Synthesis of three carbon atom bridged 2,4-diaminopyrrolo[2,3-d]- pyrimidines as nonclassical dihydrofolate reductase inhibitors

Article abstract of DOI:10.1002/jhet.5570420614

A series of seven nonclassical three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-pyrimidines 1a-g were synthesized as potential inhibitors of dihydrofolate reductase. Selective oxidation of diols 7a-g affords oe-hydroxy ketones 8a-g. Subs

Full text of DOI:10.1002/jhet.5570420614

Sep-Oct 2005
1127
Synthesis of Three Carbon Atom Bridged 2,4-Diaminopyrrolo[2,3-d]-
pyrimidines as Nonclassical Dihydrofolate Reductase Inhibitors
Aleem Gangjee* [a], Zhengqu Ye [a] and Sherry F. Queener [b]
[a] Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University,
Pittsburgh, PA 15282
[b] Department of Pharmacology and Toxicology, Indiana University, Indianapolis, IN 46202
Received February 15, 2005
A series of seven nonclassical three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-
pyrimidines 1a-g were synthesized as potential inhibitors of dihydrofolate reductase. Selective oxidation of
diols 7a-g affords α-hydroxy ketones 8a-g. Subsequent condensation with malononitrile gave the requisite
2-amino-3-cyano-4-substituted furan precursors 9a-g. Cyclocondensation with guanidine in refluxing
ethanol in one step affords the three carbon atom bridged 2,4-diamino-5-substituted-pyrrolo[2,3-d]-
pyrimidines 1a-g. Preliminary biological results indicated that these compounds showed moderate
inhibitory activities against dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii,
Mycobacterium avium and rat liver with IC values in the 0.66 µM - 70.1 µM range and some compounds
50
had marginal selectivity for T. gondii dihydrofolate reductase.
J. Heterocyclic Chem., 42, 1127 (2005).
Dihydrofolate reductase is an essential enzyme in the
5.0 and 35 ng/ml respectively. Thus TNP351 demonstrated
that truncation of the 6-6 ring system to a 6-5 ring system
can be more than compensated for by increasing the bridge
length from two to three carbon atoms. Classical antifo-
lates, like methotrexate and TNP351, utilize folate trans-
port mechanisms to gain entry into cells. Further, classical
antifolates are unable to penetrate pathogenic cells which
lack the folate transport systems. A decrease in the effi-
ciency of transport of classical antifolates leads to drug
resistance in some tumor cells.
biosynthesis of purines and pyrimidines and therefore
DNA. Inhibition of dihydrofolate reductase interrupts the
recycling of dihydrofolate back to tetrahydrofolate and
thus has a deleterious effect on cell growth. Methotrexate,
a classical dihydrofolate reductase inhibitor, is clinically
used in cancer chemotherapy [1]. Miwa et al. [2] reported
the synthesis of a classical 2,4-diamino-5-substituted
pyrrolo[2,3-d]pyrimidine (TNP351) with a three carbon
atom bridge, as an inhibitor of dihydrofolate reductase and
an antitumor agent. Inhibitory IC values for TNP351
against the growth of KB and A549 tumor cells in culture
were 27 and 4.5 ng/ml while those for methotrexate were
An important determinant of the antitumor activity of
some classical antifolates is their ability to function as sub-
strates for the enzyme folypolyglutamate synthetase (FPGS)
50

1128
A. Gangje, Z. Ye, and S. F. Queener
Vol. 42
which converts the monoglutamate forms of classical antifo-
lates into long chain noneffluxing poly-γ-glutamates within
the cell [3]. The ineffectiveness of some classical antifolates
against resistant tumor cells has been attributed, in part, to
both reduced uptake [4-7] and/or inefficient polyglutamyla-
tion [8-11]. Although polyglutamylation of certain classical
antifolates appears necessary for cytotoxicity, it has also
been implicated as a possible cause of toxicity to host cells
due to the prolonged retention of polyanionic forms of
polyglutamates of these antifolates [12].
Lipophilic, nonclassical antifolates which lack the gluta-
mate moiety do not require the reduced folate transport sys-
tems to gain access to tumor cells and hence are useful
where resistance is attributable to inefficient uptake sys-
tems. In addition, such nonclassical dihydrofolate reductase
inhibitors are also useful in the treatment of opportunistic
infections in acquired immunodeficiency syndrome (AIDS)
patients, such as those caused by Pneumocystis carinii and
Toxoplasma gondii. These opportunistic infections are
responsible for significant morbidity and mortality in AIDS
patients [13]. These organisms lack the transport systems
for classical antifolates and thus are only accessible via
nonclassical antifolates.
Selectivity of inhibitors for dihydrofolate reductase from
Pneumocystis carinii and/or Toxoplasma gondii over
mammalian dihydrofolate reductase, such as rat liver along
with high potency against these pathogenic dihydrofolate
reductases, is a desirable goal. It was thus of interest to
design and synthesize the nonclassical analogs 1a-g of
TNP351 which contain a three carbon atom bridge as
selective inhibitors of pathogen dihydrofolate reductase or
as potential antitumor agents.
2-Amino-3-cyanofurans can be readily cyclized to annu-
lated 2,4-diaminopyrrolo[2,3-d]pyrimidine ring systems by
reaction with guanidine. These 2-amino-3-cyanofurans can
be prepared by condensation of malononitrile with the appro-
priate α-hydroxy ketones [14]. With this in mind, the appro-
priate α-hydroxy ketones were synthesized by selective oxi-
dation of triol precursors (Scheme 1) [15]. Thus 1,2,4-
butanetriol was converted to its acetonide 3 in 97% yield.
1
The H nmr supported the five-membered ring structure 3
[16]. The protected alcohol 3 was oxidized with pyridinium
chlorochromate in dichloromethane under a nitrogen atmos-
phere for 10 hours to afford the corresponding aldehyde 4, in
68% yield. Wittig reaction of the corresponding triph-
enylphosphine bromide and 4 in tetrahydrofuran afforded
5a-g as a mixture of E- and Z- isomers in 38-85% yields.
Hydrogenation of 5a-g over 5% palladium on activated car-
bon for 10 hours gave 6a-g in quantitative yield. Shorter
reaction times of 5 hours or 2 hours afford 6a-g in 98% or
95% yields respectively. Deprotection of 6a-g with aqueous
acetic acid afforded 7a-g in 82%-99% yields. The key α-
hydroxy ketones 8a-g were obtained by selective oxidation
of diols 7a-g using bis(tributyltin) oxide (HBD) and
bromine. Attempted oxidation of unprotected 5g resulted in
an inseparable mixture. A possible reason for the failure of
the reaction with unprotected 5g might be that the double
bond is also susceptible to oxidation with bromine.
Condensation of malononitrile with the appropriate α-
hydroxy ketones 8a-g gave the corresponding 2-amino-3-
cyano-4-substituted-furans which were cyclized to 2,4-
diaminopyrrolo[2,3-d]pyrimidines 1a-g with guanidine in
47%-88% yields.
The compounds were evaluated as inhibitors of dihydro-
folate reductase from Pneumocystis carinii, Toxoplasma
gondii, rat liver and Mycobacterium avium using estab-
lished methods [17]; the results are listed in Table 1. The
compounds were moderately inhibitory but there was no
selectivity for Pneumocystis or Mycobacterium dihydrofo-
late reductase and only marginal selectivity for Toxoplasma
gondii dihydrofolate reductase. The most potent compound
was 1d with an IC in the submicromolar range against rat
50
liver dihydrofolate reductase. Thus the three atom bridged
nonclassical analogs synthesized are not particularly
Scheme 1

Sep-Oct 2005
Synthesis of Three Carbon Atom Bridged 2,4-Diaminopyrrolo[2,3-d]pyrimidines
1129
were purchased from Aldrich Chemical Co. and Fisher Scientific
and were used as received.
Table 1
Inhibition of Dihydrofolate Reductase from Pneumocystis carinii,
Toxoplasma gondii, Mycobacterium avium and Rat liver by compounds 1a-g
General Procedure for the Synthesis of Compounds 5a-g.
-6
IC 10
M
(Selectivity *)
To a solution of the corresponding substituted triphenylphos-
phine bromide (1.0 equivalent) in dry tetrahydrofuran was added
dropwise n-butyl lithium (1 M, 1.1 equivalents) at –78 °C under
a nitrogen atmosphere. After 10 minutes, a solution of 4 in 2 ml
of tetrahydrofuran was added to the solution, and the solution
was slowly allowed to come to room temperature. The stirring
was continued for an additional 10 hours. The solvent was evap-
orated under reduced pressure to dryness. To the residue was
added hot hexane to precipitate the triphenylphosphine oxide
which was filtered. The filtrate was evaporated to dryness to
afford a residue which was chromatographed on silica gel with
hexane-ethyl acetate (V/V). Appropriate fractions (tlc) that con-
tained the product spots were pooled and the solvent evaporated
to afford 5a-g.
50
Compound P. carinii
T. gondii
M. avium
Rat Liver
1a
1b
1c
1d
1e
1f
13.5 (0.4)
28.9 (0.4)
14.9 (0.3)
11.5 (0.1)
6.9 (0.2)
4.93 (0.2)
42.9 (0.2)
0.047 (0.17) 0.016 (0.5)
1.24 (3.9)
4.05 (2.9)
1.03 (4.7)
1.6 (0.4)
1.3 (1.2)
1.01 (1.1)
2.7 (3.2)
20.2 (0.24)
24.6 (0.5)
38.5 (0.12)
4.3 (0.15)
8.2 (0.18)
14.2 (0.08)
70.1 (0.12)
0.0015 (5.3)
4.8
11.8
4.8
0.66
1.5
1.09
8.6
1g
TMQ
PTX
a
0.008
a
0.013 (0.26) 0.0043 (0.76) 0.00061 (5.4) 0.0015
*
Selectivity is the ratio of IC for rat liver enzyme/IC for pathogen
enzyme; this ratio is in parentheses following each IC for the pathogen
50
50
50
enzymes. These assays were carried out at 37 ∞C, under conditions of sub-
strate (90 mM dihydrofolic acid) and cofactor (119 mM nicotinamide
diphosphate) in the presence of 150 mM potassium chloride and 2-mercap-
toethanol (8.9 mM), in a sodium phosphate buffer (pH 7.4) [17]. Data for
TMQ and PTX assayed under the same conditions are from reference [18].
Z- and E-O-Isopropylidene-1-(2',5'-dichlorophenyl)-1-pentene-
4,5-diol (5a).
a
Compound 5a was synthesized using the general procedure with
4 (1.50 g, 10.4 mmol) and 2,5-dichlorobenzyltriphenylphosphine
bromide (5.23 g, 10.4 mmol) to give 1.14 g (38% yield) of a yellow
1
liquid; R =0.25 (hexane-ethyl acetate, 35:1). H nmr (DMSO-d ):
f
6
δ 1.26 (s, 3H), 1.33 (s, 3H), 2.37 (m, 2H, J=6.5 Hz), 3.34 (m, 1H),
3.99 (m, 1H), 4.19 (m, 1H), 5.90 (dt, 0.6H, J=11.6 Hz, and J=7.3
Hz), 6.38 (dt, 0.4H, J=15.9 Hz, J=7.3 Hz), 6.51 (d, 0.6H, J=11.6
Hz), 6.70 (d, 0.4H, J=15.9 Hz), 7.34-7.72 (m, 3H); HRMS: m/e
potent or selective against dihydrofolate reductase.
Compared to the unsubstituted analog 1g all of the substi-
tuted analogs were more potent inhibitors (except 1b for T.
gondii and rat liver). The most potent inhibitors were those
with bulky substituents. Thus for P. carinii and T. gondii 1f
was the most potent and for rat liver and M. avium 1d was
the most potent.
calcd for (M+) C H O Cl 286.0527; found 286.0535.
14 16
2
2
Z- and E-O-Isopropylidene-1-(2',5'-dimethoxyphenyl)-1-pen-
tene-4,5-diol (5b).
Compound 5b was synthesized using the general procedure
with 4 (1.0 g, 6.9 mmol) and 2,5-dimethoxybenzyltriphenylphos-
EXPERIMENTAL
phine bromide (3.42 g, 6.9 mmol) to give 0.93 g (48% yield) of a
1
yellow liquid; R =0.30 (hexane-ethyl acetate, 9:2); H nmr
f
(DMSO-d ) δ 1.26 (s, 3H), 1.33 (s, 3H), 1.42 (m, 2H), 3.53 (m,
All evaporations were carried out in vacuo with a rotary evap-
orator. Analytical samples were dried in vacuo (0.2 Torr) in a
Chem-Dry apparatus over phosphorous pentoxide. Melting
points were determined on a Mel-Temp apparatus and are uncor-
6
1H), 3.66 (s, 3H), 3.69 (s, 3H), 3.98 (m, 1H), 4.15 (m, 1H), 5.70
(dt, 0.3H, J=7.0 and J=11.6 Hz), 6.22 (dt, 0.7H, J=7.0 and 16.1
Hz), 6.53 (d, 0.3H, J=11.6 Hz) 6.65 (d, 0.7H, J=16.1 Hz), 6.70-
1
7.08 (m, 3H); HRMS: m/e calcd for (M+) C
H O 278.1518;
rected. Nuclear magnetic resonance spectra for proton ( H nmr)
16 22 4
found 278.1527.
were recorded on a Bruker WH-300 (300 MHz) spectrometer.
The chemical shift values are expressed in ppm (parts per mil-
lion) relative to tetramethylsilane as internal standard; s = singlet,
d = doublet, dd = doublet of doublet, dt = doublet of triplet, t =
triplet, q = quartet, quin = quintet, m = multiplet, bs = broad sin-
glet. The relative integrals of peak areas agreed with those
expected for the assigned structures. High resolution mass spec-
tra (HRMS) were recorded on a VG-7070E-HF instrument. Thin
layer chromatography (tlc) was performed on POLYGRAM Sil
Z- and E-O-Isopropylidene-1-( 3',4',5'-trimethoxyphenyl)-1-pen-
tene-4,5-diol (5c).
Compound 5c was synthesized using the general procedure
with 4 (1.60 g, 11.1 mmol) and 3,4,5-trimethoxybenzyltriphenyl-
phosphine bromide (5.81 g, 11.1 mmol) to give 1.92 g (56%
yield) of a colorless liquid; R =0.30, 0.28 (hexane-ethyl acetate,
f
1
10:3). H nmr (DMSO-d ): δ 1.27 (s, 3H), 1.40 (s, 3H), 2.30-
6
2.61 (m, 2H), 3.44 (s, 3H), 3.52 (m, 1H), 3.58 (s, 3H), 3.76 (s,
3H), 3.96 (m, 1H), 4.10 (m, 1H), 5.60 (dt, 0.7H, J=7.0 and 11.6
Hz), 6.18 (dt, 0.3H, J=7.0 and 15.9 Hz), 6.25 (d, 0.7H, J=11.6
Hz), 6.40 (d, 0.3H, J=15.9 Hz), 6.69 (s, 2H); HRMS: m/e calcd
G/UV silica gel plates with fluorescent indicator, and the spots
254
were visualized under 254 and 366 nm illumination. Proportions
of solvents used for thin layer chromatography are by volume.
Elemental analyses were performed by Atlantic Microlabs Inc.,
Norcoss, GA. Analytical results indicated by element symbols
are within 0.4% of the calculated values. Fractional moles of
water or organic solvents frequently found in some analytical
samples of antifolates were not removed in spite of 24-48 hours
of drying in vacuo and were confirmed where possible by their
for (M+) C
H O 308.1623; found 308.1633.
17 24 5
Z- and E-O-Isopropylidene-1-(4'-benzyloxyphenyl)-1-pentene-
4,5-diol (5d).
Compound 5d was synthesized using the general procedure
with 4 (2.00 g, 13.9 mmol) and benzyloxyphenyltriphenyl-
1
presence in the H nmr spectrum. All solvents and chemicals

1130
A. Gangje, Z. Ye, and S. F. Queener
Vol. 42
phosphine bromide (6.85 g, 13.9 mmol) to give 3.70 g (82%
5-(2',5'-Dimethoxyphenyl)-O-isopropylidenepentane-1,2-diol
(6b).
yield) of a colorless oil, R =0.31, 0.29 (hexane-ethyl acetate,
f
1
10:1). H nmr (DMSO-d ): δ 1.26 (s, 3H), 1.31 (s, 3H), 2.35-2.42
(m, 2H), 3.53 (m, 1H), 4.00 (m, 1H), 4.14 (m, 1H), 5.09 (s, 2H),
5.50-6.50 (m, 2H), 6.69 (d, 2H), 7.00 (d, 2H), 7.24-7.45 (m, 5H).
6
Compound 6b was synthesized using the general procedure
with 5b (0.55 g, 1.96 mmol) to give 0.55 g (100% yield) of a col-
1
orless liquid; R =0.28 (hexane-ethyl acetate, 5:1); H nmr
f
(DMSO-d ) δ 1.24 (s, 3H), 1.28 (s, 3H), 1.47-1.53 (m, 4H), 2.50
Z- and E-O-Isopropylidene-1-(1'-naphthyl)-1-pentene-4,5-diol
(5e).
6
(t, 2H), 3.20 (m, 1H), 3.71 (s 3H), 3.77 (s, 3H), 3.94-4.01 (m,
2H), 6.71-6.86 (m, 3H); HRMS: m/e calcd for (M+) C
H O
16 24 4
Compound 5e was synthesized using the general procedure
with 4 (2.00 g, 13.9 mmol) and 1-naphthalenemethyltriphenyl-
phosphine chloride (6.33 g, 14.44 mmol) to give 2.40 g (64%
280.1674; found 280.1685.
5-(3',4',5'-Trimethoxyphenyl)-O-isopropylidenepentane-1,2-diol
(6c).
yield) of a colorless liquid; R =0.34, 0.32 (hexane-ethyl acetate,
f
1
15:1). H nmr (DMSO-d ): δ 1.29 (s, 3H), 1.36 (s, 3H), 2.60 (m,
2H), 3.65 (m, 1H), 4.05 (m, 1H), 4.25 (m, 1H), 5.95-7.30 (m,
2H), 7.35-8.25 (m, 7H).
Compound 6c was synthesized using the general procedure
6
with 5c (1.40 g, 44.54 mmol) to give 1.40 g (100% yield) of a
1
colorless liquid; R =0.34 (hexane-ethyl acetate, 10:3); H nmr
f
(DMSO-d ): δ 1.24 (s, 3H), 1.28 (s, 3H), 1.40-1.60 (m, 4H), 2.50
6
Z- and E-O-Isopropylidene-1-(2'-naphthyl)-1-pentene-4,5-diol
(5f).
(t, 2H), 3.24-3.38 (m, 1H), 3.44 (s, 3H), 3.52 (s, 3H), 3.73 (s,
3H), 3.90-4.05 (m, 2H), 6.48 (s, 2H); HRMS: m/e calcd for (M+)
Compound 5f (E- and Z-isomers) were synthesized using the
general procedure with 4 (1.76 g, 12.5 mmol) and 2-naphthalene-
methyltriphenylphosphine bromide (6.05 g, 12.52 mmol) to give
C
H O 310.1780; found 310.1773.
17 26 5
5-(4'-Benzyloxyphenyl)-O-isopropylidenepentane-1,2-diol (6d).
Compound 6d was synthesized using the general procedure
1.04 g (Z-isomer, 27% yield) of a colorless liquid; R =0.20
f
1
(hexane-ethyl acetate, 20:1). H nmr (DMSO-d ): δ 1.32 (s, 3H),
1.39 (s, 3H), 2.64 (m, 2H), 3.56 (m, 1H), 4.03 (m, 1H), 4.21 (m,
with 5d (3.70 g, 11.4 mmol) to give 3.70 g (100% yield) of a col-
6
1
orless liquid; R =0.33 (hexane-ethyl acetate, 5:1); H nmr
f
1H), 5.78 (dt, 1H, J=7.2 and 11.6 Hz), 6.68 (d, 1H, J=11.6 Hz),
(DMSO-d ): δ 1.20 (s, 3H), 1.24 (s, 3H), 1.42-1.58 (m, 4H), 2.54
6
(t, 2H), 3.39 (m, 1H), 3.98 (m, 2H), 5.06 (s, 2H), 6.91 (d, 2H),
7.49-8.04 (m, 7H); HRMS: m/e calcd for (M+) C
H O
18 20 2
7.10 (d, 2H), 7.32-7.45 (m, 5H); HRMS: m/e calcd for (M+)
268.1463; found 268.1469; and 2.21 g (E-isomer, 58 % yield) of
C
H O 326.1881; found 326.1897.
a white solid; R =0.18 (hexane-ethyl acetate, 20:1); mp 42-45° C
21 26 3
f
1
(hexane). H nmr (DMSO-d ): δ 1.35 (s, 3H), 1.42 (s, 3H), 2.50
6
5-(1'-Naphthyl)-O-isopropylidenepentane-1,2-diol (6e).
(m, 2H), 3.58 (m, 1H), 4.04 (m, 1H), 4.19 (m, 1H), 6.40 (dt, 1H,
J=7.0 and 15.9 Hz), 6.64 (d, 1H, J=15.9 Hz), 7.47-7.86 (m, 7H);
Compound 6e was synthesized using the general procedure
with 5e (2.4 g, 8.94 mmol) to give 2.35 g (98% yield) of a color-
less liquid, R =0.32 (hexane-ethyl acetate, 6:1); H nmr (DMSO-
HRMS: m/e calcd for (M+) C
H O 268.1463; found
18 20 2
1
f
268.1462.
d ): δ 1.24 (s, 3H), 1.27 (s, 3H), 1.52-1.75 (m, 4H), 3.06 (t, 2H),
6
Z- and E-O-Isopropylidene-1-phenyl-1-pentene-4,5-diol (5g).
3.40 (m, 1H), 3.96 (m, 1H), 4.03 (m, 1H), 7.34-8.08 (m, 7H);
HRMS: m/e calcd for (M+) C
270.1607.
H O 270.1619; found
Compound 5g was synthesized using the general procedure
with 4 (2.00 g, 13.9 mmol) and benzyltriphenylphosphine bro-
18 22 2
mide (6.52 g, 14.43 mmol) to give 2.30 g (76% yield) of a color-
5-(2'-Naphthyl)-O-isopropylidenepentane-1,2-diol (6f).
1
less oil; R =0.35, 0.32 (hexane-ethyl acetate, 12:1); H nmr
f
Compound 6f was synthesized as in the general procedure with
(DMSO-d ): δ 1.26 (s, 3H), 1.33 (s, 3H), 2.40 (m, 2H), 3.55 (m,
6
5f (1.00 g, 3.73 mmol) to give 1.00 g (100% yield) of a colorless
1H), 4.00 (m, 1H), 4.15 (m, 1H), 5.60-6.55 (m, 2H), 7.17-7.55
(m, 5H).
1
liquid; R =0.22 (hexane-ethyl acetate, 20:1); H nmr (DMSO-
f
d ): δ 1.19 (s, 3H), 1.23 (s, 3H), 1.47-1.74 (m, 4H), 2.72 (t, 2H,
6
General Procedure for the Synthesis of Compounds 6a-g.
J=7.0 Hz), 3.36-3.43 (m, 1H), 3.93-4.37 (m, 2H), 7.35-7.85 (m,
7H); HRMS: m/e calcd for (M+) C
270.1617.
H
O
270.1619; found
18 22
2
To a solution of 5a-g in anhydrous ethanol was added palla-
dium on activated carbon (10%). Hydrogenation was carried out
in a Paar hydrogenator for 10 hours with hydrogen at 50 Psi. The
reaction mixture was filtered to remove the catalyst and the fil-
trate evaporated at reduced pressure to give the crude product
which was chromatographed on silica gel with hexane-ethyl
acetate at an appropriate ratio to afford 6a-g.
5-Phenyl-O-isopropylidenepentane-1,2-diol (6g).
Compound 6g was synthesized using the general procedure
with 5g (2.3 g, 10.5 mmol) to afford 2.3 g (100% yield) of a col-
1
orless liquid; R =0.37 (hexane- ethyl acetate, 12:1); H nmr
f
(DMSO-d ): δ 1.24 (s, 3H), 1.28 (s, 3H), 1.46-1.54 (m, 4H), 2.58
6
(t, 2H), 3.39 (m, 1H), 3.96 (m, 1H), 4.01 (m, 1H), 7.17-7.27 (m,
5-(2'-5'-Dichlorophenyl)-O-isopropylidenepentane-1,2-diol
(6a)
5H); HRMS: m/e calcd for (M-CH +) C
found 205.1233.
H
O
205.1228;
3
13 17
2
Compound 6a was synthesized using the general procedure
with 5a (1.14 g, 3.97 mmol) to give 1.14 g (100% yield) of a col-
General Procedure for the Synthesis of Compounds 7a-g.
1
orless oil; R =0.35 (hexane-ethyl acetate, 35:1); H nmr (DMSO-
A mixture of 6a-g and 60% AcOH (V:V) (10 ml) was stirred
for 18 hours at room temperature. Water and AcOH were evapo-
rated under reduced pressure. To the residue was added 20 ml of
water. The solution was extracted with ethyl acetate (3x20 ml).
The combined organic phase was dried with anhydrous sodium
f
d ): δ 1.17 (s, 3H), 1.24 (s, 3H), 1.40-1.80 (m, 4H), 2.70 (t, 2H),
6
3.21-3.24 (m, 1H), 3.94-4.05 (m, 2H), 7.27-7.45 (m, 3H);
HRMS: m/e calcd for (M+) C
H O Cl 288.0683; found
14 18 2 2
288.0686.

Sep-Oct 2005
Synthesis of Three Carbon Atom Bridged 2,4-Diaminopyrrolo[2,3-d]pyrimidines
1131
sulfate and filtered and the filtrate was evaporated to afford a
residue which was chromatographed on silica gel with hexane-
ethyl acetate (appropriate ratio) to give 7a-g and the Z- and E-iso-
mers of 1- (2'- naphthyl)-1-pentane-4,5-diol.
Anal. Calcd for C H O : C, 78.23; H, 7.88. Found C, 78.12;
15 18 2
H, 7.85.
5-Phenyl-1,2-pentanediol (7g).
Compound 7g was synthesized as in the general procedure
5-(2',5'-Dichlorophenyl)-1,2-pentanediol (7a).
with 6g (2.3 g, 10.44 mmol) to give 1.65 g (88% yield) of a col-
1
Compound 7a was synthesized as in the general procedure
with 6a (1.1 g, 3.67 mmol) to give 0.91 g (99% yield) of 7a as a
orless liquid; R =0.25 (hexane- ethyl acetate, 1:3); H nmr
f
(DMSO-d ): δ 1.18-1.80 (m, 4H), 2.56 (t, 2H), 3.24 (m, 2H), 3.45
6
1
colorless liquid; R =0.55 (hexane-ethyl acetate, 1:5); H nmr
(m, 1H), 4.38 (d, 1H, D O exchangeable), 4.42 (t, 1H, D O
f
2
2
(DMSO-d ): δ 1.15-1.30 (m, 1H), 1.40-1.65 (m, 2H), 1.65-1.81
exchangeable), 7.15-7.29 (m, 5H).
6
(m, 1H), 2.65 (t, 2H), 3.23 (m, 2H), 3.41 (m, 1H), 4.44 (d, 1H,
General Procedure for the Synthesis of Compounds 8a-g.
D O exchangeable), 4.46 (t, 1H, D O exchangeable), 7.31-7.45
2
2
To a mixture of the diol in dry dichloromethane (6 ml), 7a-g (1
equivalent) and bis(tributyltin) oxide (1.3 equivalents) was added
dropwise a solution of bromine (1.3 equivalents) in 10 ml of
dichloromethane at room temperature with stirring under a nitro-
gen atmosphere. The mixture was stirred at this temperature for
additional 10 hours. The resulting solution was evaporated to
dryness to give a crude product which was chromatographed on
silica gel with hexane-ethyl acetate to afford 8a-g.
(m, 3H); HRMS: m/e calcd for (M+) C H O Cl 248.0370;
found 248.0368.
11 14
2
2
5-(2',5'-Dimethoxyphenyl)-1,2-pentanediol (7b).
Compound 7b was synthesized as in the general procedure
with 6b (0.50 g, 1.78 mmol) to afford 0.84 g (90% yield) of a col-
1
orless liquid; R =0.30 (hexane-ethyl acetate, 1:4); H nmr
f
(DMSO-d ): δ 1.12-1.25 (m, 1H), 1.30-1.55 (m, 2H), 1.59-1.71
6
(m, 1H), 2.60 (t, 2H), 3,23 (m, 2H), 3.40 (m, 1H), 3.67 (s, 3H),
5-(2',5'-Dichlorophenyl)-1-hydroxy-2-pentanone (8a).
3.72 (s, 3H), 4.71 (d, 1H, D O exchangeable), 4.43 (t, 1H, D O
2
2
Compound 8a was synthesized as in the general procedure
exchangeable), 6.70-6.88 (m, 3H); HRMS: m/e calcd for (M+)
O 240.1361; found 240.1368.
with 7a (0.86 g, 3.44 mmol) to give 0.72 g (84% yield) of a col-
C
H
13 20
4
1
orless liquid; R =0.29 (hexane-ethyl acetate, 2:1); H nmr
f
5-(3',4',5'-Trimethoxyphenyl)-1,2-pentanediol (7c).
(DMSO-d ): δ 1.70-1.81 (m, 2H), 2.45 (t, 2H), 2.65 (t, 2H, J=6.5
6
Compound 7c was synthesized as in the general procedure
Hz), 4.03 (d, 2H), 5.08 (t, 1H), 7.31-7.45 (m, 3H); HRMS: m/e
with 6c (1.30 g, 6.12 mmol) to give 1.01 g (89% yield) of a col-
calcd for (M+) C H O Cl 246.0214; found 246.0206.
11 12
2
2
1
orless liquid; R =0.28 (hexane-ethyl acetate, 1:5); H nmr
f
5-(2',5'-Dimethoxyphenyl)-1-hydroxy-2-pentanone (8b).
(DMSO-d ): δ 1.29 (m, 1H), 1.40-1.80 (m, 3H), 2.52 (t, 2H), 3.23
6
Compound 8b was synthesized as in the general procedure
with 7b (0.35 g, 1.46 mmol) to give 0.26 g (75% yield) of a col-
(m, 2H), 3.41 (m, 1H), 3.61 (s, 3H), 3.81 (s, 6H), 4.39 (d, 1H,
D O exchangeable), 4.44 (t, 1H, D O exchangeable), 6.47 (s,
2
2
1
orless oil; R =0.26 (hexane-ethyl acetate, 1:1). H nmr (DMSO-
2H); HRMS: m/e calcd for (M+) C
H
O
270.1467; found
f
14 22
5
d ): δ 1.65-1.85 (m, 2H), 2.39 (t, 2H), 2.50 (t, 2H), 3.71 9 (s, 3H
270.1464.
6
), 3.78 (s, 3H), 4.02 (d, 2H), 5.05 (t, 1H), 6.71-6.92 (m, 3H);
5-(4'-Benzyloxyphenyl)-1,2-pentanediol (7d).
HRMS: m/e calcd for (M+) C
H
O
238.1205; found
13 18
4
Compound 7d was synthesized using the general procedure
with 6d (3.60 g, 11.03 mmol) to give 3.05 g (97% yield) of a
238.1196.
5-(3',4',5'-Trimethoxyphenyl)-1-hydroxy-2-pentanone (8c).
white solid; R =0.27 (hexane- ethyl acetate, 1:5), mp 64-67 °C
f
1
Compound 8c was synthesized as in the general procedure
with 7c (0.97 g, 3.59 mmol) to give 0.89 g (92% yield) of a col-
orless oil; R =0.54 (hexane-ethyl acetate,1:5); H nmr (DMSO-
(hexane-ethyl acetate). H nmr (DMSO-d ): δ 1.15-1.70 (m, 4H),
2.50 (t, 2H), 3.22 (m, 2H), 3.40 (m, 1H), 3.60 (d, 1H, D O
6
2
1
exchangeable), 4.41 (t, 1H, D O exchangeable), 5.05 (s, 2H),
f
2
d ): δ 1.73 (quin, 2H, J=7.2 Hz), 2.45 (t, 2H, J=7.3 Hz), 2.60 (t,
6.90 (d, 2H), 7.08 (d, 2H), 7.31-7.44 (m, 5H).
6
2H, J=7.0 Hz), 3.13 (s, 3H), 3.75 (s, 3H), 3.78 (s, 3H), 4.11 (d,
Anal. Calcd for C
H O : C, 75.50; H, 7.74. Found: 75.42;
18 22 3
2H, J=5.8 Hz), 5.07 (t, 1H, J=5.8 Hz, D O exchangeable), 6.80
H, 7.62.
2
(s, 2H).
5-(1'-Naphthyl)-1,2-pentanediol (7e).
5-( 4'-Benzyloxyphenyl)-1-hydroxy-2-pentanone (8d).
Compound 7e was synthesized as in the general procedure
Compound 8d was synthesized using the general procedure
with 7d (2.97 g, 10.37 mmol) to give 2.30 g (78% yield) of a
with 6e (2.15 g, 7.95 mmol) to give 1.8 g (98% yield) of a color-
1
less liquid; R =0.26 (hexane-ethyl acetate, 1:4); H nmr (DMSO-
f
white solid; R =0.48 (hexane-ethyl acetate, 1:1); m.p. 65-68° C
d ): δ 1.35-1.82 (m, 4H), 3.02 (t, 2H), 3.24 (m, 2H), 3.45 (m,
f
6
1
1H), 4.42 (d, 1H, D O exchangeable), 4.45 (t, 1H, D O
(hexane-ethyl acetate); H nmr (DMSO-d ): δ 1.72 (quin, 2H),
2
2
6
exchangeable), 7.34-8.09 (m, 7H).
2.38 (t, 2H), 2.48 (t, 2H), 4.01 (d, 2H), 5.05 (s, 3H, one proton
D O exchangeable), 6.91 (d, 2H), 7.10 (d, 2H), 7.25-7.49 (m,
5H).
2
5-(2'-Naphthyl)-1,2-pentanediol (7f).
Compound 7f was synthesized as in the general procedure with
6f (0.80 g, 2.96 mmol) to give 0.666 g (82% yield) of a white
Anal. Calcd for C
H, 7.12.
H O : C, 76.03; H, 7.09; Found: C, 75.88;
18 20 3
solid; R =0.26 (hexane-ethyl acetate, 1:4), m.p. 72-75° C
f
5-(1'-Naphthyl)-1-hydroxy-2-pentanone (8e).
1
(hexane-ethyl acetate); H nmr (DMSO-d ) δ 1.29 (m, 1H), 1.50
(m, 1H), 1.67 (m, 1H), 1.80 (m, 1H), 2.74 (t, 2H), 3.26 (m, 2H),
6
Compound 8e was synthesized as in the general procedure
3.41 (m, 1H), 4.41 (d, 1H, D O exchangeable), 4.43 (t, 1H, D O
exchangeable), 7.37-7.87 (m, 7H).
with 7e (0.87 g, 3.91 mmol) to give 0.83 g (96% yield) of a col-
2
2
1
orless oil; R =0.50 (hexane-ethyl acetate, 1:1). H nmr (DMSO-
f

1132
A. Gangje, Z. Ye, and S. F. Queener
Vol. 42
d ): δ 1.86 (quin, 2H), 2.52 (t, 2H), 3.01 (t, 2H), 4.12 (d, 2H),
Compound 9d was synthesized as in the general procedure
with 8d (900 mg, 3.17 mmol) to yield 1.00 g (95% yield) of a
6
5.09 (t, 1H, D O exchangeable), 7.33-8.13 (m, 7H); HRMS: m/e
2
calcd for (M+) C
H
O
228.1150; found 228.1143.
white solid; R =0.28 (hexane-ethyl acetate, 2:1); mp 98-102° C
15 16
2
f
1
(hexane-ethyl acetate); H nmr (DMSO-d ): δ 1.74 (quin, 2H),
6
5-(2'-Naphthyl)-1-hydroxy-2-pentanone (8f).
2.27 (t, 2H), 2.53 (t, 2H), 5.06 (s, 2H), 6.75 (s, 1H), 6.90 (d, 2H),
Compound 8f was synthesized as in the general procedure
with 7f (1.20 g, 5.21 mmol) to give 1.02 g (86% yield) of a white
7.10 (d, 2H), 7.20 (s, 2H, D O exchangeable), 7.30-7.45 (m, 5H).
2
Anal. Calcd for C
8.38; Found: C, 75.38; H, 6.08; N, 8.23.
H N O •0.1H O: C, 75.47; H, 6.09; N,
21 20 2 2 2
solid; R =0.52 (hexane-ethyl acetate, 1:1); mp 64-67° C
f
1
(hexane). H nmr (DMSO-d ): δ 1.84-1.92 (m, 2H), 2.45 (t, 2H,
6
2-Amino-3-cyano-4-[3'-(1'-naphthyl)propyl]-furan (9e).
J=7.3 Hz), 2.73 (t, 2H, J=7.3 Hz), 4.02 (d, 2H, J=5.9 Hz), 5.07
(t, 1H, J=5.9 Hz), 7.36-7.87 (m, 7H).
Compound 9e was synthesized using the general procedure
with 8e (500 mg, 2.19 mmol) to give 500 mg (87% yield) of a
Anal. Calcd for C
H O : C, 78.92; H, 7.07; Found: C,
15 16 2
1
colorless oily liquid; R =0.18 (hexane-ethyl acetate, 2:1); H nmr
78.85; H, 7.11.
f
(DMSO-d ): δ 1.92 (m, 2H), 2.42 (t, 2H), 3.08 (t, 2H), 6.81 (s,
6
5-Phenyl-1-hydroxy-2-pentanone (8g).
1H), 7.24 (s, 2H , D O exchangeable), 7.30-8.11 (m, 7H).
2
Compound 8g was synthesized using the general procedure
2-Amino-3-cyano-4-[3'-(2'-naphthyl)propyl]-furan (9f).
with 7g (1.55 g, 8.60 mmol) to give 1.27 g (83% yield) of a col-
1
Compound 9f was synthesized as in the general procedure
with 8f (856 mg, 3.75 mmol) to give 880 mg (89% yield) of a
orless oil; R =0.48 (hexane-ethyl acetate, 1:1); H nmr (DMSO-
f
d ) δ 1.75 (quin, 2H), 2.40 (t, 2H), 2.54 (t, 2H), 4.02 (d, 2H), 5.06
6
white solid; R =0.28 (hexane-ethyl acetate, 2:1). The solid was
(t, 1H, D O exchangeable), 7.17-7.30 (m, 5H); HRMS: m/e calcd
f
2
recrystallized from hexane-ethyl acetate to afford light yellow
for (M+) C H O 178.0993; found 178.0990.
11 14
2
1
crystals; mp 113-115 °C. H nmr (DMSO-d ): δ 1.88-1.93 (m,
6
General Procedure for the Synthesis of Compounds 9a-g.
2H), 2.33 (t, 2H, J=7.3 Hz), 2.78 (t, 2H, J=7.3 Hz), 6.80 (s, 1H),
To a solution of the hydroxy ketones (1 equivalent) in
methanol (3 ml) at room temperature was added a mixture of
malononitrile (1 equivalent) and triethylamine (1 equivalent) in
methanol (1 ml), and the solution was stirred at room temperature
for an additional 20 hours. The solvent was evaporated under
reduced pressure and the residue was chromatograghed on silica
gel with hexane-ethyl acetate at appropriate ratios to give 9a-g.
7.24 (s, 2H, D O exchangeable), 7.38-7.87 (m, 7H).
2
Anal. Calcd. for C
H N O: C, 78.24; H, 5.84; N, 10.14;
18 16 2
Found: C, 77.96; H, 5.86; N, 10.16.
2-Amino-3-cyano-4-[3-(phenyl)-propyl]-furan (9g).
Compound 9g was synthesized as in the general procedure
with 8g (1.23 g, 6.90 mmol) to give 1.23 g (79% yield) of a light
yellow solid; R =0.30 (hexane-ethyl acetate, 5:2); mp 82-84 °C
f
2-Amino-3-cyano-4-[3'-(2',5'-dichlorophenyl)propyl]-furan (9a).
1
(hexane-ethyl acetate); H nmr (DMSO-d ): δ 1.80 (quin, 2H),
2.29 (t, 2H), 2.60 (t, 2H), 6.77 (s, 1H), 7.18-7.30 (m, 5H), 7.22 (s,
6
Compound 9a was synthesized as in the general procedure
with 8a (0.71 g, 2.85 mmol) to give 0.69 g (82% yield) of a white
2H, D O exchangeable).
2
Anal. Calcd. for C
H N O•0.1H O: C, 73.73; H, 6.28; N,
solid; R =0.28 (hexane-ethyl acetate, 3:1); mp 137-140 °C
14 14 2 2
f
1
12.28; Found: C, 73.59; H, 6.21; N, 12.23.
(hexane-ethyl acetate). H nmr (DMSO-d ): δ 1.77-1.82 (m,
2H), 2.33 (t, 2H, J=7.3 Hz), 2.71 (t, 2H, J=7.3 Hz), 6.80 (s, 1H),
6
General Procedure for the Synthesis of Compounds 1a-g.
7.23 (s, 2H, D O exchangeable), 7.32-7.45 (m, 3H).
2
To a solution of 9a-g (1 equivalent) in ethanol (1.7 ml) was
added 1.5 equivalents of guanidine hydrochloride and then 1.5
Anal. Calcd. for C
H ON Cl : C, 56.97; H, 4.10; N, 9.49;
14 12 2 2
Cl, 24.02; Found: C, 56.69; H, 3.98; N, 9.32; Cl, 24.08.
equivalents of NaOCH . The mixture was refluxed at 100-110° C
3
2-Amino-3-cyano-4-[3'-(2',5'-dimethoxyphenyl)propyl]-furan
(9b).
for 3 days. The solvent was evaporated under reduced pressure to
give a residue which was chromatographed on silica gel with
methanol-chloroform to give 1a-g.
Compound 9b was synthesized as in the general procedure
with 8b (253 mg, 1.06 mmol) to afford 193 mg (64% yield) of a
2,4-Diamino-5-[3-(2',5'-dichlorophenyl)propyl]-pyrrolo[2,3-d]-
pyrimidine (1a).
1
light yellow liquid; R =0.20 (hexane-ethyl acetate, 2:1). H nmr
f
(DMSO-d ): δ 1.70-1.85 (m, 2H), 2.29 (t, 2H), 2.51 (t, 2H), 3.68
6
Compound 1a was synthesized as in the general procedure
with 9a (0.57 g, 1.93 mmol) to give 0.44 g (68% yield) of a light
(s, 3H), 3.72 (s, 3H), 6.77 (s, 1H), 6.73-7.14 (m, 3H), 7.21 (2H,
D O exchangeable); HRMS: m/e calcd for (M+) C
H N O
2
16 18 2 3
yellow solid; R = 0.12 (chloroform-methanol, 20:1); mp 202-
f
286.1317; found 286.1321.
1
204 °C (decomposition); H nmr (DMSO-d ): δ 1.81-1.91 (m,
2H), 2.73 (t, 2H), 2.80 (t, 2H), 5.34 (s, 2H, D O exchangeable),
6
2-Amino-3-cyano-4-[3'-(3',4',5'-trimethoxyphenyl)propyl]-furan
(9c).
2
5.93 (s, 2H, D O exchangeable), 6.44 (s, 1H), 7.30-7.44 (m, 3H),
2
10.38 (s, 1H, D O exchangeable).
2
Compound 9c was synthesized as in the general procedure
with 8c (683 mg, 2.54 mmol) to yield 690 mg (86% yield) of a
Anal. Calcd for C
20.44; Cl, 20.69; Found: C, 53.68; H, 4.60; N, 20.10; Cl, 20.66.
H N Cl •0.2H O: C, 53.28; H, 4.65; N,
15 15 5 2 2
brown-red solid; R =0.50 (hexane-ethyl acetate, 2:1); mp 111-
f
1
113 °C (hexane-ethyl acetate); H nmr (DMSO-d ): δ 1.81 (m,
2H), 2.34 (t, 2H), 2.68 (t, 2H), 3.74 (s, 3H), 3.77 (s, 3H), 3.79 (s,
2,4-Diamino-5-[3-(2',5'-dimethoxyphenyl)propyl]-pyrrolo[2,3-d]-
pyrimidine (1b).
6
3H), 6.80 (s, 2H), 6.83 (s, 1H), 7.22 (s, 2H, D O exchangeable).
2
Compound 1b was synthesized as in the general procedure with
9b (175 mg, 0.612 mmol) to give 106 mg (53% yield) of a light
2-Amino-3-cyano-4-[3'-(4'-benzyloxyphenyl)propyl]-furan
(9d).
yellow solid; R =0.39 (chloroform-methanol, 10:1); mp 144-146°
f

Sep-Oct 2005
Synthesis of Three Carbon Atom Bridged 2,4-Diaminopyrrolo[2,3-d]pyrimidines
1133
1
2,4-Diamino-5-[(3'-phenyl)propyl]-pyrrolo[2,3-d]pyrimidine
(1g).
C (dec.); H nmr (-DMSO-d ): δ 1.75-1.86 (m, 2H), 2.59 (t, 2H),
6
2.64 (t, 2H), 3.56 (s, 3H), 3.60 (s, 3H), 5.34 (s, 2H, D O exchange-
2
able), 5.87 (s, 2H, D O exchangeable), 6.43 (s, 1H), 6.73-7.13 (m,
2
Compound 1g was synthesized as in the general procedure
with 9g (725 mg, 3.20 mmol) to give 400 mg (47% yield) of a
3H), 10.36 (s, 1H, D O exchangeable); HRMS: m/e calcd for (M+)
2
C H N O 327.1695; found 327.1691.
17 21
5 2
light yellow solid; R =0.35 (chloroform-methanol, 10:1); mp
f
1
159-161 °C (hexane-chloroform); H nmr (DMSO-d ): δ 1.82
(quin, 2H), 2.62 (m, 4H), 5.32 (s, 2H, D O exchangeable), 5.87
2,4-Diamino-5-[3-(3',4',5'-trimethoxyphenyl)propyl]-
pyrrolo[2,3-d]pyrimidine (1c).
6
2
(s, 2H, D O exchangeable), 6.41 (s, 1H), 7.18-7.27 (m, 5H),
2
Compound 1c was synthesized as in the general procedure
with 9c (859 mg, 2.72 mmol) to give 895 mg (88% yield) of a
10.35 (s, 1H, D O exchangeable).
2
Anal. Calcd for C
26.02; Found: C, 66.78; H, 6.36; N, 25.78.
H N •0.1H O: C, 66.94; H, 6.44; N,
15 17 5 2
light yellow solid; R =0.28 (chloroform-methanol,10:1); mp
f
1
160-161.5 °C (hexane-chloroform). H nmr (DMSO-d ): δ 1.81
(m, 2H), 2.72 (m, 4H), 3.73 (s, 3H), 3.75 (s, 3H), 3.78 (s, 3H),
6
Acknowledgment.
5.37 (s, 2H, D O exchangeable), 5.94 (s, 2H, D O exchange-
2
2
This work was supported, in part, by grants from the National
Institutes of Allergy and Infectious Diseases AI 47759 (AG) and
the National Cancer Institute CA 89300 (AG).
able), 6.45 (s, 1H), 6.81 (s, 2H), 10.39 (s, 1H, D O exchange-
2
able).
Anal. Calcd for C
14.69; Found: C, 47.87; H, 5.12; N, 14.82.
H N O •1.0CHCl : C, 47.86; H, 5.07; N,
18 23 5 3 3
REFERENCES AND NOTES
2,4-Diamino-5-[3-(4'-benzyloxyphenyl)propyl]-pyrrolo[2,3-
d]pyrimidine (1d).
*
To whom correspondence should be addressed. E-mail: gang-
Compound 1d was synthesized as in the general procedure
with 9d (606 mg, 1.82 mmol) to give 550 mg (78% yield) of a
light yellow solid; R =0.31 (chloroform-methanol, 10:1); mp
jee@duq.edu. Phone: 412-396-6070. Fax: 412-396-5593
[1] J. Bellmunt, J. Cos, R. Cleries, M. Perez, A. Ribas, N. Eres, J.
E. Murio, C. Margarit, J. Baselga, Cancer Investigation, 20 (5&6), 673,
(2002).
[2] T. Miwa, T. Hitaka, H. Akimoto, H. Nomura, J. Med. Chem.,
34, 555, (1991).
f
1
174-176 °C (dec. methanol-chloroform). H nmr (DMSO-d ): δ
6
1.78 (quin, 2H), 2.57 (t, 2H), 2.65 (t, 2H), 5.05 (s, 2H), 5.38 (s,
2H, D O exchangeable), 5.92 (s, 2H, D O exchangeable), 6.41
2
2
[3] D. E. McCloskey, J. J. McGuire, C. A. Russell, B. G. Rowan,
J. R. Bertino, G. Pizzorno, E. Mini, J. Biol. Chem., 266, 6181, (1991).
[4] D. W. Fry, R. C. Jackson, Cancer Surv., 5, 47, (1986).
[5] J. H. Schornagel, M. F. Pinard, G. R. Westerhof, I. Kathmann,
C. F. M. Molthoff, J. Jolivet, G. Jansen, Proc. Am. Assoc. Cancer Res.,
35, 302, (1994).
[6] M. G. Nair, J. Galivan, F. Maley, R. L. Kisliuk, R. Ferone,
Proc. Am. Assoc. Cancer Res., 30, 476, (1989).
[7] A. L. Jackman, W. Gibson, M. Brown, R. Kimbell, F. T.
Boyle, Adv. Exp. Med. Biol., 339, 265, (1993).
[8] J. J. McGuire, A. L. Jackman, Huamana Press Inc., Totowa,
NJ, 339, (1999).
[9] E. C. Taylor, D. Kuhnt, C. Shih, S. M. Rinzel, G. B. Grindey,
J. Barredo, M. Janntipour, R. A. Moran, J. Med. Chem., 35, 4450, (1992).
[10] K. Lu, M. B. Yin, J. J. McGuire, E. Bonmassar, Y. M. Rustum,
Biochem. Pharmacol., 50, 391, (1995).
(s, 1H), 6.90 (d, 2H), 7.10 (d, 2H), 7.31-7.44 (m, 5H), 10.39 (s,
1H, D O exchangeable).
2
Anal. Calcd for C
18.49; Found: C, 69.86; H, 6.12; N, 18.43.
H N O•0.3 H O: C, 69.75; H, 6.28; N,
22 23 5 2
2,4-Diamino-5-[3-(1'-naphthyl)propyl]-pyrrolo[2,3-d]pyrimidine
(1e).
Compound 1e was synthesized as in the general procedure
with 9e (475 mg, 1.81 mmol) to give 320 mg (78% yield) of a
light yellow solid; R =0.29 (chloroform-methanol, 10:1); mp 78-
f
1
80 °C (dec.). H nmr (DMSO-d ): δ 1.94 (m, 2H), 2.79 (t, 2H),
3.11 (t, 2H), 5.42 (s, 2H, D O exchangeable), 6.05 (s, 2H, D O
6
2
2
exchangeable), 6.47 (s, 1H), 7.38-8.02 (m, 7H), 10.44 (s, 1H,
D O exchangeable).
2
Anal. Calcd for C
21.22; Found: C, 69.05; H, 5.92; N, 21.18.
H N •0.7H O: C, 69.15; H, 6.23; N,
19 19 5 2
[11] G. M. Nair, A. Abraham, J. J. McGuire, R. L. Kisliuk, J.
Galivan, Cell pharmacol., 1, 245, (1994).
[12] A. Gangjee, F. Mavandadi, R. L. Kisliuk, S. F. Queener, J.
Med. Chem., 42, 2272, (1999).
2,4-Diamino-5-[3-(2'-naphthyl)propyl]-pyrrolo[2,3-d]pyrimidine
(1f).
[13] H. Masur, J. Infect. Dis., 161, 858, (1990).
[14] E. C. Taylor, H. H. Patel, J. G. Jun, J. Org. Chem. 60, 6684,
(1995).
[15] Y. Ueno, M. Okawara, Tetrahedron Lett., 4597, (1976).
[16] H. Hayashi, K. Nakanishi, C. Brandon, J. Marmur, J. Am.
Chem. Soc., 95, 8749, (1973).
Compound 1f was synthesized as in the general procedure with
9f (740 mg, 2.82 mmol) to give 580 mg (65% yield) of a light
yellow solid; R =0.25 (chloroform-methanol, 10:1); mp 214-216
f
1
°C (dec.). H nmr (DMSO-d ): δ 1.85-2.01 (m, 2H), 2.72 (t, 2H,
6
J=7.3 Hz), 2.82 (t, 2H, J=7.5 Hz), 5.36 (s, 2H, D O exchange-
2
able), 5.94 (s, 2H, D O exchangeable), 6.45 (s, 1H), 7.35-7.86
[17] A. Gangjee, O. O. Adair, S. F. Queener, J. Med. Chem., 46,
5074, (2003).
2
(m, 7H), 10.40 (s, 1H, D O exchangeable).
2
Anal. Calcd for C
21.70; Found: C, 70.88; H, 6.23; N, 21.32.
H N •0.3H O: C, 70.70; H, 6.12; N,
[18]
A. Rosowsky, R. A. Forsch, S. F. Queener, J. Med. Chem.,
19 19 5 2
46, 1726, (2003).