An 8-aminoimidazo[4,5-g]quinazoline carbocyclic nucleoside: A ring-extended analog of 5′-noraristeromycin

Article abstract of DOI:10.1016/S0040-4020(01)00909-7

The antiviral properties of 5′-noraristeromycin (3) have been attributed to its inhibition of S-adenosylhomocysteine hydrolase. As part of an effort to establish the limiting structural parameters possible for the biological properties of 3, a ring-extended analog possessing 8-aminoimidazo[4,5-g]quinazoline as the base (7) has been prepared and found to be less active than 3.

Full text of DOI:10.1016/S0040-4020(01)00909-7

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 9049±9053
An 8-aminoimidazo[4,5-g]quinazoline carbocyclic nucleoside:
a ring-extended analog of 50-noraristeromycin
Vasanthakumar P. Rajappan and Stewart W. Schnellerp
Department of Chemistry, Auburn University, 179 Chemistry Building, Auburn, AL 36849-5312, USA
Received 9 July 2001; accepted 6September 2001
AbstractÐThe antiviral properties of 50-noraristeromycin (3) have been attributed to its inhibition of S-adenosylhomocysteine hydrolase.
As part of an effort to establish the limiting structural parameters possible for the biological properties of 3, a ring-extended analog possessing
8-aminoimidazo[4,5-g]quinazoline as the base (7) has been prepared and found to be less active than 3. q 2001 Elsevier Science Ltd. All
rights reserved.
1. Introduction
is aristeromycin (2) from which 50-noraristeromycin (3) has
emerged as a compound with signi®cant antiviral effects4
that have been attributed to its selective inhibition of
S-adenosyl-l-homocysteine (AdoHcy) hydrolase5 (Fig. 1).
Over the years a number of nucleoside analogs have
emerged as potent antiviral drugs.1 Many of these
compounds attribute their therapeutic property to structural
changes in either the carbohydrate or base components of
the natural nucleoside. Examples of variations in the carbo-
hydrate region can be found with derivatives possessing
only a portion of the ribofuranose moiety (for example,
acyclovir (1))2 and analogs where the ribofuranose oxygen
is replaced by a methylene unit (carbocyclic nucleosides or
carbanucleosides).3 A representative of this latter variation
In the case of base-varied analogs, coformycin (4) and
pentostatin (5),6 potent antileukemic drugs,7 are ring-
enlarged derivatives of inosine (or adenosine). The ring
extended base series, represented by lin-benzoadenine
nucleosides (6), is another example. In this latter modi®-
cation, four sp2 carbon atoms are inserted between the
imidazole and pyrimidine rings of adenine (giving the
Figure 1.
Keywords: purines; nucleosides; polycyclic heterocyclic compounds; antiviral.
Corresponding author. Tel.: 11-334-844-5737; fax: 11-334-844-5748; e-mail: schnest@auburn.edu
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)00909-7

9050
V. P. Rajappan, S. W. Schneller / Tetrahedron 57 12001) 9049±9053
Scheme 1. Reaction conditions: (a) NaH, Pd(PPh3)4, DMSO/THF; (b) OsO4, NMO, THF/H2O; (c) NH3/MeOH, 1108C.
appearance of central benzene ring). The properties of these
analogs have been studied by Leonard and co-workers8 and
others9,10 who have shown that such derivatives provide
revealing information about the binding domain of purine
nucleoside (and nucleotide) metabolizing enzymes.
using osmium tetroxide and N-methylmorpholine N-oxide
afforded corresponding triols 11a and 11b (Scheme 1).
Structural con®rmation of the two regioisomers 11a and 11b
was considered at this stage. Since preliminary indications
suggested that a de®nitive NMR spectral distinction
between 11a and 11b would be dif®cult, a chemical study
was undertaken. In that direction, compounds 11a and 11b
were hydrolyzed in presence of 1N HCl to give 12a and 12b,
respectively, (structures still tentatively assigned at this
point) (Scheme 2). To provide an authentic reference
compound corresponding to the tentative structure 12a, an
unequivocal preparation began by reacting amine 1313 with
the quinazoline 1412 (Scheme 3) to yield 15. Catalytic
hydrogenation of the nitro group of 15 afforded the amino
compound 16. An acid promoted cyclization of 16 with
triethyl orthoformate followed by hydrolysis gave a
Throughout the structural variations of nucleosides that
have been reported in the literature, there has been relatively
limited attention10 devoted to the simultaneous modi®cation
of both the base and carbohydrate units. To explore the
limiting structural features necessary for the biological
properties of 3, this report describes the use of this double
variation by combining the ring-extended feature of 6 with
the carbocyclic feature of 3 to create 7 as a target compound.
1
compound whose H- and 13C NMR spectra were exactly
2. Chemistry
that of the product assigned previously as 12a. A mixed
melting point determination was also consistent with 12a
being the same via Scheme 2 (from 11a) and Scheme 3.
The synthesis of 7 began with the palladium (0) catalyzed
coupling of the monoacetate 811 with 8-methylthio-
imidazo[4,5-g]quinazoline (9)12 to give two products, tenta-
tively assigned for this presentation as the regioisomers 10a
and 10b. After separation, dihydroxylation of 10a and 10b
Scheme 3. Reaction conditions: (a) 1-BuOH, Et3N, re¯ux; (b) Pd/C, H2,
45 psi; (c) (i) EtO3CH, HCl, rt, (ii) H2O, 808C.
Scheme 2. Reaction conditions: (a) 1N HCl, re¯ux.

V. P. Rajappan, S. W. Schneller / Tetrahedron 57 12001) 9049±9053
9051
With the regioisomers now assigned, the ®nal product 7 was
obtained in quantitative yield by heating 11a in methanol
saturated with anhydrous ammonia in a sealed tube (Scheme
1).
15 min until the solution became clear. To this solution was
added, successively, tetrakistriphenylphosphine palladium
(115 mg, 0.1 mmol), triphenylphosphine (52.4 mg, 0.2
mmol) and monoacetate 811 (355 mg, 2.5 mmol) in anhy-
drous THF (10 mL). The ¯ask was immediately transferred
to an oil bath, preheated at 508C. The mixture was stirred
under N2 at 508C for 12 h. After rotary evaporation of
solvents at reduced pressure, the residue was suspended in
CH2Cl2 (40 mL) and ®ltered. The ®ltrate was extracted with
brine (2£30 mL) and the organic layer, after drying
(Na2SO4), was ®ltered and rotary evaporated to a thick
brown residue, which was loaded onto a silica gel column.
The impurities were eluted using CH2Cl2/MeOH (100:1 and
50:1, respectively). The next components (desired products)
were eluted using CH2Cl2/MeOH (30:1 followed by 15:1).
The fractions from the 30:1 elution were pooled and the
solvent evaporated. Trituration (hexane) of the residue
gave 10a as a tan powder (100 mg, 33.33%). An analytical
sample was recrystallized from EtOAc: mp 211±2128C. 1H
NMR (DMSO-d6) d 8.93 (s, 1H, Ar±H), 8.65 (s, 1H, Ar±H),
8.37 (s, 1H, Ar±H), 8.29 (s, 1H, Ar±H), 6.26 (dd, Jˆ5.0 and
2.5 Hz, 1H), 6.11 (dd, Jˆ5.0 and 2.5 Hz, 1H), 5.69 (dt,
Jˆ7.5 and 5.0 Hz, 1H), 5.46(d, Jˆ5.0 Hz, 1H), 4.81 (m,
1H), 3.02 (m, 1H), 2.72 (s, 3H, SCH3), 1.83 (m, 1H). 13C
NMR (DMSO-d6) d 151.72, 149.63, 144.70, 143.23,
140.19, 138.84, 130.94, 119.36, 113.04, 108.65, 74.15,
59.86, 12.61. Anal. Calcd for C15H14N4SO´0.2EtOAc: C,
60.06; H, 4.98; N, 17.73; S, 10.15. Found: C, 60.00; H,
4.86; N, 17.51; S, 9.86.
3. Results
Compound 7 was evaluated for its effectiveness towards the
following viruses: hepatitis B, in¯uenza A, in¯uenza B,
parain¯uenza-3, respiratory syncytial, varicella zoster
(TK1 and TK2), cytomegalo, vesicular stomatitis, sindbis,
punta toro, coxsackie B4, reo, herpes simplex 1 (TK1 and
TK2), herpes simplex 2, human immunode®ciency, and
vaccinia. No activity was found. Compound 7, like 3, was
also found to have no toxicity effects on the viral host cells.
4. Discussion and conclusion
The work of Leonard and coworkers8a,b found that de®ned
structural changes for substrates and inhibitors, such as
those in 7, assisted in setting the steric and size limitations
for active and cofactor sites for various enzymes. Thus, the
lack of activity for 7 suggests that the enzyme proposed to
be involved in the antiviral activity of 3 (namely, AdoHcy
hydrolase) is not suf®ciently ¯exible to accommodate the
extension imposed on 3 by 7. This, in turn, adds to what is
already known about binding capabilities of S-adenosyl-
homocysteine hydrolase.14
Following combining the 15:1 fractions and evaporation,
trituration (hexane) afforded 80 mg (28%) of 10b as a
5. Experimental
5.1. General
1
shiny yellow powder: mp 219±2208C. H NMR (DMSO-
d6) d 8.92 (s, 1H, Ar±H), 8.68 (s, 1H, Ar±H), 8.47 (s, 1H,
Ar±H), 8.22 (s, 1H, Ar±H), 6.27 (dd, Jˆ7.5 and 2.5 Hz,
1H), 6.11 (dd, Jˆ7.5 and 2.5 Hz, 1H), 5.76(d, Jˆ5.0 Hz,
1H), 5.42 (d, Jˆ5.0 Hz, 1H), 4.83 (m, 1H), 3.05 (m, 1H),
2.72 (s, 3H, SCH3), 1.83 (m, 1H). 13C NMR (DMSO-d6) d
151.74, 149.65, 144.72, 143.34, 138.88, 140.19, 130.95,
119.19, 113.05, 108.67, 74.16, 59.87, 12.61. Anal. Calcd
for C15H14N4SO: C, 60.38; H, 4.82; N, 18.78; S, 10.75.
Found: C, 60.52; H, 4.82; N, 18.64; S, 10.65.
Melting points were recorded on a Meltemp II melting point
apparatus and are uncorrected. Combustion analyses were
performed by Atlantic Microlabs Inc., Norcross, Georgia.
1H and 13C NMR spectra were recorded at 250 and 60 MHz,
respectively, and are referenced to internal tetramethyl-
silane (TMS) at 0.0 ppm. The spin multiplicities are indi-
cated by the symbols s (singlet), d (doublet), t (triplet), dd
(doublet of doublet) dt (doublet of triplet), m (multiplet),
and br (broad). The HRMS was recorded at an ionization
potential of 70 eV. The optical rotation was determined
using the sodium-D line on a JASCO DIP-360 polarimeter.
Reactions were monitored by thin-layer chromatography
(TLC) using 0.25 mm Whatman Diamond silica gel 60-
F254 precoated plates with visualization by irradiation with
a Mineralight UVGL-25 lamp. Column chromatography
5.1.2. 3-[01R,2S,3R,4S)-2,3,4-Trihydroxycyclopent-1-yl]-
8-methylthioimidazo-[4,5-g]quinazoline 011a). To a solu-
tion of 10a (1.49 g, 5 mmol) in THF (200 mL) was added
50% N-methylmorpholine N-oxide in H2O (1.82 mL,
10 mmol) followed by H2O (10 mL) and OsO4 (100 mg).
This mixture was stirred at room temperature for 5 h at
which time a TLC analysis showed the reaction to be
complete. The mixture was ®ltered through a pad of silica
gel and washed with CH2Cl2/MeOH (5:1). The ®ltrate was
evaporated. The residue was adsorbed on silica gel and this
mixture loaded onto a silica gel column. The impurities
were eluted using CH2Cl2/MeOH (®rst, 20:1 and then a
5:1). The latter solvent ratio yielded fractions containing
product. After combining the fractions, evaporation of the
solvent gave a residue that was triturated (hexane) to
provide 11a as a light yellow powder (850 mg, 51%). A
sample for microanalysis was recrystallized from ether:
Ê
was performed on Whatman silica, 230±400 mesh, 60 A,
and elution was with the indicated solvent system. Yields
refer to chromatographically and spectroscopically homo-
geneous materials.
5.1.1. 3-[01R,4S)-4-Hydroxy-2-cyclopentenyl]-8-methyl-
thioimidazo[4,5-g]quinazoline 010a) and 1-[01R,4S)-4-
hydroxy-2-cyclopentenyl]-8-methylthioimidazo-[4,5-g]-
quinazoline 010b). To a suspension of NaH (25 mg,
1 mmol, 95% in oil) in anhydrous DMSO (5 mL) in a
50 mL round-bottomed ¯ask kept under N2 was added
8-methylthioimidazo[4,5-g]quinazoline (9)12 (216mg,
1 mmol). The mixture was stirred at room temperature for
1
mp 260±2628C. H NMR (DMSO-d6) d 8.93 (s, 1H, Ar±
H), 8.71 (s, 1H, Ar±H), 8.44 (s, 1H, Ar±H), 8.37 (s, 1H, Ar±
H), 5.45 (s, 1H), 5.10 (m, 2H), 4.88 (dd, Jˆ7.5 Hz, 1H),

9052
V. P. Rajappan, S. W. Schneller / Tetrahedron 57 12001) 9049±9053
4.61 (s, 1H), 4.05 (s, 1H), 3.83 (s, 1H), 2.72 (s, 4H, H and
SCH3), 1.97 (m, 1H). 13C NMR (DMSO-d6) d 151.72,
150.49, 143.75, 143.17, 139.02, 119.30, 113.03, 108.96,
77.13, 75.53, 73.93, 60.84, 35.54, 12.64. Anal. Calcd for
C15H16N4O3S´0.5H2O: C, 52.77; H, 5.02; N, 16.41; S,
9.39. Found: C, 52.79; H, 4.87; N, 16.13; S, 9.57.
Calcd for C16H20N4O4´0.75H2O: C, 55.56; H, 6.27; N,
16.20. Found: C, 55.28; H, 6.03; N, 15.83.
5.1.6. 3-[01R,2S,3R,4S)-2,3,4-Trihydroxycyclopent-1-yl]-
imidazo[4,5-g]quinazolin-8-one 012a). From 16. To a
suspension of 16 (100 mg, 0.3 mmol) in triethyl ortho-
formate (7 mL) kept at 08C under N2 was added of conc.
HCl (1 mL). This mixture was stirred at room temperature
for 48 h and then the solvent was evaporated. Distilled H2O
(10 mL) was added to the residue. The resultant solution
was heated at 808C for 2 h. After cooling, the solution was
carefully neutralized with 3N NaOH solution and the
solvent was then evaporated under reduced pressure. The
residue was co-evaporated with EtOH (3£10 mL). The resi-
due from this treatment was adsorbed on silica gel and
loaded on a silica gel column. Elution with CH2Cl2/MeOH
(3:1) and evaporation of the combined fractions gave 12a
(40 mg, 44%) as a light yellow powder. The microanalytical
sample was recrystallized from H2O: mp 280±2838C dec.:
1H NMR (DMSO-d6) d 12.10 (br, s, 1H), 8.53 (d, Jˆ7.5 Hz,
1H), 8.38 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 5.43 (d, Jˆ
2.5 Hz, 1H), 5.12 (d, Jˆ5.0 Hz, 1H), 4.84 (dd, Jˆ10.0 and
7.5 Hz, 1H), 4.52 (s, 1H), 4.24 (m, 1H), 4.00 (m, 1H), 3.80
(s, 1H), 2.70 (m, 1H), 1.87 (m, 1H). 13C NMR (DMSO-d6) d
161.45, 147.66, 143.78, 143.18, 137.96, 117.66, 116.19,
108.35, 76.61, 75.11, 73.34, 60.18, 35.19. Anal. Calcd for
C14H14N4O4´1HCl: C, 49.64; H, 4.46; N, 16.54. Found: C,
49.32; H, 4.76; N, 16.28.
5.1.3. 1-[01R,2S,3R,4S)-2,3,4-Trihydroxycyclopent-1-yl]-
8-methylthioimidazo-[4,5-g]quinazoline 011b). Following
a procedure similar to that for the preparation of 11a, 10b
(200 mg, 0.67 mmol) yielded, after silica gel column puri®-
cation with CH2Cl2/MeOH (15:1 to remove impurities and
4:1 to elute product), 11b as a light yellow powder (105 mg,
47%): mp 231±2338C. 1H NMR (DMSO-d6) d 8.92 (s, 1H,
Ar±H), 8.73 (s, 2H, Ar±H), 8.22 (s, 1H, Ar±H), 5.52 (s,
1H), 5.12 (m, 2H), 4.85 (dd, Jˆ7.5 Hz, 1H), 4.61 (dd, Jˆ
7.5 Hz, 1H), 4.04 (s, 1H), 3.83(s, 1H), 2.72 (s, 4H, H and
SCH3), 1.98 (m, 1H). 13C NMR (DMSO-d6) d 151.43,
150.15, 142.95, 134.34, 119.93, 117.29, 105.49, 77.35,
75.95, 74.08, 61.16, 35.85, 12.94. Anal. Calcd for
C15H16N4O3S´1H2O: C, 51.42; H, 5.18; N, 15.99; S, 9.15.
Found: C, 51.51; H, 5.19; N, 15.97; S, 9.08.
5.1.4. 7-[01R,2S,3R,4S)-2,3-O-Isopropylidene-2,3,4-tri-
hydroxycyclopent-1-yl]amino-6-nitro-4-quinazolone 015).
To a suspension of 1412 (451 mg, 2 mmol) in 1-butanol
(20 mL) was added 1313 (400 mg, 2.3 mmol) followed by
Et3N (2.5 mmol). The mixture was re¯uxed for 48 h. The
solution was then allowed to cool to room temperature and
the yellow precipitate that formed was obtained by ®ltration
and dried to provide 15 (422 mg, 58%) as a yellow powder,
which was of suf®cient purity to be used directly in the next
step. For microanalytical purposes, a sample was prepared
by further puri®cation via either eluting from a column
using CH2Cl2/MeOH (8:1) or by recrystallizing from
From 11a. Compound 11a (50 mg, 0.15 mmol) was
suspended in 1N HCl (5 mL) and the mixture was re¯uxed
for 4 h. After cooling the mixture to room temp, the pH of
the solution was adjusted to 7 using 3N NaOH. The solvent
was evaporated under reduced pressure and the residue was
co-evaporated with EtOH (2£10 mL). Puri®cation of the
residue was accomplished via silica gel column chroma-
tography eluting with CH2Cl2/MeOH (3:1). Evaporation of
the combined fractions containing product afforded pure
12a (22 mg, 48%) as a light yellow powder. Recrystalli-
zation of this material from H2O gave an analytical sample
identical (NMR and mixed melting point) to 12a obtained
from 16. Anal. Calcd for C14H14N4O4´0.6HCl: C, 51.87; H,
4.54; N, 17.28. Found: C, 51.76; H, 4.82; N, 17.06.
1
EtOAc: mp 186±1888C. H NMR (DMSO-d6) d 12.17 (s,
1H), 8.78 (s, 1H), 8.61 (d, Jˆ7.5 Hz, 1H), 8.11 (s, 1H), 6.93
(s, 1H), 5.68 (d, Jˆ2.5 Hz, 1H), 4.49 (s, 2H), 4.17 (s, 1H),
4.06(dd, Jˆ7.5 Hz, 1H), 2.33 (m, 1H), 1.83 (m, 1H), 1.41
(s, 3H), 1.29 (s, 3H). 13C NMR (DMSO-d6) d 160.20,
153.68, 149.39, 146.54, 132.18, 127.21, 111.74, 110.31,
108.49, 86.25, 84.36, 75.91, 59.08, 35.82, 26.63, 24.26.
Anal. Calcd for C16H18N4O6´0.75MeOH: C, 52.07; H,
5.48; N, 14.50. Found: C, 51.80; H, 5.21; N, 14.89.
5.1.7. 1-[01R,2S,3R,4S)-2,3,4-Trihydroxycyclopent-1-yl]-
imidazo[4,5-g]-quinazolin-8-one 012b). Hydrolysis of 11b
(80 mg, 0.24 mmol) was carried out in the same manner as
the hydrolysis of 11a to produce 12a (49 mg, 67%).
Compound 12b thus obtained was recrystallized from
EtOH/isopropyl alcohol to provide an analytically pure
5.1.5. 6-Amino-7-[01R,2S,3R,4S)-2,3-O-isopropylidene-
2,3,4-trihydroxycyclopent-1-yl]amino-4-quinazolone 016).
Compound 15 (220 mg, 0.60 mmol) was dissolved in
MeOH (50 mL) and 10% Pd±C (100 mg) was added to
the solution. This mixture was treated with H2 in a Parr
hydrogenator at 45 psi for 1 h. The reaction mixture was
®ltered through a pad of Celitee and the ®ltrate concen-
trated under reduced pressure. The residue was triturated
(hexane) to afford a dull white powder, which was obtained
by ®ltration and then dried to yield 16 (160 mg, 79%). An
analytical sample was obtained by recrystallization from
1
sample: mp .2908C dec.: H NMR (DMSO-d6) d 12.15
(s, 1H), 8.63 (s, 1H), 8.61 (s, 1H), 8.00 (s, 1H), 7.91 (s,
1H), 5.46(d, Jˆ2.5 Hz, 1H), 5.22 (d, Jˆ7.5 Hz, 1H), 5.13
(d, Jˆ2.5 Hz, 1H), 4.88 (dd, Jˆ10 Hz, 1H), 4.53 (dd, Jˆ
5 Hz, 1H), 4.01 (s, 1H), 3.81 (s, 1H), 2.71 (m, 1H), 1.91 (m,
1H). 13C NMR (DMSO-d6) d 161.54, 148.48, 143.46,
142.84, 133.12, 118.27, 116.29, 108.36, 76.83, 75.63,
73.49, 60,25, 35.69, HRMS Calcd for C14H14N4O4
302.1015, found 302.1009.
1
ether: mp 275±2808C dec.: H NMR (DMSO-d6) d 11.55
(s, 1H), 7.74 (s, 1H), 7.21 (s, 1H), 6.59 (s, 1H), 5.36 (m, 2H),
4.94 (brs, 2H), 4.42 (s, 2H), 4.12 (s, 1H), 3.78 (dd, Jˆ
7.5 Hz, 1H), 2.32 (m, 1H), 1.84 (m, 1H), 1.41 (s, 3H),
1.22 (s, 3H). 13C NMR (DMSO-d6) d 160.07, 143.54,
141.87, 141.50, 135.56, 112.60, 109.92, 107.45, 104.29,
85.87, 83.96, 75.34, 58.76, 36.00, 26.51, 24.14. Anal.
5.1.8. 8-Amino-3-[01R,2S,3R,4S)-2,3,4-trihydroxycyclo-
pentyl]imidazo[4,5-g]-quinazoline 07). A solution of 11a
in anhydrous MeOH saturated with NH3 was heated in an oil

V. P. Rajappan, S. W. Schneller / Tetrahedron 57 12001) 9049±9053
9053
4. Siddiqi, S. M.; Chen, X.; Schneller, S. W.; Ikeda, S.; Snoeck,
R.; Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem.
1994, 37, 551±554.
bath at 1108C for 40 h in a sealed tube. After cooling, the
MeOH was evaporated and the gray residue obtained was
triturated (ether) to result in 7 (140 mg, 93%). This material
was recrystallized from H2O: mp .2908C; [a]24 ˆ234.828
5. (a) Patil, S. D.; Schneller, S. W.; Hosoya, M.; Snoeck, R.;
Andrei, G.; Balzarini, J.; De Clercq, E. J. Med. Chem. 1992,
35, 3372±3377. (b) De Clercq, E. Nucleosides Nucleotides
1998, 17, 625±634.
D
(c 0.37, DMSO). 1H NMR (DMSO-d6) d 8.63 (s, 1H), 8.45
(s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.70 (br, s, 2H) 5.35 (d,
Jˆ2.5 Hz, 1H), 5.06(m, 2H), 4.82 (dd, Jˆ10 Hz, 1H), 4.59
(dd, Jˆ5 Hz, 1H), 4.01 (s, 1H), 3.80 (s, 1H), 2.70 (m, 1H),
1.98 (m, 1H). 13C NMR (DMSO-d6) d 162.53, 153.85,
148.17, 145.12, 143.22, 137.77, 113.39, 110.55, 107.06,
76.80, 75.01, 73.51, 60.17, 35.24. Anal. Calcd for
C14H15N5O3´1.5H2O: C, 51.22; H, 5.53; N, 21.33. Found:
C, 51.43; H, 5.53; N, 21.35.
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Acknowledgements
This research was supported by funds from the Department
of Health and Human Services (AI31718 and AI48495) and
this is appreciated. We are indebted to Robert Sidwell of
Utah State University for providing the in¯uenza A, in¯u-
enza B, and respiratory syncytial assays; to Brent Korba of
Georgetown University for the hepatitis B virus assay; and,
to Erik De Clercq of Rega Institute, Leuven, Belgium for the
following viral assays: varicella zoster, cytomegalo, vesicu-
lar stomatitis, sindbis, punta toro, coxsackie B4, reovirus,
herpses simplex, human immunode®ciency, and vaccinia.
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