Synthesis of novel acyclonucleosides analogs of pyridothienopyrimidine as antiviral agents

Article abstract of DOI:10.1081/NCN-200067425

Nucleoside analogs of pyridothienopyramidines were prepared by condensing the sodium salt 2a,b with an acyclic side chain in the form of acetylated haloalkoxyalcohol, and subsequent removal of the protecting acetylgroup in ammonia/methanol afforded 4a,b.

Full text of DOI:10.1081/NCN-200067425

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Synthesis of Novel Acyclonucleosides Analogs of
Pyridothienopyrimidine as Antiviral Agents
Farag A. El-Essawy a
a Chemistry Department, Faculty of Science , Monoufiya University , Shebein El-Koam, Egypt
Published online: 31 Aug 2006.
To cite this article: Farag A. El-Essawy (2005) Synthesis of Novel Acyclonucleosides Analogs of Pyridothienopyrimidine as
Antiviral Agents, Nucleosides, Nucleotides and Nucleic Acids, 24:8, 1265-1276, DOI: 10.1081/NCN-200067425
To link to this article: http://dx.doi.org/10.1081/NCN-200067425
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Nucleosides, Nucleotides, and Nucleic Acids, 24 (8):1265–1276, (2005)
Copyright D Taylor & Francis, Inc.
ISSN: 1525-7770 print/ 1532-2335 online
DOI: 10.1081/NCN-200067425
SYNTHESIS OF NOVEL ACYCLONUCLEOSIDES ANALOGS OF
PYRIDOTHIENOPYRIMIDINE AS ANTIVIRAL AGENTS
5
Farag A. El-Essawy
Chemistry Department, Faculty of Science, Monoufiya University,
Shebein El-Koam, Egypt
5
Nucleoside analogs of pyridothienopyramidines were prepared by condensing the sodium salt 2a,b
with an acyclic side chain in the form of acetylated haloalkoxyalcohol, and subsequent removal of the
protecting acetyl group in ammonia/methanol afforded 4a,b. The O-tosyl derivative of 4a could then be
modified to azido- and amino derivatives. Reaction of the sodium salt of 2b with halo-ether, benzyl
halo-ether and/or halo-thioether gave N- and S-alkylated products, 8 and 9, respectively. Coupling of
10 with the sodium salt of 2a,b gave the corresponding dioxolane derivatives 11, 13, and 14, which
were treated with 80% acetic acid at room temperature to give diols 12, 15, and 16. Treatment of 16
with tosyl chloride afforded the ditosylate 17 and this could then be modified to diazido and diamino
derivatives. Some of the products were screened for their biological activity.
Keywords Acyclonucleosides, Pyridothienopyrimidines, Alkylation
INTRODUCTION
Acyclonucleosides are a group of nucleosides which differ from the
ribonucleoside only in the sugar portion. The general feature of the important
members of this class of nucleosides is the absence of one or more of the bonds of
the pentose moiety to have an open chain residue, they possess portions of the
pentose residue. Those nucleosides missing one bond of the furanosyl residue are
called seco-nucleosides. The term diseco-, triseco-, tetraseco- and pentaseco-nucleosides
are given by El Ashry et al.[1–3] Since the discovery of Acyclovir 1 [9-(2-
hydroxyethoxy)methyl]guanine as a selective antiherpes agent,[4] attention has
focused to the synthesis and antiviral evaluation of an increasing number of
acyclonucleoside analogues.[5–7] Furthermore, De Clercq et al.[8,9] reported the
Accepted 4 April 2005.
DANIDA and Danish Ministry of Foreign Affairs are gratefully acknowledged for financial support through
the project ‘‘Development of New Drugs against Hepatitis’’ at Monoufiya University, and Prof. E. B. Pedersen,
Chemistry Institute, Odence University, Denmark for recording spectra and Microanalysis.
Address correspondence to Farag A. El-Essawy, Chemistry Department, Faculty of Science, Monoufiya
University, Shebein El-Koam, Egypt.
1265
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1266
F. A. El-Essawy
antiviral properties of (S)-9-(2,3-dihydroxypropyl)adenine (S-DHPA). Several
viruses including vaccinia, HSV-1 and HSV-2, measles, and vascular stoimatitis
were inhibited by (S)-DHPA. Several acyclonucleosides analogues of DHPA were
investigated.[10] This observation leads us to report our work on the synthesis of a
new series of acyclic nucleoside analogs of pyridothienopyrimidines as a
continuation of our interest in this area.[11,12] The tricyclic pyridothienopyrimidines
are chosen as nucleobases in this series because of their known interesting
biological activities.[13–18] Moreover, in the previous report,[19] we reported that
pyridothienopyrimidine is a heterocyclic ring system that is able to co-stack with a
DNA or RNA duplex.
RESULTS AND DISCUSSION
The starting pyridothienopyrimidine derivative 2a was prepared from
thienopyridine derivative 1 and formamide by the method of Shvedov and co-
workers.[20] Reaction of 2a with phosphorus pentasulfide in dry pyridine at reflux
temperature afforded the corresponding thioxo derivative 2b in good yield.
Compunds 2a,b were alkylated with (2-acetoxyethoxy)methyl bromide by the
method of Sasaki et al.[21] to afford the corresponding N-alkylated products 3a,b in
59 and 55% yields, respectively. Treatment of 3a,b with 1:1 mixture of methanol
and conc. ammonia at room temperature for 24 h resulted in complete deprotection
of the hydroxyl group and the corresponding 3-[(2-hydroxyethoxy)methyl]pyrido-
thienopyrimidones 4a,b were obtained in good yields. The hydroxy compounds
4a was tosylated by reaction with tosyl chloride in anhydrous pyridine to give
tosylate 5, which could then be converted to the azide 6 upon treatment with
sodium azide in dry DMF, the IR, NMR and elemental analysis established the
SCHEME 1

Pyridothienopyrimidine as Antiviral Agent
1267
structure of compound 6. The IR spectrum showed an absorption band for an
azodi group at 2103 cmÀ1. The azide 6 was reduced by reaction with
triphenylphosphine in pyridine to give the corresponding amine 7, whose structure
was confirmed using NMR, HRMS and the presence of the characteristic IR band
for an NH2 group at 3430–3410 cmÀ1 (Scheme 1). The reaction of compound 2b
(X = S), after treatment with NaH in dry DMF, with chloromethyl ethyl ether gave
the N-3 alkylated product 8, whereas its reaction with either benzyl chloromethyl
ether or chloromethyl methyl sulfide under the same reaction conditions, afforded
the S-alkylated products 9a and 9b. The sites of alkylation were confirmed by the
13C-NMR spectra of these compounds, which showed a chemical shift of d 177.87
for C = S in compound 8. The absence of this peak in the spectra of compounds
9a and 9b indicates that the alkylation occurred at the S atom to afford the S-
alkylated products (Scheme 2).
As we are interested in the synthesis of chiral acyclonucleosides,[11,12] we
devised the reaction of the starting compounds 2a,b, after treatment with 60%
sodium hydride in dry DMF, with (S)-(2,2-dimethyl-1,3-dioxalane-4-yl)methyl-p-
toluenesulfonate 10.[22] As reported in Scheme 3, S-alkylated product 11 was
obtained as the sole product, in fairly good yield, on treatment of thione 2b with
10. The structure of compound 11 was confirmed using elemental analysis, MS,
1H-NMR, and 13C-NMR. 13C-NMR spectrum of 11 lacked the characteristic peak
of C = S that appear at d 175.43 in the spectrum of 2b. Two alkylated products 13
and 14 were obtained (TLC) on treatment of 2a with 10, which could be
separated by column chromatography using ethyl acetate in chloroform (0–5%) to
1
give 45% and 32% yields, respectively. The H-NMR spectrum showed that the 1,3-
dioxalanyl moiety of the O-alkylated product is shifted downfield compared with
that of the N-alkylated product. The methylene signals appeared at d 3.99–4.21
ppm for O-alkylated product 14, compared to d 3.79–3.99 ppm for N-alkylated
product 13. Also, the 13C-NMR spectra showed a chemical shift of d 66.46 for
O-CH2- in compound 14, but a chemical shift of d 48.70 for N-CH2- in compound
13, which indicates that alkylation of 2a occurred on the nitrogen atom to give 13
and on the oxygen atom to give 14. That 13 is an N-alkylated product of 2a was
confirmed by the presence of characteristic peak for an amide carbonyl at
SCHEME 2

1268
F. A. El-Essawy
SCHEME 3
1666 cmÀ1 in its IR spectrum. Subsequent treatment of compounds 11, 13, and 14
with 80% aqueous acetic acid at room temperature gave the corresponding diols 12,
16 and 15, respectively. Tosylation of 16 was easily performed in anhydrous
pyridine with p-toluenesulfonyl chloride and the product 17 was identified using
NMR, MS, elemental analysis and by a characteristic peak for ether linkage at
1175 cmÀ1 in its IR spectrum. The intermediate ditosylate 17 could then be
converted to the diazido derivative 18 with sodium azide. IR, NMR, MS and
elemental analysis established the structure of 18. The IR spectrum showed
characteristic peaks at 2110 and 2103 cmÀ1 corresponding to the azido groups.
Diazide compound 18 was converted to diamine compound 19 via its treatment
with triphenylphosphine/ammonia in anhydrous pyridine (Scheme 3).
Antiviral activity against HBV was tested at the Liver Institute, Monoufiya
University, Egypt. Preliminary screening indicated that compounds 4b, 8, 9a, and
19 showed moderate viral replication inhibition and low cytotoxicity, while
compounds 5, 6, and 12 showed high inhibition with moderate cytotoxicity.
EXPERIMENTAL
Melting points (uncorrected) were determined using an electrothermal melting
MEL-TEMP II apparatus. IR spectra were recorded on a Perkin-Elmer 1430
spectophotometer using KBr disc technique. NMR spectra were recorded on a
1
varian Germini 2000 NMR spectrometer at 300 MHZ for H and 75 MHZ for 13C
1
or on a Bruker AC-250 FT spectrometer at 250 MHZ for H and at 62.9 MHZ for
13C with TMS as an internal standard. EI mass spectra were recorded on a finnigan

Pyridothienopyrimidine as Antiviral Agent
1269
MAT SSQ 710. MALADI mass spectra were recorded on a Kratos MS50RF
spectrometer. Elemental analyses were performed at Chemistry Institute,
Copenhagen University. The progresses of reactions were monitored by TLC
(analytical silica gel plates 60 F254). Merck silica gel (0.040–0.063 mm) was used
for CC.
7,9-Dimethylpyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine-4-(1H)-
thione (2b). Compound 2a (4.6 g, 20 mmol) and P2S5 (8.9 g, 40 mmol) were
suspended in dry pyridine (30 mL) and then the mixture was heated under reflux
for 11 h. After cooling, the mixture was poured into cold water, and the product
was collected by filtration. The product was recrystallized from DMF to obtain pale
yellow crystals in 86% yield; mp > 320°C (DMF) (lit.20 mp > 320°C); IR (KBr) 3122
1
(NH), 1220 (C = S) cmÀ1; H-NMR (DMSO-d6) d 2.61 (s 3H, CH3), 2.87 (s, 3H,
CH3), 3.59 (br s, 1H, NH), 7.29 (s, 1H, arom), 8.55 (s, 1H, arom). 13C-NMR
(DMSO-d6) d 18.23, 23.62 (2CH3), 122.19, 123.40, 134.59, 145.83, 147.07, 147.20,
159.59, 161.94 (C-arom), 175.43 (C = S); MS-EI m/z (%): 247 (M+, 100).
General Procedure for the Preparation of Compounds 3a,b
To a stirred suspension of 2a,b (5 mmol) in dry DMF (10 mL), 0.2 g (5 mmol)
of sodium hydride (60% dispersion in mineral oil) was added. When liberation of
hydrogen had ceased (2 h), the (2-acetoxyethoxy)methyl bromide (1.0 g, 5.1 mmol)
was added, and the reaction mixture was stirred at room temperature 24 h. The
solvent was evaporated under reduced pressure, co-evaporated with dry toluene
(3 Â 10 mL) and purified with silica gel chromatography using 5% ethyl acetate in
chloroform to give compounds 3a,b as pure products.
3-[(2-Acetoxyethoxy)methyl]-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidin-4-one (3a). Yield (0.99 g); mp 149–152°C
1
(diethyl ether). IR (KBr) 1741 (C = O, ester), 1673 (C = O), cmÀ1; H-NMR
(CDCl3) d 2.04 (s, 3H, COCH3), 2.68 (s, 3H, CH3), 2.92 (s, 3H, CH3), 3.91 (t, J = 4
Hz, 2H, OCH2CH2OAc), 4.24 (t, J = 4 Hz, 2H, OCH2CH2OAc), 5.59 (s, 2H,
NCH2O), 7.10 (s, 1H, arom), 8.28 (s, 1H, arom); 13C-NMR (CDCl3) d 19.33, 20.74,
24.55 (3 CH3), 62.99, 68.24 (OCH2CH2OAc), 75.08 (NCH2O), 122.07, 122.76,
124.38, 146.88, 147.07, 152.00, 157.70, 160.19, 163.02 (C-arom, C = O), 170.73
(COCH3). MS-EI m/z (%): 347 (20) [M+], 43 (100). C16H17N3O4S (347.39): C, 55.32;
H, 4.93; N, 12.10. Found: C, 55.12; H, 4.90; N, 11.99.
3-[(2-Acetoxyethoxy)methyl]-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidin-4-thione (3b). Yield (55%); mp 134–136°C
(diethyl ether). IR (KBr) 1740 (C = O, ester), 1573 (C = C), 1218 (C = S) cmÀ1;
1H-NMR (CDCl3) d 2.07 (s, 3H, COCH3), 2.66 (s, 3H, CH3), 2.87 (s, 3H, CH3), 3.99
(t, J = 4.5 Hz, 2H, OCH2CH2OAc), 4.27 (t, J = 4.5 Hz, 2H, OCH2CH2OAc), 6.07

1270
F. A. El-Essawy
(s, 2H, OCH2N), 7.05 (s, 1H, arom), 8.55 (s, 1H, arom); 13C-NMR (CDCl3) d 19.32,
20.76, 24.66 (3CH3), 62.90, 68.72 (OCH2CH2OAc), 79.96 (NCH2O), 122.95, 124.51,
137.43, 145.45, 146.02, 147.97, 160.58, 164.40 (C-arom), 170.67 (COCH3), 177.94
(C = S); MS-EI m/z (%): 363 (M+, 10), 43 (100). C16H17N3O3S2 (363.44): C, 52.88; H,
4.71; N, 11.56. Found: C, 52.77; H, 4.77; N, 11.51.
General Procedure for the Deprotection of Compounds 3a,b
Compound 3a or 3b (1 mmol) in a mixture of methanol (10 mL) and
concentrated ammonia (10 mL) was stirred at RT for 24 h (TLC). The solvent was
evaporated to dryness under reduced pressure. The residue was triturated with
small volume of ethanol to give 4a or 4b as a colorless product.
7,9-Dimethyl-3-[(2-hydroxyethoxy)methyl]pyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidin-4-one (4a). Yield (77%); mp 202–205°C
1
(MeOH); H-NMR (DMSO-d6) d 2.62 (s, 3H, CH3), 2.89 (s, 3H, CH3), 3.54 (t,
J = 5.0 Hz, 2H, OCH2CH2OH), 3.66 (t, J = 5.0 Hz, OCH2CH2OH), 4.89 (br s, 1H,
OH), 5.55 (s, 2H, OCH2N), 7.31 (s, 1H, arom); 8.71 (s, 1H, arom); 13C-NMR
(DMSO-d6) d 18.78, 23.97 (2CH3), 59.93, 71.14 (OCH2CH2N), 75.34 (NCH2O),
120.67, 122.76, 123.83, 146.51, 149.47, 151.69, 156.79, 159.87, 161.58 (C-arom and
C = O); MS-EI m/z (%): 305 (M+, 20) 231 (100). C14H15N3O3S (305.35): C, 55.07; H,
4.95; N, 13.76. Found: C, 55.03; H, 4.76; N, 13.59.
7,9-Dimethyl-3-[(2-hydroxyethoxy)methyl]pyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidin-4-thione (4b). Yield (67%); mp 188–191°C
1
(MeOH); H-NMR (DMSO-d6) d 2.60 (s, 3H, CH3), 2.86 (s, 3H, CH3), 3.55 (t,
J = 4.5 Hz, 2H, OCH2CH2OH), 3.72 (t, J = 4.5 Hz, 2H, OCH2CH2OAc), 5.97 (s,
2H, OCH2N), 7.29 (s, 1H, arom), 8.99 (s, 1H, arom); 13C-NMR (DMSO-d6) d 18.81,
24.09 (2CH3), 59.95, 71.72 (OCH2CH2), 80.38 (NCH2O), 123.03, 124.07, 136.09,
145.61, 147.58, 148.58, 160.43, 163.13 (C-arom), 176.93 (C = S). HRMS m/z Calcd
for C14H15N3NaO2S2 (M++ Na) 344.0498, found 344.0494.
7,9-Dimethyl-3-[[2-(p-tolylsulfonyloxy)ethoxy]methyl]pyri-
do[3’,2’:4,5]thieno[3,2-d]pyrimidin-4-one (5). p-Toluenesulfonyl
chloride (0.19 g, 1 mmol) was added to an ice-cooled of 4a (0.3 g, 1 mmol) in
dry pyridine (5 mL) and left to stand overnight at 4°C, then 4 h at RT. The pyridine
was removed under reduced pressure at 25°C and the resulting gum was treated
with ice water. The product solidified as a white precipitate, was collected by
filtration, washed with water, a small amount of cold ethanol and ether to get the
white product. Yield (64%); mp 144–146°C (ethanole); IR (KBr) 1678 (C = O), 1573
1
(C = C), 1170 (C-O-SO2) cmÀ1; H-NMR (CDCl3) d 2.40 (s, 3H, p-CH3), 2.67 (s,
3H, CH3), 2.92 (s, 3H, CH3), 3.90 (t, J = 5 Hz, 2H, OCH2CH2OTs), 4.18 (t, J = 5
Hz, 2H, OCH2CH2OTs), 5.49 (s, 2H, OCH2N), 7.10 (s, 1H, arom), 7.30 (d, 2H,

Pyridothienopyrimidine as Antiviral Agent
1271
J = 8 Hz, Tolyl-H), 7.75 (d, 2H, J = 8 Hz, Tolyl-H), 8.19 (s, 1H, arom); 13C-NMR
(CDCl3) d 19.36, 2157, 24.56 (3CH3), 67.90, 68.56 (2CH2), 75.12 (NCH2O), 121.99,
122.81, 124.42, 127.84, 129.80, 132.70, 144.95, 146.90, 147.16, 152.11, 157.70, 160.23,
163.03 (C-arom and C = O). MS-EI m/z (%): 459 (M+, 5), 91 (100); C21H21N3O5S2
(459.54): C, 54.89; H 4.61; N, 9.14. Found: C, 55.14; H, 4.49; N, 8.84.
3-[(2-Azidoethoxy)methyl]-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidin-4-one (6). A mixture of compound 5 (0.15 g, 0.3
mmol) and NaN3 (0.02 g, 0.3 mmol) in dry DMF (5 mL) was heated for 2 h at 80°C
(TLC). The solvent was removed under reduced pressure and the remaining syrup
was triturated with ice-water. A white solid was collected by filtration, washed with
ether and recrystallized from MeOH. Yield (75%); mp 132–134°C; IR (KBr) 2103
(N3), 1680 (C = O), 1573 (C = C) cmÀ1; 1H-NMR (CDCl3) d 2.67 (s, 3H, CH3), 2.92
(s, 3H, CH3), 3.44 (t, J = 5 Hz, 2H, OCH2CH2N), 3.89 (t, J = 5 Hz, 2H,
OCH2CH2N), 5.60 (s, 2H, OCH2N), 7.09 (s, 1H, arom), 8.28 (s, 1H, arom);
13C-NMR (CDCl3) d 19.47, 24.67 (2CH2), 50.62, 69.23 (2CH2), 75.15 (NCH2O),
122.15, 122.34, 124.52, 146.98, 147.26, 152.18, 157.85, 160.33, 163.14 (C-arom and
C = O). MS-EI m/z (%): 330 (M+, 3), 245 (100); C14H14N6O2S (330.37): C, 50.90; H,
4.27; N, 25.44. Found: C, 50.85; H, 4.22; N, 25.18.
3-[(2-Aminoethoxy)methyl]-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidin-4-one (7). Azide 6 (0.17 g, 0.5 mmol) and Ph3P
(0.21 g, 0.82 mmol) were dissolved in dry pyridine (15 mL) and the mixture was
stirred at RT for 1 h. Concentrated ammonia was added (5 mL) and the solution
was stirred for 2 h. The solvent was removed under reduced pressure. Water was
added (5 mL), and then Ph3P and Ph3PO were removed by filtration. The filtrate
was extracted with benzene and to remove residual Ph3P and then concentrated
until dryness to give 7. Yield (67%); mp 147–150°C (acetic acid); IR (KBr) 3430–
3510 (NH2), 1678 (C = O) cmÀ1; 1H-NMR (D2O) d 2.68 (s, 3H, CH3), 2.93 (s, 3H,
CH3), 3.61 (br s, 2H, OCH2CH2NH2), 4.47 (br s, 2H, OCH2CH2NH2), 5.53 (br s,
2H, NH2), 6.09 (s, 2H, OCH2N), 7.20 (s, 1H, arom), 8.83 (s, 1H, arom); 13C-NMR
(D2O) d 18.58, 22.74 (2CH3), 39.98, 71.33, 76.19 (3CH2), 120.12, 122.00, 122.58,
146.8, 147.96, 150.40; 157.28; 159.52, 160.01 (C-arom and C = O). HRMS m/z calcd
for C14H16N4NaO2S (M++ Na) 327.0886, Found: 327.0884.
General Procedure for the Preparation of Compounds 8, 9a,
and 9b
Compound 2a or 2b (5 mmol) was suspended in dry DMF (20 mL), 0.2 g
(5 mmol) of sodium hydride (60% dispersion in mineral oil) was added and the
mixture was stirred at RT for 2 h, until hydrogen evolution had ceased. Then the
appropriate chloroether (5.1 mmol) was added, and the reaction mixture was
stirred for additional 24 h. The mixture was then evaporated to dryness under

1272
F. A. El-Essawy
reduced pressure and co-evaporated with dry toluene (3 Â 10 mL). The residue
was purified with silica gel chromatography using 5% ethyl acetate in chloroform to
give the alkylated products 8 and 9a,b.
7,9-Dimethyl-3-ethoxymethylpyrido[3’,2’:4,5]thieno[3,2-
1
d]pyrimidin-4-thione (8). Yield (40%); mp 128–130°C (pet. ether); H-
NMR (CDCl3) d 1.19 (t, 3H, J = 7 Hz, OCH2CH3), 2.65 (s, 3H, CH3), 2.68 (s, 3H,
CH3), 3.66 (q, 2H, J = 7 Hz, CH2), 6.03 (s, 2H, CH2), 7.04 (s, 1H, arom), 8.52 (s,
1H, arom); 13C-NMR (CDCl3) d 15.04, 19.43, 24.76 (3CH3), 64.55 (CH2), 77.78
(NCH2O), 123.02, 124.69, 137.27, 145.53, 146.72, 148.08, 160.59, 164.48 (C-arom),
177.83 (C = S). MS-EI m/z (%): 305 (M+, 2), 59 (100); C14H15N3OS2 (305.41): C,
55.06; H, 4.95; N, 13.76. Found: C, 55.14; H, 4.99; N, 13.52.
4-(Benzyloxymethylthio)-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidine (9a). Yield (66%); mp 149–150°C (diethyl
1
ether); H-NMR (CDCl3) d 2.69 (s, 3H, CH3), 3.00 (s, 3H, CH3), 4.72 (s, 2H,
SCH2OCH2Ph), 5.71 (2s, 2H, SCH2OCH2Ph), 7.12 (s, 1H, arom), 7.30–7.36 (m,
5H, PhCH2), 9.09 (s, 1H, arom). 13C-NMR (CDCl3) d, 19.71, 24.64 (2CH3); 69.85,
71.22 (2CH2); 122.87, 123.43, 128.01, 128.22, 128.42, 128.50, 136.73, 147.99, 153.63,
155.32, 161.11, 161.35, 162.56 (C-arom). MS-EI m/z (%): 3.67 (M+, 20), 91 (100).
Anal. Calcd for C19H17N3OS2 (367.5): C, 62.10; H, 4.66; N, 11.43. Found: C, 62.25;
H, 4.67; N, 11.23.
7,9-Dimethyl-4-(1,3-dithiabutyl)pyrido[3’,2’:4,5]thieno[3,2-
1
d]pyrimidine (9b). Yield (42%); mp 114–116°C (diethyl ether); H-NMR
(CDCl3) d 2.31 (s, 3H, CH3), 2.69 (s, 3H, CH3), 3.00 (s, 3H, SCH3), 4.63 (s, 2H,
SCH2S), 7.12 (s, 1H, arom), 9.06 (s, 1H, arom); 13C-NMR (CDCl3) d, 15.73, 19.66
(2CH3), 24.6 (SCH3), 35.31 (SCH2S), 122.81, 123.28, 127.79, 147.88, 153.45, 154.60,
161.01, 161.86, 162.34 (C-arom). MS-EI m/z (%): 307 (M+, 2), 260 (100); C13H13N3S3
(307.46): C, 50.78; H, 4.26; N, 13.67. Found: C, 50.79; H, 4.25; N, 13.43.
General Procedure for the Preparation of Compounds 11, 13,
and 14
To a stirred suspension of compound 2a and 2b (5 mmol) in dry DMF
(15 mL), 0.2 g (5 mmol) of sodium hydride (60% dispersion in mineral oil) was
added. After hydrogen had ceased (2 h), (S)-(2,2-dimethyl-1,3-dioxalane-4-ylmethyl)
p-toluenesulfonate 10 (0.78 g, 5.1 mmol) was added, and the reaction mixture was
stirred for 24 h at 80°C. The reaction mixture was worked up as described in
preparation of compounds 3a,b give compounds 11, 13, and 14.
4-[[(S)-2,2-Dimethyl-1,3-dioxalan-4-yl]methylthio]-7,9-dime-
thylpyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine (11). Yield (71%); mp

Pyridothienopyrimidine as Antiviral Agent
1273
1
113–115°C (diethyl ether); H-NMR (CDCl3) d 1.38 (s, 3H, CH3), 1.58 (s, 3H,
CH3), 2.68 (s, 3H, CH3), 2.99 (s, 3H, CH3), 3.66 (dd, 2H, J = 6 Hz, J = 13, Hz,
CH2), 3.86 (dd, 1H, J = 6 Hz, J = 9 Hz, H of CH2), 4.17 (dd, 1H, J = 6 Hz, J = 9
Hz, H of CH2), 4.51 (t, 1H, J = 6 Hz, CH), 7.11 (s, 1H, arom), 9.10 (s, H, arom);
13C-NMR (CDCl3) d 19.95, 24.60 (2CH3), 25.46, 26.96 (2CH3), 32.36, 68.53 (2CH2),
74.54 (CH), 109.85 [C(CH3)2], 122.82, 123.31, 127.63, 147.87, 153.47, 154.78, 160.99,
162.06, 162.39 (C-arom). MS-EI m/z (%): 361 (M+, 100); C17H19N3O2S2 (361.48): C,
56.48; H, 5.30; N, 11.62. Found: C, 56.75; H, 5.37; N, 11.53.
3-[[(S)-2,2-Dimethyl-1,3-dioxalan-4-yl]methyl]-7,9-dimethyl-
pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidin-one (13). Yield (45%); mp
1
140–143°C (diethyl ether); IR (KBr) 1666 (C = O), 1573 (C = C) cmÀ1; H-NMR
(CDCl3) d 1.33 (s, 3H, CH3), 1.45 (s, 3H, CH3), 2.66 (s, 3H, CH3), 2.91 (s, H, CH3),
3.79 (dd, 1H, J = 6 Hz, J = 9 Hz, H of CH2), 3.99 (dd, 1H, J = 7 Hz, J = 14 Hz, H
of CH2), 4.19 (dd, 1H, J = 7 Hz, J = 9 Hz, H of CH2), 4.44–4.54 (m, 2H, CH and H
of CH2), 7.07 (s, 1H, arom), 8.25 (s, 1H, arom); 13C-NMR (CDCl3) d 19.50, 24.50
(2CH3); 24.97, 26.71 (2CH3), 48.70 (N-CH2-C), 66.52 (CH2), 73.36 (CH), 109.92
[C(CH3)2], 121.88, 122.59, 124.43, 146.94, 148.08, 152.14, 157.62, 162.87, 159.92 (C-
arom and C = O); MS-EI m/z (%): 345 (M+, 5), 231 (100); C17H19N3O3S (345.42): C,
59.11; H, 5.54; N, 12.17. Found: C, 59.29; H, 5.53; N, 12.01.
4-[[(S)-2,2-Dimethyl-1,3-dioxalan-4-yl]methoxy]-7,9-dimethyl-
pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidine (14). Yield (30%); mp 105–
1
107°C (diethyl ether). IR (KBr) 1574 (C = C), 1519 (C = N) cmÀ1; H-NMR
(CDCl3) d 1.42 (s, 3H, CH3), 1.50 (s, H, CH3), 2.68 (s, 3H, CH3), 3.00 (s, 3H, CH3),
3.99 (dd, 1H, J = 6 Hz, J = 9 Hz, CH), 4.21 (dd, 1H, J = 6 Hz, J = 9 Hz, CH), 4.57–
4.68 (m, 3H, CH, CH2), 7.11 (s, 1H, arom), 8.83 (s, 1H, arom); 13C-NMR (CDCl3) d
19.58, 24.54, (2CH3), 25.41, 26.67 (2CH3), 66.46 (O-CH2-C), 66.85 (CH2), 73.64 (CH),
109.90 [C(CH3)2], 116.25, 122.56, 123.71, 147.32, 153.81, 157.88, 160.50, 162.92,
163.59 (C-arom and C = O). MS-EI m/z (%): 345 (M+, 2), 43 (100); C17H19N3O3S
(345.42): C, 59.11; H, 5.54; N, 12.17. Found: C, 59.12; H, 5.65; N, 11.99.
General Procedure for the Deprotection of Compounds 11, 13,
and 14
Compound 11, 13, or 14 (1 mmol) was stirred in 80% aqueous AcOH (10 mL)
for 24 h at RT. The solvent was removed under reduced pressure and the residue
was co-evaporated with water (4 Â 5 mL), and finally with ethanol (3 Â 5 mL). The
residue was purified by silica gel chromatography using 5% MeOH in CHCl3 to
give pure 12, 15, and 16.
4-(2,3-Dihydroxypropylthio)-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidine (12). Yield (66%); mp 165–168°C (EtOH);

1274
F. A. El-Essawy
1H-NMR (DMSO, d6) d 2.60 (s, 3H, CH3), 288 (s, 3H, CH3), 3.38–3.49 (m, 2H,
CH2), 3.71–3.82 (m, 3H, CH, CH2), 4.82 (br s, 1H, OH), 5.22 (br s, 1H, OH); 7.29
(s, 1H, arom), 9.04 (s, H, arom); 13C-NMR (DMSO, d6) d 19.00, 24.02 (2CH3);
33.35, 64.63 (2CH2), 69.93 (CH), 122.42, 122.88, 126.05, 147.24, 153.69, 153.78,
160.94, 162.68 (C-arom). MS-EI m/z (%): 321 (M+, 2), 247 (100); C14H15N3O2S2
(321.40): C, 52.31; H, 5.30; N, 13.07. Found: C, 52.22; H, 5.15; N, 12.99.
4-(2,3-Dihydroxypropoxy)-7,9-dimethylpyrido[3’,2’:4,5]-
1
thieno[3,2-d]pyrimidine (15). Yield (75%); mp 190–193°C (EtOH); H-
NMR (DMSO, d6) d 2.63 (s, 3H, CH3), 283 (s, 3H, CH3), 3.52 (d, 2H, J = 6 Hz,
CH2), 3.77–3.99 (m, 1H, CH), 4.49–4.67 (m, 2H, CH2), 4.75 (br s, 1H, OH), 5.35
(br s, H, OH), 7.25 (s, 1H, arom), 8.89 (s, 1H, arom); 13C-NMR (DMSO, d6) d
18.95, 23.96 (2CH3), 62.54, 68.76 (2CH2), 69.25 (CH), 114.90, 122.62, 146.46, 154.22,
154.27, 156.97, 160.46, 161.59, 163.51 (C-arom); MS-EI m/z (%): 305 (M+, 5), 231
(100); C14H15N3O3S (305.35): C, 55.07; H, 4.95; N, 13.76. Found: C, 55.01; H, 4.78;
N, 13.58.
3-(2,3-Dihydroxypropyl)-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidin-4 one (16). Yield (75%); mp 209–212°C (EtOH);
1H-NMR (DMSO, d6) d 2.61 (s, 3H, CH3), 288 (s, 3H, CH3), 3.46 (dd, 2H, J = 5 Hz,
J = 11 Hz, CH2), 3.77–3.83 (m, 2H, CH2), 4.42 (d, 1H, J = 11 Hz, CH), 4.55 (br s,
1H, OH), 5.19 (br s, 1H, OH), 7.29 (s, 1H, arom), 8.47 (s, H, arom); 13C-NMR
(DMSO, d6) d 18.73, 23.94 (2CH3), 49.66, 63.77 (2CH2), 68.38 (CH), 120.27, 122.64,
123.87, 146.37, 150.33, 151.64, 156.87, 161.42, 159.61 (C-arom and C = O); MS-EI
m/z (%): 305 (M+, 20), 231 (100); C14H15N3O3S (305.35): C, 55.07; H, 4.95; N, 13.76.
Found: C, 54.99; H, 4.78; N, 13.58.
3-[(2,3-Di-p-toluenesulfonyloxy)propyl]-7,9-dimethylpyri-
do[3’,2’:4,5]thieno[3,2-d]pyrimidine-4-one (17). p-Toluenesulfonyl
chloride (0.76 g, 4 mmol) was added to an ice-cooled solution of 16 (0.61 g, 2
mmol) in anhydrous pyridine (15 mL) and left to stand overnight at 4°C and then 4
h at RT. The reaction mixture was worked up as described in preparation of
compound 5 to afford the ditosylate 17. Yield (75%); mp 203–205°C (diethyl
ether); IR (KBr) 1674 (C = O), 1175 (ether linkage) cmÀ1; 1H-NMR (CDCl3) d 1.68
(s, 3H, p-CH3), 249 (s, 3H, p-CH3), 2.70 (s, 3H, CH3), 2.93 (s, 3H, CH3), 3.92 (dd,
1H, J = 10 Hz, J = 14 Hz, H of CH2), 4.42–4.52 (m, 3H, CH, CH2), 4.95 (dd, 1H,
J = 10 Hz, J = 14 Hz, H of CH2), 6.80 (d, 2H, J = 8 Hz, tolyl-H), 7.15 (s, 1H, arom),
7.43 (q, 4H, J = 6 Hz, tolyl-H), 7.87 (d, 2H, J = 8 Hz, tolyl-H), 7.94 (s, 1H, arom);
13C-NMR (CDCl3) d 19.37, 20.88 (2CH3), 21.70, 42.58 (tolyl-CH3), 47.42, 68.72
(2CH2), 74.62 (CH), 120.66, 122.79, 124.22, 127.25, 128.11, 129.35, 130.17, 131.30,
131.76, 145.16, 145.60, 147.04, 147.15, 152.04, 156.84, 160.36, 162.82, 160.36
(C-arom and C = O). MS-EI m/z (%): 613 (M+, 5), 286 (100); C28H27N3O7S3
(613.73): C, 54.80; H, 4.43; N, 6.85. Found: C, 54.66; H, 4.16; N, 6.79.

Pyridothienopyrimidine as Antiviral Agent
1275
3-(2,3-Diazidopropyl)-7,9-dimethylpyrido[3’,2’:4,5]thieno[3,2-
d]pyrimidine-4-one (18). A mixture of compound 17 (0.6 g, 1 mmol) and
NaN3 (0.13 g, 2 mmol) in dry DMF (10 mL) was heated for 2 h at 80°C, the reaction
mixture was worked up as described in the preparation of compound 6 to give the
product 18. Yield (95%); mp 173–176°C (diethyl ether); IR (KBr) 2110, 2103 (2N3),
1673 (C = O) cmÀ1; 1H-NMR (CDCl3) d 2.86 (s, 3H, CH3), 2.92 (s, 3H, CH3), 3.53
(dd, 1H, J = 6 Hz, J = 13 Hz, H of CH2), 3.73–3.88 (m, 2H, CH2), 4.18–4.21 (m,
1H, CH), 4.41 (dd, 1H, J = 6 Hz, J = 13 Hz, H of CH2), 7.09 (s, 1H, arom), 8.16 (s,
H, arom); 13C-NMR (CDCl3) d, 19.31, 42.55 (2CH3), 48.08, 52.56 (2CH2); 59.34
(CH); 121.15, 122.76, 124.34, 147.12, 147.45, 152.31, 157.55, 162.94, 160.23 (C-arom
and C = O); MS-EI m/z (%): 355 (M+, 2), 245 (100); C14H13N9OS (355.37): C, 47.32;
H, 3.69; N, 35.47. Found: C, 47.28; H, 3.58; N, 34.41.
3-(2,3-Diaminopropyl)-7,9-dimethylpyrido[3’,2’:4,5]-
thieno[3,2-d]pyrimidine-4-one (19). The diazide 18 (0.17 g, 0.5 mmol)
and Ph3P (0.43 g, 1.63 mmol) were dissolved in anhyd. pyridine (10 mL) and the
mixture was stirred for 1 h at RT Conc ammonia (10 mL) was then added and then
the solution was stirred for additional 2 h at RT. The reaction mixture was worked
up as described for compound 7. Yield (71%); mp 220–223°C (MeOH); 13C-NMR
(D2O) d 18.64, 22.77 (2CH3), 43.70 (CH2), 50.77 (CH2); 50.96 (CH) 120.04, 122.21,
122.60, 146.71, 148.57, 150.34, 157.62, 159.95, 159.38 (C-arom and C = O); HRMS
m/z calcd for C14H17N5ONaS (M++ Na) 326.1046, found 326.1047; calcd for
C14H18N5OS (M++ H) 304.1227, found 304.1234.
Biological Activity Studies
Maintenance media were added to the cell culture (Hep G2 2.2.15) together
with the tested compounds (final concentration = 10 mM). The supernatant liquid
was collected after one, two, and/or three weeks. The DNA replication was
estimated by the polymerase chain reaction technique. The percentage inhibition
could be calculated by the relation between the blank experiment (containing
maintenance media without the tested compounds) and the results obtained after
the mentioned periods. The percentage cytotoxicity could be estimated by the
relation between the number of the living and dead cells after three weeks counted
by the Haemocytometer.
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