Synthesis of non-nucleosides: 7- and 1,3-substituents of new pyrrolo[2,3-d]pyrimidin-4-ones on antiviral activity

Article abstract of DOI:10.1002/ardp.200500162

A series of non-nucleosides 9-47 were synthesized. Compounds 1-4 were reacted with formic acid (85%) to afford compounds 5-8. Then, the latter compounds were reacted with alkyl halides a-f (2-bromopropane, 2-bromobutane, benzyl bromide, benzyl chloromethy

Full text of DOI:10.1002/ardp.200500162

174
Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
Full Paper
Synthesis of Non-Nucleosides: 7- and 1,3-Substituents of
New Pyrrolo[2,3-d]pyrimidin-4-ones on Antiviral Activity
Khalid Mohammed Hassan Hilmy
Department of Chemistry, Faculty of Science, Minoufiya University, Shebin El-Kom, Egypt
A series of non-nucleosides 9–47 were synthesized. Compounds 1–4 were reacted with formic
acid (85%) to afford compounds 5-8. Then, the latter compounds were reacted with alkyl halides
a–f (2-bromopropane, 2-bromobutane, benzyl bromide, benzyl chloromethyl ether, chlorome-
thyl ethyl ether, phenacyl bromide) in the presence of NaH in dry DMF to give the desired com-
pounds 9–47, which were evaluated for activity against herpes simplex virus type-II (HSV-II).
Keywords: Pyrrolo[2,3-d]pyrimidin-4-ones / Synthesis / MIC / Antiviral activity against HSV-II /
Received: June 22, 2005; Accepted: December 9, 2005
DOI 10.1002/ardp.200500162
attachment of the alkyl group at 1- or 3-position, respec-
tively.
All the synthesized compounds were characterized by
Introduction
Pyrrolo[2,3-d]pyrimidines are known to possess a wide
range of pharmacological activities like antifungal [1],
antibacterial [2], antitumoral [3–7], antimalarial [8], and
antiviral activities [9–19]. In view of the fact that some
pyrrolo[2,3-d]pyrimidines possess antiviral activity, a ser-
ies of some novel pyrrolo[2,3-d]pyrimidin-4-ones (9–47)
were synthesized, with the aim of obtaining a new anti-
viral agent which would inhibit the replication of herpes
simplex virus type-II (HSV-II).
their physical, analytical, and spectral data (see Experi-
mental). The IR spectra of compounds 5–8 showed the
presence of characteristic absorption peak at 3080, 3089,
3090, and 3108 cm–1 (NH stretching) and also at 1680,
1688, 1677, and 1682 cm–1 (C=O stretching). Moreover,
1
the H-NMR spectra showed a broad single at d 10.09-
10.77 ppm characteristic for the NH group, besides the
13C-NMR showed d 157.13–162.94 ppm (C=O). The IR spec-
tra of the compounds 9–47 showed the presence of band
around 1676–1689 cm–1 (C=O stretching) and the absence
of a peak at 3080–3090 cm–1 for (NH stretching), due to
the alkylation at 1- or 3- position of compounds 5–8. The
disappearance of d 10.09–10.77 ppm (1H) due to the ring
NH proton, and the presence of d 157.13–162.94 ppm
(C=O) for the compounds 9–47, confirm the alkylation of
compounds 5–8. Besides, the chemical structure of iso-
Results and discussion
The target compounds were synthesized 9–47 as depicted
in Scheme 1. The starting materials 2-amino-3-pyrrolecar-
bonitriles (1–4) [20, 21] were converted into pyrrolo[2,3-
d]pyrimidin-4-ones via the reaction with formic acid. The
latter compounds 5–8 were reacted with alkyl halides a–f
(2-bromopropane, 2-bromobutane, chloromethyl ethyl
ether, benzyl bromide, benzyl chloromethyl ether) in the
presence of NaH and dry DMF to give the corresponding
alkalized derivatives 9–30 and 31–47 according to the
1
mers was based on the UV, H- and 13C-NMR spectral
results. Furthermore, the 1H- and13C-NMR spectral data of
all the synthesized compounds are in conformity with
the structure assigned.
All the tested compounds 9–47 were assayed in vitro for
antiviral activity against herpes simplex type-II (HSV-II).
The minimum inhibitory concentration (MIC) mmol/mL
was determined by tissue culture with Vero cells. The
MICs values illustrated that the most potent compounds
are 9, 10, 13, 14, 15, 25, 26, 31, 40, 42, the lesser potent
Correspondence: Khalid Mohammed Hassan Hilmy, P.O. Box 73, Shou-
bra, Misr, Cairo 1231, Egypt.
E-mail: khaledhilmy@hotmail.com, Kmhh20032000@yahoo.com
Fax: + 20 48 2235-689
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
New Pyrrolo[2,3-d]pyrimidin-4-ones
175
Scheme 1. Synthesis of 7 and 1,3-substituents of new pyrrolo[2,3-d]pyrimidin-4-ones.
compounds are 20, 21, 38, 41, 46, while compounds 16,
23, 43 showed weak anti-HSV-II activity (Table 1).
The different substituents in compounds 9–47 over the
Experimental
Chemistry
Analytical data were recorded for the compounds described
below using the following general procedures. IR spectra were
recorded on KBr pellets on a Perkin Elmer 1720, Infrared Fourier
Transform Spectrometer (Perkin Elmer, Norwalk, CT, USA). UV
spectra were measured with solutions in DMF on Unicam UV/VIS
side chain at the 1- and 3-positions of pyrrolo[2,3-d]pyri-
midin-4-one ring exert significant influence on the biolo-
gical activity. In general, substituted compounds at the 1-
and 3-positions (R1 = H, 3-CF3) were found to be biologi-
cally more active than substituted compounds (R1 = 4-Cl,
4-F). Thus, the study suggested that this class of com-
pounds could be used as potent antiviral agents to treat
various clinical condition associated with viral infection
of HSV-II. Furthermore, studies are in progress to opti-
mize these lead compounds and fully characterize their
mode of action.
1
spectrometer (Pye Unicam Ltd. Cambridge, England). H-NMR
and 13C-NMR spectra were recorded on a Varian Gemini 2000
NMR spectrometer (Varian, Palo Alto, CA, USA) at 300 MHz for
1H- and 75.5 MHz for 13C-NMR with TMS (tetramethylsilane) as an
internal standard. Chemical shifts were recorded in ppm (d)
from an internal TMS standard in deuterochloroform or deuter-
odimethyl sulphoxide as specified below. EI spectra were
recorded on a Finnigan MAT SSQ 710 (Finnigan Mat, San Josꢀ,
CA, USA). All the above analytical data were recorded at the Uni-
versity of Southern Denmark. The progress of the reaction was
monitored by TLC analytical silica gel plates. 60 F254 Merck silica
gel (0.040–0.063 mm) was used for column chromatography
(Merck, Darmstadt, Germany). Solvents were of reagent grade
and, when necessary, were purified and dried by standards
methods. Solvents were removed under reduced pressure. Melt-
Partial financial support from DANIDA at the Danish Minis-
try of Foreign Affairs is highly appreciated. The author also
wishes to thank Prof. Dr. Esmat Bauomy Ali and Dr. Magda
Abd Elmonam Gamil for their help with the biological study.
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

176
K. M. H. Hilmy
Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
Table 1. In vitro antiviral activity test of compounds against
HSV-II.
6,7-Diphenyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 5
Yield 48%; m.p. 292–2938C; IR (KBr) cm–1: 3108 (NH), 1680 (CO);
1H-NMR (DMSO-d6) ppm: 6.85–7.92 (m, 11H, Harom. and Hpyrrole),
8.20 (s, 1H, pyrimidine-2-CH), 10.12 (s, 1H, NH); 13C-NMR ppm:
157.69, 149.35, 144.15, 143.11, 136.78, 134.10, 131.12, 130.31,
128.86, 127.97, 108.40, 102.55; EI MS m/z 287 (M+) Anal. calcd. for
C18H13N3O (287.32): C, 75.25; H, 4.56; N, 14.62. Found: C, 75.50; H,
4.43; N, 14.67.
Compd.
R1
R2
Antiviral
activity (MIC#)
[lM mL–1]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
ACV
H
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
3-CF3
3-CF3
3-CF3
3-CF3
3-CF3
4-F
4-F
4-F
4-F
4-F
4-F
H
H
H
CH3CHCH3
0.19
0.19
–
CH3CHCH2CH3
CH2OCH2CH3
CH2OCH2C6H5
CH2C6H5
CH2COC6H5
CH3CHCH3
CH3CHCH2CH3
CH2OCH2CH3
CH2OCH2C6H5
CH2C6H5
–
7-(4-Chloro-phenyl)-6-phenyl-3,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 6
0.39
0.19
0.39
25.00
–
Yield 51%; m.p. 261–2628C; IR (KBr) cm–1: 3090 (NH), 1688 (CO);
1H-NMR (DMSO-d6) ppm: 6.94–7.51 (m, 10H, Harom. and Hpyrrole),
7.82 (s, 1H, pyrimidine-2-CH), 10.09 (s, 1H, NH); 13C-NMR: 158.08,
149.41, 144.43, 143.11, 135.78, 135.42, 132.49, 130.95, 130.03,
128.94, 128.65, 127.64, 108.63, 102.92; EI MS m/z 321 (M+). Anal.
calcd. for C18H12ClN3O (321.77): C, 67.19; H, 3.76; N, 13.06; Cl,
11.02. Found: C, 66.89; H, 4.06; N, 12.80; Cl, 11.20.
–
–
CH3CHCH3
6.30
6.30
–
25.00
–
0.78
0.78
–
–
–
–
0.19
–
CH3CHCH2CH3
CH2OCH2C6H5
CH2C6H5
CH2COC6H5
CH3CHCH3
CH3CHCH2CH3
CH2OCH2CH3
CH2OCH2C6H5
CH2C6H5
CH2COC6H5
CH3CHCH3
CH3CHCH2CH3
CH2OCH2C6H5
CH2COC6H5
CH3CHCH3
CH3CHCH2CH3
CH2OCH2CH3
CH2OCH2C6H5
CH2COC6H5
CH3CHCH3
CH3CHCH2CH3
CH2OCH2CH3
CH2OCH2C6H5
CH3CHCH3
CH3CHCH2CH3
CH2OCH2CH3
CH2OCH2CH3
6-Phenyl-7-(3-trifluoromethyl-phenyl)-3,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 7
Yield 55%; m.p. 272-2738C; IR (KBr) cm–1: 3089 (NH), 1677 (CO);1H-
NMR (DMSO-d6) ppm: 6.98-7.89(m, 10H, Harom. and Hpyrrole), 8.31(s,
1H, pyrimidine-2-CH), 10.33 (s, 1H, NH); 13C-NMR: 162.95, 158.00,
149.34, 144.61, 135.65, 135.50, 132.28, 130.74, 130.02, 128.43,
128.36, 128.32, 128.01, 124.91, 124.45, 113.50, 108.66, 103.09; EI
MS m/z 355 (M+). Anal. calcd. for C19H12F3N3O (355.32): C, 64.23;
H, 3.40; N, 11.83. Found: C, 64.04; H, 3.25; N, 11.93.
–
–
–
–
H
7-(4-Fluoro-phenyl)-6-phenyl-3,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 8
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
3-CF3
3-CF3
3-CF3
3-CF3
4-F
Yield 61%; m.p. 287–2868C; IR (KBr) cm–1: 3080 (NH), 1682 (CO);
1H-NMR (DMSO-d6) ppm: 7.03–7.92 (m, 10H, Harom. and Hpyrrole),
8.15 (s, 1H, pyrimidine-2-CH), 10.77 (s, 1H, NH); 13C-NMR: 162.81,
159.55, 158.04, 149.46, 144.28, 135.65, 135.41, 132.19, 130.98,
130.51, 130.21, 128.98, 128.42, 128.26, 126.65, 127.53, 115.81,
115.80, 108.41, 102.54; EI MS m/z 305 (M+). Anal. calcd. for
C18H12FN3O (305.31): C, 70.81; H, 3.96; N, 13.76. Found: C, 70.63;
H, 3.77; N, 13.61.
–
5.00
–
0.78
6.30
0.78
12.50
–
4-F
4-F
4-F
–
6.30
–
General procedure for the preparation of 1,3-Substituent
of Pyrrolo[2,3-d]pyrimidin-4-ones 9–47
0.4
Compounds 5–8 (0.006 mol) were suspended in dry DMF (30 mL).
To this suspension was added sodium hydride 60%, 0.24 g,
0.006 mol. The mixture was stirred at room temperature for
20 min and then the alkyl halide (0.006 mol) was added. The
reaction mixture was refluxed for 5 h. Then the mixture was
cooled to room temperature and the solvent was evaporated
under vacuum. The residue was dissolved in (200 mL) dichloro-
methane and the organic phase was washed with water
(2650 mL). Then organic layer was dried over anhydrous
sodium sulfate and evaporated. The residue was purified by col-
umn chromatography on a silica gel column and the product
was eluted with C2H5COOCH3/CHCl3 (1:4).
# MIC: minimum inhibitory concentration.
ing points were taken on an electro thermal melting point appa-
ratus and are uncorrected. Elemental analyses data (€0.4%) were
performed by Micro lab, Chemistry Department, Copenhagen
University, Denmark.
General procedure for the preparation of Pyrrolo{2,3-
d]pyrimidin-4-ones 5-8
Compounds 1–4 [20, 21] (0.01 mol) were added to formic acid
85% (10 mL). The reaction mixture was refluxed for 10 h, and
then poured onto cold water. The solid product was collected by
filtration, washed with water several times, dried, and recrystall-
ized from DMF.
3-Isopropyl-6,7-diphenyl-3,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 9
Yield 34%; m.p. 195–1968C; IR (KBr) cm–1: 1678 (CO); UV max 306
1
nm (e 31392); H-NMR (CDCl3-d6) ppm: 1.46,1.48 (d, 6H, 2CH3),
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
New Pyrrolo[2,3-d]pyrimidin-4-ones
177
5.32–5.42 (m, 1H, CH), 6.95-7.42 (m, 11H, Harom. and Hpyrrole), 7.91
(s, 1H, pyrimidine-2-CH); 13C-NMR: 157.86, 148.58, 142.42,
136.89, 135.99, 131.37, 128.95, 128.40, 128.16, 127.91, 127.88,
127.41, 108.38, 103.20, 45.01, 22.43; EI MS m/z 329 (M+). Anal.
calcd. for C21H19 N3O (329.41): C, 76.57; H, 5.81; N, 12.76. Found:
C, 76.51; H, 5.78; N, 12.65.
C26H19N3O2 (405.46): C, 77.02; H, 4.72; N; 10.36. Found: C, 76.89;
H, 4.63; N, 10.33.
7-(4-Chloro-phenyl)-3-isopropyl-6-phenyl-3,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 15
Yield 38%; m.p. 233–1348C; IR (KBr) cm–1: 1685 (CO); UV max 308
1
nm (e 27106); H-NMR (CDCl3-d6) ppm: 1.45, 1.64 (d, 6H, 2CH3),
3-sec-Butyl-6,7-diphenyl-3,7-dihydro-pyrrolo[2,3-
5.22–5.50 (m, 1H, CH), 6.95–7.48 (m, 10H, Harom. and Hpyrrole), 7.97
(s, 1H, pyrimidine-2-CH); 13C-NMR: 157.92, 142.65, 136.84,
134.61, 133.85, 131.18, 129.33,129.21, 129.08, 128.58, 128.46,
128.37, 127.76, 108.67, 103.65, 45.23, 22.55. EI MS m/z 363 (M+).
Anal. calcd. for C21H18ClN3O (363.85): C, 69.32; H, 4.99; N, 11.55.
Found: C, 69.26; H, 4.88; N, 11.44.
d]pyrimidin-4-one 10
1
Yield 33%; m.p. 156–1578C; IR (KBr) cm–1: 1685 (CO); H-NMR
(CDCl3-d6) ppm: 1.12–1.15 (t, 3H, CH3), 1.38, 1.40 (d, 3H, CH3),
1.81–1.86 (m, 2H, CH2), 5.49–5.53 (q, 1H, CH), 6.81–7.44 (m, 11H,
Harom. and Hpyrrole), 8.30 (s, 1H, pyrimidine-2-CH); 13C-NMR: 159.62,
151.63, 138.74, 136.31, 131.54, 129.10, 128.72, 128.22, 127.97,
127.55, 127.20, 108.23, 104.71, 73.33, 29.09, 19.41, 9.77; EI MS m/
z 343 (M+). Anal. calcd. for C22H21N3O (343.42): C, 76.94; H, 6.16; N,
12.24. Found: C, 76.88; H, 6.19; N, 12.19.
3-sec-Butyl-7-(4-chloro-phenyl)-6-phenyl-3,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 16
1
Yield 33%; m.p. 199–2008C; IR (KBr) cm–1: 1687 (CO); H-NMR
3-Ethoxymethyl-6,7-diphenyl-3,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 11
(CDCl3-d6) ppm: 1.10–1.14 (t, 3H, CH3), 1.40,1.44 (d, 3H, CH3),
1.81–1.85 (m, 2H, CH2), 5.25–5.48 (q, 1H, CH), 6.92–7.43 (m, 10H,
Harom . and Hpyrrole), 7.96 (s, 1H, pyrimidine-2-CH); 13C-NMR: 158.36,
143.10, 136.89, 134.71, 133.92, 131.30, 129.38, 129.32, 128.68,
128.56, 127.85, 108.72, 103.83, 50.78, 29.63, 20.84, 10.77. Anal.
calcd. for C22H20ClN3O (377.88): C, 69.93; H, 5.33; N, 11.12. Found:
C, 69.71; H, 5.36; N, 10.96.
Yield 63%; m.p. 157–1588C; IR (KBr) cm–1: 1680 (CO); 1H-NMR
(CDCl3-d6) ppm: 1.20–1.22 (t, 3H, CH3), 3.63–3.65 (q, 2H, CH2), 5.50
(s, 2H, CH2),7.00–7.75 (m, 11H, Harom. and Hpyrrole), 8.10 (s, 1H, pyr-
imidine-2-CH); 13C-NMR: 158.62, 149.21, 145.47, 137.37, 136.05,
131.43, 129.22, 128.67, 128.40, 128.29, 128.17, 127.76, 108.51,
103.64, 74.55, 65.25, 15.07.EI MS m/z 345 (M+). Anal. calcd. for
C21H19N3O2 (345.40): C, 73.03; H, 5.54; N, 12.17. Found: C, 73.13;
H, 5.50; N, 12.12.
7-(4-Chloro-phenyl)-3-ethoxymethyl-6-phenyl-3,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 17
1
Yield 29%; m.p. 125–1268C; IR (KBr) cm–1: 1684 (CO); H-NMR
3-Benzyloxymethyl-6,7-diphenyl-3,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 12
(CDCl3-d6) ppm: 1.21–1.29 (t, 3H, CH3), 3.60–3.65 (q, 2H, CH2), 4.92
(s, 2H, CH2), 6.97–7.48 (m, 10H, Harom. and Hpyrrole), 8.00 (s, 1H,
pyrimidine-2-CH); 13C-NMR: 158.25, 150.02, 146.28, 134.07,
129.31, 129.21, 128.58, 128.23, 127.89, 101.01, 98.91, 72.28,
65.15, 14.23. EI MS m/z 379 (M+). Anal. calcd. for
C21H18ClN3O2(379.85): C, 66.40; H, 4.78; N, 11.06. Found: C, 66.23;
H, 4.80; N, 10.89.
Yield 33%; m.p. 144–1458C; IR (KBr) cm–1: 1688 (CO); 1H-NMR
(CDCl3-d6) ppm: 4.52 (s, 2H, CH2), 5.51 (s, 2H, CH2), 6.91-7.50 (m,
16H, Harom. and Hpyrrole), 8.00 (s,1H, pyrimidine-2-CH); 13C-NMR:
158.50, 148.50, 145.43, 137.30, 136.93, 131.27, 129.09, 128.54,
128.43, 128.29, 128.19, 128.04, 127.95, 127.88, 127.65, 108.38,
103.53, 74.03, 71.44. EI MS m/z 407 (M+). Anal. calcd. for
C26H21N3O2 (407.48): C, 76.64; H, 5.19; N, 10.31. Found: C, 76.58;
H, 5.04; N, 10.19.
3-Benzyloxymethyl-7-(4-chloro-phenyl)-6-phenyl-3,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 18
Yield 33%; m.p. 170–1718C; IR (KBr) cm–1: 1683 (CO); 1H-NMR
(CDCl3-d6) ppm: 4.70 (s, 2H, CH2), 5.55 (s, 2H, CH2), 6.90-7.41 (m,
15H, Harom. and Hpyrrole), 8.11 (s, 1H, pyrimidine-2-CH); 13C-NMR:
158.36, 148.42, 145.54, 137.06, 136.85, 134.34, 133.99, 130.92,
129.28, 129.18, 128.55, 128.43, 128.41, 127.94, 127.84, 108.52,
103.81, 74.04, 71.45. EI MS m/z 441 (M+). Anal. calcd. for
C26H20ClN3O2 (411.89): C, 70.67; H, 4.56; N, 9.51. Found: C, 70.49;
H, 4.53; N, 9.42.
3-Benzyl-6,7-diphenyl-3,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 13
Yield 69%; m.p. 208–2098C; IR (KBr) cm–1: 1680; 1H-NMR (CDCl3-
d6) ppm: 5.52 (s, 2H, CH2), 7.00–7.51 (m, 16H, Harom. and Hpyrrole),
7.97 (s, 1H, pyrimidine-2-CH); 13C-NMR: 158.88,148.78, 145.32,
137.17, 136.37, 136.00, 131.38, 129.05, 128.88, 128.54, 128.27,
128.05, 128.02 127.98, 127.59, 108.78,103.37, 49.11. EI MS m/z
377 (M+). Anal. calcd. for C25H19N3O (377.45): C, 79.55; H, 5.07; N,
11.13. Found: C, 79.39; H, 4.94; N, 10.97.
3-Benzyl-7-(4-chloro-phenyl)-6-phenyl-3,7-dihydro-
3-(2-Oxo-2-phenyl-ethyl)-6,7-diphenyl-3,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 19
1
Yield 63%; m.p. 224–2258C; IR (KBr) cm–1: 1679 (CO); H-NMR
pyrrolo[2,3-d]pyrimidin-4-one 14
Yield 43%; m.p. 282–2838C; IR (KBr) cm–1: 1683,1677 (2 CO); H-
(CDCl3-d6) ppm: 5.11 (s, 2H, CH2), 6.75–7.48 (m, 15H, Harom. and
1
NMR (DMSO-d6) ppm: 5.81 (s, 2H, CH2), 7.13–7.82 (m, 16H, Harom.
and Hpyrrole), 8.11 (s,1H, pyrimidine-2-CH); 13C-NMR: 160.23,
153.41, 148.13, 147.51, 136.52, 136.41, 134.01, 134.00, 132.21,
130.46, 130.11, 128.31, 128.21, 128.00, 127.61, 125.04, 125.01,
124.23, 107.44, 120.06, 49.15. EI MS m/z 405 (M+). Anal. calcd. for
H
pyrrole), 8.25 (s, 1H, pyrimidine-2-CH); 13C-NMR: C, 157.13, 148.80,
147.10, 137.29, 136.14, 134.61, 132.55, 130.76, 130.00, 128.94,
128.48, 128.22, 128.02, 127.72, 127.47, 127.44, 106.86, 102.91,
48.25. EI MS m/z 411 (M+). Anal. calcd. for C25H18ClN3O (411.89): C,
72.90; H, 4.40; N, 10.20. Found: C, 72.79; H, 4.21; N, 9.98.
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178
K. M. H. Hilmy
Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
5.40–5.47 (m, 1H, CH), 6.97–7.41 (m, 10H, Harom. and Hpyrrole), 7.97
(s, 1H, pyrimidine-2-CH); 13C-NMR: 163.63, 160.12, 158.03,
142.73, 137.10, 131.37, 129.85, 129.74, 128.67, 128.49, 127.80,
116.36, 116.06, 103.49, 45.30, 22.05. EI MS m/z 347 (M+). Anal.
calcd. for C21H18FN3O (347.40): C, 72.61; H, 5.22; N, 12.10. Found:
C, 72.52; H, 5.13; N, 12.07.
3-Isopropyl-6-phenyl-7-(3-trifluoromethyl-phenyl)-3,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 20
Yield 37%; m.p. 150–1518C; IR (KBr) cm–1: 1688 (CO); UV max 309
nm (e 19870); 1H-NMR (CDCl3-d6) ppm: 1.47, 1.51 (d, 6H, 2CH3),
5.42–5.48 (m, 1H, CH), 6.90–7.70 (m, 10H, Harom. and Hpyrrole), 8.01
(s, 1H, pyrimidine-2-CH); 13C-NMR: 158.21, 151.54, 142.80,
136.78, 136.58, 131.21, 130.98, 129.52, 128.86, 128.64, 128.48,
127.89, 125.04, 124.99, 124.94, 124.51, 124.46, 103.96, 45.26,
22.54. EI MS m/z 397 (M+). Anal. calcd. for C22H18F3N3O (397.40): C,
66.49; H, 4.57; N, 10.57. Found: C, 66.35; H, 4.51; N, 10.41.
3-sec-Butyl-7-(4-fluoro-phenyl)-6-phenyl-3,7-dihydro-
pyrrolo[2,3-d]yrimidin-4-one 26
1
Yield 35%; m.p. 186–1878C; IR (KBr) cm–1: 1681 (CO); H-NMR
(CDCl3-d6) ppm: 1.01–1.21 (t, 3H, CH3), 1.44, 1.50 (d, 3H, CH3),
1.61–1.81 (m, 2H, CH2), 5.18–5.48 (q, 1H, CH), 6.98–7.47 (m, 10H,
Harom. and Hpyrrole), 7.91 (s, 1H, pyrimidine-2-CH); 13C-NMR: 163.49,
160.20, 158.25, 149.21, 142.92, 136.92, 131.24, 129.72, 129.60,
128.54, 128.36, 127.65, 116.22, 115.91, 108.44, 103.42, 50.60,
29.51, 20.71, 10.64. EI MS m/z 361 (M+). Anal. calcd. for
C22H20FN3O (361.42): C, 73.11; H, 5.58; N, 11.63. Found: C, 73.01;
H, 5.53; N, 11.41.
3-sec-Butyl-6-phenyl-7-(3-trifuloromethyl-phenyl)-3,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 21
1
Yield 53%; m.p. 138–1398C; IR (KBr) cm–1: 1689 (CO); H-NMR
(CDCl3-d6) ppm: 1.01–1.23 (t, 3H, CH3), 1.48, 1.54 (d, 3H, CH3),
1.80–1.90 (m, 2H, CH2), 5.15–5.28 (q, 1H, CH), 7.00–7.68 (m, 10H,
H
arom. and Hpyrrole), 7.92 (s, 1H, pyrimidine-2-CH); 13C-NMR: 158.26,
147.40, 143.15, 136.76, 136.58, 131.21, 130.99, 129.53, 128.66,
128.49, 127.90, 125.05, 125.00, 124.55, 124.51, 124.46, 50.74,
29.55, 20.75, 10.67. EI MS m/z 411 (M+). Anal. calcd. for
C23H20F3N3O (395.44): C, 67.15; H, 4.90; N, 10.21. Found: C, 66.89;
H, 4.87; N, 10.14.
3-Ethoxymethyl-7-(4-fluoro-phenyl)-6-phenyl-3,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-0ne 27
1
Yield 50%; m.p. 179–1808C; IR (KBr) cm–1: 1682 (CO); H-NMR
(CDCl3-d6) ppm: 1.18–1.25 (t, 3H, CH3), 3.61–3.66 (q, 2H, CH2), 5.51
(s, 2H, CH2), 6.98–7.32 (m, 10H, Harom. and Hpyrrole), 8.10 (s, 1H, pyr-
imidine-2-CH); 13C-NMR: 163.61, 160.31, 158.41, 148.65, 145.44,
137.21,131.89, 131.08, 129.77, 129.66, 128.58, 128.40, 127.80,
116.29, 115.99, 108.42, 103.58, 74.46, 65.18, 14.94. EI MS m/z 363
(M+). Anal. calcd. for C21H18FN3O2 (363.39): C,69.41; H, 4.99; N,
11.56. Found: C, 69.27; H, 4.94; N, 11.47.
3-Benzyloxymethyl-6-phenyl-7-(3-trifluoromethyl-
phenyl)-3,7-dihydro- pyrrolo[2,3-d] pyrimidin-4-one 22
Yield 40%; m.p. 119–1208C; IR (KBr) cm–1: 1681 (CO); H-NMR
1
(CDCl3-d6) ppm: 4.70 (s, 2H, CH2), 5.60 (s, 2H, CH2), 7.00–7.75 (m,
15H, Harom. and Hpyrrole), 8.10 (s, 1H, pyrimidine-2-CH); 13C-NMR:
158.40, 145.71, 137.10, 136.88, 136.38, 131.26, 130.77, 129.58,
128.69, 128.51, 128.46, 128.25, 127.89, 125.11, 125.06, 125.01,
124.78, 124.73, 124.68, 74.13, 71.55. EI MS m/z 475 (M+). Anal.
calcd. for C27H20F3N3O2 (475.47): C,68.21; H, 4.24; N, 8.84. Found:
C, 67.94; H, 4.25; N, 8.76.
3-Benzyloxymethyl-7-(4-fluoro-phenyl)-6-phenyl-3,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 28
1
Yield 51%; m.p. 152–1538C; IR (KBr) cm–1: 1685 (CO); H-NMR
(CDCl3-d6) ppm: 4.73 (s, 2H, CH2), 5.62 (s, 2H, CH2), 6.98–7.40 (m,
15H, Harom. and Hpyrrole), 8.00 (s, 1H, pyrimidine-2-CH); 13C-NMR:
163.50, 160.30, 158.42, 148.32, 145.53, 137.26, 136.89, 131.04,
129.76, 129.65, 128.88, 128.58, 128.43, 128.40, 127.96, 127.87,
127.81, 124.51, 116.28, 115.98, 74.05, 71.47. EI MS m/z 425 (M+).
Anal. calcd. for C26H20FN3O2 (425.47): C, 73.40; H, 4.74; N, 9.88.
Found: C, 73.21; H, 4.63; N, 9.66.
3-Benzyl-6-phenyl-7-(3-trifluoromethyl-phenyl)-3,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 23
Yield 70%; m.p. 171–1728C; IR (KBr) cm–1: 1685 (CO); 1H-NMR
(CDCl3-d6) ppm: 5.38 (s, 2H, CH2), 7.00–7.65 (m, 15H, Harom. and
Hpyrrole), 7.98 (s,1 H, pyrimidine-2-CH); 13C-NMR: C, 158.17, 148.21,
145.61, 136.95, 136.49, 136.27, 131.22, 130.88, 129.52, 128.94,
128.68, 128.50, 128.15, 128.01, 125.05, 125.00, 124.57, 124.52,
49.17. EI MS m/z 445 (M+). Anal. calcd. for C26H18F3N3O (445.45): C,
70.11; H, 4.07; N, 9.43. Found: C, 69.89; H, 3.94; N, 9.52.
3-Benzyl-7-(4-fluoro-phenyl)-6-phenyl-3,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 29
Yield 66%; m.p. 210–2118C; IR (KBr) cm–1: 1689 (CO); UV max 311
nm (e 31408); 1H-NMR (CDCl3-d6) ppm: 5.33 (s, 2H, CH2), 6.98-7.43
(m, 15H, Harom. and Hpyrrole), 7.92 (s, 1H, pyrimidine-2-CH); 13C-
NMR: C, 163.67, 160.37, 158.32, 145.54, 137.27, 136.44, 132.13,
131.28, 129.86, 129.75, 129.03, 128.71, 128.52, 128.43, 128.22,
128.11, 127.89, 116.37, 116.06, 108.93, 103.56, 49,27. EI MS m/z
395 (M+). Anal. calcd. for C25H18FN3O (395.44): C, 75.94; H, 4.59; N,
10.63. Found: C, 75.79; H, 4.52; N, 10.49.
1-(2-Oxo-2-phenyl-ethyl)-6-phenyl-7-(3-trifluoro-phenyl)-
1,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24
Yield 64%; m.p. 202–2038C; IR (KBr) cm–1: 1686, 1677 (2 CO); 1H-
NMR (DMSO-d6) ppm: 5.72 (s, 2H, CH2), 6.90–7.82 (m, 15H, Harom.
and Hpyrrole), 8.23 (s, 1H, pyrimidine-2-CH); 13C-NMR: 162.94,
157.13, 148.75, 147.70, 136.40, 136.19, 134.31, 134.09, 132.35,
130.65, 130.22, 128.69, 128.52, 128.40, 128.00, 127.82, 125.06 ,
125.01, 124.69, 107.76, 103.11, 51.74. EI MS m/z 473 (M+). Anal.
calcd. for C27H18F3N3O2 (473.46): C, 68.50; H, 3.83; N, 8.88. Found:
C, 68.33; H, 3.39; N, 8.73.
7-(4-Fluoro-phenyl)-3-(2-oxo-2-phenyl-ethyl)-6-phenyl-
3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 30
Yield 58%; m.p. 280–2818C; IR (KBr) cm–1: 1686, 1679 (2 CO); 1H-
NMR (DMSO-d6) ppm: 5.96 (s, 2H, CH2), 6.70-7.88 (m, 15H, Harom.
and Hpyrrole), 8.34 (s, 1H, pyrimidine-2-CH); 13C-NMR: 162.98,
162.45, 160.62, 158.12, 145.32, 137.01, 136.65, 132.13, 131.22,
129.56, 129.32, 129.01, 126.55, 128.32, 128.12, 128.01, 127.87,
7-(4-Fluoro-phenyl)-3-isopropyl-6-phenyl-3,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 25
Yield 40%; m.p. 196–1978C; IR (KBr) cm–1: 1687 (CO); UV max 308
nm (e 40922); 1H-NMR (CDCl3-d6) ppm: 1.49, 1.51 (d, 6H, 2CH3),
i 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
New Pyrrolo[2,3-d]pyrimidin-4-ones
179
116.23, 115.89, 108.92, 103.56, 49.12. EI MS m/z 423 (M+). Anal
calcd. for C26H18FN3O2 (423.45): C, 73.75; H, 4.28; N, 9.92. Found:
C, 73.51; H, 4.18; N, 9.78.
1-sec-Butyl-7-(4-chloro-phenyl)-6-phenyl-1,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 36
Yield 42%; m.p. 136–1378C; IR (KBr) cm–1: 1689 (CO); 1H-NMR
(CDCl3-d6) ppm: 1.10–1.14 (t, 3H, CH3), 1.42, 1.48 (d, 3H, CH3),
1.83–1.87 (m, 2H, CH2), 5.50–5.56 (q, 1H, CH), 6.71–7.48 (m, 10H,
1-Isopropyl-6,7-diphenyl-1,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 31
H
arom. and Hpyrrole), 8.50 (s, 1H, pyrimidine-2-CH); 13C-NMR: 162.74,
154.27, 151.72, 138.54, 134.85, 133.50, 131.27, 129.29, 129.11,
128.79, 128.43, 127.99, 106.36, 99.91, 73.90, 29.06, 19.53, 9.77. EI
MS m/z 377 (M+). Anal. calcd. for C22H20ClN3O (377.88): C, 69.93;
H, 5.33; N, 11.12. Found: C, 69.79; H, 5.28; N, 10.99.
Yield 40%; m.p. 199–2008C; IR (KBr) cm–1: 1683 (CO); UV max 304
nm (e 29992); 1H-NMR (CDCl3-d6) ppm: 1.46–1.48 (d, 6H, 2 CH3),
5.42-5.52 (m, 1H, CH), 6.56–7.50 (m, 11H, Harom. and Hpyrrole), 8.30
(s, 1H, pyrimidine-2-CH); 13C-NMR: 162.50, 151.74, 138.95,
136.47, 131.70, 129.21, 128.89, 128.37, 128.10, 127.90, 127.86,
106.41, 99.63, 59.28, 22.23; EI MS m/z 329 (M+). Anal. calcd. for
C21H19N3O (329.39): C, 76.57; H, 5.81; N, 12.76. Found: C, 76, 54;
H, 5.76; N, 12.72.
7-(4-Chloro-phenyl)-1-ethoxymethyl-6-phenyl-1,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 37
Yield 33%; m.p. 182–1838C; IR (KBr) cm–1: 1686 (CO); 1H-NMR
(CDCl3-d6) ppm: 1.21–1.27 (t, 3H, CH3), 3.60–3.65 (q, 2H, CH2), 5.46
(s, 2H, CH2), 6.88–7.41 (m, 10H, Harom. and Hpyrrole), 7.95 (s, 1H, pyr-
imidine-2-CH); 13C-NMR: 158.37, 148.78, 145.47, 137.03, 134.40,
134.01, 130.98, 129.83, 129.12, 128.58, 128.45, 127.85, 108.55,
103.84, 74.46, 65.19, 14.49. EI MS m/z 379 (M+). Anal. calcd. for
C21H18ClN3O2 (379.85): C, 66.40; H, 4.78; N, 11.06. Found: C, 66.19;
H, 4.63; N, 10.96.
1-sec-Butyl-6,7-diphenyl-1,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 32
1
Yield 33%; m.p. 145–1468C; IR (KBr) cm–1: 1687 (CO); H-NMR;
(CDCl3-d6) ppm: 1.11–1.13 (t, 3H, CH3), 1.37, 1.40 (d, 3H, CH3),
1.83–1.87 (m, 2H, CH2), 5.47–5.52 (q, 1H, CH), 6.85–7.51 (m, 11H,
Harom. and Hpyrrole), 8.30 (s, 1H, pyrimidine-2-CH); 13C-NMR: 162.68,
151.63,138.79,136.35, 131.58, 129.08, 128.76, 128.24, 127.97,
127.77, 127.17, 106.27, 99.52, 73.77, 29.09, 19.56, 9.79; EI MS m/z
343 (M+). Anal. calcd. for C22H21N3O (343.42): C, 76.94; H, 6.16; N,
12.24. Found: C, 76.81; H, 6.18; N, 12.14.
1-benzyloxymethyl-7-(4-chloro-phenyl)-6-phenyl-1,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 38
Yield 49%; m.p. 120–1218C; IR (KBr) cm–1: 1685 (CO); 1H-NMR
(CDCl3-d6) ppm: 4.86 (s, 2H, CH2), 5.88 (s, 2H, CH2), 6.81–7.48 (m,
15H, Harom. and Hpyrrole), 8.31 (s, 1H, pyrimidine-2-CH); 13C-NMR:
161.60, 154.34, 139.32, 137.13, 134.67, 133.69, 131.07, 129.36,
129.12, 128.87, 128.51, 128.41, 128.23, 127.96, 127.89, 106.17,
99.62, 90.01, 71.58. EI MS m/z 441 (M+). Anal. calcd. for
C26H20ClN3O2 (411.89): C, 70.67; H, 4.56; N, 9.51. Found: C, 70.49;
H, 4.53; N, 9.42.
1-Benzyloxymethyl-6,7-diphenyl-1,7-dihydro-pyrrolo[2,3-
d]pyrimidin-4-one 33
1
Yield 41%; m.p. 171–1728C; IR (KBr) cm–1: 1689 (CO); H-NMR
(CDCl3-d6) ppm: 4.51 (s, 2H, CH2), 5.51 (s, 2H, CH2), 6.50-7.20 (m,
16H, Harom. and Hpyrrole), 8.11 (s,1H, pyrimidine-2-CH); 13C-NMR:
161.51, 154.41, 151.36, 139.56, 137.17, 136.16, 131.38, 129.14,
128.84, 128.43, 128.40, 127.96, 127.87, 127.86, 106.06, 99.23,
89.95, 71.52. EI MS m/z 407 (M+). Anal. calcd. for C26H21N3O2
(407.46): C, 76.64; H, 5.19; N, 10.31. Found: C, 76.51; H, 5.04; N,
10.25.
7-(4-chloro-phenyl)-3-(2-oxo-2-phenyl-ethyl)-6-phenyl-
3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 39
Yield 56%; m.p. 277–2788C; IR (KBr) cm–1: 1676 (CO); 1H-NMR
(CDCl3-d6) ppm: 5.82 (s, 2H, CH2), 6.88–7.49 (m, 15H, Harom. and
H
pyrrole), 8.11 (s, 1H, pyrimidine-2-CH); EI MS m/z 439 (M+). Anal.
calcd. for C28H18ClN3O2 (439.91): C, 70.99; H, 4.12; N, 9.55. Found:
C, 70.79; H, 3.98; N, 9.32.
1-(2-Oxo-2-phenyl-ethyl)-6,7-diphenyl-1,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 34
Yield 37%; m.p. 290–2918C; IR (KBr) cm–1: 1681,1679 (2 CO); H-
1
NMR (DMSO-d6) ppm: 5.62 (s, 2H, CH2), 7.08-7.89 (m, 16H, Harom.
and Hpyrrole), 8.07 (s, 1H, pyrimidine-2-CH); 13C-NMR: 162.66,
157.41, 148.66, 147.53, 136.44, 136.23, 134.33, 134.26, 132.33,
130.46, 130.21, 128.94, 128.49, 128.38, 128.11, 127.82, 125.06,
125.03, 124.69, 107.68, 103.01, 51.69. EI MS m/z 405 (M+). Anal.
calcd. for C26H19N3O2 (405.46): C,77.02; H, 4.72; N, 10.36. Found:
C, 76.99; H, 4.69; N, 10.13.
1-Isopropyl-6-phenyl-7-(3-trifluoromethyl-phenyl)-1,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 40
Yield 41%; m.p. 125–1268C; IR (KBr) cm–1: 1684 (CO); UV max 305
nm (e 27063); 1H-NMR (CDCl3-d6) ppm: 1.47, 1.51 (d, 6H, 2CH3),
5.48–5.67 (m, 1H, CH), 6.80–7.70 (m, 10H, Harom. and Hpyrrole), 8.50
(s, 1H, pyrimidine-2-CH); 13C-NMR: 162.50, 151.84, 138.55,
136.84, 131.15, 131.07, 129.57, 124.31, 124.26, 124.22, 124.17,
106.46, 100.29, 69.38, 22.09. EI MS m/z 397 (M+). Anal. calcd. for
C22H18F3N3O (397.40): C, 66.49; H, 4.57; N, 10.57. Found: C, 66.31;
H, 4.63; N, 10.29.
7-(4-Chloro-phenyl)-1-isopropyl-6-phenyl-1,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 35
Yield 37%; m.p. 189–1908C; IR (KBr) cm–1: 1683 (CO); UV max 301
1
1-sec-Butyl-6-phenyl-7-(3-trifuloromethyl-phenyl)-1,7-
nm (e 31436); H-NMR (CDCl3-d6) ppm: 1.86, 1.91 (d, 6H, 2CH3),
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 41
5.50–5.65 (m, 1H, CH), 6.82–7.45 (m, 10H, Harom. and Hpyrrole), 8.49
(s, 1H, pyrimidine-2-CH); 13C-NMR: 162.43, 151.70, 138.56,
134.84, 133.51, 131.25, 129.29, 129.12, 128.79, 128.43, 128.00,
106.37, 99.91, 69.29, 22.28. EI MS m/z 363 (M+). Anal. calcd. for
C21H18ClN3O (363.85): C, 69.32; H, 4.99; N, 11.55. Found: C, 69.23;
H, 4.78; N, 11.39.
Yield 42%; m.p. 105–1068C; IR (KBr) cm–1: 1683 (CO); 1H-NMR
(CDCl3-d6) ppm: 1.01–1.21 (t, 3H, CH3), 1.45 & 1.51 (d, 3H, CH3),
1.80–1.90 (m, 2H, CH2), 5.15–5.45 (q, 1H,CH), 7.80–7.59 (m, 10H,
H
arom. and Hpyrrole), 8.38 (s, 1H, pyrimidine-2-CH); 13C-NMR: 162.83,
153.91, 151.86, 138.54, 136.86, 131.16, 131.09, 129.59, 128.88,
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180
K. M. H. Hilmy
Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
128.48, 128.16, 125.03, 124.98, 124.93, 124.27, 124.22, 124.17,
74.01, 29.08, 19.54, 9.78. EI MS m/z 411 (M+). Anal. calcd. for
C23H20F3N3O (395.44): C, 67.14; H, 4.90; N, 10.21. Found: C, 67.10;
H, 4.85; N, 10.13.
m/z 363 (M+). Anal. calcd. for C21H18FN3O2 (363.39): C, 69.41; H,
4.99; N, 11.56. Found: C, 69.33; H, 4.94; N, 11.44.
1-Benzyloxymethyl-7-(4-fluoro-phenyl)-6-phenyl-1,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 47
Yield 42%; m.p. 143–1448C; IR (KBr) cm–1: 1684 (CO); 1H-NMR
(CDCl3-d6) ppm: 4.84 (s, 2H, CH2), 5.95 (s, 2H, CH2), 6.80–7.93 (m,
15H, Harom. and Hpyrrole), 8.00 (s, 1H, pyrimidine-2-CH); 13C-NMR:
163.47, 161.59, 160.19, 156.13, 151.44, 139.52, 137.16, 131.16,
129.69, 129.58, 128.89, 128.62, 128.46, 128.42, 128.18, 127.98,
127.89, 116.33, 116.03, 106.08, 99.32, 90.00, 71.56. EI MS m/z 425
(M+). Anal. calcd. for C26H20FN3O2 (425.47): C, 73.40; H, 4.74; N,
9.88. Found: C, 73.27; H, 4.60; N, 9.69.
3-Ethoxymethyl-6-phenyl-7-(3-trifluoromethyl-phenyl)-
3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 42
Yield 67%; m.p. 164–1658C; IR (KBr) cm–1: 1680 (CO); 1H-NMR
(CDCl3-d6) ppm: 1.49-1.55 (t, 3H, CH3), 3.51–3.56 (q, 2H, CH2), 5.51
(s, 2H, CH2), 7.00–7.54 (m, 10H, Harom. and Hpyrrole), 8.10 (s, 1H, pyr-
imidine-2-CH); 13C-NMR: 158.36, 145.61, 131.25, 130.79, 129.56,
128.67, 128.49, 128.01, 125.09, 125.03, 124.98, 124.68, 124.63,
124.58, 108.67, 104.14, 74.50, 62.21, 14.94. EI MS m/z 413 (M+).
Anal. calcd. for C22H18F3N3O2 (413.40): C, 63.92; H, 4.39; N, 10.16.
Found: C, 63.74; H, 4.31; N, 10.11.
Pharmacology
Cells and virus
1-Benzyloxymethyl-6-phenyl-7-(3-trifluoromethyl-
Herpes simplex Virus type-P (HSV-II) was kindly supplied by The
National Research Center, Dokki, Egypt. The virus was propa-
gated in Vero cells, which were commercially obtained from The
Egyptian Organization of Serum and Vaccines. Minimal essen-
tial medium (MEM) was used as growth and maintenance med-
ium for tissue culture with 10% or 2% fetal calf serum (FCS),
respectively.
phenyl)-1,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 43
Yield 35%; m.p. 68–698C; IR (KBr) cm–1: 1682 (CO);1H-NMR (CDCl3-
d6) ppm: 4.85 (s, 2H, CH2), 5.82 (s, 2H, CH2), 6.90–7.70 (m, 15H,
Harom. and Hpyrrole), 8.42 (s, 1H, pyrimidine-2-CH); 13C-NMR: 161.77,
151.71, 139.40, 137.24, 136.76, 131.24, 130.97, 129.73, 129.05,
128.65, 128.53, 128.48, 128.08, 128.01, 125.07, 125.02, 124.51,
124.47, 106.34, 100.10, 90.17, 71.72. EI MS m/z 475 (M+). Anal.
calcd. for C27H20F3N3O2 (475.47): C, 68.21; H, 4.24; N, 8.84. Found:
C, 67.98; H, 4.28; N, 8.75.
Titration of HSV-P by plaque assay [22]
Cell suspension (3 mL) with the concentration 105 cells/mL GM
was dispensed into each of the wells of 6-well plates (Falcon).
Plates were incubated at 37 8C in a 0.5% CO2 for 24–48 hrs to
obtain a confluent sheet. Ten-fold dilution of the virus stock (10–
1–10–7) was done as mentioned under titration of HSV by TCID50
endpoint. Then growth medium was aspirated from the wells
and 0.2 mL/well of each virus dilution was added in duplicate
manner. For each plate, two wells were left uninoculated as cell
control, each contained 0.2 mL MEM only; incubation at 37 8C in
a 0.5% CO2 incubator for one hour, to permit virus adsorption.
Then 30 mL 1% agarose solution was melted at 48 8C in a water
bath, and mixed with 2630 mL MEM (supplied with 1% antibio-
tic solution and 2% FCS) in a ratio of 1:1 to prepare an overlay
mixture. Then 3 mL of overlay mixture was added quickly to
each well in the plate. After overlay solidification, plates were
inverted and incubated at 378C in a 0.5% CO2 incubator. Daily
observation was carried out for early plaque detection; usually it
takes 2–3 days for plaque detection. After plaques development,
cells were fixed by flooding with 10% formalin solution for 1 h
at room temperature. Agarose overlay was removed with for-
ceps; cell monolayers were washed under tap water and stained
with 10% crystal violet solution for 10 min. Plaques were
recorded as clear unstained areas against a violet background of
stained viable cells and counted either visually or using a stereo-
microscope. The infectivity titer represented as number of pla-
que forming unit/mL (PFU/mL) of the stock virus suspension. It
was calculated form the following equation:
7-(4-Fluoro-phenyl)-1-isopropyl-6-phenyl-1,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 44
Yield 34%; m.p. 177–1788C; IR (KBr) cm–1: 1686 (CO); UV max 302
nm (e 40479); 1H-NMR (CDCl3-d6) ppm: 1.41, 1.46 (d, 6H, 2CH3),
5.42–5.49 (m,1H, CH), 6.58–7.38 (m, 10H, Harom. and Hpyrrole), 8.33
(s, 1H, pyrimidine-2-CH); 13C-NMR: 163.38, 162.42, 160.12,
154.01, 151.67, 138.76, 131.34, 129.67, 129.56, 128.80, 128.37,
127.94, 116.26, 115.96, 106.28, 99.60, 69.26, 22.09. EI MS m/z 347
(M+). Anal. calcd. for C21H18FN3O (347.40): C, 72.61; H, 5.22; N,
12.10. Found: C, 72.46; H, 5.19; N, 11.99.
1-sec-Butyl-7-(4-fluoro-phenyl)-6-phenyl-1,7-dihydro-
pyrrolo[2,3-d]pyrimidin-4-one 45
Yield 36%; m.p. 146–1478C; IR (KBr) cm–1: 1683 (CO); 1H-NMR
(CDCl3-d6) ppm: 1.05–1.27 (t, 3H,CH3), 1.47 & 1.50 (d, 3H, CH3),
1.63–1.83 (m, 2H, CH2), 5.53–5.59 (q, 1H, CH), 6.73–7.43 (m, 10H,
H
arom. and Hpyrrole), 8.38 (s, 1H, pyrimidine-2-CH); 13C-NMR: 163.38,
162.72, 160.09, 153.63, 151.69, 138.73, 132.32, 131.36, 129.66,
129.55, 128.80, 128.37, 127.93, 116.26, 115.95, 106.26, 99.60,
73.88, 29.08, 19.54, 9.78. EI MS m/z 361 (M+). Anal. calcd. for
C22H20FN3O (361.42): C, 73.11; H, 5.58; N, 11.63. Found: C, 72.98,
H, 5.56; N, 11.49.
PFU/mL = No. of plaques6reciprocal of dilution6reciprocal of
volume in mL.
1-Ethoxymethyl-7-(4-fluoro-phenyl)-6-phenyl-1,7-
dihydro-pyrrolo[2,3-d]pyrimidin-4-one 46
Yield 33%; m.p. 127–1288C; IR (KBr) cm–1: 1680 (CO); 1H-NMR
(CDCl3-d6) ppm: 1.39–1.44 (t, 3H, CH3), 3.90–3.96 (q, 2H, CH2), 5.97
(s, 2H, CH2), 6.81–7.43 (m, 10H, Harom. and Hpyrrole), 8.39 (s, 1H, pyr-
imidine-2-CH); 13C-NMR: 163.43, 161.66, 160.14, 151.48, 139.41,
132.13, 131.15, 129.71, 129.33, 128.93, 128.85, 128.42, 128.12,
125.02, 116.29, 115.99, 106.02, 99.30, 90.95, 65.89, 15.19. EI MS
Determination of the solvent cytotoxicity
Growth medium was decanted from 96 well micro titer plate
after a confluent sheet of cells was formed. Ten-fold serial dilu-
tions of pyrrolo[2,3-d]pyrimidin-4-one derivatives were made in
MEM medium without FCS, starting from 5000 lm/mL till 1010
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Arch. Pharm. Chem. Life Sci. 2006, 339, 174–181
New Pyrrolo[2,3-d]pyrimidin-4-ones
181
dilution. 0.2 mL of each dilution was tested in 3 different wells
leaving two wells/row as control, receiving only maintenance
medium. The plate was incubated in a CO2 incubator at 378C and
examined for up to 3 days. Cells were checked for any physical
signs of toxicity, partial or complete loss of the monolayers,
shrinkage, or cell granulation. Then, the non-toxic concentra-
tion of each substance was used in this study.
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HSV-P yield reduction assay [22]
Vero cells were seeded into 96-well tissue culture plates at a con-
centration of 10,000 cells in 0.2 mL of minimal essential med-
ium with Earle salts, MEM(E), supplemented with 10% FCS, and
incubated at 378C in a humidified 3% CO2 – 97% air atmosphere.
After 24 h, plates were inverted over a waste vessel, medium was
shaken out, and the plates were allowed to drain for 5 to 10 s on
a sterile paper towel. Cultures were incubated with HSV-P at a
multiplicity of infection (MOI) of 5 PFU/cell in 0.2 mL of MEM (E)
supplemented with 5% FCS, 100 U penicillin/mL, and 100 lg
streptomycin sulfate/mL. Cultures were incubated at 378C for
2 h to permit virus adsorption. Virus inoculum was replaced
with 0.2 mL of fresh medium and test compounds were added to
the cultures.
The first row of 12 wells was left undisturbed and served as
virus controls. Each well in the second row received an addi-
tional 0.1 mL of MEM (E) containing 5% FCS, antibiotics, and test
compound at three times the desired final concentration. The
contents of the 12 wells were mixed by repeated pipetting and
then serially diluted 1:3 down the plate by repeated transfer and
mixing of 0.1 mL of drug-containing medium. In this manner,
six compounds could be tested in duplicate on a single plate
with a concentrations range of nearly 1000-fold between the
highest and the lowest dilutions (0.10 lM to 80 lM minuscule
example). Plates were incubated at 378C over night and then sub-
jected to one cycle of freezing at –768C and thawing at 378C to
disrupt the cells. Aliquots of 0.1 mL from each of the eight wells
of a given row were transferred to the row of a fresh 96-well
monolayers culture of Vero cells. Contents were mixed and seri-
ally diluted 1:3 across the remaining 11 rows of the second plate.
Each row of the original primary plate was diluted across a sepa-
rate plate in this manner. Cultures was incubated at 378C for 2 h
to permit virus adsorption and then the virus inoculum was
replaced with 0.2 mL of fresh medium. Cultures were incubated
for 2 days, medium was removed, and the cell sheets were
stained with 0.1% crystal violet in 20% methanol. Plaques were
counted under 20-fold magnification in the row of wells having
the dilution which gave 5 to 20 plaques per well. Virus titers
were calculated according to following formula: titer (PFU/mL) =
number of plaques6563n; where n represents the nth dilution
of the virus used to infect the well in which plaques were
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www.archpharm.com