New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with dual action at 5-HT1A serotonin receptors and serotonin transporter as a new class of antidepressants

Article abstract of DOI:10.1016/S0223-5234(00)01198-3

A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to find a new class of antidepressant drugs with dual activity at 5-HT_1A serotonin receptors and serotonin transporter. Title compounds were evaluated for in vitro activity on 5-HT_1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities, and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl] propan-1-ol (7) and 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl] propan-1-ol (8) show values (nM) of K_i = 30 and 2.3 for 5-HT_1A receptors and K_i = 30 and 12 for serotonin transporters, respectively. In GTPγS binding assays, compound 8 revealed antagonist properties to 5-HT_1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism of action.

Full text of DOI:10.1016/S0223-5234(00)01198-3

Eur. J. Med. Chem. 36 (2001) 55–61
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(00)01198-3/FLA
Original article
New 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives with
dual action at 5-HT1A serotonin receptors and serotonin transporter as a new
class of antidepressants
Javier Mart´ıneza, Silvia Pe´reza, Ana M. Oficialdeguia, Begon˜a Herasa, Lara Oru´sa,
Helena Villanuevaa, Juan A. Palopa, Joan Rocac, Marisa Mourellec, Ana Boschc,
Juan-C. Del Castilloc, Berta Lasherasb, Rosa Torderab, Joaqu´ın del R´ıob, Antonio Mongea*
aDepartment of Medicinal Chemistry and Centro de Investigacio´n en Farmacobiolog´ıa Aplicada (CIFA), Universidad de Navarra,
C/ Irunlarrea s/n, 31080 Pamplona, Spain
bDepartment of Pharmacology, Universidad de Navarra, Pamplona, Spain
cVita Invest S.A, Av. Barcelona 69, 08970 Sant Joan Desp´ı, Barcelona, Spain
Received 4 November 1999; revised 27 October 2000; accepted 29 October 2000
Abstract – A series of new 3-[4-(aryl)piperazin-1-yl]-1-(benzo[b]thiophen-3-yl)propane derivatives were synthesized in an attempt to
find a new class of antidepressant drugs with dual activity at 5-HT1A serotonin receptors and serotonin transporter. Title compounds
were evaluated for in vitro activity on 5-HT1A receptor and 5-HT transporter. They show high nanomolar affinity for both activities,
and in particular, compounds 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (7) and 1-(5-
fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol (8) show values (nM) of Ki=30 and 2.3 for 5-HT1A
receptors and Ki=30 and 12 for serotonin transporters, respectively. In GTPgS binding assays, compound 8 revealed antagonist
properties to 5-HT1A receptors. Such a pharmacological profile could lead to potent antidepressant agents with new dual mechanism
´
of action. © 2001 Editions scientifiques et me´dicales Elsevier SAS
arylpiperazines / antidepressant / 5-HT1A antagonist / serotonin reuptake inhibitor
1. Introduction
5-HT in forebrain areas coincides with the onset of
antidepressant effect [4, 5]. This hypothesis is sup-
ported by the augmentation of extracellular 5-HT
concentration in terminal fields of serotoninergic sys-
tem observed after concomitant administration of a
5-HT1A receptor antagonist such as pindolol or the
silent antagonist WAY 100635 with different SSRIs
[6–9]. Recent clinical trials indicate, on the other
hand, that a combination of the 5-HT1A receptor
antagonist pindolol and a SSRI such as fluoxetine,
paroxetine or citalopram may shorten the onset of
action and improve the efficacy of antidepressant
treatment [10–15]. Conceivably, new agents with 5-
HT1A receptor antagonist and 5-HT transporter in-
hibitor properties could produce the same therapeutic
benefits observed with the combination of a SSRI and
a 5-HT1A antagonist. However, few pharmacological
Selective serotonin (5-hydroxytriptamine, (5-HT))
reuptake inhibitors (SSRIs) are effective in the treat-
ment of depression. With these and other antidepres-
sants, several weeks of treatment are, however,
required before their therapeutic effects become ap-
parent [1, 2]. It has been hypothesized that this delay
can be explained by the initial elevation in the raphe
nuclei of extracellular 5-HT, which reduces the firing
of serotoninergic neurons by activating somatoden-
dritic 5-HT1A autoreceptors [3]. After repeated antide-
pressant treatment, somatodendritic 5-HT1A receptors
become desensitized, firing activity of serotoninergic
neurons is restored and the increase in extracellular
* Correspondence and reprints
E-mail address: amonge@unav.es (A. Monge).

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J. Mart´ınez et al. / European Journal of Medicinal Chemistry 36 (2001) 55–61
there was a hydroxyl group on Z, Ar2 was a ben-
zo[b]thiophene ring and Ar1 a 2-methoxyphenyl moi-
ety. Accordingly, we synthesized new derivatives of
general structure III (figure 4) in which substitution at
position 5 of benzo[b]thiophene ring appeared to be
the most interesting from the biological point of view
due to the presence of this substitution in molecules
with biological activity such as 5-HT. Compounds
that exhibited high affinity at 5-HT1A receptor and
5-HT transporter (6, 7 and 8) were studied for their
agonist/antagonist activity to 5-HT1A receptors using
a 5-HT1A receptor-mediated GTPgS binding assay in
rat hippocampal membranes.
Figure 1. General structure I.
data of compounds with both activities have been
reported to date [16].
We synthesized compounds with the general struc-
ture shown in figure 1 where there is an arylpiperazine
and a g-phenoxypropylamine moiety, which may
provide 5-HT1A receptor affinity and 5-HT reuptake
inhibition, respectively. Some structurally related
compounds endowed with either pharmacological ac-
tion are shown in figure 2. Preliminary studies re-
vealed, however, not only g-phenoxypropylamine
derivatives but compounds without the aromatic ring
Ar3 showed too the dual pharmacological activity
[17]. Consequently we synthesized new compounds of
general structure II (figure 3) in which Z represents
the different functional groups indicated [17]. The
best pharmacological results were obtained when
2. Chemistry
Chemical data of 3-[4-(aryl)piperazin-1-yl]-1-(ben-
zo[b]thiophen-3-yl)propane derivatives synthesized in
this work are shown in table I. Figures 5 and 6
illustrate the procedures used to synthesize 1-(5-halo-
genbenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)-
Figure 2. Serotonin reuptake inhibitors derived from g-phenoxypropylamine (A) and 5-HT1A receptor antagonist derived from
arylpiperazine (B).

J. Mart´ınez et al. / European Journal of Medicinal Chemistry 36 (2001) 55–61
57
tives (7 and 8). Hydroxyl derivatives were synthesized
by reduction of the corresponding carbonyl deriva-
tives 5 and 6 with sodium borohydride in methanol at
0 °C. Compound 5 was synthesized by the Mannich
reaction of the corresponding 3-acetyl-5-chlorobenzo-
[b]thiophene (3) and 1-(2-methoxyphenyl)piperazine
with paraformaldehyde and concentrated hydrochlo-
ric acid in refluxing ethanol. Compound 6 was syn-
thesized by nucleophylic substitution of 1-(2-
methoxyphenyl)piperazine and 3-chloro-1-(5-fluoro-
benzo[b]thiophen-3-yl)propan-1-one (4) in tetrahy-
drofurane with potassium carbonate. Compound 4
was synthesized from 5-fluorobenzo[b]thiophene (2)
by classical Friedel–Craft acylation with 3-chloropro-
pionyl chloride and aluminum chloride in dry chloro-
form. Compound 3 was synthesized following an
adaptation of the procedures described in the litera-
Figure 3. General structure II.
Figure 4. General structure III.
piperazin-1-yl] propan-1-one derivatives (5 and 6),
and figure 7 illustrates the general procedure followed
to synthesize 1-(5-halogenbenzo[b]thiophen-3-yl)-3-[4-
(2-methoxyphenyl) piperazin-1-yl]propan-1-ol deriva-
Table I. Chemical data of 1-(benzo[b]thiophene)-3-[4-(2-methoxyphenyl) piperazin-1-yl)propane derivatives 5–8.
Compound
R
Z
m.p. (°C)
238
% Yield
35
Purificationa
A
Formula
5·HCl
Cl
CO
C22H23N2ClO2S
6·2HCl
7·2HCl
F
Cl
CO
CHOH
197
187
62
42
A
A
C22H23FN2O2S
C22H25N2ClO2S
8
F
CHOH
125
60
B
C22H25FN2O2S
a
A=column chromatography on silica gel: light petroleum/AcOEt 1:1; B=recrystallization from light petroleum/i-PrOH.
Figure 5. Synthesis of 1-(5-chlorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-one.
Figure 6. Synthesis of 1-(5-fluorobenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-one.

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J. Mart´ınez et al. / European Journal of Medicinal Chemistry 36 (2001) 55–61
Figure 7. Synthesis of 1-(5-halogenbenzo[b]thiophen-3-yl)-3-[4-(2-methoxyphenyl)piperazin-1-yl]propan-1-ol derivatives.
ture [18]; the use of aluminum trichloride and acetyl
chloride slightly improved the yield. The starting
reagents for compounds 1 and 2 (5-chloroben-
zo[b]thiophene and 5-fluorobenzo[b]thiophene) were
synthesized from 1-(2-diethoxyethilthio)-4-chloroben-
zene and 1-(2-diethoxyethilthio)-4-fluorobenzene fol-
affinity at the 5-HT transporter of synthesized com-
pounds. This result confirms previous findings of our
group in which it was shown that arylpiperazine
derivatives with a benzene or thiophene ring attached
at the end of the alkyl chain could yield the desired
activities without the presence of the third aromatic
ring Ar3 [17]. The present results also confirm that the
substitution of a thiophene ring by a benzocondensed
ring, such as benzo[b]thiophene, clearly improves the
affinity.
Observation of the results shows better pharmaco-
logical results for hydroxylic derivatives than for car-
bonylic derivatives in both activities. These results are
in agreement with previous work carried out in our
laboratory in which hydroxylic derivatives present the
best results among the different functional groups
introduced, which include carbonyl, hydroxyl,
arylether, alkylether, oxime and carbamate [17].
The results of affinity of the analogues of com-
pounds synthesized in which there is no substituent at
benzo[b]thiophene ring (R=H in general structure
III, in figure 4) were obtained in previous work of our
lowing
a
previously described procedure [19].
1-(2-diethoxyethylthio)-4-chlorobenzene and 1-(2-di-
ethoxyethylthio)-4-fluorobenzene were synthesized
following an adaptation of the method described in
literature which facilitates the work procedure [20].
3. Pharmacology
Binding affinity to 5-HT1A receptor and 5-HT
transporter were determined for 5–8. The affinity for
5-HT1A receptors was determined by studying the
displacement of binding of [3H]-8-hydroxy-2-(di-n-
propylamino)tetralin ([3H]-OH-DPAT) to rat cerebral
cortex homogenates according to procedures reported
previously [21, 22]. The affinity for 5-HT transporter
was determined by studying the competition in [H3]-
paroxetine bindings to rat cerebral cortex ho-
mogenates, as described [22, 23]. Compounds were
studied for their agonist/antagonist activity to 5-HT1A
receptors using a 5-HT1A receptor-mediated GTPgS
binding assay in rat hippocampal membranes. This
assay was carried out by studying the competition in
[35S]GTPgS binding to rat hippocampal homogenates
following the method described [24].
group:
1-benzo[b]thiophen-3-yl-3-[4-(2-methoxy-
phenyl) piperazin-1-yl]propan-1-one (Ki=45 nM and
Ki=110 nM affinity at the 5-HT1A receptors and
Table II. Binding affinity (Ki, nM) at 5-HT1A receptors and
5-HT transporter of compounds 5–8.a
4. Results and discussion
Compound
R
Z
5-HT1A
receptor
5-HT
transporter
The results of binding studies for compounds 5–8
are summarized in table II. All of the compounds
showed a moderate to high affinity at both the 5-
HT1A receptor and the 5-HT transporter.
The introduction of an alkyl-benzo[b]thiophene
moiety attached to the arylpiperazine enhanced the
5
6
7
8
Cl CO
CO
250910
1592.1
260915
10095.6
3091.5
1290.8
F
Cl CHOH 3092.2
CHOH 2.390.3
F
a
Values are means9S.E.M. from at least 3 experiments.

J. Mart´ınez et al. / European Journal of Medicinal Chemistry 36 (2001) 55–61
59
Table III. Effect of WAY 100635 and compounds 5–8 on 8-OH-DPAT-stimulated GTPgS binding in hippocampus.a
Compound
Basal fmol GTPgS /mg protein
Maximal fmol GTPgS /mg proteinb
IC50 (nM)
Control+8-OH-DPAT 10–6
WAY 100635+DPAT 10–6
6 (10–10–10–5)+DPAT 10–6
7 (10–10–10–5)+DPAT 10–6
8 (10–10–10–5)+DPAT 10–6
17.990.5
18.592.4
15.991.2
18.991.6
17.391.5
32.894.2
20.291.6
30.191.8
26.091.4
21.591.2
5.790.6
\10000
10000
1492.1
a Hippocampal homogentates were incubated in the presence of graded concentrations of either WAY 100635 or compounds 6–8,
and 1 mM of 8-OH-DPAT. IC50 were calculated as measures of the potencies of these compounds as 5-HT1A receptor antagonist.
Values represent the mean9S.E.M. from at least 3 experiments.
b
The maximal response is the GTPgS binding observed at the highest concentration of the ligand that was varied.
5. Conclusion
5-HT transporter respectively), and 1-benzo-
[b]thiophen-3-yl-3-[4-(2-methoxyphenyl)piperazin-
1-yl]propan-1-ol (Ki=20 nM and Ki =20 nM affinity
at the 5-HT1A receptors and 5-HT transporter, respec-
tively) [17]. These results were improved by 5-
fluorobenzo[b]thiophene derivatives (compounds 6
and 8), but no by 5-chlorobenzo[b]thiophene deriva-
tives (compounds 5 and 7). Therefore, introduction of
fluor in the 5 position of benzo[b]thiophene ring im-
proves the affinity result when comparing with no-
substituted benzo[b]thiophene derivatives. On the
other hand, the change of chloro by fluor in the
benzo[b]thiophene ring improves the affinities at both
5-HT1A receptor and 5-HT transporter. This impair-
ment can be observed for both carbonyl (5 and 6) and
hydroxyl derivatives (7 and 8).
Compounds 6, 7 and 8 were selected to study their
agonist/antagonist activity to 5-HT1A receptors in
GTPgS binding assays. As expected, the 5-HT1A ago-
nist 8-OH-DPAT produced a concentration-depen-
dent decrease of the GTPgS binding with an
EC50 =81 9 nM. The selective 5-HT1A-receptor an-
tagonist WAY 100635 did not alter the binding by
itself. Compound 5 and 6 did not alter the GTPgS
binding, but compound 8 produced an stimulation of
50% at 10 mM. In antagonism studies WAY 100635
(0.1–10 mM) abolished the effect of 8-OH-DPAT 1
mM showing a IC50 =5.7 0.2 nM. Compound 8
showed a moderate antagonist activity to 5-HT1A
receptor since it concentration-dependently re-
duced the 8-OH-DPAT-stimulated GTPgS binding
(IC50 =140 12 nM). Compound 7 produced a small
reduction of the 8-OH-DPAT-stimulated GTPgS
binding (44% of inhibition at 10 mM). See results in
table III.
We have synthesized new arylpiperazine derivatives
with affinity at both 5-HT1A receptors and 5-HT
transporter of potential use in the treatment of de-
pression. The alkyl benzo[b]thiophene moiety in
which there is a polar group like carbonyl or hy-
droxyl, adds affinity towards the 5-HT transporter to
the arylpiperazine. From GTPgS binding assays,
compound 8 appears to be the most interesting com-
pound since it shows antagonist activity at 5-HT1A
receptors.
At this point, the introduction of new substituents
in the benzo[b]thiophene ring in position 5 and in
other positions such as 4, 7 or 2, seems to be very
interesting in order to obtain new compounds with
potent affinity for both pharmacological activities.
Further pharmacological evaluation of the com-
pounds herein described is in progress.
6. Experimental protocols
Melting points were determined using a Mettler
FP82+FP80 apparatus and are uncorrected. Elemen-
tal analyses were obtained from vacuum-dried sam-
ples (over phosphorus pentoxide at 4 mm Hg, 24 h, at
ca. 80–100 °C). Infrared spectra were recorded on a
Perkin-Elmer 1600 series FTIR apparatus, using
potassium bromide tablets for solid products and
sodium chloride plates for liquid products, the fre-
quencies are expressed in cm–1. The H-NMR spectra
1
(table IV) were obtained on a Brucker AC-200E (200
MHz) instrument with tetramethylsilane as the inter-
nal reference, at a concentration of ca. 0.1 g mL–1 and
with dimethyl solfoxide-d6 (DMSO-d6) or chloroform

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J. Mart´ınez et al. / European Journal of Medicinal Chemistry 36 (2001) 55–61
(CDCl3) as the solvent; the chemical shifts are re-
ported in parts per million (PPM) of tetramethylsilane
in d units, and the J values are given in hertz (Hz)
(table IV). The mass spectra were recorded on a
Hewlett-Packard 5988-A instrument at 70 eV.
Thin layer chromatography (TLC) was carried out
on silica gel (DSF-5, Cammaga 0.3 mm thickness)
with the indicated solvents, and the plates were
scanned under ultraviolet light at 254 and 366 nm.
Column chromatography was carried out with Merck
silica gel 60 (70–230 mesh ASTM).
portions were washed with water and dried with sodium
sulfate. The solvent was evaporated at reduced pressure.
The product was purified by flash chromatography (SP:
silica gel), eluting with toluene (60%) m.p. 80–82 °C.
6.2. Synthesis of 3-chloro-1-(5-fluorobenzo[b]thiophen-
3-yl)propan-1-one 4
A solution of 5-fluorobenzo[b]thiophene (0.80 g, 5.26
mmol) and 3-chloropropionyl chloride (0.49 mL, 6,32
mmol) in dry chloroform (35 mL) was added dropwise
to a well-stirred solution of aluminum trichloride (0.58
g) in dry chloroform (18 mL) at 0 °C. After 24 h the
reaction was quenched with 1.5 N hydrochloric acid
(100 mL), the organic layer washed with 5% sodium
bicarbonate, water, ‘brine’ and dried with sodium sul-
fate. It was then evaporated at reduced pressure. The
product was purified by flash chromatography (SP: silica
gel), eluting with light petroleum/toluene (25:75) (43%)
m.p. 80–81 °C.
Elemental analyses were performed on a Carlo-
Erba 1106 Instrumentazione and the experimentally
determined values are within 0.4% of the theoretical
values.
6.1. Synthesis of 3-acetyl-5-chlorobenzo[b]thiophene 3
A solution of 5-chlorobenzo[b]thiophene (1.00 g, 5.90
mmol) and acetyl chloride (0.49 g, 6.24 mmol) was
added dropwise to a well stirred solution of 0.86 g of
aluminum trichloride in dry dichloromethane (10 mL) at
0 °C. The temperature was allowed to rise to 25 °C and
the mixture was stirred overnight. Then, the reaction
mixture was refluxed for 1 h, and after cooling, diluted
sulfuric acid was added. The aqueous portion was ex-
tracted with dichloromethane and the combined organic
6.3. Synthesis of 1-(5-chlorobenzo[b]thiophen-3-yl)-
3-[4-(2-methoxyphenyl) piperazin-1-yl]propan-1-one
5·HCl
A mixture of 3-acetyl-5-chlorobenzo[b]thiophene (1.7
g, 8.08 mmol) and hydrochloride of 2-meth-
Table IV. 1H-NMR and IR data for new compounds.
Ref. 1H-NMR. l (ppm) (J in Hz)
IR (cm–1, KBr)
4
3.46 (t; 2H, CH2C=O); 3.96 (t; 2H, CH2Cl); 7.19 (dd; 1H, H6, J46=2.6, J67=8.4); 7.77 (dd; 1H, H7, 1672
F7=4.7); 8.38 (s; 1H, H2); 8.47 (d; 1H, H4, JF4=10.3).
J
5
3.06–3.12 (m; 4H, N1CH2’s); 3.54 (br; 6H, N4CH2’s +COCH2); 3.75 (t; 2H, COCH2CH2); 3.80 (s;
3H, OCH3); 6.91–7.00 (m; 4H, Ph); 7.55 (dd; 1H, H6, J46=1,8 and J67=8.2); 8.19 (d; 1H, H7); 8.61
(d; 1H, H4); 9.19 (s; 1H, H2).
1669; 1241
1669; 1241
1241
6
7
8
3.16 (br; 4H, N1CH2’s); 3.38–3.57 (br; 6H, N4CH2’s +COCH2); 3.73 (t; 2H, COCH2CH2); 3.78 (s;
3H, OCH3); 6.85–6.98 (m; 4H, Ph); 7.39 (dd; 1H, H6,J46=2.5, J67=8.3); 8.16 (dd; 1H, H7, JF7=5.2);
8.28 (d; 1H, H4, JF4=10.7); 9.20 (s; 1H, H2).
1.93 (t; 2H, CHOHCH2); 2.65–2.88 (m; 6H, N1CH2’s); 3.14 (br; 4H, N4CH2’s); 3.85 (s; 3H, OCH3);
5.29 (t; 1H, CHOH); 5.83 (br; 1H, OH); 6.74–6.96 (m; 4H, Ph); 7.18 (dd; 1H, H6, J46=1.5, J67=8.7);
7.36 (s; 1H, H2); 7.63 (d; 1H, H7); 7.70 (d; 1H, H4).
2.02–2.11 (m; 2H, CHOHCH2); 2.68–2.87 (m; 6H, N1CH2’s); 3.15 (br; 4H, N4CH2’s); 3.86 (s; 3H,
OꢀCH3); 5.26 (t; 1H, CHOH); 6.84–7.01 (m; 4H, Ph); 7.08 (dd; 1H, H6, J46=2.2, J67=8.8); 7.49 (s;
1H, H2); 7.50 (d; 1H, H7, JF4=10.0); 7.75 (d; 1H, H4, JF7=4.8).
3401; 1241

J. Mart´ınez et al. / European Journal of Medicinal Chemistry 36 (2001) 55–61
61
oxyphenylpiperazine (1.86 g, 8.08 mmol) dissolved in
Acknowledgements
isopropanol (40 mL) with concentrated hydrochloric
acid (pH 2–3) was refluxed, and paraformaldehyde
(0.67 g) was added. After 24 h the reaction was cooled,
poured over crushed ice and extracted with ethyl ace-
tate. The organic layer was washed with water and dried
with sodium sulfate. The solvent was evaporated at
reduced pressure. The product was purified by flash
chromatography (SP: silica gel), eluting with light
petroleum/ethyl acetate (1:1). The hydrochloride was
obtained adding concentrated hydrochloric acid to a
solution of the product in ethanol/diethyl ether (35%).
The authors are grateful to laboratories VITA for
financial support. We thank also Sandra Lizaso and
Maria Espelosin for her skilful technical support.
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Sodium borohydride, in excess, was added to a well
stirred solution or suspension of the corresponding 3-
(4-arylpiperazin-1-yl)-1-(5-halobenzo[b]thiophen-3-yl)-1-
propanone derivative (2.0 mmol) in methanol at 0 °C
over a period of 30 min. The stirring was further contin-
ued for 2 h. The reaction mixture was poured over water
and stirred at room temperature overnight. The product
was obtained by filtration and purified by recrystalliza-
tion from light petroleum/isopropanol (8) (60%) or by
flash chromatography (SP: silica gel), eluting with n-
hexane/ethyl acetate 1:1 (V/V) (7) (42%). The dihy-
drochloride of compound 7 was obtained by adding
concentrated hydrochloric acid to a solution of the
product in acetone.
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