Journal of Medicinal Chemistry
ARTICLE
1
(100 mL), using method I, except that the reaction mixture was stirred at
room temperature for 5 h.
Yellow solid; IR 3374, 2966, 2931, 1707, 1556, 1504 cm-1; H NMR
(CDCl3) δ 0.82 (3H, dd, J = 6.8 Hz, Me), 0.92 (3H, t, J = 6.8 Hz, Me), 1.17
(3H, d, J = 6.2 Hz, Me), 1.25 (3H, t, J = 6.2 Hz, Me), 1.42 (9H, s, t-Bu), 2.09
(1H, m, CHMe2), 3.29 (1H, m, NHCH2), 3.47 (2H, m, -NHCH2), 3.85
(12H, s, 4 ꢀ OCH3), 3.99 (1H, t, J = 4.59 Hz, CHOCO), 4.17 (1H, q,
J = 4.59 Hz, -NH-CH-CO), 4.62 (4H, m, 2 ꢀ ArCH2), 5.01 (2H, m,
-NH/OH), 5.24 (2H, m, -CH-OH, NH), 6.73 (1H, br s, NH),
6.78-6.93 (6H, m, Ar), 7.12 (1H, br s, -NH); LCMS 808.5 ([M þ 1]þ).
Anal. C40H57N9O9 C, H, N.
1-((4,8-Bis((3,4-dimethoxybenzyl)amino)-6-((2-hydroxypro-
pyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-yl
Phenylcarbamate (12). Yellow powder; IR 3387, 3321, 2928, 2833, 1718,
1556, 1501 cm-1; 1H NMR (CDCl3) δ 1.18 (3H, d, J = 6.3 Hz, CH3), 1.27
(3H, d, J = 6.3 Hz, CH3), 3.30 (1H, m, NHCHH), 3.52 (1H, m, NHCHH),
3.81 (3H, s, OCH3),3.84(9H,s,3ꢀ OCH3),4.60(2H,m,NHCH2Ar), 5.11
(2H, m, NH, OH), 5.17 (1H, m, CHOCONH), 6.70 (1H, m, NHCH2Ar),
6.78 (1H, d, ArH), 6.89 (4H, m, 4 ꢀ ArH), 7.03 (1H, t, ArH), 7.25 (3H, m,
3 ꢀ ArH), 7.33 (2H, d, 2 ꢀ ArH); LCMS 728.3 ([M þ 1]þ). Anal.
(C37H45N9O7) C, H, N.
(2S,20S)-((4,8-Bis((3,4-dimethoxybenzyl)amino)pyrimido-
[5,4-d]pyrimidine-2,6-diyl)bis(azanediyl))bis(propane-2,1-
diyl) Bis(2-((tert-butoxycarbonyl)amino)-3-methylbutanoate)
(32). Yellow solid; IR 3372, 2962, 2932, 1707, 1559, 1504 cm-1; 1H NMR
(CDCl3) δ 0.79 (3H, d, J = 6.7 Hz, Me), 0.85 (3H, d, J = 6.7 Hz, Me), 0.92
(6H, t, 2 ꢀ Me), 1.26 (6H, t, Me), 1.42 (9H, s, t-Bu), 1.43 (9H, s, t-Bu), 2.09
(2H, m, 2 ꢀ CHMe2), 3.44 (1H, m, -NH-CH2), 3.54 (3H, m, -NH-
CH2), 3.85 (6H, s, 2 ꢀ OMe), 3.87 (6H, 2 ꢀ OMe), 4.18 (2H, m, -NH-
CH-CO),4.64(4H,m,-NH-CH2-Ar),5.02(4H,m, NH),5.24(2H,m,
CH-O-CO), 6.83 (2H, m, Ar), 6.91 (4H, m, Ar), 6.99 (2H, br s, -NH);
LCMS 1007.5 (Mþ). Anal. C50H74N10O12 C, H, N.
(2S)-1-((4,8-Bis((3,4-dimethoxybenzyl)amino)-6-((2-hydroxy-
propyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-
yl 2-Amino-3-methylbutanoate (33). Prepared from 31 (0.50 g,
0.62 mmol) in accordance with method II to furnish 33 as a bright yellow
solid: IR 3331, 3207, 2933, 2834, 1741, 1633, 1537, 1512 cm-1; 1H NMR
(CDCl3) δ 0.86 (3H, q, J = 6.0 Hz, Me), 0.96 (3H, t, J = 6.0 Hz, Me), 1.20
(3H, d, J = 6.0 Hz, Me), 1.27 (3H, dd, J = 6.0 Hz, Me), 2.18 (2H, br s,
-NH2), 1.99 (1H, m, -CH(Me)2), 3.25 (2H, m, -NH-CH2-), 3.33
(1H, m, -CH-NH2), 3.88 (12H, s, 4 ꢀ OMe), 3.46 (2H, m, -NH-
CH2-), 4.01 (1H, m, -CH(OH)), 4.65 (4H, m, -NH-CH2-Ar), 4.96
(1H, m, OH), 5.24 (1H, m, -CH(O)-CO-), 6.68 (1H, br s, -NH),
6.83 (2H, m, Ar), 6.92 (4H, m, Ar), 7.10 (1H, br s, -NH); LCMS 708.4
([M þ 1]þ). Anal. (C35H49N9O7.0.9H2O) C,H, N.
((4,8-Bis((3,4-dimethoxybenzyl)amino)pyrimido[5,4-d]py-
rimidine-2,6-diyl)bis(azanediyl))bis(propane-2,1-diyl) Bis-
(phenylcarbamate) (13). Yellow flakes; IR 3324, 2934, 1717,
1597, 1558, 1500 cm-1
;
1H NMR (CDCl3) δ 1.29 (6H, d, 2 ꢀ
CH3), 3.54 (4H, m, 2 ꢀ NHCH2), 3.81 (6H, s, 2 ꢀ OCH3), 3.84 (6H,
s, 2 ꢀ OCH3), 4.60 (2H, m, 2 ꢀ NHCH2Ar), 5.07 (1H, br s, 2 ꢀ NH),
5.19 (1H, q, 2 ꢀ CHCH3), 6.79 (2H, d, 2 ꢀ OCONH), 6.91, 6.91,
7.06, 7.27, 7.27, 7.33 (16H, all ArH); LCMS 847.4 ([M þ 1]þ). Anal.
(C44H50N10O8) C, H, N.
Succinate Esters of 6. Succinic anhydride (0.16 g, 1.64 mmol) was
added to 6 (0.50 g, 0.41 mmol), pyridine (0.14 mL, 1.80 mmol), and
DMAP (0.03 g) in THF (20 mL). The reaction mixture was heated
under reflux for 48 h, and the volatiles were removed in vacuo to give a
yellow oil. Water (15 mL) was added, and the mixture was extracted with
EtOAc (3 ꢀ 30 mL). The combined organic layers were dried
(Na2SO4), and the solvent was removed under reduced pressure to
give a yellow solid. Purification by chromatography on silica gel,
employing DCM-MeOH (20:1) as eluent, followed by recrystallization
from EtOAc-petrol furnished the mono- and disuccinate esters as
yellow solids.
4-((1-((4,8-Bis((3,4-dimethoxybenzyl)amino)-6-((2-hydroxy-
propyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-
yl)oxy)-4-oxobutanoic Acid (27). Yellow powder; IR 3394, 3065,
2930, 2835, 1696, 1516 cm-1; 1H NMR (d6-DMSO) δ 1.16 (3H, d, CH3,
J = 6.2 Hz), 1.26 (3H, d, CH3, J = 7.1 Hz), 2.57 (4H, m, CH2CH2), 3.22-
3.50 (4H, m, 2 ꢀ CH3CHOCH2), 3.81 (6H, s, 2 ꢀ OCH3), 3.82 (6H, s,
2 ꢀ OCH3), 3.88 (1H, m, CH3CHOCH2), 4.66 (4H, s, 2 ꢀ ArCH2), 5.15
(1H, m, CH3CHOCO), 6.12 (1H, t, OH), 6.49 (2H, t, 2 ꢀ NH), 6.97-7.14
(6H, m, 6 ꢀ Ar-H), 7.61 (2H, br s, 2 ꢀ NH); LCMS 708 (Mþ). Anal.
(C34H44N8O9) C, H, N.
(2S)-1-((6-((2-(((R)-2-Amino-3-methylbutanoyl)oxy)propyl)-
amino)-4,8-bis((3,4-dimethoxybenzyl)amino)pyrimido[5,4-
d]pyrimidin-2-yl)amino)propan-2-yl 2-Amino-3-methylbutano-
ate (34). Prepared from 32 (0.5 g, 0.50 mmol) by method II to furnish
34 as a yellow powder: IR 3318, 2933, 1718, 1559, 1510 cm-1; 1H NMR
(CD3OD) δ 1.02 (12H, m, 4 ꢀ Me), 1.33 (6H, t, 2 ꢀ Me), 2.31 (2H, m,
-CHMe2), 3.32(2H, m, -NH-CH2), 3.61 (1H, br s, -NH), 3.75(2H, d,
-NH-CH2), 3.81 (6H, s, 2 ꢀ OMe), 3.85 (6H, s, 2 ꢀ OMe), 3.92 (1H, d,
-NH-CH-CO), 4.02 (1H, d, -NH-CH-CO), 4.83 (4H, m, -NH-
CH2-Ar), 5.21 (2H, d, -CH-O-CO), 6.92(2H, d, Ar), 7.00(2H, d, Ar),
4,40-((((4,8-Bis((3,4-dimethoxybenzyl)amino)pyrimido[5,
4-d]pyrimidine-2,6-diyl)bis(azanediyl))bis(propane-2,1-diyl))bis-
(oxy))bis(4-oxobutanoic acid) (28). Bright yellow solid; IR 3373, 3348,
3066, 2934, 2835, 1696, 1594 cm-1; 1H NMR (d6-DMSO) δ 1.26 (6H, d,
2 ꢀ CH3), 2.52 (8H, s, 2 ꢀ CH2CH2), 3.48 (4H, m, 2 ꢀ CH3CHOCH2-
NH),3.81(6H, s, 2ꢀ OCH3), 4.66(4H, brs, 2ꢀ ArCH2), 5.15(2H, m, 2ꢀ
CH3CHOCH2NH), 6.51 (2H, br s, 2 ꢀ NH), 6.98-7.15 (6H, m, 6 ꢀ
Ar-H), 7.68 (2H, br s, 2 ꢀ NH);LCMS809.1([Mþ 1]þ). Anal. (C38H48-
N8O12) C, H, N.
N-Boc-valine Esters of 6. N-Boc-valine (0.89 g, 4.1 mmol) was
added to 6 (1.00 g, 1.64 mmol), DMAP (0.12 g, 0.98 mmol), 1-[(3-
dimethylaminopropyl)]-3-ethylcarbodiimide hydrochloride (1.20 g,
5.75 mmol) and NEt3 (0.67 g, 6.57 mmol) in DMF (20 mL). The
reaction mixture was stirred for 48 h at 25 °C, water (100 mL) was
added, and the resulting solution was extracted with EtOAc (5 x 50 mL).
The combined organic layers were washed sequentially with water (4 ꢀ
100 mL), saturated aqueous NaHCO3 solution (100 mL), and brine
(100 mL), dried (Na2SO4), and the solvent was removed in vacuo.
Product isolation was achieved by chromatography on silica.
(2S)-1-((4,8-Bis((3,4-dimethoxybenzyl)amino)-6-((2-hydroxy-
propyl)amino)pyrimido[5,4-d]pyrimidin-2-yl)amino)propan-2-
yl 2-((tert-Butoxycarbonyl)amino)-3-methylbutanoate (31).
7.10 (2H, br s, Ar); LCMS 807.6 ([M þ 1]þ). Anal. (C40H58N10O8
3
0.5H2O) C, H, N.
1-((6-((2-((Di-tert-butoxyphosphoryl)oxy)propyl)amino)-
4,8-bis((3,4-dimethoxybenzyl)amino)pyrimido[5,4-d]pyrimidin-
2-yl)amino)propan-2-yl Phenylcarbamate (38). To a stirred solution
of 12 (1.00 g, 1.37 mmol) in THF (20 mL) were added 1H-tetrazole (0.45 M
in MeCN, 9.0 mL, 4.12 mmol) and di-tert-butyl diethylphosphoramidite
(0.411 g, 1.64 mmol). The solution was stirred for 3 h at room temperature
andcooledto-78 °C, whereupon m-CPBA (0.31 g, 1.78 mmol) was added,
and stirring was continued for a further 30 min at -78 °C, followed by 1 h at
room temperature. After the addition of aqueous NaHSO3 solution (10%,
25 mL), the reaction mixture was stirred for 15 min, and EtOAc (100 mL)
was added. The solution was washed successively with aqueous NaHSO3
solution (10%, 2 ꢀ 20 mL), aqueous NaHCO3 solution (5%, 1 ꢀ 20 mL),
and brine (20 mL), dried (Na2SO4), and concentrated in vacuo. Product
purification was achieved by chromatography on silica, employing a gradient
eluent of EtOAc-petrol (50%-100% EtOAc), to furnish 38 as a pale yellow
powder: IR 3404, 3331, 2980, 2934, 1718, 1558 cm-1; 1HNMR(CDCl3) δ
1.28 (3H, d, J= 6.3 Hz, Me), 1.33 (3H, d, J =6.3 Hz, Me), 1.46(9H, s, t-Bu),
1.47 (9H, s, t-Bu), 3.53 (4H, m, -NH-CH2), 3.82 (3H, s, OMe), 3.85
(6H, s, 2 ꢀ OMe), 3.88 (3H, s, OMe), 4.62 (4H, m, -NH-CH2-Ar),
1856
dx.doi.org/10.1021/jm101493z |J. Med. Chem. 2011, 54, 1847–1859