Molecular Modeling, Synthesis of HSV1 UDG Inhibitors
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 13 2349
EtOH. The corresponding alkylurea (100 mmol) and ethyl
cyanoacetate (100 mmol) were added, and the mixture was
refluxed for 6 h. The mixture was concentrated to one-half
volume and chilled on ice for 1 h. The product was collected
by filtration. Recrystallization from H2O (pH 7.0) gave over
90% yield of 1-alkyl-6-aminouracil.
5-H), 7.17 (dd, 4H, C6H4), 8.26 (s, 1H, NH), 10.68 (s, 1H, 3-NH).
Anal. (C19H27N3O3) C, H, N.
1-(3-Meth oxyp r op yl)-6-(4-h exyla n ilin o)u r a cil, 20. This
compound was prepared by the same procedure as above, yield
85%. Crystallization from EtOH/H2O gave white crystals, mp
1
112-113 °C. H NMR (DMSO-d6): δ 0.85 (m, 3H, CH3), 1.28
(m, 6H, 3×CH2), 1.57 (m, 2H, CH2), 1.85 (m, 2H, CH2), 2.58
(t, 2H, ArCH2), 3.23 (s, 3H, OCH3), 3.40 (t, 2H, OCH2), 4.00 (t,
2H, NCH2), 4.36 (s, 1H, 5-H), 7.19 (dd, 4 H, C6H4), 8.36 (s, 1H,
NH), 10.61 (s, 1H, 3-NH). Anal. (C20H29N3O3) C, H, N.
Dem eth yla tion of 21 a n d 22. Trimethylsilyl iodide (3
equiv) was added to a stirred solution of 21 or 22 (0.5 mmol)
in dry CHCl3 (15 mL). The reaction mixture was stirred at
room temperature until disappearance of the starting material
(TLC, about 4 h). Methanol (10 mL) and 0.5 g of sodium sulfite
were then added to the brown-purple solution. After stirring
at room temperature for 30 min, the mixture was filtered and
the solvent was removed.
1-Meth yl-6-a m in ou r a cil, 11. Yield 95%; mp 310-312 °C.
1H NMR (DMSO-d6): δ 3.17 (s, 3H, CH3), 4.54 (s, 1H, 5-H),
6.75 (s, 2H, NH2), 10.29 (s, 1H, 3-NH). Anal. (C5H7N3O2) C,
H, N.
1-Eth yl-6-a m in ou r a cil, 12. Yield 95%; mp 297-298 °C.
1H NMR (DMSO-d6): δ 1.08 (t, 3H, CH3), 3.77 (q, 2H, CH2),
4.52 (s, 1H, 5-H), 6.79 (s, 2H, NH2), 10.29 (s, 1H, 3-NH). Anal.
(C6H9N3O2) C, H, N.
1-P r op yl-6-a m in ou r a cil, 13. Yield 96%; mp 279-281 °C.
1H NMR (DMSO-d6): δ 0.85 (t, 3H, CH3), 1.51 (m, 2H, CH2),
3.67 (t, 2H, CH2), 4.51 (s, 1H, 5-H), 6.78 (s, 2H, NH2), 10.30
(s, 1H, 3-NH). Anal. (C7H11N3O2) C, H, N.
1-(2-Hyd r oxyeth yl)-6-(4-h exyla n ilin o)u r a cil, 21, was
purified by chromatography on silica gel with CHCl3/MeOH
(90:10) as eluent, to give 146 mg (88% yield). Crystallization
from EtOH/H2O gave white crystals, mp 245-247 °C. 1H NMR
(DMSO-d6): δ 0.85 (m, 3H, CH3), 1.28 (m, 6H, 3×CH2), 1.57
(m, 2H, CH2), 2.57 (t, 2H, ArCH2), 3.67 (t, 2H, OCH2), 4.05 (t,
2H, NCH2), 4.55 (s, 1H, 5-H), 5.62 (s, 1H, OH), 7.15 (dd, 4H,
C6H4), 8.50 (s, 1H, NH), 10.70 (s, 1H, 3-NH). Anal. (C18H25N3O3)
C, H, N.
1-(3-Hyd r oxyp r op yl)-6-(4-h exyla n ilin o)u r a cil, 22, was
purified by chromatography on silica gel with CHCl3/MeOH
(97:3-90:10) as eluent, to give 32 mg (30% recovery) of starting
material, 56 mg (54% yield) of 22, and 8 mg (8% yield) of
compound 23 (see below). Crystallization of 22 from EtOH/
H2O gave white crystals, mp 173-175 °C. 1H NMR (DMSO-
d6): δ 0.86 (m, 3H, CH3), 1.28 (m, 6H, 3×CH2), 1.57 (m, 2H,
CH2), 1.79 (m, 2H, CH2), 2.58 (t, 2H, ArCH2), 3.50 (t, 2H,
OCH2), 3.98 (t, 2H, NCH2), 4.41 (s, 1H, 5-H), 5.00 (s, 1H, OH),
7.19 (dd, 4H, C6H4), 8.52 (s, 1H, NH), 10.65 (s, 1H, 3-NH). Anal.
(C19H27N3O3) C, H, N.
1-Alk yl-6-(4-h exyla n ilin o)u r a cils 16-18. A few drops of
4-hexylaniline were added to wet a mixture of 1-alkyl-6-
aminouracil (10 mmol) and 4-hexylaniline hydrochloride (10
mmol). The mixture was heated at 165 °C for 6 h in an oil
bath under nitrogen. The reaction mixture was washed with
20 mL of 1:1 EtOH/H2O and filtered, and the solid crystallized
from AcOH/H2O.
1-Meth yl-6-(4-h exyla n ilin o)u r a cil, 16. Yield 85%; mp 268
°C. 1H NMR (DMSO-d6): δ 0.89 (t, 3H, CH3), 1.31 (m, 4H,
CH3CH2CH2), 1.61 (m, 4H, ArCH2CH2CH2), 2.64 (t, 2H,
ArCH2), 3.37 (s, 3H, CH3), 4.43 (s, 1H, 5-H), 7.17 and 7.28 (dd,
4H, C6H4), 8.41 (s, 1H, NH), 10.61 (s, 1H, 3-NH). Anal.
(C17H23N3O2) C, H, N.
1-Eth yl-6-(4-h exyla n ilin o)u r a cil, 17. Yield 95%; mp 222-
1
225 °C. H NMR (DMSO-d6): δ 0.86 (t, 3H, CH3), 1.18 (t, 3H,
CH3), 1.28 (m, 4H, CH3CH2CH2), 1.57 (m, 4H, ArCH2CH2), 2.59
(t, 2H, ArCH2), 3.99 (q, 2H, CH2), 4.33 (s, 1H, 5-H), 7.14 and
7.27 (dd, 4H, C6H4), 8.43 (s, 1H, NH), 10.60 (s, 1H, 3-NH). Anal.
(C18H25N3O2) C, H, N.
1-P r op yl-6-(4-h exyla n ilin o)u r a cil, 18. Yield 96%; mp 226
°C. 1H NMR (DMSO-d6): δ 0.85 (t, 3H, CH3), 0.90 (t, 3H, CH3),
1.27 (m, 4H, CH3CH2CH2), 1.55-1.63 (m, 6H, ArCH2CH2CH2
and NCH2CH2), 2.58 (t, 2H, ArCH2), 3.89 (q, 2H, NCH2), 4.31
(s, 1H, 5-H), 7.15 and 7.24 (dd, 4H, C6H4), 8.41 (s, 1H, NH),
10.60 (s, 1H, 3-NH). Anal. (C19H27N3O2) C, H, N.
1-(2-Meth oxyeth yl)-6-a m in ou r a cil, 14. Sodium methox-
ide was prepared from sodium (4.0 g, 174 mmol) and 100 mL
of anhydrous MeOH. (2-Methoxyethyl)urea (6.0 g, 50.8 mmol)
and ethyl cyanoacetate (5.75 g, 50.8 mmol) were added, and
the mixture was refluxed for 6 h. The mixture was allowed to
cool, and 2 N HCl was added until the solution was weakly
acidic. The inorganic salts were removed by filtration on a
short column of silica gel. The solvent was removed in vacuo,
and 7.7 g of 14 (82% yield) was obtained as a gray solid.
Crystallization from EtOH/H2O gave white crystals, mp 236-
238 °C. 1H NMR (DMSO-d6): δ 3.26 (s, 3H, OCH3), 3.46 (t,
2H, OCH2), 3.95 (t, 2H, NCH2), 4.55 (s, 1H, 5-H), 6.66 (s, 2H,
NH2), 10.35 (s, 1H, NH). Anal. (C7H11N3O3) C, H, N.
1-(3-Meth oxyp r op yl)-6-a m in ou r a cil, 15. This compound
was prepared by the same procedure as above, yield 86%.
Crystallization from EtOH gave white crystals, mp 209.5-211
°C. 1H NMR (DMSO-d6): δ 1.72 (m, 2H, CH2), 3.21 (s, 3H,
OCH3), 3.36 (t, 2H, OCH2), 3.77 (t, 2H, NCH2), 4.52 (s, 1H,
5-H), 6.73 (s, 2H, NH2), 10.30 (s, 1H, NH). Anal. (C8H13N3O3)
C, H, N.
1-(2-Meth oxyeth yl)-6-(4-h exyla n ilin o)u r a cil, 19. A mix-
ture of 14 (0.2 g, 1.1 mmol), 4-hexylaniline hydrochloride (0.26
g, 1.2 mmol), and a few drops of 4-hexylaniline was heated at
160 °C for 40 min. After cooling to room temperature, the
product was chromatographed on silica gel with CHCl3/MeOH
(97:3-95:5) as eluent, to give 0.32 g (86% yield) of 19.
Crystallization from EtOH/H2O gave white crystals, mp 188-
190 °C. 1H NMR (DMSO-d6): δ 0.87 (t, 3H, CH3), 1.29 (m, 6H,
3×CH2), 1.60 (m, 2H, CH2), 2.60 (t, 2H, ArCH2), 3.34 (s, 3H,
OCH3), 3.59 (t, 2H, OCH2), 4.16 (t, 2H, NCH2), 4.47 (s, 1H,
N1,N6-P r op ylen e-6-(4-h exyla n ilin o)u r a cil, 23. Trimeth-
ylsilyl iodide (0.2 mL, 1.41 mmol) was added to a stirred
solution of 20 (108 mg, 0.3 mmol) in CHCl3 (10 mL). The
reaction mixture was stirred at room temperature until
disappearance of the starting material 20 (about 14 h).
Methanol (10 mL) and 0.5 g of sodium sulfite were then added
to the brown-purple solution. After stirring at room temper-
ature for 30 min, the mixture was filtered and the solvent was
removed. The residue was purified by chromatography on silica
gel with CHCl3/MeOH (97:3) as eluent, to give 81 mg (82%) of
23. Crystallization from EtOH/H2O gave white crystals, mp
1
>220 °C. H NMR (DMSO-d6): δ 0.86 (m, 3H, CH3), 1.29 (m,
6H, 3×CH2), 1.58 (m, 2H, CH2), 2.10 (m, 2H, CH2), 2.61 (t,
2H, ArCH2), 3.55 (t, 2H, OCH2), 3.83 (m, 3H, NCH2 and 5-H),
7.29 (dd, 4H, C6H4), 10.51 (s, 1H, 3-NH). Anal. (C19H25N3O2)
C, H, N.
1-(2-Meth oxyeth yl)-6-(4-octyla n ilin o)u r a cil, 24. A mix-
ture of 14 (0.6 g, 3.24 mmol), 4-octylaniline hydrochloride (0.78
g, 3.24 mmol), and 4-octylaniline (0.74 mL, 3.24 mmol) was
heated at 160 °C for 40 min under nitrogen. After cooling to
room temperature, the residue was chromatographed on silica
gel with CHCl3/MeOH (97:3) as eluent, to give 1.02 g (85%
yield) of 24. Crystallization from EtOH/H2O gave white
crystals, mp 189-193 °C. 1H NMR (DMSO-d6): 0.89 (t, 3H,
CH3), 1.30 (m, 10H, 5×CH2), 1.58 (m, 2H, CH2), 2.60 (t, 2H,
ArCH2), 3.38 (s, 3H, OCH3), 3.60 (t, 2H, OCH2), 4.15 (t, 2H,
NCH2), 4.49 (s, 1H, 5-H), 7.18 (dd, 4H, C6H4), 8.25 (s, 1H, NH),
10.68 (s, 1H, 3-NH). Anal. (C21H31N3O3) C, H, N.
1-(2-Hyd r oxyeth yl)-6-(4-octyla n ilin o)u r a cil, 25. Dem-
ethylation was done as described for 21 and 22. The residue
was purified by chromatography on silica gel with CHCl3/
MeOH (90:10) as eluent, to give 79% yield of 25. Recrystalli-
zation from EtOH/H2O gave white crystals, mp 241-245 °C.
1H NMR (DMSO-d6): δ 0.90 (m, 3H, CH3), 1.30 (m, 10H,
5×CH2), 1.57 (m, 2H, CH2), 2.60 (t, 2H, ArCH2), 3.68 (t, 2H,
OCH2), 4.05 (t, 2H, NCH2), 4.55 (s, 1H, 5-H), 5.62 (s, 1 H, OH),