Impact on farnesyltransferase inhibition of 4-chlorophenyl moiety replacement in the Zarnestra series

Article abstract of DOI:10.1016/j.ejmech.2006.12.007

Based on the structure of R115777 (tipifarnib, Zarnestra), a series of farnesyltransferase inhibitors have been synthesized by modification of the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacem

Full text of DOI:10.1016/j.ejmech.2006.12.007

European Journal of Medicinal Chemistry 42 (2007) 702e714
http://www.elsevier.com/locate/ejmech
Short communication
Impact on farnesyltransferase inhibition of 4-chlorophenyl moiety
replacement in the ZarnestraÒ series
a
a
a
Patrick Angibaud a, , Laurence Mevellec , Christophe Meyer , Xavier Bourdrez ,
Patricia Lezouret a, Isabelle Pilatte a, Virginie Poncelet a, Bruno Roux a,
Sophie Merillon a, David W. End b, Jacky Van Dun c,
*
Walter Wouters c, Marc Venet a,1
a Medicinal Chemistry Department, Johnson & Johnson Pharmaceutical Research and Development (J&JPRD),
Campus de Maigremont BP615, 27106 Val de Reuil, France
b Early Development, Johnson & Johnson Pharmaceutical Research and Development L.L.C., Welsh and McKean Roads,
Spring-House, PA 19477-0776, USA
c Research and Early Development Operations, Johnson & Johnson Pharmaceutical Research and Development,
Turnhoutseweg 30, B-2340, Belgium
Received 3 May 2006; received in revised form 3 December 2006; accepted 5 December 2006
Available online 9 January 2007
Abstract
Based on the structure of R115777 (tipifarnib, ZarnestraÒ), a series of farnesyltransferase inhibitors have been synthesized by modification of
the 2-quinolinone motif and transposition of the 4-chlorophenyl ring to the imidazole or its replacement by 5-membered rings. This has yielded
a novel series of potent farnesyltransferase inhibitors.
Ó 2007 Elsevier Masson SAS. All rights reserved.
Keywords: Farnesyltransferase inhibition; Tipifarnib; Zarnestra; R115777; Anticancer agents
1. Introduction
become clear that the anti-tumoral activity of this class is quite
complex involving other farnesylated proteins such as RhoB,
centromer associated proteins or modulation of transcription
events [11e22]. R115777 1 (tipifarnib, ZarnestraÒ) is a 4-phe-
nylquinolinone that is currently undergoing phase II/III clini-
cal trials for the treatment of haematological and solid
tumors [23e29]. Recently, we reported the synthesis and ac-
tivity of highly potent analogues of 1, namely tetrazoloquino-
line 2 and tetrazolo[1,5-a]quinazoline 3 (Fig. 1) [30].
In this paper we report our further efforts to design novel
inhibitors of FTase using 2 and 3 as templates. To help in
this task, we initiated a molecular modeling study aiming at
better understanding of the binding mode of R115777 and
related analogs. Compound 1 was first submitted to a confor-
mational analysis then manually docked in the FTase catalytic
site by using the structural information available in the litera-
ture (Fig. 2). The docking model was checked against the
Ras gene mutations have been identified in approximately
30% of human cancers [1e4], evidence has prompted consid-
erable efforts to elucidate the pathways of Ras transforma-
tions. The discovery that farnesylation is a key step for Ras
transforming activity has generated considerable interest in
the development of farnesyltransferase inhibitors (FTIs) as
potential therapeutic agents [4e8]. And indeed, many FTIs
have demonstrated excellent anti-tumoral efficacy in preclini-
cal human xenograft models [9,10]. While some of these com-
pounds are undergoing phase II/III clinical trials, it has
* Corresponding author. Tel.: þ33 2 32 61 74 57; fax: þ33 2 32 61 72 98.
E-mail address: pangibau@prdfr.jnj.com (P. Angibaud).
1
Current address: NOVASEP, rue Democrite, 72000 Le Mans, France.
0223-5234/$ - see front matter Ó 2007 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2006.12.007

P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
703
Fig. 1. Modifications of R115777 1 and tetrazolo heterocycles 2, 3 led to novel inhibitors of FTase 4e5.
structureeactivity relationships (SAR) of the tipifarnib series
and, combined with in-house knowledge and literature data
[25e32], served as a basis for rational chemical modifications.
We hypothesized that transposition of the 4-chlorophenyl sub-
stituent to the methyl group of the imidazole ring should be
allowed without drastic effect on binding. This was confirmed
by a separate docking study of compound 4a. We also report
on the direct replacement of this substituent with 5-membered
heterocycles and emphasize on the related SAR.
2. Chemistry
Bromineelithium exchange in 2-chloroquinoline 8 [34] and
addition of aldehyde 7 [35] onto the resulting 6-lithio-quino-
line provided the alcohol 9 in low yield (Scheme 1). Tetrazo-
loquinoline backbone was then obtained by reacting the
2-chloroquinoline with sodium azide to provide 4a. The 4-
cyanobenzyl derivative 4b was obtained following the same
sequence.
Bromineelithium exchange in 10 [34] gave in situ 5-lithio-
3-(3-chlorophenyl)benzo[c]isoxazole which was reacted with
commercially available 5-chlorothiophen-2-carboxaldehyde
Fig. 2. Docking of molecule 1 (capped sticks) within the FTase catalytic site.
Alpha-hydroxyfarnesyl-phosphonic acid (HFP) (violet lines) is sitting along
the ‘‘right’’ wall of the catalytic site. The two water-mediated hydrogen bonds
between 1 and HFP are shown as yellow dashed lines. This binding mode has
been confirmed later by the elucidation of the X-ray structure of the FTase/
tipifarnib/farnesyl pyrophosphate (FPP) complex [33]. (For interpretation of
the references to colors in the figure legends, the reader is referred to the
web version of this article.)

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P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
Scheme 1. (a) n-BuLi, THF, ꢀ70 ꢁC, 1 h then addition of 7, ꢀ70 ꢁC, 1 h to RT, 16 h (16%); (b) NaN3, DMF, 140 ꢁC, 16 h (25%).
to provide alcohol 11 (Scheme 2). After oxidation of the hy-
droxyl group into a ketone moiety, the benzisoxazole ring was
reduced to ortho-aminobenzophenone 13 using titanium tri-
chloride Lewis acid. Acylation of 13 with trichloroacetyl chlo-
ride provided the corresponding amide 14 and in situ
cyclisation by heating 14 with ammonium acetate in DMSO
gave the quinazolinone 15 in good yield. Upon refluxing in
POCl3 15 was converted to 2-chloroquinazoline 16. Then 1-
methylimidazole was first deprotonated at C-2 by action of
n-butyllithium and the resulting carbanion was silylated. In
the same pot, further deprotonation at C-5 by n-butyllithium
and condensation of ketone 16 at low temperature provided
the alcohol 17 in a yield of 24%. Compound 17 was then con-
densed with sodium azide to provide the tetrazolo[1,5-a]qui-
nazoline 18, which was subsequently reacted with thionyl
chloride and ammoniac to provide 5a.
In our hands, bromineelithium exchange on quinazoline 20
[36] and subsequent reaction with DMF was unsuccessful.
Therefore we choose to convert 20 into Weinreb amide 21.
2-Methoxyquinazoline 21 was transformed into 2-chloroqui-
nazoline 22 by reaction with POCl3. Addition of 1-methyl-2-
triethylsilyl-imidazol-5-yl moiety, prepared as described in
Scheme 2, gave ketone 23 which was reduced to alcohol 24
using diisobutylaluminium hydride. After formation of the tet-
razole ring, as already described, conversion of the hydroxyl
group to chloride 26 and substitution of the chlorine atom
by various imidazoles (27e30) provided final compounds
5bee in low yields (Scheme 3).
and the laminB peptide substrate (Biotin-YRASNRSCAIM)
and compared to 1, 2 and 3. The structureeactivity relation-
ships are presented in Tables 1e2 (Fig. 3).
Compound 4a proved to be at least 28-times less potent
towards enzyme inhibition than the corresponding tetrazolo-
quinoline 2 and 100-times less potent than R115777. Docking
of 1 and 4a into the FTase catalytic site led to overall similar
binding modes and energetically stable structures (Figs. 2 and
4). As expected the major differences are due to the impact of
the 4-chlorophenyl transposition. For molecule 1 the 4-chloro-
phenyl ring sits at equal distances from the 3-chlorophenyl
ring on one hand and the HFP hydrophobic tail on the other
hand. It adopts a parallel orientation that enables ideal face-
to-face pi-stacking and alkyl-pi interactions, respectively. In
addition, the primary amino group performs a water-mediated
hydrogen bond with an hydroxyl group of the HFP head. For
molecule 4a, the transposition of the 4-chlorophenyl substit-
uent on the imidazole ring resulted in a less favorable tilted
orientation of the phenyl ring as compared to 1 and in
a docked position very close to the HFP tail. Moreover, in
contrast to compounds 1, 2 and 3, this new structure lacks
the quaternary carbon as a result of the aryl group removal.
It follows that the remaining substituents are less tightly
packed allowing more rotational flexibility around this car-
bon. Although the spatial orientation of the substituents
bearded by this carbon has been preserved during docking,
the water-mediated hydrogen bond between the hydroxyl
moiety and the HFP head got lost upon minimization due
to excessive rotation. These observations may account for
the activity drop of 4a as compared to 1 and 2. Most of
the potency was recovered when replacing the 4-Cl by a 4-cy-
ano group in 4b. This can be explained by a strong electro-
static interaction between the electron-rich cyano group and
3. Results and discussion
All compounds were evaluated for in vitro inhibition of
FTase [22] using the Amersham scintillation proximity assay

P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
705
Scheme 2. (a) n-BuLi, THF, ꢀ70 ꢁC, 1 h (68%); (b) MnO2, dioxane, reflux, 15 h (64%); (c) TiCl3, H2O/THF, RT, 3 h (100%); (d) trichloroacetyl chloride, NEt3,
CH2Cl2, RT, overnight (100%); (e) ammonium acetate, DMSO, 60 ꢁC, 4 h (83%); (f) POCl3, 100 ꢁC, 2 h (88%); (g) (1) 1-methylimidazole, n-BuLi, THF, ClSiEt3,
ꢀ70 ꢁC; (2) n-BuLi, THF, ꢀ70 ꢁC, 1 h (24%); (h) NaN3, DMF, 90 ꢁC, 3 h (66%); (i) SOCl2, 60 ꢁC, 3 h (30%); (j) NH3/iPrOH, THF, RT, 15 h (18%).
the positively charged side chain of Arg 202. However, 4b
was still 10-fold less active than R155777.
We turned our attention rather to 4-chlorophenyl replace-
ment starting from 2-chloro-5-thiophenyl 5a as thiophenyl
can be considered as a good surrogate for a phenyl ring
(Table 2, Fig. 5).
Although less potent, thiophenyl compounds 18 and 5a
were still in the high nanomolar range of activity towards
FTase inhibition thereby proving that 4-chlorophenyl can be
replaced by 5-membered rings. We therefore continued our ef-
forts and tested compounds 5bee where the 4-chlorophenyl
ring has been replaced by substituted imidazoles. When the

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P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
Scheme 3. (a) CH3NHOCH3, CO 5 bar, Pd(PPh3)4, Et3N, dioxane, 100 ꢁC, 18 h (27%); (b) POCl3, DMF, 80 ꢁC, 4 h (59%); (c) 1-methylimidazole, n-BuLi,
ClSiEt3, THF, ꢀ70 ꢁC (27%); (d) DIBAL in toluene, THF, ꢀ70 ꢁC, 4 h (86%); (e) NaN3, DMF, 90 ꢁC, 4 h (84%); (f) SOCl2, 65 ꢁC, 4 h; (g) 2-substitued-1H-im-
idazole, (K2CO3), CH3CN, reflux, 2 h (5e20%).
imidazole is substituted by an alkyl group as in 5b, activity is
comparable to 3, the tetrazoloquinazoline analogue of
R115777. When the substituent is a phenyl group, then activity
is improved to that of R115777. A few examples of
compounds with substitution on the phenyl ring retained over-
all activity. This opens an avenue for further developments.
4. Conclusion
Starting from the structure of R115777 1 (tipifarnib, Zar-
nestraÒ), a novel series of inhibitors of FTase have been
Table 1
Comparison of FPT inhibition for tetrazoloquinolines 4a, 4b, 1 and 2
Compound
R
FTase (enz) IC50 (nM)a
1
e
0.9
3.5
2
e
4a
4b
a
Cl
CN
>100b
11
The concentration required for a 50% reduction of the FPT-catalyzed incor-
porationof [3H]-farnesyl pyrophosphate into a biotinylated laminB peptide [23].
b
Fig. 3.
Inhibition (32%) at 100 nM.

P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
707
Table 2
FTase inhibition for tetrazoloquinazolines 5bee
Compound
R
X
FTase (enz) IC50 (nM)a
1
-
NH2
NH2
OH
NH2
H
0.9
3.5
3
-
18
5a
5b
5c
5d
5e
a
2-Chloro-5-thiophenyl
2-Chloro-5-thiophenyl
2-Et-1-imidazolyl
2-Ph-1-imidazolyl
2-(4-FePh)-1-imidazolyl
2-(3-CNePh)-1-imidazolyl
16
<100b
5
1
4
1
H
H
H
See footnote ‘a’ in Table 1.
Inhibition (69%) at 100 nM.
b
5.1.1. 2-Chloro-4-(3-chlorophenyl)-a-[1-[(4-chlorophenyl)-
methyl]-1H-imidazol-5-yl]-quinoline-6-methanol 9
n-BuLi 1.6 M in hexane (0.0054 mol) was added at ꢀ70 ꢁC
to a solution of 6-bromo-2-chloro-4-(3-chlorophenyl)-quinoline
8 [34] (0.0048 mol) in THF (20 ml) under N2 flow. The mixture
was stirred at ꢀ70 ꢁC for 1 h. A solution of 1-[(4-chlorophenyl)-
methyl)]-1H-imidazole-5-carboxaldehyde 7 [35] (0.0052 mol)
in THF (14 ml) was added at ꢀ70 ꢁC. The mixture was stirred
at ꢀ70 ꢁC for 1 h, then at room temperature overnight, poured
into ice water and extracted with EtOAc. The organic layer
was washed with H2O, dried (MgSO4), filtered, and the solvent
was evaporated. The residuewas purified by column chromatog-
raphy over silica gel (15e40 mm, eluent: CH2Cl2/CH3OH/
NH4OH 97/3/0.2 to 95/5/0.1). The pure fractions were collected
and the solvent was evaporated to afford 16% of 9 (0.76 g). 1H
NMR (400 MHz, DMSO, 27 ꢁC): d ¼ 5.13e5.22 (m, 2H,
CH2-Im), 5.82 (d, J ¼ 5.0 Hz, 1H, CHeOH), 6.21 (d,
J ¼ 5.0 Hz, 1H, OH), 6.59 (s, 1H, H4-imidazole), 6.86 (d,
J ¼ 8.5 Hz, 2H, 2H4-chlorophenyl), 7.17 (d, J ¼ 8.5 Hz, 2H,
2H4-chlorophenyl), 7.57 (s, 1H, H3-quinoline), 7.58e7.69 (m, 6H,
4H3-chlorophenyl, H5,7-quinoline), 7.71 (s, 1H, H2-imidazole), 7.92 (d,
J ¼ 7.5 Hz, 1H, H8-quinoline) ppm.
Fig. 4. Docking of molecule 4a (capped sticks) within the FTase catalytic site.
HFP (violet lines) is sitting along the ‘‘right’’ wall of the catalytic site. As
compared to 1, the 4-chlorophenyl ring adopts a tilted orientation less favor-
able for stacking interactions and only one water-mediated hydrogen bond
remains after minimization. (For interpretation of the references to colors in
the figure legends, the reader is referred to the web version of this article.)
synthesized by modification of the 2-quinolinone motif and re-
placement or displacement of the 4-chlorophenyl moiety. We
have identified compounds with in vitro potency in the same
range as that of R115777. These encouraging results warrant
further efforts to optimize the synthesis and pharmacokinetic
properties of these highly potent FTIs.
5. Experimental protocols
5.1. Chemistry
Proton NMR spectra were recorded at 400 MHz or at
300 MHz on a Bruker Avance 400, or 300 on a Bruker spectrom-
eter, with Me4Si as internal standard. Chemical shifts (d) are
reported in parts per million (ppm) and signals are reported as
s (singlet), d (doublet), t (triplet), m (multiplet). Coupling con-
stant are given in hertz (Hz). Electrospray mass spectra were
recorded on a Waters/Micromass LCT spectrometer. Melting
points were determined on a Mettler Toledo FP62 apparatus
and are uncorrected. All reactions were routinely checked by
TLC on silica gel Merck 60 F254. Column chromatography
was carried out on Millipore silica gel (25e45 mM).
5.1.2. 5-(3-Chlorophenyl)-a-[1-[(4-chlorophenyl)methyl]-
1H-imidazol-5-yl]-tetrazolo[1,5-a]quinoline-7-methanol 4a
A mixture of 9 (0.0002 mol) and NaN3 (0.0005 mol) in
DMF (10 ml) was stirred at 140 ꢁC overnight and H2O was
added. The mixture was extracted with CH2Cl2. The organic
layer was washed several times with H2O, dried (MgSO4), fil-
tered, and the solvent was evaporated. The residue was
purified by column chromatography over silica gel (10 mm, el-
uent: CH2Cl2/CH3OH 98/2 to 95/5). The pure fractions were
collected and the solvent was evaporated; the compound was
washed with diethyl ether and dried, yielding 0.041 g of 4a
(25%). M.p. ¼ 140 ꢁC, 1H NMR (400 MHz, DMSO-d6,
27 ꢁC): d ¼ 5.17 (m, J ¼ 16.0 Hz, 2H, CH2-Im), 5.91 (d,
J ¼ 5.0 Hz, 1H, CHeOH), 6.32 (d, J ¼ 5.0 Hz, 1H, OH),
6.66 (s, 1H, H4-(1-methylimidazole)), 6.79 (d, J ¼ 8.5 Hz, 2H,
2H4-chlorophenyl), 7.09 (d, J ¼ 8.5 Hz, 2H, 2H4-chlorophenyl),
7.51 (dd, J ¼ 1.5, 7.0 Hz, 1H, H3-chlorophenyl), 7.61e7.67 (m,
3H, 3H3-chlorophenyl), 7.69 (s, 1H, H2-(1-methylimidazole)), 7.73
(s, 1H, H6-quinoline), 7.80 (dd, J ¼ 1.5, 8.5 Hz, 1H, H8-quinoline),
Fig. 5.
8.11 (s, 1H, H4-quinoline), 8.58 (d, J ¼ 8.5 Hz, 1H, H9-quinoline
)

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P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
13
ppm. C NMR (75 MHz, DMSO-d6, 27 ꢁC): d ¼ 47.4 (CH2),
(C4-thiophene), 127.6 (C5-thiophene), 129.5 (C1
130.8 (C3
(C3
3-chlorophenyl),
or
6-chlorophenyl), 131.3 (C6-benzoisoxazole), 132.0
or
65.9 (CH), 113.0 (C4-quinoline), 117.1 (C9-quinoline), 122.9 (Cqui-
or
4
(C6-quinoline),
2C3-chlorophenyl, 4C4-chlorophenyl, C4-limidazole), 129.5 (Cquinoline),
129.6 (C3-chlorophenyl), 130.6 (C8-quinoline), 131.3
128.4e128.7
(7C,
6-chlorophenyl), 134.7 (C1
3-chlorophenyl), 141.7
or
noline),
124.9
or
4
or
(C5-benzoisoxazole), 148.8 (C2-thiophene), 157.6 (Cbenzoisoxazole),
162.5 (C3-benzoisoxazole ppm. HRMS (ESI), calcd. for
C18H11Cl2NO2S 375.9966, found 375.9969.
)
(C3-chlorophenyl), 131.8 (C4-chlorophenyl), 133.5 (C3-chlorophenyl),
133.6 (C5-imidazole), 136.3 (C4-chlorophenyl), 138.4 (C5-quinoline),
139.4 (C2-imidazole), 142.3 (C7-quinoline), 143.9 (C1-(3-chlorophenyl)),
146.4 (Cquinoline) ppm. HRMS (ESI), calcd. for C26H18Cl2N6O
501.0997, found 501.0995.
5.1.5. [3-(3-Chlorophenyl)-1,2-benzisoxazol-5-yl](5-chloro-
2-thienyl)-methanone 12
MnO2 (33 g) was added to compound 11 (0.0877 mol) in
dioxane (350 ml). The mixture was stirred and refluxed for
15 h, then cooled and filtered over Celite. The solvent was
evaporated. The residue was washed with Et2O. The precipi-
tate was filtered off and dried, yielding 21 g of 12 (64%).
5.1.3. 4-[[5-[[5-(3-Chlorophenyl)tetrazolo[1,5-a]quinolin-
7-yl]hydroxymethyl]-1H-imidazol-1-yl]methyl]-benzonitrile 4b
Compound 4b was synthesized using the same procedure as
above (yield ¼ 36%). M.p. ¼ 158 ꢁC, 1H NMR (400 MHz,
DMSO-d6, 27 ꢁC): d ¼ 5.20 (s, 2H, CH2-Im), 5.91 (d,
J ¼ 5.0 Hz, 1H, CHeOH), 6.31 (d, J ¼ 5.0 Hz, 1H, OH), 6.67
(s, 1H, H4-imidazole), 6.95 (d, J ¼ 8.5 Hz, 2H, 2H2,6-benzonitrile),
7.51e7.55 (m, 3H, H3-chlorophenyl, 2H3,5-benzonitrile), 7.62e7.68
(m, 3H, 3H3-chlorophenyl), 7.73 (s, 1H, H2-imidazole), 7.75 (s, 1H,
1
M.p. ¼ 179 ꢁC, H NMR (300 MHz, DMSO-d6, 27 ꢁC):
d ¼ 7.37 (d, J ¼ 4.0 Hz, 1H, H4-thiophene), 7.70e7.65 (m, 2H,
H
5,6-chlorophenyl), 7.74 (d, J ¼ 9.5 Hz, 1H, H6-benzoisoxazole),
7.85 (d, J ¼ 9.5 Hz, 1H, H7-benzoisoxazole), 7.87 (d, J ¼ 4.0 Hz,
1H, H3-thiophene), 8.14e8.17 (m, 1H, H4-chlorophenyl), 8.19 (s, 1H,
H
H
6-quinoline), 7.79 (d, J ¼ 8.5 Hz, 1H, H8-quinoline), 8.11 (s, 1H,
H
2-chlorophenyl), 8.59 (s, 1H, H4-benzoisoxazole) ppm. 13C NMR
4-quinoline), 8.57 (d, J ¼ 8.5 Hz, 1H, H9-quinoline) ppm. 13C
(75 MHz, DMSO-d6, 27 ꢁC): d ¼ 113.8 (C3 or 5-benzoisoxazole),
116.1 (C7-benzoisoxazole), 125.8 (C4-benzoisoxazole), 126.3
(C4-chlorophenyl), 126.9 (C2-chlorophenyl), 128.9 (C3-chlorophenyl),
NMR (75 MHz, DMSO-d6, 27 ꢁC): d ¼ 47.3 (CH2), 65.3 (CH),
109.5 (CN), 112.6 (C4-quinoline), 116.6 (C9-quinoline), 118.1
(C1-benzonitrile), 122.4 (Cquinoline), 124.4 (C6-quinoline), 127.1 (2C,
129.6
131.6
(C4-thiophene),
(C6-chlorophenyl),
131.0 (C6-benzoisoxazole),
132.0 (C5-chlorophenyl), 133.6
C3,5-benzonitrile), 128.1 (C3-chlorophenyl), 128.2 (C4-imidazole), 129.0e
129.2 (3C, Cquinoline, 2C3-chlorophenyl), 130.2 (C8-quinoline), 130.6
(C3-chlorophenyl), 131.9 (2C, C2,6-benzonitrile), 133.5 (C5-imidazole),
133.6 (C3-(3-chlorophenyl)), 138.4 (C5-quinoline), 139.6 (C2-imidazole),
142.5 (C7-quinoline), 143.1 (C4-benzonitrile), 143.8 (C1-(3-chlorophenyl)),
146.5 (Cquinoline) ppm. HRMS (ESI), calcd. for C27H18ClN7O
492.1340, found 492.1335.
(C3 or 5-benzoisoxazole), 134.7 (C2-chlorophenyl), 136.7 (C3-thiophene),
138.9 (C2-thiophene), 142.1 (C5-thiophene), 157.7 (Cbenzoisoxazole),
166.2 (C3-benzoisoxazole), 185.8 (C]O) ppm. LRMS (ESI), calcd.
for C18H9Cl2NO2S 374.2, found 374.0 [MH]þ.
5.1.6. [4-Amino-3-(3-chlorobenzoyl)phenyl]-(5-chloro-2-
thienyl)-methanone 13
5.1.4. [3-(3-Chlorophenyl)-1,2-benzisoxazol-5-yl]-(5-chloro-
2-thienyl)-methanol 11
TiCl3 15% in H2O (130 ml) was added dropwise to a solution
of 12 (0.0561 mol) in THF (200 ml). The mixturewas stirred 3 h
at room temperature. The mixture was poured into ice water, ex-
tracted with CH2Cl2, basified with K2CO3 10%, extracted and
washed with H2O. The organic layer was separated, dried
(MgSO4), filtered, and the solvent was evaporated, yielding
21.2 g of 13 (100%). M.p. ¼ 132 ꢁC, 1H NMR (300 MHz,
DMSO-d6, 27 ꢁC): d ¼ 7.00 (d, J ¼ 9.0 Hz, 1H, H5-aminophenyl),
7.25 (d, J ¼ 4.0 Hz, 1H, H4-thiophene), 7.56 (t, J ¼ 7.5 Hz, 1H,
n-BuLi 1.6 M in hexane (0.168 mol) was added dropwise at
ꢀ70 ꢁC to a solution of 5-bromo-3-(3-chlorophenyl)-1,2-ben-
zisoxazole 10 [34] (0.129 mol) in THF (400 ml). The mixture
was stirred at ꢀ70 ꢁC for 15 min. A solution of 5-chlorothio-
phene-2-carbaldehyde (0.155 mol) in THF (200 ml) was added
dropwise. The mixture was stirred at ꢀ70 ꢁC for 1 h, poured
into ice water and extracted with AcOEt. The organic layer
was separated, dried (MgSO4), filtered, and the solvent was
evaporated. The residue was purified by column chromatogra-
phy over silica gel (35e70 mm, eluent: CH2Cl2 100%). The
pure fractions were collected and the solvent was evaporated
to afford 68% of 11 (33 g). M.p. ¼ 120 ꢁC, 1H NMR
(400 MHz, DMSO-d6, 27 ꢁC): d ¼ 6.00 (d, J ¼ 4.0 Hz, 1H,
CHeOH), 6.60 (d, J ¼ 4.0 Hz, 1H, OH), 6.80 (d, J ¼ 4.0 Hz,
1H, H3-thiophene), 6.95 (d, J ¼ 4.0 Hz, 1H, H4-thiophene), 7.44
(d, J ¼ 9.5 Hz, 1H, H6-benzoisoxazole), 7.72e7.66 (m, 3H,
H
5-chlorophenyl), 7.60 (d, J ¼ 7.5 Hz, 1H, H6-chlorophenyl),
7.62 (d, J ¼ 4.0 Hz, 1H, H3-thiophene), 7.67 (d, J ¼ 7.5 Hz, 1H,
4-chlorophenyl), 7.74 (s, 1H, H2-chlorophenyl), 7.84 (dd, J ¼ 9.0,
2.0 Hz, 1H,
6-aminophenyl), 7.88 (d, J ¼ 2.0 Hz, 1H,
2-aminophenyl), 8.00 (s, 2H, NH2) ppm. 13C NMR (75 MHz,
H
H
H
DMSO-d6, 27 ꢁC): d ¼ 114.9 (C3-aminophenyl), 117.7
(C5-aminophenyl), 122.5 (C1-aminophenyl), 127.6 (C6-chlorophenyl),
128.6 (2C, C2-chlorophenyl, C4-thiophene), 130.7 (C5-chlorophenyl),
H7-benzoisoxazole,
4-chlorophenyl), 8.08 (d,
131.4 (C4-chlorophenyl), 133.5 (C1
3-chlorophenyl), 133.9
or
5-chlorophenyl,
6
or
J ¼ 7.0 Hz, 1H, H6 or 4-chlorophenyl), 8.09 (s, 1H, H2-chlorophenyl),
8.13 (s, 1H, H4-benzoisoxazole) ppm. 13C NMR (75 MHz,
DMSO-d6, 27 ꢁC): d ¼ 70.6 (CHeOH), 114.3 (Cbenzoisoxazole),
115.8 (C7-benzoisoxazole), 116.7 (C4-benzoisoxazole), 124.2 (C3-thio-
phene), 125.4 (C4 or 6-chlorophenyl), 126.0 (C2-chlorophenyl), 126.8
(C3-thiophene), 135.1 (C6-aminophenyl), 136.8 (C2-thiophene), 138.1
(C2-aminophenyl), 141.5 (C1 or 3-chlorophenyl), 142.4 (C5-thiophene),
155.9
(C]Ochlorophenyl
C18H11Cl2NO2S 373.9966, found 373.9963.
(C4-aminophenyl),
183.6
(C]Othiophene),
196.2
)
ppm. HRMS (ESI), calcd. for

P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
709
5.1.7. 2,2,2-Trichloro-N-[2-(3-chlorobenzoyl)-4-[(5-chloro-
2-thienyl)carbonyl]phenyl]-acetamide 14
with K2CO3, extracted with CH2Cl2 and washed with H2O.
The organic layer was separated, dried (MgSO4), filtered,
and the solvent was evaporated. The residue was crystallized
from CH3CN. The precipitate was filtered off and dried, yield-
ing: 10.35 g of 16 (88%). M.p. ¼ 186 ꢁC, 1H NMR (400 MHz,
DMSO, 27 ꢁC): d ¼ 7.40 (d, J ¼ 3.5 Hz, 1H, H4-thiophene), 7.69
(t, J ¼ 7.5 Hz, 1H, H5-chlorophenyl), 7.76 (d, J ¼ 8.0 Hz, 1H,
H4 or 6-chlorophenyl), 7.82 (d, J ¼ 3.5 Hz, 1H, H3-thiophene), 7.88 (d,
J ¼ 7.5 Hz, 1H, H4 or 6-chlorophenyl), 8.02 (s, 1H, H2-chlorophenyl),
8.22 (d, J ¼ 8.5 Hz, 1H, H8-quinazoline), 8.43 (d, J ¼ 8.5 Hz,
1H, H7-quinazoline), 8.48 (s, 1H, H5-quinazoline) ppm. 13C NMR
(75 MHz, DMSO-d6, 27 ꢁC): d ¼ 121.0 (Cquinazoline), 128.7
(C8-quinazoline), 129.3 (C6-chlorophenyl), 129.5 (C4-thiophene), 130.0
(C5-quinazoline), 130.2 (C2-chlorophenyl), 130.8 (C5-chlorophenyl),
131.3 (C4-chlorophenyl), 133.9 (C3-chlorophenyl), 134.9 (C7-quinazoline),
Trichloroacetyl chloride (0.0416 mol) and Et3N
(0.0416 mol) were added dropwise at 5 ꢁC to a solution of
13 (0.0347 mol) in CH2Cl2 (130 ml) under N2 flow. The
mixture was stirred at room temperature overnight, poured
into ice water and extracted with CH2Cl2. The organic layer
was separated, dried (MgSO4), filtered, and the solvent was
1
evaporated, yielding 18.1 g of 14 (100%). M.p. ¼ 194 ꢁC, H
NMR (300 MHz, DMSO-d6, 27 ꢁC): d ¼ 7.43 (d, J ¼ 4.0 Hz,
1H, H4-thiophene), 7.64 (d, J ¼ 7.5 Hz, 1H, H5-chlorophenyl),
7.76 (m, 1H, H3
H2,3
6-chlorophenyl), 7.76e7.79 (m, 2H,
6-chlorophenyl), 7.82 (d, J ¼ 4.0 Hz, 1H, H3-thiophene),
or
or
7.97 (d, J ¼ 8.5 Hz, 1H, H6-2,2,2 trichlorophenylacetamide), 8.02 (d,
J ¼ 2.0 Hz, 1H, H3-2,2,2 trichlorophenylacetamide), 8.24 (dd,
J ¼ 8.5, 2.0 Hz, 1H, H5-2,2,2 trichlorophenylacetamide), 11.6 (br s,
136.2 (C
), 136.7 (C3-thiophene), 137.2 (C1-chlorophenyl), 139.4
quinazoline
13
1H, NH) ppm. C NMR (75 MHz, DMSO-d6, 27 ꢁC):
(C2-thiophene), 141.6 (C5-thiophene), 154.3 (Cquinazoline), 158.0
(C2-quinazoline), 171.5 (C4-quinazoline), 185.4 (C]O) ppm. HRMS
(ESI), calcd. for C19H9Cl3N2OS 418.9579, found 418.9598.
d ¼ 80 (CCl3), 125.28 (C6-2,2,2 trichlorophenylacetamide), 128.7
(C3
130.85
6-chlorophenyl), 129.5 (2C, C4-thiophene, C2-chlorophenyl),
132.0
or
(2C,
C2,4-2,2,2-trichlorophenylacetamide),
(C3-2,2,2-trichlorophenylacetamide), 133.2 (C3 or 6-chlorophenyl), 133.4
(C5-2,2,2-trichlorophenylacetamide), 133.7 (C1 or 3-chlorophenyl), 133.9
(C4-2,2,2-trichlorophenylacetamide), 136.4 (C3-thiophene), 138.9 (3C,
5.1.10. 2-Chloro-4-(3-chlorophenyl)-a-(5-chloro-2-thienyl)-
a-(1-methyl-1H-imidazol-5-yl)-quinazoline-6-methanol 17
n-BuLi 1.6 M in hexane (0.0404 mol) was added dropwise
C1
141.7 (C5-thiophene), 160.0 (C]OCCl ), 185.06 (C]Othiophene),
3-chlorophenyl, C2-thiophene, C1-2,2,2-trichlorophenylacetamide),
at ꢀ70 ꢁC to
a
solution of 1-methyl-1H-imidazole
or
(0.0404 mol) in THF (40 ml) under N2 flow. The mixture
was stirred for 15 min. Chlorotriethylsilane (0.0414 mol) was
added dropwise and the mixture stirred at ꢀ70 ꢁC for 15 min.
n-BuLi 1.6 M in hexane (0.0356 mol) was added dropwise, the
mixture was stirred for 15 min. A solution of 16 (0.023 mol) in
THF (100 ml) was added at ꢀ70 ꢁC. The mixture was stirred
at ꢀ70 ꢁC for 1 h, poured into ice water, extracted with
CH2Cl2 and washed with H2O. The organic layer was sepa-
rated, dried (MgSO4), filtered, and the solvent was evaporated.
The residue was purified by column chromatography over
silica gel (15e40 mm, eluent: CH2Cl2/CH3OH/NH4OH
96/4/0.2). The pure fractions were collected and the solvent
was evaporated, yielding 2.75 g of 17 (24%). 1H
NMR (400 MHz, DMSO-d6, 27 ꢁC): d ¼ 3.38 (s, 3H,
CH3(1-methylimidazole)), 6.35 (s, 1H, H4-(1-methylimidazole)), 6.60
(d, J ¼ 4.0 Hz, 1H, H4-thiophene), 6.97 (d, J ¼ 4.0 Hz, 1H,
3
193.8 (C]O3-chlorophenyl) ppm.
5.1.8. 4-(3-Chlorophenyl)-6-[(5-chloro-2-thienyl)carbony]-
2(1H )quinazolinone 15
Ammonium acetate (0.0694 mol) was added to a solution
of 14 (0.0347 mol) in DMSO (180 ml). The mixture was
stirred at 60 ꢁC for 4 h, then cooled and poured into ice water.
The precipitate was filtered, taken up in CH3CN (warm), fil-
tered, washed with CH3CN and diethyl ether and dried under
vacuum, yielding 11.7 g of 15 (83%). M.p. > 260 ꢁC, 1H NMR
(300 MHz, DMSO-d6, 27 ꢁC): d ¼ 7.31 (d, J ¼ 4.0 Hz, 1H, H4-
thiophene), 7.46 (d, J ¼ 8.5 Hz, 1H, H8-quinazolinone), 7.58e7.66
(m, 2H,
H
4,5-chlorophenyl), 7.69 (dd, J ¼ 7.5, 1.5 Hz,
1H, H6-chlorophenyl), 7.71 (d, J ¼ 4.0 Hz, 1H, H3-thiophene), 7.84
(t, J ¼ 1.5 Hz, 1H, H2-chlorophenyl), 8.02 (d, J ¼ 1.5 Hz, 1H,
H
11.3 (br s, 1H, NH
5-quinazolinone), 8.14 (dd, J ¼ 8.5, 2.0 Hz, 1H, H7-quinazolinone),
H
3-thiophene), 7.58 (s, 1H, HOH), 7.61e7.78 (m, 5H,
4H3-chlorophenyl, H2-(1-methylimidazole)), 7.97 (d, J ¼ 1.5 Hz, 1H,
5-quinazoline), 8.08 (d, J ¼ 8.5 Hz, 1H, H8-quinazoline), 8.12
(dd, J ¼ 8.5, 1.5 Hz, 1H, H7-quinazoline) ppm.
) ppm. 13C NMR (75 MHz, DMSO-
quinazolinone
d6, 27 ꢁC): d ¼ 113.7 (Cquinazolinone), 116.78 (C8-quinazolinone),
H
127.63 (C6-chlorophenyl), 129.3 (2C, C2-chlorophenyl, C4-thiophene),
131.0
(C1 or 3-chlorophenyl), 135.4 (C7-quinazolinone), 135.7 (C3-thiophene),
138.2 (C ), 138.5 (C2-thiophene), 141.84 (C5-thiophene), 146.9
(3C,
C5-quinazolinone
,
C5,4-chlorophenyl),
133.67
5.1.11.
5-(3-Chlorophenyl)-a-(5-chloro-2-thienyl)-a-(1-
methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-
methanol 18
1 or 3-chlorophenyl
(Cquinazolinone), 155.2 (C2-quinazolinone), 174.2 (C4-quinazolinone),
184.7 (C]O) ppm. HRMS (ESI), calcd. for C19H10Cl2N2O2S
400.9918, found 400.9925.
A mixture of 17 (0.0040 mol) and NaN3 (0.0119 mol) in
DMF (40 ml) was stirred at 90 ꢁC for 3 h, cooled and poured
into ice water. The precipitate was filtered. The filtrate was ex-
tracted with CH2Cl2. The organic layer was brought together
with the precipitate dissolved in CH2Cl2 and dried (MgSO4), fil-
tered, and the solvent was evaporated. The residue was crystal-
lized from CH3CN/DIPE. The precipitate was filtered off and
5.1.9.
[2-Chloro-4-(3-chlorophenyl)-6-quinazolinyl](5-
chloro-2-thienyl)-methanone 16
Compound 15 (0.0279 mol) in POCl3 (70 ml) was stirred at
100 ꢁC for 2 h and cooled. POCl3 was evaporated. The residue
was taken up in CH2Cl2. The solvent was evaporated and the
residue was taken up in CH2Cl2, poured into ice water, basified
1
dried, yielding 1.33 g of 18 (66%). M.p. ¼ 202 ꢁC, H NMR
(300 MHz, DMSO-d6, 27 ꢁC): d ¼ 3.38 (s, 3H, NCH3 imidazole),

710
P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
6.34 (s, 1H, H4-(1-methylimidazole)), 6.60 (d, J ¼ 4.0 Hz, 1H,
(Cquinazoline), 167.5 (Cquinazoline). HRMS (ESI), calcd. for
C23H16Cl2N8S 507.0674, found 507.0669.
H3-thiophene), 6.99 (d, J ¼ 4.0 Hz, 1H, H4-thiophene), 7.64e7.78
(m, 6H, OH, H2-(1-methylimidazole), H2,4,5,6-chlorophenyl), 8.08 (d,
J ¼ 1.5 Hz, 1H, H6-quinoline), 8.26 (dd, J ¼ 8.5, 1.5 Hz, 1H,
H
8-quinazoline), 8.74 (d, J ¼ 8.5 Hz, 1H, H9-quinazoline) ppm. 13C
5.1.14. 4-(3-Chlorophenyl)-N,2-dimethoxy-N-methyl-6-
quinazolinecarboxamide 21
NMR (75 MHz, DMSO-d6, 27 ꢁC): d ¼ 116.7 (C9-quinazoline),
118.2 (Cquinazoline), 125.7 (C3-thiophene), 126.6 (C6-quinazoline),
127.0 (C4-thiophene), 128.7 (C5-thiophene), 128.8 (Cchlorophenyl),
129.8 (Cchlorophenyl), 130.4 (C4-(1-methylimidazole)), 131.0 (2C,
A mixture of 6-bromo-2-methoxy-4-(3-chlorophenyl)-qui-
nazoline 20 (0.03146 mol), Pd(PPh3)4 (0.003146 mol) and
N,O-dimethylhydroxylamine hydrochloride (0.06923 mol) in
Et3N (22 ml) and dioxane (90 ml) was stirred at 100 ꢁC for
18 h under a 5 bar pressure of CO, then cooled, poured into
ice water, extracted with CH2Cl2 and filtered over Celite.
The organic layer was separated, dried (MgSO4), filtered and
the solvent was evaporated. The residue was purified by col-
umn chromatography over silica gel (15e35 mm, eluent:
CH2Cl2/EtOAc 85/15 then CH2Cl2/CH3OH/NH4OH 98/2/
0.4). The pure fractions were collected and the solvent was
evaporated, yielding 3 g of 21 (27%). M.p. ¼ 118 ꢁC, 1H
NMR (400 MHz, DMSO, 27 ꢁC): d ¼ 3.33 (s, 3H, NCH3),
3.55 (s, 3H, NOCH3), 4.10 (s, 3H, OCH3(2-quinazoline)),
7.64e7.84 (m, 4H, 4H3-chlorophenyl), 7.93 (d, J ¼ 8.5 Hz, 1H,
Cchlorophenyl), 133.8 (Cquinazoline), 133.9 (C1
3-chlorophenyl),
or
134.3 (C5-(1-methylimidazole)), 134.8 (C8-quinazoline), 138.1
(C1 3-chlorophenyl), 141.6 (C2-(1-methylimidazole)), 145.4
or
(C7-quinazoline), 149.2 (C2-thiophene), 152.8 (Cquinazoline), 167.9
(C5-quinazoline) ppm. HRMS (ESI), calcd. for C23H15Cl2N7OS
508.0514, found 508.0522.
5.1.12. 7-[Chloro-(5-chloro-2-thienyl)(1-methyl-1H-
imidazol-5-yl]-5-(3-chlorophenyl)-tetrazolo-
[1,5-a]quinazoline 19
Compound 18 (0.0019 mol) in SOCl2 (20 ml) was stirred at
60 ꢁC for 3 h and 30 min, then cooled and the solvent was
evaporated. The residue was taken up twice in CH2Cl2 and
the solvent was evaporated, yielding 19, which was used with-
out further purification.
H
8-quinazoline), 8.16 (dd, J ¼ 8.5, 1.5 Hz, 1H, H7-quinazoline),
8.21 (d, J ¼ 1.5 Hz, 1H, H8-quinazoline
)
ppm. 13C
NMR (75 MHz, DMSO-d6, 27 ꢁC): d ¼ 33.1 (NCH3),
54.9 (NOCH3), 60.9 (OCH3), 118.5 (Cquinazoline), 126.5
(C9-quinazoline), 127.4 (C6-quinazoline), 128.5 (C3-chlorophenyl),
129.3 (C2-(3-chlorophenyl)), 130.3 (C7-quinazoline), 130.4
(C3-chlorophenyl), 130.6 (C3-chlorophenyl), 133.4 (C3-chlorophenyl),
134.0 (C8-quinazoline), 137.9 (C3-chlorophenyl), 153.1 (C]O),
5.1.13. 5-(3-Chlorophenyl)-a-(5-chloro-2-thienyl)-a-(1-
methyl-1H-imidazol-5-yl)-tetrazolo[1,5-a]quinazoline-7-
methanamine 5a
NH3/iPrOH (20 ml) was added dropwise at 5 ꢁC compound
of 19 (0.0019 mol) in THF (20 ml) under N2 flow. The mixture
was stirred at 5 ꢁC for 45 min, then at room temperature over-
night, poured into ice water and extracted with CH2Cl2. The
organic layer was separated, dried (MgSO4), filtered, and the
solvent was evaporated. The residue was purified by column
chromatography over silica gel (15e40 mm, eluent: CH2Cl2/
CH3OH/NH4OH 97/3/0.1) and again over silica gel (10 mm,
eluent: CH3CN/H2O 40/60). The pure fractions were collected
and the solvent was evaporated. This fraction was crystallized
from CH3CN. The precipitate was filtered off and dried,
yielding 0.018 g of 5a (18%). M.p. ¼ 220 ꢁC, 1H
NMR (400 MHz, DMSO, 27 ꢁC): d ¼ 3.42 (s, 3H,
CH3(1-methylimidazole)), 3.55 (s, 2H, NH2), 6.22 (s, 1H,
162.5 (C3-quinazoline), 167.3 (Cquinazoline), 170.8 (C5-quinazoline)
ppm. Anal. (C18H16ClN3O3, 0.05 CH2Cl2) calcd. C 59.88, H
4.48, N 11.61, found C 59.97, H 4.48, N 11.54.
5.1.15. 2-Chloro-4-(3-chlorophenyl)-N-methoxy-N-methyl-
6-quinazolinecarboxamide 22
POCl3 (0.084 mol) was added dropwise at room tempera-
ture to a solution of 21 (0.042 mol) in DMF (110 ml). The
mixture was stirred at 80 ꢁC for 4 h, cooled, poured into ice
water, extracted with EtOAc and basified with K2CO3 solid.
The organic layer was separated, dried (MgSO4), filtered,
and the solvent was evaporated. The residue was crystallized
from DMF. The precipitate was filtered off and dried, yielding
9 g of 22 (59%). M.p. ¼ 110 ꢁC, 1H NMR (400 MHz, DMSO,
27 ꢁC): d ¼ 3.32 (s, 3H, NCH3), 3.55 (s, 3H, NOCH3), 7.68e
7.80 (m, 3H, H4,5,6-chlorophenyl), 7.88 (s, 1H, H2-chlorophenyl),
H
4-(1-methylimidazole)), 6.65 (d, J ¼ 3.5 Hz, 1H, H4-thiophene),
6.98 (d, J ¼ 3.5 Hz, 1H, H3-thiophene), 7.61e7.77 (m, 5H,
4H3-chlorophenyl, H2-(1-methylimidazole)), 7.91 (d, J ¼ 2.0 Hz, 1H,
H
6-quinazoline), 8.39 (dd, J ¼ 8.5, 2.0 Hz, 1H, H8-quinazoline),
8.12 (d, J ¼ 9.0 Hz, 1H,
H8-quinazoline), 8.28 (m, 2H,
8.57 (d, J ¼ 8.5 Hz, 1H, H9-quinazoline) ppm. 13C NMR
(75 MHz, DMSO-d6, 27 ꢁC): d ¼ 33.1 (CH3(1-methylimidazole)),
59.5 (CH), 116.2 (C9-quinazoline), 117.6 (Cquinazoline), 125.6
(C4-thiophene), 126.5 (C3-thiophene), 126.7 (C6-quinazoline),
H6,7-quinazoline) ppm. C NMR (75 MHz, DMSO-d6, 27 ꢁC):
d ¼ 34.4 (NCH3), 62.5 (NOCH3), 122.1 (Cquinazoline),
13
128.5 (C5
7-quinazoline), 128.8 (C8-quinazoline), 130.2
6-(3-chlorophenyl)), 131.0 (C2-(3-chlorophenyl)), 132.1 (2C,
or
(C4
C5,4
or
127.9 (C3-chlorophenyl),
(C4-(1-methylimidazole)),
128.4
130.5
(C3-chlorophenyl),
(C3-chlorophenyl),
129.4
130.6
6-(3-chlorophenyl)), 134.9 (C1
3-(3-chlorophenyl)),
7-quinazoline), 138.4
3-(3-chlorophenyl)), 154.4 (C6-quinazoline), 158.3
or
or
135.4 (Cquinazoline), 136.2 (C5
(C1
or
(C3-chlorophenyl), 132.3 (Cquinazoline), 133.4 (C1 or 3-(3-chlorophenyl)),
135.1 (C8-quinazoline), 135.7 (C5-(1-methylimidazole)), 137.7
or
(C2-quinazoline), 168.2 (C]O), 172.1 (C4-quinazoline) ppm.
Anal. (C17H13Cl2N3O2) calcd. C 56.37, H 3.62, N 11.60,
found C 56.49, H 3.54, N 11.42.
(C1
(C7-quinazoline), 150.9 (C2-thiophene
3-(3-chlorophenyl)), 140.8 (C2-(1-methylimidazole)), 146.4
,
or
C5-thiophene), 152.5

P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
711
5.1.16. [2-Chloro-4-(3-chlorophenyl)-6-quinazolinyl]-
(1-methyl-1H-imidazol-5-yl)-methanone 23
stirred at 90 ꢁC for 4 h, then cooled, poured into ice water
and stirred at room temperature for 1 h. The precipitate
was filtered off and dried at 80 ꢁC under vacuo, yielding
3.4 g of 25 (84%). M.p. ¼ 190 ꢁC, 1H NMR (400 MHz,
DMSO, 27 ꢁC): d ¼ 3.60 (s, 3H, CH3(1-methylimidazole)), 6.60
(d, J ¼ 5.5 Hz, 1H, OH), 6.33 (d, J ¼ 5.5 Hz, 1H, CHe
n-BuLi 1.6 M in hexane (0.042 mol, 26.2 ml) was added
dropwise at ꢀ70 ꢁC to a mixture of 1-methyl-1H-imidazole
(0.042 mol) in THF (80 ml) under N2 flow. The mixture was
stirred for 15 min. Chlorotriethylsilane (0.043 mol) was added.
The mixture was stirred for 15 min. n-BuLi 1.6 M in hexane
(0.037 mol, 23.2 ml) was added at ꢀ70 ꢁC, and the mixture
was stirred for 15 min. A solution of 22 (0.024 mol) in THF
(80 ml) was added at ꢀ70 ꢁC, and the mixture was stirred at
ꢀ70 ꢁC for 30 min, poured into H2O and extracted with
EtOAc. The organic layer was separated, dried (MgSO4),
filtered, and the solvent was evaporated. The residue was
purified twice by column chromatography over silica gel
(15e35 mm, eluent: CH2Cl2/CH3OH 97/3) followed by (15e
40 mm, eluent: CH2Cl2/EtOAc 50/50 then CH2Cl2/CH3OH
97/3). The pure fractions were collected and the solvent was
evaporated, yielding 2.46 g of 23 (27%). M.p. ¼ 190 ꢁC,
1H NMR (400 MHz, DMSO, 27 ꢁC): d ¼ 3.92 (s, 3H,
CH3(1-methylimidazole)), 7.60e7.75 (m, 2H, 2H3-chlorophenyl),
OH), 6.36 (s, 1H,
H4-(1-methylimidazole)), 7.58 (s, 1H,
H2-(1-methylimidazole)), 7.68e7.86 (m, 4H, 4H3-chlorophenyl),
8.21 (m, 2H, H6,8-quinazoline), 8.71 (d, J ¼ 7.5 Hz, 1H,
H9-quinazoline) ppm.
5.1.19. 7-[Chloro(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-
chlorophenyl)-tetrazolo[1,5-a]quinazoline
monohydrochloride 26
Compound 25 (0.0025 mol) in SOCl2 (10 ml) was stirred at
65 ꢁC for 4 h, then cooled and the solvent was evaporated till
dryness. The residue was taken up twice in CH2Cl2. The sol-
vent was evaporated till dryness, yielding 26. This product
was used directly in the next reaction step.
7.77 (s, 1H,
H
(s, 1H,
H
3-chlorophenyl), 7.97e7.99 (m, 1H, H3-chlorophenyl), 8.08
4-(1-methylimidazole)), 7.83e7.89 (m, 1H,
H
2-(1-methylimidazole)), 8.21 (d, J ¼ 8.5 Hz, 1H,
5.1.20. 5-(3-Chlorophenyl)-7-[(2-ethyl-1H-imidazol-1-yl)(1-
methyl-1H-imidazol-5-yl)methyl]-tetrazolo-
[1,5-a]quinazoline 5b
H
8-quinazoline), 8.41 (dd, J ¼ 8.5, 2.0 Hz, 1H, H7-quinazoline),
8.44 (d, J ¼ 2.0 Hz, 1H, H5-quinazoline) ppm.
A mixture of 26 (0.0010 mol) and 2-ethyl-1H-imidazole
(0.0015 mol) in CH3CN (5 ml) was stirred and refluxed
for 2 h, cooled, poured into ice water, extracted with
CH2Cl2 and washed with K2CO3 10%. The organic layer
was separated, dried (MgSO4), filtered, and the solvent
was evaporated. The residue was purified by column chro-
matography over silica gel (10 mm, eluent: CH2Cl2/
CH3OH/NH4OH 95/5/0.2). The pure fractions were
collected and the solvent was evaporated, yielding 0.084 g
of 5b (17.5%). M.p. ¼ 120 ꢁC, 1H NMR (400 MHz,
5.1.17. 2-Chloro-4-(3-chlorophenyl)-a-(1-methyl-1H-
imidazol-5-yl)-6-quinazolinemethanol 24
DIBAL-H in toluene (10 ml) was added dropwise at
ꢀ70 ꢁC to compound 23 (0.012 mol) in THF (150 ml) under
N2 flow. The mixture was stirred at ꢀ70 ꢁC for 30 min. DI-
BAL-H in toluene (50 ml) was added. The mixture was stirred
at ꢀ70 ꢁC for 3 h, poured into ice water, extracted with
CH2Cl2 and filtered over Celite. The organic layer was sepa-
rated, dried (MgSO4), filtered, and the solvent was evaporated,
yielding 4 g of 24 (86%). M.p. ¼ 140 ꢁC, 1H NMR (400 MHz,
DMSO, 27 ꢁC): d ¼ 3.59 (s, 3H, CH3(1-methylimidazole)), 6.03 (d,
J ¼ 5.5 Hz, 1H, CHeOH), 6.24 (d, J ¼ 5.5 Hz, 1H, OH), 6.38
(s, 1H, H4-(1-methylimidazole)), 7.55 (s, 1H, H2-(1-methylimidazole)),
7.64e7.78 (m, 3H, 3H3-chlorophenyl), 7.84e7.86 (m, 1H,
DMSO,
27 ꢁC):
d
¼ 1.09
(t,
J ¼ 7.5 Hz,
3H,
CH3(2-ethylimidazole)), 2.45e2.53 (m, 1H, CH2(2-ethylimidazole)),
2.70e2.80 (m, 1H, CH2(2-ethylimidazole)), 3.39 (s, 3H,
CH3(1-methylimidazole)), 6.32 (s, 1H, H4-(1-methylimidazole)), 6.65
(s, 1H, H5-(2-ethylimidazole)), 6.85 (s, 1H, H4-(2-ethylimidazole)),
7.24 (s, 1H, CH), 7.65e7.67 (m, 2H, 2H3-chlorophenyl),
H
H
3-chlorophenyl), 8.01e8.08 (m, J ¼ 8.5, 1.5 Hz, 2H,
7.74e7.76 (m, 3H, 2H3-chlorophenyl, H5-(1-methylimidazole)),
6-quinazoline), 8.11 (d, J ¼ 8.5 Hz, 1H,
7,8-quinazoline), 8.15 (s, 1H, H5-quinazoline) ppm. 13C NMR
7.81 (s, 1H,
H
(75 MHz, DMSO-d6, 27 ꢁC): d ¼ 31.5 (NCH3), 65.1 (CH),
120.0 (Cquinazoline), 123.3 (C5-quinazoline), 127.2 (C7-quinazoline),
127.7 (C4-(1-methylimidazole)), 128.7 (C3-chlorophenyl), 129.5
(C2-(3-chlorophenyl)), 130.5 (C3-chlorophenyl), 130.6 (C3-chlorophenyl),
133.4 (C3-chlorophenyl), 134.8 (C8-quinazoline), 137.5 (C3-chlorophenyl),
139.2 (C2-(1-methylimidazole)), 143.6 (C6-quinazoline), 152.0
(Cquinazoline), 155.6 (C2-quinazoline), 169.7 (C4-quinazoline) ppm.
HRMS (ESI), calcd. for C19H14Cl2N4O 385.0623, found
385.0618.
H
8-quinazoline), 8.79 (d, J ¼ 8.5 Hz, 1H, H9-quinazoline) ppm.
13C NMR (75 MHz, DMSO-d6, 27 ꢁC): d ¼ 12.8
(CH3(2-ethylimidazole)),
20.4
(CH2(2-ethylimidazole)),
31.8
(CH3(1-methylimidazole)), 53.5 (CH), 117.8 (C9-quinazoline),
117.2 (C5-(2-ethylimidazole)), 119.3 (Cquinazoline), 128.1
(C6-quinazoline),
(C3-chlorophenyl),
128.3
130.3
(C4-(2-ethylimidazole)),
(C3-chlorophenyl),
129.3
130.5
(C5-(1-methylimidazole)), 130.8 (C4-(1-methylimidazole)), 131.5
(C3-chlorophenyl), 131.6 (C3-chlorophenyl), 133.7 (Cquinazoline),
134.3 (C1
(C1
3-(3-chlorophenyl)), 135.6 (C8-quinazoline), 138.6
3-(3-chlorophenyl)), 139.8 (C7-quinazoline), 141.1
or
5.1.18. 5-(3-Chlorophenyl)-a-(1-methyl-1H-imidazol-5-yl)-
tetrazolo[1,5-a]quinazoline-7-methanol 25
NaN3 (0.031 mol) was added at room temperature to com-
pound 24 (0.0103 mol) in DMF (40 ml). The mixture was
or
(C2-(1-methylimidazole)), 149.6 (C2-(2-ethylimidazole)), 153.3
(Cquinazoline), 168.3 (C5-quinazoline) ppm. HRMS (ESI), calcd.
for C24H20ClN9 470.1608, found 470.1604.

712
P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
5.1.21.
5-(3-Chlorophenyl)-7-[[2-phenyl-1H-imidazol-1-
(CH3(1-methylimidazole)), 55.0 (CH), 116.5 (2C, JCeF ¼ 22 Hz,
yl](1-methyl-1H-imidazol-5-yl)methyl]-tetrazolo-
[1,5-a]quinazoline 5c
C3,5-(4-fluoropheny)), 117.9 (C9-quinazoline), 119.2 (Cquinazoline),
120.5 (C5-(4-fluorophenylimidazole)), 127.6 (C1-(4-fluorophenyl)),
2-Phenyl-1H-imidazole (0.0038 mol) was added at room
temperature to compound 26 (0.0025 mol) in CH3CN
(10 ml). The mixture was stirred and refluxed for 2 h, poured
into ice water and extracted with CH2Cl2/CH3OH. The organic
layer was washed with K2CO3, separated, dried (MgSO4), fil-
tered and the solvent was evaporated. The residue was purified
by column chromatography over silica gel (15e40 mm, eluent:
CH2Cl2/CH3OH/NH4OH 96/4/0.2). The pure fractions were
collected and the solvent was evaporated, yielding 0.17 g of
5c (13%). M.p. ¼ 150 ꢁC, 1H NMR (400 MHz, DMSO,
27 ꢁC): d ¼ 3.31 (s, 3H, CH3(1-methylimidazole)), 6.30 (s, 1H,
128.3
(C6-quinazoline),
129.3
(C3-chlorophenyl),
129.8
(C4-(4-fluorophenylimidazole)), 130.2 (C3-chlorophenyl), 130.7
(C5-(1-methylimidazole)), 131.0 (C4-(1-methylimidazole)), 131.5
(C3-chlorophenyl),
JCeF ¼ 9.2 Hz, C2,6-(4-fluoropheny)), 133.7 (Cquinazoline), 134.4
(C3-chlorophenyl), 135.5 (C8-quinazoline), 138.6 (C3-chlorophenyl),
139.8 (C7-quinazoline), 141.1 (C2-(1-methylimidazole)), 147.3
(C2-(4-fluorophenylimidazole)),
(C4-(4-fluorophenyl)), 168.3
131.6
(C3-chlorophenyl),
131.8
(2C,
153.3
(C5-quinazoline
(Cquinazoline),
ppm.
157.7
Anal.
)
(C28H19ClFN9, 0.35 H2O, 0.25 CH2Cl2) calcd. C 60.21, H
3.61, N 22.37, found C 60.00, H 3.45, N 22.04.
H4-(1-methylimidazole)), 6.93 (s, 1H, Hphenylimidazole), 7.10 (s, 1H,
Hphenylimidazole), 7.16 (s, 1H, CH), 7.37e7.46 (m, 5H, Hphenyl),
7.61e7.68 (m, 2H,
H
5.1.23. 3-[1-[[5-(3-Chlorophenyl)tetrazolo[1,5-a]quinazolin-
7-yl](1-methyl-1H-imidazol-5-yl)methyl]-1H-imidazol-2-
yl]-benzonitrile 5e
H5,6-chlorophenyl), 7.71 (s, 1H,
2-(1-methylimidazole)), 7.76 (m, 2H, H2,4-chlorophenyl), 7.83 (s,
1H, H6-quinazoline), 8.14 (d, J ¼ 8.5 Hz, 1H, H8-quinazoline),
8.78 (d, J ¼ 8.5 Hz, H9-quinazoline) ppm. 13C NMR (75 MHz,
DMSO-d6, 27 ꢁC): d ¼ 31.2 (CH3(1-methylimidazole)), 54.5
(CH), 117.3 (C9-quinazoline), 118.7 (Cquinazoline), 119.9
A
solution
of
3-(1H-imidazol-2-yl)-benzonitrile
(0.0026 mol) and K2CO3 (0.0053 mol) was added at room
temperature to compound 26 (0.0017 mol) in CH3CN
(10 ml). The mixture was stirred and refluxed for 2 h, poured
into ice water and extracted with CH2Cl2/CH3OH. The organic
layer was separated, dried (MgSO4), filtered, and the solvent
was evaporated. The residue was purified by column chroma-
tography over silica gel (15e40 mm, eluent: CH2Cl2/CH3OH/
NH4OH 95/5/0.2) and then again over silica gel (10 mm eluent:
CH2Cl2 100%). The pure fractions were collected and the
solvent was evaporated, yielding: 0.048 g of 5e (5%). 1H
NMR (300 MHz, DMSO, 27 ꢁC): d ¼ 3.35 (s, 3H,
CH3(1-methylimidazole)), 6.27 (s, 1H, H4-(1-methylimidazole)), 6.98
(d, J ¼ 2.0 Hz, 1H, H5-(phenylimidazole)), 7.16 (d, J ¼ 2.0 Hz,
1H, H4-phenylimidazole), 7.29 (s, 1H, CH), 7.57e7.69 (m, 5H,
(C3
(C6-(3-chlorophenyl)), 128.9 (2C, Cphenyl), 129.0 (2C, Cphenyl),
129.3 (Cphenyl), 129.4 (C3 4-(2-phenylimidazole)), 129.7
(C2-(3-chlorophenyl)), 130.3
(C1-phenyl), 130.6
4-(2-phenylimidazole)), 127.7 (C6-quinazoline), 128.8
or
or
(C5-(1-methylimidazole)),
(C4-(1-methylimidazole)),
130.4
131.0
(C5-(3-chlorophenyl)), 131.1 (C4-(3-chlorophenyl)), 133.2 (Cquinazoline),
133.9 (C1
138.0 (C1
3-(3-chlorophenyl)), 134.0 (C8-quinazoline),
3-(3-chlorophenyl)), 139.4 (C7-quinazoline), 140.6
or
or
(C2-(1-methylimidazole)), 147.7 (C2-(2-phenylimidazole)), 152.8
(Cquinazoline), 167.8 (C5-quinazoline) ppm. HRMS (ESI), calcd.
for C28H20ClN9 518.1608, found 518.1614.
3H3-chlorophenyl, 2H4
H3-chlorophenyl), 7.73 (s, 1H, H2-(1-methylimidazole)), 7.78 (d,
5-benzonitrile), 7.75e7.77 (m, 1H,
and
5.1.22. 5-(3-Chlorophenyl)-7-[[2-(4-fluorophenyl)-1H-
imidazol-1-yl](1-methyl-1H-imidazol-5-yl)methyl]-
tetrazolo[1,5-a]quinazoline 5d
J ¼ 2.0 Hz, 1H, H6-quinazoline), 7.85 (s, 1H, H2-benzonitrile),
7.90 (d, 1H, H6-benzonitrile), 8.08 (dd, J ¼ 8.5, 2.0 Hz, 1H,
2-(4-Fluorophenyl)-1H-imidazole (0.0015 mol) was added
at room temperature to compound 26 (0.001 mol) in CH3CN
(5 ml). The mixture was stirred and refluxed for 2 h, then
cooled, poured into ice water and extracted with CH2Cl2.
The organic layer was washed with K2CO3 10%, separated,
dried (MgSO4), filtered and the solvent was evaporated. The
residue was purified by column chromatography over silica
gel (10 mm, eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.2). The
pure fractions were collected and the solvent was evaporated,
yielding 0.11 g of 5d (20%). M.p. ¼ 154 ꢁC, 1H NMR
H
8-quinazoline), 8.78 (d, J ¼ 8.5 Hz, 1H, H9-quinazoline) ppm.
13C NMR (75 MHz, DMSO-d6, 27 ꢁC): d ¼ 31.2
(CH3(1-methylimidazole)), 54.3 (CH), 112.1 (C1
3-benzonitrile),
or
117.3 (C9-quinazoline), 118.5 (CN), 118.6 (Cquinazoline), 120.7
(C5-(phenylimidazole)), 127.5 (C6-quinazoline), 128.7 (Cphenyl),
129.6 (C4-(phenylimidazole)), 129.8 (C5-(1-methylimidazole)), 130.2
(Cphenyl), 130.5 (C4-(1-methylimidazole)), 130.8 (Cphenyl), 130.9
(2C, Cphenyl), 131.5 (Cphenyl), 132.1 (C2-benzonitrile), 132.9
(Cquinazoline), 133.1 (C6-benzonitrile), 133.5 (Cphenyl), 133.8
(Cphenyl), 134.8 (C8-quinazoline), 137.8 (Cphenyl), 138.8
(400 MHz,
CH3(1-methylimidazole)), 6.29 (s, 1H, H4-(1-methylimidazole)),
6.93 (s, 1H, 5-(4-fluorophenylimidazole)), 7.10 (s, 1H,
DMSO,
27 ꢁC):
d ¼ 3.32
(s,
3H,
(C7-quinazoline),
(C2-(phenylimidazole)), 152.7 (Cquinazoline), 167.3 (C5-quinazoline
140.6
(C2-(1-methylimidazole)),
145.5
)
H
ppm. HRMS (ESI), calcd. for C29H19ClN10 543.1561, found
543.1557.
H
4-(4-fluorophenylimidazole)),7.12 (s, 1H, CH), 7.25 (t, J ¼ 9.0 Hz,
2H, H3,5-(4-fluorophenyl)), 7.38e7.42 (m, 2H, H2,6-(4-fluorophenyl)),
7.62e7.68 (m, 2H, H3-chlorophenyl), 7.72 (s, 1H,
5.2. Molecular modeling
H2-(1-methylimidazole)), 7.76e7.77 (m, 2H, H3-chlorophenyl), 7.83
(d, J ¼ 2.0 Hz, 1H, H6-quinazoline), 8.13 (dd, J ¼ 8.5, 2.0 Hz,
1H, H8-quinazoline), 8.79 (d, J ¼ 8.5 Hz, H9-quinazoline) ppm.
13C NMR (75 MHz, DMSO-d6, 27 ꢁC): d ¼ 31.7
5.2.1. Conformational analysis
The conformational analysis of 1 has been achieved by
using the Random Search tool available in the Sybyl 6.8

P. Angibaud et al. / European Journal of Medicinal Chemistry 42 (2007) 702e714
713
positioned such as to coordinate the zinc atom while the qui-
nolinone carbonyl group was moved close to a structured wa-
ter molecule known to form an hydrogen bond with other
FTase inhibitors [40]. Molecule 1 was then rotated around
this N/C]O axis in order to orient the two chlorophenyl
substituents towards the hydrophobic rear of the catalytic cav-
ity (Fig. 2). The FTase/molecule 1/HFP ternary complex was
subsequently minimized using the Tripos force field and the
kollman All-Atom charge set. During the minimization, the li-
˚
gands along with all residues included in a 10 A sphere around
the molecule 1 were allowed to move, while the remaining
part of the protein structure, including the zinc atom, was
kept rigid. Molecule 4a was constructed by structural modifi-
cation of 1 which was used as a template. The molecule was
then submitted to a conformational analysis and docked man-
ually using the procedure described above (Fig. 4).
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