Synthesis and hypolipidemic activities of novel 2-[4-[(diethoxyphosphoryl)methyl]phenyl]quinazolines and 4(3H)-quinazolinones

Article abstract of DOI:10.1021/jm9506938

The novel compound NO-1886, 4-[(diethoxyphosphoryl)methyl]-N-(4-bromo-2-cyanophenyl)-benzamide, is a hypolipidemic agent, which appears to increase lipoprotein lipase activity in rats. Various analogs of NO-1886 were synthesized to study the structure-act

Full text of DOI:10.1021/jm9506938

J . Med. Chem. 1996, 39, 1433-1437
1433
Syn th esis a n d Hyp olip id em ic Activities of Novel
2-[4-[(Dieth oxyp h osp h or yl)m eth yl]p h en yl]qu in a zolin es a n d
4(3H)-Qu in a zolin on es
Yasuhisa Kurogi,* Yasuhide Inoue, Kazuhiko Tsutsumi, Shizuo Nakamura, Kazushi Nagao,
Hiroki Yoshitsugu, and Yoshihiko Tsuda
Nutrition Research Institute, Otsuka Pharmaceutical Factory, Inc., Muya-cho, Naruto, Tokushima 772, J apan
Received September 20, 1995X
The novel compound NO-1886, 4-[(diethoxyphosphoryl)methyl]-N-(4-bromo-2-cyanophenyl)-
benzamide, is a hypolipidemic agent, which appears to increase lipoprotein lipase activity in
rats. Various analogs of NO-1886 were synthesized to study the structure-activity relationship
of this hypolipidemic drug. A novel series of quinazolines and 4(3H)-quinazolinones were
prepared by cyclization of NO-1886 derivatives. Derivatives bearing a 4-[(diethoxyphosphoryl)-
methyl]phenyl group at the 2-position were found to lower triglyceride and total cholesterol
levels. In accord with the decrease in log P*, quinazolines and 4(3H)-quinazolinones showed
good absorption and hypolipidemic activity. When the quinazolinone ring system is substituted
at positions 6 and 7 with methoxy groups, increased hypolipidemic activity was observed. The
highest hypolipidemic activity was observed when the 3-position was substituted by a methyl
or benzyl group.
Lowering the serum triglyceride levels and increasing
the high-density lipoprotein (HDL) levels are now
accepted means of treating patients suffering from
hyperlipoproteinemia and atherosclerosis.1 Current
treatment centers primarily on the strict control of
dietary intake of fats and cholesterol, with drug treat-
ment playing a secondary but increasingly important
role. This role is likely to be vastly accentuated by the
imminent advent of new drugs that inhibit the biosyn-
thesis of cholesterol (HMG-CoA reductase inhibitors;
lovastatin, simvastatin, and pravastatin) and drugs that
prevent the absorption of dietary cholesterol and/or the
retention of cholesterol in arterial smooth muscle cells
(cholesterol acyltransferase (ACAT) inhibitors; CI-976
and DuP-128).1
levels and to increase the HDL levels in diet-induced
hyperlipidemic rats and normal rats.
Hypertriglyceridemia can be caused by either in-
creased synthesis or inadequate removal of triglycerides
or both. We hoped to obtain compounds which would
increase lipoprotein lipase (LPL) activity, an important
enzyme in the removal of triglycerides, because such
compounds should enhance triglyceride catabolism via
the enzyme’s catalytic action and lower the plasma
triglyceride levels. In addition, since a precursor-
product relationship appears to exist between tri-
glyceride-rich lipoproteins and HDL levels, compounds
that increase LPL activity are expected to increase the
level of HDL.2 Several years ago, we discovered the
novel compound NO-1886, 4-[(diethoxyphosphoryl)-
methyl]-N-(4-bromo-2-cyanophenyl)benzamide, which
appears to increase LPL activity in rats,3 and is now in
early phase II clinical trials in J apan. Within the past
several years, various analogs of NO-1886 were syn-
thesized to study the structure-activity relationship
(SAR) of the hypolipidemic activity.
The HDL-elevating profile of 4H-3,1-benzoxazin-4-
ones led us to design a novel series of quinazolines (4
and 5) and 4(3H)-quinazolinones (6) bearing a 4-[(di-
ethoxyphosphoryl)methyl]phenyl group at the 2-posi-
tion, which were prepared by cyclization of NO-1886
derivatives. Quinazolines and 4(3H)-quinazolinones are
well-known as biologically active compounds which
exhibit antimalarial,5 sedative,6 anti-Parkinson,7 anti-
convulsant,8 antimitotic,9 antihypoxic,10 and antihyper-
tensive activities.11 In this paper, we first report on the
synthesis and hypolipidemic activity of a novel series
of 2-[4-[(diethoxyphosphoryl)methyl]phenyl]quinazolines
(4 and 5) and 4(3H)-quinazolinones (6).
Ch em istr y
The preparation of quinazolines 4 and 5 and 4(3H)-
quinazolinones 6 is summarized in Scheme 1. Anthra-
nilonitriles (2-aminobenzonitriles) were prepared by
procedures reported in the literature or were com-
mercially available. 4-[(Dialkoxyphosphoryl)methyl]-
benzoic acids were prepared by the Arbuzov reaction,
which was carried out with 4-(bromomethyl)benzoic acid
and the corresponding trialkoxyphosphine.12 Treatment
of anthranilonitriles with 4-[(dialkoxyphosphoryl)meth-
yl]benzoyl chlorides 2, which were prepared from 4-[(di-
In 1989, Rhone Poulenc Ltd. reported a series of
2-substituted 4H-3,1-benzoxazin-4-ones as new hypo-
lipidemic agents.4 They showed that 6-bromo-2-[4-(1,1-
dimethylethyl)phenyl]-4H-3,1-benzoxazin-4-one (1) has
the ability to lower plasma cholesterol and triglyceride
X Abstract published in Advance ACS Abstracts, March 1, 1996.
0022-2623/96/1839-1433$12.00/0 © 1996 American Chemical Society

1434 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7
Kurogi et al.
Sch em e 1a
a
Reagents: (a) pyridine; (b) TsOH, R4OH, ∆ (R4 ) Me, Et); (c) R4ONa, THF, ∆ (R4 ) Ph); (d) 30% H2O2 (aqueous), NaOH, EtOH; (e)
R4I (or Br), BuOK, CH3OH.
t
Ta ble 1. Physical Properties of Quinazolines 4 and 5
entry
R1
R2
R3
R4
R5
mp, °C
methoda
yield, %
4a
4b
4c
4d
4e
4f
4g
4h
4i
H
F
H
H
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
Et
Et
Et
Me
Et
Et
Et
Et
Et
Et
Et
Et
Me
iPr
Et
Et
Et
Et
Me
iPr
85-86
80-81
A
B
A
A
A
C
B
B
B
A
B
B
B
A
D
D
D
D
D
D
48
2
H
H
H
H
H
H
H
H
H
H
H
H
H
F
148-149
93-94
79
36
62
12
9
2
6
40
7
4
99-100
141-143
124-125
101-102
170 dec
138-139
109-110
141-142
138-139
133-134
187-189
172-173
211-212
185-186
232 dec
Ph
CH2CHdCH2
CH2(2-F,4-Br)Ph
CH2CO2H
Me
CH2CHdCH2
CH2Ph
Me
Me
H
H
H
H
H
Br
H
4j
4k
4l
OMe
OMe
OMe
OMe
OMe
H
H
Br
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
OMe
OMe
OMe
4m
4n
5a
5b
5c
5d
5e
5f
2
31
66
50
72
75
39
82
H
H
H
H
H
190-191
a
Method A: TsOH, R4OH, reflux. Method B: tBuOK, R4I, CH3OH. Method C: PhONa, THF, reflux. Method D: H2O2, NaOH, EtOH.
i
Me ) methyl, Et ) ethyl, Pr ) isopropyl, Ph ) phenyl.
alkoxyphosphoryl)methyl]benzoic acids by treatment
with the appropriate thionyl chloride in methylene
chloride and dimethylformamide (DMF), formed 4-[(di-
a lkoxyph osph or yl)m et h yl]-N-(2-cya n oph en yl)ben z-
amide (3).
On the other hand, ring closures of 3 were performed
in the presence of alkaline hydrogen peroxide to produce
2-[4-[(dialkoxyphosphoryl)methyl]phenyl]-4-hydroxy-
quinazoline (5).14 Finally, N-alkylations of hydroxy-
qinazoline 5 in alkaline methanol gave the desired
3-substituted 2-[4-[(dialkoxyphosphoryl)methyl]phenyl]-
4(3H)-quinazolinones 6, accompanied with a small
amount of 4-substituted 2-[4-[(dialkoxyphosphoryl)-
methyl]phenyl]quinazolines 4 as byproducts. Physical
properties of these quinazolines (4) and 4(3H)-quinazoli-
nones (6) are presented in Tables 1 and 2, respectively.
4-Alkoxyquinazolines, at first, were prepared by the
treatment of 3 with alkaline alkoxide described in the
literature,13 but this reaction was low yielding (4c, 35%;
4e, 15%). After several attempts to improve the yield,
we found that 4-alkoxyquinazolines were obtained by
the treatment of 3 with 0.4 equiv of p-toluenesulfonic
acid monohydrate in the corresponding alcohol. By this
new reaction, 4-alkoxyquinazolines (4c, 79%; 4e, 62%)
were obtained in high yield. To our regret, this reaction
was unsuccessful when R3 was an aromatic group.
Therefore, 4-phenoxyquinazoline 4f was prepared by the
treatment of 3 with PhONa in tetrahydrofuran (THF).13
Resu lts a n d Discu ssion
Firstly, we prepared 6-bromoquinazoline derivatives
4c-i by cyclization of our lead compound NO-1886. The
hypolipidemic activity was evaluated in Triton-induced
hypertriglycemic rats16 (see the Experimental Section).

2-[4-[(Diethoxyphosphoryl)methyl]phenyl]quinazolines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7 1435
Ta ble 2. Physical Properties of 4(3H)-Quinazolinones 6
entry
R1
R2
R3
R4
R5
mp, °C
methoda
yield, %
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
H
F
H
H
Br
Br
Br
Br
Br
Br
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Et
CH2Ph
CH2CHdCH2
CH2(2-F,4-Br)Ph
CH2CO2H
Me
CH2CHdCH2
CH2Ph
Et
Et
Et
iPr
Et
Et
Et
Et
Et
Et
Et
Et
Me
iPr
128-129
155-156
99-100
123-124
77-78
B
B
B
B
B
B
B
B
B
B
B
B
B
B
49
53
55
47
4
H
H
H
H
H
H
H
H
H
H
H
H
120-121
65-66
9
27
14
24
68
16
29
43
65
106-107
217 dec
Br
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
147-148
117-118
149-150
193-194
166-167
Me
Me
a
Method A: TsOH, R4OH, reflux. Method B: tBuOK, R4I, CH3OH. Method C: PhONa, THF, reflux. Method D: H2O2, NaOH, EtOH.
i
Me ) methyl, Et ) ethyl, Pr ) isopropyl, Ph ) phenyl.
Ta ble 3. Biological Properties of Quinazolines 4 and 5 and 4(3H)-Quinazolinones 6
entry
log P* a
TGb
TCc
entry
6a
log P* a
TGb
31*
-12
-35**
-37**
-42**
-54**
-43**
-16
13
-86***
-21*
-61**
-85***
-30**
-41**
-81***
-8
TCc
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
5.26
5.13
6.37
5.61
7.01
7.67
ND
ND
ND
4.51
ND
ND
-5
56
3.29
3.18
4.09
4.88
ND
5.17
ND
ND
38
-28
-25
6b
6c
6d
6e
6f
6g
6h
6i
-15*
-16*
-11
2
1
-9
-29*
16**
-9
-14
-29**
-34**
-25*
-1
4
-18
-2
-12*
-14
-60***
-35**
-21**
-48**
-60***
-4
-2
ND
3.41
5
-86***
-71***
-40**
-52**
-81***
6j
-51***
-11*
-41**
-60***
-15**
-27**
-58***
-4
(10 mg/kg po)
6k
6l
ND
4.49
3.75
5.53
(10 mg/kg po)
(10 mg/kg po)
6m
6n
2.65
4.20
5a
5b
5c
5d
5e
5f
2.55
3.13
3.35
3.36
2.60
4.38
ND
-8
ND
-37**
-11
-32
ND
-8
ND
-22**
NO-1886
(10 mg/kg po)
3.21
-85***
-54**
-69***
-27**
-18
-35**
a
Apparent partition coefficients were estimated from the retention time of HPLC. b,c Percent change in plasma triglycerides (TG) and
total cholesterol (TC) on Triton-induced hyperlipidemic rats; see the Experimental Section. All compounds were tested at 100 mg/kg po.
NO-1886 and 6j,l,n were evaluated at 10 mg/kg po for the further study. Results significantly different from controls: *p < 0.05, **p <
0.01, ***p < 0.001. ND ) not determined.
However, these compounds showed no hypolipidemic
activity (Table 3). One possible reason for this may be
that absorption of 6-bromoquinazolines 4c-i into the
body is poor. When 100 mg/kg 4c and NO-1886 were
administered orally to Sprague-Dawley rats, the peak
plasma concentrations (Cmax) were 2 and 89 µM, respec-
tively. We considered that the poor absorption of
6-bromoquinazolines may be due to the higher hydro-
phobicity of 6-bromoquinazolines (e.g., 4c, apparent
partition coefficient log P* ) 6.37) as compared to NO-
1886 (log P* ) 3.21).
To improve the absorption of these compounds, we
prepared less hydrophobic compounds such as unsub-
stituted quinazolines, fluoroquinazolines, and 6,7-
dimethoxyquinazolines 4a ,b,j-n . As we expected, log
P* values of these compounds (4a ,b,j-n , log P* ) 3.75-
5.53) were lower than that of 6-bromoquinazolines 4c-i
(log P* ) 5.61-7.67). The Cmax of 6,7-dimethoxyquinazo-
line derivative 4j was 40 µM at 100 mg/kg po. In accord
with the decrease in log P*, 6,7-dimethoxyquinazolines
4j-n showed hypolipidemic activity (Table 3). These
results led us to design 4(3H)-quinazolinone derivatives
6 to lower the hydrophobicity.
As described in Table 3, 4(3H)-quinazolinone deriva-
tives 6 had lower hydrophobicity (6a -c,j, log P* ) 3.29,
3.18, 4.09, and 3.41) than that of the corresponding
quinazolines 4a -c,j, log P* ) 5.26, 5.13, 6.37, and 4.51).
When 100 mg/kg 6c,j was administered orally to
Sprague-Dawley rats, Cmax was 29 and 214 µM, re-
spectively. Hypolipidemic activities were also observed
accompanied with the increasing absorption, and 6,7-
dimethoxy-4(3H)-quinazolinones 6j,l,n showed hypo-
lipidemic activities comparable to that of NO-1886 at
100 mg/kg po. The comparison of 6j,l,n at 10 mg/kg po
indicates that 6l is the most potent compound.
In summary, potent hypolipidemic activities were

1436 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7
Kurogi et al.
was prepared in a manner similar to that described for 6a .
Recrystallization from CH2Cl2/Et2O produced colorless prisms
of 6l (yield 29%): 1H-NMR (CDCl3) δ 1.28 (6H, t, J ) 6.9 Hz),
3.19 (2H, d, J ) 21.8 Hz), 3.99-4.11 (10H, m), 5.27 (2H, s),
6.93 (2H, t, J ) 3.5 Hz), 7.17-7.32 (7H, m), 7.69 (1H, s); MS
(EI) m/z 522 M+. Anal. (C28H31N2O6P) C, H, N.
attained in a novel series of 4(3H)-quinazolinones bear-
ing a 4-[(diethoxyphosphoryl)methyl]phenyl group at the
2-position. In accord with the decrease in log P*,
quinazolines and 4(3H)-quinazolinones showed good
absorption and hypolipidemic activity. The 6,7-
dimethoxy-4(3H)-quinazolinone derivatives lowered the
plasma total cholesterol and triglyceride of Triton-
induced hyperlipidemic rats, which suggests that this
series of compounds might possess a similar pharma-
cological profile as NO-1886. A detailed pharmacologi-
cal evaluation of the most potent compound (6l) in this
series is currently in progress in order to select a
compound for clinical use.
2-[4-[(Diisop r op oxyp h osp h or yl)m et h yl]p h en yl]-6,7-
d im eth oxy-3-m eth yl-4(3H)-qu in a zolin e (6n ). This com-
pound was prepared in a manner similar to that described for
6a . Recrystallization from CH2Cl2/Et2O produced colorless
1
prisms of 6n : yield 65%; H-NMR (CDCl3) δ 1.27 (12H, dd, J
) 5.9, 21.3 Hz), 3.19 (2H, d, J ) 21.8 Hz), 3.49 (3H, s), 3.98
(3H, s), 4.03 (3H, s), 4.63-4.71 (2H, m), 7.15 (1H, s), 7.48-
7.53 (4H, m), 7.64 (1H, s); MS (EI) m/z 474 M+. Anal.
(C24H31N2O6P) C, H, N.
Meth od C: 2-[4-[(Dieth oxyp h osp h or yl)m eth yl]p h en yl]-
6-br om o-4-p h en oxyqu in a zolin e (4f). A mixture of 4-[(di-
ethoxyphoshoryl)methyl]-N-(4-bromo-2-cyanophenyl)benz-
amide (4.5 g, 10 mmol) and sodium phenoxide (1.2 g, 10 mmol)
in 100 mL of THF was refluxed for 20 h. After evaporating
the solvent, the residue was purified by chromatography on a
silica gel column using chloroform as the eluent to give the
title compound 4f as a brown solid. Recrystallization from
CH2Cl2/n-hexane produced colorless needles: 0.6 g (12%); mp
141-143 °C; 1H-NMR (CDCl3) δ 1.23 (6H, t, J ) 7.2 Hz), 3.21
(2H, d, J ) 21.8 Hz), 3.98 (4H, q, J ) 7.2 Hz), 7.33-7.36 (5H,
m), 7.50 (2H, d, J ) 7.9 Hz), 7.91-7.94 (2H, m), 8.26 (2H, d,
J ) 7.9 Hz), 8.52 (1H, d, J ) 2.3 Hz); MS (EI) m/z 527 M+.
Meth od D: 2-[4-[(Dieth oxyp h osp h or yl)m eth yl]p h en yl]-
4-h yd r oxyqu in a zolin e (5a ). A mixture of 4-[(diethoxyphos-
phoryl)methyl]-N-(2-cyanophenyl)benzamide (3.1 g, 8.3 mmol),
hydrogen peroxide (30 wt % solution in water, 20 mL, 170
mmol), and sodium hydroxide (0.33 g, 8.3 mmol) in 50 mL of
ethanol was stirred for 24 h. After evaporating the solvent,
the residue was purified by chromatography on a silica gel
column using CH2Cl2/CH3OH (50:1) as the eluent to give the
title compound 5a as a pale yellow solid. Recrystallization
from Et2O produced colorless prisms: 2.0 g (66%); 1H-NMR
(CDCl3/CD3OD) δ 1.28 (6H, t, J ) 6.9 Hz), 3.26 (2H, d, J )
22.3 Hz), 4.05 (4H, q, J ) 6.9 Hz), 7.47-7.53 (3H, m), 7.80-
7.82 (2H, m), 8.11 (2H, d, J ) 7.9 Hz), 8.30 (2H, d, J ) 7.4
Hz); MS (EI) m/z 372 M+.
log P * Deter m in a tion s. The apparent partition coefficient
(log P*) values for selected compounds were estimated from
the retention time of reverse-phase HPLC using as standards
methylbenzoate, ethyl benzoate, n-propyl benzoate, n-butyl
benzoate, and n-hexyl benzoate, which modified the method
described in the literature.15 Chromatographic conditions were
as follows: column, Capcell pak C18 SG120 (4.6 × 100 mm);
temperature, 40 °C; mobile phase, CH3OH/0.05 M (NH4)2HPO3
(pH 7.4); flow rate, 1.0 mL/min; wavelength, UV at 230 nm;
injection size, 20 µL.
Tr iton -In d u ced Hyp er lip id em ic Ra ts. The preventive
and therapeutic effects of the compound on hyperlipidemia
were determined using rats with Triton-induced hyper-
lipidemia according to the method of Kuroda et al.16 as follows.
Using 6-7-week-old male Wistar rats (body wt ) 210-250 g)
in groups of five (test group), we administered a solution of
300 mg/kg Triton (Triton WR-1339) in physiological saline into
the tail vein, and at the same time 100 mg/kg of the test
compound suspended in 0.5% CMC-Na solution was admin-
istered orally. As a control group, a group of five rats given
Triton were orally dosed with 0.5% aqueous CMC-Na solution.
After 24 h, blood was taken from the rats. Then, the plasma
TC and TG levels were determined by Cholesterol C-Test Wako
and Triglyceride G-Test Wako (both available from Wako Pure
Chemical Industries, Ltd.), respectively. The experimentally
determined values for TC and TG for the Triton-treated and
CMC-Na solution-treated (control) rat groups were 308 ( 23
and 1394 ( 222 mg/dL, respectively. Using the measured
values in the control group as references, the rates of decrease
(%) in plasma TC and TG levels in the test group were
calculated by the following equation:
Exp er im en ta l Section
Column chromatography was performed on silica gel 60
(Merck; particle size 63-200 µm). All melting points were
determined on a Yamato micromelting point apparatus (MP-
21). 1H-NMR spectra were measured on a J EOL GX-270 (270
MHz) spectrometer, and chemical shifts are indicated in δ
units from tetramethylsilane (TMS) as an internal standard.
Mass spectra (EI-MS) were obtained with a HITACHI M-80A
mass spectrometer. High-performance liquid chromatography
(HPLC) analyses were performed using TOSOH CCPM, UV-
8010, and CO-8010 instruments. Elemental analyses (C, H,
N) of the final compounds 6j,l,n were performed in this
laboratory, using a Perkin-Elmer 2400 CHN analyzer; the
results obtained were all within (0.4 of the calculated
percentages.
Meth od A: 2-[4-[(Dieth oxyp h osp h or yl)m eth yl]p h en yl]-
4-m eth oxyqu in a zolin e (4a ). Treatment of anthranilonitrile
(1; 15.7 g, 0.13 mol) in 100 mL of pyridine with 4-[(diethoxy-
phosphoryl)methyl]benzoyl chloride (2), which was prepared
from 4-[(diethoxyphosphoryl)methyl]benzoic acid (38.0 g, 0.14
mol) by treatment with thionyl chloride (11 mL, 0.15 mol) in
methylene chloride and DMF, gave 4-[(diethoxyphosphoryl)-
methyl]-N-(2-cyanophenyl)benzamide (3; 25.9 g, yield 52%).
A mixture of 4-[(diethoxyphosphoryl)methyl]-N-(2-cyano-
phenyl)benzamide (3.7 g, 10 mmol) and p-toluenesulfonic acid
monohydrate (0.8 g, 4 mmol) in 100 mL of methanol was
refluxed for 10 h. After evaporating the solvent, the residue
was purified by chromatography on a silica gel column using
chloroform as the eluent to give the title compound 4a as a
pale yellow solid. Recrystallization from CH2Cl2/n-hexane
produced colorless needles: 1.9 g (48%); mp 85-86 °C; 1H-
NMR (CDCl3) δ 1.19 (6H, t, J ) 7.2 Hz), 3.16 (2H, d, J ) 22.3
Hz), 3.98 (4H, q, J ) 7.2 Hz), 4.10 (3H, s), 7.36-7.38 (3H, m),
7.66 (1H, t, J ) 7.9 Hz), 7.85 (1H, d, J ) 8.4 Hz), 7.95 (1H, d,
J ) 7.9 Hz), 8.47 (2H, d, J ) 7.9 Hz); MS (EI) m/z 386 M+.
Meth od B: 2-[4-[(Dieth oxyp h osp h or yl)m eth yl]p h en yl]-
3-m eth yl-4(3H)-qu in a zolin on e (6a ). A mixture of 2-[4-
[(diethoxyphosphoryl)methyl]phenyl]-4-hydroxyquinazoline (5a;
5.9 g, 16 mmol), potassium tert-butoxide (1.8 g, 16 mmol), and
methyl iodide (2.26 g, 16 mmol) in 100 mL of methanol was
heated at 40 °C for 12 h. After evaporating the solvent, the
residue was purified by chromatography on a silica gel column
using CH2Cl2/CH3OH (100:1) as the eluent to give the title
compound 6a with a small amount of 4-methoxyquinazoline
4a as byproduct. Recrystallization from CH2Cl2/Et2O produced
1
colorless prisms: 3.0 g (49%); H-NMR (CDCl3) δ 1.29 (6H, t,
J ) 7.4 Hz), 3.23 (2H, d, J ) 22.3 Hz), 3.50 (3H, s), 4.08 (4H,
q, J ) 7.4 Hz), 7.45-7.56 (5H, m), 7.74-7.77 (2H, m), 8.33
(2H, d, J ) 8.4 Hz); MS (EI) m/z 386 M+.
2-[4-[(D i e t h o x y p h o s p h o r y l)m e t h y l]p h e n y l]-6,7-
d im eth oxy-3-m eth yl-4(3H)-qu in a zolin on e (6j). This com-
pound was prepared in a manner similar to that described for
6a . Recrystallization from CHCl3/n-hexane produced colorless
1
prisms of 6j: yield 68%; H-NMR (CDCl3) δ 1.29 (6H, t, J )
6.9 Hz), 3.23 (2H, d, J ) 22.3 Hz), 3.50 (3H, s), 3.98 (3H, s),
4.03 (3H, s), 4.08 (4H, q, J ) 6.9 Hz), 7.15 (1H, s), 7.45-7.54
(4H, m), 7.65 (1H, s); MS (EI) m/z 446 M+. Anal. (C22H27N2O6P)
C, H, N.
test group’s value
control group’s value
2-[4-[(Diet h oxyp h osp h or yl)m et h yl]p h en yl]-3-b en zyl-
6,7-d im eth oxy-4(3H)-qu in a zolin on e (6l). This compound
rate of decrease (%) ) 1 -
× 100
(
)

2-[4-[(Diethoxyphosphoryl)methyl]phenyl]quinazolines
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 7 1437
(9) J iang, J . B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.; Kang,
G. J .; Hamel, E. Synthesis and Biological Evaluation of
2-Styrylquinazolin-4(3H)-ones, a New Class of Antimitotic An-
ticancer Agents Which Inhibit Tubulin Polymerization. J . Med.
Chem. 1990, 33, 1721-1728.
(10) Hori, M.; Iemura, R.; Hara, H.; Ozaki, A.; Sukamoto, T.; Ohtaka,
H. Novel 4-Substituted 2-piperazinylquinazolines as Potent
Anticonvulsive and Antihypoxic Agents. Chem. Pharm. Bull.
1990, 38, 1286-1291.
The test rats were deprived of food before Triton administra-
tion through completion of blood sampling but were allowed
free access to drinking water.
Ack n ow led gm en t. We thank Dr. K. Miyata, Mr. Y.
Shoji, and Mrs. K. Miyashita, Nutrition Research
Institute, Otsuka Pharmaceutical Factory, Inc., for their
cooperation.
(11) (a) Prazosin (R1-Adrenergic blocker). The Merck Index, 11th ed.;
Merck and Co., Inc.: Rahway, NJ , 1989; pp 1222-1223. (b)
Levin, J . I.; Aranapakam, M. V. New quinazolinone derivatives
are angiotensin II antagonists - for treating hypertension and
congestive heart failure. U.S. Patent 5284853-A, 1993.
(12) (a) Bloom, S. M.; Rochester, N. Y.; Hill, J . A. Preparation of
Symmetrically and Unsymmetrically Substituted Stilbene-
bisbenzoxazoles. U.S. Patent 3-586-673, 1971. (b) Bellucci, C.;
Gualtieri, F.; Chiarini, A. Negative inotropic activity of para-
substituted diethyl benzylphosphonates related to fostedil. Eur.
J . Med. Chem. 1987, 22, 473-477.
(13) Breukink, K. W.; Krol, L. H.; Verkade, P. E.; Wepster, B. M.
Preparation of Quinazoline Derivatives through Ring-closure of
Aromatic ortho-cyano-acylamino Compounds in Alkaline Alco-
holic or Phenolic Medium. RECUEIL 1957, 76, 401-414.
(14) McKee, R. L.; McKee, M. K.; Bost, R. W. Some Basically
Substituted Quinazolines. J . Am. Chem. Soc. 1946, 68, 1902-
1903.
(15) Hulshoff, A.; Perrin, J . H. A Comparison of the Determination
of Partition Coefficients of 1,4-Benzodiazepines by High-
Performance Liquid Chromatography and Thin-layer Chroma-
tography. J . Chromatogr. 1976, 129, 263-276. Henry, D.;
Block, J . H.; Anderson, J . L.; Carlson, G. R. Use of High-
Performance Liquid Chromatography for Quantitative Structure-
Activity Relationship Studies of Sulfonamides and Barbiturates.
J . Med. Chem. 1976, 5, 619-626.
Refer en ces
(1) Larsen, S. D.; Spilman, C. H. New Potential Therapies for the
Treatment of Atherosclerosis. Annu. Rep. Med. Chem. 1993, 28,
217-225.
(2) Patch, J . R.; Gotto, A. M., J r.; Olivecrona, T.; Eisenberg, S.
Formation of High Density Lipoprotein2-like Particles during
Lipolysis of Very Low Density Lipoproteins in vitro. Proc. Natl.
Acad. Sci. U.SA. 1978, 75, 4519-4523.
(3) Tsutsumi, K.; Inoue, Y.; Shima, A.; Iwasaki, K.; Kawamura, M.;
Murase, T. The Novel Compound NO-1886 Increase Lipoprotein
Lipase Activity with Resulting Elevation of High Density Lipo-
protein Cholesterol, and Long-term Administration Inhibits
Atherogenesis in the Coronary Arteries of Rats with Experi-
mental Atherosclerosis. J . Clin. Invest. 1993, 92, 411-417.
(4) Fenton, G.; Newton, G. C.; Wyman, M. B.; Bagge, P.; Dron, D.
I.; Riddell, D.; J ones, D. G. Hypolipidemic 2-[4-(1,1-Dimethyl-
ethyl)phenyl]-4H-3,1-benzoxazin-4-ones. Structure-Activity Re-
lationships of
a Novel Series of High-Density Lipoprotein
Elevators. J . Med. Chem. 1989, 32, 265-272.
(5) Curd, F. H.; Landquist, J . K.; Rose, F. L. Synthetic Antimalari-
als. Part XIV. Some 2-Arylamino-4-aminoalkylaminoquinazo-
lines. J . Chem. Soc. 1994, 775-783.
(6) Parmar, S. S.; Singh, S. P. Synthesis of Substituted 2-Methyl-
3-(3,4-dimethoxy/dihydroxyphenylethyl)-4-quinazolines as Pos-
sible AntiParkinson Drugs. J . Heterocycl. Chem. 1979, 16, 449-
452.
(16) Kuroda, M.; Tanzawa, K.; Tsujita, Y.; Endo, A. Mechanism for
Elevation of Hepatic Cholesterol Synthesis and Serum Choles-
terol Levels in Triton WR-1339-induced Hyperlipidemia. Bio-
chim. Biophys. Acta 1977, 489, 119-125.
(7) Methaqualone. The Merck Index, 11th ed.; Merck and Co.,
Inc.: Rahway, NJ , 1989; pp 939-940.
(8) Wolfe, J . F.; Rathman, T. L.; Sleevi, M. C.; Campbell, J . A.;
Greenwood, T. D. Synthesis and Anticonvulsant Activity of Some
New 2-Substituted 3-Aryl-4(3H)-quinazolines. J . Med. Chem.
1990, 33, 161-166.
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