2276 Journal of Medicinal Chemistry, 2008, Vol. 51, No. 7
Elzein et al.
with water to afford compounds 51-54 (88–93% yield) that were
used without further purification.
(m, 2H), 7.50-7.57 (m, 2H), 8.12 (s, 1H), 8.52 (s, 1H), 13.55 (s,
1H); MS m/z 409 (M + H)+; Anal. (C21H21FN6O20.5H2O) C,
H, N.
8-(1-(3-(Trifluoromethyl)benzyl)-1-pyrazol-4-yl)-1-(cyclopro-
pylmethyl)-3-ethyl-1H-purine-2,6(3H,7H)-dione (65). Yield 0.11 g,
82%. 1H NMR (DMSO-d6): δ 0.35-0.48 (m, 4H), 1.20-1.26 (m,
4H), 3.80 (d, J ) 8.0 Hz, 2H), 4.06 (q, J ) 8.0 Hz, 2H), 5.52 (s,
2H), 7.58-7.64 (m, 2H), 7.68-7.72 (m, 2H), 8.13 (s, 1H), 8.55
(s, 1H), 13.56 (s, 1H); MS m/z 459 (M + H)+; Anal.
(C22H21F3N6O2) C, H, N.
3-Ethyl-1-isobutyl-8-(1H-pyrazol-4-yl)-1H-purine-2,6(3H,7H)-
dione (66). Yield 0.06 g, 71%. 1H NMR (DMSO-d6): δ 0.88 (d, J
) 8.0 Hz, 6H), 1.26 (t, J ) 8.0 Hz, 3H), 2.06-2.12 (m, 1H), 3.76
(d, J ) 8.0 Hz, 2H), 4.08 (q, J ) 8.0 Hz, 2H), 8.12 (s, 1H), 8.40
(s, 1H), 13.42 (s, 1H), 13.49 (s, 1H); MS m/z 303 (M + H)+; Anal.
(C14H18N6O2) C, H, N.
8-(1-(3-Fluorobenzyl)-1H-pyrazol-4-yl)-3-ethyl-1-isobutyl-1H-
purine-2,6(3H,7H)-dione (67). Yield 0.10 g, 83%. 1H NMR
(DMSO-d6): δ 0.86 (d, J ) 8.0 Hz, 6H), 1.26 (t, J ) 8.0 Hz, 3H),
2.04-2.10 (m, 1H), 3.75 (d, J ) 8.0 Hz, 2H), 4.05 (q, J ) 8.0 Hz,
2H), 5.45 (s, 2H), 7.12-7.18 (m, 3H), 7.40-7.46 (m, 1H), 8.12
(s, 1H), 8.52 (s, 1H), 13.55 (s, 1H); MS m/z 411 (M + H)+; Anal.
(C21H23FN6O2) C, H, N.
8-(1-(3-(Trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-ethyl-1-
isobutyl-1H-purine-2,6(3H,7H)-dione (68). Yield 0.11 g, 81%.
1H NMR (DMSO-d6): δ 0.86 (d, J ) 8.0 Hz, 6H), 1.26 (t, J ) 8.0
Hz, 3H), 2.04-2.10 (m, 1H), 3.75 (d, J ) 8.0 Hz, 2H), 4.05 (q, J
) 8.0 Hz, 2H), 5.55 (s, 2H), 7.61-7.64 (m, 2H), 7.68-7.71 (m,
2H), 8.12 (s, 1H), 8.58 (s, 1H), 13.57 (s, 1H); MS m/z 461 (M +
H)+; Anal. (C22H23F3N6O2) C, H, N.
3-Ethyl-1-propyl-8-(1-((pyridin-2-yl)methyl)-1H-pyrazol-4-
yl)-1H-purine-2,6(3H,7H)-dione (69). Yield 0.08 g, 73%. 1H NMR
(DMSO-d6): δ 0.87 (t, J ) 8.0 Hz, 3H), 1.24 (t, J ) 8.0 Hz, 3H),
1.52-1.61 (m, 2H), 3.82–3.86 (m, 2H), 4.05 (q, J ) 8.0 Hz, 2H),
5.65 (s, 2H), 7.35-7.39 (m, 1H), 7.54-7.58 (m, 1H), 8.03–8.07
(m, 1H), 8.15 (s, 1H), 8.55 (s, 1H), 8.68-8.70 (m, 1H); MS m/z
379 (M + H)+; Anal. (C19H21N7O2) C, H, N.
6-Amino-1-ethyl-5-nitroso-3-propylpyrimidine-2,4(1H,3H)-di-
one (51). Yield 1.1 g, 92%; MS m/z 227 (M + H)+.
6-Amino-3-butyl-1-ethyl-5-nitrosopyrimidine-2,4(1H,3H)-di-
one (52). Yield 1.0 g, 88%; MS m/z 241 (M + H)+.
6-Amino-1-ethyl-3-isobutyl-5-nitrosopyrimidine-2,4(1H,3H)-
dione (53). Yield 1.0 g, 88%; MS m/z 241 (M + H)+.
6-Amino-3-(cyclopropylmethyl)-1-ethyl-5-nitrosopyrimidine-
2,4(1H,3H)-dione (54). Yield 1.1 g, 93%; MS m/z 239 (M + H)+.
5,6-Diamino-1-ethyl-3-alkyl-pyrimidine-2,4(1H,3H)-dione(55-58).
A solution of 6-amino-1-ethyl-3-alkyl-5-nitrosouracils (51-54, 3
mmol) in 15 mL MeOH was prepared by heating the mixture at 70
°C. To the solution was added 10% Pd/C, and the mixture was
hydrogenated at 25 psi for 1.5 h. The mixture was filtered through
celite and washed with MeOH. The solvent was evaporated, and
the products were taken immediately to the next step without further
purification.
8-(1-Benzyl-1H-pyrazol-4-yl)-3-ethyl-1-alkyl-1H-purine-
2,6(3H,7H)-dione (59-75). General Procedure. 5,6-Diamino-3-
alkyl-1-ethylpyrimidine-2,4(1H,3H)-dione (55-58, 1.0 mmol) were
suspended in 15 mL of MeOH. To the suspension was added
1-substituted-1H-pyrazole-4-carboxylic acid (I, 1.3 mmol) and then
EDCI (1.3 mmol, 0.25 g). The mixture was stirred at rom
temperature for 24 h. TLC (DCM/MeOH 10:1 ) showed no starting
material. The solvent was evaporated, and the residue was purified
by using Biotage (DMC/MeOH 20:1) to afford the N-(6-amino-3-
alkyl-1,2,3,4-tetrahydro-1-benzyl-2,4-dioxopyrimidin-5-yl)-1-meth-
yl-1H-pyrazole-4-carboxamides II.
The carboxamides (II, 0.3 mmol) were dissolved in a mixture
of 1:2 MeOH/10% NaOH. The solution was stirred at 100 °C for
3-5 h. The MeOH was evaporated, and the aqueous solution was
acidified to pH 4-5 by using concentrated HCl. The precipitate
formed was collected by filtration, washed with water and ether,
and air-dried under vacuum to afford compounds 59-75 in 65–85%.
3-Ethyl-1-propyl-8-(1H-pyrazol-4-yl)-1H-purine-2,6(3H,7H)-
1
dione (59). Yield 0.06 g, 70%. H NMR (DMSO-d6): δ 0.87 (t, J
) 8.0 Hz, 3H), 1.24 (t, J ) 8.0 Hz, 3H), 1.52-1.61 (m, 2H),
3.82–3.86 (m, 2H), 4.05 (q, J ) 8.0 Hz, 2H), 8.14 (s, 1H), 8.35 (s,
1H), 13.32 (s, 1H), 13.52 (s, 1H); MS m/z 289 (M + H)+; Anal.
(C13H16N6O2) C, H, N.
3-Ethyl-1-propyl-8-(1-((pyridin-3-yl)methyl)-1H-pyrazol-4-
yl)-1H-purine-2,6(3H,7H)-dione (70). Yield 0.08 g, 73%. 1H NMR
(DMSO-d6): δ 0.87 (t, J ) 8.0 Hz, 3H), 1.24 (t, J ) 8.0 Hz, 3H),
1.52-1.61 (m, 2H), 3.82–3.86 (m, 2H), 4.05 (q, J ) 8.0 Hz, 2H),
5.65 (s, 2H), 7.25-7.29 (m, 1H), 7.44-7.48 (m, 3H), 8.50–8.53
(m, 2H); MS m/z 379 (M + H)+; Anal. (C19H21N7O2) C, H, N.
3-Ethyl-8-(1-((6-methylpyridin-3-yl)methyl)-1H-pyrazol-4-yl)-
1-propyl-1H-purine-2,6(3H,7H)-dione (71). Yield 0.08 g, 65%.
1H NMR (DMSO-d6): δ 0.87 (t, J ) 8.0 Hz, 3H), 1.24 (m, J ) 8.0
Hz, 3H), 1.55-1.60 (m, 2H), 2.68 (s, 3H), 3.82–3.86 (m, 2H), 4.05
(q, J ) 8.0 Hz, 2H), 5.58 (s, 2H), 7.78 (d, J ) 0.72 Hz, 1H), 8.18
(s, 1H), 8.20 (d, J ) 0.72 Hz, 1H), 8.59 (s, 1H), 8.77 (s, 1H),
13.62 (s, 1H); MS m/z 394 (M + H)+; Anal. (C20H23N7O2.HCl) C,
H, N.
8-(1-Benzyl-1H-pyrazol-4-yl)-3-ethyl-1-propyl-1H-purine-
2,6(3H,7H)-dione (60). Yield 0.09 g, 80%. 1H NMR (DMSO-d6):
δ 0.87 (t, J ) 8.0 Hz, 3H), 1.24 (t, J ) 8.0 Hz, 3H), 1.52–1.61 (m,
2H), 3.82–3.86 (m, 2H), 4.05 (q, J ) 8.0 Hz, 2H), 5.40 (s, 2H),
7.21-7.33 (m, 5H), 8.13 (s, 1H), 8.47 (s, 1H), 13.55 (s, 1H); MS
m/z 379 (M + H)+; Anal. (C20H22N6O2.0.5H2O) C, H, N.
8-(1-(3-Fluorobenzyl)-1H-pyrazol-4-yl)-3-ethyl-1-propyl-1H-
purine-2,6(3H,7H)-dione (61). Yield 0.10 g, 81%. 1H NMR
(DMSO-d6): δ 0.87 (t, J ) 8.0 Hz, 3H), 1.24 (t, J ) 8.0 Hz, 3H),
1.52-1.61 (m, 2H), 3.82–3.86 (m, 2H), 4.05 (q, J ) 8.0 Hz, 2H),
5.40 (s, 2H), 7.12-7.18 (m, 3H), 7.40–7.46 (m, 1H), 8.12 (s, 1H),
8.52 (s, 1H), 13.55 (s, 1H); MS m/z 397 (M + H)+; Anal.
(C20H21FN6O2) C, H, N.
3-Ethyl-8-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-
pyrazol-4-yl)-1-propyl-1H-purine-2,6(3H,7H)-dione (72). Yield
1
0.09 g, 65%. H NMR (DMSO-d6): δ 0.87 (t, J ) 8.0 Hz, 3H),
1.24 (m, 3H, J ) 8.0 Hz), 1.55-1.60 (m, 2H), 3.82-3.86 (m, 2H),
4.05 (q, J ) 8.0 Hz, 2H), 5.59 (s, 2H), 7.91-7.95 (m, 2H), 8.14
(s, 1H), 8.59 (s, 1H), 8.76 (s, 1H); MS m/z 448 (M + H)+; Anal.
(C20H20F3N7O2) C, H, N.
8-(1-(3-(Trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-ethyl-1-
propyl-1H-purine-2,6(3H,7H)-dione (62). Yield 0.11 g, 82%. 1H
NMR (DMSO-d6): δ 0.87 (t, J ) 8.0 Hz, 3H), 1.24 (t, J ) 8.0 Hz,
3H), 1.52-1.61 (m, 2H), 3.82–3.86 (m, 2H), 4.05 (q, J ) 8.0 Hz,
2H), 5.52 (s, 2H), 7.58-7.64 (m, 2H), 7.68-7.72; MS m/z 447 (M
+ H)+; Anal. (C21H21F3N6O2) C, H, N.
1-(Cyclopropylmethyl)-3-ethyl-8-(1H-pyrazol-4-yl)-1H-purine-
2,6(3H,7H)-dione (63). Yield 0.06 g, 71%. 1H NMR (DMSO-d6):
δ 0.35-0.48 (m, 4H), 1.20-1.28 (m, 4H), 3.80 (d, J ) 8.0 Hz,
2H), 4.10 (q, J ) 8.0 Hz, 2H), 8.18 (s, 1H), 8.36 (s, 1H), 13.32 (s,
1H), 13.50 (s, 1H); MS m/z 301 (M + H)+; Anal. (C14H16N6O2)
C, H, N.
3-Ethyl-8-(1-((6-(trifluoromethyl)pyridin-3-yl)methyl)-1H-
pyrazol-4-yl)-1-isobutyl-1H-purine-2,6(3H,7H)-dione (73). Yield
1
0.09 g, 66%. H NMR (DMSO-d6): δ 0.84 (d, J ) 8.0 Hz, 6H),
1.26 (t, J ) 8.0 Hz, 3H), 2.04-2.10 (m, 1H), 3.75 (d, J ) 8.0 Hz,
2H), 4.05 (q, J ) 8.0 Hz, 2H), 5.58 (s, 2H), 7.88-7.91 (m, 2H),
8.10 (s, 1H), 8.57 (s, 1H), 8.74 (s, 1H); MS m/z 462 (M + H)+;
Anal. (C21H22F3N7O2.HCl) C, H, N.
1-(Cyclopropylmethyl)-3-ethyl-8-(1-((6-(trifluoromethyl)py-
ridin-3-yl)methyl)-1H-pyrazol-4-yl)-1H-purine-2,6(3H,7H)-di-
8-(1-Benzyl-1H-pyrazol-4-yl)-1-(cyclopropylmethyl)-3-ethyl-
1
1
1H-purine-2,6(3H,7H)-dione (64). Yield 0.10 g, 84%. H NMR
one (74). Yield 0.09 g, 66%. H NMR (DMSO-d6): δ 0.35-0.48
(DMSO-d6): δ 0.35-0.48 (m, 4H), 1.20-1.26 (m, 4H), 3.80 (d, J
) 8.0 Hz, 2H), 4.06 (q, J ) 8.0 Hz, 2H), 5.48 (s, 2H), 7.12-7.19
(m, 4H), 1.20-1.26 (m, 4H), 3.80 (d, J ) 8.0 Hz, 2H), 4.06 (q, J
) 8.0 Hz, 2H), 5.61 (s, 2H), 7.91-7.98 (m, 2H), 8.18 (s, 1H),