A novel Pd-catalyzed cyclization reaction of ureas for the synthesis of dihydroquinazolinone p38 kinase inhibitors

Article abstract of DOI:10.1016/j.bmcl.2003.11.006

A series of potent p38 inhibitors based on the dihydroquinazoline scaffold was synthesized using a novel Pd-catalyzed cyclization reaction of aryl-benzyl ureas. Optimization of this compound class led to compound 20, which inhibits p38α in vitro with IC₅₀=14 nM and is active in the mouse TNFα-release model.

Full text of DOI:10.1016/j.bmcl.2003.11.006

Bioorganic & Medicinal Chemistry Letters 14 (2004) 357–360
A novel Pd-catalyzed cyclization reaction of ureas for the
synthesis of dihydroquinazolinone p38 kinase inhibitors
Achim Schlapbach,* Richard Heng and Franco Di Padova
Novartis Institute for Biomedical Research, Arthritis and Bone Metabolism, Lichtstrasse, CH-4002 Basel, Switzerland
Received 25 August 2003;revised 29 October 2003;accepted 3 November 2003
Abstract—A series of potent p38 inhibitors based on the dihydroquinazoline scaffold was synthesized using a novel Pd-catalyzed
cyclization reaction of aryl-benzyl ureas. Optimization of this compound class led to compound 20, which inhibits p38a in vitro
with IC50=14 nM and is active in the mouse TNFa-release model.
# 2003 Elsevier Ltd. All rights reserved.
1. Introduction
In recent years enormous interest has been generated in
the evaluation of inhibitors of p38 MAP kinase as anti-
inflammatory drugs.1 It is well established that inhibi-
tion of p38 blocks release of IL-1, TNFa, IL-6 and
other cytokines from monocytes.2 As these cytokines
are recognized as key players in the development and
progression of inflammatory conditions like RA, an
orally bioavailable small molecule p38 inhibitor would
be highly desirable.
Scheme 1.
Synthesis of the dihydroquinazolinones started with a-
arylamino phenylacetic acids, the most prominent
example being diclofenac 3 (Scheme 2). Curtius degra-
dation using DPPA6 led directly to the formation of the
desired core structure 2 via intramolecular ring closure
of the intermediate isocyanate. The 6-position could
now easily be further functionalized. Bromination of the
dihydroquinazolinone 2 followed by Pd-catalyzed cou-
pling with 2,4-difluoro-thiophenol gave diaryl sulfide 4.
2. Results and discussion
While the prototypic p38 inhibitor SB203580,3 a pyr-
idyl-imidazole served as lead in our initial drug design
efforts,4 we performed a high throughput screen to
identify structurally novel p38 inhibitors. One of the hits
identified was the quinazolinone 1, which inhibited p38
with an IC50 of 14 mM. At the same time a vaguely
related structure VX475 was published by Vertex.5 We
recognized some similarities of these two novel tem-
plates and speculated that they could adopt similar
binding modes. Variations of the initial hit structure
based on this hypothesis led to the dihy-
droquinazolinone template, exemplified by the proto-
type compound 2. Herein, we now wish to report on the
synthesis as well as the SAR of this novel series of p38
inhibitors (Scheme 1).8
Scheme 2. (a) Diphenylphosphoryl azide, NEt3, dimethoxyethane,
reflux, 2 h, 63%;(b) Br , CH2Cl2, rt, 12 h, 35%;(c) 2,4-difluoro-thio-
phenol, Pd(PPh3)4, NaOtBu, toluene, reflux, 16 h, 10%.
* Corresponding author. Tel.: +41-61-324-4308;fax: +41-61-324-
8847;e-mail: achim.schlapbach@pharma.novartis.com
2
0960-894X/$ - see front matter # 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2003.11.006

358
A. Schlapbach et al. / Bioorg. Med. Chem. Lett. 14 (2004) 357–360
Nitration (Scheme 3), followed by reduction of the nitro
group with H2/Pd gave the 6-amino-dihydroquinazolinone
5, which served as starting material for arylamines,
benzylamines, carboxamides or sulfonamides.
sulfonamide moiety improved potency significantly.
Encouraged by this initial result the sulfonamide series
was chosen for further optimization. SAR around the
sulfonamide moiety is given in Table 2.
Table 2. SAR of sulfonamide derivatives
R1
R2
p38a
IC50 (mM)
TNFa-release
IC50 (mM)
8
10
11
Phenyl
2-Chlorophenyl
2,5-Dichlorophenyl
H
H
H
H
H
0.053
0.180
0.100
0.570
1.80
0.140
0.510
0.390
n.d.
>10
0.084
1.20
12 2-Hydroxy-5-chlorophenyl
13
14
15
4-Tolyl
3-Chloro-4-fluorophenyl
2,5-Dichlorophenyl
H
CH3
0.034
0.780
Scheme 3. (a) KNO3, H2SO4, 0 ꢀC–rt, 18 h, 81%;(b) H , Pd/C, etha-
2
The unsubstituted benzene sulfonamide 8 is already a
very potent inhibitor of p38. Substituents in ortho posi-
tion reduce activity;the same is true for substitutions in
para position. A lipophilic substituent in meta position,
however, leads to an increase in potency. The optimal
substitution pattern is present in the 3-chloro-4-fluoro-
benzene sulfonamide 14. Interestingly, alkylation of
either the sulfonamide nitrogen, or the dihy-
droquinazolinone nitrogen (data not shown) reduce
activity dramatically.
nol, rt, 16 h, 88%;(c) 2,4-difluoro-bromobenzene, Pd 2dba3, DPEphos,
NaOtBu, toluene, reflux 5 h, 10%;(d) benzaldehyde, NaBH 3CN, 3%
AcOH in DMF, rt, 16 h, 31%;(e) benzoyl chloride, NEt , THF, rt, 3
3
h, 90%;(f) benzenesulfonyl-chloride, cat. DMAP, pyridine, rt, 16 h,
56%.
In Table 1, p38 inhibition data9 as well as cellular
activities, TNFa release from LPS stimulated
hPBMCs10 of these initial 6-substituted derivatives are
given.
Next, we turned our attention to the 1-aryl substituent
of the dihydroquinazolinone core. It quickly became
apparent that for compounds containing aryl residues
which did not have two ortho substituents, a different
synthesis strategy was necessary as in these cases the
main product from the Curtius reaction protocol was
simply the cyclic amide. Thus we explored the intramo-
lecular cyclization reaction of phenyl-benzyl ureas to
give the desired dihydroquinazolinone core structure.
(Scheme 4).
Table 1. SAR of the dihydroquinazolinone-6-substituent
R1
X
p38a
IC50 (mM)
TNFa-release
IC50 (mM)
2
6
4
7
8
9
H
Phenyl
2,4-Difluorophenyl
2,4-Difluorophenyl
Phenyl
—
CONH
S
11.8
8.5
0.47
0.38
0.053
0.150
n.d.
10
0.96
0.29
0.140
1.20
N
SO2NH
CH2–N
Phenyl
As expected from our binding hypothesis, an aromatic
substituent in the 6-position of the dihydroquinazo-
linone is crucial for potent inhibition of p38. Further-
more the linking unit has a great influence on potency as
well. Thus, the benzamide 6 is only marginally more
potent than the unsubstituted core structure. In contrast
to our expectations, a 2,4-difluorophenyl thioether 4 as
well as the corresponding diarylamine 7 improved
potency only modestly and both were still rather weak
p38 inhibitors. We were, however, pleased to see that a
Scheme 4. (a) Boc2O, DMAP, CH2Cl2, rt–40 ꢀC, 16 h, 59%;(b)
CH2Cl2, rt, 16 h, 49–91%.

A. Schlapbach et al. / Bioorg. Med. Chem. Lett. 14 (2004) 357–360
359
Table 3. Intramolecular cyclization of phenyl benzyl ureas
Yield (%)a,b
Monodentate ligands, for example P(o-tolyl)3 or P(2-
furyl)3 have been reported for the intramolecular cycli-
zation of secondary amides.11b Some of the most effi-
cient ligands for the amination of aryl chlorides are
bulky electron rich ones.13 In our hands, for the cycli-
zation of ureas, 2-(dicyclohexylphosphino)-biphenyl
was found to be the ligand of choice. Employing K3PO4
as base and Pd2dba3 as the palladium source, aryl-benzyl
ureas cyclized smoothly to the desired dihydroquin-
azolinones (Table 3). The reaction works using either
activated aryl-chlorides (entries 1–6) or aryl bromides
(entry 7). Good to excellent yields were obtained
regardless of the substitution pattern of the aryl sub-
stituent. Suitable solvents were found to be dimethoxy-
ethane, dioxane or DMF. In the case of the silyl-
protected phenol 17a cyclization and removal of the
silyl group to give 18b could be achieved in one step
using DMF instead of dimethoxyethane (entry 2).14
Urea
Product
1
53c
2
3
4
5
6
7
92d
60e
88e
67e
89d
93c
Further elaboration of compound 18b via alkylation of
the phenolic hydroxy group, nitro reduction and finally
acylation using 3-chloro-4-fluoro-benzene-sulfonyl
chloride led to compound 20 (Scheme 5).
Scheme 5. (a) Chloropropyl-morpholine, cat. CsI, DMF, 130 ꢀC, 16 h,
49%;(b) H 2, Pd/C, MeOH, rt, 16 h, 98%;(c) 3-chloro-4-fluoro ben-
zenesulfonylchloride, pyridine, DMAP, CH2Cl2, rt, 16 h, 27%.
Compound 20 now has a much more favorable polarity
profile, while still being highly potent (14 nM) on p38.
20 was profiled in an acute in vivo model and showed a
42% inhibition of TNFa release after LPS stimulation
in mice at a dose of 30 mg/kg, po.15 The compound is
highly selective over a series of other kinases and does
not interfere with Cyp450 enzymes.
a All reactions were performed using 0.04 equiv Pd2dba3, 0.12 equiv
2-(dicyclohexyl-phosphino)biphenyl and 1.4 equiv K3PO4 at 100 ꢀC
for 16 h.
b Isolated yield.
c Reaction performed in 1,4-dioxane.
d Reaction performed in DMF.
e Reaction performed in DME.
3. Summary
N-Benzyl-N-phenyl ureas were obtained either by direct
condensation of the benzylamine with phenyl iso-
cyanates, or by treatment of the 4-substituted 2,6-dime-
thyl-phenylamine with Boc2O, DMAP in dichloro-
methane7 followed by the addition of 2-chloro-4-nitro-
benzylamine 16.
In summary, we herein described a novel, very efficient
Pd-catalyzed cyclization sequence leading to potent and
selective p38 inhibitors based on a dihydroquin-
azolinone scaffold which could be used as a starting
point for further optimization.
References and notes
Even though Pd-catalyzed intramolecular cyclizations
are well documented,11 intramolecular cyclizations of
unprotected ureas using Pd have not been reported so
far.12 In order to quickly access diverse dihydro-
quinazolinones the direct Pd-catalyzed cyclization route
was investigated.
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A. Schlapbach et al. / Bioorg. Med. Chem. Lett. 14 (2004) 357–360
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10. Human peripheral blood mononuclear cells were incubated
with the inhibitor and stimulated with LPS/IFNg for 3 h.
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1
mg (92%) of the cyclic urea 18b as a brown powder. H
NMR (DMSO-d6) d 1.9 (6H, s), 4.55 (2H, s), 6.12 (2H, d),
6.52 (2H, s), 7.54 (1H, s, NH), 7.95 (1H, dd), 8.18 (1H, s),
9.55 (1H, s, OH);MS (ESI–): m/z: 312 (100%, (MÀH)À).
15. 8-Week old female OF1 mice were dosed perorally by
gavage with solutions of the compound in DMSO/cor-
noil. 1 h after dosing LPS (20 mg/kg) was injected iv.
After another hour blood was collected and TNFa levels
were determined using a mouse-specific ELISA.
9. A phosphorylated form of His-p38a MAP kinase of
murine origin (10 ng/well) and immobilized GST-ATF-2