-agonists, which limits their broad applica-
Therefore, we planned to synthesize the morphan-analo-
gous bicycles 3 with an arylacetyl residue at the ring
nitrogen atom and amino substituents in different ring po-
sitions, particularly in position 6, 7, or 8. Here, the position
and the stereochemistry of the amino moiety controls the
three dimensional arrangement of the pharmacophoric ele-
ments arylacetamide and amino group.
tion[1]
.
Recently, we described the preparation of N-acylated
epoxyazocanes without further substituents in the ring sys-
tem[4]. Herein, we report on the synthesis of the first repre-
sentatives of morphan analogous bicycles 3 with an
additional amino functionality in position 6. The κ- and
µ-receptor affinities of the amino substituted bicycles are
also studied.
Chemistry
The glucose derivative methyl 4,6-O-benzylidene-α-D-glu-
copyranoside (4) was employed as enantiomerically pure
starting material. At first the free hydroxy groups of 4 should
be reductively eliminated to produce the alkene 5. A few
methods[5] are described for this transformation. We chose
the one-pot procedure of Bessodes and coworkers using
triphenylphosphane, iodoform, and imidazole[6]. After opti-
mization of the reaction conditions we obtained the alkene
5 in 75% yield. The yield of the alkene 5 is strongly
dependent on the reaction time. Shortening of the reaction
time from 2.25 h to 1.75 h reduced the yield of the alkene
5 to 40% and the intermediate hydroxy-iodide 12, giving an
insight into the reaction course, was isolated in 23% yield
(see Figure 2).
Figure 1
I n
Fi
gure 1 the prototypical κ-agonist U 50,488 (1) is shown.
Several highly potent κ-agonists have been derived from
U 50,488, all containing the κ-pharmacophoric elements
arylacetamide and pyrrolidine, usually at a distance of two
carbon atoms[1,2]
.
In order to find novel ligands for opioid receptors, in particu-
lar for κ-receptors, we intended to combine the structural
features of typical κ-ligands (arylacetamide, amine) withthe
———
Correspondence: Prof. B. Wünsch, Pharmazeutisches Institut
der Universität Freiburg, Hermann-Herder-Straße 9, D-79104
Freiburg, Germany.
E-mail: wuensch@ruf.uni-freiburg.de
Fax: +49 761 203-6351
During hydrogenation of the alkene 5 with the catalyst
Pd/C[7,8] hydrogenolytic cleavage of the benzaldehyde
acetal occurred to afford the methyl didesoxy-glucoside 13
as main product. This hydrogenolysis could not be control-
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/0809/0284 $17.50 +.50/0

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 284–290
Amino-substituted morphan analogues 285
Scheme 1
led by the reaction conditions. However, catalyzing the
hydrogenation with Raney nickel we obtained the pyran 6
in reproducible high yields (96%) without hydrogenolytic
cleavage of the benzylidene protective group.
and saponification of the ester moiety to afford an amino-
alcohol, which was acylated with (3,4-dichlorophenyl)acetyl
chloride (DCPA-Cl) in a biphasic system (CH2Cl2/NaOH) to
give the (dichlorophenyl)acetamide 9 in 86% yield.
Treatment of the benzaldehyde acetal 6 with N-bromosuc-
cinimide (NBS) afforded the bromo-ester 7[8]. In contrast to
ref.[8], addition of the radical initiator AIBN was necessary
for high yields of 7 (62%). Nevertheless, we were able to
isolate small amounts of the anomeric β-glucoside 14 and
the dibenzoate 16, which were formed as side products
during the radical substitution of the benzylidene derivative
6.
Attempts to obtain a bicyclic N/O-acetal of general structure
3 by cyclization of the amide 9 with catalytic amounts of
acid failed. Therefore the residual hydroxy group of 9 was
first used to introduce an equivalent of the envisaged amino
group. Reaction of the alcohol 9 with tosyl chloride fur-
nished the tosylate 10, which was substituted with NaN3 to
yield the azide 11. The nucleophilic substitution of the
equatorially oriented tosyloxy substituent of 10 with azide
occurred with complete inversion of configuration providing
a product with an axially positioned azido moiety. This
inversion of configuration is clearly indicated by the struc-
ture of the 3-H signals in the 1H NMR spectra. Whereas a
ddd (J = 15.2/10.1/5.1 Hz) is caused by the axially posi-
tioned 3-H of the tosylate 10 only a broad singlet is ob-
served for the equatorially positioned 3-H of the azide 11.
The bromo-ester 7 as well as its β-anomer 14 reacted with
KCN to provide the anomeric cyano-esters 8[4] and 15,
respectively. After careful optimization of these four reac-
tion steps, the cyano-ester 8 was accessible in 41% yield
starting from the glucose derivative 4.
Treatment of the cyano-ester 8 with H2 and Raney nickel
in the presence of NaOH led to reduction of the cyano group
Heating of the azido substituted amidoacetal 11 with a
catalytic amount of p-toluenesulfonic acid provided the
bicyclic N/O-acetal 17 in 53% yield. Obviously the axial
orientation of the C-3substituent promotes theintramolecu-
lar N/O-acetal formation. We presume, that the conforma-
tional equilibrium of the pyran chairs of 11 is shifted to a
6
small extent towards the C3-conformation, which is able
to cyclize.
The bicyclic azide 17 was reduced with H2 and Pd/C to yield
the primary amine 18a, which was reductively methylated
with formaldehyde and NaBH3CN[9] to afford the dimethyl-
amine 18c. The benzylamine 18b was obtained by conden-
sation of the primary amine 18a with benzaldehyde and
subsequent reduction with NaBH4[10]. The pharmacologi-
cally most interesting pyrrolidin-1-yl substituent (18d) was
introduced by reductive alkylation[9] of the primary amine
Figure 2

286 Amino-substituted morphan analogues
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 284–290
The same order of activity is found for µ-receptor binding
of the amines 18 (18b > 18c > 18d). All investigated
compounds reveal higher affinities for µ-receptors than for
κ-receptors, the benzylamine 18b showing the best µ/κ-se-
lectivity (60:1). The very low Ki-value (14 nM) of the ben-
zylamine 18b is surprising. We presume, that the aryl
substituents of the benzylamine 18b occupy two different
binding sites at µ-receptors as is postulated for the aryl
residues (4-hydroxyphenyl of Tyr1 and phenyl of Phe4) of
opioid peptides[12]
.
Acknowledgements
We wish to thank the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie for financial support.
Thanks are also due to the Degussa AG, Janssen Cilag GmbH
and Upjohn Pharmacia for donation of chemicals.
Experimental
Scheme 2
Chemistry
18a with NaBH3CN and 2,5-dimethoxytetrahydrofuran as
an equivalent of succinaldehyde.
General: Unless otherwise noted, moisture sensitive reactions
were conducted under dry nitrogen.– Thin layer chromatogra-
phy: Silica gel 60 F254 plates (Merck).– Flash chromatography
(FC)[13]: Silica gel 60, 0.040–0.063 mm (Merck); parentheses
include: Diameter of the column [cm], eluent, fraction size [mL],
Rf.– Melting points: Melting point apparatus Dr. Tottoli (Büchi),
uncorrected.– Optical rotation: Polarimeter 241 (Perkin Elmer);
1.0 dm tube; concentration c [g/100 ml]; temperature 20 °C.–
Elemental analyses: CHN elemental analyzer Rapid (Heraeus)
and Elemental Analyzer 240 (Perkin Elmer).– MS: Mass spec-
trometer 5989A (Hewlett Packard); EI = electron impact, CI =
chemical ionization.– IR: IR spectrophotometer 1600 FT-IR and
2000 FT–IR.(Perkin-Elmer).– 1H NMR (400 MHz): GSX FT
NMR spectrometer (Jeol); tetramethylsilane as internal stand-
ard, δ in ppm; coupling constants are given with 0.5 Hz resolu-
tion.
Receptor binding studies
The affinity of the amines 18a–18d for κ- and µ-receptors
was determined in receptor binding studies with radioli-
gands. Bovine striatal membrane preparations were used
as receptor material. κ-receptors were labeled with the
radioligand [3H]-U-69.593 and the tritiated pentapeptide
[3H]-DAMGO was employed in µ-receptor affinity tests[11]
.
Table 1
————————————————————————————–
Compound Ki (nM) ± SEM
κ (U-69.593) µ (DAMGO)
————————————————————————————–
(2R,4aR,6S,8aS)-(+)-6-Methoxy-2-phenyl-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (5)[6]
Under a nitrogen atmosphere methyl 4,6-O-benzylidene-α-D-
glucopyranoside (4, 3.0 g, 10.6 mmol) was dissolved in toluene
(600 mL) and stirred for 30 min at room temperature. Then,
PPh3 (11.1 g, 42.4 mmol), CHI3 (8.35 g, 21.2 mmol) and
imidazole (1.44 g, 21.2 mmol) were successively added and the
reaction mixture was heated to reflux for 2.25 h with vigorous
stirring. After cooling to room temperature methanol (120 mL)
and a saturated solution of NaHCO3 (12 mL) were added. The
organic layer was separated, the aqueous layer was extracted
with petroleum ether (3 × 200 mL), the combined organic layers
were dried (MgSO4) and concentrated in vacuo. The residue
was purified by FC (8 cm, petroleum ether/ethyl acetate 9:1,
50 mL). Fractions 15–23 were concentrated in vacuo. Colorless
solid (petroleum ether), mp 117–119 °C (ref.[6] 118–120 °C),
yield 1.94 g (75%).
18a
–
–
18b
832 ± 54
1,500 ± 80
18,900
14 ± 1.3
1,150 ± 120
9,530
18c
18d
Morphine
Tramadol
U 50,488
111 ± 12
51,000 ± 3,700
1.44 ± 0.025
1.64 ± 0.26
1,690 ± 210
–
————————————————————————————–
The results of the receptor binding studies are summarized
in Table 1. The Ki-values of the primary amine 18a were not
determined, because of low competition at the test concen-
tration of 100 µM. In this series of compounds the κ-recep-
tor affinity is decreasing in the order benzylamine 18b >
dimethylamine 18c > pyrrolidine 18d. Thebenzylamine18b
represents the most κ-active ligand binding in the submi-
cromolar range (Ki = 832 nM) at κ-receptors. In contrast to
observations with known κ-agonists, κ-receptor binding of
the pyrrolidine derivative 18d is lower than κ-receptor
binding of the analogous dimethylamine 18c and benzyl-
amine 18b.
(2R,4aR,6S,8aS)-(+)-6-Methoxy-2-phenyl-4,4a,6,8a-tetra-
hydropyrano[3,2-d][1,3]dioxine (5) and
(2R,4aR,6S,7S,8S,8aR)-(+)-8-Iodo-6-methoxy-2-phenyl-
4,4a,6,7,8,8a-hexahydropyrano[3,2-d][1,3]dioxin-7-ol (12)
As described above a mixture of methyl 4,6-O-benzylidene-α-
D-glucopyranoside (4, 0.70 g, 2.48 mmol), triphenylphosphane
(2.60 g, 9.90 mmol), iodoform (1.95 g, 4.97 mmol), imidazole

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 284–290
Amino-substituted morphan analogues 287
(339 mg, 4.97 mmol), and toluene (140 mL) was heated to reflux
for 1.75 h. After work-up the products were purified by FC (4 cm,
petroleum ether/ethyl acetate 9:1, then 7:3, 30 mL).
H, CH2OBz), 4.58 (dd, J = 12.0/2.6 Hz, 1 H, CH2OBz), 4.79 (d,
J = 2.6 Hz, 1 H, 6-H), 5.11 (ddd, J = 15.4/10.2/5.1 Hz, 1 H, 3-H),
7.41 (t, J = 7.5 Hz, 2 H, arom.), 7.43 (t, J = 7.7 Hz, 2 H, arom.),
7.54 (t, J = 7.5 Hz, 1 H, arom.), 7.56 (t, J = 7.5 Hz, 1 H, arom.),
8.03 (d, J = 8.1 Hz, 4 H, arom.).
5 (fractions 8–12): Colorless solid, yield 248 mg (40%).
12 (fractions 18–24, Rf 0.08 with the eluent petroleum
ether/ethyl acetate 9:1): Pale yellow solid (iPr2O), mp 76 °C,
yield 222 mg (23%).– [α]589 = +42.1 (0.97, CHCl3).– C14H17IO5
(392.2) calcd. C 42.9 H 4.37 found C 42.7 H 4.51.– MS (EI):
m/z = 392 (M+).– IR (KBr): ν = 3470 (OH), 1117 (C-O), 1085
(C-O), 1073 (C-O), 1057 cm–1 (C-O).– 1H NMR (CDCl3): δ (ppm)
= 2.75 (s, broad, 1 H, OH), 3.00 (dd, J = 9.0/3.8 Hz, 1 H, 8a-H),
3.43–3.50 (m, 4 H, OCH3, 7-H), 3.82 (t, J = 10.3 Hz, 1 H, 4-H
axial), 4.07 (td, J = 9.8/5.1 Hz, 1 H, 4a-H), 4.34 (dd, J = 10.3/5.1
Hz, 1 H, 4-H equatorial), 4.78 (d, J = 3.8 Hz, 1 H, 6-H), 4.83 (t,
J = 4.0 Hz, 1 H, 8-H), 5.69 (s, 1 H, 2-H), 7.35–7.41 (m, 3 H,
arom.), 7.53 (dd, J = 7.3/2.1 Hz, 2 H, arom.). The signals were
assigned by a H/H-correlated spectrum.
(+)-[(2R,3S,6S)-2-Cyanomethyl-6-methoxyoxan-3-yl] ben-
zoate (8)[4]
The bromide 7 (772 mg, 2.34 mmol) was dissolved in DMSO
(10 mL). Then, KCN (457 mg, 7.02 mmol) was added and the
solution was stirred for 1 h at 70 °C. After addition of water
(10 mL) and petroleum ether (20 mL) the aqueous layer was
separated and extracted with a mixture of petroleum ether and
ethyl acetate (95:5, 3 × 20 mL). The organic layer was dried
(MgSO4), concentrated in vacuo and the residue was purified
by FC (4 cm, petroleum ether/ethyl acetate 9:1, 25 mL, Rf 0.25).
The solvent of the fractions 29–37 was evaporated in vacuo
leaving the nitrile 8 as colorless solid, mp 61–63 °C (petroleum
ether/diethyl ether), yield 583 mg (91%).
(2R,4aR,6S,8aS)-(+)-6-Methoxy-2-phenyl-4,4a,6,7,8,8a-
hexahydropyrano[3,2-d][1,3]dioxine (6)[8]
(+)-[(2R,3S,6R)-2-Cyanomethyl-6-methoxyoxan-3-yl] ben-
zoate (15)
Raney nickel (1.58 g, Aldrich, 50% in water, pH > 9) and solid
NaOH (236 mg) were added to a solution of 5 (1.58 g, 6.36
mmol) in methanol (20 mL). The reaction mixture was hydro-
genated (5.3 bar, 40 °C) for 24 h. The catalyst was removed by
filtration and the filtrate was concentrated in vacuo. Colorless
solid (petroleum ether), mp 81 °C (ref.[8] 82–84 °C), yield 1.53 g
(96%).– [α]589 = +115 (0.98, CHCl3) [ref. [8] [α]589 = +118±1 (1.0,
CHCl3).
As described for the anomeric glycoside 8 the bromide 14 (214
mg, 0.65 mmol) was reacted with KCN (127 mg, 1.95 mmol) in
DMSO (5 mL). Work-up and purification were performed as
described for 8. FC (2 cm, petroleum ether/ethyl acetate 9:1,
10 mL, Rf = 0.18). Colorless solid (petroleum ether/diethyl
ether), mp 87 °C, yield 117 mg (87%).– [α]589 = +13.6 (0.99,
CHCl3).– C15H17NO4 (275.3) calcd. C 65.4 H 6.22 N 5.09 found
C 65.4 H 6.28 N 5.13.– MS (EI): m/z = 244 (M+–OCH3).– IR
(KBr): ν = 2249 (CN), 1711 (C=O), 1268 (O=C-O) , 1061 cm–1
(C-O).– 1H NMR (CDCl3): δ (ppm) = 1.69–1.85 (m, 2 H, 4-H,
5-H), 2.04–2.07 (m, 1 H, 5-H), 2.38–2.43 (m, 1 H, 4-H), 2.71
(dd, J = 16.9/8.3 Hz, 1 H, CH2CN), 2.80 (dd, J = 16.9/4.1 Hz,
1 H, CH2CN), 3.61 (s, 3 H, OCH3), 3.96 (td, J = 8.6/4.3 Hz, 1 H,
2-H), 4.59 (dd, J = 8.5/2.1 Hz, 1 H, 6-H), 4.85 (td, J = 9.4/4.7
Hz, 1 H, 3-H), 7.52 (t, J = 7.7 Hz, 2 H, arom.), 7.65 (td, J =
8.1/1.3 Hz, 1 H, arom.), 8.07 (d, J = 7.7 Hz, 2 H, arom.).
(+)-[(2S,3S,6S)-2-Bromomethyl-6-methoxyoxan-3-yl] ben-
zoate (7)[8] and
(+)-[(2S,3S,6R)-2-bromomethyl-6-methoxyoxan-3-yl] ben-
zoate (14) and
(+)-[(2R,3S,6S)-2-(benzoyloxymethyl)-6-methoxyoxan-3-
yl] benzoate (16)
A mixture of 6 (950 mg, 3.79 mmol), N-bromosuccinimide (NBS,
900 mg, 5.05 mmol), BaCO3 (1.23 g), 2,2′-azodi(2-methyl-
propanenitrile) (AIBN, 47.5 mg), and CCl4 (35 mL) was heated
to reflux for 30 min. The mixture was washed with saturated
solutions of NaHSO3 (1 ×) and NaCl (1 ×), dried (MgSO4),
concentrated in vacuo and purified by FC (4 cm, petroleum
ether/ethyl acetate 9:1, 25 mL).
(+)-2-(3,4-Dichlorophenyl)-N-{2-[(2R,3S,6S)-3-hydroxy-6-
methoxyoxan-2-yl]ethyl}acetamide (9)
A solution of 8 (225 mg, 0.82 mmol) in methanol (12 mL) and
5 N NaOH (1 mL) was shaken for 10 min at room temperature.
Then, freshly prepared Raney nickel (112 mg) and 5 N NaOH
(3 mL) were added. The mixture was shaken under a H2
atmosphere (5.3 bar) for 14 h at room temperature. Raney
nickel was filtered off and after addition of water (7 mL) the
filtrate was concentrated to about 13 mL. CH2Cl2 (15 mL) and
2-(3,4-dichloropenyl)acetyl chloride (365 mg, 1.63 mmol) were
added and the mixture was stirred for 30 min at room tempera-
ture. The aqueous layer was separated, extracted with CH2Cl2
(4 × 15 mL), the combined organic layers were dried (MgSO4)
and concentrated in vacuo. Colorless solid (iPr2O/CH2Cl2), mp
124 °C, yield 158 mg (53%). FC purification (3 cm, ethyl acetate,
30 mL, Rf 0.36) of the mother liquor gave further 96 mg (32.4%)
of 9. Total yield 254 mg (86%).– [α]589 = +54.9 (0.93, CHCl3).–
C16H21Cl2NO4 (362.2) calcd. C 53.0 H 5.84 N 3.87 found C 53.2
H 5.71 N 3.86.– MS (EI): m/z = 334, 332, 330 (M+–OCH3).– IR
(KBr): ν = 3312 (OH), 1652 (C=O), 1560 (amide II), 1128 (C-O),
1055 cm–1 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.54–1.86 (m,
5 H, 2 × 4-H, 2 × 5-H, CH2CH2NH), 2.01–2.08 (m, 1 H,
CH2CH2NH), 3.18 (s, 3 H, OCH3), 3.19–3.26 (m, 1 H,
CH2CH2NH), 3.28–3.33 (m, 1 H, CH2CH2NH), 3.45–3.49 (m, 1
H, 2-H), 3.50 (s, 2 H, aryl-CH2), 3.61–3.64 (m, 1 H, 3-H), 4.37
(s broad, 1 H, 6-H), 6.17 (s broad, 1 H, NH), 7.12 (dd, J = 8.1/2.1
Hz, 1 H, 6-H arom.), 7.37 (d, J = 2.1 Hz, 1 H, 2-H arom.), 7.40
(d, J = 8.5 Hz, 1 H, 5-H arom.). A signal for the OH-proton was
not found.
7 (fractions 23–29, Rf 0.37): Colorless oil, yield 772 mg (62%).–
[α]589 = +131 (0.95, CHCl3) [ref.[8] [α]589 = +133 (1.1, CHCl3).
14 (fractions 31–35, Rf 0.29): Colorless solid (petroleum
ether/diethyl ether), mp 98 °C, yield 117 mg (9%).– [α]589
=
+11.5 (1.02, CHCl3).– C14H17BrO4 (329.2) calcd. C 51.1 H 5.21
found C 51.2 H 5.05.– MS (CI): m/z = 331, 329 (MH+), 299, 297
(MH+– CH3OH).– IR (KBr): ν = 1720 (C=O), 1267 (O=C-O),
1115 (C-O), 1063 cm–1 (C-O).– 1H NMR (CDCl3): δ (ppm) =
1.67–1.77 (m, 2 H, 4-H, 5-H), 1.97–2.02 (m, 1 H, 5-H), 2.31–
2.36 (m, 1 H, 4-H), 3.50 (dd, J = 11.1/7.7 Hz, 1 H, CH2Br), 3.56
(s, 3 H, OCH3), 3.62 (dd, J = 11.1/3.4 Hz, 1 H, CH2Br), 3.85 (td,
J = 8.2/3.4 Hz, 1 H, 2-H), 4.54 (dd, J = 8.3/2.3 Hz, 1 H, 6-H),
4.92 (td, J = 9.3/4.7 Hz, 1 H, 3-H), 7.46 (t, J = 7.7 Hz, 2 H,
arom.), 7.60 (td, J = 7.4/1.5 Hz, 1 H, arom.), 8.02 (dd, J = 8.3/1.1
Hz, 2 H, arom.). The signals were assigned by a H/H-correlated
spectrum.
16 (fractions 37–39, Rf 0.26): Colorless oil, yield 31 mg (2.9%).–
[α]589 = +138.2 (0.91, CHCl3).– C21H22O6 (370.4) calcd. C 68.1
H 5.99 found C 68.3 H 6.23.– MS (EI): m/z = 339 (M+–OCH3).–
IR (film): ν = 1722 (C=O), 1267 (O=C-O) , 1112 (C-O), 1053
cm–1 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.91–2.06 [m, 3 H,
4-H, 5-H (2)], 2.15–2.20 (m, 1 H, 4-H), 3.43 (s, 3 H, OCH3), 4.24
(ddd, J = 9.8/6.0/3.0 Hz, 1 H, 2-H), 4.41 (dd, J = 12.0/6.0 Hz, 1

288 Amino-substituted morphan analogues
Arch. Pharm. Pharm. Med. Chem. 2001, 334, 284–290
less oil, yield 29.6 mg (53%).– [α]589 = –7.86 (0.56, CHCl3).–
C15H16Cl2N4O2 (355.2) calcd. C 50.7 H 4.54 N 15.77 found C
50.6 H 4.76 N 15.65.– MS (CI): m/z = 359, 357, 355 (MH+).– IR
(film): ν = 2100 (N3), 1647 (C=O), 1046 cm–1 (C-O).– 1H NMR
(CDCl3): δ (ppm) = 1.63–2.13 (m, 6 H, 4-CH2, 7-CH2, 8-CH2 ),
3.26–3.34 (m, 0.22 H, 3-H) 3.40 (ddd, J =12.4/9.0/6.0 Hz, 0.78
H, 3-H), 3.50–3.60 (m, 0.78 H, 3-H), 3.58 (s, 2 H, aryl-CH2),
3.77 (dt, J = 10.4/5.1 Hz, 0.78 H, 6-H), 3.88 (dt, J = 11.1/5.7
Hz, 0.22 H, 6-H), 3.97 (t, J = 5.8 Hz, 0.22 H, 5-H), 4.07 (dt, J =
9.0/4.7 Hz, 0.78 H, 5-H), 4.24–4.28 (m, 0.22 H, 3-H), 5.33 (d, J
= 3.4 Hz, 0.22 H, 1-H), 5.55 (d, J = 3.0 Hz, 0.78 H, 1-H), 7.00
(dd, J = 8.1/2.1 Hz, 1 H, 6-H arom.), 7.26 (d, J = 1.7 Hz, 1 H,
2-H arom.), 7.32 (d, J = 8.1 Hz, 0.22 H, 5-H arom.), 7.33 (d, J
= 8.5 Hz, 0.78 H, 5-H arom.). Ratio of rotational isomers 78:22.
(+)-(2R,3S,6S)-2-{2-[2-(3,4-Dichlorophenyl)acetylamino]-
ethyl}-6-methoxyoxan-3-yl-4-methylbenzenesulfonate (10)
At about 5 °C 4-(dimethylamino)pyridine (2.47 g, 12.5 mmol)
was added to a solution of 9 (727 mg, 2.08 mmol), triethylamine
(2.47 g, 24.4 mmol) and p-toluenesulfonyl chloride (3.62 g,
12.5 mmol) in CHCl3 (60 mL). The mixture was heated to reflux
for 1 h. The mixture was washed with 1 N HCl (2 × 60 mL), with
saturated solutions of NaHCO3 (30 mL) and NaCl (30 mL), dried
(MgSO4), and concentrated in vacuo. The residue was purified
by FC (4 cm, petroleum ether/ethyl acetate 3:7, 25 mL, Rf 0.38).
The solvent of the fractions 8–14 was evaporated in vacuo.
Colorless oil, yield 1.03 g (96%).– [α]589 = +35.0 (1.09, CHCl3).–
C23H27Cl2NO6S (516.4) calcd. C 53.5 H 5.27 N 2.71 found C
53.4 H 5.36 N 2.66.– MS (EI): m/z = 488, 486, 484 (M+–OCH3).–
IR (film): ν = 3299 (N-H), 1647 (C=O), 1560 (amide II), 1128
(C-O), 1055 cm–1 (C-O).– 1H NMR (CDCl3): δ (ppm) = 1.56–
1.65 (m, 2 H, 5-H), 1.79–1.94 (m, 4 H, 4-H, CH2CH2NH), 2.46
(s, 3 H, CH3), 3.06–3.11 (m, 1 H, CH2CH2NH), 3.13 (s, 3 H,
OCH3), 3.46–3.56 (m, 1 H, CH2CH2NH), 3.48 (s, 2 H, aryl-CH2),
3.64 (td, J = 10.2/2.3 Hz, 1 H, 2-H), 4.18 (ddd, J = 15.2/10.1/5.1
Hz, 1 H, 3-H), 4.33 (d, J = 2.6 Hz, 1 H, 6-H), 5.98 (s broad, 1
H, NH), 7.11 (dd, J = 8.1/1.7 Hz, 1 H, 6-H dichlorophenyl),
7.33–7.36 (m, 3 H, arom.), 7.41 (d, J = 8.1 Hz, 1 H, 5-H
dichlorophenyl), 7.76 (d, J = 8.1 Hz, 2 H, tosyl).
A
1H/1H-COSY-spectrum was recorded to assign the signals.
After irradiation at δ = 5.55 ppm (1-H) a NOE was found at δ =
1.79–1.91 ppm (8-H), 3.50–3.60 ppm (3-H), 3.58 ppm (aryl-
CH2), 7.00, 7.26, and 7.33 ppm (H arom.). The signal at δ =
5.33 ppm (1-H) was also saturated after irradiation at δ = 5.55
ppm, showing the existence of rotational isomers.– 1H NMR
(100 °C, Cl2CD-CDCl2): δ (ppm) = 1.67–2.10 (m, 6 H, 4-CH2,
7-CH2, 8-CH2 ), 3.54–3.62 (m, 2 H, 3-H), 3.58 (s, 2 H, aryl-CH2),
3.80–3.85 (m, 1 H, 6-H), 4.05–4.11 (m, 1 H, 5-H), 5.57 (s, 1 H,
1-H), 7.05 (dd, J = 8.1/2.1 Hz, 1 H, 6-H arom.), 7.31 (d, J = 2.1
Hz, 1 H, 2-H arom.), 7.37 (d, J = 8.1 Hz, 1 H, 5-H arom.).– 13
C
(+)-N-{2-[(2R,3R,6S)-3-Azido-6-methoxyoxan-2-yl]ethyl}-
2-(3,4-dichlorophenyl)acetamide (11)
NMR (CDCl3): δ (ppm) = 21.0 (C-7), 21.8 (C-7), 22.3 (C-4), 24.3
(C-4), 27.2 (C-8), 29.7 (C-8), 37.0 (C-3), 38.7 (C-3), 39.7
(aryl-CH2), 40.3 (aryl-CH2), 58.2 (C-6), 58.3 (C-6), 66.7 (C-5),
67.5 (C-5), 76.7 (C-1), 77.0 (C-1), 128.3 (C arom.), 128.3 (C
arom.), 130.6 (C arom.), 130.8 (C arom.), 130.9 (C arom.),
131.2 (C arom.), 132.7 (C arom.), 134.5 (C arom.), 168.0 (C=O),
169.1 (C=O).– 1H/13C-COSY- and 13C-DEPT-spectra were re-
corded to assign the signals.
A solution of 10 (1.03 g, 2.00 mmol) and NaN3 (1.30 g,
20.0 mmol) in DMSO (30 mL) was heated to reflux for 2.5 h.
After cooling to room temperature water (100 mL) was added
and the mixture was extracted with diethyl ether (5 × 50 mL).
The organic layer was dried (MgSO4) and concentrated in
vacuo. Colorless needles (ethyl acetate/iPr2O), mp 158 °C,
yield 495 mg (64%). The mother liquor was purified by FC
(3 cm, petroleum ether/ethyl acetate 3:7, 25 mL, Rf 0.52). The
solvent of the fractions 4–8 was evaporated in vacuo to provide
129 mg (17%) of the azide 11. Total yield 624 mg (81%).– [α]589
= +10.2 (1.16, CHCl3).– C16H20Cl2N4O3 (387.3) calcd. C 49.6
H 5.20 N 14.47 found C 49.6 H 5.32 N 14.41.– MS (EI): m/z =
359, 357, 355 (M+–OCH3).– IR (KBr): ν = 3297 (N-H), 2108 (N3),
1645 (C=O), 1558 (amide II), 1126 (C-O), 1043 cm–1 (C-O).–
1H NMR (CDCl3): δ (ppm) = 1.51–1.56 (m, 1 H, 5-H), 1.57–1.61
(m, 1 H, CH2CH2NH), 1.70–1.78 (m, 1 H, CH2CH2NH), 1.79–
1.89 (m, 2 H, 4-H, 5-H), 2.03–2.08 (m, 1 H, 4-H), 3.00–3.08 (m,
1 H, CH2CH2NH), 3.11 (s, 3 H, OCH3), 3.38 (s broad, 1 H, 3-H
equatorial), 3.42 (s, 2 H, aryl-CH2), 3.57–3.61 (m, 1 H,
CH2CH2NH), 3.75 (dd, J = 9.9/4.7 Hz, 1 H, 2-H), 3.46 (s, 1 H,
6-H), 5.86 (s broad, 1 H, NH), 7.05 (dd, J = 8.3/1.9 Hz, 1 H, 6-H
arom.), 7.30 (d, J = 1.7 Hz, 1 H, 2-H arom.), 7.35 (d, J = 8.1 Hz,
1 H, 5-H arom.).– 1H NOE (PD = 8, IRATN = 300): After
irradiation at δ = 3.75 ppm (2-H) a NOE was found at δ =
1.57–1.61 ppm (CH2CH2NH), 1.70–1.78 ppm (CH2CH2NH),
2.03–2.08 ppm (4-H), 3.11 ppm (OCH3), and 3.38 ppm (3-H).–
(+)-{(1R,5R,6R)-2-[2-(3,4-Dichlorophenyl)acetyl]-9-oxa-2-
azabicyclo[3.3.1]nonan-6-yl}-ammonium chloride
(18a.HCl)
A mixture of 17 (269 g, 0.76 mmol), Pd/C (10%, 50 mg), and
ethyl acetate (25 mL) was hydrogenated (1 bar) for 3 h at room
temperature. It was filtered and the solvent was evaporated in
vacuo. Colorless oil of 18a (base), yield 245 mg (98%).– 1H
NMR spectrum of the primary amine 18a (CDCl3): δ (ppm) =
1.46–2.04 (m, 6 H, 4-CH2, 7-CH2, 8-CH2), 3.08–3.15 (m, 1 H,
6-H), 3.38–3.41 (m, 0.31 H, 3-H), 3.42–3.60 (m, 2 × 0.69 H, 2
× 3-H), 3.58 (s, 2 H, aryl-CH2), 3.80–3.84 (m, 0.31 H, 5-H), 3.93
(dt, J = 8.8/4.3 Hz, 0.69 H, 5-H), 4.13–4.17 (m, 0.31 H, 3-H),
5.32 (d, J = 4.7 Hz, 0.31 H, 1-H), 5.55 (d, J = 3.0 Hz, 0.69 H,
1-H), 7.01 (dd, J = 8.1/2.1 Hz, 1 H, 6-H arom.), 7.27 (d, J = 2.1
Hz, 1 H, 2-H arom.), 7.32 (d, J = 8.1 Hz, 0.31 H, 5-H arom.),
7.33 (d, J = 8.1 Hz, 0.69 H, 5-H arom.). Signals for the NH2-pro-
tons were not found. Ratio of rotational isomers 69:31.
A
1H/1H-COSY-spectrum was recorded to assign the signals.
(+)-1-[(1R,5R,6R)-6-Azido-9-oxa-2-azabicyclo[3.3.1]-
For the preparation of 18a.HCl the crude amine 18a (245 mg,
0.74 mmol) was dissolved in Et2O (10 mL), a saturated solution of
gaseous HCl in Et2O was added and the precipitate was collected.
Colorless solid (methanol/ethyl acetate), mp 237 °C (decomposi-
tion), yield 147 mg (54%). Concentration of the mother liquor gave
further 112 mg (41%) of 18a.HCl. Total yield 259 mg (95%).– [α]589
= +14.2 (0.25, CH3OH).– C15H19Cl3N2O2 (365.7) calcd. C 49.3 H
5.24 N 7.66 found C 49.2 H 5.26 N 7.69.– MS (CI): m/z = 333, 331,
329 (MH+–HCl).– IR (KBr): ν = 3426 (NH3+), 1637 (C=O),
1025 cm–1 (C-O).
nonan-2-yl]-2-(3,4-dichlorophenyl)ethan-1-one (17)
A solution of 11 (60.5 mg, 0.16 mmol) and p-toluenesulfonic
acid (29.7 mg, 0.16 mmol) in 1,2-dichloroethane (7 mL) was
heated to reflux for 55 min. A saturated solution of NaHCO3
(7 mL) was added, the organic layer was separated and the
aqueous layer was extracted with CHCl3 (3 × 5 mL). The
combined organic layers were dried (MgSO4), concentrated in
vacuo and the residue was purified by FC (2 cm, petroleum
ether/ethyl acetate 5:5 (200 mL) then petroleum ether/ethyl
acetate 3:7, 30 mL, Rf 0.43 (petroleum ether/ethyl acetate 5:5).
The solvent of the fractions 3–5 was removed in vacuo. Color-

Arch. Pharm. Pharm. Med. Chem. 2001, 334, 284–290
Amino-substituted morphan analogues 289
(+)-N-Benzyl-N-{(1R,5R,6R)-2-[2-(3,4-dichlorophenyl)-
acetyl]-9-oxa-2-azabicyclo[3.3.1]nonan-6-yl}ammonium
sulfate ((18b)2.H2SO4)
(+)-2-(3,4-Dichlorophenyl)-1-[(1R,5R,6R)-6-(pyrrolidin-1-
yl)-9-oxa-2-azabicyclo[3.3.1]nonan-2-yl]ethan-1-one (18d)
18a.HCl (102.6 mg, 0.28 mmol) was dissolved in a mixture of
THF (20 mL), water (20 mL) and acetic acid (20 mL). Sub-
sequently, 2,5-dimethoxytetrahydrofuran (48.2 mg, 0.36 mmol)
and NaBH3CN (176.3 mg, 2.81 mmol) were added and the
reaction mixture was heated to reflux for 4 h. The mixture was
concentrated to a volume of about 10 mL, then 2 N NaOH
(40 mL) and CH2Cl2 (50 mL) were added, the aqueous layer
was separated and extracted with CH2Cl2 (3 × 50 mL). The
combined organic layers were dried (MgSO4), concentrated in
vacuo, and the residue was purified by FC (2 cm,
CH2Cl2/methanol 95:5, 20 mL, Rf 0.38). Fractions 6–10 con-
tained 18d. Colorless oil, yield 24.2 mg (23%).– [α]589 = +13.8
(0.84, CHCl3).– C19H24Cl2N2O2 (383.3) calcd. C 59.5 H 6.31 N
7.31 found C 59.8 H 6.57 N 7.15.– MS (EI): m/z = 386, 384, 382
(M+).– IR (film): ν = 1635 (C=O), 1047 cm–1 (C-O).– 1H NMR
(CDCl3): δ (ppm) = 1.47–2.05 (m, 10 H, CH2CH2 (pyrrolidine),
4-CH2, 7-CH2, 8-CH2 ), 2.26–2.49 (m, 4 H, CH2NCH2 (pyrrolid-
ine)), 3.18–3.79 (m, 2.74 H, 3-H, 6-H), 3.52 (s, 2 H, aryl-CH2),
3.98–4.01 (m, 0.26 H, 5-H), 4.10 (dt, J = 8.6/4.3 Hz, 0.74 H,
5-H), 4.20–4.25 (m, 0.26 H, 3-H), 5.32 (d, J = 4.7 Hz, 0.26 H,
1-H), 5.59 (d, J = 3.0 Hz, 0.74 H, 1-H), 7.01 (dd, J = 8.1/2.1 Hz,
1 H, 6-H arom.), 7.26 (d, J = 2.1 Hz, 1 H, 2-H arom.), 7.32 (d,
J = 8.1 Hz, 1 H, 5-H arom.). Ratio of rotational isomers 74:26.
A mixture of 18a.HCl (50 mg, 0.14 mmol), benzaldehyde
(21.7 mg, 0.20 mmol), abs. CH2Cl2 (5 mL), Na2SO4 (100 mg,
0.7 mmol) and Na2CO3 (50 mg, 0.5 mmol) was stirred for 72 h
at room temperature. Then, it was filtered and the filtrate was
concentrated in vacuo. The residue (56.9 mg, 0.14 mmol) was
dissolved in methanol (5 mL) and after addition of NaBH4
(15.5 mg, 0.4 mmol) the mixture was stirred for 11 h at room
temperature. After concentration in vacuo 2 N NaOH (5 mL) and
CH2Cl2 (5 mL) were added, the aqueous layer was separated
and extracted with CH2Cl2 (3 × 5 mL). The combined organic
layers were dried (MgSO4), concentrated in vacuo and the
residue was purified by FC (3 cm, CH2Cl2/methanol 95:5,
30 mL, Rf 0.52) to provide the benzylamine 18b. Colorless oil,
yield 40.7 mg (71%).– 1H NMR spectrum of the benzylamine
18b (CDCl3): δ (ppm) = 1.43–2.11 (m, 6 H, 4-CH2, 7-CH2, 8-CH2
), 3.01 (dt, J = 11.5/4.7 Hz, 0.76 H, 6-H), 3.09–3.14 (m, 0.24 H,
6-H), 3.37–3.83 (m, 1.76 H, 3-H), 3.63 (s, 2 H, aryl-CH2), 3.75
(s, 2 × 0.76 H, C6H5-CH2), 3.76 (s, 2 × 0.24 H, C6H5-CH2), 4.04
(t, J = 5.1 Hz, 0.24 H, 5-H), 4.12 (dt, J = 8.5/4.1 Hz, 0.76 H,
5-H), 4.23–4.30 (m, 0.24 H, 3-H), 5.39 (d, J = 4.3 Hz, 0.24 H,
1-H), 5.62 (d, J = 3.4 Hz, 0.76 H, 1-H), 7.07 (dd, J = 8.1/2.1 Hz,
1 H, 6-H dichlorophenyl), 7.23–7.40 (m, 7 H, arom.). The signal
for the NH-proton was not found. Ratio of rotational isomers
76:24.
[11]
Receptor binding studies
General: Filter: Whatman GF/C, presoaked in buffer for 1–1.5 h
before use.– Filtration was performed with a Brandel 24-well
cell harvester.– Scintillation cocktail: Rotiszint eco plus (Carl
Roth GmbH).– Liquid scintillation analyzer: TriCarb 1600 (Can-
berra Packard), counting efficiency 55%.– All experiments were
carried out in triplicates.– IC50 values were determined with the
program Inplot 4.0 (GraphPad Software TM) by nonlinear re-
gression analysis.– Ki values were calculated according to
Cheng and Prusoff[14].– For compounds with high affinity (low
Ki values) mean values ± SEM from three independent experi-
ments are given.
(18b)2.H2SO4 was prepared by addition of a stoichiometric
amount of conc. H2SO4 (4.4 mg, 0.044 mmol) to a solution of
18b (36.2 mg, 0.09 mmol) in Et2O (10 mL). Colorless solid (ethyl
acetate/methanol) mp 178 °C (decomposition), yield 21.9 mg
.
(54%).– [α]589 = +24.6 (0.49, CH3OH).– (C22H24Cl2N2O2)2
H2SO4 (936.7) calcd. C 56.4 H 5.38 N 5.98 S 3.42 found C 56.5
H 5.52 N 5.72 S 3.36.– MS (CI): m/z = 423, 421, 419 (MH+–
H2SO4).– IR (KBr): ν = 3318 (R2NH2+), 1640 (C=O), 1044 cm–1
(C-O).
(+)-N-{(1R,5R,6R)-2-[2-(3,4-Dichlorophenyl)acetyl]-9-oxa-
2-azabicyclo[3.3.1]nonan-6-yl}-N,N-dimethylammonium
chloride (18c.HCl)
Investigation of the µ-receptor affinity[11]
The test was performed with the radioligand [3H]-DAMGO
(2053.5 GBq/mmol; Du Pont de Nemours) and bovine striatal
membrane preparations as receptor material. Buffer: Tris HCl
50 mM, pH = 7.5. Nonspecific binding was determined with 1
µM Naloxon.
A solution of 18a.HCl (101 mg, 0.28 mmol), formaldehyde (40%
in water, 0.2 mL, 2.6 mmol) and NaBH3CN (173.4 mg, 2.76
mmol) in methanol (10 mL) was stirred at room temperature for
6 h. 2 N NaOH (10 mL) was added and the mixture was
extracted with CH2Cl2 (5 × 10 mL). The organic layer was dried
(MgSO4), concentrated in vacuo and the residue was purified
by FC (2 cm, ethyl acetate/methanol/conc. NH3 85:10:5, 10 mL,
Rf 0.57). The solvent of the fractions 4–6 was evaporated in
vacuo to provide the dimethylamine 18c. Colorless oil, yield
76.3 mg (77%).– 1H NMR spectrum of the dimethylamine 18c
(CDCl3): δ (ppm) = 1.46–2.41 (m, 6 H, 4-CH2, 7-CH2, 8-CH2 ),
2.22 (s, 3 H, N(CH3)2), 2.24 (s, 3 H, N(CH3)2), 3.38–3.51 (m,
1 H, 6-H), 3.55–3.61 (m, 0.78 H, 3-H), 3.64 (s, 2 H, aryl-CH2),
3.63–3.67 (m, 1 H, 3-H), 4.14–4.17 (m, 0.22 H, 5-H), 4.24–4.30
(m, 1 H, 3-H, 5-H), 5.38 (d, J = 4.3 Hz, 0.22 H, 1-H), 5.62 (d, J
= 3.5 Hz, 0.78 H, 1-H), 7.08 (dd, J = 8.5/2.1 Hz, 1 H, 6-H arom.),
7.34 (d, J = 2.1 Hz, 1 H, 2-H arom.), 7.38 (d, J = 8.1 Hz, 1 H,
5-H arom.). Ratio of rotational isomers 78:22.
Performance: According to ref.[11a]
.
Investigation of the κ-receptor affinity[11]
The test was performed with the radioligand [3H]-U 69,593
(1753 GBq/mmol; Du Pont de Nemours) and bovine striatal
membrane preparations as receptor material. Buffer: Tris HCl
50 mM, pH = 7.5. Nonspecific binding was determined with 1
µM U 50,488.
Performance: According to ref.[11a]
.
References
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0.097 mmol) was dissolved in Et2O and a saturated solution of
gaseous HCl in Et2O was added. Colorless solid (metha-
nol/ethyl acetate), mp 167 °C (decomposition), yield 20.6 mg
(54%).– [α]589 = +36.3 (0.84, CHCl3).– C17H23Cl3N2O2 (393.7)
calcd. C 51.8 H 5.89 N 7.11 found C 51.6 H 6.09 N 7.04.– MS
(CI): m/z = 361, 359, 357 (MH+–HCl).– IR (KBr): ν = 3332
(R3NH+), 1644 (C=O), 1033 cm–1 (C-O).
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