Synthesis and structure-activity relationships of 6,7-benzomorphan derivatives as antagonists of the NMDA receptor-channel complex

Article abstract of DOI:10.1021/jm970131j

We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA) receptor-channel complex in vitro and in vivo. The ability of the compounds

Full text of DOI:10.1021/jm970131j

2922
J . Med. Chem. 1997, 40, 2922-2930
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of 6,7-Ben zom or p h a n
Der iva tives a s An ta gon ists of th e NMDA Recep tor -Ch a n n el Com p lex
Matthias Grauert,*,† Wolf Dietrich Bechtel,‡ Helmut A. Ensinger,‡ Herbert Merz,† and Adrian J . Carter‡
Departments of Medicinal Chemistry and Biological Research, Boehringer Ingelheim KG,
D-55216 Ingelheim am Rhein, Federal Republic of Germany
Received March 4, 1997X
We have synthesized a series of stereoisomeric 6,7-benzomorphan derivatives with modified
N-substituents and determined their ability to antagonize the N-methyl-D-aspartate (NMDA)
receptor-channel complex in vitro and in vivo. The ability of the compounds to displace [3H]-
MK-801 from the channel site of the NMDA receptor in rat brain synaptosomal membranes
and to inhibit NMDA-induced lethality in mice was compared with their ability to bind to the
µ opioid receptor. Examination of structure-activity relationships showed that the absolute
stereochemistry is critically important for differentiating these two effects. (-)-1R,9â,2′′S-
enantiomers exhibited a higher affinity for the NMDA receptor-channel complex than for the
µ opioid receptor. The aromatic hydroxy function was also found to influence the specificity of
the compounds. Shift of the hydroxy group from the 2′-position to the 3′-position significantly
increased the affinity for the NMDA receptor-channel complex and considerably reduced the
affinity for the µ opioid receptor. From this series of 6,7-benzomorphan derivatives, the
compound 15cr ‚HCl [(2R)-[2R,3(R*),6R]-1,2,3,4,5,6-hexahydro-3-(2-methoxypropyl)-6,11,11-
trimethyl-2,6-methano-3-benzazocin-9-ol hydrochloride] was chosen as the optimum candidate
for further pharmacological investigations.
In tr od u ction
depolarizes. This site, or at least sites close to the Mg2+
site, can be blocked by various synthetic compounds,
such as MK-801,10 PCP,11 ketamine,12 or CNS 1102,13
or benzomorphans, such as (()-SKF 10,04714 (Figure 1).
All of these so-called open channel blockers are able to
displace [3H]MK-801 from its binding site at the NMDA
receptor-channel complex. We assume that noncom-
petitive blockers of the NMDA receptor-channel com-
plex possess two inherent advantages compared with
blockers of the competitive site. First, by definition,
these compounds do not have to compete with the
endogenous agonist when the glutamatergic system is
overstimulated in a situation such as stroke, trauma,
or epilepsy. Thus, the dose of a noncompetitive antago-
nist does not have to be increased to secure an effect in
the damaged brain region. Second, potent open channel
blockers produce the block of the channel complex in a
use-dependent manner, i.e. the onset of the block
depends on agonist application.15 This means that
compounds which act with a pronounced use depen-
dency will have a preference for the damaged brain
region where the overstimulation occurs. However,
some of the aforementioned open channel blockers
demonstrate a lack of specificity for the NMDA receptor
complex16 or, as with MK-801, exhibit a very long
duration of action.17 Due to serious side effects of
NMDA channel blockers, such as neuronal vacuoliza-
tion,18 the long duration of action may preclude their
use in the clinic. Therefore, the development of potent
use-dependent, short-acting blockers of the NMDA
receptor-channel complex seems to be an interesting
alternative to overcome the problems of the other
compounds.
The amino acids glutamate and aspartate play a key
role as excitatory neurotransmitters in the central
nervous system (CNS).1 However, overstimulation by
these excitatory amino acids can cause neuronal cell
death.2 Microdialysis studies in animals have demon-
strated that large amounts of glutamate and aspartate
are released during ischemia.3 Thus, it seems likely
that this mechanism is very important in the patho-
physiology of acute and chronic neurological disorders
such as stroke, trauma, epilepsy, Alzheimer’s disease,
Huntington’s disease, or amyotrophic lateral sclerosis
(ALS).4 The effects of excitatory amino acids are medi-
ated by glutamate receptors which can be classified into
ionotropic and metabotropic subtypes. The N-methyl-
D-aspartate (NMDA) receptor is currently the most
widely studied subtype of the ionotropic glutamate
receptors.5 In addition, two ionotropic non-NMDA
receptor subtypes, the R-amino-3-hydroxy-4-methylisox-
azolepropionic acid (AMPA) and kainate (KA) receptor,
have been identified.6 Blockade of either NMDA or non-
NMDA receptors can protect neurons against ischemic
brain damage and traumatic brain injury.7
The NMDA receptor-channel complex consists of a
voltage-dependent channel which is permeable to Ca2+
and Na+ in a ratio of five to one.8 Furthermore, there
are at least three regulatory domains.9 Beside the
recognition site of the neurotransmitters glutamate and
aspartate or the synthetic compound NMDA, a modula-
tory binding site for glycine also exists. Both glutamate
and glycine must be present for activation of the NMDA
receptor channel. A further site is located in the
channel pore which is blocked by Mg2+ under resting
conditions. However, this block is removed if the cell
The racemate (()-SKF 10,047 is the prototypic drug
for the so-called σ site.19 It is now known that (()-SKF
10,047 binds to different receptor sites, and depending
on its absolute stereochemistry, the enantiomers exhibit
moderate receptor preference: The (-)-enantiomer binds
* Author to whom correspondence should be addressed.
† Department of Medicinal Chemistry.
‡ Department of Biological Research.
X Abstract published in Advance ACS Abstracts, August 1, 1997.
S0022-2623(97)00131-3 CCC: $14.00 © 1997 American Chemical Society

Antagonists of the NMDA Receptor-Channel Complex
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2923
In the case of the hydroxy derivatives 4k r and 4k s, the
N-substituent was introduced by using an epoxide as
the alkylating agent (method C).24
The synthesis of the 5,9,9-trimethyl-6,7-benzomor-
phan derivatives 14, 15, and 16 is illustrated in Scheme
2. Unsubstituted or methoxy-substituted benzyl cya-
nide 5 was treated with ethyl 2-bromoisobutyrate 6 in
a Reformatsky-type reaction. The intermediate imine
was reduced with NaBH3CN and subsequently con-
verted into the diester derivative 8 by a Michael-type
reaction with ethyl acrylate. Dieckmann condensation
and subsequent decarboxylation with NaOH yields the
piperidone derivative 9. Wittig reaction with methyl-
triphenylphosphonium bromide and KOtBu followed by
formylation of the nitrogen of 11 with n-butyl formate
and cyclization with HBr provided the desired nor
compounds of the benzomorphan derivatives 12 as
racemic mixtures. In the case of 3-methoxy-substituted
benzyl cyanide, we obtained a 2:1 mixture of the
3′-hydroxy-5,9,9-trimethyl-6,7-benzomorphan and the
1′-hydroxy-5,9,9-trimethyl-6,7-benzomorphan which can
be separated by column chromatography. Introduction
of the N-substituent was carried out as described for
the 5,9-dimethyl-2′-hydroxy-6,7-benzomorphan deriva-
tives. Due to the chiral N-substituent, it was possible
to separate the diastereomeric benzomorphan deriva-
tives 15 and 16 by column chromatography. Configu-
rational assignment follows the general observation that
the (-)-enantiomers of the 5,9-dimethyl-2′-hydroxy-6,7-
benzomorphan have the 1R-configuration. Single-
crystal X-ray crystallography of the (-)-enantiomer 15cr
was performed and proved the assumed absolute con-
figuration to be (-)-1R,2′′R (Figure 2).
F igu r e 1. Open channel blockers of the NMDA receptor-
channel complex.
preferentially to the µ and κ opiate receptors, whereas
the (+)-enantiomer exhibits the higher specificity for the
σ site. Both enantiomers bind to the NMDA receptor-
channel complex with similar affinities.20
We now report on the synthesis and structure-
activity relationships (SAR) of stereoisomeric 6,7-ben-
zomorphan derivatives. Starting with the enantiomers
of SKF 10,047 and under consideration of the absolute
and relative stereochemistry of the 6,7-benzomorphan
system, we tested a series of compounds with modified
N-substituents. By modification of the substitution
pattern of the 6,7-benzomorphan system, we were able
to optimize the affinity and specificity of compounds for
the NMDA receptor-channel complex. During these
studies, we discovered (2R)-[2R,3(R*),6R]-1,2,3,4,5,6-
hexahydro-3-(2-methoxypropyl)-6,11,11-trimethyl-2,6-
methano-3-benzazocin-9-ol hydrochloride (15cr ‚HCl).
This compound has been selected for further assessment
of neuroprotective properties.21
In order to remove the phenolic hydroxy group in
15br and 15bs, we treated these compounds with
5-chloro-1-phenyl-1H-tetrazole to give the corresponding
phenyltetrazolyl ethers, which were subsequently hy-
drogenated to yield 15er and 15es, respectively (Scheme
3).26
Biologica l Activity a n d Discu ssion
All compounds were tested for binding affinity at the
NMDA receptor-channel complex by their ability to
inhibit [3H]MK-801 binding in rat brain cortical mem-
branes. The antagonism of the NMDA-induced lethality
in mice was used to assess NMDA antagonistic activity
in vivo. Furthermore, the ability to displace [3H]-
dihydromorphine (DHM) was used to determine the
specificity of the compounds versus the µ opioid receptor.
The results are summarized in Tables 2-4. In addition,
the affinity at the NMDA receptor complex was cor-
related with the NMDA antagonistic activity in vivo
(Figure 3). The correlation demonstrates (r ) 0.57, p
< 0.01) that the affinity at the MK-801 binding site is
an important factor determining the in vivo activity of
these compounds. However, additional properties might
also influence the in vivo activity. For instance, com-
pounds showing an in vivo protection lower than the
average could have pharmacokinetic disadvantages,
whereas compounds with in vivo protection higher than
the average might have superior pharmacokinetic prop-
erties or an additional mechanism of action.
Ch em istr y
The 5,9-dimethyl-2′-hydroxy-6,7-benzomorphan (nor-
metazocine) derivatives were synthesized starting from
the R-epimers (+)-(1S,5S,9S)- and (-)-(1R,5R,9R)-
normetazocine as well as from the â-epimers (+)-
(1S,5S,9R)- and (-)-(1R,5R,9S)-normetazocine. Several
of the compounds discussed here are already outlined
in the literature.25 New compounds are listed in Table
1. As indicated in Scheme 1 and the tables, compounds
are assigned to a code of a number and letter depending
on the stereochemistry of the normetazocine and the
side chain. A second letter indicates the stereochem-
istry of the side chain: R-stereochemistry of the side
chain is indicated by r, S-stereochemistry is indicated
by s (example in Scheme 1).
The synthesis and optical resolution of the normeta-
zocine compounds are described in the literature.22 The
N-substituted derivatives were synthesized either di-
rectly by alkylation of the nor compounds with ap-
propriate alkyl halides (method A) or by acylation with
suitable acid chlorides and subsequent reduction of the
amides with LiAlH4 (method B). The corresponding acid
derivatives were prepared according to the literature.23
Both enantiomers of SKF 10,047 (1a and 2a , Table
2) exhibit moderate affinity for the NMDA receptor
channel complex. In contrast, the (-)-enantiomer of
SKF 10,047 (2a ) showed an affinity for the µ opioid

2924 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Grauert et al.
Ta ble 1. Physical Properties of New N-Substituted Normetazocine Derivatives
b
compd
R
stereo
method
mp, °Ca
[R]20
% yieldc
D
3b‚HCl
4b‚HCl
1cr ‚HCl
1cs‚HCl
3cr ‚HCl
3cs‚HCl
4cr ‚HCl
4cs‚HCl
4e‚HCl
4fr ‚HCl
4fs‚HCl
4gr ‚HCl
4gs‚HCl
4h r ‚HCl
4h s‚HCl
4ir ‚HCl
4is
Pr
Pr
(+)-1S,9â
A
A
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
C
C
>300
>300
141
119
254
270
270
243
227
252
265
245
226
235
237
229
oil
+82.3
-81.4
+57.9
+85.7
-57.5
nd
-83.2
-56.5
nd
+86.53
-39.7
-112.6
-53.9
nd
76
74
71
73
83
74
74
71
78
74
79
85
82
76
73
77
68
68
50
(-)-1R,9â
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2C(OMe)Me2
CH2CH(OEt)Me
CH2CH(OEt)Me
CH2CH(SMe)Me
CH2CH(SMe)Me
CH2CH(OMe)Et
CH2CH(OMe)Et
CH2CH(OMe)Pr
CH2CH(OMe)Pr
CH2CH(OH)Me
CH2CH(OH)Me
(+)-1S,9R,2′′R
(+)-1S,9R,2′′S
(+)-1S,9â,2′′R
(+)-1S,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
nd
-90.0
nd
-97.1
-57.1
4k r ‚HCl
4k s‚HCl
270
248
a
b
Melting points are uncorrected. Optical rotation [c 1.0, MeOH]. c Yields were not optimized.
Sch em e 1
with an ID50 of 0.6 mg/kg, although it did not differ
significantly from the potency of 4cr . Evaluation of the
affinity for the [3H]DHM binding site revealed that 4cs
had a higher affinity for the µ opioid binding site than
for the NMDA channel. In contrast, the (-)-1R,9â,2′′R-
stereoisomer 4cr was the first compound with a higher
affinity for the NMDA receptor than for the µ opioid
receptor.
Further variations of the side chain of normetazocine
revealed that the 2-methoxypropyl substituent seems
to be an optimized structural element at the NMDA
receptor binding site. A 3-methoxypropyl (2d ), 2-meth-
oxy-2-methylpropyl (2e, 4e), 2-ethoxypropyl (2fr , 2fs,
4fr , and 4fs), 2-methoxypentyl (4ir , 4is), or 2-hydroxy-
propyl substitution (4k r , 4k s) of the normetazocine
resulted in compounds with diminished NMDA receptor
affinity. Only the (-)-1R,9â,2′′S-enantiomers 4h s and
4gs of the (2-methoxybutyl)- or [2-(methylthio)propyl]-
normetazozine have a comparable affinity for the
NMDA receptor site. However, the in vivo NMDA-
antagonistic activity of the last mentioned compound
was markedly reduced. This is probably due to a high
metabolic vulnerability of the thioether functionality.
Because â-epimers of the normetazocine derivatives
have a higher affinity for the NMDA receptor site than
the R-epimers, we investigated the 5,9,9-trimethyl-6,7-
benzomorphan derivatives 14 (Table 3). In addition to
the 9,9-dimethyl substitution, we evaluated the influ-
ence of the aromatic hydroxy function. The 1′-, 2′-, and
3′-hydroxy derivatives 14a , 14b, and 14c showed a
significant increase of the affinity to the NMDA receptor
site compared with SKF 10,047. Conversely, the 4′-
hydroxy derivative 14d showed only a slight improve-
ment of the NMDA receptor affinity. The in vivo data
confirmed this observation. 14a , 14b, and 14c exhibited
comparable potency in the antagonism of the NMDA-
induced lethality in mice, whereas 14d had a diminished
activity. These data indicate that an introduction of a
second methyl substituent in the 9-position of the
normetazocine improves the affinity for the NMDA
receptor site, whereas the aromatic hydroxy function
does not appear to be as important for activity at the
NMDA receptor. Moreover, a hydroxy function in the
4′-position decreased the NMDA affinity probably due
to steric or electronic repulsion with the receptor binding
site.
receptor site almost 2000 times higher than for the
NMDA site. Comparison of the propyl analogues of SKF
10,047 (1b and 2b) and the corresponding â-epimers (3b
and 4b) revealed an increased affinity of the (-)-
enantiomers for the NMDA receptor. The (-)-1R,9â-
epimer 4b possessed the highest affinity. This obser-
vation could be validated by comparing the eight
stereoisomers of the 2-methoxypropyl-substituted
normetazocine derivatives (1cr to 4cs). Again the
NMDA receptor affinity resided in the (-)-1R-enanti-
omers and the 9â-epimers showed the higher affinity
compared with the R-epimers. The stereochemistry of
the side chain seemed to have a minor influence on the
NMDA receptor affinity. However, the (-)-1R,9â,2′′S-
enantiomer 4cs showed the highest affinity for the
NMDA receptor site with a Ki of 35 nmol/L. Compari-
son of the ability of these stereoisomers to antagonize
NMDA-induced lethality in mice confirmed this obser-
vation. Again 4cs exhibited the highest potency in vivo

Antagonists of the NMDA Receptor-Channel Complex
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2925
Sch em e 2a
a
Reagents: (a) Zn, CH2Cl2; (b) NaBH3CN, EtOH; (c) CH2dCHCOOEt, EtOH; (d) KOtBu, C6H5CH3; (e) NaOH, EtOH; (f) Ph3P-CH3Br,
KOtBu, THF; (g) HCOOnBu, C6H5CH3; (h) HBr; (i) CH2dCHCH2Br, KHCO3, DMF; (j) R′′-COCl, Et3N, CH2Cl2; (k) LiAlH4, THF; (l)
separation by column chromatography.
F igu r e 2. X-ray structure of compound 15cr ‚HCl (thermal
ellipsoids). Anisotropic displacement ellipsoids are drawn at
the 50% probability level.
Sch em e 3a
F igu r e 3. Correlation between the affinity of various 6,7-
benzomorphan derivatives at the NMDA receptor-channel
complex and their ability to inhibit NMDA-induced lethality
in mice.
the stereochemistry of the compounds, we obtained very
potent blockers of the NMDA receptor channel. Again,
the highest affinity resided in the (-)-1R,2′′S-enanti-
omer, whereas the position of the aromatic hydroxy
function had only a minor influence on receptor affinity.
Thus, we synthesized the nonhydroxylated compounds
15er and 15es which also had affinity comparable to
those of the hydroxylated compounds. However, the
comparison of the in vivo data of these compounds
revealed a decreased antagonistic activity perhaps due
a
Reagents: (a) 5-chloro-1-phenyl-1H-tetrazole, K2CO3, acetone;
to pharmacokinetic disadvantages.
The evaluation of the 2-methoxypropyl-substituted
(b) H2, Pd/C, AcOH.
The next step was to evaluate the optimized 2-meth-
oxypropyl side chain in the case of the 5,9,9-trimethyl-
6,7-benzomophan derivatives (Table 4). Depending on
5,9,9-trimethyl-6,7-benzomorphan derivatives in the
[3H]DHM binding assay revealed that the aromatic
hydroxy function has a critical influence on the µ opioid

2926 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Grauert et al.
Ta ble 2. Receptor Binding Data and NMDA Lethality Data for N-Substituted Normetazozine Derivatives
Ki (nmol/L)
compd
R
stereo
[3H]MK-801a
[3H]DHMb
NMDA letc ID50 (mg/kg)
1a
2a
1b
3b
2b
4b
1cr
1cs
3cr
3cs
2cr
2cs
4cr
4cs
2d
CH2CHdCH2
CH2CHdCH2
Pr
Pr
Pr
(+)-1S,9R
1210 [1075; 1352]
1500 [1355; 1648]
2850 [3234; 2463]
43650 [47300; 40000]
588 [716; 460]
8.2 [3.3-25.0]
(-)-1R,9R
>30
(+)-1S,9R
>30
nd
>30
nd
(+)-1S,9â
(-)-1R,9R
Pr
(-)-1R,9â
373 [299; 447]
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH(OMe)Me
CH2CH2CH2OMe
CH2C(OMe)Me2
CH2C(OMe)Me2
CH2CH(OEt)Me
CH2CH(OEt)Me
CH2CH(OEt)Me
CH2CH(OEt)Me
CH2CH(SMe)Me
CH2CH(SMe)Me
CH2CH(SMe)Me
CH2CH(SMe)Me
CH2CH(OMe)Et
CH2CH(OMe)Et
CH2CH(OMe)Pr
CH2CH(OMe)Pr
CH2CH(OH)Me
CH2CH(OH)Me
(+)-1S,9R,2′′R
(+)-1S,9R,2′′S
(+)-1S,9â,2′′R
(+)-1S,9â,2′′S
(-)-1R,9R,2′′R
(-)-1R,9R,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9R
9550 [8520; 10585]
22000 [22744; 21273]
76600 [78250; 74985]
>100000 (3)
248 [221; 275]
234 [248; 221]
18400 [19802; 17003]
5300 [5758; 4838]
34800 [35929; 33726]
66600 [70451; 62701]
146 [137; 155]
1.0 ( 0.4 (4)
212 [162; 262]
3.5 [1.88; 5.2]
>30
>30
>30
nd
7.2 ( 1.7 (4)
2.3 [0.6-4.7] (2)
0.9 ( 0.3 (4)
0.6 ( 0.2 (3)
>30
195 ( 33.6 (4)
35.7 [41.1; 30.3]
991 [960; 1022]
281 [250; 312]
2e
4e
(-)-1R,9R
(-)-1R,9â
5.6 ( 1.0 (3)
2.9
221 [235; 206]
5.5 [2.2-13.4]
nd
nd
nd
nd
nd
1.7 [0.6-4.4]
nd
2.1 [0.9-5.8]
3.0 [1.2-5.9]
0.3 ( 0.1 (3)
2fr
2fs
4fr
4fs
2gr
2gs
4gr
4gs
4h r
4h s
4ir
4is
4k r
4k s
(-)-1R,9R,2′′R
(-)-1R,9R,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9R,2′′R
(-)-1R,9R,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
(-)-1R,9â,2′′R
(-)-1R,9â,2′′S
1840 [1870; 1810]
1150 [1600; 709]
1290 [1390; 1180]
1260 [1540; 989]
1090 [880; 1300]
223 [180; 265]
406 [344; 467]
83 [62.7; 103]
557 [510; 603]
66 [41.0; 90.5]
7.7 [7.0; 8.4]
3.2 [3.0; 3.3]
236 [251; 220]
97 [115; 78.5]
1840 [880; 2800]
490 [490; 490]
425 [499; 350]
nd
nd
2340 [2580; 2100]
a
Inhibition of [3H]MK-801 binding at rat brain cortical membranes. The results are the mean of two different experiments [single
b
data in brackets] or the mean ( SEM of three to four different experiments (number of experiments in brackets). Inhibition of
[3H]dihydromorphine binding at rat brain cortical membranes. c The ID50 values represent the effective dose at which half of the mice
were protected against the lethality induced by 200 mg/kg NMDA. The results are calculated by log-probit analysis from four different
doses [confidence intervals in brackets] or calculated as the mean ( SEM of up to four independent experiments (number of experiments
in brackets). nd represents not determined.
Ta ble 3. Receptor Binding Data and NMDA Lethality Data for
N-Allyl-9,9-dimethyl-6,7-benzomorphan Derivatives
Benzomorphan derivatives, which have been used for
decades in the treatment of pain, have favorable phar-
[3H]MK-801a
NMDA letc
macokinetic properties. They are readily absorbed and
have a fast onset of action. They have also a short half-
life after parenteral administration.27 In the case of
15cr this short half-life could be confirmed by examin-
ing the duration of action in the NMDA-induced lethal-
ity test.21 Moreover, whole-cell electrophysiological
experiments indicated that 15cr causes a pronounced
use-dependent block of the NMDA-induced current in
hippocampal neurones.28 After reaching the steady
state the compound remains in the channel for a long
period of time. Due to this use dependency, 15cr should
have a preference for brain regions where the NMDA
receptor channel is overstimulated by an increased
glutamate release as occurs in situations such as stroke.
In the damaged brain regions the compound will remain
in the channel for a long period of time, whereas in other
brain regions the compound will be eliminated rapidly.
In vivo experiments in a rat model of focal ischemia
clearly demonstrated a neuroprotective action of 15cr .29
Indeed, 15cr is currently one of the most potent NMDA
receptor antagonists in development and it has a very
promising profile.
compd substitution stereo
Ki (nmol/L)
ID50 (mg/kg)
14a
14b
14c
14d
1′-OH
2′-OH
3′-OH
4′-OH
rac
rac
rac
rac
106 [125; 87.2] 1.7 [0.6-4.7]
380 [250; 510] 4.7 ( 0.7 (3)
99 [96.5; 101]
5.0 ( 0.9 (3)
10.4 [4.5-30.0]
630 ( 100 (3)
a,c See corresponding footnotes to Table 2.
receptor binding. Shifting this group from the 2′-
position to the 3′- or 4′-position resulted in a significant
reduction of the affinity (about 10 times). Removal of
the hydroxy function resulted in a further diminution
of the affinity (about 75 times). In summary, we have
observed the following SAR: The 9,9-dimethyl substitu-
tion as well as the 2-methoxypropyl substituent seems
to be a key structural feature for high NMDA receptor
affinity, whereas the absolute stereochemistry of the
side chain and the aromatic hydroxy function have only
a minor influence. In contrast, the aromatic hydroxy
function as well as the absolute stereochemistry of the
side chain is critical for the µ opioid receptor affinity.
The stereochemistry of the benzomophan ring system
is important for both receptor assays.
Exp er im en ta l Section
On the basis of the highest NMDA receptor affinity
and the highest specificity versus the µ-opioid receptor
site as well as an optimal in vivo antagonistic activity
as criteria, we have chosen 15cr (BIII 277CL) as an
optimized candidate for further pharmacological inves-
tigations.
Ch em istr y. 1H NMR spectra were recorded with a Bruker
AM250 spectrometer. Chemical shifts are reported as δ values
(ppm) relative to internal tetramethylsilane. Melting points
were obtained in a Bu¨chi 510 apparatus and are uncorrected.
Elemental analyses were obtained from the Analytical Depart-
ment of the Boehringer Ingelheim KG. Silica gel 60, 230-

Antagonists of the NMDA Receptor-Channel Complex
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2927
Ta ble 4. Receptor Binding Data and NMDA Lethality Data for N-(2-Methoxypropyl)-6,7-benzomorphan Derivatives
Ki (nmol/L)
compd
R
stereo
[3H]MK-801a
[3H]DHMb
NMDA letc ID50 (mg/kg)
15a r
15a s
16a r
16a s
15br
15bs
16br
16bs
15cr
15cs
16cr
16cs
15er
15es
1′-OH
1′-OH
1′-OH
1′-OH
2′-OH
2′-OH
2′-OH
2′-OH
3′-OH
3′-OH
3′-OH
3′-OH
H
(-)-1R,2′′R
(-)-1R,2′′S
(+)-1S,2′′R
(+)-1S,2′′S
(-)-1R,2′′R
(-)-1R,2′′S
(+)-1S,2′′R
(+)-1S,2′′S
(-)-1R,2′′R
(-)-1R,2′′S
(+)-1S,2′′R
(+)-1S,2′′S
(-)-1R,2′′R
(-)-1R,2′′S
34 [33.3; 35.1]
15 [13.3; 15.6]
364 [385; 342]
2780 [3251; 2306]
12.4 ( 2.4 (4)
11414 [10202; 12625]
20.9 [24.6; 17.2]
nd
0.5 [0.2-1.3]
0.8 [0.4-2.5]
nd
nd
nd
108 ( 4 (4)
1.6 [1.6; 1.6]
0.7 ( 0.1 (4)
0.2 [0.1-0.7]
nd
5.6 [6.6; 4.6]
13950 [11724; 16180]
50370 [72000; 28744]
4.5 ( 0.3 (4)
14049 [13776; 14321]
6017 [8222; 3813]
3400 [3477; 3323]
18.2 [22.4; 14.0]
nd
1340 [1117; 1564]
42350 [45530; 39170]
144 [164; 124]
>30
0.4 ( 0.1 (4)
2.1 [0.9-5.8]
nd
7.1 [6.4; 7.7]
545 [561; 529]
685 [583; 788]
29.9 [30.6; 29.2]
15.8 [15.7; 15.8]
81 ( 7 (3)
6.8 [2.8-17.5]
23 ( 6 (3)
H
a-c See corresponding footnotes to Table 2.
400 mesh, was used for flash chromatography. Optical
rotations were measured on a Perkin-Elmer 241 polarimeter.
Eth yl 3-Am in o-4-(3-m eth oxyp h en yl)-2,2-d im eth ylbu -
tyr a te (7c). Trimethylsilyl chloride (230 mL) was added to a
slurry of zinc (229.3 g, 3.5 mol) in dichloromethane (3.0 L) and
stirred at ambient temperature under nitrogen. After 20 min
THF (1.1 L) was added, the slurry was heated under reflux,
and a mixture of ethyl 2-bromoisobutyrate (500 g, 2.65 mol)
and 2-methoxybenzyl cyanide (226.4 g, 1.5 mol) was added.
The mixture was heated for 1.5 h at reflux temperature, the
solution was cooled to 10 °C, excess zinc was removed by
filtration, and sodium cyanoborohydride (96.7 g, 1.5 mol) was
added. Subsequently, 300 mL of ethanol was added cautiously,
after 20 min concentrated ammonia was added, the phases
were separated, and the organic phase was washed with
ammonia and water and dried. After filtering, the solvent was
removed in vacuo to give 256.4 g (64.4%) of 7c as an oil: 1H
NMR (CDCl3) δ 1.2 (br s, 2H), 1.24 (s, 3H), 1.25 (s, 3H), 1.28
(t, 3H, J ) 7.5 Hz), 2.23 (dd, 1H, J ) 13.3, 12.0 Hz), 2.82 (dd,
1H, J ) 13.3, 3.0 Hz), 3.19 (dd, 1H, J ) 12.0, 3.0 Hz), 3.80 (s,
3H), 4.17 (q, 2H, J ) 7.5 Hz), 6.77 (m, 3H), 7.28 (m, 1H).
Eth yl 3-[[2-(Eth oxyca r bon yl)eth yl]a m in o]-4-(3-m eth -
oxyp h en yl)-2,2-d im eth ylbu tyr a te (8c). A solution of 7c
(382.2 g, 1.4 mol) and ethyl acrylate (195.4 g, 1.8 mol) in 570
mL of ethanol was heated for 7 d under reflux. The solvent
was removed in vacuo to give 469.2 g (89%) of 8c as an oil.
2-[(3-Met h oxyp h en yl)m et h yl]-3,3-d im et h yl-4-p ip er i-
d on e Hyd r och lor id e (9c‚HCl). Potassium tert-butoxide
(158.3 g, 1.4 mol) was added to a solution of 8c (469.2 g, 1.3
mol) in 7.8 L of toluene, and the mixture was heated for 40
min at reflux temperature while the formed ethanol was
distilled off. The solution was cooled to 5 °C, and 1.2 L of
cooled water and 280 mL of hydrochloric acid were added.
Subsequently, ether (1.2 L) and ammonia (220 mL) were
added, the phases were separated, and the water phase was
extracted twice with ether. The organic phase was dried and
filtered, and the solvent was removed in vacuo. The residue
was dissolved in a mixture of sodium hydroxide (204.8 g, 5.1
mol) in 680 mL of ethanol and water and heated under reflux
for 20 min. Afterward, the solvent was removed in vacuo, and
the residue was dissolved in acetone and converted into the
hydrochloride salt with ethereal hydrogen chloride to give
311.9 g (86%) of 9c‚HCl: mp 224-225 °C; 1H NMR (CDCl3) of
the base δ 1.19 (s, 3H), 1.23 (s, 3H), 1.68 (br s, 1H), 2.22-3.30
(m, 7H), 3.80 (s, 3H), 6.77 (m, 3H), 7.24 (m, 1H).
filtered, and the solvent was removed in vacuo. The residue
was dissolved in 85 mL of 2-propanol and cooled, and subse-
quently 5.7 mL of concentrated hydrochloric acid and 150 mL
of diethyl ether were added to give 15.8 g (93%) of 10c‚HCl:
1
mp 230-231 °C; H NMR (CDCl3) of the base δ 1.26 (s, 3H),
1.35 (s, 3H), 2.38-3.39 (m, 7H), 3.80 (s, 3H), 4.80 (br s, 1H),
5.00 (s, 1H), 5.03 (s, 1H), 6.89 (m, 3H), 7.28 (m, 1H).
1-F or m yl-2-[(3-m eth oxyp h en yl)m eth yl]-3,3-d im eth yl-
4-m eth en ylp ip er id in e (11c). A solution of 10c (11.0 g, 45
mmol; after previous liberation of the base from the hydro-
chloride salt) and butyl formate (23.1 g, 22 mmol) in 75 mL of
toluene was refluxed for 4 h. The solvent was removed in
vacuo. The residue was recrystallized from cyclohexane to
yield 12.2 g (99%) of 11c: mp 121-122 °C;
1H NMR (CDCl3)
δ 1.26 (s, 3H), 1.26 (s, 3H), 2.20 (dd, 1H, J ) 15.0, 4.5 Hz),
2.40-2.95 (m, 5H), 3.27 (dd, 1H, J ) 13.0, 3.0 Hz), 3.76 (s,
3H), 4.34 (dd, 1H, J ) 13.0, 6.0 Hz), 4.88 (s, 1H), 4.99 (s, 1H),
6.52-7.22 (m, 4H), 7.51, 7.89 (s, 1H).
3′-Hyd r oxy-5,9,9-tr im eth yl-6,7-ben zom or p h a n Hyd r o-
ch lor id e (12c‚HCl) a n d 1′-Hyd r oxy-5,9,9-tr im eth yl-6,7-
ben zom or p h a n Hyd r och lor id e (12a ‚HCl). A solution of
11c (52.8 g, 191 mmol) in 300 mL of hydrobromic acid (48%)
was refluxed for 2 d. Afterward, the cooled solution was
diluted with 150 mL of ice water and extracted twice with
dichloromethane (50 mL). Then, cooled ammonia (400 mL)
was added, and the solution was extracted three times with
dichloromethane (100 mL). The combined organic phases were
dried and filtered, and the solvent was removed in vacuo. The
residue was purified by flash chromatography (silica gel, 230-
400 mesh, ethyl acetate/methanol/ammonia, 80/20/59) to give
20.8 g (47%) of 12c and 11.5 g (26%) of 12a as oils. Both
compounds were dissolved in acetone and converted to the
hydrochloride salts with ethereal hydrogen chloride.
12c‚HCl: mp >250 °C; 1H NMR (CDCl3) of the base δ 0.86
(s, 3H), 0.99 (dd, 1H, J ) 14.5, 3.5 Hz), 1.21 (s, 3H), 1.31 (s,
3H), 1.96 (dt, 1H, J ) 12.5, 6.0 Hz), 2.65 (dt, 1 H, J ) 12.5,
6.0 Hz), 2.80 (m, 3 H), 3.15 (dd, 1H, J ) 14.5, 7.5 Hz), 3.53 (br
s, 2H), 6.44 (d, 1H, J ) 3.0 Hz), 6.68 (dd, 1H, J ) 9.0, 3.0 Hz),
7.15 (d, J ) 9.0 Hz).
12a ‚HCl: mp >250 °C; 1H NMR (CDCl3) of the base δ 0.90
(s, 3H), 1.24 (s, 3H), 1.50 (dd, 1H, J ) 14.5, 3.5 Hz), 1.55 (s,
3H), 1.87 (dt, 1H, J ) 12.5, 5.5 Hz), 2.55 (dt, 1 H, J ) 12.5,
5.5 Hz), 2.76 (m, 3 H), 3.00 (br s, 2H), 3.35 (dd, 1H, J ) 14.5,
6.5 Hz), 6.45 (d, 1H, J ) 9.0 Hz), 6.64 (d, 1H, J ) 9.0 Hz),
6.93 (t, J ) 9.0 Hz).
Compounds 12b and 12d were prepared in an analogous
manner.
2-[(3-Me t h oxyp h e n yl)m e t h yl]-3,3-d im e t h yl-4-m e t h -
en ylp ip er id in e Hyd r och lor id e (10c‚HCl). Potassium tert-
butoxide (8.1 g, 72 mmol) was added to a suspension of
methyltriphenylphosphonium bromide (25.7 g, 72 mmol) in 205
mL of THF under nitrogen. After being stirred at 40 °C for
30 min, the mixture was allowed to cool to ambient temper-
ature and a solution of 9c (14.8 g, 60 mmol; after previous
liberation of the base from the hydrochloride salt) in 30 mL of
THF was added. After 1 h at ambient temperature, the
solution was cooled to 10 °C and 66 mL of water was added.
THF was removed in vacuo and the residue extracted twice
with dichloromethane. The organic phase was dried and
2-Allyl-1′-h yd r oxy-5,9,9-t r im et h yl-6,7-b en zom or p h a n
Hyd r och lor id e (14a ‚HCl). Meth od A. A mixture of 12a
(1.5 g, 60 mmol), allyl bromide (0.53 mL, 60 mmol), and KHCO3
(0.65 g, 60 mmol) in 30 mL of DMF were refluxed with stirring
for 4 h. The solvent was removed in vacuo and the residue
partitioned between dichloromethane and water (30 mL of
each). The organic layer was separated, and the water layer
was extracted two times with dichloromethane (2 × 50 mL).
The combined organic phases were dried and filtered, and the
solvent was removed in vacuo. The residue was dissolved in

2928 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18
Grauert et al.
acetone and converted into the hydrochloride salt using
ethereal hydrogen chloride to give 1.7 g (92%) of 14a ‚HCl: mp
224-226 °C; 1H NMR (CD3OD) δ 1.05 (s, 3H), 1.86 (s, 3H),
1.63 (s, 3H), 1.90 (dd, 1H, J ) 14.5, 5.0 Hz), 2.17 (dt, 1H, J )
13.5, 6.0 Hz), 2.62 (dt, 1 H, J ) 13.5, 6.0 Hz), 3.07-3.50 (m, 4
H), 3.82 (dq, 2H, J ) 13.0, 8.5 Hz), 5.61 (m, 2H), 5.94 (m, 1H),
6.66 (m, 2H), 7.00 (t, 1H, J ) 9.0 Hz). Anal. (C18H25NO‚HCl)
C, H, N.
chloride. The analogous synthesis affords 16a s‚HCl (0.39 g,
23%) and 15a s‚HCl (0.37 g, 22%).
16a s‚HCl: mp 85-90 °C; [R]20D ) +96.2° (c 1.0, MeOH); 1H
NMR (CD3OD) cf. 15a r . Anal. (C19H29NO2‚HCl) C, H, N.
15a s HCl: mp 90-92 °C; [R]20 ) -64.0° (c 1.0, MeOH); 1H
D
NMR (CD3OD) cf. 16a r . Anal. (C19H29NO2‚HCl) C, H, N.
(-)-(1R,5S,2′′R)-2′-Hyd r oxy-2-(2-m eth oxyp r op yl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (15br ‚HCl)
a n d (+)-(1S,5R,2′′R)-2′-H yd r oxy-2-(2-m et h oxyp r op yl)-
5,9,9-tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (16br ‚-
HCl). These compounds were prepared as described for 15a r
and 16a r from 12b (2.3 g, 10 mmol) and (R)-(+)-2-methoxy-
propionyl chloride.
Compounds 14b, 14c, and 14d were prepared in an analo-
gous manner from 12b, 12c, and 12d , respectively.
2-Allyl-2′-h ydr oxy-5,9,9-tr im eth yl-6,7-ben zom or ph an h y-
1
d r och lor id e (14b HCl): mp 231-232 °C; H NMR (CD3OD)
δ 1.00 (s, 3H), 1.37 (s, 3H), 1.38 (s, 3H), 1.40 (m, 1H), 2.29 (dt,
1H, J ) 13.5, 6.0 Hz), 2.71 (dt, 1 H, J ) 13.5, 6.0 Hz), 3.00-
3.52 (m, 4 H), 3.88 (m, 2H), 5.62 (m, 2H), 6.03 (m, 1H), 6.66
(dd, 1H, J ) 8.5, 2.5 Hz), 6.81 (d, 1H, J ) 2.5 Hz), 7.03 (d, 1H,
J ) 8.5 Hz). Anal. (C18H25NO‚HCl) C, H. N.
16br ‚HCl: mp 236-237 °C; [R]20 ) +86.3° (c 1.0, MeOH);
D
1H NMR (CD3OD) δ 0.98 (s, 3H), 1.24 (d, 3H, J ) 7.0 Hz), 1.38
(s, 3H), 1.39 (s, 3H), 1.38 (m, 1H), 2.35 (dt, 1H, J ) 13.0, 6.0
Hz), 2.80 (dt, 1 H, J ) 13.0, 6.0 Hz), 3.10-3.60 (m, 6 H), 3.42
(s, 3H), 3.90 (m, 1H), 6.66 (dd, 1H, J ) 8.5, 2.5 Hz), 6.81 (d,
1H, J ) 2.5 Hz), 7.02 (d, 1H, J ) 8.5 Hz). Anal. (C19H29NO2‚-
HCl) C, H, N.
2-Allyl-3′-h ydr oxy-5,9,9-tr im eth yl-6,7-ben zom or ph an h y-
1
d r och lor id e (14c‚HCl): mp 253-255 °C; H NMR (CD3OD)
δ 0.97 (s, 3H), 1.35 (m, 1H), 1.37 (s, 3H), 1.38 (s, 3H), 2.29 (dt,
1H, J ) 14.5, 6.0 Hz), 2.68 (dt, 1 H, J ) 14.5, 6.0 Hz), 3.06-
3.49 (m, 4 H), 3.87 (dq, 2H, J ) 13.0, 7.5 Hz), 5.64 (m, 2H),
5.97 (m, 1H), 6.66 (m, 2H), 7.19 (d, 1H, J ) 9.0 Hz). Anal.
(C18H25NO‚HCl) C, H, N.
15br ‚HCl: mp 270 °C dec; [R]20 ) -117.4° (c 0.5, MeOH);
D
1H NMR (CD3OD) δ 1.05 (s, 3H), 1.24 (d, 3H, J ) 7.0 Hz),
1.35 (m, 1H), 1.36 (s, 3H), 1.38 (s, 3H), 2.30 (dt, 1H, J ) 13.0,
6.0 Hz), 2.78 (dt, 1H, J ) 13.0, 6.0 Hz), 2.90-3.60 (m, 6H),
3.52 (s, 3H), 3.90 (m, 1H), 6.66 (dd, 1H, J ) 8.5, 2.5 Hz), 6.81
2-Allyl-4′-h ydr oxy-5,9,9-tr im eth yl-6,7-ben zom or ph an h y-
d r och lor id e (14d ‚HCl): mp 247 °C; 1H NMR (CD3OD) δ 0.98
(s, 3H), 1.37 (s, 3H), 1.38 (s, 3H), 1.43 (m, 1H), 2.30 (dt, 1H, J
) 14.5, 6.0 Hz), 2.73 (dt, 1 H, J ) 14.5, 6.0 Hz), 2.85-3.60 (m,
4 H), 3.88 (m, 2H), 5.64 (m, 2H), 6.00 (m, 1H), 6.71 (d, 1H, J
) 8.5 Hz), 6.90 (d, 1H, J ) 8.5 Hz), 7.09 (t, 1H, J ) 8.5 Hz).
Anal. (C18H25NO‚HCl) C, H, N.
(d, 1H, J ) 2.5 Hz), 7.02 (d, 1H, J ) 8.5 Hz). Anal. (C19H29
NO2‚HCl) C, H, N.
-
(-)-(1R,5S,2′′S)-2′-Hyd r oxy-2-(2-m eth oxyp r op yl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (15bs‚HCl)
an d (+)-(1S,5R,2′′S)-2′-Hydr oxy-2-(2-m eth oxypr opyl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (16bs‚HCl).
These compounds were prepared as described for 15a r and
16a r from 12b and (S)-(-)-2-methoxypropionyl chloride. The
analogous synthesis affords 16bs‚HCl (0.42 g, 25%) and
15bs‚HCl (0.39 g, 23%).
(-)-(1R,5R,2′′R)-1′-Hyd r oxy-2-(2-m eth oxyp r op yl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (15a r ‚HCl)
an d (+)-(1S,5S,2′′R)-1′-Hydr oxy-2-(2-m eth oxypr opyl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (16a r HCl).
Meth od B. A solution of (R)-(+)-2-methoxypropionyl chloride
(1.3 g, 10 mmol) in 10 mL of dichloromethane was added to a
solution of 12a (2.3 g, 10 mmol) and triethylamine (2.1 mL,
15 mmol) in 25 mL of dichloromethane at ambient tempera-
ture. The solution was allowed to stir for 1.5 h at ambient
temperature, the solvent was removed in vacuo, and the
residue was shaken with ethyl acetate (100 mL) and water
(30 mL). The organic layer was separated and washed with 2
N hydrochloric acid and water, dried, filtered, and evaporated
in vacuo to yield a residue consisting of a mixture of the
diastereomeric amides. A solution of this residue in 25 mL of
THF was added dropwise into a vigrously stirred suspension
of LiAlH4 (0.65 g, 17 mmol) in 12 mL of THF. Afterward the
mixture was refluxed for 2 h, cooled again, and treated with
water (2 mL) and a saturated solution of ammonium tartrate
(10 mL). The organic phase was separated, and the aqueous
layer was extracted with ethyl acetate (3 × 60 mL). The
organic phases were combined, dried, and filtered, and the
solvent was removed in vacuo. The residue was purified by
flash chromatography (silica gel, 230-400 mesh, dichlo-
romethane/methanol, 95/5). Both separated compounds were
dissolved in ether and converted to the hydrochloride salts
using ethereal hydrogen chloride to give 16a r ‚HCl (1.02 g,
30%) and 15a r ‚HCl (0.75 g, 22%).
16bs‚HCl: mp 270 °C dec; [R]20 ) +117.0° (c 0.5, MeOH);
D
1H NMR (CD3OD) cf. 15br . Anal. (C19H29NO2‚HCl) C, H, N.
15bs‚HCl: mp 228-230 °C; [R]20 ) -85.9° (c 0.5, MeOH);
D
1H NMR (CD3OD) cf. 16br . Anal. (C19H29NO2‚HCl) C, H, N.
(-)-(1R,5S,2′′R)-3′-Hyd r oxy-2-(2-m eth oxyp r op yl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (15cr ‚HCl)
a n d (+)-(1S,5R,2′′R)-3′-H yd r oxy-2-(2-m et h oxyp r op yl)-
5,9,9-tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (16cr ‚-
HCl). These compounds were prepared as described for 15a r
and 16a r from 12c and (R)-(+)-2-methoxypropionyl chloride.
16cr ‚HCl: mp 250-251 °C; [R]20 ) +57.1° (c 1.0, MeOH);
D
1H NMR (CD3OD) δ 0.95 (s, 3H), 1.24 (d, 3H, J ) 7.0 Hz),
1.32 (m, 1H), 1.36 (s, 3H), 1.38 (s, 3H), 2.38 (dt, 1H, J ) 13.0,
6.0 Hz), 2.78 (dt, 1 H, J ) 13.0, 6.0 Hz), 3.10-3.60 (m, 6 H),
3.40 (s, 3H), 3.90 (m, 1H), 6.63 (d, 1H, J ) 2.5 Hz), 6.69 (dd,
1H, J ) 8.5, 2.5 Hz), 7.18 (d, 1H, J ) 8.5 Hz). Anal. (C19H29
-
NO2‚HCl) C, H, N.
15cr ‚HCl: mp 240-242 °C; [R]20 ) -90.9° (c 1.0, MeOH);
D
1H NMR (CD3OD) δ 1.00 (s, 3H), 1.25 (d, 3H, J ) 7.0 Hz).
1.27 (m, 1H), 1.36 (s, 3H), 1.38 (s, 3H), 2.30 (dt, 1H, J ) 13.0,
6.0 Hz), 2.74 (dt, 1 H, J ) 13.0, 6.0 Hz), 2.92-3.55 (m, 6H),
3.45 (s, 3H), 3.81 (m, 1H), 6.64 (d, 1H, J ) 2.5 Hz), 6.70 (dd,
1H, J ) 8.5, 2.5 Hz), 7.19 (d, 1H, J ) 8.5 Hz). Anal. (C19H29
NO2‚HCl) C, H, N.
-
16a r ‚HCl: mp 89-90 °C; [R]20 ) +50.4° (c 1.0, MeOH);
(-)-(1R,5S,2′′S)-3′-Hyd r oxy-2-(2-m eth oxyp r op yl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (15cs‚HCl)
an d (+)-(1S,5R,2′′S)-3′-Hydr oxy-2-(2-m eth oxypr opyl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (16cs‚HCl).
These compounds were prepared as described for 15a r and
16a r from 12c and (S)-(-)-2-methoxpropionyl chloride.
D
1H NMR(CD3OD) δ 1.05 (s, 3H), 1.23 (d, 3H, J ) 7.0 Hz), 1.40
(s, 3H), 1.64 (s, 3H), 1.87 (dd, 1H, J ) 12.0, 4.0 Hz), 2.25 (dt,
1H, J ) 13.0, 6.0 Hz), 2.63 (dt, 1 H, J ) 13.0, 6.0 Hz), 3.11-
3.56 (m, 6 H), 3.40 (s, 3H), 3.85 (m, 1H), 6.65 (m, 2H), 7.00 (d,
1H, J ) 9.0 Hz). Anal. (C19H29NO2‚HCl) C, H, N.
15a r ‚HCl: mp 130-135 °C; [R]20D ) -100.5° (c 1.0, MeOH);
1H NMR (CD3OD) δ 1.07 (s, 3H), 1.23 (d, 3H, J ) 7.0 Hz),
1.35 (s, 3H), 1.64 (s, 3H), 1.85 (dd, 1H, J ) 12.0, 4.0 Hz), 2.18
(dt, 1H, J ) 13.0, 6.0 Hz), 2.65 (dt, 1 H, J ) 13.0, 6.0 Hz),
2.86-3.46 (m, 6 H), 3.44 (s, 3H), 3.78 (m, 1H), 6.65 (m, 2H),
7.00 (d, 1H, J ) 9.0 Hz). Anal. (C19H29NO2‚HCl) C, H, N.
(-)-(1R,5R,2′′S)-1′-Hyd r oxy-2-(2-m eth oxyp r op yl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (15a s‚HCl)
an d (+)-(1S,5S,2′′S)-3′-Hydr oxy-2-(2-m eth oxypr opyl)-5,9,9-
tr im eth yl-6,7-ben zom or p h a n Hyd r och lor id e (16a s‚HCl).
These compounds were prepared as described for 15a r and
16a r from 12a (1.7 g, 5 mmol) and (S)-(-)-2-methoxypropionyl
16cs‚HCl: mp 239-240 °C; [R]20 ) +90.7° (c 1.0, MeOH);
D
1H NMR (CD3OD) cf. 15cr . Anal. (C19H29NO2‚HCl) C, H, N.
15cs‚HCl: mp 250-252 °C; [R]20 ) -56.5° (c 1.0, MeOH);
D
1H NMR (CD3OD) cf. 16cr . Anal. (C19H29NO2‚HCl) C, H, N.
(-)-(1R,5S,2′′R)-2-(2-Met h oxyp r op yl)-5,9,9-t r im et h yl-
6,7-ben zom or p h a n Hyd r och lor id e (15er ‚HCl). A mixture
of 15br (1.36 g, 4 mmol), K2CO3 (1.33 g, 8 mmol), and 5-chloro-
1-phenyl-1H-tetrazole (0.79 g, 4.4 mmol) in 78 mL of acetone
was refluxed for 6 d. The reaction mixture was allowed to cool
to room temperature. After filtration the filtrate was evapo-
rated in vacuo. The residue was converted into the hydro-
chloride salt using ethereal hydrogen chloride, dissolved in

Antagonists of the NMDA Receptor-Channel Complex
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 18 2929
glacial AcOH (70 mL), mixed with Pd/C (10%, 700 mg), and
hydrogenated at room temperature and 5 bar for 11 h. The
catalyst was filtered off and washed with glacial AcOH, and
the filtrate was evaporated in vacuo. The residue was dis-
solved in water, made alkaline with concentrated ammonia,
and extracted three times with dichloromethane (3 × 50 mL).
The organic layer was dried and filtered, and the solvent of
the filtrate was removed in vacuo. The residue was converted
into the hydrochloride salt using ethereal hydrogen chloride
were incubated for 30 min at 25 °C with 1 nmol/L [3H]MK-
801 in 5 mmol/L Tris-HCl buffer at pH 7.4 in the presence of
1 mmol/L glutamate and the test compound. Binding was
terminated by rapid filtration through Whatman GF/B filters
and washing with ice-cold buffer.
[3H]Dihydromorphine binding was measured in rat brain
without cerebellum as described by Ensinger.32 Membrane
suspensions were incubated for 30 min at 25 °C with 0.5
nmol/L [3H]dihydromorphine. Binding was terminated by
rapid filtration through Millipore AP40 filters.
to yield 0.58 g (45%) of 15er ‚HCl: mp 225 °C dec; [R]20
)
D
-101.7° (c 0.5, MeOH); 1H NMR (CD3OD) δ 1.00 (s, 3H), 1.25
(d, 3H, J ) 7.0 Hz), 1.36 (m, 1H), 1.38 (s, 3H), 1.42 (s, 3H),
2.32 (dt, 1H, J ) 13.0, 6.0 Hz), 2.70 (dt, 1 H, J ) 13.0, 6.0 Hz),
2.92-3.58 (m, 6H), 3.45 (s, 3H), 3.85 (m, 1H), 7.14-7.47 (m,
4H). Anal. (C19H29NO‚HCl) C, H, N.
The radioactivity on the filter disks was measured with a
scintillation counter. Ki values were determined by computer-
aided curve fitting.33
An ta gon ism of NMDA-In d u ced Leth a lity. The ability
of the compounds to inhibit NMDA-induced lethality was
determined according to a previously described method.17
Different doses of test compound were administered by sub-
cutaneous injection (0.01 mL/g body weight) to groups of five
male mice (20 to 30 g). NMDA (200 mg/kg) was administered
by intraperitoneal injection 15 min later. The animals were
then placed in individual glass jars (9 × 13 cm) which were
covered with a metal mesh. The mice were observed for 20
min, and the percentage of animals that died during this period
was determined. The dose required to inhibit NMDA-induced
lethality by 50% (ID50) was calculated by log-probit analysis
from four different doses of each test compound.
(-)-(1R,5S,2′′S)-2-(2-Met h oxyp r op yl)-5,9,9-t r im et h yl-
6,7-ben zom or p h a n Oxa la te (15es‚OX). This compound was
prepared as described for 15er from 15bs and crystallized as
the oxalate.
15es‚OX: mp 135 °C; [R]20 ) -60.0° (c 0.5, MeOH); 1H
D
NMR (CD3OD) δ 0.98 (s, 3H), 1.24 (d, 3H, J ) 7.0 Hz), 1.38
(m, 1H), 1.40 (s, 3H), 1.43 (s, 3H), 2.38 (dt, 1H, J ) 13.0, 6.0
Hz), 2.75 (dt, 1 H, J ) 13.0, 6.0 Hz), 3.15-3.62 (m, 6 H), 3.42
(s, 3H), 3.85 (m, 1H), 7.14-7.47 (m, 4H). Anal. (C19H29
NO‚C2H2O4) C, H, N.
-
(-)-(1R,5R,9â,2′′R)-2′-Hyd r oxy-2-(2-h yd r oxyp r op yl)-5,9-
d im et h yl-6,7-ben zom or p h a n Hyd r och lor id e (4k r ‚HCl).
Meth od C. A mixture of (-)-(1R,5R,9S)-normetazocine (0.87
g, 4 mmol) and 2 mL of (R)-(+)-propylene oxide was heated
for 30 min to 100 °C. The mixture was diluted with 50 mL of
acetone, and the hydrochloride salt was formed with ethereal
Ack n ow led gm en t. The authors thank Hanfried
Baltes, Regina Beckhaus, Rosi Ewen, Rainer Fro¨hlich,
Susanne Heinz, Silvia Hermann, Rudolf Keilhofer,
Stephan Kurtze, Udo Ko¨hl, Gisela Mengeling, Karl-
Gottfried Schmitt, and Heinz J o¨rg Wennesheimer for
their excellent technical assistance, as well as Dr. Karl
Heinz Pook of the Department of Analytics for providing
spectral data. We further appreciate the help of Prof.
Dr. Ernst Egert and Dr. Michael Bolte, Institute of
Organic Chemistry, University of Frankfurt, in prepar-
ing the X-ray analysis.
hydrogen chloride to yield 0.75 g (68%) of 4k r ‚HCl: mp 270
1
°C; [R]20 ) -97.1° (c 0.5, MeOH); H NMR (CD3OD) δ 1.25
D
(d, 3H, J ) 6.5 Hz), 1.36 (d, 3H, J ) 7.5 Hz), 1.38 (s, 3H), 1.39
(m, 1H), 2.25 (m, 2H), 2.75 (dt, 1 H, J ) 13.0, 6.0 Hz), 2.82-
3.40 (m, 6H), 3.95 (m, 1H), 4.15 (m, 1H), 6.68 (dd, 1H, J )
8.5, 2.5 Hz), 6.84 (d, 1H, J ) 2.5 Hz), 7.03 (d, 1H, J ) 8.5 Hz).
Anal. (C17H25NO2‚HCl) C, H, N.
(-)-(1R,5R,9â,2′′S)-2′-Hyd r oxy-2-(2-h yd r oxyp r op yl)-5,9-
d im et h yl-6,7-b en zom or p h a n Hyd r och lor id e (4k s‚HCl).
This compound was prepared as described for 4k r . 4k s‚HCl:
1
mp 248 °C; [R]20 ) -57.1° (c 0.5, MeOH); H NMR (CD3OD)
D
Refer en ces
δ 1.26 (d, 3H, J ) 6.5 Hz), 1.38 (d, 3H, J ) 7.5 Hz), 1.40 (s,
3H), 1.43 (m, 1H) 2.27 (m, 2H), 2.75 (dt, 1 H, J ) 13.0, 6.0
Hz), 3.12-3.40 (m, 6H), 4.00 (m, 1H), 4.22 (m, 1H), 6.66 (dd,
1H, J ) 8.5, 2.5 Hz), 6.84 (d, 1H, J ) 2.5 Hz), 7.03 (d, 1H, J
) 8.5 Hz). Anal. (C17H25NO2‚HCl) C, H, N.
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