Synthesis of novel polysubstituted (2SR,4RS)-2-heteroaryltetrahydro-1,4- epoxy-1-benzazepines and cis-2-heteroaryl-4-hydroxytetrahydro-1H-1-benzazepines as antiparasitic agents

Article abstract of DOI:10.1016/j.ejmech.2014.08.055

New series of polysubstituted (2SR,4RS)-2-heteroaryltetrahydro-1,4-epoxy-1- benzazepines and cis-2-heteroaryl-4-hydroxytetrahydro-1H-1-benzazepines were designed and synthesized in moderate to high yields using a three-step procedure from ortho-allylanilines. Their antiparasitic activity was evaluated against the extracellular and intracellular forms of Trypanosoma cruzi and Leishmania (Leishmania) infantum parasites. Their cytotoxicity was also determined on Vero and THP-1 mammalian cells. Many of the tested compounds inhibited significantly the growth of extracellular forms of T. cruzi and L. (L.) infantum without showing cytotoxicity on Vero and HTP-1 cells. Only compounds 10h and 14f demonstrated good activity against amastigotes of T. cruzi, but none was able to inhibit the growth of L. (L.) infantum amastigotes.

Full text of DOI:10.1016/j.ejmech.2014.08.055

European Journal of Medicinal Chemistry 86 (2014) 291e309
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis of novel polysubstituted (2SR,4RS)-2-heteroaryltetrahydro-
1,4-epoxy-1-benzazepines and cis-2-heteroaryl-4-hydroxytetrahydro-
1H-1-benzazepines as antiparasitic agents
María C. Blanco a, Patricia Escobar b, Sandra M. Leal b, Alí Bahsas c, Justo Cobo d,
,
*
Manuel Nogueras d, Alirio Palma a
a
ꢀ
Laboratorio de Síntesis Organica, Escuela de Química, Universidad Industrial de Santander, A.A. 678, Bucaramanga, Santander, Colombia
Centro de Investigacion de Enfermedades Tropicales, Departamento de Ciencias Basicas, Escuela de Medicina, Universidad Industrial de Santander, A.A.
b
ꢀ
ꢀ
678, Bucaramanga, Santander, Colombia
c
ꢀ
Laboratorio de RMN, Grupo de Productos Naturales, Departamento de Química, Universidad de los Andes, Merida 5101, Venezuela
d
ꢀ
ꢀ
Inorganic and Organic Department, University of Jaen, Campus Las Lagunillas s/n, 23071 Jaen, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
New series of polysubstituted (2SR,4RS)-2-heteroaryltetrahydro-1,4-epoxy-1-benzazepines and cis-2-
heteroaryl-4-hydroxytetrahydro-1H-1-benzazepines were designed and synthesized in moderate to
high yields using a three-step procedure from ortho-allylanilines. Their antiparasitic activity was eval-
uated against the extracellular and intracellular forms of Trypanosoma cruzi and Leishmania (Leishmania)
infantum parasites. Their cytotoxicity was also determined on Vero and THP-1 mammalian cells. Many of
the tested compounds inhibited significantly the growth of extracellular forms of T. cruzi and L. (L.)
infantum without showing cytotoxicity on Vero and HTP-1 cells. Only compounds 10h and 14f demon-
strated good activity against amastigotes of T. cruzi, but none was able to inhibit the growth of L. (L.)
infantum amastigotes.
Received 15 May 2014
Received in revised form
4 August 2014
Accepted 15 August 2014
Available online 17 August 2014
Keywords:
(2SR,4RS)-2-heteroaryltetrahydro-1,4-
epoxy-1-benzazepines
cis-2-Heteroaryltetrahydro-1H-1-
benzazepin-4-ols
© 2014 Elsevier Masson SAS. All rights reserved.
Antiparasitic activity
Trypanosoma cruzi
Leishmania (Leishmania) infantum
Cytotoxicity
1. Introduction
the infected people, leads after several years to cardiac, digestive,
neurological or mixed clinical alterations [2]. Nifurtimox (Nfx) and
Chagas disease and leishmaniasis remain a major public health
problem due to the inadequate therapy, and to the ineffective
vaccines available [1]. Chagas disease is caused by the flagellate
protozoan Trypanosoma cruzi mainly transmitted by the infected
faeces of triatomine bugs. Nevertheless, it could also be transmitted
by blood transfusions and organs transplants, as well as, congeni-
tally and orally from contaminated food. It has been estimated that
about 7e8 million people worldwide are infected, spreading from
Latin America to non-endemic countries [2]. In Colombia, it has
been assessed that about 1 million people are infected and 3 million
are at risk of acquiring the infection [3]. Chagas disease presents an
initial acute phase with a high number of parasites circulating the
blood followed by a chronic phase which, in approximately 30% of
benznidazole are drugs currently recommended mainly for the
treatment during the acute and early chronic phase, along with
immunoreactive diseases or congenital infections. Unfortunately,
these drugs are related to significant side effects such as edema,
fever, skin rash, articular and muscular pain, peripheral neuropathy,
neutropenia, sore throat, fever, septicemia, thrombocytopenic
purpura, nausea and vomiting [4].
Leishmaniasis is a poverty-related group of diseases caused by
several species of protozoan parasites belonging to the genus
Leishmania and transmitted by the bite of a female phlebotomine
sandfly [5]. They are digenetic parasites that proliferate as motile
promastigotes in the gut of sandflies and as amastigotes inside
vertebrate-host macrophages. There are two main forms of leish-
maniasis, cutaneous (the most common), and visceral leishmani-
asis (fatal in 85e90% of untreated cases). Currently, leishmaniasis is
endemic in 98 countries, and approximately 58,000 cases of
* Corresponding author.
E-mail address: apalma@uis.edu.co (A. Palma).
http://dx.doi.org/10.1016/j.ejmech.2014.08.055
0223-5234/© 2014 Elsevier Masson SAS. All rights reserved.

292
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
visceral leishmaniasis (VL) and 220,000 cases of cutaneous leish-
maniasis (CL) are officially reported each year. Based on under-
reporting assessments, 0.2e0.4 million new cases of VL and
0.7e1.2 million new cases of CL are estimated to occur every year
[6]. Pentavalent antimony compounds (sodium stibogluconate and
meglumine antimoniate) followed by amphotericin B (both the free
and liposomal amphotericin B), pentamidine isothionate, paro-
momycin and miltefosine constitute the major drug options for the
disease. These drugs present significant side-effects, such as
toxicity, expensiveness, low availability, variable effectiveness and
high risk of resistance. It is clear that alternative drugs are
desperately needed to treat Chagas disease and leishmaniasis [5,7].
The tetrahydro-1-benzazepine nucleus has attracted wide in-
terest since several derivatives bearing this heterocyclic unit have
shown useful pharmaceutical applications [8e12]. Many tetrahy-
dro-1-benzazepine derivatives were developed and evaluated as
potent and orally active non-peptide arginine vasopressin antago-
nists for both V1A and V2 receptors [13e18], as potent inhibitors of
cyclin-dependent kinases [19e22], as potent and orally bioavailable
growth hormone secretagogue [23e26], and as agents against HIV-
1 infection [27]. Some derivatives containing this frame, such as
paullones, completely inhibit the growth of Leishmania mexicana
promastigotes in vitro [28], and others are considered as promising
inhibitors of T. cruzi dihydrofolate reductase [29].
(epimastigotes T. cruzi)
¼
9.0
m
M; II:
R
¼
Cl, R1
mM) [30]. By the
¼
Br,
R2 ¼ R3 ¼ R4 ¼ H, IC50 (promastigotes L. (L.) infantum) ¼ 9.5
same manner, the incorporation of thiophene, furan and pyrrole
nuclei in the molecules is in concordance with the several examples
reported of antiparasitic agents possessing this substitution
[34e38].
In the present study, we report the synthesis and antiparasitic
activity of new series of polysubstituted (2SR,4RS)-2-
heteroaryltetrahydro-1,4-epoxy-1-benzazepines
heteroaryl-4-hydroxytetrahydro-1H-1-benzazepines,
and
cis-2-
resulting
from the replacement of the aryl moiety at C-2 by substituted
thiophene, furan and pyrrole rings. The results obtained in the
evaluation of new compounds were compared to those of the
parent compounds I and II and of control drugs. We also theoret-
ically determined the octanol/water partition coefficients (log P)
and dipoles (D) and tried to find a relationship between these two
quantitative parameters and antiparasitic activity presented by
active compounds.
2. Results and discussion
2.1. Chemistry
In a previous work we presented the synthesis and biological
evaluation against the extracellular and intracellular forms of
T. cruzi and L. (L.) infantum parasites of a series of diverse func-
tionalized 2-aryltetrahydro-1-benzazepines of the types I and II
(Fig. 1). While these compounds were inactive or displayed only
limited activity against the intracellular forms of the parasites,
several showed a high level of activity against the extracellular
The investigation started with the synthesis of ortho-allyl-N-
(heteroarylmethyl)anilines 6e9, which are the building blocks to
the target heterocycles. For this task, the ortho-allylanilines 1aed
were treated with 2-thiophene-carboxaldehydes 2aed, 2-
furaldehydes 3aec, 3-furaldehyde 4, and N-methyl-2-
pyrrolecarboxaldehyde 5 in methanol to generate the corre-
sponding imine intermediates. The imines were easily transformed
in situ in very high yields to the secondary aromatic amines 6aep,
7aek, 8a,b and 9a,b by reduction with a threefold excess of sodium
borohydride (Scheme 1).
epimastigotes (IC50
¼
6.1e35.4
mM) and promastigotes
(IC50 ¼ 9.5e49.1 M). Structureeactivity relationship (SAR) studies
m
showed that the antiparasitic properties of these compounds
greatly depended on the number and the chemical nature of the
substituents on the aromatic rings (benzene-fused ring, and
pendant aryl moiety at C-2), being the halogen-substituted and the
methyl-substituted derivatives the most promising [30]. With the
aim of synthesizing new analogues with comparable or better
antiparasitic activity and taking into account the flexibility of our
synthetic approach to incorporate moieties other than aryl into the
final products, we centered our efforts on the replacement of aryl
moiety at C-2 in compounds I and II by an isosteric thiophene ring
and its closely related furan and pyrrole nuclei, while at the same
time maintaining a similar halogen substitution pattern at C-7
position of the benzene-fused ring. The halogen-substitution
pattern in this study was selected not only taking into account
the fact that in medicinal chemistry the halogenation of molecules
allows the modulation of their physicochemical properties, such as
free energy of binding, selectivity, lipophilicity and pharmacoki-
netics [31e33], but also based on the previously obtained results,
where a remarkable activity against the extracellular forms of
parasites was observed (I: R ¼ F, R1 ¼ R2 ¼ R3 ¼ R4 ¼ H, IC50 (epi-
As we have already demonstrated, the intramolecular 1,3-
dipolar cycloaddition of nitrones derived from ortho-allyl-N-ben-
zyl(alkenyl)anilines is a versatile route to effectively build the tet-
rahydro-1-benzazepine ring [39e41]. Using this methodology, key
precursors 6e9 were transformed into the target 2-
heteroaryltetrahydro-1,4-epoxy-1-benzazepines 10e12 in moder-
ate to good yields (Scheme 2). The low yields obtained for 1,4-
epoxycycloadducts 13 can be explained considering the concomi-
tant oxidation of the
p-electron rich pyrrole nucleus, which is
probably carried out by hydrogen peroxide, leading to the forma-
tion of considerable amounts of no identifiable degradation
products.
In all the cases, the intramolecular 1,3-dipolar cycloaddition of
the intermediate nitrones was entirely stereoselective leading to
the
exclusive
formation
of
2-exo-heteroaryl-1,4-
epoxycycloadducts. It was unambiguously determined by the
chemical shifts and coupling constant values of the 1,4-
epoxytetrahydroazepine ring protons (see Experimental Section),
and specially by the absence of NOE cross-signal between tertiary
2eH and 4eH protons in their NOESY spectra. Definitive structural
elucidation was achieved by single-crystal X-ray analysis on com-
pounds type 10, 11, and 13 [42e44]. The molecular structures of 10j,
11g and 13b (see Fig. 2), are in agreement with the stereochemistry
deduced from NMR analysis.
¼ 7.7
m
M; R ¼ Cl, R1 ¼ R2 ¼ R3 ¼ R4 ¼ H, IC50
mastigotes T. cruzi)
Finally, most of the obtained 1,4-epoxycycloadducts were sub-
jected to NeO bond reductive cleavage using an excess of zinc in a
mixture of glacial acetic acid and concentrated hydrochloric acid at
temperature ranging from 0 to 25 ꢀC (Scheme 3). Under such
conditions, the reductive cleavage of 10aec, 10eeg, 10iek, 10meo,
11a,b, 11deg, 11i,j, and 12a,b proceeded smoothly and was
completed within 0.5e1 h affording the desired 2-heteroaryl-4-
Fig. 1. Potential antichagasic and antileishmanial agents of the series 2-aryltetrahydro-
1,4-epoxy-benzo[b]azepines I and cis-2-aryl-4-hydroxytetrahydro-1H-1-benzazepines
II.

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
293
Scheme 1. Synthesis of key precursors 6aep, 7aek, 8a,b and 9a,b.
Scheme 2. Oxidation and subsequent intramolecular 1,3-dipolar cycloaddition of key precursors 6e9.
Fig. 2. Single crystal X-ray structures of 10j, 11g and 13b (ORTEP views).

294
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
and L. (L.) infantum parasites. The cytotoxicity of compounds was
also evaluated on Vero epithelial cells (the host cells of T. cruzi) and
on THP-1 transformed human macrophages (the host cells of L. (L.)
infantum) in parallel with the antiparasitic activity. To study the
effects of structural modifications on inhibitory activity and cyto-
toxicity, different substituents (R ¼ H, Cl, F, OCF3) were introduced
at the C-7 position of the benzene-fused ring, and an appropriate
substituted thiophene, furan and pyrrole rings were also linked to
tetrahydro-1-benzazepine nucleus at the C-2 position. Complete
data concerning anti-trypanosomal, anti-leishmanial and cytotoxic
activities as well as the calculated octanol/water partition co-
efficients (log P) and dipoles (D) of the active compounds are re-
ported in Tables 1e3.
From the forty nine compounds evaluated in the T. cruzi assays,
eighteen [nine of the 2-(thiophen-2-yl)-1,4-epoxytetrahydro-1-
benzazepine series 10, three of the 2-(furan-2-yl)-1,4-
epoxytetrahydro-1-benzazepine series 11, five of the 2-(thiophen-
2-yl)-4-hydroxytetrahydro-1-benzazepine series 14, and one of the
2-(furan-2-yl)-4-hydroxy-tetrahydro-1-benzazepine series 15]
were active against epimastigostes with IC50 values lying in the
Scheme 3. NeO bond reductive cleavage in 1,4-epoxycycloadducts 10e12.
hydroxytetrahydro-1-benzazepines 14ael, 15aeh, and 16a,b,
respectively, in good to excellent yields.
The reductive cleavage of the bromo-substituted cycloadducts
10d,h,l,p also proceeded very easy affording, in these cases, the
debrominated amino-alcohols 14a,d,g,j instead of the expected 5-
bromothiophene substituted amino-alcohols. These results were
deduced from NMR and MS analysis. The formation of 14a,d,g,j
(84e92% yields) can be explained by the concomitant generation of
thienylzinc bromide intermediate and its subsequent hydrolysis.
Unfortunately, the reductive cleavage of the 5-nitrofuran-2-yl and
the N-methylpyrrolo-substituted cycloadducts 11c,h,k, and 13a,b
gave a very complex mixture of no identifiable degradation
products.
10.7e47.9
mM range (Table 1). Compounds 14l (amino-alcohol
bearing a trifluoromethoxy group at C-7 and a 3-methylthiophen-
2-yl-moiety at C-2), 10g (1,4-epoxycycloadduct bearing a chlorine
atom at C-7 and a 3-methylthiophen-2-yl-moiety at C-2), 14e
The structures and stereochemistry of these novel compounds
were determined mainly by 1D and 2D NMR spectroscopy. As ex-
pected, the reductive cleavage of the 1,4-epoxycycloadducts 10e12
afforded stereospecifically the 2,4-cis stereoisomeric amino-
alcohols 14e16 with the tetrahydroazepine ring adopting a chair
conformation. The stereochemistry and conformation were
unambiguously determined by the chemical shifts and coupling
constant values of the six tetrahydroazepine ring protons (see
Experimental Section), and, specially, by the NOE cross-signal be-
tween the double doublet (dd) of proton at position C-2
(3.91e4.32 ppm) and the triple double doublet (tdd) of proton at
position C-4 (3.82e4.07 ppm). Confirmation of this structural
assignment was made by single-crystal X-ray analysis of 14a and
14b [45]. The X-ray crystal structures of these compounds with the
atomic numbering scheme are shown in Fig. 3, and are in agree-
ment with the stereochemistry deduced from NMR analysis.
(amino-alcohol bearing
methylthiophen-2-yl-moiety
epoxycycloadduct bearing a chlorine atom at C-7 and a 5-
bromothiophen-2-yl-moiety at C-2), showed the best activities
with IC50 values of 10.7, 11.7, 14.6 and 14.7 mM, respectively. These
a
chlorine atom at C-7 and
at C-2), and 10h
a
5-
(1,4-
IC50s are quite similar to that measured for the most active mem-
bers of the series I and II [30], and only 2.7e3.7 times higher than
that of nifurtimox, found to be 4.0
the most active compound 14l was also toxic for Vero cells, with a
CC50 ¼ 26.7 M and a SI ¼ 2.5. On the contrary, compound 10h
possesses the highest CC50 value of 1664.2 M and has the
mM in the same assay. However,
m
m
maximum SI value of 113.4, which are several folds better than that
measured for the most active members of the series I and II and
nifurtimox (CC50 ¼ 67.5 M and SI ¼ 17.0).
m
Unfortunately, the majority of the evaluated compounds were
unable to inhibit the growth of amastigotes, due, may be, to the
difficult to penetrate the cell membrane of parasite (see data in
Supplementary material). Only two compounds, the 1,4-
epoxycycloadduct 10h and the amino-alcohol 14f (this last
bearing a chlorine atom at C-7 and a 3-methylthiophen-2-yl-moi-
2.2. Antiparasitic activity
The majority of the synthesized compounds were in vitro
screened against the extracellular and intracellular forms of T. cruzi
ety at C-2), exhibited considerable (IC50 ¼ 23.9
mM) or limited
Fig. 3. Single crystal X-ray structures of 14a and 14b (ORTEP views, atom-labeling schemes were numbered as 1ꢁ and 2ꢁ for the two independent molecules appear in asymmetric
unit in both cases, representing here just one of them).

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
295
Table 1
In vitro antiparasitic activity and cytotoxicity of active 2-exo-heteroaryltetrahydro-1,4-epoxy- (10, 11) and cis-2-heteroaryl-4-hydroxytetrahydro-1-benzazepines (14, 15)
against T. cruzi parasite and Vero cells.
Compound
Epimastigotes/Amastigotes
IC50 M)
SI
Vero cells
CC50 M)
Compound
Epimastigotes/Amastigotes
IC50 M)
SI
Vero cells
CC50 M)
(
m
(
m
(
m
(m
27.6 2.1/NA
25.4 0.2/NA
16.4
452.7 2.4
46.2 2.4/NA
47.7 3.2/NA
25.1
1158.7 12.6
>14.2
>361.0
>8.6
>408.0
24.8 1.2/NA
11.7 0.9/NA
46.1
15.6
1144.7 19.4
182.9 7.5
29.7 1.4/NA
22.8 0.9/NA
14.2
41.9
421.5 5.1
956.4 7.5
14.7 0.1/23.9 0.0
30.9 0.4/NA
113.4/69.8
30.6
1664.2 3.5
944.0 0.0
14.6 0.6/NA
10.5
153.7 3.8
200.3 6.6
47.9 2.2/41.5 0.4
4.2/4.8
34.7 0.1/NA
43.9 3.4/NA
>8.5
>295.0
45.9 1.4/NA
10.7 0.2/NA
5.3
2.5
243.1 0.6
26.7 2.9
3.9
169.9 20.1
47.2 0.9/NA
1.3
61.7 3.8
67.5 4.0
42.7 2.3/NA
1.9
82.1 1.5
Nfx
4.0 0.0/1.6 0.0
17.0/43.0
IC: inhibitory concentration; CC: cytotoxic concentration; SI: selectivity index; Nfx: nifurtimox; NA: compounds that were inactive at the lowest tested concentration.
Note: Data for non-active compounds can be seen in the Supporting material.
activity (IC50 ¼ 41.5
showing toxicity on Vero cells. It is interesting to note that 10h also
demonstrated noteworthy inhibitory activity against epi-
mastigotes. In comparison to inhibitory activity of the most
prominent members of the series I and II, compound 10h exhibited
an improved activity.
m
M), respectively, against amastigotes without
moiety at C-2), 10o (1,4-epoxy-cycloadduct bearing a tri-
fluoromethoxy group at C-7 and a 3-methylthiophen-2-yl-moiety
at C-2), and 10i (1,4-epoxycycloadduct bearing a fluorine atom at C-
7 and a thiophen-2-yl-moiety at C-2), exhibited the best activities
a
with IC50 values of 7.3, 10.5, 10.7, 10.8, 11.3, 11.4 and 11.5
mM,
respectively. These IC50s are similar or only slightly better than that
In the cytotoxicity assays, with the exception of 10o, 11c, 11i, 14j,
14k, 14l, 15h and 16b, the compounds did not show toxicity on Vero
cells at the CC50 level (see data in Supplementary material). As a
result, 34 of the examined compounds have SI higher than 3,
indicating that such compounds were more active against the
parasite than against the Vero cells.
measured for the most active members of the series I and II [30]; in
comparison with amphotericin B (IC50 ¼ 0.03
compounds are far less active. In addition, compound 10o has
shown the lowest cytotoxicity with a CC50 > 1759.2 M and has the
mM), the above
m
maximum SI value of >153.9, which are more than three folds
better than that measured for compound 10l and at least six folds
Of all the evaluated compounds in the L. (L.) infantum assays,
twenty six (ten of the series 10, seven of the series 11, one of the 2-
(furan-3-yl)-1,4-epoxytetrahydro-1-benzazepine series 12, five of
the series 14, two of the series 15, and one of the 2-(furan-3-yl)-4-
hydroxytetrahydro-1-benzazepine series 16), showed inhibitory
lower than that measured for amphotericin B (CC50 ¼ 29.7
mM and
SI ¼ 927.5).
Analogously to compounds of the series I and II, none of the
examined compounds inhibited the growth of L. (L.) infantum
amastigotes at the concentrations employed.
activity of less than 50
epoxycycloadduct bearing
m
a
M (Table 2). Compounds 10l (1,4-
fluorine atom at C-7 and 5-
In the cytotoxicity assays, with the exception of 14j, 14k and 14l,
the compounds were nontoxic to THP-1 cells at the CC50 level (see
data in Supplementary material). As a result, 38 of the examined
compounds have SI higher than 3, indicating that such compounds
were more active against the parasite than against the HTP-1 cells.
As shown above, these three compounds were also toxic to Vero
cells.
a
bromothiophen-2-yl-moiety at C-2), 10n (1,4-epoxycycloadduct
bearing a trifluoromethoxy group at C-7 and a 5-methylthiophen-
2-yl-moiety at C-2), 11h (1,4-epoxycycloadduct bearing a fluorine
atom at C-7 and a 5-nitrofuran-2-yl-moiety at C-2), 11j (1,4-
epoxycycloadduct bearing a trifluoromethoxy group at C-7 and a
5-methylfuran-2-yl-moiety at C-2), 14k (amino-alcohol bearing a
trifluoromethoxy group at C-7 and a 5-methylthiophen-2-yl-
The lack of or the limited in vitro inhibitory activity of com-
pounds against the intracellular form of T. cruzi or Leishmania

296
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
Table 2
In vitro antiparasitic activity and cytotoxicity of active 2-exo-heteroaryltetrahydro-1,4-epoxy- (10e12) and cis-2-heteroaryl-4-hydroxytetrahydro-1-benzazepines (14e16)
against L. (L.) infantum promastigotes and THP-1 cells.
Compound
Promastigotes
IC50 M)
SI
HTP-1 cells
CC50 M)
Compound
Promastigotes
IC50 M)
SI
HTP-1 cells
CC50 M)
(
m
(
m
(
m
(m
15.9 1.4
45.7
34.7
727.44 8.0
19.1 1.4
19.6
374.4 1.5
36.1 0.6
20.7 0.2
1251.9 24.9
10.7 0.1
16.0 0.7
50.4
19.9
538.9 1.3
318.9 5.2
>17.5
>361.0
32.3 5.2
32.3 5.2
>63.8
>2061.5
10.8 0.0
25.2 0.5
16.3
175.8 19.6
7.7
250.2 18.1
>76.6
>1928.8
14.3 0.7
11.5 0.4
7.3 0.3
>117.9
86.6
>1690.4
991.3 2.2
>295.0
49.5 0.5
16.9 0.1
13.8 0.2
2.3
18.5
4.4
114.9 5.5
311.5 16.8
61.5 0.7
>40.6
10.5 0.1
11.4 0.1
26.8
282.0 2.0
11.3 0.1
16.4 0.2
8.6
5.5
98.0 3.5
89.7 2.5
>153.9
>1759.2
45.3 6.5
27.3 1.6
14.7
14.5
663.1 24.5
394.5 14.1
45.9 0.8
12.8 0.1
43.1 1.3
2.9
9.7
134.5 13.4
124.1 9.1
460.4 4.2
47.3 0.1
>24.3
>114 9.2
10.7
AmB.
0.03 0.00001
927.5
29.7 3.6
IC: inhibitory concentration; CC: cytotoxic concentration; SI: selectivity index; AmB: amphotericin B.
Note: Data for non-active compounds can be seen in the Supporting material.
(compared with the inhibitory activity of the active compounds
against the extracellular forms) could be due to an unsuccessful
cooperation between compounds and the hosteparasite cell.
Though the mechanism of action of the tested compounds is not
known, the active compounds could be able to activate different
mechanism, such as elicit of death intracellular signals, enzymatic
transformation of prodrugs in active ones or penetration inside the
cells, reaching the infected cellular compartments and expressing
their activity in the corresponding environment [46]. The intra-
cellular environmental circumstances where the parasite survives
are complex and not always well understood. In T. cruzi, the
infective trypomastigotes, after reaching the cell lysosomal
compartment of the host cell, are released into cytosol where
transformation and replication of intracellular amastigotes occur
[47]. In Leishmania, once the promastigotes are phagocytosed by
mammalian host macrophages, they are transformed into amasti-
gotes which multiplies within the phagolysosome of the host cell.
Intracellular amastigotes must grow continuously and released
after destruction of highly infected macrophages to enter into un-
infected macrophages and get again a parasitophorous vacuole
throughout a progressive infection [48].
Finding active compounds in the process of small molecule drug
discovery against the intracellular forms of the parasite is more
complicated than in promastigotes or axenic amastigotes [49]. The
promastigotes are easily cultivated in culture medium, but are the
form of the parasite in the insect vector. In addition, although

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
297
Table 3
10h also exerted a remarkable inhibitory activity against T. cruzi
amastigotes. Due to its lower cytotoxicity on Vero and THP-1 cells
Anti-trypanosomal and anti-leishmanial in vitro activities of active 2-exo-hetero-
aryltetrahydro-1,4-epoxy- (10, 11, 12) and cis-2-heteroaryl-4-hydroxytetrahydro-1-
benzazepines (14, 15, 16), and their calculated log P and dipole.
(CC50 ¼ 1664.2 and >1690.4
mM, respectively) and better selectivity
indexes (SI ¼ 113.4 and >117.9, respectively), this compound can
serve as a promising candidate for further development of more
potent antichagasic and antileishmanial agents. Although no
treatment for leishmaniasis is used to treat Chagas disease, sus-
ceptibility of parasites in vitro and in experimental models to the
same drug has been demonstrated. Both parasites have been sus-
ceptible in vitro to different drugs such as miltefosine, ketocona-
zole, AmB (both the free and liposomal AmB) and tafenoquine
[52e55]. This could be explained by the existing similarity be-
tween both parasites; both are flagellated protozoa belonging to
the same Trypanosomatidae family, share biological and genetic
features such as the presence of a single mitochondrion where the
genetic material is packaged (kinetoplast), both are transmitted by
insect vectors and both have an intracellular cycle where the par-
asites are transformed in a replicative amastigote forms.
In terms of the structureeactivity relationships, the presence of
halogen atoms, especially a chlorine atom, or a trifluoromethoxy
group at the C-7 position and a 3(5)-methyl- or 5-bromothiophen-
2-yl-moiety at the C-2 position (series 10 and 14) positively influ-
enced the activity against epimastigotes and amastigotes of T. cruzi,
prominent examples being the 7-chloro-2-(3(5)-methylthiophen-
2-yl)-substituted derivatives 10g and 14e, the 7-chloro-2-(5-
bromothiophen-2-yl)-substituted derivative 10h, and the 7-
trifluoromethoxy-2-(3-methylthiophen-2-yl)-substituted deriva-
tive 14l; compounds 10n, 10o and 14f are the exception. On the
contrary, the anti-T. cruzi activity is reduced (e.g., compounds 11e,
11f, 11h, and 15h) or eliminated (most of the compounds of the
series 11, 12, 13, 15 and 16) by replacing the thiophen-2-yl-moiety
with furan-2-yl- (series 11 and 15), furan-3-yl- (series 12 and 16)
and N-methylpyrrol-2-yl- (series 13) moieties. Similar reduction
(e.g., compounds 10c and 14b) or loss (e.g., compounds 10a, 10b,
10d, 11a, 11b, 11c, 14a, 14c, 15a and 15b) of activity was also
observed for all non-substituted (R ¼ H), at the C-7 position
compounds.
Compound
Epimastigotes
Promastigotes
IC50 M)
Log P
Dipole (D)
IC50
(m
M)
(m
10a
10c
10d
10e
10f
10g
10h
10i
e
15.9 1.4
e
2.71
3.17
3.56
3.54
4.00
4.00
4.39
3.00
3.46
3.85
3.29
3.13
2.19
2.65
3.02
3.48
2.48
1.88
2.32
2.78
2.33
2.46
2.78
3.48
3.24
2.90
2.90
2.85
3.31
3.31
2.33
2.79
2.35
2.26
2.12
2.59
2.42
2.36
2.13
2.29
2.62
2.49
2.33
3.18
3.09
2.70
2.66
2.55
2.52
2.52
5.03
3.00
3.18
3.037
3.28
3.58
3.78
3.79
4.21
4.14
4.63
4.90
4.73
4.26
4.75
4.20
27.6 2.1
e
36.1 0.6
20.7 0.2
32.3 5.2
32.3 5.2
14.3 0.7
11.5 0.4
e
25.4 0.2
24.8 1.2
11.7 0.9
14.7 0.1
e
10j
10l
30.9 0.4
34.7 0.1
43.9 3.4
47.2 0.9
7.3 0.3
10.5 0.1
11.4 0.1
45.3 6.5
27.3 1.6
47.3 0.1
19.1 1.4
e
10n
10o
11a
11b
11d
11e
11f
11h
11i
e
e
e
46.2 2.4
47.7 3.2
29.7 1.4
e
10.7 0.1
16.0 0.7
10.8 0.0
25.2 0.5
e
11j
e
12b
14b
14d
14e
14f
14h
14i
14j
14k
14l
e
22.8 0.9
e
49.5 0.5
e
14.6 0.6
47.9 2.2
e
e
16.9 0.1
e
45.9 1.4
e
13.8 0.2
11.3 0.1
16.4 0.2
45.9 0.8
12.8 0.1
43.1 1.3
e
10.7 0.2
e
15g
15h
16b
42.7 2.3
e
axenic amastigotes clearly resembled intracellular amastigotes in
their ultra-structural, biological, biochemical, and immunological
properties [50], they have shown differences in several cellular
processes [51]. The intracellular forms are dependent on energy
and nutrients produced by the host cells. They could adapt to the
particular environmental conditions by activating some additional
genes present in their genome. In amastigotes of Leishmania main
variation have been found in genes involved in metabolism, cellular
organization, biogenesis and transport, as well as in genes encoding
unknown functions [51]. However, the promastigote or axenic
amastigote assays not always serve to identify active compounds
and, generally, they lead to a rate of high percent of false positives
because such compounds, in fact, kill the parasite. In a screening
approach (as is the case of the present work), different aspects
related with host cell: parasite interactions such as parasite target,
cell toxicity, ability to cross host cell membranes, stability under
low pH, accumulation or intracellular distribution are unknown.
However, the data of antiparasitic activity and cytotoxicity obtained
in this work are necessary to progress to new stages of drug-
discovery. In fact, the levels of mammalian cell toxicity compared
with the antiparasitic activities calculated as SI on free forms were
very encouraging.
On the other hand, the presence of a fluorine atom or a tri-
fluoromethoxy group at the C-7 position and 5-bromothiophen-2-
yl-, 3(5)-methyl- or thiophen-2-yl-moieties at the C-2 position
appeared to be the best combinations to enhance the inhibitory
activity against L. (L.) infantum promastigotes, prominent examples
being the 7-fluoro-2-(5-bromothiophen-2-yl)-substituted deriva-
tive 10l, the 7-fluoro-2-(thiophen-2-yl)-substituted derivative 10i,
the
7-trifluoromethoxy-2-(3-methylthiophen-2-yl)-substituted
derivative 10o, and the 7-trifluoromethoxy-2-(5-methyl-thiophen-
2-yl)-substituted derivatives 10n and 14k. In addition, the presence
of the above two substituents at the C-7 position and a 5-nitro(5-
methyl)furan-2-yl-moiety at the C-2 position also produced com-
pounds with remarkable inhibitory activity, prominent examples
being the 7-fluoro-2-(5-nitrofuran-2-yl)-substituted derivative
11h, and the 7-trifluoro-2-(5-methylfuran-2-yl)-substituted de-
rivatives 11j and 15h. Other combinations between the substituents
at the C-7 position and the heterocyclic moieties at the C-2 position
generally reduced or eliminated the activity.
The data reported in Tables 1 and 2 also indicated that, in most
of the cases, compounds of the series 10 tended to show better
activity than compounds of the series 11, 14 and 15. The data also
revealed that the incorporation of a furan-3-yl-moiety at C-2 did
not exert influence on anti-T. cruzi activity, but exerted only a
modest influence on anti-L. (L.) infantum activity (compounds 12b
and 16b). Similarly, the incorporation of a N-methylpyrrol-2-yl-
moiety at C-2 did not exert influence on both anti-T. cruzi and anti-
L. (L.) infantum activities (compound 13b).
From the antiparasitic and cytotoxic data reported in Tables 1
and 2, it can be observed that, of all active compounds against
T. cruzi and L. (L.) infantum parasites, eleven compounds (10e, 10f,
10g, 10h, 10l, 10n, 10o, 11e, 11h, 14l and 15h) demonstrated a
noteworthy or a moderate affinity for both extracellular epi-
mastigote and promastigote forms of parasites with the com-
pounds 10h and 14l being the most active. Interestingly, compound

298
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
In order to correlate the structureeactivity relationships
3. Conclusion
described above with quantitative parameters, we theoretically
determined the octanol/water partition coefficients (log P) and
dipole (D) for the 1,4-epoxy-tetrahydro-1-benzazepines (10, 11, 12)
and 4-hydroxytetrahydro-1-benzazepines (14, 15, 16) that were
active against epimastigostes of T. cruzi and promastigotes of L. (L.)
infantum (Table 3), and tried to establish a relationship between
In summary, we have designed and synthesized small libraries
of structurally diverse and novel (2SR,4RS)-2-heteroaryl-1,4-
epoxytetrahydro-1-benzazepines
and
cis-2-heteroaryl-4-
hydroxytetrahydro-1-benzazepines, starting from readily avail-
able and highly economical substrates and reagents following
simple protocols. In the present study, we identified several com-
pounds with high affinity for the extracellular forms of both T. cruzi
and L. (L.) infantum parasites without showing toxicity on Vero and
THP-1 cells. We also found that compound 10h possessed the most
promising activity against amastigotes of T. cruzi with an IC50 value
their IC50 (mM) and values of these two parameters (Figs. 4 and 5).
For the calculation of log P and dipole, the geometries for all mol-
ecules studied were fully optimized with the parametric method 3
(PM3) implemented in MOPAC2012 program [56e58]. The models
were minimized until the root mean square (RMS) gradient value
reached a value smaller than 0.0001 kcal/mol. Frequency calcula-
tions were performed in order to determine the character of the
stationary point: zero imaginary frequency for minima. The lowest
energy structure was used for each molecule to calculate dipole
moment. Theoretical log P (octanol/water partition coefficient)
values were obtained using Advanced Chemistry Development Inc.
(ACD/Labs) software, version 14.01 (1994e2013).
From the data consigned in Table 3 and Figs. 3 and 4, it can be
observed that there is not a clear correlation between IC50 values of
all active compounds and their lipophilicities and dipoles. However,
the high inhibitory activity against epimastigotes of T. cruzi of
compounds 10h, 10g, 14e and 14l with IC50 values of 14.7, 11.7, 14.6
of 23.9
mM. Due to its lower cytotoxicity on Vero and THP-1 cells
(CC50 ¼ 1664.2 and >1690.4
mM, respectively) and better selectivity
indexes (SI ¼ 113.4 and >117.9, respectively), this compound can
serve as a promising candidate for further development of more
potent antichagasic and antileishmanial agents. This conclusion is
also supported by the fact that this compound is fully compatible
with Lipinski's rules. Structureeactivity relationships established
that the inhibitory activity against epimastigotes and amastigotes
of T. cruzi was greatly enhanced by the presence of a chlorine atom
or a trifluoromethoxy group at the C-7 position and a 3(5)-methyl-
or 5-bromothiophen-2-yl-moiety at the C-2 position, while the
presence of a fluorine atom or a trifluoromethoxy group at the C-7
position and 5-bromothiophen-2-yl-, 3(5)-methyl-, or thiophen-2-
yl-moieties at the C-2 position enhanced the inhibitory activity of
the molecules against L. (L.) infantum promastigotes. Experiments
aimed at improving the activity of these classes of compounds and
determining their modes of action are underway, and the results
from these studies will be published in the near future.
and 10.7 mM, respectively, positively correlated with the values of
Log P (Fig. 4). Similarly, compounds 10l, 10i, 10o, 10n and 14k,
which showed the best inhibitory activities against L. (L.) infantum
promastigotes with IC50 values of 7.3, 11.5, 11.4, 10.5, 11.4
mM,
respectively, also presented appropriate values of Log P higher than
3.0 (Fig. 5). On the contrary, the Log P and dipole values for com-
pound 11h disagree with its high antileishmanial activity
(IC50 ¼ 10.7
group in the molecule. It is important to note, that compound 10h,
which not only possesses the highest CC50 value of 1664.2 M and
mM), what can be attributed to the presence of the nitro
4. Experimental section
m
4.1. General
has the maximum SI value of 113.4, but also demonstrated a
noteworthy inhibitory activity against epimastigotes and was one
of the few compounds who exhibited activity against amastigotes
of T. cruzi, presented the highest Log P value of all the evaluated
compounds, thus validating the importance of this property in the
process of small molecule drug discovery. Finally, the remaining
compounds presented lower values of Log P and higher values of
dipole which agree with the moderate or limited antiparasitic ac-
tivity observed against T. cruzi and L. (L.) infantum parasites (Figs. 4
and 5).
All the reagents and solvents were purchased from Sigma-
eAldrich or Merck companies, and used without further purifica-
tion. Monitoring of the reactions was performed using silica gel TLC
plates (silica Merck 60 F254). Spots were visualized by UV light at
254 and 365 nm. Column chromatography was performed on
Merck Kieselgel 60e230 mesh (ASTM). All the chromatographic
solvent proportions were volume to volume. Melting points were
determined with a MEL-TEMP 1201D capillary apparatus and were
not corrected. IR spectra were recorded on a Nicolet Avatar 360-
Fig. 4. Log
P and dipole vs. in vitro anti-trypanosomal activity against epimastigotes of active 2-exo-heteroaryltetrahydro-1,4-epoxy- (10, 11) and cis-2-heteroaryl-4-
hydroxytetrahydro-1-benzazepines (14, 15).

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
299
Fig. 5. Log
P and dipole vs. in vitro anti-leishmanial activity against promastigotes of active 2-exo-heteroaryltetrahydro-1,4-epoxy- (10, 11, 12) and cis-2-heteroaryl-4-
hydroxytetrahydro-1-benzazepines (14, 15, 16).
FTIR spectrometer and were referenced to polystyrene standard,
solution (12 mmol). The resulting mixtures were stirred at 0 ꢀC
during 30 min and then at room temperature for further
11.5e18.5 h. Each mixture was filtered, extracted with ethyl acetate,
and then dried over anhydrous sodium sulfate. The solvent was
removed under reduced pressure and toluene (30 mL) was added to
the organic black residue. The resulting solution was heated at
100 ꢀC for 6e8 h. After cooling each solution to ambient temper-
ature, the solvent was removed under reduced pressure and the
crude product was purified on silica gel column chromatography
using heptaneeethyl acetate (compositions in the range from 15:1
to 10:1 v/v) as eluent, to give the expected compounds as yellow
viscous oils or colorless crystalline substances.
using cells equipped with potassium bromide windows. 1H and 13
C
NMR spectra were measured at 25 ꢀC on a Bruker Avance III-400
spectrometer, using CDCl3 as the solvent. Chemical shifts ( ) and
d
coupling constant (J) values are reported in ppm and Hz, respec-
tively. Chemical shifts are relative to the solvent peaks used as
reference [CDCl3: dH ¼ 7.26, and dC ¼ 77.0]. For 1H NMR, the as-
signments are: q ¼ quartet, t ¼ triplet, d ¼ doublet, s ¼ singlet,
br ¼ broad and m ¼ multiplet. A Hewlett Packard HP 5890 A series
II Gas Chromatograph interfaced to a Hewlett Packard 5972 Mass
Selective Detector with a HP MS ChemStation Data system, and
High Resolution Mass Spectrometer Waters Micromass AutoSpect
NT (equipped with a direct inlet probe) operating at 70 eV were
used for MS identification. Compounds of 1 were prepared ac-
cording to our previously established experimental conditions [40].
4.1.2.1. (2SR,4RS)-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1-
benzazepine 10a. Reaction time: 20 h. Yield: 61%. 1H NMR
(400 MHz, CDCl3):
d
¼ 7.24 (dd, J ¼ 4.8, 1.5 Hz, 1H, H50), 7.17 (dd,
4.1.1. General procedure for the preparation of 2-allyl-N-
(heteroarylmethyl)anilines 6e9
J ¼ 7.4, 2.0 Hz, 1H, H6), 7.15 (td, J ¼ 7.4, 2.0 Hz, 1H, H8), 7.15 (td,
J ¼ 7.4, 2.0 Hz, 1H, H7), 7.14 (dd, J ¼ 7.4, 2.0 Hz, 1H, H9), 6.97 (dd,
J ¼ 4.8, 1.5 Hz, 1H, H30), 6.96 (dd, J ¼ 4.8, 4.8 Hz, 1H, 40-H), 5.01 (ddd,
J ¼ 7.7, 5.3, 2.0 Hz,1H, H4), 4.86 (dd, J ¼ 8.2, 2.2 Hz,1H, H2), 3.42 (dd,
J ¼ 16.5, 5.3 Hz, 1H, HB5), 2.72 (dddd, J ¼ 12.6, 7.7, 2.2, 1.2 Hz, 1H,
HB3), 2.56 (ddd, J ¼ 12.6, 8.2, 2.0 Hz,1H, HA3), 2.55 (br d, J ¼ 16.5 Hz,
To a stirred solution of the appropriately N-substituted ortho-
allylanilines 1 (6 mmol) in methanol (50 mL) was added the
respective heteroaromatic aldehydes 2e5 (6.2 mmol). The reaction
mixtures were heated at 40e50 ꢀC for 4e6 h. Once the corre-
sponding imines were formed (TLC monitoring), to these meth-
anolic solutions sodium borohydride (18 mmol) was slowly added
in small portions at 0 ꢀC. After adding the reductive agent, the re-
action mixtures were stirred at room temperature for further 6 h.
Finally, water (60 mL) was added and the reaction mixtures were
heated at 45e50 ꢀC for 4 h. Each mixture was extracted with
chloroform (2 ꢁ 100 mL). The combined organic extracts were dried
over anhydrous sodium sulfate, filtered and then concentrated
under reduced pressure. The resulting crude products were puri-
fied by silica gel column chromatography using heptaneeethyl
acetate (compositions ranged from 30:1 to 15:1 v/v) as eluent to
give 6aep, 7aek, 8a,b and 9a,b as viscous pale yellow oils. The
spectroscopic data of these compounds are reported in the
Supporting material.
1H, HA5). 13C NMR (100 MHz, CDCl3):
d
¼ 149.1 (C9a), 146.9 (C20),
129.3 (C6), 126.2 (C8), 126.0 (C7), 125.7 (C50), 124.5 (C5a), 124.3
(C40), 123.4 (C30), 121.6 (C9), 74.5 (C4), 71.3 (C2), 41.9 (C3), 34.2 (C5).
IR (liquid film, cmꢂ1): ṽ ¼ 1048 (CeO), 980 (NeO). GCeMS (EI,
70 eV): m/z (%) ¼ 243 (Mþꢃ, 41), 226 (29), 213 (18),130 (12),110 (29),
105 (53), 104 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for
C14H13NOS: 243.0718; found: 243.0719.
4.1.2.2. (2SR,4RS)-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 10b. Reaction time: 23 h. Yield: 61%. White
solid. mp 85 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.16 (dd,
J ¼ 8.4, 1.5 Hz, 1H, H6), 7.14 (td, J ¼ 8.4, 1.5 Hz, 1H, H8), 7.13 (td,
J ¼ 8.4, 2.0 Hz, 1H, H7), 7.11 (dd, J ¼ 8.4, 2.0 Hz, 1H, H9), 6.75 (d,
J ¼ 3.4 Hz, 1H, H30), 6.60 (d, J ¼ 3.4 Hz, 1H, H40), 4.99 (ddd, J ¼ 7.8,
5.2, 2.0 Hz, 1H, H4), 4.78 (dd, J ¼ 8.3, 2.0 Hz, 1H, H2), 3.41 (dd,
J ¼ 16.5, 5.2 Hz, 1H, HB5), 2.70 (dddd, J ¼ 12.6, 7.8, 2.0, 1.0 Hz, 1H,
HB3), 2.53 (br d, J ¼ 16.5 Hz,1H, HA5), 2.51 (ddd, J ¼ 12.6, 8.3, 2.0 Hz,
4.1.2. General procedure for the synthesis of (2SR,4RS)-2-
heteroaryl-2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepines 10e13
To a stirred and cooled (ice-bath) solution of the appropriately
N-substituted ortho-allylanilines (6aep), (7aek), (8a,b) and (9a,b),
(4 mmol), in methanol (20 mL), were added sodium tungstate
dihydrate (10 molar%) and 30% aqueous hydrogen peroxide
1H, HA3), 2.50 (s, 3H, 50-CH3). 13C NMR (100 MHz, CDCl3):
d
¼ 149.1
(C9a), 144.3 (C20), 138.9 (C50), 129.3 (C6), 126.2 (C8), 125.7 (C7),
124.5 (C5a), 123.9 (C40), 123.3 (C30), 121.6 (C9), 74.5 (C4), 71.6 (C2),
41.5 (C3), 34.2 (C5), 14.8 (50-CH3). IR (KBr, cmꢂ1): ṽ ¼ 1053 (CeO),

300
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
990 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 257 (Mþꢃ, 59), 240 (58),
227 (12),130 (12),124 (100),105 (50),104 (78). HRMS (EI, 70 eV): m/
z [M]þ calcd for C15H15NOS: 257.0874; found: 257.0873.
123.5 (C9), 74.4 (C4), 71.9 (C2), 41.9 (C3), 34.5 (C5), 15.2 (50-CH3). IR
(KBr, cmꢂ1): ṽ ¼ 1049 (CeO), 971 (NeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 291 (Mþ
ꢃ
,
35Cl, 27), 274 (21), 261 (5),164 (6),139 (34),138 (40),
124 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H14ClNOS:
4.1.2.3. (2SR,4RS)-2-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-1,4-
291.0485; found: 291.0490.
epoxy-1-benzazepine 10c. Reaction time: 21 h. Yield: 58%. White
solid. mp 54 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.21e7.16
4.1.2.7. (2SR,4RS)-7-chloro-2-(3-methylthiophen-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 10g. Reaction time: 20 h.
Yield: 73%. White solid. mp 125 ꢀC (heptane). 1H NMR (400 MHz,
(m, 2H, H7, H8), 7.15e7.12 (m, 3H, H50, H6, H9), 6.80 (d, J ¼ 5.0 Hz,
1H, H40), 5.04 (ddd, J ¼ 7.5, 5.4, 2.1 Hz, 1H, H4), 4.90 (dd, J ¼ 8.2,
2.5 Hz, 1H, H2), 3.44 (dd, J ¼ 16.7, 5.4 Hz, 1H, HB5), 2.65 (dddd,
J ¼ 12.6, 7.5, 2.5, 1.1 Hz, 1H, HB3), 2.58 (ddd, J ¼ 12.6, 8.2, 2.1 Hz, 1H,
HA3), 2.55 (br d, J ¼ 16.7 Hz, 1H, HA5), 2.24 (s, 3H, 30-CH3). 13C NMR
CDCl3):
d
¼ 7.16 (dd, J ¼ 8.4, 2.4 Hz, 1H, H8), 7.14 (d, J ¼ 5.2 Hz, 1H,
H50), 7.13 (d, J ¼ 2.4 Hz, 1H, H6), 7.06 (d, J ¼ 8.4 Hz, 1H, H9), 6.80 (d,
J ¼ 5.2 Hz, 1H, H40), 5.00 (ddd, J ¼ 7.6, 5.2, 2.0 Hz, 1H, H4), 4.80 (dd,
J ¼ 8.4, 2.4 Hz, 1H, H2), 3.40 (dd, J ¼ 16.8, 5.2 Hz, 1H, HB5), 2.60
(dddd, J ¼ 12.8, 7.6, 2.4, 1.6 Hz, 1H, HB3), 2.55 (ddd, J ¼ 12.8, 8.4,
2.0 Hz, 1H, HA3), 2.52 (br d, J ¼ 16.8 Hz, 1H, HA5), 2.23 (s, 3H, 30-
(100 MHz, CDCl3):
d
¼ 149.9 (C9a), 140.4 (C20), 132.9 (C30), 130.0
(C6), 129.8 (C40), 126.8 (C8), 126.3 (C7), 125.2 (C5a), 123.2 (C50),
122.1 (C9), 75.2 (C4), 70.4 (C2), 42.5 (C3), 34.7 (C5), 14.3 (30-CH3). IR
(KBr, cmꢂ1): ṽ ¼ 1050 (CeO), 977 (NeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 257 (Mþꢃ, 39), 240 (30), 227 (9), 130 (18), 124 (67), 105 (67),
104 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H15NOS:
257.0874; found: 257.0878.
CH3). 13C NMR (100 MHz, CDCl3):
d
¼ 148.6 (C9a), 140.2 (C20), 132.8
(C30), 131.5 (C7), 129.8 (C6), 129.8 (C40), 127.1 (C5a), 126.9 (C8), 123.5
(C9), 123.2 (C50), 74.6 (C4), 70.4 (C2), 42.5 (C3), 34.6 (C5), 14.2 (30-
CH3). IR (KBr, cmꢂ1): ṽ ¼ 1050 (CeO), 973 (NeO). GCeMS (EI,
70 eV): m/z (%) ¼ 291 (Mþ
,
35Cl, 41), 274 (22), 261 (7), 164 (10), 139
ꢃ
4.1.2.4. (2SR,4RS)-2-(5-bromothiophen-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 10d. Reaction time: 23 h. Yield: 68%. White
solid. mp 106 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
(68), 138 (87), 124 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for
C15H14ClNOS: 291.0485; found: 291.0482.
d
¼ 7.20e7.15 (m, 2H, H7, H8), 7.12 (dd, J ¼ 7.4, 1.8 Hz, 1H, H6), 7.10
4.1.2.8. (2SR,4RS)-7-chloro-2-(5-bromothiophen-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 10h. Reaction time: 21 h.
Yield: 64%. White solid. mp 89 ꢀC (heptane). 1H NMR (400 MHz,
(dd, J ¼ 7.4, 2.3 Hz, 1H, H9), 6.89 (d, J ¼ 3.7 Hz, 1H, H40), 6.69 (d,
J ¼ 3.7 Hz, 1H, H30), 4.98 (ddd, J ¼ 7.6, 5.2, 2.0 Hz, 1H, H4), 4.75 (dd,
J ¼ 8.1, 2.0 Hz, 1H, H2), 3.42 (dd, J ¼ 16.6, 5.2 Hz, 1H, HB5), 2.66
(dddd, J ¼ 12.6, 7.6, 2.0, 1.0 Hz, 1H, HB3), 2.53 (br d, J ¼ 16.6 Hz, 1H,
HA5), 2.52 (ddd, J ¼ 12.6, 8.1, 2.0 Hz, 1H, HA3). 13C NMR (100 MHz,
CDCl3):
d
¼ 7.15 (dd, J ¼ 8.4, 2.2 Hz, 1H, H8), 7.11 (d, J ¼ 2.2 Hz, 1H,
H6), 7.03 (d, J ¼ 8.4 Hz, 1H, H9), 6.89 (d, J ¼ 4.0 Hz, 1H, H40), 6.68 (d,
J ¼ 4.0 Hz, 1H, H30), 4.95 (ddd, J ¼ 7.6, 5.6, 2.2 Hz, 1H, H4), 4.70 (dd,
J ¼ 8.4, 1.8 Hz, 1H, H2), 3.37 (dd, J ¼ 16.8, 5.6 Hz, 1H, HB5), 2.65
(dddd, J ¼ 13.0, 7.6, 1.8, 1.0 Hz, 1H, HB3), 2.50 (br d, J ¼ 16.8 Hz, 1H,
HA5), 2.49 (ddd, J ¼ 13.0, 8.4, 2.2 Hz, 1H, HA3). 13C NMR (100 MHz,
CDCl3):
d
¼ 149.3 (C9a), 149.3 (C20), 130.0 (C6), 129.3 (C40), 126.9
(C8), 126.5 (C7), 125.1 (C5a), 124.1 (C30), 122.2 (C9), 111.9 (C50), 75.2
(C4), 72.1 (C2), 42.1 (C3), 34.7 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1028 (CeO),
993 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 321 (Mþ
,
79Br, 15), 304
CDCl3):
d
¼ 148.8 (C20), 147.8 (C9a), 131.7 (C7), 129.8 (C6), 129.3
ꢃ
(12), 291 (6), 188 (30), 130 (12), 105 (70), 104 (100). HRMS (EI,
70 eV): m/z [M]þ calcd for C14H12BrNOS: 320.9823; found:
320.9818.
(C40), 127.1 (C5a), 127.0 (C8), 124.1 (C30), 123.6 (C9), 111.9 (C50), 74.7
(C4), 72.0 (C2), 42.1 (C3), 34.6 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1047 (CeO),
967 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 355 (Mþ
ꢃ
,
35Cl, 79Br, 10),
338 (6), 325 (2), 188 (31), 164 (7), 139 (81), 138 (100). HRMS (EI,
70 eV): m/z [M]þ calcd for C14H11BrClNOS: 354.9433; found:
354.9448.
4.1.2.5. (2SR,4RS)-7-chloro-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 10e. Reaction time: 22 h. Yield: 62%. White
solid. mp 73 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.24 (dd,
J ¼ 4.4, 4.0 Hz, 1H, H50), 7.15 (dd, J ¼ 8.4, 2.0 Hz, 1H, H8), 7.12 (d,
J ¼ 2.0 Hz,1H, H6), 7.07 (d, J ¼ 8.4 Hz, 1H, H9), 6.96 (d, J ¼ 4.4 Hz,1H,
H30), 6.95 (d, J ¼ 4.0 Hz, 1H, H40), 4.98 (ddd, J ¼ 7.4, 5.6, 2.0 Hz, 1H,
H4), 4.81 (dd, J ¼ 8.4, 2.0 Hz, 1H, H2), 3.39 (dd, J ¼ 16.8, 5.6 Hz, 1H,
HB5), 2.73 (dddd, J ¼ 13.0, 7.4, 2.0, 1.0 Hz, 1H, HB3), 2.53 (ddd,
4.1.2.9. (2SR,4RS)-7-fluoro-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 10i. Reaction time: 22 h. Yield: 63%. 1H NMR
(400 MHz, CDCl3):
d
¼ 7.24 (dd, J ¼ 4.4, 4.0 Hz, 1H, H50), 7.10 (dd,
J ¼ 8.8, 5.2 Hz, 1H, H9), 6.96 (d, J ¼ 4.4 Hz, 1H, H30), 6.95 (d,
J ¼ 4.0 Hz, 1H, H40), 6.88 (td, J ¼ 8.8, 3.3 Hz, 1H, H8), 6.83 (dd, J ¼ 9.1,
3.3 Hz, 1H, H6), 4.98 (ddd, J ¼ 7.0, 5.2, 2.0 Hz, 1H, H4), 4.80 (dd,
J ¼ 8.2, 2.2 Hz, 1H, H2), 3.40 (dd, J ¼ 16.8, 5.2 Hz, 1H, HB5), 2.73
(dddd, J ¼ 13.0, 7.0, 2.2, 1.0 Hz, 1H, HB3), 2.54 (ddd, J ¼ 13.0, 8.2,
J ¼ 13.0, 8.4, 2.0 Hz, 1H, HA3), 2.52 (br d, J ¼ 16.8 Hz, 1H, HA5). 13
C
NMR (100 MHz, CDCl3):
d
¼ 148.3 (C9a), 147.2 (C20), 131.5 (C7),129.9
(C6),127.1 (C5a),127.0 (C8),126.7 (C50),125.0 (C40),124.1 (C30),123.6
(C9), 74.6 (C4), 71.9 (C2), 42.4 (C3), 34.6 (C5). IR (KBr, cmꢂ1):
2.0 Hz, 1H, HA3), 2.53 (br d, J ¼ 16.8 Hz, 1H, HA5). 13C NMR
ṽ ¼ 1048 (CeO), 979 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 277 (Mþ
,
(100 MHz, CDCl3):
d
¼ 160.8 (d, JC,F ¼ 248.8 Hz, C7), 147.4 (C20),
1
ꢃ
35Cl, 37), 260 (16), 247 (10), 164 (5), 139 (73), 138 (100), 110 (44).
HRMS (EI, 70 eV): m/z [M]þ calcd for C14H12ClNOS: 277.0328;
found: 277.0328.
145.7 (C9a), 127.3 (d, JC,F ¼ 7.8 Hz, C5a), 126.7 (C50), 125.0 (C40),
124.0 (C30), 123.9 (d, 3JC,F ¼ 8.4 Hz, C9), 116.3 (d, 2JC,F ¼ 22.6 Hz, C6),
113.7 (d, 2JC,F ¼ 22.2 Hz, C8), 74.5 (C4), 71.9 (C2), 42.5 (C3), 34.9 (C5).
IR (liquid film, cmꢂ1): ṽ ¼ 1048 (CeO), 965 (NeO). GCeMS (EI,
70 eV): m/z (%) ¼ 261 (Mþꢃ, 32), 244 (15), 231 (11), 148 (7), 123 (56),
122 (100), 110 (32). HRMS (EI, 70 eV): m/z [M]þ calcd for
3
4.1.2.6. (2SR,4RS)-7-chloro-2-(5-methylthiophen-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 10f. Reaction time: 23 h. Yield:
63%. White solid. mp 106 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
C14H12FNOS: 261.0624; found: 261.0623.
d
¼ 7.14 (dd, J ¼ 8.4, 2.2 Hz, 1H, H8), 7.11 (d, J ¼ 2.2 Hz, 1H, H6), 7.06
(d, J ¼ 8.4 Hz,1H, H9), 6.73 (d, J ¼ 3.4 Hz,1H, H30), 6.59 (d, J ¼ 3.4 Hz,
1H, H40), 4.97 (ddd, J ¼ 7.8, 5.1, 2.0 Hz, 1H, H4), 4.72 (dd, J ¼ 8.2,
2.0 Hz, 1H, H2), 3.38 (dd, J ¼ 16.6, 5.1 Hz, 1H, HB5), 2.70 (dddd,
J ¼ 12.6, 7.8, 2.0, 1.2 Hz, 1H, HB3), 2.50 (br d, J ¼ 16.6 Hz, 1H, HA5),
2.48 (ddd, J ¼ 12.6, 8.2, 2.0 Hz, 1H, HA3), 2.46 (s, 3H, 50-CH3). 13C
4.1.2.10. (2SR,4RS)-7-fluoro-2-(5-methylthiophen-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 10j. Reaction time: 23 h. Yield:
64%. White solid. mp 103 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.08 (dd, J ¼ 8.6, 5.3 Hz, 1H, H9), 6.87 (td, J ¼ 8.6, 2.8 Hz, 1H, H8),
6.82 (dd, J ¼ 9.0, 2.8 Hz, 1H, H6), 6.74 (d, J ¼ 3.4 Hz, 1H, H30), 6.60 (d,
J ¼ 3.4 Hz, 1H, H40), 4.96 (ddd, J ¼ 7.6, 5.3, 1.6 Hz, 1H, H4), 4.72 (dd,
J ¼ 8.3, 2.0 Hz, 1H, H2), 3.39 (dd, J ¼ 16.6, 5.3 Hz, 1H, HB5), 2.70
NMR (100 MHz, CDCl3):
d
¼ 148.1 (C9a), 144.3 (C20), 139.5 (C50),
131.3 (C7), 127.6 (C6), 127.0 (C5a), 126.8 (C8), 124.4 (C40), 123.8 (C30),

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
301
(dddd, J ¼ 12.6, 7.6, 2.0, 1.2 Hz, 1H, HB3), 2.52 (br d, J ¼ 16.6 Hz, 1H,
HA5), 2.48 (ddd, J ¼ 12.6, 8.3, 1.6 Hz, 1H, HA3), 2.46 (s, 3H, 50-CH3).
4.1.2.14. (2SR,4RS)-7-trifluoromethoxy-2-(5-methylthiophen-2-yl)-
2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepine 10n. Reaction time:
26 h. Yield: 62%. White solid. mp 96 ꢀC (heptane). 1H NMR
13C NMR (100 MHz, CDCl3):
d
¼ 160.7 (d, 1JC,F ¼ 244.3 Hz, C7), 145.6
(d, 4JC,F ¼ 2.7 Hz, C9a),144.6 (C20), 139.0 (C50), 127.2 (d, 3JC,F ¼ 8.3 Hz,
(400 MHz, CDCl3):
d
¼ 7.14 (d, J ¼ 8.7 Hz, 1H, H9), 7.04 (dd, J ¼ 8.7,
3
C5a), 124.5 (C40), 123.8 (C30), 123.7 (d, JC,F ¼ 8.5 Hz, C9), 116.2 (d,
2.4 Hz, 1H, H8), 6.99 (d, J ¼ 2.4 Hz, 1H, H6), 6.75 (d, J ¼ 3.4 Hz, 1H,
H30), 6.60 (d, J ¼ 3.4 Hz, 1H, H40), 4.98 (ddd, J ¼ 7.7, 5.2, 2.0 Hz, 1H,
H4), 4.75 (dd, J ¼ 8.4, 2.0 Hz, 1H, H2), 3.41 (dd, J ¼ 16.8, 5.2 Hz, 1H,
HB5), 2.72 (dddd, J ¼ 12.6, 7.7, 2.0, 1.2 Hz, 1H, HB3), 2.54 (br d,
J ¼ 16.8 Hz, 1H, HA5), 2.51 (ddd, J ¼ 12.6, 8.4, 2.0 Hz, 1H, HA3), 2.47
2JC,F ¼ 22.4 Hz, C6), 113.6 (d, 2JC,F ¼ 22.6 Hz, C8), 74.4 (C4), 72.0 (C2),
42.0 (C3), 34.9 (C5), 15.4 (50-CH3). IR (KBr, cmꢂ1): ṽ ¼ 1043 (CeO),
978 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 275 (Mþꢃ, 52), 258 (36),
245 (12), 148 (12), 123 (82), 122 (79), 124 (100). HRMS (EI, 70 eV):
m/z [M]þ calcd for C15H14FNOS: 275.0780; found: 275.0784.
(s, 3H, 50-CH3). 13C NMR (100 MHz, CDCl3):
d
¼ 148.2 (C9a), 147.0
(C7), 144.4 (C20), 139.6 (C50), 127.1 (C5a), 124.5 (C40), 123.9 (C30),
123.6 (C9), 122.3 (C6), 120.5 (q, 1JC,F ¼ 257.6 Hz, 7-OCF3), 119.5 (C8),
74.4 (C4), 72.0 (C2), 42.1 (C3), 34.7 (C5), 15.3 (50-CH3). IR (KBr,
cmꢂ1): ṽ ¼ 1050 (CeO), 991 (NeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 341 (Mþꢃ, 21), 324 (18), 311 (3), 214 (6), 189 (39), 188 (61), 124
(100). HRMS (EI, 70 eV): m/z [M]þ calcd for C16H14F3NO2S:
341.0697; found: 341.0704.
4.1.2.11. (2SR,4RS)-7-fluoro-2-(3-methylthiophen-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 10k. Reaction time: 20 h.
Yield: 66%. White solid. mp 126 ꢀC (heptane). 1H NMR (400 MHz,
CDCl3):
d
¼ 7.14 (d, J ¼ 5.1 Hz, 1H, H50), 7.04 (dd, J ¼ 8.6, 5.2 Hz, 1H,
H9), 6.88 (td, J ¼ 8.6, 2.8 Hz, 1H, H8), 6.84 (dd, J ¼ 9.0, 2.8 Hz, 1H,
H6), 6.80 (d, J ¼ 5.1 Hz, 1H, H40), 5.00 (ddd, J ¼ 7.2, 5.4, 1.8 Hz, 1H,
H4), 4.84 (dd, J ¼ 8.1, 2.6 Hz, 1H, H2), 3.40 (dd, J ¼ 16.8, 5.4 Hz, 1H,
HB5), 2.65 (dddd, J ¼ 12.5, 7.2, 2.6, 1.2 Hz, 1H, HB3), 2.58 (ddd,
J ¼ 12.5, 8.1, 1.8 Hz,1H, HA3), 2.54 (br d, J ¼ 16.8 Hz,1H, HA5), 2.24 (s,
4.1.2.15. (2SR,4RS)-7-trifluoromethoxy-2-(3-methylthiophen-2-yl)-
2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepine 10o. Reaction time:
23 h. Yield: 69%. White solid. mp 78 ꢀC (heptane). 1H NMR
3H, 30-CH3). 13C NMR (100 MHz, CDCl3):
d
¼ 160.7 (d, 1JC,F ¼ 244.4
4
(400 MHz, CDCl3):
d
¼ 7.14 (d, J ¼ 8.7 Hz, 1H, H9), 7.14 (d, J ¼ 5.1 Hz,
Hz, C7), 145.8 (d, JC,F ¼ 2.7 Hz, C9a), 140.3 (C20), 132.7 (C30), 129.7
(C40), 127.2 (d, 3JC,F ¼ 8.2 Hz, C5a), 123.6 (d, 3JC,F ¼ 8.5 Hz, C9), 123.1
(C50), 116.3 (d, 2JC,F ¼ 22.4 Hz, C6), 113.6 (d, 2JC,F ¼ 22.6 Hz, C8), 74.5
1H, H50), 7.05 (dd, J ¼ 8.7, 1.7 Hz, 1H, H8), 7.01 (d, J ¼ 1.7 Hz, 1H, H6),
6.81 (d, J ¼ 5.1 Hz, 1H, H40), 5.02 (ddd, J ¼ 7.5, 5.4, 2.0 Hz, 1H, H4),
4.87 (dd, J ¼ 8.4, 2.6 Hz, 1H, H2), 3.43 (dd, J ¼ 16.8, 5.4 Hz, 1H, HB5),
2.67 (dddd, J ¼ 12.8, 7.5, 2.6,1.2 Hz,1H, HB3), 2.59 (ddd, J ¼ 12.8, 8.4,
2.0 Hz, 1H, HA3), 2.56 (br d, J ¼ 16.8 Hz, 1H, HA5), 2.24 (s, 3H, 30-
(C4), 70.3 (C2), 42.4 (C3), 34.8 (C5), 14.2 (30-CH3). IR (KBr, cmꢂ1):
ṽ ¼ 1036 (CeO), 977 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 275 (Mþ
,
ꢃ
52), 258 (30), 245 (9), 148 (15), 124 (79), 123 (91), 122 (100). HRMS
(EI, 70 eV): m/z [M]þ calcd for C15H14FNOS: 275.0780; found:
275.0782.
CH3). 13C NMR (100 MHz, CDCl3):
d
¼ 148.4 (C9a), 146.0 (C7), 143.0
(C20), 132.9 (C30), 129.7 (C40), 127.1 (C5a), 123.4 (C50), 123.2 (C9),
122.4 (C6), 120.5 (q, 1JC,F ¼ 257.5 Hz, 7-OCF3), 119.5 (C8), 74.4 (C4),
70.2 (C2), 42.2 (C3), 34.7 (C5),14.2 (30-CH3). IR (KBr, cmꢂ1): ṽ ¼ 1053
(CeO), 975 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 341 (Mþꢃ, 30), 324
(21), 311 (6), 214 (9), 189 (67), 188 (100), 124 (70). HRMS (EI, 70 eV):
m/z [M]þ calcd for C16H14F3NO2S: 341.0697; found: 341.0709.
4.1.2.12. (2SR,4RS)-7-fluoro-2-(5-bromothiophen-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 10l. Reaction time: 21 h. Yield:
61%. White solid. mp 107 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.06 (dd, J ¼ 8.6, 5.2 Hz,1H, H9), 6.89 (d, J ¼ 4.0 Hz,1H, H40), 6.87
(td, J ¼ 8.6, 3.3 Hz, 1H, H8), 6.83 (dd, J ¼ 9.0, 3.3 Hz, 1H, H6), 6.68 (d,
J ¼ 4.0 Hz, 1H, H30), 4.95 (ddd, J ¼ 7.2, 5.2, 2.0 Hz, 1H, H4), 4.70 (dd,
J ¼ 8.2, 2.0 Hz, 1H, H2), 3.38 (dd, J ¼ 16.8, 5.2 Hz, 1H, HB5), 2.66
(dddd, J ¼ 12.0, 7.2, 2.0, 1.0 Hz, 1H, HB3), 2.52 (br d, J ¼ 16.8 Hz, 1H,
HA5), 2.50 (ddd, J ¼ 12.0, 8.2, 2.0 Hz, 1H, HA3). 13C NMR (100 MHz,
4.1.2.16. (2SR,4RS)-7-trifluoromethoxy-2-(5-bromothiophen-2-yl)-
2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepine 10p. Reaction time:
24 h. Yield: 61%. White solid. mp 99 ꢀC (heptane). 1H NMR
(400 MHz, CDCl3):
d
¼ 7.12 (d, J ¼ 8.4 Hz, 1H, H9), 7.03 (d, J ¼ 8.4 Hz,
1H, H8), 6.99 (s, 1H, H6), 6.89 (d, J ¼ 3.6 Hz, 1H, H40), 6.69 (d,
J ¼ 3.6 Hz, 1H, H30), 4.97 (ddd, J ¼ 7.2, 5.2, 1.6 Hz, 1H, H4), 4.73 (dd,
J ¼ 8.4, 1.2 Hz, 1H, H2), 3.41 (dd, J ¼ 16.8, 5.2 Hz, 1H, HB5), 2.68
(dddd, J ¼ 12.8, 7.2, 1.2, 0.8 Hz, 1H, HB3), 2.54 (br d, J ¼ 16.8 Hz, 1H,
HA5), 2.51 (ddd, J ¼ 12.8, 8.4, 1.6 Hz, 1H, HA3). 13C NMR (100 MHz,
CDCl3):
d
¼ 160.9 (d, 1JC,F ¼ 243.8 Hz, C7), 149.0 (C20), 145.2 (C9a),
3
129.3 (C40), 127.2 (d, JC,F ¼ 8.1 Hz, C5a), 124.1 (C30), 123.8 (d,
3JC,F ¼ 8.7 Hz, C9), 116.3 (d, JC,F ¼ 22.8 Hz, C6), 113.8 (d,
2
2JC,F ¼ 22.5 Hz, C8), 111.9 (C50), 74.6 (C4), 72.1 (C2), 42.1 (C3), 34.9
(C5). IR (KBr, cmꢂ1): ṽ ¼ 1051 (CeO), 979 (NeO). GCeMS (EI, 70 eV):
CDCl3):
d
¼ 148.8 (C20), 147.8 (C9a), 147.3 (C7), 129.3 (C40), 127.1
m/z (%) ¼ 339 (Mþ
,
79Br, 13), 322 (6), 309 (3), 188 (27), 148 (9), 123
ꢃ
(C5a), 124.2 (C30), 123.6 (C9), 122.4 (C6), 120.6 (q, 1JC,F ¼ 257.5 Hz, 7-
(76), 122 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for C14H11BrFNOS:
OCF3), 119.7 (C8), 112.0 (C50), 74.6 (C4), 72.0 (C2), 42.1 (C3), 34.8
(C5). IR (KBr, cmꢂ1): ṽ ¼ 1046 (CeO), 963 (NeO). GCeMS (EI, 70 eV):
338.9729; found: 338.9740.
m/z (%) ¼ 405 (Mþ
,
79Br, 19), 388 (13), 375 (7), 214 (6), 189 (60), 188
ꢃ
4.1.2.13. (2SR,4RS)-7-trifluoromethoxy-2-exo-(thiophen-2-yl)-
2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepine 10m. Reaction time:
23 h. Yield: 67%. White solid. mp 90 ꢀC (heptane). 1H NMR
(100). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H11BrF3NO2S:
404.9646; found: 404.9656.
(400 MHz, CDCl3):
d
¼ 7.25 (dd, J ¼ 4.8, 4.8 Hz, 1H, H50), 7.16 (d,
4.1.2.17. (2SR,4RS)-2-(furan-2-yl)-2,3,4,5-tetrahydro-1,4-epoxy-1-
benzazepine 11a. Reaction time: 18 h. Yield: 69%. White solid. mp
J ¼ 8.8 Hz, 1H, H9), 7.04 (d, J ¼ 8.8 Hz, 1H, H8), 7.00 (s, 1H, H6), 6.97
(d, J ¼ 4.8 Hz,1H, H30), 6.96 (d, J ¼ 4.8 Hz,1H, H40), 5.00 (ddd, J ¼ 7.2,
5.2, 2.2 Hz, 1H, H4), 4.84 (dd, J ¼ 8.4, 2.0 Hz, 1H, H2), 3.42 (dd,
J ¼ 16.8, 5.2 Hz, 1H, HB5), 2.75 (dddd, J ¼ 13.2, 7.2, 2.0, 1.2 Hz, 1H,
HB3), 2.56 (br d, J ¼ 16.8 Hz,1H, HA5), 2.55 (ddd, J ¼ 13.2, 8.4, 2.2 Hz,
86 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.40 (d, J ¼ 3.2 Hz,
1H, H50), 7.21e7.17 (m, 2H, H7, H8), 7.16e7.14 (m, 2H, H6, H9), 6.36
(dd, J ¼ 3.3, 3.2 Hz, 1H, H40), 6.34 (d, J ¼ 3.3 Hz, 1H, H30), 4.99 (ddd,
J ¼ 7.8, 5.8, 1.7 Hz,1H, H4), 4.65 (dd, J ¼ 8.7, 2.4 Hz, 1H, H2), 3.42 (dd,
J ¼ 16.5, 5.8 Hz, 1H, HB5), 2.79 (dddd, J ¼ 12.7, 7.8, 2.4, 1.1 Hz, 1H,
HB3), 2.55 (br d, J ¼ 16.5 Hz, 1H, HA5), 2.42 (ddd, J ¼ 12.7, 8.7, 1.7 Hz,
1H, HA3). 13C NMR (100 MHz, CDCl3):
d
¼ 148.2 (C9a), 147.2 (C7),
147.1 (C20), 127.2 (C5a), 126.7 (C50), 125.0 (C40), 124.1 (C30), 123.7
(C9), 122.4 (C6), 120.6 (q, 1JC,F ¼ 258.2 Hz, 7-OCF3), 119.6 (C8), 74.5
(C4), 71.9 (C2), 42.5 (C3), 34.8 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1045 (CeO),
968 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 327 (Mþꢃ, 42), 310 (21),
297 (14), 214 (7), 189 (61), 188 (100), 110 (28). HRMS (EI, 70 eV): m/z
[M]þ calcd for C15H12F3NO2S: 327.0538; found: 327.0533.
1H, HA3). 13C NMR (100 MHz, CDCl3):
d
¼ 155.3 (C20), 149.9 (C9a),
143.1 (C50), 129.9 (C6), 126.8 (C8), 126.3 (C7), 125.3 (C5a), 122.2 (C9),
110.5 (C40), 106.6 (C30), 74.9 (C4), 69.7 (C2), 38.7 (C3), 34.7 (C5). IR
(KBr, cmꢂ1): ṽ ¼ 1015 (CeO), 980 (NeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 227 (Mþꢃ, 47), 210 (18), 197 (18), 130 (12), 105 (59), 104 (100),

302
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
94 (29). HRMS (EI, 70 eV): m/z [M]þ calcd for C14H13NO2: 227.0946;
108 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H14ClNO2:
found: 227.0943.
275.0713; found: 275.0716.
4.1.2.18. (2SR,4RS)-2-(5-methylfuran-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 11b. Reaction time: 19 h. Yield: 61%. White
4.1.2.22. (2SR,4RS)-7-fluoro-2-(furan-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 11f. Reaction time: 22 h. Yield: 65%. White
solid. mp 102 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.16e7.10
solid. mp 84 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.39 (d,
(m, 4H, H6, H7, H8, H9), 6.20 (d, J ¼ 3.0 Hz, 1H, H30), 5.93 (d,
J ¼ 3.0 Hz, 1H, H40), 4.98 (ddd, J ¼ 7.8, 5.3, 1.6 Hz, 1H, H4), 4.59 (dd,
J ¼ 8.7, 2.3 Hz, 1H, H2), 3.41 (dd, J ¼ 16.6, 5.3 Hz, 1H, HB5), 2.76
(dddd, J ¼ 12.6, 7.8, 2.3, 1.0 Hz, 1H, HB3), 2.54 (br d, J ¼ 16.6 Hz, 1H,
HA5), 2.39 (ddd, J ¼ 12.6, 8.7, 1.6 Hz, 1H, HA3), 2.31 (s, 3H, 50-CH3).
J ¼ 2.0 Hz, 1H, H50), 7.11 (dd, J ¼ 8.8, 5.2 Hz, 1H, H9), 6.88 (td, J ¼ 8.8,
3.0 Hz, 1H, H8), 6.83 (dd, J ¼ 9.0, 3.0 Hz, 1H, H6), 6.36 (dd, J ¼ 3.0,
2.0 Hz, 1H, H40), 6.33 (d, J ¼ 3.0 Hz, 1H, H30), 4.95 (ddd, J ¼ 7.2, 5.2,
1.6 Hz, 1H, H4), 4.60 (dd, J ¼ 8.8, 2.2 Hz, 1H, H2), 3.40 (dd, J ¼ 16.8,
5.2 Hz, 1H, HB5), 2.78 (dddd, J ¼ 12.8, 7.2, 2.2, 1.0 Hz, 1H, HB3), 2.53
(br d, J ¼ 16.8 Hz, 1H, HA5), 2.41 (ddd, J ¼ 12.8, 8.8, 1.6 Hz, 1H, HA3).
13C NMR (100 MHz, CDCl3):
d
¼ 153.4 (C20), 151.9 (C50), 150.1 (C9a),
129.9 (C6), 126.8 (C8), 126.3 (C7), 125.3 (C5a), 122.3 (C9), 107.5 (C30),
106.4 (C40), 74.9 (C4), 69.8 (C2), 38.5 (C3), 34.7 (C5), 13.8 (50-CH3). IR
(KBr, cmꢂ1): ṽ ¼ 1019 (CeO), 953 (NeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 241 (Mþꢃ, 36), 224 (24), 211 (9), 130 (12), 108 (100), 105 (42),
104 (73). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H15NO2: 241.1103;
found: 241.1106.
13C NMR (100 MHz, CDCl3):
d
¼ 160.9 (d, 1JC,F ¼ 243.8 Hz, C7), 155.2
(C20), 145.9 (C9a), 142.2 (C50), 127.3 (d, 3JC,F ¼ 7.8 Hz, C5a), 123.9 (d,
3JC,F ¼ 8.3 Hz, C9), 116.3 (d, JC,F ¼ 22.4 Hz, C6), 113.7 (d,
2
2JC,F ¼ 22.1 Hz, C8), 110.5 (C40), 106.7 (C30), 74.4 (C4), 69.7 (C2), 36.7
(C3), 34.9 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1014 (CeO), 979 (NeO). GCeMS
(EI, 70 eV): m/z (%) ¼ 245 (Mþꢃ, 32), 228 (9), 215 (10), 148 (8), 123
(52), 122 (100), 94 (32). HRMS (EI, 70 eV): m/z [M]þ calcd for
4.1.2.19. (2SR,4RS)-2-(5-nitrofuran-2-yl)-2,3,4,5-tetrahydro-1,4-
C14H12FNO2: 245.0852; found: 245.0849.
epoxy-1-benzazepine 11c. Reaction time: 19 h. Yield: 64%. White
solid. mp 138 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.31 (d,
4.1.2.23. (2SR,4RS)-7-fluoro-2-(5-methylfuran-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 11g. Reaction time: 24 h. Yield:
63%. White solid. mp 102 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
J ¼ 3.7 Hz, 1H, H40), 7.22e7.18 (m, 2H, H7, H8), 7.16e7.10 (m, 2H, H6,
H9), 6.71 (d, J ¼ 3.7 Hz, 1H, H30), 4.98 (ddd, J ¼ 7.8, 5.3, 2.0 Hz, 1H,
H4), 4.68 (dd, J ¼ 8.6, 1.8 Hz, 1H, H2), 3.43 (dd, J ¼ 16.8, 5.3 Hz, 1H,
HB5), 2.82 (ddd, J ¼ 12.8, 7.8, 1.8 Hz,1H, HB3), 2.57 (br d, J ¼ 16.8 Hz,
1H, HA5), 2.52 (ddd, J ¼ 12.8, 8.6, 2.0 Hz, 1H, HA3). 13C NMR
d
¼ 7.13 (dd, J ¼ 8.6, 5.3 Hz, 1H, H9), 6.87 (td, J ¼ 8.6, 2.8 Hz, 1H, H8),
6.82 (dd, J ¼ 9.0, 2.8 Hz, 1H, H6), 6.18 (d, J ¼ 3.1 Hz, 1H, H30), 5.92
(dd, J ¼ 3.1, 0.8 Hz, 1H, H40), 4.95 (ddd, J ¼ 7.5, 5.4, 1.8 Hz, 1H, H4),
4.52 (dd, J ¼ 8.6, 2.6 Hz, 1H, H2), 3.38 (dd, J ¼ 16.8, 5.4 Hz, 1H, HB5),
2.76 (dddd, J ¼ 12.8, 7.5, 2.6, 1.3 Hz, 1H, HB3), 2.52 (br d, J ¼ 16.8 Hz,
1H, HA5), 2.37 (ddd, J ¼ 12.8, 8.6, 1.8 Hz, 1H, HA3), 2.30 (d, J ¼ 0.8 Hz,
(100 MHz, CDCl3):
d
¼ 159.7 (C20), 151.3 (C50), 149.2 (C9a), 130.3
(C6), 127.4 (C8), 127.2 (C7), 125.3 (C5a), 122.4 (C9), 113.3 (C40), 110.3
(C30), 75.4 (C4), 69.7 (C2), 39.4 (C3), 34.8 (C5). IR (KBr, cmꢂ1):
ṽ ¼ 1561 (eNO2), 1318 (eNO2), 1021 (CeO), 980 (NeO). GCeMS (EI,
70 eV): m/z (%) ¼ 272 (Mþꢃ, 30), 255 (3), 242 (3), 130 (10), 105 (67),
104 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for C14H12N2O4:
272.0797; found: 272.0791.
3H, 50-CH3). 13C NMR (100 MHz, CDCl3):
d
¼ 160.7 (d, 1JC,F ¼ 244.3
Hz, C7), 153.1 (C20), 151.9 (C50), 145.9 (d, 4JC,F ¼ 2.6 Hz, C9a), 127.3 (d,
3JC,F ¼ 8.2 Hz, C5a), 123.7 (d, JC,F ¼ 8.5 Hz, C9), 116.2 (d,
3
2JC,F ¼ 22.5 Hz, C6), 113.6 (d, JC,F ¼ 22.6 Hz, C8), 107.5 (C30), 106.3
2
(C40), 74.2 (C4), 69.6 (C2), 38.4 (C3), 34.7 (C5), 13.7 (50-CH3). IR (KBr,
cmꢂ1): ṽ ¼ 1024 (CeO), 955 (NeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 259 (Mþꢃ, 33), 242 (18), 229 (6), 148 (9), 123 (27), 122 (52), 108
(100). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H14FNO2: 259.1009;
found: 259.1007.
4.1.2.20. (2SR,4RS)-7-chloro-2-(furan-2-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 11d. Reaction time: 23 h. Yield: 65%. White
solid. mp 95 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.39 (br s,
1H, H50), 7.15 (dd, J ¼ 8.4, 1.6 Hz, 1H, H8), 7.11 (s, 1H, H6), 7.07 (d,
J ¼ 8.4 Hz, 1H, H9), 6.36e6.35 (m, 1H, H40), 6.32 (d, J ¼ 3.2 Hz, 1H,
H30), 4.96 (ddd, J ¼ 7.6, 5.2, 1.6 Hz, 1H, H4), 4.58 (dd, J ¼ 8.8, 2.4 Hz,
1H, H2), 3.37 (dd, J ¼ 16.8, 5.2 Hz, 1H, HB5), 2.78 (dddd, J ¼ 12.8, 7.6,
2.4, 1.2 Hz, 1H, HB3), 2.50 (br d, J ¼ 16.8 Hz, 1H, HA5), 2.38 (ddd,
4.1.2.24. (2SR,4RS)-7-fluoro-2-(5-nitrofuran-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 11h. Reaction time: 25 h.
Yield: 63%. White solid. mp 168 ꢀC (heptane). 1H NMR (400 MHz,
J ¼ 12.8, 8.8, 1.6 Hz, 1H, HA3). 13C NMR (100 MHz, CDCl3):
d
¼ 155.0
CDCl3):
d
¼ 7.31 (d, J ¼ 3.7 Hz, 1H, H40), 7.09 (dd, J ¼ 8.6, 5.2 Hz, 1H,
(C20), 148.5 (C9a), 142.2 (C50), 131.5 (C6), 129.7 (C7), 127.2 (C5a),
H9), 6.89 (td, J ¼ 8.6, 2.8 Hz, 1H, H8), 6.85 (dd, J ¼ 9.0, 2.8 Hz, 1H,
H6), 6.69 (d, J ¼ 3.7 Hz, 1H, H30), 4.96 (ddd, J ¼ 7.9, 5.4, 1.9 Hz, 1H,
H4), 4.63 (dd, J ¼ 8.6, 2.3 Hz, 1H, H2), 3.40 (dd, J ¼ 16.9, 5.4 Hz, 1H,
HB5), 2.82 (dddd, J ¼ 12.9, 7.9, 2.3, 1.1 Hz, 1H, HB3), 2.57 (br d,
126.9 (C8), 123.6 (C9), 110.5 (C40), 106.7 (C30), 74.4 (C4), 69.6 (C2),
38.6 (C3), 34.6 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1015 (CeO), 982 (NeO).
GCeMS (EI, 70 eV): m/z (%) ¼ 261 (Mþ
,
35Cl, 35), 244 (10), 231 (8),
ꢃ
164 (8), 139 (63), 138 (100), 94 (36). HRMS (EI, 70 eV): m/z [M]þ
J ¼ 16.9 Hz, 1H, HA5), 2.51 (ddd, J ¼ 12.9, 8.6, 1.9 Hz, 1H, HA3). 13
C
1
calcd for C14H12ClNO2: 261.0557; found: 261.0563.
NMR (100 MHz, CDCl3):
d
¼ 161.0 (d, JC,F ¼ 245.5 Hz, C7), 159.0
(C20), 151.5 (C50), 144.7 (d, 4JC,F ¼ 2.8 Hz, C9a), 127.1 (d, 3JC,F ¼ 8.3 Hz,
C5a), 123.7 (d, 3JC,F ¼ 8.6 Hz, C9), 116.4 (d, 2JC,F ¼ 22.7 Hz, C6), 113.9
(d, 2JC,F ¼ 22.7 Hz, C8), 112.9 (C40), 109.9 (C30), 74.4 (C4), 69.2 (C2),
38.9 (C3), 34.6 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1522 (eNO2), 1315 (eNO2),
1024 (CeO), 968 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 290 (Mþꢃ, 15),
273 (1), 260 (1), 148 (6), 123 (67), 122 (100). HRMS (EI, 70 eV): m/z
[M]þ calcd for C14H11FN2O4: 290.0703; found: 290.0707.
4.1.2.21. (2SR,4RS)-7-chloro-2-(5-methylfuran-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 11e. Reaction time: 20 h. Yield:
67%. White solid. mp 113 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.15 (dd, J ¼ 8.6, 2.2 Hz, 1H, H8), 7.11 (d, J ¼ 2.2 Hz, 1H, H6), 7.10
(d, J ¼ 8.6 Hz, 1H, H9), 6.18 (d, J ¼ 3.0 Hz, 1H, H30), 5.93 (d, J ¼ 3.0 Hz,
1H, H40), 4.96 (ddd, J ¼ 7.4, 5.2, 1.6 Hz, 1H, H4), 4.54 (dd, J ¼ 8.6,
2.3 Hz, 1H, H2), 3.38 (dd, J ¼ 16.8, 5.2 Hz, 1H, HB5), 2.76 (dddd,
J ¼ 12.8, 7.4, 2.3, 1.2 Hz, 1H, HB3), 2.51 (br d, J ¼ 16.8 Hz, 1H, HA5),
2.36 (ddd, J ¼ 12.8, 8.6, 1.6 Hz, 1H, HA3), 2.30 (s, 3H, 50-CH3). 13C
4.1.2.25. (2SR,4RS)-7-trifluoromethoxy-2-(furan-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 11i. Reaction time: 23 h. Yield:
60%. White solid. mp 79 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d
¼ 153.0 (C20), 152.1 (C50), 148.6 (C9a),
131.5 (C7), 129.8 (C6), 127.3 (C5a), 127.0 (C8), 123.7 (C9), 107.7 (C30),
d
¼ 7.40 (d, J ¼ 1.0 Hz, 1H, H50), 7.17 (d, J ¼ 8.6 Hz, 1H, H9), 7.04 (dd,
106.4 (C40), 74.4 (C4), 69.8 (C2), 38.5 (C3), 34.6 (C5), 13.8 (50-CH3). IR
J ¼ 8.6, 1.8 Hz, 1H, H8), 6.99 (d, J ¼ 1.8 Hz, 1H, H6), 6.36 (dd, J ¼ 3.2,
1.0 Hz, 1H, H40), 6.33 (d, J ¼ 3.2 Hz, 1H, H30), 4.99 (ddd, J ¼ 8.1, 5.6,
1.2 Hz, 1H, H4), 4.62 (dd, J ¼ 8.7, 2.4 Hz, 1H, H2), 3.42 (dd, J ¼ 16.8,
(KBr, cmꢂ1): ṽ ¼ 1013 (CeO), 971 (NeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 275 (Mþ
,
35Cl,18), 258 (12), 245 (3),164 (6),139 (27),138 (33),
ꢃ

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
303
5.6 Hz, 1H, HB5), 2.81 (dddd, J ¼ 12.8, 8.1, 2.4, 1.0 Hz, 1H, HB3), 2.56
(br d, J ¼ 16.8 Hz, 1H, HA5), 2.42 (ddd, J ¼ 12.8, 8.7, 1.2 Hz, 1H, HA3).
Yield: 63%. White solid. mp 72 ꢀC (heptane). 1H NMR (400 MHz,
CDCl3):
d
¼ 7.45 (dd, J ¼ 1.6, 0.9 Hz, 1H, H20), 7.40 (t, J ¼ 1.6 Hz, 1H,
13C NMR (100 MHz, CDCl3):
d
¼ 154.8 (C20), 148.4 (C9a), 147.0 (C7),
H50), 7.11 (d, J ¼ 8.6 Hz,1H, H9), 7.03 (dd, J ¼ 8.6,1.7 Hz,1H, H8), 6.99
(d, J ¼ 1.7 Hz, 1H, H6), 6.48 (dd, J ¼ 1.6, 0.9 Hz, 1H, H40), 4.95 (ddd,
J ¼ 7.6, 5.4, 2.1 Hz,1H, H4), 4.52 (dd, J ¼ 8.3, 2.4 Hz,1H, H2), 3.40 (dd,
J ¼ 16.8, 5.4 Hz, 1H, HB5), 2.55 (dddd, J ¼ 12.6, 7.6, 2.4, 1.2 Hz, 1H,
HB3), 2.54 (br d, J ¼ 16.8 Hz,1H, HA5), 2.44 (ddd, J ¼ 12.6, 8.3, 2.1 Hz,
142.2 (C50), 127.2 (C5a), 123.5 (C9), 122.3 (C6), 120.5 (q, 1JC,F ¼ 257.1
Hz, 7-OCF3), 119.5 (C8), 110.4 (C40), 105.7 (C30), 74.3 (C4), 69.5 (C2),
38.6 (C3), 34.6 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1019 (CeO), 985 (NeO).
GCeMS (EI, 70 eV): m/z (%) ¼ 311 (Mþꢃ, 21), 294 (6), 281 (6), 214 (6),
189 (55), 188 (100), 94 (33). HRMS (EI, 70 eV): m/z [M]þ calcd for
1H, HA3). 13C NMR (100 MHz, CDCl3):
d
¼ 145.9 (C7), 143.4 (C50),
C
15H12F3NO3: 311.0769; found: 311.0767.
142.6 (C9a), 139.2 (C20), 128.1 (C30), 127.1 (C5a), 123.4 (C9), 122.3
(C6), 120.5 (q, 1JC,F ¼ 257.0 Hz, 7-OCF3), 119.4 (C8), 109.5 (C40), 74.2
(C4), 68.2 (C2), 41.2 (C3), 34.8 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1035 (CeO),
989 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 311 (Mþꢃ, 20), 294 (6), 281
(1), 214 (3), 189 (52), 188 (100), 94 (12). HRMS (EI, 70 eV): m/z [M]þ
calcd for C15H12F3NO3: 311.0769; found: 311.0766.
4.1.2.26. (2SR,4RS)-7-trifluoromethoxy-2-(5-methylfuran-2-yl)-
2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepine 11j. Reaction time:
22 h. Yield: 67%. White solid. mp 93 ꢀC (heptane). 1H NMR
(400 MHz, CDCl3):
d
¼ 7.18 (d, J ¼ 8.6 Hz, 1H, H9), 7.04 (dd, J ¼ 8.6,
2.1 Hz, 1H, H8), 6.98 (d, J ¼ 2.1 Hz, 1H, H6), 6.19 (d, J ¼ 3.1 Hz, 1H,
H30), 5.93 (d, J ¼ 3.1 Hz, 1H, H40), 4.97 (ddd, J ¼ 7.9, 5.3, 1.8 Hz, 1H,
H4), 4.56 (dd, J ¼ 8.6, 2.4 Hz, 1H, H2), 3.40 (dd, J ¼ 16.8, 5.3 Hz, 1H,
HB5), 2.77 (dddd, J ¼ 12.9, 7.9, 2.4, 1.2 Hz, 1H, HB3), 2.54 (br d,
J ¼ 16.8 Hz,1H, HA5), 2.38 (ddd, J ¼ 12.9, 8.6,1.8 Hz,1H, HA3), 2.31 (s,
4.1.2.30. (2SR,4RS)-7-chloro-2-(1-methyl-1H-pyrrol-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 13a. Reaction time: 20 h.
Yield: 39%. White solid. mp 170 ꢀC (heptane). 1H NMR (400 MHz,
CDCl3):
d
¼ 7.16 (dd, J ¼ 8.3, 2.2 Hz, 1H, H8), 7.13 (d, J ¼ 2.2 Hz, 1H,
3H, 50-CH3). 13C NMR (100 MHz, CDCl3):
d
¼ 152.9 (C20), 152.0 (C50),
H6), 7.07 (d, J ¼ 8.3 Hz, 1H, H9), 6.64 (dd, J ¼ 3.2, 1.6 Hz, 1H, H50),
6.13 (dd, J ¼ 3.2, 1.6 Hz, 1H, H30), 6.08 (t, J ¼ 3.2 Hz, 1H, H40), 4.99
(ddd, J ¼ 7.3, 5.3, 2.0 Hz, 1H, H4), 4.60 (dd, J ¼ 8.5, 2.1 Hz, 1H, H2),
3.80 (s, 3H, NeCH3), 3.38 (dd, J ¼ 16.6, 5.3 Hz, 1H, HB5), 2.86 (dddd,
J ¼ 12.9, 7.3, 2.1, 1.2 Hz, 1H, HB3), 2.53 (br d, J ¼ 16.6 Hz, 1H, HA5),
2.38 (ddd, J ¼ 12.9, 8.5, 2.0 Hz, 1H, HA3). 13C NMR (100 MHz, CDCl3):
148.5 (C9a), 146.0 (C7), 127.2 (C5a), 123.6 (C9), 122.3 (C6), 120.5 (q,
1JC,F ¼ 256.9 Hz, 7-OCF3), 119.5 (C8), 107.6 (C30), 106.3 (C40), 74.2
(C4), 69.5 (C2), 38.4 (C3), 34.6 (C5), 13.7 (50-CH3). IR (KBr, cmꢂ1):
ṽ ¼ 1021 (CeO), 983 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 325 (Mþ
,
ꢃ
18), 308 (12), 295 (3), 214 (6), 189 (27), 188 (45), 108 (100). HRMS
(EI, 70 eV): m/z [M]þ calcd for C16H14F3NO3: 325.0926; found:
325.0919.
d
¼ 149.1 (C9a), 132.6 (C20), 131.7 (C7), 130.3 (C6), 128.0 (C5a), 127.1
(C8), 123.7 (C9), 123.4 (C50), 108.2 (C30), 107.0 (C40), 74.7 (C4), 68.9
(C2), 38.8 (C3), 35.2 (C5), 34.9 (NeCH3). IR (KBr, cme1): ṽ ¼ 1026
ꢃ
,
35Cl, 24),
4.1.2.27. (2SR,4RS)-7-trifluoromethoxy-2-(5-nitrofuran-2-yl)-
2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepine 11k. Reaction time:
25 h. Yield: 66%. White solid. mp 165 ꢀC (heptane). 1H NMR
(CeO), 977 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 274 (Mþ
257 (15), 244 (1), 164 (3), 139 (6), 138 (12), 107 (100). HRMS (EI,
70 eV): m/z [M]þ calcd for C15H15ClN2O: 274.0873; found: 274.0879.
(400 MHz, CDCl3):
d
¼ 7.31 (d, J ¼ 3.7 Hz, 1H, H40), 7.15 (d, J ¼ 8.6 Hz,
1H, H9), 7.06 (dd, J ¼ 8.6, 1.7 Hz, 1H, H8), 7.02 (d, J ¼ 1.7 Hz, 1H, H6),
6.69 (d, J ¼ 3.7 Hz, 1H, H30), 4.99 (ddd, J ¼ 7.8, 5.4, 2.0 Hz, 1H, H4),
4.66 (dd, J ¼ 8.6, 2.2 Hz, 1H, H2), 3.43 (dd, J ¼ 16.8, 5.4 Hz, 1H, HB5),
2.85 (dddd, J ¼ 12.9, 7.8, 2.2, 1.2 Hz, 1H, HB3), 2.60 (br d, J ¼ 16.8 Hz,
1H, HA5), 2.52 (ddd, J ¼ 12.9, 8.6, 2.0 Hz, 1H, HA3). 13C NMR
4.1.2.31. (2SR,4RS)-7-fluoro-2-(1-methyl-1H-pyrrol-2-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 13b. Reaction time: 20 h.
Yield: 31%. White solid. mp 154 ꢀC (heptane). 1H NMR (400 MHz,
CDCl3):
d
¼ 7.11 (dd, J ¼ 8.6, 5.2 Hz, 1H, H9), 6.89 (td, J ¼ 8.6, 2.7 Hz,
1H, H8), 6.85 (dd, J ¼ 9.3, 2.7 Hz,1H, H6), 6.64 (dd, J ¼ 2.8,1.2 Hz,1H,
H50), 6.14 (dd, J ¼ 3.2, 1.2 Hz, 1H, H30), 6.09 (dd, J ¼ 3.2, 2.8 Hz, 1H, H
40), 4.99 (ddd, J ¼ 8.0, 5.2,1.9 Hz,1H, H4), 4.60 (dd, J ¼ 8.4,1.9 Hz,1H,
H2), 3.81 (s, 3H, NeCH3), 3.39 (dd, J ¼ 16.7, 5.2 Hz, 1H, HB5), 2.86
(dddd, J ¼ 12.8, 8.0, 1.9, 1.0 Hz, 1H, HB3), 2.54 (br d, J ¼ 16.7 Hz, 1H,
(100 MHz, CDCl3):
d
¼ 158.7 (C20), 151.5 (C50), 147.4 (C7), 147.2 (C9a),
127.0 (C5a), 123.5 (C9), 122.4 (C6), 120.4 (q, 1JC,F ¼ 257.4 Hz, 7-OCF3),
119.8 (C8), 112.9 (C40), 110.0 (C30), 74.4 (C4), 69.2 (C2), 38.9 (C3),
34.5 (C5). IR (KBr, cmꢂ1): ṽ ¼ 1527 (eNO2), 1356 (eNO2), 1023
(CeO), 964 (NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 356 (Mþꢃ, 9), 339
(1), 326 (1), 214 (12),189 (70),188 (100). HRMS (EI, 70 eV): m/z [M]þ
calcd for C15H11F3N2O5: 356.0620; found: 356.0630.
HA5), 2.40 (ddd, J ¼ 12.8, 8.4, 1.9 Hz, 1H, HA3). 13C NMR (100 MHz,
4
CDCl3):
d
¼ 161.0 (d, 1JC,F ¼ 244.3 Hz, C7), 146.5 (d, JC,F ¼ 2.8 Hz,
C9a), 132.8 (C20), 128.0 (d, 3JC,F ¼ 8.1 Hz, C5a), 123.6 (C50), 123.5 (d,
3JC,F ¼ 8.5 Hz, C9), 116.8 (d, JC,F ¼ 22.4 Hz, C6), 113.9 (d,
2
4.1.2.28. (2SR,4RS)-7-fluoro-2-(furan-3-yl)-2,3,4,5-tetrahydro-1,4-
epoxy-1-benzazepine 12a. Reaction time: 18 h. Yield: 61%. 1H NMR
2JC,F ¼ 22.5 Hz, C8), 108.1 (C30), 107.0 (C40), 74.6 (C4), 68.9 (C2), 38.8
(C3), 35.4 (C5), 34.9 (NeCH3). IR (KBr, cmꢂ1): ṽ ¼ 1023 (CeO), 976
(NeO). GCeMS (EI, 70 eV): m/z (%) ¼ 258 (Mþꢃ, 30), 241 (18), 228
(1), 148 (9), 123 (9), 122 (15), 107 (100). HRMS (EI, 70 eV): m/z [M]þ
calcd for C15H15FN2O: 258.1168; found: 258.1157.
(400 MHz, CDCl3):
d
¼ 7.44 (dd, J ¼ 1.7, 0.6 Hz, 1H, H20), 7.39 (t,
J ¼ 1.7 Hz, 1H, H50), 7.05 (dd, J ¼ 8.4, 5.3 Hz, 1H, H9), 6.86 (td, J ¼ 8.4,
2.8 Hz, 1H, H8), 6.82 (dd, J ¼ 9.2, 2.8 Hz, 1H, H6), 6.47 (dd, J ¼ 1.7,
0.6 Hz, 1H, H40), 4.93 (ddd, J ¼ 7.2, 5.3, 1.2 Hz, 1H, H4), 4.48 (dd,
J ¼ 8.3, 2.4 Hz, 1H, H2), 3.38 (dd, J ¼ 16.8, 5.3 Hz, 1H, HB5), 2.54
(dddd, J ¼ 12.4, 7.2, 2.4, 1.2 Hz, 1H, HB3), 2.51 (br d, J ¼ 16.8 Hz, 1H,
4.1.3. General procedure for the synthesis of cis-2-heteroaryl-
2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols 14e16
HA5), 2.43 (ddd, J ¼ 12.4, 8.3, 1.2 Hz, 1H, HA3). 13C NMR (100 MHz,
To a stirred and cooled (ice-bath) solution of the appropriately
2-substituted 1,4-epoxytetrahydro-1-benzazepines (10aec, 10eeg,
10iek, 10meo), (11a,b, 11deg, 11i,j), and (12a,b), (1.5 mmol), in
methanol (10 mL) were added zinc powder (15.0 mmol), glacial
acetic acid (7.5 mmol) and hydrochloric acid (37%, 7.5 mmol). The
resulting mixtures were stirred at 0 ꢀC during 20e30 min and then
at room temperature for further 10e30 min (TLC monitoring). Each
mixture was filtered, neutralized with a 25% ammonium hydroxide
solution to pH ¼ 8, and then extracted with ethyl acetate
(2 ꢁ 100 mL). The organic layer was dried over anhydrous sodium
sulfate, and concentrated in vacuum to give crude products which
were purified on silica gel column chromatography using
4
CDCl3):
d
¼ 160.6 (d, 1JC,F ¼ 244.2 Hz, C7), 146.0 (d, JC,F ¼ 2.6 Hz,
C9a), 143.4 (C50), 139.1 (C20), 127.2 (d, 3JC,F ¼ 8.2 Hz, C5a), 123.6 (d,
3JC,F ¼ 8.5 Hz, C9), 128.2 (C30), 116.2 (d, 2JC,F ¼ 22.4 Hz, C6), 113.5 (d,
2JC,F ¼ 22.5 Hz, C8), 109.6 (C40), 74.2 (C4), 68.3 (C2), 41.1 (C3), 34.9
(C5). IR (liquid film, cmꢂ1): ṽ ¼ 1024 (CeO), 985 (NeO). GCeMS (EI,
70 eV): m/z (%) ¼ 245 (Mþꢃ, 21), 228 (6), 215 (1), 148 (6), 123 (45),
122 (100), 94 (12). HRMS (EI, 70 eV): m/z [M]þ calcd for
C
14H12FNO2: 245.0852; found: 245.0841.
4.1.2.29. (2SR,4RS)-7-trifluoromethoxy-2-(furan-3-yl)-2,3,4,5-
tetrahydro-1,4-epoxy-1-benzazepine 12b. Reaction time: 20 h.

304
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
heptaneeethyl acetate (compositions in the range from 5:1 to 2:1
v/v) as eluent; the expected compounds were obtained as yellow
viscous oils or crystalline substances.
J ¼ 13.8, 2.0 Hz, 1H, Heq5), 2.34 (ddd, J ¼ 12.9, 4.0, 2.0 Hz, 1H, Heq3),
2.16 (ddd, J ¼ 12.9, 11.6, 10.4 Hz, 1H, Hax3). 13C NMR (100 MHz,
CDCl3):
d
¼ 147.2 (C9a), 147.0 (C20), 131.3 (C6), 130.1 (C5a), 127.4
(C8), 127.0 (C7), 126.8 (C50), 124.6 (C40), 124.2 (C30), 121.7 (C9), 69.4
4.1.3.1. cis-2-(Thiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-
4-ol 14a. Reaction time: 30 min. Yield: 84%. White solid. mp 122 ꢀC
(C4), 56.3 (C2), 49.3 (C3), 44.0 (C5). IR (liquid film, cmꢂ1): ṽ ¼ 3347
(NeH, OeH), 1250 (CeN), 1024 (CeO). GCeMS (EI, 70 eV): m/z
(heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.27 (d, J ¼ 5.0 Hz, 1H,
(%) ¼ 279 (Mþ
,
35Cl, 23), 261 (1), 235 (7), 152 (8), 151 (10), 141 (58),
ꢃ
H50), 7.17 (br d, J ¼ 7.4 Hz, 1H, H6), 7.10 (td, J ¼ 7.4, 0.7 Hz, 1H, H8),
7.06 (d, J ¼ 3.4 Hz, 1H, H30), 7.00 (dd, J ¼ 5.0, 3.4 Hz, 1H, H40), 6.92 (t,
J ¼ 7.4 Hz, 1H, H7), 6.74 (d, J ¼ 7.4 Hz, 1H, H9), 4.32 (dd, J ¼ 11.4,
2.0 Hz, 1H, Hax2), 3.88 (tdd, J ¼ 10.0, 3.8, 2.0 Hz, 1H, Hax4), 3.74 (br s,
1H, NeH), 3.12 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5), 3.01 (dt, J ¼ 13.6,
2.0 Hz, 1H, Heq5), 2.36 (ddd, J ¼ 12.8, 3.8, 2.0 Hz, 1H, Heq3), 2.19
(ddd, J ¼ 12.8, 11.4, 10.0 Hz, 1H, Hax3), 1.97 (br s, 1H, 4-OH). 13C NMR
140 (62), 139 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for
C14H14ClNOS: 279.0485; found: 279.0484.
4.1.3.5. 7-Chloro-cis-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-
1H-1-benzazepin-4-ol 14e. Reaction time: 60 min. Yield: 80%. 1H
NMR (400 MHz, CDCl3):
d
¼ 7.13 (d, J ¼ 2.5 Hz, 1H, H6), 7.03 (dd,
J ¼ 8.3, 2.5 Hz, 1H, H8), 6.80 (d, J ¼ 3.4 Hz, 1H, H30), 6.64 (d,
J ¼ 8.3 Hz, 1H, H9), 6.62 (d, J ¼ 3.4 Hz, 1H, H40), 4.17 (dd, J ¼ 11.4,
2.0 Hz, 1H, Hax2), 3.83 (tdd, J ¼ 10.0, 3.8, 2.0 Hz, 1H, Hax4), 3.72 (br s,
1H, NeH), 3.04 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5), 2.93 (dt, J ¼ 13.6,
2.0 Hz,1H, Heq5), 2.48 (s, 3H, 50-CH3), 2.32 (ddd, J ¼ 12.8, 3.8, 2.0 Hz,
1H, Heq3), 2.11 (ddd, J ¼ 12.8, 11.4, 10.0 Hz, 1H, Hax3), 1.95 (br s, 1H,
(100 MHz, CDCl3):
d
¼ 148.6 (C9a), 147.7 (C20), 131.8 (C6), 128.2
(C5a), 128.2 (8-C), 126.8 (C50), 124.5 (C40), 124.0 (C30), 122.3 (C7),
120.5 (C9), 69.8 (C4), 56.3 (C2), 49.2 (C3), 44.4 (C5). IR (KBr, cmꢂ1):
ṽ ¼ 3301 (NeH, OeH), 1246 (CeN), 1016 (CeO). GCeMS (EI, 70 eV):
m/z (%) ¼ 245 (Mþꢃ, 64), 227 (3), 199 (21), 139 (52), 118 (21), 107
(82), 106 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for C14H15NOS:
245.0874; found: 245.0874.
4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 147.2 (C9a), 144.9 (C20), 139.2
(C50), 131.3 (C6), 129.9 (C5a), 127.3 (C8), 126.7 (C7), 124.7 (C40), 123.9
(C30), 121.6 (C9), 69.5 (C4), 56.4 (C2), 48.7 (C3), 44.0 (C5). 15.5 (50-
4.1.3.2. cis-2-(5-Methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-
CH3). IR (liquid film, cmꢂ1): ṽ ¼ 3348 (NeH, OeH), 1250 (CeN),
1025 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 293 (Mþ
,
35Cl, 18), 275
ꢃ
benzazepin-4-ol 14b. Reaction time: 45 min. Yield: 93%. Pale yellow
solid. mp 93 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.15 (dd,
(1), 249 (3), 153 (100), 152 (6), 141 (24), 140 (21). HRMS (EI, 70 eV):
J ¼ 7.4, 1.1 Hz, 1H, H6), 7.09 (td, J ¼ 7.4, 1.1 Hz, 1H, H8), 6.91 (td,
J ¼ 7.4, 1.1 Hz, 1H, H7), 6.81 (d, J ¼ 3.4 Hz, 1H, H30), 6.72 (dd, J ¼ 7.4,
1.1 Hz, 1H, H9), 6.62 (dd, J ¼ 3.4, 1.0 Hz, 1H, H40), 4.21 (dd, J ¼ 11.5,
2.0 Hz, 1H, Hax2), 3.86 (tdd, J ¼ 10.0, 3.8, 2.0 Hz, 1H, Hax4), 3.71 (br s,
1H, NeH), 3.09 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5), 3.00 (dt, J ¼ 13.6,
2.0 Hz, 1H, Heq5), 2.49 (d, J ¼ 1.0 Hz, 3H, 50-CH3), 2.34 (ddd, J ¼ 12.8,
3.8, 2.0 Hz,1H, Heq3), 2.14 (ddd, J ¼ 12.8,11.5, 10.0 Hz,1H, Hax3),1.99
m/z [M]þ calcd for C15H16ClNOS: 293.0641; found: 293.0630.
4.1.3.6. 7-Chloro-cis-2-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-
1H-1-benzazepin-4-ol 14f. Reaction time: 30 min. Yield: 80%. 1H
NMR (400 MHz, CDCl3):
d
¼ 7.18 (d, J ¼ 5.1 Hz, 1H, H50), 7.15 (d,
J ¼ 2.5 Hz, 1H, H6), 7.04 (dd, J ¼ 8.3, 2.5 Hz, 1H, H8), 6.83 (d,
J ¼ 5.1 Hz, 1H, H40), 6.64 (d, J ¼ 8.3 Hz, 1H, H9), 4.26 (dd, J ¼ 11.5,
2.0 Hz, 1H, Hax2), 3.86 (tdd, J ¼ 10.0, 4.0, 2.1 Hz, 1H, Hax4), 3.70 (br s,
1H, NeH), 3.08 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5), 2.95 (dt, J ¼ 13.6,
2.1 Hz, 1H, Heq5), 2.29 (ddd, J ¼ 12.8, 4.0, 2.0 Hz, 1H, Heq3), 2.22 (s,
3H, 30-CH3), 2.15 (ddd, J ¼ 12.8,11.5, 10.0 Hz,1H, Hax3),1.90 (br s, 1H,
(br s, 1H, 4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 148.9 (C9a), 145.6
(C20), 139.3 (C50), 132.0 (C6), 128.5 (C5a), 127.9 (C8), 125.0 (C40),
124.1 (C30), 122.5 (C7), 120.7 (C9), 70.1 (C4), 56.8 (C2), 49.3 (C3),
44.7 (C5), 15.8 (50-CH3). IR (KBr, cmꢂ1): ṽ ¼ 3342 (NeH, OeH), 1251
(CeN), 1025 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 259 (Mþꢃ, 42), 241
(1), 215 (9), 153 (100), 118 (15), 107 (70), 106 (67). HRMS (EI, 70 eV):
m/z [M]þ calcd for C15H17NOS: 259.1031; found: 259.1034.
4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 147.5 (C9a), 140.6 (C20), 133.3
(C30), 131.3 (C6), 130.1 (C40), 130.0 (C5a), 127.4 (C8), 126.8 (C7), 123.2
(C50), 121.5 (C9), 69.7 (C4), 54.3 (C2), 48.2 (C3), 44.1 (C5). 14.0 (30-
CH3). IR (liquid film, cmꢂ1): ṽ ¼ 3347 (NeH, OeH),1249 (CeN),1030
ꢃ
,
35Cl, 24), 275 (1), 249
4.1.3.3. cis-2-(3-Methylthiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-
(CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 293 (Mþ
benzazepin-4-ol 14c. Reaction time: 30 min. Yield: 83%. 1H NMR
(3), 153 (100), 152 (6), 141 (3), 140 (27). HRMS (EI, 70 eV): m/z [M]þ
(400 MHz, CDCl3):
d
¼ 7.18 (dd, J ¼ 7.4, 1.1 Hz, 1H, H6), 7.17 (d,
calcd for C15H16ClNOS: 293.0641; found: 293.0636.
J ¼ 5.1 Hz, 1H, H50), 7.10 (td, J ¼ 7.4, 1.1 Hz, 1H, H8), 6.93 (td, J ¼ 7.4,
1.1 Hz, 1H, H7), 6.84 (d, J ¼ 5.1 Hz, 1H, H40), 6.73 (dd, J ¼ 7.4, 1.1 Hz,
1H, H9), 4.31 (dd, J ¼ 11.4, 2.1 Hz, 1H, Hax2), 3.88 (tdd, J ¼ 10.1, 3.8,
2.1 Hz, 1H, Hax4), 3.66 (br s, 1H, NeH), 3.13 (dd, J ¼ 13.5, 10.1 Hz, 1H,
4.1.3.7. 7-Fluoro-cis-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-
benzazepin-4-ol 14g. Reaction time: 30 min. Yield: 80%. 1H NMR
(400 MHz, CDCl3):
d
¼ 7.25 (dd, J ¼ 5.2, 0.6 Hz, 1H, H50), 7.04 (dd,
H
ax5), 3.01 (dt, J ¼ 13.5, 2.1 Hz, 1H, Heq5), 2.30 (ddd, J ¼ 12.7, 3.8,
J ¼ 3.6, 0.6 Hz, 1H, H30), 6.98 (dd, J ¼ 5.2, 3.6 Hz, 1H, H40), 6.87 (dd,
J ¼ 9.2, 2.8 Hz, 1H, H6), 6.78 (td, J ¼ 8.8, 2.8 Hz, 1H, H8), 6.67 (dd,
J ¼ 8.8, 5.2 Hz, 1H, H9), 4.24 (dd, J ¼ 11.6, 1.6 Hz, 1H, Hax2), 3.83 (tdd,
J ¼ 10.0, 4.0, 2.0 Hz, 1H, Hax4), 3.11 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5),
2.92 (dt, J ¼ 13.6, 2.0 Hz, 1H, Heq5), 2.34 (ddd, J ¼ 12.9, 4.0, 1.6 Hz,
2.1 Hz, 1H, Heq3), 2.23 (s, 3H, 30-CH3), 2.18 (ddd, J ¼ 12.7, 11.4,
10.1 Hz, 1H, Hax3), 1.96 (br s, 1H, 4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 149.1 (C9a), 141.3 (C20), 133.4 (C30), 132.0 (C6), 130.3 (C40), 128.1
(C5a), 127.9 (C8), 123.4 (C50), 122.6 (C7), 120.7 (C9), 70.3 (C4), 54.6
(C2), 48.7 (C3), 44.8 (C5), 14.4 (30-CH3). IR (liquid film, cmꢂ1):
ṽ ¼ 3342 (NeH, OeH), 1249 (CeN), 1029 (CeO). GCeMS (EI, 70 eV):
m/z (%) ¼ 259 (Mþꢃ, 52), 241 (1), 215 (12), 153 (100), 118 (18), 107
(99), 106 (91). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H17NOS:
259.1031; found: 259.1027.
1H, Heq3), 2.15 (ddd, J ¼ 12.9, 11.6, 10.0 Hz, 1H, Hax3). 13C NMR
1
(100 MHz, CDCl3):
d
¼ 158.4 (d, JC,F ¼ 245.2 Hz, C7), 147.3 (C20),
144.5 (d, 4JC,F ¼ 2.6 Hz, C9a),130.5 (d, 3JC,F ¼ 8.0 Hz, C5a),126.8 (C50),
3
124.5 (C40), 124.0 (C30), 121.7 (d, JC,F ¼ 8.8 Hz, C9), 117.9 (d,
2JC,F ¼ 22.6 Hz, C6), 113.8 (d, 2JC,F ¼ 22.4 Hz, C8), 69.5 (C4), 56.5 (C2),
49.1 (C3), 44.2 (C5). IR (liquid film, cmꢂ1): ṽ ¼ 3346 (NeH, OeH),
1245 (CeN), 1023 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 263 (Mþ
,
ꢃ
4.1.3.4. 7-Chloro-cis-2-(thiophen-2-yl)-2,3,4,5-tetrahydro-1H-1-
benzazepin-4-ol 14d. Reaction time: 60 min. Yield: 86%. 1H NMR
30), 245 (1), 219 (12), 139 (96), 136 (22), 135 (23), 125 (96), 124
(100). HRMS (EI, 70 eV): m/z [M]þ calcd for C14H14FNOS: 263.0780;
found: 263.0781.
(400 MHz, CDCl3):
d
¼ 7.26 (dd, J ¼ 4.0, 1.0 Hz, 1H, H50), 7.13 (d,
J ¼ 2.4 Hz, 1H, H6), 7.03 (dd, J ¼ 5.2, 1.0 Hz, 1H, H30), 7.03 (dd, J ¼ 8.0,
2.4 Hz, 1H, H8), 6.98 (dd, J ¼ 5.2, 4.0 Hz, 1H, H40), 6.66 (d, J ¼ 8.0 Hz,
1H, H9), 4.27 (dd, J ¼ 11.6, 2.0 Hz, 1H, Hax2), 3.84 (tdd, J ¼ 10.4, 4.0,
2.0 Hz, 1H, Hax4), 3.06 (dd, J ¼ 13.8, 10.4 Hz, 1H, Hax5), 2.94 (dt,
4.1.3.8. 7-Fluoro-cis-2-(5-methylthiophen-2-yl)-2,3,4,5-tetrahydro-
1H-1-benzazepin-4-ol 14h. Reaction time: 30 min. Yield: 88%. 1H

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
305
NMR (400 MHz, CDCl3):
d
¼ 6.87 (dd, J ¼ 8.8, 2.9 Hz,1H, H6), 6.80 (d,
124.1 (C6), 123.9 (C30), 121.0 (C9), 120.6 (q, 1JC,F ¼ 256.1 Hz, 7-OCF3),
120.1 (C8), 69.3 (C4), 56.3 (C2), 48.6 (C3), 44.0 (C5), 15.4 (50-CH3). IR
(liquid film, cmꢂ1): ṽ ¼ 3352 (NeH, OeH), 1245 (CeN), 1027 (CeO).
GCeMS (EI, 70 eV): m/z (%) ¼ 343 (Mþꢃ, 12), 325 (1), 299 (3), 202 (6),
191 (21), 190 (24), 153 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for
J ¼ 3.4 Hz, 1H, H30), 6.76 (td, J ¼ 8.5, 2.9 Hz, 1H, H8), 6.66 (dd, J ¼ 8.5,
5.0 Hz, 1H, H9), 6.62 (dd, J ¼ 3.4, 1.0 Hz, 1H, H40), 4.13 (dd, J ¼ 11.5,
2.0 Hz, 1H, Hax2), 3.82 (tdd, J ¼ 10.3, 3.9, 2.0 Hz, 1H, Hax4), 3.63 (br s,
1H, NeH), 3.08 (dd, J ¼ 13.6, 10.3 Hz, 1H, Hax5), 2.91 (dt, J ¼ 13.6,
2.0 Hz, 1H, Heq5), 2.42 (d, J ¼ 1.0 Hz, 3H, 50-CH3), 2.32 (ddd, J ¼ 12.8,
3.9, 2.0 Hz, 1H, Heq3), 2.11 (ddd, J ¼ 12.8, 11.5, 10.3 Hz, 1H, Hax3), 1.87
C16H16F3NO2S: 343.0854; found: 343.0844.
(br s, 1H, 4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 158.2 (d,
4.1.3.12. 7-Trifluoromethoxy-cis-2-(3-methylthiophen-2-yl)-2,3,4,5-
tetrahydro-1H-1-benzazepin-4-ol 14l. Reaction time: 45 min. Yield:
1JC,F ¼ 244.6 Hz, C7), 144.9 (C20), 144.6 (d, 4JC,F ¼ 2.4 Hz, C9a), 139.0
(C50), 130.3 (d, 3JC,F ¼ 7.4 Hz, C5a), 124.6 (C40), 123.7 (C30), 121.4 (d,
82%. 1H NMR (400 MHz, CDCl3):
d
¼ 7.18 (d, J ¼ 5.1 Hz, 1H, H50), 7.04
3JC,F ¼ 8.4 Hz, C9), 117.8 (d, JC,F ¼ 22.1 Hz, C6), 113.7 (d,
(d, J ¼ 2.0 Hz, 1H, H6), 6.94 (dd, J ¼ 8.4, 2.0 Hz, 1H, H8), 6.84 (d,
J ¼ 5.1 Hz, 1H, H40), 6.70 (d, J ¼ 8.4 Hz, 1H, H9), 4.30 (dd, J ¼ 11.4,
2.0 Hz, 1H, Hax2), 3.88 (tdd, J ¼ 10.0, 4.0, 2.0 Hz, 1H, Hax4), 3.68 (br s,
1H, NeH), 3.11 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5), 2.98 (dt, J ¼ 13.6,
2.0 Hz,1H, Heq5), 2.48 (s, 3H, 30-CH3), 2.30 (ddd, J ¼ 12.8, 4.0, 2.0 Hz,
1H, Heq3), 2.17 (ddd, J ¼ 12.8, 11.4, 10.0 Hz, 1H, Hax3), 1.99 (br s, 1H,
2
2JC,F ¼ 21.9 Hz, C8), 69.4 (C4), 56.6 (C2), 48.9 (C3), 44.1 (C5), 15.4 (50-
CH3). IR (liquid film, cmꢂ1): ṽ ¼ 3345 (NeH, OeH),1251 (CeN),1025
(CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 277 (Mþꢃ, 18), 259 (1), 233 (3),
153 (100), 136 (9), 125 (39), 124 (45). HRMS (EI, 70 eV): m/z [M]þ
calcd for C15H16FNOS: 277.0937; found: 277.0936.
4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 147.8 (C9a), 144.1 (C7), 140.8
4.1.3.9. 7-Fluoro-cis-2-(3-methylthiophen-2-yl)-2,3,4,5-tetrahydro-
(C20), 133.5 (C30), 130.3 (C40), 130.1 (C5a), 124.6 (C6), 123.5 (C50),
121.3 (C9), 120.6 (q, 1JC,F ¼ 256.0 Hz, 7-OCF3), 120.5 (C8), 69.7 (C4),
54.5 (C2), 48.4 (C3), 44.4 (C5), 14.3 (30-CH3). IR (liquid film, cmꢂ1):
ṽ ¼ 3356 (NeH, OeH), 1244 (CeN), 1032 (CeO). GCeMS (EI, 70 eV):
m/z (%) ¼ 343 (Mþꢃ, 15), 325 (1), 299 (3), 202 (6), 191 (30), 190 (30),
153 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for C16H16F3NO2S:
343.0854; found: 343.0865.
1H-1-benzazepin-4-ol 14i. Reaction time: 45 min. Yield: 84%. 1H
NMR (400 MHz, CDCl3):
d
¼ 7.17 (d, J ¼ 5.1 Hz, 1H, H50), 6.89 (dd,
J ¼ 8.8, 2.8 Hz, 1H, H6), 6.83 (d, J ¼ 5.1 Hz, 1H, H40), 6.78 (td, J ¼ 8.5,
2.8 Hz, 1H, H8), 6.67 (dd, J ¼ 8.5, 5.0 Hz, 1H, H9), 4.24 (dd, J ¼ 11.4,
1.8 Hz, 1H, Hax2), 3.84 (tdd, J ¼ 10.2, 3.4, 2.5 Hz, 1H, Hax4), 3.55 (br s,
1H, NeH), 3.12 (dd, J ¼ 13.8, 10.2 Hz, 1H, Hax5), 2.93 (dt, J ¼ 13.8,
2.5 Hz, 1H, Heq5), 2.29 (ddd, J ¼ 12.8, 3.4, 1.8 Hz, 1H, Heq3), 2.23 (s,
3H, 30-CH3), 2.15 (ddd, J ¼ 12.8, 11.4, 10.2 Hz, 1H, Hax3), 1.95 (br s,1H,
4.1.3.13. cis-2-(Furan-2-yl)-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ol
4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 158.3 (d, 1JC,F ¼ 244.6 Hz, C7),
15a. Reaction time: 30 min. Yield: 84%. 1H NMR (400 MHz, CDCl3):
4
145.0 (d, JC,F ¼ 2.4 Hz, C9a), 140.8 (C20), 133.1 (C30), 130.5 (d,
d
¼ 7.40 (dd, J ¼ 1.9, 0.7 Hz, 1H, H50), 7.16 (dd, J ¼ 7.4, 1.5 Hz, 1H, H6),
3JC,F ¼ 7.0 Hz, C5a), 130.0 (C40), 123.1 (C50), 121.4 (d, JC,F ¼ 8.0 Hz,
7.11 (td, J ¼ 7.4, 1.5 Hz, 1H, H8), 6.92 (td, J ¼ 7.4, 1.0 Hz, 1H, H7), 6.81
(dd, J ¼ 7.4, 1.0 Hz, 1H, H9), 6.37 (dd, J ¼ 3.3, 1.9 Hz, 1H, H40), 6.27
(dd, J ¼ 3.3, 0.7 Hz, 1H, H30), 4.11 (dd, J ¼ 11.4, 1.9 Hz, 1H, Hax2), 3.89
(tdd, J ¼ 10.0, 4.0, 2.3 Hz, 1H, Hax4), 3.93 (br s, 1H, NeH), 3.10 (dd,
J ¼ 13.8, 10.0 Hz, 1H, Hax5), 3.01 (dt, J ¼ 13.8, 2.3 Hz, 1H, Heq5), 2.39
(ddd, J ¼ 12.8, 4.0, 1.9 Hz, 1H, Heq3), 2.16 (ddd, J ¼ 12.8, 11.4, 10.0 Hz,
1H, Hax3), 1.75 (br s, 1H, 4-OH). 13C NMR (100 MHz, CDCl3):
3
C9), 115.9 (d, 2JC,F ¼ 22.8 Hz, C6), 113.9 (d, 2JC,F ¼ 22.6 Hz, C8), 69.8
(C4), 54.6 (C2), 48.4 (C3), 44.3 (C5), 14.0 (30-CH3). IR (liquid film,
cmꢂ1): ṽ ¼ 3345 (NeH, OeH), 1251 (CeN), 1029 (CeO), GCeMS (EI,
70 eV): m/z (%) ¼ 277 (Mþꢃ, 21), 259 (1), 233 (6), 153 (100), 136 (9),
125 (52), 124 (48). HRMS (EI, 70 eV): m/z [M]þ calcd for
C
15H16FNOS: 277.0937; found: 277.0947.
d
¼ 156.0 (C20), 148.6 (C9a), 141.9 (C50), 131.6 (C6), 128.3 (C5a), 127.5
4.1.3.10. 7-Trifluoromethoxy-cis-2-(thiophen-2-yl)-2,3,4,5-
tetrahydro-1H-1-benzazepin-4-ol 14j. Reaction time: 60 min. Yield:
(C8), 122.2 (C7), 120.4 (C9), 110.4 (C40), 105.5 (C30), 69.6 (C4), 53.8
(C2), 44.3 (C3), 44.2 (C5). IR (liquid film, cmꢂ1): ṽ ¼ 3360 (NeH,
OeH), 1253 (CeN), 1012 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 229
(Mþꢃ, 52), 211 (1), 185 (18), 123 (36), 118 (15), 107 (67), 106 (100).
HRMS (EI, 70 eV): m/z [M]þ calcd for C14H15NO2: 229.1103; found:
229.1098.
82%. 1H NMR (400 MHz, CDCl3):
d
¼ 7.26 (dd, J ¼ 4.8,1.2 Hz,1H, H50),
7.05 (dd, J ¼ 3.6,1.2 Hz,1H, H30), 7.03 (d, J ¼ 2.0 Hz,1H, H6), 6.99 (dd,
J ¼ 4.8, 3.6 Hz, 1H, H40), 6.94 (dd, J ¼ 8.4, 2.0 Hz, 1H, H8), 6.74 (d,
J ¼ 8.4 Hz, 1H, H9), 4.30 (dd, J ¼ 11.6, 2.0 Hz, 1H, Hax2), 3.88 (tdd,
J ¼ 10.0, 4.0, 2.0 Hz, 1H, Hax4), 3.11 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5),
2.98 (dt, J ¼ 13.6, 2.0 Hz, 1H, Heq5), 2.36 (ddd, J ¼ 12.8, 4.0, 2.0 Hz,
1H, Heq3), 2.20 (ddd, J ¼ 12.8, 11.6, 10.0 Hz, 1H, Hax3). 13C NMR
4.1.3.14. cis-2-(5-Methylfuran-2-yl)-2,3,4,5-tetrahydro-1H-1-
benzazepin-4-ol 15b. Reaction time: 30 min. Yield: 92%. 1H NMR
(100 MHz, CDCl3):
d
¼ 147.0 (C7), 147.0 (C20), 144.0 (C9a), 129.9
(400 MHz, CDCl3):
d
¼ 7.15 (dd, J ¼ 7.5, 1.0 Hz, 1H, H6), 7.11 (td,
(C5a), 126.9 (C50), 124.7 (C6), 124.3 (C40), 124.3 (C30), 121.4 (C9),
J ¼ 7.5, 1.0 Hz, 1H, H8), 6.91 (td, J ¼ 7.5, 1.0 Hz, 1H, H7), 6.81 (dd,
J ¼ 7.5, 1.0 Hz, 1H, H9), 6.12 (d, J ¼ 3.1 Hz, 1H, H30), 5.93 (dd, J ¼ 3.1,
1.0 Hz, 1H, H40), 4.03 (dd, J ¼ 11.4, 2.0 Hz, 1H, Hax2), 3.86 (tdd,
J ¼ 10.0, 3.9, 2.2 Hz, 1H, Hax4), 3.09 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5),
2.99 (dt, J ¼ 13.6, 2.2 Hz, 1H, Heq5), 2.36 (ddd, J ¼ 12.8, 3.9, 2.0 Hz,
1H, Heq3), 2.31 (d, J ¼ 1.0 Hz, 3H, 50-CH3), 2.14 (ddd, J ¼ 12.8, 11.4,
120.7 (q, 1JC,F ¼ 255.6 Hz, 7-OCF3), 120.2 (C8), 69.4 (C4), 56.3 (C2),
48.8 (C3), 44.1 (C5). IR (liquid film, cmꢂ1): ṽ ¼ 3351 (NeH, OeH),
1248 (CeN), 1024 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 329 (Mþ
,
ꢃ
61), 311 (1), 285 (13), 202 (9), 201 (14), 191 (68), 190 (63), 139 (100).
HRMS (EI, 70 eV): m/z [M]þ calcd for C15H14F3NO2S: 329.0697;
found: 329.0709.
10.0 Hz, 1H, Hax3). 13C NMR (100 MHz, CDCl3):
d
¼ 154.2 (C20), 151.6
(C50), 148.7 (C9a), 131.6 (C6), 128.3 (C5a), 127.5 (C8), 122.1 (C7),
120.4 (C9), 106.2 (C40), 106.2 (C30), 69.6 (C4), 53.9 (C2), 44.3 (C3),
44.2 (C5), 13.6 (50-CH3). IR (liquid film, cmꢂ1): ṽ ¼ 3359 (NeH,
OeH), 1254 (CeN), 1023 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 243
(Mþꢃ, 30), 225 (1), 199 (6), 137 (100), 118 (12), 107 (58), 106 (55).
HRMS (EI, 70 eV): m/z [M]þ calcd for C15H17NO2: 243.1259; found:
243.1251.
4.1.3.11. 7-Trifluoromethoxy-cis-2-(5-methylthiophen-2-yl)-2,3,4,5-
tetrahydro-1H-1-benzazepin-4-ol 14k. Reaction time: 30 min.
Yield: 84%. 1H NMR (400 MHz, CDCl3):
d
¼ 7.01 (d, J ¼ 2.3 Hz, 1H,
H6), 6.93 (dd, J ¼ 8.4, 2.3 Hz, 1H, H8), 6.81 (d, J ¼ 3.4 Hz, 1H, H30),
6.69 (d, J ¼ 8.4 Hz,1H, H9), 6.62 (dd, J ¼ 3.4,1.1 Hz,1H, H40), 4.19 (dd,
J ¼ 11.5, 2.0 Hz, 1H, Hax2), 3.85 (tdd, J ¼ 10.0, 3.9, 2.0 Hz, 1H, Hax4),
3.74 (br s, 1H, NeH), 3.07 (dd, J ¼ 13.7, 10.0 Hz, 1H, Hax5), 2.96 (dt,
J ¼ 13.7, 2.0 Hz, 1H, Heq5), 2.48 (d, J ¼ 1.1 Hz, 3H, 50-CH3), 2.33 (ddd,
J ¼ 12.9, 3.9, 2.0 Hz, 1H, Heq3), 2.13 (ddd, J ¼ 12.9, 11.5, 10.0 Hz, 1H,
4.1.3.15. 7-Chloro-cis-2-(furan-2-yl)-2,3,4,5-tetrahydro-1H-1-
benzazepin-4-ol 15c. Reaction time: 60 min. Yield: 81%. White
H
ax3), 1.95 (br s, 1H, 4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 147.3
solid. mp 109e110 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
d
¼ 7.39
(C9a), 144.7 (C20), 143.6 (C7), 139.1 (C50), 129.6 (C5a), 124.6 (C40),
(d, J ¼ 1.2 Hz, 1H, H50), 7.11 (d, J ¼ 2.0 Hz, 1H, H6), 7.04 (dd, J ¼ 8.4,

306
M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
2.0 Hz, 1H, H8), 6.71 (d, J ¼ 8.4 Hz, 1H, H9), 6.35 (dd, J ¼ 3.2, 1.2 Hz,
1H, H40), 6.25 (d, J ¼ 3.2 Hz, 1H, H30), 4.03 (dd, J ¼ 11.2, 1.2 Hz, 1H,
HRMS (EI, 70 eV): m/z [M]þ calcd for C15H16FNO2: 261.1165; found:
261.1156.
Hax2), 3.84 (tdd, J ¼ 10.0, 3.6, 2.2 Hz, 1H, Hax4), 3.03 (dd, J ¼ 13.6,
10.0 Hz, 1H, Hax5), 2.93 (dt, J ¼ 13.6, 2.2 Hz, 1H, Heq5), 2.36 (ddd,
4.1.3.19. 7-Trifluoromethoxy-cis-2-(furan-2-yl)-2,3,4,5-tetrahydro-
1H-1-benzazepin-4-ol 15g. Reaction time: 45 min. Yield: 79%. Pale
yellow solid. mp 85 ꢀC (heptane). 1H NMR (400 MHz, CDCl3):
J ¼ 12.8, 3.6, 1.2 Hz, 1H, Heq3), 2.12 (ddd, J ¼ 12.8, 11.2, 10.0 Hz, 1H,
H
ax3). 13C NMR (100 MHz, CDCl3):
d
¼ 155.8 (C20), 147.2 (C9a), 142.2
(C50), 131.3 (C6), 130.2 (C5a), 127.3 (C8), 126.8 (C7), 121.7 (C9), 110.5
(C40), 105.7 (C30), 69.3 (C4), 53.9 (C2), 44.0 (C3), 44.0 (C5). IR (KBr,
d
¼ 7.40 (dd, J ¼ 1.9, 0.7 Hz, 1H, H50), 7.02 (d, J ¼ 2.1 Hz, 1H, H6), 6.96
(dd, J ¼ 8.5, 2.1 Hz, 1H, H8), 6.78 (d, J ¼ 8.5 Hz, 1H, H9), 6.37 (dd,
J ¼ 3.2, 1.9 Hz, 1H, H40), 6.27 (dd, J ¼ 3.2, 0.7 Hz, 1H, H30), 4.10 (dd,
J ¼ 11.6, 1.9 Hz, 1H, Hax2), 3.96 (br s, 1H, NeH), 3.89 (tdd, J ¼ 9.9, 3.7,
2.1 Hz, 1H, Hax4), 3.07 (dd, J ¼ 13.7, 9.9 Hz, 1H, Hax5), 2.97 (dt,
J ¼ 13.7, 2.1 Hz, 1H, Heq5), 2.39 (ddd, J ¼ 12.8, 3.7, 1.9 Hz, 1H, Heq3),
cmꢂ1): ṽ ¼ 3296 (NeH, OeH), 1245 (CeN), 1019 (CeO). GCeMS (EI,
70 eV): m/z (%) ¼ 263 (Mþ
ꢃ
,
35Cl, 55), 219 (15), 218 (13),190 (27),152
(11), 151 (15), 141 (65), 140 (70), 123 (100). HRMS (EI, 70 eV): m/z
[M]þ calcd for C14H14ClNO2: 263.0713; found: 263.0719.
2.15 (ddd, J ¼ 12.8, 11.6, 9.9 Hz, 1H, Hax3), 2.07 (br s, 1H, 4-OH). 13
C
4.1.3.16. 7-Chloro-cis-2-(5-methylfuran-2-yl)-2,3,4,5-tetrahydro-1H-
NMR (100 MHz, CDCl3):
d
¼ 155.6 (C20),147.3 (C9a),143.7 (C7),142.0
1-benzazepin-4-ol 15d. Reaction time: 60 min. Yield: 82%. 1H NMR
(C50), 129.8 (C5a), 124.2 (C6), 121.1 (C9), 120.6 (q, 1JC,F ¼ 256.1 Hz, 7-
OCF3), 120.1 (C8), 110.5 (C40), 105.7 (C30), 69.2 (C4), 53.7 (C2), 44.0
(C5),43.9 (C3). IR (KBr, cmꢂ1): ṽ ¼ 3362 (NeH, OeH), 1248 (CeN),
1013 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 313 (Mþꢃ, 36), 295 (1),
269 (12), 202 (6), 191 (52), 190 (67), 123 (100). HRMS (EI, 70 eV): m/
z [M]þ calcd for C15H14F3NO3: 313.0926; found: 313.0921.
(400 MHz, CDCl3):
d
¼ 7.12 (d, J ¼ 2.4 Hz, 1H, H6), 7.04 (dd, J ¼ 8.4,
2.4 Hz, 1H, H8), 6.73 (d, J ¼ 8.4 Hz, 1H, H9), 6.11 (d, J ¼ 3.1 Hz, 1H,
H30), 5.93 (d, J ¼ 3.1 Hz, 1H, H40), 4.00 (dd, J ¼ 11.4, 2.0 Hz, 1H, Hax2),
3.84 (tdd, J ¼ 10.0, 4.0, 2.0 Hz, 1H, Hax4), 3.03 (dd, J ¼ 13.6, 10.0 Hz,
1H, Hax5), 2.93 (dt, J ¼ 13.6, 2.0 Hz,1H, Heq5), 2.34 (ddd, J ¼ 12.8, 4.0,
2.0 Hz, 1H, Heq3), 2.30 (s, 3H, 50-CH3), 2.11 (ddd, J ¼ 12.8, 11.4,
10.0 Hz, 1H, Hax3). 13C NMR (100 MHz, CDCl3):
d
¼ 153.8 (C20), 151.6
4.1.3.20. 7-Trifluoromethoxy-cis-2-(5-methylfuran-2-yl)-2,3,4,5-
tetrahydro-1H-1-benzazepin-4-ol 15h. Reaction time: 60 min.
(C50), 147.2 (C9a), 131.1 (C6), 129.9 (C5a), 127.1 (C8), 126.5 (C7), 121.4
(C9), 106.3 (C30), 106.2 (C40), 69.2 (C4), 53.8 (C2), 43.9 (C3), 43.8
Yield: 84%. 1H NMR (400 MHz, CDCl3):
d
¼ 7.01 (d, J ¼ 1.9 Hz, 1H,
(C5). 13.5 (50-CH3). IR (liquid film, cmꢂ1): ṽ ¼ 3364 (NeH, OeH),
H6), 6.95 (dd, J ¼ 8.5,1.9 Hz,1H, H8), 6.78 (d, J ¼ 8.5 Hz,1H, H9), 6.12
(d, J ¼ 3.1 Hz, 1H, H30), 5.93 (d, J ¼ 3.1 Hz, 1H, H40), 4.04 (dd, J ¼ 11.4,
1.9 Hz, 1H, Hax2), 3.96 (br s, 1H, NeH), 3.89 (tdd, J ¼ 9.8, 3.8, 2.7 Hz,
1H, Hax4), 3.07 (dd, J ¼ 13.7, 9.8 Hz, 1H, Hax5), 2.97 (dt, J ¼ 13.7,
2.7 Hz, 1H, Heq5), 2.36 (ddd, J ¼ 12.8, 3.8, 1.9 Hz, 1H, Heq3), 2.30 (s,
3H, 50-CH3), 2.14 (ddd, J ¼ 12.8, 11.4, 9.8 Hz, 1H, Hax3), 2.07 (br s, 1H,
1252 (CeN), 1024 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 277 (Mþ
,
ꢃ
35Cl, 12), 259 (1), 233 (3), 152 (3), 141 (18), 140 (18), 137 (100). HRMS
(EI, 70 eV): m/z [M]þ calcd for C15H16ClNO2: 277.0870; found:
277.0874.
4.1.3.17. 7-Fluoro-cis-2-(furan-2-yl)-2,3,4,5-tetrahydro-1H-1-
4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 154.2 (C20), 152.1 (C50), 147.8
benzazepin-4-ol 15e. Reaction time: 30 min. Yield: 85%. 1H NMR
(C9a), 144.1 (C7), 130.0 (C5a), 124.6 (C6), 121.4 (C9), 121.0 (q,
1JC,F ¼ 257.5 Hz, 7-OCF3), 120.4 (C8), 106.7 (C30), 106.6 (C40), 69.6
(C4), 54.2 (C2), 44.3 (C5), 44.3 (C3), 14.0 (50-CH3). IR (liquid film,
cmꢂ1): ṽ ¼ 3366 (NeH, OeH), 1246 (CeN), 1023 (CeO). GCeMS (EI,
70 eV): m/z (%) ¼ 327 (Mþꢃ, 12), 309 (1), 283 (3), 202 (6), 191 (18),
190 (24), 137 (100). HRMS (EI, 70 eV): m/z [M]þ calcd for
(400 MHz, CDCl3):
d
¼ 7.39 (d, J ¼ 1.6 Hz, 1H, H50), 6.86 (dd, J ¼ 9.2,
2.8 Hz, 1H, H6), 6.79 (td, J ¼ 8.8, 2.8 Hz, 1H, H8), 6.74 (dd, J ¼ 8.8,
5.0 Hz, 1H, H9), 6.36 (dd, J ¼ 3.2, 1.6 Hz, 1H, H40), 6.25 (d, J ¼ 3.2 Hz,
1H, H30), 4.02 (dd, J ¼ 11.4, 1.2 Hz, 1H, Hax2), 3.85 (tdd, J ¼ 10.0, 4.0,
2.0 Hz, 1H, Hax4), 3.06 (dd, J ¼ 13.6, 10.0 Hz, 1H, Hax5), 2.91 (dd,
J ¼ 13.6, 2.0 Hz, 1H, Heq5), 2.36 (ddd, J ¼ 12.8, 4.0, 1.2 Hz, 1H, Heq3),
C16H16F3NO3: 327.1082; found: 327.1092.
2.12 (ddd, J ¼ 12.8, 11.4, 10.0 Hz, 1H, Hax3). 13C NMR (100 MHz,
1
CDCl3):
d
¼ 158.4 (d, JC,F ¼ 244.8 Hz, C7), 155.9 (C20), 144.7 (d,
4.1.3.21. 7-Fluoro-cis-2-(furan-3-yl)-2,3,4,5-tetrahydro-1H-1-
4JF,C ¼ 2.8 Hz, C9a), 141.9 (C50), 130.7 (d, 3JC,F ¼ 8.2 Hz, C5a), 121.6 (d,
benzazepin-4-ol 16a. Reaction time: 60 min. Yield: 89%. 1H NMR
3JC,F ¼ 8.8 Hz, C9), 117.9 (d, JC,F ¼ 22.8 Hz, C6), 113.8 (d,
(400 MHz, CDCl3):
d
¼ 7.44 (dd, J ¼ 1.7, 0.8 Hz, 1H, H20), 7.42 (t,
2
2JC,F ¼ 22.6 Hz, C8), 110.5 (C40), 105.6 (C30), 69.3 (C4), 54.2 (C2), 44.2
(C3), 44.1 (C5). IR (liquid film, cmꢂ1): ṽ ¼ 3358 (NeH, OeH), 1248
(CeN), 1016 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 247 (Mþꢃ, 56), 203
(16), 202 (16), 174 (33), 136 (18), 135 (18), 125 (83), 124 (100). HRMS
(EI, 70 eV): m/z [M]þ calcd for C14H14FNO2: 247.1009; found:
247.1012.
J ¼ 1.7 Hz, 1H, H50), 6.87 (dd, J ¼ 9.0, 2.9 Hz, 1H, H6), 6.77 (td, J ¼ 8.5,
2.9 Hz, 1H, H8), 6.65 (dd, J ¼ 8.5, 5.0 Hz, 1H, H9), 6.48 (dd, J ¼ 1.7,
0.8 Hz, 1H, H40), 3.91 (dd, J ¼ 11.4, 2.0 Hz, 1H, Hax2), 3.82 (tdd,
J ¼ 10.3, 4.0, 2.2 Hz,1H, Hax4), 3.50 (br s,1H, NeH), 3.07 (dd, J ¼ 13.6,
10.3 Hz, 1H, Hax5), 2.91 (dt, J ¼ 13.6, 2.2 Hz, 1H, Heq5), 2.21 (ddd,
J ¼ 12.9, 4.0, 2.0 Hz, 1H, Heq3), 2.12 (br s, 1H, 4-OH), 2.05 (ddd,
J ¼ 12.9, 11.4, 10.3 Hz, 1H, Hax3). 13C NMR (100 MHz, CDCl3):
4.1.3.18. 7-Fluoro-cis-2-(5-methylfuran-2-yl)-2,3,4,5-tetrahydro-1H-
d
¼ 158.1 (d, 1JC,F ¼ 239.8 Hz, C7), 145.0 (d, 4JC,F ¼ 2.3 Hz, C9a), 143.6
1-benzazepin-4-ol 15f. Reaction time: 45 min. Yield: 90%. 1H NMR
(C50), 138.7 (C20), 130.2 (d, 3JC,F ¼ 7.4 Hz, C5a), 128.8 (C30), 121.3 (d,
2
(400 MHz, CDCl3):
d
¼ 6.86 (dd, J ¼ 9.2, 2.8 Hz, 1H, H6), 6.77 (td,
3JC,F ¼ 8.0 Hz, C9), 117.9 (d, JC,F ¼ 22.1 Hz, C6), 113.7 (d,
J ¼ 8.8, 2.8 Hz, 1H, H8), 6.75 (dd, J ¼ 8.8, 5.2 Hz, 1H, H9), 6.11 (d,
J ¼ 3.1 Hz, 1H, H30), 5.93 (d, J ¼ 3.1 Hz, 1H, H40), 3.96 (dd, J ¼ 11.4,
1.9 Hz, 1H, Hax2), 3.83 (tdd, J ¼ 10.1, 3.9, 2.4 Hz, 1H, Hax4), 3.07 (dd,
J ¼ 13.6, 10.1 Hz, 1H, Hax5), 2.91 (dt, J ¼ 13.6, 2.4 Hz, 1H, Heq5), 2.35
(ddd, J ¼ 12.7, 3.9, 1.9 Hz, 1H, Heq3), 2.30 (s, 3H, 50-CH3), 2.11 (ddd,
J ¼ 12.7, 11.4, 10.1 Hz, 1H, Hax3). 13C NMR (100 MHz, CDCl3):
2JC,F ¼ 22.0 Hz, C8), 108.7 (C40), 69.6 (C4), 52.6 (C2), 47.5 (C3), 44.2
(C5). IR (liquid film, cmꢂ1): ṽ ¼ 3358 (NeH, OeH), 1252 (CeN), 1023
(CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 247 (Mþꢃ, 94), 229 (3), 203
(36), 136 (27), 125 (79), 124 (100), 123 (42). HRMS (EI, 70 eV): m/z
[M]þ calcd for C14H14FNO2: 247.1009; found: 247.1014.
d
¼ 158.2 (d, 1JC,F ¼ 243.8 Hz, C7), 154.2 (C20), 151.7 (C50), 144.9 (d,
4.1.3.22. 7-Trifluoromethoxy-cis-2-(furan-3-yl)-2,3,4,5-tetrahydro-
1H-1-benzazepin-4-ol 16b. Reaction time: 60 min. Yield: 84%. 1H
4JC,F ¼ 2.8 Hz, C9a), 130.5 (d, JC,F ¼ 8.4 Hz, C5a), 121.5 (d,
3
3JC,F ¼ 8.8 Hz, C9), 117.9 (d, JC,F ¼ 22.6 Hz, C6), 113.8 (d,
NMR (400 MHz, CDCl3):
d
¼ 7.45 (dd, J ¼ 1.5, 0.8 Hz, 1H, H20), 7.43 (t,
2
2JC,F ¼ 22.4 Hz, C8), 106.3 (C40), 106.3 (C30), 69.5 (C4), 54.3 (C2), 44.3
(C3), 44.2 (C5), 13.6 (50-CH3). IR (liquid film, cmꢂ1): ṽ ¼ 3361 (NeH,
OeH), 1252 (CeN), 1022 (CeO). GCeMS (EI, 70 eV): m/z (%) ¼ 261
(Mþꢃ, 18), 243 (1), 217 (3), 137 (100), 136 (9), 125 (30), 124 (33).
J ¼ 1.5 Hz, 1H, H50), 7.01 (d, J ¼ 1.8 Hz, 1H, H6), 6.93 (dd, J ¼ 8.4,
1.8 Hz, 1H, H8), 6.69 (d, J ¼ 8.4 Hz, 1H, H9), 6.48 (dd, J ¼ 1.5, 0.8 Hz,
1H, H40), 3.97 (dd, J ¼ 11.5, 2.0 Hz, 1H, Hax2), 3.85 (tdd, J ¼ 9.9, 4.0,
2.1 Hz, 1H, Hax4), 3.62 (br s, 1H, NeH), 3.06 (dd, J ¼ 13.7, 9.9 Hz, 1H,

M.C. Blanco et al. / European Journal of Medicinal Chemistry 86 (2014) 291e309
307
Hax5), 2.95 (dt, J ¼ 13.7, 2.1 Hz, 1H, Heq5), 2.22 (ddd, J ¼ 12.9, 4.0,
2.0 Hz, 1H, Heq3), 2.07 (ddd, J ¼ 12.9, 11.5, 9.9 Hz, 1H, Hax3), 2.05 (br
reference drugs at 37 ꢀC, 5% CO2, and 95% of humidity for 24 h.
Control parasites were maintained without compound. The inhi-
bition of parasite growth was microscopically determined by
counting parasite numbers in a hemocytometer as above.
s, 1H, 4-OH). 13C NMR (100 MHz, CDCl3):
d
¼ 147.6 (C9a), 143.6 (C50),
143.6 (C7), 138.8 (C20), 129.5 (C5a), 128.6 (C30), 124.3 (C6), 120.9
(C9), 120.6 (q, 1JC,F ¼ 256.1 Hz, 7-OCF3), 120.1 (C8), 108.6 (C40), 69.4
(C4), 52.3 (C2), 47.2 (C3), 44.2 (C5). IR (liquid film, cmꢂ1): ṽ ¼ 3359
(NeH, OeH), 1249 (CeN), 1024 (CeO). GCeMS (EI, 70 eV): m/z
(%) ¼ 313 (Mþꢃ, 94), 295 (1), 269 (42), 202 (21), 191 (70), 190 (100),
123 (76). HRMS (EI, 70 eV): m/z [M]þ calcd for C15H14F3NO3:
313.0926; found: 313.0914.
For intracellular amastigote test, both T. cruzi and L. (L.) infantum
parasites were used. Vero cells were infected with T. cruzi TDT, and
THP-1 transformed cells were infected with late phase growth
promastigotes of L. (L.) infantum in a 1:10 ratio cell: parasite for
24 h. The infected cells were treated with two doses of serial di-
lutions of each evaluated compound and reference drugs. A second
dose was added on the third day of treatment with medium change.
Control cells were maintained without compound. The percentage
of infected cells was determined by counting infected and non-
infected cells on methanol fixed and Giemsa-stained slides on
300 cells. Each parasite experiment was tested in duplicate and
each concentration for triplicate.
4.2. Biological screening
4.2.1. Materials and methods
4.2.1.1. Parasites and cells. Epimastigotes of T. cruzi (Sylvio X10
strain, ATCC-50823) were cultured in Liver Infusion Tryptose (LIT)
medium supplemented with heat inactivated fetal calf serum
(hiFCS, Gibco, Grand Island, NY, USA) at 28 ꢀC. Promastigotes of
Leishmania chagasi (MHOM/BR/74/PP75), actually classified as
Leishmania (L.) infantum, were maintained at 28 ꢀC in RPMI 1640
medium (Gibco) containing hemin (Sigma Chemical Company, St.
Louis, MO, USA), HEPES (Gibco) and 10% of hiFCS. Vero (ATCC,
CCL81) and THP-1 (ATCC-TIB202) mammalian cells were cultured
in RPMI 1640 medium supplemented with 10% of hiFCS, at 37 ꢀC, 5%
CO2 and 95% of humidity.
4.2.1.5. Analysis of results. The antiparasitic activity was expressed
as the concentration of compound that inhibited 50% of parasites
(IC50), and the mammalian cell toxicity was expressed as the con-
centration of compound required for 50% cell killing (CC50). They
were calculated by sigmoidal regression analysis (Msxlfit™; ID
Business Solution, Guildford, UK).The obtained results were
expressed as mean
compound with an IC50 > 50
standard deviation (SD). In this work, a
M and a CC50 < 100 M was
m
m
considered as inactive for parasites and toxic for the mammalian
cell lines used. In order to compare the concentration of compound
that causes cell toxicity with the concentration that causes the
antichagasic or antileishmanial effect, the Selectivity Index (SI) was
determined. They were calculated using the following ratio:
SI ¼ CC50 in Vero (THP-1) cells/IC50 in parasites. SI ꢄ 3 were arbi-
trarily defined as parasite-selective compound. A higher thera-
peutic index is preferable to a lower one; consequently, lower SI
values indicate a narrow therapeutic range.
4.2.1.2. Reference drugs and stock solutions. Nifurtimox (Nfx, kindly
donated by Professor Simon Croft from the LSHTM) and Ampho-
tericin B (AmB, from Sigma) were used as reference drugs. Stock
solutions of each evaluated compound and parasite reference drugs
were prepared in dimethyl sulfoxide (DMSO, Carlo Erba Reagenti
Rodano, Italy) at a final concentration of 0.1% v/v. Work solutions
were prepared in RPMI 1640 culture medium immediately before
assays. DMSO was not toxic for the cells at the working
concentrations.
Acknowledgments
4.2.1.3. Mammalian cell toxicities assays. Vero monolayers and
THP-1 cells (this last transformed to its adherent phenotype with
10 ng/mL of phorbol myristate acetate (PMA, from Sigma) were
A. Palma and M. C. Blanco would like to thank Colombian
Institute for Science and Research (COLCIENCIAS, Grant No. 1102-
521-28229), for financial support. A. Palma also thanks Dr. E. Sta-
shenko (Laboratorio de Cromatografía, Escuela de Química, Uni-
versidad Industrial de Santander) and Dr. Daniel Molina
(Laboratorio de RMN, Escuela de Química, Universidad Industrial de
Santander) for providing GCeMS and 1H, 13C NMR spectra. J. Cobo
incubated with each new compound (0.3e300
mg/mL) or with
reference drugs (0.1e100
m
M) for 72 h at 37 ꢀC in a 5% CO2, 95% air
mixture. Control cells were maintained without compound. The
cell toxicity was determined colorimetrically using tetrazolium salt
(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide,
ꢀ
and M. Nogueras thank “Centro de Instrumentacion Científico
MTT, from Sigma). The optical density (OD) of the formazan crystals
dissolved with DMSO was measured using a microplate reader at a
wavelength of 580 nm. The percentage of cytotoxicity was calcu-
lated using the following equation:
ꢀ
ꢀ
Tecnica” of Universidad de Jaen and the staff for data collection and
supporting. The financial support from the Consejería de Economía,
ꢀ
Innovacion y Ciencia (Junta de Andalucía, Spain), and the Uni-
ꢀ
versidad de Jaen is thanked.
Cytotoxicity ð%Þ ¼ 100 ꢁ ðOD control group
ꢂ OD treatment groupÞ=OD control group:
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.ejmech.2014.08.055.
4.2.1.4. Parasites assays. Epimastigotes of T. cruzi and promasti-
gotes of L. (L.) infantum in exponential phase of growth were treated
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