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Substituted Quinazolines Part 2. Synthesis and In-Vitro Anticancer Evaluation of New 2-Substituted Mercapto-3H-quinazoline Analogs

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Arch. Pharm. Pharm. Med. Chem. 2003, 2, 95–103
Ashraf A. Khalil,
Sami G. Abdel Hamide,
Abdulrahman M. Al-Obaid,
Hussein I. El-Subbagh
Department of Pharmaceutical
Chemistry,
College of Pharmacy,
King Saud University, Riyadh,
Saudi Arabia
Substituted Quinazolines 95
Substituted Quinazolines, Part 2.
Synthesis and In-Vitro Anticancer Evaluation of
New 2-Substituted Mercapto-3H-quinazoline
Analogs
A new series of 2-substituted mercapto-3H-quinozolines bearing 6-iodo and 2-heteroarylthio functions was synthesized and screened for their in vitro antitumor activity. Eighteen compounds were identified as active anticancer agents. N⬘-[(3-Benzyl4-oxo-6-iodo-3H-quinazoline-2-yl)thioacetyl]-N 3-ethylthiosemicarbazide (10), Nbenzoyl-N⬘-[2-(3-benzyl-4-oxo-6-iodo-3H-quinozolin-2-yl)thioacetyl]hydrazine (12),
and 2-[(3,6-dioxo-pyridazin-4-yl)thio]-3-benzyl-4-oxo-6-iodo-3H-quinazoline (20)
proved to be the most active members in this study. They showed MG-MID, GI50
values of 12.8, 11.3, and 13.8 µM, respectively.The detailed synthesis and biological
screening data are reported.
Keywords: Synthesis; 4-(3H)-Quinazolinone; Antitumor activity
Received: April 4, 2002 [FP688]
Interest in quinazolines as anticancer agents has further
increased since the discovery of raltitrexed (1) and
thymitaq (2) (Figure 1) and their activity as thymidylate
enzyme inhibitors [1, 2]. 4-Anilinoquinazolines represent
as a new class of antitumor drugs [3, 4].They were found
to inhibit the epidermal growth factor receptor (EGFR)
tyrosine kinase overexpression through the inhibition of
EGFR autophosphorylation and EGF-stimulated signal
transduction [5, 6]. Furthermore, quinazolines exert their
antitumor activity through inhibition of the DNA repair
enzyme system. Enzyme-mediated repair of strand
lesions in DNA is an established mechanism for resistance toward antitumor DNA-damaging drugs and radiotherapy [7–9].
Figure 1
In the present study, and as a continuation of our previous efforts [10], a new series of 2-substituted mercapto3-benzyl-6-iodo-4(3H)-quinazolinone was designed and
Correspondence: Hussein I. El-Subbagh, Department of
Pharmaceutical Chemistry, College of Pharmacy, P.O. Box
2457, King Saud University, Riyadh-11451, Saudi Arabia.
Phone: +966 1 4682134, e-mail: subbagh@yahoo.com.
© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
synthesized, in such a fashion that the 5-thioether function of 1 was moved to position 2. A variety of heterocycles were linked to the 2-SH function of the quinazoline ring through -CH2- or -CH2CO- bridges or directly
hooked to the sulfur atom to produce the target
thioethers. Thioether is a functional group known to enhance the antitumor activity [11]. The objective of forming these hybrids is an attempt to reach an active antitumor agent(s) with potential selectivity toward cancerous
cells and less toxicity toward normal cells.
Results and discussion
Chemistry
The synthesis of the target compounds 4–30 is depicted
in Schemes 1–3. The starting material 2-(ethoxycarbonylmethyl)thio-3-benzyl-4-oxo-6-iodo-3H-quinazoline (3)
was prepared according to a reported procedure [12],
and allowed to react with 1,2-phenylenediamine to produce its benzimidazole analog 4. Compound 3 was reacted with hydrazine hydrate to get the hydrazide 5
which reacted with CS2 to give the 5-thioxo-1,3,4-oxadiazole derivative 6. Meanwhile, this study required the resynthesis of some previously reported analogs to compare their antitumor potency, such as compounds 7 and
8 [12]. The hydrazide derivative 5 was reacted with
phthalic and succinic anhydrides to give the 1-phthalimido and 1-succinimido analogs 7 and 8, respectively
(Scheme 1).The hydrazide analog 5 was also allowed to
react with a variety of isothiocyanates, benzoyl chloride,
and benzaldehyde to afford the thiosemicarbazides
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Introduction
96 Khalil et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 95–103
Scheme 1. (i) 1,2-Phenylenediamine, (ii) NH2NH2, (iii) CS2, EtOH, (iv) succinic anhydride (v) phthalic anhydride, (vi)
RNCS, (vii) PhCoCl, (viii) P2O5, (ix) PhCHO, (x) (CH3CO)2O2, (xi) HSCH2COOH, (xii) ClCOCH2Cl.
9–11, the benzamide analog 12, and the benzylidine derivative 14, respectively. Compound 12 was subjected to
cyclodehydration reaction using P2O5 to afford the 5phenyl-1,3,4-oxadiazole analog 13. The benzylidine derivative 14 was reacted with acetic anhydride, thioglycolic acid, and chloroacetyl chloride to produce 3-acetyl-5phenyl-1,3,4-oxadiazoline (15), 2-phenyl-4-oxo-1,3thiazolidine (16), and 2-oxo-3-chloro-4-phenyl-azetidine
(17), respectively (Scheme 1).The hydrazine function of
5 was also allowed to react with chloroacetamide, ethyl
acetoacetate, and acetylacetone to give 5-oxo-1,6-dihydro-6H-1,2,4-triazine (18), 3-methyl-5-oxo-4,5-dihydropyrazole (21), and 3,5-dimethylpyrazole (22), respectively (Scheme 2). Reacting the hydrazide 5 with chloro-
acetyl chloride at room temperature produced the N-(1oxo-2-chloroethyl) derivative 19; repetition of this reaction under refluxing conditions gave the cyclized product
3,6-dioxopyridazine (20). Meanwhile, heating compound 19 at its melting point for 30min afforded material
which proved to be identical with compound 20 (Scheme
2). The hydrazide 5 was reacted with triethylorthoformate or formic acid to produce the N-ethoxymethine (23)
or the N-formyl (24) analogs, respectively. Heating the Nethoxymethine derivative 23 afforded the 1,3,4-oxadiazole 25, meanwhile the N-formyl derivative 24 was
cyclodehydrated using P2O5 or P2S5 to give a compound
which proved to be identical to 25 in addition to the 1,3,4thiadiazole 26, respectively (Scheme 2). Reacting the
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 95–103
Substituted Quinazolines 97
Scheme 2. (i) H2NCOCH2Cl; (ii) ClCH2COCl; (iii) ∆; DMF (iv) ClCH2COCl; (v) CH3COCH2COOEt; (vi) (CH3CO)2CH2;
(vii) CH(OEt)3; (viii) HCOOH; (ix) P2O5 or P2S5; (x) ∆.
Scheme 3. (i) NH2(CH2)2OH, 1 mol; (ii) conc. H2SO4; (iii) NH2(CH2)2OH, excess; (iv) SOCl2.
98 Khalil et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 95–103
Table 1. Physicochemical properties and primary antitumor activity of the synthesized compounds.
Compd
Solvent
Yield (%)
Mp (°C)
Molecular formulae
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
AcOH
Dioxane
EtOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
EtOH
AcOH
AcOH
Toluene
Dioxane
EtOH
AcOH
DMF
EtOH
EtOH
AcOH
AcOH
EtOH
EtOH
Dioxane
AcOH
AcOH
EtOH
75
80
55
70
66
70
65
60
63
50
70
40
40
35
30
70
40
50
55
60
70
50
45
60
60
70
50
>300
210–212
182–187
282–284
206–207
225–227
230–231
243–245
243–244
170–172
215–217
269–270
>300
250–251
160–162
245–246
168–170
138–139
99–101
190–192
185–186
260–261
248–250
214–216
>300
252–257
270–271
C23H17IN4OS
a
b
c
d
d
C18H13IN4O2S2
Primary
antitumor assaya
b
c
c
d
c
d
c
C19H18IN5O2S2
C20H20IN5O2S2
C24H20IN5O2S2
C24H19IN4O3S
C24H17IN4O2S
C24H19IN4O2S
C26H21IN4O3S
C26H21IN4O3S2
C26H20IClN4O3S
C19H16IN5O2S
C19H16IClN4O3S
C19H15IN4O3S
C21H17IN4O3S
C22H19IN4O2S
C20H19IN4O3S
C18H15IN4O3S
C18H13IN4O2S
C18H13IN4OS2
d
C19H16IN3O2S
C17H16IN3O2
C17H14IN3O
nt
c
c
c
b
c
b
c
nt
c
nt
c
c
c
c
c
c
c
nt
b
nt
c
Compounds which reduce the growth of any one of the cell lines NCI-H460 (lung), SF-268 (CNS) and MCF7 (breast)
to 32 % or less are passed on for evaluation in the full panel of 60 cell lines.
Inactive compound.
Active compound. nt, compound not tested.
Compounds previously reported in [12].
starting material 3 with ethanolamine at two different
concentrations afforded the previously reported N-(2hydroxyethylamino) derivative 27 using only one mole of
ethanolamine [12], while the use of a large excess of the
same reagent displaced the 2-alkylthio function of 3, producing the 2-hydroxyethylamino derivative 29 (Scheme
3). Compound 27 was cyclodehydrated using concentrated H2SO4 to produce the 2-oxopyrrolidine analog 28.
On the other hand, compound 29 was cyclized using
SOCl2 to produce the imidazo[2,3-b]quinazoline 30
(Scheme 3). Structure elucidation of the new compounds was attained with the aid of elemental analyses
(C, H, N) and 1H NMR spectra.
Antitumor testing
The synthesized compounds were subjected to the
NCI’s in vitro, one dose primary anticancer assay, using
a 3-cell line panel consisting of MCF-7 (breast), NCIH460 (lung), and SF-268 (CNS) cancers. Compounds
which reduce the growth of any one of the cell lines to
32 % or less are passed on for evaluation in the full panel
of 60 cell lines over a 5-log dose range [13–15].Three response parameters, median growth inhibition (GI50), total growth inhibition (TGI), and median lethal concentration (LC50) were calculated for each cell line [16].The NCI
antitumor drug discovery screen has been designed to
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 95–103
Substituted Quinazolines 99
Table 2. Growth inhibitory and lethal concentrations (GI50, TGI, and LC50) of some selected in vitro tumor cell lines
(µM)a.
Compd
Activity
HL-60 (TB)
6
10
20
24
30
a
b
Leukemia
MOLT-4
Renal Cancer
RXF393
A498
RPMI-8226
CAKI-1
6.3
22.4
61.8
<0.01
10.9
36.7
18.6
34.2
62.7
0.3
12.3
10.4
65.6
13.2
b
b
UP-31
GI50
TGI
LC50
4.7
16.5
54.2
20.7
65.3
16.3
b
b
GI50
TGI
LC50
0.3
12.1
6.3
11.0
b
b
b
b
b
b
GI50
TGI
LC50
20.1
38.4
73.5
14.3
42.5
17.0
45.5
b
b
2.8
11.2
40.0
nt
nt
nt
12.7
29.7
69.3
0.6
2.0
5.6
GI50
TGI
LC50
47.6
89.7
0.4
22.2
57.5
29.1
81.4
37.9
b
b
b
b
b
1.7
3.9
9.0
GI50
TGI
LC50
0.6
4.5
92.8
b
b
b
b
23.6
49.4
0.7
94.1
57.5
b
b
b
b
b
b
b
b
b
b
<0.01
23.8
61.7
b
b
0.7
3.4
46.4
0.03
0.2
0.6
b
Data obtained from NCI’s in vitro disease oriented human tumor cell screen.
Value >100 µM.
distinguish between broad-spectrum antitumor and
tumor or sub-panel-selective compounds [15]. In the
present study, compounds 5–8, 10–12, 14, 16, 18,
20–26, and 30 passed the primary anticancer assay at
an arbitrary concentration of 100 µM (Table 1). Consequently, those active compounds were carried over and
tested against a panel of 60 different tumor cell lines.The
tested quinazoline analogs showed a distinctive potential pattern of selectivity as well as broad-spectrum antitumor activity. With regard to sensitivity against individual cell lines, compounds 6 and 24 showed GI50 effectiveness against the renal cancer RXF 393, and leukemia
RPMI-8226 at concentrations of <0.01 µM. Compound
10 showed a remarkable activity against the renal cancer UO-31 with GI50, TGI, and LC50 concentrations of
0.03, 0.2, and 0.6 µM, respectively. Compounds 10 and
30 showed activity against leukemia L-60 (TB) cell line at
GI50 levels of 0.3 and 0.6 µM, respectively (Table 2).
With regard to broad-spectrum antitumor activity, the
tested compounds showed GI50, TGI, and LC50 (MGMID) values <100 µM, against leukemia, non-small cell
lung, colon, CNS, melanoma, ovarian, renal, prostate,
and breast cancer subpanel cell lines. Compounds 11,
22, 23, and 30 showed (MG-MID) values <100 µM at only
the GI50 and TGI levels, while the rest of compounds
showed activity at the three levels of activity, GI50, TGI,
and LC50 (Table 3).
Structure-activity correlation of the synthesized compounds showed that the hydrazide 5 exhibited antitumor
potency at a GI50 concentration of 20.6 µM. Conversion
of the hydrazine moiety of 5 into its corresponding
phthalamide analog 7 (GI50 14.9 µM), increased the antitumor potency while the succinamide analog 8 (GI50
40.0 µM) decreased the activity. Conversion of the
hydrazine moiety of 5 into the corresponding thiosemicarbazides 10 and 11 or the benzoyl derivative 12 increased the antitumor potency. Cyclization of 12 into the
5-phenyl-1,3,4-oxadiazole analog 13, abolished the activity. Conversion of 5 into the azomethine derivative 14
(GI50 23.8 µM) caused a marginal decrease in activity.
Subsequent cyclization of 14 gave the thiazolidine analog 16 with almost equal activity (GI50 24.0 µM) in addition to the inactive 1,3,4-oxadiazoline 15. Further cyclization of 5 produced the 1,2,4-triazine derivative 18, the
pyridazine 20, and the pyrazoles 21 and 22 with GI50 values in the range of 13.8–44.5 µM. Meanwhile, the hydrazine function of 5 was used to prepare the ethoxymethine (23) and the N-formyl (24) analogs. Compound
100 Khalil et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 95–103
Table 3. Median growth inhibitory concentration (GI50, µM) of in vitro subpanel tumor cell lines.
Compd
5
6
7
8
10
11
12
14
16
18
20
21
22
23
24
25
26
30
Melphalan
a
b
c
I
II
III
18.9
15.8
27.0
34.7
5.1
10.8
29.7
54.1
24.6
19.0
12.3
26.9
94.5
40.9
18.8
57.1
12.5
70.4
20.1
21.5
17.1
14.2
38.7
24.3
10.8
9.8
20.7
23.9
28.8
17.1
29.5
37.3
56.0
32.7
77.3
15.1
82.2
38.5
24.5
17.4
26.4
48.3
16.3
27.6
23.2
59.9
24.3
28.3
17.4
33.3
64.7
51.9
31.3
93.8
34.6
c
42.1
Subpanel tumor cell linesa
IV
V
VI
VII
20.9
16.0
9.4
50.2
49.8
41.3
12.1
14.8
31.4
25.7
16.6
29.8
39.7
45.8
39.8
92.5
17.6
57.3
17.1
19.8
16.4
18.9
56.7
20.8
48.9
16.6
43.5
23.1
21.7
15.7
29.2
69.2
71.4
31.4
93.7
25.1
c
31.9
24.5
19.5
15.5
44.1
32.6
37.6
13.1
24.3
29.2
29.2
15.6
37.4
49.6
81.1
42.1
96.8
34.7
83.7
43.0
16.4
11.6
11.5
36.4
11.2
28.4
9.5
20.3
22.6
19.6
11.3
31.8
31.5
74.3
28.0
60.4
14.3
66.2
34.4
VIII
IX
GI50
26.9
32.1
14.7
65.1
36.7
54.8
12.3
24.8
29.3
23.4
18.5
27.1
32.1
72.0
41.2
26.3
17.9
19.9
49.8
19.7
40.5
14.3
41.5
27.3
25.7
17.0
30.9
53.4
53.4
34.9
86.4
40.0
81.4
39.2
20.6
14.2
14.9
40.0
12.8
17.2
11.3
23.8
24.0
22.6
13.8
27.3
44.5
51.7
25.4
72.0
16.7
64.0
27.1
c
18.5
c
34.7
MG-MIDb
TGI
LC50
52.0
35.3
50.0
87.6
73.4
92.4
39.3
65.6
65.6
61.4
30.1
77.0
89.7
96.2
78.8
88.3
85.5
98.5
35.3
92.4
71.9
95.0
98.5
91.2
c
75.9
96.2
92.5
89.3
61.4
98.2
c
c
92.5
96.3
96.3
c
65.5
GI50 values against I, leukemia; II, non-small cell lung cancer; III, colon cancer; IV, CNS cancer; V. melanoma;
VI, ovarian cancer; VII, renal cancer; VIII, prostate cancer; IX, breast cancer cell lines.
GI50, TGI and LC50 full panel mean-graph mid point (µM).
Values >100 µM.
24 is twice as active as compound 23 (GI50 25.4 and
51.7 µM, respectively), the activity of 24 may be attributed to the –CHO group. Cyclization of both 23 and 24 afforded the oxadiazole 25 (GI50 72.0 µM) and the thiadiazole 26 (GI50 16.7 µM). As can be seen, replacing the
oxygen atom of the oxadiazole nucleus in 25 by a sulfur
atom as in 26, increases the antitumor activity almost
fourfold. Cyclization of the 2-hydroxyethylamino derivative 29 to the fused heterocycle imidazo[2,3-b]quinazoline analog (30) produced a moderate antitumor activity
with GI50 value of 64.0 µM.
1
In conclusion, compounds N -[2-(3-benzyl-4-oxo-6iodo-3H-quinazolin-2-yl)thioacetyl-N 3-ethyl-thiosemicarbazide (10), N-benzoyl-N 1-[2-(3-benzyl-4-oxo-6iodo-3H-quinazolin-2-yl)thioacetyl]hydrazine (12), and
2-[(3,6-dioxo-pyridazin-4-yl)thio]-3-benzyl-4-oxo-6iodo-3H-quinazoline (20) proved to be the most active
members in the present study, as compared to the
known drug melphalan. These three quinazolinones
could be considered as useful templates for future development to obtain more potent antitumor agent(s).
Acknowledgements
This work was supported by the Research Center of College of Pharmacy, King Saud University (C.P.R.C. 80).
The authors wish to thank the National Cancer Institute
(Bethesda, MD) for testing the compounds in the drugscreening program.
Experimental part
Synthesis
Melting points were determined on a Mettler FP80 melting
point apparatus and are uncorrected. Microanalyses were performed on a Perkin-Elmer 240 elemental analyzer at the Central Research Laboratory, College of Pharmacy, King Saud University. All of the new compounds were analyzed for C, H, and N
and agreed with the proposed structures within ±0.4 % of the
theoretical values. 1H NMR spectra were recorded on a Varian
XL 400 MHz FT spectrometer, chemical shifts are expressed in
δ ppm with reference to TMS. Thin-layer chromatography was
performed on Merck 5 × 10 cm precoated (0.25 mm) silica gel
GF254 plates; compounds were detected with a 254-nm UV
lamp. Silica gel (60–320 mesh) was employed for routine
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 95–103
column chromatography separations. Syntheses of compounds 3, 5, 7, 8, and 27 were previously reported [12]. The
synthesized compounds were tested in-vitro for their antitumor
activity at the NCI, Bethesda, USA.
2-[(2-Benzimidazole)methylthio]-3-benzyl-4-oxo-6-iodo-3Hquinazoline (4)
Equimolar amounts of 2-(ethoxycarbonylmethyl)thio-3-benzyl4-oxo-6-iodo-3H-quinazoline (3; 4.8 g, 0.01 mol) and 1,2-phenylenediamine (1.1 g, 0.01 mol) were fused at 180 °C for
30 min. The reaction mixture was triturated with boiling AcOH,
filtered, cooled, and poured onto ice. The solid was filtered off,
dried, and recrystallized to give 4 (Table 1). 1H NMR (DMSO-d6)
δ 4.15 (s, 2 H, CH2CO), 5.52 (s, 2 H, -CH2Ph), 7.20–7.52 (m,
10 H, ArH), 8.21 (d, J = 15 Hz, 1 H, ArH), 8.68 (d, J = 15 Hz,
1 H, ArH), 9.62 (brs, 1 H, NH).
2-[(5-Thioxo-1,3,4-oxadiazol-2-yl)methylthio]-3-benzyl-4-oxo6-iodo-3H-quinazoline (6)
A mixture of 2-[(3-benzyl-4-oxo-6-iodo-3H-quinazoline-2-yl)thio]acetylhydrazine (5; 4.7 g, 0.01 mol), carbon disulfide
(20 mL), and potassium hydroxide (0.5 g) in ethanol (50 mL)
was heated under reflux for 20 h. Solvents were removed under
reduced pressure, and the obtained residue was dissolved in
water and neutralized with dilute HCl. The solid was filtered off,
dried, and recrystallized to give 6 (Table 1). 1H NMR (DMSO-d6)
δ 4.12 (s, 2 H, CH2CO), 5.50 (s, 2 H, -CH2Ph), 7.16–7.45 (m,
6 H, ArH), 8.19 (d, J = 15 Hz, 1 H, ArH), 8.61 (d, J = 15 Hz, 1 H,
ArH), 10.02 (brs, 1 H, NH).
N 1 -[(3-Benzyl-4-oxo-6-iodo-3H-quinazolin-2-yl)thioacetyl]N3-substituted thiosemicarbazides (9–11)
A mixture of 5 (0.01 mol) and the appropriate isothiocyanate
derivatives (0.012 mol) in dioxane (50 mL) was heated under
reflux for 4 h. The solid was filtered, dried, and recrystallized to
give 9–11 (Table 1). 1H NMR (DMSO-d6), 9: δ 2.52 (d, J = 6 Hz,
3 H, -NHCH3), 4.15 (s, 2 H, CH2CO), 5.51 (s, 2 H, -CH2Ph),
7.22–7.46 (m, 6 H, ArH), 8.21 (d, J = 14 Hz, 1 H, ArH), 8.71 (d,
J = 14 Hz, 1 H, ArH), 9.02 (brs, 2 H, NH), 10.12 (brs, 1 H, NH).
10: δ 1.10 (t, J = 7 Hz, 3 H, CH3CH2-), 3.21 (m, 2 H, CH3CH2-),
4.18 (s, 2 H, CH2CO), 5.49 (s, 2 H, -CH2Ph), 7.23–7.49 (m, 7 H,
ArH & NH), 8.20 (d, J = 15 Hz, 1 H, ArH), 8.70 (d, J = 15 Hz,
1 H, ArH), 10.01 (brs, 2 H, NH), 11: δ 4.20 (s, 2 H, CH2CO), 5.51
(s, 2 H, -CH2Ph), 7.21–7.67 (m, 11 H, ArH), 8.21 (d, J = 15 Hz,
1 H, ArH), 8.34 (brs, 1 H, NH), 8.68 (d, J = 15 Hz, 1 H, ArH),
9.34 (brs, 2 H, NH).
N-Benzoyl-N⬘-[2-(3-benzyl-4-oxo-6-iodo-3H-quinazolin-2-yl)thioacetyl]hydrazine (12)
A mixture of 5 (4.7 g, 0.01 mol) and benzoyl chloride (2.1 g,
0.015 mol) in dimethylformamide (25 mL) was heated under
reflux for 5 h.The reaction mixture was cooled, poured onto ice,
and stirred.The solid was filtered off, washed with water, dried,
and recrystallized to afford 12 (Table 1). 1H NMR (DMSO-d6) δ
4.15 (s, 2 H, CH2CO), 5.52 (s, 2 H, -CH2Ph), 7.16–7.67 (m,
12 H, ArH & NH), 8.21 (d, J = 15 Hz, 1 H, ArH), 8.68 (d, J =
15 Hz, 1 H, ArH), 9.12 (brs, 1 H, NH).
2-[(5-Phenyl-1,3,4-oxadiazol-2-yl)methylthio]-3-benzyl-4-oxo-6iodo-3H-quinazoline (13)
To a suspension of 12 (0.6 g, 0.001 mol) in dry xylene (50 mL),
phosphorus pentoxide (2.0 g) was added portionwise. The reaction mixture was heated under reflux for 3 h, and then filtered.
Solvent was removed under reduced pressure, and the residue
was recrystallized (Table 1). 1H NMR (CDCl3) δ 4.13 (s, 2 H,
CH2CO-), 5.53 (s, 2 H, -CH2Ph), 7.16–7.65 (m, 11 H, ArH), 8.18
(d, J = 15 Hz, 1 H, ArH), 8.62 (d, J = 15 Hz, 1 H, ArH).
Substituted Quinazolines 101
N-Benzylidine-N⬘-[2-(3-benzyl-4-oxo-6-iodo-3H-quinazolin-2yl)thioacetyl]hydrazine (14)
A mixture of 5 (0.5 g, 0.001 mol) and benzaldehyde (0.16 g,
0.0015 mol) in glacial AcOH (30 mL) was heated under reflux
for 6 h. The reaction mixture was cooled, and the solid was filtered off, washed with petroleum ether, dried, and recrystallized (Table 1). 1H NMR (DMSO-d6) δ 4.15 (s, 2 H, CH2CO), 5.51
(s, 2 H, -CH2Ph), 7.16–7.69 (m, 11 H, ArH), 8.20 (s, 1 H, ArH),
8.68 (s, 1 H, ArH), 9.81 (s, 1 H, CH=N), 10.08 (brs, 1 H, NH).
2-[(3-Acetyl-5-phenyl-1,3,4-oxadiazolin-2-yl)methylthio]-3benzyl-4-oxo-6-iodo-3H-quinazoline (15)
Compound 14 (0.6 g, 0.001 mol) was dissolved in acetic anhydride (20 mL), and heated under reflux for 1 h. The reaction
mixture was concentrated to half its volume under vacuum.The
solid obtained after cooling was filtered off, washed with petroleum ether, dried, and recrystallized (Table 1). 1H NMR (CDCl3)
δ 2.12 (s, 3 H, COCH3), 4.15 (s, 2 H, CH2CO), 5.55 (s, 2 H,
-CH2Ph), 7.21–7.69 (m, 12 H, ArH), 8.21 (d, J = 15 Hz, 1 H,
ArH), 8.68 (d, J = 15 Hz, 1 H, ArH).
N-(2-Phenyl-4-oxo-1,3-thiazolidin-3-yl)-2-[(3-benzyl-4-oxo-6iodo-3H-quinazolin-2-yl)thio]acetamide (16)
Compound 14 (0.6 g, 0.001 mol) and thioglycolic acid (2.0 mL)
in dioxane (30 mL) was heated under reflux for 18 h. Solvent
was then removed and the reaction mixture was neutralized
with 10 % sodium carbonate solution.The solid was filtered off,
washed with water, dried, and recrystallized (Table1). 1H NMR
(DMSO-d6) δ 4.16 (s, 2 H, CH2CO), 4.28 (s, 2 H, thiazolidine-H),
5.60 (s, 2 H, -CH2Ph), 7.20–7.68 (m, 12 H, ArH), 8.19 (s, 1 H,
ArH), 8.62 ((s, 1 H, ArH), 9.34 (brs, 1 H, NH).
N-(2-Oxo-3-chloro-4-phenyl-azetidin-1-yl)-2-[(3-benzyl-4-oxo6-iodo-3H-quinazolin-2-yl)thio]acetamide (17)
Chloroacetyl chloride (0.1 g, 0.001 mol) was added dropwise to
a solution of compound 14 (0.6 g, 0.001 mol) and triethylamine
(2.0 mL) in dioxane (30 mL) at 0–5 °C. The reaction mixture
was stirred at room temperature for 3 h, and then heated under
reflux for 8 h. Solvent was then removed under reduced pressure and the residue was triturated with water, filtered off, dried
and recrystallized (Table 1). 1H NMR (CDCl3) δ 4.15 (s, 2 H,
CH2CO), 5.52 (s, 2 H, -CH2Ph), 6.52–6.61 (m, 2 H, azetidineH), 7.16–7.69 (m, 11 H, ArH), 8.21 (s, 1 H, ArH), 8.69 (s, 1 H,
ArH), 9.32 (brs, 1 H, NH).
2-[(5-Oxo-1,6-dihydro-6H-1,2,4-triazin-2-yl)methylthio]-3-benzyl-4-oxo-6-iodo-3H-quinazoline (18)
An equimolar mixture of 5 (0.5 g, 0.001 mol) and chloroacetamide (0.1 g, 0.001 mol) in dimethylformamide (25 mL) was
heated under reflux for 12 h. The solid obtained upon cooling
was filtered off, dried, and recrystallized (Table 1). 1H NMR
(DMSO-d6) δ 4.12 (s, 2 H, CH2CO), 4.62 (m, 2 H, triazine-H),
5.52 (s, 2 H, CH2CO), 7.20–7.45 (m, 6 H, ArH), 8.18 (m, 2 H,
ArH & NH), 8.62 (d, J = 15 Hz, 1 H, ArH), 9.62 (brs, 1 H, NH).
N-(1-Oxo-2-chloroethyl)-N ⬘ -[2-(3-benzyl-4-oxo-6-iodo-3Hquinazolin-2-yl)thioacetyl]hydrazine (19)
Chloroacetyl chloride (0.1 g, 0.001 mol) was added dropwise to
a solution of compound 5 (0.5 g, 0.001 mol) in dimethylformamide (20 mL) and stirred at room temperature for 1 h, then
poured into ice-water. The solid was filtered off, dried, and recrystallized (Table 1). 1H NMR (DMSO-d6) δ 3.95 (s, 2 H,
CH2CO), 4.28 (s, 2 H, COCH2Cl), 5.45 (s, 2 H, -CH2Ph), 7.15–
7.42 (m, 6 H, ArH), 8.20 (d, J = 15 Hz, 1 H, ArH), 8.45 (s, 1 H,
ArH), 9.42 (brs, 2 H, NH).
102 Khalil et al.
Arch. Pharm. Pharm. Med. Chem. 2003, 336, 95–103
2-[(3,6-Dioxopyridazin-4-yl)thio]-3-benzyl-4-oxo-6-iodo-3Hquinazoline (20)
2-[(2-Oxopyrrolidin-3-yl)thio]-3-benzyl-4-oxo-6-iodo-3H-quinazoline (28)
Chloroacetyl chloride (0.1 g, 0.001 mol) was added dropwise to
a solution of compound 5 (0.5 g, 0.001 mol) in dimethylformamide (20 mL). The reaction mixture was heated under reflux
for 4 h. The solid obtained upon cooling was filtered off, dried,
and recrystallized (Table 1). 1H NMR (DMSO-d6) δ 4.32 (m, 2 H,
CH2CO), 5.21 (m, 1 H, S-CH), 5.52 (s, 2 H, -CH2Ph), 7.21–7.44
(m, 6 H, ArH), 8.19 (d, J = 15 Hz, 1 H, ArH), 8.47 (d, J = 15 Hz,
1 H, ArH), 8.92 (brs, 2 H, NH).
A suspension of compound 27 (0.5 g, 0.001 mol) in concentrated H2SO4 (10 mL) was stirred at room temperature for 6 h.The
reaction mixture was poured onto ice and stirred, then neutralized with 10 % NaOH solution. The solid was filtered off,
washed with water, dried, and recrystallized (Table 1). 1H NMR
(DMSO-d6) δ 1.92 (m, 2 H, pyrrolidine-H), 2.56 (m, 2 H, pyrrolidine-H), 3.41 (m, 1 H, pyrrolidine-H), 5.43 (s, 2 H, -CH2Ph),
7.21–7.61 (m, 6 H, ArH), 8.15 (brs, 1 H, NH), 8.21 (d, J = 15 Hz,
1 H, ArH), 8.67 (d, J = 15 Hz, 1 H, ArH).
2-[(3-Methyl-5-oxo-4,5-dihydropyrazol-1-yl)carbonylmethylthio]-3-benzyl-4-oxo-6-iodo-3H-quinazoline (21)
2-(2-Hydroxyethylamino)-3-benzyl-4-oxo-6-iodo-3H-quinazoline (29)
Ethyl acetoacetate (2.0 g, 0.015 mol) was added to a solution of
compound 5 (4.7 g, 0.01 mol) in ethanol (30 mL). The reaction
mixture was heated under reflux for 6 h. Solvent was then removed under reduced pressure and the residue was recrystallized (Table 1). 1H NMR (DMSO-d6) δ 2.32 (s, 3 H, CH3), 4.15 (s,
2 H, CH2CO), 4.46 (s, 2 H, CH2CO), 5.52 (s, 2 H, -CH2Ph),
7.20–7.60 (m, 6 H, ArH), 8.16 (d, J = 15 Hz, 1 H, ArH), 8.65 (d, J
= 15 Hz, 1H, ArH).
A mixture of 3 (4.8 g, 0.1 mol) and excess ethanolamine (5 mL)
was heated under reflux for 5 h. The reaction mixture was
cooled and poured into ice water. The solid was filtered off,
dried, and recrystallized (Table 1). 1H NMR (DMSO-d6) δ 2.70
(m, 2 H, -CH2CH2-), 3.45 (m, 2 H, -CH2CH2-), 3.72 (brs, 1 H,
OH), 5.51 (s, 2 H, -CH2Ph), 7.21–7.45 (m, 6 H, ArH), 8.15 (s,
1 H, ArH), 8.52 (s, 1 H, ArH), 9.21 (brs, 1 H, NH).
2-[(3,5-Dimethylpyrazol-1-yl)carbonylmethylthio]-3-benzyl-4oxo-6-iodo-3H-quinazoline (22)
4-Benzyl-5-oxo-7-iodo-1,2,-dihydro-4H-imidazo[2,3-b]quinazoline (30)
Acetylacetone (1.5 g, 0.015 mol) was added to a solution of
compound 5 (4.7 g, 0.01 mol) in ethanol (30 mL). The reaction
mixture was heated under reflux for 6 h. Solvent was then removed under reduced pressure and the residue was recrystallized (Table 1). 1H NMR (DMSO-d6) δ 2.34 (s, 3 H, CH3), 4.18 (s,
2 H, CH2CO), 5.52 (s, 2 H, -CH2Ph), 7.21–7.61 (m, 7 H, ArH &
pyrazole-H), 8.16 (d, J = 15 Hz, 1 H, ArH), 8.64 (d, J = 15 Hz,
1 H, ArH).
A mixture of 29 (0.4 g, 0.001 mol) and thionyl chloride (20 mL)
was heated under reflux for 3 h. Excess of thionyl chloride was
distilled off and the remaining oily residue was triturated with
water, the solid was filtered off, dried, and recrystallized (Table
1). 1H NMR (CDCl3) δ 3.4–4.2 (m, 4 H, NCH2CH2N), 5.49 (m,
2 H, -CH2Ph), 7.26–7.62 (m, 6 H, ArH), 8.32 (d, J = 11 Hz, 1 H,
ArH), 8.63 (d, J = 11 Hz, 1 H, ArH).
N-Ethoxymethine-N⬘-[2(3-benzyl-4-oxo-6-iodo-3H-quinazolin2-yl)thioacetyl]hydrazine (23)
A mixture of 5 (0.5 g, 0.001 mol), and triethylorthoformate
(10 mL) was heated under reflux for 30 min. The reaction mixture was filtered while hot, then cooled. The solid was filtered
off, dried, and recrystallized (Table 1). 1H NMR (DMSO-d6) δ
1.34 (t, J = 7 Hz, 3 H, CH3), 3.91 (q, J = 7 Hz, 2 H, CH2), 4.15 (s,
2 H, CH2CO), 5.51 (s, 2 H, -CH2Ph), 7.16–7.69 (m, 6 H, ArH),
8.21 (d, J = 15 Hz, 1 H, ArH), 8.69 (d, J = 15 Hz, 1 H, ArH), 9.92
(s, 1 H, CH=N), 10.05 (brs, 1 H, NH).
N-Formyl-N⬘-[2-(3-benzyl-4-oxo-6-iodo-3H-quinazolin-2-yl)thioacetyl]hydrazine (24)
A solution of compound 5 (0.5 g, 0.001 mol) in formic acid
(25 mL) was heated under reflux for 30 min. The solid separated upon cooling was filtered off, washed with petroleum ether,
dried, and recrystallized (Table 1). 1H NMR (CDCl3) δ 4.18 (s,
2 H, CH2CO), 5.49 (s, 2 H, -CH2Ph), 7.17–7.48 (m, 6 H, ArH),
8.16 (s, 1 H, ArH), 8.23 (brs, 1 H, NH), 8.65 (s, 1 H, ArH), 9.12
(brs, 1 H, NH), 9.95 (s, 1 H, CHO).
2-[(1,3,4-Oxadiazol-2-yl or 1,3,4,-thiadiazol-2-yl)methylthio]-3benzyl-4-oxo-6-iodo-3H-quinazoline (25 and 26)
To a solution of 24 (0.001 mol) in xylene (50 mL), phosphorus
pentoxide or pentosulfide (2.0 g) was added. The reaction mixture was heated under reflux for 3 h. The solid obtained after
concentration of the reaction mixture was filtered off, washed,
dried, and recrystallized (Table 1). 1H NMR (DMSO-d6) δ 4.13
(s, 2 H, CH2CO), 5.52 (s, 2 H, -CH2Ph), 7.16–7.45 (m, 6 H, ArH),
7.88 (s, 1 H, oxadiazole-H), 8.21 (d, J = 15 Hz, 1 H, ArH), 8.65
(d, J = 15 Hz, 1 H, ArH). 26: δ 4.15 (s, 2 H, CH2CO), 5.50 (s, 2 H,
-CH2Ph), 7.18–7.52 (m, 6 H, ArH), 8.10 (s, 1 H, thiadiazole-H),
8.19 (d, J = 15 Hz, 1 H, ArH), 8.60 (d, J = 15 Hz, 1 H, ArH).
Antitumor screening
The prepared compounds were selected and evaluated in the
drug screening program at the National Cancer Institute (NCI),
Bethesda, MD. Cytotoxicity tests were performed on 60 human
cancer cell lines derived from nine different tissues and compounds were tested at five concentrations and 10-fold dilutions.
A 48 h continuous drug exposure protocol was used, and a
SRB protein assay was employed to estimate cell viability or
growth [16].
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International Union of Pure and
Applied Chemistry (IUPAC)
An essential step
in the preclinical phase
of drug development
P. Heinrich Stahl / Camille G. Wermuth (Eds.)
Handbook of Pharmaceutical Salts
Properties, Selection, and Use
2002. 388 pages. Hardcover. E 149.00* / sFr 220.00 / £ 85.00.
ISBN 3-906390-26-8.
*The e-Price is valid only for Germany.
O–
NH
Cl
47523025_ba
Contents:
The Physicochemical Background: Fundamentals of Ionic
Equilibria • Solubility and Dissolution of Weak Acids, Bases,
and Salts • Evaluation of Solid-State Properties of Salts •
Pharmaceutical Aspects of the Drug Salt Form • Biological
Effects of the Drug Salt Form • Salt-Selection Strategies • A
Procedure For Salt Selection and Optimization • Large-Scale
Aspects of Salt Formation: Processing of Intermediates and
Final Products • Patent Aspects of Drug-Salt Formation •
Regulatory Requirements for Drug Salts in the European
Union, Japan, and the United States • Selected Procedures
for the Preparation of Pharmaceutically Acceptable Salts of
Acids and Bases • Monographs on Acids and Bases
Wiley-VCH, Customer Service Department, P.O. Box 10 11 61 ,
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Na+
O
Cl
The majority of medicinal chemists in pharmaceutical industry whose primary focus is the
design and synthesis of novel compounds as future drug entities are organic chemists for whom
salt formation is often a marginal activity restricted to the short-term objective of obtaining
crystalline material. Because a comprehensive resource that addresses the preparation, selection,
and use of pharmaceutically active salts has not been available, researchers may forego the
opportunities for increased efficacy and improved drug delivery provided by selection of an
optimal salt. To fill this gap in the pharmaceutical bibliography, we have gathered an international
team of seventeen authors from academia and pharmaceutical industry who, in the contributions
to this volume, present the necessary theoretical foundations as well as a wealth of detailed
practical experience in the choice of pharmaceutically active salts.
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