Exploring the neuroleptic substituent in octoclothepin: Potential ligands for positron emission tomography with subnanomolar affinity for α1-adrenoceptors

Article abstract of DOI:10.1021/jm100652h

A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the 8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide substituents are described. The compounds were designed using the previously reported Liljefors- B?ges? pharmacophore model for dopamine D₂ and α₁-adrenoceptor antagonists, with the aim of obtaining selective α₁-adrenoceptor antagonists suitable for development as radioligands for imaging of central α₁-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-10, 11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl) methyl)isobutyramide (S)-35, showed a similar subnanomolar affinity compared to α_1a, α_1b, and α_1d- adrenoceptors and a selectivity ratio of 20, 440, and 20 with respect to D ₂, 5-HT_2C, and H₁ receptors, respectively.

Full text of DOI:10.1021/jm100652h

J. Med. Chem. 2010, 53, 7021–7034 7021
DOI: 10.1021/jm100652h
Exploring the Neuroleptic Substituent in Octoclothepin: Potential Ligands for Positron Emission
Tomography with Subnanomolar Affinity for r1-Adrenoceptors
†
‡
Jesper L. Kristensen, Ask Puschl, Martin Jensen,†,‡ Rune Risgaard,†,‡ Claus T. Christoffersen,§
€
Benny Bang-Andersen,‡ and Thomas Balle*,†
†Department of Medicinal Chemistry, The Faculty of Pharmaceutical Sciences, University of Copenhagen,
Universitetsparken 2, 2100 Copenhagen, Denmark, ‡Medicinal Chemistry Research, and §Discovery Pharmacology Research,
H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
Received May 31, 2010
A series of 1-(10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methylpiperazine analogues substituted in the
8-position of the 10,11-dihydrodibenzo[b,f]thiepine scaffold with aryl, heteroaryl, amine, and amide
substituents are described. The compounds were designed using the previously reported Liljefors-
Bøgesø pharmacophore model for dopamine D2 and R1-adrenoceptor antagonists, with the aim of
obtaining selective R1-adrenoceptor antagonists suitable for development as radioligands for imaging of
central R1-adrenoceptors by positron emission tomography. Sixteen aryl and heteroaryl substituted
octoclothepin analogues were prepared by a convergent synthesis via coupling of 1-methyl-4-(8-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-10,11-dihydrodibenzo[b,f]thiepin-10-yl)piperazine with aryl and
heteroaryl halides under palladium catalysis. The most selective compound obtained, (S)-N-((11-(4-
methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-2-yl)methyl)isobutyramide (S)-35, showed a
similar subnanomolar affinity compared to R1a, R1b, and R1d-adrenoceptors and a selectivity ratio of
20, 440, and 20 with respect to D2, 5-HT2C, and H1 receptors, respectively.
Introduction
positron emission tomography (PET) ligands exist for these
receptors.5 At D2 receptors, for example, the typical antipsycho-
tics like haloperidol may provide optimal antipsychotic re-
sponse with little extrapyramidal side effects (EPS) at D2 receptor
occupancies of 60-80%, while EPS will appear at D2 receptor
occupancies above 80%. The various atypical antipsychotic
drugs differ with respect to their D2 receptor occupancy, but in
general all atypical antipsychotics display a higher occupancy of
the 5-HT2A than D2 receptors. Thus, the means for measuring
D2 and 5-HT2A receptor occupancies in preclinical models and
in man exist and can significantly aid the translation of pre-
clinical data to the clinic and backward.6 In contrast, the role of
the R1-adrenceptor component in these drugs is still relatively
unclear but could most likely be better understood if imaging
ligands were available. Several drug augmentation studies have
indicated the importance of R1-adrenoceptor blockade both in
relation to antipsychotic efficacy7 and in relation to the pro-
pensity to induce EPS.8 An important role of the R1-component
in distinguishing typical from atypical antipsychotics is also
indicated by the different effects of haloperidol and clozapine in
up-regulation of R1-adrenoceptors in the CNS in rats follow-
ing chronic treatment; both drugs result in up-regulation of
R1-adrenoceptors in the thalamus, whereas clozapine selectively
up-regulates R1-adrenoceptors in the frontal cortex.9 Recently
Cohen et al. have reviewed the role of R1-adrenoceptors in
relation to antipsychotic drugs and also shown that expression
of R1-adrenoceptors is a common feature for rat neurons
responding to antipsychotic drug treatment.10
The R1-adrenoceptors belong to the superfamily of G-pro-
tein-coupled receptors and are subdivided into three subtypes
R1A, R1B, and R1D. The receptors mediate the response of the
endogenous transmitters adrenaline and noradrenaline and
are widespread in both the peripheral nervous system and the
central nervous system (CNSa). In the peripheral nervous
system the effects of adrenaline and noradrenaline have been
associated with “fight and flight” and result in effects like
vasoconstriction, increase in heart rate, and increase in blood
sugar levels, all of which may be considered to prepare the
organism to survive a threat.1 The role of R1-adrenoceptors in
the central nervous system is much more complex; noradren-
ergic nerves innervate almost all areas of the brain, suggesting
that noradrenaline and adrenergic receptors may play an
important role in central processing2 and a detailed under-
standing of the role of R1-adrenoceptors in relation to CNS-
related diseases3 has only started to emerge.
Interestingly, a common feature of atypical antipsychotic
drugs such as clozapine and sertindole (1, Table 1) is in vitro
nanomolar affinity for R1-adrenoceptors in addition to high
affinity for dopamine D2 and serotonin 5-HT2A receptors.4 In
man, the receptor occupancy of these drugs at D2 and 5-HT2A
receptors at therapeutic doses is relatively well understood, as
*To whom correspondence should be addressed. Phone: þ45 3533
6409. Fax: þ45 3533 6041. E-mail: tb@farma.ku.dk.
aAbbreviations: PET, positron emission tomography; CNS, central
nervous system; EPS, extrapyramidal side effects; S-Phos, 2-dicyclohex-
ylphosphino-20,60-dimethoxybiphenyl; PCy3, tricyclohexylphosphane;
SFC, super critical fluid chromatography; dppf, 1,10-bis(diphenylphos-
phino)ferrocene; ELSD, evaporative light scattering detection.
Thorough in vivo investigation of the role of R1-adreno-
ceptors in relation to CNS-related disorders has been ham-
pered by the lack of selective and subtype selective tool
r
2010 American Chemical Society
Published on Web 09/21/2010
pubs.acs.org/jmc

7022 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Table 1. Receptor Binding Affinities for Reference Compoundsf
Kristensen et al.
a Reference 11. b Reference 27. c Reference 12. d Reference 15. e IC50, ref 17. f NT = not tested.
compounds efficiently penetrating the blood-brain barrier.
We have previously reported a series of R1-adrenoceptor
antagonists derived from the atypical antipsychotic sertin-
dole (1).11 Replacement of the “neuroleptic” chlorine atom in 1
with heteroaromatic substituents led to a series of compounds
(2 and 3, Table 1) with significantly reduced affinity for D2
and 5-HT2A/C receptors, while affinity for R1-adrenoceptors
was significantly less affected (compound 3) or even intact
(compound 2). Similarly, an aminomethyl substituent in the
indole 5-position (4) also gave rise to high selectivity.12 In
contrast, replacement of chlorine with more flexible substitu-
ents led to unselective compounds, as exemplified by the
acetylaminomethyl derivative 5, and the tetrazolylmethyl
derivative 6 (Table 1).12 On the basis of molecular modeling
studies, it was concluded that substituents coplanar with the
indole ring favored R1/D2 selectivity whereas substituents
introducing bulk above or below the plane of the indole ring
did not. Carbon-11 labeled analogues of 2 and 3 were investi-
gated as potential PET ligands in cynomolgus monkeys but
failed because of lack of brain uptake.13 Subsequent investi-
gation of the SAR around the piperidinyl substituent has
recently led to the identification of the pyrimidyl analogue 7 as
a new potential PET ligand (Table 1).14 [11C]7 efficiently pene-
trates into the brain of cynomolgus monkeys, and high uptake
of radioactivity is observed in regions known to have high
concentrations of R1-adrenoceptors.15 However, the binding
could not be displaced by prazosin, indicating that the ob-
served in vivo binding was either not R1-adrenoceptor specific
or the dose of prazosin was to low. As part of our continuous
effort to develop a PET tracer for imaging of R1-adrenoceptors
in the CNS in man, we turned our attention to the 10,11-
dihydrodibenzo[b,f]thiepine scaffold present in the antipsycho-
tic octoclothepin (8, Table 1). Like 1, 8 exerts in vitro nanomo-
lar affinity for dopamine D2, serotonin 5-HT2A, and adrenergic
R1 adrenoceptors. The uncluttered Liljefors-Bøgesø pharma-
cophore model for dopamine D2 receptor antagonists based on
superimposition (S)-8 and (1R,2S)-tefludazine16,17 provides a
solid framework for this investigation; numerous dopamine D2
receptor antagonists, including indoles, have over the years
been included in the model, and it has been shown to be valid
19
,
also for dopamine D4,18 serotonin 5-HT2A
and R1-adreno-
ceptor antagonists.11 A study of the enantiomers of 8has shown
that the highest binding affinity for dopamine D2,17 D4,18 and
R1-receptors11 resides in the (S)-enantiomer. However, the
eudismic ratio is consistently low (<5) and has been shown
to correlate with the conformational energy penalty paid by
(R)-8 to assume a conformation almost identical to the pro-
posed bioactive conformation of (S)-8. Superposition of (S)-8
and 1 in their proposed bioactive conformations,20 as shown in
Figure 1, suggests that the neuroleptic chloro substituent of

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7023
Scheme 1a
Figure 1. Superimposition of (S)-8 (gray) and 1 (cyan) in their pro-
posed bioactive conformations. The imidazolidinone ethyl side chain of
1 is replaced with a methyl group for clairity. Nonpolar hydrogens have
been removed for clarity: carbon, gray/cyan; nitrogen, blue; sulfur,
yellow; chlorine, green; fluorine, pale cyan; hydrogen, white.
a Reagents and conditions: (a) Cu, KOH, H2O, reflux 24 h. R = Cl: 95%.
R = Br: 100%. (b) Polyphosphoric acid, 140 °C, 2 h. R = Cl: 73%. R = Br:
73%. (c) 1-Methylpiperazine, TiCl4, toluene, reflux24h. R=Cl: 99%. R=
Br: 94%. (d) NaBH4, CH3CO2H, room temp, 24 h. R = Cl: 80%. R = Br:
92%. (e) From 8: bis(pinacolato)diboron, Pd2dba3/PCy3, 80 °C, 44 h, 66%.
From 10: bis(pinacolato)diboron, PdCl2(dppf), 100 °C, 18 h, 77%. (f) Zn-
(CN)2, Pd(PPh3)4, DMF, 165 °C, 120 s, microwave, then NaN3, 165 °C,
30 min, then K2CO3, MeI, 200 °C, 40 min. 12: 26%, 13: 11%.
1 and (S)-8 points in the same direction. Since selective
R1-adrenoceptor antagonists could be obtained by replacing
the chlorine of 1 with heteroaromatic substituents, it was
hypothesized that a similar change in activity could be obtained
within this series of compounds upon replacement of the
chlorine in 8 with more bulky groups. However, the aromatic
rings bearing the neuroleptic substituents are not completely
coplanar, as shown in Figure 1. This detail suggests that the
structure-activity relationships for the two series of compounds
may not turn out to be entirely parallel. With the aim of identi-
fying new tools for imaging of central R1-adrenoceptors in vivo,
we here report the results of a thorough investigation of the
effects of introducing bulky substituents in the 8-position of the
10,11-dihydrodibenzo[b,f]thiepine scaffold.
found that a combination of Pd2dba3 and S-Phos with K3PO4
in THF or dioxane promotes the coupling of 11 with hetero-
aryl bromides and iodides, giving the desired products
(14-20, 22) in 48-86% isolated yield. Aryl iodides were the
most efficiently coupled using Pd2dba3/PCy3 as catalyst,
giving 24-29 in 75-88% yield. Fourteen different substituted
octoclothepin derivatives were prepared from 11, in addition
to those prepared directly from 8, giving a total of 16 aryl and
heteroaryl substituted octoclothepin derivatives (14-29) (see
Table 2).
The tetrazole derivatives 12 and 13 were prepared in a one-
pot procedure from 10, as shown in Scheme 1, via Pd-
catalyzed cyanation with Zn(CN)2 followed by tetrazole
formation using NaN3 and finally methylation with MeI.24
The isomeric tetrazoles 12 and 13 were separated using silica
gel chromatography and isolated in 26% and 11% yield,
respectively.
Chemistry
In order to access the appropriately substituted octoclothepin
analogues, it was investigated if 8 could be used directly as a
substrate in various palladium (Pd) catalyzed cross-coupling
reactions. In particular, the use of 8 as the precursor for the
corresponding pinacol boronic ester 11 via coupling with bis-
(pinacolato)diboron was pursued, as 11 would be suitably
poised to be coupled with aryl and heteroaryl halides.21 Cou-
pling of aryl chloride 8 proved to be difficult, presumably
because of the electron-rich nature of the aromatic ring. There-
fore, the bromo analogue of octoclothepin 10, which in theory
should enter more readily into Pd-catalyzed reaction, was
prepared and tested in parallel (see Scheme 1). Racemic 8 was
prepared from p-chlorothiophenol and (2-iodophenyl)acetic
acid via 9a in four steps in 67% overall yield.22 The correspond-
ing bromo analogue 10 was accessed, using a similar approach
from p-bromothiophenol, in 63% yield over four steps.23
Coupling of 8 with bis(pinacolato)diboron to give the
pinacol boronic ester 11 required very electron rich alkylphos-
phines and extended reaction times (Pd2dba3/PCy3, 80 °C,
44 h, 66% isolated yield), whereas 10 reacted much more readily
with less sensitive catalysts, within shorter reaction times, and
in higher yield (PdCl2(dppf), 100 °C, 18 h, 77% isolated yield).
Aryl bromide 10 could also be coupled directly with arylboro-
nic acids using Pd(PPh3)4 as catalyst (see Table 1, compounds
21 and 23), but because of the ready availability of a wide
selection of aryl and heteroaryl halides, 11 was chosen as the
key intermediate for the synthesis of the desired compounds.
After a series of different conditions were screened, it was
Cyanation of 10 gave the cyano derivative 30 that subse-
quently was reduced to the aminomethyl derivative 31 using
LiAlH4, as shown in Scheme 2. The amides 34-36 were
obtained via reaction of 31 with the corresponding acid
chlorides. The enantiomers of 34 and 35 were separated using
chiral supercritical fluid chromatography (SFC), and crystals
suitable for X-ray analysis were obtained of both enantiomers
of 35, unveiling the absolute configuration. Unfortunately, we
were not able to get crystals of 34 of sufficient quality, and the
absolute configuration of the two enantiomeres of 34 is thus
tentatively assigned based on order of elution on the chiral
SFC column and the pharmalogical data discussed below.
The extended tetrazoles 32 and 33 were accessed as shown
in Scheme 2. Coupling of tert-butyl cyanoacetate with 10 gave
the indicated intermediate in 87% yield.25 Subsequent tetra-
zole formation using sodium azide with concomitant decar-
boxylation gave the crude tetrazole in quantative yield. Methyla-
tion of the tetrazole gave a mixture of 32 and 33 which could
be separated by silica gel chromatography, albeit in very low
yield presumably due to competing quarternization of the
piperazine ring. The relative positions of the methyl groups in
32 and 33 were distinguished by their different chemical shifts
in the 1H NMR spectra.26

7024 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Table 2. Synthesis of Aryl- and Heteroaryl Octoclothepin Derivatives
Kristensen et al.
Scheme 2a
a Reagents and conditions: (a) Zn(CN)2, Pd(PPh3)4, DMF, 140 °C, 20
min, 95%; (b) LiAlH4, THF, roomtemp, 100%; (c) RCOCl, NEt3, THF.
34: 88%. 35: 82%. 36: 98%. (d) tert-Butyl cyanoacetate, Pd((P-tert-
butyl)3)2, Na3PO4, toluene, 100 °C, 87%; (e) (i) NaN3, DMF, 165 °C, 1 h,
100%; (ii) K2CO3, MeI, DMF, 200 °C, 40 min. 32: 4%. 33: 1%.
compound 8. For most compounds the increase is 2- to 3-fold,
whereas compounds 17 and 12 show 7- and 10-fold increased
affinity, respectively. A similar trend (2- to 3-fold increase) is
observed for R1b receptors, whereas affinities at R1d and D2
receptors are unchanged or slightly decreased (2- to 8-fold)
compared to 8.
In contrast, the affinities of the compounds with the most
bulky substituents (24-29) show decreased affinity compared
to 8. This is most pronounced at R1d receptors, where the affinities
are reduced by a factor of 7-41 compared to 8. These results are
in good agreement with results from a previous 3D-QSAR
study, indicating more sterical hindrance in R1d-adrenoceptors
compared to R1a and R1b in the area corresponding to the neuro-
leptic substituent of 127 and thus presumably also 8.
The compounds substituted with heteroaromatic substitu-
ents (12-22) tend to have higher affinities compared to those
substituted with phenyl or methyl-substituted phenyl rings
(23-29). In the indole series,11 a hydrogen bond acceptor in
the heteroaromatic substituent was proposed to be responsible
for the high affinity of the compounds.27 Furthermore, indoles
substituted with five-membered heterocyclic substituents bear-
ing a methyl group in the 2-position relative to the point of
attachment to the indole ring (as in 13) were less R1/D2 selective
compared to those bearing the methyl substituent in the
3-position11 (asin12), a fact that supported the need of coplanar-
ity12 of the two rings to obtain selectivity. The same trends are
not observed in the octoclothepin series; comparing the com-
pound bearing a phenyl substituent (23) to the pyridines 19-21,
where the pyridine nitrogen is systematically shuffled in all
possible positions of the ring, does not indicate a direct hydrogen
bond to the receptor and nor does the position of the methyl
group in the five-membered heterocycles seem to influence
R1/D2 selectivity as apparent by comparing the affinities of
pyrazole 14 to those of pyrazoles 15 and 16. Similarly, introduc-
ing mono-, di-, and trimethyl substituted phenyl groups in the
octoclothepin 8-position to challenge the steric capabilities of
the receptors did not lead to R1/D2 selective ligands.
a Prepared directly from 10 via coupling with either phenylboronic
acid or 4-pyridylboronic acid. See Experimental Section for details.
Results and Discussion
The prepared compounds were characterized in receptor
binding assays at cloned bovine R1a, hamster R1b, and rat R1d
adrenoceptors by displacement of [3H]prazosin and at cloned
human dopamine D2 receptors using [3H]spiperone as radio-
ligand. The data are compiled in Table 3. The compounds
displaying the highest R1/D2 selectivity ratio were further
tested at serotonin 5-HT2C receptors and histamine H1 recep-
tors by displacement of [3H]mesulergine and [3H]pyrilamine
(Table 4). For compounds 32 and 33 binding at R1-adreno-
ceptors in rat cerebral cortex membranes was determined
using [3H]prazosin, and to ensure comparability with data
on the remaining compounds, analogue 12 was assayed under
the same conditions.
In general, compounds with aromatic or heteroaromatic
substituents directly attached to the 8-position of the 10,11-
dihydrodibenzo[b,f]thiepine scaffold (12-23) show increased
binding affinity at R1a receptors compared to the reference
Interestingly, the substituents that gave rise to the least
selective compounds in the indole series (e.g., 5 and 6) turned

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7025
Table 3. Receptor Binding Affinities for New Octoclothepin Analoguesd
a All compounds were tested as racemates. b [3H]Prazosin, rat cerebral cortex membranes. c [3H]Spiperone, HEK293 cells. d NT: not tested.
out to give rise to the most selective compounds in the octo-
clothepin series with the aminomethyl derivative 31 represent-
ing the link between the two series. Compound 31 has a
receptor binding profile very similar to that of the correspond-
ing compound in the indole series (4) with high affinity at R1-
adrenoceptors and significantly reduced affinity at dopamine
D2 receptors. Superimposing 31 and 4 as shown in Figure 2
suggests thatthe aminogroup mayendupin the sameposition
in space despite the lack of coplanarity of the aromatic rings
bearing the substituent and may thus account for the similar
receptor binding profile of the two compounds. Intrigued by
these results, more flexible analogues (32-34) that would

7026 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Kristensen et al.
Table 4. Receptor Binding Profile for Individual Enantiomers of 34 and 35
Ki (nM)
compd
R1a
R1b
R1d
D2
5-HΤ2C
H1
1
0.37a
0.66
0.70
0.28
0.088
0.42
0.34
0.12
0.43
0.16
0.33a
0.56
0.42
0.099
0.081
0.90
0.42
0.31
0.27
0.20
0.66a
0.77
0.23
0.076
0.14
1.5
0.45b
0.67
7.3
1.1
7.1
27
0.51b
0.19
NT
2.9
NT
3.9
12
(R/S)-8
(R)-8
(S)-8
15
(R/S)-34
(R)-34c
(S)-34c
(R/S)-35
(R)-35
(S)-35
NT
3.1
NT
3.6
2.5
NT
4.5
5.0
0.98
0.17
0.64
0.21
3.3
12
26
NT
8.0
31
4.5
93
a Reference 11. b Reference 4. c Absolute configuration tentatively assigned
(see Chemistry).
Figure 3. Superimposition of (A) R1/D2 selective compounds (S)-
35 (gray) and 2 (cyan) and of (B) R1/D2 unselective compounds (S)-
12 (gray) and 6 (cyan). Nonpolar hydrogens have been removed for
clarity: carbon, gray/cyan; nitrogen, blue; sulfur, yellow; chlorine,
green; fluorine, pale cyan; hydrogen, white.
Figure 2. Superimposition of and (S)-31 (gray) and 4 (cyan). Non-
polar hydrogens have been removed for clarity: carbon, gray/cyan;
nitrogen, blue; sulfur, yellow; chlorine, green; fluorine, pale cyan;
hydrogen, white.
that the steric bulk of the two substituents may also be
superimposed, thus explaining the “antiparallel” behavior of
the two series.
allow for a head to head comparison with compounds in the
indole series were prepared. The methyltetrazolylmethyl deriv-
atives 32 and 33 have subnanomolar affinity for R1-adreno-
ceptors, and 33 shows a 12-fold R1/D2 selectivity ratio. The
acetylaminomethyl derivative 34 displays significant (5- to
7-fold) increased affinity for R1-adrenoceptors and a 10-fold
reducedaffinityfor dopamine D2 receptors whencomparedto
(R/S)-8, which results in an R1/D2 selectivity ratio of 50. The
selectivity ratio for the corresponding compounds in the
indole series (5 and 6) is close to unity.
Increasing the steric bulk by replacement of the acetyl
moiety of 34 with an isobutyryl moiety (35) resulted in a
compound with a similar level of subnanomolar affinity for R1
adrenoceptors and an R1/D2 selectivity ratio of 38. Introduc-
tion of the more bulky pivalyl derivative36 resulted inreduced
affinity for R1a adrenoceptors by a factor of 10 compared to
35, indicating the limitations to the amount of bulk allowed in
the binding cavity.
Heteroaromatic substituents directly attached to the indole
nucleus resulted in R1/D2 selective compounds,11 whereas the
same substituents directly attached to the octoclothepin 8-po-
sition did not. A similar discrepancy is observed for the more
flexible analogues 5 and 6 which in the indole series are
nonselectivebut have increasedselectivityin the octoclothepin
series (33-35). This apparently “antiparallel” behavior may
be explained by the lack of coplanarity of the two aromatic
rings bearing the substituents as illustrated in Figure 2; super-
imposition of the selective compounds 2 and (S)-35 (Figure 3A)
shows that the steric bulk of the isobutyryl moiety of (S)-35
may be positioned in the same area as the bulk of the
heteroaromatic substituent of 2, whereas superimposition of
the nonselective compounds 6 and (S)-12 (Figure 3B) shows
As evident from the results described above, three com-
pounds (31, 34, and 35) show slightly increased affinity for R1
adrenoceptors and decreased affinity for D2 receptors compared
to 8. The most selective of these compounds, the aminomethyl
derivative 31, was disregarded because it has previously been
found to be without significant CNS activity.28 The compound
is likely diprotonated under physiological conditions, and dia-
mines in general are likely to bind to polyanions and phospho-
lipids29 which would result in high degrees of nonspecific bind-
ing. For compounds 34 and 35,havingR1/D2 selectivity ratios of
50-87 and 38-100, respectively, additional pharmacological
data to illustrate selectivity with regard to serotonin 5-HT2A and
histamine H1 receptors are shown in Table 4 for the individual
enantiomers of the compounds. The affinity for serotonin
5-HT2C receptors was significantly decreased compared to 8,
and both enantiomers of 34 and 35 bind with nanomolar affinity
to histamine H1 receptors and do not display any stereoselec-
tivity at this receptor. As expected, on the basis of the results
previously reported for the enantiomers of 8,17 the eutomer of 35
with regard to affinity for adrenergic R1 and dopamine D2
receptors is the (S)-enantiomer. The eudismic ratio at R1a, R1d,
and D2 receptors correlates well with the conformational energy
penalty paid by (R)-8 to adopt a conformation very similar to
that of (S)-8.17 These results strongly indicate that the com-
pounds bind in a mode similar to that of 8 and therefore that the
substituents investigated in the present study adds information
about the area in the receptor complementary to the area of the
neuroleptic substituents in antipsychotic drugs. The absolute
stereochemistry of (R)-and(S)-34 was not experimentally deter-
mined but tentatively assigned based on comparison of the
eudismic ratios of the two enantiomers to those of 8 and 35.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7027
Table 5. Permeability and Lipophilicity for 34 and 35 Compared to
Previously Investigated PET Ligands
each other which may place bulk from “out of plane” substit-
uents in the same area in space as occupied by heteroaromatic
substituents directly attached to the indole ring. The most
selective compound obtained in the present study, (S)-35, binds
with similar subnanomolar affinity to R1a-, R1b-, and R1d-
adrenoceptors and is selective with regard to D2, 5-HT2C, and
H1 receptors by factors of 21, 442, and 23, respectively. Com-
pound 35 has a log D7.4 value of 3.1 and permeability properties
in CACO-2 cells comparable to those of the well-established
PET-ligand raclopride. Despite the relatively low selectivity
ratios and high lipophilicity that may give rise to a low signal-to-
noise ratio in vivo, the ease of labeling and the high rates and
nonpolarized transport across a monolayer of CACO-2 cells
suggest that (S)-35 could be suitable for evaluation as a PET
ligand for in vivo imaging of R1-adrenoceptors in both the
peripheral nervous system and the CNS.
Caco-2
compd
Papp, 10-6 cm s-1
ratio
log D
raclopride
2
66c
12b
13c
33
0.50c
2.8b
0.7c
1.7
2.35a
3.06b
1.90c
2.65
7
34
35
57
a Referenc 36. b Referrence 13. c Reference 14.
0.60
3.10
Interestingly, the eutomer of 34 and 35 at 5-HT2C receptors was
the (R)-enantiomer, a detail that could indicate a different bind-
ing mode in the 5-HT2C receptor binding site compared to R1a,
D2, D4, and 5-HT2A receptors where the eutomer consistently is
the (S)-enantiomer as discussed above.
The most selective compounds investigated in the present
study are (S)-35 and the opposite enantiomer (R)-35. Both
compounds display similar subnanomolar affinity for R1-
adrenoceptors, and the selectivity ratios with regard to D2,
5-HT2C, and H1 receptors are 20, 440, 20 and 45, 10, 7 for the
(S)- and (R)-enantiomer, respectively.
Experimental Section
General. Dry THF was distilled under N2 from sodium/
benzophenone immediately before use. Thin layer chromatography
was performed on Merck 60 F254 0.25 μm silica gel plates. Solvent A
consisted of 75% EtOAc and 25% heptane. Solvent B consisted of
90% EtOAc and 10% MeOH, and solvent C consisted of 20%
MeOH and 80% EtOAC. The spots were visualized with UV 254 nm,
iodine, and the phenols with FeCl3. Microwave-assisted reac-
Apart from high affinity and selectivity, permeability and
lipophilicity also play an important role for a PET ligand. As
shown in Table 5, compound 35 displays high permeability
across a monolayer of CACO-2 cells and has a profile compar-
able to that of raclopride. A drawback of compound 35 in
relation to the use as PET ligand is the relatively high log D7.4
value of 3.10 (Table 4) which is considerably higher than for
raclopride but within the range of lipophilicities of other well
established CNS PET tracers.30 Previous studies have shown
that ratios of specific to nonspecific binding of radioligands in
brain depend on both binding potential (Bmax/KD) and lipophi-
licity,31 suggesting that high lipophilicity to some extent may be
tolerated if Bmax/KD is also high. Considering this, (S)-35 could
turn out to be superior to the PET ligand [11C]2. WithR1/D2 and
R1/H1 selectivity ratios around 20, specific binding to dopamine
D2 receptors and histamine H1 receptors is a concern. However,
for both receptor types, selective ligands are available that could
potentially be used to displace specific binding to these receptors
and therefore to increase the potential of (S)-35 as a CNS R1
selective PET ligand.
tions were performed with Emrys Optimizer from Personal Chem-
istry. Melting points were measured on a Buchi 535 apparatus. H
1
€
NMR and 13C NMR were recorded at 500.13 and 125.67 MHz on a
Bruker Advance DRX 500 instrument. Chemical shifts for 1H
NMR are reported in ppm with TMS as internal reference.
Chemical shifts for 13C NMR are reported in ppm relative to
chemical shifts of the deuterated solvents. Coupling constants
(J values) are in hertz. The following abbreviations are used for
multiplicity of NMR signals: s = singlet, d = doublet, t = triplet,
q = quartet, qui = quintet, dd = double doublet, m = multiplet,
br = broad. LC-MS data were obtained on a PE Sciex API150EX
instrument equipped with an ion spray source and Shimadzu LC-
8A/SLC-10A LC system: column, 30 mm ꢀ 4.6 mm Waters
Symmmetry C18 column with 3.5 μm particle size; solvent system,
A = water/TFA (100:0.05) and B = water/acetonitrile/TFA
(5:95:0.03) (TFA = trifluoroacetic acid); method, linear gradient
elution with 90% A to 100% B in 2.4 min and then 10% B in 0.4
min, with a flow rate of 3.3 mL/min. Total time including equilibra-
tion was 2.8 min. Injection volume was 10 μL from a Gilson 215
autosampler. The purity of compounds submitted for biological
testing were in all cases g95% as determined using evaporative light
scattering detection32 (ELSD) and g95% using UV detection (254
nm) unless specifically indicated below. Preparative LC-MS were
performed on a PE Sciex API150EX instrument equipped with an
ion spray source and Shimadzu LC-8A/SLC-10A LC system:
column, 50 mm ꢀ 10 mm Waters Symmetry C18 column with
5 μm particle size; solvent system, A = water/TFA (100:0.05) and
B = water/acetonitrile/TFA (5:95:0.03); method, linear gradient
elution with 90% A to 100% B in 7 min and then 10% B in 1 min,
with a flow rate of 5.7 mL/min. Injection volume was 0-300 μL
from a Gilson 233XL autosampler. HRMS spectra were obtained
on a Bruker Daltonic MicroTOF with internal calibration using
ESI in positive mode. Chiral compounds 34 and 35 were resolved
by chiral super critical fluid chromatography (SFC) on a Berger
SFC multigram II instrument equipped with a Chiralpak AD
21.2 mm ꢀ 250 mm column. The solvent system is specified
below. The method consisted of a constant gradient with a flow
rate of 50 mL/min. The fraction collection was performed by UV
230 nm detection.
Conclusions
On the basis of the Liljefors-Bøgesø pharmacophore
model for dopamine D2, D4, serotonin 5-HT2A, and adrenergic
R1-adrenoceptor antagonists and a series of selective R1-adreno-
ceptor antagonists derived from the antipsychotic sertindole
(1), a series of octoclothepin derivatives were designed and
prepared by palladium catalyzed cross-couplings directly from
8 or from the corresponding bromo- (10) or pinacolatoboronic
ester (11) derivatives. Interestingly, the heteroaromatic substit-
uents, observed to lower affinity for dopamine D2 receptors
when compared to R1-adrenoceptor in the sertindole series, did
not affect this ratio in the octoclothepin series. In contrast, the
“out of plane” substituents like the acetylaminomethyl substit-
uent which did not affect dopamine D2 receptor affinity in the
sertindole series gave rise to diminished D2 receptor affinity in
the octoclothepin series when compared to R1-adrenoceptor and
thus to compounds that are relatively selective for R1. This
apparently “antiparallel” behavior may be explained by the lack
of coplanarity of the aromatic rings of the indole and the 10,11-
dihydrodibenzo[b,f]thiepine scaffold when superimposed on
8-Chlorodibenzo[b,f]thiepin-10(11H)-one (9a). 4-Chlorothio-
phenol (20.45 g, 141.4 mmol) was added to a solution of KOH
(26.0 g, 472 mmol) in water (270 mL). The solution was heated to
50 °C, and copper powder (2.61 g, 41.8 mmol) was added,

7028 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Kristensen et al.
followed by 2-iodophenylacetic acid (35.3 g, 135 mmol). The
mixture was refluxed for 24 h under stirring, cooled, and
filtrated. The filtrate was acidified with 2 M HCl (20 mL), and
EtOAc (250 mL) was added. The phases were separated, and the
aqueous phase was extracted with EtOAc (5 ꢀ 250 mL). The
combined organic phases were washed with brine, dried
(MgSO4), and concentrated to give 35.6 g (95%) of 2-(2-((4-
chlorophenyl)thio)phenyl)acetic acid as a light yellow solid.
LC-MS: ELSD, 92.1%; UV, 93.2%; Mþ, 278.0. This material
(17.00 g, 60.98 mmol) was added in small portions to polypho-
sphoric acid (68 g) at 135-140 °C under rapid stirring. After 2 h
the mixture was cooled and ice-water (330 mL) was added and
the mixture was extracted with EtOAc (4 ꢀ 250 mL). The
combined organic phases were washed with brine, dried
(MgSO4), and concentrated to give 13.0 g of 9a as dark brown
solid. The crude product was filtered through silica gel (heptane/
EtOAc) and recrystallized from EtOH/water to yield 11.6 g
(73%) of 9a as light yellow crystals: mp 124-125 °C (lit.
125 °C23). LC-MS: ELSD, 98.6%; UV, 94.6%; MHþ, 261.0;
Rf = 0.53 (solvent A). 1H NMR (500 MHz, CDCl3) δ: 8.15 (d,
2.4), 7.65 (d, J = 7.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.45 (d,
J = 6.6 Hz, 1H), 7.40 (m, 2H), 7.20 (dt, J = 1.4 Hz, J = 8.0 Hz,
1H), 4.35 (s, 2H). 13C NMR (CDCl3) δ: 190.7, 139.0, 137.7,
137.6, 134.4, 133.7, 132.8, 132.7, 131.8, 131.5, 130.6, 130.0,
127.8, 51.2. Anal. Calcd for C14H9ClO2S: C, 64.49; H, 3.48.
Found: C, 64.30; H, 3.56.
8-Bromodibenzo[b,f]thiepin-10(11H)-one (9b). 4-Bromothio-
phenol (74.3 g, 0.393 mol) was added to a solution of KOH
(72.1 g, 1.31 mol) in water (750 mL). The solution was heated to
50 °C, and copper powder (7.25 g, 0.116 mol) was added,
followed by 2-iodophenylacetic acid (98.0 g, 0.374 mol). The
mixture was refluxed for 24 h under stirring, cooled, and
filtrated. The filtrate was acidified with 2 M HCl (200 mL),
and EtOAc (600 mL) was added. The phases were separated,
and the aqueous phase was extracted with EtOAc (2 ꢀ 500 mL).
The combined organic phases were washed with brine, dried
(MgSO4), and concentrated to give 120.5 g (100%) of 2-(2-((4-
bromophenyl)thio)phenyl)acetic acid as a light yellow solid.
LC-MS: ELSD, 98.3%; UV, 79.2%; MHþ, 324.0. This mate-
rial (120 g, 0.373 mol) was added in small portions to polypho-
sphoric acid (417 g) at 140-145 °C under rapid stirring. After
1.5 h the mixture was cooled and ice-water (1.5 L) was added
and the mixture was extracted with EtOAc (3 ꢀ 750 mL). The
combined organic phases were washed with 2 M NaOH (750
mL), brine, dried (MgSO4), and concentrated to give 105.6 g of
9b as a dark brown solid. The crude product was recrystallized
from EtOH/water to yield 83.2 g (73%) of 9b as light yellow
crystals: mp 112-113 °C (lit. 113 °C23). LC-MS: ELSD, 98.8%;
UV, 94.3%; MHþ, 305.9; Rf = 0.58 (solvent A). 1H NMR (500
MHz, CDCl3) δ: 8.13 (d, 2.4), 7.63 (dd, J = 7.5 Hz, J = 0.9 Hz,
1H), 7.52 (dd, J = 8.5 Hz, J = 2.4 Hz, 1H), 7.47 (d, J = 8.5 Hz,
1H), 7.44 (d, J = 7.5 Hz, 1H), 7.38 (dt, J = 0.94 Hz, J = 7.5 Hz,
1H), 7.21 (dt, J = 1.4 Hz, J = 7.5 Hz, 1H), 4.36 (s, 2H). 13C
NMR (CDCl3) δ: 190.7, 139.0, 137.7, 137.6, 134.4, 133.7, 132.8,
132.7, 131.8, 131.5, 130.6, 130.0, 127.8, 51.2. Anal. Calcd for
C14H9BrO2S: C, 55.09; H, 2.97. Found: C, 55.11; H, 2.79.
(R/S)-Octoclothepin (8). A stirred solution of 9a (3.47 g, 13.3
mmol) and 1-methylpiperazine (6.53 g, 65.2 mmol) in toluene
(133 mL) was slowly treated with TiCl4 (1.89 g, 10.0 mmol)
under an argon atmosphere. The mixture was heated to reflux
and stirred for 24 h. After the mixture was cooled, ice-water
(300 mL) was added and TiO2 was filtered off and washed with
THF (3 ꢀ 100 mL). The phases were separated, and the aqueous
phase was extracted with EtOAc (2 ꢀ 250 mL). The combined
organic phases were washed with saturated NaHCO3, brine,
dried (MgSO4), and concentrated to give 1-(8-chlorodibenzo-
[b,f]thiepin-10-yl)-4-methylpiperazine 4.50 g (99%) as a dark
red solid. LC-MS: ELSD, 99.6%; UV, 86.6%; MHþ, 343.2. To
a cold (0 °C) solution of this material (4.50 g, 13.31 mmol) in
CH3CO2H (97.2 mL), NaBH4 (7.35 g, 194 mmol) was added in
small portions. The resulting mixture was stirred at room
temperature for 23 h. EtOAc (250 mL) was added, and the
mixture was quenched with saturated NaHCO3 (100 mL) and 9
M NaOH (100 mL) to pH 6-7. The phases were separated and
the aqueous phase was extracted with EtOAc (3 ꢀ 250 mL). The
combined organic phases were washed with brine, dried
(MgSO4), and concentrated. The crude product was purified
by flash chromatography (20% MeOH in EtOAc) to yield 3.65 g
(80%) of 8 as a white solid: mp 99-100 °C (lit. 99-101 °C23).
LC-MS: ELSD, 99.2%; UV, 99.0%, Mþ, 345.1; Rf = 0.30
(solvent C). 1H NMR (500 MHz, CDCl3) δ: 7.65 (d, J = 2.4 Hz,
1H), 7.50 (d, J = 7.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H),
7.23-7.30 (m, 2H), 7.11 (dt, J = 1.4 Hz, J = 7.1 Hz, 1H), 7.05
(dd, J = 2.4 Hz, J = 8.5 Hz, 1H), 3.96 (dd, J = 3.3 Hz, J = 11.7
Hz, 1H), 3.88 (t, J = 12.3 Hz, 1H), 3.17 (dd, J = 3.3 Hz, J = 12.3
Hz, 1H), 2.50-2.90 (m, 8H), 2.44 (s, 3H). 13C NMR (CDCl3) δ:
142.5, 142.3, 136.6, 134.1, 133.5, 133.2, 132.5, 131.7, 130.0,
129.4, 127.4, 126.9, 65.9, 55.6, 47.9, 45.8, 32.9. Anal. Calcd for
C19H21ClN2S: C, 66.17; H, 6.14; N, 8.12. Found: C, 65.71; H,
6.18; N, 8.06.
1-(8-Bromo-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methyl-
piperazine (10). A stirred solution of 9b (68.9 g, 0.226 mol) and
1-methylpiperazine (100 g, 0.111 mol) in toluene (1.13 L) was
slowly treated with TiCl4 (32.12 g, 0.169 mol) under an argon
atmosphere. The mixture was heated to reflux and stirred for
24 h. After the mixture was cooled to 0 °C, ice-water (1.0 L) was
added and TiO2 was filtered off and washed with THF (300 mL).
The phases were separated, and the aqueous phase was extracted
with EtOAc (3 ꢀ 500 mL). The combined organic phases were
washed with saturated NaHCO3, brine, dried (MgSO4), and
concentrated to give 1-(8-bromodibenzo[b,f]thiepin-10-yl)-4-
methylpiperazine, 82.0 g (94%), as a dark red solid. LC-MS:
ELSD, 98.6%; UV, 89.5%; MHþ, 388.1. To a cold (0 °C)
solution of this material (82.0 g, 0.212 mmol) in CH3CO2H
(1.54 L), NaBH4 (117 g, 3.09 mol) was added in small portions
over 30 min. The resulting mixture was stirred at room tem-
perature for 24 h. EtOAc (500 mL) was added. The mixture was
quenched with saturated NaHCO3 (500 mL), and 9 M NaOH
(1.00 L) was added to obtain pH 6-7. The phases were
separated, and the aqueous phase was extracted with EtOAc
(3 ꢀ 500 mL). The combined organic phases were washed with
brine, dried (MgSO4), and concentrated. The crude product was
filtered through silica gel (300 g) (20% MeOH in EtOAc) and
recrystallized from EtOH/water to yield 76.2 g (92%) of 10 as
white crystals: mp 116-117 °C (lit. 118-119 °C23). LC-MS:
ELSD, 99.2%; UV, 95.7%; Mþ, 389.2; Rf = 0.16 (solvent B). 1H
NMR (500 MHz, CDCl3) δ: 7.82 (d, J = 1.9 Hz, 1H), 7.49 (dd,
J = 7.5 Hz, J = 0.9 Hz, 1H), 7.22-7.30 (m, 3H), 7.18 (dd, J =
8.0 Hz, J = 1.9 Hz, 1H), 7.10 (dt, J = 7.5 Hz, J = 1.9 Hz, 1H),
3.94 (dd, J = 11.8 Hz, J = 3.3 Hz, 1H), 3.87 (t, J = 12.7 Hz, 1H),
3.16 (dd, J = 12.7 Hz, J = 3.3 Hz, 1H), 2.36-2.80 (m, 8H), 2.33
(s, 3H). 13C NMR (CDCl3) δ: 142.8, 142.8, 136.5, 135.5, 134.7,
133.3, 131.7, 130.1, 129.9, 129.3, 126.8, 121.5, 65.8, 55.9, 48.5,
46.4, 33.0. Anal. Calcd for C19H21BrN2S: C, 58.61; H, 5.44; N,
7.26. Found: C, 58.77; H, 5.45; N, 7.09.
1-Methyl-4-(8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
10,11-dihydrodibenzo [b,f]thiepin-10-yl)piperazine (11). 10 (3.89 g,
10.0 mmol), PdCl2(dppf) CH2Cl2 [1:1] (0.366 g, 0.50 mmol,
3
5 mol %), bis(pinacolato)diboron (3.18 g, 12.5 mmol), and KOAc
(3.93 g, 40.0 mmol) were dissolved in anhydrous DMF (60 mL).
The flask was flushed with Ar, and the solution was heated at
1
100 °C for 14 h. Then
/ saturated NaHCO3 (150 mL) and
2
EtOAc (150 mL) were added and the phases were separated. The
aqueous phase was extracted with EtOAc (3 ꢀ 250 mL). The
combined organic phases were washed with brine, dried
(MgSO4), and concentrated. The crude product was purified
by flash chromatography (5% Et3N in EtOAc) to yield 3.36 g
(77%) as white crystals: mp 271-272 °C. LC-MS: ELSD,
99.3%; UV, 92.4%; Mþ, 437.2; Rf = 0.18 (solvent C). 1H
NMR (500 MHz, CDCl3) δ: 7.88 (s, 1H), 7.48 (d, J = 6.4 Hz,

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7029
1H), 7.41 (d, J = 7.5 Hz, 1H), 7.27 (d, J = 6.4 Hz, 1H), 7.20 (dt,
J = 7.5 Hz, J = 0.9 Hz, 1H), 7.05 (dt, J = 7.5 Hz, J = 0.9 Hz,
1H), 4.02 (dd, J = 11.3 Hz, J = 4.2 Hz, 1H), 3.86 (dd, J = 13.2
Hz, J = 11.3 Hz, 1H), 3.19 (dd, J = 13.6 Hz, J = 4.2 Hz, 1H),
2.29-2.75 (m, 8H), 2.26 (s, 3H), 1.31 (s, 12H). 13C NMR
(CDCl3) δ: 142.4, 139.6, 139.3, 139.1, 137.3, 133.1, 130.2,
128.8, 126.6, 84.2, 66.3, 56.1, 49.1, 46.5, 34.9, 25.3, 25.2. Anal.
Calcd for C25H33BN2O2S: C, 68.80; H, 7.62; N, 6.42. Found: C,
68.63; H, 7.60; N, 6.13.
1-Methyl-4-(8-(2-methyl-2H-tetrazol-5-yl)-10,11-dihydrodiben-
zo[b,f]thiepin-10-yl)piperazine (12) and 1-Methyl-4-(8-(1-methyl-
1H-tetrazol-5-yl)-10,11-dihydrodibenzo[b,f]thiepin-10-yl)pipera-
zine (13). A 25 mL vial was charged with 10 (389 mg, 1.00 mmol),
Zn(CN)2 (117 mg, 1.00 mmol), and Pd(PPh3)4 (116 mg, 0.100
mmol) dissolved in DMF (10 mL) and flushed with argon. The
vial was capped and heated for 120 s at 165 °C (100 W) in a
microwave reactor. The vial was allowed to reach room tem-
perature before it was charged with NaN3 (780 mg, 12.0 mmol)
and NH4Cl (642 mg, 12.0 mmol) and flushed with argon. The
vial was recapped and heated for 30 min at 165 °C (100 W) in a
microwave reactor. The reaction tube was allowed to reach
room temperature before it was charged with K2CO3 (1.65 g,
14.0 mmol) and MeI (705 mg, 5.00 mmol). The vial was
recapped and heated for 40 min at 200 °C (150 W, max 11 bar)
in a microwave reactor. The vial was allowed to reach room
temperature before saturated NaHCO3 (100 mL) and EtOAc
(100 mL) were added. The phases were separated, and the
aqueous phase was extracted with EtOAc (3 ꢀ 100 mL). The
combined organic phases were washed with brine, dried (MgSO4),
and concentrated. The crude product was purified directly by
column chromatography on silica gel (20% MeOH in EtOAc).
cap and evacuated and refilled with argon three times. THF
(3 mL) was added, and the resulting mixture was stirred for 15
min at room temperature, then for 20 h at 85 °C, concentrated,
and purified directly by column chromatography on silica gel
(20% MeOH in EtOAc).
Procedure C. 11 (200 mg, 0.458 mmol), heteroaryl halide
(0.687 mmol), Pd2dba3 (4.2 mg, 0.005 mmol), and PCy3 (3.1 mg,
0.011 mmol) were added to a 5 mL vial. The vial was sealed with
a pressure sure cap and evacuated and refilled with argon three
times. Dioxane (1.22 mL) and aqueous K3PO4 (1.27 M, 0.61 mL,
0.78 mmol) were added by syringe. The mixture was then stirred
at room temperature for 30 min and then at 100 °C for 14 h with
vigorous stirring. The mixture was concentrated and purified
directly by column chromatography on silica gel (up to 20%
MeOH in EtOAc).
1-Methyl-4-(8-(1-methyl-1H-pyrazol-5-yl)-10,11-dihydrodiben-
zo[b,f]thiepin-10-yl)piperazine (14). General procedure A and
5-iodo-1-methyl-1H-pyrazole were used. Yield: 59.5 mg (67%)
of 14 as a white solid. The product was dissolved in MeOH (1.0
mL), and 2 M HCl in Et2O (1.5 mL) was added slowly. The
generated HCl salt was filtered and dried in vacuum. Yield: 71.6
mg (67%) of 14 2HCl as white crystals, mp 246-247 °C.
3
LC-MS: ELSD, 99.0%; UV, 98.9%, MHþ, 391.3; Rf = 0.07
(solvent C). 1H NMR (500 MHz, DMSO) δ: 7.77-7.87 (b, 1H),
7.66-7.69 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.52 (d,
J = 7.5 Hz, 1H), 7.43-7.48 (m, 2H), 7.36 (dt, J = 7.5 Hz, J =
0.9 Hz, 1H), 7.22 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 6.53 (s, 1H),
3.95 (t, J = 11.8 Hz, 1H), 3.93 (s, 3H), 3.00-3.70 (m, 8H), 2.77
(s, 3H). HRMS C23H26N4S [M þ Hþ] calcd 391.1951, found
391.1937.
1-Methyl-4-(8-(1-methyl-1H-pyrazol-3-yl)-10,11-dihydrodiben-
zo[b,f]thiepin-10-yl)piperazine (15). General procedure A and
5-iodo-1-methylpyrazole were used. Yield: 85 mg (48%) of 15 as
a white solid. The product was dissolved in MeOH (2.0 mL), and
2 M HCl in Et2O (3.0 mL) was added slowly. The generated HCl
salt was filtered and dried in vacuum. Yield: 99.3 mg (47%) of
Yield: 240 mg (26%) of 12 2HCl as white crystals. 12: mp
3
259-260 °C. LC-MS: ELSD, 98.7%; UV, 93.7%; MHþ,
393.4; Rf = 0.13 (solvent C). 1H NMR (500 MHz, DMSO) δ:
8.26 (d, J = 1.4 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.70 (d, J =
8.0 Hz, 1H), 7.56 (dd, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.51 (dd, J =
7.5 Hz, J = 0.9 Hz, 1H), 7.35 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H),
7.21 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 4.43 (s, 3H), 3.89 (t, J =
11.8 Hz, 1H), 2.90-3.55 (m, 8H), 2.73 (s, 3H). HRMS C21H24-
N6S [M þ Hþ] calcd 393.1856, found 393.1859.
15 2HCl as white crystals: mp 259-260 °C. LC-MS: ELSD,
3
1
99.2%; UV, 97.7%, MHþ, 391.5; Rf = 0.05 (solvent C). H
NMR (500 MHz, DMSO) δ: 8.06-8.16 (b, 1H), 7.75 (d, J = 2.4
Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.55
(dd, J = 8.0 Hz, J = 0.9 Hz, 1H), 7.50 (d, J = 7.1 Hz, 1H), 7.33
(dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.21 (dt, J = 7.5 Hz, J = 0.9
Hz, 1H), 6.80 (s, 1H), 4.80-5.70 (b, 8H), 3.94 (t, J = 11.8 Hz,
1H), 3.92 (s, 3H), 2.77 (s, 3H). HRMS C23H26N4S [M þ Hþ]
calcd 391.1951, found 391.1967.
The fractions containing 13 were purified by HPLC. Yield: 53
mg (11%) of 13 TFA salt as pale yellow oil. 13: LC-MS,
3
ELSD, 98.0%; UV, 97.6%, MHþ, 393.4; Rf = 0.15 (solvent
C). 1H NMR (500 MHz, DMSO) δ: 9.82-9.96 (b, 1H), 8.04 (d,
J = 1.4 Hz, 1H), 7.65-7.70 (m, 2H), 7.57 (dd, J = 7.5 Hz, J =
0.9 Hz, 1H), 7.52 (dd, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.37 (dt, J =
7.5 Hz, J = 0.9 Hz, 1H), 7.22 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H),
4.30-4.74 (b, 2H), 4.27 (dd, J = 11.3 Hz, J = 4.2 Hz, 1H), 4.17
(s, 3H), 3.80 (dd, J = 13.2 Hz, J = 11.3 Hz, 1H), 3.44 (d, J =
11.8 Hz, 1H), 3.34 (d, J = 11.3 Hz, 1H), 3.24 (dd, J = 13.2
Hz, J = 4.2 Hz, 1H), 3.15 (d, J = 11.8 Hz, 1H), 3.02-3.12 (m,
1H), 2.62-2.87 (m, 7H). 13C NMR (DMSO) δ: 153.8, 141.7,
140.2, 138.4, 135.5, 133.2, 132.2, 131.3, 130.7, 129.6, 127.5, 127.2,
123.0, 64.5, 53.6, 46.9, 42.5, 35.6, 32.9. HRMS C21H24N6S
[M þ Hþ] calcd 393.1856, found 393.1860.
1-Methyl-4-(8-(1-methyl-1H-pyrazol-4-yl)-10,11-dihydrodiben-
zo[b,f]thiepin-10-yl)piperazine (16). General procedure B and
4-bromo-1-methylpyrazole were used. Yield: 69 mg (78%) of
16 as a white solid. The product was dissolved in MeOH
(1.0 mL), and 2 M HCl in Et2O (1.5 mL) was added slowly.
The generated HCl salt was filtered and dried in vacuum. Yield:
76 mg (72%) of 16 2HCl as white crystals: mp 218-219 °C.
3
LC-MS: ELSD, 98.7; UV, 97.1%; MHþ, 388.3; Rf = 0.05
(solvent C). 1H NMR (500 MHz, DMSO) δ: 8.18 (s, 1H),
7.87-7.98 (b, 2H), 7.47-7.56 (m, 3H), 7.43 (d, J = 7.5 Hz,
1H), 7.33 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.20 (dt, J = 7.5 Hz,
J = 0.9 Hz, 1H), 3.81-3.93 (b, 4H), 2.97-3.68 (m, 8H), 2.77
(s, 3H). HRMS C23H26N4S [M þ Hþ] calcd 391.1951, found
391.1947.
General Procedures A, B, and C for the Coupling of 11 with
Heteroaryl Bromides and Iodides. Procedure A. A 5 mL vial was
charged with 11 (100 mg, 0.229 mmol), Pd2(dba)3 (5.2 mg,
0.0057 mmol, 5 mol %), S-Phos (9.4 mg, 0.023 mmol), hetero-
aryl halide (0.344 mmol), and K3PO4 (195 mg, 0.917 mmol). The
vial was sealed with a pressure sure cap and evacuated and
refilled with argon three times. THF/H2O (10:1) (2 mL) was
added, and the resulting mixture was stirred for 15 min at room
temperature, then for 13 h at 85 °C, concentrated, and purified
directly by column chromatography on silica gel (20% MeOH in
EtOAc).
1-Methyl-4-(8-(1-methyl-1H-1,2,4-triazol-3-yl)-10,11-dihydro-
dibenzo[b,f]thiepin-10-yl)piperazine (17). General procedure C
and 3-bromo-1-methyl-1,2,4-triazole were used. Yield: 117.4 (66%)
of 17 as white crystals. The product was dissolved in MeOH (5.0
mL), and 2 M HCl in Et2O (4.0 mL) was added slowly. The
generated HCl salt was filtered and dried in vacuum. Yield: 135 mg
(64%) of 17 2HCl as white crystals: mp 240-241 °C. LC-MS:
3
Procedure B. A 5 mL vial was charged with 11 (100 mg, 0.229
mmol), Pd2(dba)3 (5.2 mg, 0.0057 mmol, 5 mol %), S-Phos (9.4
mg, 0.023 mmol), heteroaryl halide (0.344 mmol), and K3PO4
(145 mg, 0.687 mmol). The vial was sealed with a pressure sure
ELSD, 99.8%; UV, 99.6%; MHþ, 392.4; Rf = 0.02 (solvent C). 1H
NMR (500 MHz, DMSO) δ: 11.38-11.62 (b, 1H), 8.65 (s, 1H),
8.17 (d, J = 1.4 Hz, 1H), 7.87 (dd, J = 8.0 Hz, J = 1.9 Hz, 1H),
7.67 (d, J=8.0Hz,1H),7.55(dd,J=7.5Hz, J= 0.9 Hz, 1H), 7.58

7030 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Kristensen et al.
(d, J = 6.6 Hz, 1H), 7.34 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.21 (dt,
J = 7.5Hz, J = 0.9 Hz, 1H), 3.97 (t, J = 12.7 Hz, 1H), 3.92 (s, 3H),
3.12-3.76 (m, 8H), 2.75 (s, 3H). HRMS C22H25N5S [M þ Hþ]
calcd 392.1903, found 392.1910.
1-Methyl-4-(8-(5-methylthiophen-2-yl)-10,11-dihydrodibenzo-
[b,f]thiepin-10-yl)piperazine (18). General procedure C and
2-iodo-5-methylthiophene were used. Yield: 152 mg (82%)
of 18 as white crystals. The product was dissolved in MeOH
(5.0 mL), and 2 M HCl in Et2O (4.0 mL) was added slowly. The
generated HCl salt was filtered and dried in vacuum. Yield: 177
1-Methyl-4-(8-(pyridin-4-yl)-10,11-dihydrodibenzo[b,f]thiepin-
10-yl)piperazine (21). Arylboronic acid: 4-pyridinylboronic acid
(184 mg, 1.50 mmol). Yield: 282 mg (73%) of 21 as a pale yellow
solid. The product was dissolved in MeOH (5.0 mL), and 2 M
HCl in Et2O (7.0 mL) was added slowly. The generated HCl salt
was filtered and dried in vacuum. Yield: 276 mg (60%) of
21 2HCl as white crystals: mp 220-221 °C. LC-MS: ELSD,
3
1
99.18%; UV, 94.9%; MHþ, 388.3; Rf = 0.03 (solvent C). H
NMR (500 MHz, DMSO) δ: 8.99 (d, J = 6.6 Hz, 2H), 8.50 (d,
J = 5.7 Hz, 2H), 8.31-8.40 (b, 1H), 7.92 (d, J = 8.0 Hz, 1H),
7.77 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.55 (d, J =
7.5 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.23 (t, J = 7.5 Hz, 1H),
3.91 (t, J = 11.8 Hz, 1H), 2.88-3.68 (m, 8H), 2.77 (s, 3H).
HRMS C24H25N3S [M þ Hþ] calcd 388.1842, found 388.1848.
1-Methyl-4-(8-phenyl-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-
piperazine (23). Arylboronic acid: phenylboronic acid (183 mg,
1.50 mmol). Yield: 302 mg (78%) of 23 as a white solid. The
product was dissolved in MeOH (5.0 mL), and 2 M HCl in Et2O
(7 mL) was added slowly. The generated HCl salt was filtered
mg (80%) of 18 HCl as white crystals: mp 180-181 °C.
3
LC-MS: ELSD, 99.5%; UV, 99.3%; MHþ, 407.4; Rf = 0.02
1
(solvent C). H NMR (500 MHz, DMSO) δ: 10.93-11.28 (b,
1H), 7.86 (s, 1H), 7.50 (m, 3H), 7.41 (d, J = 7.0 Hz, 1H), 7.37 (m,
1H), 7.34 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 6.83 (d,
J = 2.4 Hz, 1H), 4.51-4.76 (br, 37H), 2.92-3.99 (m, 10H), 2.75
(s, 3H), 2.46 (s, 3H). HRMS C24H26N2S2 [M þ Hþ] calcd
407.1610, found 407.1601.
1-Methyl-4-(8-(pyridin-2-yl)-10,11-dihydrodibenzo[b,f]thiepin-
10-yl)piperazine (19). General procedure B and 2-iodopyridine
were used. Yield: 83 mg (47%) of 19 as a white solid. The product
was dissolved in MeOH (1.0 mL), and 2 M HCl in Et2O (1.5 mL)
was added slowly. The generated HCl salt was filtered and dried in
and dried in vacuum. Yield: 363 mg (79%) of 23 2HCl as white
3
crystals: mp 223-225 °C. LC-MS: ELSD, 98.8%; UV, 94.4%;
MHþ, 387.4; Rf = 0.28 (solvent C). 1H NMR (500 MHz,
CDCl3) δ: 7.80-7.90 (b, 1H), 7.62 (d, J = 7.0 Hz, 2H), 7.53
(d, J = 7.5 Hz, 1H), 7.47 (t, J = 6.6 Hz, 1H), 7.42 (d, J = 5.5 Hz,
1H), 7.36 (t, J = 7.0 Hz, 2H), 7.28 (t, J = 7.5 Hz, 1H), 7.25 (dt,
J = 7.5 Hz, J = 0.9 Hz, 1H), 7.11 (dt, J = 7.5 Hz, J = 0.9 Hz,
1H), 3.83 (t, J = 11.8 Hz, 1H), 2.76-3.65 (m, 8H), 2.66 (s, 3H).
HRMS C25H27N2S [M þ Hþ] calcd 287.1889, found 387.1887.
General Procedure for the Coupling of 11 with Aryl Iodides. 11
(300 mg, 0.687 mmol), aryl iodide (1.03 mmol), Pd2dba3 (6.3 mg,
0.007 mmol), and PCy3 (4.6 mg, 0.016 mmol) were added to a
5 mL thick walled vial. The vial was sealed with a pressure sure
cap and evacuated and refilled with argon three times. Dioxane
(1.8 mL) and aqueous K3PO4 (1.27 M, 0.92 mL, 1.17 mmol) were
added by syringe. The mixture was stirred at room temperature
for 30 min and then at 100 °C for 13 h with vigorous stirring. The
mixture was concentrated and purified directly by column
chromatography on silica gel (up to 20% MeOH in EtOAc).
1-Methyl-4-(8-o-tolyl-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-
piperazine (24). Aryl iodide: 1-iodo-2-methylbenzene. Yield:
206 mg (75%) of 24 as white crystals. The product was dissolved
in MeOH (5.0 mL), and 2 M HCl in Et2O (7.0 mL) was added
slowly. The generated HCl salt was filtered and dried in vacuum.
vacuum. Yield: 101 mg (48%) of 19 2HCl as white crystals: mp
3
246-247 °C. LC-MS: ELSD, 98.7; UV, 97.1%; MHþ, 391.4;Rf =
0.07 (solvent C). 1H NMR (500 MHz, DMSO) δ: 8.78 (d, J = 5.2
Hz, 1H), 8.37-8.41 (b, 1H), 8.25-8.31 (m, 2H), 7.99 (d, J=8.0Hz,
1H), 7.68-7.75 (m, 2H), 7.58 (dd, J=8.0Hz, J=0.9Hz, 1H), 7.54
(dd, J = 8.0 Hz, J = 0.9 Hz, 1H), 7.37 (dt, J = 7.5 Hz, J = 0.9 Hz,
1H), 7.23 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 3.91 (t, J = 11.8 Hz,
1H), 2.93-3.60 (m, 8H), 2.75 (s, 3H). HRMS C24H25N3S[Mþ Hþ]
calcd 388.1842, found 388.1845.
1-Methyl-4-(8-(pyridin-3-yl)-10,11-dihydrodibenzo[b,f]thiepin-
10-yl)piperazine (20). General procedure A and 3-iodopyridine
were used. Yield: 69 mg (78%) of 20 as a white solid. The
product was dissolved in MeOH (1.0 mL), and 2 M HCl in Et2O
(1.5 mL) was added slowly. The generated HCl salt was filtered
and dried in vacuum. Yield: 71.7 mg (68%) of 20 2HCl as white
3
crystals, mp 234-236 °C. LC-MS: ELSD, 99.5%; UV, 98.6%;
MHþ, 388.2; Rf = 0.05 (solvent C). 1H NMR (500 MHz,
DMSO) δ: 9.31 (s, 1H), 8.87 (d, J = 5.2 Hz, 2H), 8.10-8.20
(b, 1H), 8.07 (dd, J = 8.0 Hz, J = 5.6 Hz, 1H), 7.76 (d, J = 7.5
Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.54
(d, J = 7.5 Hz, 1H), 7.36 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.22
(dt, J=7.5 Hz, J = 0.9 Hz, 1H), 3.96 (t, J = 11.8 Hz, 1H), 2.86-
3.77 (m, 8H), 2.77 (s, 3H). HRMS C24H25N3S [M þ Hþ] calcd
388.1842, found 388.1839.
Yield: 220 mg (68%) of 24 2HCl as white crystals: mp 264-
3
266 °C. LC-MS: ELSD, 99.1%; UV, 98.6%; MHþ, 401.3; Rf =
0.55 (solvent C). 1H NMR (500 MHz, DMSO) δ: 7.52-7.60 (m,
3H), 7.47-7.51 (d, J = 6.6 Hz, 1H), 7.35 (dt, J = 7.5 Hz, J = 0.9
Hz, 1H), 7.16 (m, 6H), 4.36-4.97 (m, 5,7H), 3.87 (t, J = 12.3 Hz,
1H), 2.79-3.50 (m, 8H), 2.73 (s, 3H), 2.21 (s, 3H). HRMS
C26H28N2S [M þ Hþ] calcd 401.2046, found 401.2050.
5-(11-(4-Methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thie-
pin-2-yl)pyrimidine (22). General procedure B and 5-bromopyr-
imidine were used. Yield: 153 mg (86%) of 22 as a white solid.
The product was dissolved in MeOH (5.0 mL), and 2 M HCl in
Et2O (6.0 mL) was added slowly. The generated HCl salt was
1-Methyl-4-(8-m-tolyl-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-
piperazine (25). Aryl iodide: 1-iodo-3-methylbenzene. Yield: 208
mg (76%) of 25 as white crystals. The product was dissolved in
MeOH (5.0 mL), and 2 M HCl in Et2O (7.0 mL) was added
slowly. The generated HCl salt was filtered and dried in vacuum.
filtered and dried in vacuum. Yield: 205 mg (97%) of 22 2HCl
3
as white crystals, mp 246-247 °C. LC-MS: ELSD, 97.7; UV,
99.8%; MHþ, 389.3; Rf = 0.07 (solvent C). 1H NMR (500 MHz,
DMSO) δ: 9.23-9.27 (b, 2H), 9.20 (s, 1H), 8.11-8.23 (b, 1H),
7.75 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.58 (d, J =
7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.36 (dt, J = 7.5 Hz, J =
0.9 Hz, 1H), 7.22 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 3.97 (t, J =
11.8 Hz, 1H), 2.99-3.88 (m, 8H), 2.77 (s, 3H). HRMS
C23H24N4S [M þ Hþ] calcd 389.1794, found 389.1806.
Yield: 222 mg (68%) of 25 2HCl as white crystals: mp 231-
3
233 °C. LC-MS: ELSD, 99.6%; UV, 98.9%; MHþ, 401.3; Rf =
0.55 (solvent C). 1H NMR (500 MHz, DMSO) δ: 7.90-8.00 (b,
1H), 7.62 (d, J = 8.0 Hz, 1H), 7.48-7.58 (m, 5H), 7.30-7.38 (m,
2H), 7.18 (d, J = 8.0 Hz, 1H), 7.21 (dt, J = 7.5 Hz, J = 0.9 Hz,
1H), 4.62-5.66 (m, 2H), 3.94 (t, J = 11.8 Hz, 1H), 2.91-3.77
(m, 8H), 2.75 (s, 3H), 2.35 (s, 3H). HRMS C26H28N2S [M þ Hþ]
calcd 401.2046, found 401.2050.
Synthesis of 21 and 23 via Coupling of 8 with R-B(OH)2. A
5 mL vial was charged with 10 (389 mg, 1.00 mmol), Pd(PPh3)4
(58 mg, 0.50 mmol, 5 mol %), and arylboronic acid (1.50 mmol).
The vial was sealed with a pressure sure cap and evacuated
and refilled with argon three times. Then 2 M aqueous Na2CO3
(2.0 mL) and toluene (3.0 mL) were added and the resulting
mixture was stirred for 15 min at room temperature, then for
18 h at 100 °C, concentrated, and purified directly by column
chromatography on silica gel (20% MeOH in EtOAc).
1-Methyl-4-(8-p-tolyl-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-
piperazine (26). Aryl iodide: 1-iodo-4-methylbenzene. Yield: 210
mg (76%) of 26 as white crystals. The product was dissolved in
MeOH (5.0 mL), and 2 M HCl in Et2O (7.0 mL) was added slowly.
The generated HCl salt was filtered and dried in vacuum. Yield: 225
mg (69%) of 26 2HCl as white crystals: mp 252-253 °C. LC-MS:
3
ELSD, 99.6%; UV, 98.8%; MHþ, 401.3; Rf = 0.55 (solvent C).

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7031
1H NMR (500 MHz, DMSO) δ: 7.84-7.94 (b, 1H), 7.53-7.63
(m, 4H),7.47-7.53 (m, 2H), 7.34 (dt, J=7.53Hz, J= 0.9 Hz, 1H),
7.26 (d, J = 8.0 Hz, 2H), 7.20 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H),
4.01-4.40 (m, 6H), 3.90 (t, J = 12.2 Hz, 1H), 2.85-3.60 (m, 8H),
2.74 (s, 3H), 2.33 (s, 3H). HRMS C26H28N2S [M þ Hþ] calcd
401.2046, found 401.2064.
1-(8-(2,3-Dimethylphenyl)-10,11-dihydrodibenzo[b,f]thiepin-
10-yl)-4-methylpiperazine (27). Aryl iodide: 1-iodo-2,3-dime-
thylbenzene. Yield: 242 mg (85%) of 27 as white crystals. The
product was dissolved in MeOH (5.0 mL), and 2 M HCl in Et2O
(7.0 mL) was added slowly. The generated HCl salt was filtered
(11-(4-Methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepin-
2-yl)methanamine (31). 30 (1.50 g, 4.47 mmol) dissolved in dry
THF (26.8 mL) was cooled to 0 °C. Then 1 M LiAlH4 (17.9
mL,17.9 mmol, 4 equiv) in THF was slowly added over 3-4 min.
The mixture was allowed to reach room temperature and was
stirred for a further 1.5 h. The mixture was cooled on an ice bath
and quenched with wet Na2SO4 and Et2O (10 mL). The mixture
was filtered through Na2SO4 and washed with Et2O (200 mL).
The filtrate was evaporated to dryness yielding 1.63 g of 31
(quantitative) as light yellow oil. A sample of 200 mg was
dissolved in MeOH (5 mL), and 2 M HCl in Et2O (4.0 mL) was
added slowly. The generated HCl salt was filtered and dried in
and dried in vacuum. Yield: 288 mg (85%) of 27 2HCl as white
3
vacuum. Yield: 241 mg (98%) of 31 3HCl as white crystals, mp
crystals, mp 251-252 °C. LC-MS: ELSD, 99.5%; UV, 98.5%;
MHþ, 415.3.; Rf = 0.55 (solvent C). 1H NMR (500 MHz,
DMSO) δ: 7.48-7.60 (m, 4H), 7.35 (dt, J = 7.5 Hz, J = 0.9
Hz, 1H), 7.21 (dt, J = 7.5 Hz, J = 1.4 Hz, 1H), 7.13-7.19 (m,
2H), 7.11 (t, J = 7.5 Hz, 1H), 7.02-7.08 (m, 1H), 4.36-5.07 (m,
5H), 3.88 (t, J = 12.2 Hz, 1H), 2.83-3.56 (m, 8H), 2.73 (s, 3H),
2.28 (s, 3H), 2.08 (s, 3H). HRMS C27H30N2S [M þ Hþ] calcd
415.2203, found 415.2201.
3
207-208 °C. LC-MS: ELSD, 99.1%; UV, 94.4%; MHþ, 340.1;
Rf = 0.02 (solvent C). 1H NMR (500 MHz, DMSO) δ: 8.57-8.78
(b, 3H), 7.88 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 8.0
Hz, J = 0.9 Hz, 1H), 7.51 (d, J = 7.0 Hz, 1H), 7.42 (d, J = 8.0
Hz, 1H), 7.35 (dt, J = 7.5 Hz, J = 1.42 Hz, 1H), 7.20 (dt, J = 7.5
Hz, J = 0.9 Hz, 1H), 4.02-5.00 (m, 4H), 3.84-4.02 (m, 3H),
3.00-3.70 (m, 9H), 2.77 (s, 3H). HRMS C20H25N3S [M þ Hþ]
calcd 340.1842, found 340.1843.
1-(8-(2,5-Dimethylphenyl)-10,11-dihydrodibenzo[b,f]thiepin-
10-yl)-4-methylpiperazine (28). Aryl iodide: 1-iodo-2,6-di-
methylbenzene. Yield: 252 mg (88%) of 69 as white crystals.
The product was dissolved in MeOH (5.0 mL), and 2 M HCl in
Et2O (7.0 mL) was added slowly. The generated HCl salt was
N-((11-(4-Methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thie-
pin-2-yl)methyl)acetamide (34). 31 (300 mg, 0.884 mmol) and
triethylamine (0.20 mL, 1.43 mmol) were dissolved in dry THF
(6.8 mL) and cooled to 0 °C. Acetyl chloride (90 mg, 1.15 mmol)
dissolved in dry THF (2.0 mL) was added over 2 min to the
solution. After the mixture was stirred for 30 min at room tem-
filtered and dried in vacuum. Yield: 281 mg (84%) of 28 2HCl as
3
white crystals, mp 264-265 °C. LC-MS: ELSD, 99.5%; UV,
99.3%; MHþ, 415.4; Rf = 0.55 (solvent C). 1H NMR (500 MHz,
DMSO) δ: 7.57 (dd, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.49-7.56
(m, 2H), 7.43 (b, 1H), 7.36 (dt, J = 7.5 Hz, J = 1.4 Hz, 1H), 7.22
(dt, J = 7.5 Hz, J = 1.4 Hz, 1H), 7.06-7.17 (m, 3H), 6.96-7.03
(m, 1H), 4.87-5.42 (m, 4H), 3.86 (t, J = 12.2 Hz, 1H), 2.74-3.47
(m, 8H), 2.72 (s, 3H), 1.99 (s, 3H), 1.88 (s, 3H). HRMS
C27H30N2S [M þ Hþ] calcd 415.2203, found 415.2202.
1
perature, /2 saturated NaHCO3 (50 mL) and EtOAc (50 mL)
were added. The phases were separated, and the aqueous phase
was extracted with EtOAc (3 ꢀ 50 mL). The combined organic
phases were washed withbrine, dried(MgSO4), and concentrated.
The crude product was purified by flash chromatography (10%
MeOH in EtOAc) to yield 298 mg (88%) of 34 as a colorless oil.
The product was dissolved in MeOH (5.0 mL), and 2 M HCl in
Et2O (7.0 mL) was added slowly. The generated HCl salt was
1-(8-Mesityl-10,11-dihydrodibenzo[b,f]thiepin-10-yl)-4-methyl-
piperazine (29). Aryl iodide: 1-iodo-2,4,6-trimethylbenzene.
Yield: 259 mg (88%) of 70 as white crystals. The product was
dissolved in MeOH (5.0 mL), and 2 M HCl in Et2O (7.0 mL) was
added slowly. The generated HCl salt was filtered and dried in
filtered and dried in vacuum. Yield: 353 mg (88%) of 34 2HCl as
3
white crystals: mp 185-186 °C. LC-MS: ELSD, 99.0%; UV,
95.2%; MHþ, 382.3; Rf = 0.04 (solvent C). 1H NMR (500 MHz,
DMSO) δ: 11.54-11.79 (b, 1H), 8.37 (t, J = 5.8 Hz, 1H), 7.48-
7.63 (m, 4H), 7.34 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.20 (t, J =
7.5 Hz, 1H), 4.27-5.27 (m, 6H), 4.22 (dd, J = 15.5 Hz, J = 5.6
Hz, 1H), 4.18 (dd, J = 15.5 Hz, J = 5.6 Hz, 1H), 3.95 (t, J = 12.3
Hz, 1H), 3.25-3.85 (m, 9H), 2.79 (s, 3H), 1.87 (s, 3H). HRMS
C22H27N3OS [M þ Hþ] calcd 382.1948, found 382.1935.
vacuum. Yield: 301 mg (87%) of 29 2HCl as white crystals, mp
3
265-266 °C. LC-MS: ELSD, 99.2%; UV, 99.2%; MHþ, 429.3;
Rf = 0.55 (solvent C). 1H NMR (500 MHz, DMSO) δ: 7.48-7.60
(m, 3H), 7.45 (b, 1H), 7.37 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.22
(dt, J = 7.5 Hz, J = 1.4 Hz, 1H), 6.95-7.02 (m, 1H), 6.92 (s, 1H),
6.89 (s, 1H), 5.33-5.85 (m, 2H), 3.86 (t, J = 12.2 Hz, 1H),
2.78-3.55 (m, 8H), 2.72 (s, 3H), 2.20 (s, 3H), 1.97 (s, 3H), 1.83 (s,
3H). HRMS C28H32N2S [M þ Hþ] calcd 429.2359, found
429.2365.
The enantiomers of 34 (200 mg, 0.49 mmol) were separated
using SFC (solvent system, CO2/EtOH/Et2NH 80/20/0.1) to
afford approximately 100 mg of (R)-34 and approximately 100
mg of (S)-34. (R)-34 was dissolved in a minimum amount of
MeOH, and HCl in Et2O was added slowly. The precipitated salt
11-(4-Methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thiepine-
2-carbonitrile (30). 10 (7.00 g, 18.0 mmol), Zn(CN)2 (2.10 g, 18.0
mmol), and Pd(PPh3)4 (2.08 g, 1.80 mmol) dissolved in DMF
(180 mL) was flushed with Ar. The mixture was stirred in a
preheated oil bath at 140 °C for 20 min. After the mixture was
was filtered off and dried. Yield: 59 mg of (R)-34 2HCl as a
þ3
white solid. LC/MS: ELSD, 100%; UV, 100%; MH , 382.1.%;
>98.0% ee. Mp 169-171 °C. (S)-34 was dissolved in a mini-
mum amount of MeOH, and HCl in Et2O was added slowly. The
precipitated salt was filtered off and dried. Yield: 54 mg of
1
cooled, /2 saturated NaHCO3 (250 mL) and EtOAc (250 mL)
were added. The phases were separated, and the aqueous phase
was extracted with EtOAc (3 ꢀ 250 mL). The combined organic
phases were washed with brine, dried (MgSO4), and concentrated
to give 8.32 g of light red crystals. The crude product was purified
by flash chromatography (10% MeOH in EtOAc) to yield 5.72 g
(95%) of 30 as a white solid: mp 172-173 °C (lit. mp 171-173
°C28). LC-MS: ELSD, 99.5%; UV, 95.3%; MHþ, 336.4; Rf =
0.15 (solvent C). 1H NMR (500 MHz, DMSO) δ: 8.10 (d, J = 1.4
Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H),
7.26-7.33 (m, 3H), 7.11-7.16 (m, 1H), 3.90 (dd, J = 11.8 Hz,
J = 2.8 Hz, 1H), 3.85 (dd, J = 12.7 Hz, J = 11.8 Hz, 1H), 3.17
(dd, J = 12.7 Hz, J = 2.8 Hz, 1H), 2.34-2.83 (m, 8H), 2.31
(s, 3H). 13C NMR (CDCl3) δ: 143.0, 142.2, 141.8, 136.6, 135.2,
131.9, 131.6, 129.8, 129.7, 127.0, 119.3, 110.7, 76.9, 65.6, 55.9,
55.0, 46.4, 32.4. Anal. Calcd for C20H21N3S: C, 71.60; H, 6.31; N,
12.53. Found: C, 71.51; H, 6.26; N, 12.44.
(S)-34 2HCl as a white solid. LC/MS: ELSD, 100%; UV,
3
100%; MHþ, 382.1; >99.6% ee. Mp 169-171 °C. The absolute
stereochemistry of (R)-34 and (S)-34 is tentatively assigned
based on the order of elution on the SFC column and the
pharmacological data, both compared to those of (R)-35 and
(S)-35.
N-((11-(4-Methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thie-
pin-2-yl)methyl)isobutyramide (35). 31 (300 mg, 0.884 mmol) and
triethylamine (0.20 mL, 1.43 mmol) were dissolved in dry THF
(6.8 mL) and cooled to 0 °C. Isobutyryl chloride (122 mg, 1.15
mmol)dissolvedindryTHF(2.0 mL) was addedover 2min. After
1
/
2
the mixture was stirred for 30 min at room temperature,
saturated NaHCO3 (50 mL) and EtOAc (50 mL) were added.
The phases were separated, and the aqueous phase was extracted
with EtOAc (3 ꢀ 50 mL). The combined organic phases were
washed with brine, dried (MgSO4), and concentrated. The crude

7032 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19
Kristensen et al.
product was purified by flash chromatography (10% MeOH in
EtOAc) toyield297mg (82%) of 35 aswhite crystals. Theproduct
was dissolved in MeOH (5.0 mL), and 2 M HCl in Et2O (7.0 mL)
was added slowly. The generatedHClsaltwas filteredanddried in
t
R = 0.74; ELSD, 100.0%; UV, 38.3%; MHþ, 450.2). To a vial
containing this intermediate (500 mg, 1.1 mmol) dissolved in
DMF (11.2 mL), NaN3 (870 mg, 13.3 mmol) and NH4Cl (715
mg, 13.3 mmol) were added. The vial was flushed with argon and
the reaction mixture heated at 165 °C for 60 min in a microwave
reactor. Then 2 M HCl (40 mL) and EtOAc (10 mL) were added.
The phases were separated, and another 100 mL of EtOAc was
added. The water phase was made basic by slowly adding 12 M
NaOH. The phases were separated and the organic phase dried
over Na2SO4 and concentrated to yield 390 mg (100%) of
1-methyl-4-[8-(1H-tetrazol-5-ylmethyl)-10,11-dihydrodibenzo-
[b,f]thiepin-10-yl]piperazine. LC/MS: ELSD, 96.2%; UV,
62.1%; MHþ, 393.1. To a vial containing this intermediate
(390 mg, 1.0 mmol) dissolved in DMF, K2CO3 (690 mg, 5.0
mmol) and MeI (310 μL, 5.0 mmol) were added. The vial was
flushed with argon, and the mixture was heated at 200 °C for 40
min. The mixture was poured into water (30 mL), and EtOAc
(50 mL) was added. The phases were separated and the organic
phase washed with brine, dried over Na2SO4, and concentrated.
The crude product was purified using silica gel chromatography
(eluent, EtOAc in heptane 0-100%, MeOH in EtOAc 0-10%)
and HPLC to yield 15 mg (3.7%) of 32. LC/MS: ELSD, 100%;
UV, 100%; MHþ, 407.7. 1H NMR (500 MHz, DMSO) δ:
2.53-2.66 (m, 2H), 2.72 (d, J = 12.1, 1H), 3.78 (s, 3H), 2.84
(d, J = 8.69, 1H), 3.04 (q, J = 9.23 Hz, 1H), 3.16 (t, J = 15.5 Hz,
2H), 3.34 (d, J = 11.5 Hz, 1H), 3.42 (d, J = 11.5 Hz, 2H), 3.73 (t,
J = 12.1 Hz, 1H), 4.10-4.20 (m, 3H), 4.28 (s, 3H), 7.08 (d, J =
8.11 Hz, 1H), 7.16 (t, J = 7.45 Hz, 1H), 7.31 (t, J = 7.16 Hz, 1H),
7.38 (d, J = 7.64, 1H), 7.44 (d, J = 7.16, 3H), 7.46-7.52 (m,
2H). HRMS C22H27N6S1 [M þ Hþ] calcd 407.2012, found
407.2017. The column was eluted further to give 5 mg (1.2%)
of 33. LC/MS: ELSD, 100%; UV, 94%; MHþ, 407.6. 1H NMR
(500 MHz, DMSO) δ: 2.47-2.60 (m, 1H), 2.60-2.73 (m, 2H),
3.78 (s, 4H), 2.97 (q, J = 10.2 Hz, 1H), 3.12 (d, J = 12.1 Hz, 1H),
3.18 (d, J = 12.5 Hz, 1H), 3.25-3.58 (m, 2H), 3.72 (t, J = 12.1
Hz, 1H), 3.96 (s, 3.00), 4.14 (d, J = 9.33 Hz, 1H), 4.27 (s, 2H),
7.07 (d, J = 7.90 Hz, 1H), 7.17 (t, J = 7.18 Hz, 1H), 7.31 (t, J =
7.18 Hz, 1H), 7.40 (d, J = 7.90, 1H), 7.44 (s, 3H), 7.50 (d, J =
7.90, 1H). HRMS C22H27N6S1 [M þ Hþ] calcd 407.2012, found
407.2023.
vacuum. Yield: 369 mg (87%) of 35 2HCl as white crystals, mp
3
209-210 °C. LC-MS: ELSD, 99.5%; UV, 99.2%; MHþ, 410.3;
Rf = 0.06 (solvent C). 1H NMR (500 MHz, DMSO) δ:
11.71-12.12 (b, 1H), 8.26 (t, J = 8.3 Hz, 1H), 7.61 (s, 1H), 7.57
(d, J = 8.0 Hz, 1H), 7.55 (dd, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.51
(d, J = 7.1 Hz, 1H), 7.34 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 7.2 (m,
2H), 5.70-6.60 (b, 2H), 5.10-5.30 (b, 1H), 4.25 (dd, J = 15.5 Hz,
J=5.6 Hz, 1H), 4.18 (dd, J=15.5 Hz, J=5.6 Hz, 1H), 3.98 (t,
J = 12.3 Hz, 1H), 3.30-3.95 (m, 9H), 2.79 (s, 3H), 2.48 (heptet,
J=7.1 Hz, 1H), 1.02 (d, J=7.1 Hz, 3H), 1.00 (d, J=7.1 Hz, 3H).
HRMS C24H31N3OS [M þ Hþ] calcd 410.2261, found 410.2257.
The enantiomers of 35 (200 mg, 0.49 mmol) were separated by
SFC (solvent system, CO2/EtOH/Et2NH 70/30/0.5) to afford 86
mg of (R)-35 and 79 mg of (S)-35. (R)-35 (86 mg, 0.21 mmol) was
dissolved in a minimum amount of MeOH, and HCl in Et2O was
added. The precipitated salt was filtered off and dried. Yield: 88
mg (87%) of (R)-35 2HCl as a white solid. LC/MS (method
3
350): tR = 0.88; ELSD, 100%; UV, 95.0%; MHþ, 410.5;
>97.6% ee. Mp 216-217 °C. (S)-35 (79 mg, 0.19 mmol) was
dissolved in a minimum amount of MeOH, and HCl in Et2O was
added. The precipitated salt was filtered off and dried. Yield: 87
mg (93%) of (S)-35 2HCl as a white solid. LC/MS (method
3
350): tR = 0.89; ELSD, 100%; UV, 96.0%; MHþ, 410.5;
>96.0% ee. Mp 213-215 °C. The absolute configuration was
determined by X-ray crystallography after recrystallization
from MeOH.
N-((11-(4-Methylpiperazin-1-yl)-10,11-dihydrodibenzo[b,f]thie-
pin-2-yl)methyl)pivalamide (36). 31 (300 mg, 0.884 mmol) and
triethylamine (0.20 mL, 1.43 mmol) were dissolved in dry THF
(6.8 mL) and cooled to 0 °C. Pivaloyl chloride (139 mg, 1.15
mmol) dissolved in dry THF(2.0 mL) was added over 2 min tothe
solution. After the mixture was stirred for 30 min at room
temperature,
1
/ saturated NaHCO3 (50 mL) and EtOAc (50
2
mL) were added. The phases were separated, and the aqueous
phase was extracted with EtOAc (3 ꢀ 50 mL). The combined
organic phases were washed with brine, dried (MgSO4), and
concentrated. The crude product was purified by flash chroma-
tography (10% MeOH in EtOAc) to yield 332 mg (98%) of 36 as
colorless oil. The product was dissolved in MeOH (5.0 mL), and 2
M HCl in Et2O (7.0 mL) was added slowly. The generated HCl
salt was filtered and dried in vacuum. Yield: 393 mg (90%) of
In Vitro Binding Assays. CHO cell lines expressing the rat R1d
and human D2 and BHK cells expressing bovine R1a adreno-
ceptors were generated in-house at H. Lundbeck using standard
stable transfection techniques. The rat-1 cell line expressing the
hamster R1B adrenoceptor was obtained from the University of
Utah, Salt Lake City, UT. The CHO cell lines expressing the
human 5-HT2C (VSV) and human H1 receptors was purchased
from Euroscreen (Brussels, Belgium) and grown according to
the company’s instructions.
The cells were grown to 90% confluence, detached, and
homogenized in ice-cold 50 mM Tris, pH 7.4, using an Ultra-
Turrax, and the homogenates were either kept on ice or stored at
-80 °C until used.
36 2HCl as white crystals: mp 210-211 °C. LC-MS: ELSD,
3
99.6%; UV, 98.8%; MHþ, 424.3; Rf = 0.10 (solvent C). 1H NMR
(500 MHz, DMSO) δ: 11.70-11.96 (b, 1H), 8.01 (t, J = 5.7 Hz,
1H), 7.52-7.59 (m, 3H), 7.50 (d, J = 6.6 Hz, 1H), 7.34 (dt, J =
7.5 Hz, J = 0.9 Hz, 1H), 7.20 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H),
7.14 (d, J = 8.0 Hz, 1H), 4.67-6.13 (m, 5H), 4.26 (dd, J = 15.5
Hz, J = 5.6 Hz, 1H), 4.20 (dd, J = 15.5 Hz, J = 5.6 Hz, 1H), 3.97
(t, J = 12.3 Hz, 1H), 3.11-3.91 (m, 10H), 2.78 (s, 3H), 2.51 (s,
9H). HRMS C25H33N3OS [M þ Hþ] calcd 424.2417, found
424.2409.
In all R1 assays 50 mM Tris, pH 7.7, was used as assay buffer
and [3H]prazosin was used as radioligand at 0.3 nM (R1a and
R1d) or 0.5 nM (R1b), and nonspecific binding was defined as the
1-Methyl-4-[8-(2-methyl-2H-tetrazol-5-ylmethyl)-10,11-dihy-
dro-dibenzo[b,f]thiepin-10-yl]piperazine (32) and 1-Methyl-
4-[8-(1-methyl-1H-tetrazol-5-ylmethyl)-10,11-dihydrodibenzo-
[b,f]thiepin-10-yl]piperazine (33). Bis(tri-tert-butylphosphine)-
palladium(0) (0.4 g, 0.8 mmol), Na3PO4 (8.0 g, 50 mmol), and
tert-butyl cyanoacetate (6.6 mL, 45 mmol) were added to a
solution of 10 (6.0 g, 15 mmol) in toluene (150 mL). The mixture
was stirred at 100 °C for 4 h, cooled to room temperature, and
filtered. Water (100 mL) was added, and the phases were
separated. The organic phase was washed with brine, dried over
Na2SO4, and concentrated. The crude product was purified by
silica gel chromatography (eluent: EtOAc in heptane 0-100%,
MeOH in EtOAc 0-10%) to yield 6.0 g (87%) of crude
cyano-[11-(4-methyl-piperazin-1-yl)-10,11-dihydrodibenzo[b,f]-
thiepin-2-yl]acetic acid tert-butyl ester. LC/MS (method 350):
binding in the presence of WB-4101 (1 μM). Then 50 mM Tris,
pH 7.7, was used as assay buffer in the h5-HT2C assay, 0.5 nM
[3H]mesulergine was used as radioligand, and nonspecific bind-
ing was defined as the binding in the presence 1 μM mianserine.
For the D2 assay 50 mM Tris, pH 7.4, was used as assay buffer
and [3H]spiperone (0.1 nM) was used as radioligand. Nonspe-
cific binding was defined as the binding in the presence haloper-
idol (10 μM).
The human H1 assay was performed as a SPA-based competi-
tion-binding assay in a 50 mM Tris, pH 7.4, assay buffer
containing 120 mM NaCl, 5 mM KCl, 4 mM MgCl2, 1.5 mM
CaCl2, and 1 mM EDTA. 1.0 nM [3H]pyrilamine was used as
radioligand and nonspecific binding defined as the binding in
the presence of 10 μM clozapine.

Article
Journal of Medicinal Chemistry, 2010, Vol. 53, No. 19 7033
In all the R1 assays, samples were incubated at 25 °C for
Acknowledgment. T.B. was supported by grants from the
Carlsberg Foundation and The Lundbeck Foundation.
20 min. The D2 and 5-HT2C assay were incubated for 30 min at
37 °C, and the H1 assay was incubated for 60 min at room
temperature.
Supporting Information Available: Ellipsoid plots of the
refined structures of (R)-35 and (S)-35. This material is available
free of charge via the Internet at http://pubs.acs.org.
In the R1, D2, and 5-HT2C assays bound and free radioactivity
was separated by vacuum filtration on GF/B filters, scintillation
fluid (Optiphase Supermix, PerkinElmer) was added, and the
samples were counted in a scintillation counter (Wallac Trilux).
External testing of indicated compounds was done at Cerep
according to the assays catalog reference 802-1a (unselective R1)
and catalog reference 803-2h (human D2s).
Data shown in the tables are the mean from a minimum of
two full concentration-response curves using 10 concentrations
of drugs (covering 3 decades). The results are given as Ki values
(nM) derived from computer fitted IC50 values converted to Ki
values using the Cheng-Prusoff equation33 ((Ki = IC50/(1 þ
(L/KD))). Standard errors for pKi values were within 0.3 for all
reported compounds.
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(Figure 1). In all subsequent calculations these conformations
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Crystal Data. (S)-35. C24H35Cl2N3O2S, M = 500.52 g mol-1
,
P212121, a= 6.2789(6) A;b= 14.0206(19) A, c= 29.065(5)°, R=
90°,β=90°,γ=90°, volume of 2558.7(6) A3, temp of 295 K, Z=4,
Dx = 1.299 g cm-3, F(000) = 1064.0, μ = 0.361 mm-1, R =
0.0517(2921), wR2 = 0.1040(4781). The data are deposited at
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6.2752(6) A, b = 14.0077(17) A, c = 29.032(3) A, R = 90°, β =
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