Discovery and SAR of potent, orally available and brain-penetrable 5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and 4,5-dihydro-6-oxa-3-thia-1-aza- benzo[e]azulen derivatives as neuropeptide Y Y5 receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2004.03.014

Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5 affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)- piperidin-4-ylmethyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2- yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.

Full text of DOI:10.1016/j.bmcl.2004.03.014

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2451–2457
Discovery and SAR of potent, orally available and brain-penetrable
5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen- and
4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen derivatives as
neuropeptide Y Y5 receptor antagonists
Heinrich Rueeger,a,* Marc Gerspacher,a Peter Buehlmayer,a Pascal Rigollier,a
Yasuchika Yamaguchi,b Tibur Schmidlin,a Steven Whitebread,c
Barbara Nuesslein-Hildesheim,a Hanspeter Nicka and Leoluca Cricionea
aNovartis Pharma AG, Novartis Institutes for BioMedical Research Basel, CH-4002 Basel, Switzerland
bNeurogen Corporation, Branford, CT 06405, USA
cNovartis Institutes for BioMedical Research, Inc., Cambridge, MA 02139, USA
Received 13 November 2003; revised 11 February 2004; accepted 4 March 2004
Abstract—Combination of structural elements from a potent Y5 antagonist (2) with thiazole fragments that exhibit weak Y5
affinities followed by lead optimisation led to the discovery of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-yl-
methyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino derivatives. Both classes of
compounds are capable of delivering potent and selective orally and centrally bioavailable NPY Y5 receptor antagonists.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
4-ylmethyl-amine and (4,5-dihydro-6-oxa-3-thia-1-aza-
benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine deriva-
tives as potent and selective orally bioavailable and
brain penetrable Y5 antagonists, which may ultimately
be valuable in several therapeutic areas including
obesity.3
Neuropeptide Y (NPY) is a 36 amino acid peptide
neurotransmitter widely expressed in both the peripheral
and central nervous system.1 Cloned receptors for NPY
and related family members peptide YY and pancreatic
polypeptide are classified as Y-type receptors (Y1, Y2,
Y4 and Y5; note there is also a Y6 receptor gene that is
absent in the rat and a pseudogene in human). NPY is
considered to regulate a variety of physiological pro-
cesses, including vasoconstriction, nasal congestion,
blood pressure, intestinal motility, anxiety, depression,
pain, feeding, reproductive endocrinology, neuronal
excitability and memory retention.2 As such, receptor
specific ligands modulating NPY receptor signalling
may have therapeutic value.
Previously, we reported the discovery of potent and
selective Y5 antagonists 1 (CGP71683A) and 2. Despite
potent Y5 antagonistic properties these compounds
exhibited only little absorption and permeability to the
brain after oral administration (Fig. 1).
NH2
N
S
N
HN
N
In this report, we describe the discovery and SAR of 5,6-
dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-
O
O
N
H
N
N
H
N
H
N
S
N
H
O
O
Keywords: NPY Y5 antagonists; Neuropetide Y receptors.
* Corresponding author. Tel.: +41-61-696-32-55; fax: +41-61-696-86-
76; e-mail: heinrich.rueeger@pharma.novartis.com
2
hY5 IC50: 2 nM
1 (CGP71683A) hY5 IC50: 3 nM
Figure 1.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.03.014

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H. Rueeger et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2451–2457
S
S
N
N
N
H
S
S
S
R
N
N
H
N
NH2
N
H
X, Y
X, Y
F
A
O
O
screening hit, hY5 IC50: 1800nM
screening hit, hY5 IC50: 1600nM
S
S
N
N
S
H
N
N
H
N
H
O
O
O
O
N
N
R
R
S
S
S
N
H
S
N
N
S
H
5
B
N
N
H
N
N
H
F
S
O
3
hY5 IC50: 23 nM
4
hY5 IC50: 15 nM
N
N
H
O
O
X, Y
C
S
S
N
N
S
H
N
N
H
Figure 3. Tricyclic thiazole derivatives.
5
hY5 IC50: 3 nM
O
Figure 2. Binding affinities4 of screening hits and thiazole variations.
O
O
OH
b
c
a
OH
77%
71%
96%
We suspected that replacement of the quinazoline and
sulfamyl residues might lead us to discover structurally
novel series of compounds that possess more favourable
pharmacokinetic properties. From screening in-house
compound collections thiazole derivatives were obtained
as weakly active Y5 antagonists (Fig. 2).
O
8
7
9
S
O
g, h
88%
H2N
H2N
N
H
+
N
O
N
O
Br
O
O
O
12
10
11
Structural variations at the thiazole scaffolds and com-
bination with the cyclohexylmethyl–sulfamyl residue
that is present in compound 2, led to the identification of
the 4-phenyl-thiazol-2-ylamino, the 1,8-dithia-3-aza-
dibenzo[e,h]azulen-2-ylamino and the 4,5-dihydro-3,6-
dithia-1-aza-benzo[e]azulen-2-ylamino derivatives 3, 4
and 5, respectively, as potent Y5 antagonists.
d
81%
O
O
S
S
e
N
N
N
N
H
99%
H
NH
N
O
O
It appears that formal removal of one of the phenyl
groups from the ring system of 4 is responsible for the 5-
fold increase in Y5 receptor affinity of the resulting
‘tricyclic thiazole’ (5,6-dihydro-4H-3-thia-1-aza-benzo-
[e]azulene)derivative 5. Consequently 5 was chosen as a
lead compound for further optimisation work. Struc-
tural modifications aiming at the elimination of the
sulfur in the seven-membered ring and at the replace-
ment of the sulfamyl residue, both potential metabolic
weak points, led to the identification of the following
tricyclic thiazole derivatives: (4-amino-cyclohexyl-
methyl)-(5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-
yl)-amines (A), (5,6-dihydro-4H-3-thia-1-aza-benzo-
[e]azulen-2-yl)-piperidin-4-ylmethyl-amines (B) and (4,5-
dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperi-
din-4-ylmethyl-amines (C) as potent, highly selective
and orally bioavailable brain-penetrable Y5 antagonists
(Fig. 3).
14
85%
13
f
O
S
N
N
H
N
O
O
6
Scheme 1. Reagents and conditions: (a) NaOMe, c-butyrolactone, 1,2-
dichlorobenzene, EtOH, 150 °C; (b) PPA, 110 °C; (c) Br2, Et2O, 25 °C;
(d) DIPEA, EtOH, reflux; (e) TFA, CH2Cl2, 25 °C; (f) (R)-(þ)-tetra-
hydro-2-furoic acid, EDC, pyridine, CH2Cl2, 25 °C; (g) PhCONCS,
THF, reflux; (h) K2CO3, MeOH/H2O 3:1, reflux.
Compound 6 was prepared starting from p-cresol.
Alkylation of the oxygen with c-butyrolactone followed
by cyclisation in the presence of polyphosphoric acid led
to benzo[e]oxepinone 9. Bromination of this compound
and subsequent reaction of the resulting bromide 10
with the thiourea derivative 11 yielded the tricyclic thi-
azole derivative 13. Boc deprotection followed by acyl-
ation of the piperidine nitrogen led to the final product
{4-[(9-methyl-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]-
azulen-2-ylamino)-methyl]piperidin-1-yl}-((R)-tetrahydro-
2. Chemistry
The syntheses of the tricyclic thiazole derivatives 6
(Scheme 1) 16 and 20 (Scheme 2) are illustrative for
the preparation of all the various thiazole amides.

H. Rueeger et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2451–2457
2453
Table 1. In vitro binding affinities4 of tricyclic thiazole derivatives to
hY5 receptors
a-d
S
N
58% overall
N
H
F
S
N
O
F
N
R
O
16
15
a
90%
F
S
Compound #
R
HY5 binding
IC50 (nM)a
e, f
H2N
O
H2N
N
H
O
+
N
O
N
H
O
F
71%
H
O
O
Br
O
5
3
S
N
N
17
15a
18
H
HN
g
66%
O
21
22
25
15
HN
N
O
S
S
h, i
93%
N
N
N
O
N
H
O
H
Ph
N
N
H
O
F
F
H
O
O
20
19
N
HN
Scheme 2. Reagents and conditions: (a) Br2, AcOH, 25 °C; (b) 11,
DIPEA, EtOH, reflux; (c) 5 N HCl in iPrOH, 25 °C; (d) acetyl chloride,
NEt3, CH2Cl2, 0–25 °C; (e) PhCONCS, THF, reflux; (f) K2CO3,
MeOH/H2O 3:1, reflux; (g) DIPEA, EtOH, reflux; (h) TMS–I, aceto-
nitrile, 0–25 °C; (i) cyclopropane carboxylic acid chloride, NEt3,
CH2Cl2, 0–25 °C.
H
N
23
24
78
81
N
O
HN
HN
O
N
N
H
furan-2-yl)-methanone 6. Thiourea derivative 11 was
prepared in two steps from the aminomethyl-piperidine
derivative 12 and phenylisocyanate as described in
Scheme 1.
HN
HN
O
25
26
27
6
4
2
N
H
Starting from the commercially available benzosuberone
derivative 15, 16 (1-{4-[(9-fluoro-5,6-dihydro-4H-3-thia-
1-aza-benzo[e]azulen-2-ylamino)-methyl]-piperidin-1-yl}-
ethanone) was prepared using the same reaction
sequence as described for the preparation of 6. Also the
preparation of aminocyclohexyl derivatives such as 20
was carried out using the same reaction sequence as de-
scribed for the preparation of 6 and 16. However, instead
of using thiourea derivative 11 (4-thioureidomethyl-
cyclohexyl)-carbamic acid benzyl ester 18 was used
(Scheme 2).
N
N
O
O
HN
N
a Values are means of three experiments.
amide series we prepared additional derivatives. A
variety of acyl residues were chosen in view of pro-
ducing final compounds that should possess drug like
properties (c log P < 5, MW < 500, PSA < 100 A,
SumCa < 10).
3. Results and discussion
ꢀ
In an attempt to identify a replacement residue for the
sulfamyl–cyclohexyl moiety in 5 a variety of selected
residues were attached to the tricyclic thiazole part.
Selected residues consist of a carbon linker with an
amidic H-bonding acceptor functionality instead of the
undesired sulfonamide (or sulfamyl acceptor group).
The results are summarised in Table 2. As can be seen from
the Y5 receptor affinities it appears that in general lipo-
philic amide substituents at the cyclohexyl-amino group
are well tolerated and lead to potent Y5 antagonists. An
increase in water solubility and a decrease of the lipophi-
licity was achieved by the introduction of additional het-
eroatoms, that is, nitrogen. However, the resulting
compounds exhibit a significantly lowered binding affinity
to the Y5 receptor as exemplified by 35–38.
As can be seen from the Y5 receptor binding data shown
in Table 1 compounds with either 4-amino-cyclohexyl-
amide or even better 4-aminomethyl-piperidine-amide
moieties display Y5 receptor affinities that are as potent
as the sulfamyl derivative 5.
A different picture is observed in the 4-aminomethyl-
piperidine-amide series. As shown in Table 3 a much
larger variety of amide substituents at the piperidine
In order to further explore the potential of the 4-amino-
cyclohexyl-amide and of the 4-aminomethyl-piperidine-

2454
H. Rueeger et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2451–2457
Table 2. In vitro binding affinities4 of compounds to hY5 receptor
Table 3 (continued)
Compound #
X
F
R
hY5 binding-
IC50 (nM)a
S
N
N
H
O
O
N
H
R
F
46
3
N
O
Compound #
R
hY5 binding
IC50 (nM)a
O
N
H
29
30
–OMe
–nBu
2
6
47
48
F
F
6
6
O
O
O
O
20
31
6
6
N
H
N
49
16
F
F
3
2
S
32
33
15
5
O
NH-CO-R =
N
N
50
51
F
F
2
O
O
34
35
6
20
29
F
N
O
52
53
54
F
F
F
4
2
2
N
N
O
O
36
37
38
210
150
290
O
N
O
O
O
N
a Values are means of three experiments.
O
55
F
4
O
Table 3. In vitro binding affinities4 of tricyclic thiazoles to hY5
receptors
O
56
57
F
F
1
2
S
O
O
O
N
N
H
N
R
X
O
O
Compound #
X
R
hY5 binding-
IC50 (nM)a
58
F
2
39
40
41
H
Cl
F
6
7
4
N
O
a Values are means of three experiments.
N
N
42
F
2
O
O
O
O
N
nitrogen is tolerated. In contrast to the 4-amino-cyclo-
hexyl-amide series nonpolar as well as amide substitu-
ents with additional polar (nitrogen or oxygen)
functionalities are tolerated and compounds with highly
potent Y5 receptor affinities are obtained from the 4-
aminomethyl-piperidine-amide series. Replacement of
the fluoro substituent at the phenyl ring of 41 with either
hydrogen or chlorine leads to equipotent compounds 39
and 40.
43
44
F
F
24
15
N
H
O
O
N
H
45
F
2
O

H. Rueeger et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2451–2457
2455
In an attempt to further decrease the lipophilicity and to
increase water solubility of the resulting compounds an
oxygen atom was introduced into the seven-membered
ring. When compared to the carbocycle analogues this
alteration unfortunately led to a more or less pro-
nounced decrease in potency of the resulting com-
pounds depending on the amide residue and on the
substituent(s) on the phenyl ring of the tricyclic thiazole
part. As can be seen from the data in Table 4, surpris-
ingly in selected cases only, that is, compounds 79 and
81, the tetrahydrofuran substituted analogues are as
potent as the corresponding carbocycle analogues (57,
58). The influence of a variety of substituents on the
phenyl ring of the thiazole on receptor affinity of the
resulting compounds is also shown in Table 4. Methyl
(e.g., 69) appears to be a good replacement for the flu-
oro substituent (68) producing even more potent com-
pounds in some cases, whereas a methoxy group (67)
leads to a slight reduction in the Y5 affinity of the
corresponding compound. Introduction of a second
halogen substituent is not very well tolerated and leads
to a significant loss of binding affinity of the resulting
Table 4. In vitro binding affinities4 of oxygen containing tricyclic thiazoles to hY5 receptor
S
O
N
N
H
N
R
Y
X
Compound #
X
F
Y
R
hY5 binding IC50 (nM)a
71
N
59
H
H
O
60
OMe
2460
N
N
61
62
F
F
H
H
41
18
O
O
O
63
64
Me
F
H
H
25
69
N
O
O
65
66
67
68
69
F
Cl
F
38
20
17
7
F
OMe
F
Me
H
H
H
O
7
70
71
72
73
Me
Cl
F
H
F
5
13
99
40
O
Cl
F
F
O
O
74
75
F
F
H
H
37
22
O
O
O
O
76
77
F
Me
H
H
28
18
78
Me
H
21
O
O
O
O
79
80
F
Me
H
H
19
17
81
6
F
Me
H
H
5
5
O
O
a Values are means of three experiments.

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H. Rueeger et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2451–2457
Table 5. In vitro binding affinities4 to Y receptors and Y5 antagonistic properties of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-
ylmethyl-amine and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine derivatives
#
hY5 IC50 (nM)a
hY5 [Ca2þ
]
rY5 IC50 (nM)a
hY1 IC50 (lM)a
hY2 IC50 (lM)a
hY4 IC50 (lM)a
i
response IC50 (nM)a
16
68
70
6
2
7
5
5
254
100
61
ND
6
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
>30
ND
2.9
40
a Values are means of three experiments.
Table 6. Concentrations of (5,6-dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine and (4,5-dihydro-6-oxa-3-thia-1-aza-
benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amine derivatives in rat plasma and hypothalamus after oral dosing at 30 mg/kg p.o.5
#
2 h Plasma (lg/mL)
6 h Plasma (lg/mL)
2 h Hypothalamus (lg/g)
6 h Hypothalamus (lg/g)
41
16
56
57
58
68
70
79
81
6
0.24
0.95
0.54
1.60
0.32
0.74
0.84
0.93
0.97
0.87
0.13
0.07
0.14
0.32
0.22
0.07
0.33
0.14
0.39
0.26
1.17
3.70
1.22
6.69
0.86
2.23
2.42
5.48
2.44
1.46
0.62
0.29
0.44
1.33
0.67
0.26
0.88
0.64
1.08
0.40
compounds as can be observed in derivatives 65, 66 and
71–73, which exhibit 3–20-fold less potent Y5 receptor
affinities in comparison to the mono halogenated com-
pound 68.
levels of 2.42 and 0.88 lg/g, respectively, clearly dem-
onstrate that the tricyclic thiazole series of Y5 antago-
nists is capable of delivering potent and selective orally
and centrally bioavailable compounds.
The data of the exemplified compounds given in Table 5
show, that these are functional Y5 antagonists4 and in
addition are very selective for the Y5 receptor as no
appreciable affinity to human Y1, Y2 or Y4 receptors
can be observed. Also, selected members of this tricyclic
thiazole class of Y5 antagonists (6, 68 and 76) did not
have any significant activity at over 30 receptors and
ion channels (<50% inhibition at 1 lM).
In addition, protein binding data6 obtained from com-
pound 6 (3.6% free, rat) indicates that this compound is
suitable for in vivo studies. Compound 6 was taken into
further pharmacological evaluation and orally admin-
istered 6 (30 mg/kg) was actually shown to completely
inhibit feeding induced by a selective NPY5 agonist
(i.c.v.) in rats. However, similar to the negative results
previously reported,3n;q 6 (30 mg/kg, p.o.) also did not
reduce free- or fasting-induced feeding in rats.7
In order to assess the potential of the (5,6-dihydro-4H-3-
thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-
amine and (4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azu-
len-2-yl)-piperidin-4-ylmethyl-amine classes as orally
active and brain penetrable NPY Y5 antagonists, plasma
and hypothalamus concentrations at 2 and 6 h after oral
administration of a 30 mg/kg dose to rats were deter-
mined.5 The results are summarised in Table 6. The data
shows that after oral administration both, the (5,6-di-
hydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-
ylmethyl-amino derivatives and (4,5-dihydro-6-oxa-
3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-
amino derivatives, appear to be well absorbed and reach
moderate to high plasma levels and high to very high
hypothalamus levels 2 h after administration. 6 h after
administration both plasma and hypothalamus levels
decreased by a factor of 2–4 in the case of compounds 41,
56–58, 70, 79, 81 and 6. An apparently higher clearance
can be observed for compounds 16 and 68. Several
compounds, that is, 70 with 2 h and 6 h hypothalamus
4. Summary
We have shown that initial combination of structural
elements from a potent Y5 antagonist (2) with thiazole
fragments that exhibit weak Y5 affinities followed
by lead optimisation led to the discovery of (5,6-dihy-
dro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-piperidin-4-yl-
methyl-amino and (4,5-dihydro-6-oxa-3-thia-1-aza-
benzo[e]azulen-2-yl)-piperidin-4-ylmethyl-amino deriva-
tives. Both classes of compounds are capable of deliv-
ering potent and selective orally and centrally available
NPY Y5 receptor antagonists. Despite an attractive
pharmacokinetic profile, and inhibition of Y5 receptor
agonist mediated feeding in rats following oral admin-
istration, compounds such as 6 did not reduce free- or
fasting-induced feeding in rats, which indicates that the
Y5 receptor alone has no significant role in feeding in
these models.

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Acknowledgements
The authors would like to thank S. Di Bello, R. Flam-
mer, R. Gasser, P. Huber, F. Lugrin, M. Mele, D.
Monna, M. Muller, A. Naegele, V. Pawelzik, K. Ryffel,
J. Schmid and R. Wicki for their excellent technical
assistance.
€
References and notes
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5. The oral dose of compounds (30 mg/kg dosed in 20%
Cremophore EL/water (w/w)) was administered via oral
gavage (5 mL/kg) to overnight fasted rats (RA238, Iffa
Credo, males). Samples were collected at 2 and 6 h post-
dosing and concentrations determined by LC–MS. Data
represent mean of 3–6 animals at each time point.
6. Protein binding determined by ultrafiltration as described
by Sebille, B.; Zini, R.; Madjar, C. V.; Thuaud, N.;
Tillement, J. P. J. Chromatogr. 1990, 531, 51.
7. Detailed pharmacology data of 6 will be published in due
course.