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A. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 691e703
ArH), 5.75 (s, 1H, dihydroquinazolinone-H), 3.99 (t, 2H, J ¼ 6.5 Hz,
1ꢃꢀOCH2ꢀ), 3.86 (s, 3H, 1ꢃꢀOCH3), 3.45 (t, 2H, J ¼ 6.5 Hz,
1ꢃꢀCH2Br), 1.77e2.02 (m, 4H, 2ꢃꢀCH2ꢀ), 1.59e1.72 (m, 2H,
1ꢃꢀCH2ꢀ); MS (ESI): m/z 420 (M þ H)þ.
isoxazolineꢀH), 3.31 (dd, 1H, J ¼ 16.6, 9.0 Hz, isoxazolineꢀH),
2.15e2.02 (m, 4H, 2ꢃꢀCH2ꢀ); 13C NMR (75 MHz, CDCl3):
d 164.9,
156.0,153.4,149.6,147.3,136.4,133.8,131.1,130.7,128.4,126.3,124.5,
119.9, 119.3, 115.3, 114.4, 112.2, 110.0, 103.9, 102.5, 82.6, 72.8, 68.7,
68.5, 60.7, 56.1, 56.0, 55.8, 43.4, 26.5, 25.6 ppm; MS (ESI): m/z 714
(M þ H)þ;HRMS (ESI) m/z calcd for C39H43N3O10 (M þ H)þ, 714.3026;
found, 714.3058.
5.1.19. 2-(3-(4-Bromobutoxy)-4-methoxyphenyl)-2,3-dihydroquina
zolin-4(1H)-one (18d)
This compound was prepared according to the method described
for compound 18a, employing compound 17b (270 mg,1 mmol) and
1,4 dibromobutane (860 mg, 4 mmol). The crude product was
chromatographed using ethyl acetate/light petroleum (20%) as
eluent to obtain the pure product 18d as a pale yellow solid (356 mg,
5.1.22. 2-(4-(5-(2,6-Dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)-4,5-
dihydroisoxazole-3-yl)phenoxy)pentyloxy)-3-methoxyphenyl)-2,3-
dihydroquinazolin-4(1H)-one (4c)
This compound was prepared according to the method described
for compound 4a, employing compound 18c (419 mg, 1 mmol) and
10a (389 mg,1 mmol). The crude product thus obtained was purified
by column chromatography using ethyl acetate/hexane (50%) as
eluant to afford the pure compound 4c as a pale yellow solid
88%). Mp: 143e145 ꢂC; 1H NMR (DMSO-d6, 300 MHz):
d 8.23 (br s,
1H, N3H), 7.70 (d,1H, J ¼ 7.4 Hz, ArH), 7.39e7.30 (m, 2H, ArH), 7.22 (s,
1H, ArH), 7.10 (br s, 1H, N1H), 7.02 (d, 1H, J ¼ 8.3 Hz, ArH), 6.96e6.83
(m, 1H, ArH), 6.68 (d, 1H, J ¼ 6.7 Hz, ArH), 5.70 (s, 1H, dihy-
droquinazolinone-H), 4.03 (t, 2H, J ¼ 5.8 Hz,1ꢃꢀOCH2ꢀ), 3.81 (s, 3H,
1ꢃꢀOCH3), 3.52 (t, 2H, J ¼ 6.6 Hz, 1ꢃꢀCH2Br), 1.87e2.14 (m, 4H,
2ꢃꢀCH2ꢀ); MS (ESI): m/z 406 (M þ H)þ.
(581 mg, 80%). Mp: 76e78 ꢂC; 1H NMR (DMSO-d6, 300 MHz):
d 8.19
(br s,1H, N3H), 7.84 (dd,1H, J ¼ 7.4,1.5 Hz, ArH), 7.25 (ddd,1H, J ¼ 7.4,
7.4,1 Hz, ArH), 7.10 (br s,1H, N1H), 6.92 (d,1H, J ¼ 7.4 Hz, ArH), 6.84 (s,
2H, ArH), 6.79(d,1H, J¼ 8.3 Hz, ArH), 6.62(d,1H, J¼ 7.4 Hz, ArH), 6.54
(s, 2H, ArH), 5.75 (s, 1H, dihydroquinazolinone-H), 5.60 (dd, 1H,
J ¼ 10.5, 8.3 Hz, isoxazolineꢀH), 4.11 (t, 2H, J ¼ 5.6 Hz, 1ꢃꢀOCH2ꢀ),
4.01 (t, 2H, J ¼ 5.6 Hz, 1ꢃꢀOCH2ꢀ), 3.89 (s, 3H, 1ꢃꢀOCH3), 3.84 (s,
6H, 2ꢃꢀOCH3), 3.87 (s, 9H, 3ꢃꢀOCH3), 3.74 (dd,1H, J ¼ 16.6,10.5 Hz,
isoxazolineꢀH), 3.31 (dd, 1H, J ¼ 16.6, 9.0 Hz, isoxazolineꢀH),
2.11e2.01 (m, 4H, 2ꢃꢀCH2ꢀ), 1.74e1.56 (m, 2H, 1ꢃꢀCH2ꢀ); 13C
5.1.20. Synthesis of 2-(4-(3-(2,6-dimethoxy-4-(5-(3,4,5-trimethoxy
phenyl)-4,5-dihydroisoxazol-3-yl)phenoxy)propoxy)-3-methoxyphe
nyl)-2,3-dihydroquinazolin-4(1H)-one (4a)
To a solution compound 18a (391 mg, 1 mmol) in DMF (5 mL)
anhydrous K2CO3 (552 mg, 4 mmol) and the compound 10a
(389 mg, 1 mmol) were added. The reaction mixture was stirred at
room temperature for 24 h. After completion of the reaction as
indicated by TLC, ice was added to the reaction mixture followed by
extraction with ethyl acetate and then washed with brine solution.
The solvent was removed under vacuum. The crude product thus
obtained was purified by column chromatography using ethyl
acetate/hexane (50%) as eluant to afford the pure compound 4a as
a pale yellow solid (559 mg, 80%). Mp: 84e86 ꢂC; 1H NMR (DMSO-
NMR (75 MHz, CDCl3): d 164.8,156.0,153.4,149.7,147.3,136.4,133.9,
131.1, 130.7, 128.5, 126.7, 124.5, 120.0, 119.4, 114.5, 112.1, 110.0, 104.0,
102.5, 82.7, 73.1, 68.8, 60.7, 56.2, 56.1, 55.9, 43.4, 29.7, 29.6, 28.7,
22.2 ppm; MS (ESI): m/z 728 (M þ H)þ; HRMS (ESI) m/z calcd for
C40H45N3O10Na (M þ Na)þ, 750.3002; found, 750.2999.
5.1.23. 2-(4-Methoxy-3-(4-(2-methoxy-5-(5-(3,4,5-trimethoxyphe
nyl)isoxazol-3-yl) phenoxy)butoxy)phenyl)-2,3-dihydroquinazolin-
4(1H)-one (4d)
This compound was prepared according to the method described
for compound 4a, employing compound 18d (405 mg, 1 mmol) and
10b (357 mg,1 mmol). The crude product thus obtained was purified
by column chromatography using ethyl acetate/hexane (50%) as
eluant to afford the pure compound 4d as a pale yellow solid
(544 mg, 80%). Mp: 126e128 ꢂC; 1H NMR (DMSO-d6, 300 MHz):
d6, 300 MHz):
d
8.22 (br s, 1H, N3H), 7.84 (dd, 1H, J ¼ 7.5, 1.4 Hz,
ArH), 7.25 (ddd, 1H, J ¼ 7.5, 7.5, 1 Hz, ArH), 7.13 (br s, 1H, N1H),
7.02e6.91 (m, 3H, ArH), 6.89 (s, 2H, ArH), 6.86 (d, 1H, J ¼ 7.5 Hz,
ArH), 6.67 (dd, 1H, J ¼ 7.5, 7.5 Hz, ArH), 6.60 (s, 2H, ArH), 5.84 (s, 1H,
dihydroquinazolinone-H), 5.65 (dd, 1H, J ¼ 10.5, 8.3 Hz, iso-
xazolineꢀH), 4.08 (t, 2H, J ¼ 5.6 Hz, 1ꢃꢀOCH2ꢀ), 4.03 (t, 2H,
J ¼ 5.6 Hz, 1ꢃꢀOCH2ꢀ), 3.89 (s, 3H, 1ꢃꢀOCH3), 3.87 (s, 9H,
3ꢃꢀOCH3), 3.84 (s, 6H, 2ꢃꢀOCH3), 3.74 (dd, 1H, J ¼ 16.6, 10.5, Hz,
isoxazolineꢀH), 3.31 (dd, 1H, J ¼ 16.6, 9.0 Hz, isoxazolineꢀH),
d
8.20 (br s, 1H, N3H), 7.93 (dd, J ¼ 7.5, 1.5 Hz, 1H, ArH), 7.45 (dd,1H,
2.33e2.18 (m, 2H, 1ꢃꢀCH2ꢀ); 13C NMR (75 MHz, CDCl3):
d
164.7,
J ¼ 8.3,1.9 Hz, ArH), 7.33 (d,1H, J ¼ 1.9 Hz, ArH), 7.28 (d,1H, J ¼ 8.3 Hz,
ArH), 7.23 (br s, 1H, N1H), 7.03 (d, 1H, J ¼ 7.9 Hz, ArH), 7.04 (s, 2H,
ArH), 6.92 (d,1H, J ¼ 7.9 Hz, ArH), 6.87 (d,1H, J ¼ 8.4 Hz, ArH), 6.84 (d,
1H, J ¼ 8.4 Hz, ArH), 6.70 (s,1H, isoxazoleꢀH), 6.65 (d,1H, J ¼ 7.9 Hz,
ArH), 5.81 (s, 1H, dihydroquinazolinone-H), 4.11e4.24 (m, 4H,
2ꢃꢀOCH2ꢀ), 3.95 (s, 6H, 2ꢃꢀOCH3), 3.91 (s, 3H,1ꢃꢀOCH3), 3.89 (s,
3H, 1ꢃꢀOCH3), 3.86 (s, 3H, 1ꢃꢀOCH3), 2.17e1.99 (m, 4H,
156.0,153.4,149.7,147.3,136.4,133.8,131.1,130.7,128.4,126.3,124.5,
119.9, 119.3, 115.3, 114.4, 112.2, 110.0, 103.9, 102.5, 82.6, 72.8, 68.7,
68.5, 60.7, 56.1, 56.0, 55.8, 43.4, 29.6 ppm; MS (ESI): m/z 700
(M þ H)þ; HRMS (ESI) m/z calcd for C38H41N3O10Na (M þ Na)þ,
722.2689; found, 722.2666.
5.1.21. 2-(4-(4-(2,6-Dimethoxy-4-(5-(3,4,5-trimethoxyphenyl)-4,5-
dihydroisoxazol-3-yl)phenoxy)butoxy)-3-methoxyphenyl)-2,3-dihy
droquinazolin-4(1H)-one (4b)
2ꢃꢀCH2ꢀ); 13C NMR (75 MHz, CDCl3):
d 165.0, 162.0, 153.3, 149.2,
148.1, 147.4, 145.3, 133.0, 128.3, 124.5, 120.0, 119.5, 113.1, 112.2, 111.8,
107.8,101.4, 98.5, 74.2, 69.0, 60.8, 56.2, 55.8, 26.8, 25.2; MS (ESI): m/z
682 (M þ H)þ; HRMS (ESI) m/z calcd for C38H39N3O9 (M þ H)þ,
682.2764; found, 682.2773.
This compound was prepared according to the method described
for compound 4a, employing compound 18b (405 mg, 1 mmol) and
10a (389 mg,1 mmol). The crude product thus obtained was purified
by column chromatography using ethyl acetate/hexane (50%) as
eluant to afford the pure compound 4b as a pale yellow solid
5.1.24. 2-(3-Methoxy-4-(3-(2-methoxy-5-(3-(3,4,5-trimethoxyphe
nyl)-4,5-dihydroisoxazol-5-yl)phenoxy)propoxy)phenyl)-2,3-dihyd
roquinazolin-4(1H)-one (5a)
(570 mg, 80%). Mp: 80e82 ꢂC; 1H NMR (DMSO-d6, 300 MHz):
d 8.20
(br s, 1H, N3H), 7.84 (dd, 1H, J ¼ 7.2, 1.4 Hz, ArH), 7.25 (ddd, 1H, J ¼ 1,
7.2, 7.2 Hz, ArH), 7.12 (br s,1H, N1H), 7.02e6.91 (m, 3 H, ArH), 6.84 (s,
2H, ArH), 6.79 (d,1H, J ¼8.3 Hz, ArH), 6.62(d,1H, J ¼7.2Hz, ArH), 6.54
(s, 2H, ArH), 5.75 (s, 1H, dihydroquinazolinone-H), 5.62 (dd, 1H,
J ¼ 10.5, 8.3 Hz, isoxazolineꢀH), 4.11 (t, 2H, J ¼ 5.6 Hz, 1ꢃꢀOCH2ꢀ),
4.01 (t, 2H, J ¼ 5.6 Hz, 1ꢃꢀOCH2ꢀ), 3.89 (s, 3H, 1ꢃꢀOCH3), 3.87 (s,
9H, 3ꢃꢀOCH3), 3.84 (s, 6H, 2ꢃꢀOCH3), 3.74 (dd,1H, J ¼ 16.6,10.5 Hz,
This compound was prepared according to the method described
for compound 4a, employing compound 18a (391 mg, 1 mmol) and
15a (359 mg,1 mmol). The crude product thus obtained was purified
by column chromatography using ethyl acetate/hexane (50%) as
eluant to afford the pure compound 5a as a pale yellow solid
(535 mg, 80%). Mp: 120e122 ꢂC; 1H NMR (DMSO-d6, 300 MHz):
d
8.24 (br s,1H, N3H), 7.95 (dd,1H, J ¼ 7.5,1.5 Hz, ArH), 7.34 (ddd,1H,