Azepino- and diazepinoindoles: Synthesis and dopamine receptor binding profiles

Article abstract of DOI:10.1002/1521-4184(20009)333:9<287::AID-ARDP287>3.0.CO;2-R

Starting from the readily available building blocks 7, 10, 11, and 15, the synthesis of the fused indoles 1, 2, 5, and 6, respectively, is reported. The syntheses involved Pictet-Spengler cyclizations, Michael addition reactions, lactamization, directed m

Full text of DOI:10.1002/1521-4184(20009)333:9<287::AID-ARDP287>3.0.CO;2-R

Azepino- and Diazepinoindoles
287
Azepino- and Diazepinoindoles: Synthesis and Dopamine Receptor
Binding Profiles
Johannes Kraxner, Harald Hübner, and Peter Gmeiner*
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstrabe 19, D-91052 Erlangen, Germany
Key Words: Dopamine receptor binding; D ; D ; D ; D ; indoles; bioisosteric replacement
1
2
3
4
Summary
Starting from the readily available building blocks 7, 10, 11, and
15, the synthesis of the fused indoles 1, 2, 5, and 6, respectively,
is reported. The syntheses involved Pictet-Spengler cyclizations,
Michael addition reactions, lactamization, directed metallation,
and reductive amination as the key reaction steps. Radioligand
displacement studies comprising the dopamine receptor subtypes
D1, D2long D2short, D3, and D4.4 were performed when the diazepi-
noindole 6 revealed D1 and D4 affinities (Ki = 0.11 µM and
1.7 µM, respectively) which are comparable to the partial D1
agonist SKF 38393 (3b). In contrast to the benzazepine 3b, the
indole based test compounds turned out less selective over the D2
and D3 receptor subtype.
Introduction
Dysfunction of CNS dopaminergic neurotransmission has
been implicated in several neuropsychiatric diseases with
treatments based on the use of dopamine receptor agonists or
[1]
antagonists . Dopamine receptors can be classified into the
two main categories, the D and the D receptors on the basis
1
2
[2]
of the accumulated biochemical and pharmacological data
Due to molecular cloning techniques, several additional types
of dopamine receptors , notably the D -like D and D recep-
.
2
3
4
[3]
tors and the D -like D subtype, were identified . Balancing
1
5
the opposing action of D and D regulation may hold the key
1
2
[4]
to optimal drug therapy . Thus, SAR studies in this field are
of special interest.
Scheme 1
With the availability of the first D selective antagonist
1
[5]
SCH 23390 (3a) , SKF 38393 (3b) and related partial
agonists were evaluated when the structural requirements
[6]
Synthesis
for D affinity proved to be more stringent than those for the
1
The synthesis of the target compound 1 was performed
[11]
D subtype. Very interesting studies of Seiler and coworkers
2
starting from the indole-4-carbaldehyde 7
(Scheme 2).
demonstrated that the bioisosteric replacement ofthe unstable
catechol substructure of dopamine by the indole nucleus,
Treatment of 7 with PhMgBr resulted in formation of the
secondary alcohol 8a in 98% yield. Subsequent transforma-
tion of 8a into the chloride 8b was accomplished under mild
combined with conformational restrictions leads to the D
active benzergolines . Application of this strategy to the
1
[7]
reaction conditions using PPh and CCl . Since an attempted
3
4
phenylbenzazepines of type 3 leads to phenylazepinoindole
displacement reaction of 8b in the presence of NaCN resulted
[8]
derivatives . As an extension of recent investigations of the
in destruction of the starting material we used the system
[9]
peri-fused congener 4 , we herein describe our studies on
[12]
TMSCN/TiCl
for the preparation of 8c. Employing these
4
the synthesis and dopamine receptor binding properties of
regioisomeric analogs (Scheme 1). Since we were intrigued
by the SARs produced by the spatial relationships between
the indole nucleus, the amino group and the phenyl ring as
the potential pharmacophoric substructures, we planned to
reaction conditions we obtained the nitrile 8c in 96% yield.
Subsequent LiAlH reduction of 8c afforded the primary
4
amine 9a which on reaction with ethyl formate, followed by
reduction with LiAlH gave the N-methylated product 9b.
4
[10]
Finally, Pictet-Spengler cyclization of 9b, using formalde-
hyde and acetic acid, afforded the azepinoindole 1 in 62%
yield.
approach the test compounds of type 1, 2, 5 , and 6. Thus,
both the position of the nitrogen atom, relative to the aromatic
moieties, and the type of annelation should be considered.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0365-6233/00/0909/0287 $17.50 +.50/0

288
Kraxner, Hübner, and Gmeiner
13 lead to an inseparable mixture of the desired 1-phenyl-
1,2,3,4,5,6-hexahydroazepino[4,5-b]indole together with the
indoline derivative 1-phenyl-1,2,3,4,5,5a,6,10b-octahy-
droazepino[4,5-b]indole as a pure diastereomer (the relative
configuration was not established). To circumvent the purifi-
cation problems, the mixture was reacted with formaldehyde
in the presence of NaCNBH , resulting in the formation of
3
the N-methyl derivatives 5 and 14. After flash chroma-
tographic separation, the azepinoindole 5 and the undesired
product 14 could be isolated in 43% and 38% yield, respec-
tively.
Our approach for the synthesis of the target compound 6
[15]
involved directed metallation of the acetal 15
and Michael
addition of the corresponding indolyl lithium intermediate to
β-nitrostyrene (Scheme 4). Reduction of the nitro derivative
16 with H and Pd/C provided the primary amine 17. Since
2
our attempts to convert the amino acetal 17 into the cyclic
imine 19 using p-TosOH and toluene as solvent resulted in
complete destruction of the starting material, we developed a
one pot procedure for the synthesis of the diazepinoindole 6.
According to our very recently reported method for the syn-
[16]
thesis of pyrido- and pyrimidoindoles , treatment of the
nitro acetal 16 with aqueous hydrochloric acid and sub-
sequent addition of zinc dust afforded the ring closure product
18. Finally, reductive methylation of the secondary amine 18
with formaldehyde and NaCNBH gave the target compound
6 in 85% yield.
3
Scheme 2
In a similar manner we prepared the regioisomer 2. Treat-
[13]
ment of the secondary amine 10
with benzaldehyde and
acetic acid resulted in formation of the tricyclic test com-
pound 2.
The preparation of the azepino[4,5-b]indole 5 was elabo-
rated starting from the indole-2-acetic acid ethyl ester 11
[14]
(Scheme 3). Heating of 11
with β-nitrostyrene gave the
Michael addition product 12 in 76% yield. Subsequent reduc-
tion of the nitro group was accomplished by catalytic hydro-
genation using Pd/C and methanol as solvent. Under these
conditions, ring closure of the intermediate primary amine
occurred and we obtained the lactam 13. Borane reduction of
Scheme 4
Receptor Binding Studies
The ability of the fused indoles 1, 2, 5, and 6 to displace the
3
3
radioligands [ H]-SCH 23390 and [ H]-spiperone labeling
[17]
[18]
[19]
bovine D and human D
receptors was evaluated (Table 1) . The K values of the
, D
2long
, D
, and D
1
2short
[20]
3
4
i
test compounds were compared to those of the selective D
1
ligand SKF 38393 (3b). Both affinities and selectivities for
the azepinoindoles 1, 2, and 5 including the indoline 14 were
Scheme 3
Arch. Pharm. Pharm. Med. Chem. 333, 287–292 (2000)

Azepino- and Diazepinoindoles
289
Table 1. Binding data (Ki values [µM]) of the test compounds employing bovine dopamine D1 and human D2 long, D2 short, D3, and D4.4 receptors.
—————————————————————————————————————————————————————————————
Compound D1 D2long D2short D3 D4.4
—————————————————————————————————————————————————————————————
1
1.6 ± 0.15
15.0 ± 5.4
30.0 ± 8.0
8.5 ± 3.5
12.0 ± 2.0
36.0 ± 9.0
7.0 ± 0.70
0.34 ± 0.010
32.0 ± 4.0
10.0 ± 3.0
11.0 ± 1.8
17.0 ± 4.0
8.8 ± 0.15
0.76 ± 0.095
8.6 ± 1.3
3.7 ± 0.15
12.0 ± 2.0
3.2 ± 0.050
1.7 ± 0.10
6.5 ± 0.50
4.4 ± 0.75
2
3.2 ± 0.50
5
2.6 ± 0.050
0.11 ± 0.0050
16.0 ± 2.0
6
0.63 ± 0.045
32.0 ± 9.0
17.0 ± 0.0
14
SKF 38393 (3b)
0.068 ± 0.015
13.0 ± 0.50
—————————————————————————————————————————————————————————————
tion mass spectroscopy: Finnigan MAT 8200. NMR : Bruker AM 360,
disappointing when the data indicated K values in the micro-
molar range for the receptors investigated. However, the
i
Bruker AC 250. NMR spectra were measured in CDCl3 using TMS as an
internal standard. Elemental analyses were performed by Beetz Microana-
lysis Laboratory and by the Organic Chemistry Department of the Friedrich-
Alexander University Erlangen-Nürnberg and the results were within the
range of ±0.4% of the calculated values.
binding profile of the diazepinoindole 6 displayed D affinity
1
(K = 0.11 µM) which is comparable to SKF 38393 (K =
i
i
0.07 µM). Due to the poor bio-availability that is known for
catechol derivatives, the indole bioisostere 6 is expected to
be superior to 3b under in vivo conditions. In contrast to SKF
38393 (3b), the diazepinoindole 6 is substantially less selec-
4-Methyl-6-phenyl-3,4,5,6-tetrahydro-1H-azepino[3,4,5-cd]indole (1)
tive over D
, D
, and D . Competition experiments
2long
2short 3
To a solution of 9b (17 mg, 0.07 mmol) in MeOH (5 ml) and acetic acid
(1 ml) was added formaldehyde (0.05 ml, 37% in H2O). After stirring for
22 h at room temperature the solution was basified with 2N NaOH and
extracted with CH2Cl2 (15 ml). The organic layer was dried (Na2SO4) and
evaporated and the residue was purified by flash chromatography
(CH2Cl2/MeOH 95:5) togive 1 (11mg, 62%) as a colorless solid, mp. 58 °C.–
Anal. C18H18N2 (262.35).– EI-MS 262 (M•+).– IR (NaCl): ν = 3400, 2930,
1490, 750, 700 cm–1.– 1H NMR (CDCl3): δ = 2.55 (s, 3H, CH3), 3.23–3.29
(m, 2H, CHCH2), 3.99 (dd, J = 14.5, 1.2 Hz, 1H, ArCH2), 4.11 (d, J =
14.5 Hz, 1H, ArCH2), 4.54–4.60 (m, 1H, CHCH2), 6.53 (ddd, J = 7.2, 7.2,
1.0 Hz, 1H, H-arom), 6.98–7.03 (m, 2H, H-arom), 7.17–7.33 (m, 6H, H-
arom), 8.21 (br. s, 1H, NH).
employing human D4.4 receptors gave K values of 1.7 and
i
4.4 µM for 6 and 3b, respectively. To acquire evidence for a
probable agonistic effect of the test compounds, the hill
slopes (h) of the corresponding receptor binding curves were
calculated. According to the low affinities of most of the
compounds to the dopamine receptors only the binding ex-
periments of 3b (at bovine D ) and 6 (at bovine D , human
1
1
D , and human D
2 long
) provided complete sigmoid
2 short
curves which could be analyzed. The resulting h = –0.66 for
3b represents a reliable feature of a D agonist or partial
1
agonist. In contrast, the hill slopes h = –1.00 (for D ), h =
1
–1.09 (for D
), and h = –0.93 (D
) for the diazepi-
2 long
2 short
4-Methyl-3-phenyl-3,4,5,6-tetrahydro-1H-azepino[3,4,5-cd]indole (2)
noindole 6 indicate an antagonistic effect. Due to the current
To a solution of 10[13] (80 mg, 0.46 mmol) in MeOH (10 ml) and acetic
acid (1 ml) was added benzaldehyde (0.2 ml, 2 mmol). After stirring for 1 h
at 60 °C the solution was basified with 2N NaOH and extracted with CH2Cl2
(30 ml). The organic layer was dried (Na2SO4) and evaporated and the
residue was purified by flash chromatography (CH2Cl2/MeOH 95:5) to give
2 (87mg, 73%) as a colorless solid, mp. 213 °C.– Anal. C18H18N2 (262.35).–
EI-MS 262 (M•+).– IR (NaCl): ν = 3105, 2890, 1455, 760, 700 cm–1.– 1H
NMR (CDCl3): δ = 2.46 (s, 3H, CH3), 3.04 (dd, J = 11.6, 7.9 Hz,1H, NCH2),
3.18–3.26 (m, 1H, NCH2), 3.34–3.43 (m, 2H, ArCH2), 4.99 (s, 1H, Ar2CH),
6.55–6.58 (m, 1H, H-2), 6.93 (dd, J = 7.2, 1.0 Hz, 1H, H-arom), 7.12 (dd, J
= 7.2, 7.2 Hz, 1H, H-arom), 7.19–7.33 (m, 6H, H-arom), 8.04 (br. s, 1H, NH).
interest in receptor binding profiles combining D affinity
1
[4]
and graduated binding to the receptors of the D family ,
2
further investigations in this field are envisaged.
Acknowledgments
The authors wish to thank Dr. H.H.M. Van Tol (Clarke Institute of
Psychiatry, Toronto), Dr. J.-C. Schwartz and Dr. P. Sokoloff (INSERM,
Paris) as well as Dr. J. Shine (The Garvan Institute of Medical Research,
Sydney) for providing dopamine D4, D3, and D2 receptor expressing cell
lines, respectively. Mrs. U. Ohnmacht is acknowledged for helpful discus-
sions. Thanks are due to Mrs. B. Linke, Mrs. P. Schmitt and Mrs. H.
Szczepanek for skillful technical assistance. This work was supported by the
Fonds der Chemischen Industrie.
3-Methyl-1-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5)
3,6-Dimethyl-1-phenyl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole
(14)
Experimental Section
To a solution of 13 (185 mg, 0.7 mmol) in THF (20 ml) was added
BH3×THF (7 ml, 1M in THF) at room temperture. After being refluxed for
2 h it was cooled to 0 °C when 2N HCl (4 ml) was added. After being stirred
for 1 h at 60 °C the mixture was basified with 2N NaOH and extracted with
CH2Cl2 (45 ml). The organic layer was dried (Na2SO4) and evaporated and
the residue was purified by flash chromatography (CH2Cl2/MeOH 9:1) to
give a mixture of 1-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole to-
gether with 1-phenyl-1,2,3,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole
(145 mg, 83%).
General
THF was distilled from Na, CH2Cl2, and DMF from CaH2 immediately
before use. Unless otherwise noted, reactions were conducted under dry N2.
Evaporations of final product solutions were done under vacuum with a
rotary evaporator. Flash chromatography was carried out with 230–400 mesh
silica gel. Melting points: Büchi melting point apparatus, uncorrected. IR:
Jasco FT/IR-410. Mass spectrometry: Finnigan MAT TSQ 70. High resolu-
Arch. Pharm. Pharm. Med. Chem. 333, 287–292 (2000)

290
Kraxner, Hübner, and Gmeiner
To a solution of the above mixture (90 mg, 0.4 mmol) in MeOH (5 ml)
Phenyl-[(1-toluene-4-sulfonyl)indol-4-yl]acetonitrile (8c)
were added NaCNBH3 (65 mg, 1 mmol) and formaldehyde (0.5 ml, 37% in
H2O). After being stirred for 1 h at room temperature 2N HCl (5 ml) was
added and stirring was continued for 15 min. Then the mixture was basified
with 2N NaOH and extracted with CH2Cl2 (30 ml). The organic layer was
dried (Na2SO4) and evaporated and the residue was purified by flash chro-
matography (CH2Cl2/MeOH 95:5) to give 14 (38 mg, 38%) followed by 5
(41 mg, 43%).
14: colorless oil.– HR-EI-MS for C20H24N2 : calcd 292.1939, found
292.1934.– IR (NaCl): ν = 2930, 2800, 1600, 1480, 750, 700 cm–1.– 1H NMR
(CDCl3): δ = 1.88–2.02 (m, 1H, CHCH2CH2NCH3), 2.31–2.39 (m, 4H,
NCH3, CHCH2CH2NCH3), 2.57 (ddd, J = 12.7, 10.3, 5.5 Hz, 1H,
CH2CH2NCH3), 2.67 (dd, J = 14.1, 3.3 Hz, 1H, ArCHCH2), 2.72 (s, 3H,
ArNCH3), 2.85–3.01 (m, 3H, CHCH2CH2, CH2CH2NCH3, ArCHCH2), 3.30
(ddd, J = 10.9, 10.9, 3.3 Hz, 1H, ArCHCH2), 3.62 (dd, J = 10.9, 10.9 Hz, 1H,
ArCH) , 6.22 (d, J = 7.6 Hz, 1H, H-arom), 6.45 (ddd, J = 7.6, 7.6, 1.1 Hz,
1H, H-arom), 6.50(d, J = 7.6 Hz, 1H, H-arom), 7.01 (ddd, J = 7.6, 7.6, 1.0 Hz,
1H, H-arom), 7.26–7.30 (m, 1H, H-arom), 7.33–7.40 (m, 2H, H-arom),
7.43–7.49 (m, 2H, H-arom).
5: colorless solid, mp 54–56 °C.– HR-EI-MS for C19H20N2: calcd
276.1627, found 276.1629.– IR (NaCl): ν = 3400, 2930, 1460, 740,
700 cm–1.– 1H NMR (CDCl3): δ = 2.43 (s, 3H, CH3), 2.74 (ddd, J = 12.4,
10.2, 2.4 Hz, 1H, NCH2CH2), 2.90 (ddd, J = 15.9, 6.1, 2.4 Hz, 1H, ArCH2),
2.94–3.07 (m, 2H, CHCH2, NCH2CH2), 3.20 (ddd, J = 15.9, 10.2, 3.2 Hz,
1H, ArCH2), 3.36 (dd, J = 13.2, 6.2 Hz, 1H, CHCH2), 4.42–4.48 (m, 1H,
CHCH2), 6.87–6.97 (m, 2H), 7.03–7.09 (m, 1H), 7.14–7.20 (m, 1H), 7.22–
7.29 (m, 5H), 7.79 (br. s 1H).
To a solution of 8b (2.14 g, 5.4 mmol) and trimethylsilyl cyanide (0.72 ml,
5.4 mmol) in CH2Cl2 (25 ml) was added titanium tetrachloride (5.4 ml, 1M
in CH2Cl2, 5.4 mmol). After stirring for 4 h MeOH (10 ml), H2O (30 ml) and
CH2Cl2 (75 ml) were added successively. The organic layer was washed with
a saturated solution of NaHCO3 (50 ml) and H2O (50 ml), dried (Na2SO4)
and concentrated in vacuo. The residue was purifiedbyflashchromatography
(petroleum ether/EtOAc 7:3) to give 8c (2.00 g, 96%) as a colorless solid mp.
54–56 °C.– Anal. C23H18NO2S (386.47).– EI-MS 386 (M•+).– IR (KBr): ν
= 3140, 2920, 2240, 1175, 1130, 760, 700 cm–1.–1H NMR (CDCl3): δ = 2.35
(s, 3H, CH3), 5.39 (s, 1H, Ar2CH), 6.63 (dd, J = 3.7, 0.8 Hz, 1H, H-3),
7.21–7.37 (m, 9H, H-arom), 7.59 (d, J = 3.7 Hz, 1H, H-arom), 7.73–7.80 (m,
2H, H-arom), 7.99 (ddd, J = 8.1, 8.1, 0.8 Hz, 1H, H-arom).
2-(Indol-4-yl)-2-phenylethylamine (9a)
To a suspension of LiAlH4 (78 mg, 2 mmol) in THF (10 ml) was added a
solution of 8c (211 mg, 0.5 mmol) in THF (10 ml) at 0 °C. After stirring for
24 h at 60 °C a saturated solution of Na2SO4 was added slowly until the color
of the suspension changed from light grey to white, followed by addidtion of
EtOAc (20 ml). The mixture was filtered and the residue washed with MeOH
(20 ml). The organic layer was evaporated and the residue was purified by
flash chromatography (CH2Cl2/MeOH 9:1) to give 9a (51 mg, 40%) as a
colorless oil.– Anal. C16H16N2 (236.32).– EI-MS 236 (M•+).– IR (NaCl): ν
= 3400, 3050, 2920, 1450, 740, 700 cm–1.– 1H NMR (CDCl3): δ = 3.40 (dd,
J = 12.4, 7.6 Hz, 1H, CH2), 3.49 (dd, J = 12.4, 7.6 Hz, 1H, CH2), 4.46 (dd,
J = 7.6, 7.6 Hz, 1H, CHCH2), 6.54–6.57 (m, 1H, H-arom), 7.04 (d, J = 7.1 Hz,
1H, H-arom), 7.11–7.35 (m, 8H, H-arom), 8.32 (br. s, 1H, NH).
3-Methyl-1-phenyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (6)
[2-(Indol-4-yl)-2-phenylethyl]methylamine (9b)
To a solution of 18 (47 mg, 0.18 mmol) in MeOH (5 ml) were added
NaCNBH3 (24 mg, 0.4 mmol) and formaldehyde (0.2 ml, 37% in H2O).
After being stirred for 1 h at room temperature 2N HCl (4 ml) was added and
stirring was continued for 15 min. Then the mixture was basified with 2N
NaOH and extracted with CH2Cl2 (30 ml). The organic layer was dried
(Na2SO4) and evaporated and the residue was purified by flash chromatog-
raphy (CH2Cl2/MeOH 97.5:2.5) to give 6 (42 mg, 85%) as a colorless solid,
mp. 107 °C.– HR-EI-MS for C19H20N2: calcd 276.1627, found 276.1631.–
IR (NaCl): ν = 2940, 2800, 1460, 730, 700 cm–1.– 1H NMR (CDCl3): δ =
2.30 (s, 3H, CH3), 2.52–2.61 (m, 1H, ArCH2CH2), 2.88–2.99 (m, 1H,
ArCH2CH2), 3.02–3.16 (m, 2H, CHCH2), 4.27 (dd, J = 14.7, 9.3 Hz, 1H,
ArCH2), 4.36–4.50 (m, 2H, ArCH2, Ar2CH), 5.73 (s, 1H, H-3), 7.03 (ddd, J
= 7.3, 7.3, 0.9 Hz, 1H, H-arom), 7.16 (ddd, J = 7.3, 7.3, 0.9 Hz, 1H, H-arom),
7.24–7.41 (m, 6H, H-arom), 7.44 (d, J = 7.9 Hz, 1H, H-arom).
A solution of 9a (260 mg, 1.1 mmol) in 1,4-dioxane (5 ml) and ethyl
formate (10 ml) was stirred for 16 h at 65 °C. Then, the solvent was evapo-
rated and the crude product was dissolved in THF (10 ml) and treated with
LiAlH4 (5 ml, 1M in THF, 5 mmol). After stiring for 4 h at 60 °C a saturated
solution of Na2SO4 was added slowly until the color of the suspension
changed from light grey to white, followed by addition of EtOAc (25 ml).
The mixture was filtered and the residue washed with MeOH (25 ml). The
organic layer was evaporated and the residue was purified by flash chroma-
tography (CH2Cl2/MeOH 9:1) to give 9b (178 mg, 65%) as a colorless solid,
mp.111 °C.– HR-EI-MS for C17H18N2: calcd 250.1470, found 250.1468.–
IR (KBr): ν = 3400, 2900, 1450, 750, 700 cm–1.– 1H NMR (CDCl3): δ = 2.47
(s, 3H, CH3), 3.31 (dd, J = 11.9, 7.6 Hz, 1H, CH2), 3.39 (dd, J = 11.9, 7.6 Hz,
1H, CH2), 4.69 (dd, J = 7.6, 7.6 Hz, 1H, CHCH2), 6.58–6.61 (m, 1H,
H-arom), 7.04 (d, J = 7.2 Hz, 1H, H-arom), 7.13–7.20 (m, 3H, H-arom),
7.24–7.30 (m, 3H, H-arom), 7.32–7.36 (m, 2H, H-arom), 8.25 (br. s, 1H, NH).
Phenyl-[(1-toluene-4-sulfonyl)indol-4-yl]methanol (8a)
To a solution of 7[11] (2.79 g, 9.3 mmol) in THF (40 ml) was added
PhMgBr (7 ml, 3M in Et2O, 21 mmol) at 0°C. After stirring for 2 h at room
temperature a saturated solution of NH4Cl (10 ml), H2O (20 ml), and EtOAc
(90 ml) were added. The organic layer was dried (Na2SO4) and evaporated,
and the residue was purified by flash chromatography (petroleum
ether/EtOAc 7:3) to give 8a (3.45 g, 98%) as a colorless solid, mp. 119 °C.–
Anal. C22H19NO3S (377.46).– EI-MS 377 (M•+).– IR (KBr): ν = 3540, 3390,
[3-(2-Nitro-1-phenylethyl)indol-2-yl]acetic acid ethyl ester (12)
A mixture of 11 (104 mg, 0.5 mmol) and β-nitrostyrene (150 mg,
1.0 mmol) was heated for 5 h at 130 °C. Subsequently the product was
purified by flash chromatography (petroleum ether/EtOAc 4:1) to give 12
(137 mg, 76%) as a yellowish oil.– Anal. C20H20N2O4 (352.39).– EI-MS 352
(M•+).–IR (NaCl): ν = 3405, 1725, 1550, 740, 700 cm–1.–1H NMR (CDCl3):
δ = 1.21 (t, J = 7.2 Hz, 3H, CH3), 3.71 (d, J = 16.8 Hz, 1H, ArCH2), 3.78 (d,
J = 16.8 Hz, 1H, ArCH2), 4.13 (q, J = 7.2 Hz, 2H, OCH2CH3), 5.07 (dd, J =
10.6, 7.2 Hz, 1H, CHCH2), 5.12–5.24 (m, 2H, 1 x CHCH2, CHCH2), 6.99
(ddd, J = 7.6, 7.6, 1.0 Hz, 1H, H-arom), 7.11 (ddd, J = 7.6, 7.6, 1.0 Hz, 1H,
H-arom), 7.15–7.37 (m, 7H, H-arom), 8.74 (br. s, 1H, NH).
1
1175, 1130 cm–1.– H NMR (CDCl3): δ = 2.32 (s, 3H, CH3), 6.09 (s, 1H,
Ar2CH), 6.70 (dd, J = 3.6, 0.9 Hz, 1H, H-3), 7.15–7.34 (m, 9H, H-arom),
7.51 (d, J = 3.6 Hz, 1H, H-2), 7.71–7.78 (m, 2H, H-arom), 7.88–7.95 (m, 1H,
H-arom).
4-(1-Chloro-1-phenyl)methyl-1-(toluene-4-sulfonyl)indole (8b)
To a solution of 8a (772 mg, 2 mmol) in DMF (10 ml) and carbon tetra-
chloride (1 ml) was added triphenylphosphine (590 mg, 2.2 mmol). After
stirring for 22 h at room temperature H2O (30 ml) and EtOAc (90 ml) were
added. The organic layer was washed with water (60 ml), dried (Na2SO4)
and evaporated and the residue was purified by flash chromatography (pe-
troleum ether/EtOAc 7:3) to give 8b (601 mg, 74%) as a colorless solid, mp.
1-Phenyl-1,2,3,4,5,6-hexahydroazepino-1H-[4,5-b]indol-4-on (13)
A mixture of 12 (534 mg, 1.5 mmol) and Pd/C (120 mg, 10%) in MeOH
(15 ml) was stirred under H2 (1 bar) at room temperature for 16 h. The
mixture was filtered through celite and the filtrate was evaporated. The
residue was purified by flash chromatography (CH2Cl2/MeOH 9:1) to give
13 (234 mg, 61%) as a colorless solid, mp. 124 °C.– HR-EI-MS for
C18H16N2O: calcd 276.1263, found 276.1260.– IR (NaCl): ν = 3280, 1660,
1455, 740, 700 cm–1.– 1H NMR (DMSO-d6): δ = 3.52–3.67 (m, 2H,
CHCH2), 3.79 (br. d, J = 16.0 Hz, 1H, ArCH2), 4.04 (br. d, J = 16.0 Hz, 1H,
ArCH2), 4.25–4.30 (m, 1H, CHCH2), 6.68–6.76 (m, 2H, H-arom), 6.91–6.98
51 °C.– Anal. C22H18ClNO2S (395.90).– EI-MS 395 (M•+ 35Cl), 397 (M•+
, ,
37Cl).– IR (KBr): ν = 3030, 1175, 1160, 675 cm–1.– 1H NMR (CDCl3): δ =
2.33 (s, 3H, CH3), 6.41 (s, 1H, Ar2CH), 6.69 (dd, J = 3.7, 0.8 Hz, 1H, H-3),
7.18–7.43 (m, 9H, H-arom), 7.56 (d, J = 3.7 Hz, 1H, H-arom), 7.72–7.79 (m,
2H, H-arom), 7.92–7.98 (m, 1H, H-arom).
Arch. Pharm. Pharm. Med. Chem. 333, 287–292 (2000)

Azepino- and Diazepinoindoles
291
(m, 1H, H-arom), 7.13–7.29 (m, 6H, H-arom), 7.65–7.72 (m, 1H, CONH),
10.95 (s, 1H, NH).
Trilux (Wallac ADL, Freiburg, Germany). Protein concentration was estab-
lished by the method of Lowry using bovine serum albumine as standard[21]
.
Binding Assay with Cloned Human Receptors
1-(2,2-Diethoxyethyl)-2-(2-nitro-1-phenylethyl)indole (16)
Binding analysis with human dopamine receptors[20] was done in the same
manner as described for the bovine D1 receptors. In brief, cell membranes
containing the D2 long, D2 short, D3, and D4.4 receptors were diluted in binding
buffer to a final protein concentration of 10–20 µg/assay tube. [3H]Spiperone
(0.5 nM) was used as the radioligand and haloperidol (10 µM) to determine
unspecific binding. Eight concentrations of the test compounds between 0.01
and 100,000 nM were investigated.
To a solution of 15[15] (2.972 g, 12.8 mmol) in THF (80 ml) was added
t-BuLi (9.4 ml, 1.5 M in pentane) at 0 °C. After stirring for 15 min at 0 °C
and further 1 h at room temperature the mixture was cooled to –78 °C. Then,
a solution of β-nitrostyrene (1.908 g, 12.8 mmol) in THF (5 ml) was added.
After being stirred for 1 h at –78 °C sat. aq NaHCO3 (5 ml), H2O (40 ml) and
EtOAc (150 ml) were added. The organic layer was dried (Na2SO4) and
evaporated and the residue was purified by flash chromatography (petroleum
ether/EtOAc 9:1) to give 16 (747 mg, 15%) as a light orange solid, mp.
99 °C.– Anal. C22H26N2O4 (382.46).– EI-MS 382 (M•+).– IR (KBr): ν =
2975, 1555, 1460, 1125, 1060, 750, 700 cm–1.– 1H NMR (CDCl3): δ = 1.07
(t, J = 7.0 Hz, 3H, CH3), 1.14 (t, J = 7.0 Hz, 3H, CH3), 3.20 (dq, J = 9.3,
7.0 Hz, 1H, OCH2CH3), 3.39 (dq, J = 9.3, 7.0 Hz, 1H, OCH2CH3), 3.53–3.68
(m, 2H, OCH2CH3), 3.93 (dd, J = 15.1, 7.2 Hz, 1H, ArCH2), 4.05 (dd, J =
15.1, 3.4 Hz, 1H, ArCH2), 4.45 (dd, J = 7.2, 3.4 Hz, 1H, NCH2CH), 4.82 (dd,
J = 13.0, 7.4 Hz, 1H, CHCH2), 5.07 (dd, J = 13.0, 8.6 Hz, 1H, CHCH2),
5.38–5.44 (m, 1H, CHCH2), 6.53 (s, 1H, H-3), 7.12 (ddd, J = 7.2, 7.2, 1.1 Hz,
1H, H-arom), 7.16–7.35 (m, 7H, H-arom), 7.61 (d, J = 7.2 Hz, 1H, H-arom).
Data Analysis
The resulting competition curves were analyzed by nonlinear regression
using the algorithms in PRISM (GraphPad Software, San Diego, USA) when
the hill slopes were set as h = –1. IC50 values were transformed to Ki values
according to the equation of Cheng and Prusoff[22]
.
References
2-[1-(2,2-Diethoxyethyl)indol-2-yl]-2-phenylethylamine (17)
[1] The Dopamine Receptors (Eds.: K.A. Neve, R.L. Neve), Humana Press,
Totowa, New Jersey, 1997.
A mixture of 16 (55 mg, 0.14 mmol) and Pd/C (25 mg, 10%) in MeOH
(5 ml) was stirred under H2 (1 bar) at room temperature for 16 h. The mixture
was filtered through celite and the filtrate was evaporated. The residue was
purified by flash chromatography (CH2Cl2/MeOH 95:5) to give 17 (36 mg,
71%) as a colorless oil.– HR-EI-MS for C22H28N2O: calcd 352.2151, found
352.2146.– IR (NaCl): ν = 2975, 1460, 1125, 1060, 750, 700 cm–1.– 1H NMR
(CDCl3): δ = 0.96 (t, J = 7.0 Hz, 3H, CH3), 1.13 (t, J = 7.0 Hz, 3H, CH3),
3.04 (dq, J = 9.3, 7.0 Hz, 1H,OCH2CH3), 3.15–3.52 (m, 4H, OCH2CH3,
CHCH2), 3.59 (dq, J = 9.3, 7.0 Hz, 1H, OCH2CH3), 3.99–4.06 (m, 2H,
ArCH2), 4.29 (dd, J = 6.7, 4.5 Hz, 1H, NCH2CH), 4.32–4.39 (m, 1H,
CHCH2), 6.54 (s, 1H, H-3), 7.05–7.39 (m, 8H, H-arom), 7.58–7.64 (m, 1H,
H-arom).
[2] J.W. Kebabian, D.B. Calne, Nature (London) 1979, 277, 93–96.
[3] D.R. Sibley, F.J. Monsma jr., Trends Pharmacol. Sci. 1992, 13, 61–69.
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[5] A. Barnett, Drugs Fut. 1986, 11, 49–56.
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1-Phenyl-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,7-a]indole (18)
[8] For recent investigations on azepinoindols, see: a) Y. Yokoyama, T.
Matsumoto, Y. Murakami, J. Org. Chem. 1995, 60, 1486–1487; b) Y.S.
Lee, B.J. Min, Y.K. Park, J.Y. Lee, S.J. Lee, H. Park, Tetrahedron 1999,
55, 12991–12996; c) L. Novák, M. Hanania, P. Kovács, J. Rohály, P.
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4491.
A solution of 16 (137 mg, 0.4 mmol) in THF (5 ml) and 5M HCl (2 ml)
was heated under reflux for 1 h. Then the solution was cooled to 0 °C, when
zinc dust (780 mg, 12 mmol) was added and stirring was continued for 1.5 h.
After filtration 2N NaOH was added (pH 10) and the mixture was extracted
with CH2Cl2 (45 ml). The organic layer was dried (Na2SO4) and evaporated
and the residue was purified by flash chromatography (CH2Cl2/MeOH 95:5)
to give 18 (35 mg, 37%) as a colorless solid, mp. 131 °C.– HR-EI-MS for
C18H18N2: calcd 262.1470, found 262.1464.– IR (NaCl): ν = 2920, 2850,
1460, 750, 700 cm–1.– 1H NMR (CDCl3): δ = 2.99–3.10 (m, 1H,
ArCH2CH2), 3.15–3.28 (m, 1H, ArCH2CH2), 3.38 (dd, J = 13.3, 2.0 Hz, 1H,
CHCH2), 3.47– 3.59 (m, 1H, CHCH2), 4.21–4.40 (m, 3H, ArCH2, Ar2CH),
5.91 (s, 1H, H-3), 7.01–7.08 (m, 1H, H-arom), 7.13–7.42 (m, 7H, H-arom),
7.48 (d, J = 7.9 Hz, 1H, H-arom).
[9] P. Gmeiner, J. Sommer, G. Höfner, Arch. Pharm. (Weinheim) 1995,
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Bovine Radioreceptor Assay
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see: J. Lehmann, N. Jiang, A. Behnke, Arch. Pharm. (Weinheim) 1993,
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[20]
For the D1 receptor binding assay bovine striatal membranes
were
diluted with binding buffer (50 mM TrisHCl, 1 mM EDTA, 5 mM MgCl2,
0.1 mM DL-dithiothreitol, 100 µg/mL bacitracin, 5 µg/mL soybean trypsin
inhibitor; pH 7.4) to a final concentration of 25 µg protein/assay tube. Tubes
were prepared with the radioligand [3H]SCH 23390 (0.3 nM) (specific
activity 83.0 Ci/mmol; Amersham Pharmacia Biotech, Freiburg, Ger) and
varying concentrations of test compounds (from 0.01–100,000 nM). Total
binding of [3H]SCH 23390 was measured in the absence of any competing
drug, nonspecific binding was determined by coincubation with butaclamol
(1 µM). Incubation started by adding membranes to the assay tube with a
final volume of 200 µL. It was carried on for 60 min at 37°C and stopped by
rapid filtration through GF/B filters precoated with 0.3% polyethylenimine,
using an automated cell harvester (Inotech, Dottikon, CH). Filters were
washed 5 times with ice-cold wash buffer (50 mM TrisHCl, 120 mM NaCl;
pH 7.4) dried and the radioactivity (on the filters) was counted ina MicroBeta
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[12] H.E. Zieger, S. Wo, J. Org. Chem. 1994, 59, 3838–3840.
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Arch. Pharm. Pharm. Med. Chem. 333, 287–292 (2000)

292
Kraxner, Hübner, and Gmeiner
[17] G. Hayes, T.J. Biden, L.A. Selbie, J. Shine, Mol. Endocrinol. 1992, 6,
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Received: April 18, 2000 [FP481]
Arch. Pharm. Pharm. Med. Chem. 333, 287–292 (2000)