Design and synthesis of novel potent and selective integrin αvβ3 antagonists-Novel synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates

Article abstract of DOI:10.1016/j.bmcl.2007.11.089

An unexpected ring contraction of benzazepinone based α_vβ₃ antagonists led to the design of quinolinone-type derivatives. Novel and efficient synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates were establis

Full text of DOI:10.1016/j.bmcl.2007.11.089

Available online at www.sciencedirect.com
Bioorganic & Medicinal Chemistry Letters 18 (2008) 527–531
Design and synthesis of novel potent and selective integrin
avb3 antagonists—Novel synthetic routes to isoquinolinone,
benzoxazinone, and quinazolinone acetates
c
a,
b
b
c
*
´
Werner Seitz, Herve Geneste, Gisela Backfisch, Jurgen Delzer, Claudia Graef,
¨
Wilfried Hornberger,a Andreas Kling,a Thomas Subkowskic and Norbert Zimmermannc
aAbbott, Neuroscience Discovery, D-67008 Ludwigshafen, Germany
bAbbott, DMPK, D-67008 Ludwigshafen, Germany
cBASF AG, Main Research Laboratory, D-67056 Ludwigshafen, Germany
Received 26 September 2007; revised 21 November 2007; accepted 21 November 2007
Available online 28 November 2007
Abstract—An unexpected ring contraction of benzazepinone based avb3 antagonists led to the design of quinolinone-type deriva-
tives. Novel and efficient synthetic routes to isoquinolinone, benzoxazinone, and quinazolinone acetates were established. Nanomo-
lar avb3 antagonists based on these new scaffolds were prepared. Moreover, benzoxazinones 15a and 15b exhibited high microsomal
stability and good permeability.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The avb3 receptor belongs to the integrin class of cell
adhesion receptors which are capable of mediating both
cell–cell and cell-extracellular matrix (ECM) interac-
tions.1 The integrins were named in 1986 by Hynes to
emphasize their role in integrating the intracellular cyto-
skeleton with the external milieu.2 These cell surface
receptors are composed of noncovalently associated a
and b chains that combine to give a wide array of het-
erodimers with distinct cellular and adhesive specifici-
ties. At least 18 a subunits and 8 b subunits form a
superfamily of 24 receptors. These multifunctional mol-
ecules have been shown to play a role in the regulation
of cellular adhesion, migration, invasion, proliferation,
apoptosis, and gene expression. Antagonists of integrins
aIIbb3 (also called GPIIb/IIIa) and avb3 have typically
been designed after the bioactive arginine–glycine–
aspartate (RGD) conformations of peptides derived
from their primary ligands, fibrinogen and vitronectin,
respectively.3 Examples of the disease states that have
a strong b3 integrin-dependent component in their etiol-
ogies are thrombosis (integrin aIIbb3), unstable angina
(GPIIb/IIIa), and restenosis (integrins avb3 and aIIbb3).4
The selective inhibition of the avb3 integrin has been
postulated to present a therapeutic approach for the
treatment of a variety of diseases, including diabetic ret-
inopathy and a variety of remodeling disorders such as
osteoporosis, restenosis, and the angiogenesis compo-
nent of cancer.1,5
In a previous report,6 we showed that the oral bioavail-
ability (in rat) of a tetrahydrobenzazepinone derivative
could be substantially enhanced when administered as
ethyl ester prodrug (compound 2b, Scheme 1). Two
ways were tried in parallel for its preparation7: transeste-
rification of the tert-butyl ester 2a, or esterification of
the corresponding acid 1. Surprisingly, under transeste-
rification conditions,7 the expected 1,3,4,5-tetrahydrob-
enzazepinone ethyl-acetate 2 was obtained only as side
product.8 The structure of the major product could be
elucidated by means of 2D NMR experiments as the
3,4-dihydroquinolinone ethylpropanoate 3 (see Support-
ing Information). The following mechanism was postu-
lated for the ring contraction9: cleavage of the amide
bond of the 7-membered lactam under acidic attack
and formation of the thermodynamically favored 6-
membered ring (Scheme 1). The nanomolar activity of
4 (IC50 27.3 nM, in a competitive ELISA using vitronec-
tin as natural ligand) prompted us to look in more detail
Keywords: Ring contraction; Benzazepinone; Isoquinolinone; Benzox-
azinone; Quinazolinone; Integrin; avb3; 2D NMR; ELISA; Micro-
somal metabolic stability; Caco-2 permeability.
*
Corresponding author. Tel.: +49 621 589 3423; fax: +49 621 589
63423; e-mail: herve.geneste@abbott.com
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.11.089

528
W. Seitz et al. / Bioorg. Med. Chem. Lett. 18 (2008) 527–531
O
saponification (Scheme 2). 1H-Quinolin-2-one deriva-
tives 9 (Table 2) were prepared from 812,13 following
the same route.
O
NHR´
NHR´
O
NH
NH
O
OEt
OEt
For the analogous propionic acids (compounds 4), an
alternative synthetic route to the ring contraction of
the corresponding benzazepinone derivative (Scheme
1) was established. Synthesis started with diester 10,13
hydrogenation was carried out smoothly on PtO2, and
final compounds 4 were obtained following a 3-step se-
quence similar to the one described above (Scheme 3).
OEt
O
O
OEt
a or b
O
O
N
NHR´
O
NHR´
N
A novel synthetical path, which is common to both the
1,4-dihydro-benzo[d][1,3]oxazin-2-one (15, X = O) and
the 3,4-dihydro-1H-quinazolin-2-one (20, X = NH)
derivatives, was designed starting from the correspond-
ing 3-hydroxy-3-(2-amino-phenyl)-propionic ester 1114
and the protected 3-amino-3-(2-amino-phenyl)-propi-
onic ester 16b,15 respectively. Anilines 11 and 16b were
N-alkylated and the formed intermediates 12 and 17
cyclized using ‘triphosgene’ or CDI, respectively. Final
compounds 15 and 20 were obtained after cleavage of
esters 13 and 18, condensation with the required amine,
and final cleavage of the tert-butyl esters 14 and 19
(Scheme 4).
O
OR
O
O
OR´´
R = H (1) or t-Bu (2a)
[R = Et (2b)]
R´´ = Et (3)
R´´ = H (4)
c
Scheme 1. Reagents and conditions: (a) from 1: EtOH, HCl, 5 d, rt;
(b) from 2a: EtOH, HCl, 4 h, reflux, 83%; (c) NaOH, EtOH, H2O, 1 h,
reflux, 35%.
at quinolinone-type derivatives for their potential as
avb3 antagonists.
The commercially available 2-cyanomethyl-benzoic acid
ethyl ester 21 was chosen as starting material for the
synthesis of the 3,4-dihydro-2H-isoquinolin-1-one deriv-
atives 26. The benzylic position of 21 was deprotonated
with LDA and quenched with tert-butyl bromo acetate.
Nitrile 22 was hydrogenated to afford intermediate 23
which cyclized spontaneously (yield 64%). Finally after
N-alkylation, saponification of the methyl ester, conden-
sation, and tert-butyl ester cleavage, compounds 26 were
isolated with 64–66% yield (Scheme 5).
Here we present the synthesis and SAR of novel avb3
antagonists based on the 3,4-dihydro-1H-quinolin-2-
one, 1,4-dihydro-benzo[d][1,3]oxazin-2-one, 3,4-dihy-
dro-1H-quinazolin-2-one, 1H-quinolin-2-one, and 3,4-
dihydro-2H-isoquinolin-1-one cores.
3,4-Dihydro-1H-quinolin-2-one derivatives 7 were pre-
pared starting from ethyl ester 510 after N-alkylation,
cleavage of the tert-butyl ester, condensation of acid 6
with the corresponding amine [(4-trans-aminomethyl-
cyclohexyl)-(1H-benzoimidazol-2-yl)-amine or (4-ami-
nomethyl-phenyl)-(1H-benzoimidazol-2-yl)-amine)]
using TOTU11 as coupling reagent, and subsequent
Compounds 4, 7, 9, 15, 20, and 26 were evaluated for
avb3 inhibition by means of competitive ELISA using
vitronectin as natural ligand. Compounds displaying
IC50 values >10 lM were considered as ‘not active’.
Specificity versus aIIbb3 was examined routinely for
compounds displaying an IC50 avb3 < 100 nM. All com-
pounds discussed showed at least 1000-fold selectivity. If
not indicated otherwise, compounds were screened as
racemic mixtures.
O
O
NHR´
O
OR
O
H
N
O
N
N
c
a
CO2Et
CO2R
CO2Et
-Bu
R =
t
R = Et
R = H (7)
b
d
5
R = H
(6)
O
O
O
O
OtBu
O
OR
O
NHR´
O
N
N
N
NHR´
O
a
c
H
N
O
N
CO2Et
CO2Et
CO2R
n = 1,2
(
(
)
)
n
n
CO2Et
CO2H
R = Et
R = H
R = t-Bu
d
b
10
9
8
(4)
R = H
Scheme 2. Reagents and conditions: (a) tert-butyl bromo acetate,
K2CO3, DMF, 12 h, rt, quant.; (b) TFA, CH2Cl2, 5 h, rt, 72%; (c)
R0NH2, TOTU, NMM, DMF, 12 h, 0 ꢁC-rt, 84% (Q = 1,4-trans-
cyclohexyl)/34% (Q = 1,4-phenyl); (d) NaOH (1 M), dioxane, H2O,
3 h, rt, 90% (Q = 1,4-trans-cyclohexyl)/84% (Q = 1,4-phenyl).
Scheme 3. Reagents and conditions: (a) H2, PtO2, 9 h, rt, 67%; (b)
TFA, CH2Cl2, 12 h, rt, 59%; (c) R0NH2, TOTU, NMM, DMF, 14 h,
0 ꢁC-rt, 25% (Q = 1,4-trans-cyclohexyl)/29% (Q = 1,4-phenyl); (d)
NaOH (1 M), dioxane, H2O, 4 h, rt, 79% (Q = 1,4-trans-cyclohexyl)/
76% (Q = 1,4-phenyl).

W. Seitz et al. / Bioorg. Med. Chem. Lett. 18 (2008) 527–531
529
NH2
OH
11
a
O
Ot-Bu
OMe
NH2
O
O
Ot-Bu
23
O
H
N
O
O
O
OBn
O
O
Ot-Bu
b
b
a
OMe
CN
NH
OR
O
NHR´
O
OMe
CN
N
OH
O
O
N
d
12
Ot-Bu
Ot-Bu
X
X
24
k
21
22
H
O
N
O
Ot-Bu
OR
OMe
Ot-Bu
O
O
O
O
NHR´
OR
(X=O)
(X=NH)
NH2
O
(X=O) (X=NH)
(14 , 19)
N
O
N
O
e
c
R =
t
-Bu
R = Bn (13) or Me (18)
R = H
O
17
O
c or l
e
(15 , 20)
R = H
OR
j
Ot-Bu
NO2
R = H, R´ = Me
R = Cbz, R´= Me
R = Cbz, R´= H
NH2
(16a)
R =
t-Bu
i
f
g
(25)
R = Me
R = H
f
d
(26)
R = H
OR´
Ot-Bu
h
O
NHCbz
NHR O
R = Cbz, R´= t-Bu
Scheme 5. Reagents and conditions: (a) LDA, tert-butyl bromo
acetate, THF, 1 h, ꢀ78 ꢁC, 57%; (b) H2, PtO2, EtOH, AcOH, 2.5 h,
rt, 64%; (c) methyl bromo acetate, K2CO3, DMF, 2 d, rt; (d) NaOH
(1 M), dioxane, H2O, 4 h, rt, 46%; (e) R0NH2, TOTU, NMM, DMF,
2 d, 0 ꢁC-rt, 69% (Q = 1,4-trans-cyclohexyl)/48% (Q = 1,4-phenyl); (f)
HCl(4 N)/AcOH (1:1, vol/vol), dioxane, 12 h, rt, 66% (Q = 1,4-trans-
cyclohexyl)/64% (Q = 1,4-phenyl).
16b
Scheme 4. Reagents and conditions: (a) benzyl bromo acetate,
DIPEA, DMF, 3 d, rt, 77%; (b) 1—bis(trichloromethyl)carbonate
(‘triphosgene’), DIPEA, THF, 1.5 h, rt; 2—CH3CN, DMAP, 1 h, rt;
(c) if X = O: H2, Pd/C, EtOAc, 40 min, rt, 75%; (d) R0NH2, TOTU,
NMM, DMF, 1 h, 0 ꢁC, X = O 69% (Q = 1,4-trans-cyclohexyl)/75%
(Q = 1,4-phenyl); X = NH 52% (Q = 1,4-trans-cyclohexyl)/84%
(Q = 1,4-phenyl); (e) HCl(4 N)/AcOH (1:1, vol/vol), dioxane, 3–12 h,
rt, X = O 35% (Q = 1,4-trans-cyclohexyl)/12% (Q = 1,4-phenyl);
X = NH 67% (Q = 1,4-trans-cyclohexyl)/51% (Q = 1,4-phenyl); (f)
CbzCl, DIPEA, CH2Cl2, 12 h, rt, 95%; (g) NaOH (1 M), dioxane,
H2O, 12 h, rt, quant.; (h) Perchloric acid, tert-butyl acetate, 6 h, rt,
82%; (i) H2, RaNi, MeOH, 1 h, rt, 97%; (j) 1—Methyl bromo acetate,
DIPEA, DMF, 50 h, rt, 84%; 2. H2, Pd/C (10%), MeOH, 40 min, rt,
98%; (k) CDI, dioxane, 12 h, rt, 72%; (l) if X = NH: NaOH (1 M),
dioxane, H2O, 30 min, 10 ꢁC, 81%.
Table 1. Dihydroquinolinones, dihydrobenzoxazinones, and dihydro-
quinazolinones
O
H
N
H
N
N
H
Q
N
O
N
X
(
)
n
COOH
a
Compound
X
n
Q
avb3 IC50 (nM)
Based on the SAR gained with previous series,6,16,17 two
basic moieties were selected to test the potential of the
new scaffolds as cores for avb3 antagonists. These two
aminobenzimidazole residues, whose spacer to the argi-
nine mimetic differs in terms of length and flexibility (in
one case a cyclohexyl, in the other a phenyl group), have
been shown to contribute to high affinity to the avb3
receptor when combined with various other cores.6,16,17
1a6
1b6
7a
(CH2)2
(CH2)2
CH2
CH2
CH2
CH2
O
1
1
1
1
2
2
1
1
1
1
Cyclohexyl
Ph
1.5
4.4
7.4
50
Cyclohexyl
Ph
7b
4a
Cyclohexyl
Ph
27
4b
50000
0.7
4.2
13
15a
15b
20a
20b
Cyclohexyl
Ph
O
NH
Cyclohexyl
Ph
NH
37
Compared to the data obtained within the correspond-
ing benzazepinone series 1,6 the fused 6-membered ring
(X = CH2) is better tolerated when Q is cyclohexyl and
n = 1 (compound 7a, Table 1). The diminished distance
between the Asp and Arg mimetics—induced by the
smaller ring size—cannot be compensated by a longer
spacer to the acidic function (n = 2, compounds 4a and
4b), as one might have thought. As already reported
by us,6 replacement of phenyl by cyclohexyl favors
nanomolar and in one case sub-nanomolar activity
(compound 15a, X = O). The variation of X within the
cyclohexyl series only plays a ‘fine tuning’ role (IC50 of
ca. 10 nM and below), whereas the activity of the phenyl
derivatives highly depends on the central bicycle and
varies between 4.2 and 50 nM (compounds 15b and 7b,
resp.). However, the geometry of the benzoxazinone
a Values are means of three experiments; intra-assay variation <10%,
inter-assay variation < factor 2; cyclohexyl: 1,4-trans-cyclohexyl; Ph:
1,4-phenyl.
scaffold (X = O) seems to be preferred affording the
most active compounds in the two series (15a and
15b). The large difference in activity between derivatives
4a and 4b in the elongated series (n = 2) was unexpected:
the more flexible cyclohexyl group seems to better
accommodate the elongated propionic acid chain.
The former observations were confirmed in the 1H-quin-
olin-2-one series 9 (Table 2):

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W. Seitz et al. / Bioorg. Med. Chem. Lett. 18 (2008) 527–531
Table 2. Quinolinones
Table 3. Dihydro-isoquinolinones
O
O
N
H
N
H
N
H
N
N
H
Q
Q
N
H
N
X
N
H
N
O
N
O
COOH
(
)
n
COOH
a
Compound
X
Q
avb3 IC50 (nM)
a
Compound
n
Q
avb3 IC50 (nM)
27a6
27b6
26a
(CH2)2
(CH2)2
CH2
Cyclohexyl
Ph
11
122
9a
9b
9c
9d
1
1
2
2
Cyclohexyl
Ph
10
50
Cyclohexyl
Ph
10,000
10,000
Cyclohexyl
Ph
1000
500
26b
CH2
a Values are means of three experiments; intra-assay variation <10%,
inter-assay variation < factor 2; cyclohexyl: 1,4-trans-cyclohexyl; Ph:
1,4-phenyl.
a Values are means of three experiments; intra-assay variation <10%,
inter-assay variation < factor 2; cyclohexyl: 1,4-trans-cyclohexyl; Ph:
1,4-phenyl.
Table 4. Potency, selectivity, and ADME parameters of selected
compounds
• elongation of the spacer (n = 2) disfavors the avb3
activity (compounds 9c and 9d);
• when n is 1, only the cyclohexyl spacer allows low nM
activity (compound 9a).
Compound aVb3/VN
aIIbb3/Fg
a5b1/FN
Caco-2
ELISAa
ELISAa
Adhesionb Permeation
c
IC50 (nM) IC50 (nM) Inhibition assay Papp
at 10ꢀ5 M (cm/s · 10ꢀ6
)
15a
15b
0.7
4.2
>10,000
>10,000
25%
8%
3.23
3.48
The retro-orientation of the lactam in the 3,4-dihydro-
2H-isoquinolin-1-one series is detrimental for the avb3
activity (compounds 26a and 26b, Table 3). Compared
to the benzazepinone series (compounds 27a and
27b),6 this effect is even more pronounced, again con-
firming that the distance between the acidic and the ba-
sic group has a major influence on the activity of avb3
antagonists.1 However, the spatial arrangement of the
acidic and basic groups is also a determining parameter:
comparison of benzazepinones 27 with the more con-
strained isoquinolinones 26 suggests that the more flex-
ible 7-membered ring might compensate more efficiently
the shorter distance between the 2 groups.
a Values are means of three experiments; intra-assay variation <10%,
inter-assay variation < factor 2.
b Cell adhesion and migration: values are means of 4 experiments;
intra-assay variation <20%, inter-assay variation < factor 2.
c Papp = Apparent Permeability coefficient; n = 2, intra-assay variation
<20% (Papp values >2eꢀ7 cm/s are considered as medium,
>2eꢀ6 cm/s as high transport rate). Abbreviations: VN, vitronectin;
Fg, fibrinogen; FN, fibronectin; r-d-h, rat, dog, human.
Hoffmann, Michael Lang, and Dirk Mayer for assay
development and screening.
Benzoxazinones 15 with nanomolar and sub-nanomolar
avb3 activity were further characterized and exhibited
(Table 4):
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.bmcl.2007.11.089.
• high selectivity versus aIIbb3 and a5b1;
• microsomal metabolic stability18 in rat, dog, and
human;
• good permeability in the Caco-2 model.19
References and notes
In summary, novel routes for the synthesis of 3,4-dihy-
dro-1H-quinolin-2-ones 7, 1,4-dihydro-benzo[d][1,3]-
oxazin-2-ones 13, 3,4-dihydro-1H-quinazolin-2-ones
18, and 3,4-dihydro-2H-isoquinolin-1-ones 24 were pre-
sented. These new scaffolds could serve as central core
for the design of potent and selective integrin avb3
antagonists (e.g., benzoxazinones 15 with nanomolar
and sub-nanomolar avb3 activity). Based on their favor-
able in vitro ADME profile, PK studies as well as in vivo
screening in different disease models are planned for 15a
and 15b.
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Acknowledgments
7. Transesterification has been run under acidic conditions in
ethanol for 2 h at reflux; esterification of acid 1 in ethanol
catalyzed by HCl for 5 d at rt.
We thank Egon Fleischer, Alfred Michel, for supporting
chemical synthesis, our analytical department, Ramona

W. Seitz et al. / Bioorg. Med. Chem. Lett. 18 (2008) 527–531
531
8. HPLC analysis after transesterification and esterification7
revealed 2 peaks depicting the same molecular mass (LC–
MS: 532) but with opposite (HPLC-) ratios: ca. 30:70 after
transesterification and ca. 80:20 after esterification. When
reflux was continued (further 2 h) under transesterification
conditions, a single product was obtained (corresponding to
the major component of the former mixture). Structure
assignment of 3,4-dihydroquinolinone ethylpropanoate 3
was achieved by means of 2D NMR experiments (HSQC,
HMBC, see Supporting Information). The corresponding
1,3,4,5-tetrahydrobenzazepinone ethyl-acetate 2 could be
finally prepared by activating the carboxyl group with the
BOP reagent in smooth conditions, according to: Diago-
Meseguer, J.; Palomo-Coll, A. L.; Fernandez-Lizarbe, J. R.;
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18. Measured in % recovery of parent after 1-h incubation at
37 ꢁC with liver microsomes (rat, dog, and human) in the
presence of NADPH: 98–100% stable, 92–97% moderate
stability, <92% unstable.
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