2236 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
van Muijlwijk-Koezen et al.
3
3
δ 6.82 (dd, J 4′5′ ) 3.4 Hz, J 4′3′ ) 1.8 Hz, 1H, H4′), 7.14-7.23
(m, 1H, H4′′), 7.41-7.49 (m, 3H, H5′ and H3′′), 7.64 (ddd, 1H,
H7), 7.78 (d, 2H, H2′′), 7.92-7.96 (m, 2H, H8 & H6), 8.14 (sd,
ArH), 7.51-7.92 (m, 5H, H6, H7, H3′, H4′, and H5′). 8.24 (d,
3J 87 ) 8.0 Hz, 1H, H8), 8.43-8.55 (m, 2H, H2′ & H6′), 8.70
(dd, J 56 ) unsolved, J 57 ) unsolved, 1H, H5), 10.58 (bs, 1H,
NH), and 12.19 (bs, 1H, NH). Anal. (C22H18N4O‚0.2MeOH) C,
H, N.
3
4
3J 3′4′ ) 1.7 Hz, 1H, H3′), 8.74 (d, J 56 ) 8.2 Hz, 1H. H5), 10.65
(bs, 1H, NH) and 12.81 (s, 1H, NH). Anal. (C19H14N4O2‚
0.1MeOH) C, H, N.
3
N-(3,4-Dich lor op h en yl)-N′-(2-p h en ylq u in a zolin -4-yl)-
1
N-(2-Dieth yla m in oqu in a zolin -4-yl)-N′-p h en ylu r ea (5j).
The reaction was carried out at room temperature: yield 77%;
u r ea (9c): yield 81%; mp 282-284 °C; H NMR (DMSO-d6,
ref DMSO-d5-H ) 2.49 ppm) δ 7.16-7.21 (m, 3H, ArH), 7.47-
7.50 (m, 2H, H6 and H7), 7.75-7.84 (m, 5H, H2′, H3′, H4′,
1
mp 211 °C; H NMR (DMSO-d6, ref DMSO-d5-H ) 2.49 ppm)
δ 1.20 (t, 3J ) 7.0 Hz, 6H, CH3), 3.70 (q, 3J ) 7.0 Hz, 4H, CH2),
7.11-7.16 (m, 3H, H7 & ArH), 7.34-7.42 (m, 2H, H6 & ArH),
7.55-7.66 (m, 3H, H8 & ArH), 8.40 (d, 3J 56 ) 7.8 Hz, 1H, H5),
10.15 (bs, 1H, NH) and 11.59 (s, 1H, NH). Anal. (C19H21N5O)
C, H, N.
H5′, and H6′), 8.24 (dd, J 87 ) 8.2 Hz, J 86 ) unsolved, 1H,
3 4
3
4
H8), 8.45 (dd, J 56 ) 8.7 Hz, J 57 ) 1.9 Hz, 1H, H5), 10.69 (bs,
1H, NH), and 12.32 (bs, 1H, NH). Anal. (C21H14Cl2N4O‚
0.3MeOH) C, H, N.
N -(4-Me t h oxyp h e n yl)-N ′-(2-p h e n ylq u in a zolin -4-yl)-
1
N-P h en yl-N′-[(2-p yr r olid in -1-yl)q u in a zolin -4-yl]u r ea
(5k ). The reaction was carried out at room temperatur: yield
u r ea (9d ): yield 72%; mp 259-261 °C; H NMR (DMSO-d6,
ref DMSO-d5-H ) 2.49 ppm) δ 3.77 (s, 3H, OCH3), 7.01 (d, 3J 2′′3′′
) 9.0 Hz, 4H, ArH), 7.56-7.60 (m, 5H, H6, H7, H3′ & H4′),
7.97 (dd, 3J 87 ) unsolved, 4J 86 ) unsolved, 1H, H8), 8.37-8.42
1
76%; mp 238 °C dec; H NMR (DMSO-d6, ref DMSO-d5-H )
2.49 ppm) δ 1.88 (bs, 4H, CH2), 3.53 (bs, 4H, CH2), 7.05-7.19
(m, 2H, H7 & ArH), 7.29-7.48 (m, 3H, H6 & ArH), 7.52-7.67
3
4
(m, 2H, H2′), 8.76 (dd, J 56 ) unsolved, J 57 ) unsolved, 1H,
H5), 10.56 (bs, 1H, NH), and 12.15 (bs, 1H, NH). Anal.
(C22H18N4O2‚0.3MeOH) C, H, N.
3
(m, 3H, H8 & ArH), 8.51 (d, J 56 ) 7.9 Hz, 1H, H5), 10.22 (bs,
1H, NH), and 11.99 (s, 1H, NH). Anal. (C19H19N5O) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of 8a -b,d . One
equivalent of 6 was dissolved in acetonitrile at 50 °C (5 mL/
mmol) and a solution of 1 equiv of phenyl isocyanate (7i) in
acetonitrile was added (2 mL/mmol) (3-mmol scale). The
mixture was stirred at 50 °C for 1 h. The precipitate was
isolated, washed several times with subsequently acetonitrile,
methanol, and petroleum ether, dried and recrystallized.
N-P h en yl-N′-(isoqu in olin -1-yl)u r ea (8a ). Recrystalliza-
tion from DMF/EtOH yielded 99% of white crystals: mp 221-
223 °C; 1H NMR (DMSO-d6, ref DMSO-d5-H ) 2.49 ppm) δ
N -(3-Me t h oxyp h e n yl)-N ′-(2-p h e n ylq u in a zolin -4-yl)-
1
u r ea (9e): yield 57%; mp 255-258 °C; H NMR (DMSO-d6,
ref DMSO-d5-H ) 2.49 ppm) δ 3.79 (s, 3H, OCH3), 6.70-6.74
(m, 1H, H4′′), 7.27-7.38 (m, 3H, H2′′, H5′′, and H6′′), 7.62-
3
7.70 (m, 5H, H6, H7, H3′ & H4′), 7.99 (dd, J 87 ) unsolved,
4J 86 ) unsolved, 1H, H8), 8.39-8.41 (m, 2H, H2′), 8.75 (dd,
4
3J 56 ) 8.4 Hz, J 57 ) unsolved, 1H, H5), 10.60 (bs, 1H, NH),
and 12.28 (bs, 1H, NH). Anal. (C22H18N4O2‚0.2H2O) C, H, N.
N -(2-Me t h oxyp h e n yl)-N ′-(2-p h e n ylq u in a zolin -4-yl)-
1
u r ea (9f): yield 32%; mp 227-229 °C; H NMR (DMSO-d6,
3
3
7.07 (t, J 4′3′ ) 7.3 Hz, 1H, ArH), 7.36 (t, J 3′2′ ) 7.8 Hz, 2H.
ref DMSO-d5-H ) 2.49 ppm) δ 3.62 (s, 3H, OCH3), 7.00-7.13
(m, 4H, ArH), 7.51-7.69 (m, 3H, H3′, ArH, and H5′), 7.97-
3
ArH), 7.49 (d, J 3,4 ) 5.8 Hz, 1H, H3), 7.61-7.73 (m, 3H, H7
3
3
4
& ArH), 7.76-7.84 (m, 1H, H6), 7.94 (d, J 87 ) 8.2 Hz, 1H,
7.99 (m, 2H, H6 and H7), 8.19 (dd, J 87 ) 8.1 Hz, J 86 )
3
3
H8), 8.22 (d, J 43 ) 5.8 Hz, 1H, H4), 8.70 (d, J 56 ) 8.3 Hz,
H5), 9.96 (bs, 1H, NH), and 12.70 (bs, 1H, NH). Anal.
(C16H13N3O) C, H, N.
unsolved, 1H, H8), 8.45-8.49 (m, 2H, H4′ and H6′), 8.77 (dd,
3J 56 ) 8.5 Hz, J 57 ) unsolved, 1H, H5), 10.58 (bs, 1H, NH),
4
and 11.89 (bs, 1H, NH). Anal. (C22H18N4O2‚0.2H2O) C, H, N.
N -(2-C h lo r o p h e n y l)-N ′-(2-p h e n y lq u in a zo lin -4-y l)-
N-P h en yl-N′-[3-(2-p yr id yl)isoq u in olin -1-yl]u r ea (8b ).
Recrystallization from DMF/MeOH yielded 98% of yellow/
white crystals: mp 228 °C; 1H NMR (DMSO-d6, ref DMSO-
d5-H ) 2.49 ppm) δ 7.40-7.58 (m, 3H, ArH), 7.61 (m, 1H, H4′),
7.67-7.92 (m, 4H, ArH & H6 & H7), 8.02-8.16 (m, 2H, H3′ &
H5′), 8.30 (dd, 3J 87 ) 8.0 Hz, 4J 86 ) unsolved, 1H, H8), 8.41 (s,
1H, H4), 8.74 (d, J 56 ) 8.6 Hz, 1H, H5), 8.83-8.88 (m, 1H,
H6′), 10.15 (bs, 1H, NH), and 13.09 (bs, 1H, NH). Anal.
(C21H16N4O‚0.3MeOH) C, H, N.
N-P h en yl-N′-(3-p h en ylisoqu in olin -1-yl)u r ea (8d ). Re-
crystallization from DMF/MeOH yielded 98% of yellow/white
crystals: mp 250-251 °C; 1H NMR (DMSO-d6, ref DMSO-d5-H
) 2.49 ppm) δ 7.42-7.62 (m, 3H, ArH), 7.71-7.94 (m, 9H, ArH
& H6 & H7), 8.26 (dd, 3J 87 ) 7.9 Hz, 4J 86 ) unsolved, 1H, H8),
8.39 (s, 1H, H4), 8.70 (d, 3J 56 ) 8.4 Hz, 1H, H5), 10.04 (bs, 1H,
NH), and 12.89 (bs, 1H, NH). Anal. (C22H17N3O‚0.2MeOH) C,
H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of 9a -h , 10a ,b,
a n d 11. One equivalent of 2-phenyl-4-quinazolineamine (4d )
was dissolved in acetonitrile at 30-50 °C (5 mL/mmol) and a
solution of 1 equiv of isocyanate 7 in acetonitrile was added
(2 mL/mmol). The mixture was stirred at 30-50 °C for 0.5-4
h. The precipitate was isolated, washed several times with
different solvents, dried and recrystallized.
1
u r ea (9g): yield 69%; mp 233-234 °C; H NMR (DMSO-d6,
ref DMSO-d5-H ) 2.49 ppm) δ 7.17 (t, 3J 4′′3′′ ) 6.9 Hz, 1H, H4′′),
7.35-7.58 (m, 5H, H3′, H2′′ & H3′′), 7.62-7.74 (m, 1H, H5′),
7.92-8.01 (m, 2H, H4′ & H8), 8.13 (d, 3J 6′5′ ) 7.1 Hz, 1H, H6′),
3
8.28-8.46 (m, 2H, H6 & H7), 8.77 (d, J 56 ) 7.3 Hz, 1H, H5),
3
10.78 (bs, 1H, NH), and 11.99 (bs, 1H, NH). Anal. (C21H15-
ClN4O‚0.2MeOH) C, H, N.
N -(2-Me t h y lp h e n y l)-N ′-(2-p h e n y lq u in a zo lin -4-y l)-
1
u r ea (9h ): yield 45%; mp 120-121 °C; H NMR (DMSO-d6,
ref DMSO-d5-H ) 2.49 ppm) δ 2.18 (s, 3H, CH3), 7.05-7.32
(m, 3H, ArH), 7.48-7.56 (m, 3H, ArH), 7.60-7.78 (m, 2H, H6
& H7), 7.89-8.03 (m, 2H, ArH), 8.23-8.30 (m, 2H, H8 & H6′),
8.78 (d,3J 56 ) 8.2 Hz 1H, H5), 10.62 (bs, 1H, NH), and 11.71
(bs, 1H, NH). Anal. (C22H18N4O‚0.2MeOH) C, H, N.
N-(2-Meth oxyp h en yl)-N′-[2-(3-p yr id yl)qu in a zolin -4-yl]-
u r ea (10a ): yield 77%; mp 257-258 °C; 1H NMR (DMSO-d6,
ref DMSO-d5-H ) 2.49 ppm) δ 3.62 (s, 3H, OCH3), 6.98-7.15
(m, 3H, H3′′, H4′′ & H5′′), 7.62-7.79 (m, 2H, H6 & H7), 8.03
3
(m, 2H, H5′ & H6′′), 8.11 (d, J 87 ) 8.4 Hz, 1H, H8), 8.71-
8.83 (m, 3H, H4′, H6′ & H5), 9.61 (s, 1H, H2′), 10.65 (bs, 1H,
NH), and 11.80 (bs, 1H, NH). Anal. (C21H17N5O2) C, H, N.
N-(2-Meth ylp h en yl)-N′-[2-(3-p yr id yl)qu in a zolin -4-yl]-
u r ea (10b): yield 50%; mp 227-228 °C; 1H NMR (DMSO-d6,
ref DMSO-d5-H ) 2.49 ppm) δ 2.19 (s, 3H, CH3), 7.14-7.27
(m, 3H, H5′ & ArH), 7.61-7.81 (m, 3H, H8, H6 & H7), 8.02-
N -(4-C h lo r o p h e n y l)-N ′-(2-p h e n y lq u in a zo lin -4-y l)-
1
u r ea (9a ): yield 88%; mp 291-292 °C; H NMR (DMSO-d6,
3
3
ref DMSO-d5-H ) 2.49 ppm) δ 6.51 (d, J AB ) 8.8 Hz, 2H,
8.04 (m, 2H, ArH), 8.62 (d, J 56 ) 8.0 Hz, 1H, H5), 8.74-8.82
3
AA′BB′ ArH), 7.01 (d, J BA ) 8.7 Hz, 2H, AA′BB′ ArH), 7.47-
(m, 2H, H4′ & H6′), 9.41 (s, 1H, H2′), 10.70 (bs, 1H, NH), and
11.50 (s, 1H, NH). Anal. (C21H17N5O) C, H, N.
7.62 (m, 2H, H6 and H7), 7.62-7.76 (m, 3H, H3′, H4′, and H5′),
3
4
8.24 (dd, J 87 ) 8.3 Hz, J 86 ) unsolved, 1H, H8), 8.43-8.46
N-(2-Meth oxyp h en yl)-N′-[2-(2-p yr id yl)qu in a zolin -4-yl]-
u r ea (11): yield 68%; mp 190 °C; 1H NMR (DMSO-d6, ref
DMSO-d5-H ) 2.49 ppm) two isomeric forms A:B ) 4:1, A δ
3.40 (s, 3H, OCH3), 6.98-7.10 (m, 4H, ArH), 7.55-8.14 (m,
5H, H4′, H5′, H6, H7 & H8), 8.39-8.43 (m, 1H, H3′), 8.77-
8.84 (m, 2H, H6′ & H5), 10.65 (bs, 1H, NH), and 12.29 (bs,
1H, NH), B δ 3.90 (s, 3H, OCH3), 6.98-7.10 (m, 4H, ArH),
7.55-8.11 (m, 5H, H4′, H5′, H6, H7 & H8), 8.52-8.56 (m, 1H,
3
4
(m, 2H, H2′ and H6′), 8.73 (dd, J 56 ) unsolved, J 57
)
unsolved, 1H, H5), 10.70 (bs, 1H, NH), and 12.29 (bs, 1H, NH).
Anal. (C21H15ClN4O) C, H, N.
N -(4-Me t h y lp h e n y l)-N ′-(2-p h e n y lq u in a zo lin -4-y l)-
1
u r ea (9b): yield 66%; mp 258-260 °C; H NMR (DMSO-d6,
3
ref DMSO-d5-H ) 2.49 ppm) δ 3.61 (s, 3H, CH3), 6.50 (d, J AB
) 8.9 Hz, 2H, AA′BB′ ArH), 6.63 (d, 3J BA ) 8.9 Hz, 2H, AA′BB′