Synthesis, σ receptor affinity, and pharmacological evaluation of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-benzazepines

Article abstract of DOI:10.1002/cmdc.201402110

In accordance with a novel strategy for generating the 2-benzazepine scaffold by connecting C6-C1 and C3-N building blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tetrahydro-2-benzazepines was synthesized and pharmacologically evaluated. Key steps of the synthesis were the Heck reaction, the Stetter reaction, a reductive cyclization, and the introduction of diverse N substituents at the end of the synthesis. High σ₁ affinity was achieved for 2-benzazepines with linear or branched alk(en)yl residues containing at least an n-butyl substructure. The butyl- and 4-fluorobenzyl-substituted derivatives, (±)-5-benzyl-2-butyl- 2,3,4,5-tetrahydro-1H-2-benzazepine (19 b) and (±)-5-benzyl-2-(4- fluorobenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine (19 m), show high selectivity over more than 50 other relevant targets, including the σ₂ subtype and various binding sites of the N-methyl-D-aspartate (NMDA) receptor. In the Irwin screen, 19 b and 19 m showed clean profiles without inducing considerable side effects. Compounds 19 b and 19 m did not reveal significant analgesic and cognition-enhancing activity. Compound 19 m did not have any antidepressant-like effects in mice.

Full text of DOI:10.1002/cmdc.201402110

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DOI: 10.1002/cmdc.201402110
Synthesis, s Receptor Affinity, and Pharmacological
Evaluation of 5-Phenylsulfanyl- and 5-Benzyl-Substituted
Tetrahydro-2-benzazepines
Peer Hasebein,[a] Bastian Frehland,[a] Dirk Schepmann,[a] and Bernhard Wꢀnsch*[a, b]
In accordance with a novel strategy for generating the 2-ben-
zazepine scaffold by connecting C6–C1 and C3–N building
blocks, a set of 5-phenylsulfanyl- and 5-benzyl-substituted tet-
rahydro-2-benzazepines was synthesized and pharmacological-
ly evaluated. Key steps of the synthesis were the Heck reaction,
the Stetter reaction, a reductive cyclization, and the introduc-
tion of diverse N substituents at the end of the synthesis. High
s1 affinity was achieved for 2-benzazepines with linear or
branched alk(en)yl residues containing at least an n-butyl sub-
structure. The butyl- and 4-fluorobenzyl-substituted deriva-
tives, (Æ)-5-benzyl-2-butyl-2,3,4,5-tetrahydro-1H-2-benzazepine
(19b) and (Æ)-5-benzyl-2-(4-fluorobenzyl)-2,3,4,5-tetrahydro-
1H-2-benzazepine (19m), show high selectivity over more than
50 other relevant targets, including the s2 subtype and various
binding sites of the N-methyl-d-aspartate (NMDA) receptor. In
the Irwin screen, 19b and 19m showed clean profiles without
inducing considerable side effects. Compounds 19b and 19m
did not reveal significant analgesic and cognition-enhancing
activity. Compound 19m did not have any antidepressant-like
effects in mice.
Introduction
Tetrahydro-2-benzazepines 2 can be regarded as regioisomers
of tetrahydro-3-benzazepines 1 (Figure 1) and homologues of
tetrahydroisoquinolines. Compounds with the 3-benzazepine
pines 1 (R2: Ph) have been reported to interact with the dopa-
mine D1 and D2 receptors, and the 3-benzazepine SCH-23390
represents a prototypical D1 receptor antagonist.[2,3] The inser-
tion of a methylene moiety or a bioisosteric equivalent be-
tween the 3-benzazepine ring and the phenyl moiety at the 1-
position of 1 (for example, R2: CH2Ph, SPh, or N(Ac)Ph) provid-
ed N-methyl-d-aspartate (NMDA) receptor antagonists, which
block the NMDA-receptor-associated ion channel by interac-
tion with the phencyclidine binding site.[4,5] Moreover, some
promising s1 receptor ligands based on the 3-benzazepine
scaffold with various substituents have been identified.[6–8]
Very recently, we have reported on the synthesis and s re-
ceptor affinity of regioisomeric tetrahydro-2-benzazepines 2
with a phenyl moiety in the 5-position. The 2-butyl-5-phenylte-
trahydro-2-benzazepine, 2a (R1: C4H9; R2: Ph), interacts with
low nanomolar affinity (inhibition constant (Ki)=2.0 nm) and
high selectivity with s1 receptors.[9] It has been shown that the
s1 receptor can modulate the permeability of ion channels[10,11]
and the activity of neurotransmitter systems.[12,13] In 2007, the
role of the s1 receptor as a ligand-operated chaperon was sug-
gested.[14] Due to the various modulatory effects of s1 recep-
tors in the central nervous system, potent and selective s1 re-
ceptor ligands represent potential drugs for the treatment of
neurological and psychiatric diseases,[15–18] including neuro-
pathic pain,[19,20] schizophrenia,[21,22] major depression,[12,23,24]
and Alzheimer’s disease.[25]
Figure 1. Development of novel tetrahydro-2-benzazepines 3 with a spacer
X between the 2-benzazepine scaffold and the aryl moiety of the lead com-
pounds 1 and 2.
scaffold show promising neuropharmacological properties. For
example, the introduction of a small methyl moiety in the 1-
position of the 3-benzazepine ring of 1 (R2: CH3) leads to lorca-
serin, a potent 5-HT2C agonist, which can be used for the treat-
ment of obesity.[1] 1-Phenyl-substituted tetrahydro-3-benzaze-
[a] Dr. P. Hasebein, B. Frehland, Dr. D. Schepmann, Prof. Dr. B. Wꢀnsch
Institut fꢀr Pharmazeutische und Medizinische Chemie der Universitꢁt
Mꢀnster, Corrensstraße 48, 48149 Mꢀnster (Germany)
E-mail: wuensch@uni-muenster.de
Neuropathic pain is defined as spontaneous hypersensitive
pain response, which is recognized even when the origin of
the pain has been cured.[26,27] Medical treatment is rather diffi-
cult, because of the diffuse origin of neuropathic pain condi-
tions. With the help of s1 receptor knockout mice, the positive
effects of s1 receptor antagonists on neuropathic pain condi-
[b] Prof. Dr. B. Wꢀnsch
Cells-in-Motion Cluster of Excellence (EXC 1003-CiM)
University of Mꢀnster, Waldeyerstraße 15, 48149 Mꢀnster (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201402110: physical, spectroscopic, and
purity data for all compounds, synthetic methods, and descriptions of re-
ceptor binding assays; Figures SI1–SI5 show results of animal assays.
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tions was demonstrated.[28] As proof of principle, the potent
and selective s1 receptor antagonist S1RA has entered phase II
clinical trials for the treatment of neuropathic pain.[20,29,30]
According to pharmacophore models, a basic N atom sur-
rounded by two hydrophobic regions is required to achieve
high s1 receptor affinity.[31] When the structural elements of the
pharmacophore models are transferred to the s1 ligand 2a,
the N atom of the 2-benzazepine ring represents the basic N
atom, as postulated by the pharmacophore model, and the hy-
drophobic regions are formed by the n-butyl residue on the N
atom and the phenyl moiety in the 5-position of the 2-benza-
zepine system. However, in the pharmacophore models, the
distance between the basic N atom and the primary hydropho-
bic region is longer (6–10 ꢂ;[32,33] 6.3 and 9.8 ꢂ[34]) than the dis-
tance found in 2a (4.66–5.98 ꢂ). Therefore, we planned to in-
crease this distance by the introduction of a one-atom spacer,
X, between the phenyl moiety in the 5-position and the 2-ben-
zazepine scaffold (see compound 3 in Figure 1). The energeti-
cally most favored conformations of 3 (X: CH2) possess N–aryl
distances of 6.03–6.45 ꢂ, which exactly fit into the range
postulated by the pharmacophore models. The envisaged
structural modification could not only lead to ligands with
high s1 receptor affinity but could also result in promising
NMDA receptor ligands with increased affinity toward the
phencyclidine binding site, as already observed for the class of
tetrahydro-3-benzazepines 1.[4]
Herein, we report on the synthesis, s1 and s2 receptor affini-
ty, and NMDA receptor affinity of 5-phenylsulfanyl- and 5-
benzyl-substituted tetrahydro-2-benzazepines of type 3 (X: S,
CH2) with various substituents at the N atom. The selectivity
over further receptors, the in vitro absorption, distribution, me-
tabolism, and excretion (ADME) parameters, and the cognition-
enhancing and analgesic activity of the most promising ligands
was investigated. For the introduction of a wide variety of sub-
stituents, the late-stage diversification strategy was followed,
which makes use of the introduction of different substituents
at the end of the synthesis into a central building block.[35]
Scheme 1. Synthesis of 5-phenylsulfanyl-substituted tetrahydro-2-benzaze-
pine 10. Reagents and conditions: a) CH2=CHCN, Pd(OAc)2, Bu4NBr, NaHCO3,
DMF, 1408C, 24 h, 99%;[9] b) PhSH, nBuLi, THF, RT, 16 h, 88%; c) LiAlH4, THF,
0–48C, 16 h, 38%; d) p-TolSO3·H2O, THF, RT, 2 h; e) NaBH3CN, RT, 1 h, 30%. p-
Tol : para-tolyl.
to result in cinnamonitrile 5, which was reduced by LiAlH4 to
give the primary amine 7. To inhibit the b elimination, a conju-
gate Suzuki reduction[36] of 6 with NaBH4 and CoCl2 in boiling
methanol was performed. However, the reaction provided ex-
clusively the primary amine 7 in 61% yield. A decreased reac-
tion temperature of 0–48C during the LiAlH4 reduction of 6 led
to an increased amount of the desired phenylsulfanyl-substi-
tuted primary amine 8, which was isolated in 38% yield.
Finally, the 2-benzazepine scaffold was prepared in a two-
step process consisting of an acid-catalyzed hydrolysis of the
dimethyl acetal of 8 and subsequent formation of imine 9,
which was reduced by NaBH3CN to afford the tetrahydro-2-
benzazepine 10 with a phenylsulfanyl substituent in the 5-po-
sition in 30% yield.
Due to the problems during the synthesis, we decided to
focus on the corresponding benzyl derivatives, 19. For this pur-
pose, a benzyl nucleophile needed be added to the a,b-unsa-
turated nitrile 5. However, all attempts to make cinnamonitrile
5 react with BnMgBr or corresponding cuprates (for example,
Bn2CuMgBr) failed to give the 1,4 addition product.
Results and Discussion
Synthesis
For the synthesis of the 2-benzazepine system, we planned to
follow the recently reported strategy of connecting C6–C1 and
C3–N building blocks.[9] The synthesis of the 5-phenylsulfanyl-
substituted tetrahydro-2-benzazepine 10 started with the con-
jugate addition of thiophenol to the a,b-unsaturated nitrile 5,
which was prepared by the Heck reaction of 2-iodobenzalde-
hyde acetal 4 with acrylonitrile[9] (Scheme 1). Different bases
were investigated to enhance the activity of thiophenol for the
conjugate addition. Whereas K2CO3 and triethylamine gave
very low yields (0–16%), n-butyllithium afforded the addition
product 6 in 88% yield.
Therefore, the benzyl substituent was introduced by a Stetter
reaction.[37,38] The highest yield (49%) of ketonitrile 11 was ob-
tained by the reaction of the a,b-unsaturated nitrile 5 with
benzaldehyde and NaCN at 358C (Scheme 2). Lower (208C) or
higher (408C) temperature, as well as the use of benzoin[38] in-
stead of benzaldehyde, gave considerably lower yields. Re-
placement of NaCN with a thiazolium salt (3-ethyl-5-(2-hydrox-
yethyl)-4-methylthiazolium bromide)[39,40] led predominantly to
hydrolysis of the acetal moiety of 5.
The reduction of ketonitrile 11 with NaBH4 at 08C provided,
diastereoselectively, the like-configured hydroxynitrile 12 in
82% yield. The relative configuration of the racemic mixture of
12 was confirmed by transformation of hydroxynitrile 12 into
2-benzopyran 13 upon treatment with BF3·OEt2. The trans con-
figuration of the 3-phenyl and 4-cyanomethyl moieties was
The reduction of nitrile 6 with LiAlH4 in THF led to the pri-
mary amines 7 and 8,[9] which were isolated in 64 and 13%
yields, respectively. The formation of the primary amine 7 is ex-
plained by b elimination of thiophenolate catalyzed by LiAlH4
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hyde and NaBH(OAc)3. In general, the reductive alky-
lation gave higher yields of the tertiary amines 19.
Various alkyl and alkenyl substituents, derived from
the dimethylallyl moiety of the prototypical s1 ago-
nist (+)-pentazocine, and substituted and unsubsti-
tuted (hetero)arylalkyl substituents, derived from
benzylated spirocyclic s1 receptor antagonists, were
selected.[4142]
Scheme 2. Synthesis of 2-benzopyran 13. Reagents and conditions: a) PhCH=O, NaCN,
DMF, 358C, 12 h, 49%; b) NaBH4, CH3OH, 08C, 16 h, 82%; c) BF3·OEt2, THF, RT, 16 h, 70%.
Only one enantiomer of the racemic mixtures 12 and 13 is shown here.
Pharmacological evaluation
Affinity toward s receptors
proven by the large coupling constant of J=10.2 Hz for the
trans diaxially oriented protons in the 3- and 4-positions.
In the next step, the hydroxy moiety in the benzyl position
of 12 needed to be removed by hydrogenolysis. However,
treatment of hydroxynitrile 12 with H2 in the presence of Pd/C
afforded predominantly the 2-benzopyran 13. This intramolec-
ular transacetalization of 12 to form the 2-benzopyran 13 is
catalyzed by traces of acid in the Pd/C catalyst, so K2CO3 was
added to remove the acid from the reaction mixture. In fact,
the hydroxy moiety was cleaved off by hydrogenolysis after
the addition of K2CO3, but instead of the expected butyroni-
trile, the primary amide 15 was isolated in 98% yield
(Scheme 3). The formation of primary amide 15 is explained by
base-catalyzed cyclization of the hydroxynitrile 12 to afford the
imidolactone 14, which was cleaved by hydrogenolysis to give
the primary amide 15.
The affinities of the 5-substituted tetrahydro-2-benzyzepines
10, 18, and 19 toward s1 and s2 receptors were determined in
radioligand receptor binding studies. In this type of assay, the
test compound competes with a potent and selective radioli-
gand for the respective binding sites. The radioligands [3H]-
(+)-pentazocine (s1 assay),[43,44] and [3H]-1,3-di(ortho-tolyl)gua-
nidine (s2 assay)[43,44] were employed. In the s2 assay, an excess
of nonlabeled (+)-pentazocine was added in order to mask the
s1 receptors. Membrane preparations from guinea pig brains
and rat liver served as receptor materials in the s1 and s2
assays, respectively.
In Table 1, the s receptor affinities of the 5-phenylsulfanyl-
and 5-benzyl-substituted 2-benzazepines 10, 18, and 19 are
summarized and compared with the s receptor affinities of the
corresponding 5-phenyl-substituted analogues 2 and
selected reference compounds. A proton or a small
methyl moiety at the N atom (10, 18, and 19a) led
to low s1 affinity. However, an increase in the size of
the N-alkyl substituent to an n-butyl or even n-pentyl
group resulted in the high affinity s1 receptor ligands
19b and 19c. Whereas short branched and small
cyclic N substituents, like isobutyl (19d) and cyclo-
propylmethyl (19 f) groups, are less tolerated by the
s1 receptor, larger branched and cyclic N substitu-
ents, like dimethylallyl (19e) and cyclohexylmethyl
(19g) groups, are well accepted. A similar tendency
was found in the corresponding class of 5-phenyl-
Scheme 3. Synthesis of 5-benzyl-substituted 2-benzazepines 19a–n. Reagents and condi-
tions: a) H2 (1 bar), Pd/C, CH3OH, K2CO3, RT, 16 h, 98%; b) LiAlH4, THF, 48C, 4 h, then RT,
12 h, 76%; c) p-TolSO3H·H2O, RT, 2 h; d) NaBH3CN, RT, 1 h 48%; e) alkyl halide, CH3CN,
K2CO3, reflux, 16 h, 14–55%; f) R1CH=O, NaBH(OAc)3, CH2Cl2, RT, 16 h, 44–76%.
substituted 2-benzazepines 2; the n-butyl-substituted
derivative 2a shows the highest s1 receptor affinity
for this type of compounds.
Replacement of the cyclohexylmethyl moiety (in
19g) by the aromatic benzyl group (in 19h) resulted
Reduction of the primary amide 15 with LiAlH4 provided the
primary amine 16 in 76% yield. For the cyclization of primary
amine 16, the same two-step procedure as for the cyclization
of the phenylsulfanyl-substituted amine 8 was used; this com-
prised an acid-catalyzed acetal hydrolysis followed by the for-
mation of imine 17, which was reduced with NaBH3CN. The re-
sulting 5-benzyltetrahydro-2-benzazepine 18 represents the
central building block for the introduction of various substitu-
ents at the N atom. The diversification at the last stage of the
synthesis[35] was performed by alkylation with the appropriate
alkyl halide or reductive alkylation with the appropriate alde-
in eightfold decreased s1 affinity. However, the s1 affinity of
the 5-benzyl derivative 19h is about three times higher than
the s1 affinity of the corresponding 5-phenyl-substituted 2-
benzazepine 2b, which proved the favorable effect of the
methylene spacer between the aryl moiety and the 2-benzaze-
pine scaffold. The 2-benzazepine 19i with a 2-phenylethyl sub-
stituent shows a similar s1 affinity to the benzyl derivative
19h, but the 4-phenylbutyl derivative 19j reveals considerably
lower s1 affinity. The furan (19k) and thiophene (19l) bioisos-
teres of 19h are less tolerated by the s1 receptor than the
parent benzyl derivative 19h. Whereas an electron-donating
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the corresponding analogues with larger N substitu-
ents (for example, benzyl or dimethylallyl) interact
with the s1 receptors.[45–47] Moreover, in the class of
3-benzazepines 1, PhX substituents in the 1-position
led to potent NMDA receptor antagonists, as detailed
in the Introduction. Therefore, the interactions of the
tetrahydro-2-bnzazepines 10, 18, and 19 with various
binding sites of the NMDA receptor were recorded.
However, at a test compound concentration of
10 mm, the 2-benzazepines did not compete consid-
erably with the radioligands [3H]-MDL-105519 (gly-
cine binding site), [3H]-(+)-MK-801[47,48] and [3H]- 1-[1-
(2-thienyl)cyclohexyl])piperidine (phencyclidine bind-
ing site), [3H]-ifenprodil (ifenprodil binding site), and
[3H]-CGP-39653 (glutamate binding site). The low af-
finity toward the different binding sites of the NMDA
receptor indicates very high selectivity, at least for
the most potent s1 ligands.
Table 1. s1 and s2 receptor affinities of 5-phenylsulfanyl- and 5-benyzl-substituted tet-
rahydro-2-benzazepines.
Compd
X
R1
Ki [nm][a]
Selectivity
s1
s2
178
>1 mm[b]
>1 mm[b]
>1 mm[b]
>1 mm[b]
345
54Æ7
339
256
149
125
>1 mm[b]
476
s1/s2
2a[9]
2b[9]
10
–
–
S
n-C4H9
CH2C6H5
H
2.0Æ0.10
61Æ8
88
>16
–
1850
1910
18
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
H
CH3
n-C4H9
n-C5H11
–
19a
19b
19c
19d
19e
19 f
19g
19h
19i
19j
19k
19l
19m
19n
282Æ40
>4
41
13
8
71
3
52
–
30
2
28
–
125
–
–
13
0.6
8.5Æ0.37
4.9Æ1.1
45Æ6.9
3.6Æ1.2
53Æ7.5
2.4Æ0.9
19Æ0.9
16Æ0.9
118 Æ13
60Æ4.7
70Æ20
CH2CH(CH3)2
CH2CH=C(CH3)2
CH2-cyclopropyl
CH2-cyclohexyl
CH2C6H5
(CH2)2C6H5
(CH2)4C6H5
CH2-2-furyl
CH2-2-thienyl
CH2C6H4-4-F
CH2C6H4-4-OMe
Affinity of 19b and 19m toward other receptors
On the basis of the s1 affinity and s1/s2 selectivity,
the butyl- and 4-fluorobenzyl-substituted 2-benzaze-
pines 19b and 19m were selected for further evalua-
tion. Both compounds were tested in 53 assays for
relevant receptors (for example, noradrenaline, dopa-
mine, histamine, serotonin, glutamate, GABA, opioid,
and progesterone receptors), transporters (such as
noradrenaline, dopamine, and serotonin transport-
ers), ion channels (for example, Na+, Ca2+, and ClÀ
channels), and enzymes (like the monoaminoxidases).
At a test compound concentration of 1.0 mm, both
compounds showed a rather good selectivity against
201
1670
>1 mm[b]
889
7.1Æ3.2
24Æ3.5
5.7Æ2.2
6.3Æ1.6
89Æ29
>1 mm[b]
–
(+)-pentazocine
haloperidol
di-o-tolylguanidine
78Æ2.3
58Æ18
[a] All values were determined in triplicate (n=3), and data represent the meanÆ
SEM; for compounds showing very low affinity in the first experiment, repetitions
were not performed (n=1). [b] At a test compound concentration of 1 mm, the de-
crease in radioligand binding was <30%.
substituent on the benzyl moiety, such as a methoxy group (in
19n), decreased the s1 affinity, an electron-accepting substitu-
ent like a fluoro group (in 19m) increased the s1 affinity.
Altogether, the butyl (19b: Ki =8.5 nm), pentyl (19c: Ki =
4.9 nm), dimethylallyl (19e: Ki =3.6 nm), cyclohexylmethyl
(19g: Ki =2.4 nm), and 4-fluorobenzyl (19m: Ki =7.1 nm) deriv-
atives represent the most potent s1 ligands within this series
of compounds.
these molecular targets. The butyl derivative 19b revealed
only interactions with the a1A receptor (63% inhibition of
radioligand binding) and the dopamine transporter (66% in-
hibition of radioligand binding). Competition between radioli-
gands and the 4-fluorobenzyl-substituted derivative 19m was
found in the D4 (91% inhibition) and H2 (59%) receptor assays
and in the noradrenaline (71%) and dopamine (85%) trans-
porter assays.
The s2 affinity of the 5-benzyl-substituted 2-benzazepines 18
and 19 is considerably lower than the s1 affinity, which
showed their preference for the s1 subtype. The pentyl deriva-
tive 19c is the only ligand with a s2 affinity below 100 nm. As
a general tendency, the s2 affinity of the (hetero)arylmethyl de-
rivatives is lower than the s2 affinity of the alkyl-substituted 2-
benzazepines. Thus, the 4-fluorobenzyl derivative 19m shows
the highest s1/s2 selectivity (factor of 125) for this series of
compounds. However, the s1/s2 selectivity of the cyclohexyl-
methyl derivative 19g (factor of 52) is also very high.
Animal experiments performed with 19b and 19m
To get an idea about the tolerability of the 2-benzazepines
19b and 19m, the Irwin test[49] was performed. In this assay,
increasing doses of 19b and 19m (1–100 mgkgÀ1 body
weight) were injected intraperitoneally and the behavior of the
mice was observed for 24 h. The mice did not show unusual
reactions after intraperitoneal application of either 19b or
19m. Only at the highest dose of 100 mgkgÀ1 body weight,
was a decreased abdominal tone observed with both test com-
pounds during the first 1–2 h. This result indicates that 2-
benzazepines 19b and 19m are well tolerated by the mice.
It has been reported that s1 modulators are able to improve
neuronal deficits,[17] so a cognition test[50] was performed. In
this test, the recognition of an object after scopolamine-in-
Affinity toward various binding sites of the NMDA receptor
It has been reported that compounds with a small substituent
at the N atom (such as H or CH3) interact preferentially with
the phencyclidine binding site of the NMDA receptor, whereas
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duced amnesia was recorded. Doses of 1, 3, 10, and
30 mgkgÀ1 body weight of the 2-benzazepines 19b and 19m
were injected intraperitoneally into mice 40 min before the
first and 110 min before the second trial. Scopolamine
(0.3 mgkgÀ1 body weight) was injected to induce amnesia
10 min after injection of the test compound. (For the setup of
the experiment, see figure SI1 in the Supporting Information).
The butyl derivative 19b did not improve object recognition,
even at the highest dose of 30 mgkgÀ1 body weight (Fig-
ure SI2 in the Supporting Information). However, the 4-fluoro-
benzyl derivative 19m showed a weak but not significant im-
provement in object recognition. At doses of 10 and
30 mgkgÀ1 body weight, the object exploration during the
second trial was similar to the object exploration with the ref-
erence compound thioperamide (Figure SI3 in the Supporting
Information). It can be concluded that the 4-fluorobenzyl deriv-
ative 19m represents a weak cognition-enhancing drug.
with N substituents larger than a linear propyl group. The
butyl, dimethylallyl, cyclohexylmethyl, and 4-fluorobenzyl de-
rivatives 19b, 19e, 20g, and 19m represent potent s1 ligands
with Ki values below 10 nm and s1/s2 selectivity greater than
40. The butyl and 4-fluorobenzyl derivatives 19b and 19m
show high selectivity over more than 50 further relevant tar-
gets. The clean profile in the Irwin screen indicates a low side
effect potential for both 19b and 19m. Whereas the butyl de-
rivative 19b did not show analgesic activity or improved
object recognition, the 4-fluorobenzyl derivative 19m revealed
weak but not significant activity in the formalin assay of neuro-
pathic pain and the object recognition assay. Thus, the 4-fluo-
robenzyl derivative 19m represents a promising starting point
for the development of s1 ligands with cognition-enhancing
and analgesic activity.
Experimental Section
s1 Receptor antagonists represent a promising class of new
drugs for the treatment of neuropathic pain.[20] Therefore, the
potential of the 2-benzazepines 19b and 19m in the formalin
assay[51] as a model for neuropathic pain was investigated. In
this assay, doses of 1, 3, and 10 mgkgÀ1 body weight of the s1
ligands 19b and 19m were injected intraperitoneally into
mice. After 15 min, an inflammatory process was induced upon
injection of formalin into the hind paw. During the acute pain
phase (0–5 min), the number of licking activities per second
was regarded as a correlate for pain intensity. After 5 min, the
acute pain phase decreased and a phase of neuropathic pain
developed. In this situation, pain stimuli were set by pushing
a von Frey filament on the inflamed paw of the mice and the
reactions of the mice were recorded for 10–35 min after for-
malin injection. During the late phase of neuropathic pain, the
butyl derivative 19b did not decrease the pain reactions of the
mice, which indicates low analgesic activity. However, after ad-
ministration of the 4-fluorobenzyl derivative 19m, weak anal-
gesic activity was observed at the highest recorded dose of
10 mgkgÀ1 body weight. However, the weak analgesic activity
is not statistically significant.
Chemistry
1
General: H NMR (400 MHz) and 13C NMR (100 MHz) spectroscopy:
Mercury-400BB spectrometer (Varian); chemical shift (d) in ppm re-
lated to tetramethylsilane; coupling constants are given with
0.5 Hz resolution. HPLC: Merck Hitachi equipment; UV detector: l-
7400; autosampler: l-7200; pump: l-7100; degasser: l-7614.
Unless otherwise stated, the purity of all of the test compounds
was greater than 95% according to two different HPLC methods.
(Æ)-3-[2-(Dimethoxymethyl)phenyl]-4-oxo-4-phenylbutyronitrile
(11): Under N2, a solution of benzaldehyde (1.33 mL, 13.2 mmol) in
DMF (6.6 mL) was added slowly (1 h) to a suspension of NaCN
(323 mg, 6.58 mmol) in DMF (6.6 mL) at 358C. The mixture was
stirred at 358C for 2 h. A solution of 5 (2.00 g, 9.86 mmol) in DMF
(13.2 mL) was then added within 4 h, and the suspension was
stirred for 12 h at 358C. H2O (600 mL) was added, and the mixture
was extracted with Et2O (4ꢃ100 mL). The combined organic layers
were washed with H2O (3ꢃ100 mL), dried (K2CO3), and concentrat-
ed in vacuo, and the residue was purified by flash chromatography
(6ꢃ18 cm, petroleum ether/EtOAc (9/1), 65 mL, Rf =0.17). The
product was recrystallized with petroleum ether/EtOAc (8/2). Color-
1
less crystals; yield: 1.48 g (49%); mp: 1008C; H NMR (CDCl3): d=
2.86 (dd, J=16.4, 4.5 Hz, 1H; CH2CN), 3.07 (dd, J=16.4, 8.5 Hz, 1H;
CH2CN), 3.48 (s, 3H; OCH3), 3.51 (s, 3H; OCH3), 5.41 (s, 1H;
CH(OCH3)2), 5.54 (dd, J=8.5, 4.4 Hz, 1H; CHCH2CN), 7.02–7.06 (m,
1H; Harom), 7.19–7.28 (m, 2H; Harom), 7.31–7.37 (m, 2H; Harom), 7.41–
7.49 (m, 2H; Harom), 8.02–8.05 ppm (m, 2H; Harom).
Additionally, the antidepressive effect of the s1 ligand 19m
was evaluated in the forced swim test, the open field test, and
the home cage activity test after oral administration of 50 and
100 mgkgÀ1 body weight in mice. Compound 19m did not
produce any significant behavioral changes in the forced swim
test, did not have any effect on anxiety-related behavior or on
locomotor activity in the open field test, and did not produce
any behavioral changes during long-term home cage monitor-
ing. It can be concluded that the 4-fluorobenzyl derivative
19m does not have any antidepressant-like effect in mice.
(Æ)-3-[2-(Dimethoxymethyl)phenyl]-4-phenylbutyramide (15): Al-
cohol 12 (2.03 g, 6.5 mmol), K2CO3 (3.59 g, 25.9 mmol), and Pd/C
(10%, 1.20 g) were suspended in CH3OH (300 mL), and the mixture
was stirred at room temperature under H2 (1 bar) for 16 h. The mix-
ture was filtered through Celite. A saturated solution of NaCl
(100 mL) was added to the filtrate, and the mixture was extracted
with CH2Cl2 (4ꢃ60 mL). The combined organic layers were dried
(Na2SO4) and concentrated in vacuo, and the residue was purified
by flash chromatography (6.5ꢃ24 cm, EtOAc, 65 mL, Rf =0.34). Pale
yellow oil; yield: 1.99 g (98%); 1H NMR (CDCl3): d=2.81–2.87 (m,
2H; CH2Ph), 2.98 (dd, J=13.2, 7.5 Hz, 1H; CH2CONH2), 3.13 (dd, J=
13.2, 7.1 Hz, 1H; CH2CONH2), 3.40 (s, 3H; OCH3), 3.53 (s, 3H; OCH3),
3.92–4.06 (m, 1H; CHCH2CONH2), 5.31 (s, 1H; CH(OCH3)2), 7.25–7.31
(m, 2H; Harom), 7.35–7.48 (m, 4H; Harom), 7.56–7.63 ppm (m, 3H;
Harom); the signal for the protons of the NH2 group is not visible in
the 1H NMR spectrum.
Conclusions
The novel synthetic strategy of connecting a C6–C1 building
block with a C3–N fragment by a Heck reaction, a Stetter reac-
tion, and reductive cyclization led to the tetrahydro-2-benzaze-
pine building block 18, which allowed the introduction of di-
verse substituents at the N atom during the last step of the
synthesis. High s1 affinity was observed for 2-benzazepines
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CHEMMEDCHEM
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(Æ)-2-(4-Amino-1-phenylbutan-2-yl)benzaldehyde
dimethyl
EtOAc (7/3), 10 mL, Rf =0.35). Pale yellow oil; yield: 79 mg (55%);
C24H24FN (345.2); purity (HPLC, method I): 97.9%; purity (HPLC,
method II): 96.3%; 1H NMR ([D8]toluene): d=1.58–1.69 (m, 1H; 4-
CH2), 1.83–2.02 (m, 1H; 4-CH2), 2.75–2.87 (m, 1H; CH2Ph), 2.89–3.01
(m, 1H; CH2Ph), 3.10–3.27 (m, 2H; 3-CH2), 3.27–3.37 (m, 1H; 5-CH),
3.47 (s, 2H; CH2C6H4F), 3.92 (d, J=14.3 Hz, 1H; 1-CH2), 3.96–4.14
(m, 1H; 1-CH2), 6.97–7.04 (m, 2H; Harom), 7.14–7.36 ppm (m, 11H;
Harom); 13C NMR ([D8]toluene): d=29.5 (1C; 4-CH2), 40.3 (1C; CH2Ph),
58.1 (1C; CH2C6H4F), 59.5 (1C; 1-CH2), 115.4, 115.6, 125.5, 125.7,
126.5, 126.6, 127.8, 128.1, 128.3, 128.6, 129.8, 130.8, 130.9, 137.8,
139.3, 141.5, 161.6, 163.9 ppm (18C; Carom); the signals for the C3
and C5 carbon atoms are not visible in the 13C NMR spectrum; IR
(ATR): n˜ =3025 (CÀHarom), 2922, 2850 (CH2), 756 (1,2-disubstituted
arom), 698 cmÀ1 (monosubstituted arom); MS (ESI): m/z (%): 346
[M+H+] (100).
acetal (16): Under N2, the primary amide 15 (1.38 g, 4.41 mmol)
was dissolved in THF (150 mL), and the solution was cooled to 48C
in an ice bath. LiAlH4 (834 mg, 21.9 mmol) was added, and the mix-
ture was stirred for 4 h at 48C and for 12 h at room temperature.
The suspension was diluted with THF (50 mL), a small amount of
water was added carefully, and the precipitate was removed by fil-
tration. The solvent was evaporated in vacuo, and the residue was
purified by flash chromatography (6ꢃ20 cm, EtOAc/CH3OH/N,N-di-
methylethanamine (8/2/0.01), 65 mL, Rf =0.22). Colorless oil; yield:
1.00 g (76%); 1H NMR (CDCl3): d=1.52 (brs, 2H; NH2), 1.85–1.97
(m, 2H; CH2CH2NH2), 2.47–2.57 (m, 1H; CH2NH2), 2.58–2.66 (m, 1H;
CH2NH2), 2.85–2.95 (m, 1H; CH2Ph), 2.96–3.04 (m, 1H; CH2Ph), 3.18
(s, 3H; OCH3), 3.35 (s, 3H; OCH3), 3.79 (quint, J=7.4 Hz, 1H;
PhCHCH2), 5.47 (s, 1H; CH(CH3)2), 7.17–7.36 (m, 6H; Harom) 7.38–7.47
(m, 2H; Harom), 7.81 ppm (d, J=7.9 Hz, 1H; Harom).
(Æ)-5-Benzyl-2,3,4,5-tetrahydro-1H-2-benzazepine (18): Under N2,
p-toluenesulfonic acid (1.04 g, 5.48 mmol) was added to a solution
of primary amine 16 (1.09 g, 3.65 mmol) in THF (450 mL), and the
mixture was stirred at room temperature for 2 h. NaBH3CN
(459 mg, 7.30 mmol) was then added, and the mixture was stirred
at room temperature for 1 h. A saturated solution of NaHCO3
(100 mL) was added, and the mixture was extracted with CH2Cl2
(4ꢃ100 mL). The combined organic layers were dried (K2CO3), fil-
tered, and concentrated in vacuo, and the residue was purified by
flash chromatography (3.5ꢃ20 cm, EtOAc/CH3OH/N,N-dimethyle-
thanamine (8/2/0.01), 20 mL, Rf =0.24). Colorless oil; yield: 417 mg
Receptor binding studies
For details of the s1 and s2 assays, see references [43,44]. For de-
tails of the NMDA assay, see references [47,48].
Acknowledgements
This work was supported by the Deutsche Forschungsgemein-
schaft (DFG).We are very grateful to Schwarz Pharma AG, Mon-
heim, for supporting this project and performing the receptor
screening and animal tests of compounds 19b and 19m. Thanks
are also due to Affectis Pharmaceuticals, Martinsried, Germany,
for performing the antidepressant animal tests.
1
(48%); H NMR ([D8]toluene): d=1.03 (brs, 1H; NH), 1.62–1.75 (m,
1H; 4-CH2), 1.86–1.96 (m, 1H; 4-CH2), 2.99–3.08 (m, 1H; CH2Ph),
3.08–3.16 (m, 1H; CH2Ph), 3.18–3.39 (m, 2H; 3-CH2), 3.40–3.48 (m,
1H; 5-CH), 4.13 (d, J=14.9 Hz, 1H; 1-CH2), 4.22 (d, J=14.9 Hz, 1H;
1-CH2), 7.21–7.48 ppm (m, 9H; Harom); 13C NMR ([D8]toluene): d=
35.2 (1C; 4-CH2), 40.3 (1C; CH2Ph), 50.3 (1C; 5-CH), 55.7 (1C; 1-
CH2), 123.6, 125.2, 125.5, 125.7, 126.5, 127.4, 128.1, 128.3, 137.8,
141.6, 143.6, 145.5 ppm (12C; Carom); the signal for the C3 carbon
atom is not observed in the 13C NMR spectrum.
Keywords: antidepressant
neuropathic pain · receptors · structure–activity relationships
activity
·
benzazepines
·
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Received: April 4, 2014
Published online on June 4, 2014
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ChemMedChem 2014, 9, 1697 – 1703 1703