Synthesis, molecular modelling and biological evaluation of 4-amino-2(1H)-quinazolinone and 2,4(1H,3H)-quinazolidone derivatives as antitumor agents

Article abstract of DOI:10.1002/ardp.201000312

A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)- quinazolinones and -2,4(1H,3H)-quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the NCI-60 cancer cell lines. A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)- quinazolinones and -2,4(1H,3H)-quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the NCI-60 cancer cell lines. Copyright

Full text of DOI:10.1002/ardp.201000312

810
Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
Full Paper
Synthesis, Molecular Modelling and Biological Evaluation of
4-Amino-2(1H)-quinazolinone and 2,4(1H,3H)-Quinazolidone
Derivatives as Antitumor Agents
Stephanie Richter and Barbara Gioffreda
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Heinrich Heine University, Du¨sseldorf,
Germany
A series of 6-benzoyl-, 6-arylthio- and 6-arylsulfonyl-4-amino-2(1H)-quinazolinones and -2,4(1H,3H)-
quinazolinediones were prepared. They were evaluated in vitro for their cytotoxicity against the
NCI-60 cancer cell lines.
Keywords: 4-Amino-2(1H)-quinazolinone / Antitumor activity / 2,4(1H,3H)-Quinazolidone
Received: October 18, 2010; Revised: December 1, 2010; Accepted: December 14, 2010
DOI 10.1002/ardp.201000312
Introduction
Looking on structures which were synthesized to bind in
the ATP/ADP-binding site, a broad amount of heterocyclic
compounds was found. Starting from anthraquinones like
emodine 1, indoles like IQA 2 or halogenated benzoimida-
zoles like DMAT 3 as inhibitors of CK2 [6, 7], over flavones like
quercetin 4 and its derivatives as inhibitors of EGRF [5] to
purines 7 [8], pyrazoles and phenolic [8, 9] structures (6 and 8)
as inhibitors of HSP90 were found. They all show ATPase
inhibiting activity at micromolar range and cell growth
arrest with IC50 values up to micromolar range [4–9].
Cancer poses a serious human health problem despite much
progress in understanding its biology and pharmacology.
Consequently, the design of new lead structures of antitumor
agents is one of the most urgent research areas in contem-
porary medicinal chemistry. Among the wide range of
pharmacologically active heterocycles some have attracted
great attention as potential chemotherapeutic agents [1–3].
In the last years anticancer drug strategies involve molecular
targets which are crucial for tumorigenesis. Targets like EGF
receptor tyrosine kinase (EGFR), the protein kinases like CK2
or the chaperone HSP90 have moved into the circle of inter-
est. All these targets are involved in maturation and activity
of a diverse group of proteins involved in signal transduction,
cell cycle regulation and apoptosis. All of them show over-
expression in a variety of cancer cell lines. These protein
targets have all a weak ATPase activity and it could be shown,
that blocking of the ATPase activity leads to apoptosis and cell
death [4–6]. Known cytotoxic compounds (see Scheme 1) like
radicicol 6 (HSP90) [4], quercetine 5 (EGRF) [5] or emodine 1
(CK2) [6] bind to ATP/ADP domains of the protein, so the
synthesis of novel heterocyclic compounds, which underlie
ATP mimicry, seem to be a successful way to find antitumoric
lead compounds.
Motivated by the above mentioned findings, the aim of our
study was to find novel lead structures with cytostatic activi-
ties, which may underlie ATP/ADP mimicry. In a thought
experiment we substituted the adenine ring system of ATP
by the pyrimidine base cytosine and enlarged it to the 4-
amino-2(1H)-quinazolinone ring system. Comparison of the
known structures which underlie ADP/ATP mimicry show
that most of them combine the heterocyclic ring system over
a linking structure with an aromatic system. So we combined
the quinazoline system over different linkers with an aromatic
ring system to get the described quinazoline derivatives (see
Scheme 2). As variation of the heterocyclic ring system some
analogous quinazolinedione derivatives were synthesized
too. The in-vitro antitumor activity of the newly synthesized
compounds was evaluated on the NCI-60 cell line.
Results and discussion
Correspondence: Dr. Barbara Gioffreda, Department of Pharmaceutical
Chemistry, Faculty of Pharmacy, Heinrich Heine University, Du¨sseldorf,
Germany.
E-mail: gioffreda@uni-duesseldorf.de
Fax: þ49-211-8113847
Chemistry
Synthesis of intermediate and target compounds was per-
formed according to the reactions outlined in Schemes 3
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Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
Aminoquinazolinones and Quinazolidones as Antitumor Agents
811
O
O
N
O
P
H2N
O
P
N
P
O
O
O
O
O
N
O
O
N
HO
OH
ATP
CK2-inhibitors
O
Br
Br
H
OH
H3C
H
N
N
Br
Br
N
O
R
N
OH
O
OH
Emodine 1
IQA 2
DMAT 3
EGFR-inhibitors
OH
O
O
O
OH
OH
OH
OH
HO
OH
Butein 4
Quercetine 5
Hsp90-inhibitors
NH2
H
Cl
O
N
N
N
O
O
OMe
HO
H3C
F
N
HO
O
OH
N
Cl
N
H
MeO
PU derivative 7
HC
OH
Radicicol 6
Dihydroxyphenylpyrazole 8
Scheme 1. Known anticancer compounds with ATPase inhibiting activity.
NH2
N
NH2
NH2
X
N
N
Scheme 2. Development of the novel scaffold
4-amino-2(1H)-quinazolinone.
N
H
O
N
H
O
N
H
O
R
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812
S. Richter and B. Gioffreda
Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
O
O
R1
AlCl3, ClCH2CH2Cl,
RT, over night
R1
R2
Cl
R2
+
NO2
NO2
10
9 a-e
11 a-e
O
O
FeSO4, NH4Cl,
Zn, EtOH, H2O,
ICl, AcOH,
30°C, 30 min
R1
R2
I
R1
R2
50°C, 2 h
NH2
NH2
13 a-e
12 a-e
NH
O
O
OCNSO2Cl,
CuCN, DMF,
rf, 3 h
R1
R2
CN
R1
R2
SO2Cl
O
CH2Cl2,
N
RT, 3 h
NH2
N
H
14 a-e
15 a-e
NH2
O
NH
O
H2O, EtOH,
RT, 60 min
R1
R2
R1
NH
O
N
H
R2
O
N
H
17 a-e
16 a-e
Scheme 3. Synthesis of compounds 17a–e (a: R1 ¼ R2 ¼ H; b: R1 ¼ H, R2 ¼ OCH3; c: R1 ¼ R2 ¼ OCH3; d: R1 ¼ R2 ¼ CH3;
e: R1 ¼ H, R2 ¼ Cl).
and 4. The 6-benzoyl-derivates were synthesized by Friedel-
Crafts-acylation starting from commercially available 4-nitro-
benzoylchloride 10 to obtain the (4-nitrophenyl)arylmetha-
nones 11a–e [11, 12]. After reduction of the nitro group with
the help of iron(II) and elemental zinc [14], iodine was
inserted by treating the resulting amine 12a–e with iodine
monochloride in acetic acid for 30 min to obtain (4-amino-3-
iodophenyl)arylmethanone 13a–e [18]. The iodine was
replaced by a nitril group by heating 13a–e in the presence
of copper(I)cyanide in DMF for 3 h [19]. Cyclocondensation of
the resulting 2-amino-5-benzoylbenzonitrile derivatives 14a–
e with chlorosulfonyl isocyanate and subsequent hydrolysa-
tion in alkaline solution leads to the desired 6-benzoyl-4-
amino-2(1H)-quinazolinone derivatives 17a–e [20].
The classes 20–22 were synthesized from 2-amino-5-iodo-
benzonitrile 18 by cyclisation with chlorosulfonyl isocyanate
to get 19. On the basis of [20a,b] the iodine compound 18 was
coupled to different thiols to achieve the desired thioethers
20. They were hydrolyzed to quinazolinediones 21a–d by
refluxing the compounds in concentrated potassium hydrox-
ide for 4 h and oxidized to sulfones 22a–g using potassium
permanganate in acetic acid [20c]. For coupling the thiols
with 19 copper(I)iodide is used as a catalyst, which complexes
the desired quinazolinones. Although the copper is removed
with ethylene diamine as a ligand, the elemental analysis
differs by more than 0.4% from the calculated data. A
HPLC method was developed to confirm the purity of the
compounds by values more than 95% AUC.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
Aminoquinazolinones and Quinazolidones as Antitumor Agents
813
NH2
NH2
I
S
I
CN
ii
i
N
Ar
N
N
H
O
N
H
O
NH2
19
20
18
iii
iv
X
O
O
O
S
S
Ar
NH
Ar
NH
iv
X = NH, O
N
H
O
N
H
O
22
21
No.
Ar
20a C6H5
b
c
d
e
f
4-(CH3)C6H4
4-(OCH3)C6H4
4-ClC6H4
No.
Ar
X
4-FC6H4
22a
4-(CH3)C6H4
4-(OCH3)C6H4
4-ClC6H4
NH
NH
NH
NH
NH
O
4-(CH(CH3)2)C6H4
2-C10H7
b
c
d
e
f
g
21a C6H5
2-C10H7
b
c
4-(CH3)C6H4
4-(CH(CH3)2)C6H4
4-ClC6H4
4-ClC6H4
4-FC6H4
d
g
4-(CH3)C6H4
O
1): OCNSO2Cl, CH2Cl2, rt. 3 h; 2): K2CO3, CuI, DMF, H2NC2H4NH2, argon, 120°C, 16 h; 3): KOH, rt, 6 h; 4):
KMnO4, HOAc, rt, 1 h
Scheme 4. Synthesis of the classes 20–22.
In structures of type 16 two isomeric forms 16 and 17 are
thinkable. The infrared spectrum (KBr) of 16a shows a band
exist in the tautomeric form 17 in the solid state and as well
in solution in polar liquids like DMSO. In compounds 21a–d
and 22f and g the band at 1620 cmꢀ1 has disappeared and a
new band around 1730 cmꢀ1 from the imide can be detected.
All the other analytical data indicate the given compounds
(see Table 1).
at about 1621 cmꢀ1, which indicates a C N–bonding. At
–
–
1680 cmꢀ1 a shoulder indicates the CO stretching of
the cyclic urea derivative. The CO stretching mode at
1650 cmꢀ1 is typical for a diaryl ketone. The region between
3100 and 3400 cmꢀ1 shows no clear signals, so no statement
about the existence of the imino nor of the amino group can
be made. Further, the 1H-NMR spectrum (DMSO-d6) of the
compound shows three separated signals for NH, two of them
coalescing. This might be affected by H-bonds between two
molecules, so that the two protons of the amino group are no
longer equivalent. The authors assume that the compounds
Bioactivity
Out of the compounds derivatives 17a–c, 17e, 20b–3, 21b–d,
22a–c and 22g were selected by the National Cancer Institute
(NCI) in-vitro disease-oriented human cells screening panel
assay to be evaluated for their in-vitro antitumor activity.
The effective one-dose assay has been added to the NCI 60
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S. Richter and B. Gioffreda
Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
Table 1. Analytical data of compound classes 17, 20–22.
No.
Ar
X
Yield (%)
mp (8C)
IR shift
NH2
X
Ar
N
N
H
O
17a
b
c
d
e
20a
b
c
d
e
f
g
22a
b
c
C6H5
4-(OCH3)C6H4
3,4-(OCH3)2C6H3
3,4-(CH3)2C6H3
4-ClC6H4
CO
CO
CO
CO
CO
S
S
S
S
S
23
31
25
44
33
17
21
9
13
22
18
23
21
29
14
18
15
>350
303–306
310–313
337–340
>350
>350
352
334–337
>350
>350
>350
>350
>350
350–352
>350
>350
1698, 1650, 1621
1684, 1652, 1620
1623
1677, 1639, 1623
1698, 1646, 1622
1671, 1631
C6H5
4-(CH3)C6H4
4-(OCH3)C6H4
4-ClC6H4
4-FC6H4
4-(CH(CH3)2)C6H4
2-C10H7
4-(CH3)C6H4
4-(OCH3)C6H4
4-ClC6H4
2-C10H7
4-(CH(CH3)2)C6H4
1680,1627
1668, 1628
1673, 1627
1671,1630
1671, 1630
1667, 1630
1669, 1621
S
S
SO2
SO2
SO2
SO2
SO2
1687, 1656, 1625
1683, 1658, 1622
1684, 1653, 1619
1673, 1650, 1624
d
e
>350
O
X
Ar
NH
N
H
O
21a
b
c
d
22f
22g
C6H5
S
S
S
S
SO2
SO2
45
51
63
38
11
20
>350
>350
325
307–310
>350
>350
1727, 1698
1728, 1699
1735, 1688
1731, 1698
1727, 1680
1720, 1675
4-(CH3)C6H4
4-ClC6H4
4-FC6H4
4-ClC6H4
4-(CH3)C6H4
cell screen in order to increase the compound throughput
and reduce data turnaround time to suppliers while main-
taining efficient identification of active compounds [21–23].
In this protocol, all compounds submitted to the NCI 60 cell
screen are tested initially at a single high dose (10 mM) in the
full NCI 60 cell panel including leukemia, non-small lung,
colon, CNS, melanoma, ovarian, renal, prostate and breast
cancer cell lines. Only compounds which satisfy pre-determi-
nate would progress to five-dose screen. The threshold inhi-
bition criteria for progression to the five dose screen were
designed to efficiently capture compounds with antiprolifer-
ative activity and are based on careful analysis of historical
Development Therapeutic Program (DTP) screening data. The
data are reported as a mean graph of the percent growth of
the treated cells, and presented as percentage growth inhi-
bition (GI%) caused by the test compounds (see Table 2).
The obtained data revealed that some of the tested subpanel
tumor cell lines exhibited variable sensitivity profiles against
most of the tested compounds. Among these, the leukemia SR
cell line shows moderate sensitivity against compounds 17c,
17e, 20b, 20d, 22c and 22g with GI range between 14.1 to
22.7%. Furthermore, the growth of the non-small cell lung
cancer NCI-H55 cell line was moderately affected by com-
pounds 17e, 20b, 20e, 21b–d, 22a and 22g, whereas com-
pounds 20c and 22g were most active on the A549/ATCC
cell line of the same panel (GI value of 19.7 and 19.3% respect-
ively). The CNS cancer SNB-75 cell line showed moderate
sensitivity against compounds 17b, 20b, 20e, 21c, 22b and 22g.
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Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
Aminoquinazolinones and Quinazolidones as Antitumor Agents
815
Table 2. Growth inhibition rate of four cell lines after treating with compound classes 17, 20–22.
Growth inhibitory activity [%]
SNB-75
No. NSC No.
SR
NCI-H522
Most active (GI [%]), panel
17a
17b
17c
17e
20b
20c
751601
751602
751603
751604
752549
752551
–
2
–
2.7
13.2
17.8
15.7
–
12.8
26.2
22.8
18.9
27
17.9
10.4
13.5
15
9.6
14.2
11.3
13.8
22.4
8.7
12.5
22.5
20
27.3
3.8
10.4
21.8
11.5
17.5
CCRF-CEM (16.6), leukemia
SNB-75 (14.2), CNS cancer
SR (14.1), leukemia
14.1
20.6
22.7
12.9
15.5
8.5
9.8
12
15
8.3
SR (20.6), leukemia
SR (22.7), leukemia
A549/ATCC (19.7), non small cell lung cancer
SR (15.5), leukemia
NCI-H522 (26.2), non small cell lung cancer
NCI-H522 (22.8), non small cell lung cancer
SNB-75 (27.3), CNS cancer
NCI-H522 (27.0), non small cell lung cancer
NCI-H522 (17.9), non small cell lung cancer
SNB-75 (21.8), CNS cancer
20d 752550
20e
21b
21c
752552
752556
752557
21d 752558
22a
22b
22c
22g
752553
752555
752554
752559
9.2
20.9
17.7
SR (20.9), leukemia
A549/ATCC (19.3), non small cell lung cancer
– ¼ no growth inhibition detected
Due to the small number of tested compounds and the
small variety of derivatives a structure–activity relationship
is hard to find, but the moderate growth inhibitory potential
on leukemia SR cell lines, non-small cell lung cancer NCI-
H522 and A549/ATCC cell lines and CNS cancer SNB-75 cell
lines shows that the 4-amino-2(1H)-quinazolinone and
2,4(1H,3H)-quinazolinediones heterocyclic structures could
be considered as useful templates for future development
and derivatization to obtain more potent and selective anti-
cancer agents. To understand the mode of action and evalu-
ate whether the antitumor activity of these compounds is
caused by inhibition of the ATPase activity of antitumor
targets further investigations have to be carried out. So as
the next step molecular modeling studies on ATP/ADP bind-
ing targets and investigation on the inhibition of the ATPase
activity of the pure enzymes by the novel compounds should
be carried out.
Synthesis of 4-nitrobenzophenones 11a–d
To a solution of 11.7 g (63 mmol) 4-nitrobenzoyl chloride 10 in
1,2-dichlorethane 9.6 g (72 mmol) anhydrous aluminum
chloride were added. To this mixture the corresponding aro-
matic compound was added from a dropping-funnel under cool-
ing in an ice-bath, so that the temperature did not rise over 208C.
Then the ice-bath was removed and the mixture was stirred
overnight at room temperature. It was poured on ice and
extracted with dichloromethane two times. The combined
extracts where washed with water, 5% sodiumhydroxide
solution and again water. The organic layer was dried (MgSO4)
and the solvent was evaporated under reduced pressure.
(4-Nitrophenyl)(phenyl)methanone (11a)
Yield: 87%, yellowish crystals, mp 1398C ([10]: 138–1398C).
(4-Methoxyphenyl)(4-nitrophenyl)methanone (11b)
Yield: 66%, yellowish crystals, mp 123–1258C ([11]: 126–1278C).
(3,4-Dimethoxyphenyl)(4-nitrophenyl)methanone (11c)
Yield: 71%, yellow crystals, mp 1668C ([12]: 174–1758C).
Experimental
(3,4-Dimethylphenyl)(4-nitrophenyl)methanone (11d)
Yield: 74%, yellowish crystals, mp 125–1288C ([4]: 1118C). 1H-NMR
(CDCl3): 2.34 (s, 3H), 2.37 (s, 3H), 7.27 (d, 1H, 3J ¼ 7.8 Hz), 7.52
Synthesis
All reagents were purchased from commercial sources and were
used without further treatment, unless otherwise indicated.
Melting points were determined with a Gallenkamp melting
point apparatus MPD350 and have not been corrected. The
1H-NMR spectra were recorded on a Bruker AC200, using TMS
as the internal standard. IR spectra were taken as KBr pellets on a
Perkin Elmer 1600 FT-IR. Mass spectra were recorded using a
Finnigan 4000.
The HPLC data were recorded on a VWR Hitachi LaChrom Elite
with a LiChroCART1 125-4 LiChrospher1 60 column. The com-
pounds were dissolved in methanol, the mobile phase is a
mixture of methanol and phosphate buffer (5 mM, pH 7.2). A
gradient was run from methanol/buffer (65:35) to methanol
100% at minute 14, the run stopped after 22 min.
(d, 1H, 3J ¼ 7.8 Hz), 7.60 (s, 1H), 7.91 (d, 2H, 3J ¼ 8.9 Hz), 8.34
3
–
(d, 2H, J ¼ 8.9 Hz); IR: 1645 (C O). MS: 255, 133, 105; Anal. calcd.
–
(%) for C15H13NO3: C 70.50; H 5.13; N 5.49. Found: C 70.31; H 5.17;
N 5.48.
Synthesis of (4-chlorophenyl)(4-nitrophenyl)methanone (11e)
11.7 g (63 mmol) nitrobenzoyl chloride 10 was dissolved in
chlorobenzene, then 9.6 g (72 mmol) anhydrous aluminum
chloride were added carefully. The reaction mixture was heated
to 508C for 4 h and stirred at room temperature overnight. The
next steps were carried out as described above for compounds
11a–d.
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816
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Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
3J ¼ 8.57 Hz), 7.72 (d, 1H, 3J ¼ 8.57), 7.82 (d, 2H, 3J ¼ 8.57 Hz),
8.23 (s, 1H); 13C-NMR (DMSO-d6): 55.42 (–OCH3), 82.20, 112.89,
113.43 (s, 2C), 128.52, 130.62, 131.79 (s, 2C), 131.99, 141.60,
(4-Chlorophenyl)(4-nitrophenyl)methanone (11e)
Yield: 69%, yellowish crystals, mp 988C ([11]: 102–1038C).
–
151.22, 162.57, 192.57 (C O); IR: 3460, 3358, 2837, 1620.
–
MS: 353, 246, 135, 119. Anal. calcd. (%) for C14H12INO2: C
Synthesis of 4-aminobenzophenones 12a–e
According to [13] 10 mmol of the nitrobenzophenone 11a–e were
suspended in 50 mL ethanol in a 250 mL-round-bottomed flask.
8.3 g (30 mmol) iron(II)sulfate heptahydrate, 9 mL water, 4.3 g
(80 mmol) ammonium chloride and 2.0 g (30 mmol) powdered
zinc were added subsequently with efficient stirring. The reac-
tion was slightly exothermic and the mixture was stirred at 508C
(bath temperature) for 2 h. After cooling it has been filtered and
the residue has been washed with warm ethanol. The combined
filtrates were concentrated under reduced pressure, ethylacetate
was added and the organic phase was washed with 25%
ammonium chloride solution and water. The organic layer
was dried (MgSO4) and the solvent was evaporated under reduced
pressure.
47.61; H 3.43; N 3.97. Found: C 47.33; H 3.61; N 4.11.
(4-Amino-3-iodophenyl)(3,4-dimethoxyphenyl)methanone
(13c)
Yield: 45%, orange solid, mp 1738C. 1H-NMR (CDCl3): 3.94 (s, 3H),
3.96 (s, 3H), 6.76 (d, 1H, 3J ¼ 8.3 Hz), 6.91 (d, 1H, 3J ¼ 8.3 Hz),
7.34 (d, 1H, 3J ¼ 8.2 Hz), 7.38 (s, 1H), 7.66 (d, 1H, 3J ¼ 8.3 Hz),
8.17 (s, 1H); 13C-NMR (DMSO-d6): 55.84 (–OCH3), 56.04 (–OCH3),
81.77, 110.96, 112.34, 113.07, 123.92, 127.09, 130.68, 132.07,
–
141.76, 148.81, 152.33, 153.01, 191.67 (C O); IR: 3446, 3341,
–
2836, 1616. MS: 383, 246, 165, 119, 91. Anal. calcd. (%)
for C15H14INO3: C 47.02; H 3.68; N 3.66. Found: C 47.27;
H 3.73; N 3.45.
(4-Aminophenyl()phenyl)methanone (12a)
Yield: 63%, yellow crystals, mp: 1238C ([14]: 1248C).
(4-Amino-3-iodophenyl)(3,4-dimethylphenyl)methanone
(13d)
(4-Aminophenyl)(4-methoxyphenyl)methanone (12b)
Yield: 68%, yellow crystals, mp: 139–1408C ([15]: 1408C).
Yield: 55%; orange solid, mp 1528C. 1H-NMR (CDCl3): 2.32 (s, 3H),
2.34 (s, 3H), 4.58 (s, 2H, NH2), 6.75 (d, 1H, 3J ¼ 8.4 Hz), 7.22 (d, 1H,
3J ¼ 7.7 Hz), 7.45 (d, 1H, 3J ¼ 7.7 Hz), 7.53 (s, 1H), 7.66 (d, 1H,
3J ¼ 8.4 Hz), 8.19 (s, 1H); 13C-NMR (DMSO-d6): 19.73 (CH3), 19.97
(CH3), 82.44, 112.96, 127.46, 129.33, 129.37, 130.74, 132.29,
(4-Aminophenyl)(3,4-dimethoxyphenyl)methanone (12c)
Yield: 75%, yellowish crystals, mp 1918C ([16]: 191–1928C).
–
135.81, 141.24, 141.95, 150.43, 193.96 (C O); IR: 3462, 3340,
–
2935, 1608. MS: 351, 336, 246, 225, 133, 120; Anal. calcd. (%)
for C15H14INO: C 51.30; H 4.02; N 3.99. Found: C 51.39; H 3.80;
N 3.83.
(4-Aminophenyl)(3,4-dimethylphenyl)methanone (12d)
Yield: 93%, brownish crystals, mp 122–1258C. 1H-NMR (CDCl3):
2.31 (s, 3H), 2.33 (s, 3H), 4.10 (s, 2H, NH2) 6.69 (d, 2H, 3J ¼ 8.6 Hz),
7.20 (d, 1H, 3J ¼ 7.7 Hz), 7.46 (d, 1H, 3J ¼ 7.7 Hz), 7.53 (s, 1H), 7.71
(4-Amino-3-iodophenyl)(4-chlorophenyl)methanone (13e)
Yield: 41%, yellowish solid, mp 1458C. 1H-NMR (CDCl3): 4.58
(s, 2H, NH2), 6.74 (d, 1H, 3J ¼ 8.4 Hz), 7.45 (d, 2H, 3J ¼ 8.5 Hz),
7.64 (d, 1H, 3J ¼ 8,4 Hz), 7.67 (d, 2H, 3J ¼ 8.5 Hz), 8.16 (s, 1H);
13C-NMR (DMSO-d6): 81.75, 112.69, 126.42, 128.28 (s, 2C), 131.92
3
–
(d, 2H, J ¼ 8.6 Hz); IR: 3453, 3351, 3221 (NH ), 1636 (C O), MS:
–
225, 210, 133, 120, 105, 92; Anal. calcd. (%) C15H15NO: C 79.97; H
2
6.71; N 6.22. Found: C 79.97; H 6.42; N 6.19.
(4-Aminophenyl)(4-chlorophenyl)methanone (12e)
Yield: 82%, yellowish crystals, mp 179–1808C ([17]: 1858C).
–
(s, 2C), 141.58, 152.57, 191.56 (C O); IR: 3462, 3340, 1618. MS:
–
357, 246, 230, 195, 167, 139, 111, 91; Anal. calcd. (%)
for C13H9ClINO: C 43.67; H 2.54; N 3.92. Found: C 43.88; H
2.46; N 3.83.
Synthesis of 4-amino-3-iodobenzophenones 13a–e
The corresponding aminobenzophenone (10 mmol) 12a–e was
dissolved in a small amount of acetic acid. A solution of iodine
monochloride (1.62 g, 10 mmol) in 5 mL acetic acid was added
slowly so that the temperature of the reaction mixture did not
rise over 308C. After 15 to 30 min a solid product appeared.
500 mL water were added and excessive iodine monochloride
was reduced by aqueous sodium hydrogen sulfite. The residue
was filtered off, washed with water and dissolved in dichloro-
methane. The organic phase has been washed with sodium
hydrogen carbonate solution and water, dried over MgSO4 and
evaporated under reduced pressure.
Synthesis of 3-cyano-4-amino-benzophenones 14a–e
According to [19] 0.51 g (5 mmol) copper(I) cyanide were added
to 5 mmol of the iodinated compound 13a–e in 15 mL DMF. The
mixture was heated under reflux for 3 h. After cooling it was
stirred with 10% aqueous ethylenediamine and extracted two
times with dichloromethane. The solid appearing between the
layers containing copper was filtered off. The combined organic
layers were washed with water, 10% sodium cyanide solution
and water again, dried over MgSO4 and evaporated under
reduced pressure.
(4-Amino-3-iodophenyl)(phenyl)methanone (13a)
Yield: 49%, yellow solid, mp 1738C ([18]: 1778C).
2-Amino-5-benzoyl-benzonitrile (14a)
Yield: 43%, brown solid, mp 157–1598C. 1H-NMR (DMSO-d6): 6.88
(d, 1H, 3J ¼ 8.4 Hz), 7.04 (s, 2H, NH2), 7.61 (m, 5H), 7.76 (d, 1H,
3J ¼ 8.5 Hz), 7.77 (s, 1H); IR: 3464, 3328, 3222 (-NH2), 2214 (–CN),
(4-Amino-3-iodophenyl)(4-methoxyphenyl)methanone
(13b)
–
1651 (C O). MS: 222, 145, 117, 105, 77. Anal. calcd. (%)
–
Yield: 53%, yellowish crystals, mp 1408C. 1H-NMR (CDCl3): 3.96 (s,
3H), 4.64 (s, 2H, NH2), 6.82 (d, 1H, 3J ¼ 8.57 Hz), 7.04 (d, 2H,
for C14H10N2O: C 75.66; H 4.54; N 12.60. Found: C 75.37; H
4.48; N 12.60.
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
Aminoquinazolinones and Quinazolidones as Antitumor Agents
817
–
–
–
162.69 (C NH), 194.69 (biaryl-C O); IR: 3424, 1698, 1651,
–
2-Amino-5-(4-methoxybenzoyl)-benzonitrile (14b)
Yield: 39%, brown solid, mp 2008C. 1H-NMR (DMSO-d6): 3.85
(s, 1H), 6.87 (d, 1H, 3J ¼ 9.4 Hz), 6.96 (s, 2H, –NH2), 7.07 (d, 2H,
3J ¼ 8.8 Hz), 7.70 (m, 4H); 13C-NMR (DMSO-d6): 55.84 (–OCH3),
92.89, 114.15 (s, 2C), 115.16 (–CN), 117.65, 125.20, 130.28,
1621, 1596. MS: 265, 222, 189, 145, 105. Anal. calcd. (%) for
C15H11N3O2 ꢁ 0.5 H2O: C 68.07; H 5.00; N 9.92. Found: C
68.02; H 4.73; N 9.84. HPLC: 5.4 min, 99.2%.
–
131.94 (s,2C), 135.71, 136.50, 154.87, 162.73, 191.60 (C O);
–
4-Amino-6-(4-methoxybenzoyl)-2(1H)-quinazolinone
IR: 3400, 3367, 3225, 2222, 1657. MS: 252, 145, 135, 117, 107;
Anal. calcd. (%) for C15H12N2O2: C 71.41; H 4.79; N 11.11. Found: C
71.24; H 4.70; 10.91.
(17b)
Yield: 31%, white solid, mp 303–3068C. 1H-NMR (DMSO-d6): 3.87
(s, 3H), 7.10 (d, 2H, 3J ¼ 8.7 Hz), 7.23 (d, 1H, 3J ¼ 8.5 Hz), 7.75
(d, 2H, 3J ¼ 8.7 Hz), 7.85 (s, 1H, NH), 7.88 (d, 1H, 3J ¼ 8.6 Hz), 8.14
(s 1H, NH), 8.45 (s, 1H), 11.00 (s, 1H, NH); 13C-NMR (DMSO-d6):
55.92 (–OCH3), 108.12, 114. 25 (s, 2C), 115.20, 127.28, 129.99,
2-Amino-5-(3,4-dimethoxybenzoyl)-benzonitrile (14c)
Yield: 34%, brown solid, mp 2088C. 1H-NMR (DMSO-d6): 3.94
(s, 3H), 3.97 (s, 3H), 4.90 (s, 2H, NH2), 6.81 (d, 1H, 3J ¼ 7.9 Hz),
6.91 (d, 1H, 3J ¼ 8.4 Hz), 7.30 (d, 1H, 3J ¼ 8.3 Hz), 7.39 (s, 1H), 7.87
(d, 1H, 3J ¼ 8.0 Hz), 7.90 (s, 1H); 13C-NMR (DMSO-d6): 55.84, 92.89,
114.15 (s, 2C), 115.16, 117.65, 125.20, 130.28, 131.94 (s, 2C),
–
–
–
132.56, 134.91 (s, 2C), 145.71, 156.34 (C NH), 163.21(C O cycl.),
–
–
164.13, 193.40 (biaryl-C O); IR: 3400, 3083, 2859, 1684, 1652,
–
1620, 1597. MS: 295, 252, 221, 145, 135. Anal. calcd. (%) for
C16H13N3O3: C 65.08; H 4.44; N 14.23. Found: C 64.82; H 4.73;
N 14.35. HPLC: 5.7 min, 95.3%.
–
135.71, 136.50, 154.87, 162.73, 191.60 (C O); IR: 3456, 3362,
–
3232, 2218, 1639. MS: 282, 251, 165, 145; Anal. calcd. (%)
for C16H14N2O3: C 68.07; H 5.00; N 9.92. Found: C 68.02; H
4.73; N 9.84.
4-Amino-6-(3,4-dimethoxybenzoyl)-2(1H)-quinazolinone
(17c)
Yield: 25%, white solid, mp 310–3138C. 1H-NMR (DMSO-d6):
3.82 (s, 3H), 3.88 (s, 3H), 7.12 (d, 1H, 3J ¼ 8.3 Hz), 7.30
(d, 1H, 3J ¼ 8.5 Hz), 7.32 (d, 1H, 3J ¼ 8.2 Hz), 7.36 (s, 1H),
8.04 (d, 1H, 3J ¼ 8.5 Hz), 8.19 (s, 1H); 13C-NMR (DMSO-d6):
55.92 (–OCH3), 56.15 (–OCH3), 11.09, 112.25, 114.19, 116.08,
124.87, 129.61, 129.69, 13.73, 136.11, 144.13, 149.07, 150.58,
2-Amino-5-(3,4-dimethylbenzoyl)-benzonitrile (14d)
Yield: 45%, brown solid, mp 1718C. 1H-NMR (DMSO-d6): 2.29
(s, 3H), 2.31 (s, 3H), 6.85 (d, 1H, 3J ¼ 6.8 Hz), 6.99 (s, 2H, NH2),
7.29 (d, 1H, 3J ¼ 7.8 Hz), 7.39 (d, 1H, 3J ¼ 7.8 Hz), 7.45 (s, 1H), 7.72
(d, 1H, 3J ¼ 6.9 Hz), 7.75 (s, 1H); 13C-NMR (DMSO-d6): 19.71 (CH3),
19.88 (CH3), 92.93, 115.16, 117.61, 124.99, 127.25, 129.77, 130.39,
–
–
153.17 (C O cycl.), 162.80 (C ¼ NH), 192.99 (diaryl-C O);
–
–
–
135.70, 141.34, 155.01, 192.68 (C O); IR: 3400, 3338, 3227,
–
IR: 3200, 1736, 1688, 1653, 1617. MS: 325, 282, 165. Anal. calcd.
(%) for C17H15N3O4: C 62.76; H 4.65; N 12.92. Found: C 63.00;
H 8.84; N 12.65. HPLC: 5.1 min, 95.2%.
2224, 1658. MS: 250, 235, 145, 133, 117, 105. Anal. calcd. (%)
for C16H14N2O: C 76.78; H 5.64; N 11.19. Found: C 77.01; H 5.51;
N 10.91.
4-Amino-6-(3,4-dimethylbenzoyl)-2(1H)-quinazolinone
2-Amino-5-(4-chlorobenzoyl)-benzonitrile (14e)
(17d)
Yield: 41%, brown solid, mp: 223–2258C. 1H-NMR (DMSO-d6): 6.87
(d, 1H, 3J ¼ 8.4 Hz), 7.07 (s, 2H, NH2), 7.60 (d, 2H, 3J ¼ 8.7 Hz),
7.69 (d,2H, 3J ¼ 8.7 Hz), 7.73–7.78 (m, 2H); 13C-NMR (DMSO-d6):
55.87 (–OCH3), 56.06 (–OCH3), 92.91, 111.02, 112.23, 115.12,
117.65, 124.18, 125.26, 130.23, 135.77, 136.50, 148.93, 152.60,
Yield: 44%, white solid, mp 3158C. 1H-NMR (DMSO-d6): 2.30 (s, 3H),
2.33 (s, 1H), 7.24 (d, 1H, 3J ¼ 8.6 Hz), 7.33 (s, 1H, 3J ¼ 7.8 Hz), 7.46
(d, 1H, 3J ¼ 7.9 Hz), 7.54 (s, 1H), 7.90 (d, 1H, 3J ¼ 8.6 Hz), 7.96
(s, 1H, NH), 8.34 (s, 1H, NH), 8.50 (s, 1H), 11.13 (s, 1H, NH); 13C-NMR
(DMSO-d6): 19.25 (CH3), 19.47 (CH3), 107.67, 114.84, 127.10,
127.49, 129.47, 130.38, 130.50, 134.78, 134.83, 136.61, 141.69,
145.28, 155.28, 163.34, 194.06; IR: 3383, 3183, 2975, 1677, 1639,
1623, 1589. MS: 293, 279, 250, 209, 189, 133. Anal. calcd. (%) for
C17H15N3O2: C 69.61; H 5.15; N 14.33. Found: C 69.33; H 5.43;
N 14.01. HPLC: 7.4 min, 99.1%.
–
154.84, 191.67 (C O); IR: 4000, 3338, 3227, 2224, 1658. MS: 256,
–
221, 145, 139, 117, 111. Anal. calcd. (%) for C14H9ClN2O: C 65.51;
H 3.53; N 10.92. Found: C 65.29; H 3.67; N 11.05.
Synthesis of 4-aminoquinazolinones 17a–e, 19
According to [20] 2.5 mmol starting material 14a–e, 18 were
suspended in 10 mL dry dichloromethane. 0.24 mL of chlorosul-
fonyl isocyanate (2.8 mmol) in 5 mL dry dichloromethane were
added slowly. After stirring for 3 h at room temperature the
solvent is removed under reduced pressure and 20 mL ethanol/
water (1:1) were added. After 60 min the residue is filtered off,
washed with water and stirred in sodium hydrogencarbonate
solution (10%) for 30 min to achieve the free base. The solid is
filtered off and dried to give the crude product.
4-Amino-6-(4-chlorobenzoyl)-2(1H)-quinazolinone (17e)
Yield: 33%, white solid; mp 3258C. 1H-NMR (DMSO-d6): 7.27 (d, 1H,
3J ¼ 8.6 Hz), 7.64 (d, 2H, 3J ¼ 8.5 Hz), 7.75 (d, 2H, 3J ¼ 8.4 Hz),
7.98 (d, 1H, 3J ¼ 8.7 Hz), 8.10 (s, 1H, NH), 8.50 (s, 1H, NH), 8.51
(s, 1H), 11.25 (s, 1H, NH); 13C-NMR (DMSO-d6): 107.57, 115.25,
127.63, 128.62 (s, 2C), 129.66, 131.43 (s, 2C), 134.99, 135.80,
–
–
137.30, 144.81, 145.58, 154.66 (C O cycl.), 162.98 (C NH),
–
–
–
193.09 (biaryl-C O); IR: 3348, 1706, 1648, 1623, 1588. MS:
–
299/301, 256/258, 145, 139/141. Anal. calcd. (%) for C15H10ClN3O2:
C 60.11; H 3.36; N 14.02. Found: C 59.86; H 3.56; N 13.73. HPLC:
6.6 min, 99.5%.
4-Amino- 6-benzoyl-2(1H)-quinazolinone (17a)
Yield: 23%, white solid, mp >3508C. 1H-NMR (DMSO-d6): 7.26
(d, 1H, 3J ¼ 8.6 Hz), 7.57 (t, 2H, 3J ¼ 7.6 Hz), 7.68 (t, 1H,
3J ¼ 7.4 Hz), 7.74 (d, 2H, 3J ¼ 7.8 Hz), 7.92 (d, 1H, 3J ¼ 8.5 Hz),
7.96 (s, 1H, NH), 8.29 (s, 1H, NH), 8.52 (s, 1H), 11.11 (s, 1H, NH);
13C-NMR (DMSO-d6): 108.21, 115.44, 127.78, 128.98 (s, 2C), 130.04
–
4-Amino-6-iodo-2(1H)-quinazolinone (19)
Yield: 15%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 6.95
(d, 1H, 3J ¼ 8.7 Hz), 7.83 (d, 1H, 3J ¼ 8.7 Hz), 7.90–7.92 (d, 2H,
NH), 8.39 (s, 1H), 10.77 (s, 1H, NH); 13C-NMR (DMSO-d6): 83.89,
(s, 2C), 130.39, 132.94, 135.37, 137.54, 145.99, 155.81 (C O cycl.),
–
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

818
S. Richter and B. Gioffreda
Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
110.77, 117.51, 132.90, 142.08, 142.49, 156.12, 162.93; IR: 3352,
3118, 1669, 1628, 1592. MS: 287, 244, 160. Anal. calcd. (%) for
C8H6IN3O: C 33.47; H 2.11; N 14.64. Found: C 33.39; H 1.90;
N 14.24. HPLC: 5.5 min, 98.4%.
IR: 3280, 3018, 1673, 1627, 1584. MS: 303/305, 260/262, 224,
196, 160, 149,105; Anal. calcd. (%) for C14H10ClN3OS: C 55.35;
H 3.32; N 13.84. Found: C 53.87; H 3.14; N 13.79; HPLC: 9.3 min,
97.0%.
4-Amino-6-(4-fluorophenylthio)-2(1H)-quinazolinone (20e)
Yield: 22%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.11–7.22
Synthesis of 6-phenylthio-2(1H)-quinazolinones 20a–g
In a 25-mL 2-neck pear-shaped flask dry argon was bubbled
through 5 mL dimethyl formamide. Consecutively 2.5 mmol
of 19 and 5 mmol (0.72 g) potassium carbonate were added
and the mixture was stirred for 5 min. After adding 0.25 mmol
(50 mg) copper(I)iodide and 0.3 mL ethylene diamine the argon
flow was stopped, the flask was sealed and the mixture was
stirred for 16 h on an oil bath at 1208C.
After cooling water was added and the precipitate was filtered
off. It was treated with ethanol and diethyl ether, then it was
stirred with 10 mL ethylene diamine solution (20%) and 10 mL
methanol for 30 min. The solution turned deep purple, the solid
was filtered off and washed with water, methanol and diethyl
ether.
3
(m, 4H), 7.25–7.28 (m, 2H), 7.58 (d, 1H, J ¼ 8.6 Hz), 7.82 (s, 1H,
NH), 7.95 (s, 1H, NH), 8.27 (s, 1H); 13C-NMR (DMSO-d6): 109.11,
2
116.74–116.91 (d, 2C, JCF ¼ 22 Hz), 116.89, 127.00, 130.20,
2
4
131.13–131.19 (d, 2C, JCF ¼ 9 Hz), 132.86 (d, 1C, JCF ¼ 3 Hz),
1
138.99, 143.25, 156.26, 160.51–162.48 (d, 1C, JCF ¼ 248 Hz),
–
163.50; IR: 3291, 3034 (NH), 1630 (C N), 1585 (NH). MS:
–
287, 244, 212, 149. Anal. calcd. (%) for C14H10FN3OS: C 58.53;
H 3.51 N 14.63. Found: C 58.78; H 3.41; N 14.36. HPLC: 7.9 min,
95.2%.
4-Amino-6-[(4-isopropylphenyl)thio]-2(1H)-quinazolinone
(20f)
Yield: 18%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 1.15
(s, 3H, CH3), 1.17 (s, 3H, CH3), 7.12 (d, 2H, 3J ¼ 8.1 Hz), 7.15
(d, 1H, 3J ¼ 8.7 Hz), 7,20 (d, 2H, 3J ¼ 8.2 Hz), 7.58 (d, 1H,
3J ¼ 8.5 Hz), 7.84 (s, 1H, NH), 7.94 (s, 1H, NH), 8.28 (s, 1H),
10.83 (s, 1H, NH); 13C-NMR (DMSO-d6): 24.08 (s, 2C, (CH3)2CH),
33.35 ((CH3)2CH), 108.79, 117.79, 127.94 (s, 2C), 128.03, 129.97
4-Amino-6-phenylthio-2(1H)-quinazolinone (20a)
Yield: 17%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.15–7.22
(m, 4H), 7.31 (t, 2H, 3J ¼ 7.7 Hz), 7.61 (d, 1H, 3J ¼ 8.6 Hz), 7.82
(s, 1H, NH), 7.95 (s, 1H, NH), 8.30 (s, 1H), 10.84 (s, 1H, NH);13C-NMR
(DMSO-d6): 109.51, 116.90, 123.96, 126.53, 128.02 (s, 2C),
–
–
129.73 (s, 2C), 130.95, 137.86, 139.68, 143.40, 156.29 (C O),
–
(s, 2C), 130.16, 132.96, 140.72, 142.06, 147.96, 150.20 (C O),
–
–
–
163.52 (C NH); IR: 3410, 3070, 1671, 1631, 1590. MS: 269, 226,
–
149. Anal. calcd. (%) for C15H13N3OS: C 62.43; H 4.12; N 15.60.
160.73 (C NH); IR: 3419, 3048, 2962, 2865, 1671, 1631, 1587.
–
MS: 311, 296, 268. Anal. calcd. (%) for C17H17N3OS: C 65.57;
H 5.50; N 13.49. Found: C 61.92; H 5.13; N 12.59. HPLC:
17.3 min, 95.2%.
Found: C 61.32; H 4.21; N 15.34. HPLC: 7.5 min, 97.0%.
4-Amino-6-(4-tolylthio)-2(1H)-quinazolinone (20b)
Yield: 21%, white solid. 1H-NMR (DMSO-d6): 2.26 (s, 3H), 7.11–7.15
(m, 5H), 7.54 (d, 1H, 3J ¼ 8.6 Hz), 7.84 (s, 1H, NH), 7.94 (s, 1H, NH),
8.26 (s, 1H), 10.84 (s, 1H, NH); 13C-NMR (DMSO-d6): 104.99, 116.30,
124.87, 128.73 (s, 2C), 129.48, 129.91 (s, 2C), 133.22, 135.99,
1384.1, 142.56, 155.79, 163.04; IR: 3284, 3018, 1671, 1630,
1581. MS: 283, 240, 224, 196, 160, 149, 105. Anal. calcd. (%)
for C15H13N3OS: C 63.58; 4.62; N 14.83. Found: C 62.28; H 4.68;
N 14.73; HPLC: 9.5 min, 97.3%.
4-Amino-6-(2-naphthylthio)-2(1H)-quinazolinone (20g)
Yield: 23%, white solid; mp >3508C (lit.: 380–3828C). 1H-NMR
(DMSO-d6): 7.20 (d, 1H, 3J ¼ 8.5 Hz), 7.30 (d, 1H, 3J ¼ 8.6 Hz), 7.48
(m, 2H), 7.65 (d, 1H, 3J ¼ 8.5 Hz), 7.70 (s, 1H), 7.80 (s, 1H, NH), 7.82
(d, 1H, 3J ¼ 7.5 Hz), 7.87 (d, 2H, 3J ¼ 8.7 Hz), 7.96 (s, 1H, NH), 8.34
(s, 1H), 10.86 (s, 1H, NH). IR: 3411, 3052, 1667, 1630, 1591. MS:
319, 276, 149, 127. Anal. calcd. (%) for C18H13N3OS: C 67.69; H
4.10; N 13.16. Found: C 68.31; H 4.65; N 12.69. HPLC: 16.3 min,
98.4%.
4-Amino-6-(4-methoxyphenylthio)-2(1H)-quinazolinone
Synthesis of 6-(4-phenylthio)-2,4(1H,3H)-
quinazolinediones 21a–d
100 mg aminoquinazolinone were suspended in 20 mL concen-
trated potassium hydroxide solution and refluxed for 6 h. The
deposit was filtered of and washed with methanol. Then it was
stirred with 5 mL acetic acid/sodium acetate buffer (pH 5.5) for
1 h and filtered off again. It was washed with water.
(20c)
Yield: 9%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 3.74 (s, 3H,
–OCH3), 6.94 (d, 2H, 3J ¼ 8.7 Hz), 7.10 (d, 1H, 3J ¼ 8.6 Hz), 7.28 ((d,
2H, 3J ¼ 8.7 Hz), 7.46 (d, 1H, 8.7), 7.79 (s, 1H, NH), 7.94 (s, 1H, NH),
8.20 (s, 1H), 10.79 (s, 1H, NH); 13C-NMR (DMSO-d6): 55.62 (–O–CH3),
109.34, 115.50 (s, 2C), 116.64, 126.54, 127.33, 128.36, 132.71
–
–
(s, 2C), 137.56, 142.62, 156.28, 159.20 (C O), 163.55 (C NH);
–
–
IR: 3350, 3105, 1668, 1628, 1590. MS: 299, 256, 224, 196, 149.
Anal. calcd. (%) for C15H13N3O2S: C 60.18; H 4.38; N 14.04. Found:
C 59.35; H 4.33; N 13.70. HPLC: 8.0 min, 97.8%.
6-(4-Phenylthio)-2,4(1H,3H)-quinazolinedione (21a)
Yield: 45%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.14
(d, 1H, 3J ¼ 8.5 Hz), 7.25 (m, 3H), 7.35 (d, 2H, 3J ¼ 7.5 Hz), 7.59
(d, 1H, 3J ¼ 8.5 Hz), 7.79 (s, 1H); 13C-NMR (DMSO-d6): 115.33,
116.88, 126.88, 127.15, 129.33, 129.49, 130.38, 130.99, 138.49,
139.67, 150.75 (C ¼ O), 162.09 (C ¼ NH); IR: 3461, 3053,
1727, 1698, 1617, 1613. MS: 270, 227, 199, 172. Anal.
calcd. (%) for C14H10N2O2S: C 62.21; H 3.73; N 10.36. Found: C
58.33; H 3.39; N 9.55. HPLC: 13.9 min, 99.13%. HPLC: 8.8 min,
97.7%.
4-Amino-6-(4-chlorophenylthio)-2(1H)-quinazolinone (20d)
Yield: 13%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.15
(d, 2H, 3J ¼ 8.6 Hz), 7.18 (d, 1H, 3J ¼ 8.6 Hz), 7.37 (d, 2H,
3J ¼ 8.6 Hz), 7.63 (d, 1H, 3J ¼ 8.6 Hz), 7.83 (s, 1H, NH), 7.95
(s, 1H, NH), 8.30 (s, 1H), 10.86 (s, 1H, NH); 13C-NMR (DMSO-d6):
107.04, 116.57, 124.51, 129.09 (s, 2C), 129.12 (s, 2C), 130.69,
–
–
130.80, 136.61, 139.15, 145.00, 156.24 (C O), 161.78 (C NH);
–
–
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Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
Aminoquinazolinones and Quinazolidones as Antitumor Agents
819
56.17 (–OCH3), 108.62, 115.30 (s, 2C), 116.42, 125.43, 129.78
–
6-(4-Tolylthio)-2,4(1H,3H)-quinazolinedione (21b)
Yield: 51%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 2.30
(s, 3H, CH3), 7.17 (d, 1H, 3J ¼ 8.5 Hz), 7.21 (d, 2H, 3J ¼ 8.0 Hz),
7.25 (d, 2H, 3J ¼ 8.0 Hz), 7.61 (d, 1H, 3J ¼ 8.4 Hz), 7.71 (s, 1H),
11.25 (s, 1H, NH), 11.38 (s, 1H, NH); 13C-NMR (DMSO-d6): 21.00
(CH3), 115.62, 117.15, 129.08, 129.11, 130.66 (s, 2C), 131.41 (s, 2C),
131.51, 137.71, 137.77, 1450.52, 150.44, 162.54; IR: 3247, 3057,
1717, 1701, 1687, 1674, 1614. MS: 284, 241, 213, 186. Anal. calcd.
(%) for C15H12N2O2S: C 63.36; H 4.25; N 9.85. Found: C 63.55; H
4.32; N 9.67. HPLC: 10.2 min, 98.0%.
(s, 2C), 132.11, 133.44, 134.22, 146.20, 156.02 (C O), 163.37
–
–
(C NH), 163.51; IR: 3437, 3053, 1687, 1656, 1625, 1595. MS:
–
331, 288, 208, 176, 165, 133. Anal. calcd. (%) for C15H13N3O4S:
C 54.37; H 3.95; N 12.68. Found: C 54.28; H 3.71; N 12.39. HPLC:
5.0 min, 95.2%.
4-Amino-6-(4-chlorophenylsulfonyl)-2(1H)-quinazolinone
(22c)
Yield: 14%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.26
(d, 1H, 3J ¼ 8.8 Hz), 7.72 (d, 2H, 3J ¼ 8.6 Hz), 7.97 (d, 2H,
3J ¼ 8.7 Hz), 8.01 (s, 1H, NH), 8.06 (d, 1H, 3J ¼ 8.7 Hz), 8.31
(s, 1H, NH), 8.74 (s, 1H), 11.11 (s, 1H, NH); 13C-NMR (DMSO-d6):
108.77, 116.61, 126.08, 129.42 (s, 2C), 130.28 (s, 2C), 132.39,
6-(4-Chlorophenylthio)-2,4(1H,3H)-quinazolinedione (21c)
Yield: 63%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.21
(d, 1H, 3J ¼ 8.5 Hz), 7.27 (d, 2H, 3J ¼ 8.4 Hz), 7.42 (d, 2H,
3J ¼ 8.4 Hz), 7.69 (d, 1H, 3J ¼ 8.5 Hz), 7.84 (s, 1H), 11.38 (s, 2H,
NH); 13C-NMR (DMSO-d6): 115.81, 117.50, 126.70, 129.86, 131.13,
–
–
132.72, 138.99, 140.77, 146.63, 156.00 (C O), 163.49 (C NH);
–
–
IR: 3481, 3052, 1683, 1658, 1621, 1593. MS: 303/305, 260/262,
224, 196, 160, 149, 105. Anal. calcd. (%) for C14H10ClN3O3S: C
50.08; H 3.00; N 12.51. Found: C 50.37; H 3.18; N 12.30. HPLC:
5.8 min, 95.4%.
–
–
–
132.10, 135.43, 139.36, 141.29, 150.46 (C O), 162.48 (C O); IR:
–
3424, 3048, 1735, 1688, 1616. MS: 304/306, 261/263, 206/208,
150. Anal. calcd. (%) for C14H9ClN2O2S: C 55.18; H 2,98; N 9,19.
Found: C 55.00; H 3.10; N 9.08. HPLC: 10.2 min, 96.9%.
4-Amino-6-(4-naphthylsulfonyl)-2(1H)-quinazolinone
(22d)
6-(4-Fluorophenylthio)-2,4(1H,3H)-quinazolinedione (21d)
Yield: 38%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.18
(d, 1H, 3J ¼ 8.5 Hz), 7.24 (m, 2H), 7.39 (m, 2H), 7.64 (d, 1H,
3J ¼ 8.5 Hz), 7.75 (s, 1H), 11.35 (s, 2H, NH); 13C-NMR (DMSO-d6):
Yield: 18%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.26
(d, 1H, 3J ¼ 8.8 Hz), 7.72 (m, 2H), 7.93 (d, 1H, 3J ¼ 8.7 HZ), 8.05
(d, 1H, 3J ¼ 7.9 Hz), 8.06 (s, 1H, NH), 8.11 (d, 1H, 3J ¼ 8.7 Hz), 8.15
(d, 1H, 3J ¼ 8.8 Hz), 8.20 (d, 1H, 3J ¼ 7.9 Hz), 8.34 (s, 1H, NH),
8.67 (s, 1H), 8.81 (s, 1H), 11.10 (s, 1H, NH); 13C-NMR (DMSO-d6):
108.74, 116.56, 122.66, 126.02, 128.29, 128.65, 129.80, 129.97,
130.33, 132.09, 132.45, 133.24, 134.84, 138.85, 141.55, 146.49,
2
115.70, 117.02–117.20 (d, 2C, JCF ¼ 22 Hz), 117.34, 128.41,
4
129.65, 130.93 (d, 1C, JCF ¼ 3 Hz), 133.39–133.46 (d, 2C,
2JCF ¼ 8 Hz), 138.18, 140.86, 150.47, 161.05–163.01 (d, 1C,
1JCF ¼ 245 Hz), 162.52; IR: 3189, 3055, 1731, 1698, 1673, 1613.
MS: 288, 245, 217, 189. Anal. calcd. (%) for C14H9FN2O2S: C 58.32;
H 3.15; N 9.72. Found: C 54.47; H 3.01; N 8.75. HPLC: 8.7 min,
90.1%.
–
–
–
–
156.02 (C O), 163.53 (C NH); IR: 3468, 3052, 1653, 1640,
1619, 1592. MS: 351, 208, 176, 165, 133. Anal. calcd. (%) for
C18H13N3O3S: C 61.53; H 3.73; N 11.96: Found: C 59.99; H 3.48;
N 11.58. HPLC: 6.8 min, 96.6%.
Synthesis of 6-(4-phenylsulfonyl)quinazolinones 22 a–g
100 mg thioaminoquinazolinone was suspended in 5 mL acetic
acid. 0.1 g potassium permanganate in 5 mL acetic acid was
added over 30 min. After another hour the brown solution
was basified with concentrated ammonia. The precipitate was
filtered off, washed with water and methanol and was then
treated with 1 mL of hot dimethyl formamide in the filter.
The solution was diluted with water until a deposit appears,
which was filtered off and washed with water.
4-Amino-6-[(4-isopropylphenyl)sulfonyl]-2(1H)-
quinazolinone (22e)
Yield: 15%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 1.18
(s, 3H, CH3), 1.19 (s, 3H, CH3), 2.96 (m, 1H, CH), 7.24 (d, 1H,
3J ¼ 8.8 Hz), 7.49 (d, 2H, 3J ¼ 8.3 Hz), 7.88 (d, 2H, 3J ¼ 8.3 Hz),
8.00 (s, 1H, NH), 8.04 (d, 1H, 3J ¼ 8.8 Hz), 8.32 (s 1H, NH), 8.73
(s, 1H), 11.09 (s, 1H, NH). IR: 3347, 3053, 2963, 2871, 1673, 1650,
1624, 1593. MS: 343, 328, 208, 176, 165, 133. Anal. calcd. (%)
for C17H17N3O3S: C 59.46; H 4.99; N 12.24. Found: C 59.53; H 5.13;
N 12.11.
4-Amino-6-(4-tolylsulfonyl)-2(1H)-quinazolinone (22a)
Yield: 21%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 2.36
(s, 3H, CH3), 7.24 (d, 1H, 3J ¼ 8.8 Hz), 7.43 (d, 2H, 3J ¼ 8.1 Hz),
7.85 (d, 2H, 3J ¼ 8.2 Hz), 8.00 (s, 1H, NH), 8.02 (d, 1H, 3J ¼ 8.8 Hz),
8.32 (s, 1H, NH), 8.72 (s, 1H), 11.09 (s, 1H, NH); 13C-NMR: 21.36
(CH3), 108.66, 116.47, 125.70, 127.50 (s, 2C), 130.52 (s, 2C), 132.26,
6-(4-Chlorophenylsulfonyl)-2,4(1H,3H)-quinazolinedione
(22f)
Yield: 11%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 7.32
(d, 1H, 3J ¼ 8.7 Hz), 7.70 (d, 2H, 3J ¼ 8.2 Hz), 7.99 (d, 2H,
3J ¼ 8.2 Hz), 8.16 (d, 1H, 3J ¼ 8.6 Hz), 8.33 (s, 1H), 11.62 (s, 2H,
NH); 13C-NMR (DMSO-d6): 115.25, 117.49, 127.48, 129.64, 130.38,
133.69, 134.19, 139.23, 140.23, 145.17, 150.41, 162.13; IR: 3450,
3058, 1727, 1680, 1618. MS: 336/338, 209, 166, 161, 111/113.
Anal. calcd. (%) for C14H9ClN2O4S: C 49.93; H2.69; N 8.32. Found:
C 49.99; H 2.91; N 8.11. HPLC: 5.3 min, 97.7%.
–
–
133.69, 139.10, 144.51, 146.35, 156.03 (C O), 163.51 (C NH); IR:
–
–
3399, 3035, 1668, 1621, 1593. MS: 315, 287, 208, 176, 165, 133.
Anal. calcd. (%) for C15H13N3O3S: C 57.13; H 4.16; N 13.33. Found:
C 55.39; H 3.90; N 13.14. HPLC: 5.3 min, 98.5%.
4-Amino-6-(4-methoxyphenylsulfonyl) -2(1H)-
quinazolinone (22b)
Yield: 29%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 3.82
(s, 3H, CH3), 7.14 (d, 2H, 3J ¼ 9.0 Hz), 7.23 (d, 1H, 3J ¼ 8.8 Hz),
7.89 (d, 2H, 3J ¼ 9.0 Hz), 7.98 (s, 1H, NH), 8.02 (d, 1H, 3J ¼ 8.7 Hz),
8.30 (s, 1H, NH), 8.71 (s, 1H), 11.07 (s, 1H, NH); 13C-NMR (DMSO-d6):
6-(4-Tolylsulfonyl)-2,4(1H,3H)-quinazolindione (22g)
Yield: 20%, white solid; mp >3508C. 1H-NMR (DMSO-d6): 2.37
(s, 3H), 7.30 (d, 1H, 3J ¼ 8.7 Hz), 7.43 (d, 2H, 3J ¼ 8.2 Hz), 7.84
(d, 2H, 3J ¼ 8.2 Hz), 8.13 (d, 1H, 3J ¼ 8.7 Hz), 8.29 (s, 1H), 11.59
ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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820
S. Richter and B. Gioffreda
Arch. Pharm. Chem. Life Sci. 2011, 344, 810–820
(s, 2H, NH). IR: 3259, 3040, 1720, 1675, 1616. MS: 316, 230, 209,
166,139. Anal. calcd. (%) for C15H12N2O4S: C 56.95; H 3.82; N 8.86.
Found: C 57.21; H 3.66; N 8.99.
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2423.
The authors like to thank the staff members of the Department of Health
and Human Services, NCI, Bethesda, MD, USA for carrying out the
anticancer screening of the novel compounds.
ˇ
ˇˇ´
[12] Z. Vejdelek, J. Holubek, M. Budesınsky, et al., Collect. Czech.
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The authors have declared no conflict of interest.
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Thanusu, Catal. Communi. 2005, 753–756.
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ß 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com