Structure-activity relationships in 1,4-benzodioxan-related compounds. 9. 1 From 1,4-benzodioxane to 1,4-dioxane ring as a promising template of novel α1D-adrenoreceptor antagonists, 5-HT1A full agonists, and cytotoxic agents

Article abstract of DOI:10.1021/jm800461k

Novel 1,4-dioxane compounds structurally related to WB 4101 (1) were prepared in order to investigate the possibility that the quite planar 1,4-benzodioxane template of 1 might be replaced by the less conformationally constrained 1,4-dioxane ring. The biological profiles of the new compounds were assessed using binding assays at human cloned α₁-adrenoreceptor (α¹-AR) subtypes and 5-HT_1A receptors, expressed in Chinese hamster ovary and HeLa cell membranes, respectively, and by functional experiments in isolated rat vas deferens (α_1A), spleen (α_1B), and aorta (α_1D). Moreover, the cytotoxic effects of the novel compounds were determined in PC-3 prostate cancer cells. The results showed that the properly substituted 1,4-dioxane nucleus proved to be a suitable scaffold for selective α_1D-AR antagonists (compound 14), potential anticancer agents (compound 13), and full 5-HT_1A receptor agonists (compound 15). In particular, compound 15 may represent a novel lead in the development of highly potent 5-HT_1A receptor full agonists useful as antidepressant and neuroprotective agents.

Full text of DOI:10.1021/jm800461k

J. Med. Chem. 2008, 51, 6359–6370
6359
Structure-Activity Relationships in 1,4-Benzodioxan-Related Compounds. 9.1 From
1,4-Benzodioxane to 1,4-Dioxane Ring as a Promising Template of Novel r1D-Adrenoreceptor
Antagonists, 5-HT1A Full Agonists, and Cytotoxic Agents†
Wilma Quaglia,*,§ Alessandro Piergentili,§ Fabio Del Bello,§ Yogita Farande,§ Mario Giannella,§ Maria Pigini,§
Giovanni Rafaiani,§ Antonio Carrieri,| Consuelo Amantini,# Roberta Lucciarini,# Giorgio Santoni,# Elena Poggesi,‡ and
Amedeo Leonardi‡
Dipartimento di Scienze Chimiche, UniVersita` di Camerino, Via S. Agostino 1, 62032 Camerino, Italy, Dipartimento Farmaco-Chimico,
UniVersita` degli Studi di Bari, Via E. Orabona 4, 70125 Bari, Italy, Dipartimento di Medicina Sperimentale e Sanita` Pubblica, UniVersita` di
Camerino, Via Madonna delle Carceri 3, 62032 Camerino, Italy, and Recordati S.p.A., Drug DiscoVery, Via CiVitali 1, 20148 Milano, Italy
ReceiVed April 22, 2008
Novel 1,4-dioxane compounds structurally related to WB 4101 (1) were prepared in order to investigate the
possibility that the quite planar 1,4-benzodioxane template of 1 might be replaced by the less conformationally
constrained 1,4-dioxane ring. The biological profiles of the new compounds were assessed using binding
assays at human cloned R1-adrenoreceptor (R1-AR) subtypes and 5-HT1A receptors, expressed in Chinese
hamster ovary and HeLa cell membranes, respectively, and by functional experiments in isolated rat vas
deferens (R1A), spleen (R1B), and aorta (R1D). Moreover, the cytotoxic effects of the novel compounds were
determined in PC-3 prostate cancer cells. The results showed that the properly substituted 1,4-dioxane nucleus
proved to be a suitable scaffold for selective R1D-AR antagonists (compound 14), potential anticancer agents
(compound 13), and full 5-HT1A receptor agonists (compound 15). In particular, compound 15 may represent
a novel lead in the development of highly potent 5-HT1A receptor full agonists useful as antidepressant and
neuroprotective agents.
Chart 1. Chemical Structures of WB 4101 (1), Phendioxan (2),
and Compound 3
Introduction
The sympathetic nervous system is the main regulator of
homeostasis and mediates most of its effects via the R1-, R2-,
and ꢀ-adrenoreceptors (R1-, R2-, and ꢀ-ARsa).2 Each of these
classes is further subdivided into three subtypes, resulting in
nine pharmacologically distinct ARs (R1a/A, R1b/B, R1d/D; R2a/A
,
R
2b/B, R2c/C; ꢀ1, ꢀ2, ꢀ3), which have all been cloned, expressed,
and sequenced and have been found to be heptahelical (7TM)
G-protein-coupled receptors. These nine subtypes do not explain
all of the biological responses to native or synthetic AR agonists,
3
leading to the postulation of additional subtypes, namely, R1L
and ꢀ4.4 Because of their widespread expression in many human
tissues and their involvement in several physiological processes,
ARs have proved to be highly attractive pharmacological targets
for the treatment of various pathologies. In particular, each R1-
AR subtype has a distinct pharmacology and shows discrete
tissue distribution.5 R1A- and R1B-AR subtypes play an important
role in cardiac development and/or function as well as in blood
pressure via vasoconstriction,6 while the R1A subtype, dominant
in the prostate, bladder neck, and urethra, contributes to the
dynamic (phasic) component of increased bladder outlet resis-
tance7 and together with the R1D subtype, located in the bladder
or the spinal cord, mediates lower urinary tract symptoms
(LUTS) caused by benign prostatic hyperplasia (BPH).8 Owing
to these effects, R1-antagonists were initially developed for the
treatment of hypertension and subsequently for symptomatic
BPH. At present, while the use of R1-antagonists in hypertension
is declining,9 R1-antagonists, in particular those selective for
R1A- and/or R1A- + R1D-AR subtypes with respect to the R1B-
AR subtype, are the first-line pharmacotherapeutic approach to
BPH,10 as they are useful for the prompt and effective relief of
LUTS, avoiding cardiovascular side effects such as orthostatic
hypotension and syncope.11
Our research group has long been involved in designing new
R1-AR antagonists structurally related to 1 (WB 4101) (Chart
1) and in studying structure-affinity and structure-selectivity
relationships in order to develop high-affinity, subtype-selective
ligands for each of the three R1-AR subtypes.12 The present
study expands on previous structure-activity relationship studies
by investigating the possibility that the quite planar 1,4-
benzodioxane structure of 1 might be replaced by the less
†
This article is dedicated to Dr. Francesco Gentili.
* Corresponding author. Phone: +390737402237. Fax: +390737637345.
E-mail: wilma.quaglia@unicam.it.
§
Dipartimento di Scienze Chimiche, Universita` di Camerino.
Universita` degli Studi di Bari.
Dipartimento di Medicina Sperimentale e Sanita` Pubblica, Universita`
|
#
di Camerino.
‡
Recordati S.p.A.
a Abbreviations: AR, adrenoreceptor; TM, transmembrane; LUTS, lower
urinary tract symptoms; BPH, benign prostatic hyperplasia; CHO, Chinese
hamster ovary; PC-3, human prostate cancer cells; SRB, sulforhodamine
B; GI, growth inhibition; TGI, total growth inhibition; LC, lethal concentra-
tion; PS, phosphatidylserine; MFI, mean fluorescence intensity; Ki, inhibition
or dissociation constant; Kb, dissociation constant.
10.1021/jm800461k CCC: $40.75
2008 American Chemical Society
Published on Web 09/26/2008

6360 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Chart 2. Chemical Structures of Compounds 4-15
Quaglia et al.
afforded the amides 24a, 24b, 25b, 26, 35a, 35b, 36a, 36b,
37a, 37b, and 38, whose reduction with the borane-methyl
sulfide complex in dry THF gave the final amines 5a, 5b, 6b,
12, 7a, 7b, 8a, 8b, 9a, 9b, and 15. The stereochemical
relationship between the 2-carboxylic function and the 5-phenyl
ring in 22a and 22b was determined by 1H NMR. The strategy
used to identify the individual diastereoisomers was based on
the analysis of the coupling constant (J) data, as reported for
the axial and equatorial protons of 1,4-dioxane.26 In the 1H NMR
spectrum of diastereoisomer 22a, the proton in position 5 at δ
4.62 ppm showed two coupling constants (J ) 2.56 Hz and J
) 10.26 Hz) with the protons in position 6. The presence of a
large constant indicated an axial position for such a proton. In
addition, the proton in position 2 showed two coupling constants
(J ) 3.42 Hz and J ) 10.69 Hz) with the protons in position 3.
Since one of the constants was large, such a proton was axial.
Therefore, the stereochemical relationship between the 2-car-
boxylic function and the 5-phenyl substituent was trans diequa-
torial in 22a.
In the 1H NMR spectrum of diastereoisomer 22b, the situation
of the proton in position 5 at δ 4.67 ppm (J ) 2.99 Hz and J
) 10.26 Hz) was similar to that of the proton in the same
position of diastereoisomer 22a, indicating an axial position for
such a proton. However, the proton in position 2 at δ 4.38 ppm
of 22b showed two small coupling constants (J ) 1.11 Hz and
J ) 2.99 Hz) with the protons in position 3, indicating an
equatorial position for this proton and, consequently, a cis
equatorial-axial stereochemical relationship between the 5-phe-
nyl substituent and the 2-carboxylic function.
The stereochemical relationship between the 2-carboxylic
function and the 6-phenyl ring in 33a and 33b was determined
by 1D NOE measurements and confirmed by analysis of the
coupling constant (J) data. In compound 33b, the irradiation of
C2-H caused the NOE effect at C6-H, whereas no NOE effect
was observed at C6-H by the irradiation of the same proton in
compound 33a, indicating a cis and trans relationship, respec-
tively, for the two compounds.
Moreover, in the 1H NMR spectrum of isomer 33b the proton
in position 6 at δ 4.78 ppm showed two coupling constants (J
) 2.84 Hz and J ) 10.44 Hz) with the protons in position 5.
The presence of a large constant indicated an axial position for
such a proton. In addition, the proton in position 2 at δ 4.54
ppm showed two coupling constants (J ) 3.20 Hz and J )
10.71 Hz) with the protons in position 3. Since one of the two
constants was large, such a proton was axial. Therefore, the
stereochemical relationship between the 2-carboxylic function
and the 6-phenyl substituent was cis in 33b.
conformationally constrained 1,4-dioxane ring. This investiga-
tion was also prompted by our recent study in which the 1,4-
dioxane nucleus proved to be a suitable scaffold for efficacious
and selective muscarinic agonists.13 Considering that the ste-
reochemically defined insertion of a phenyl ring in position 3
of 1 (phendioxan, 2)14,15 (Chart 1) or in position 4 of its
methylene bioisostere (compound 3)16 (Chart 1) induced a
significant modulation of R1-AR subtype selectivity, we de-
signed the cis and trans 5- or 6-phenyl derivatives (compounds
4-9) (Chart 2). Moreover, the enlargement of the 1,4-benzo-
dioxane scaffold of 1 by fusion with an additional benzene ring17
produced a significant R1a-AR subtype selectivity, and its
replacement with a 2,2-diphenyl-1,3-dioxolanyl structure, along
with the simultaneous removal of one or two methoxy groups
in the 2,6-dimethoxyphenoxy moiety, afforded antagonists
selective for the R1D-AR subtype.18 These results prompted the
design of the 5- or 6-diphenyl derivatives 10-15. In addition,
it is well-known that the 5-HT1A serotoninergic receptor exhibits
a high degree of homology to R1-ARs19 and benzodioxane
derivatives,20 and in particular, 1 and related compounds21 are
effective ligands for the 5-HT1A receptor. Therefore, the
synthesis of compounds 4-15 (Chart 2) allowed us to inves-
tigate the possibility that the increased flexibility of the 1,4-
dioxane moiety might produce a better or more selective
interaction with the 5-HT1A receptor versus the R1-AR system.
The biological profiles of the novel compounds were assessed
using binding assays at human cloned R1-adrenoreceptor
subtypes and 5-HT1A receptors, expressed in Chinese hamster
ovary and HeLa cell membranes, respectively, and by functional
experiments in isolated rat vas deferens (R1A), spleen (R1B), and
aorta (R1D). Moreover, following our recent observation that
R1D- and R1B-ARs are expressed in PC-3 prostate cancer cells
and are involved in the modulation of apoptosis and cell
proliferation,12 the cytotoxic effects of the new compounds and
1 on this cell line were determined.
In the 1H NMR spectrum of diastereoisomer 33a, the situation
of the proton in position 6 at δ 5.16 ppm (J ) 3.13 Hz and J
) 9.78 Hz) was similar to that of the proton in the same position
of diastereoisomer 33b, indicating an axial position for such a
proton. However, the proton in position 2 at δ 4.52 ppm of 33a
showed two small coupling constants (J ) 1.57 Hz and J )
3.91 Hz) with the protons in position 3, indicating an equatorial
position for this proton and, consequently, a trans stereochemical
relationship between the 2-carboxylic function and the 6-phenyl
substituent.
Compounds 4a, 4b, 6a, 10, 11, 13, and 14 were synthesized
according to Scheme 2 starting from the intermediate alcohols
16,17,and28,whichweresubjectedtooxymercuration-reduction
reaction with mercury(II) acetate, followed by an aqueous
solution of iodine and potassium iodide, to afford a mixture of
the diastereoisomeric forms 39a/39b, whose diastereoisomers
were separated by column chromatography, 40 and 41, respec-
Chemistry
The new compounds 4-15 were synthesized according to
the methods reported in Schemes 1 and 2. Epoxidation of the
olefines 16, 17, 27, and 28 (Scheme 1), obtained by opening
2,2-diphenyloxirane22 with allyl alcohol in acidic or basic
conditions (17 and 28, respectively) or as previously described
in the literature23,24 (16 and 27), afforded compounds 18, 19,
29, and 30, respectively. Treatment with (1S)-(+)-10-camphor-
sulfonic acid [(1S)-(+)-10-CSA] in CH2Cl2 led to alcohols 20a/
20b, 21, 31a/31b, and 32. The diastereoisomers of the mixtures
20a/20b and 31a/31b were separated by column chromatogra-
phy. Oxidation of alcohols 20a, 20b, 21, 31a, 31b, and 32 to
the corresponding acids 22a, 22b, 23, 33a, 33b, and 34, followed
by amidation with the suitable amines, 2-phenoxyethanamine,
2-(2-methoxyphenoxy)ethanamine,18 or 2-(2,6-dimethoxyphe-
noxy)ethanamine,25 in the presence of Et3N and EtOCOCl

1,4-Benzodioxan-Related Compounds
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6361
Scheme 1a
a Reagents: (a) HClO4, allyl alchool; (b) Na, allyl alchool; (c) m-CPBA/CH2Cl2; (d) (1S)-(+)-10-CSA/CH2Cl2; (e) KMnO4/1 N KOH; (f) Et3N, EtOCOCl,
2-phenoxyethanamine, or 2-(2-methoxyphenoxy)ethanamine or 2-(2,6-dimethoxyphenoxy)ethanamine/CHCl3; (g) BH3 ·MeSMe/THF.
tively. The amination of the iodide derivatives with the suitable
amines, 2-phenoxyethanamine, 2-(2-methoxyphenoxy)etha-
namine,18 or 2-(2,6-dimethoxyphenoxy)ethanamine,25 afforded
the final compounds. The structures of the two diastereoisomers
39a and 39b were assigned by treating trans-2-(iodomethyl)-
5-phenyl-1,4-dioxane 39a with Ag2O to afford the corresponding
Functional Studies. The pharmacological profiles of com-
pounds 4-15 were further determined at R1-ARs on different
isolated tissues using 1 and BMY-7378 as reference compounds.
R1-AR subtypes blocking activity was assessed by antagonism
of (-)-noradrenaline-induced contraction of rat prostatic vas
30
31
deferens (R1A
)
or thoracic aorta (R1D
)
and by antagonism
1
alcohol, whose H NMR spectrum was similar to that of the
trans isomer 20a obtained in Scheme 1.
of (-)-phenylephrine-induced contraction of rat spleen (R1B).32
Furthermore, the agonist efficacy of compounds 5b, 8b, and
13-15 toward the 5-HT1A receptor was assessed by determining
the induced stimulation of [35S]GTPγS binding in cell mem-
branes from HeLa cells transfected with human cloned 5-HT1A
receptor33 using 8-OH-DPAT, 5-hydroxytryptamine (5-HT), and
5-carboxamidotryptamine (5-CT) as reference compounds.
In Vitro Cytotoxic Activity. The in vitro cytotoxic activity
of compounds 4-15, and 1 in human PC-3 prostate cancer cells
using 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(1,4-benzo-
dioxan-2-ylcarbonyl)piperazine (doxazosin)34 as a comparison,
was carried out using the sulforhodamine B (SRB) assay
according to the National Cancer Institute protocol.35 The
Biology
Binding Experiments. The pharmacological profiles of
compounds 4-15 were evaluated by radioreceptor binding
assays using 1, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-
8-azaspiro[4.5]decane-7,9-dione (BMY-7378) and 8-hydroxy-
2-(di-n-propylamino)tetralin (8-OH-DPAT) as reference com-
pounds. [3H]Prazosin was used to label cloned human R1-ARs
expressed in CHO cells.27 Furthermore, [3H]8-OH-DPAT was
used to label cloned human 5-HT1A receptors expressed in HeLa
cells.28,29

6362 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Quaglia et al.
Scheme 2a
a Reagents: (a) Hg(Ac)2/AcOH, H2O; (b) KI, I2/CHCl3; (c) 2-phenoxyethanamine or 2-(2-methoxyphenoxy)ethanamine or 2-(2,6-dimethoxyphenoxy)-
ethanamine/CH3CH2OCH2CH2OH, ∆; (d) Ag2O/1,4-dioxane, H2O.
Table 1. Affinity Constants, Expressed as pKi, of Compounds 4-15,
antitumor activity was estimated on the basis of the measure-
WB 4101, BMY-7378, and 8-OH-DPAT for Human Recombinant
R1-AR Subtypes and 5-HT1A Receptora
ments of three parameters: GI50, the molar concentration of the
compound that inhibited 50% net of cell growth; TGI, the molar
concentration of the compound that caused total inhibition; and
LC50, the molar concentration of the compound that caused 50%
net of cell death. Moreover, apoptosis of PC-3 cells, treated
with compound 13 at the LC50 concentration, was evaluated by
annexin V-FITC binding cytofluorimetric analysis.36
pKi, human cloned receptors
R1a R1b R1d 5-HT1A
6.27 <6
<6 <6
compd
R
R1
R2
Results and Discussion
4a (trans)
4b (cis)
5a (trans)
5b (cis)
6a (trans)
6b (cis)
7a (trans)
7b (cis)
8a (trans)
8b (cis)
9a (trans)
9b (cis)
10
5-C6H5
5-C6H5
5-C6H5
5-C6H5
5-C6H5
5-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
5,5-(C6H5)2
Η
Η
OCH3
OCH3
Η
<6
6.45
6.83
7.59
7.41
8.46
6.63
6.59
7.28
7.27
8.22
8.38
6.38
Η
Η
Η
An analysis of the results reported in Table 1 revealed that
all the compounds showed affinity values at R1-ARs that were
significantly lower than those of 1, with the exception of
compound 14 at R1D subtype. All the modifications performed
were detrimental to R1b subtype affinity and especially to R1a-
AR affinity, where all compounds showed approximately 100-
to 1000-fold lower affinity than that shown by 1. This observa-
tion indicated that the replacement of the planar condensed
aromatic portion of 1 with the pendant phenyl rings inserted in
position 5 or 6 of the 1,4-dioxane nucleus altered the optimal
molecule geometry, which gave the best interaction with these
receptor subtypes.
The stereochemical relationship between the phenyl group
in position 5 or 6 and the chain in position 2 did not affect
binding to either one of the AR subtypes, the cis diastereoiso-
mers showing affinity values similar to the corresponding trans
forms. The only exception was the pair 5a/5b, in which the cis
diastereoisomer 5b showed an affinity value approximately 10-
fold higher than that of trans 5a at R1d-AR subtype. The insertion
of a second phenyl ring in position 5 of the 1,4-dioxane nucleus,
which afforded compounds 10-12, did not substantially affect
affinity and subtype selectivity with respect to the corresponding
monosubstituted derivatives. Instead, the same modification at
position 6 was more productive, with the bis-phenyl compounds
6.80 6.55 7.01
6.36 6.58 7.79
OCH3 OCH3 6.29 <6
<6
OCH3 OCH3 <6
<6
6.39 <6
<6 <6
<6
Η
Η
OCH3
OCH3
Η
Η
Η
Η
6.81
7.14
7.06 6.52 7.50
6.70 6.57 7.36
OCH3 OCH3 <6
<6
<6
<6
OCH3 OCH3 6.33 <6
<6
Η
Η
Η
6.65 6.85 6.90
7.13 7.13 6.99
5,5-(C6H5)2 OCH3 OCH3 7.05 6.90 6.77
7.43
8.12
6.64
9.23
9.18
8.85
8.68
9.43
8.47
11
12
5,5-(C6H5)2 OCH3
13
14
15
6,6-(C6H5)2
6,6-(C6H5)2 OCH3
6,6-(C6H5)2 OCH3 OCH3 6.47 6.49 7.18
9.37 8.0 9.29
6.42 6.15 8.89
<6 <6 <6
Η
Η
6.77 6.92 8.44
7.56 7.25 8.94
Η
WB 4101 (1)
BMY-7378
8-OH-DPAT
a Equilibrium dissociation constants (Ki) were derived from IC50 values
using the Cheng-Prusoff equation.50 The affinity estimates were derived
from displacement of [3H]prazosin and [3H]-8-hydroxy-2-(di-n-propylami-
no)tetralin binding for R1-ARs and 5-HT1A receptor, respectively. Each
experiment was performed in triplicate. Ki values were from two to three
experiments, which agreed within (20%.
13-15 showing affinities significantly higher than the corre-
sponding monosubstituted compounds. Such an increase was

1,4-Benzodioxan-Related Compounds
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6363
Table 2. Antagonist Affinities, Expressed as pKb Values,a of Compounds 4-15, WB 4101, and BMY-7378 at R1-ARs on Isolated Rat Vas Deferens
(R1A), Spleen (R1B), and Thoracic Aorta (R1D) and Agonist Efficacy, Expressed as pD2,b of Compounds 5b, 8b, 13-15 on 5-HT1A Receptor in
Comparison to 8-OH-DPAT, 5-CT, and 5-HTc
pKb
binding [35S]GTP
5-HT1Α pD2 % max
compd
R
R1
R2
R1A
R1B
R1D
4a (trans)
4b (cis)
5a (trans)
5b (cis)
6a (trans)
6b (cis)
7a (trans)
7b (cis)
8a (trans)
8b (cis)
9a (trans)
9b (cis)
10
5-C6H5
5-C6H5
5-C6H5
5-C6H5
5-C6H5
5-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
5,5-(C6H5)2
5,5-(C6H5)2
5,5-(C6H5)2
6,6-(C6H5)2
6,6-(C6H5)2
6,6-(C6H5)2
Η
Η
7.0 ( 0.07
6.89 ( 0.08
7.10 ( 0.12
6.47 ( 0.09
7.21 ( 0.11
5.96 ( 0.10
7.21 ( 0.11
6.72 ( 0.06
7.22 ( 0.09
6.57 ( 0.01
5.80 ( 0.04
6.42 ( 0.02
6.15 ( 0.13
6.37 ( 0.07
6.08 ( 0.05
6.93 ( 0.04
6.65 ( 0.14
6.71 ( 0.01
9.51 ( 0.06
7.01 ( 0.08
6.97 ( 0.13
6.68 ( 0.06
7.44 ( 0.09
6.89 ( 0.03
7.02 ( 0.10
6.70 ( 0.02
6.88 ( 0.06
7.12 ( 0.11
7.96 ( 0.08
7.40 ( 0.07
5.75 ( 0.07
5.84 ( 0.07
6.28 ( 0.12
6.81 ( 0.04
5.74 ( 0.15
7.84 ( 0.07
6.86 ( 0.06
6.24 ( 0.13
8.16 ( 0.09
7.48 ( 0.09
6.56 ( 0.16
7.05 ( 0.07
7.48 ( 0.16
6.84 ( 0.16
7.26 ( 0.09
6.08 ( 0.06
6.38 ( 0.20
6.77 ( 0.16
7.83 ( 0.04
7.20 ( 0.08
7.11 ( 0.02
6.55 ( 0.06
7.19 ( 0.17
7.71 ( 0.11
7.38 ( 0.04
7.60 ( 0.12
8.32 ( 0.17
7.22 ( 0.07
8.80 ( 0.12
8.40 ( 0.09
Η
Η
OCH3
OCH3
OCH3
OCH3
Η
Η
Η
7.88
7.83
85.5
78.1
OCH3
OCH3
Η
Η
Η
OCH3
OCH3
OCH3
OCH3
Η
Η
Η
OCH3
OCH3
Η
11
12
13
14
OCH3
OCH3
Η
OCH3
OCH3
Η
OCH3
Η
Η
OCH3
9.11
9.40
8.28
77.1
81.5
106.3
15
WB 4101 (1)
BMY-7378
8-OH-DPAT
5-HT
9.27
7.60
7.30
8.45
26
100
100
96
5-CT
a pKb values were calculated according to van Rossum51 in the range 0.01-10 µM. Each concentration [B] of antagonist was tested four times. b pD2
values are the negative logarithm of the agonist concentration required to obtain 50% of the maximal stimulation of [35S]GTPγS binding and were calculated
from two to three experiments, which agreed within (20. c 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin; 5-HT, 5-hydroxytryptamine; 5-CT,
5-carboxamidotryptamine.
more significant at the R1d subtype. In particular, compound 14
displayed the highest affinity for R1d-AR subtype with a pKi
value of 8.94, which was not significantly different from 1 and
BMY-7378. Moreover, the replacement of the condensed
benzene ring with two phenyl rings inserted in position 6 of
the 1,4-dioxane nucleus, along with the simultaneous removal
of one methoxy group in the 2,6-dimethoxyphenoxy moiety,
was highly detrimental toward R1a and R1b subtypes (pKi of 7.56
and 7.25, respectively), indicating an unfavorable binding to
these subtypes. Therefore, favorable R1d subtype selectivity was
observed.
An analysis of the functional activities, expressed as pKb and
reported in Table 2, revealed that all synthesized compounds
behaved as antagonists at R1-ARs with pKb values significantly
lower than those of 1, with the exception of compounds 8a and
13 at R1B and compound 14 at R1D subtype. The pKb values
observed in functional experiments were comparable, in most
cases, with the pKi affinities derived from the binding assays.
The discrepancies often observed between functional and
binding affinities may not represent an anomaly because in
screening procedures a homogeneous population of cloned
receptors is used, which can be organized differently from native
receptors in functional tissues, and consequently, their biological
behavior may not be coincident. Recently other explanations
have been considered.18,37,38 However, although binding and
functional data allow similar structure-activity relationships to
be deduced, two aspects, concerning the influence of stereo-
chemistry and diphenyl substitution, deserve consideration. The
stereochemical relationship between the phenyl ring in position
5 or 6 and the side chain in position 2 seems to affect activity
and selectivity differently, depending on the methoxy substitu-
tion in the 2,6-dimethoxyphenoxy moiety. In fact, considering
the unsubstituted phenoxy derivatives, no significant differences
in activity for either one of the AR subtypes were observed
between the two diastereoisomers. When one or two methoxy
groups were present, the trans diastereoisomers were more potent
than the corresponding cis compounds at all the R-ARs, with
the exception of trans compound 9a, which had a higher pKb
only at R1D subtype, a lower pKb at R1A, and a similar pKb at
R1B with respect to its corresponding cis diastereoisomer,
showing good R1D subtype selectivity. With regard to the
diphenyl substitution, the insertion of a second phenyl ring in
position 5 of the 1,4-dioxane nucleus, obtaining compounds
10-12, seemed to favor a selective R1D-AR profile. However,
from the functional data the most interesting result was obtained
with compound 14, whose highest pKb value of 8.32 for the
R
1D-AR subtype was not significantly different from that of 1.
Moreover, its functional profile was similar to that displayed
by BMY-7378 (R1D > R1B > R1A), and because of its lower
pKb values at R1A and R1B subtypes, it proved to be even slightly
more selective than BMY-7378 for R1D versus the other two
subtypes.
To support the experimental observations and to get an
indication of the molecular determinants and stereochemical
requirements likely to affect R1-AR antagonist potency, flexible
superimpositions of 15 on 1, 2, and 3 were carried out (Figure
1). Considering that the eutomers of 1 and related compounds15,39
have an (S)-configuration at 2-carbon atom, the absolute
configuration-(S) at this stereogenic center was fixed for
compounds 1, 2, and 3, while both enantiomers were considered
for 15. The molecular overlay shown in Figure 1 may indicate
that in the case of 15, but the same also applies to 13 and 14
(superimpositions not shown); both (S) and (R) enantiomers
generated a good overlap with the eutomers of this data set.

6364 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Quaglia et al.
Figure 1. Flexible fit of (S)-WB 4101 (1), trans-(SS)-2, cis-(SR)-3,
and (S)-15 (top) or (R)-15 (bottom). Color codes are as follows: yellow
(1), red (2), magenta (3), and blue (15). Molecules are rendered with
PYMOL available at http://www.pymol.org.
Figure 2. Flexible fit of (S)-WB 4101 (1), BMY-7378, and (S)-14
(top) or (R)-14 (bottom). Color codes are as follows: yellow (1), orange
(BMY-7378), and cyan (14). Molecules are rendered with PYMOL
available at http://www.pymol.org.
Regardless of the absolute configuration of the stereogenic
center, it is worth noting that a kind of reVersed-Y conformation
was achieved by the dioxane derivatives that allowed a good
fit of the pharmacophoric moieties (i.e., the 6,6-diphenyl group
close to the aromatic rings of compounds 2 and 3, and the
aminoalkyl chain). This evidence may suggest that the eudismic
ratio for all three 6,6-diphenyldioxane derivatives 13-15 should
not have a large value but does not exclude the possibility that
useful information might come from the synthesis and biological
evaluation of the pure enantiomers.
With regard to the 5-HT1A receptor, some interesting observa-
tions about structure-affinity relationships may be drawn (Table
1). In fact, among all the 5-phenyl, 6-phenyl, and 5,5-diphenyl
derivatives, the presence of a 2-methoxy substituent in the
2-phenoxyethyl moiety was beneficial for high affinity for this
receptor. When two phenyl rings were inserted in position 6,
the methoxy substitution in the 2-phenoxyethyl moiety did not
seem to affect binding to the 5-HT1A receptor. All three
derivatives 13-15 showed similar nanomolar affinity values.
In particular, compounds 13 and 14 showed affinity that was
significantly higher than 1 and the reference compound 8-OH-
DPAT and similar to BMY-7378.
The binding data together with the observation that the three
6,6-diphenyl substituted compounds showed affinity profiles
different from that of 1 and overlapping that of BMY-7378 (5-
HT1A > R1d > R1a > R1b) allowed us to hypothesize that BMY-
7378 and compounds 13-15 have a similar binding interaction
mode. Moreover, compound 15, with a low affinity for R1d
subtype, displayed a selectivity profile similar to that of 8-OH-
DPAT. The better fit of the enantiomers of 14 to BMY-7378
rather than to (S)-1 (Figure 2) might justify the analogies
between 6,6-diphenyl-substituted derivatives and BMY-7378.
In addition, the different effects of the methoxy substitution in
the phenyl group of the side chain of 1, 13-15, and BMY-
7378 on R1-AR subtype affinity support such an assessment. In
fact, it is known that the two methoxy groups at positions 2
and 6 of the phenoxy unit confer optimum affinity in prototype
1,40 while in the novel series of compounds only one methoxy
group confers the highest affinity at all the R1-ARs. Similar
effects on the affinity at R1-ARs were instead obtained by the
same chemical modification on 14 and BMY-7378. In fact,
analogous to what occurred for BMY-7378,41 removal of the
methoxy group of 14, obtaining 13, did not alter the R1-AR
profile.
A few compounds (5b, 8b, and 13-15), selected on the basis
of the highest affinity shown at the 5-HT1A receptor, were
examined in the [35S]GTPγS binding at the human cloned
5-HT1A receptor, and their pD2 values are reported in Table 2,
along with those of the full 5-HT1A receptor agonists 8-OH-
DPAT, 5-HT, and 5-CT, which were included for comparison.
Among these compounds, 5b, 8b, 13, and 14 proved to be potent
partial agonists, with compounds 13 and 14 showing pD2 values
significantly higher than those of the reference compounds. More
interestingly, compound 15 was a potent full agonist with a pD2
value similar to that of 5-CT and significantly higher than those
of 5-HT and 8-OH-DPAT. Compound 15 also showed good
selectivity for 5-HT1A toward the R1A-, R1B-, and R1D-AR
subtypes (binding assays, 240, 229, and 47; functional assays,
37.2, 109.6, and 11.5, respectively), representing a new lead in
the design of potent full 5-HT1A agonists significantly selective
over R-ARs and structurally unrelated to 5-CT.
With regard to the cytotoxic assays, only the diphenyl-
substituted derivatives 10-15 were active at low micromolar
concentration and were more effective than both lead 1 and
doxazosin in suppressing cell growth in PC-3 cells (Table 3).
Moreover, the unsubstituted phenoxy moiety or the presence
of only one methoxy group seemed to favor PC-3 cell growth
inhibition, with compound 13 exhibiting the highest potency
(GI50 ) 1.0 ( 0.09 µM; TGI ) 3.9 ( 0.09 µM).
Compound 13 also showed the highest cytotoxic effect (LC50
) 6.2 ( 0.8 µM), which was significantly higher than that of

1,4-Benzodioxan-Related Compounds
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6365
Table 3. Cytotoxic Activity of Compounds 4-15 and WB 4101 in Comparison with Doxazosina
compd
R
R1
R2
GI50
TGI
LC50
4a (trans)
4b (cis)
5a (trans)
5b (cis)
6a (trans)
6b (cis)
7a (trans)
7b (cis)
8a (trans)
8b (cis)
9a (trans)
9b (cis)
10
5-C6H5
5-C6H5
5-C6H5
5-C6H5
5-C6H5
5-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
6-C6H5
5,5-(C6H5)2
5,5-(C6H5)2
5,5-(C6H5)2
6,6-(C6H5)2
6,6-(C6H5)2
6,6-(C6H5)2
Η
Η
177 ( 1.9
190 ( 0.7
30.1 ( 0.9
199 ( 1.2
29 ( 0.5
199 ( 1.5
158 ( 1.4
158 ( 1.2
199 ( 1.3
79 ( 1.5
112 ( 0.6
79.4 ( 0.8
9.9 ( 0.2
7.8 ( 0.3
19.9 ( 0.1
1.0 ( 0.09
6.3 ( 0.3
25.1 ( 0.4
64.56 ( 0.4
26.9 ( 1.3
252 ( 2.1
239 ( 1.7
NAb
>300
Η
Η
>300
OCH3
OCH3
OCH3
OCH3
Η
Η
Η
NAb
251 ( 2.2
>300
OCH3
OCH3
Η
NAb
NAb
251 ( 2.1
223 ( 3.0
223 ( 2.5
251 ( 3.2
158 ( 2.1
199 ( 1.8
178 ( 1.9
19.4 ( 0.5
16.1 ( 0.6
31.6 ( 1.1
3.9 ( 0.09
15.4 ( 1.0
31.6 ( 1.1
199 ( 1.6
49.0 ( 2.5
>300
>300
281 ( 2.3
>300
Η
Η
OCH3
OCH3
OCH3
OCH3
Η
Η
Η
251 ( 3.1
288 ( 3.1
282 ( 2.8
45.2 ( 1.7
35.8 ( 1.0
40 ( 1.0
6.2 ( 0.8
35.1 ( 1.2
35 ( 1.1
>200
OCH3
OCH3
Η
11
12
13
14
OCH3
OCH3
Η
OCH3
OCH3
Η
OCH3
Η
Η
OCH3
15
WB 4101 (1)
doxazosin
75.8 ( 3.6
a In vitro cytotoxic activity in human PC-3 prostate cancer cells was carried out using sulforhodamine B (SRB) assay, according to the National Cancer
Institute protocol.35 GI50 represents growth inhibition and is the drug concentration (µM) required to inhibit 50% net of cell growth. Total growth inhibition
(TGI) represents the drug concentration (µM) required to inhibit 100% of cell growth. LC50 represents the lethal concentration of drug required to kill 50%
of the initial cell number. Each quoted value represents the mean of quadruplicate determinations ( standard error (n ) 5). b NA: not active.
Figure 3. Treatment with compound 13 at the dose corresponding to the LC50 markedly induces translocation of PS (MFI of 76.98) in PC-3 cells,
whereas very low levels of PS exposure are observed in untreated or vehicle-treated cells (MFI of 30.51 and 35.67, respectively).
1 (LC50 > 200 µM) and doxazosin (LC50 ) 75.8 ( 3.6 µM).
Compounds 4-9 and 1 were devoid of cytotoxic activity.
Finally, since serotonin has been reported to show an enhancing
effect on human PC-3 cell growth,42 the effect produced by
5b, 8b, and 13-15, endowed with 5-HT1A partial or full agonist
activities, was also evaluated in the presence of the 5-HT1A
antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)piperazin-1-
yl)-2-phenylpropanamide [(S)-WAY 100135], which has been
reported to have no significant effect on PC-3 cell proliferation.42
The observation that the inhibitory effects induced by the above
compounds on PC-3 cell growth were not reversed by (S)-WAY
100135 (data not shown) indicates that their cytotoxic activity
was not prevented by the potential proliferative effect because
of their efficacy for the 5-HT1A receptor.
A characteristic feature of apoptotic cell death is the loss of
phospholipid asymmetry and expression of phosphatidylserine
(PS) on the outer layer of the plasma membrane. We analyzed
whether treatment for 48 h with compound 13 induced exter-
nalization of PS residues from the inner to the outer leaflet of
the plasma membrane in PC-3 cells. To this end, PC-3-treated
cells were stained with annexin V-FITC and analyzed by flow
cytometry.36 As shown in Figure 3, treatment with compound
13, at the dose corresponding to the LC50, markedly induced
translocation of PS (MFI, 76.98), whereas very low levels of
PS exposure were observed in untreated or vehicle-treated cells
(MFI, 30.51 and 35.67, respectively). Previous reports have
indicated that doxazosin induced apoptosis of PC-3 cells via a
death receptor mediated pathway.43 In this regard, our prelimi-
nary results, which showed no change in mitochondrial potential
in compound 13-treated PC-3 cells (data not shown), suggested
that this compound seemed to activate a mitochondrial-
independent apoptotic pathway. Thus, the ability of compound
13 to induce apoptosis at micromolar doses may be particularly
relevant in view of the strong chemoresistance shown by PC-3
cells.
In conclusion, the present study highlights that the less
conformationally constrained properly substituted 1,4-dioxane
nucleus may be considered a suitable scaffold for building
selective R1D-AR antagonists (compound 14), potential anti-
cancer agents (compound 13), or full 5-HT1A receptor agonists
(compound 15). The behavior of compound 15 is particularly
interesting because the 5-HT1A receptor is involved in psychiatric
disorders, such as anxiety and depression,44,45 and 5-HT1A
agonists may be useful as antidepressants46,47 and neuropro-

6366 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Quaglia et al.
tective agents.48 Since the limited clinical efficacy of the 5-HT1A
partial agonists as antidepressants (e.g., buspirone) seems to be
related to their low level of intrinsic activity,49 compound 15
may represent a novel lead in the design of highly potent and
efficacious 5-HT1A receptor agonists.
To study these aspects in detail, future efforts will be devoted
to identifying further structural requirements for selective R1-
AR and 5-HT1A receptor binding sites recognition. In particular,
since the enantiomers of 1 have different affinities for R1-
adrenergic and 5-HT1A receptors,39 with the intention of
verifying the indications that emerged from the flexible super-
impositions, the synthesis of the enantiomers of 13-15 is
already being planned. In addition, it would be of interest to
verify whether there is a relationship between stereochemistry
and the anticancer activity of compound 13.
with D2O), 2.47-2.85 (four dd, 4, CH2O cycle), 3.17 (m, 2, CHO
cycle), 3.25-3.80 (m, 8, OCH2 and CH2OH), 4.48 (two dd, 2,
OCHAr), 7.22-7.42 (m, 10, ArH).
2-(Oxiran-2-ylmethoxy)-2,2-diphenylethanol (19). This was ob-
tained following the procedure described for 18 starting from 17
to afford an oil: 50% yield. 1H NMR (CDCl3): δ 1.62 (br s, 1, OH,
exchangeable with D2O), 2.90 (m, 2, CH2O cycle), 3.24 (m, 1, CHO
cycle), 3.43 and 3.64 (two dd, 2, OCH2), 4.30 (dd, 2, CH2OH),
7.17-7.50 (m, 10, ArH).
2-(Oxiran-2-ylmethoxy)-1-phenylethanol (29). This was obtained
as a mixture of the two diastereoisomers following the procedure
described for 18 starting from 2724 to afford an oil: 89% yield. 1H
NMR (CDCl3): δ 2.61-2.82 (m, 4, CH2O cycle), 3.07 (br s, 2,
OH, exchangeable with D2O), 3.20 (m, 2, CHO cycle), 3.42-3.90
(m, 8, CH2OCH2), 4.90 (m, 2, CHAr), 7.22-8.06 (m, 10, ArH).
2-(Oxiran-2-ylmethoxy)-1,1-diphenylethanol (30). This was ob-
tained following the procedure described for 18 starting from 28
1
to afford a solid: mp 83-84 °C; 90% yield. H NMR (CDCl3): δ
Experimental Section
1.60 (br s, 1, OH, exchangeable with D2O), 2.55 and 2.80 (two dd,
2, CH2O cycle), 3.16 (m, 1, CHO cycle), 3.52 and 3.90 (two dd, 2,
OCH2), 4.10 (dd, 2, CH2O), 7.18-7.52 (m, 10, ArH).
Chemistry. Melting points were taken in glass capillary tubes
on a Bu¨chi SMP-20 apparatus and are uncorrected. IR and NMR
spectra were recorded on Perkin-Elmer 297 and Varian EM-390
instruments, respectively. Chemical shifts are reported in parts per
million (ppm) relative to tetramethylsilane (TMS), and spin
multiplicities are given as s (singlet), d (doublet), dd (double
doublet), t (triplet), q (quartet), or m (multiplet). Mass spectra were
obtained using a Hewlett-Packard 1100 MSD instrument utilizing
electron-spray ionization (ESI). IR spectral data (not shown because
of the lack of unusual features) were obtained for all compounds
reported and are consistent with the assigned structures. The
microanalyses were performed by the Microanalytical Laboratory
of our department. The elemental composition of the compounds
agreed to within (0.4% of the calculated values. Chromatographic
separations were performed on silica gel columns (Kieselgel 40,
0.040-0.063 mm, Merck) by flash chromatography. The term
“dried” refers to the use of anhydrous sodium sulfate. Compounds
were named following IUPAC rules as applied by Beilstein-Institut
AutoNom (version 2.1), a software for systematic names in organic
chemistry.
2-(Allyloxy)-2,2-diphenylethanol (17). Perchloric acid (70%,
0.75 mL) was added to a stirred solution of 2,2-diphenyloxirane22
(3.0 g, 15.3 mmol) in allyl alcohol (7.5 mL) at 0 °C. After 0.5 h at
room temperature the reaction mixture was poured in H2O (75 mL)
and extracted with Et2O. The organic phase was washed with H2O
and dried over Na2SO4. Removal of dried solvents gave a residue,
which was purified by column chromatography, eluting with
cyclohexane to afford an oil: 3.1 g; 80% yield. 1H NMR (CDCl3):
δ 1.85 (br s, 1, OH, exchangeable with D2O), 3.82 (d, 2, OCH2),
4.35 (s, 2, CH2OH), 5.13-5.47 (m, 2, CdCH2), 5.98 (m, 1, CHdC),
7.15-7.52 (m, 10, ArH).
trans-(5-Phenyl-1,4-dioxan-2-yl)methanol (20a) and cis-(5-Phen-
yl-1,4-dioxan-2-yl)methanol (20b). A solution of 18 (29.4 g, 151.4
mmol) and (1S)-(+)-10-camphorsulfonic acid (3.3 g, 142.1 mmol)
in CH2Cl2 (1340 mL) was refluxed for 8 h. The reaction mixture
was then washed with NaHCO3 saturated solution and dried over
Na2SO4. Removal of the solvent afforded a residue, which was
purified by column chromatography gradient eluent, eluting first
with cyclohexane/EtOAc (8:2) and then with cyclohexane/EtOAc
(6:4). The trans diastereoisomer 20a eluted first as a solid: 10.0 g;
1
34% yield; mp 79-81 °C. H NMR (CDCl3): δ 1.93 (t, 1, OH,
exchangeable with D2O), 3.52-4.04 (m, 7, OCH2 and
OCH2CHCH2), 4.58 (dd, 1, CHAr), 7.28-7.40 (m, 5, ArH). The
second fraction was the cis diastereoisomer 20b as an oil: 2.0 g;
1
7% yield. H NMR (CDCl3): δ 1.86 (br s, 1, OH, exchangeable
with D2O), 3.67-4.15 (m, 7, OCH2 and OCH2CHCH2), 4.63 (dd,
1, CHAr), 7.25-7.40 (m, 5, ArH).
(5,5-Diphenyl-1,4-dioxan-2-yl)methanol (21). This was obtained
following the procedure described for 20 starting from 19. The
residue was purified by column chromatography, eluting with
cyclohexane/EtOAc (8:2) to afford a solid: 50% yield; mp 95-97
°C. 1H NMR (CDCl3): δ 1.82 (br s, 1, OH, exchangeable with D2O),
3.40-3.75 (m, 4, OCH2 and CH2OH), 3.88 (m, 1, OCH), 3.79 and
4.69 (two d, 2, CH2O), 7.11-7.56 (m, 10, ArH).
cis-(6-Phenyl-1,4-dioxan-2-yl)methanol (31b) and trans-(6-Phen-
yl-1,4-dioxan-2-yl)methanol (31a). These were obtained following
the procedure described for 20 starting from 29 to afford a mixture
of diastereoisomers, which were separated by column chromatog-
raphy, eluting with cyclohexane/EtOAc (8:2). The cis diastereoi-
1
somer 31b eluted first as a solid: 33% yield; mp 72-73 °C. H
2-(Allyloxy)-1,1-diphenylethanol (28). 2,2-Diphenyloxirane22
(6.3 g, 32.1 mmol) was added dropwise to a stirred solution of
freshly cut sodium (0.22 g, 9.56 mmol) in allyl alcohol (22 mL) at
room temperature. After 1 h at room temperature the reaction
mixture was refluxed for 20 h. Most of the unreacted allyl alcohol
was then separated by distillation at atmospheric pressure. After
cooling to room temperature, 6 N H2SO4 (0.6 mL) was added to
the residual solution to neutralize the sodium alloxide, and solvent
removal was continued to afford a residual oil, which was purified
by column chromatography, eluting with cyclohexane/EtOAc (10:
NMR (CDCl3): δ 2.13 (br s, 1, OH, exchangeable with D2O),
3.38-3.98 (m, 7, CH2OCH2OCHCH2), 4.71 (dd, 1, CHAr),
7.28-7.40 (m, 5, ArH). The second fraction was the trans
diastereoisomer 31a as an oil: 37% yield. 1H NMR (CDCl3): δ
1.68 (br s, 1, OH, exchangeable with D2O), 3.61-4.16 (m, 7,
CH2OCH2OCHCH2), 4.87 (dd, 1, CHAr), 7.28-7.48 (m, 5, ArH).
(6,6-Diphenyl-1,4-dioxan-2-yl)methanol (32). This was obtained
following the procedure described for 20 starting from 30. The
residue was purified by column chromatography, eluting with
cyclohexane/EtOAc (9:1) to afford a solid: 60% yield; mp 114-115
°C. 1H NMR (CDCl3): δ 1.84 (br s, 1, OH, exchangeable with D2O),
3.53-3.83 (m, 5, OCH2CHCH2), 3.64 and 4.61 (two d, 2, CH2O),
7.20-7.58 (m, 10, ArH).
trans-5-Phenyl-1,4-dioxane-2-carboxylic Acid (22a). A solution
of KMnO4 (3.25 g, 20.6 mmol) in H2O (15 mL) was added dropwise
to a stirred mixture of 20a (2.16 g, 11.1 mmol) in 1 N KOH (15
mL) such that the temperature was maintained below 10 °C. After
18 h at room temperature the mixture was filtered over Celite,
MeOH was added, and the solvent was concentrated under vacuum.
The resulting aqueous solution was acidified with 6 N H2SO4 and
extracted with CHCl3. After evaporation of the dried solvent, the
1
0.05) to give a solid: 6.9 g; 85% yield; mp 29-31 °C. H NMR
(CDCl3): δ 3.54 (br s, 1, OH, exchangeable with D2O), 4.02 (s, 2,
CH2O), 4.15 (d, 2, OCH2), 5.28 (m, 2, CdCH2), 5.94 (m, 1,
CHdC), 7.21-7.53 (m, 10, ArH).
2-(Oxiran-2-ylmethoxy)-2-phenylethanol (18). m-Chloroper-
benzoic acid (50%) (11.6 g, 33.6 mmol) was added to a solution
of 1623 (3.0 g, 16.8 mmol) in CH2Cl2 (120 mL). After 20 h at
room temperature under stirring the reaction mixture was washed
with 10% Na2SO3, 5% Na2CO3, and H2O. Removal of dried solvents
afforded a mixture of the two diastereoisomers as an oil: 2.77 g;
1
85% yield. H NMR (CDCl3): δ 2.42 (br s, 2, OH, exchangeable

1,4-Benzodioxan-Related Compounds
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6367
residue was crystallized from EtOAc/petroleum ether: 0.92 g; 40%
yield; mp 165-167 °C. H NMR (CDCl3): δ 3.62 (dd J ) 10.26,
3.78-4.20 (m, 6, CH2OAr and cycle), 3.82 (s, 6, OCH3), 4.63 (two
dd, 2, cycle), 6.55-7.42 (m, 8, ArH), 7.83 (br t, 1, NH, exchange-
able with D2O).
1
11.97 Hz, 1, 6-CH2), 3.81 (dd, J ) 10.69, 11.54 Hz, 1, 3-CH2),
4.07 (dd, J ) 2.56, 11.97 Hz, 1, 6-CH2), 4.35 (dd, J ) 3.42, 11.54
Hz, 1, 3-CH2), 4.41 (dd, J ) 3.42, 10.69 Hz, 1, 2-CH), 4.62 (dd,
J ) 2.56, 10.26 Hz, 1, 5-CH), 5.91 (br s, 1, COOH, exchangeable
with D2O), 7.31-7.41 (m, 5, ArH).
N-(2-(2,6-Dimethoxyphenoxy)ethyl)-5,5-diphenyl-1,4-dioxane-2-
carboxamide (26). This was obtained following the procedure
described for 24a starting from 23 and 2-(2,6-dimethoxyphenoxy)-
ethanamine.25 The residue was purified by column chromatography,
eluting with cyclohexane/EtOAc (8:2) to afford a solid: 52% yield;
cis-5-Phenyl-1,4-dioxane-2-carboxylic Acid (22b). This was ob-
tained following the procedure described for 22a starting from 20b:
1
mp 168-170 °C. H NMR (CDCl3): δ 3.52-4.67 (m, 7, NCH2,
1
93% yield. H NMR (CDCl3): δ 3.84 (dd J ) 2.99, 11.97 Hz, 1,
CH2OAr, and cycle), 3.82 (s, 6, OCH3), 4.26 (dd, 1, cycle), 4.68
(d, 1, cycle), 6.54-7.46 (m, 13, ArH), 7.52 (br t, 1, NH,
exchangeable with D2O).
6-CH2), 4.07 (dd, J ) 10.26, 11.97 Hz, 1, 6-CH2), 4.11 (dd, J )
3.85, 11.97 Hz, 1, 3-CH2), 4.38 (dd, J ) 1.11, 2.99 Hz, 1, 2-CH),
4.51 (dd, J ) 1.11, 11.97 Hz, 1, 3-CH2), 4.67 (dd, J ) 2.99, 10.26
Hz, 1, 5-CH), 7.30-8.28 (m, 5, ArH), 9.61 (br s, 1, COOH,
exchangeable with D2O).
trans-N-(2-Phenoxyethyl)-6-phenyl-1,4-dioxane-2-carboxam-
ide (35a). This was obtained following the procedure described for
24a starting from 33a and 2-phenoxyethanamine. The residue was
purified by column chromatography, eluting with cyclohexane/
EtOAc (8.5:1.5) to afford a solid: 63% yield; mp 123-125 °C. 1H
NMR (CDCl3): δ 3.60-4.35 (m, 8, NCH2, CH2OAr, and cycle),
4.42 (dd, 1, cycle), 4.78 (dd, 1, cycle), 6.82-7.42 (m, 10, ArH),
7.13 (br t, 1, NH, exchangeable with D2O).
5,5-Diphenyl-1,4-dioxane-2-carboxylic Acid (23). This was ob-
tained following the procedure described for 22a starting from 21:
82% yield; mp 188-190 °C. 1H NMR (CDCl3): δ 3.72 (dd, 1,
3-CH2), 3.95 (d, 1, 6-CH2), 4.15 (dd, 1, 3-CH2), 4.41 (dd, 1, 2-CH),
4.66 (d, 1, 6-CH2), 6.87 (br s, 1, COOH, exchangeable with D2O),
7.20-7.54 (m, 10, ArH).
cis-N-(2-Phenoxyethyl)-6-phenyl-1,4-dioxane-2-carboxamide (35b).
This was obtained following the procedure described for 24a starting
from 33b and 2-phenoxyethanamine. The residue was purified by
column chromatography, eluting with cyclohexane/EtOAc (9:1) to
afford a solid: 61% yield; mp 95-97 °C. 1H NMR (CDCl3): δ
3.41 (m, 2, cycle), 3.70 (q, 2, NCH2), 3.88 (dd, 1, cycle), 4.05 (t,
2, CH2OAr), 4.32 (dd, 1, cycle), 4.40 (dd, 1, cycle), 4.75 (dd, 1,
cycle), 6.82-7.53 (m, 10, ArH), 7.13 (br t, 1, NH, exchangeable
with D2O).
trans-6-Phenyl-1,4-dioxane-2-carboxylic Acid (33a). This was
obtained following the procedure described for 22a starting from
31a: 54% yield; mp 110-112 °C. 1H NMR (CDCl3): δ 3.55 (dd J
) 9.78, 11.53 Hz, 1, 5-CH2), 3.92 (dd, J ) 11.73, 3.13 Hz, 1,
5-CH2), 3.95 (dd, J ) 3.91, 11.73 Hz, 1, 3-CH2), 4.36 (dd, J )
1.57, 11.73 Hz, 1, 3-CH2), 4.52 (dd, J ) 1.57, 3.91 Hz, 1, 2-CH),
5.16 (dd, J ) 3.13, 9.78 Hz, 1, 6-CH), 7.30-8.36 (m, 5, ArH),
8.43 (br s, 1, COOH, exchangeable with D2O).
cis-6-Phenyl-1,4-dioxane-2-carboxylic Acid (33b). This was
obtained following the procedure described for 22a starting from
31b: 54% yield; mp 117-120 °C. 1H NMR (CDCl3): δ 3.46 (dd J
) 10.44, 11.90 Hz, 1, 5-CH2), 3.61 (dd, J ) 10.71, 11.54 Hz, 1,
3-CH2), 3.89 (dd, J ) 2.84, 11.90 Hz, 1, 5-CH2), 4.23 (dd, J )
3.20, 11.54 Hz, 1, 3-CH2), 4.54 (dd, J ) 3.20, 10.71 Hz, 1, 2-CH),
4.78 (dd, J ) 2.84, 10.44 Hz, 1, 6-CH), 7.30-8.12 (m, 5, ArH),
8.61 (br s, 1, COOH, exchangeable with D2O).
6,6-Diphenyl-1,4-dioxane-2-carboxylic Acid (34). This was ob-
tained following the procedure described for 22a starting from 32:
52% yield; mp 197-199 °C. 1H NMR (CDCl3): δ 3.62 (d, 1,
5-CH2), 3.68 (dd, 1, 3-CH2), 4.21 (dd, 1, 3-CH2), 4.35 (dd, 1, 2-CH),
4.61 (d, 1, 5-CH2), 7.08 (br s, 1, COOH, exchangeable with D2O),
7.27-7.54 (m, 10, ArH).
trans-N-(2-(2-Methoxyphenoxy)ethyl)-5-phenyl-1,4-dioxane-2-
carboxamide (24a). Et3N (0.35 g, 3.46 mmol) and EtOCOCl (0.38
g, 3.46 mmol) were added to a solution of 22a (0.72 g, 3.46 mmol)
in dry CHCl3 (30 mL) at 0 °C. After 30 min a solution of 2-(2-
methoxyphenoxy)ethanamine18 (0.58 g, 3.46 mmol) in CHCl3 (10
mL) was added and the reaction mixture was left at room
temperature for 3 h. The solution was then washed with 2 N HCl
and 2 N NaOH, and the organic phase was dried over Na2SO4.
Removal of the solvent gave a solid, which was crystallized from
EtOAc/cyclohexane: 0.95 g; 77% yield; mp 100-102 °C. 1H NMR
(CDCl3): δ 3.52-3.78 (m, 4, NCH2 and cycle), 3.90 (s, 3, OCH3),
4.0 (dd, 1, cycle), 4.23 (dd, 1, cycle), 4.15 (t, 2, CH2OAr), 4.41
(dd, 1, cycle), 4.58 (dd, 1, cycle), 6.88-7.48 (m, 9, ArH), 7.27 (br
t, 1, NH, exchangeable with D2O).
trans-N-(2-(2-Methoxyphenoxy)ethyl)-6-phenyl-1,4-dioxane-2-
carboxamide (36a). This was obtained following the procedure
described for 24a starting from 33a and 2-(2-methoxyphenoxy)-
ethanamine.18 The residue was purified by column chromatography,
eluting with cyclohexane/EtOAc (7:3) to afford an oil: 57% yield.
1H NMR (CDCl3): δ 3.60-4.34 (m, 8, NCH2CH2OAr and cycle),
3.63 (s, 3, OCH3), 4.45 (dd, 1, cycle), 4.84 (dd, 1, cycle), 6.81-7.40
(m, 9, ArH), 7.42 (br t, 1, NH, exchangeable with D2O).
cis-N-(2-(2-Methoxyphenoxy)ethyl)-6-phenyl-1,4-dioxane-2-car-
boxamide (36b). This was obtained following the procedure
described for 24a starting from 33b and 2-(2-methoxyphenoxy)-
ethanamine.18 The residue was purified by column chromatography,
eluting with cyclohexane/EtOAc (7:3) to afford an oil: 60% yield.
1H NMR (CDCl3): δ 3.32-4.34 (m, 8, NCH2, CH2OAr, and cycle),
3.68 (s, 3, OCH3), 4.40 (dd, 1, cycle), 4.72 (dd, 1, cycle), 6.81-7.56
(m, 9, ArH), 7.83 (br t, 1, NH, exchangeable with D2O).
trans-N-(2-(2,6-Dimethoxyphenoxy)ethyl)-6-phenyl-1,4-dioxane-
2-carboxamide (37a). This was obtained following the procedure
described for 24a starting from 33a and 2-(2,6-dimethoxyphenoxy)-
ethanamine.25 The residue was purified by column chromatography,
eluting with cyclohexane/EtOAc (7.5:2.5) to afford an oil: 35%
yield. 1H NMR (CDCl3): δ 3.40-4.35 (m, 8, NCH2, CH2OAr, and
cycle), 3.62 (s, 6, OCH3), 4.51 (dd, 1, cycle), 4.95 (dd, 1, cycle),
6.42-7.47 (m, 8, ArH), 7.89 (br t, 1, NH, exchangeable with D2O).
cis-N-(2-(2,6-Dimethoxyphenoxy)ethyl)-6-phenyl-1,4-dioxane-2-
carboxamide (37b). This was obtained following the procedure
described for 24a starting from 33b and 2-(2,6-dimethoxyphenoxy)-
ethanamine.25 The residue was purified by column chromatography,
eluting with cyclohexane/EtOAc (7.5:2.5) to afford an oil: 66%
yield. 1H NMR (CDCl3): δ 3.38-4.40 (m, 8, NCH2, CH2OAr, and
cycle), 3.66 (s, 6, OCH3), 4.44 (dd, 1, cycle), 4.78 (dd, 1, cycle),
6.47-7.55 (m, 8, ArH), 7.68 (br t, 1, NH, exchangeable with D2O).
N-(2-(2,6-Dimethoxyphenoxy)ethyl)-6,6-diphenyl-1,4-dioxane-2-
carboxamide (38). This was obtained following the procedure
described for 24a starting from 34 and 2-(2,6-dimethoxyphenoxy)-
ethanamine.25 The residue was purified by column chromatography,
eluting with cyclohexane/EtOAc (7.5:2.5) to afford an oil: 70%
yield. 1H NMR (CDCl3): δ 3.51-4.26 (m, 8, NCH2, CH2OAr, and
cycle), 3.77 (s, 6, OCH3), 4.62 (d, 1, cycle), 6.57-7.57 (m, 13,
ArH), 7.82 (br t, 1, NH, exchangeable with D2O).
cis-N-(2-(2-Methoxyphenoxy)ethyl)-5-phenyl-1,4-dioxane-2-car-
boxamide (24b). This was obtained following the procedure
described for 24a starting from 22b. The residue was purified by
column chromatography, eluting with cyclohexane/EtOAc (7:3) to
1
afford an oil: 42% yield. H NMR (CDCl3): δ 3.68-4.20 (m, 8,
NCH2, CH2OAr and cycle), 3.71 (s, 3, OCH3), 4.50-4.66 (two
dd, 2, cycle), 6.80-7.41 (m, 9, ArH), 7.22 (br t, 1, NH, exchange-
able with D2O).
cis-N-(2-(2,6-Dimethoxyphenoxy)ethyl)-5-phenyl-1,4-dioxane-2-
carboxamide (25b). This was obtained following the procedure
described for 24a starting from 22b and 2-(2,6-dimethoxyphenoxy)-
ethanamine.25 The residue was purified by column chromatography,
eluting with cyclohexane/EtOAc (7:3) to afford a solid: 43% yield;
mp 111-112 °C. 1H NMR (CDCl3): δ 3.62 (q, 2, NCH2),

6368 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20
Quaglia et al.
trans-2-(2-Methoxyphenoxy)-N-((5-phenyl-1,4-dioxan-2-yl)meth-
yl)ethanamine (5a). A solution of 10 M BH3 ·CH3SCH3 (0.9 mL)
in dry THF (3 mL) was added dropwise at room temperature to a
stirred solution of 24a (0.95 g, 2.66 mmol) in dry THF (50 mL)
under a stream of dry nitrogen with exclusion of moisture. When
the addition was completed, the reaction mixture was heated at
reflux temperature for 8 h. After the mixture was cooled to 0 °C,
excess borane was destroyed by cautious dropwise addition of EtOH
(5 mL). The resulting mixture was left to stand overnight at room
temperature, cooled to 0 °C, acidified with concentrated HCl, and
then heated to 60 °C for 1 h. Removal of the solvent under reduced
pressure gave a residue, which was dissolved in H2O. The aqueous
solution was basified with 2 N NaOH and extracted with CHCl3.
Removal of dried solvents gave a residue, which was purified by
column chromatography, eluting with CHCl3/EtOH (9.5:0.5) to
) 344.1 (M + H+). The free base was transformed into the oxalate
salt and crystallized from EtOH: mp 178-179 °C. Anal.
(C20H25NO4 ·H2C2O4) C, H, N.
cis-2-(2-Methoxyphenoxy)-N-((6-phenyl-1,4-dioxan-2-yl)methyl)-
ethanamine (8b). This was obtained following the procedure
described for 5a starting from 36b: 70% yield. 1H NMR (CDCl3):
δ 1.93 (br s, 1, NH, exchangeable with D2O), 2.72-3.08 (m, 4,
CH2NCH2), 3.32-4.18 (m, 7, CH2OAr and cycle), 3.78 (s, 3,
OCH3), 4.68 (dd, 1, cycle), 6.83-7.36 (m, 9, ArH). MS (ESI): m/z
) 344.1 (M + H+). The free base was transformed into the oxalate
salt and crystallized from EtOH: mp 162-164 °C. Anal.
(C20H25NO4 ·H2C2O4) C, H, N.
trans-2-(2,6-Dimethoxyphenoxy)-N-((6-phenyl-1,4-dioxan-2-yl)-
methyl)ethanamine (9a). This was obtained following the procedure
described for 5a starting from 37a: 80% yield. 1H NMR (CDCl3):
δ 1.99 (br s, 1, NH, exchangeable with D2O), 2.81-3.27 (m, 4,
CH2NCH2), 3.70-4.24 (m, 7, CH2OAr and cycle), 3.75 (s, 6,
OCH3), 4.87 (dd, 1, cycle), 6.52-7.45 (m, 8, ArH). MS (ESI): m/z
) 374.1 (M + H+). The free base was transformed into the oxalate
salt and crystallized from EtOH: mp 150-152 °C. Anal.
(C21H27NO5 ·H2C2O4) C, H, N.
cis-2-(2,6-Dimethoxyphenoxy)-N-((6-phenyl-1,4-dioxan-2-yl)m-
ethyl)ethanamine (9b). This was obtained following the procedure
described for 5a starting from 37b: 73% yield. 1H NMR (CDCl3):
δ 2.05 (br s, 1, NH, exchangeable with D2O), 2.82-3.02 (m, 4,
CH2NCH2), 3.32-4.27 (m, 7, CH2OAr and cycle), 3.72 (s, 6,
OCH3), 4.72 (dd, 1, cycle), 6.50-7.41 (m, 8, ArH). MS (ESI): m/z
) 374.1 (M + H+). The free base was transformed into the oxalate
salt and crystallized from 2-PrOH: mp 183-184 °C. Anal.
(C21H27NO5 ·H2C2O4) C, H, N.
2-(2,6-Dimethoxyphenoxy)-N-((6,6-diphenyl-1,4-dioxan-2-yl)m-
ethyl)ethanamine (15). This was obtained following the procedure
described for 5a starting from 38: 66% yield. 1H NMR (CDCl3): δ
2.02 (br s, 1, NH, exchangeable with D2O), 2.62-2.97 (m, 4,
CH2NCH2), 3.50-4.20 (m, 6, CH2OAr and cycle), 3.80 (s, 6,
OCH3), 4.62 (d, 1, cycle), 6.54-7.58 (m, 13, ArH). MS (ESI): m/z
) 450.2 (M + H+). The free base was transformed into the oxalate
salt and crystallized from 2-PrOH: mp 151-153 °C. Anal.
(C27H31NO5 ·H2C2O4) C, H, N.
1
afford an oil: 0.84 g; 92% yield. H NMR (CDCl3): δ 2.25 (br s,
1, NH, exchangeable with D2O), 2.80-3.18 (m, 4, CH2NCH2),
3.48-4.25 (m, 7, CH2OAr and cycle), 3.88 (s, 3, OCH3), 4.58 (dd,
1, cycle), 6.83-7.42 (m, 9, ArH). MS (ESI): m/z ) 344.1 (M +
H+). The free base was transformed into the oxalate salt and
crystallized from MeOH: mp 206-207 °C. Anal. (C20H25NO4 ·
H2C2O4) C, H, N.
cis-2-(2-Methoxyphenoxy)-N-((5-phenyl-1,4-dioxan-2-yl)meth-
yl)ethanamine (5b). This was obtained following the procedure
described for 5a starting from 24b: 78% yield. 1H NMR (CDCl3):
δ 1.68 (br s, 1, NH, exchangeable with D2O), 2.78-3.35 (m, 4,
CH2NCH2), 3.72-4.24 (m, 7, CH2OAr and cycle), 3.83 (s, 3,
OCH3), 4.65 (dd, 1, cycle), 6.83-7.44 (m, 9, ArH). MS (ESI): m/z
) 344.1 (M + H+). The free base was transformed into the oxalate
salt and crystallized from MeOH: mp 223-225 °C. Anal.
(C20H25NO4 ·H2C2O4) C, H, N.
cis-2-(2,6-Dimethoxyphenoxy)-N-((5-phenyl-1,4-dioxan-2-yl)meth-
yl)ethanamine (6b). This was obtained following the procedure
described for 5a starting from 25b: 76% yield. 1H NMR (CDCl3):
δ 1.89 (br s, 1, NH, exchangeable with D2O), 2.75-3.32 (m, 4,
CH2NCH2), 3.74-4.28 (m, 7, CH2OAr and cycle), 3.85 (s, 6,
OCH3), 4.66 (dd, 1, cycle), 6.53-7.48 (m, 8, ArH). MS (ESI): m/z
) 374.1 (M + H+). The free base was transformed into the oxalate
salt and crystallized from EtOH: mp 198-199 °C. Anal.
(C21H27NO5 ·H2C2O4) C, H, N.
trans-2-(Iodomethyl)-5-phenyl-1,4-dioxane (39a) and cis-2-(Io-
domethyl)-5-phenyl-1,4-dioxane (39b). A solution of mercury(II)
acetate (6.33 g, 19.9 mmol) in H2O (25 mL) and acetic acid (0.025
mL) was added to a stirred solution of 1623 (4.42 g, 24.8 mmol).
The reaction mixture was heated to reflux for 45 min, then allowed
to stand overnight at room temperature. After the reaction mixture
was filtered, a solution of KI (4.0 g, 24.2 mmol) in H2O (26 mL)
was added to the filtrate and ((5-phenyl-1,4-dioxan-2-yl)methyl)m-
ercury(II) iodide separated as an oil, which was dissolved in CHCl3
(16 mL). A solution of I2 (4.73 g, 18.6 mmol) in CHCl3 was added,
and the reaction mixture was heated to boiling and then allowed to
stand at room temperature for 18 h. The organic phase was washed
with 10% Na2SO3 and 10% KI and dried over Na2SO4. The eva-
poration of the solvent in vacuo afforded a mixture of the two
diastereoisomers, which were separated by column chromatography,
eluting with cyclohexane/EtOAc (99:1). The trans isomer 39a eluted
first: 5.3 g; 56% yield. 1H NMR (CDCl3): δ 3.15 (d, 2, CH2I),
3.50-3.78 (m, 3, cycle), 3.99 (dd, 1, cycle), 4.17 (dd, 1, cycle),
4.58 (dd, 1, cycle), 7.28-7.42 (m, 5, ArH). The second fraction
was the cis isomer 39b as a solid: 2.2 g; 23% yield; mp 43-45 °C.
1H NMR (CDCl3): δ 3.50-4.18 (m, 7, CH2I, cycle), 4.65 (dd, 1,
cycle), 7.28-7.53 (m, 5, ArH).
2-(2,6-Dimethoxyphenoxy)-N-((5,5-diphenyl-1,4-dioxan-2-yl)meth-
yl)ethanamine (12). This was obtained following the procedure
described for 5a starting from 26: 56% yield; mp 83-85 °C. H
1
NMR (CDCl3): δ 1.99 (br s, 1, NH, exchangeable with D2O),
2.52-2.92 (m, 4, CH2NCH2), 3.32-4.18 (m, 7, CH2OAr and cycle),
3.81 (s, 6, OCH3), 3.73 (d, 1, cycle), 4.64 (d, 1, cycle), 6.52-7.52
(m, 13, ArH). MS (ESI): m/z ) 450.2 (M + H+). The free base
was transformed into the oxalate salt and crystallized from EtOH:
mp 190-191 °C. Anal. (C27H31NO5 ·H2C2O4) C, H, N.
trans-2-Phenoxy-N-((6-phenyl-1,4-dioxan-2-yl)methyl)etha-
namine (7a). This was obtained following the procedure described
for 5a starting from 35a: 96% yield. 1H NMR (CDCl3): δ 1.90 (br
s, 1, NH, exchangeable with D2O), 2.80-3.38 (m, 4, CH2NCH2),
3.66-4.20 (m, 7, CH2OAr and cycle), 4.87 (dd, 1, cycle), 6.82-7.49
(m, 10, ArH). MS (ESI): m/z ) 314.1 (M + H+). The free base
was transformed into the oxalate salt and crystallized from EtOH:
mp 209-210 °C. Anal. (C19H23NO3 ·H2C2O4) C, H, N.
cis-2-Phenoxy-N-((6-phenyl-1,4-dioxan-2-yl)methyl)etha-
namine (7b). This was obtained following the procedure described
for 5a starting from 35b: 81% yield. 1H NMR (CDCl3): δ 1.80 (br
s, 1, NH, exchangeable with D2O), 2.68-3.08 (m, 4, CH2NCH2),
3.32-4.11 (m, 7, CH2OAr and cycle), 4.68 (dd, 1, cycle), 6.81-7.42
(m, 10, ArH). MS (ESI): m/z ) 314.1 (M + H+). The free base
was transformed into the oxalate salt and crystallized from MeOH:
mp 212-213 °C. Anal. (C19H23NO3 ·H2C2O4) C, H, N.
trans-2-(2-Methoxyphenoxy)-N-((6-phenyl-1,4-dioxan-2-yl)meth-
yl)ethanamine (8a). This was obtained following the procedure
described for 5a starting from 36a: 82% yield. 1H NMR (CDCl3):
δ 2.55 (br s, 1, NH, exchangeable with D2O), 2.87-3.43 (m, 4,
CH2NCH2), 3.58-4.27 (m, 7, CH2OAr and cycle), 3.68 (s, 3,
OCH3), 4.87 (dd, 1, cycle), 6.81-7.48 (m, 9, ArH). MS (ESI): m/z
5-(Iodomethyl)-2,2-diphenyl-1,4-dioxane (40). This was obtained
following the procedure described for 39 starting from 17: 47%
1
yield; mp 170-172 °C. H NMR (CDCl3): δ 3.05 (d, 2, CH2I),
3.35 (dd, 1, cycle), 3.78-3.94 (m, 3, cycle), 4.63 (d, 1, cycle),
7.13-7.52 (m, 10, ArH).
6-(Iodomethyl)-2,2-diphenyl-1,4-dioxane (41). This was obtained
following the procedure described for 39 starting from 28: 28%
yield; mp 76-79 °C. 1H NMR (CDCl3): δ 3.19 (d, 2, CH2I),
3.44-3.63 (m, 3, cycle), 3.92 (dd, 1, cycle), 4.60 (d, 1, cycle),
7.12-7.57 (m, 10, ArH).

1,4-Benzodioxan-Related Compounds
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 20 6369
trans-2-Phenoxy-N-((5-phenyl-1,4-dioxan-2-yl)methyl)etha-
namine (4a). A solution of 39a (0.5 g, 1.6 mmol) and 2-phenoxy-
ethanamine (1.13 g, 9.0 mmol) in 2-ethoxyethanol (10 mL) was
heated to reflux for 5 h. Removal of the solvent under reduced
pressure gave a residue, which was dissolved in water. The aqueous
solution was basified with NaOH and extracted with CHCl3.
Removal of dried solvents gave a residue, which was purified by
column chromatography, eluting with EtOAc to afford a solid:
trans-(5-Phenyl-1,4-dioxan-2-yl)methanol (20a). A suspension of
Ag2O (2.12 g, 9.2 mmol) in H2O (7 mL) was added to a solution
of 39a (2.8 g, 9.2 mmol) in 1,4-dioxane (30 mL), and the mixture
was refluxed for 48 h. After filtration and evaporation of the solvent,
the residue was purified by column chromatography, eluting with
cyclohexane/EtOAc (6:4) to afford a solid: 75% yield; mp 79-81
1
°C. The H NMR results were similar to the results of the same
product obtained from 18.
1
0.21 g; 40% yield; mp 37-39 °C. H NMR (CDCl3): δ 2.0 (br s,
Acknowledgment. We thank the MIUR (Rome) and the
University of Camerino for financial support.
1, NH, exchangeable with D2O), 2.75-3.12 (m, 4, CH2NCH2),
3.47-4.09 (m, 5, cycle), 4.12 (t, 2, CH2OAr), 4.57 (dd, 1, cycle),
6.87-7.39 (m, 10, ArH). MS (ESI): m/z ) 314.1 (M + H+). The
free base was transformed into the hydrochloride salt and crystal-
lized from 2-PrOH: mp 216-217 °C. Anal. (C19H23NO3 · HCl ·
0.5H2O) C, H, N.
Supporting Information Available: Experimental details for
in vitro assays and molecular modeling; elemental analysis results
for compounds 4-15. This material is available free of charge via
the Internet at http://pubs.acs.org.
cis-2-Phenoxy-N-((5-phenyl-1,4-dioxan-2-yl)methyl)ethanamine (4b).
This was obtained following the procedure described for 4a starting
from 39b: 33% yield. 1H NMR (CDCl3): δ 1.98 (br s, 1, NH,
exchangeable with D2O), 2.80-3.20 (m, 4, CH2NCH2), 3.23-4.0
(m, 5, cycle), 4.13 (t, 2, CH2OAr), 4.67 (dd, 1, cycle), 6.86-7.52
(m, 10, ArH). MS (ESI): m/z ) 314.1 (M + H+). The free base
was transformed into the oxalate salt and crystallized from MeOH:
mp 226-228 °C. Anal. (C19H23NO3 ·H2C2O4) C, H, N.
References
(1) For part 8, see ref 12.
(2) Bylund, D. B.; Eikenberg, D. C.; Hieble, J. P.; Langer, S. Z.; Lefkowitz,
R. J.; Minneman, K. P.; Molinoff, P. B.; Ruffolo, R. R., Jr.;
Trendelenburg, U. IV. International Union of Pharmacology Nomen-
clature of Adrenoceptors. Pharmacol. ReV. 1994, 46, 121–136.
(3) Docherty, J. R. Subtypes of Functional R1- and R2-Adrenoceptors. Eur.
J. Pharmacol. 1998, 361, 1–15.
(4) Kauman, A. J.; Molenaar, P. Modulation of Human Cardiac Function
through 4 ꢀ-Adrenoceptor Populations. Naunyn-Schmiedeberg’s Arch.
Pharmacol. 1997, 355, 667–681.
trans-2-(2,6-Dimethoxyphenoxy)-N-((5-phenyl-1,4-dioxan-2-yl)-
methyl)ethanamine (6a). This was obtained following the procedure
described for 4a starting from 39a and 2-(2,6-dimethoxyphenoxy)-
1
ethanamine:25 19% yield. H NMR (CDCl3): δ 2.05 (br s, 1, NH,
exchangeable with D2O), 2.79-3.0 (m, 4, CH2NCH2), 3.47-4.30
(m, 7, CH2OAr and cycle), 3.88 (s, 6, OCH3), 4.60 (dd, 1, cycle),
6.55-7.43 (m, 8, ArH). MS (ESI): m/z ) 374.1 (M + H+). The
free base was transformed into the oxalate salt and crystallized from
2-PrOH: mp 167-169 °C. Anal. (C21H27NO5 ·H2C2O4 ·0.5H2O) C,
H, N.
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namine (10). This was obtained following the procedure described
1
for 4a starting from 40: 36% yield. H NMR (CDCl3): δ 1.98 (br
s, 1, NH, exchangeable with D2O), 2.62-3.08 (m, 4, CH2NCH2),
3.44 (dd, 1, cycle), 3.66-4.01 (m, 3, cycle), 4.08 (t, 2, CH2OAr),
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H2C2O4) C, H, N.
N-((5,5-Diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)-
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3.39 (dd, 1, cycle), 3.68-4.01 (m, 3, cycle), 3.86 (s, 3, OCH3),
4.11 (t, 2, CH2OAr), 4.62 (d, 1, CH2O), 6.84-7.56 (m, 14, ArH).
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°C. Anal. (C26H29NO4 ·H2C2O4) C, H, N.
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exchangeable with D2O), 2.66-3.12 (m, 4, CH2NCH2), 3.51-4.19
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