J. Ramírez et al. / European Journal of Medicinal Chemistry 92 (2015) 866e875
873
Table 2
Inhibition percentages of 7aeg against C. albicans ATCC 10231 and C. neoformans ATCC 32264 at the range of compound concentrations 250e3.9
mg/mL.
Concentrations
250
m
g/mL
125
m
g/mL
62.5
m
g/mL
31.25
m
g/mL
15.62
m
g/mL
7.81
mg/mL
3.9 mg/mL
Compound
Inhibition percentages (%) against C. albicans ATCC 10231
7a
7b
7c
7d
7e
7f
100
100
100
100
100
100
100
100
62.03 2.08
100
17.89 0.23
1.41 0.99
15.66 0.89
0
21.51 1.94
48.31 1.27
0
0
12.45 1.06
0
0
4.92 0.36
22.24 0.80
0
0
10.45 0.62
0
0
59.90 1.35
55.45 0.67
62.64 0.64
14.96 1.31
56.75 2.31
51.72 1.27
21.31 0.23
54.60 1.15
10.53 0.59
48.07 0.19
43.26 1.59
13.49 1.09
23.17 1.08
7.26 0.53
41.58 2.04
21.33 0.25
8.70 0.62
21.22 0.62
9.84 0.73
24.27 1.41
7g
0
Inhibition percentages against C. neoformans ATCC 32264
7a
7b
7c
7d
7e
7f
100
74.31 1.44
58.21 1.76
24.63 1.63
18.29 1.14
46.88 1.20
27.16 1.08
36.91 1.99
21.77 1.08
40.48 1.49
12.81 0.95
9.20 0.77
23.06 0.81
9.28 0.72
19.53 1.07
7.0 0.62
2.53 0.13
13.08 1.09
7.17 0.04
4.57 1.16
7.79 0.12
5.52 0.19
5.35 1.57
0
0
0
78.73 2.12
25.48 1.34
59.09 1.10
77.11 1.18
77.53 1.39
58.47 2.48
30.53 1.65
11.04 0.05
6.47 1.45
13.15 0.21
7.09 0.57
7.07 0.44
3.56 0.73
5.01 0.30
0.93 0.46
6.04 0.77
2.99 0.03
3.92 0.21
3.83 0.64
0
0
1.65 0.11
0
7g
(400 MHz, DMSO-d6):
d
2.95 (d, J ¼ 14.1 Hz, 1H, H7A), 3.75 (dd,
(dd, J ¼ 14.4, 5.7 Hz,1H, H7M), 5.20 (s, 2H, 2-NH2), 5.34 (d, J ¼ 3.9 Hz,
1H, H8X), 5.89 (s, 2H, 4-NH2), 6.53 (s, 1H, eNH), 6.98e7.08 (m, 2H,
J ¼ 14.1, 5.4 Hz, 1H, H7M), 5.46 (s, 1H, H8X), 6.07 (s, 2H, OeCH2eO),
6.63 (s, 2H, 4-NH2), 6.88 (d, J ¼ 8.1 Hz, 1H, Hm), 7.20 (d, J ¼ 8.1 Hz,
1H, Ho), 7.58 (s, 1H, eNH), 7.63 (d, J ¼ 5.9 Hz, 1H, Ho’), 7.81 (s, 1H, H2)
Hm), 7.65 (dd, J ¼ 8.9 y JHF ¼ 5.3 Hz, 2H, Ho) ppm. NMR-13
C
(100 MHz, CDCl3):
d 37.6 (C), 53.2 (C8), 103.7 (C4a), 115.4 (d,
ppm. NMR-13C (100 MHz, DMSO-d6):
d36.3 (CH2), 56.4 (CH), 101.9
JCF ¼ 21.7 Hz, Cm), 128.1 (d, JCF ¼ 8.4 Hz, Co), 131.8 (C4 ), 136.2 (d,
2
3
0
4
0
(CH2), 107.1 (CH), 108.0 (CH), 108.6 (Cc), 121.8 (CH), 130.4 (Cc), 134.2
(Cc), 139.8 (Cc), 148.1 (Cc), 149.3 (Cc), 149.4 (Cc), 152.5 (Cc), 155.6
(CH), 161.5 (Cc), 162.2 (Cc) ppm. MS (IE, 70 eV) m/z (%): 436/434
[Mþ] (54.5/83.1), 401/399 (45.1/100), 385/383 (8.9/22.3), 255
(30.0). Anal. Calcd. C17H12Cl2N6O2S: C, 46.91; H, 2.78; N, 19.31;
Found: C, 47.09; H, 2.99; N, 19.35.
JCF ¼ 3.1 Hz, Ci), 136.4 (C5 ), 150.9 (C4), 153.3 (C9a), 155.6 (C2), 160.3
(C]N), 163.1 (d, 1JCF ¼ 246.9 Hz), 164.9 (C2’) ppm. MS (IE, 70 eV) m/z
(%): 425/423 [Mþ] (7.1/12.5), 390/388 (16.0/40.6), 352 (19.5), 244
(100). Anal. Calcd. C16H12Cl2FN7S: C, 45.29; H, 2.85; N, 23.11; Found:
C, 45.36; H, 2.89; N, 23.21.
4.2.11. 2,4-Diamino-8-(2,4-dichlorothiazol-5-yl)-6-(p-tolyl)-8,9-
dihydro-7H-pyrimido[4,5-b][1,4]diazepine (7d)
4.2.8. 2,4-Diamino-8-(2,4-dichlorothiazol-5-yl)-6-phenyl-8,9-
dihydro-7H-pyrimido[4,5-b][1,4]diazepine (7a)
m.p 217e218 ꢁC; FT-IR (KBr), (cmꢀ1): 3471, 3439 and 3313
y
p.f. 172e173 ꢁC; FT-IR (KBr),
y
(cmꢀ1): 3468, 3444 and 3310
(eNH, 2-NH2, 4-NH2), 1641, 1588 and 1550 (C]N and C]C).
(eNH, 2-NH2, 4-NH2), 1551, 1579 and 1548 (C]N and C]C).
NMR-1H (400 MHz, CDCl3):
d
2.36 (s, 3H, pCH3) 3.06 (dd, J ¼ 14.6,
NMR-1H (400 MHz, CDCl3):
d
2.89 (dd, J ¼ 14.6,1.8 Hz,1H, H7A), 3.81
2.0 Hz, 1H, H7A), 3.69 (dd, J ¼ 14.6, 6.1 Hz, 1H, H7M), 5.16 (s, 2H, 2-
NH2), 5.35 (d, J ¼ 4.3 Hz, 1H, H8X), 5.89 (s, 2H, 4-NH2), 6.48 (s, 1H,
eNH), 7.14 (d, J ¼ 8.2 Hz, 2H, Hm), 7.57 (d, J ¼ 8.2 Hz, 2H, Ho) ppm.
(dd, J ¼ 14.6, 5.5 Hz, 1H, H7M), 5.31e5.42 (m, 1H, H8X), 5.89 (s, 2H, 2-
NH2), 6.36 (s, 2H, 4-NH2), 7.28e7.40 (m, 4H, eNH, Hm y Hp),
7.65e7.75 (m, 2H, Ho) ppm. NMR-13C (100 MHz, CDCl3):
d
36.7
NMR-13C (100 MHz, CDCl3):
d 21.2 (CH3), 37.5 (CH2), 53.3 (CH), 103.2
(CH2), 53.5 (CH), 102.3 (s), 126.4 (CH), 128.6 (CH), 129.6 (CH), 130.4
(Cc), 132.3 (Cc), 140.6 (Cc), 153.9 (CH), 154.7 (Cc), 160.8 (Cc), 163.8
(Cc), 167.4 (Cc) ppm.MS (IE, 70 eV) m/z (%): 407/405 [Mþ] (4.1/25.3),
372/370 (7.1/17.1), 226 (56.5), 91 (100). Anal. Calcd. C16H13Cl2N7S: C,
47.30; H, 3.23; N, 24.13; Found: C, 47.59; H, 3.50; N, 24.32.
(Cc), 126.2 (CH), 129.2 (CH), 131.8 (Cc), 136.7 (Cc), 137.3 (Cc), 138.7
(Cc), 150.8 (Cc), 153.3 (Cc), 156.8 (Cc), 160.2 (Cc), 163.8 (Cc) ppm. MS
(IE, 70 eV) m/z (%): 421/419 [Mþ] (19.1/54.0), 386/384 (10.8/31.4),
370/368 (6.1/15.9), 240 (100). Anal. Calcd. C17H15Cl2N7S: C, 48.58; H,
3.60; N, 23.33; Found: C, 48.83; H, 3.89; N, 23.57.
4.2.9. 6-(4-Chlorophenyl)-2,4-diamino-8-(2,4-dichlorothiazol-5-
yl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepine (7b)
4.2.12. 2,4-Diamino-8-(2,4-dichlorothiazol-5-yl)-6-(4-
methoxyphenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepine
(7e)
m.p 215e216 ꢁC; FT-IR (KBr), (cmꢀ1): 3476, 3446 and 3311
y
(eNH, 2-NH2, 4-NH2), 1648, 1585 and 1549 (C]N and C]C).
m.p 202e203 ꢁC; FT-IR (KBr), (cmꢀ1): 3460, 3433 and 3309
y
NMR-1H (400 MHz, CDCl3):
d
3.06 (dd, J ¼ 14.6, 2.0 Hz, 1H, H7A),
(eNH, 2-NH2, 4-NH2), 1648, 1584 and 1551 (C]N and C]C).
3.67 (dd, J ¼ 14.6, 6.1 Hz, 1H, H7M), 5.16 (s, 2H, 2-NH2), 5.34 (d,
J ¼ 4.5 Hz, 1H, H8X), 5.88 (s, 2H, 4-NH2), 6.48 (s, 1H, eNH), 7.31 (d,
NMR-1H (400 MHz, CDCl3):
d
3.06 (d, J ¼ 13.3, 1H, H7A), 3.69 (dd,
J ¼ 14.4, 6.0 Hz, 1H, H7M), 3.83 (s, 3H, pOCH3), 5.06 (s, 2H, 2-NH2),
5.36 (s, 1H, H8X), 5.82 (s, 2H, 4-NH2), 6.31 (s, 1H, eNH), 6.86 (d,
J ¼ 8.7 Hz, 2H, Hm), 7.60 (d, J ¼ 8.7 Hz, 2H, Ho) ppm. NMR-13
C
(100 MHz, CDCl3):
d
37.6 (CH2), 53.0 (CH), 103.0 (Cc), 127.4 (CH),
J ¼ 8.8 Hz, 2H, Hm), 7.64 (d, J ¼ 8.8 Hz, 2H, Ho) ppm. NMR-13
C
128.6 (CH), 131.9 (Cc), 135.6 (Cc), 136.3 (Cc), 138.4 (Cc), 151.0 (Cc),
153.4 (Cc), 155.2 (Cc), 160.4 (Cc), 163.9 (Cc) ppm. MS (IE, 70 eV) m/z
(%): 443/441/439 [Mþ] (29/57/58), 406/404 (35.8/52.4), 370/368
(11.2/24.6), 262/260 (48.3/100). Anal. Calcd. C16H12Cl3N7S: C, 43.60;
H, 2.74; N, 22.25; Found: C, 43.71; H, 2.85; N, 22.45.
(100 MHz, CDCl3): d37.1 (CH2), 53.8 (CH), 55.3 (CH3), 103.3 (Cc),
113.8 (CH), 127.8 (CH), 131.6 (Cc), 132.66 (Cc), 136.8 (Cc), 150.84 (Cc),
153.2 (Cc), 156.8 (Cc), 160.7 (Cc), 160.9 (Cc), 163.6 (Cc) ppm.MS (IE,
70 eV) m/z (%): 437/435 [Mþ] (15.4/21.8), 401.90/399.95 (14.7/41.9),
386/384 (2.3/6.3), 269 (31.7), 256 (100). Anal. Calcd. C17H15Cl2N7OS:
C, 46.80; H, 3.47; N, 22.47; Found: C, 47.09; H, 3.61; N, 22.46.
4.2.10. 2,4-Diamino-8-(2,4-dichlorothiazol-5-yl)-6-(4-
fluorophenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepine (7c)
4.2.13. 2,4-Diamino-8-(2,4-dichlorothiazol-5-yl)-6-(3,4,5-tri
m.p 214e215 ꢁC; FT-IR (KBr),
y
(cmꢀ1): 3475, 3446 and 3309
methoxyphenyl)-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepine (7f)
(eNH, 2-NH2, 4-NH2), 1651, 1587 and 1552 (C]N and C]C).
m.p 223e224 ꢁC; FT-IR (KBr), (cmꢀ1): 3476, 3439 and 3311
y
NMR-1H (400 MHz, CDCl3):
d
3.06 (dd, J ¼ 14.5,1.9 Hz,1H, H7A), 3.68
(eNH, 2-NH2, 4-NH2), 1661,1581 and 1556 (C]N and C]C).