New substituted triaza-benzo[cd]azulen-9-ones as promising phosphodiesterase-4 inhibitors

Full text of DOI:10.1016/j.bmcl.2004.03.067

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3303–3306
New substituted triaza-benzo[cd]azulen-9-ones as promising
phosphodiesterase-4 inhibitors
*
ꢀ
Ingrid Devillers, Isabelle Pevet, Henry Jacobelli, Corinne Durand, Veronique Fasquelle,
ꢁ
Jocelyne Puaud, Bernard Gaudilliere, Moulay Idrissi, Franßcois Moreau
and Roger Wrigglesworth
Pfizer Global Research and Development, Fresnes Laboratories, 3-9 Rue de la Loge, F-94265 Fresnes Cedex, France
Received 18 November 2003; revised 23 March 2004; accepted 25 March 2004
O
O
Cyclic nucleotide phosphodiesterases (PDEs) are a
broad family of enzymes responsible for the hydrolysis
of cyclic c-AMP and c-GMP.1 PDE4 is a specific c-AMP
isoenzyme that is particularly abundant in airway
smooth muscle, immune, and inflammatory cells and is
therefore considered as a potential molecular target for
the development of new immunomodulatory and anti-
inflammatory drugs.2 A number of selective PDE4
inhibitors are under clinical evaluation for the treatment
of asthma, chronic obstructive pulmonary disease
(COPD), and atopic dermatitis.3 Although interest has
grown steadily, the therapeutic potential of PDE4
inhibitors remains hampered by their dose-limiting side
effects such as nausea and emesis.4
N
N
NH
O
NH
O
N
N
R1
N
H2N
N
PDE4 IC50
PDE4 IC50
0.27 µM
1 R1 = Me CI-1018
2 R1= OMe
1.1 µM
4.4 µM
3 -CI-1044
Despite its promising pharmacological profile, the ani-
line structural fragment contained in CI-1044 (3) struc-
ture was considered as
a
toxicophore.7 Aniline
fragments have been implicated in two principal meta-
bolic mechanisms of toxicity. Oxidation of the aromatic
ring either ortho or para to the nitrogen or of the aniline
nitrogen can lead to reactive metabolites, which are
implicated in toxic side effects.
Recently we reported a novel series of tetrahydrodiaze-
pinoindole PDE4 inhibitors. The initial structure–
activity relationship (SAR) studies led to the identifica-
tion of a first candidate for development, CI-1018 (1),5
which was further improved by the discovery of a new
family of 9-amino-tetrahydrodiazepinoindoles. This new
series displayed improved in vitro PDE4 activity and
selectivity versus other PDEs. One specific compound
CI-1044 (3) provided efficient in vivo activity in models
of antigen-induced eosinophil recruitment and produc-
tion of LPS-induced TNFa in rats. This compound was
registered as a candidate for development.6
We now report the targeted synthesis and evaluation of
the triaza-benzo[cd]azulen-9-one system (4) containing
the substituted azaindoline residue obtained by the
replacement of the aniline moiety. Other substituents
were chosen based on previous SAR evaluation with
a methoxy group at position 9 and nicotinic acyl as
an optimized side chain.
O
N
NH
N
MeO 9
N
Keywords: PDE4 inhibitor; Azabenzodiazepine; CI-1044; ortho-Direc-
ted metallation; Pyridine.
O
N
* Corresponding author. Tel.: +33-1-45-80-74-86; fax: +33-1-45-60-38-
01; e-mail: ingriddevillers@hotmail.com
4
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.03.067

3304
I. Devillers et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3303–3306
O
N
NH
NH
O
N
MeO
N
O
N
MeO
N
5
7
5
4
C4
NH2
C2
OtBu
4
N
2
O
MeO
N
O
7
MeO
N
6
7
C2
Pathway 1
C4
Pathway 2
4
NH2
2
MeO
N
8
Scheme 1. Retrosynthetic analysis of 2,3-dihydro-pyrrolo[2,3-c]pyridine.
The retrosynthetic analysis we envisaged is described in
Scheme 1. The key step in the synthesis was the prepa-
ration of 5-methoxy-7-benzoyl substituted 6-azaindoline
(2,3-dihydro-pyrrolo[2,3-c]pyridine) (5). To the best of
our knowledge only few examples of a 2,4-substituted-3-
aminopyridine synthesis are described in the literature.8
Most of the methodologies concerned 4-aminopyridine.9
In this context, we investigated different pathways based
on the ortho-lithiation at halogenated C2 then C4
(pathway 1) or directed ortho-metallation at C4 then C2
(pathway 2), respectively (Scheme 1).
We initially started with our attempts to introduce both
substituent following a general ortho-lithiation strategy.
Unfortunately, in each pathway, the reaction with the
second electrophile failed.10 Therefore we focussed our
attention to the functionalization at position 7 of the
6-azaindoline in the second pathway (step C2, Scheme
1), which ultimately lead to the successful synthesis of
PDE4 inhibitor (4) described in Scheme 2.
The synthesis started with the conversion of the
2-methoxy-5-aminopyridine to the corresponding car-
OH
H
OtBu
N
NH2
N
O
b
c, d
MeO
O
O
MeO
a
N
MeO
N
N
8
9
10
7
O
N
NH
Br
NH
h
f, g
MeO
e
O
N
MeO
N
N
MeO
N
11
5
12
O
O
N
N
i, j
k
l
4a RT = 5.79 min (ee > 99%)
4b RT = 8.15 min (ee = 99%)
NH
NH2
N
N
MeO
N
MeO
N
O
N
13
4
Scheme 2. Reagents and conditions: (a) Boc2O, dioxane, 96%; (b) n-BuLi, TMEDA, ethylene oxide, ether, )78 °C, 57%; (c) MsCl, CH2Cl2, 90%; (d)
LiHMDS, THF, )78 °C, 91%; (e) HBr, H2O2, 75%; (f) Zn(CN)2, Pd2(dba)3, dppf, DMF, 74%; (g) PhMgBr, THF, 55%; (h) methyl glycinate
hydrochloride, pyridine, 48 h, 43%; (i) t-BuOK, trisyl azide, CH3CO2H, THF, )78 °C, 26%; (j) PPh3, H2O, THF, 69%; (k) TOTU, DIPEA, nicotinic
acid, CH2Cl2, 84%; (l) chiral preparative chromatography Chiralcel OD-H, 17 mL/min, 100% CH3CN, 220 nM.

I. Devillers et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3303–3306
Table 1. Phosphodiesterase inhibitory activities for compounds
3305
O
N
R2
N
MeO
X
14
PDE4
Entry
Compounds
X
R2
PDE1
PDE3
PDE5
IC50a, lMa
1
2
14a
12
C
H
H
40
23
52
>100
77
>100
NDb
91
N
NH
3
4
5
6
2e;c
C
4.4
6.1
4.3
73
16
14
5.8
28
41
ND
>100
95
N
O
NH
4 (rac)
4ad
N
N
N
12
O
N
N
N
NH
31
O
NH
4bd
>100
>100
O
a Values are means of three experiments.
b Not determined.
c See Ref. 6.
d Single enantiomer.
bamate (9). The ortho-lithiation of the carbamate at C4
on the pyridine ring using BuLi followed by addition of
ethylene oxide afforded the 4-(2-hydroxyethyl) substi-
tuted amino pyridine (10). The amino alcohol was then
cyclized by conversion to the methylsulfonate. Although
this primary mesylate derivative underwent direct in situ
cyclization, we improved yields by treatment with Li-
HMDS to furnish the pyrrolidino–pyridine compound
(7) as previously described in the literature.9 Again, all
attempts to introduce the substituent at C2 on the pyr-
idine ring failed using the ortho-lithiation reaction.
Therefore we then performed aromatic functionalization
of the pyridine ring. Bromination using HBr in H2O2
gave the N-deprotected 2-brominated pyrrolidino–pyr-
idine compound (11) in one step in good yield.11 Sub-
sequent cyanation12 was performed with an optimized
palladium catalyzed reaction and introduction of the
benzoyl group was achieved by the Grignard reaction13
with phenylmagnesium bromide giving the desired
phenylmethanone compound (5). The latter was con-
verted to the seven-membered ring (12) using methyl-
glycinate hydrochloride following the procedure
previously described.6 The introduction of the primary
amino function was first investigated via oxime con-
version but the subsequent reduction failed or gave a
poor yield for the two steps. Then we turned our
attention to the direct azidation14 using trisyl azide to
favor the azide transfer under carefully controlled
reaction conditions.15 Mild reduction to the primary
amine was accomplished using triphenylphosphine in
THF/H2O16 to provide intermediate (13) while catalytic
hydrogenation led to overreduction of the diazepine
ring. Classical condensation with the appropriate acid
provided final targeted compound (4). Pure enantiomers
(4a and 4b) were obtained after resolution of the racemic
mixture by chiral chromatography.
Inhibitory activities of these compounds have been
determined on different PDE isoenzymes following
procedures previously described.6 Results are presented
in Table 1.
Based on our previous SAR studies, we were interested
to compare whether the introduction of a nitrogen atom
on the benzodiazepine ring would affect the PDE4
activity and selectivity versus other PDEs. Synthetic
intermediates (12 and 14a) already showed weak activity
(entries 1 and 2). According to known SAR, introduc-
tion of the aromatic side chain R2 led to improved
activities for pyridino compounds. Furthermore the
activity range was conserved with the replacement of the
aniline moiety (entries 3 and 4) and only one single
enantiomer (4a) was shown to be active (entry 5).
These promising data open large perspectives for
the preparation of corresponding 9-amino-triaza-benzo-
[cd]azulen-9-one, which remains to be investigated.
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