Synthesis and evaluation of dibenzothiazepines: A novel class of selective cannabinoid-1 receptor inverse agonists

Article abstract of DOI:10.1021/jm801534c

A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships (SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were evaluated in a mammalian cell-based func

Full text of DOI:10.1021/jm801534c

J. Med. Chem. 2009, 52, 1975–1982
1975
Synthesis and Evaluation of Dibenzothiazepines: A Novel Class of Selective Cannabinoid-1
Receptor Inverse Agonists
Hanna Pettersson,† Anne Bu¨low,† Fredrik Ek,† Jacob Jensen,† Lars K. Ottesen,† Alma Fejzic,† Jian-Nong Ma,#
Andria L. Del Tredici,# Erika A. Currier,# Luis R. Gardell,# Ali Tabatabaei,# Darren Craig,# Krista McFarland,# Thomas R. Ott,#
Fabrice Piu,# Ethan S. Burstein,# and Roger Olsson*,†
ACADIA Pharmaceuticals AB, Medeon Science Park, S-205 12 Malmo¨, Sweden, and ACADIA Pharmaceuticals Inc.,
3911 Sorrento Valley BouleVard, San Diego, California 92121
ReceiVed December 4, 2008
A novel class of CB1 inverse agonists was discovered. To efficiently establish structure-activity relationships
(SARs), new synthetic methodologies amenable for parallel synthesis were developed. The compounds were
evaluated in a mammalian cell-based functional assay and in radioligand binding assays expressing
recombinant human cannabinoid receptors (CB1 and CB2). In general, all of the compounds exhibited high
binding selectivity at CB1 vs CB2 and the general SAR revealed a lead compound 11-(4-
chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12e) which showed excellent in vivo
activity in pharmacodynamic models related to CB1 receptor activity. The low solubility that hampered the
development of 12e was solved leading to a potential preclinical candidate 11-(3-chloro-4-fluorophenyl)-
dibenzo[b,f][1,4]thiazepine-8-carboxylic acid butylamide (12h).
Chart 1. Examples of CB1 Antagonists and Initial ACADIA
Hit
Introduction
The cannabinoid receptor 1 (CB1a) is widely expressed in
the central nervous system (CNS) and also at significant levels
in peripheral tissues and represents a potentially useful thera-
peutic target for many indications including type II diabetes,
obesity, drug addiction, and smoking cessation.1 Consequently,
the development of CB1 antagonists and inverse agonists as
therapeutic agents has been the subject of intense research. The
majority of compounds that have been described belong to the
diarylpyrazole structural class of compounds or derivatives
thereof such as inverse agonists rimonabant (1)2,3 and 2
(SLV319)4 (Chart 1). Rimonabant (1) was approved in the
European Union (EU) for the treatment of obesity.5 However,
the FDA Advisory Committee did not recommend approval of
1 because of the severe psychiatric side effects in some patients;
consequently, the new drug application (NDA) was withdrawn
in the U.S.6 Recently the EU has followed the FDA and removed
1 from the market. Development of another CB1 inverse agonist
taranabant (3) was discontinued in 2008 because of similar side
effects at high doses.7 Whether the psychiatric side effects arise
from the mechanism of action itself or if these are compound
specific remains uncertain. It is therefore important to identify
and develop novel, structurally unique, and selective CB1
antagonists/inverse agonists that may provide a distinct thera-
peutic profile.
novel CB1 inverse agonist 4 showing affinity for the CB1
receptor in the submicromolar range was identified. Although
the tricyclic core is shared with a well-known class of antip-
sychotic compounds, e.g., quetiapine, clozapine, and olanzapine
showing biological activity at CNS targets such as D2 and 5HT2A
receptors,9 it turned out that the scaffold functionalized with
an amide side chain and not having a basic amine functionality
constituted a unique class of molecules that showed high
selectivity toward CB1. Several hundred molecules of this class
were synthesized in parallel to establish the SAR. A representa-
tive set of compounds stating the most obvious trends in the
SAR as well as activities in rodent in vivo models relating to
CB1 activity are discussed herein.
A high-throughput screen (HTS) of a 270 000 compound
library using the proprietary mammalian cell-based functional
assay receptor selection and amplification technology (R-SAT)
was employed to screen for novel CB1 inverse agonists.8 A
* To whom correspondence should be addressed. Telephone: +46 40
6013 466. Fax: +46 40 6013 405. E-mail: roger@acadia-pharm.com.
†
ACADIA Pharmaceuticals AB.
ACADIA Pharmaceuticals Inc.
#
a Abbrevations: CB1, cannabinoid receptor 1; CNS, central nervous
system; DFT, density functional theory; DIO, diet-induced obese; EU,
European Union; HTS, high-throughput screen; ip, intraperitoneal; mCPBA,
m-chloroperbenzoic acid; NDA, new drug application; NSA mice, non-
Swiss albino mice; PEG, polyethylene glycol; po, per oral; qd, quaque die
(everyday); R-SAT, receptor selection and amplification technology; SD,
standard deviation; SAR, structure-activity relationship.
Chemistry
A synthetic route that enabled the synthesis of a large number
of compounds in a combinatorial mode was developed. Lactam
9 was synthesized in multigram scale from commercially
available starting materials in a high overall yield (84%) over
10.1021/jm801534c CCC: $40.75
2009 American Chemical Society
Published on Web 03/11/2009

1976 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Scheme 1. Synthesis of Key Intermediate 8a
Pettersson et al.
Scheme 3. Synthesis of Ketone 13a
a Reagents: (a) SOCl2, 80 °C, 1 h, quant; (b) PrMgCl, Fe(acac)3, THF/
NMP, room temp, 20 min, 78%.
a Reagents: (a) Cs2CO3, DMF, 40 °C, 45 min (92%); (b) LiOH (aq, 1
M), THF, 60 °C, 2 h (99%); (c) PtO2, Pd/C, H2, MeOH, room temp, 16 h
(96%); (d) CDI, THF, room temp, 16 h (91%).
ture), yielding amidines 12b and 12c in 99% and 67% yields,
respectively.
Scheme 2. Synthesis of Target Molecules 4 and 12a
To investigate the amide bond in the 8-position, ketone 13
was synthesized in a high overall yield (78%) over two steps
(Scheme 3). The amide 12e was treated with thionyl chloride
at 80 °C for 1 h, the imidoyl chloride formed was concentrated
to dryness and reacted with n-propylmagnesium chloride in an
iron-catalyzed cross-coupling reaction, and the subsequent acidic
workup gave ketone 13. This new amide to ketone transforma-
tion is mild, fast, and high yielding.
The conformational influence by the heteroatom in the central
azepine ring of the tricyclic framework was explored by the
synthesis of compounds containing CH2 (14a), O (14b), NH
(14c), SO (14d), and SO2 (14e) as replacement of S (e.g., 12a
and 12d) (Table 2). The CH2 and O analogues 14a and 14b,
respectively, were synthesized in the same way as the corre-
sponding S analogue (12a), via the lactam, and subsequently
similarly sequentially derivatized, as described in the Supporting
Information. The NH analogue 14c was synthesized as described
in Scheme 4, starting from the 8-chlorolactam 15. A coupling
reaction with molybdenum hexacarbonyl was used in the final
step to introduce the amide bond (14c).12 The sulfoxide 14d
and the sulfone 14e were obtained by an oxidation of the
corresponding S analogue (12d) with hydrogen peroxide and
mCPBA, respectively.
a Reagents: (a) SOCl2, DMF, toluene, 80 °C, 17 h, 84%; (b) R1-NH2,
1
DCM, 0 °C to room temp, /2 h, 72-88% yield; (c) R2-MgX, Fe(acac)3,
THF, NMP, -78 °C to room temp, 2 h; (d) R2-NH, toluene, 90 °C,
overnight, 67% and 99% yields; (e) R2-ZnX, PdCl2(PPh3)2, THF, 2 h.
three steps (Scheme 1). Dichloride 10, set up to be easily
functionalized at both the 8- and the 11-position, was formed
in a high yield from lactam 9 via a double chlorination (Scheme
2). A sequential diversification of 10 was possible because of
the difference in reactivity between the acid chloride and the
imidoyl chloride functionalities. The amides 11a-f containing
a reactive imidoyl chloride functionality were isolated by silica
gel column chromatography in high yields (72-88%) and stored
for days under vacuum, from a reaction between the corre-
sponding amines and the acid chloride (10) at 0 °C to room
temperature.
As previously reported, imines (e.g., 12, R2 ) alkyl or aryl)
can be obtained by an iron-catalyzed cross-coupling of Grignard
reagents with imidoyl chlorides.10 However, the iron-catalyzed
reaction conditions with aromatic Grignard reagents gave poor
yields because of an extensive side reaction, a homocoupling
forming biaryls. Therefore, in order to synthesize imines with
R2 equaling aryl or R2 equaling heteroaryl (12d-k) efficiently,
a palladium-catalyzed Negishi cross-coupling reaction using
aromatic zinc reagents was developed.11 This new method turned
out to be convenient for parallel synthesis and gave the final
products in good to excellent yields in a fast and mild reaction,
30 min, at room temperature. A nucleophilic substitution
reaction gave access to a third series of compounds. Piperidines
were added to the imidoyl chloride moiety at an elevated
temperature (no reaction took place at 0 °C to room tempera-
Results and Discussion
All compounds were evaluated in vitro using the proprietary
mammalian cell-based functional assay R-SAT.8 Binding studies
were performed on most of the compounds using HEK293 cells
transiently transfected with human CB1 and CB2 receptors. The
in vitro activities are summarized in Tables 1 and 2. In general,
the compounds were selective, displaying high activity at CB1
and little or no activity at the CB2 receptor. Introducing more
lipophilic groups at both R1 and R2 increased the biological
activity; for example, compounds more lipophilic than 4
exhibited an increased activity (Table 1), which is not surprising
because of the lipophilic character of CB1 ligands in general.13
As soon as the polarity of the compound was increased
especially with heteroatoms in the periphery of the structure,
the activity decreased (e.g., 4).
With the hit 4 in hand, a general structural comparison with
rimonabant and taranabant was made. In the place of one of
the aryls in rimonabant and taranabant which resides in a
hydrophobic pocket engaged in aromatic stacking interactions,
hit 4 had an n-propyl (see Figure 1, overlays of 12e with
rimonabant and taranabant; 4 has a n-propyl in the 11-postion
instead of the 4-chlorophenyl (12e)). Since n-propyl cannot
participate in aromatic stacking interactions (e.g., π-π stacking),
its contribution to binding, if any, would be of a lipophilic

Dibenzothiazepines as SelectiVe CB1 InVerse Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1977
Table 1. In Vitro Results for Inverse Agonist, Binding, and Microsomal Assaysa
a nd, not determined; na, not active at 10 µM. pIC50 and pKi values are the mean values of at least three experiments ( SD. pIC50 (R-SAT inverse agonist
assays) was calculated as the negative logarithm of the concentration of test article that repressed the basal activity 50%. pKi (binding assays) was determined
3
from the pIC50 values (concentration of test article that caused 50% displacement of radioligand H-SR141716A) using the Cheng-Prusoff correction (see
ref 8c).
nature. Introducing the hydrazide side chain (R1) also found in
rimonabant and a cyclohexyl in place of the n-propyl gave a
compound 12a equipotent with rimonabant (1) and (()-SLV319
(2). Keeping R1 fixed (3-chlorobenzyl) provided an opportunity
to compare amidines 12b and 12c and the 4-fluorophenyl 12d.
Compounds 12b and 12d were equipotent in the inverse agonist
assay; thus, an aromatic substituent in the 11-position did not
increase the functional activity compared with an aliphatic one.
Geminal 4,4-difluoro substituents in the piperidinyl (12c),
introduced to increase the metabolic stability, gave a slight
decrease in the activity compared with having an unsubstituted
piperidinyl (12b). Compounds having R2 equaling an aryl or
heteroaryl (12d-k) generally showed high activity at the CB1
receptor. Changes in CB1 potency depending on the position
of the substituent on the phenyl were observed, exemplified
by 12e-g. While the 3- and 4-chlorophenyls 12f and 12e,
respectively, exhibited similar activities, they were at least
10 times more active than the 2-chloro derivative (12g). The
latter may be the result of a conformational restriction
enforced by having the larger chlorine in the 2-position.
Changing R2 from phenyl to a substituted thienyl (12j) or a
pyridinyl (12k) also gave high affinity compounds (pKi of
8.9 and 8.8, respectively); thus, heteroaryls were well
tolerated by the CB1 receptor.

1978 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Table 2. Effect of Bridging Atom on the R-Angle
Pettersson et al.
Figure 1. (a) Overlay of 12e (yellow) with rimonabant (cyan). (b)
Overlay of 12e (yellow) and taranabant (green).
binding to the receptor but to different sites; rimonabant
hydrogen-binds via the carbonyl oxygen to a lysine and
taranabant via the amide NH to serine.14a Molecular mechanical
calculations (MMFF force field) were performed on 12e, and
49 unique conformers were all found within 4 kcal/mol having
the central thiazepine ring in a boat conformation. As expected,
since most of the structural variations were associated with the
butyl part, these conformers could be divided into two subsets
depending on the conformation of the amide bond.15 The
energetically more favorable conformation with the carboxamide
oxygen pointing toward the sulfur had a 1.5 kcal/mol preference
using the MMFF force field. To further look at the amide bond
conformers, density functional theory (DFT) calculations (B3LYP/
6-31G*) were used. Again, the same conformer was found to
be more energetically favorable, but this time the separation
between the two was only 0.4 kcal/mol.16 The conformation of
rimonabant (1) has been well studied, and the conformer
previously used for docking studies was selected and evaluated
for overlap with the conformers of 12e.17 The conformer deemed
the best fit belonged to the energetically less favorable amide
bond conformation (Figure 1a). The triad, the two phenyls and
the carboxamide oxygen, important for rimonabant binding to
the CB1 receptor had a good fit with 12e. Similarly 12e was,
including both sets of enantiomeric conformers, evaluated with
the taranabant conformer D, the conformer used in the docking
studies.14b As also seen in the rimonabant-12e and the
taranabant-rimonabant14a overlays, the aryls residing in hy-
drophobic pockets of the CB1 receptor overlapped well in the
taranabant-12e overlay. However, including the amide NH of
taranabant together with the two aryls in the model, all three
reported to be important for the binding of taranabant, resulted
in a less optimal fit with 12e compared to the 12e-rimonabant
overlay (Figure 1b).
a The R-angle is for C(7)-X-C(3). b pIC50 values are the mean values
of at least three experiments ( SD. c The SO oxygen is in pseudoequatorial
conformation.
Scheme 4. Synthesis of the NH Analogue 14ca
a Reagents: (a) POCl3, N-dimethylaniline, toluene, 95 °C, 2 h, 72%; (b)
PdCl2(PPh3)2, 4-FPhZnBr, THF, room temp, 45 min, 72%; (c) 4-FBnNH2,
Mo(CO)6, cataCXium, [(CH3)3C]3P·HBF4, DBU, THF, 170 °C, microwave,
20 min, 30%.
No apparent trend in activity was observed when R1, the
amide group, was varied. However, the NH in the amides (e.g.,
12e) and the hydrazide (12a) was important for activity;
replacement of the amide with a ketone functionality reduced
the activity (13). This suggests that the amide bond is involved
in binding either directly via hydrogen bonding or indirectly
via the iminol tautomer. In addition, this pharmacophore element
is also seen in the clinical compounds (1 and 2, Chart 1). It has
been suggested in docking studies of rimonabant (1) and
taranabant (3) that the amide bond has great importance for
Exchanging the heteroatom in the central azepine ring
changed the dihedral angle between the two planar aryls in the
tricyclic framework. DFT calculations (B3LYP/6-31G*) showed

Dibenzothiazepines as SelectiVe CB1 InVerse Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1979
Table 3. In Vivo Results for Hypothermia and Anorexia Assaysa
that the angle increased when going from S to C, from C to O,
and from O to N (Table 2).18,19 By comparison of 12a with
14a and 14b, it is seen that increasing the dihedral angle between
the two aryls, which results in a more planar structure,
significantly reduces activity. This is further emphasized by the
N-analogue 14c. In contrast, decreasing the angle when replacing
S with SO in the ring also gave a reduction in activity (12d
and 14d). This may indicate that the optimum R-angle for
activity at the CB1 receptor is around 110°; however, 14d was
tested as a racemic mixture which made it difficult to draw a
definitive conclusion from this experiment. A small shift in the
R-angle was seen when replacing S with SO2, which correlates
with the observed change in activity (12d and 14e).
hypothermia, % inhibition
food intake,
compd
3 mg/kg ip
1 mg/kg ip
% inhibition, 10 mg/kg po
1
2
12e
12h
12i
12j
nd
82
82
94
58
73
70
51
71
70
nd
nd
55
nd
69
59
nd
54
a nd, not determined.
induced hypothermia. As seen in Table 3, several compounds
showed good to excellent in vivo activity in a dose-dependent
manner comparable to rimonabant and SLV-319, especially
compounds 12e and 12h.
Metabolic Stability. The stability in human and rat mi-
crosomes was analyzed for a representative set of compounds
(Table 1). Introducing an aryl group at R2 not only improved
activity, it also appeared to have a positive influence on the
stability in microsomes. As seen in Table 1, the compounds
having R2 equaling alkyl (4, 12a) or piperidinyl (12b) showed
high in vitro clearance values, especially in rat but also in human
microsomes, compared to the compounds having R2 equaling
aryl (12d-j). However, the clearance was significantly reduced
in the piperidinyl series by introducing geminal fluorines in the
4-position (12c). In vitro clearance values of less than 75 and
50 µL/(min·mg) represent moderate to low clearance com-
pounds (less than 70% liver blood flow) in rat and human,
respectively. An exception to the general trend that an aryl group
at R2 improved the microsomal stability significantly was the
pyridinyl 12k; however, this was also the only aryl in the
experimental set not having a halogen substituent, and in
addition, the aromatic nitrogen is a potential oxidation site.
Anorexia Assay. Given the interest in developing CB1
antagonists for treating obesity, we tested several of the
compounds that displayed good activity in the hypothermia
assays for inhibition of feeding in fasted male Sprague Dawley
rats. Rats were fasted for a period of 18 h (water was always
available). After the fasting period, test compounds were
administered orally (po). Dosed animals were immediately
returned to their home cage for 30 min following compound
administration, after which the rats were removed from their
home cages and placed individually into clean cages with a
premeasured amount of food. Food consumption was monitored
for a period of 2 h (i.e., 2.5 h after test compound administration)
and expressed as percent inhibition of food consumption in
vehicle-treated animals. As shown in Table 3, compounds 12e,
12h, and 12j had activity that was comparable to or better than
that of rimonabant (1) in suppressing food intake. In addition,
these experiments showed that these compounds are orally
active.
The major problem with this lipophilic class of compounds
is the low solubility not only in phosphate buffer solution but
also in other formulations frequently used in in vivo pharmacol-
ogy. Compound 12e, the first selected lead compound, has
excellent CB1 activity and reasonable metabolic stability in both
rat and human microsomes but has moderate solubility, for
example, in polyethylene glycol (PEG) (3.7 mg/mL). One
potential rationale for this low solubility is π-π stacking
between molecules, giving stable crystals.20 Therefore, two
halogens were added to the R2 phenyl as a way to try to disrupt
the π-π stacking between the molecules. The melting point
and the solubility in PEG were measured, and a correlation
between the melting point and the solubility in PEG was found;
thus, the melting points were indicative of the solubility.
Introduction of two halogens at the 3- and 4-position in the
aryl 12h (mp 154-157 °C, solubility (PEG) of >13 mg/mL)
and 12i (mp 168-172 °C, solubility (PEG) of >14 mg/mL)
lowered the melting point and increased the solubility in PEG
compare with 12e (mp 217-219 °C, solubility (PEG) of >3.7
mg/mL). Besides improving solubility, this change maintained/
slightly improved CB1 activity and significantly increased
metabolic stability in both rat and human microsomes.
Hypothermia Assay. The compounds from Table 1 showing
promise as drug-like molecules were also tested in hypothermia
assays, a convenient in vivo measurement of CB1-receptor
activation or blockade for CB1 agonists and CB1 antagonists,
respectively.21 Hypothermia assays were performed as follows:
administration of a 1 mg/kg dose of the potent CB1 agonist
CP55940 caused a body temperature drop of approximately 6
°C in male, NSA mice. Test compounds were administered ip
in NSA mice 30 min prior to ip administration of CP55940.
After 60 min the body core temperature was measured to test
to what extent the test compound could reverse the CP 55940
Weight Loss Assay. Male C57BL/6 diet-induced obese (DIO)
mice (Taconic Laboratories, Oxnard, CA), approximately 16-17
weeks old and within a weight range of approximately 40-45
g, were maintained on a high-fat diet (Research Diets D12492)
and had access to food and water ad libitum. Mice were housed
individually and were allowed to acclimate to the vivarium for
a period of at least 3 days, during which body weight was
monitored. Test article was prepared in a lipid based formulation
at a concentration of 8 mg/mL and dosed at a volume of 1.25
mL/kg for a final dose concentration of 10 mg/kg. Oral
administration of vehicle or test compound occurred once daily,
between 1500 and 1600 h each day, beginning on day 1 through
day 15, the end of the study, as indicated. Additionally, a “no-
treatment” group was included in which only body weights were
monitored. As shown in Figure 2, 12h dosed at 10 mg/kg
produced robust weight loss of approximately 13% of initial
body weight compared to vehicle-treated animals. There was
no animal loss and no clinical observations noted for the duration
of the study. Similar results were observed with 12e (data not
shown).
Conclusion
In summary, we have developed new synthetic routes to a
novel class of CB1 inverse agonists involving sequential addition
of substituents to a reactive bifunctionalized intermediate,
amenable for combinatorial chemistry. A large number of
compounds in this class were synthesized, and a general SAR
was established. All compounds exhibited high CB1 vs CB2
receptor subtype selectivity, and the lead compounds showed
excellent in vivo activities. Subsequent experiments demon-
strated that both 12e and 12h promoted weight loss in rodents
in chronic (multiday) dosing experiments. The solubility of the

1980 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Pettersson et al.
Fe(acac)3 (26 mg, 0.075 mmol), cyclohexylmagnesium chloride in
diethyl ether (2M, 1.5 mL, 3.0 mmol), NMP (3 mL), and
tetrahydrofuran (30 mL). The product was purified by silica gel
column chromatography (0-50% ethyl acetate in heptane) to afford
12a (460 mg, 77%): mp 123-136 °C; LCMS tR ) 4.98 min, m/z
420 [M + H]+, purity (UV) 100%; 1H NMR (400 MHz, CDCl3) δ
7.46-7.27 (m, 7H), 6.74 (br s, 1H), 2.92-2.74 (m, 5H), 2.16 (d,
1H, J ) 13.6 Hz), 1.93 (d, 1H, J ) 13.6 Hz), 1.86-1.64 (m, 8H),
1.48-1.24 (m, 6H); 13C NMR (100 MHz, CDCl3) δ 177.8, 164.6,
148.8, 140.2, 139.1, 134.9, 132.7, 132.6, 131.9, 130.5, 128.8, 127.3,
123.8, 123.3, 57.3, 49.0, 32.5, 30.1, 26.8, 26.3, 26.0, 25.4, 23.4;
HRMS m/e calcd, 419.2031; found, 420.2106.
General Procedure for Amidine Formation. The appropriate
imidoyl chloride (5 mg, 0.013 mmol) was mixed with an excess of
the appropriate amine in dry toluene. The mixture was shaken for
18 h at 80 °C. Concentration of the reaction mixture at reduced
pressure gave a crude product, which was purified by column
chromatography (ethyl acetate/heptane 1:1 to 3:1).
Figure 2. Weight-loss-promoting effects of compound 12h. Compound
12h was administered orally, qd, at 10 mg/kg to DIO mice as described
above. Body weights were measured daily and are reported as
normalized to initial body weight. Body weights for the animals used
in these studies were between 40 and 44 g at the start of the study.
N-(3-Chlorobenzyl)-11-(piperidin-1-yl)-dibenzo[b,f][1,4]thia-
zepine-8-carboxamide (12b). The title compound was synthesized
according to the general procedure for amidine formation using
11c (840 mg, 2.0 mmol), piperidine (1.0 mL, 10 mmol), and toluene
(25 mL). The product was purified by silica gel column chroma-
tography (1:1 ethyl acetate/heptane) to give 12b (911 mg, 99%) as
a white solid: LCMS tR ) 5.27 min, m/z 462 [M + H]+, purity
(UV) 97; 1H NMR (400 MHz, CDCl3) δ 7.52-7.49 (m, 1H), 7.45
(dd, 1H, J ) 0.3, 8.0 Hz), 7.41 (d, 1H, J ) 1.9 Hz), 7.36-7.23
(m, 7H), 7.21-7.16 (m, 1H), 6.37 (br s, 1H), 4.55 (dd, 2H, J )
2.8, 6.0 Hz), 3.48 (br s, 4H), 1.80-1.50 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 167.0, 161.3, 149.4, 140.3, 138.8, 134.9, 134.5,
134.4, 132.5, 132.2, 131.8, 130.8, 129.9, 128.8, 128.5, 127.8, 127.7,
125.9, 123.2, 120.9, 43.4, 25.0. Anal. (C26H24ClN3OS) C, H, N.
N-(3-Chlorobenzyl)-11-(4,4-difluoropiperidin-1-yl)dibenzo-
[b,f][1,4]thiazepine-8-carboxamide (12c). The title compound was
synthesized according to the general procedure for amidine forma-
tion using 11c (400 mg; 0.97 mmol), 4,4-difluoropiperidine
hydrochloride (700 mg, 4.4 mmol), and toluene (10 mL). Since
the hydrochloride of the amine was used, triethylamine (1.2 mL)
was also added to the mixture. The product was purified by silica
gel column chromatography (1:9 ethyl acetate/heptane to pure ethyl
acetate) to give 12c (326 mg, 67%): LCMS tR ) 5.02 min, m/z
498 [M + H]+, purity (UV) 100%; 1H NMR (400 MHz, CDCl3) δ
7.54-7.50 (m, 1H), 7.46 (dd, 1H, J ) 0.4, 8.0 Hz), 7.43 (d, 1H, J
) 2.0 Hz), 7.40-7.27 (m, 5H), 7.25-7.22 (m, 2H), 7.20-7.16
(m, 1H), 6.37 (br s, 1H), 4.56 (d, 2H, J ) 6.0 Hz), 4.00-3.60 (br
s, 2H), 3.56-3.43 (br s, 2H), 2.20-1.88 (m, 4H); 13C NMR (100
MHz, CDCl3) δ 166.9, 160.7, 148.8, 140.2, 139.0, 135.0, 133.7,
132.5, 132.5, 131.8, 131.3, 130.0, 128.8, 128.7, 127.8, 127.7, 125.9,
123.3, 121.5, 43.4, 31.9, 22.7, 14.1; HRMS m/e calcd, 497.1140;
found, 498.1219.
lead compound 12e was improved by the introduction of a 3,4-
dihalogenated phenyl group, which resulted in compound 12h,
a potential preclinical candidate as a CB1 inverse agonist.
Experimental Section
Chemistry. 1H NMR and 13C NMR spectra were recorded on a
Varian mercury 400 VX (1H NMR at 400 MHz and 13C NMR at
100 MHz) spectrometer with solvent resonance as the internal
standard: CDCl3 (δH 7.26, δC 77.16); DMSO-d6 (δH 2.50, δC 39.52);
acetone-d6 (δH 2.05, δC 29.84, 206.26); MeOH-d4 (δH 3.31, δC
1
49.00). H NMR are reported as follows: chemical shifts in ppm,
coupling constants in Hz, multiplicity (s ) singlet, br s ) broad
singlet, d ) doublet, dd ) double doublet, dt ) double triplet, t )
triplet, tt ) triple triplet, m ) multiplet). Unless otherwise
mentioned, purities were determined by LCMS, equipped with 996
photodiode array detector (190-450 nm) and run in 10 mM
NH4OAc buffer with H2O/MeCN gradient (0-0.5 min 30% MeCN,
0.5-5.5 min 30-100% MeCN, 5.5-7 min 100% MeCN). The
column was am Xterra MS C18 3.5 µm 30 × 4.6 mm i.d., and
elemental analysis results were obtained from a “2400 CHN
elemental analyzer” by Perkin-Elmer in the microanalytical labo-
raties of Fakulta¨t fu¨r Chemie, Universita¨t Wien. The microwave-
assisted reactions were carried out using a SmithCreator single mode
cavity, producing continuous irradiation at 2450 MHz. Reaction
temperature and pressure were determined using the built-in, online
IR and pressure sensors. Analytical thin layer chromatography
(TLC) was performed on silica gel 60 F254. Visualization was
accomplished with UV light. Purification of the reaction products
was carried out by column chromatography using SiO2 (60 Å, 200
µm). Melting points were obtained using SMP3 melting point
apparatus with an open capillary tube and are uncorrected. HRMS
analyses were recorded in FAB(+) mode using direct inlet at the
University of Lund, Sweden. Unless otherwise noted, all reagents
were obtained from commercial sources and used without further
purification.
General Procedure for Iron-Catalyzed Alkylimidoyl Chlo-
ride Cross-Coupling. A flame-dried flask was charged under argon
with the imidoyl chloride (0.05 mmol), Fe(acac)3 (0.9 mg, 0.0025
mmol), tetrahydrofuran (1 mL), and NMP (0.1 mL). A solution of
alkylmagnesium halide (2 M in Et2O, 100 µL, 0.20 mmol) was
slowly added to the resulting red solution, causing an immediate
color change to dark brown. The resulting mixture was stirred for
10 min, and the reaction was then carefully quenched with NH4Cl
(aq) and diluted with Et2O. The organic phase was washed with
brine, dried (Na2SO4), filtered, and concentrated to give the crude
product. Purification by column chromatography (ethyl acetate/
heptane/MeOH 1:1:0.05) gave the product (27-77%).
General Procedure for Palladium Catalyzed Negishi Cross-
Coupling. The arylzinc halide (3-5 equiv) was added to the
imidoyl chloride (10 mg) and PdCl2(PPh3)2 (10 mol%) in dry
tetrahydrofuran (1 mL) at room temperature. After 30 min saturated
aqueous NH4Cl and ethyl acetate was added and the aqueous phase
was extracted once with ethyl acetate. The combined organic phases
were washed with water, brine and then dried (Na2SO4). Filtration
and concentration under reduced pressure of the organic phase
followed by purification of the crude product by column chroma-
tography (ethyl acetate/heptane, 1:1) gave the product.
N-(3-Chlorobenzyl)-11-(4-fluorophenyl)-dibenzo[b,f][1,4]thia-
zepine-8-carboxamide (12d). The title compound was synthesized
according to the general procedure using 11c (681 mg, 1.65 mmol),
4-fluorophenylzinc iodide (0.5 M in tetrahydrofuran, 13.2 mL, 6.6
mmol), PdCl2(PPh3)2 (70 mg, 0.10 mmol), and tetrahydrofuran (20
mL). Purification was by silica gel column chromatography (4:1
to 1:1, ethyl acetate/tetrahydrofuran). The isolated solid was
recrystallized from ethyl acetate to give 12d (514 mg, 66%) as
light-yellow crystals: LCMS tR ) 5.32 min, m/z 473 [M + H]+,
11-Cyclohexyl-N-(piperidin-1-yl)dibenzo[b,f][1,4]thiazepine-
8-carboxamide (12a). The title compound was synthesized ac-
cording to the general procedure using 11b (530 mg, 1.43 mmol),
1
purity (UV) 98%; H NMR (400 MHz, CDCl3) δ 7.85-7.80 (m,
2H), 7.73-7.70 (m, 2H), 7.58-7.51 (m, 3H), 7.44 (dt, 1H, J )

Dibenzothiazepines as SelectiVe CB1 InVerse Agonists
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 1981
1.6, 7.4 Hz), 7.34-7.29 (m, 2H), 7.28-7.20 (m, 3H), 7.18 (dd,
1H, J ) 1.6, 7.7 Hz), 7.15-7.09 (m, 2H), 6.45 (br s, 1H), 4.60 (d,
2H, J ) 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 168.7, 166.6,
140.3, 134.9 (d, J ) 210), 135.3, 133.0, 132.2, 132.1, 131.9, 130.8,
130.3, 128.4, 128.1 (d, J ) 9), 126.2, 124.7, 123.9, 115.6 (d, J )
22), 43.8; HRMS m/e calcd, 472.0812; found, 473.0891.
7.33 (ddd, 1H, J ) 1.3, 7.5, 7.7 Hz, ArH), 7.21-7.15 (m, 2H, ArH),
6.03 (br m, 1H, NH), 3.46-3.41 (m, 2H, NCH2), 1.62-1.55 (m,
2H, CH2), 1.45-1.36 (m, 2H, CH2), 0.95 (t, 3H, J ) 7.3 Hz, CH3);
13C NMR (100 MHz, CDCl3) δ 166.5, 148.4, 140.3, 136.4, 135.9,
132.7, 132.5, 131.9, 131.9, 131.7, 130.1, 129.8, 129.7, 128.2, 124.4,
123.6, 116.4, 116.2, 77.3, 77.0, 76.7, 39.8, 31.7, 20.1, 13.7. Anal.
(C24H20ClFN2OS) C, H, N.
N-Butyl-11-(4-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-car-
boxamide (12e). The title compound was synthesized according
to the general procedure using 11d (530 mg, 1.5 mmol), 4-chlo-
rophenylzinc iodide (0.5 M in tetrahydrofuran, 6.0 mL, 3.0 mmol),
PdCl2(PPh3)2 (55 mg, 0.078 mmol), and tetrahydrofuran (15 mL).
Purification was by silica gel column chromatography (5-10% ethyl
acetate in heptane). The isolated solid was recrystallized from ethyl
acetate to give 12e (383 mg, 59%) as light-yellow crystals: mp
217-219 °C; LCMS tR ) 5.35 min, m/z 421 [M + H]+, purity
N-Butyl-11-(3,4-dichlorophenyl)dibenzo[b,f][1,4]thiazepine-
8-carboxamide (12i). The title compound was synthesized accord-
ing to the general procedure using 11d (100 mg, 0.29 mmol), 3,4-
dichlorophenylzinc iodide (0.5 M in tetrahydrofuran, 2.4 mL, 1.2
mmol), PdCl2(PPh3)2 (20 mg, 0.029 mmol), and tetrahydrofuran
(10 mL). Purification was by silica gel column chromatography
(0-5% ethyl acetate in toluene), and 12i (120 mg, 94%) was
isolated as a crystalline solid: mp 168-172 °C; LCMS (10 mM
NH4OAc buffer MeCN/H2O, 0-0.5 min 50% MeCN, 0.5-10.5
min 50-100% MeCN, 10.5-12 min 100% MeCN) tR ) 6.83 min,
m/z 455 [M + H]+, purity (UV) 100; 1H NMR (400 MHz, CDCl3)
δ 7.96 (d, 1H, J ) 2.0 Hz, ArH), 7.63 (d, 1H, J ) 1.1 Hz, ArH),
7.60 (dd, 1H, J ) 2.0, 8.4 Hz, ArH), 7.56 (d, 1H, J ) 7.8 Hz,
ArH), 7.51 (m, 3H Hz, ArH), 7.44 (ddd, 1H, J ) 1.2, 7.5, 7.7 Hz,
ArH), 7.32 (ddd, 1H, J ) 1.2, 7.5, 7.7 Hz, ArH), 7.15 (dd, 1H, J
) 1.3, 7.7 Hz, ArH), 6.04 (br m, 1H Hz, NH), 3.46-3.41 (m, 2H,
NCH2), 1.62-1.53 (m, 2H, CH2), 1.45-1.36 (m, 2H, CH2), 0.95
(t, 3H, J ) 7.4 Hz, CH3); 13C NMR (100 MHz, CDCl3) δ 166.8,
148.3, 140.4, 139.9, 136.3, 132.8, 132.5, 131.7, 131.3, 130.2, 130.0,
128.8, 128.2, 124.5, 123.6, 47.4, 28.6, 20.1. Anal. (C24H20Cl2N2OS)
C, H, N.
1
(UV) 99%; H NMR (400 MHz, CDCl3) δ 7.77-7.73 (m, 2H),
7.64 (m, 1H), 7.56-7.53 (m, 1H), 7.51-7.48 (m, 2H), 7.45-7.38
(m, 3H), 7.30 (dt, 1H, J ) 1.6, 7.6 Hz), 7.16 (dd, 1H, J ) 1.6, 7.6
Hz), 6.06 (br s, 1H), 3.46-3.40 (m, 2H), 1.62-1.53 (m, 2H),
1.45-1.34 (m, 2H), 0.94 (t, 3H, J ) 7.2 Hz); 13C NMR (100 MHz,
CDCl3) δ 168.3, 166.8, 148.72, 140.5, 138.6, 137.5, 137.0, 136.1,
132.8, 132.5, 132.2, 131.7, 131.2, 130.5, 128.7, 128.3, 124.5, 123.9,
40.1, 31.9, 20.3, 13.9. Anal. (C24H21ClN2OS) C, H, N.
11-(3-Chlorophenyl)-N-isobutyldibenzo[b,f][1,4]thiazepine-8-
carboxamide (12f). The title compound was synthesized according
to the general procedure using 11e (243 mg, 0.7 mmol), 3-chlo-
rophenylzinc iodide (0.5 M in tetrahydrofuran, 3.0 mL, 1.5 mmol),
PdCl2(PPh3)2 (28 mg, 0.040 mmol), and tetrahydrofuran (8 mL).
Purification was by silica gel column chromatography (0-10% ethyl
acetate in toluene). The isolated solid was recrystallized from ethyl
acetate/heptane to give 12f (103 mg, 35%) as light-yellow crystals:
11-(5-Chlorothiophen-2-yl)-N-isobutyldibenzo[b,f][1,4]thia-
zepine-8-carboxamide (12j). The title compound was synthesized
according to the general procedure using 11e (0.38 g, 1.1 mmol),
5-chloro-2-thienylzinc bromide (0.5 M in tetrahydrofuran, 8.8 mL,
4.4 mmol), PdCl2(PPh3)2 (78 mg, 0.11 mmol), and dry tetrahydro-
furan (10 mL). The mixture was purified by silica gel column
chromatography (toluene) and crystallized from toluene to give 12j
1
LCMS tR ) 5.25 min, m/z 421 [M + H]+, purity (UV) 100%; H
NMR (400 MHz, CDCl3) δ 7.87 (d, 1H, J ) 1.8, 1.8 Hz),
7.67-7.60 (m, 2H), 7.56 (dd, 1H, J ) 1.1, 7.8 Hz), 7.52 (d, 2H, J
) 1.2 Hz), 7.50-7.41 (m, 2H), 7.36 (dd, 2H, J ) 7.7, 7.7 Hz),
7.32 (dd, 1H, J ) 1.3, 7.5 Hz), 7.18 (dd, 1H, J ) 1.4, 7.7 Hz),
6.13 (br s, 1H), 3.34-3.23 (m, 2H), 1.89 (dt, 1H, J ) 6.7, 13.4
Hz), 0.98 (d, 6H, J ) 6.7 Hz); 13C NMR (100 MHz, CDCl3) δ
167.8, 166.6, 148.5, 141.9, 140.3, 136.7, 135.9, 134.5, 132.7, 132.3,
132.0, 131.5, 130.8, 130.2, 129.5, 128.2, 127.9, 124.4, 123.5, 47.4,
28.6, 20.2; HRMS m/e calcd, 420.1063; found, 421.1144.
(88 mg, 19%) as a yellow solid: mp 217-219 °C; LCMS tR
)
1
5.37 min, m/z 427 [M + H]+, purity (UV) 97%; H NMR (400
MHz, CDCl3) δ 7.55 (ddd, 2H, J ) 0.7, 1.4, 7.7 Hz), 7.50 (d, 2H,
J ) 1.6 Hz), 7.47 (dd, 1H, J ) 1.7, 7.5 Hz), 7.43 (dd, 1H, J ) 1.7,
7.6 Hz), 7.37 (ddd, 1H, J ) 1.3, 7.5, 7.5 Hz), 6.91 (dd, 2H, J )
4.0, 15.8 Hz), 6.12 (br s, 1H), 3.36-3.18 (m, 2H), 1.87 (dt, 1H, J
) 6.7, 13.5 Hz), 0.96 (d, 6H, J ) 6.7 Hz); 13C NMR (100 MHz,
CDCl3) δ 166.6, 162.4, 148.2, 144.9, 140.2, 136.8, 136.0, 135.1,
132.8, 132.6, 131.8, 131.7, 131.7, 130.0, 128.1, 127.1, 124.4, 123.6,
47.4, 28.6, 20.1; HRMS m/e calcd, 426.0627; found, 427.0704.
N-Isopentyl-11-(pyridin-2-yl)dibenzo[b,f][1,4]thiazepine-8-
carboxamide (12k). The title compound was synthesized according
to the general procedure using 11f (220 mg, 0.61 mmol),
PdCl2(PPh3)2 (28 mg, 0.04 mmol), 2-pyridylzinc bromide (0.5 M
in tetrahydrofuran, 2.8 mL, 1.4 mmol), and tetrahydrofuran (10 mL).
Purification by silica gel column chromatography (25% ethyl acetate
in toluene) followed by ion exchange on an acidic SPE column,
eluting with 1 M NH3 in MeOH, gave 12k (127 mg, 52%) as a
yellow solid: LCMS tR ) 4.17 min, m/z 402 [M + H]+, purity
N-Butyl-11-(2-chlorophenyl)dibenzo[b,f][1,4]thiazepine-8-car-
boxamide (12g). The title compound was synthesized according
to the general procedure for palladium catalyzed cross coupling
using 11d (40 mg, 0.11 mmol), 2-chlorophenylzinc iodide (0.5 M
in tetrahydrofuran, 880 µL, 0.44 mmol), PdCl2(PPh3)2 (8.3 mg,
0.011 mmol), and tetrahydrofuran (2 mL). The crude was purified
by silica gel column chromatography (5-10% ethyl acetate in
heptane) to give 12g (27.5 mg, 59%) as a red solid: LCMS tR )
4.88 min, m/z 421 [M + H]+, purity (UV) 99; 1H NMR (400 MHz,
CDCl3) δ 7.82-7.78 (m, 1H), 7.70 (d, 1H, J ) 1.8 Hz), 7.55 (dd,
1H, J ) 1.9, 8.1 Hz), 7.53 (s, 1H), 7.52-7.49 (m, 1H), 7.42-7.39
(m, 3H), 7.37 (dd, 1H, J ) 1.4, 7.6 Hz), 7.22 (ddd, 1H, J ) 1.3,
7.6, 7.6 Hz), 6.18 (s, 1H), 3.42 (dd, 2H, J ) 7.1, 12.9 Hz),
1.62-1.52 (m, 2H), 1.33-1.44 (m, 2H), 0.94 (t, 3H, J ) 7.3 Hz);
13C NMR (100 MHz, CDCl3) δ 168.8, 166.5, 148.1, 140.5, 139.7,
138.7, 135.8, 133.2, 132.8, 132.2, 132.0, 131.5, 131.3, 130.8, 130.3,
129.2, 128.4, 126.8, 125.0, 124.1, 39.8, 31.7, 20.1, 13.7; HRMS
m/e calcd, 420.1063; found, 421.1145.
1
(UV) 99%; H NMR (400 MHz, CDCl3) δ 8.69-8.66 (m, 1H),
8.63-8.59 (m, 1H), 8.30-8.25 (m, 1H), 7.84 (dt, 1H, J ) 1.7, 7.6
Hz), 7.72-7.81 (m, 1H), 7.56-7.50 (m, 2H), 7.42-7.18 (m, 5H),
6.16 (br s, 1H), 3.44 (q, 2H, J ) 6.8 Hz), 1.66 (m, 1H, J ) 6.8
Hz), 1.48 (q, 2H, J ) 6.8 Hz), 0.93 (d, 6H, J ) 6.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 168.0, 166.6, 157.2, 149.1, 148.5, 139.9,
136.9, 136.7, 135.8, 132.8, 132.5, 132.4, 131.5, 130.9, 127.9, 124.9,
124.9, 124.2, 124.1, 38.6, 38.6, 26.0, 22.6. Anal. (C24H23N3OS) C,
H, N.
N-Butyl-11-(3-chloro-4-fluorophenyl)dibenzo[b,f][1,4]thiazepine-
8-carboxamide (12h). The title compound was synthesized ac-
cording to the general procedure using 11d (100 mg;, 0.29 mmol),
3-chloro-4-fluorophenylzinc iodide (0.5 M in tetrahydrofuran, 2.4
mL, 1.2 mmol), PdCl2(PPh3)2 (20 mg, 0.029 mmol), and tetrahy-
drofuran (10 mL). Purification by silica gel column chromatography
(0-5% ethyl acetate in toluene) gave 12h (120 mg, 94%) as a
crystalline solid: mp 154-157 °C; LCMS tR ) 5.42 min, m/z 439
Acknowledgment. We thank Sine Mandrup Bertozzi, Robert
W. Johnson, Bryan Clemmons, and Dr. Martin Carnerup for
expert analytical assistance, and we thank Carl Johan Wallentin
for assistance with calculation of the R-angles.
1
[M + H]+, purity (UV) 100; H NMR (400 MHz, CDCl3) δ 7.94
(dd, 1H, J ) 2.2, 7.2 Hz, ArH), 7.67-7.63 (m, 1H, ArH),
7.63-7.62 (m, 1H, ArH), 7.55 (dd, 1H, J ) 0.9, 7.8 Hz, ArH),
7.51-7.50 (m, 2H, ArH), 7.43 (ddd, 1H, J ) 1.5, 7.4, 7.8 Hz, ArH),
Supporting Information Available: Synthetic procedures,
characterization for all exemplified compounds, biological methods,

1982 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Pettersson et al.
(10) Ottesen, L. K.; Ek, F.; Olsson, R. Iron-catalyzed cross-coupling of
imidoyl chlorides with grignard reagents. Org. Lett. 2006, 8, 1771–
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(11) Nadin, A.; Lopez, J. M. S.; Owens, A. P.; Howells, D. M.; Talbot,
A. C.; Harrison, T. New synthesis of 1,3-dihydro-1,4-benzodiazepin-
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via the Internet at http://pubs.acs.org.
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